The Central Nervous System

The Central Nervous System
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THE CENTRAL
NERVOUS SYSTEM
Structure and Function
Fourth Edition
PER BRODAL, MD, PHD

Institute of Basic Medical Sciences
University of Oslo
Oslo, Norway
1
2010
1
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Library of Congress Cataloging-in-Publication Data

Brodal, Per.
The central nervous system : structure and function / Per Brodal. 4th ed.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-0-19-538115-3 (alk. paper)
ISBN-10: 0-19-538115-7 (alk. paper)
1. Central nervous system. I. Title.
[DNLM: 1. Central Nervous Systemphysiology. WL 300 B8645c 2010]
QP370.B76 2010
612.82dc22
2009028992
1 3 5 7 9 8 6 4 2
Printed in the United States of America

on acid-free paper
Preface
This book is intended primarily for use by students of Textbooks sharing this goal nevertheless differ mark-
medicine, physical therapy, and psychologythat is, edly in how they present the material and where they
for use in neuroscience or neuroanatomy courses by put the emphasis. Perhaps because my own field of
students who need knowledge of the nervous system as research is the wiring patterns of the brain, I strongly
a basis for later clinical study and practice. This fourth feel that knowledge of how the nervous system is
edition has been thoroughly revised and renewed. In builtin particular, how the various parts are intercon-
addition to the updated and rewritten text, all figures nected to form functional systemsis a prerequisite for
have been redrawn and printed in full color to improve proper understanding of data from other fields. A fair
their impact, and many new ones have been added. The knowledge of brain anatomy is especially important for
number of chapters has been increased to facilitate sound interpretations of the symptoms of brain disease.
reading and grasp of the material. Further, each chapter Textbooks of neuroanatomy often overwhelm the
begins with a short overview, setting the stage for what reader with details that are not strictly relevant for
to come and emphasizing salient points. either functional analysis or clinical thinking. Neither
My intentions remain the same as those of my father, does a strong emphasis on cellular mechanisms at the
Alf Brodal, when he wrote the Norwegian forerunner expense of the properties of neural systems seem the
of this book more than 60 years ago: to stimulate under- right choice if the aim is to help readers understand how
standing rather than memorization of isolated facts, the brain performs its tasks and how the site of a disease
while at the same time fostering a realistic attitude process relates to a patients symptoms. Therefore, nei-
toward our still-limited ability to explain the marvels of ther anatomical nor cellular and molecular details are
the human brain. included in this book if they cannot in some way be
The book aims to present the difficult subject of neu- related to function. My hope is that the book presents a
roscience so that those approaching it for the first time balance of cellular and neural systems material that is
can understand it. Therefore, many details are left out right for students.
that might be of great interest to the specialist but In-depth sections and more advanced clinical mate-
would merely obscure the essentials for the beginner. rial are clearly marked so that they should not disturb
Everyday experiences and clinical examples are inte- reading of the main text. Because the needs of readers
grated throughout the text to help students link the new differ, however, they are encouraged to read selectively
material with their prior knowledge and future profes- and pick the material they find most relevant and inter-
sion. The nervous system, however, is exceedingly com- esting from their perspective, regardless of whether it is
plex, both structurally and functionally, and much placed in the main text or in boxes. The frequent sub-
remains to be learned before we can answer many fun- headings should facilitate such selective reading.
damental questions. Thus, while an undergraduate During the preparation of the former and the present
course can provide only partial insights, no one is served editions, I have received help from several colleagues,
by a presentation that avoids controversial issues and for which I am truly grateful. Jan Bjaalie, Niels Christian
areas of ignorance. Indeed, pointing out what we do Danbolt, Paul Heggelund, Jan Jansen, Harald Kryvi,
not know is sometimes better than presenting an over- Kirsten Osen, Ole Petter Ottersen, Eric Rinvik, and Jon
simplified version. For this reason I have also discussed Storm-Mathisen have all provided constructive criti-
how the data were obtained and the limitations inher- cism and advice. I also gratefully acknowledge the
ent in the various methods. expert help of Gunnar Lothe and Carina Knudsen, who
The main challengefor both the student and the produced the photographic work.
scientistis to understand how the nervous system
solves its multifarious tasks. This requires an integrated Per Brodal, MD, PhD
approach, drawing on data from all fields of neurobiol- Oslo, Norway
ogy, as well as from psychology and clinical research.
v
Contents
Preface, v The Brain Stem, 80

The Cerebrum, 89
Introduction, xi
The Cerebellum, 95
A Birds Eye View of the Nervous System, xi
Studying the Structure and Function of the 7. The Coverings of the Brain and the
Nervous System, xii Ventricular System, 97
Overview, 97
The Meninges, 97
PART I MAIN FEATURES OF The Cerebral Ventricles and the
STRUCTURE AND FUNCTION Cerebrospinal Fluid, 99
1. Structure of the Neuron and 8. The Blood Supply of the CNS, 104
Organization of Nervous Tissue, 5 Overview, 104
Overview, 5 Cerebral Microcirculation and the
Neurons and Their Processes, 5 BloodBrain Barrier, 104
Coupling of Neurons: Pathways for Signals, 12 Arterial System, 108
The Cytoskeleton and Axonal Transport, 16 Venous System, 111
2. Glia, 19
Overview, 19 PART II DEVELOPMENT, AGING,
Types of Glial Cells, 19
AND PLASTICITY
Glial Cells and Homeostasis, 19
Insulation and Protection of Axons, 23 9. Prenatal and Postnatal Development, 117
Microglia and Reactions of the Overview, 117
CNS to Injury, 26 Prenatal Development, 117
Mechanisms for Establishment of
3. Neuronal Excitability, 28
Specic Connections, 130
Overview, 28
The Role of the Environment in
Basis of Excitability, 28
Development of the
The Action Potential, 34
Nervous System, 135
Impulse Propagation, 36
How Nerve Cells Vary Their Messages, 38 10. The Nervous System and Aging, 139
Overview, 139
4. Synaptic Function, 40
Age-Related Changes in the Normal Brain and
Overview, 40
Their Consequences, 139
Neurotransmitter Handling at the Synapse, 41
Neurodegenerative Diseases
Synaptic Potentials and Types of Synapses, 44
and Dementia, 143
Synaptic Plasticity, 49
11. Restitution of Function after
5. Neurotransmitters and Their Receptors, 53
Brain Damage, 147
Overview, 53
Overview, 147
General Aspects, 53
Brain Injuries and Possible Reparative
Specic Neurotransmitters, 57
Processes, 147
Actions of Drugs on the Nervous System, 70
Brain Processes Underlying Recovery
6. Parts of the Nervous System, 72 of Function, 150
Overview, 72 Restitution after Damage in
The Spinal Cord, 74 Early Childhood, 155
vii
viii CONTENTS
PART III SENSORY SYSTEMS 19. Olfaction and Taste, 266

Overview, 266
12. Sensory Receptors in General, 159 The Olfactory System, 266
Overview, 159 Gustatory System (The Sense of Taste), 271
Sensory Units and Their Receptive Fields, 159
Transduction: The Translation of
Stimuli to Action Potentials, 160 PART IV MOTOR SYSTEMS
Properties and Classication of Receptors, 161
Receptors and Subjective 20. Motor Systems and Movements
Sensory Experience, 163 in General, 277
Overview, 277
13. Peripheral Parts of the Motor and Other Systems Are Mutually
Somatosensory System, 165 Dependent, 277
Overview, 165 Classication of Movements, 278
Exteroceptors: Cutaneous Sensation, 166
Proprioceptors: Deep Sensation, 173 21. The Peripheral Motor Neurons
The Sensory Fibers and the and Reexes, 280
Dorsal Roots, 183 Overview, 280
Motoneurons and Muscles, 280
14. Central Parts of the Reexes, 288
Somatosensory System, 190 Muscle Tone, 296
Overview, 190 Injury of Peripheral Motor Neurons
Central Somatosensory Pathways, 190 and Regeneration, 299
The Somatosensory Cortical Regions, 200
22. The Motor Cortical Areas and
15. Pain, 204 Descending Pathways, 301
Overview, 204 Overview, 301
Some Distinctive Features of Pain, 204 The Pyramidal Tract
When the Pain System Gets Out (The Corticospinal Tract), 301
of Control, 205 Indirect Corticospinal Pathways, 308
Central Control of Transmission from Control of Automatic Movements, 311
Nociceptors and Pain Sensation, 208 Motor Cortical Areas and Control of
Placebo and Nocebo, 211 Voluntary Movements, 313
Modern Views on Pain and Symptoms Caused by Interruption of
Pain Treatment, 213 Central Motor Pathways (Upper
16. The Visual System, 215 Motor Neurons), 319
Overview, 215 23. The Basal Ganglia, 324
The Eyeball and the Refracting Media, 215 Overview, 324
The Retina, 218 Structure and Connections of the
Organization of the Visual Pathways, 227 Basal Ganglia, 324
The Visual Cortex and the Final The Ventral Striatum, 336
Processing of Visual Information, 233 Functions of the Basal Ganglia, 338
17. The Auditory System, 240 Diseases of the Basal Ganglia, 339
Overview, 240 24. The Cerebellum, 343
The Cochlea, 240 Overview, 343
The Auditory Pathways, 247 Subdivisions and Afferent Connections of
The Auditory Cortex, 251 the Cerebellum, 343
18. The Sense of Equilibrium, 253 The Cerebellar Cortex and the Mossy and
Overview, 253 Climbing Fibers, 350
Structure and Function of the Vestibular Efferent Connections of the Cerebellum, 354
Apparatus, 253 Cerebellar Functions and Symptoms
Connections of the Vestibular Nuclei, 256 in Disease, 357
Vestibular Reexes: Control of Eye 25. Control of Eye Movements, 362
Movements and Bodily Posture, 259 Overview, 362
Cortical Processing of Movements of the Eyes and the
Vestibular Signals, 263 Eye Muscles, 362
CONTENTS ix
Brain Stem and Cerebellar Control 30. The Central Autonomic System:
of Eye Movements, 365 The Hypothalamus, 440
Cortical Control of Eye Movements, 369 Overview, 440
Centers in the Brain Stem for
Coordination of Behavior, 440
PART V THE BRAIN STEM AND THE Structure and Connections of
CRANIAL NERVES the Hypothalamus, 441
The Hypothalamus and the
26. The Reticular Formation: Premotor
Endocrine System, 445
Networks, Consciousness, and Sleep, 373
Functional Aspects, 449
Overview, 373
The Hypothalamus and the
Structure and Connections of the
Immune System, 454
Reticular Formation, 373
The Hypothalamus and
Functions of the Reticular Formation, 381
Mental Functions, 455
Consciousness, 383
Sleep, 387
27. The Cranial Nerves, 391 PART VII LIMBIC STRUCTURES

Overview, 391
31. The Amygdala, the Basal Forebrain,
General Organization of the
and Emotions, 461
Cranial Nerves, 391
Overview, 461
The Hypoglossal Nerve, 396
What Is the Limbic System?, 461
The Accessory Nerve, 397
The Amygdala, 462
The Vagus Nerve, 398
Some Aspects of Cortical Control of
The Glossopharyngeal Nerve, 401
Autonomic Functions and Emotions, 468
The Vestibulocochlear Nerve, 401
Neuronal Groups in the Basal Parts of the
The Facial and Intermediate Nerves, 402
Hemispheres: The Basal Forebrain, 470
The Trigeminal Nerve, 404
The Abducens, Trochlear, and 32. The Hippocampal Formation:
Oculomotor Nerves, 406 Learning and Memory, 473
Overview, 473
The Hippocampal Formation, 473
PART VI THE AUTONOMIC Functional Aspects, 477
NERVOUS SYSTEM
28. Visceral Efferent Neurons: The Sympathetic PART VIII THE CEREBRAL CORTEX
and Parasympathetic Divisions, 413
Overview, 413 33. The Cerebral Cortex: Intrinsic
General Organization, 413 Organization and Connections, 485
Peripheral Parts of the Overview, 485
Sympathetic System, 418 Structure of the Cerebral Cortex, 485
Peripheral Parts of the Connections of the Cerebral Cortex, 493
Parasympathetic System, 422
34. Functions of the Neocortex, 500
The Enteric Nervous System, 424
Overview, 500
Functional Aspects of the Autonomic
Association Areas, 500
Nervous System, 425
Language Functions and Speech Areas
Neurotransmitters in the Autonomic
of the Cerebral Cortex, 509
Nervous System, 429
The Division of Tasks between
29. Sensory Visceral Neurons and the Hemispheres, 511
Visceral Reexes, 432 Sex Differences and the
Overview, 432 Cerebral Cortex, 515
Visceral Receptors and
Afferent Pathways, 432
Literature, 519
Visceral Reexes, 434
Visceral Pain, 436 Index, 569
Introduction
A BIRDS EYE VIEW OF THE NERVOUS SYSTEM The nervous system can elicit an external response
only by acting on effectors, which are either muscles or
What are the main tasks of the nervous system? This glands. The response is either movement or secretion.
question is not easily answeredour brains represent Obviously, muscle contraction can have various expres-
most of what we associate with being a human. At a sions, from communication through speech, facial
superior level, the brain creates our reality: it selects, expression, and bodily posture to walking and running,
sorts, and interprets the overwhelming amount of infor- respiratory movements, and changes of blood pressure.
mation we receive from our bodies and the environment, But one should bear in mind that the nervous system
and it controls behavior in accordance with its interpre- can only act on muscles and glands to express its will.
tations of reality. This control concerns behavior in a Conversely, if we are to judge the activity going on in
wide sense: one aspect is control and maintenance of the the brain of another being, we have only the expres-
body and its inner milieu; another is our interaction with sions produced by muscle contraction and secretion to
our surroundings and other human beings through go by.
actions and speech. A third aspect is our inner, subjec- On an anatomic basis we can divide the nervous
tive, mental reality that others can only partially know. system into the central nervous system (CNS), consist-
In early childhood, the brain must create order and pre- ing of the brain and the spinal cord, and the peripheral
dictability so that we learn to relate successfully to our- nervous system (PNS), which connects the CNS with
selves and our environment. the receptors and the effectors. Although without sharp
The essential building block of the nervous system is transitions, the PNS and the CNS can be subdivided
the neuron (nerve cell), specialized for rapid conveyance into parts that are concerned primarily with the regula-
of signals over long distances and in a very precise tion of visceral organs and the internal milieu, and parts
manner. Together, billions of neurons in the brain form that are concerned mainly with the more or less con-
complicated and highly organized networks for com- scious adaptation to the external world. The first divi-
munication and information processing. sion is called the autonomic or visceral nervous system;
The nervous system receives a wealth of information the second is usually called the somatic nervous system.
from an individuals surroundings and body. From all The second division, also called the cerebrospinal ner-
this information, it extracts the essentials, stores what vous system, receives information from sense organs
may be needed later, and emits a command to muscles capturing events in our surroundings (vision, hearing,
or glands if an answer is appropriate. Sometimes the receptors in the skin) and controls the activity of volun-
answer comes within milliseconds, as a reflex or auto- tary muscles (made up of cross-striated skeletal muscle
matic response. At other times it may take considerably cells). In contrast, the autonomic nervous system controls
longer, requiring cooperation among many parts of the the activity of involuntary muscles (smooth muscle and
brain and involving conscious processes. In any case, heart muscle cells) and gland cells. The autonomic
the main task of the nervous system is to ensure that the system may be further subdivided into the sympathetic
organism adapts optimally to the environment. system, which is mainly concerned with mobilizing the
The nervous system is equipped with sense organs, resources of the body when demands are increased (as
receptors, that react to various forms of sensory infor- in emergencies), and the parasympathetic system, which
mation or stimuli. Regardless of the mode of stimula- is devoted more to the daily maintenance of the body.
tion (the form of energy), the receptors translate the The behavior of a vertebrate with a small and
energy of the stimulus to the language spoken by the comparatively speakingsimple brain (such as a frog)
nervous system, that is, nerve impulses. These are tiny is dominated by fairly fixed relationships between stim-
electric discharges rapidly conducted along the nerve uli and their response. Thus, a stimulus, produced for
processes. In this way signals are conveyed from the example by a small object in the visual field, elicits a
receptors to the regions of the nervous system where stereotyped pattern of goal-directed movements. Few
information processing takes place. neurons are intercalated between the sense organ and
xi
xii INTRODUCTION
the effector, with correspondingly limited scope of so that today problems can be approached that were
response adaptation. Much of the behavior of the ani- formerly only a matter of speculation. The number of
mal is therefore instinctive and automatic, and not neuroscientists has also increased almost exponentially,
subject to significant change by learning. In mammals and they are engaged in problems ranging from molec-
with relatively small brains compared with their body ular genetics to behavior. Although the mass of knowl-
weights (such as rodents) a large part of their brain is edge in the field of neurobiology has increased accordingly,
devoted to fairly direct sensorimotor transformations. more importantly, the understanding of how our brains
In primates, the relative brain weight has increased dra- work has improved considerably. Nevertheless, the
matically during some million years of evolution. This steadily expanding amount of information makes it dif-
increase is most marked in humans with relative brain ficult for the scientist to have a fair knowledge outside
weight double that of the chimpanzee. In humans, there his or her specialty. It follows that the scientist may not
are few fixed relationships between sensations and be able to put findings into the proper context, with dan-
behavior (apart from a number of vital reflexes). Thus, ger of drawing erroneous conclusions
a certain stimulus may cause different responses depend- Traditionally, methods used for neurobiological
ing on its context and the antecedents. Consequently, research were grouped into those dealing with structure
we often can choose among several responses, and the (neuroanatomy) and those aiming at disclosing the
response can be changed on the basis of experience. function of the structures (neurophysiology, neuropsy-
Such flexibility requires, however, increased computa- chology). The borders are far from sharp, however, and
tional power in terms of number of neurons available it is typical of modern neuroscience that anatomic,
for specific tasks. The more an animal organizes its physiological, biochemical, pharmacological, psycho-
activities on the basis of previous experience, and the logical, and other methods are combined. Especially,
more it is freed from the dominance of immediate sen- cell biological methods are being applied with great
sations, the more complex are the processes required of success. Furthermore, the introduction of modern com-
the central nervous system. The behavior of humans can- puter-based imaging techniques has opened exciting
not be understood merely on the basis of what happened possibilities for studying the relation between structure
immediately before. The British neuropsychologist Larry and function in the living human brain. More and more
Weiskrantz (1992) puts it this way: We are controlled of the methods originally developed in cell biology and
by predicted consequences of our behavior as much as immunology are being applied to the nervous system,
by the immediate antecedents. We are goal-directed and we now realize that neurons are not so different from
creatures. other cells as was once assumed.
The higher processes of integration and association
that is, what we call mental processesare first and
Animal Experiments Are Crucial for Progress
foremost a function of the cerebral cortex. It is primar-
ily the vast number of neurons in this part of the brain Only a minor part of our present knowledge of the ner-
that explains the unique adaptability and learning vous system is based on observations in humans; most
capacity of human beings. Indeed, the human brain not has been obtained in experimental animals. In humans
only permits adaptation to extremely varied environ- we are usually limited to a comparison of symptoms
ments, it also enables us to change our environment to that are caused by naturally occurring diseases, with
suite our needs. This entails enormous possibilities but the findings made at postmortem examination of the
also dangers, because we produce changes that are favor- brain. Two cases are seldom identical, and the struc-
able in the short run but in the long run might threaten tural derangement of the brain is often too extensive to
the existence of our species. enable unequivocal conclusions.
In animals, in contrast, the experimental conditions
can be controlled, and the experiments may be repeated,
STUDYING THE STRUCTURE AND FUNCTION to reach reliable conclusions. The properties of the ele-
OF THE NERVOUS SYSTEM ments of neural tissue can be examined directlyfor
example, the activity of single neurons can be correlated
Some of the many methods used for the study of the with the behavior of the animal. Parts of the nervous
nervous system are described in the following chapters system can also be studied in isolationfor example,
that is, in conjunction with discussion of results pro- by using tissue slices that can be kept viable in a dish
duced by the methods. Here we limit ourselves to some (in vitro) for hours. This enables recordings and experi-
general features of neurobiological research. mental manipulations to be done, with subsequent
Many approaches have been used to study the structure structural analysis of the tissue. Studies in invertebrates
and function of the nervous system, from straightforward with a simple nervous system have made it possible to
observations of its macroscopic appearance to determina- discover the fundamental mechanisms that underlie
tion of the function of single molecules. In recent years synaptic function and the functioning of simple neu-
we have witnessed a tremendous development of methods, ronal networks.
INTRODUCTION xiii
When addressing questions about functions specific authorities and by the scientific community itself to
to the most highly developed nervous systems, however, ensure that only properly trained persons perform ani-
experiments must be performed in higher mammals, mal experiments and that the experiments are con-
such as cats and monkeys, with a well-developed cerebral ducted so that discomfort and pain are kept at a
cortex. Even from such experiments, inferences about minimum. Most international neuroscience journals
the human nervous system must be drawn with great require that the experiments they publish have been
caution. Thus, even though the nervous systems in all conducted in accordance with such rules.
higher mammals show striking similarities with regard
to their basic principles of organization, there are
Sources of Error in All Methods
important differences in the relative development of the
various parts. Such anatomic differences indicate that Even though we will not treat systematically the sources
there are functional differences as well. Thus, results of error inherent in the various methods discussed in
based on the study of humans, as in clinical neurology, this book, certainly all methods have their limitations.
psychiatry, and psychology, must have the final word One source of error when doing animal experiments is
when it comes to functions of the human brain. But to draw premature conclusions about conditions in
because clinicians seldom can experiment, they must humans. In general, all experiments aim at isolating
often build their conclusions on observations made in structures and processes so that they can be observed
experimental animals and then decide whether findings more clearly. However necessary this may be, it also
from patients or normal volunteers can be explained on means that many phenomena are studied out of their
such a basis. If this is not possible, the clinical findings natural context. Conclusions with regard to how the
may raise new problems that require studies in experi- parts function in conjunction with all of the others must
mental animals to be solved. Basically, however, the therefore be speculative.
methods used to study the human brain are the same as Purely anatomic methods also have their sources of
those used in the study of experimental animals. error and have led to many erroneous conclusions in
the past about connections between neuronal groups.
In turn, such errors may lead to misinterpretations of
Ethics and Animal Experiments
physiological and psychological data. The study of
Experiments on animals are often criticized from an humans also entails sources of errorfor example, of a
ethical point of view. But the question of whether such psychological nature. Thus, the answers and informa-
experiments are acceptable cannot be entirely separated tion given by a patient or a volunteer are not always
from the broader question of whether mankind has the reliable; for example, the patient may want to please
right to determine the lives of animals by using them for the doctor and answer accordingly.
food, by taking over their territories, and so forth. With
regard to using animals for scientific purposes, one has
Revising Scientic Truths from Time to Time
to realize that a better understanding of human beings
as thinkers, feelers, and actors requires, among other That our methods have sources of error and that our
things, further animal experiments. Even though cell interpretations of data are not always tenable are wit-
cultures and computer models may replace some of nessed by the fact that our concepts of the nervous
them, in the foreseeable future we will still need animal system must be revised regularly. Reinterpretations of
experiments. Computer-based models of the neuronal old data and changing concepts are often made neces-
interactions taking place in the cerebral cortex, for sary by the introduction of new methods. As in all areas
example, usually require further animal experiments to of science, conclusions based on the available data
test their tenability. should not be regarded as final truths but as more or
Improved knowledge and understanding of the human less probable and preliminary interpretations. Natural
brain is also mandatory if we want to improve the pros- science is basically concerned with posing questions to
pects for treatment of the many diseases that affect the nature. How understandable and unequivocal the
nervous system. Until today, these diseasesmost often answers are depends on the precision of our questions and
leading to severe suffering and disabilityhave only how relevant they are to the problem we are studying:
occasionally been amenable to effective treatment. stupid questions receive stupid answers. It is further-
Modern neurobiological research nevertheless gives more fundamental to sciencealthough not always easy
hope, and many promising results have appeared in the for the individual scientist to live up tothat conclu-
last few years. Again, this would not have been possible sions and interpretations be made without any bias and
without animal experiments. solely on the strength of the facts and the arguments. It
Yet there are obviously limits to what can be defended should be irrelevant whether the scientist is a young
ethically, even when the purpose is to alleviate human student or a Nobel laureate.
suffering. Strict rules have been made by government
The Central Nervous System
I MAIN FEATURES OF STRUCTURE
AND FUNCTION
G ENERAL information about the structure and

function of the nervous system forms a necessary
basis for treatment of the specific systems described in
nerve cells. Chapter 6 provides an overview of the
macroscopic (and, to some extent, the microscopic)
structure of the nervous system with brief descriptions
subsequent parts of this book. Chapters 1 and 2 describe of functions. Chapter 7 treats the membranes covering
the structure of nervous tissue and some basic features the central nervous system, the cavities within the brain,
of how neurons are interconnected, while Chapters 3, and the cerebrospinal fluid produced in these. Finally,
4, and 5 deal with the functional properties of neurons Chapter 8 describes the blood supply of the brain and
as a basis for understanding communication between the spinal cord.
1 Structure of the Neuron and
Organization of Nervous Tissue
OVERVIEW
synaptic contacts from many others (convergence).
The nervous system is built up of nerve cells, neurons, A neuron contains a cytoskeleton consisting of various
and special kinds of supporting cells, glial cells (dis- kinds of neurofibrils. They are instrumental in forming
cussed in Chapter 2). The nerve cells are responsible for the neuronal processes and in transport of substances
the functions that are unique to the nervous system, along them. By axonal transport, building materials
whereas the glial cells are non-neuronal cells that pri- and signal substances can be brought from the cell soma
marily support and protect the neurons. Neurons are to the nerve terminals (anterograde transport), and sig-
composed of a cell body called the soma (plural somata) nal substances are carried from the nerve terminal to
and several processes. Multiple short dendrites extend the soma (retrograde transport).
the receiving surface of the neuron, while a single axon
conducts nerve impulses to other neurons or to muscle
NEURONS AND THEIR PROCESSES
cells. Neurons are characterized by their ability to
respond to stimuli with an electrical discharge, a nerve
Neurons Have Long Processes
impulse, and, further, by their fast conduction of the
nerve impulse over long distances. In this way, signals Like other cells, a neuron has a cell body with a nucleus
can be transmitted in milliseconds from one place to surrounded by cytoplasm containing various organ-
another, either within the central nervous system (CNS) elles. The nerve cell body is also called the perikaryon
or between it and organs in other systems of the body. or soma (Figs. 1.1, 1.2, and 1.3). Long processes extend
When the nerve impulse reaches the synapse, which is from the cell body. The numbers and lengths of the
the site of contact between the axon and the next neu- processes can vary, but they are of two main kinds:
ron, a substance called a neurotransmitter is released dendrites and axons (Fig. 1.1). The dendrites usually
from the axon terminal that conveys a chemical signal branch and form dendritic trees with large surfaces
from one neuron to the next. that receive signals from other nerve cells. Each neuron
Neurons are classified into two broad groups: projec- may have multiple dendrites, but has only one axon,
tion neurons that transmit signals over long distances which is specially built to conduct the nerve impulse
and interneurons that mediate cooperation among from the cell body to other cells. The axon may have
neurons that lie grouped together. Many axons are sur- many ramifications, enabling its parent cell to influence
rounded with a myelin sheath to increase the speed of many other cells. Side branches sent off from the parent
impulse propagation. Nervous tissue contains some axon are termed axon collaterals (Fig. 1.1). The term
areas that look graygray matterand others that nerve fiber is used synonymously with axon.
look whitishwhite matter. White matter consists of
axons and no neuronal somata, and the color is due to
Neurons Are Rich in Organelles for Oxidative
the whitish color of myelin. Gray matter consists mainly
Metabolism and Protein Synthesis
of somata and dendrites, which have a gray color.
Neuronal somata are collected in groups sharing con- When seen in a microscopic section, the nucleus of a
nections and functional characteristics. In the CNS, neuron is characterized by its large size and light stain-
such a group is called a nucleus and in the peripheral ing (i.e., the chromatin is extended, indicating that
nervous system (PNS), a ganglion. A bundle of axons much of the genome is in use). There is also a promi-
that interconnect nuclei is called a tract. A nerve con- nent nucleolus (Figs. 1.2 and 1.3). These features make
nects the CNS with peripheral organs. Groups of neu- it easy to distinguish a neuron from other cells (such as
rons that are interconnected form complex neuronal glial cells), even in sections in which only the nuclei are
networks that are responsible for performing the tasks of clearly stained. The many mitochondria in the neuronal
the CNS. A fundamental principle of the CNS is that each cytoplasm are an indication of the high metabolic activity
neuron influences many others (divergence) and receives of nerve cells. The mitochondria depend entirely on
5
6 THE CENTRAL NERVOUS SYSTEM
Spine Dendrite
rER
Dendrites Nucleolus
Nucleus
Cell body (soma) Dendrite
gure 1.2 Neuronal somata (cell bodies). Two motor neurons, one
small and one large, are shown. The large, pale nucleus has a distinct
nucleolus. Only the cell body and the proximal parts of the dendrites
are visible with the staining method used here. The stain (thionine)
binds primarily to nucleic acids (DNA in the nucleus and RNA in the
Axon Axon collateral cytoplasm and nucleolus). The deeply stained clumps in the cyto-
plasm represent aggregates of rough endoplasmic reticulum (rER).
Photomicrographs taken with a light microscope of a 20 m thick
section of the spinal cord. Magnication, 800.
Nerve terminals
(boutons) Different staining methods make it possible to distinguish
the whole neuron or parts of it from the surrounding
elements (Figs. 1.2 and 1.4). It then becomes evident
that the morphology of neurons may vary, with regard
gure 1.1 A neuron. Half-schematic to illustrate the neurons main to both the size of the cell body and the number, length,
parts. The axon is red.
and branching of the dendrites (Fig. 1.2; see also
Figs. 33.56). The size of the dendritic tree is related to
aerobic adenosine triphosphate (ATP) production and, the number of contacts the cell can receive from other
unlike those in most other cell types, cannot utilize nerve cells. Dendrites often have small spikes, spinae
anaerobic ATP synthesis. Glucose is the substrate for (sing. spina) or spines, which are sites of contact with
ATP production in the mitochondria of nerve cells, which other neurons (Figs. 1.1, 1.7, and 1.8). The axons also
cannot, unlike in muscle cells, for example, use fat. vary, from those that ramify and end close to the cell
Neuronal somata also contain conspicuous amounts body to those that extend for more than 1 meter (see
of free ribosomes and rough endoplasmic reticulum Fig. 1.10; see also Figs. 21.3, 33.5, and 33.6). These
(rER) for synthesis of proteins. Large clumps of rER are structural differences are closely connected to func-
seen via light microscopy in the cytoplasm of neurons tional differences.
greater than a certain size (Figs. 1.2 and 1.3). These
were called tigroid granules or Nissl bodies long before
Most Neurons Are Multipolar
their true nature was known. There are also as a rule
several Golgi complexes, which modify proteins before Most neurons have several processes and are therefore
they are exported or inserted in membranes. The large called multipolar (Fig. 1.5). Special kinds of neurons,
neuronal production of proteins probably reflects the however, may have a different structure. Thus, neurons
enormous neuronal surface membrane, which contains that conduct sensory signals from the receptors to the
many protein molecules that must be constantly CNS have only one process that divides close to the cell
renewed. Membrane proteins, for example, form ion body. One branch conducts impulses from the receptor
channels and receptors (binding sites) for neurotrans- toward the cell soma; the other conducts impulses toward
mitters, are constantly being recycled. and into the CNS. Such neurons are called pseudounipo-
lar (Fig. 1.5). In accordance with the usual definition, the
process conducting signals toward the cell body should
Dendrites Are Equipped with Spines
be termed a dendrite. In terms of both structure and
To study the elements of nervous tissue, it is necessary to function, however, this process must be regarded as an
use thin sections that can be examined microscopically. axon. Some neurons have two processes, one conducting
1: STRUCTURE OF THE NEURON AND ORGANIZATION OF NERVOUS TISSUE 7
A The term terminal bouton is used when the bouton sits

at the end of an axon branch, and we also use the term
nerve terminal. In other instances, the bouton is only a
a thickening along the course of the axon, with several
such en passage boutons along one terminal branch
(Fig. 1.8). In any case, the bouton lies close to the
surface membrane of another cell, usually on the den-
drites or the cell body. Such a site of close contact
between a bouton and another cell is called a synapse.
In the PNS, synapses are formed between boutons and
muscle cells. The synapse is where information is trans-
mitted from one neuron to another. This transmission
does not occur by direct propagation of the nerve
impulse from one cell (neuron) to another, but by lib-
eration of signal molecules that subsequently influence
the other cell. Such a signal molecule is called a neu-
rotransmitter or, for short, a transmitter (the term
b b transmitter substance is also used). The neurotrans-
B
d mitter is at least partly located in small vesicles in the
d bouton called synaptic vesicles (Figs. 1.6 and 1.7). How
the synapse and the transmitters work is treated in
b Chapters 4 and 5. Here we restrict ourselves to the
structure of the synapse.
b
The membrane of the nerve terminal is separated
from the membrane of the other nerve cell by a narrow
cleft approximately 20 nm wide (i.e., 2/100,000 mm).
This synaptic cleft cannot be observed under a light
microscope. Only when electron microscopy of nervous
tissue became feasible in the 1950s could it be demon-
strated that neurons are indeed anatomically separate
entities. In the electron microscope, one can observe
that the membranes facing the synaptic cleft are thick-
ened (Figs. 1.6 and 1.7), due to accumulation of specific
proteins that are of crucial importance for transmission
of the synaptic signal. Many of these protein molecules
gure 1.3 Ultrastructure of the neuron. Electron micrograph show-
ing the cell body of a small neuron (A) and parts of a larger neuron are receptors for neurotransmitters; others form chan-
(B). The nucleus (N) is light, due to extended chromatin, and contains nels for passage of charged particles. The membrane of
a nucleolus (Nu). The cytoplasm contains rough endoplasmic reticu- the bouton facing the cleft is called the presynaptic
lum (rER) and a Golgi complex (G)that is, organelles involved in membrane, and the membrane of the cell that is con-
protein synthesis. The presence of many mitochondria (m) reects the
tacted is called the postsynaptic membrane (Fig. 1.6).
high oxidative metabolism of neurons. Nerve terminals, or boutons
(b), forming axosomatic and axodendritic synapses are also seen. We also use the terms pre- and postsynaptic neurons.
Glial processes (g) follow closely the surface of the cell body and the The postsynaptic density (Fig. 1.6; see also Fig. 4.17)
dendrites (d). a, axon; My, myelin. Magnications, 9000 (top) and connects to the cytoskeleton with actin filaments and
15,000 (bottom). other proteins. This connection probably anchors the
postsynaptic receptors to the site of neurotransmitter
release. In addition, certain proteins in the postsynaptic
toward the cell body, the other away from it (Fig. 1.5). density, such as cadherins, bind to corresponding pro-
Such neurons, present in the retina (see Fig. 16.7) and the teins in the presynaptic membrane to keep the nerve
inner ear (see Fig. 17.5B), are called bipolar. Also in these terminal in place (cadherins are present also in many
neurons both processes function as axons. other cell-to-cell contacts, e.g., in adherence contacts
between epithelial cells). Other proteins in the postsyn-
aptic density have modulatory actions on synaptic func-
Communication between Nerve Cells Occurs at
tion, for example, by changing receptor properties.
Synapses
Synaptic modifications associated with learning involve
The terminal branches of an axon have club-shaped structural and functional changes of the postsynaptic
enlargements called boutons (Figs. 1.1 and 1.6). density.
Myelinated
axons Dendrites
Cell bodies (somata)
gure 1.4 Neurons. Photomicrographs of sections stained with two also stained. Right: The same cell group, but treated via the Golgi
different methods. Left: Only the cell bodies (somata) of a group of method so that the dendrites and the cell bodies are visualized.
neurons are stained and visible in the section. The dark region sur- Magnication, 150.
rounding the group of neurons contains myelinated bers that are
Synapses formed on the cell soma are called axosomatic, formed with the spine head (Figs. 1.7B, 1.8, and 1.9).
while synapses on dendrites are called axodendritic The functional role of spines is not fully understood
(Figs. 1.3 and 1.8). Where dendrites are equipped with (see Chapter 4). Boutons may also form a synapse with
spines, one or two axospinous synapses are always an axon (usually close to a terminal bouton of that
axon), and such synapses are called axoaxonic (Fig. 1.8
and 1.9B). This enables selective control of one termi-
nal only without influencing the other terminals of
A the parent axon. Axoaxonic synapses thus increase the
precision of the signal transmission.
There are many more axodendritic than axosomatic
synapses because the dendritic surface is so much larger.
Every neuron has many thousands of synapses on its
surface, and the sum of their influences determines how
active the postsynaptic neuron will be at any moment.
Two Main Kinds of Nerve Cell: Projection Neurons

and Interneurons
B
Some neurons influence cells that are at a great distance,
and their axons are correspondingly long (more than a
meter for the longest). They are called projection neu-
rons, or Golgi type 1 (Fig. 1.10). Neurons that convey
signals from the spinal cord to the muscles are examples
of projection neurons; other examples are neurons in
C the cerebral cortex with axons that contact cells in the
brain stem and the spinal cord (see Fig. 33.5). As a rule,
the axons of projection neurons send out branches, or
collaterals, in their course (Figs. 1.1 and 1.11; see also
gure 1.5 Neurons exemplifying three different arrangements of Fig. 33.5). Thus, one projection neuron may send sig-
processes. Multipolar (A), pseudounipolar (B), bipolar (C). Arrows nals to neurons in various other parts of the nervous
show the direction of impulse conduction. system.
A B
Axon
Cell body
Presynaptic Glia
neuron
Nerve terminal
Synaptic vesicles
Axon Presynaptic
membrane
Nerve terminales
Synaptic cleft
gure 1.6 The synapse. A: Postsynaptic membrane
Schematic overview of pre- and
Postsynaptic
postsynaptic neurons B: The main Dendrite density (PSD)
structural elements of a typical
synapse. Based on electron micro- Synapse Postsynaptic
graphs. Compare with Figs. 1.3 Postsynaptic neuron
and 1.7. neuron
The other main type of neuron is the interneuron, or with the rest of the body, as a rule varies more with the
Golgi type 2 (Fig. 1.10, see also Fig. 33.6), character- size of the body than with the stage of development.
ized by a short axon that branches extensively in the The distinction between projection neurons and
vicinity of the cell body. Its name implies that an interneurons is not always very clear, however. Many
interneuron is intercalated between two other neurons neurons previously regarded as giving off only local
(Fig. 1.12). Even though, strictly speaking, all neurons branches have been shown via modern methods also to
with axons that do not leave the CNS are thus interneu- give off long axonal branches to more distant cell
rons, the term is usually restricted to neurons with short groups. Thus, they function as both projection neurons
axons that do not leave one particular neuronal group. and interneurons. In contrast, many of the classical
The interneurons thus mediate communication between projection neurons, for example, in the cerebral cortex
neurons within one group. Because interneurons may (Fig. 33.5), give off collaterals that end within the cell
be switched on and off, the possible number of interre- group in which the cell body is located.
lations among the neurons within one group increases
dramatically. The number of interneurons is particu-
Tasks of Interneurons
larly high in the cerebral cortex, and it is the number of
interneurons that is so much higher in the human brain Figure 1.12 shows how an interneuron (b) is interca-
than in that of any other animal. The number of typical lated in an impulse pathway. One might perhaps think
projection neurons interconnecting the various parts of that the simpler direct pathway shown below from neu-
the nervous system, and linking the nervous system ron A to neuron C would be preferable. After all, the
A B
d g
Mt
Mt
b
b a
gure 1.7 Synapses. A, B: Electron micro- a

graphs showing boutons (b) in synaptic con- g g
d
g
tacts with dendrites (d), and dendritic spines
(Sp). Note how processes of glia (g) cover b
the dendrites and nerve terminals except at
the site of synaptic contact. Note bundle of b
unmyelinated axons (a) in B. Microtubules g
(Mt) are responsible for axonal transport.
Magnications, 20,000 (A) and 40,000 (B).
interneuron leads to a delay in the propagation of the

signal from A to C, and this would be a disadvantage.
Most important, however, is that the interneuron
provides added flexibility. Thus, whether the signal is
transmitted from a to c can be controlled by other syn-
Axodendritic aptic inputs to interneuron b. Identical synaptic inputs
synapses on spines to a neuron a may in one situation be propagated
further by neuron c but in another situation not,
depending on the state of interneuron b. This kind of
arrangement may partly explain why, for example,
identical stimuli may cause pain of very different inten-
sity: interneurons along the pathways conveying
Axodendritic synapse sensory signals are under the influence of other parts of
on dendritic shaft the brain (e.g., neurons analyzing the meaning of the
sensory stimulus).
Figure 1.13 illustrates another important task per-
Axosomatic formed by interneurons. Interneuron B enables neuron
synapse
A to act back on itself and reduce its own firing of
impulses. The arrangement acts to prevent neuron A
from becoming excessively active. Thus, the negative
feedback provided by the interneuron would stop the
firing of neuron A. Such an arrangement is present, for
example, among motor neurons that control striated
muscle contraction (see Fig. 21.14).
Axosomatic synapse
near the axon hillock
Many Axons Are Isolated to Increase the Speed of
Impulse Propagation
The velocity with which the nerve impulse travels
Axoaxonic synapse depends on the diameter of the axon, among other
factors. In addition, how well the axon is insulated is of
crucial importance. Many axons have an extra layer of
gure 1.8 The placement of synapses. The position of a synapse
insulation (in addition to the axonal membrane) called
determines (together with other factors) its effect on the postsynaptic
neuron. A synapse close to the exit of the axon, for example, has a myelin sheath. Such axons are therefore called myeli-
much greater impact that a synapse located on a distal dendrite. nated, to distinguish them from those without a myelin
sheath, which are called unmyelinated (see Figs. 2.6
and 2.7).
A B
Nerve terminals Terminals en passage Presynaptic nerve terminal
Spine
Dendrite Postsynaptic
nerve terminal
Postsynaptic
neuron
Axon Glia
gure 1.9 A: Axodendritic synapses. A nerve terminal (bouton) synapse. The presynaptic nerve terminal inuencesby usually inhib-
may form a synapse directly on the shaft of the dendrite or on a spine. itingthe release of neurotransmitter from the postsynaptic nerve
The axon may also have several boutons en passage. B: Axoaxonic terminal.
Dendrites
Dendrites
gure 1.10 Projection neuron and
interneuron. A projection neuron sends
its axon to neurons in other nuclei (cell
groups), often at a long distance. The
axon of an interneuron ramies and
makes synaptic contacts in its vicinity
(within the same nucleus). Examples Axon
from the brain stem of a monkey, based
on sections treated via the Golgi method,
which impregnate the whole neuron Soma
with silver salts. The photomicrograph
to the left is from the Golgi-stained
Axon
section containing the drawn projection
neuron. The depth of eld is only a Axonal
fraction of the thickness of the section ramifications
(100 m). Therefore, only part of the
projection neuron is clearly visible in the
photomicrograph. Projection neuron Interneuron
Many of the tasks performed by the nervous system

require very rapid conduction of signals. If unmyeli-
nated axons were to do this, they would have to be
extremely thick. Nerves bringing signals to the muscles
Axon of the hand, for example, would be impossibly thick,
collateral and the brain would also have to be much larger.
Insulation is thus a very efficient way of saving space
and expensive building materials. Efficient insulation of
axons is, in fact, a prerequisite for the dramatic devel-
opment of the nervous system that has taken place in
vertebrates as compared with invertebrates.
Myelin and how it is formed is treated in Chapter 2,
while the conduction of nerve impulses is discussed
Chapter 3.
gure 1.11 Collateral of a projection neuron. By sending off collat-
erals, a projection neuron may establish synapses in different cell
groups (nuclei). Arrows show the direction of impulse conduction. White and Gray Matter
The surfaces made by cutting nervous tissue contain
some areas that are whitish and others that have a gray
color. The whitish areas consist mainly of myelinated
axons, and the myelin is responsible for the color;
such regions are called white matter. The gray regions,
called gray matter, contain mainly cell bodies and den-
a b c drites (and, of course, axons passing to and from the
neurons). The neurons themselves are grayish in color.
Owing to this difference in color, one can macroscopi-
A cally identify regions containing cell bodies and regions
C
that contain only nerve fibers in brain specimens
(Fig. 1.14).
Neurons Are Collected in Nuclei and Ganglia

gure 1.12 An interneuron (b) intercalated in a pathway from
neuron a to neuron c. This arrangement increases the exibility, as
When examining sections from the CNS under the
compared with the direct pathway from neuron A to C shown below. microscope, one sees that the neuronal cell bodies are
Arrows show the direction of impulse conduction. not diffusely spread out but are collected in groups.
with another is called a tract (tractus; Figs. 1.15 and

A 1.16). In the PNS, a collection of axons is called a nerve
+
(nervus; Fig. 1.16, see also Figs. 11.1 and 28.3). We
also use the term peripheral nerve to emphasize that a
nerve is part of the PNS. Tracts form white matter of
the CNS, and likewise, peripheral nerves containing
B myelinated axons are whitish.
+
Schematically, the large tracts of the nervous system
are the main routes for nerve impulsesto some extent,
gure 1.13 An interneuron (B) mediates negative feedback to they are comparable to highways connecting big cities.
the projection neuron (A). Arrows show the direction of impulse
In addition, there are numerous smaller pathways often
conduction.
running parallel to the highways, and many smaller
bundles of axons leave the big tracts to terminate in
Such a group is called a nucleus (Figs. 1.14, 1.15, and nuclei along the course. The number of smaller foot-
1.16). Neurons collected in this manner share connec- paths interconnecting nuclei is enormous, making pos-
tions with other nuclei and constitute in certain respects sible, at least theoretically, the spread of impulses from
a functional unit; thus, the neurons in a nucleus receive one nucleus to almost any part of the nervous system.
the same kind of information and act on the same (or Normally, the spread of impulses is far from random
similar) target. In the PNS, a corresponding collection but, rather, is highly ordered and patterned. As a rule,
of cell bodies is called a ganglion. the larger tracts have more significant roles than the
Axons that end in a nucleus are termed afferent, smaller ones in the main tasks of the nervous system.
whereas axons that leave the nucleus are efferent. We Consequently, diseases affecting such tracts usually
also use the terms afferent and efferent for axons con- produce marked symptoms that can be understood only
ducting toward and away from the CNS, respectively. if one has a fair knowledge of the main features of the
Thus, sensory axons conveying information from sense wiring patterns of the brain.
organs are afferent, while the motor axons innervating
muscles are efferent.
COUPLING OF NEURONS: PATHWAYS FOR SIGNALS
Axons Form Tracts and Nerves
In addition to the properties of synapses, which deter-
Axons from the neurons of one nucleus usually have mine the transfer of signals among neurons, the func-
common targets and therefore run together, forming tion of the nervous system depends on how the various
bundles. Such a bundle of axons connecting one nucleus neuronal groups (nuclei) are interconnected (often called
A B
Gray matter gure 1.14 Gray and white
(cortex) matter. A: Drawing and photo-
graph of an unstained frontal
section through the human brain.
B: The white matter consists only
C of axons and glial cells, whereas
White matter the gray matter contains the cell
bodies, dendrites, and nerve ter-
minals. C: Low-power photomi-
Gray matter crograph of a section through
(nuclei) the cerebral cortex (frame in A)
D stained so that only neuronal
somata are visible (as small dots)
D: Drawing of neurons in a sec-
tion through the cerebral cortex
(Golgi method). Only a small
fraction of the neurons present
in the section are shown.
BRAIN STEM Nucleus
Tract
gure 1.15 Nucleus and tract. Left: Schematic

of part of the brain stem, showing the three-
dimensional shape of two nuclei and a tract. Right:
Photomicrograph showing the same structures in a
section stained to visualize somata and myelinated
axons. Magnication, 75.
the wiring pattern of the brain). This pattern determines knowledge is important for understanding the specific
the pathways that signals may take and the possibilities examples of connections dealt with in later chapters.
for cooperation among neuronal groups. Thus, although
each neuron is to some extent a functional unit, it is
Divergence and Convergence
only by proper cooperation that neurons can fulfill
their tasks. We will describe here some typical examples A fundamental feature of the CNS is that each neuron
of how neurons are interconnected, as such general influences manyperhaps thousandsof others; that
is, information from one source is spread out. This phe-
nomenon is called divergence of connections. Figure 1.17
shows schematically how a sensory signal (e.g., from
a fingertip) is conducted by a sensory neuron to the
spinal cord and there diverges to many spinal neurons.
BRAIN STEM Each of the spinal neurons acts on many neurons at
Nucleus
higher levels.
Tract
Nerve
Sensory
neuron
Skin
Muscle Spinal cord neurons
Nucleus SPINAL CORD

gure 1.17 Divergence of neural connections. Highly simplied
gure 1.16 Nucleus, tract, and nerve. Three-dimensional schematic diagram. The axon collaterals of one sensory neuron contact many
of parts of the brain stem, spinal cord, and a muscle in the upper arm. neurons in the spinal cord (red). Each of the spinal neurons contacts
Axons from a nucleus in the brain stem form a tract destined for a many other neurons (blue) in the cord or in the brain stem. In this
nucleus in the spinal cord. The axons of the neurons in the spinal way, the signal spreads from one neuron to many others. Arrows
nucleus leave the CNS and form a nerve passing to the muscle. show the direction of impulse conduction.
Another equally ubiquitous feature, convergence of b

connections, is shown schematically in Fig. 1.18. It
means that each neuron receives synaptic contacts from
B
many other neurons. The motor neuron in Fig. 1.18
controls the contraction of a number of striated muscle
cells (but could have been almost any neuron in the a
CNS). The motor neuron receives synaptic contacts A
from many sources (peripheral sense organs, motor
neurons in the cerebral cortex that initiate voluntary
movements, and so forth). In this case, the motor neu- C
ron represents the final common pathway of all the
neurons acting on it. c
The nerve impulses may not necessarily follow all
the available pathways shown in Figs. 1.17 and 1.18 gure 1.19 Summation. Many synapses must act on a neuron at the
because, as a rule, many synapses must be active almost same time to make it re impulses. Axon a makes many synaptic
simultaneously to make a neuron fire impulses. Thus, contacts with neuron A, and their effects summate so that the neuron
more than one of the blue neurons in Fig. 1.18 must be A res impulses. In contrast, axon a forms only few synapses with
active at the same time to bring the motor neuron to neurons B and C and is not able on its own to re these neurons. If,
however, also axons b and c send impulses at the same time as a, sum-
fire impulses and make the muscle contract. This phe- mation ensures that neurons B and C re impulses. Arrows show the
nomenon is termed summation and is exemplified fur- direction of impulse conduction.
ther in Fig. 1.19. The many synapses axon a makes on
neuron A brings the latter to fire a series of nerve
impulses whenever axon a is active. But because of
Parallel Pathways and Reciprocal Connections
fewer synapses, the impact of axon a on neurons B and
C is too weak to make them fire impulses. If, however, Figure 1.20 illustrates common types of connections
axons b and c are active simultaneously with a, their among neuronal groups (nuclei). Figure 1.20A shows
effects are summated so that neurons B and C may fire the principle of parallel pathways. There is one direct
impulses. Summation is discussed further in Chapter 4. pathway from nucleus N1 to N2, and one indirect
pathway that is synaptically interrupted in other nuclei
(n1 and n2). Thus, some of the information reaching
N2 is a direct consequence of the activity in N1, whereas
information passing through n1 and n2 is modified by
other connections acting on these nuclei (not shown).
The abundance of such parallel pathways in the human
cerebral cortex is one of the factors that explain its
enormous flexibility and capacity for information pro-
Neurons with signals
cessing (Fig. 1.23). Parallel pathways may, further, be
from other parts of
the CNS of practical importance after partial brain injury. If, for
example, the direct pathway between N1and N2 is
interrupted, the indirect one may at least partly take
over the tasks formerly performed by the direct one
(examples of this are discussed in Chapter 11, under
Restitution of Function).
Sensory neurons
with signals from Reciprocal connections represent another common
the body arrangement, in which a nucleus receives connections
Motor neuron from the nuclei to which it sends axons (Fig. 1.20B).
In many cases, such back-projections serve as feedback,
whereby the first nucleus is informed of the outcome of
Muscle cell
the impulses emitted to the second one. If the influence
was too strong, the feedback may serve to reduce activ-
gure 1.18 Convergence of neural connections. Synaptic inputs ity, and vice versa if the influence was too weak. Among
from many neurons (blue) converge onto one neuron (red). In this other actions, such feedback connections serve to stabi-
example, the red neuron is motor and sends its axon to striated lize the functioning of the nervous system. Thus, many
muscle cells. The sum of all converging synaptic inputs determines
the frequency of impulses sent from the motor neuron to the muscle
of the symptoms appearing in neurological diseases are
cellsand thus their strength of contraction. Arrows show the direction due to the failure of feedback mechanisms. Often, how-
of impulse conduction. ever, it is not obvious which one should be regarded as
a feedback connection and which one as a feed-forward
A
connection. Presumably, a single pathway may serve
both purposes. a
Couplings Contributing to Continuous

Neuronal Activity
Interneuron 2
There is always electric activity in the CNS, because
numerous neurons are firing impulses at any given time. Interneuron 1
In the cerebral cortex, for example, even during sleep
there is considerable neuronal activity. How is this gure 1.21 Interneurons that prolong the activity of a projection
neuron (A) when activated by impulses in axon a. Arrows show the
activity sustained, even in the absence of sensory inputs?
direction of impulse conduction.
In early embryonic life, groups of neurons become
spontaneously activethat is, they fire impulses with-
out any external influence (this is caused by develop-
ment of special membrane properties). As the nervous Connections between the Two Halves of the Central
system matures, neuronal behavior is governed more Nervous System
and more by synaptic connections with other neurons;
nevertheless, some neurons remain spontaneously Another important general feature of the CNS is that
active. Another feature contributing to continuous many nuclei have connections with both sides of the
activity is that, when activated, most neurons fire a brainso-called bilateral connections (Fig. 1.22A).
train of impulses, not just one. Further, interneurons Some tracts supply both sides with approximately the
contribute to prolongation of activity, as schematically same number of axons (i.e., equal numbers of crossed
exemplified in Fig. 1.21. Impulses in axon a make and uncrossed axons), whereas other tracts are pre-
neuron A fire impulses, propagated along its axon. At dominantly crossed (contralateral), with only a few
the same time, axon a makes interneuron 1 fire impulses, axons supplying the same (ipsilateral) side. Although
which act on neuron A and interneuron 2. The latter the functional significance of such bilateral connections
acts on neuron A to produce impulses. Owing to a delay may not always be clear, they can contribute to recovery
of a few milliseconds at each synapse and the time for of function after partial brain damage.
conducting the impulse in the axons, neuron A receives That the two sides of the CNS cooperate extensively
synaptic inputs over a prolonged period. This kind of is witnessed by the vast number of commissural connec-
coupling (in reality far more elaborate than shown in tionsthat is, direct connections between correspond-
Fig. 1.21) can translate a brief synaptic input to long- ing parts in the two brain halves (Fig. 1.22B). Such
lasting neuronal firing in a neuronal network. Working connections occur at all levels of the CNS, but the most
memory, that is, the ability to keep task-relevant infor- prominent one connects the two halves of the cerebral
mation in mind for a while, depends on neurons that hemispheres (corpus callosum; see Figs. 3.26 and 3.27).
continue firing after a stimulus has stopped. In humans, this pathway contains approximately 200
million axons.
A B
A B
N1
n1
n2
N2
Parallel pathways Reciprocal (feedback) Commissural connections

connections
Bilateral connections
gure 1.20 Examples of organization of neuronal pathways. Arrows
show the direction of impulse conduction; N1, N2, n1, and n2 are gure 1.22 Examples of organization of neuronal pathways. Arrows
nuclei in different parts of the CNS. show the direction of impulse conduction.
Data-based models of neural networks have provided

Single Neurons Are Parts of Neural Networks
new insight into the workings of the cerebral cortex
The tasks of a neuron can be understood only in con- and how symptoms arise from partial destruction of
junction with the thousands of neurons with which it is networks.
synaptically interconnected. Further, functions of the
brain are very seldom the responsibility of one neuronal
Injuries of Neural Networks
group or center but, rather, the result of cooperation
among many neuronal groups. Such cooperating groups An important feature of distributed systems is that
or nuclei often lie far apart. For example, proper volun- partial damage can degrade their performance but
tary movements require cooperation among specific seldom eliminate it. Sometimes partial damage may
neuronal groups in the cerebral cortex, the cerebellum, become evident only in situations with very high
and the basal ganglia deep in the cerebral hemispheres. demands, for example, with regard to the speed and
Today we use the term distributed system rather than accuracy of movements, the capacity of short-term
center when referring to the parts of the brain that are memory, and so forth. If the number of neurons par-
responsible for a specific function. Such a distributed ticipating in the network undergoes further reduction,
system is a complicated neural network of spatially however, performance may deteriorate severely. In such
separate but densely interconnected neuronal groups. cases, symptoms may occur rather abruptly, even
Figure 1.23 gives a very simplified example of such a though the disease process responsible for the cell loss
network that could be dedicated to, for example, the may have been progressing slowly for years. This is
subjective sensation of pain. Owing to the abundance typical of degenerative brain diseases such as Parkinsons
of reciprocal connections, the signal traffic can take disease and Alzheimers disease.
various routes within the network, and each neuronal
group has connections outside the network. This means
that a variety of inputs can activate the networkall THE CYTOSKELETON AND AXONAL TRANSPORT
presumably giving the same functional result (the sen-
sation of pain, a specific memory, an emotion, and so The cell bodies and processes of neurons contain thin
forth). Nevertheless, it should not be surprising that threads called neurofibrils, which can be observed in
each group, or node, might participate in several differ- specially stained microscopic sections (Fig. 1.24). The
ent, function-specific networks. Thus, as a rule one neurofibrils are of different kinds, but together they
neuronal group participates in several tasks. form the cytoskeletonthe name refers to its importance
The organization of the brain in distributed systems for development and maintenance of neuronal shape.
is particularly clear with regard to higher mental func- The fact that neurons have very different shapeswith
tions. Language is a good example: there is not one cen- regard to dendrites, cell bodies, and axonsis due to
ter for language but specific neuronal groups in many cytoskeletal specializations. For example, the neurofi-
parts of the cerebral cortex that cooperate. Other net- brils have a decisive role when axons grow for long
works are responsible for attention, spatial orientation, distances, and the cytoskeleton serves to anchor synap-
object identification, short-term memory, and so forth. tic elements at the postsynaptic density (see Fig. 4.6).
Afferent connections with

different kinds of information
Neuronal group
specialized for
processing of
certain kinds of
information
gure 1.23 Distributed neural networks.
Simplied. Three regions (groups of neu-
rons) in the cerebral cortex are intercon-
nected by reciprocal connections (red
arrows). The collective activity of all parts of
Reciprocal connections between the network is responsible for its product
specialized neuronal groups for example, the sensation of pain.
The neurofibrils of the cytoskeleton are also respon- molecules of various kinds that are taken up by the
sible for another important cellular function: the trans- nerve terminals to the cell body (Fig. 1.25). Often such
port of organelles and particles in the neuronal molecules are produced by postsynaptic cells and
processes. Although such transport takes place in both released to the extracellular space. In the cell body
dendrites and axons, axonal transport (Fig. 1.25) has (nucleus) the signal molecules can influence genetic
been most studied (mainly because, for technical expressionsthat is, they can change protein synthesis.
reasons, transport in dendrites is much harder to study). In this way, the properties of the neuron can be changed
It is obvious that neurons need direction-specific trans- transiently or in some instances permanently. This is a
port mechanisms. Thus, the organelles necessary for form of feedback: ensuring that the neuron is informed
protein synthesis and degradation of particles are pres- of its effects on other cells and of the state of its target
ent almost exclusively in the cell body. Nevertheless, cells. In some instances, neurons even require this kind
dendrites contain small amounts of mRNA located at of feedback to survive. Retrograde transport also moves
the base of dendritic spines, which may enable a limited worn-out organelles to the cell body for degradation
amount of protein synthesis important for synaptic in lysosomes.
changes related to learning and memory.
Transport from the cell body toward the nerve termi-
Components of the Cytoskeleton
nals is called anterograde axonal transport (Fig. 1.25).
Examples of particles transported anterogradely are Electron microscopic and biochemical analyses have
mitochondria, synaptic vesicles, proteins to be inserted shown that the cytoskeleton consists of various kinds of
in the axonal membrane, and enzymes for transmitter fibrillary proteins, making threads of three main kinds:
synthesis and degradation in the nerve terminals.
1. Actin filaments (microfilaments) and associated
Growth factors, synthesized in the cell body but liber-
protein molecules (approximately 5 nm thick)
ated far away at the synapses, also require efficient
2. Microtubules (narrow tubes) and associated
anterograde axonal transport. Transport toward the
proteins (approximately 20 nm thick)
cell body from the nerve terminals is called retrograde
3. Intermediary filaments or neurofilaments (approx-
axonal transport. Retrograde transport brings signal
imately 10 nm thick)
Actin (microfilaments) is present in the axon, among
other places. There it has an important role during
development. When the axon elongates, actin together
with microtubules serves to produce movements of the
growth cone (Fig. 9.16) at the tip of the axon (in gen-
eral, actin is present in cells capable of movement, such
as muscle cells). The growth cone continuously sends
out thin fingerlike extensions (filopodia) in various
directions. These probably explore the environment for
specific molecules that mark the correct direction of
growth. In addition, actin is probably important in
maintaining the shape of the fully grown axon.
Microtubules and microtubule-associated proteins
(MAPs) are present in all kinds of neuronal processes
and are most likely important for their shape (Figs. 1.7
and 2.7). Of special interest is the relation of microtu-
bules to the transport of substances in the neuronal
processes. As mentioned, there is a continuous move-
ment of organelles, proteins, and other particles in the
axons and dendrites. Destruction of microtubules by
drugs (such as colchicine) stops axonal transport.
The functional role of the intermediary filaments
(neurofilaments) is uncertain, although they make up
about 10% of axonal proteins. One function might be
to maintain the diameter of thick myelinated axons, as
internal scaffolding. Whatever their normal role is, it is
gure 1.24 The cytoskeleton in neurons. Drawing of neurons from
the cerebral cortex, as appearing in sections stained with heavy met-
noteworthy that neurofilaments are altered in several
als to visualize neurobrils. Both dendrites and axons (a) contain degenerative neurological diseases. In Alzheimers dis-
numerous neurobrils. (From Cajal 1952.) ease, for example, a characteristic feature is disorganized
ANTEROGRADE TRANSPORT RETROGRADE TRANSPORT
Injected tracer Injected tracer
gure 1.25 Axonal transport. The

photomicrographs illustrate the use of
axonal transport for tract tracing, that is,
to map the connections in the CNS. A cat
received injections of an enzyme (horse-
radish peroxidase, HRP) in the cerebel-
Cerebral cortex Cerebellum lum and in the cerebral cortex (0.2 L in
each). The enzyme was taken up by endo-
cytosis of neuronal cell bodies and termi-
Tracer in axonal Tracer in cell bodies nals. Vesicles with enzyme were then
ramifications transported anterogradely from the cere-
bral cortex to the brain stem (left) and
retrogradely from the cerebellum to the
brain stem (right). A black reaction prod-
uct in the upper photomicrographs shows
the extension of the tracer at the injection
site. The anterogradely labeled terminal
ramications of the axons appear as black
dust in the left lower photomicrograph,
while retrogradely labeled cell bodies are
Brain stem seen in the right lower photomicrograph.
Brain stem
Magnications, 8 (upper) and 150 (lower)
tangles of intermediary filaments in the cerebral cortex anterograde and retrograde transport, respectively,
(neurofibrillary tangles). serving as the motors of axonal transport. These
MAPs are ATPases (enzymes that split ATP), and the
released energy alters their form, thus producing move-
More about Axonal Transport and Its Machinery
ment. The transported particles, such as vesicles and
The injection of radioactively labeled substances taken mitochondria, move by temporarily binding to MAPs
up by neurons has shown that axonally transported protruding from the microtubule, so that they appear
material moves in at least two phases. One phase is to walk along the microtubule. One microtubule can
rapid, with particles moving up to half a meter per day; transport in both directions, depending on the kind of
the other is slow, with movement of between 1 and motor to which a particle binds. Proteins belonging to
3 mm per day. The rapid phase carries mainly organ- the kinesin family are responsible for anterograde
elles and vesicles, that is, membrane-bound structures. movement. Different varieties of kinesin appear to
The slow phase carries primarily enzymes and compo- transport different cargo; for example, one variety
nents of the cytoskeleton. As mentioned, microtubules transports mitochondria and another transports pre-
are of particular importance for axonal transport. Each cursors of synaptic vesicles. Dynein, which is a more
microtubule is composed of smaller building blocks of complex protein than kinesin, is responsible for the
the protein tubulin. MAPs help the formation of tubes bulk of retrograde transport, although certain kinesins
from many tubulin molecules. MAPs also anchor the probably also contribute.
microtubules to the cell membrane and to other parts of Injections into nervous tissue of substances that are
the cytoskeleton, such as neurofilaments. Two kinds of transported axonally and later can be detected in tissue
MAPs found only in neuronsMAP2 and taustiffen sections are widely used for tract tracing, that is, to
the microtubules. Specific kinds of MAPs perform reveal the wiring pattern of the brain (Fig. 1.25).
2 Glia
OVERVIEW
Specialized Forms of Glial Cells
Glial cells are the most numerous cells in the brain and In addition to the three main kinds, there are other,
are indispensable for neuronal functioning. Glial cells specialized forms of glial cells. The surface of the cavi-
are of three kinds that differ structurally and function- ties inside the CNS is lined with a layer of cylindrical
ally. Astrocytes have numerous processes that contact cells called ependyma (Fig. 2.3; see also Fig. 9.6). There
capillaries and the lining of the cerebral ventricles. They are also special types of glial cells in the retina (Mller
serve important homeostatic functions by controlling cells), the cerebellum (Bergman cells), and the posterior
the concentrations of ions and the osmotic pressure of pituitary gland (pituicytes).
the extracellular fluid (water balance), thereby helping
to keep the neuronal environment optimal. Astrocytes
also take part in repair processes. Oligodendrocytes GLIAL CELLS AND HOMEOSTASIS
insulate axons by producing myelin sheaths in the cen-
tral nervous system (CNS). Microglial cells are the Astrocytes Contact Capillaries, Cerebrospinal Fluid,
macrophages of nervous tissue. Schwann cells are a spe- and Neurons
cialized form of glial cells that form myelin sheaths in
Astrocytes have structural features that make them well
the peripheral nervous system (PNS). Apart from these
suited to control the extracellular environment of the
specific functions, glial cells are involved in the prenatal
neurons:
development of the nervous system, for example, by
providing surfaces and scaffoldings for migrating 1. They have numerous short or long processes that
neurons and outgrowing axons. extend in all directions (Figs. 2.1 and 2.2). Thus, the
astrocytes have a very large surface area that enables
efficient exchange of ions and molecules with the extra-
TYPES OF GLIAL CELLS cellular fluid (ECF).
2. Some processes contact the surface of capillaries
Although they do not take part in the fast and precise with expanded end feet and cover most of the capil-
information processing in the brain, glial cells are nev- lary surface (Figs. 2.3 and 2.4).
ertheless of crucial importance to proper functioning of 3. Some processes form a continuous, thin sheet
neurons. In fact, the number of glial cells in the brain is (membrana limitans, also called glia limitans) where
much higher than the number of neurons. The name nervous tissue borders the cerebrospinal fluid (CSF),
glia derives from the older notion that glial cells served that is, in the cavities inside the CNS and against the
as a kind of glue, keeping the neurons together. connective tissue membranes on its exterior (Fig. 2.3).
Although improved methods have revealed hitherto 4. Other processes contact neuronal surfaces; in this
unknown properties of glial cells, much still remains manner, parts not contacted by boutons are covered by
to be understood about their functional roles in the glia (Figs. 2.3 and 2.5). Glial processes usually enclose
nervous system. the nerve terminal (see Figs. 1.6 and 1.7).
It is customary to group glial cells into three catego- 5. Numerous gap junctions (nexus) couple astro-
ries: astrocytes, or astroglia; oligodendrocytes, or oligo- cytes, allowing free passage of ions and other small par-
dendroglia; and microglial cells, or microglia. Each is ticles among them (Fig. 2.4). Thus, apart from allowing
structurally and functionally different from the others. electric currents to spread, astrocytes form continuous,
Astrocytes have numerous processes of various shapes large fluid volumes for distribution of substances
whereas oligodendrocytes have relatively few and short removed from the ECF.
processes (oligo means few, little). In routinely stained
sections, glial cells can be distinguished from neurons
Glial Cells Communicate with Electric Signals and
by their much smaller nuclei. The identification of
Inuence Cerebral Blood Flow
the various types, however, requires immunocytochem-
ical methods to identify proteins that are specific to Although glial cells do not send precise signals over
each type. long distances, they can produce brief electric impulses
19
A B
Astrocyte
Capillary
gure 2.1 Astrocytes. Photomicrographs

Capillary
of Golgi-stained sections from the cere-
bral cortex. No neurons are visible. Note
50 m 25 m the close relationship between astrocytic
processes and capillaries.
(currents) by opening of membrane channels for Ca2+. that the population can be surprisingly small, enabling
Such an opening can be evoked by binding of neuro- spatially precise interactions among neurons and astro-
transmitters (e.g., glutamate) to G-proteincoupled cytes. Thus, although it is well known that a specific
receptors in the glial cell membrane. Thus, neuronal sensory input (e.g., from a small spot in the visual
activity can directly influence the astrocytes, whereas field) activates neurons in a precisely defined, small
the latter affects neuronal activity. Owing to the electric part of the cortex, recent experiments (Schummers
coupling (nexus) of the astrocytes, the calcium signal et al. 2008) suggest that astroglial cells are activated
can presumably spread rapidly in networks of astroglial in a similarly precise manner (although a few seconds
cells, and thus influence many neurons almost simulta- later than the neurons). Presumably, inputs from the
neously, which, among other roles, can help synchro- periphery activate neurons that in turn activate astro-
nize the activity of neurons in a group. In light of the cytes in their immediate vicinity. When activated, the
electric coupling among astrocytes, one might expect astrocytes increase local blood flow (see Chapter 8,
the population of neurons influenced by an astrocytic under Regional Cerebral Blood Flow and Neuronal
network to be quite large. Recent data, however, indicate Activity).
A B C
20 m
gure 2.2 Astrocytes. A: Astrocytic processes visualized using an obvious that the astrocytic processes are much more abundant and of
antibody against glial brillary acidic protein (GFAP) present in inter- ner caliber than in A. C: View of the injected astrocyte in B in isola-
mediary laments. The antibody was labeled with a substance with tion, showing to advantage its dense and bushy halo of processes.
red uorescence. B: One of the astrocytes in A has been lled com- (Reproduced with permission from Wilhelmsson et al. (2004) and
pletely with intracellular injection of a substance with green uores- The Journal of Neuroscience.)
cence (Lucifer yellow), and reconstructed three-dimensionally. It is
2: GLIA 21
Artery
Pia
Cerebrospinal fluid
Astrocyte
Glia
Astrocyte
processes
Nexus
Capillary
Ependyma (Gap junction)
Taurine Glutamate K+ H O
2
Neuron
Capillary Cerebral ventricle with

cerebrospinal fluid Neuron
gure 2.3 The relationship between astroglia and neurons, blood

vessels and the CSF. The astrocytes cover the surface of the neurons
and are also closely related to vessels, ependymal cells, and the inner-
most part of the cerebral meninges (pia).
gure 2.4 Astroglia and the homeostasis of nervous tissue. Schematic
shows the close contacts between astroglial cells on the one hand and
neurons, capillaries, and the CSF on the other. The astroglial cells are
coupled by nexus (gap junctions), and thus form a large uid volume
for distribution of substances. Some important substances handled by
Astroglia and the Control of Neuronal Homeostasis astroglia are indicated (the transport is not always in the direction of
the arrows). Surplus of water, K+ ions, and the amino acid taurine
Their intimate contact with neurons, capillaries, and can be transported to the blood and the CSF, thereby preventing
the CSF places astroglial cells in a unique position to their accumulation in the ECF. Next to glutamate, taurine is the
control the environment of the neurons, that is, the amino acid with the highest concentration in the CNS and therefore
extracellular (interstitial) fluid of the brain (see signicantly contributes to the osmolarity of the ECF. Taurine does
Fig. 1.28). Such control is vitally important for three not appear to function as a neurotransmitter, but its transport in and
out of astroglia may be a mechanism for controlling the volume of
main reasons. First, neurons are exquisitely sensitive to the neurons. The neurotransmitter glutamate is treated differently,
changes in extracellular concentrations of ions and neu- however. Glutamate is transformed to glutamine after uptake in
rotransmitters. Second, the osmotic pressure (the water glia, and thus loses its transmitter actions and becomes neutral to
concentration) must be tightly controlled because the the neurons. Glutamine can therefore be returned to the ECF for sub-
brain cannot expand in the skull. Third, adding even sequent uptake into neurons where it is used for resynthesis of gluta-
mate. Because the neurons need large amounts of glutamate, this is an
minute amounts of a substance may produce a substan- economic means to ensure a sufcient supply. (Based on Nagelhus
tial increase in its extracellular concentration, owing to 1998.)
the very limited extracellular space in the brain (less
than 20% of total volume), as illustrated in electron
micrographs showing only narrow slits between the
cellular elements (see Figs. 1.3 and 1.7). Further, the Extracellular neurotransmitter concentration must
tortuous shape of the extracellular space hampers free be tightly controlled, because proper synaptic function-
diffusion of particles. ing requires that their extracellular concentrations be
+
With regard to extracellular ions, the control of K very low, except during the brief moments of synaptic
(potassium ions) is particularly important. Thus, neu- release. Most neurotransmitters are indeed removed
ronal excitability is strongly influenced even by small from the ECF near the synapses by transporter proteins
changes in the amount of K+ ions extracellularly, and as in the membranes of neurons and astrocytes. Specific
neurons fire impulses, K+ ions pass out of the cell transporters have been identified for several neurotrans-
(Fig. 2.4). Prolonged or intense neuronal activity would mitters (discussed further in Chapter 5). Figure 2.5
therefore easily produce dangerously high extracellular gives an impression of the abundance of a specific kind
levels of K+ ions were it not for their efficient removal of transporter proteins (for the ubiquitous neurotrans-
by glia. Further, astrocytes contribute to extracellular mitter glutamate, which is neurotoxic in abnormally
pH control by removing CO2. high concentrations).
Glial cell nuclei

A B
Glial cell nuclei
Dendrite
Motor neuron
cell body
Motor
neuron
5 m 15 m
Capillaries Large nerve Astrocyte processes

terminal (black)
gure 2.5 Astroglial processes in nervous tissue. A: Photomicrograph and neuronal somata are uneven because of synaptic contacts (thin
showing the distribution of a glutamate-transporter protein, as arrow) breaking the otherwise continuous layer of astroglia.
visualized via an immunocytochemical technique. In this 1 m thick Capillaries are marked with asterisks. The cell body of an astroglial
section from the spinal cord, the dark spots and bands are astrocytic cell is marked with a thick arrow. (Courtesy of Drs. J. Storm-Mathisen
processes expressing glutamate transporters. They outline the somata, and N.C. Danbolt, Department of Anatomy, University of Oslo.)
dendrites, and capillaries. The picture illustrates both the capacity of B: For comparison, a photomicrograph of a thionine-stained section
astroglia to take up glutamate from the ECF and the enormous astro- from the same part of the spinal cord as in A.
glial surface facing neurons and capillaries. The contours of dendrites
As mentioned, astrocytes are also involved in the capillaries and in glial processes bordering the CSF.
control of the extracellular osmotic pressure, that is, in AQP1 is present in epithelial cells of the choroid plexus
controlling the water balance of the brain (Fig. 2.4). Of (which produces the CSF; see Chapter 7). In general,
particular interest in this respect are channels for trans- aquaporins increase water permeability of the cell mem-
port of wateraquaporinsthat are present in the brane, thus allowing water to follow active ion trans-
membranes of astrocytes. Aquaporins were first port. A function of AQP4 in the normal brain is
described in kidney tubular systems, where they were probably to export water. Thus, AQP4-deficient mice
shown to increase significantly the capacity for water have increased ECF volume compared to normal mice.
passage. Interestingly, in the brain they are most abun- Further, in so-called vasogenic brain edema, wherein
dant on the glial processes that are in close contact with water accumulates extracellularly, AQP4 contributes to
capillaries and the CSF, that is, where one would expect removal of excess water. This kind of edema arises
them to be if they were involved in brain water balance. when the brain capillaries become leaky due to, for
Exchange by astroglial cells of small neutral molecules, example, traumatic brain injury. On the other hand,
such as the amino acid taurine, may be another mecha- when water accumulates intracellularly, as typically
nism to control extracellular osmolarity. occurs in cerebral ischemia or hypoxia (e.g., in stroke),
Finally, the layer of astrocytic processes surrounding the presence of AQP4 seems to increase the edema by
brain capillaries helps to prevent many potentially allowing more water to enter the astrocytes. Such cyto-
harmful substances from entering the brain (see toxic brain edema is caused by failure of energy-dependent
Chapter 7, under The BloodBrain Barrier). ion pumping, which reduces the ability of the cells to
maintain osmotic stability. Brain edema is a serious and
often life-threatening complication in many brain dis-
Aquaporins in Health and Disease
orders, such as stroke and traumatic brain injuries.
Two varieties of aquaporin are present in the brain. Therefore, the discovery of a relationship between
AQP4 is located in the astrocyte membrane, and par- aquaporins and brain edema led to an intensive search
ticularly concentrated in the end-feet region close to for drugs that can modulate the activity of aquaporins.
2: GLIA 23
Unmyelinated
Axon Myelin lamellae axons
gure 2.6 Myelin sheath, myelination, and

unmyelinated axons. Schematics based on A B C
electron microscopic observations. A: Cell
body with proximal parts of the dendrites
and myelinated axon. The myelin sheath con-
sists of lamellae formed by the membrane of
glial cells (oligodendroglia, or Schwann cells).
Each cell produces one segment of myelin. Schwann cells
The node of Ranvier is the site of contact
between two segments of myelin. The nerve Axon
impulse usually starts in the initial segment of
the axon, and then jumps from one node
of Ranvier to the next. B: Cross section of an
axon in the process of becoming myelinated.
The myelin sheath is formed when a glial cell
wraps itself around the axon. C: Unmyelinated
axons in the peripheral nervous system are Initial segment of
Myelin lamellae Node of Ranvier
surrounded by Schwann cell cytoplasm. the axon
In animal experiments, inhibitors of AQP4 can reduce the CNS, however, such regeneration of axons does not
cytotoxic edema whereas they seem to worsen vasogenic normally occur, mainly because of inhibiting factors
edema. This complicates the search for the ideal drug produced by oligodendrocytes.
because in human brain disorders the two kinds of In addition to forming myelin sheaths, oligodendro-
brain edema usually coexist (although one may domi- cytes and Schwann cells are important for survival of
nate depending on the specific disorder). the axons. Thus, diseases affecting oligodendrocytes
or Schwann cells produce axonal loss in addition to loss
of myelin. In addition, oligodendrocytes and Schwann
INSULATION AND PROTECTION OF AXONS cells influence axonal thickness and axonal transport.
Oligodendrocytes and Schwann Cells

The Myelin Sheath
The myelin sheaths, which insulate axons, are formed
The myelin sheath forms an insulating cylinder around
by oligodendrocytes1 in the CNS and by Schwann cells
the axons (Fig. 2.6), reducing the loss of current from the
in the PNS. Although the structure and function of the
axon to the surrounding tissue fluid during impulse
myelin sheaths they produce are the same,2 oligoden-
conduction. This contributes to the much higher
drocytes and Schwann cells are not identical. One dif-
conduction velocity in myelinated axons than in unmy-
ference is that a single oligodendrocyte usually sends
elinated axons (discussed further in Chapter 3 under
out processes to produce myelin segments for several
Impulse Conduction in Axons). The thickest myeli-
axons (up to 40), whereas each Schwann cell forms a
nated axons conduct at approximately 120 m/sec (versus
myelin segment for only one axon (Fig. 2.6). A particu-
less than 1 m/sec in unmyelinated axons).
larly interesting difference concerns their differential
The myelin sheath consists almost exclusively of
influence on regeneration of damaged axons. In the
numerous layers of cell membrane, as evident from
PNS, a cut axon can regenerate under favorable condi-
electron micrographs (Figs. 2.6 and 2.7). The layers, or
tions, provided that viable Schwann cells are present. In
lamellae, are formed when a glial cell wraps itself
around the axon (Fig. 2.6B). During this process, the
1 We do not know whether all oligodendrocytes form myelin. Thus, their cell cytoplasm of the glial cell is squeezed away so that the
bodies are often closely apposed to neuronal cell bodies, suggesting that they
may have other tasks in addition to myelination.
layers of cell membrane lie closely apposed. The com-
2 Even though the myelin sheaths produced by oligodendroglial cells and by posite of material ensheathing the axons is called
Schwann cells look the same, they differ signicantly in their lipid and protein myelin. Myelin is whitish in color because of its high
composition. For example, myelin basic protein (MBP) makes up a much larger
fraction of the total myelin protein in the CNS than in the PNS, whereas periph-
lipid content.
eral myelin protein-22 (PMP-22) is absent in the CNS. Another example is The cell membrane forming the myelin has a unique
myelin-oligodendrocyte glycoprotein (MOG), which is expressed in the CNS lipid and protein composition. Among other compo-
only. Such differences may help explain why some diseases affect only myeli-
nated axons in the CNS (e.g., multiple sclerosis), whereas others are restricted
nents, myelin has a high content of cholesterol and
to peripheral axons. various glycolipids. The glycolipids appear to be crucial
Schwann
cell cytoplasm
Collagen fibrils
Axon
Microtubules
Axon
Axon
Axon
Myelin Axon
Schwann
cell cytoplasm
gure 2.7 Myelinated and unmyeli-

nated axons. (Detail from Fig. 2.8.) An
axon is surrounded by myelin. The
Collagen fibrils myelin lamellae are seen as dark stripes,
Axon arranged concentrically. The cytoplasm
of the Schwann cell that is responsible
for producing the myelin is seen exter-
nally. The unmyelinated axons are com-
pletely surrounded by Schwann cells.
Axon
Between the axons are numerous colla-
gen brils. Magnication, 30,000.
for the insulating properties of myelin. Certain mem- in the opposite direction). This arrangement makes it
brane proteins related to the immunoglobulins bind the possible for the nerve impulse to jump from node to
external (apposing) sides of the membranes tightly node, thus increasing the speed of impulse propagation
together. Another membrane protein, myelin basic pro- (discussed further in Chapter 3). The distance between
tein (MBP), seals the cytoplasmic sides of the mem- two nodes of Ranvier in the PNS may be 0.5 mm or
branes in the myelin lamellae so that very little cytoplasm greater.
(with poor insulating properties) takes up space in the
myelin sheath. Mice with a mutation of the MBP gene
Multiple Sclerosis
make abnormal myelin and develop serious movement
disorders. In demyelinating diseases of the nervous system, the
Myelination of the axons starts prenatally, but myelin sheaths degenerate. The most common of these
many neural pathways in the human are not fully myeli- diseases is multiple sclerosis (MS), which typically man-
nated until 2 years after birth (see Chapter 9, under ifests in young adults and usually has a long course of
Myelination). The process of myelination is closely increasing disability. Its cause is still unknown, but
related to functional maturation of the brain. most likely environmental factors precipitate an inflam-
matory process in individuals with a certain inherited
susceptibility. Histopathologically, isolated and appar-
Nodes of Ranvier
ently randomly distributed regions of inflammation and
Longitudinal views of axons show that the myelin demyelination are characteristic. In these regions, called
sheath is interrupted at intervals, forming the nodes of plaques, impulse conduction in the axons is severely
Ranvier (Fig. 2.6A). The nodes of Ranvier exist because slowed or halted, and usually the symptoms are ascribed
the glial cells forming myelin lie in a row along the to the loss of myelin. For some reason, the optic nerve
axon, each cell making myelin only for a restricted is often the first to be affected, resulting in reduced
length, or segment, of the axon. When viewed in the vision. Later symptoms that usually occur in varying
electron microscope, the axolemma (the axonal mem- proportions are muscle weakness, incoordination, and
brane) is naked at the node; that is, it is exposed to sensory disturbances. In most patients, exacerbations
the ECF. Thus, only at the node of Ranvier can current of the symptoms occur episodically in the beginning,
in the form of ions pass from the axon to the ECF (and associated with fluctuation in the inflammatory process.
2: GLIA 25
Thus, periods of marked symptoms (such as paresis of will be shown to have a (genetically determined) diathesis
extremities) are followed by periods of partial recovery. [disease disposition] that does indeed predispose
The improvement of symptoms is ascribed to partial to neurodegeneration . . . but the exposure of that
remyelination of the affected regions. After a variable vulnerability requires an inflammatory insult without
time (often many years), the disease becomes progres- which the degenerative component does not manifest
sive, with a steady deterioration of the patients condition. (Compston, 2006, p. 563).
There is not always a clear relationship between With regard to the inflammatory process, T lympho-
degree of demyelination and symptoms, suggesting that cytes, microglial cells, brain endothelial cells, and
the disease process also directly harms axonal conduc- numerous immune mediators are involved, but their
tance and axonal viability. Indeed, it is now well relative contributions are not fully understood. The role
established that in MS not only myelin sheets but also of microglia illustrates the complexity: they may con-
axons degenerate from the beginning of the disease. tribute both to destruction of myelin and axons and to
Presumably, the number of axons lost at early stages is regenerative processes (such as remyelination), presum-
modest and brain plasticity may compensate for their ably depending on the local situation.
loss. As the disease progresses, however, the axon loss
becomes so large that permanent and steadily progress-
Unmyelinated Axons
ing disability ensues.
Intense research activity is devoted to clarifying the As mentioned, unmyelinated axons conduct much more
etiology and pathogenesis of MS. Although clearly the slowly (at less than 1 m/sec) than myelinated ones,
disease process includes both inflammation and degen- because they are thinner and lack the extra insulation
eration, it was long held that inflammation was the provided by the myelin sheath. In the CNS, unmyeli-
primary phenomenon (perhaps evoked by autoimmu- nated axons often lie in closely packed bundles without
nity), and that loss of nervous tissue was secondary. any glial cells separating them (see Fig. 1.7). In the PNS,
This is now being questioned, however. Thus, it seems however, unmyelinated axons are always ensheathed
possible that . . . people who develop multiple sclerosis in Schwann cells that do not make layers of myelin
Perineurium
Perineurium
Collagen
fibrils Unmyelinated
Fibroblast Fibroblast axons
Schwann Fibroblast
cell cytopl.
Myelin
Collagen
fibrils
gure 2.8 Peripheral nerve. Electron
micrograph of cross section of the
sciatic nerve. The picture shows a small,
peripheral part of a nerve fascicle.
The perineurium surrounding the fas- Axon
cicle, is formed by several lamellae of
attened cells. Note the large difference
in diameter among various myelinated
axons. The thickness of the myelin
sheath increases apace with the increase
in axonal diameter. Between the myeli- Schwann
nated axons are numerous unmyeli- cell nucl. Axon
nated ones. Collagen brils, produced by
broblasts, ll most of the space between Unmyelinated
the axons. Magnication, 4000. axons
(Figs. 2.62.8). During early development, several MICROGLIA AND REACTIONS OF

axons become embedded in the cytoplasm of the Schwann THE CNS TO INJURY
cells by invagination of the Schwann cell membrane.
This arrangement probably serves to protect the axon Microglial Cells Are Phagocytes
from harmful substances in the interstitial fluid. Such
protection may not be necessary in the CNS, as the The third kind of glial cell, microglia, is so named
composition of the interstitial fluid is governed by because of its small size. Studies with immunocy-
astroglia cells and by the bloodbrain barrier. tochemical identification of specific membrane proteins
show unequivocally that microglial cells constitute a
distinct kind. Estimates indicate that microglia may
Peripheral Nerves Are Built for Protection
constitute 5% to 20% of all glial cells, being fairly
of the Axons
evenly distributed through all parts of the CNS.
Fresh nervous tissue is soft, almost jellylike, with virtu- Microglial cells are of mesodermal origin. Thus, animal
ally no mechanical strength in itself. Protection of the experiments indicate that monocytes invade the ner-
CNS against external mechanical forces is afforded by vous system from the bone marrow during embryonic
its location within the skull and the vertebral canal and development and perhaps shortly after birth. This may
by its wrapping in membranes of connective tissue correspond with periods of high rate of cell death
(see Fig. 6.1). For peripheral parts of the nervous sys- (a surplus of neurons is formed in early embryonic
tem, the situation is different. Often located superfi- life, with subsequent elimination of a large number).
cially, the peripheral bundles of axons and groups of After invading nervous tissue, the monocytes undergo
nerve cells are exposed to various mechanical stresses. changessuch as development of processesthat
They are also subject to considerable stretching forces transform them to microglial cells, as identified in the
by movements of the body. Axons can be stretched only adult. Nevertheless, microglial cells retain the typical
slightly before their impulse conduction suffers, and phagocytic capacity of monocytes. Further, several sur-
they may even break. To prevent this, peripheral nerves face markers (antigens) are common to blood mono-
contain large amounts of dense connective tissue with cytes and microglia, and cells that express such antigens
numerous collagen fibers arranged largely longitudi- first occur in the CNS (of rodents) in late embryonic
nally (Fig. 2.7). The collagen fibers, specialized to resist development.
stretching, protect the axons effectively. The presence The number of microglial cells is relatively stable
of connective tissue in peripheral nerves is the reason after the prenatal invasion. Under normal conditions,
that the nerves become much thicker where they leave the stock of microglial cells does not appear to be sup-
the skull or the vertebral canal. plemented from the bloodstream. After injury, the
The connective tissue components of peripheral number of cells with phagocytic activity (macrophages)
nerves form distinctive layers. The epineurium is an increases in the CNS. The increase appears to be due
external thick layer of mostly longitudinally running both to invasion of monocytes from the bloodstream
collagen fibers. Internal to this layer, the axons are and to activation of local microglial cells. The invasion
arranged into smaller bundles, or fascicles, which are of monocytes after injury probably depends on damage
wrapped in the perineural sheath or perineurium to the bloodbrain barrier (i.e., brain capillaries allow
(Fig. 2.8). The collagen fibers and fibroblasts within the passage of elements of the blood they normally restrict).
fascicles constitute the endoneurium. The perineurium In the normal brain, microglial cells are probably not
is special in that it contains several layers of flattened solely in a resting: state in anticipation of challenges
cells. The cells, which in some respects resemble epithe- (e.g., intruding microorganisms, trauma, ischemia, and
lial cells, interconnect by various kinds of junctions. In so forth). Thus, their processes are steadily moving and
addition, the capillaries within the endoneurium are renewed, and are therefore believed to constantly
unusually tight and prevent passage of many substances scan their immediate environment for foreign mate-
from reaching the axons, consistent with experimental rial and sick or dead cellular elements. In addition,
data showing that the perineurium constitutes a blood microglial cells are equipped with receptors for several
nerve barrier preventing certain substances from reach- neurotransmitters, suggesting that they also may sense
ing the interior of the fascicles with the axons. It is not the state of neuronal activity in their vicinity. If they
surprising that PNS tissue also needs extra protective detect something unusual, more microglial cells move
mechanisms to ensure that its environment is kept opti- quickly to the site. They release inflammatory media-
mal for conducting impulses. The protection is not as tors and phagocytose foreign or dead material. These
efficient as in the CNS, however, and may perhaps responses of microglial cells generally serve to minimize
explain why peripheral nerves are often subject to damage and protect neurons; that is, microglial cells
diseases that affect their conductive properties. serve to conserve homeostasis. For example, animal
2: GLIA 27
experiments show that the presence of microglial cells osmotically active, the astrocytes may swell quickly:
reduces ischemic brain damage (after loss of blood seconds or minutes after the damage (if the normal
supply). Removal of dead material by microglia seems uptake capacity is surpassed). This may contribute to
to be necessary for regeneration of neuronal processes brain edema, a dangerous complication of head inju-
to occur. Nevertheless, in certain diseases with strong ries. In the long term, astrocytes produce a kind of scar
activation of microglial cells (and astrocytes) they pro- tissue at sites where neurons are lost.
mote tissue injury rather than repair. Activation of In Chapters 9 and 11, we discuss the plastic processes
microglial cells in the spinal cord also seems to contrib- of the nervous system that permit functional recovery
ute to persistence of pain after nerve damage. after injuries (such as stroke).
Reaction of Nervous Tissue to Injury and Inammation Diseases of Peripheral Nerves

Tissue damage leads to an inflammatory reaction in Diseases involving degeneration of peripheral nerves
which the invasion and activation of immunocompe- are called neuropathies and in humans can have various
tent cells have a central role. The purpose of the inva- causes. In any case, the symptoms are due to transitory
sion is to kill microorganisms, remove debris, and aid or permanent loss of impulse conduction. Neuropathy
reparative processes. However, the inflammatory reac- is a well known complication of metabolic diseases
tion is different in the CNS than in other tissues. Thus, such as diabetes but can also be caused by toxic sub-
there is often no invasion of neutrophil granulocytes, stances (e.g., lead). Some neuropathies are due to
and the activation of microglia and invading monocytes attacks of the immune system on axons or myelin. This
to macrophages may take several days. Overall, immune sometimes occurs after an infectious disease or in the
reactions are weaker and slower in the CNS than else- course of cancer, probably because the immune system
where. This may be explainedat least in partby the produces antibodies that cross-react with normal anti-
lack of lymphatic drainage from the CNS. The immune gens expressed by axonal or Schwann cell membranes.
system, therefore, does not possess much information Axons express some antigens that are specific to whether
about nervous tissue conditions, in contrast to tissues the axons are motor or sensory, thick or thin, and so
of most other organs. Normally, only a small number forth. Thus, it may be understandable why neuropa-
of T lymphocytes, entering from the bloodstream, thies often affect certain nerves only or certain kinds of
3
patrol the CNS. Perhaps these special conditions are axons only. Thus, when motor axons are affected, the
necessary to prevent neuronal damage from the potent patient presents with pareses in certain muscles, while
substances that are liberated from granulocytes and affection of sensory axons might produce loss of cuta-
activated macrophages. For example, edemaa central neous sensation and joint sense. Neuropathies may also
component of inflammationmay become harmful affect subgroups of sensory axons, for example, affect-
and even life threatening when it occurs in the brain ing only the very thin axons mediating sensations of
(because of the limited possibilities of expansion within pain and temperature but sparing axons related to
the skull). Nevertheless, immune reactions do occur in touch. In other cases only axons mediating joint sense
the brain, sometimes with serious consequences, as in are affected, whereas cutaneous sensation is spared
multiple sclerosis. (examples are described in Chapter 13, under Clinical
The main task of astrocytes after injury is probably Examples of Loss of Sensory Information).
to strengthen their normal function of keeping the ECF A large group of neuropathies is inherited, among
composition constant. Tissue damageregardless of them, CharcotMarieTooth disease (peroneal muscle
whether it is caused by bleeding, contusion, or circula- atrophy). In most cases, the disease is inherited domi-
tory arrestincreases the flow of ions and transmitters nantly. The disease usually starts before the age of
from the neurons to the ECF. Astrocytes increase their 20 years and leads to gradually increasing pareses and
uptake to counteract such disturbances of the neuronal sensory loss, starting distally in the legs. Loss of myelin
environment. Because the substances taken up are and degeneration of axons cause the symptoms. Most
patients with CharcotMarieTooth disease have a
doubling of the gene coding for the peripheral myelin
3 HIV (human immune deciency virus) can enter the CNS via infected T lym- protein (PMP-22). Animal models with overexpression
phocytes. Microglial cells then become infected because they express surface of PMP-22 suggest that this defect alone can cause
receptors that bind the virus. After being infected, microglial cells secrete toxic
substances that kill neurons, thus producing the neurological symptoms occur-
deficient myelination and symptoms corresponding to
ring in AIDS (acquired immune deciency syndrome). CharcotMarieTooth disease in humans.
3 Neuronal Excitability
OVERVIEW of Na+ ions, the membrane potential is restored by the

outward flow of K+ ions. Restoration of the membrane
In Chapter 1 we considered some of the characteristic potential is called repolarization. An increase of the
properties of neurons, such as their excitability and membrane potentialhyperpolarizationmakes the
their ability to conduct impulses. The term excitability neuron less excitable (more depolarization is necessary
means that when a cell is sufficiently stimulated, it can to elicit an action potential). In a short period after an
react with a brief electrical discharge, called an action action potential, the membrane is in a refractory state,
potential. The action potential (the nerve impulse) trav- which means that another action potential cannot be
els along the axon and is a major component in the elicited. This ensures that neurons can maintain the
communication among nerve cells and between nerve correct ion concentration balance. Once an action
cells and other cells of the body. The action potential potential is elicited, it is conducted along the axon. This
results from movement of charged particlesions is not merely a passive movement of charged particles
through the cell membrane. A prerequisite for such a in the fluid inside the axon. Because axons are poor
current across the membrane is an electric potential conductors (compared with a metal thread), the action
the membrane potentialbetween the interior and the potential has to be renewed along the axonal membrane
exterior of the cell, and the presence of ion channels by cycles of depolarization and repolarization. In unmy-
that are more or less selective for the passage of particu- elinated axons, these cycles move along the axon as a
lar ions. The opening of ion channels is controlled by continuous wave, while in myelinated axons renewal of
neurotransmitters binding to the channel (transmitter the action potential occurs only at the nodes of Ranvier.
or ligand-gated channels) or by the magnitude of the Because the process of depolarizationrepolarization
membrane potential (voltage-gated channels). The takes some time, the speed of conduction is very much
membrane potential results from an unequal distribu- slower in unmyelinated axons than in myelinated ones.
tion of positively and negatively charged particles on The action potential, when first elicited, is of the same
either side of the membrane.1 Energy-requiring ion magnitude. Neurons are nevertheless able to vary their
pumps are responsible for maintaining the membrane messages because of the varying frequency and pattern
potential. The resting potential, that is, the membrane of action potentials. Generally, the more synaptic inputs
potential when the neuron is not receiving any stimula- depolarize a neuron, the higher will be the frequency of
tion, is due mainly to unequal distribution of K+ ions axonal action potentials.
and the fact that the membrane is virtually imperme-
able to all ions other than K+ in the resting state. The
resting potential, with the interior of the cell negative
BASIS OF EXCITABILITY
compared with the exterior, is typically approxi-
mately 60 mV. The action potential is a brief change
Cell Membrane Permeability Is Determined
of the membrane potential, caused by opening of
by Ion Channels
channels that allow cations (especially Na+) to enter the
neuron, followed by an outward flow of K+ ions. A net Ions cross the cell membrane almost exclusively through
influx of cations reduces the membrane potential by specific, water-filled channels because their electrical
making the interior less negative. This is called depolar- charges prevent them from passing through the lipid
ization, and if it is sufficiently strong, an action poten- bilayer (Figs. 3.1 and 3.2). The channels are more or
tial is elicited due to opening of voltage-gated Na+ less selective for particular ions, that is, some ions pass
channels. After the brief depolarization caused by influx more easily through a channel than others. Some chan-
nels are very selective, allowing passage of only one
+
kind of ion (e.g., Na ions), whereas other channels are
1 Neither membrane potentials nor action potentials are properties unique to less selective (e.g., letting through several cations such
nerve cells. All cells have a membrane potential, although usually of less
magnitude than that of neurons. Muscle cells and endocrine gland cells also
as Na+, K+, and Ca2+). It follows that the ease with
produce action potentials in relation to contraction and secretion, respectively. which an ion can pass through the membranethat is,
28
3: NEURONAL EXCITABILITY 29
Binding site for
Ion
transmitter molecule
Transmitter
molecule
Ion channel Open Closed

Cell membrane
(lipid double layer)
Inside of cell
gure 3.1 Ion channels. Schematic of a small part of
the lipid bilayer of the cell membrane with interspersed
ion channels. Binding of a transmitter molecule alters
the opening state of the ion channel.
the membrane permeability2 to that particular kind of the voltage gradient across the membrane (i.e., the
iondepends on (1) the presence of channels that let membrane potential) will also be important (Fig. 3.3).
the ion through, (2) how densely these channels are dis- This means that if the interior of the cell is negative in
tributed in the membrane, and (3) their opening state. relation to the exterior, the cations (positively charged
The current of ions through the membrane, however, ions) on the exterior will be exposed to a force that
does not depend solely on the density and opening of attracts them into the cell, while the interior cations
channels; an additional important factor is the concen- will be subjected to forces that tend to drive them out.
tration gradient across the membrane for the ion. That The strength of these attractive and expulsive forces
is, the steeper the gradient, the greater the flow of ions depends on the magnitude of the membrane potential.
will be from high to low concentration (provided that Therefore, the concentration gradient and the membrane
the membrane is not totally impermeable to the ion). potential together determine the flow of a particular ion
Further, because ions are electrically charged particles, through the membrane (Fig. 3.3).
2 The term conductance expresses the membrane permeability of a particular The Membrane Potential
kind of ion more precisely. The conductance is the inverse of the membrane
resistance. In an electrical circuit the current is I = V/R, where V is the voltage In a typical nerve cell, the potential across the cell mem-
and R is the resistance (Ohms law). This may be rewritten by using conduc- brane is stable at approximately 60 mV (millivolts) in
tance (g ) instead of R, as I = g V. In this way, one may obtain quantitative
measures of membrane permeability under various conditions. For our the resting state, that is, as long as the cell is not exposed
purpose, however, it is sufcient to use the less precise term permeability. to any stimuli. We therefore use the term resting potential
Subunit Ion Transmitter

molecule
Outside
Binding
site
gure 3.2 Ion channels. Five protein subunits are

arranged around a central opening that can admit Inside
ions. At the outer side, the channel proteins are Ion channel
equipped with receptor sites for neurotransmitter
molecules that regulate the opening of the channel.
The gure shows the probable appearance of an
acetylcholine receptor. (Based on Changeux 1993.)
+ from the interior of the cell, making the interior negative
+
Concentration gradient K+
compared to the exterior, thereby creating a membrane
+
+
|
|
+
+ Electric gradient potential. The membrane potential reaches only a cer-
+
|
+
+
+
(potential)
+
+
+
+ |
tain value, however, because it will oppose the move-
+
|
|
|
|
|
+
+
|
|
ment of K+ ions out of the cell. Two opposite forces are
|
+
|
+ |
+
|
+ | | + at work: the concentration gradient tending to drive K
+
+
+ | K+ |
+ + + out of the cell and the electrical gradient (the membrane
|
|
| +
|
| | + + potential) tending to drive K into the cell (Fig. 3.3).
+
+
+ |
|
When the membrane potential is about 75 mV, +these
|
+
|
|
|
|
+ |
| + two forces are equally strong: that is, the flow of K into
|
|
|
|
+ |
|
|
+
+
+
| the cell equals the flow out. This is therefore called the
+
+ |
+
+
+
+
+ | | equilibrium potential for K , and its magnitude is deter-
+ |
| + +
mined by the concentration gradient for K ions (the
|
| + 60 mV
concentration gradient varies somewhat among neu-
+
+
|
|
|
|
|
|
+ | rons). The resting potential in most neurons, however,

|
+
+
+
+
+
+
is lower than the equilibrium potential for K because

+
|
|
|
|
the cell membrane is slightly permeable to Na+ (about
+
+
+
1/50th of the permeability to K+). Therefore, some pos-

+
+
itive charges (Na+) pass into the cell, driven by both the
concentration gradient and the membrane potential,
gure 3.3 Forces acting on the K ions. At the resting potential there
+ making the interior of the cell less negative than the
is equilibrium between the inward and outward forces (large arrows) equilibrium potential for K+. The membrane potential
acting on the K+ ions. One intracellular and one extracellular electrode is consequently changed somewhat in the direction of
(cones) measure the membrane potential. the equilibrium potential for Na+: that is, +55 mV. In
the resting state, the inflow of positive charges is equal
to their outflow, and the membrane potential is there-
fore stable. Even though the two opposite currents of
in this situation (in different kinds of nerve cells, the K+ and Na+ are small, over time they would eliminate
resting potential may vary from about 45 mV to the concentration gradients across the membrane. This
approximately 75 mV). The resting potential is due to a is prevented, however, by energy-requiring pumps in
small surplus of negatively charged ions, anions, inside the cell membrane that actively transport ions through
the cell versus the outside, and it has arbitrarily been the membrane against a concentration gradient.
decided to define the resting potential as negative, for This sodiumpotassium pump expels Na+ ions from the
example, 60 mV (Fig. 3.3).
The resting potential is caused primarily by two
factors:
1. The concentration of K+ ions is about 30 times 117 Na+
higher inside than outside the cell (Figs. 3.4 and 3.5).
2. The cell membrane is selectively permeable to K+ 3 K+
ions in the resting state (Fig. 3.5), that is, no other ions 30 Na+
pass the membrane with comparable ease (the mem-
brane, e.g., is about 50 times more permeable to K+ +
90 K
than to Na+).
Although the concentration differs greatly inside and
outside the cell for ions other than K+ (Fig. 3.4), the
membrane is, as mentioned, almost impermeable to 4 Cl
them (there are, e.g., very few open Na+ channels in the
resting state). Other ions therefore influence the resting 116 Prot
Cl
membrane potential only slightly. Therefore, to explain 120
the membrane potential we can, for the time being,
0 Prot
ignore ions other than
+
K+. The concentration gradient
will tend to drive K out of the cell, and further, K+ ions
can pass the membrane with relative ease through a gure 3.4 Distribution of ions of particular importance for the
particular kind of potassium channel that is open in the membrane potential. The exact concentrations depend on the resting
resting state. This means that positive charges are lost potential (in this case 85 mV). Concentrations in mM.
Na+ electrodes can be used to record the activity of single

K+
neurons in relation to specific stimuli or behavioral
tasks. This method has, for example, provided new
insight into functional specializations within various
areas of the cerebral cortex. By combining anatomic
and physiological techniques, it has been possible to
Outside
determine the functional properties of structurally
defined cell types. After an intracellular recording has
been made from a neuronal cell body or its axon, it can
Cell be filled with a tracer substance through the same
membrane pipette. Afterward, the neuron with all its processes can
be visualized in sections.
Inside
Anions Are Also Unevenly Distributed
For simplicity, we have so far dealt with only two
cations, K+ and Na+, because they are the most impor-
gure 3.5 The unequal distribution of K and Na ions, together
+ +
with open K+ channels, largely explain the resting membrane potential.

tant ones for the membrane potential and also for the
action potential (discussed later in this chapter).
Nevertheless, there are as many anions as cations.
Chloride ions (Cl) and negatively charged protein mol-
interior, in exchange for K+, at the same rate that the ecules (Prot ) are the major anions (Fig. 3.4). These ions
ions leak through the membrane. In this way, the are also unevenly distributed across the cell membrane:
concentration gradients across the cell membrane are the concentration of Cl is 20 to 30 times higher outside
maintained. than inside the cell, whereas the opposite situation
Normally, the extracellular K+ concentration is under exists for Prot. Therefore, chloride is the major extra-
tight control, as discussed in Chapter 2 (Astroglia and cellular anion, whereas proteins are the major intracel-
the Control of Neuronal Homeostasis). Such control lular ones. The proteins are so large that they cannot
is necessary because even small alterations in K+ pass through the membrane; the membrane is imperme-
concentration influence the excitability of neurons able to protein molecules. The membrane is somewhat
significantly. For example, increased extracellular con- permeable to Cl, however. The concentration gradient
centration moves more K+ ions into the cell, thus depo- tends to drive chloride into the cell, whereas the mem-
larizing the neuron (making the membrane potential brane potential tends to drive it out, making the net
less negative) and lowering the threshold for eliciting flow of Cl small. In fact, the equilibrium potential for
action potentials. Cl, 65 mV, is close to the resting potential of most
nerve cells. Therefore, no active mechanism for pump-
ing of chloride is needed.
Recording of Single-Cell Activity
Microelectrodes, with tips less than 1 m thick, can be
The SodiumPotassium Pump and Osmotic Equilibrium
used to record the activity of single neurons and their
processes (single units) intracellularly. Among other All cells depend on the sodiumpotassium pump to
things, this has made it possible to study in detail the maintain the membrane potential and osmotic equilib-
electrical events at the synapses and how they are influ- rium between the intracellular and extracellular fluid
enced by various experimental manipulations. The compartments. Particular to neurons is their need for
effects of different concentrations of intra- and extra- increased pumping in association with the firing of
cellular ions have been studied, as have the synaptic action potentials, which arise because of a current of
effects of various transmitter candidates and drugs. The Na+ into the cell and of K+ out of it. The speed of pump-
voltage clamp technique, which permits manipulation ing increases with increasing intracellular Na+ concen-
of the membrane potential, has been instrumental to tration. A significant part of our energy in the form of
our understanding of the properties of synapses and the ATP is spent on driving the sodiumpotassium pump.
basic mechanisms underlying their operations. Likewise, In the resting state of nerve cells, this may constitute
great progress has been made with the patch clamp approximately one-third of the total energy require-
technique, making possible measurements of ion cur- ment, whereas after high-frequency trains of action
rents limited to even a single ion channel. The study of potentials it may increase to two-thirds.
the properties of ion channels and membrane receptors The unequal distribution of ions is of fundamental
is today highly interdisciplinary. Implanted extracellular importance also for the ability of neurons to maintain
osmotic equilibrium. The distribution of ions must be allowing a brief current of ions to pass through the
such that the total concentrations of water-dissolved membrane. In this way, a chemical signal from a
particles are equal inside and outside the cell. In other presynaptic neuronthe neurotransmitterelicits an
words, osmotic equilibrium means that the water con- electric current through the postsynaptic membrane.
centration is equal inside and outside the cell (osmosis As mentioned, ion channels are more or less selec-
is the movement of water molecules from sites of high tively permeable, that is, they let certain kinds of ions
to sites of low water concentration). In case of osmotic pass through more easily than others. Some channels
imbalance, the cell will either swell or shrink (depend- are highly selective, allowing the passage of one kind
2+
ing on whether the water concentration is lower inside only (such as Ca ions), whereas others are less selec-
or outside, respectively). An essential condition for tive and will allow passage of, for example, most cat-
osmotic balance is the low resting membrane permea- ions. Channels that are permeable for anions in general
+
bility to Na , as both the concentration gradient and are usually termed chloride (Cl ) channels because Cl is
+
the membrane potential tend to drive Na into the cell. the only abundant anion that can pass through the
This situation changes dramatically when the cells fire membrane. Size and charge of the ion influence its per-
+
action potentials, because the membrane then becomes meability. For example, the Na ions are more hydrated
+ +
highly permeable to Na . Long trains of high-frequency (bind more water molecules) than the K ion and there-
action potentials may threaten the osmotic balance fore are larger (Fig. 3.5). This may explain some of their
because more Na+ ions enter the cell than can be pumped differences in permeability. By regulating the channel
out. Fortunately, neurons have properties that limit opening, the transmitter controls the flow of ions
their maximal firing rate and the duration of active through the postsynaptic membrane. However, the
periods. Under pathological conditions, however, these transmitter only alters the probability of the channel
safeguards may fail. In severe epileptic seizures, for being in an open state; it does not induce a permanent
example, neurons fire with abnormal frequency for open or closed state.
long periods, and this may probably contribute to cell
damage by causing osmotic imbalance. Further, in situ-
Voltage-Gated Ion Channels
ations with insufficient blood supply (ischemia), for
example, after a stroke, ATP production suffers, result- Many channels are not controlled primarily by chemi-
ing in slowing of the sodiumpotassium pump. This, in cal substances but by the magnitude of the membrane
turn, leads to osmotic imbalance and swelling of neu- potential and are therefore called voltage-gated.
rons. Such swelling is dangerous because neurons may Voltage-gated Na+ and K+ channels, for example, are
be injured directly but also because swelling of the brain responsible for the action potential and therefore also
inside the skull (brain edema) reduces the blood supply. for the propagation of impulses in the axons. There are
also several kinds of voltage-gated Ca2+ channels, which
control many important neuronal processes, for exam-
Transmitter-Gated Ion Channels
ple, the release of neurotransmitters. Voltage-gated
Neurotransmitters control neuronal excitability by channels are responsible for the activation of nerves
changing the opening state of ion channels (Figs. 3.1 and muscles by external electrical stimulation. Electrical
and 3.2). A channel that is controlled by neuro- stimulation of a peripheral nerve may produce muscle
transmitters (or other chemical substances) is called twitches by activating motor nerve fibers, as well as
transmitter-gated or ligand-gated (the term transmitter- sensations due to activation of sensory nerve fibers.
activated is also used). A large number of ion channels
are now characterized that differ with regard to ion
The Structure of Ion Channels
selectivity and transmitter specificity, that is, the ions
that can pass a channel and the transmitter that con- The structure of several ligand-gated ion channels has
trols it. The transmitter can either bind directly to the now been determined. They consist of five polypeptide
channel polypeptides (proteins) or act indirectly via subunits arranged around a central pore. Three families
chemical intermediates. In most known cases, the trans- of ligand-gated channels have been identified: the nico-
mitter opens the channel to increase the permeability of tinic receptor superfamily (GABAA, glycine, serotonin,
the relevant ions. We consider here only the effects of and nicotinic acetylcholine receptors), the glutamate
directly acting neurotransmitters (indirect effects are receptor family, and the ionotropic ATP receptors. The
discussed later in this chapter). Binding of a transmitter subunits span the membrane and extend to the external
molecule to a specific receptor site at the external face and internal faces of the membrane (Fig. 3.2). Therefore,
of a channel polypeptide may change the form of the signal molecules inside the cell may also influence the
polypeptides, thereby changing the diameter of the opening of ion channels. As an example, members of the
channel (Figs. 3.1 and 3.2). Usually, the channel is open nicotinic receptor family consist of five equal subunits
only briefly after binding of a transmitter molecule, (Fig. 3.2), all contributing to the wall of the channel.
The subunits are large polypeptides with molecular Sodium Channels, and Channelopathies). A number
masses of approximately 300,000. The transmitter of mutations affect channels in striated muscle mem-
binds extracellularly at the transition between two sub- branes, many of them associated with myotonia (inability
units but it is still unknown how the rapid binding to relax after a voluntary muscle contraction).
(in less than 1 msec) produces conformational change Different mutations of one gene can give different
in parts of the channel located, relatively speaking, phenotypes, such as reduced density of channels or
3
far away. reduced opening probability. It is noteworthy, however,
Voltage-gated channels resemble ligand-gated ones; that the same mutation can produce different symptoms
they consist of four subunits arranged around a central in different individuals, even within the same family.
pore. The amino-acid sequence has been determined This strongly suggests that the genes coding for the
for several of the subunits, although lack of three- proteins of a channel do not alone determine its final
dimensional data has prevented clarification of the properties. Additional factors, such as the products
mechanisms that control their opening and ion selectiv- of other genes and environmental factors, must also
ity. Presumably, subtle differences between the subunits contribute. Many features of channelopathies are still
forming the channel explain their high selectivity to unexplainedthat they tend to occur episodically, that
particular ions. the symptoms often start at a certain age (in spite of the
defect being present from birth), and that some forms
remit spontaneously.
Inherited Channelopathies
Many different genes code for channel proteins. Because
Alteration of the Membrane Potential: Depolarization
ion channels determine the excitability of neurons, it is
and Hyperpolarization
not surprising that mutations of such genes are associ-
ated with dysfunctions of neurons and muscle cells. As previously mentioned, in the resting state the mem-
Common to many such channelopathies is that the brane permeability for Na+ is low. If for some reason
symptoms occur in bouts. Of particular clinical interest Na+ channels are opened so that the permeability is
is that many of the channelopathies affecting neurons increased, Na+ ions will flow into the cell and thereby
are associated with epilepsy. Although channelopathies reduce the magnitude of the membrane potential. Such
may not be the primary cause in the majority of patients a reduction of the membrane potential is called depo-
with epilepsy, they may increase the susceptibility to larization. The membrane potential is made less nega-
other factors. For example, mutations associated with tive by depolarization. Correspondingly, one may
epilepsy affect ligand-gated channels that are receptors predict that when the membrane permeability for K+ is
for the neurotransmitters -aminobutyric acid (GABA) increased, more positive charges will leave the cell and
and acetylcholine. Mutations affecting channels gated the membrane potential will become more negative
by glycine (an inhibitory transmitter) are associated than the resting potential. This is called hyperpolariza-
with abnormal startle reactions. This may probably be tion. The same would be achieved by opening channels
related to the fact that glycine is preferentially involved for chloride ions, enabling negative charges (Cl) to
in inhibition of motor neurons. Patients with a certain flow into the cell, provided that the membrane poten-
kind of headachefamilial hemiplegic migrainehave tial is more negative than the resting potential of Cl.
2+
a mutation of the gene coding for a specific Ca -channel In conclusion, the membrane potential is determined
protein. Other mutations of the same gene are associ- by the relative permeability of the various ions that can
ated with other rare nervous diseases, for example, pass through the membrane. At rest, the membrane is
some that affect the cerebellum and lead to ataxic move- permeable primarily to K+, and the resting potential is
ments. Mutations of a kind of voltage-gated potassium therefore close to the equilibrium potential of K+.
channel (K 1.1)expressed in highest density around Synaptic influences can change this situation by opening
V
the initial segment of axonsproduce abnormal repo- Na+ channels, thereby making the permeability to Na+
larization of motor axons and lead to repetitive dis- dominant. This changes the membrane potential toward
charges. This may explain the muscle cramps of such the equilibrium potential of Na+ (at 55 mV). As shown
patients. Their episodes of ataxic movements are pre- in the following discussion, the action potential is caused
sumably caused by abnormal excitability of cerebellar by a further, sudden increase in the Na+ permeability.
neurons. Mutations of voltage-gated sodium channels
(among other factors) cause bursts of intense pain (see
Markers of Neuronal Activity
also Chapter 15, under Nociceptors, Voltage-Gated
Several methods can be used to visualize the activity of
neurons. One method involves intracellular injection of
3 The binding of the transmitter most likely elicits a wave of conformational
change in specic parts of the channel polypeptides. The actual opening of the a voltage-sensitive fluorescent dye. The intensity of flu-
channel may be caused by conformational change of just one, specic amino acid. orescence (as recorded with fluorescence microscopy
and advanced computer technology) gives an impres- Membrane potential

sion of neuronal activity at a given time. Thus, this mV
(indirect) measure of activity can be correlated with Depolarization
experimental manipulation of a specific transmitter, the
execution of specific tasks, and so forth. Another 0 Repolarization
method takes advantage of the fact that optic proper-
ties of nervous tissue change with the degree of neu- Na+ in K+ out
ronal activity. This enables the recording of slow as
well as rapid changes in neuronal activity in relation to Hyperpolarization
experimental influences (it has been applied, e.g., in Resting
conscious persons during neurosurgery that necessitates potential
exposure of the cerebral cortex). Other methods enable
mapping of variations in neuronal activity at the time
0 1 2 3 msec
of death in experimental animals. Intravenously injected
radiolabeled deoxyglucose is taken up by cells in the gure 3.6 The action potential.
same way as glucose. It is not broken down, however,
and therefore accumulates in the cells. Because glucose
is the substrate for oxidative metabolism in the neu-
rons, its uptake correlates with degree of neuronal producing an action potential (Fig. 3.6). When voltage-
activity. After exposing an animal to certain kinds of gated channels are opened, the permeability to Na+ is
stimulation or eliciting certain behaviors, one can after- increased beyond what was achieved by the opening of
wards determine with autoradiography which neuronal transmitter-gated channels, and Na+ flows into the cell
groups were particularly active during stimulation or at driven by both the concentration gradient and the mem-
the time of certain actions. Another method utilizes the brane potential. The membrane becomes more depolar-
fact that a few minutes with excitatory synaptic input ized; in turn, this opens more voltage-gated channels,
induces expression of so-called immediate early-genes and so on. In this way, as soon as the membrane is
in many neurons. Most studied among such genes is depolarized to the threshold value, the permeability to
c-fos. Without extra stimulation, C-fos mRNA and its Na+ increases in an explosive manner. Even with all
protein product are present in only minute amounts in sodium channels fully open, however, the inward cur-
most neurons. Detection of increased levels of c-fos rent of Na+ ions stops when the membrane is depolar-
mRNA in tissue sections is therefore used as a marker ized to +55 mV; at that value the inward concentration
of neurons that were particularly active in a certain force is equal to the outward electrical force (the mem-
experimental situation. This method is also used to brane potential). As mentioned, +55 mV is the equilib-
determine where in the brain a drug exerts its effect. rium potential of Na+. Figure 3.6 shows how, during an
The method has its limitations, however. Thus, c-fos action potential, the membrane potential quickly
expression may be caused by nonspecific influences, changes to positive values and then returns almost as
and not all neurons express c-fos even when properly rapidly to approximately the resting value. This occurs
activated. because the membrane again becomes impermeable to
Na+; the Na+ channels are closed or inactivated.4
Therefore, at the peak of the action potential and for a
+
short time afterward, no Na can pass through the
THE ACTION POTENTIAL
membrane. In this situation with a positive membrane
potential, K+ is driven out by both the concentration
Voltage-Gated Sodium Channels Are Instrumental in
gradient and the membrane potential (electrical force).
Evoking an Action Potential
Because no Na+ can enter the cell, there is a net outward
The basis of the action potential is found in the pres- flow of positive charges, again making the interior of
+
ence of voltage-gated Na channels, which are opened the cell negative. We say that the membrane is repolar-
by depolarization of the membrane (Fig. 3.6). ized. The speed of repolarization is increased by the
Depolarization may be induced in several ways; for presence of voltage-gated K+ channels, which open
example, under artificial conditions by direct electrical when the membrane is sufficiently depolarized. The
stimulation. Normally, however, it is caused by neu- opening of the voltage-gated K+ channels is somewhat
rotransmitters acting on transmitter-gated channels.
The opening of transmitter-gated Na+ channels often
starts depolarization. Opening of the voltage-gated 4 Inactivation and closure involve different parts of the voltage-gated Na+
channel. This is indicated by, among other ndings, that whereas closure of the
channels requires that the membrane be depolarized channel lasts as long as the membrane potential remains below threshold, inac-
to a certain threshold value, that is, the threshold for tivation is transitory and lasts only some milliseconds.
+
delayed compared with the Na channels, but whereas volume compared to the membrane surface area, only
+ + +
the Na channels inactivate after about 1 msec, the K 1 of 3000 K ions moves out during the action poten-
channels stay open for several milliseconds. tial. In addition, active pumping (the sodiumpotassium
+ +
In summary, the action potential is caused by a brief pump) ensures that Na is moved out and K is moved
+
inward current of Na ions, followed by an outward in between each action potential and during periods of
+
current of K ions. The whole sequence of depolarization rest. Even when the sodiumpotassium pump is blocked
repolarization is generally completed in 1 to 2 msec. If experimentally, a nerve cell can produce several thou-
the threshold is reached, an action potential of a certain sand action potentials before concentration gradients
magnitude arises, regardless of the strength of the stim- are reduced so much that the cell loses its excitability.
ulus that produced the depolarization.
The Refractory Period
Where Does the Action Potential Arise?
After an action potential, some time must elapse before
The action potential usually arises in the first part of the neuron can again produce an action potential in
the axon, the initial segment (Fig. 3.7; see also Fig. 2.6), response to a stimulus. The cell is said to be in a refrac-
+
where the density of voltage-gated Na channels is tory state. This ensures at least a minimal rest for the
higher than in the membrane of the dendrites and the cell between each action potential and thereby puts an
cell soma. The current spreads electrotonically (pas- upper limit on the frequency with which the cell can
sively) from dendritic and somatic synapses toward the fire. The length of the refractory period, and therefore
initial segment. If the depolarization is sufficiently also the maximal frequency of firing, varies consider-
strong (reaches threshold), voltage-gated Na+ and K+ ably among different kinds of nerve cells.
channels open and produce an action potential that is Two conditions are responsible for the refractory
propagated along the axon. Although action potentials period. One is the aforementioned inactivation of the
can be elicited in dendrites, their threshold is usually voltage-gated Na+ channels, and the other is the fact
much higher than in the initial segment owing to lower that the membrane is hyperpolarized immediately after
density of voltage-gated channels. the action potential (Fig. 3.6). The inactivation of Na+
channels means that they cannot be opened, regardless
of the strength of the stimulus and the ensuing depolar-
The Action Potential and Changes of Ion
ization. Hyperpolarization occurs because the K+ chan-
Concentrations
nels remain open longer than required just to bring the
One might think that an action potential would cause membrane potential back to resting value. These two
significant changes in the concentrations of Na+ and K+ different mechanisms can account for why the refrac-
on the two sides of the membrane, but this is not the tory period consists of two phases. During the first
case. The number of ions actually passing through the phase, the absolute refractory period, the cell cannot be
membrane during an action potential is extremely small made to discharge, however strong the stimulus may
compared with the total number inside the cell and in be; during the relative refractory period, stronger depo-
its immediate surroundings. Even in an axon with a larization than normal is needed to produce an action
diameter of about 1 m, with a very small intracellular potential.
Calcium and Neuronal Excitability

A cation other than Na+namely, Ca2+may also
Initial segment contribute to the rising phase of the action potential.
For Ca2+, as for Na+, the extracellular concentration is
much higher than the intracellular one, and there are
voltage-gated calcium channels in the membrane.
Axon Cellular influx of calcium can be visualized after
intracellular injection of a substance that fluoresces
when Ca2+ binds to it. During the action potential, cal-
Dendrite cium enters the cellpartly through Na+ channels and
partly through voltage-gated calcium channels, which
have a more prolonged openingclosing phase than the
sodium channels. There are also transmitter-gated cal-
gure 3.7 The initial segment of the axon is where the action poten- cium channels. In most neurons, the contribution of
tial usually arises. Photomicrograph of a motoneuron from the spinal Ca2+ to the action potential is nevertheless small com-
cord stained with a silver-impregnation method. pared with that of Na+. In certain other cells such as
heart muscle, however, calcium is the ion largely respon- resistance (its diameter), the membrane resistance (how
sible for the action potential. Because the calcium well insulated it is), and the capacity of the axonal
+
channels open and close more slowly than the Na membrane. If the propagation of the action potential
channels, an action potential produced by calcium cur- along the axon occurred only by passive, electrotonic
+
rents lasts longer than one produced by flow of Na . movement of charged particles, the internal resistance
Another aspect of the functional role of calcium is and loss of charges to the exterior would cause the
that the extracellular calcium concentration influences action potential to move only a short distance before it
the membrane excitability, which is most likely mediated died out. The solution to this problem is that the
+ +
through effects on the Na and K channels. Reducing action potential is regenerated as it moves along the
the calcium concentration in the blood and interstitial axon. Therefore, it is propagated with undiminished
fluidhypocalcemialowers the threshold for evoking strength all the way from the cell body to the nerve
action potentials in neurons and muscle cells, whereas terminals. As discussed, the strength of the action
increasing the concentrationhypercalcemiahas the potentialthat is, the magnitude of the changes of the
opposite effect. A typical symptom of hypocalcemia is membrane potential taking placeis the same regard-
muscle spasmstetanydue to hyperexcitability of less of the strength of the stimulus that produced
nerves and muscles. Severe hypercalcemia can cause it (as long as the stimulus depolarizes the membrane
drowsiness, nausea, and anorexia. to threshold). Thus, increasing the strength of the stim-
ulus increases the frequency of action potentials,
whereas the magnitude of each action potential remains
constant.
IMPULSE PROPAGATION
When the cell membrane at the initial segment
(Fig. 3.7) is depolarized to threshold, an action poten-
Electrical Properties of Axons
tial is produced and is conducted passively a short
We now consider how the action potential moves along distance along the axon. From then on, what occurs
the axon. The ability of the axon to conduct electrical differs somewhat in myelinated and unmyelinated
current depends on several conditions, some of which axons (Figs. 3.8 and 3.9).
are given by the physical properties of axons, which are
very different from, for example, those of copper wire.
In addition, some conditions vary among axons of dif-
ferent kinds. An axon is a poor conductor compared
with electrical conductors made of metal because the
axoplasm through which the current has to pass con-
sists of a weak solution of electrolytes (i.e., low concen-
Na+
+
+-
- -+ +
trations of charged particles in water). In addition, the 1.
-
- - - - +++++++++++++++++
diameter of an axon is small (from <1 to 20 m) with a +++++ - - - - - - - - - - - - - - - -
correspondingly enormous internal resistance to the +++++ ----------------
current in the axoplasm. Further, the axonal membrane - - - - - ++++++++++++++++
is not a perfect insulator, so that charged particles are
lost from the interior of the axon as the current passes +
Na+
- +
- -+ +
along its length. The amount of current being lost is

-
2. - +- +- +- +- -+ -+ -+ -+ +- -+ -+ +- +- +- +- +- +- +-+-+-
+
determined by the degree of membrane resistance (i.e., +
K
the resistance of the membrane to charged particles try-
ing to pass). Finally, the axonal membrane (like all cell
membranes) has an electrical capacity; that is, it can
store a certain number of charged particles in the same +
Na+
+
--
- -+ +
way a battery does. This further contributes to the rapid +++++++++++++ - - - - - +++
- - - ++++- - - - - - - - - - - - - -
attenuation of a current that is conducted along an 3.
K+
axon: the membrane has to be charged before the
current can move on.
The Action Potential Is Regenerated as It Moves Along

the Axon gure 3.8 Impulse conduction in unmyelinated axons. Arrows show
direction of movement of charged particles. The action potential is
From the foregoing it can be concluded that how well renewed continuously along the axonal membrane by a wave of
the current is conducted in an axon depends on its internal depolarizationrepolarization.
body, the action potential spreads toward both the cell
body and the end ramifications (orthodromic impulse
+ Na+ conduction). Antidromic impulse conduction may
- - +- + +
++++++++++
occur in branches of peripheral sensory axons on natu-
- ++++++++++
-
1.
+
+
+
--- ++
+
- - - - - - - - - - - - - - - - - - - - - - - - +++ ral stimulation and may play a part in certain disease
symptoms (see Chapter 29, Antidromic Impulses and
the Axonal Reflex).
+ Na+
- -+ + +
-
-- ++++++++++ ++++++++++ Impulse Conduction in Myelinated Axons
+
+
+
++ --
+
2. - - - - - - - - - -+++- - - - - - - - - - - - -
In myelinated axons, the action potential is also regen-
erated along the axon (Fig. 3.9). However, in contrast
to that in unmyelinated axons, the action potential is
regenerated only at each node of Ranvierthat is,
where the axon membrane lacks a myelin covering and
gure 3.9 Impulse conduction in myelinated axons. Arrows show is in direct contact with the extracellular fluid (see
direction of movement of charged particles. The current moves
electrotonically in the myelinated part of the axons, and the action
Fig. 2.6). As in unmyelinated axons, the action poten-
potential is renewed only at the node of Ranvier, causing a small tial arises in the initial segment of the axon. The current
delay in impulse propagation. then spreads passively (electrotonically) to the first
node of Ranvier. Here, the depolarization of the mem-
brane leads to opening of voltage-gated channels and a
new action potential. The density of voltage-gated
sodium channels is particularly high in the axonal mem-
Impulse Conduction in Unmyelinated Axons
brane at the node of Ranvier. The current can flow elec-
The action potential is produced by positive charges trotonically as far as the first node of Ranvier (and
penetrating to the interior of the axon, which at that probably sometimes farther) because the axon is so well
point becomes positive relative to more distal parts insulated by myelin, preventing loss of charges from the
along its length (Fig. 3.8). Positive charges then start interior of the axon. (Myelin dramatically increases
moving in the distal direction (along the electrical gra- the resistance across the membrane and also reduces
dient that has been set up). Outside the axon, a corre- the membrane capacity.) In addition, the axonal diam-
sponding current of positive charges moves in the eter is larger in myelinated than in unmyelinated axons,
opposite direction, so that an electrical circuit is estab- thus reducing the internal resistance.
lished. Movement of positive charges in the distal direc- In conclusion, in myelinated axons the action poten-
tion inside the axon means that the membrane is tial does not move smoothly and slowly along, as in
depolarized as the charges move along. This depolar- unmyelinated axons, but instead jumps from one
ization leads to the opening of enough voltage-gated node of Ranvier to the next. Although the impulse
+ +
Na and K channels to produce a new action poten- propagation is very rapid between nodes, at each
tial. In this manner, the action potential moves along node there is a delay due to the time required for open-
the axon at a speed that depends on the speed with ing of channels and establishment of sufficient flow of
which the charged particles (i.e., ions) move inside the current.
axon and on the time needed for full opening of the ion
channels. The membrane capacity represents a further
Conduction Velocities in Myelinated and
factor slowing the propagation because the membrane
Unmyelinated Axons
has to be charged before there can be a net flow of
charges through it. The main reason myelinated axons conduct so much
In essence, the action potential is propagated as a more rapidly than unmyelinated ones is that the action
wave of depolarization, followed closely by a corre- potential needs to be regenerated only at certain sites.
sponding wave of repolarization. When the membrane A figure for conduction velocity (expressed in meters
has just completed this cycle, it is in the refractory state per second) in myelinated axons is obtained by multi-
for some milliseconds. This delay prevents the action plying the axonal diameter (in micrometers) by 6.
potential from spreading backward toward the cell An axon of 20 m (the maximal diameter) therefore
body (antidromic impulse conduction), and ensures conducts at approximately 120 m/sec, whereas the thin-
that under normal conditions the impulse conduction is nest myelinated axons of about 3 m conduct at 18 m/sec.
unidirectional. If, however, the axon is artificially stim- In comparison, a typical unmyelinated axon of about
ulated (e.g., electrically) at some distance from the cell 1 m conducts at less than 1 m/sec.
HOW NERVE CELLS VARY THEIR MESSAGES
Frequency Coding and Firing Patterns

So far we have treated the action potential as a unitary
phenomenon. As mentioned, the strength of each action
potential of a neuron does not vary: whenever depolar- Action potentials with even
ized to the threshold, the cell fires action potentials of frequency
constant magnitude. Therefore, the action potential is
an all-or-none phenomenon, and one might think that
each neuron would only be able to tell whether or not a
stimulus occurs. We know, however, that the individual
nerve cell can communicate to others about the strength
of the stimulation it receivessuch as the intensity of
light or a sound, of something touching the skin, and so
forth. It does so by varying the frequency and pattern of Action potentials in bursts
action potentials. To understand this, we need to know
that a neuron is more or less continuously influenced by
impulses from many other neurons. A sustained synap- gure 3.11 Different patterns of nerve impulses provide neurons
tic input that is strong enough to depolarize the cell to with an additional means to vary the information they send to other
neurons and muscle cells.
threshold does not merely produce one action potential
but rather several in succession. The stronger the depo-
larization, the shorter the time required reaching the
threshold after each action potential. Consequently, the
firing frequency depends on the strength of depolariza- inputs (see earlier, The Refractory Period). Two neu-
tion (Fig. 3.10). We say that the neuron uses a frequency rons may both fire with an average frequency of, for
code to tell how strongly it has been stimulated. The example, 10 per second but nevertheless influence a
maximal frequency of action potentials in some neu- postsynaptic cell differently. So-called burst neurons
rons is more than 100 per second (100 Hz), whereas in produce trains of action potentials with a high fre-
others it is much lower. quency and then pause for a while before a new train
The average firing frequency is not the only way by (burst) of impulses arises. Other neuronsso-called
which the neuron can alter its message. The firing single-spike neuronsproduce action potentials with
pattern also carries information, and each neuronal regular intervals (Fig. 3.11).
type has its characteristic firing pattern that is caused Some neurons can switch between these two modes
by differences in membrane properties and synaptic of firing. In such cases, the relationship is not linear
between the strength of synaptic input and the firing
frequency. The transition between the different firing
patterns is evoked by a specific neurotransmitter, which
does not in itself produce action potentials in the post-
synaptic cell but changes its reactions to other inputs.
For example, the neuron may change from burst to
single-spike patterns or from a high firing frequency to
no firing at all.
In conclusion, because the strength of action poten-
Weak depolarization tial is constant, the code for the information carried
by an axon is the frequency and pattern of action
potentials.
Plateau Potentials
In some neurons, the occurrence of so-called plateau
Strong depolarization potentials causes the switch from low-frequency firing
to high-frequency or bursting firing pattern. This has
gure 3.10 The frequency of action potentials depends on the
been shown for many neurons that control rhythmic
magnitude of depolarization. Therefore, the frequency of action muscle contractions. Plateau potentials are produced
potentials reects the total synaptic input to a neuron. by a slow, depolarizing current, for example, by certain
2+
voltage-gated Ca channels that are open in a limited (see Chapter 21, under Muscle Cramps and Plateau
range of membrane potentials. Such a neuron can there- Potentials, and Chapter 22, under Monoaminergic
fore change abruptly between two entirely different Pathways from the Brain Stem to the Spinal Cord).
behaviors. The neurotransmitter serotonin can evoke Release of this transmitter relates to motivation and
plateau potentials in groups of spinal motor neurons attention rather than to specific information.
4 Synaptic Function
OVERVIEW the cells firing is diminished. If the transmitter produces

an EPSP, we use the terms excitatory synapse and excit-
In Chapter 3, we discussed the basis of nerve impulses atory transmitter. Likewise, an inhibitory transmitter
and their conduction in axons. This chapter deals with produces an IPSP at an inhibitory synapse.
the properties of synapses. We discuss mainly chemical Because the depolarization caused by one EPSP is
synapses: synapses in which the signal is mediated by a small, summation of many EPSPs is usually needed to
neurotransmitter. Synapses with direct electric coupling reach a threshold for eliciting an action potential. This
(gap junctions) are common among glial cells but occur enables the neuron to integrate information from often
infrequently among neurons. The key events underlying many thousand synapses.
signal transfer at chemical synapses are as follows: Synapses are plastic; that is, they can change their
First, an action potential reaches the nerve terminal properties by use. This implies that certain kinds of
(bouton) and depolarizes it. This depolarization opens activity can enhance or reduce the subsequent effect of
Ca 2+ channels, enabling Ca2+ to enter the nerve termi- a synapse on the postsynaptic neuron for a variable
nal. Increase in intracellular Ca2+ concentration is a sig- period (from milliseconds to years). Most likely, such
nal for release of neurotransmitter from vesicles by use-dependent synaptic plasticity is the neuronal basis
exocytosis. This produces a high concentration of neu- for learning and memory.
rotransmitter in the synaptic cleft. The released trans-
mitter binds briefly to receptors in the postsynaptic
Unusual Synapses: Electrotonic and
membrane. After activation of the receptor, the trans-
Dendrodendritic Transmission
mitter must be inactivated quickly to reestablish a low
background activity of the receptors, that is, to ensure Although it is rare, the pre- and postsynaptic elements
a high signal-to-noise ratio at the synapse. Inactivation are electrically rather than chemically coupled at some
occurs partly by diffusion of the transmitter, partly by synapses. Electron microscopically, such electronic
enzymatic degradation, and partly by specific uptake synapses differ from chemical synapses in that the syn-
mechanisms (transporter proteins). aptic cleft is only 2 nm compared to about 20 nm. This
There are two main kinds of transmitter receptors. kind of cell contact is called a nexus or gap junction; it
Ionotropic receptors are parts of ion channels and consists of channels that span the synaptic cleft.
therefore influence the functional state of the channel Through these channels ion currents can pass directly
directly. Therefore, transmitter actions elicited by iono- and quickly from one cell to another with no synaptic
tropic receptors are fast and precise. Metabotropic delay. In invertebrates and lower vertebrates, electro-
receptors are coupled indirectly (via intracellular tonic synapses are formed between neurons mediating
second messengers) to ion channels. Their effects are short-latency responses to stimuli (e.g., escape reac-
therefore slower to start and longer lasting than effects tions). Electrotonic synapses may also provide electrical
mediated by ionotropic receptors. We also use the term coupling between many neurons in a group, so that
modulatory of the synaptic effects of metabotropic their activity may be synchronized. Chemical synapses
receptors, because they adjust the excitability of the may occur close to electrical ones and serve to uncouple
postsynaptic neuron so that it responds more or less the electrical synapse so that these apparently can be
vigorously to the precise effects of ionotropic receptors switched on and off. Even a small number of gap junc-
(in addition, metabotropic receptors may have effects on tions between nerve cellstoo small to produce effi-
the growth and survival of the postsynaptic neuron). cient electric couplingmay be important by enabling
2+
The change of the membrane potential arising as a transfer of small signal molecules, such as Ca , cyclic
result of synaptic influence is called a synaptic poten- AMP, and inositol triphosphate (IP3). In this way, one
tial. If the synaptic influence depolarizes the postsynap- neuron may alter the properties of another without
tic cell, the probability that the cell will fire action ordinary synaptic contact. Electrical coupling by gap
potentials is increased. This synaptic effect is called an junctions is much more common among glial cells than
excitatory postsynaptic potential (EPSP). If the synaptic among neurons, and it occurs regularly among cardiac,
potential hyperpolarizes the cell, it is called an inhibitory smooth-muscle, and epithelial cells. There are also other
postsynaptic potential (IPSP) because the probability of unusual types of synapses. Contacts between dendrites
40
4: SYNAPTIC FUNCTION 41
with all the morphological characteristics of synapses
have been observed in several places in the central ner-
vous system (CNS). Such dendrodendritic synapses are Glia
often part of more complex synaptic arrangements.

Through dendrodendritic synapses, adjacent neurons Transporters for
Action potential reuptake of
can influence each other without being connected with Synaptic vesicles transmitter
axons. The function of such synapses, however, is not Presynaptic
receptor
fully understood.
Voltage-gated
calcium channel
NEUROTRANSMITTER HANDLING AT THE SYNAPSE
Ca2+
Release of Neurotransmitters
Postsynaptic Postsynaptic
We have previously described transmitter-containing receptor membrane
synaptic vesicles, aggregated near the presynaptic mem-

gure 4.1 Signal transmission at the synapse. Schematic of some
brane of boutons (Figs. 4.1 and 5.9). Depolarization of important features: calcium-dependent transmitter release, reuptake
the presynaptic membrane by an action potential is the of transmitter by glia and neurons, and recycling of synaptic vesicles.
normal event preceding transmitter release. The depo-
larization opens voltage-gated calcium channels and
allows a flow of Ca2+ ions into the bouton. The rise in
Ca2+ concentration triggers the release of transmitter by
exocytosis of vesicles (Fig. 4.1). The more calcium that
enters, the more transmitter is released. By exocytosis,
the membrane of synaptic vesicles fuses with the pre-
synaptic membrane. The fusion opens the vesicle so
that its content flows quickly into the cleft (Figs. 4.1
and 4.2). It takes only 0.1 to 0.2 msec from calcium
inflow to the occurrence of release, which means that
only vesicles already attached to the presynaptic mem- Nerve terminal
brane empty their contents. Further, although voltage-

gated Ca2+ channels are present in all parts of the nerve
terminal membrane, only those situated in the presyn-
aptic membrane can influence the fusion of the vesicle
with the presynaptic membrane.1 The part of the syn-
apse where the vesicles attach to the presynaptic mem-
brane is called the active zone, and is characterized by
cytoskeletal components that probably bind the vesicles Microtubule
to the calcium channels. That fusion really occurs dur-
Synapsin
ing release is supported by, among other data, electron
Actin filament
microscopic observations showing that the number of Synaptic
vesicle
vesicles drops with long-term stimulation (trains of
Vesicle without
action potentials), while the number increases after a synapsin
period of rest. anchorage Ca2+
Exocytosis of vesicles is controlled by a large number Fusion Presynaptic
of regulatory proteins that appear to be the same in all membrane
kinds of cells. Two features are nevertheless specific to Transmitter Ca2+ Synaptic
exocytosis in neurons as compared with that in other cleft
cells: one is the speed of the process (<1 msec from Ion channel Postsynaptic
arrival of the action potential to release); the other is (ionotropic density
receptor) (various proteins)
that the release is restricted to a specific site (the synapse).
Metabotropic Cytoskeleton
receptor
1 This is because the fusion requires a very high concentration of Ca2+, which
occurs only close to the intracellular opening of the channel. In fact, there is
evidence that the calcium channel constitutes a part of the protein complex gure 4.2 Transmitter release and some of its machinery. Calcium
that binds the vesicle to the presynaptic membrane. This ensures maximal Ca
2+
channels are located close to where the vesicles fuse with the presyn-
concentration around the vesicle. aptic membrane. (Based on Walmsey et al. 1998.)
This indicates that some proteins are specific to the to require that the complex include synaptotagmin,
2+
control of exocytosis in neurons. The fusion requires which binds Ca with low affinity (i.e., the concentra-
2+
specific binding of vesicle-surface receptors to receptors tion of Ca must be high for bonding to occur).
in the presynaptic membrane. In addition, during According to one hypothesis, synaptotagmin acts as a
2+
fusion, various proteins dissolved in the cytoplasm par- brake on fusion, and the binding of Ca releases the
ticipate by binding to the membrane-bound receptors, brake. Mice lacking the gene for synaptotagmin have
thus forming large complexes. only reduced transmitter release, however, suggesting
New, empty vesicles are formed by the opposite pro- that other factors also play a role.
cess of exocytosis, endocytosis. The endocytotic vesicles
are coated with proteins (among them clathrin and
Neurotransmitters Are Released in Quanta
dynamin) that are thought to help in budding of the
vesicles from the membrane and in selecting their con- There is convincing evidence that transmitters are
tent. The recycled vesicles undergo a series of regulated released in packets, or quanta, corresponding to the
steps until they are again filled with neurotransmitter transmitter content of one vesicle. For synapses between
(Fig. 4.1). motor nerve terminals and striated muscle cells, one
Several of the proteins involved in vesicle transport vesicle contains on average 10,000 transmitter mole-
and fusion alter their activity in a use-dependent man- cules. Only a few thousand molecules of each quantum
ner; that is, they may be involved in synaptic plasticity are likely to bind to a receptor before they diffuse away
during development, recovery after brain damage, and or are removed by other means. Release of one quan-
learning in general. Some are also targets of drugs and tum elicits a tiny excitatory postsynaptic potential
toxins. (EPSP)a miniature EPSP. If stimulation is increased,
so that more transmitter is released, the depolarization
of the muscle cell membrane increases in steps corre-
Mechanisms for Vesicle Transport and Fusion
sponding to one miniature EPSP. In the CNS, each bou-
Specific transporter proteins in the vesicle membrane ton probably releases from none to a few quanta for
fill the vesicles with neurotransmitter. After filling, the each presynaptic action potential. This means that an
vesicles are moved toward the presynaptic membrane action potential does not necessarily elicit transmitter
by a regulated process (Fig. 4.2). While some vesicles release; it merely increases the probability of release.
empty their contents, others move toward the presyn- As discussed later, many presynaptic action potentials
aptic membrane and prepare for fusion. The synaptic must coincide to fire a postsynaptic neuron.
vesicles can therefore be divided into two main groups:
those situated close to the membrane that are ready for
2+ Transmitters Act on Ionotropic and Metabotropic
release when the Ca concentration rises around them,
Receptors
and those that must move to the membrane before they
can release their contents. The movement of vesicles The effects of a neurotransmitter depend primarily on
requires the presence of actin filaments, and microtubules the properties and localization of the receptors it can
may also play a role. A group of proteins, synapsins, bind activate. There are two main kinds of transmitter recep-
the vesicles to the actin filaments (Fig. 4.2), which tors: ionotropic and metabotropic. Ionotropic receptors
probably serves to assemble the vesicles in positions for are parts of ion channels (Fig. 4.3A). Ionotropic recep-
+ 2+
further movement and is triggered by the rise in the cal- tors that are parts of Na or Ca channels evoke fast
cium concentration. Certain protein kinases (phospho- and brief depolarizations of the postsynaptic mem-
rylating proteins) regulate the activity of the synapsins. brane, thus exerting excitatory actions. Ionotropic
Phosphorylation of synapsins increases mobility of the receptors coupled to Cl channels as a rule hyperpolar-
vesicles and is most likely another way of controlling ize the postsynaptic membrane and inhibit the postsyn-
the amount of transmitter released by an action poten- aptic neuron. Synapses equipped with ionotropic
tial, for example, in response to altered use of the syn- receptors mediate fast and precise informationfor
apse. Several proteins take part in the docking of the example, about when, what, and where con-
vesicle at the presynaptic membrane, and they probably cerning a sensory stimulus.
also prepare the vesicles for fusion. Vesicle-bound recep- The other main kindmetabotropic receptoris not
tors, such as synaptobrevin/VAMP (vesicle-associated coupled directly to ion channels but acts indirectly by
membrane protein), mediate attachment to receptors in way of G proteins and intracellular second messengers
the presynaptic membrane (syntaxin is one such recep- (Fig. 4.3B). G proteins may be regarded as universal
tor). These receptors interact with several others translators, translating various kinds of extracellular
among them, SNAP-25 that is free in the cytoplasmthus signals to a cellular response (e.g., the translation of
forming large protein complexes that anchor the vesi- light and of gaseous and watery chemical substances to
cles to the presynaptic membrane. The fusion appears nerve impulses).
A B Receptor
Transmitter protein Transmitter
Ion channel
Adenylate
cyclase
Na+
gure 4.3 Two kinds of transmitter

receptors. A: Ionotropic receptor with
direct action on the ion channel. Note that
the receptor is part of the channel proteins. K+
Inside G-protein
B: Metabotropic receptor with indirect
Cyclic AMP ATP
action on ion channels. Schematic. All
indirectly coupled receptors act via G pro-
Protein kinase
Pro
teins, whereas other elements of the intra-
cellular signal pathway may vary among
different receptors. In this example cyclic IONOTROPIC METABOTROPIC
AMP serves as the second messenger.
Most neurotransmitters act on both ionotropic and

Inactivation of Neurotransmitters
metabotropic receptors. That is, a neurotransmitter can
exert both fast, direct synaptic effects and slow, indirect Synaptic signal transfer is characterized by a precisely
ones (at the same or different synapses). Glutamate and timed start and stop. We have looked into the mecha-
GABA (-aminobutyric acid) are by far the most abun- nisms responsible for precise timing of transmitter
dant and ubiquitous transmitters acting on ionotropic release. It is also necessary, however, that the transmitter,
receptors, although they also act on several kinds of once released, be quickly removed from the synaptic
metabotropic receptors. Several important neurotrans- cleft after receptor activation. Simple diffusion of the
mitters, such as norepinephrine, dopamine, and sero- transmitter seems to play an important part, especially
tonin, exert their main actions on metabotropic during the first few milliseconds after release. Some
receptors. We can conclude that to predict the actions transmitters (acetylcholine and neuropeptides) are
of a neurotransmitter on a neuronal group, we must degraded extracellularly by specific enzymes. The
know the repertoire of receptors expressed by those majority of transmitters, however, are removed from
neurons. Further, because the distribution of receptors the extracellular fluid by uptake into glial cells or neu-
differs, one transmitter may exert different actions in rons (see also Chapter 2, under Astroglia and the
different parts of the brain. Control of Neuronal Homeostasis). Specific trans-
porter proteins in the cell membrane (see Figs. 2.5, 4.1,
and 5.5) carry out the transmitter uptake. The trans-
Toxins Can Prevent Transmitter Release
mitter transporters are driven by ion-concentration
Some of the proteins necessary for fusion are degraded gradients across the cell membrane. There are two fam-
by tetanus toxin and botulinum toxin (produced in cer- ilies of such transporter proteins. One is driven by the
+
tain foods if not treated properly). Both toxins are pro- concentration gradients of Na and Cl and transports
duced by anaerobic bacteria (i.e., they only grow in the the transmitters GABA, glycine, dopamine, norepi-
absence of oxygen) and produce violent muscle spasms nephrine, and serotonin. The other comprises five
and paralysis, respectively. The toxins are proteases different transporters for glutamate and is driven by the
acting on the proteins that are involved in docking and concentration gradients of Na+ and K+.
fusion of synaptic vesicles. While tetanus toxin and The task of the transporters is not to remove all traces
some botulinum toxins degrade synaptobrevin, other of neurotransmitters from the extracellular fluid.
botulinum toxins destroy SNAP-25, or syntaxin. Even Because both number and activity of the transporters
extremely small amounts of the toxins produce muscle are regulated, they rather serve to modulate up or down
spasms (tetanus toxin) or paralysis (botulinum toxins) a certain baseline extracellular transmitter concentra-
by preventing transmitter release. They evoke opposite tion. Even a small alteration of transporter activity can
effects because they act on different kinds of synapses: cause changes of transmitterreceptor activation. In
the tetanus toxin affects primarily a type of inhibitory areas with a high density of transporters, they also
synapse, whereas botulinum toxin acts at the neuro- influence the ease by which neurotransmitters may acti-
muscular junction, preventing release of the excitatory vate receptors outside the synaptic cleft (on nerve ter-
transmitter acetylcholine. minals, dendrites, and cell bodies). In this way, the
transmitter transporters participate in the control of

synaptic transmission and neuronal excitability.
Recording electrode
Because the transporter proteins have important
physiological roles, they are also interesting from a
pharmacological aspect. Drugs that alter their function
can be used therapeutically (such as antidepressants
that are selective serotonin reuptake inhibitors), but
some also have potential for abuse (such as cocaine,
which inhibits the dopamine-reuptake transporter). Dendrite
SYNAPTIC POTENTIALS AND TYPES OF SYNAPSES

mV Release of transmitter
Mechanisms of Postsynaptic Potentials (EPSPs and IPSPs)
Membrane potential
Synaptic potentials arise when neurotransmitters acti-
EPSP
vate ion channels. An excitatory postsynaptic potential
(EPSP) arises at synapses where the transmitter depo-
larizes the postsynaptic membrane. An inhibitory post-
65
synaptic potential (IPSP) arises at synapses where the
Time
transmitter hyperpolarizes the membrane.
Opening of cation channels allowing Na+ to enter
and K+ to leave the cell produces an EPSP. Because the
cations outside the cell are driven inward, by both the IPSP
concentration gradient and the membrane potential,
65
whereas K+ inside the cell is driven out only by its con-
centration gradient, at first the inward current is largest
(see Figs. 3.3, 3.4, and 3.5). As the membrane becomes
more and more depolarized, however, the outward flow
of K+ increases and counteracts further depolarization gure 4.4 Synaptic potentials. Alterations of the membrane poten-
(Fig. 4.4). Transmitter-gated channel opening is not tial evoked by a single presynaptic action potential that releases a
subject to self-reinforcement, unlike the voltage-gated transmitter into the synaptic cleft. An EPSP (excitatory postsynaptic
synaptic potential) is evoked by an excitatory transmitter (typically
channels that produce the action potential. This means
glutamate), while an inhibitory transmitter (typically GABA) pro-
that the synaptic potentials rise and fall gradually duces an IPSP (inhibitory postsynaptic synaptic potential).
(Fig. 4.4 and 4.5) and last longer than the action poten-
tial. We use the term graded potential, as opposed to
the all-or-none behavior of the action potential. The
current spreads passively (electrotonically) from the Cl is close to the resting potential in many neurons.
synapse outward in all directions along the cell mem- If the resting potential is equal to the equilibrium poten-
brane. In this way, the potential becomes gradually tial of Cl, there is no net flow of Cl ions and, conse-
weaker, unlike the action potential that is constantly quently, no IPSP is evoked.2 Even in this case, however,
regenerated. Because typical EPSPs in neurons are small opening of chloride channels can counteract the effects
(<1 mV), and the membrane has to be depolarized at of excitatory transmitters. Thus, as long as the chloride
about 10 mV near the initial segment to reach threshold channels remain open, even the slightest depolarization
for an action potential, it follows that many EPSPs must will cause Cl ions to flow into the cell and thereby min-
be summated to fire the neuron. We return to summa- imize the change of the membrane potential. In this
tion of EPSPs later. case, opening of chloride channels by an inhibitory
The mechanism behind an IPSP is usually the open- transmitter short-circuits the depolarizing currents at
ing of transmitter-gated K + or Cl channels. This results nearby excitatory synapses.
in an outward flow of K+ or an inward flow of Cl. In
both cases, the inside of the cell becomes more negative,
that is, the membrane is hyperpolarized. This is only
true if the membrane potential is less negative than the 2 If the resting potential is more negative than the equilibrium potential of Cl,
equilibrium potentials of the ions in question, however. opening of chloride channels causes a net outward ow of chloride ions and the
cell is depolarized. This is the case in early embryologic development; the trans-
Although this is the normal situation for K+ (equilib- mitter GABA, which is inhibitory in the adult nervous systems, has excitatory
rium potential 90 mV), the equilibrium potential of actions in the immature brain.
A or it may be in space, and is then called spatial summa-

Membrane tion. In temporal summation, impulses may follow one
potential
another in rapid succession in one terminal, whereas in
Action potential spatial summation, nerve terminals at different places
on the cell surface release transmitter and depolarize
the cell almost simultaneously. In addition, IPSPs are
subject to spatial and temporal summation.
Summation
An EPSP increases the probability that the postsyn-
EPSP EPSP EPSP
Threshold aptic neuron produce an action potential: for a moment
the neuron is more responsive to other inputs. Likewise,
Resting
potential an IPSP decreases this probability.
2 6 10 14 msec
B Slow Synaptic Effects Modulate the Effect of Fast Ones
Because neurons are equipped with both ionotropic
and metabotropic transmitter receptors, we may safely
assume that every neuron receives both fast (direct) and
IPSP IPSP EPSP slow (indirect) synaptic inputs. The slow effects modu-
Threshold
late the effects of the fast ones, and we therefore use the
Resting term modulatory transmitter actions. A modulatory
potential transmitter (when binding to an indirectly acting recep-
tor) does not by itself evoke action potentials but alters
msec the response of a neuron to fast, ionotropic transmitter
actions. Usually, modulatory synaptic effects are medi-
+ 2+
gure 4.5 Synaptic potentials. A: The time course and polarity of an ated by altering opening states of K or Ca channels,
excitatory postsynaptic synaptic potential (EPSP). In this example, thereby modulating both the membrane potential and
one EPSP alone does not depolarize the membrane to threshold for
eliciting an action potential (AP), but if one EPSP (or more) follows
the refractory period. The effects are nevertheless much
shortly after the rst one, the threshold is reached (summation). more varied because there are several kinds of potas-
B: The time course and polarity of an inhibitory postsynaptic synap- sium and calcium channels, and several transmitters
tic potential (IPSP) and how the hyperpolarization is reduced when may influence each channel.
an EPSP is added to an IPSP. A brief train of impulses in axons releasing a trans-
mitter that binds to indirectly acting receptors may keep
the membrane depolarized or hyperpolarized for sec-
onds after the train of impulses ends (slow EPSP or
Summation of Stimuli Is Necessary to Evoke an
IPSP; Fig. 4.6). More intense stimulation may produce
Action Potential
depolarization that lasts minutes in some neurons.
One or a few presynaptic action potentials leading to
transmitter release do not evoke an action potential in
the postsynaptic cell. As previously mentioned, the
membrane has to be depolarized to a threshold value
(Fig. 4.5A) for an action potential to be evoked. Usually, Membrane
potential
the threshold is approximately 10 mV more positive mV Fast EPSP
than the resting potential, and the size of an EPSP is
probably in most cases less than 1 mV. As previously 40 Slow EPSP
mentioned, to produce an action potential the current
50
produced at synaptic sites must be strong enough to
reach the initial segment and depolarize the membrane 60
+
to threshold (by opening voltage-gated Na channels).
A subthreshold depolarization may nevertheless be
of functional significance. If the synaptic potential is 2 min
Stimulus
followed by another depolarization before the mem-
brane potential has returned to resting value, the second
depolarization is added to the first one so that thresh- gure 4.6 Fast and slow synaptic actions. Schematic. A fast
EPSP lasts milliseconds and is caused by binding of transmitter mol-
old is reached. This phenomenon is called summation ecules directly to channel proteins. A slow EPSP may last seconds or
(Fig. 4.5A). The summation may be in time, as in the minutes and is due to activation of receptors indirectly coupled to
example above, and is then called temporal summation, ion channels.
An example may make this clearer: motor neurons in The stronger the sum of excitatory effects, the shorter
the cord receive fast, excitatory synaptic input from the time necessary to depolarize the cell to the threshold
the cerebral cortex. These signals mediate the precise, for eliciting another action potential. This means that
voluntary control of muscle contraction. In addition, the frequency of action potentials, or firing frequency,
the motor neurons receive slow, modulatory synaptic is an expression of the total synaptic input to a neuron.
inputs from cell groups in the brain stem whose activity Total synaptic input here means the sum of both excit-
is related to the degree of motivation for a particular atory and inhibitory synaptic influences. Most neurons
movement. The modulatory input influences the receive thousands of synapses; for example, large neu-
strength of the response (frequency of action potentials) rons in the motor cortex of the monkey may receive
to signals from the cerebral cortex, that is, how fast the as many as 60,000 synapses. Often a neuron is strongly
movement will be. However, the modulatory input does influenced (many synaptic contacts) by one neuronal
not initiate movements on its own. group and weakly influenced by many others. This
means that while such a neuron primarily transmits
signals from one nucleus to another, many other
Mechanisms of Modulatory Synaptic Effects
cell groups facilitate or inhibit the efficiency of signal
Slow EPSPs may be mediated by transmitters closing a transmission.
kind of voltage-gated K+ channel that is open at the
resting membrane potential. This leads to lowered K+
Examples of Synaptic Integration
permeability and reduced flow of K+ out of the cell,
which results in depolarization. Because the membrane We will provide two examples of the integration of
potential is shifted toward the threshold, fast depolar- different synaptic inputs. The first concerns motor
ization is more likely to elicit an action potential. In neurons of the spinal cord. Such a neuronsending its
addition, the effect on this kind of channel makes a fast axon to innervate hundreds of striated muscle cells in
EPSP larger and longer-lasting because the fast trans- a particular muscleis synaptically contacted by neu-
mitter opens the K+ channel during the repolarization rons in many parts of the nervous system. It may
phase of the EPSP. When the modulatory transmitter receive around 30,000 synapses, distributed over its
counteracts the opening of the channel in this phase, dendrites and cell body. Some synapses inform the cell
the depolarization becomes stronger, and the repolar- about sensory stimuli that are important for the move-
ization phase is prolonged. In this way the fast trans- ment produced by the muscle, others about the pos-
mitter, rather than eliciting one, may produce a train of ture of the body, others about how fast an intended
action potentials. movement should be, and so forth. The sum of all
Modulatory synaptic effects may not change the rest- these synaptic inputssome of them excitatory, oth-
ing membrane potential, if they are confined to chan- ers inhibitorydetermines the frequency of action
nels that are not open at the resting potential. A kind of potentials sent to the muscle and by that means the
K+ channelclosed at the resting potentialis opened force of muscle contraction (each muscle, however,
by Ca2+ entering the cell during the action potential. is governed by many such neurons, so that their collec-
This produces a relatively long-lasting hyperpolariza- tive activity determines the behavior of the whole
tion (the refractory period). A modulatory transmitter muscle).
that reduces the opening of the K+ channel would The other example concerns neurons in the spinal
shorten the refractory period. As in the preceding exam- cord that mediate information about painful stimuli.
ple, a fast excitatory input might produce a train of Although such a neuron receives its strongest synaptic
impulses rather than only one, or the frequency of input (most synapses) from sensory organs reacting to
impulses during a train might be higher than without painful stimuli, it is also contacted by thousands of syn-
the modulatory influence. apses from other sources, such as cell groups that are
Slow, long-lasting hyperpolarizing synaptic effects active when the person is anxious. This means that the
(slow IPSPs) are usually mediated by the indirect open- final firing frequency of this pain-transmitting neu-
ing of K+ channels. As we discussed later, the ubiqui- ron depends not only on the actual stimuli reaching the
tous inhibitory transmitter GABA can act on receptors receptors but also on the activity within the CNS itself.
with such effect. This correlates well with the everyday experience that
the pain we feel depends not only on the strength of the
peripheral painful stimulus (such as dental drilling) but
A Neuron Integrates Information from Many Others
also on our state of mind. Although the main task of
We have seen that as a rule many impulses must reach a the neuron is to convey sensory information to the
neuron almost simultaneously to make it fire, that is, to brain, this information is integrated in the spinal cord
send an action potential through its axon. In other words, with signals from other sources conveying information
summation of excitatory synaptic effects is necessary. the salience of the sensory information.
laboratory cages. Further, the density of spines in the
The Placement of Synapses Has Functional Signicance
cerebral cortex is markedly reduced in individuals with
Where a synapse is located on the neuronal surface is severe mental retardation. Animal experiments with
obviously not a matter of chance (Fig. 1.8). There are electric stimulation indicate that long-term increases in
several examples of axons arising from different cell synaptic efficacy (long-term potentiation, LTP) are
groups that end on different parts: for example, some associated with changes of spine morphology and num-
end only on proximal dendrites, others on distal den- ber. This effect is observed only among synapses
drites or a particular segment of the dendrite. Further, affected by the increased stimulation and may be
inhibitory synapses are often located on or near the directly related to learning and memory.
soma of the nerve cell, whereas excitatory ones are most An important function of spines may be to facilitate
abundant on dendrites. The placement can be of func- local synaptic changes. The narrow neck of the spines
tional importance, because synapses close to the initial may ensure that the concentration of signal molecules
2+
segment of the axon would be expected to have a greater responsible for LTP induction, such as Ca , reach much
chance of eliciting (or preventing) an action potential higher levels in the spine head than in the dendrite. This
than synapses far out on the dendrites. (This is due to would facilitate changes in those synapses contacting a
3
the loss of current during electrotonic spread of the syn- particular spine, leaving other synapses unaffected.
2+
aptic potential over long distances.) In some neurons, Spatial restriction of increased Ca concentration may
powerful inhibitory synapses are even located on the also serve a protective role since high intracellular Ca2+
initial segment itself, thereby forming a very efficient concentration may damage the neuron.
brake on neuronal firing.
In general, a synapse far out on a dendrite would be
Axoaxonic Synapses Enable Presynaptic Control of
expected to exert a weaker effect on the excitability of
Transmitter Release
the neuron than one placed close to the soma, and, con-
sequently, that more summation would be needed for In axoaxonic synapses, the presynaptic bouton makes
distal synapses than for proximal ones to fire the neu- synaptic contact with a postsynaptic bouton, which, in
ron. New findings suggest that this may not always turn, contacts a cell body or a dendrite (Fig. 4.7).
hold true, however. Studies of pyramidal neurons (in Release of transmitter from the presynaptic bouton
the hippocampus) indicate that an EPSP recorded in the serves to regulate the amount of transmitter released by
soma is of about equal magnitude regardless of whether the postsynaptic bouton. This enables inhibition or
it is evoked by a synapse that is proximal or distal on a facilitation of a subset of synaptic inputs to a neuron.
dendrite. This means that a stronger depolarizing action The excitability of the postsynaptic neuron is unaltered,
at distal synapses compensates for their greater loss of in contrast to the situation described above with post-
current by electrotonic spread. synaptic inhibition by IPSPs.
Another important point regarding the placement of In the best-studied kind of axoaxonic contacts, action
synapses is that most excitatory synapses are located on potentials in the presynaptic bouton lead to reduced
dendritic spines (Figs. 1.1, 1.7, and 1.9). Most of the transmitter release from the postsynaptic bouton; that
neurons in the cerebral cortex conform to this arrange- is, the effect is inhibitory with regard to the neuron con-
ment. Because cortical neurons constitute a large pro- tacted by the postsynaptic bouton (the postsynaptic
portion of all neurons in the human brain, suggestions bouton usually has an excitatory action). A prerequisite
that about 90% of all excitatory synapses are located for this inhibitory effect to occur, however, is that
on spines may be realistic. the presynaptic bouton be depolarized (by an action
potential) at the same time as or immediately before an
action potential reaches the postsynaptic bouton. This
Spines: Crucial for Learning?
phenomenon is termed presynaptic inhibition to distin-
The functional significance of dendritic spines is still guish it from postsynaptic inhibition. Presynaptic inhi-
under debate. It is not simply a matter of increasing the bition has been found most frequently among fiber
receiving surface of the neuron because the dendritic systems that transmit sensory information; for example,
membrane between spines may be virtually free of syn- sensory fibers entering the spinal cord are subject to
apses. A spine typically consists of a narrow neck and
an expanded part called the spine head (see Fig. 1.9).
Since their microscopic identification more than 100 3 Indeed, experiments performed in slices of tissue from the hippocampus
(a region involved in learning and memory)enabling stimulation of single
years ago, spines have been implicated in learning and axospinous synapsessuggest that enduring changes (LTP) may be limited to
memory, and recent animal experiments support this the stimulated synapse. However, it seems that nearby synapses (1020 syn-
hypothesis. For example, the density of spines in the apses within a distance of 10 m along the dendrite) have lowered thresholds
for induction of LTP for some minutes after the stimulation. Such crosstalk
cerebral cortex is higher in rats that live in a challenging among nearby synapses is presumably caused by dendritic spread of a diffusible
environment than in those that are confined to standard substance produced in the stimulated spine.
Postsynaptic when chloride channels open. But how can depolariza-

nerve terminal
Sensory nerve tion of the presynaptic terminal reduce transmitter
Glutamate Cl fiber release? The answer seems to be that depolarization
Spine Cl transporter reduces the amplitude of action potentials as they
invade the postsynaptic terminal; in turn, this leads to
opening of fewer voltage-gated calcium channels.
Because the amount of transmitter released is propor-
2+
GABA receptor
tional to the influx of Ca , less transmitter will be
Cl
GABA
released. It remains to be explained why depolarization
of the postsynaptic terminal reduces the amplitude of
Presynaptic the action potential. The most likely explanation is that
nerve terminal depolarization inactivates some voltage-gated sodium
Glutamate receptor channels in the postsynaptic terminal. In addition,
2+
direct influence on Ca channels by the transmitter
released from the presynaptic terminal may also con-
mV tribute to presynaptic inhibition.
35 Presynaptic facilitation can be elicited by axoaxonic
60 synapses by increasing Ca2+ influx in the postsynaptic
bouton. Closure of K+ channels by the presynaptic
50 100 msec transmitter prolongs the action potential by slowing the
repolarization phase, thereby allowing more Ca2+ to
gure 4.7 Presynaptic inhibition is mediated by axoaxonic synapses. enter the postsynaptic bouton.
The example is from the spinal cord where an inhibitory interneuron
contacts the terminal of a sensory nerve ber (from a spinal ganglion
cell). The interneuron releases GABA that opens Cl channels and Why Do We Need Inhibitory Synapses?
thereby depolarizes the postsynaptic nerve terminal (frame). This
leads to release of less transmitter. See text for further explanations. Inhibitory synapses are present everywhere in the CNS
(Based on Alvarez 1998.) and are of vital importance for its proper functioning.
For example, inhibition is necessary to suppress irrele-
vant sensory information, thereby enabling us to con-
centrate on certain events and leave others out. Inhibitory
powerful presynaptic inhibition. In this way, signals to synapses also serve to increase the precision of sensory
a sensory neuron from pain receptors can be selectively information by, for example, enhancing contrast
inhibited, while signals from other receptors are passed between regions with different light intensity in visual
on unaltered. images.
Inhibition is also necessary for another reason
namely, to interrupt or dampen excitation, which might
Mechanisms of Presynaptic Inhibition and Facilitation
otherwise lead to cell damage. As mentioned earlier,
Several mechanisms may be involved in presynaptic ions have to be pumped through the cell membrane
inhibition. The phenomenon has been most studied in in order to maintain osmotic equilibrium. If many neu-
the spinal cord dorsal horn, where axoaxonic synapses rons fire continuously with high frequency, even maxi-
are formed by inhibitory interneurons as they contact mal pumping may be insufficient in this respect.
terminals of primary sensory afferents (Fig. 4.7). The Increased extracellular potassium concentration depo-
transmitter released from the interneuron (usually larizes neurons, thereby increasing further the neuronal
GABA) opens chloride channels in the postsynaptic ter- excitation; this leads to more potassium extracellularly,
minal (bouton). In most neurons, opening of chloride and so on. Epileptic seizures are due to uncontrolled
channels either hyperpolarizes or short-circuits the firing of groups of neurons, and drugs reducing the ten-
membrane, as described. In the sensory terminals in dency for seizures generally increase the effect of inhib-
the cord, however, opening of chloride channels itory transmitters. Figure 4.8 shows how an excitatory
depolarizes the membrane, due to an unusually high neuron can limit its firing by way of an inhibitory
intracellular chloride concentration. (To uphold this interneuron. Although not shown in the figure, the
concentration gradient, these sensory neurons are interneuron is influenced by many other neurons that
equipped with a special transport mechanism for chlo- serve to adjust the brake, as it were. Such arrangements
ride coupled to the sodiumpotassium pump). In this are common, for example, among the motor neurons
way, the equilibrium potential of Cl is more positive that control muscle contractions (see Fig. 21.14). In
(30 mV) than the resting potential (65 mV) and, con- general, inhibitory interneurons increase the flexibility
sequently, chloride ions move out of the nerve terminal of the nervous system.
that for a shorter or longer period, the postsynaptic
A action may be enhanced or reduced, as evidenced by
+
altered amplitude of the postsynaptic potentials.
_ Further, much experimental evidence supports the
hypothesis that synaptic plasticity is the cellular basis of
learning and memory. Martin, Grimwood, and Morris
B +
(2000, p. 650) express the hypothesis as follows:
Activity-dependent synaptic plasticity is induced at
appropriate synapses during memory formation, and is
gure 4.8 Inhibitory interneuron (B) mediating negative feedback both necessary and sufficient for the information stor-
to the projection neuron (A). Arrows show the direction of impulse
age underlying the type of memory mediated by the
conduction.
brain area in which that plasticity is observed. When
we learn, most likely numerous synapses change their
efficacy within distributed neural networks; when we
Signaling by Disinhibition
later can recall what we learned, it must mean that syn-
In some instances, inhibitory synaptic couplings may aptic changes have been retained. When we forget, one
lead to increased rather than decreased excitation. This reason may be the decay of learning-related synaptic
occurs when inhibitory neurons inhibit other inhibitory changes. Obviously, the most difficult part of the
neurons that in their turn act on excitatory ones hypothesis to prove is a causal relationship between spe-
(Fig. 4.9). With such an arrangement, firing of the first cific synaptic changes and memory in behavioral terms.
inhibitory interneuron (green) inhibits the next inhibi-
tory interneuron, which thereby reduces its activity.
Under Which Conditions do Synaptic Changes Occur?
Thereby, the excitatory neuron (red) receives less inhi-
bition and increases its firing. This is called disinhibi- Only a minute fraction of all the information reaching
tion, and it plays an important role in diverse structures the brain is retained in memory, and correspondingly,
such as the retina and the basal ganglia (Fig. 23.14). use of a synapse does not always change its subsequent
If an inhibitory interneuron contacts both excitatory behavior. To induce a change, the presynaptic influ-
and inhibitory neurons, it might produce both inhibi- ences must conform to certain patterns. In general,
tion and disinhibition at the same time in different neu- plastic changes are likely to occur when the presynaptic
rons. By controlling the firing of such interneurons, activity is particularly strong and coincide in time with
4
central command centerssuch as the motor cortex the postsynaptic neuron firing an action potential. This
can direct the signals in the desired direction. This makes sense, as the immediate firing of an action poten-
occurs, for example, in the spinal cord where inhibitory tial after a synaptic input might be regarded as a sign of
interneurons serve to select the muscles that are best success. This situation is likely to arise only when sev-
suited for a particular task. eral excitatory synaptic inputs reach the neuron at the
same time. Looking for the functional meaning of
simultaneous inputs, a crucial point may be the ability
SYNAPTIC PLASTICITY
of neurons to detect coincidences. For example, a sen-
sory input is significant only in a certain context, and
Basis of Learning and Memory?
only then should it be remembered. Accordingly, syn-
There is much evidence that synapses can alter their aptic changes would occur only when information
structure and function in an activity-dependent or use- about the sensory event and its context coincide.
dependent manner: that is, they are plastic. This means However, contextual information should lead to synap-
tic change only if it signals that the sensory stimulus is
important or unexpected. Indeed, in many situations, it
appears that synaptic change depends on the coinci-
dence of a specific input mediated by activation of
ionotropic receptors and a modulatory input mediated
_ _ + by metabotropic receptors (Fig. 4.10). The first input
provides fast and precise informationfor example,
4 This was postulated by the Canadian psychologist Donald Hebb in 1949

(p. 62) in an inuential attempt to explain the cellular basis of learning: when
an axon of cell A is near enough to excite a cell B and repeatedly or persistently
takes part in ring it, some growth process or metabolic change takes place
gure 4.9 Disinhibition. Two inhibitory neurons (green) coupled in in one or both cells such that As efciency, as one of the cells ring B, is
series increases the activity of an excitatory neuron (red). increased.
Precise information about Modulating information about correlated with altered synaptic efficacy. Further,
what, where, and motivation, attention, the formation of new synapses (synaptogenesis) and
when emotions elimination of old ones is very prominent during
Transmitters: Transmitters: pre- and postnatal development but occur throughout
Glutamate (excitatory) Norepinephrine, dopamine,
GABA (inhibitory) acetylcholine, serotonin,
adult life.
and others Enduring changes in neuronsat either a molecular
or a structural levelrequire altered protein synthesis.5
Proteins have a restricted lifetime, however, and long-
term change would therefore require long-term (in
many instances life-long) alteration of gene expression.
We now have much evidence that even synaptic activity
lasting for minutes or less may produce altered expres-
sion of certain genes that encode for transcription
factors (see Chapter 3, under Markers of Neuronal
Activity). The experimental evidence so far mainly
concerns transitory changes of gene expression; never-
theless, a number of genes have been shown to alter
their expression in long-term synaptic changes.
Although the complex signaling pathways that link
gure 4.10 Synaptic plasticity. Learningthat is, synaptic change neuronal activity to gene expression are thus starting to
depends in this example on simultaneous action of a specic synaptic be revealed, many questions remain. It is not clear,
input and a modulatory one. The latter provides a signal about the
for example, how the altered gene expression can
salience of the specic stimulus.
be directed to certain synapses (those subjected to a
memorable input) and not to others.
about the nature of a sensory stimulusthe other about

Kinds of Synaptic Plasticity
the salience of the stimulus.
Several kinds of synaptic plasticity have been described
on the basis of animal experiments, and more are prob-
Mechanisms for Synaptic Plasticity
ably yet to be discovered. It is customary to distinguish
Broadly speaking, a change of synaptic efficacy may between short-term and long-term synaptic plasticity,
arise because: without a sharp transition. Short-term plasticity lasts
from less than a second to some minutes, whereas long-
The presynaptic terminal releases more or less neu-
term plasticity can last for at least several weeks. For
rotransmitter in response to an action potential.
practical reasons it is not feasible to study the phenom-
The postsynaptic neuron has increased or reduced
enon for longer periods in experimental animals.
its response to the transmitter.
Nevertheless, if synaptic plasticity underlies memories,
We have discussed the complex cellular processes that we know from our own experience that some synaptic
link an action potential to transmitter release (see, e.g., changes must last for a lifetime.
Figs. 4.1 and 4.2), and many of the factors involved The ability of synapses to express plastic changes is
have been shown experimentally to change their activ- subject to regulation by various signal substances. This
ity in a use-dependent manner. For example, there may phenomenon is called metaplasticity. Generally, meta-
be changes in the amount and activity of intracellular plasticity may serve homeostatic purposes, by keeping
second messengers and protein kinases (among other plastic changes within certain limits. However, plastic-
things, regulating ion channels and receptor proteins). ity may probably also be up- or down-regulated by
The properties, number, and distribution of transmitter environmental challenges (enriched environment,
receptors are also subject to activity-dependent modifi- stress), and in neurological diseases (e.g., Alzheimers
cations. Nevertheless, in spite of the large number of disease, stroke, and Parkinsons disease).
molecular mechanisms involved in induction and
maintenance of synaptic plasticity, increased intrac-
ellular calcium concentration appears as a rule to
initiate the process. The further pathways from a cal-
cium signal to altered synaptic efficacy are multifari- 5 Brain-derived neurotrophic factor (BDNF) is an example of a growth factor
ous and only partly known. With regard to structural that appears to be instrumental for induction of certain forms of long-term
synaptic plasticity. Interestingly, BDNF plays a role in many brain processes in
correlates of synaptic plasticity, we mentioned above which synaptic plasticity plays a prominent role (from brain development to
that spines undergo changes of size and form that are mental diseases).
or two inputs that are out of phase induces LTD.
Short-Term Plasticity
It seems reasonable that intense activity and synchroni-
When action potentials reach the nerve terminal at zation of specific inputs strengthens connections within
relatively brief intervals, the amplitude of the ensuing a network, whereas low activity or desynchronized
postsynaptic potentials often increases gradually. This inputs reduce strength of connectivitythe latter being
phenomenon is called facilitation and is due to increased interpreted as noise rather than meaningful informa-
transmitter release by each presynaptic action poten- tion. Further, it appears that LTP is induced if a presyn-
tial. The postsynaptic effect increases for each action aptic action potential repeatedly precedes firing of the
potential until reaching a steady state after about 1 sec postsynaptic cell, whereas LTD occurs if the postsynap-
and then decays rapidly when stimulation stops. tic firing precedes the presynaptic action potential. In
Further, at some synapses a series of presynaptic action this way, inputs that cause postsynaptic firing (that is,
potentials produce increased synaptic efficacy for min- successful ones) are strengthened, whereas inputs that
utes after the stimulation ends. This is called (synaptic) do not contribute to postsynaptic firing are weakened.
potentiation, and like facilitation, it is due to increased It may seem paradoxical that the opposite phenomena
transmitter release from the nerve terminal. Potentiation LTP and LTDare both induced by an increase in
2+
can be particularly strong and long lasting after tetanic intracellular Ca . There is evidence, however, that
stimulation (action potentials with maximal frequency). intracellular responses to calcium transients can vary
This is called posttetanic potentiation. The presynaptic depending on their magnitude, time course, and site of
terminal remembers that it recently received unusu- origin.
ally intense stimulation and alters its behavior accord-
ingly. Facilitation and posttetanic potentiation are
Silent Synapses
examples of short-term plasticity that are important
for the nervous systems capacity for storage of infor- It might seem unlikely that the brain contains a large
mation. Short-term depressionthat is, a weaker post- number of synapses that are not in use. Nevertheless,
synaptic response with repeated presynaptic action there is now strong evidence that some synapses do not
potentialsis probably due to insufficient renewal of transmit a signal, even though the nerve terminal is
the releasable synaptic pool (Fig. 4.2). invaded by action potentials (this is mainly studied in
Long-Term Plasticity: LTP and LTD

Long-term plasticity means changes of synaptic efficacy
lasting for hours to weeks (years). Long-term potentia- Nerve terminal
tion (LTP) and long-term depression (LTD) can some-
what arbitrarily be defined as activity-dependent
increases or decreases of synaptic efficacy that lasts for
more than 1 hour. Presumably, LTP and LTD represent AMPA
storage of information that is in some way meaningful receptor
to the individual (or interpreted as such). With these
forms of long-term plasticity, cellular changes occur NMDA Ca2+
receptor
presynaptically and postsynaptically (not only presyn-
aptically, as do facilitation and posttetanic potentia- Myosin
tion). Different forms of both LTP and LTD have been Spine
e
Actin filament
described; they differ with regard to duration, the kind
of activity that induces them, and molecular mecha-
nisms. One important mechanism seems to be the inser- Dendrite
tion of new receptors in the postsynaptic membranes,
which increases the receptor density and the effect of AMPA
each quanta of transmitter released from the presynap- receptor
tic terminal (see Silent Synapses later). Regardless of
Recycling
molecular mechanisms involved in the expression of endosome
LTP and LTD, the end results are input-specific altera-
tions of synaptic efficacy (see also Chapter 32, under gure 4.11 Getting silent synapses to speak up. Activation of
LTP and Memories). NMDA receptors leads to rapid inux of Ca2+ ions into the spine.
This induces transport of so-called recycling endosomescontaining
LTP and LTD are evoked by different patterns of AMPA receptorsfrom the dendrite to the spine head. The transport
synaptic inputs. Whereas high-frequency firing or two depends on interaction between actin laments and a special form of
simultaneous inputs induces LTP, low-frequency firing myosin molecules in the spine shaft.
the cord and the hippocampus). This is not just a case are silent because normal presynaptic glutamate
of low release probability, because even repeated pre- release does not activate them. This is because the open-
synaptic firing is without effect (the probability that a ing of NMDA receptors requires a certain magnitude of
presynaptic action potential releases the content of a depolarization in addition to binding of glutamate. If
synaptic vesicle varies enormously in the CNS). Further, NMDA receptors are opened by particularly strong
in some areas stimulation of an axon evokes a weaker depolarization of the postsynaptic membrane, however,
response than expected from the number of terminals. this may, in turn, lead to the insertion of AMPA recep-
The reason for synapses being silent can be lack of tors in the postsynaptic membrane (Fig. 4.11). The
either transmitter release or a postsynaptic response to receptors are transported rapidly from endosomes to
the transmitter (due to lack of receptors or that the the postsynaptic density, as shown with fluorescence
receptors are blocked). There is evidence of both mech- labeling methods. Afterward, the synapse is no longer
anisms. For example, some glutamatergic synapses silent but speaks up when glutamate is released. In
in the hippocampus lack the ionotropic amino- many instances, LTP may be caused by silent synapses
methylisoxazole-propionic acid (AMPA) receptors, being activated by insertion of AMPA receptors. The
while expressing voltage-dependent N-methyl-D-aspartate finding that silent synapses appear to be most numer-
(NMDA) receptors (these are further described in ous shortly after birth (in rats) supports their possible
Chapter 5, under Glutamate Receptors). Such synapses role in learning and memory.
5 Neurotransmitters and Their Receptors
OVERVIEW whereas the NMDA receptors have properties that

make them especially suited to detect coincidences and
Certain general properties of neurotransmitters were induce long-term potentiation (LTP). GABA acts on
outlined in the preceding chapters. We recall that a sig- ionotropic GABAA receptors and metabotropic GABAB
nal is conveyed from one neuron to the next by release receptors.
of a neurotransmitter (transmitter). Conventional or Acetylcholine is used as transmitter by a limited num-
classical neurotransmitters are small molecules, such ber of neurons in the brain stem and basal forebrain,
as amino acids and amines. Another important group while axonal ramifications of the neurons occur in most
of signal substances, released at synapses, are peptide parts of the brain. Acetylcholine acts on ionotropic nic-
molecules, called neuropeptides. Although the typi- otinic receptors and metabotropic muscarinic receptors.
cal transmitter is released and acts at receptors in a The latter type dominates in the CNS, and the actions
synapse, many transmitter receptors are found extra- of acetylcholine are especially related to motivation,
synaptically, that is, without connection to a synapse. sleepwakefulness, and memory. The group of biogenic
Indeed, many transmitters act both at synapses and amines includes the monoamines dopamine, norepi-
extrasynaptically. The latter action is called volume nephrine (epinephrine), and serotonin (and in addition
transmission, and is obviously less precise than synaptic histamine). Like acetylcholine, these transmitters are
transmission. Many receptors are located presynapti- produced in a small number of neurons but neverthe-
cally on nerve terminals. Some of them are autorecep- less act in most parts of the brain. They bind mostly to
tors (binding the transmitter released from the terminal), metabotropic receptors, with actions related to arousal,
and others are heteroreceptors (binding other transmit- mood (emotions), and synaptic plasticity. In general,
ters released from neurons in the vicinity). Many nerve acetylcholine and the biogenic amines have modulatory
terminals contain more than one transmitter; often a actions that serve to regulate the excitability of neu-
classical transmitter is colocalized with one or more rons, thus determining the magnitude of response to
neuropeptides. fast-acting transmitters such as glutamate and GABA.
Synthesis of a transmitter usually depends on the Adenosine triphosphate (ATP) and nitric oxide (NO)
activity of a key enzyme, which controls the amount function as signal substances with transmitter-like
of transmitter available at a synapse. Transmitter actions in the CNS.
receptors far outnumber the transmitters; thus each A large number of neuropeptides have modulatory
transmitter usually acts on several ionotropic and and metabolic actions in the brain, and influence a
metabotropic receptors. The effects of a transmitter on variety of processes, from basic homeostasis to complex
a certain neuron therefore depend on which receptors behaviors.
the neuron expresses. Both the amount of transmitter
available for release and the postsynaptic receptors are
subject to use-dependent plasticity.
GENERAL ASPECTS
The most important amino acid transmitters are
glutamate and -aminobutyric acid (GABA). Both are
How to Prove that a Substance Functions as a
present in virtually all parts of the central nervous sys-
Neurotransmitter
tem (CNS), and are responsible for most of the fast and
precise synaptic transmission, by acting on ionotropic Many signal substances present in the brain are small
receptors. Glutamate is the dominant excitatory trans- molecules, including the amino acids glutamate,
mitter, whereas GABA is inhibitory. These transmitters glycine, and GABA, and the amines norepinephrine,
mediate most of the spatially and temporally precise dopamine, serotonin, and histamine. Acetylcholine and
excitation and inhibition needed for perception, move- ATP also belong to this group. Other signal substances
ments, and cognition. Glutamate binds to three families are peptides and therefore fairly large. Such neuropep-
of receptors (amino-methylisoxazole propionic acid tides are chains of 5 to 30 amino acids. In general, the
[AMPA], N-methyl-D-aspartate [NMDA], and meta- functions of the neuropeptides are far less clarified than
botropic glutamate receptors). The AMPA receptors are those of the small-molecule transmitters. To prove that
typical ionotropic receptors with fast excitatory action, a substance present in a neuron actually functions as a
53
neurotransmitter is not easy. It is not sufficient that potentially interesting substance present in nervous
neurons express specific binding sites for a substance; tissue, antibodies may be raised against it. The antibod-
hormones, growth factors, and other molecules also ies bind antigens where they are exposed in the tissue
bind to neuronal membrane receptors. Neither are there sections, and the antibodies can be visualized subse-
clear-cut chemical differences between neurotransmit- quently with the use of secondary antibodies. The sec-
ters and other intercellular signal molecules. Indeed, the ondary antibodies may be labeled with a fluorescent
same molecule may function in several roles; for exam- molecule, or they may be identified in other ways. Such
ple, norepinephrine is both a neurotransmitter and a methods have been widely used to demonstrate the
hormone. Further, some moleculessuch as glutamate localization of enzymes that are critical for synthesis or
and glycineare intercellular signal molecules and have degradation of certain transmitters, such as tyrosine
a role in cellular metabolism (e.g., as building blocks hydroxylase, which is necessary for the synthesis of
for proteins). dopamine and norepinephrine (Fig. 5.1A), choline
To prove that a substance functions as a signal mol- acetyltransferase (ChAT) for synthesis of acetylcholine
ecule, one must show the presence of corresponding (Fig. 5.1B), and glutamic acid decarboxylase (GAD) for
receptors and that the substance is released in sufficient GABA. Even transmitter molecules that are themselves
amounts (under physiological conditions) to activate too small to serve as antigens can be specifically identi-
the receptors. Additional criteria must be met to clas- fied in tissue sections via immunocytochemical methods
sify such a signal substance as a neurotransmitter, how- when conjugated to tissue proteins (with glutaralde-
ever. The substance must be produced by neurons, it hyde). This is the case for GABA (Fig. 5.1C), glutamate,
must be stored in nerve terminals and released by depo- and glycine. Immunocytochemical methods can also be
larization, and the release must be calcium dependent. applied to ultrastructural analysis, in order to deter-
In addition, the released substance must be directly mine the transmitter accumulated at specific synapses
responsible for the postsynaptic changes. Finally, there and also whether the transmitter is localized to certain
must exist mechanisms for inactivation of the transmit- organelles, such as presynaptic vesicles (Fig. 5.2).
ter after release. Only a few signal substances have met Combination of axonal transport methods and immuno-
all of these criteria when tested experimentally. For cytochemical procedures makes it possible to determine
several others, the probability that they function as the connections, as well as the transmitter candidates
transmitters is nevertheless high, and they are often and other neuroactive substances of specific neuronal
described as transmitters without reservation. Strictly groups.
speaking, however, they should be termed transmitter Even though the determination of the transmitter
candidates or putative transmitters. Acetylcholine candidates present in a neuron is of great importance, it
was the first substance to be classified with certainty as is not always possible to know whether the substance
a transmitter. The excitatory action of glutamate was has been synthesized in the cell or whether it has merely
discovered in the 1950s, but only toward 1990 was the been taken up. Further, the concentration of a transmit-
neurotransmitter status of this ubiquitous amino acid ter in parts of a neuron may be so low that it cannot be
verified. reliably detected with immunocytochemical methods.
The use of in situ hybridization techniques helps to
overcome this kind of problem. By these methods, it is
Determination of Neuronal Content of
not the neuropeptides or enzymes related to transmitter
Neurotransmitters and Distribution of Receptors
metabolism that are demonstrated but the presence of
With biochemical methods, the content of transmitters the corresponding mRNA.
in parts of the brain and in subcellular fractions can be
determined. To obtain further knowledge, however, it
Volume Transmission: Extrasynaptic Transmitter
is also necessary to link the transmitters to specific neu-
Release and Actions
rons with known connections and physiological prop-
erties. The first possibilities of studying the anatomy of A neurotransmitter (transmitter) is usually defined as a
neurons with known transmitters arose in the 1960s, chemical substance that is released at a synapse and
when it was discovered that monoamine-containing transmits a signal from one neuron to another (or to
neurons could be made fluorescent by a special treat- muscle cells or glandular cells). However, not all sub-
ment with formaldehyde. This marked the beginning of stances, otherwise behaving as neurotransmitters, are
intense investigations, with other methods as well, to released at synapses (Fig. 5.3). In some places, neu-
characterize neurons with regard to connections and at rotransmitters are released from axonal varicosities
the same time with regard to their transmitters. The that do not form synapses. Further, many transmitter
introduction of immunological methods, such as immu- receptors are present extrasynapticallythat is, in
nocytochemistry, to localize substances in nervous the neuronal membrane outside synapses (Fig. 5.3).
tissue has been of particular importance. By purifying a Therefore, some neurotransmitters act both at typical
5: NEUROTRANSMITTERS AND THEIR RECEPTORS 55
A B C
Tyrosine hydroxylase Choline acetyltransferase GABA

(Dopamine) (Acetylcholine)
gure 5.1 Immunocytochemical demonstrations of neurotransmitters. neurons (basal nucleus) are visualized with an antibody against the
A: Dopaminergic neurons (substantia nigra) are visualized with an enzyme choline acetyltransferase C: GABAergic neurons are visual-
antibody against the enzyme tyrosine hydroxylase, which is involved ized with an antibody that binds to a GABAprotein complex in the
in the synthesis of dopamine (Fig. 5.7). Neurons in between the black, section. The brown cell bodies, showing GABA-like immunoreactiv-
labeled onesnot containing the enzymeare not visible. Note that ity, are interneurons in a brain stem nucleus (monkey). The small
the method does not demonstrate the transmitter itself. B: Cholinergic brown dots are partly dendrites, partly axons and nerve terminals.
synapses and more diffusely like local hormonesthat

is, on all receptors with the proper specificity within a
certain distance from its release site. The distance
depends on how quickly the transmitter is inactivated
and how easily it diffuses. It appears that the effective
distance is in the range of a few micrometers from the
release site. We use the term volume transmission to
b distinguish this kind of transmitter action from the spa-
tially precise action at synapses. The narrow definition
of transmitters, focusing on their actions at synapses,
fits well for transmitters such as glutamate and GABA
b with spatially and temporally precise actions. Other
transmitters with mainly modulatory actions, such as
norepinephrine, dopamine, and serotonin, act also by
volume transmission. These different forms of trans-
mitter actions complicate the analysis of how neu-
rotransmitters control neurons and human behavior.
Mf b
Colocalization of Transmitters
gure 5.2 Electron microscopic, immunocytochemical demonstration
of neurotransmitters. The small black dots represent gold particles
It was formerly assumed that each neuron releases only
bound in the tissue where GABA is present. The gold particles are one transmitter. Recent studies have shown, however,
conjugated to an antibody directed against a GABAprotein com- that nerve terminals often contain more than one trans-
plex. The gold particles are concentrated over a particular kind of mitter. Such colocalization of transmitters appears to
bouton (b), whereas dendrites (d) and part of a cell body (Gr) are not be the rule rather than an exception. In most cases
labeled. Another kind of nerve terminal (Mf) is also unlabeled and
most likely contains a neurotransmitter other than GABA. Rat cere-
described so far, a small-molecule, classical transmit-
bellum. (Courtesy of Prof. O. P. Ottersen, Department of Anatomy, ter is colocalized with one or several neuropeptides.
University of Oslo.) In such cases, the terminal can evoke both fast synaptic
Autoreceptor
Nerve terminal Glia
Axon
Nerve terminal
Soma Autoreceptor
Spine
Varicosities
gure 5.3 Extrasynaptic receptors and trans-
mitter release outside synapses. Extrasynaptic
receptors are localized both at the nerve termi-
Presynaptic Postsynaptic nals and on the somatic and dendritic surfaces
receptors receptors
of the neuron. Autoreceptors bind the transmit-
ter released by the neuron itself. Note the release
Extrasynaptic of transmitter from varicosities that do not
receptors form typical synaptic contacts.
actions mediated by ionotropic receptors and slow of the receptor site has been determined. After cloning
effects mediated by metabotropic receptors. of the protein, one can then determine whether it binds
Colocalization of two classical transmitters such as the transmitter (and agonists and antagonists) and pro-
GABA and glycineboth acting on ionotropic recep- duces the expected physiological effects.
torshas also been reported. GABA and glycine are As discussed in Chapter 3 (under The Structure of
both inhibitory, and it seems reasonable that colocal- Ion Channels), all the directly acting, ionotropic,
ized transmitters exert similar postsynaptic actions. receptorsbeing part of ion channel proteinsare sim-
Even this may not be universally true, however. For ilarly built, with several subunits arranged around a
example, certain spinal interneurons and neurons in the central pore (see Fig. 3.2). In addition, the indirectly
hypothalamus release ATP (excitatory) together with acting, metabotropic receptors share several structural
GABA (inhibitory); this means that both act on iono- features, although they are quite different from the ion-
tropic receptors but apparently with opposite effects. otropic receptors. The metabotropic receptors usually
The widespread occurrence of colocalization compli- consist of one large protein that makes several turns
cates the interpretation of one particular transmitters through the membrane with hydrophilic (water-soluble)
contribution to synaptic effects, and accordingly, its groups on the interior and exterior of the membrane.
contribution to certain behaviors. Hypotheses about The receptors mediate their effects via G proteins (see
neural functions and disease symptoms have often been Fig. 4.2). Several receptor types with different postsyn-
based on the erroneous belief that a particular neuronal aptic actions have been identified for each of the
group or fiber system uses only one transmitter (the one best-known transmitters.
that was first discovered). The most abundant transmitters, such as glutamate
and GABA, act on both ionotropic and metabotropic
receptors. The link between a neurotransmitter and its
Transmitter Receptors in General
actions is made even more complex by the existence of
The many transmitters and transmitter candidates subtypes of each main kind of receptor. Subtypes of the
(more than 50, including the neuropeptides) have an ionotropic (directly acting) GABA receptor (GABAA)
even larger variety of receptor types to act on. More exemplify this. Each of the protein subunits forming the
than 200 different metabotropic (G proteincoupled) receptor (and the ion channel) comes in several variet-
receptors have been identified in the CNS. (Not all bind ies, and different combinations of them produce numer-
neurotransmitters, however; many bind hormones and ous subtypes of the GABAA receptor. These subtypes
a variety of growth factors.) are differently distributed in the brain. This may explain
Several requirements have to be met to conclude that why drugs acting on different subtypes of the GABAA
a binding site for a transmitter functions as a receptor. receptor have different physiological and behavioral
The final proof requires that the amino-acid sequence effects: they act on different neuronal networks.
that the functional roles of presynaptic receptors are
Regulation of Receptor Density
not fully understood.
The transmitter receptors are not static, immutable
elements of the nervous system. We have discussed
Synthesis of Neurotransmitters
how changes in receptor density and activity may medi-
ate synaptic plasticity. This means that learning The small-molecule, classical neurotransmitters
would be expected to be associated with receptor (Table 5.1) are synthesized in the nerve terminals, the
changes. In animal experiments, for example, stressful synthesis being catalyzed by enzymes transported
psychological experiences leading to altered behavior axonally from the cell body. As a rule, the rate of trans-
also alter the activity of specific transmitter receptors. mitter synthesis is determined by the activity of one key
Drugs that interfere with transmitter actions often enzyme. Up- or down-regulation of the enzymatic activ-
induce changes in the receptors. A drug that blocks the ity represents one way of changing the properties of
effect of a transmitter on a particular receptor type nerve cellswith regard to learning, for example.
(antagonist) may indirectly produce increased postsyn- Activation of enzymes often requires that they be phos-
aptic receptor density. The reverse may occur with phorylated, and this may be a result of external stimuli
drugs that mimic the transmitter (agonist). Probably that, via membrane receptors, induce increased intrac-
such up- or down-regulation of receptors represents an ellular concentration of second messengers (such as
adaptive response: an abnormally high concentration Ca2+ or cyclic AMP).
of the transmitter (or an agonist) is counteracted by As the organelles necessary for protein synthesis are
reduced receptor activity to maintain normal synaptic present almost exclusively in the cell body, the neuro-
transmission. Down-regulation of receptors may peptides must be synthesized in the cell body and subse-
explain many of the dramatic withdrawal symptoms quently transported to the terminals. Accordingly,
that occur when an addicted individual abruptly dis- substances that block axonal transport, such as colchi-
continues a narcotic drug. cine, lead to accumulation of neuropeptides in the cell
body. Usually, the neuropeptides are produced as larger
polypeptides (prepropeptides) that most likely are split
Presynaptic Transmitter Receptors
into smaller units on their way to the terminals.
Transmitter receptors are also localized to the presyn-
aptic membrane and can thereby modulate transmitter
release (Fig. 5.3). We have discussed the axoaxonic syn-
SPECIFIC NEUROTRANSMITTERS
apses that mediate presynaptic inhibition by acting on
receptors in the presynaptic membrane (see Fig. 4.7).
Excitatory Amino Acid Transmitters: Glutamate and
In addition, the presynaptic membrane can express
Aspartate
receptors for the transmitter released by the nerve ter-
minal itself (see Fig. 4.1). Here we use the term autore- The amino acid group contains the ubiquitous excit-
ceptors. Often, autoreceptors inhibit transmitter release atory transmitter, glutamate (Fig. 5.4). Neurons that
as a kind of negative feedback. Some neurons, for release glutamate at their synapses are called gluta-
example, dopaminergic ones, are equipped with autore- matergic. The dominant effect of glutamate in the CNS
ceptors also on the cell body and dendrites. In addition is fast excitation by direct action on ion channels,
to autoreceptors, nerve terminals may express heterore- although it also acts on metabotropic receptors.
ceptors, that is, receptors for transmitters other than Glutamate is responsible for fast and precise signal
those they release themselves (often released by nearby transmission in the majority (all?) of the large sensory
terminals). Nerve terminals releasing norepinephrine and motor tracts, as well as in the numerous connec-
can exemplify the complexity of presynaptic modula- tions between various parts of the cerebral cortex that
tion. Such terminals can express 2 adrenergic autore- form the networks responsible for higher mental func-
ceptors and muscarinic (acetylcholine), opiate, and tions. The total concentration of glutamate in the brain
dopamine receptors that inhibit release of norepineph- is very high, although the distribution is uneven.
rine from the terminal. In addition, the terminals also Notably, effective uptake mechanisms keep the extra-
express 2 adrenergic autoreceptors and nicotinic (ace- cellular concentration very low (about 1/1000 of
tylcholine) receptors that facilitate transmitter release. intracellular concentration). This is a prerequisite for
Thus, the amount of transmitter released by such a glutamates function as a neurotransmitteracting
nerve terminal depends not only on the presynaptic only on specific receptors after controlled release from
activity of the neuron but also on the local milieu of the nerve terminals. Low extracellular concentration is also
terminal (the concentration of various transmitters and mandatory because even a small increase is toxic to the
other signal substances, as well as the presence of drugs neurons. Transporter proteins in astroglial membranes
or toxic substances). It should not come as a surprise maintain the concentration gradient (probably with a
table 5.1 The Best-Known Small-Molecule (Classical) Neurotransmitters
Localization of Neurons
Receptor Name Mechanism, Distribution of Receptors Synthesizing the Transmitter Localization of
Transmitter Chemical Ion Permeability* Synaptic Action in the CNS in the CNS Neurons in the PNS
+
Glutamate Amino acid AMPA, ionotropic, Na Fast, excitation Everywhere Everywhere Spinal ganglion cells
NMDA, ionotropic, Ca2+ Fast, excitation
MGluR1-5, metabotropic Slow, excitation or
inhibition, metabolic
effects

GABA Amino acid GABA ionotropic, Cl Fast, inhibition Everywhere Everywhere Gut, ganglia
GABAB, metabotropic, K+, Ca2+ Slow, inhibition

Glycine Amino acid Ionotropic, Cl Fast, inhibition Brain stem, spinal cord, cerebellum
+
Acetylcholine Quaternary amine Nicotinic, ionotropic, Na Fast, excitation Cerebral cortex, spinal Motoneurons, preganglionic
cord (and other places) autonomic neurons, basal nucleus,
+
Muscarinic, metabotropic K , Slow, excitation or Cerebral cortex, septal nuclei, nuclei in the reticular Parasympathetic
Ca2+ inhibition hippocampus, thalamus formation of the brain stem (and ganglia
(and other places) other places)
Norepinephrine Amine (12), metabotropic Slow Everywhere Locus coeruleus and diffuse cell Sympathetic ganglia
(12), metabotropic Slow groups in the reticular formation
Dopamine Amine D1(D1, D5), metabotropic, Slow Everywhere (especially Mesencephalon (Substantia nigra
increase cyclic AMP basal ganglia and and ventral tegmental area)
D2(D2, D3, D4), metabotropic, Slow pre-frontal cortex)
decrease cyclic AMP
+
Serotonin (5-HT) Amine 5-HT1A, metabotropic, K Slow, inhibition Everywhere Raphe nuclei (brain stem)
5-HT2, metabotropic Slow, excitation
5-HT3, ionotropic, Na+ Fast, excitation
*There are more receptor subtypes than shown here.

The table is not complete regarding distribution of neurons and receptors.
NH2

HOOCCH2 CH2 CHCOOH GLUTAMATE
Gln Gln
Glutaminase Gln
Glutamic acid decarboxylase (GAD)
Glutamine
synthetase
NH2 Glu

HOOCCH2CH2 CH GABA Glu
H (gamma- Glu Glu
amino butyric Glutamate
Glu transporter
acid)
NH2

H2C COOH GLYCINE Glutamate receptor
gure 5.5 The glutamateglutamine circuit. The enzyme glu-

gure 5.4 Amino acid transmitters. The enzyme glutamic acid decar-
tamine synthetase converts glutamate (Glu) to glutamine (Gln) after
boxylase (GAD) is specic for neurons that synthesize GABA.
uptake by glial cells. In contrast to glutamate, glutamine is neutral to
neurons. Glutamine is transferred to nerve terminals where it is used
to synthesize new glutamate that is concentrated in vesicles for
release, and so forth.
smaller contribution from transporters in neuronal
membranes). In situations with poor energy supply,
such as reduced blood flow or low blood sugar, gluta-
mate leaks from the cells because the uptake mecha- circuit is that glutamine, unlike glutamate, does not
nisms fail. The ensuing rise in extracellular glutamate influence neuronal excitability, and is not toxic in high
concentration contributes significantly to the rapid concentrations. Therefore, its concentration need not
occurrence of neuronal damagefor example, in cases be strictly controlled.
of cardiac arrest (see also Chapter 11, under Ischemic
Cell Damage). Glutamate Receptors
The amino acid aspartate is also highly concentrated
in the CNS. It exerts an excitatory action by binding to As mentioned, the dominant action of glutamate in the
glutamate receptors. Although decisive evidence is still CNS is fast excitation by direct binding to ionotropic
lacking, recent studies speak in favor of aspartate being receptors. In the early 1980s, however, additional kinds
a neurotransmitter. For example, aspartate was found of glutamate receptors (GluRs) were found. We now
to be colocalized with glutamate in synaptic vesicles recognize three groups or families of receptors that glu-
and released by exocytosis. Nevertheless, the distribu- tamate can bind to: AMPA/kainate receptors,1 NMDA
tion of possible aspartatergic synapses seems to be receptors, and metabotropic glutamate receptors
very limited in the brain. Therefore, with regard to (mGluRs). The two first groups are glutamate-gated
excitatory synaptic transmission, aspartate must play a ion channels (ionotropic receptors). The metabotropic
minor role compared with glutamate. glutamate receptors are G proteincoupled, like other
metabotropic receptors. The various glutamate recep-
tors were discovered via use of glutamate analogs that
Synthesis of Glutamate turned out to act only on certain kinds of receptors.
Glutamate is synthesized from two sources in the nerve The receptors were named after the analog that acti-
terminals: glucose (via the Krebs cycle) and glutamine vated them selectively (amino-methylisoxazole propi-
that is synthesized in glial cells and thereafter trans- onic acid [AMPA]; N-methyl-D-aspartate [NMDA]).
ported into the neurons (Fig. 5.5). Glutamine is con- Cloning of the receptor proteins in the early 1990s
verted in mitochondria to glutamate by the enzyme showed that AMPA, NMDA, and metabotropic recep-
glutaminase. Specific transport proteins in the vesicle tors belonged to different protein families. To date, 10
membrane fill the synaptic vesicles with glutamate.
Glutamate is released as other transmitters by calcium-
dependent exocytosis. Released glutamate is taken up by 1 Kainate receptors belong to the same family of ionotropic receptors as
AMPA receptors. They have been identied in many parts of the CNS and can
glia and converted to glutamine by the enzyme glutamine be localized both pre- and postsynaptically. The concentration of kainate recep-
synthetase. Glutamine is then transported to nerve ter- tors is low in most areas, and they have not been as extensively studied as AMPA
minals, converted to glutamate, and so forth. Figure 5.5 and NMDA receptors. Their total contribution to fast excitationas compared
to that of AMPA receptorsis therefore still not claried. Kainate receptors are
shows the glutamateglutamine circuit, which ensures expressed in spinal ganglion cells (sensory neurons), and animal experiments
reuse of the transmitter. Another advantage with the suggest that blockage of these receptors may alleviate chronic pain.
varieties of AMPA/kainate receptors, 5 NMDA receptors, metabolic effects that influence various neuronal
2
and 8 metabotropic receptors have been cloned. processesamong them, the induction of LTP and
+
AMPA receptors are ion channels admitting Na (and LTD. As mGluRs are thought to be involved in a sev-
+
K ), which is typical of fast, excitatory synapses. The eral brain diseases (e.g., epilepsy, schizophrenia, and
current view is that AMPA receptors are responsible for stroke), drugs modulating the function mGluRs are
the majority of the fast excitatory signals in the CNS being developed and tested in animal models of human
(mediating, e.g., precise sensory information and motor diseases.
commands).
NMDA receptors have properties that distinguish
NMDA Receptors: Mediators of Both Learning and
them from other ionotropic receptors. They have
Neuronal Damage
attracted much interest due to their role in long-term
potentiation (LTP), and, therefore, most likely in learn- Long-term potentiation (LTP) was described in Chapter 4.
ing and memory. They have a much slower synaptic The transmission at an excitatory synapse can be
action than the AMPA receptors and are engaged in changed for a long time when the synapse is active
other tasks. One important feature of NMDA-gated simultaneously with other excitatory synapses in the
ion channels is that they are much more permeable to vicinity (associative LTP). In many areas in the CNS,
Ca2+ than to Na+ (in contrast to AMPA-gated channels). the induction of LTP depends on activation of NMDA
This makes possible many postsynaptic effects of gluta- receptors, and the NMDA receptors appear to have just
mate binding in addition to depolarization, because the right properties for this task because they require
Ca2+ can trigger a number of intracellular processes both postsynaptic depolarization and glutamate bind-
(e.g., related to synaptic plasticity). Another special ing. (Not all LTP depends on NMDA receptors, how-
feature of NMDA receptors is that they are voltage- ever.) NMDA receptors have binding sites for substances
dependent and remain closed at resting membrane other than glutamate, also. The amino acid glycine
potential. Binding of glutamate (or NMDA) to the (otherwise acting as an inhibitory transmitter) binds to
receptor opens it only if the membrane is already depo- the NMDA receptor, and such binding is necessary for
larizedfor example, by the opening of AMPA recep- glutamate to open the NMDA channel. Other sub-
tors in the vicinity. Depolarization removes Mg2+ ions stances that occur naturally in the brain also influence
that otherwise block the channel. A final characteristic the activity of the NMDA receptors, and thereby pre-
feature is that when the NMDA channel is opened, the sumably determine how plastic many synapses are
flow of Ca2+ through it lasts much longer than an ordi- (metaplasticity). Changes in the concentrations of such
nary EPSP (which is produced by opening the AMPA substances might be relevant for learning and memory
channels). in general and for recovery after brain damage.
Metabotropic glutamate receptors (mGluRs) are The NMDA receptor is also one among several
located both postsynaptically and presynaptically.3 candidates for mediating cell damage after abnormal
They fall into three groups, differing with regard to excitatory activation (see also Chapter 11, under
which intracellular signal pathway they activate. As to Ischemic Cell Damage). This occurs when nervous
postsynaptic effects, it appears that group I mGluRs tissue receives insufficient oxygen (hypoxia), as in
produce a long-lasting depolarization (slow EPSP), severely reduced blood pressure, stroke, cerebral bleed-
whereas group II has the opposite effect (slow IPSP). ing, and so forth. Abnormally intense excitation may
Obviously, the existence of glutamate receptors with also occur during epileptic seizures. In such circum-
inhibitory actions further complicates the analysis of stances, extracellular glutamate concentration rises
glutamate as a transmitter. In addition, mGluRs have steeply and presumably, all kinds of glutamate recep-
tors are activated (see later, Glutamate Transporters).
Activation of NMDA receptors may nevertheless be
2 Glutamate receptors are expressed also in peripheral tissues such as bone especially important because it can lead to a rapid
(osteoblasts and osteoclasts), in taste cells, in some ganglion cells, and in insulin- 2+
producing cells in the pancreas where they modulate insulin secretion. NMDA increase of the intracellular Ca concentration. There
receptors (and other kinds of glutamate receptors) are expressed in the mem- is evidence that increased calcium concentration is cru-
brane of unmyelinated axons that lead from nociceptors (pain receptors) in the cial for cell death, among other things by increasing
skin. The functions of glutamate receptors in peripheral tissues are less under-
stood than in the brain. depolarization and initiating a vicious cycle that acti-
3 Studies with immunogold labeling indicate that metabotropic glutamate vates proteolytic enzymes and induces large concentra-
receptors (mGluR1) are located at the periphery of synapses, whereas AMPA tion changes of ions. In turn, this causes osmotic
receptors occupy the central region. In addition, mGluRs are found without
relation to synapses (enabling extrasynaptic transmission, see Fig. 5.1). Such imbalance with cell swelling and potential destruction.
segregation might allow the receptors to respond differentially to glutamate: If activation of glutamate receptors has a crucial role
the AMPA receptors would be activated by normal presynaptic stimulation for cell death after a stroke, blockage of glutamate
(low frequency of action potentials), whereas mGluRs would be activated only
by high-frequency stimulation that releases large amounts of glutamate at the receptors might be effective in reducing the damage (if
synapse, or by spillover of glutamate from nearby synapses. started within 12 hours after onset of the symptoms).
Animal experiments have yielded positive results, but into the neurons, probably initiating a vicious cycle
so far they have not been confirmed in humans. leading to cell death (see also earlier, NMDA Receptors:
Excitatory amino acid transmitters and the NMDA Mediators of Both Learning and Neuronal Damage,
receptor may also be involved in the cell damage that and Chapter 11, under Ischemic Cell Damage).
occurs in various neurodegenerative disorders of the
nervous system, such as amyotrophic lateral sclerosis
Inhibitory Amino Acid Transmitters: GABA and Glycine
(ALS) and Huntingtons disease.
While excessive NMDA-receptor activation can harm GABA is the dominant inhibitory transmitter, being
neurons, blockage can also produce dramatic symp- present in nearly all parts of the CNS (Figs. 5.1 and
toms. This is exemplified by the drugs ketamine 5.2). As many as 20% of all synapses in the CNS may
(Ketalar, used as a short-acting anesthetic) and phency- be GABAergic. GABA is used as a transmitter mainly
clidine (PCP, or angel dust) that block NMDA recep- by interneurons (most projection neurons are gluta-
tors. Both drugs influence consciousness and disturb matergic). It is synthesized from glutamic acid in a sin-
thought processes. Side effects of ketamine used for gle step by the enzyme glutamic acid decarboxylase
anesthesia are nightmares and hallucinations during (GAD, Fig. 5.4). GABA acts on ionotropic GABAA
awakening. The thought disturbances resemble those receptors, and metabotropic GABAB receptors. GABA
occurring in schizophrenia, and this led to the gluta- is removed from the extracellular space by high-affinity
mate hypothesis for this disease. Ketamine in low transporters (GAT), which are mainly localized to neu-
doses may be effective for treating chronic pain, prob- ronal membranes (differing in this respect from gluta-
ably by blocking NMDA receptors on sensory neurons mate transporters).
in the cord. Alcohol (ethanol) also influences NMDA GABA appears to play an important role during
receptors (besides many other actions in the nervous development of the nervous system, and occurs very
system; see later, GABA Receptors Are Influenced by earlyeven before synapses are established. When
Drugs, Alcohol, and Anesthetics). synapses start to occur, GABA acts as an excitatory
transmitter because it depolarizes rather than hyperpo-
larizes the postsynaptic neuron (by acting on GABAA
Glutamate Transporters
receptors).4 GABA is possibly the first excitatory trans-
Five structurally different glutamate transporter proteins mitter to shape neuronal networks (before glutamate
are identified, which also differ with regard to their dis- has taken over as the dominant excitatory transmitter).
tribution in the brain. The quantitatively dominant In addition, GABA influences proliferation, migration,
transporters are concentrated in glial membranes appos- and maturation of neurons.
ing neurons, particularly around synapses (see Fig. 4.1; Glycine (Fig. 5.4) is also an inhibitory transmitter,
see also Fig. 2.5). It is not unexpected that the concen- although with a much more limited distribution than
tration of transporters is highest in parts of the brain GABA. Glycine is used as transmitter by a population
with a high density of glutamatergic nerve terminals. of spinal interneurons and by some brain stem and cer-
The transport of glutamate into glial cells is driven by ebellar neurons. Glycine receptors are parts of chloride
+ +
concentration gradients of Na and K . That is, the elec- channels and have fast excitatory actions. Strychnine
trochemical gradient is crucial for the activity of the blocks glycine receptors (thereby blocking inhibition of
transporters. Other factors also influence their activity, spinal and brain stem motor neurons), and this explains
however. Thus, the expression of transporter proteins why strychnine poisoning produces muscle cramps.
increases with activation of glutamate receptors, while Likewise, the tetanus toxin provokes violent muscle
the expression decreases after removal of glutamatergic spasms because it inhibits synaptic release of glycine.
innervation.
GABA Receptors
Glutamate Transporters and Brain Damage
In most areas, GABA acts by opening chloride chan-
Under pathologic conditions with insufficient energy nels, thereby producing a brief hyperpolarizing current
supply (e.g., low blood flow) the electrochemical gradi- (IPSP) or short-circuiting excitatory currents (see
ent cannot be maintained. Because of the high intracel- Chapter 3, Mechanisms of Postsynaptic Potentials
lular concentration of glutamate, the transporters (EPSPs and IPSPs)). The receptor that forms the
reverse their direction of transport so that glutamate is
released into the extracellular space instead of being 4 This is probably due to high intracellular chloride concentration in embry-
removed from it. In this way, the extracellular gluta-
onic neurons. The equilibrium potential for Cl is therefore more negative than
mate concentration can reach levels several hundred in mature neurons, so that opening of chloride channels leads to net ow of

Cl out of the neuron. The same situation appears to arise in the adult spinal
times that of the normal resting level. This leads to mas- cord in certain conditions with chronic pain, that is, GABAergic interneurons
sive receptor activation and high flow of Na+ and Ca2+ may lose their normal inhibitory action on pain transmission.

Cl channel is termed GABAA; it consists of five under Spasticity).6 Certain steroid hormones, among
membrane-spanning subunits (similar to the acetylcho- them the female sex hormone progesterone, also bind
line receptor shown in Fig. 4.2). There are several sub- to GABAA receptors and produce actions similar to
types of the GABAA receptor, as mentioned (see earlier, barbiturates. An anesthetic drug (alphaxalone) was
Transmitter Receptors in General). Besides the bind- developed on this basis.
ing site for GABA, the GABAA receptor has several oth- The central nervous effects of both alcohol and inha-
ers, which are targets of alcohol and several common lation anesthetics (i.e., gases used for general anesthe-
drugs. GABA is normally present in low concentrations sia, such as halothane) were formerly ascribed to
extracellularly, and may bind to extrasynaptic GABAA unspecific membrane influences. It now seems, how-
receptors (Fig. 5.3). This would mediate a tonic, fairly ever, that they act mainly by way of receptor binding.
diffuse inhibition (in addition to the phasic one pro- Both alcohol and gaseous anesthetics bind to (among
duced at GABAergic synapses). Although the function others) GABAA receptors and increase their activity by
of this tonic inhibition is unknown, it is modulated by increasing inhibition. Chronic alcohol consumption
anesthetics, certain drugs, and alcohol. down-regulates GABAA receptors, and this may con-
GABA can also produce slow IPSP (long-lasting tribute to the development of tolerance (i.e., the dose
+
hyperpolarization) by indirectly opening K channels or must be increased to achieve the same effect) and the
2+
blocking Ca channels. The receptors producing these heightened excitability by abstinence. As mentioned,
effects are termed GABAB, and are G proteincoupled, alcohol also binds to NMDA receptors. There is evi-
metabotropic receptors. GABAB receptors are found dence that chronic alcohol intake leads to up-regulation
both presynaptically and postsynaptically.5 GABAB of NMDA receptors in the frontal lobes, probably
receptors inhibit several reflexes, such as the spinal because alcohol inhibits NMDA-receptor activation.
stretch reflex (contraction in response to rapid stretch Alcohol also increases the amount of the transmitter
of a muscle) and the cough reflex. Although GABAB dopamine in parts of the brain (especially in the nucleus
receptors are present in many parts of the CNS, the accumbens), perhaps as a consequence of reduced
concentration in most places is much lower than that of NMDA-receptor activation (glutamate is believed to
GABAA. Accordingly, blockage of GABAB receptors reduce dopamine release). Other transmitters, such as
produces fewer behavioral effects than does blockage serotonin and neuropeptides, as well as several intracel-
of GABAA. It is possible that GABAB receptors are acti- lular signal pathways, are influenced by alcohol. Genetic
vated only under special circumstances, whereas GABAA variations in transmitter receptors and enzyme systems
receptors are more continuously active. may at least partly explain why people react so differ-
ently to alcohol.
GABA Receptors Are Inuenced by Drugs, Alcohol,
and Anesthetics Acetylcholine
Benzodiazepines, barbiturates, and some anesthetics The actions of acetylcholine in the CNS are especially
bind to different sites at the GABAA receptor, but all important with regard to attention, learning, and mem-
potentiate the synaptic effect of GABA. The benzodiaz- ory (see Fig. 4.10; see also Chapter 26 under Multiple
epines (e.g., diazepam) act by increasing the opening Pathways and Transmitters Are Responsible for Cortical
frequency of the Cl channels, whereas the barbiturates Activation).7 In Alzheimers diseasewith memory
prolong their opening time. Benzodiazepines are used impairment as a key featureacetylcholine and acetyl-
to reduce anxiety and provide muscle relaxation, and choline receptors in the cerebral cortex are severely
some derivatives are used as hypnotics. The barbitu- reduced (see also Chapter 10, under Alzheimers
rates have similar effects and were formerly widely used Disease and Frontotemporal Dementia [Picks Disease],
as sedatives and hypnotics (they are now mainly used to and Chapter 31, under Cholinergic Neurons Projecting
induce general anesthesia and to treat epilepsy). Another to the Cerebral Cortex).
drug, baclofen (Lioresal), binds selectively to the GABAB
receptor and potentiates the effect of GABA. It is
used to reduce abnormal muscle tension occurring after
6 It was initially assumed that baclofen reduces muscle tension by increasing
damage to descending motor pathways (see Chapter 22, presynaptic inhibition of sensory nerve terminals in the spinal cord, thereby
reducing the depolarization of motor neurons. Recent data indicate that axoax-
onic synapses on sensory terminals act mainly on GABAA receptors, however,
and that baclofen acts directly on the motor neurons and interneurons rather
than presynaptically.
5 Some sensory neurons express GABAB receptors in their peripheral ramica- 7 Acetylcholine also inuences the microcirculation of the brain, by producing
tions, where GABA inhibits release of other transmitters. Peripheral release of vasodilatation via muscarinic receptors and release of nitric oxide (see later,
neuropeptides can cause increased local blood ow, edema, and stimulation of Nitric Oxide and Blood Vessels). The cholinergic bers innervating brain
pain receptors (see Chapter 13, under Release of Neuropeptides from vessels arise in the basal forebrain and not in the peripheral parts of the auto-
Peripheral Branches of Sensory Neurons). nomic nervous system.
derive from the early observations that nicotine and
O CH3 muscarine mimicked the effects of acetylcholine (nico-

CH3 COCH2 CH2 NCH3
tine and muscarine are plant alkaloids; muscarine is
present in certain kinds of poisonous mushrooms). The

CH3 nicotinic receptors produce fast, excitatory synaptic
actions, whereas the muscarinic receptors mediate indi-
ACETYLCHOLINE rect, modulatory effects on neuronal excitability.
Depending on the subtype of muscarinic receptor pres-
gure 5.6 Structure of the neurotransmitter acetylcholine.
ent, the effect may be inhibitory or excitatory. Nicotinic
and muscarinic receptors are distributed differently in
the nervous system, and there are several subtypes of
Acetylcholine is a quaternary amine (Fig. 5.6) synthe- both (which can be distinguished pharmacologically by
sized through the binding of choline to acetyl-coenzyme use of different agonists and antagonists). For example,
A by the enzyme choline acetyltransferase (ChAT). The different subtypes of nicotinic receptors are expressed
presence of this enzyme is characteristic of cholinergic in striated muscle cells, in autonomic ganglia, and in
neurons (neurons containing acetylcholine, Fig. 5.1). the CNS.
Acetylcholine is present in somatic and autonomic Seven subtypes of the nicotinic receptor have been
motor neurons in the spinal cord and brain stem and in identified. There are three main groups: receptors in
autonomic (parasympathetic) ganglia. In addition, cho- skeletal muscle, in autonomic ganglia, and in the CNS.
linergic neurons make up several diffusely organized The functional role of nicotinic receptor in the CNS is
cell groups in the brain stem (parabrachial nucleus) and not well understood, but they are present in many
in the basal forebrain (the basal nucleus and the septal places and are localized both presynaptically and post-
nuclei; see Fig. 10.1). synaptically. They therefore may influence neuronal
After release, acetylcholine is broken down to cho- excitability both directly and indirectly by modulating
line and acetate by the enzyme acetylcholine esterase release of other transmitters (e.g., glutamate). Much
(AchE). The enzyme is very efficient: one molecule can better known are the actions of acetylcholine at the
hydrolyze 5000 molecules of acetylcholine per second. cholinergic synapses between motor neurons and skel-
Choline (but not acetylcholine) is taken up into nerve etal muscle cells (see Figs. 21.4 and 21.5). Binding of
terminals by high-affinity transporter proteins. Uptake acetylcholine opens the channel for cations, but the per-
+
of choline appears to be the most important factor in meability is largest for Na . Opening of such channels
regulating the synthesis of acetylcholine. elicits an action potential that spreads out in all direc-
An important feature of cholinergic neurons with tions to reach all parts of the muscle cell membrane.
axon ramifications within the CNS is that they to only This is the signal that leads to muscle contraction.
a limited extent release transmitter at typical synapses. (Whereas skeletal muscle cells contain only nicotinic
In the cerebral cortex, for example, axons from cholin- receptors, smooth muscle cells are equipped only with
ergic neurons form widespread ramifications with vari- muscarinic receptors.)
cosities (Fig. 5.3). Only about 10% of the varicosities Muscarinic receptors are quantitatively the dominant
were estimated to form typical synapses when exam- acetylcholine receptors in the CNS. So far, five subtypes
ined via serial sections and electron microscopy. (m1m5) have been cloned (all are blocked by atropine)
Therefore, acetylcholine must be expected to act rather but m1 and m2 are the quantitatively most important
diffusely on all neurons in the vicinity equipped with ones. Whereas m1 receptors are located postsynapti-
the appropriate receptors--that is, it acts mainly via cally, m2 receptors are found predominantly presynap-
volume transmission. This fits with the fact that both tically. In the cerebral cortex, which receives many
nicotinic and muscarinic receptors in the cerebral cor- cholinergic nerve terminals, a major effect of acetylcho-
tex are localized extrasynaptically on dendrites, neu- line is to reduce the permeability of a K+ channel by
ronal somata, and nerve terminals (presynaptically). acting on m1 receptors. This makes the neurons more
The same arrangement holds for other cell groups with susceptible to other excitatory inputs so that, for exam-
widespread axon ramifications that release modulatory ple, a neuron will react more easily to a specific sensory
transmitters (such as monoaminergic ones, discussed stimulus. Another kind of muscarinic receptor opens a
later). K+ channel, thereby producing long-lasting hyperpolar-
ization, while a third type closes a Ca2+ channel.
Acetylcholine Receptors (AchRs)
Blockers of Acetylcholine Receptors
Acetylcholine can bind to two kinds of receptors: iono-
tropic nicotinic receptors (nAchR; see Fig. 4.2), and Curare is an antagonist (blocker) of the nicotinic recep-
metabotropic muscarinic receptors (mAchR). The names tors and was used as an arrow poison by South American
natives to paralyze victims. Derivatives of curare are COOH

used to achieve muscle relaxation during surgery.

CH2CHNH2
Atropine and scopolamine are relatively unselective
antagonists of muscarinic receptors (i.e., they block all TYROSINE
HO
subtypes). The snake venom -bungarotoxin binds spe-
cifically to muscle nicotinic receptors and blocks the Tyrosine hydroxylase
effect of acetylcholine (and kills the victim by paralyz-
COOH
ing all skeletal muscles). The French neuroscientist

Jean-Pierre Changeux and coworkers achieved the first CH2CHNH2
DOPA
isolation and characterization of a transmitter receptor Dihydroxyphenylala-
HO
by use of bungarotoxin. To obtain sufficient amounts nine
of the receptor, electric eels (Torpedo) were chosen for OH
study because they are equipped with electric organs that Dopa decarboxylase
produce strong electric shocks by activating nicotinic H
receptors. CH2CHNH2
DOPAMINE
HO
Nicotine Addiction
OH Dopamine hydroxylase
Genetic variability among AchR subunits appears to be
related to nicotine dependence; that is, persons with OH

genes for a certain subunit might have an increased risk CHCH2NH2
of becoming nicotine dependent. The development of NOREPINEPHRINE
addictive behavior depends, at least partly, on nicotine- HO
receptor-mediated stimulation of dopaminergic neu- OH
rons (that release dopamine in the nucleus accumbens;
see Chapter 23, under The Ventral Striatum, Psychosis,
gure 5.7 The catecholamines dopamine and norepinephrine and
and Drug Addiction). However, the relation between the key enzymes in their synthesis.
nicotine and addictive behavior is complex and several
transmitters other than dopamine are involved (e.g.,
glutamate and GABA). Further, chronic nicotine con-
sumption induces plastic changes in several neuronal norepinephrine, dopamine, serotonin, and histamine
groups. At the cerebral cortical level, a region called are said to be noradrenergic, dopaminergic, serotoner-
insula (see Chapter 34 under The Insula) may be gic, and histaminergic, respectively (the same terminol-
particularly important. For example, activation of neu- ogy is used for the receptors corresponding to these
ronal groups in the insula was found in a brain imaging transmitters).
study to increase in relation to the person feeling an
urge for a drug. Further, smokers suffering a stroke that
damaged the insula were much more likely to quit
smoking than were smokers suffering lesions in other
parts of the brain. COOH

CH2CHNH2 TRYPTOPHAN
Biogenic Amines N
The biogenic amines constitute a subgroup of the small- Tryptophan hydroxylase

molecule transmitters. The group includes the mono-
amines norepinephrine, epinephrine, dopamine, and 5-hydroxytryptophan-decarboxylase
serotonin (one amine group), and in addition histamine HO
H

(two amine groups). Neurons that use monoamines as CH2CHNH2 SEROTONIN

transmitters are called monoaminergic. The monoam- (5-hydroxytryptamine)
N
ines are synthesized by enzymatic removal of the carbox-
ylic group from an aromatic amino acid (Figs. 5.7 and Monoamine oxidase (MAO)
5.8). Norepinephrine, epinephrine, and dopamine are
8
catecholamines. Neurons that contain the monoamines
gure 5.8 Serotonin. This neurotransmitter synthesized from tryp-
8 Catecholamines: Compounds consisting of a catechol group (benzene ring tophan in two enzymatic steps. It is broken down by monoamine
with two hydroxyl groups) with an attached amine group. oxidase in the nerve terminals.
A common feature of the biogenic amines is that they of this enzyme in tissue sections is used to identify
are synthesized only in a small number of neurons, noradrenergic neurons.
which, however, have widely branching axons. In this Serotonin (5-hydroxytryptamine [5-HT]) is synthe-
way, these few neurons ensure that the transmitters can sized from the amino acid tryptophan (Fig. 5.8). The
act in most parts of the CNS. Like acetylcholine, the reaction is catalyzed by the enzyme tryptophan hydrox-
biogenic amines are to a large extent released from var- ylase (and the same aromatic amino acid decarboxylase
icosities without typical synaptic contacts (Fig. 5.3); that catalyzes DOPA to dopamine). Tryptophan
therefore, their effects are presumably mainly mediated hydroxylase is rate limiting for the synthesis of sero-
9
by volume transmission and binding to extrasynaptic tonin, although other factors also contribute. The
receptors. Localization and functions of monoaminer- serotonin concentration is much higher in certain cell
gic cell groups are discussed in Chapters 23 (dopamine) types peripherally than in the brain (blood platelets,
and 26 (norepinephrine and serotonin). mast cells, chromaffin cells in the gut, and others).
It is therefore mandatory that serotoninlike other
transmitterscannot pass the bloodbrain barrier.
Actions of the Biogenic Amines
Peripherally, serotonin produces contraction of smooth
The biogenic amines act (with one exception) on muscle cells, among other effects.
metabotropic receptors; that is, they exert mainly slow, Histamine hardly passes the bloodbrain barrier,
modulatory actions. Monoaminergic (like cholinergic) and is synthesized in the brain from the amino acid
neurons are therefore suited to modulate simultane- histidine.
ously the specific information processing mediated by
glutamate and GABA in many anatomically separate
Monoamine Receptors
neuronal groups. This is related to regulation of atten-
tion, motivation, and mood. In addition, the monoam- Like the other neurotransmitters discussed so far, each
ines play important roles with regard to plasticity and of the monoamines bind to several different receptors
learning. (see Table 5.1). Monoamine receptors are found both
Drugs used to treat diseases such as schizophrenia, presynaptically and postsynaptically (as mentioned, the
Parkinsons disease, and depression alter the functioning majority are most likely localized extrasynaptically).
of monoamines. Their effects are correspondingly diverse: some mono-
aminergic receptors inhibit transmitter release, others
increase it; some produce slow EPSPs, others produce
Synthesis of Biogenic Amines
slow IPSPs. Consequently, each monoamine can have
Norepinephrine (noradrenaline), epinephrine (adrena- diverse effects, depending on the receptor repertoire of
line), and dopamine are all synthesized from the amino the target neurons.
acid tyrosine (Fig. 5.7). Tyrosine is taken up from the Norepinephrine (and epinephrine, which mainly
bloodstream by active transport mechanisms and functions as a hormone) binds to two main receptor
concentrated in the nervous tissue. The synthesis of types, - and -adrenergic receptors. Their effects are
catecholamines goes through several enzymatic steps. often opposite, and they are differentially distributed
The first is the conversion of tyrosine to dihydroxyphe- (these receptors are treated in more detail in Chapter 28).
nylalanine (DOPA) by the enzyme tyrosine hydroxylase In the cerebral cortex, norepinephrine produces a slow
(Fig. 5.7), which appears to be rate limiting for the depolarization by binding to receptors (by indirect,
+
synthesis of catecholamines under most conditions. G proteincoupled closure of a K channel).
The activity of tyrosine hydroxylase is regulated by Dopamine acts on two main types of receptorsD1
negative feedback from released catecholamines by way and D2with different properties and different distri-
of presynaptic autoreceptors (other factors also influ- bution in the CNS. Common to the dopamine receptors
ence the activity, however). DOPA is converted to dop- in the D1 group is that they act by increasing the synthe-
amine by the enzyme aromatic amino acid decarboxylase sis of cyclic AMP, whereas the D2 receptors decrease it.
(DOPA decarboxylase). The reaction is so rapid that Usually, one uses the terms D1-like (D1 and D5) and
very little DOPA can be detected in the brain normally. D2-like receptors (D2, D3, and D4). Dopamine receptors
Therefore, the synthesis of dopamine can be increased are discussed further in Chapter 23 (under Actions of
by artificial supply of DOPA (in the form of levodopa, Dopamine in the Striatum).
Sinemet, Parcopa), as done in Parkinsons disease in Serotonin receptors fall into seven groups5-HT1 to
which parts of the brain have very low levels of dop- 5-HT7with further subtypes of each (see Table 5.1).
amine. (Dopamine itself does not pass the bloodbrain
barrier and therefore cannot be used therapeutically.)
9 In contrast to catecholamines, the synthesis of serotonin appears not be regu-
Norepinephrine is synthesized from dopamine by the lated by negative feedback by way of autoreceptor stimulation; that is, increased
enzyme dopamine -hydroxylase (Fig. 5.7). The detection extracellular transmitter concentration does not inhibit the synthesis.
All of the serotonin receptors are metabotropic except however, so that, for example, the dopamine trans-
the 5-HT3 receptor, which is ionotropic (belonging to porter also can take up norepinephrine, if it is present
the same protein family as the other ion channel recep- in the vicinity. After uptake into nerve terminals, the
tors). The metabotropic serotonin receptors act through monoamines are partly transported into vesicles, partly
different intracellular signal pathways and can have broken down by the enzyme monoamine oxidase
either excitatory or inhibitory effects (evoking slow (MAO).
EPSPs and IPSPs). For example, activation of 5-HT1
+
receptors causes inhibition by opening certain K chan-
Monoamine Oxidase, Serotonin Transporters, and
nels. The same neurons may also be equipped with
+ Behavior
another kind serotonin receptor that closes K chan-
nels, making it difficult to sort out the total effect of There are two varieties of monoamine oxidase (MAO).
serotonin. Serotonin is further discussed in Chapter 13 MAO-A has the highest affinity to the monoamine
(under Nociceptors), Chapter 22 (Monoaminergic transmitters and is particularly concentrated in cate-
Pathways to the Brain Stem and Spinal Cord), and cholaminergic neurons. MAO-B is concentrated in
Chapter 26 (under The Raphe Nuclei and Pathways serotonergic and histaminergic neurons and in glia.
and Transmitters Responsible for Cortical Activation). Mutation of the gene coding for MAO-A (located on
the X chromosome) was found in a Dutch family with
lack of MAO-A, and abnormal aggressiveness among
Histamine ReceptorsHomeostasis and Wakefulness?
the male members. Correspondingly, knockout mice
Histamine receptors occur extrasynaptically and on that lack the MAO-A gene behave aggressively and
varicosities in many parts of the CNS. In the thalamus have increased brain levels of monoamines. These and
and the cerebral cortex, histamine actions appear to be other findings have led some to suggest that individual
involved in arousal and wakefulness. Histamine recep- variations among the genes for monoamine oxidase
tors in the hypothalamus are most likely involved in may dispose for excessive aggressiveness and violent
homeostatic processes (e.g., food and water intake, behaviors.
temperature regulation, and hormone secretion). The Individual differences in personality and behavior
axon ramifications releasing histamine contact not only have also been associated with genetic polymorphism
neurons but also glial cells and small blood vessels. in monoamine metabolism. For example, certain variet-
Presumably, this also relates to homeostatic control. ies of the gene coding for the serotonin transporter are
Three varieties of the histamine receptorH1-H3 associated with high levels of anxiety and depression.
have been identified in the CNS; all acting indirectly via These traits appear to be associated with a heritable
G proteins. H1 receptors mediate the effect of histamine reduced functioning of the serotonin transporter (not
on wakefulness, partly directly on neurons in the cere- increased as one might have expected, because antide-
10
bral cortex, partly on subcortical cholinergic and mono- pressants inhibit reuptake of monoamines). Further,
aminergic neurons, which in their turn influence the animal experiments indicate that symptoms in adult
cerebral cortex. The antihistamines used against travel animals depend on reduced transporter activity during
sickness and allergy are H1 antagonists, and this prob- a short period after birth. Only animals with genetic
ably explains why drowsiness is a frequent side effect of vulnerability plus experience of psychological trauma
such drugs. Activation of H1 receptors in the hypothal- in this period (such as separation from the mother)
amus reduces food intake in experimental animals. developed behavioral disturbances as adults. Therefore,
Many psychoactive drugs have antihistaminergic side it seems that normal serotonin transmission in early
effects, which may be one reason why weight gain is postnatal development is necessary for the development
common among patients with long-term treatment with of neuronal networks handling emotions and stress.
such drugs. This assumption is further supported by other animal
experiments showing that the presence of the 5-HT1A
receptor in early development is necessary and suffi-
Monoamine Removal
cient for normal anxiety-related behavior as an adult,
Transporter proteins in the membrane of nerve termi- regardless of whether or not the receptor is expressed in
nals end the transmitter action and control the extracel- the adult animals.
lular concentration of monoamines. Glial cells do When interpreting findings such as those described
not appear to play an important part in uptake of here, one should bear in mind that they say more about
monoamines (in contrast to glutamate). There are spe-
cific transporters for norepinephrine, dopamine, and
serotoninall belonging to the same protein family 10 This seeming paradox can probably be explained by complex compensa-
tory processes initiated by inhibition of the transporter, such as up- and down-
(called NAT, DAT, and SERT/5-HTT, respectively). regulation of receptors, enzymes, and feedback loops. Therefore, reduced
The two catecholamine transporters have low selectivity, transporter activity does not necessarily lead to increased transmitter activity.
the behavior of a brain with disturbed monoamine These anatomic and physiological features imply that
functions than about the normal functions of monoam- the monoaminergic and cholinergic cell groups do not
ines. Serotonin is, for example, certainly not the sub- mediate precise temporal or spatial information. They
strate of aggression but maytogether with many other are well suited, however, to modulate the functions of
transmittersbe necessary for normal signal process- specific glutamatergic and GABAergic systems, for
ing in the complex networks that generate and control example, by improving the signal-to-noise ratio. In this
certain emotions and their behavioral expressions. way, they may increase the precision of information
Further, genetic vulnerability of the kind described handling in many parts of the brainfor example, in
above increases the probability of developing certain the cerebral cortex during processing of complex cogni-
mental disorders or personality traits, but does not tive tasks. Their widespread connections furthermore
determine their development. How easily a person ensure that many neuronal groups receive a similar
becomes mentally disturbed as an adult depends on modulatory input, as would be important for control of
how certain brain networks developed in early child- consciousness, awareness, different phases of sleep,
hood. This, in turn, depends on a complex interaction emotions, motivation, and so forth. Monoamines fur-
between inherited traits (e.g., variety of the serotonin thermore set the level of excitability of spinal neurons
transporter) and the environment. to control voluntary movements and of neurons that
are transmitting specific sensory information. For
example, brain stem serotonergic neurons with axonal
Localization of Monoaminergic Neurons
ramifications in the cord appear to both facilitate move-
Neurons that synthesize catecholamines are largely ment and inhibit sensory transmission.
restricted to some small cell groups in the brain stem, Trying to bind together seemingly disparate actions,
hypothalamus, and peripheral nervous system. Most one might speculate that the modulatory transmitter
noradrenergic neurons in the CNS occur in somewhat systems ensure that sensory, motor, and cognitive
diffuse cell groups in the brain stem reticular forma- processes are coordinated toward a common goal. The
tion, the locus coeruleus being the largest and most dis- modulatory transmitters would do this by mediating a
tinct one (see Fig. 26.7). The majority of dopaminergic signal about the value of specific events. These specula-
neurons are localized to the mesencephalon, in one tions are supported by the well-established roles of
large nucleus called the substantia nigra (see Fig. 23.5) monoamines and acetylcholine in synaptic plasticity
and more diffuse cells groups in the vicinity (ventral (Fig. 4.10).
tegmental area, VTA). In addition, smaller numbers of In spite of their homogeneities, it is an oversimplifi-
dopaminergic neurons are found in the retina, in the cation to regard each transmitter-specific group as a
olfactory bulb, and the hypothalamus. functional entity and to use terms such as the sero-
Serotonergic neurons lie almost exclusively in a group tonin system, the dopamine system, and so on.
of nuclei near the midline of the brain stem reticular First, the large number of receptors for each transmit-
formation, called the raphe nuclei (see Fig. 26.1). ter, with different distributions and effects in the brain,
Histamine is synthesized only in the small tubero- indicate that each transmitter-specific cell group has
mammillary nucleus in the hypothalamus. complex relations to behavior. For example, dopamin-
ergic neurons influence neuronal networks engaged in
quite different behavioral tasks. Second, even if local-
Modulatory Transmitter Systems
izations are not sharp, each transmitter-specific group
We described some features shared by monoaminergic contains subgroups that differ in where they send their
and cholinergic neuronal groups (with the exception of axons, and from where they receive afferents. For
cholinergic motor neurons). First, a small number of example, the various serotonergic raphe nuclei (see
neurons send axons to large parts of the CNSthat is, Fig. 26.6) send axons to different parts of the CNS.
the cell bodies producing the enzymes necessary for Third, most or all monoaminergic neurons also contain
transmitter synthesis are very restricted in distribution, one or more neuropeptides. The effects obtained by
whereas the transmitters and their receptors are present stimulation of one of these cell groups therefore cannot
almost everywhere. Second, each axon ramifies exten- be ascribed to one transmitter alone.
sively, and the terminal branches are equipped with
numerous varicosities (Fig. 5.3). As mentioned, these
Adenosine Triphosphate and Adenosine
varicosities only infrequently form typical synapses but
release transmitters more diffusely (volume transmis- The purines adenosine triphosphate (ATP) and adenos-
sion), presumably by acting largely on extrasynaptic ine can exert marked effects on neuronal excitability,
receptors. Finally, the transmitters act predominantly both in the CNS and peripherally. Only ATP, however,
via metabotropic receptorsexerting slow, modulatory appears to act as a transmitter (it is, e.g., concentrated
effects on neuronal excitability. in vesicles and its release is calcium dependent).
The effects are mediated by purinoceptors, localized The other group (P2Y) consists of seven metabotropic
both pre- and postsynaptically. (Many other cell types receptors. Both groups are widely distributed in the
than neurons express purinoceptorse.g., smooth CNS, although the transmitter role of ATP is reason-
muscle cells.) P1 receptors bind adenosine, while P2 ably certain only in a few areas. The study of ATP as a
receptors bind ATP. After release, ATP is enzymatically neurotransmitter has so far been hampered by the lack
degraded. The transmitter role of ATP is best known in of specific receptor antagonists. P1 receptors are blocked
the autonomic nervous system, where it is usually colo- by xanthenes, such as caffeine and theophylline.
calized with acetylcholine or norepinephrine and. ATP Theophylline inhibits bronchial smooth muscle cells
and the classic transmitter are found in the same ves- and is used therapeutically in asthma.
icles, and they are released together (see Chapter 28,
under Noncholinergic and Nonadrenergic Transmis-
Nitric Oxide
sion in the Autonomic Nervous System). As a rule, ATP
excites neurons and smooth muscle cells by acting on Nitric oxide (NO) is a gas that diffuses freely through
ionotropic receptors. There are, however, examples of biologic membranes. It functions as a signal molecule in
inhibitory effects of ATP (probably by way of metabotro- many organs of the body, among them the nervous sys-
pic receptors) on smooth muscle cellsfor example, in tem. Its functional role in the nervous system is only
the longitudinal muscle layer of the large intestine. In partly clear, however. Even though NO often is called
the inner ear, efferent nerve fibers to the sensory cells an unconventional neurotransmitter, it does not meet
(hair cells) release ATP together with acetylcholine, and the criteria used to define a transmitter: it is not stored
modulate the sensitivity of the sensory cells. in vesicles, it is not released by calcium-dependent
So far, little is known with certainty about the trans- exocytosis, and it does not bind to membrane-bound
mitter role of ATP in the CNS, in spite of the wide dis- receptors.
tribution of purinoceptors. Some brain stem neuronal In the peripheral nervous system, autonomic nerve
groups appear to use ATP as transmitter (notably locus fibers release NO that acts on smooth muscle cells. In
coeruleus, where it colocalizes with norepinephrine). It the CNS, NO has a number of cellular effects and
is probably also used as transmitter in a subgroup of appears to take part in the control of various systems; it
spinal ganglion cellsthat is, sensory neurons conduct- also influences behavior. It has quite different effects in
ing impulses from peripheral receptors to the spinal the brain depending on its concentration, however: in
cord (see Chapter 13, under Primary Sensory Fibers low concentrations, it functions as a signal molecule
and Neurotransmitters). A population of spinal that modulates neuronal behavior, whereas it is toxic in
interneurons seems to release ATP in parts of the cord higher concentrations (which is perhaps not surprising
that receives signals from pain receptors (laminae I and because NO is a free radical and as such very reactive).
II; see Fig. 6.10). Ionotropic P2 receptors increase the NO is synthesized from the amino acid arginine by
release of glutamate and substance P from terminals of specific enzymes, NO synthases, of which there are sev-
spinal ganglion cells in the dorsal horn. This may con- eral different types. Synthesis of NO in nerve terminals
2+
tribute to the heightened excitability of spinal neurons, is probably induced by the increase of intracellular Ca
which is typical of chronic pain conditions. concentration that is triggered by a presynaptic action
ATP and purinoceptors mediate signals between neu- potential. After synthesis, NO diffuses freely in all
rons and glial cells, and may participate in the interac- directions. It is not only delivered into the synaptic cleft
tion between the immune system and neurons. but also enters all cells that are near the nerve terminal.
As mentioned, adenosine has marked effects on neu- Calculations from the cerebral cortex indicate that NO
rons, even though it is unlikely to act as a transmitter. can diffuse more than 100 m from its release site and
Injection of minute amounts of adenosine inhibits reach about 2 million synapses. The most abundant
spinal cord neurons that mediate signals from pain NO receptor is a water-soluble, cytoplasmic enzyme,
receptors to the brain. Adenosine also appears to be guanylyl cyclase, which controls synthesis of cyclic
involvedin some yet unknown waywith the analge- GMP. This is an intracellular messenger with various
sic effects of morphine and the morphine-like substances effects, such as activating protein kinases and acting
produced in the brain (opioids). directly on ion channels. In this way NO can modulate
neuronal excitability and firing frequency.
NO synthases are present in neurons in several parts
Purinoceptors
of the central and peripheral nervous system. In the
There are two main groups of P2 receptors. One group cerebral cortex, they are found in GABAergic neurons,
(P2X) consists of six ionotropic receptors with fast, excit- which, in addition, contain neuropeptides (substance P
atory action. The channels are most permeable to Ca2+ and somatostatin). In other parts of the brain, NO
and have a longer opening time than, for example AMPA synthases occur in cholinergic and monoaminergic
receptors (but much shorter than NMDA receptors). neurons. Although we do not know the functions of
NO liberated from such neurons, there is some evidence may perhaps fit an emergency role: it seems that
that NO is one of numerous factors that are involved in neuropeptide release requires a high firing frequency or
the induction of LTP, and therefore presumably also in burst firing, whereas low-frequency firing suffices to
neuronal plasticity. NO also appears to play a special release small molecule (classical) transmitters.
role in neurons with rhythmic firingsuch as the brain The duration of action appears to be longer for neu-
stem and thalamic neurons that regulate sleepwakeful- ropeptides than for other neuromodulators (in spite of
ness, and the hypothalamic neurons that control bodily the presence of extracellular peptidases). Thus, the half-
functions with daily variations (circadian rhythms). life after release can be very long (about 20 minutes for
Presumably, NO, due to its fast and wide diffusion, is vasopressin, for example)giving ample time for extra-
particularly suited to synchronize the activity of many cellular diffusion. In addition, at least some neuropep-
neurons. tides are released from dendrites. Thus, it seems that
In situations with insufficient energy supply (most the actions of the neuropeptides are, as a rule, rather
often due to reduced blood flow), increased intracellu- diffuse. Some of the neuropeptides may thus function
2+
lar Ca concentration leads to increased NO synthesis. more like local hormones than like neurotransmitters,
This seems likely to contribute to the neuronal damage as also suggested by a mismatch between the distribu-
in such situations (see Fig. 10.2). On the other hand, tion of receptors for a neuropeptide and nerve termi-
release of NO might improve the blood supply by nals containing the neuropeptide.
producing local vasodilatation. A characteristic feature of neuropeptides is that they
are colocalized in nerve terminals with small-molecule
(classical) transmitters. Whereas small-molecule trans-
NO and Blood Vessels
mitters are stored in small, electron-lucent vesicles, neu-
NO was first discovered in endothelial cells and named ropeptides are found in larger vesicles with an
endothelium-derived relaxing factor. In fact, its main electron-dense center (dense-core vesicles; Fig. 5.9).
effect in most organs is relaxation of smooth muscle Two or more peptides may also coexist, and there may
cells, causing vasodilatation and increased blood flow. be more than one small-molecule transmitter together
NO released from autonomic (parasympathetic) nerve with the peptides.
fibers, for example, is responsible for penile erection. Several neuropeptides will be mentioned in subse-
Nitroglycerin and similar drugs give vasodilatation by quent chapters in relation to various cell groups and
inducing synthesis of NO. neuronal systems.
Vessels in the CNS are also affected by NO. There is
evidence that NO, together with other signal molecules,
mediates the increased local blood flow associated with
increased neuronal activity (e.g., the blood flow in the
cortical motor area increases when the neurons increase
their firing during execution of voluntary movements).
Neuropeptides
A large number of neuroactive peptides have so far
been identified in the CNS, but many of them were first
found in the peripheral nervous system and in the gut.
Although there is firm evidence of a transmitter func-
tion for only a few neuropeptides, many of them have
marked effects on physiological processes and behavior
when administered locally in the CNS. Several of the
neuropeptides elicit slow inhibitory or excitatory syn-
aptic potentials when administered in minute amounts
close to neurons, suggesting a modulatory transmitter
role. This assumption is supported by the identification
of several G proteincoupled neuropeptide receptors.
Neuropeptides can also elicit intracellular responses
related to growth and development. Normally, the con-
centrations of neuropeptides are low in neurons. The gure 5.9 Nerve terminal containing both a classical transmitter
and neuropeptides. Large arrows show the dense-core vesicles that
synthesis increases, however, when the homeostasis of contain neuropeptides with transmitter actions. Small arrows
the nervous system is challenged (e.g., in infections, show the small, clear vesicles that contain small molecule classical
stroke, trauma). The way neuropeptides are released transmitters.
Examples of Colocalization of Neuropeptides and

Examples: Drugs Altering Monoamine
Small-Molecule Transmitters
Activity in the Brain
Terminals of nerve fibers innervating salivary glands
The most common antipsychotic drugs (neuroleptics)
contain both acetylcholine and the neuropeptide vaso-
all block dopamine receptors. Their therapeutic effects
active intestinal polypeptide (VIP). Both substances are
are primarily related to altering the transmitter func-
released when the nerves are stimulated, but they act on
tions of dopamine, although they also influence other
different target cells: acetylcholine elicits secretion from
transmitters (they exhibit, for example, more or less
glandular cells, whereas VIP produces vasodilatation
anticholinergic and antihistaminergic effects). In addi-
by relaxing smooth muscle cells, thereby increasing
tion, dopamine receptors are present in neuronal groups
blood flow to the organ at the same time as its secretion
related to movement control and muscle tone, and this
is increased. Another example concerns primary sen-
explains why motor dysfunctions are common side
sory neurons (spinal ganglion cells; see Figs. 6.9 and
effects of antipsychotics. Conversely, patients with
13.16) mediating information from peripheral sense
Parkinsons disease who are treated with levodopa to
organs to the spinal cord. Some of theseparticularly
increase dopamine levels in the brain may develop psy-
those related to painful stimulicontain both gluta-
chotic symptoms during treatment. Nevertheless, the
mate and the peptides substance P and calcitonin gene-
dopamine hypothesis of schizophrenia, which states
related peptide. When released with glutamate, these
that the symptoms can be explained as a result of dop-
peptides appear to have several actions: they can bind
aminergic overactivity, is too simplistic. Not all symp-
to specific postsynaptic receptors, they can act presyn-
toms can be explained in this way, and dopaminergic
aptically to increase their own release and the release of
overactivity does not appear to be present in all patients.
glutamate, and they can sensitize the postsynaptic glu-
Further, psychotic symptoms can also be treated effec-
tamate receptors to enhance the effect of glutamate.
tively with drugs that block serotonin receptors (so-
Spinal interneurons that receive sensory information
called atypical antipsychotic drugs, such as clozapine,
exhibit different transmitter combinations. One group
have higher affinity for serotonin receptors than for
of interneurons contains GABA and the peptide enkeph-
dopamine receptors). MAO inhibitors were the first
alin. Another group contains both enkephalin and
drugs with significant effects on major depressions.
substance P in combination with (most likely) gluta-
Later, tricyclic antidepressants (TCAs) were introduced,
mate. Therefore, one neuropeptide (enkephalin) may be
which inhibit relatively selectively the norepinephrine
colocalized with either an inhibitory or an excitatory
transporter. The new antidepressants, such as fluox-
transmitter with fast synaptic actions. Apparently,
etine (Prozac), inhibit rather selectively the serotonin
spinal interneurons may express a variety of transmitter
transporter (selective serotonin-uptake inhibitors
combinations with correspondingly complex synaptic
[SSRIs]). Although the clinical effects of antidepressants
actions. When we also think of the variety of receptors
may appear to be caused simply by increased levels of
each neuron expresses, it is easy to understand why
monoamines available at the synapses, this cannot be
unraveling the functional role of a single transmitter
the whole story. For example, while inhibition of the
can be difficult.
transporters occurs immediately, the clinical effect
comes after days or weeks with treatment. Therefore,
clinical effects were sought in compensatory processes,
ACTIONS OF DRUGS ON THE NERVOUS SYSTEM
such as up- and down-regulation of receptors. Recent
research has revealed a number of effects of antidepres-
Most Drugs Inuence Synaptic Function
sants other than altering monoamine levelsfor exam-
Several drugs have been mentioned in connection with ple, on expression of neurotrophins and neuronal
discussions of synaptic function and neurotransmitters. plasticity. The fact that antidepressants, in spite of
Most drugs acting on the nervous system do so by influ- acting on different monoamine transporters, have simi-
encing synaptic transmission directly or indirectly, lar clinical effects prompted the hypothesis that they act
regardless of whether their aim is to alleviate disorders by regulating transcription of the same set of genes.
of mood, cognition, movements, memory, or behavior. This has received some experimental support. For
The drugs may interfere presynaptically in the synthesis, example, one study identified gene transcripts that were
release, degradation, or reuptake of transmitters or post- equally regulated by treatment with different classes of
synaptically in the activity, numbers, or localization of antidepressants.
receptors. Certain drugs have one or more of these Cocaine inhibits the dopamine transporter very selec-
actions regarding one or several transmitters. Some tively; that is, its affinity to the dopamine transporter is
drugs also seem to influence synaptic functions indi- much higher than to other monoamine transporters.
rectly by changing the expression of neurotrophic fac- The dopamine transporter has even been called a
tors that (among other tasks) govern synaptic plasticity. cocaine receptor. Amphetamine inhibits the dopamine
transporter but also other monoamine transporters, by feedback loops that up- or down-regulate the trans-
although relatively weakly compared with cocaine. In mitter release, the transporters, the receptors, and so
addition, amphetamine increases the release of cate- forth. For example, when the activity of tryptophan
cholamines and has other synaptic effects as well. hydroxylase (the rate-limiting enzyme in serotonin syn-
thesis) is reduced, the neurons respond by increasing
synthesis of the enzyme and its axonal transport to the
Drug Effects Are Often Multifarious 11
nerve terminals. Finally, we should keep in mind that
Most transmitters are present in several parts of the alteration of one transmitters activity as a rule leads to
nervous system, which differ anatomically and physio- alterations of other transmitters as well. One mecha-
logically. Therefore, it should not be surprising that nism behind this is the action on presynaptic receptors:
even drugs that apparently influence the actions of only a cholinergic terminal in the cerebral cortex may be
one transmitter nevertheless have multifarious effects. equipped with serotonin receptors, so that a drug with
Some of these are desired therapeutic effects, whereas specific action on serotonergic transmission may never-
others are disturbing or even dangerous side effects. theless also alter cholinergic transmission. Another
Development of more specific drugsfor example, mechanism is postsynaptic: many dopaminergic neu-
drugs acting on only one receptor subtypemay reduce rons receive glutamatergic synapses, so that drugs
the side effects but will hardly eliminate them. This is altering the action of glutamate will change dopamine
because each receptor type (even one among several release as well.
subtypes for one transmitter) occurs in functionally
different parts of the nervous system.
11 Lithium, used prophylactically for major bipolar disorder (manic depres-

Drugs Interact with Dynamic Processes in the Brain sion), increases tryptophan uptake and initially increases serotonin synthesis
(this is only one of several cellular effects of lithium). After 2 to 3 weeks with
Another important point is that storage, release, and treatment, however, the tryptophan uptake is still increased, but the tryptophan
uptake of transmitters, as well as the expression of hydroxylase activity is reduced so that the rate of serotonin synthesis is normal.
It is possible that the therapeutic effect of lithium is due to stabilization of
receptors, are dynamic processes. The acute perturba- serotonin metabolism, which makes it less vulnerable to psychological stress or
tions caused by a drug are usually counteracted quickly spontaneous chemical changes in the brain.
6 Parts of the Nervous System
OVERVIEW The brain stem is a rostral continuation of the spinal

cord but has a more complex internal organization. On
In this chapter, we describe the main features of the a purely anatomical basis, the brain stem is divided
anatomy of the central nervous system (CNS), with (starting caudally) into the medulla oblongata, the
brief mention of the functional significance of the vari- pons, the mesencephalon, and the diencephalon (often,
ous parts. We will treat structure and function of many however, we do not include the diencephalon). Twelve
of these parts in more depth in later chapters dealing cranial nerves emanate from the brain stem being num-
with functional systems. It will then be assumed, how- bered from rostral to caudal. With some exceptions, the
ever, that the reader is familiar with the names and the cranial nerves innervate structures in the head (spinal
locations of the major cell groups and tracts of the CNS. nerves of the head) and contain sensory and motor nerve
The CNS can be subdivided anatomically into differ- fibers. The first cranial nervethe olfactory nerve
ent parts. The spinal cord lies in the vertebral canal, serves the sense of smell. The secondthe optic nerve
whereas the brain is located in the cranial cavity. The transmit signals from the retina, while the third
brain is further subdivided into the brain stem, which (oculomotor), fourth (trochlear), and sixth (abducens)
constitutes the upward continuation of the spinal cord, nerves control the movements of the eye ball. The fifth
the cerebellum (little brain), and the cerebrum or nervethe trigeminalemanates from the pons and
cerebral hemispheres. The cerebellum and cerebrum brings sensory signals from the face as well as motor
largely cover the brain stem and constitute the major signals to the masticatory muscles. The seventh nerve
part of the brain in higher mammals and particularly in the facialinnervates the mimic muscles of the face.
humans. The eighth nervethe vestibulocochlearcarries sig-
The spinal cord consists of a central region with gray nals from the vestibular apparatus (recording move-
matter surrounded by white matter. The gray matter ments and positions of the head in space) and the
contains neurons that may be subdivided based on cochlea (recording sound waves). The ninth nervethe
where they send their axons. Motor neurons send their glossopharyngealis concerned mainly with sensations
axons out of the cord to reach muscles and glands. and movements of the pharynx, including taste impulses
Sensory neurons receive signals from sense organs in from the back of the tongue. The tenth nervethe
the body and transmit this information to the brain. vagus nerveparticipates in the innervation of the
The spinal interneurons or propriospinal neurons pharynx but in addition innervates the larynx, and
ensure communication among neurons in the spinal sends (autonomic) motor signals to the heart, the lungs,
cord. The white matter contains ascending tracts carry- and the most of the gastrointestinal tract. The eleventh
ing signals to higher levels, and descending tracts nervethe accessoryinnervates two muscles in the
enabling the brain to control spinal cord neurons (e.g., neck (the trapezius and the sternocleidomastoid). The
motor neurons). In addition, many propriospinal axons twelfth nervethe hypoglossalis the motor nerve of
interconnect neurons in different parts of the cord. The the tongue. The cranial nerves arise in cranial nerve
cord consists of segments, each giving rise to a pair of nuclei; some of which are sensory, others are motor.
spinal nerves. The spinal nerves and their peripheral Diffuse collections of neurons in between the cranial
branches transmit sensory signals from the tissues of nerve nuclei are collectively termed the reticular forma-
the body and motor signals to muscles and glands. Each tion. The reticular formation consists of neuronal
spinal nerve connects with the cord through a dorsal groups with different tasks. Some groups are concerned
and a ventral nerve root. The dorsal roots carry only with control of circulation and respiration; some regu-
sensory nerve fibers, and the cell bodies of the sensory late sleep and wakefulness, while others control eye
neurons of each root form a spinal ganglion, which movements.
appears as an ovoid enlargement of the dorsal root. The thalamus and the hypothalamus make up the
Functionally, the cord enables fast, automatic responses bulk of the diencephalon. The thalamus is a large, egg-
to signals from the body (e.g., withdrawal of the hand shaped collection of nuclei in the centre of the cerebral
from a hot object). Nevertheless, most tasks carried hemispheres. The thalamic nuclei transmit sensory
out by the cord are controlled or modulated by higher information (of all kinds except smell) to the cerebral
levels of the CNS. cortex. In addition, thalamic nuclei transmit information
72
6: PARTS OF THE NERVOUS SYSTEM 73
to the cerebral cortex from subcortical motor regions, position of structures in relation to a midsagittal plane
notably the basal ganglia and the cerebellum. The hypo- of the body. The terms cranial (or rostral), toward the
thalamus is concerned mainly with the control of auto- head or nose, and caudal, toward the tail, are used to
nomic and endocrine functions that serve to maintain describe the relative position of structures along a lon-
bodily homeostasis (e.g., circulation, digestion, and gitudinal axis of the body. Thus, for example, nucleus
temperature control). A in the brain stem lies medial to and rostral to nucleus
The cerebral cortex is a folded sheet of gray matter B, which in turn lies lateral to and caudal to A. The
covering the cerebral hemispheres. It consists of six layers terms ventral and dorsal are used to describe the rela-
of neurons, each layer characterized by the morphology tive position of structures in relation to the front (venter
and connectivity of its neurons. In addition, the cortical means belly) and the back (dorsum) of the body, respec-
mantle is divided into many areas, differing with regard tively. Anterior (front) and posterior (rear) are used
to, among other things, their thalamic connections. Even interchangeably with ventral and dorsal, except for the
though each area is to some extent specialized, most tasks human forebrain, where anterior means toward the
of the cerebral cortexwhether they are motor, sensory, nose and ventral means toward the base of the skull.
or cognitiveare carried out by distributed networks
interconnecting neurons in many areas of the cerebral
The Living Human Brain Can Be Studied with
cortex. Among the many descending tracts from the cere-
Computer-Based Imaging Techniques: CT, MRI,
bral cortex, the pyramidal tract targets motor neurons in
and DWI
the spinal cord and brain stem. The corpus callosum,
consisting of commissural fibers, enables cooperation Techniques for computer-based image analysis of the
between the two cerebral hemispheres. living human brain have revolutionized the possibilities
The basal ganglia consist of several large nuclei in the for localizing disease processes in the brain and for
interior of the cerebral hemispheres. The striatum con- studying normal structure and function.
sists of putamen and the caudate nucleus, and receive The first of the imaging techniques that enabled us to
its main afferents from the cerebral cortex. The stria- identify smaller parts of the living brain is computer
tum send efferents to the globus pallidus and the tomography (CT). This method makes it possible to see
substantia nigra. From these, signals are directed to the X-ray pictures of thin slices through the brain. The
brain stem, and back to the cerebral cortex via the thal- examiner may choose the plane of sectioning. CT
amus. By influencing motor neuronal groups in the affords much more precise visualization of brain struc-
frontal lobe of cerebral cortex (and in the brain stem), tures than conventional X-ray examination, which
the basal ganglia contribute to the control of move- includes all tissue between the X-ray tube and the film.
ments. Connections with other frontal areas in cerebral It also provides good visualization of the ventricular
cortex (and certain subcortical nuclei) enable the basal system, which previously could be visualized only by
ganglia to influence cognitive functions. replacing the cerebrospinal fluid with air and then mak-
The cerebellum, situated dorsal to the brain stem in ing an X-ray examination. CT can also visualize the
the posterior cranial fossa, consists of a thin sheet of distribution of a radioactive substance in the living
highly folded gray matter, and a group of centrally brain, enabling the study of the distribution of neuroac-
located, deep cerebellar nuclei. The cerebellum is tive substances and also the comparison of blood flow
divided anatomically into a narrow middle part called in different parts the brain.
the vermis, and more bulky lateral parts called the cer- Magnetic resonance imaging (MRI) represents a fur-
ebellar hemispheres. In addition, a deep fissure divides ther technical development. This technique is based not
the cerebellum into an anterior lobe and a posterior on X-rays but on signals emitted by protons when they
lobe. These anatomic subdivisions correspond largely are placed in a magnetic field. Depending on the proton
to differences with regard to connections. Thus, the concentration in different tissue components, the pic-
vermis has reciprocal connections with the spinal cord tures may show clearly, for example, the contrast
and motor nuclei in the brain stem, whereas the cere- between gray and white matter (Figs. 6.1 and 6.28).
bellar hemispheres are reciprocally connected with the The bone of the skull gives very little or no signal and is
cerebral cortex. These connections enable the cerebel- seen as black in the pictures. With this technique, the
lum to play a decisive role in coordination of voluntary brain can be visualized in slices with a resolution not
movements by acting on motor neurons in the cerebral far from that of a corresponding section through a fixed
cortex, the brain stem, and the spinal cord. brain. Areas with changes in the tissuefor example,
infarction, bleeding, or tumorcan be identified. In
addition, blood vessels can be visualized to advantage
Some Anatomic Terms Used in this Book
(see Fig. 8.3 and 8.8). Apart from the diagnostic advan-
The terms medial, toward the midline, and lateral, away tages, the MRI technique also improves the correlation
from the midline, are used to describe the relative of the functional disturbances with the actual damage
primordium of the vertebral column are equally long

(see Fig. 9.12).
The spinal cord is somewhat flattened in the antero-
posterior direction and is not equally thick along its
length. In general, the thickness decreases caudally, but
there are two marked intumescences (Fig. 6.3): the
cervical and lumbar enlargements (intumescentia cervi-
calis and lumbalis). The intumescences supply the
extremities with sensory and motor nerves, hence the
increased thickness.
In the midline along the anterior aspect of the cord,
there is a longitudinal furrow or fissure, the anterior
(ventral) median fissure (Fig. 6.4). Some of the vessels
of the cord enter through this fissure and penetrate
deeply into the substance of the cord. At the posterior
aspect of the cord, there is a corresponding, but shal-
lower, furrow in the midlinethe posterior (dorsal)
median fissure. In addition, on each side there are shal-
low, longitudinal sulci anteriorly and posteriorlythe
anterior and posterior lateral sulci. These laterally
gure 6.1 Magnetic resonance image (MRI). This is taken at a level
corresponding to the drawing in Fig. 3.1. Most of the structures
seen in Fig. 3.1 can be identied in this picture. (Courtesy of
Dr. S. J. Bakke, Rikshospitalet University Hospital, Norway.)
Subarachnoid space
Brain ventricles with cerebrospinal fluid
Mesencephalon Cerebral hemisphere
of the brain. MRI can also be used to study dynamic
processes in the brain (see Chapter 14, under Methods
to Study Neuronal Activity and Metabolism in the Skull
Living Human Brain).
Dura
Further developments of the MRI technology have 3
added new applications. For example, with diffusion-
weighted imaging (DWI) a region devoid of blood sup- Pons
ply can be detected only minutes after occlusion of an 4
4
artery (much earlier than with conventional functional Cerebellum
[fMRI]). Further, DWI also enables study of myelina- Medulla
tion during normal brain development, and even the oblongata
visualization of major fiber tracts. Cisterna magna
THE SPINAL CORD
In humans, the spinal cord is a 40 to 45 cm-long cylinder Spinal cord

of nervous tissue of approximately the same thickness
as a little finger. It extends from the lower end of the Dura
brain stem (at the level of the upper end of the first cer-
vical vertebra) down the vertebral canal (Figs. 6.2 and
6.3) to the upper margin of the second lumbar vertebra
(L2). Here the cord has a wedge-shaped end called the
medullary conus (or simply conus). In children, the
spinal cord extends more caudally, however, and
reaches to the third lumbar vertebra in the newborn.
This difference between the position of the lower end of
the spinal cord in adults and infants is caused by the
vertebral column growing more rapidly than the spinal gure 6.2 The central nervous system, as viewed in a midsagittal
cord. In early embryonic life, the neural tube and the section.
Pons Posterior funicle

(dorsal column)
Dorsal (posterior) horn Central canal
Medulla
oblongata
2
Lateral
3 funicle
4 (column)
5 Cervical vertebrae (7)
Cervical enlarge-
ment 6
1
2 Ventral (anterior) horn
3
Anterior (ventral) Anterior (ventral) median
4
funicle (column) fissure
5
Thoracic vertebrae (12)
Dura 6 gure 6.4 Cross section of the spinal cord at a lumbar level. There is
7 a central H-shaped region of gray matter, and the surrounding white
8 matter is subdivided into funiculi.
9
Dorsal root
Spinal ganglion
Ventral root Spinal Nerves Connect the Spinal Cord with the Body
Lumbar 11
enlarge- Spinal nerve
ment 12 Axons mediating communication between the CNS and
other parts of the body make up the peripheral nerves.
1
The axons (nerve fibers) leave and enter the cord in
Lumbar vertebrae (5) small bundles called rootlets (Fig. 6.5). Several adjacent
Conus
2 rootlets unite to a thicker strand, called a root or nerve
root. In this manner, rows of roots are formed along
3 the dorsal and ventral aspects of the cord: the ventral
Cauda 4 (anterior) roots and the dorsal (posterior) roots, respec-
equina tively. Each dorsal root has a swelling, the spinal gan-
5 Dural sac
glion, which contains the cell bodies of the sensory
1 axons that enter the cord through the dorsal root
(Figs. 6.3 and 6.5). A dorsal and a ventral root unite to
2
form a spinal nerve. The spinal ganglion lies in the
Sacrum
3
5 4
Dorsal horn
Ventral horn
gure 6.3 The spinal cord. Left: The cord from the ventral side, with Dorsal root
the cervical and lumbar enlargements. Right: The cord and the verte- Meningeal
Dorsal ramus Spinal
bral column from the side, but the right halves of the vertebrae have ramus ganglion
been removed to expose the vertebral canal with its contents. Below
the rst and second lumbar vertebrae, the vertebral canal contains
only nerve roots (the cauda equina), which then unite to form the
spinal nerves. Ventral
root
Ventral Spinal
ramus nerve
placed sulci mark where the spinal nerves connect with

the cord.
The color of the spinal cord is whitish because the gure 6.5 Two segments of the spinal cord, as viewed from the ven-
tral aspect. In the upper part, the white matter has been removed. The
outer part consists of axons, many of which are myeli- dorsal and ventral roots emerge from the posterior and anterior lat-
nated. The consistency of the cord, as of the rest of the eral sulci, respectively, and unite to form spinal nerves. The spinal
CNS, is soft and jellylike. ganglion is located at the site where the roots unite.
Vertebral arch
Fat, vessels
Dura Cerebrospinal fluid
Intervertebral Dorsal root
foramen
Ventral root
Spinal ganglion
Dorsal ramus gure 6.6 Cross section of the vertebral column

showing the positions of the spinal cord and the spinal
nerves. The spinal ganglion is located in the interverte-
Ventral ramus bral foramen. The spinal cord is surrounded by the
cerebrospinal uid contained within the dura. Outside
Epineurium the dura there is fat and a venous plexus, which also
Vertebral body serve as soft padding for the cord and the spinal
nerves.
intervertebral foramen just where the dorsal and ven- therefore, as many segments as there are pairs of spinal
tral roots unite (Fig. 6.6). There is an important func- nerves. They are numbered accordingly, the first cervi-
tional difference between the ventral and dorsal roots: cal segment giving origin to the first cervical nerves,
the ventral roots consist of efferent (motor) fibers, and and so on. There are no surface markings of the cord to
the dorsal roots of afferent (sensory) fibers. indicate borders between the segments, but the rootlets
In total, 31 spinal nerves are present on each side, nevertheless outline them rather precisely (Fig. 6.5).
forming symmetrical pairs (Fig. 6.3). They all leave the The cervical enlargement (intumescence) corresponds
vertebral canal through the intervertebral foramina on to the fourth cervical (C4) segment through the second
each side. As mentioned, the ventral and dorsal roots thoracic (T2) segment, the lumbar enlargement to the
unite at the level of the intervertebral foramen to form
the spinal nerves. The spinal nerves are numbered (as a
general rule) in accordance with the number of verte-
brae above the nerve. We therefore have 12 pairs of
thoracic nerves, 5 pairs of lumbar nerves, and 5 pairs of
sacral nerves. In humans, there is only 1 pair of coccy- Motor neurons
(motoneurons)
geal nerves. There are seven cervical vertebrae but
8 pairs of cervical nerves because the first cervical nerve
leaves the vertebral canal above the first cervical verte-
bra (Fig. 6.3). Therefore, the numbering of the cervical
nerves differs from the numbering of the other spinal
nerves.
The spinal cord extends caudally only to the level of
between the first and the second lumbar vertebrae. Interneurons
Whereas the upper spinal nerves pass approximately
horizontally from the cord to the intervertebral fora-
men, the lower ones have to run obliquely downward
in the vertebral canal to reach the corresponding inter-
vertebral foramen, and the distance between the site of
exit from the cord and the site of exit from the canal
increases steadily (Fig. 6.3). Below the conus, the verte- Sensory neurons
bral canal contains only spinal nerve roots running lon-
gitudinally. This collection of dorsal and ventral roots
is called the cauda equina (the horsetail).
gure 6.7 Three main types of neurons in the spinal cord. Schematic
of neuronal types classied in accordance with where their axons
The Spinal Cord Is Divided into Segments terminate: Motor neurons supply skeletal muscles, smooth muscles,
and glands. The interneurons ensure communication among neurons
The part of the spinal cord that gives origin to a pair of in the cord, and the sensory neurons send their axons to higher levels
spinal nerves is called a spinal segment. There are, of the central nervous system. (See also Fig. 6.9.)
first lumbar (L1) segment through the second sacral (S2) the rostral direction, the proportion of white to gray
segment. matter increases from caudal to rostral.
The difference in rostrocaudal level between the The white matter is divided into funicles, or columns,
spinal segments and the exit from the vertebral canal of by drawing lines in the transverse plane from the sulci
the spinal nerves is of practical importance. Thus, iden- on the surface of the cord to the center (Fig. 6.4). Thus,
tical symptoms may be provoked by a process close to in each half of the cord, the white matter is divided into
the cord at one level and by one close to the interverte- a ventral or anterior funicle (funiculus), a lateral funi-
bral foramen at a considerably lower level (as should be cle, and a dorsal or posterior funicle. For the latter, the
clear from the preceding description; however, this does term dorsal column is used most frequently.
not concern the nerves in the cervical region).
The Spinal Gray Matter Contains Three Main
The Spinal Cord Consists of Gray and White Matter Types of Neurons
When cut transversely, the fresh spinal cord can be seen Among neurons in the gray matter of the spinal cord,
to consist of an outer zone of white matter and a cen- there are both morphological and functional differ-
tral, H-shaped region of gray matter. The arms of the ences. Three main types may be identified according to
H, extending dorsally and ventrally, are called the dor- where they send their axons (Fig. 6.7):
sal horn and ventral horn, respectively (Figs. 6.4 and
1. Neurons sending their axons out of the CNS
6.8). The gray matter extends as a column through the
2. Neurons sending their axons to higher levels of
length of the spinal cord (Fig. 6.5). The central canal is
the CNS (such as the brain stem)
seen as a narrow opening in the center of the cord
3. Neurons sending their axons to other parts of the
(Fig. 6.4). The central canal ends blindly in the caudal
spinal cord
end of the cord, whereas it continues rostrally into the
ventricular system of the brain (Fig. 6.1). Often neurons of the same kind lie together in the gray
The white matter of the cord contains axons running matter of the cord. We will now consider in some detail
longitudinally. Some of these axons convey signals from each of these three groups.
the cord to higher levels of the CNS; others, from higher
levels to the cord. Finally, a large proportion of the
Efferent Fibers from the Cord Control Muscles
fibers serve the signal traffic, and hence cooperation,
and Glands
between the segments of the cord. Because the first two
groups of axons become successively more numerous in The cell bodies of the first kind of neuron listed above
are located in the ventral horn and at the transition
between the dorsal and ventral horns. The somatic
motor neurons or motoneurons have large, multipolar
cell bodies and are located in the ventral horn proper
(Fig. 6.8; see also Figs. 1.2 and 21.3). The dendrites
Dorsal horn extend for a considerable distance in the gray matter
Intermedio- (Fig. 6.12). The axons leave the cord through the ven-
lateral cell tral root, follow the spinal nerves, and end in skeletal
column
muscles (muscles that are controlled voluntarily). The
Substantia
gelatinosa motoneurons are discussed further in Chapter 21.
There is also another group of neurons that sends its
axons out of the cord through the ventral rootthe
Lateral horn autonomic motor neurons. These supply smooth mus-
cles and glands with motor signals. They belong to the
Motonerons
autonomic nervous system, which controls the vascular
smooth muscles and visceral organs throughout the
body. These neurons are termed preganglionic because
Ventral horn they send their axons to a ganglion (see Figs. 28.1 and
28.2). The cell bodies lie in the lateral horn (Fig. 6.8).
Most of them form a long, slender column, the interme-
diolateral cell column. This column is present only in
gure 6.8 Cross section of the spinal cord at the thoracic level. the thoracic and upper two lumbar segments of the
Photomicrograph of a section stained so that myelinated axons
appear dark. The large motoneurons in the ventral horn have also
cord and belongs to the sympathetic part of the auto-
been stained (Nissl staining) and are just visible. Owing to shrinkage, nomic nervous system. A corresponding, smaller group
the motoneurons are surrounded by a clear zone. of neurons is present in the sacral cord (S3S4) and
belongs to the parasympathetic part of the autonomic axons and dendrites, the peripheral process (conduct-
nervous system. ing toward the cell body) should be called a dendrite,
Both the somatic and the autonomic motor neurons whereas the central process is an axon. Both processes
are under synaptic influence from higher levels of the are, however, morphologically and functionally axons
CNS. (e.g., by conducting action potentials and by being
myelinated).
The dorsal root fibers form synaptic contactsin part
Sensory Neurons in the Cord Are Inuenced from the
directly, in part indirectly through the interneurons
Dorsal Roots and Convey Signals to the Brain
with neurons in the spinal cord, sending their axons
The second main type of spinal neuron sends axons to to various parts of the brain. Such axons, destined for
higher levels of the CNS. Their cell bodies lie mainly in a common target in the brain, are grouped together
the dorsal horn and in the transition zone between the in the spinal white matter, forming tracts (Latin:
dorsal and ventral horn (Figs. 6.7 and 6.9). Their job is tractus). Such tracts are named after the location of
to inform the brain of the activities of the spinal cord, the cell bodies and after the target organ. A tract
and especially about what is going on in the body. To leading from the spinal cord to the cerebellum, for
fulfill the latter task, the neurons must receive signals example, is named the spinocerebellar tract (tractus
from sense organsreceptorsin various parts of the spinocerebellaris).
body (in the skin, muscles, viscera, and so on). Sensory,
or afferent, nerve fibers conducting impulses from the
Interneurons Enable Cooperation between Different Cell
receptors enter the spinal cord through the dorsal roots
Groups in the Spinal Cord
and ramify, forming terminals in the gray matter of the
cord (Fig. 6.9; see also Fig. 13.12). The sensory neurons The axons of the third type of spinal neuron do not
have their cell bodies in the spinal ganglia (Fig. 6.5; see leave the spinal cord. Usually, the axons ramify exten-
also) and are therefore called spinal ganglion cells (see sively and establish synaptic contacts with many other
Fig. 13.13). These are morphologically special, as they neurons in the cord, within the segment in which the
have only one process, which divides shortly after leav- cell body is located, and in segments above and below
ing the cell body: One peripheral process connects with (Fig. 6.7). Such neurons are called spinal interneurons,
the sense organs, and the other extends centrally and to emphasize that they are intercalated between other
enters the spinal cord (pseudounipolar neuron; see neurons.1 Many spinal interneurons are found in an
Fig. 1.5). In accordance with the usual definition of intermediate zone between the dorsal and ventral horns,
where they receive major synaptic inputs from sensory
fibers in the dorsal roots. Many of these interneurons
To the brain stem establish synaptic contacts with motoneurons in the
ventral horn, thus mediating motor responses to
sensory stimuli. Most interneurons, however, receive
additional strong inputs from other spinal interneurons
and from the brain.
As mentioned, spinal interneurons also send collater-
als to terminate in segments of the cord other than
the one in which their cell body and local ramifications
Spinal ganglion cell are found. Such collaterals enter the white matter,
run there for some distance, and reenter the cord
at another segmental level, to ramify and establish syn-
aptic contacts in the gray matter (Fig. 6.7). Axons of
this kind in the white matter are called propriospinal
fibers (i.e., fibers belonging to the spinal cord itself),
to distinguish them from the long ascending and
descending fibers that connect the cord with the brain.
Sensory neuron
gure 6.9 Sensory neuron in the gray substance of the spinal cord.
The neuron, which sends its axon to the brain stem, is synaptically 1 Strictly speaking, most neurons in the CNS are interneurons according to this
contacted by sensory afferents that enter the cord through the dorsal denitionincluding, for example, spinal neurons with axons ascending to the
root (pseudounipolar ganglion cell). The presentation is very simpli- brain. In practice, the term interneurons is nevertheless restricted to neurons
ed; in reality, every sensory neuron is contacted by numerous dorsal with an axon ramifying near the cell body, thus synaptically coupling neurons
root afferents. within one nucleus.
Propriospinal neuron is, therefore, another term used Thick, myelinated
2 dorsal root fibers
for a spinal interneuron. Zona terminalis
Propriospinal fibers provide opportunities for coop- (thin, unmyelinated
fibers)
eration among the spinal segments. Most of movements
necessitate close coordination of the activity in many I
segments, each controlling different groups of muscles. II
III
Some propriospinal connections are very long and IV
Substantia
interconnect segments in the cervical and lumbar parts gelatinosa
V
of the cord that control muscles in the forelimb and VI

hindlimb, respectively. Cooperation between the fore-
VII
limbs and hind limbs is necessary, for example, during
walking. IX IX
VIII
IX
Spinal interneurons are discussed further in Chapter 13,
under Sensory Fibers Are Links in Reflex Arcs: Spinal IX
Interneurons, and in Chapter 22, under The Pyramidal
Tract Can Open and Close Spinal Reflex Arcs.
The Spinal Gray Matter Can Be Divided into Zones

Called Rexeds Laminae gure 6.10 Cross section of the spinal cord at the lumbar level
(lumbar intumescence). Left: Photomicrograph of section stained to
Systematic observations with the microscope of trans- show myelin and neuronal cell bodies. Right: The borders between
verse sections of the spinal cord stained to visualize cell Rexeds laminae. The groups of motoneurons in the ventral horn
( and motoneurons) constitute lamina IX; the zona terminalis
bodies show that neurons with different sizes and
(tract of Lissauer) consists primarily of thin dorsal root bers.
shapes are also differently distributed (Fig. 6.10; see
also Fig. 13.16). Essentially, neurons with common
morphological features are collected into transversely
oriented bands or zones. What appear as bands in the Even though the cell bodies are arranged in laminae,
transverse plane are, three-dimensionally, longitudinal the dendrites extend much wider, as shown in Fig. 6.12.
slabs or sheets. This laminar pattern is most clear-cut in Thus, a neuron belonging to a particular lamina receives
the dorsal horn, whereas in the ventral horn neurons synaptic inputs from nerve terminals in neighboring
are collected into regions that form longitudinal col- laminae. Nevertheless, experimental studies of the con-
umns rather than plates (see Fig. 21.2). Nevertheless, nections of the spinal cord and of the functional prop-
the columns in the ventral horn, as well as the slabs in erties of single spinal neurons have shown that the
the dorsal horn, are termed laminae. This pattern was various laminae differ in these respects. Thus, the lami-
first described in 1952 by the Swedish neuroanatomist nae may be regarded, at least to some extent, as the
Bror Rexed and has since proved to be of great help for nuclei of the spinal cord. We will return to Rexeds
investigations of the spinal cord. Altogether, Rexed laminae when dealing with the functional organization
described 10 laminae; laminae IVI constitute the dor- of the spinal cord in later chapters.
sal horn, whereas lamina IX is made up of columns of
motoneurons in the ventral horn. Lamina II (substantia
The Spinal Nerves Divide into Branches
gelatinosa; Figs. 6.8, 6.10, and 6.11) is of particular
importance for the control of signals from pain recep- The dorsal (sensory) and ventral (motor) roots join to
tors, and thus how much a painful stimulus hurts. form spinal nerves, as described. Each spinal nerve then
Lamina VII constitutes the transition between the dor- divides into several branches (rami) just outside the
sal and ventral horns and contains mainly interneurons. intervertebral foramen (Figs. 6.5 and 6.6). The thickest
Lamina VIII, located medially in the ventral horn, con- one, the ventral ramus (ramus ventralis), passes
tains many neurons that send axons to the other side of ventrally. A thinner branch, the dorsal ramus (ramus
the cord (commissural fibers). dorsalis), bends in the dorsal direction. In contrast to
the spinal roots, the ventral and dorsal rami contain
both sensory and motor fibers. This is caused by mixing
of fibers from dorsal and ventral roots as they continue
into the spinal nerves.
2 It was formerly believed that propriospinal neuronsthat is, spinal neurons The dorsal rami innervate muscles and skin on
with axons entering the white matter but not leaving the spinal cordand the back, whereas the ventral rami innervate skin and
interneurons represented two distinct cell groups. Recent studies have shown
that spinal interneurons have local (intrasegmental) branches, as well as col- muscles on the ventral aspect of the trunk and neck
laterals destined for other segments (intersegmental). and, in addition, the extremities. Thus, the ventral rami
Thick, myelinated Dura

dorsal root fibers
Zona
terminalis
Substantia gure 6.11 Cross section of the spinal

gelatinosa cord at the cervical level (cervical intu-
Dorsal horn mescence). The broad ventral horns con-
tain the motoneurons that supply muscles
Ventral horn of the arm and shoulder girdle. Compared
with the lumbar cord (Fig. 6.10), the cer-
vical cord contains more white matter in
proportion to gray matter; this is because
Spinal nerve roots all descending and ascending bers to and
from the lower levels pass through the
cervical cord.
innervate much larger parts of the body than the dorsal

The Spinal Cord Consists of Subunits that Are Controlled
ones, which explains why the ventral rami contain more
from the Brain
nerve fibers and are considerably thicker than the dor-
sal ones. Some of the ventral rami join each other to Each segment of the spinal cord is to some extent a
form plexuses (see Fig. 21.1). functional unit, since, as we will see in Chapter 13, a pair
Each spinal nerve also sends off a small branch, the of spinal nerves relates to a particular segment of the
meningeal ramus, which passes back through the inter- body (see Fig. 13.14). A spinal segment may be regarded
vertebral foramen to reenter the vertebral canal as the local government of a part of the body: it receives
(Fig. 6.5). These branches supply the meninges of the sensory information from its own district, processes
spinal cord with sensory and autonomic (sympathetic) this information, and issues orders through motor nerves
fibers. to muscles and glands to ensure adequate responses.
However, just as local governing bodies in our society
must take orders from higher ones (e.g., county versus
national governments), the spinal segments have only
limited independence. Many of the functional tasks of
Incoming fibers
Neurons in the from the brain stem the spinal cord are under strict control and supervision
substantia gelatinosa and cerebral cortex from higher levels of the CNS. This control is mediated
by fibers from the brain stem and cerebral cortex, which
descend in the white matter of the cord and terminate
in the gray matter of the spinal segments that are to be
influenced. The brain also ensures that the activity of
the various spinal segments is coordinated, so that it
serves the body as a whole and not only a small part.
Inter- To be able to carry out this coordination, the brain
neurons must continuously receive information about condi-
tions in all the local districts of the body and in the
spinal segments related to them. This information is
mediated by long, ascending fibers (forming various
tracts) in the white matter of the cord that terminates in
the brain stem. The local cooperation among spinal
segments is taken care of by the numerous propriospinal
Motoneuron fibers coming from spinal interneurons.
gure 6.12 Dendritic arborizations of spinal neurons extend beyond

the laminae of their cell bodies. Composite drawing based on obser- THE BRAIN STEM
vations in many Golgi-impregnated transverse sections from the spi-
nal cord of the cat. The dendrites extend far, not only in the transverse
plane as shown here but also longitudinally. To the right (at A) are
The brain stem represents the upward (rostral, cranial)
the terminal ramications of axons descending to the cord from continuation of the spinal cord (Fig. 6.1). It consists of
higher levels of the CNS. (From Scheibel and Scheibel 1966.) several portions with, in part, clear-cut surface borders
between them (Figs. 6.13 to 6.15). Whereas the lower- situated in the diencephalon. We return to the ventricular
most (caudal) part of the brain stem is structurally sim- system in Chapter 7.
ilar to the spinal cord, the upper parts are more
complicated. The subdivisions of the brain stem are as
The Cranial Nerves
follows (from caudal to rostral): the medulla oblongata
(often just called medulla), the pons (the bridge), the Examination of the internal structure of the brain stem
mesencephalon (the midbrain), and the diencephalon. shows that it is more complicated than that of the spi-
Usually, however, often we use a more restricted defini- nal cord (see, e.g., Fig. 6.16). Even though gray matter
tion including only the parts that extrude from the base is generally located centrally, surrounded by a zone of
of the brain: the medulla, pons, and mesencephalon. white matter in both the brain stem and the cord, the
gray matter of the brain stem is subdivided into several
regions separated by strands of white matter. The white
The Brain Stem Contains the Third and Fourth Ventricles
matter of the brain stem consists of myelinated fibers,
A continuous, fluid-filled cavity varying in diameter as in other parts of the CNS. The regions with gray
stretches through the brain stem (Fig. 6.2). It is the matter contain various nuclei, or groups of neurons
upward continuation of the thin central canal of the with common tasks.
spinal cord, and it continues rostrally into the cavities Many of the nuclei belong to the cranial nerves.
of the cerebrum (see Figs. 7.3 and 7.5). Together, these In total, there are 12 pairs of cranial nerves, which,
cavities constitute the ventricular system of the brain with the exception of the first, all emerge from the brain
and spinal cord. The cavity in the brain stem has two stem (Figs. 6.13 and 6.15). They correspond to the
dilated parts: one, the fourth ventricle, is at the level of spinal nerves but show a more complex and less regular
the medulla and pons, whereas the third ventricle is organization. Thus, there is no clear separation of
Olfactory nerve (1)
Olfactory bulb
Olfactory tract
Optic nerve (2)

Optic chiasm
Pituitary gland
Mammillary body
Oculomotor nerve (3)
Trochlear nerve (4)
Pons
Trigeminal nerve (5)
Abducens nerve (6)
Facial & Vestibulo-
cochlear nerves (7, 8)
Flocculus
Glossopharyngeal &
Vagus nerves (9, 10)
Hypoglossal nerve (12)

Medulla oblongata
Cerebellar hemisphere
Tonsilla cerebelli
gure 6.13 The basal aspect First cervical nerve
of the brain. Only some of the
cranial nerves are shown. Vermis Spinal cord
Thalamus sensory (dorsal) and motor (ventral) roots. The cranial

nerves are numbered from rostral to caudal, in accor-
dance with where they emerge on the surface of the
DIENCEPHALON brain stem. Figure 8.9 shows the places on the base of
Internal the skull where the cranial nerves leave through small
capsule holes or fissures.
Many of the cranial nerves contain fibers that con-
Superior duct impulses out of the brain stem; that is, the fibers
Optic nerve
colliculus are efferent, or motor. These fibers belong to neurons
MESENCEPHALON
Inferior with their cell bodies in nuclei that are called motor
Crus cerebri
colliculus cranial nerve nuclei. They correspond to the groups
Superior cerebellar
(columns) of neurons in the ventral and lateral horns of
peduncle (brachium the spinal cord. The cranial nerves, like the spinal
conjunctivum) nerves, also contain sensory, afferent fibers that bring
PONS
Middle cerebellar impulses from sense organs. The brain stem cell groups
peduncle in which these afferent fibers terminate are, accord-
(brachium pontis)
ingly, called sensory cranial nerve nuclei; they corre-
spond to the laminae of the spinal dorsal horn. The
MEDULLA sensory fibers entering the brain stem have their cell
OBLONGATA
bodies in ganglia just outside the brain stem, cranial
nerve ganglia, corresponding to the spinal ganglia of
the spinal nerves. Most cranial nerves are mixedthat
is, they contain both motor and sensory fibersbut a
gure 6.14 The brain stem, as viewed from the left side. The levels few are either purely sensory or purely motor.
of sections shown in several of the following gures are indicated. The only cranial nerve not emerging from the brain
stem is the first cranial nerve, the olfactory nerve (ner-
vus olfactorius). This consists of short axons coming
from sensory cells in the roof of the nasal cavity, which,
immediately after penetrating the base of the skull,
terminate in the olfactory bulb (bulbus olfactorius)
(Fig. 6.13). The other cranial nerves are briefly men-
tioned in the next section in connection with a descrip-
tion of the main structural features of the brain stem.
Optic chiasm The cranial nerves and their central connections are
Stalk of the
treated more thoroughly in later chapters, particularly
pituitary gland Optic nerve (2) Chapter 27.
Optic tract
Oculomotor nerve (3)
Trochlear nerve (4) The Reticular Formation Extends through Central Parts
MESENCEPHALON
of the Brain Stem
Mammillary
Among the cranial nerve nuclei and other clearly delim-
Abducens nerve (6)
body ited cell groups, there are more diffuse collections of
Facial nerve (7) neurons. In microscopic sections stained to visualize the
PONS Vestibulocochlear n. (8) neuronal processes, a network-like pattern is seen. The
old anatomists therefore termed this partpresent in
Glossopharyngeal n. (9)
the core of most of the brain stemthe reticular forma-
Vagus nerve (10) tion (formatio reticularis; Figs. 6.166.18; see also
Oliva Fig. 26.1). In reality, however, the reticular formation
Hypoglossal nerve (12)
is not one homogeneous structure but, rather, a con-
Pyramid Accessory nerve (11)
MEDULLA glomerate of cell groups with different connections and
OBLONGATA
functional tasks. For example, some parts of the reticu-
Pyramidal
lar formation are primarily concerned with control of
decussation circulation and respiration; other parts regulate sleep
and wakefulness. However, the collective term, the
gure 6.15 The cranial nerves. The brain stem is seen from the reticular formation, is still in common use, and it may
ventral side. be practical to retain it to denote parts of the brain stem
Hypoglossal nucleus
Gracile nucleus (leg)
Cuneate nucleus (arm)
Sensory trigeminal
nucleus (face)
Reticular formation
Medial lemniscus
gure 6.16 Lower part of the medulla

Inferior olive oblongata. Cross section. Inset shows
level and plane of the section. Left half
shows photomicrograph of a section with
darkly stained myelinated bers (Woelke
Pyramid method); that is, white matter appears
dark and gray matter appears light.
with certain common anatomic features, without imply- protrude on each side of the longitudinal sulcus. Each
ing that they have common functional tasks. The retic- pyramid is formed by a thick bundle of axons belong-
ular formation is treated more comprehensively in ing to the pyramidal tract, which conveys signals from
Chapter 26. the cerebral cortex to the spinal cord and is essential for
our control of voluntary movements (the pyramidal
tract is discussed in Chapter 22). Close to the lower
The Medulla Oblongata
end of the medulla, on the transition to the cord, bun-
Ventrally in the midline, the medulla has a longitudinal dles of fibers can be seen to cross the midline, forming
sulcus, which is a continuation of the ventral median the pyramidal decussation (Fig. 6.15). Lateral to the
fissure of the cord (Fig. 6.15). The sulcus ends abruptly pyramid is an oval protrusion (the olive), which is
at the lower end of the pons. The so-called pyramids formed by a large nucleus, the inferior olivary nucleus
Sulcus limitans
Motor vagus
nucleus Vestibular nuclei
Hypoglossal nucleus
Solitary tract and nucleus
(sensory vagus nucleus)
Inferior cerebellar
peduncle
Vagus nerve
(root fibers)
Sensory trigeminal
nucleus
Hypoglossal nerve
(root fibers)
Reticular formation
Medial lemniscus
Inferior olive
Pyramid
gure 6.17 Upper part of the medulla oblongata. Cross section; myelin stained.
Medial longitudinal Vestibular nuclei

fasciculus
Superior cerebellar
peduncle
Reticular formation
Sensory trigeminal nucleus
Motor trigeminal nucleus
Medial lemniscus
Middle cerebellar
peduncle
Pontine nuclei
Pyramidal tract + corticobulbar

and corticopontine tracts
gure 6.18 Upper part of the pons. Cross section; myelin-stained.
(inferior olive), which sends its efferents to the cerebel- pyramids, where they form a triangular area of cross-
lum. Between the olive and the pyramid is a row of sectioned fibers. This is an important sensory tract, the
small bundles of nerve fibers (Fig. 6.15; see also medial lemniscus (lemniscus medialis), that leads from
Fig. 27.1), which are the rootlets of the hypoglossal neurons in the dorsal column nuclei to nuclei in the
nerve (the twelfth cranial nerve, nervus hypoglossus). diencephalon (see Fig. 13.17). The dorsal column nuclei
This nerve supplies the striated muscles of the tongue receive afferent fibers that ascend in the dorsal columns
with motor fibers. Lateral to the olive, the rootlets of (or dorsal funicles) and convey impulses from sense
the glossopharyngeal and vagus nerves (ninth and tenth organs in the skin and muscles and around joints. Close
cranial nerves, nervus glossopharyngeus and nervus to the midline, just ventral to the central canal, lies the
vagus) leave the brain stem. These two nerves supply hypoglossal nucleus, consisting of the cell bodies of the
the pharynx, the larynx, and most of the viscera with motor fibers that form the hypoglossal nerve. The effer-
motor and sensory fibers. The accessory nerve (eleventh ent fibers of the hypoglossal nucleus pass ventrally and
cranial nerve, nervus accessorius) runs cranially along leave the medulla at the lateral edge of the pyramid
the lateral aspect of the medulla. Most of its fibers come (Fig. 6.15). Lateral to the motor cranial nerve nuclei are
from the upper cervical spinal segments but enter found several sensory cranial nerve nuclei, among them
the cranial cavity to leave the skull together with the the big sensory trigeminal nucleus that receives sensory
glossopharyngeal and vagus nerves (see Fig. 27.8). The impulses from the face, carried in the trigeminal nerve
accessory nerve supplies two muscles in the neck with (the fifth cranial nerve, nervus trigeminus). Note how
motor fibers. the nuclei that are transmitting sensory impulses from
Figure 3.16 shows a cross section through the lower the leg, arm, and face are distributed from medial to
part of the medulla, at a level below the caudal end of lateral in the dorsal part of the medulla (Fig. 6.16).
the fourth ventricle. The section is stained so that A cross section through the upper part of the medulla
regions with white matter (the myelinated fiber tracts) (Fig. 6.17) shows partly the same fiber tracts and nuclei
are dark, whereas gray matter (the nuclei) appears light. as the section at a lower level (Fig. 6.16). In addition,
The ventrally located bundle of cross-sectioned fibers is we may notice the big vestibular nuclei situated dor-
the pyramidal tract, forming the pyramid (Fig. 6.15), sally and laterally under the floor of the fourth ventricle
and containing about 1 million fibers. Dorsal to the (these nuclei also extend cranially into the pons; see
pyramid lies a highly convoluted band of gray matter, Fig. 19.7). They receive sensory impulses from the ves-
the inferior olivary nucleus. The dorsal column nuclei, tibular apparatus in the inner ear via the vestibular
the gracile and cuneate (nucleus gracilis and nucleus nerve (the eighth cranial nerve). One of the main effer-
cuneatus), are located dorsally in the medulla. The ent pathways from the vestibular nuclei forms a distinct
efferent fibers from these nuclei arch ventrally and tract, the medial longitudinal fasciculus (fasciculus
take up a position close to the midline dorsal to the longitudinalis medialis), close to the midline under the
floor of the fourth ventricle (Fig. 6.18). This tract Figure 6.18 also shows the sensory trigeminal nucleus
terminates in the motor nuclei of the cranial nerves sup- laterally (this nucleus extends as a slender column
plying the eye muscles, thus conveying influences on through the medulla, pons, and mesencephalon;
eye movements from the receptors for equilibrium. see also Figs. 6.166.18, and 27.2). Medial to the
Further, Fig. 3.17 shows the motor and sensory nuclei sensory nucleus lies the motor trigeminal nucleus (the
of the vagus, and some of the fibers of the vagus nerve, masticatory muscles), but this nucleus is present only in
which pass laterally and ventrally, to leave the medulla the pons.
lateral to the olive (Fig. 6.15).
The Medulla and Pons Seen from the Dorsal Side
The Pons
At the dorsal side of the medulla oblongata, at caudal
The pons forms a bulbous protrusion at the ventral levels, there are two longitudinal protrusions, the grac-
aspect of the brain stem, with clear-cut transversely ile and cuneate tubercles (Fig. 6.19). These are formed
running fiber bundles (Figs. 6.13 and 6.14). It is sharply by the dorsal column nuclei, mentioned earlier (they are
delimited both caudally and cranially. The transverse relay stations in pathways for sensory information from
fiber bundles are formed by fibers from large cell groups the body to the cerebral cortex). The most medial of
in the pons, the pontine nuclei, and terminate in the these nuclei, the gracile nucleus, receives impulses from
cerebellum. The fiber bundles join at the lateral aspect the leg and lower part of the trunk, whereas the later-
of the pons to form the middle cerebellar peduncle ally situated cuneate nucleus receives impulses from the
(brachium pontis) (Figs. 6.14 and 6.18). Several cranial arm and upper part of the trunk. Further laterally,
nerves leave the brain stem at the ventral aspect of another oblong protrusion (tuberculum cinereum) is
the pons. At the lower (caudal) edge, just lateral to the formed by the sensory trigeminal nucleus, the relay
midline, a thin nerve emerges on each side. This is the station for sensory impulses from the face.
abducens nerve (the sixth cranial nerve, nervus Rostral to the upper end of the dorsal column nuclei,
abducens) that carries motor fibers to one of the exter- there is a flattened, diamond-shaped area, the rhom-
nal eye muscles (rotates the eye laterally). Still at the boid fossa, extending rostrally onto the posterior face
lower edge of the pons, but more laterally, two other of the pons (Fig. 6.18). This constitutes the floor of
cranial nerves leave the brain stem. Most ventrally lies the fourth ventricle (Fig. 6.19). Laterally and rostrally,
the facial nerve (seventh cranial nerve, nervus facialis), the cerebellar peduncles delimit the rhomboid fossa
which brings motor impulses to the mimetic muscles of (these have been cut in Fig. 6.19). Some of the cranial
the face (it also contains some other kinds of fibers that nerve nuclei and some fiber tracts form small protru-
are considered in Chapter 27). Closely behind the facial sions medially at the floor of the fourth ventricle
nerve lies the vestibulocochlear nerve (the eighth cra- notably the hypoglossal nucleus (hypoglossal trigone),
nial nerve, nervus vestibulocochlearis), which carries the vagus nucleus (vagal trigone) and more rostrally the
sensory impulses from the sense organs for equilibrium root fibers of the facial nervethe latter forming the
and hearing in the inner ear. The trigeminal nerve (the facial colliculus. (Figure 27.11 explains how the facial
fifth cranial nerve, nervus trigeminus) leaves the brain colliculus is formed.)
stem laterally at middle levels of the pons. The largest
portion of the nerve consists of sensory fibers from the
The Mesencephalon (Midbrain)
face, whereas a smaller (medial) portion contains motor
fibers destined for the masticatory muscles. The part of the brain stem rostral to the pons, the mes-
In a cross section through the pons, the large pontine encephalon, is relatively short (Figs. 6.14 and 6.15).
nuclei can be seen easily (Fig. 6.18). As mentioned, the Ventrally, an almost half-cylindrical protrusion is pres-
neurons of the pontine nuclei send their axons to the cer- ent on each side of the midlinethe crus cerebri, or
3
ebellum. Because their main afferent connections come cerebral peduncle (Figs. 6.15 and 6.20). Crus cerebri
from the cerebral cortex, the pontine nuclei mediate infor- consists of nerve fibers descending from the cerebral
mation from the cerebral cortex to the cerebellum. The cortex to the brain stem and spinal cord; among these
medial lemniscus borders the pontine nuclei dorsally and fibers are those of the pyramidal tract. The fibers con-
has turned around and moved laterally compared with its tinue into the pons, where they spread out into several
location in the medulla (Fig. 6.16). In the lower part of smaller bundles among the pontine nuclei (Fig. 6.18).
the pons, the nucleus of the abducens nerve, the abducens
nucleus, is located dorsally and medially, whereas the 3 Strictly speaking, the term cerebral peduncle denotes both the crus cerebri
facial nucleus lies more ventrally and laterally (see and parts of the mesencephalon dorsal to the crus except the colliculi (the latter
Fig. 27.11; Fig. 17.11 also shows the course taken by the collectively termed the tectum). The region between the crus cerebri and the
tectum is called the tegmentum and includes the periaqueductal gray, the red
efferent fibers of the abducens and facial nuclei, forming nucleus, and the substantia nigra. Previously, however, the crus cerebri and the
the sixth and seventh cranial nerves, respectively). cerebral peduncle were both applied to the ventralmost, ber-rich part.
Third ventricle
Thalamus
Pineal body
Superior colliculus
Medial geniculate body
Inferior colliculus
Trochlear nerve (4)
Cerebellar peduncles

Facial colliculus
Facial nerve (7)
Vestibulocochlear nerve (8)
Rhomboid fossa
Hypoglossal nucleus (hypogl. trigone)
Vagus nucleus (vagal trigone)
Tuberculum cinereum
Cuneate tubercle
Gracile tubercle
gure 6.19 The brain stem. Viewed
Dorsal columns
from the dorsal aspect.
In the furrow between the two crura, the oculomotor canal that interconnects the third and fourth ventricles
nerve emerges (third cranial nerve, nervus oculomoto- (Figs. 6.23 and 7.5). Surrounding the aqueduct is a
rius) (Figs. 6.13 and 6.15). As the name implies, the region of gray matter called the periaqueductal gray
nerve carries motor impulses to muscles that move the substance (substantia grisea centralis), which coordi-
eye. The oculomotor nerve innervates four of the six nates behavioral responses to stressful events and influ-
extraocular (striated) muscles and, in addition, two ences pain perception. Ventral to the periaqueductal
smooth internal muscles that regulate the diameter of gray, close to the midline, we find the oculomotor
the pupil and the curvature of the lens. nucleus (or nucleus of the oculomotor nerve). Further
At the dorsal side of the mesencephalon, there is a ventrally lies the large red nucleus (nucleus ruber), so
characteristic formation of four small, rounded protru- named because of its slightly reddish color. Just dorsal
sions, two on each side of the midline (Fig. 6.18). These to the crus and ventral to the red nucleus is the substan-
are called the colliculi (corpora quadrigemina) and con- tia nigra (the black substance). The neurons of the sub-
sist of, on each side, the superior colliculus and the infe- stantia nigra contain a dark pigment, making the
rior colliculus. The superior colliculus consists of cell nucleus clearly visible macroscopically. The red nucleus
groups that control reflex movements of the eyes and the and the substantia nigra are both important for the
head, while the inferior colliculus is a relay station in the control of movements.
pathways that bring auditory impulses to awareness.
A thin fiber bundle, the trochlear nerve (fourth cranial
The Diencephalon Contains the Thalamus and
nerve, nervus trochlearis), emerges on each side below
the Hypothalamus
the inferior colliculi (Fig. 6.19). This is the only cranial
nerve that emerges on the dorsal side of the brain stem. Figure 6.21 shows how the diencephalon merges
It supplies one of the extraocular muscles with motor with the mesencephalon caudally without any clear
fibers. transition. Neither rostrally is the diencephalon clearly
In a cross section of the mesencephalon (Fig. 6.20), delimited (Fig. 6.13) because in early embryonic life it
the crus cerebri can be recognized ventrally, and the fuses with the primordium of the cerebral hemispheres.
superior colliculus dorsally. In the midline just ventral The optic nerve (the second cranial nerve, nervus
to the colliculi there is a small hole, which is a cross sec- opticus) carrying afferent fibers from the retina ends in
tion of the aqueduct (aquaeductus cerebri), a narrow the diencephalon.
Medial longitudinal Superior colliculus

faciculus
Aqueduct
Periaqueductal gray (PAG)
Medial lemniscus
Reticular formation
Oculomotor
Crus cerebri nucleus
Red nucleus
Substantia
nigra
gure 6.20 The mesencephalon.

Cross section. The major nuclei are
indicated in red and the major
Oculomotor nerve
tracts are in gray.
The largest part of the diencephalon is occupied by three main parts: an anterior nuclear group (or com-
the thalamus, situated on each side of the third ventricle plex), a medial nuclear group, and a lateral part or
4
(Figs. 6.22, 6.24, and 6.27). The thalamus consists of region made up of a dorsal and a ventral nuclear group.
many smaller nuclei and is a relay station for almost all The pulvinar, continuous with the lateral part, makes
information transmitted from the lower parts of the up most of the posterior part of the thalamus (Figs. 6.21
CNS to the cerebral cortex (notably most kinds of sen- and 6.22). In addition, the posterior part of the thala-
sory information). Each thalamus is approximately mus includes two nuclei partly covered by the pulvinar,
egg-shaped with a flattened side toward the third ven- the lateral geniculate body (corpus geniculatum later-
tricle (Fig. 6.22). Lateral to the thalamus lies a thick ale) and the medial geniculate body (corpus genicula-
sheet of white matter, the internal capsule (capsula tum mediale). Each of the thalamic nuclei connects to
interna). It consists mainly of fiber tracts connecting the
cerebral cortex with the thalamus, the brain stem, and
the spinal cord, among them the pyramidal tract
(Figs. 6.14, 6.24, 6.27, and 6.30). The crus cerebri is a 4 The nomenclature of thalamic nuclear subdivisions may appear bewildering,
and matters are not made easier by lack of agreement among leading investiga-
caudal continuation of fibers of the internal capsule. tors. For example, the nomenclature presented in the Terminologia Anatomica
In a frontal section of the brain (Fig. 6.24) the thala- (1998) differs from that used in the scholarly book The Human Nervous
mus is subdivided by narrow bands of white matter System, edited by Paxinos and Mai (2004). Throughout the present book when
dealing with the thalamus, I have tried to simplify matters to provide just
forming a Y, called the internal medullary lamina (see enough anatomical detail to help the reader understand the functional organi-
also Fig. 6.22). This divides the thalamic gray matter in zation of the thalamus.
Habenula
Pulvinar
Lateral
geniculate
body
Medial genicu-
late body
Substantia
nigra
Crus cerebri
Red nucleus
gure 6.21 Transition between the mesencephalon and the dien-

cephalon. Oblique frontal section; myelin stained. Inset shows plane
and level of the section.
Medial nuclei
Massa intermedia The optic nerves from the two eyes unite just under-
Third ventricle neath the diencephalon (Figs. 6.13 and 6.15) to form
the optic chiasm (chiasma opticum, or just chiasma), in
Dorsal Anterior which there is a partial crossing of the optic nerve fibers
(see Fig. 16.14). In their further course from the optic
Anterior chiasm to the lateral geniculate body, the fibers form
Posterior
nuclei the optic tract (Figs. 6.15 and 6.24). The fibers from the
lateral geniculate body to the visual cortex form the
optic radiation (Fig. 16.15).
Pulvinar
Dorsal and
Anterior and inferior to the thalamus lies the hypo-
Medial ventral nuclei thalamus (Fig. 6.23), which exerts central control of the
geniculate autonomic nervous systemthat is, with control of the
body Lateral genicu- Internal medullary
lamina visceral organs and the vessels. The hypothalamus
late body Ventral forms the lateral wall of the anterior part of the third
ventricle. The border between the thalamus and the
gure 6.22 The thalamus. Drawing of the thalami of both sides, to
hypothalamus is marked by the shallow hypothalamic
indicate their three-dimensional form.
sulcus (Figs. 6.23 and 6.24). The mammillary body
(corpus mammillare), a special part of the hypothala-
mus, protrudes downward from its posterior part
different parts of the cerebral cortex (see Fig. 34.7). For (Figs. 6.13, 6.23, and 6.29). The fornix is a thick, arch-
example, the lateral and medial geniculate bodies are ing bundle of fibers originating in the cerebral cortex
relay stations for visual and auditory impulses, respec- (in the so-called hippocampal region in the temporal
tively. Thus, fibers of the optic nerve end in the lateral lobe) and terminating in the mammillary bodies (see
geniculate body while fibers from the inferior colliculus Fig. 32.2). The major efferent pathway of the mammil-
end in the medial geniculate body. lary body goes to the thalamus, forming a distinct fiber
Choroid plexus (of

Fornix third ventricle)
Interventricular
Corpus foramen
callosum
Thalamus
Hypothalamic
sulcus
Pineal body
Hypothalamus Aqueduct
Infundibulum gure 6.23 The hypothala-
mus. Drawing of midsagittal
Pituitary section showing the upper parts
of the brain stem. The hypo-
Mammillary body
thalamus is indicated in red.
Anterior nuclei
Internal medullary
lamina
Medial nuclei
Dorsal and ventral
nuclei
Mammillo-
thalamic fascicle
Internal capsule
Hypothalamic
sulcus
Hypothalamus
Putamen
Fornix
Globus pallidus
Third ventricle
Optic tract
Arcuate nucleus
(hypothalamus)
gure 6.24 The diencephalon. Frontal section; myelin stained.
bundle, the mammillothalamic tract (fasciculus mam- show a cyclic variation. This is discussed more thor-
millothalamicus) (Figs. 6.24 and 30.6). In front of the oughly in Chapter 30, under Hypothalamus and
mammillary bodies, the floor of the third ventricle Circadian Rhythms and under Melatonin.
bulges downward like a funnel and forms the stalk of The habenula (Fig. 6.21) lies just underneath the
the pituitary gland, the infundibulum. The region pineal body (one on each side). This small nucleus
between the mammillary bodies and the infundibulum (composed of several subnuclei) receives afferents from
is called the tuber cinereum (see Fig 30.3). It contains the hypothalamus and the septal nuclei, among other
neuronal groups that influence the activity of the sources. Its main efferents go to nuclei in the mesen-
pituitary gland. cephalon. The functional role of the habenula is not
The pituitary (Figs. 6.13 and 6.23) consists of a known, but the pathway from the hypothalamus via
posterior lobe, developed from the CNS, and an ante- habenula to the mesencephalon may be engaged in the
rior lobe, developed from the epithelium in the roof of bodily expressions of strong emotionsfor example,
the mouth. The anterior lobe, secreting several hor- rage or fear. The habenula is one among several neuronal
mones that control important bodily functions, is itself groups that are altered in severe depression.
under the control of the hypothalamus. This is discussed
further in Chapter 30.
THE CEREBRUM
Epithalamus and the Pineal Body
The cerebrum has an ovoid shape and fills most of the
The diencephalon also includes a small area called the cranial cavity. Whereas its convexitythat is, its upper
epithalamus, located posteriorly in the roof of the third and lateral surfacesare evenly curved, the basal sur-
ventricle. In addition to a small nucleus, the habenula face is uneven. In the center of the basal surface, the
(Fig. 6.21), the epithalamus contains the pineal body or brain stem emerges (Fig. 6.13). The cerebrum is almost
gland (corpus pineale) (Figs. 6.19, 6.23, and 6.31). This completely divided in two by a vertical slit, the longitu-
peculiar structure lies in the midline (unpaired) and is dinal cerebral fissure (fissura longitudinalis cerebralis),
formed by an evagination of the roof of the third ven- so that it consists of two approximate half-spheres or
tricle. It contains glandular cells, pinealocytes, which cerebral hemispheres (Figs. 6.25 and 6.26). Each of the
produce the hormone melatonin (and several neuropep- cerebral hemispheres contains a central cavity, the
tides). It also contains large amounts of serotonin, lateral ventricle (Figs. 6.29 and 7.3). The lateral ven-
which is a precursor of melatonin. Melatonin influences tricles are continuous, with the third ventricle through
several physiological parameters, especially those that a small opening, the interventricular foramen (Fig. 6.37).
Central sulcus
Precentral gyrus Postcentral gyrus
PARIETAL LOBE
FRONTAL Angular gyrus

LOBE
OCCIPITAL
LOBE
Inferior frontal gyrus

Superior temporal gyrus gure 6.25 The left cerebral hemi-
Lateral sulcus
sphere. Viewed from the lateral
TEMPORAL LOBE
aspect.
The lateral ventricles are surrounded by masses of white neurons in various parts of the cerebral cortex of one
matter with some embedded nuclei. The surface of the hemisphere. Finally, a vast number of commissural
hemisphere is covered everywhere by a 3 to 5 mm-thick fibers interconnect neurons in the two hemispheres.
layer of gray substance, the cerebral cortex (cortex cere- Most of the commissural fibers are collected into a
bri). The structure, connections, and functions of the thick plate of white matter, the corpus callosum, which
cerebral cortex are covered most completely in Chapters joins the two hemispheres across the midline (Figs. 6.26,
33 and 34, but some main features are briefly described 6.27, 6.28, and 6.29). The fibers in the corpus callosum
here because knowledge of them is necessary for the enable impulses to travel from one hemisphere to the
chapters dealing with sensory and motor systems. other and thus ensure that the right and left hemispheres
The neurons of the cerebral cortex receive impulses can cooperate (see Chapter 34, under The Function of
from lower parts of the CNS, most of which are relayed the Commissural Connections). A few commissural
through the thalamus. In addition, there are numerous fibers pass in the anterior commissure (commissura
association fibersthat is, fibers interconnecting anterior) (Fig. 6.26).
Fornix Cingulate gyrus

Corpus callosum
Cingulate sulcus
PARIETAL LOBE
FRONTAL
Parieto-occipital
LOBE
sulcus
Calcarine
sulcus
OCCIPITAL
LOBE
Anterior commissure
Brain stem (cut) TEMPORAL LOBE

Hippocampal gure 6.26 The left cerebral hemi-
sulcus Parahippocampal Uncus sphere. Viewed from the medial aspect.
gyrus The brain stem has been cut off.
The Surface of the Hemisphere Is Highly Convoluted and The Hemisphere Can Be Divided into Four Lobes
Forms Gyri and Sulci
With more or less sharply defined borders (formed by
During embryonic development, the cerebral hemi- fissures and sulci), one can distinguish four lobes of the
spheres fold as they grow in size (see Fig. 7.4). This cerebral hemispheres (Figs. 6.25 and 6.26). They are
leads to a great increase in their surface area and thus in named in accordance with the bone of the skull under
the amount of cortex relative to their volume (only which they are located. The frontal lobe (lobus fronta-
about one-third of the total cortical surface is exposed). lis) lies in the anterior cranial fossa above the orbit. The
The furrowed, walnut-like appearance of the cerebral frontal lobe is separated from the parietal lobe (lobus
hemispheres of humans and some higher mammals is parietalis) by the central sulcus, which extends from the
highly characteristic (Figs. 6.25,6.26, and 6.28). The medial edge of the hemisphere laterally to the lateral
folding of the hemisphere produces deep fissures and sulcus. Below the lateral sulcus lies the temporal lobe
more shallow sulci. Between the sulci, the surface of the (lobus temporalis). Neither the parietal nor the tempo-
cortex forms rounded gyri. Apart from the fissure that ral lobe has any clearly defined border posteriorly
divides the two hemispheres along the midline, the lon- toward the occipital lobe. The occipital lobe lies above
gitudinal cerebral fissure, the largest fissure in each the cerebellum, which is located in the posterior cranial
hemisphere is the lateral cerebral sulcus (fissure) or the fossa (Fig. 6.1). On the medial aspect of the hemisphere,
Sylvian fissure (Fig. 6.25). This fissure follows a course the border between the parietal and the occipital lobe is
upward and backward and extends deep into the hemi- marked by the parieto-occipital sulcus (sulcus parieto-
sphere (Fig. 6.27). The small gyri in the bottom of the occipitalis) (Fig. 6.26).
lateral sulcus form the insula (the island) (Figs. 6.27
and 6.30). More sulci and gyri will be mentioned when
Some Functional Subdivisions of the Cerebral Cortex
dealing with the lobes of the cerebrum.
The pattern of the fissures and the larger sulci in the Anatomically and functionally, we divide the cerebral
human brain is fairly constant. Nevertheless, variations cortex into different regions, which do not, however,
are great enough to make it impossible to know exactly coincide with the different lobes. Here, only a few
where a certain sulcus is located only from landmarks points are mentioned. The gyrus in front of the central
on the outside of the skull. The smaller sulci and gyri sulcus, the precentral gyrus (gyrus precentralis)
are subject to considerable individual variation. (Fig. 6.25), coincides with the motor cortex (MI), which
Corpus callosum
Caudate nucleus
Fornix
Thalamus
Third ventricle
Putamen
Insula
Lateral sulcus
Internal capsule
Red nucleus
Lateral geniculate
body
Temporal horn of
lateral ventricle
gure 6.27 The cere-
bral hemispheres and Hippocampus
upper part of the brain Substantia nigra
stem. Photograph of
Pyramidal tract
frontal section. Compare
with Fig. 6.28. Pons
A is of special significance for the execution of voluntary

movements. Destruction of this gyrus in one hemi-
sphere, cause pareses in the opposite side of the body.
Many of the fibers in the pyramidal tract come from the
C precentral gyrus, and, as mentioned, most of these
fibers cross the midline on their way to the spinal cord.
The postcentral gyrus, situated just posterior to the cen-
B tral sulcus, is the major receiving region for sensory
impulses from the skin, the musculoskeletal system,
and the viscera. This region is called the somatosensory
cortex (SI). The tracts that conduct impulses from the
sense organs to the cortex are also crossed. Thus,
destruction of the postcentral gyrus on one side leads
B to lowered sensibility (for example, of the skin) on the
opposite side of the body. We have previously men-
tioned the medial lemniscus, which is part of the path-
ways from the sense organs to the postcentral gyrus.
The fibers of the medial lemniscus terminate in a subdi-
vision of the lateral thalamic nucleus (Fig. 6.24), and
the neurons there send their axons to the postcentral
gyrus.
The visual cortexthe main cortical region receiving
information from the eyesis located in the occipital
lobe around a deep sulcus (fissure), the calcarine sulcus
(sulcus calcarinus) (Fig. 6.26). The impulses start in the
retina and are conducted in the optic nerve and the
C optic tract to the lateral geniculate body (Figs. 6.21 and
6.22), and from there to the visual cortex (see Fig. 16.14).
The visual cortex can be distinguished from the sur-
rounding parts of the cortex in sections perpendicular
to the surface: it contains a thin whitish stripe running
parallel to the surface (caused by a large number of
myelinated fibers). Because of the stripe, this part of the
cortex was named the striate area by the early anato-
mists (see Fig. 16.18).
The auditory cortexthe cortical region receiving
impulses from the cochlea in the inner earis located
in the superior temporal gyrus of the temporal lobe
(Fig. 6.25; see also Fig. 17.11). The pathway for audi-
tory impulses is synaptically interrupted in the medial
geniculate body (Figs. 6.21 and 6.22).
The olfactory cortex is a small region on the medial
aspect of the hemisphere near the tip of the temporal
lobe. It is part of the so-called uncus (Fig. 6.26; see also
Fig. 18.3) and extends somewhat onto the adjoining
parahippocampal gyrus. The olfactory cortex receives
gure 6.28 Magnetic resonance images (MRI) in the three conven-
tional planes. A: Midsagittal plane. B: frontal (coronal) plane; corre-
fibers from the olfactory bulb (bulbus olfactorius)
sponding to Fig. 3.27. C: Horizontal (transverse) plane. A and B through the olfactory tract (tractus olfactorius)
are T1 weighted with water appearing dark. C is T2 weighted with (Fig. 6.13). The cortex of the parahippocampal gyrus
water appearing white. (Courtesy of Dr. S. J. Bakke, Rikshospitalet extends into the hippocampal sulcus (fissure), forming
University Hospital, Norway.) a longitudinal elevation, the hippocampus (Figs. 6.27
and 6.31; see also Fig. 32.2). The hippocampus belongs
to the phylogenetically oldest parts of the cerebral
cortex and has a simpler structure than the newer parts.
The hippocampus and adjoining cortical regions in the
medial part of the temporal lobe are of particular interest
with regard to learning and memory (this is treated when all layers all over the cortex are systematically
further in Chapter 32). compared. Such cytoarchitectonic differences (i.e., dif-
ferences in size, shape, and packing density of the cell
bodies) form the basis of a parcellation of the cerebral
The Cerebral Cortex Consists of Six Cell Layers
cortex of each hemisphere into approximately 50 corti-
Examination of a microscopic section cut perpendicu- cal areas (areae). Maps of the cerebral cortex showing
lar to the surface of the cerebral cortex shows that the the positions of the various areas were published by
neuronal cell bodies are not randomly distributed (see several investigators around year 1900 and are still in
Figs. 34.1 and 34.2). They are arranged into layers or use. The German anatomist Brodmann (see Fig. 20.3)
laminae parallel to the surface. Each layer is character- published the most widely used map. Such cytoarchi-
ized by a certain shape, size, and packing density of the tectonically-defined areas have later been shown, in
cell bodies (compare with the Rexeds laminae of the many cases, to differ also with regard to connections
spinal cord). We number the layers from the surface and functional properties. The numbering of the corti-
inward to the white matter. Layer 1 is cell poor and cal areas may appear illogical. For example, the motor
consists largely of dendrites from neurons with cell cortex in the precentral gyrus corresponds to area 4 of
bodies in deeper layers and of axons with terminals Brodmann. This borders posteriorly on area 3 but on
making synapses on the dendrites. Layers 2 and 4 are area 6 anteriorly. Area 3 borders on area 1, which bor-
made up of predominantly small, rounded cells and are ders on area 2, and so on (see Fig. 34.3). It is not neces-
therefore called the external and internal granular layer, sary to learn the position of more than a few of the
respectively. These two layers have in common that cortical areas, however, and these will be dealt with in
they largely have a receiving function: many of the connection with the various functional systems in
afferent fibers to the cerebral cortex terminate and form Parts IIVI of this volume.
synapses in layers 2 and 4. Fibers conveying sensory
information from lower levels of the CNS end predom-
The Basal Ganglia
inantly in layer 4, and consequently this layer is partic-
ularly well developed in the sensory cortical regions The interior of the hemispheres contains large masses
mentioned above. Layers 3 and 5 contain cells that are of gray substance. Largest among these are the so-called
larger than those in layers 2 and 4 are, and the cell bod- basal ganglia, which perform important tasks related to
5
ies tend to be of pyramidal shape, hence the name pyra- the control of movements. Other nuclear groups (the
midal cells. Many of the pyramidal cells in layer 5 send amygdala, the septal nuclei, and the basal nucleus) are
their axons to the brain stem and spinal cord, where discussed in Chapter 31, and the basal ganglia are dis-
they influence motor neurons. Layer 5 is therefore espe- cussed in Chapter 23. Here we mention only a few main
cially well developed in the motor cortex in the precen- points with regard to the anatomy of the basal ganglia.
tral gyrus. The pyramidal neurons in layer 3 send their The basal ganglia receive massive afferent connec-
axons primarily to other parts of the cerebral cortex, tions from the cerebral cortex and acts, by way of their
either in the same hemisphere (association fibers) or to efferent fibers, primarily back on motor regions of the
cortex in the hemisphere of the other side (commissural cortex. Sections through the hemispheres show that the
fibers). The cell bodies of layer 6 are smaller and more basal ganglia consist of two main parts (Figs. 6.29 and
spindle-shaped than those in layer 5 are. Many of the 6.30). In a horizontal section (Fig. 6.30) one large part
neurons send their axons to the thalamus, enabling the lies lateral to the internal capsule, and a smaller part
cerebral cortex to influence the impulse traffic from the lies medial to the internal capsule and anterior to the
thalamus to the cortex (feedback connections). thalamus. The largest part is called the lentiform nucleus
There are also numerous interneurons in the cerebral (nucleus lentiformis) because of its shape. It consists of
cortex, providing opportunity for cooperation between two closely apposed parts: the lateral or external part is
the various layers (interneurons with vertically ori- the putamen, and the medial or internal part is the glo-
ented axons) and between neurons in different parts of bus pallidus. The part of the basal ganglia situated
one layer (interneurons with horizontally oriented medial to the internal capsule is the caudate nucleus
axons). The layers are obviously not independent units. (nucleus caudatus). The name describes its form: a large
part of the nucleus forms a long, curved tail (Fig. 7.4,
see also Fig. 23.1). The putamen and the caudate
The Cerebral Cortex Can Be Divided into Many Areas
on a Cytoarchitectonic Basis
We mentioned that some layers are particularly well 5 The name basal ganglia has been retained from a time when all collections of
developed in certain regions of the cortexfor exam- neurons were called ganglia, regardless of whether they were located inside or
outside the CNS. Today we use the term ganglion only for collections of neu-
ple, layer 4 in the sensory receiving areas and layer 5 in rons outside the CNS, as discussed in Chapter 1. However, the name basal
the motor cortex. There are many more differences ganglia is so well established that is not practical to exchange it.
Corpus callosum
Septum pellucidum
Lateral ventricle
Caudate nucleus
Fornix
Internal capsule
Putamen
Insula
Globus pallidus
Third ventricle
Claustrum
Hypothalamus
Mammillary body
Amygdala
gure 6.29 The cerebral hemispheres.
Oculomotor nerve
Frontal section, placed more frontally
Pons
than as shown in Fig. 3.27, showing
the basal ganglia and amygdala.
nucleus together are called the striatum (or neostria- this peculiar form can be explained on the basis of the
tum). The caudate nucleus consists of an anterior bulky embryonic development of the cerebral hemispheres.
part, the caput (head), and a progressively thinner The claustrum forms a sheet of grey matter lateral to
cauda (tail). The cauda extends first backward and then the putamen (Fig. 6.29). It has reciprocal connections
down and forward into the temporal lobe, located in most parts of the cerebral cortex. Little is known about
the wall of the lateral ventricle. Figure 7.4 shows how its function or clinical significance, but based on its
Corpus callosum
Frontal horn of
lateral ventricle
Caudate nucleus
Putamen
Globus pallidus
Insula
Claustrum
Internal capsule
Third ventricle
Thalamus
Choroid plexus
Temporal horn of
lateral ventricle
Hippocampus
Mesencephalon
Cerebellum
gure 6.30 The internal structure of the cerebral

hemisphere. The left half is a photograph of a
horizontal section through the left hemisphere.
Compare with Fig. 6.28.
Corpus callosum
Caudate nucleus (caput)
Fornix
Choroid plexus
Third ventricle
Hippocampus
Fimbria
Temporal horn of the
lateral ventricle
Thalamus
Pineal body
gure 6.31 The internal structure of
the cerebral hemispheres. The upper Mesencephalon
parts of the right hemisphere has been
cut away to open the lateral ventricles.
Cerebellum
In the anterior part, the caudate
nucleus forms the bottom and lateral
wall of the ventricle. In the temporal
horn of the ventricle, the hippocampus
forms the medial wall.
connections it has been suggested to deal with sensory Like the cerebrum, the cerebellum is covered by a
integration. One hypothesis proposes that by virtue of layer of gray substance, the cerebellar cortex (cortex
its integrative potential, claustrum may be linked with cerebelli), with underlying white matter. Enclosed in
the formation of conscious percepts. the white matter are regions of gray matter, the central
(deep) cerebellar nuclei (see Fig. 24.14). From the neu-
rons in these nuclei come the majority of efferent fibers
THE CEREBELLUM that convey information from the cerebellum to other
parts of the CNS (the cerebral cortex, various brain
The cerebellum (the little brain) is first and foremost stem nuclei, and the spinal cord).
of importance for the execution of movements; like the The cerebellar surface is extensively folded, forming
basal ganglia, it belongs to the motor system. The cer- numerous narrow sheets, or folia, that are predomi-
ebellum is located in the posterior cranial fossa, dorsal nantly oriented transversely (Fig. 6.32). The fissures
to the brain stem (Figs. 6.2 and 6.32). It is connected and sulci between the folia are partly very deep; the
with the brain stem anteriorly by way of three stalks of deepest among them divide the cerebellum into lobes
white matter on each side: the inferior, middle, and (Fig. 6.32A; see also Fig. 24.2). In addition, the cerebel-
superior cerebellar peduncles (Figs. 6.14 and 3.19). In lum can be subdivided macroscopically on another
general, the inferior cerebellar peduncle, or restiform basis. In the posterior part of the cerebellum a narrow
body (corpus restiforme), contains fibers that carry middle region is situated deeper than the much larger
impulses from the spinal cord to the cerebellum, whereas lateral parts (Fig. 6.32B). This middle part of the cere-
the middle cerebellar peduncle, or the brachium pontis, bellum is called the vermis (worm) and is present also in
conveys information from the cerebral cortex. The the anterior part of the cerebellum, although not as
superior cerebellar peduncle, or the brachium conjunc- clearly distinguished from the lateral parts as posteri-
tivum, contains most of the fibers conveying impulses orly. The lateral parts are called the cerebellar hemi-
out of the cerebellumthat is, the cerebellar efferent spheres. A small bulbous part on each is connected
fibers. medially with a thin stalk to the vermis. This part is
A B
Vermis
Anterior lobe Vermis Primary fissure Superior cerebellar peduncle
Middle cerebellar
peduncle
Flocculus
Hemisphere
Vermis Tonsilla cerebelli
Posterior lobe
C Anterior lobe
Primary fissure
Arbor vitae
(white matter)
Pons
Posterior lobe
Fourth ventricle
Tonsilla cerebelli
gure 6.32 The cerebellum. A: Seen from the rostroposterior aspect. with white matter underneath (white matter indicated in black in the
B: Seen from the ventral aspect (the side facing the brain stem). drawing).
C: Midsagittal section showing the cerebellar cortex as a thin layer
called the flocculus (Fig. 6.31B) and lies close to the treelike structure called the arbor vitae (the tree of life,
middle cerebellar peduncle, just posterior to the seventh which is not very fitting since the cerebellum is not nec-
and eighth cranial nerves (Fig 6.13). A midsagittal sec- essary for life). The fourth ventricle, extending into the
tion through the cerebellum (Fig. 6.32C) shows clearly cerebellum like the apex of a tent, is also evident in the
the deep sulci and fissures. The white substance forms a midsagittal section.
7 The Coverings of the Brain and
the Ventricular System
OVERVIEW pass from the pia into the substance of the brain and
supply the external parts, such as the cerebral cortex,
The central nervous system (CNS) is well protected with blood (the deeper parts of the brain are supplied
against external forces as it lies inside the skull and the by vessels entering the brain at its basal surface). The
vertebral canal. In addition to this bony protection, the next membrane, the arachnoid, does not follow the
CNS is wrapped in three membranes of connective uneven surface of the brain but extends across depres-
tissuethe meningeswith fluid-filled spaces between sions, fissures, and sulci. Between the pia and the arach-
the membranes. In fact, it is loosely suspended in a fluid- noid exists a narrow space, the subarachnoid space,
filled container. The innermost membranepiais which is filled with CSF (Figs. 6.1, 7.1, and 7.5).
thin and adheres to the surface of the brain at all places. Numerous thin threads of connective tissue connect the
The outermost membranedurais thick and fibrous pia with the arachnoid, thus spanning the subarachnoid
and covers the inside of the skull and spinal canal. The space. The depth of the subarachnoid space varies from
arachnoid is a thin membrane attached to the inside of place to place because the arachnoid, as mentioned,
the dura. The subarachnoid space is with cerebrospinal does not follow the surface of the brain. Where it crosses
fluid (CSF) and lies between the pia and the arachnoid. larger depressions, the subarachnoid space is consider-
The ventricular system consists of irregularly shaped, ably widened, forming so-called cisterns filled with
fluid-filled cavities inside the CNS. There are four dila- CSF. Several cisterns are found around the brain stem,
tations or ventricles. The two lateral ventricles are larg- but the largest one, the cisterna magna, or cerebellom-
est and are located in the cerebral hemispheres. They edullary cistern, is located posterior to the medulla
communicate with the third ventricle lying between the below the cerebellum (Figs. 6.1 and 7.5). The CSF
two thalami. The third ventricle, situated between enters the cisterna magna from the fourth ventricle
the cerebellum and the brain stem, communicates with (Fig. 7.5).
the fourth ventricle via the narrow cerebral aqueduct. The subarachnoid space is continuous around the
Vascular choroid plexuses in the ventricles produce whole CNS. Substances released into the subarachnoid
about 0.5 liters of CSF per day. The CSF leaves the ven- space at one place therefore quickly spread out. A suba-
tricular system through openings in the fourth ventricle rachnoid hemorrhage, for example, most often caused
and enters the subarachnoid space. Drainage of CSF by rupture of a vessel at the base of the brain, quickly
occurs through small evaginationsarachnoid villiof leads to mixing of the CSF with blood. Thus, a sample
the arachnoid emptying into venous sinuses and along of CSF taken from the dural sac at lumbar levels will be
cranial and spinal nerve roots and then into extracra- bloody.
nial lymphatic vessels. The CSF has a protective func-
tion, it minimizes accumulation of harmful substances
The Dura Mater
in the nervous tissue, and it probably serves as a signal
pathway. The outermost membrane, the dura mater (usually just
called the dura), is thick and strong because it consists
of dense connective tissue (Figs. 7.1, 7.2, and 7.5). The
dura covers closely the inside of the skull, and its outer-
THE MENINGES
most layers constitute the periosteum. The arachnoid
follows the inside of the dura closely so that there is
The Pia Mater, the Arachnoid, and
only a very narrow space between these two meninges,
the Subarachnoid Space
the subdural space (Figs. 7.1 and 7.2). The dura extends
The innermost one is the vascular pia mater (usually down into the vertebral canal to enclose the spinal cord.
just called pia). It follows the surface of the brain and It extends further down than the cord, however, form-
spinal cord closely and extends into all sulci and depres- ing a sac around the roots of the lower spinal nerves
sions of the surface (Figs. 7.1 and 7.2). Thin vessels (the cauda equina). This dural sac extends down to the
97
A level of the second-third sacral vertebra (Fig. 6.3). Thus

below the level of the first and second lumbar vertebrae
Dura (mater)
(the lower end of the cord), the dural sac contains only
Arachnoid spinal nerve roots and CSF (Fig. 6.3). This is a safe
Pia place to perform a lumbar puncturethat is, enter the
Denticulate subarachnoid space with a needle to take samples of the
ligament CSF, as there is no danger of harming the cord.
Subarachnoid
space with Anchoring of the Brain and Spinal Cord
cerebrospinal
fluid In a few places, the dura forms strong infoldings, serv-
ing to restrict the movements of the brain within the
B skull. Large movements can stretch and damage vessels
Dura and nerves connecting the brain with the skull (one of
the possible effects of head injuries). From the midline,
Subdural the falx cerebri extends down between the two hemi-
space spheres (Figs. 7.2 and 8.7). Posteriorly, the falx divides
Arachnoid into two parts that extend laterally over the superior
face of the cerebellum and attach to the temporal pyra-
Subarachnoid mid. These two folds meet in the midline and form the
space
cerebellar tentorium (see Fig. 8.9). In the anterior part
Pia
of the tentorium, there is an elongated opening for the
Layer of brain stem. If the pressure in the skull above the tento-
astrocytic rium increases (due to bleeding, a tumor, or brain
processes
edema), part of the temporal lobe may be pressed down
or herniate between the tentorium and the brain stem,
Artery
harming the brain stem temporarily or permanently.
The spinal cord is anchored to the meninges partly by
the spinal nerves and partly by two thin bands, the den-
ticulate ligaments (Fig. 7.1A), extending laterally from
gure 7.1 The meninges and the subarachnoidal space of the spinal the cord to the arachnoid and dura (this is not a con-
cord. tinuous ligament but one that forms 21 lateral exten-
sions from the cord to the dura). The spinal cord
nevertheless moves considerably up and down in the
dural sac with movements of the vertebral column (the
length of the vertebral canal varies by almost 10 cm
from maximal flexion, when it is longest, to maximal
extension).
Arachnoid granulation Superior sagittal sinus
Emissary vein
Skull
Dura
Subdural
space
Subarachnoid
space
Pia
Cortex
Bridging vein gure 7.2 The meninges, the subarachnoidal
space, and the superior sagittal sinus. Schematic
Artery Falx cerebri Arachnoid of a frontal section through the head, with the
(dura) skull and the brain. See also Figs. 1.27 and 3.37.
7: THE COVERINGS OF THE BRAIN AND THE VENTRICULAR SYSTEM 99
hemispheres become closely apposed to the diencepha-
The Meninges and Stiffness of the Neck
lon (see Fig. 9.13). The loose masses of connective
Infection of the meninges, meningitis, typically pro- tissue between the hemispheres form an approximately
duces stiffness of the neck. Every attempt to bend the horizontal plate that constitutes the roof of the third
neck or the back forward evokes an immediate reflex- ventricle. The choroid plexus is attached to the inside of
ive muscular resistance. When the doctor tries to lift the roof (see Figs. 6.23 and 7.5).
the patients head off the pillow, the neck is kept The two lateral ventricles represent the first and
straight. The infection causes inflammation of the second ventricles, but these terms are not used. From a
meninges, which also extends onto the vessels and the central part in the parietal lobe, the lateral ventricles
nerve roots in the subarachnoid space. Forward bend- have processes called horns into the three other lobes:
ing (flexion) of the vertebral column elongates the spi- an anterior (frontal) horn, a posterior (occipital) horn,
nal canal, as mentioned, and that stretches the meninges, and an inferior (temporal) horn extending downward
the vessels, and the nerve roots. Most likely, this and anteriorly into the temporal lobe (Fig. 7.3; see also
accounts for the intense pain associated with any effort Figs. 6.29 and 6.31). The anterior horn is the largest
1
to flex the back or neck (similar to the pain felt by and is bordered medially by the septum pellucidum,
stretching an inflamed area of the skin or a joint cap- whereas the head of the caudate nucleus bulges into it
sule). Straining or coughing also causes pain in patients from the lateral side (Figs. 6.29 and 7.5). The central
with meningitis. However, other means than infections part of the ventricle lies just above the thalamus
by bacteria and viruses can produce such irritation of (Fig. 6.31). The inferior horn starts at the transition
the meninges. For example, one strong irritant is blood between the central part and the posterior horn and fol-
in the subarachnoid space. Thus, stiffness of the neck is lows the temporal lobe almost to its tip (Fig. 7.3).
by itself only a sign of meningeal irritation and does not Medially in the inferior horn there is an elongated ele-
indicate a specific cause. vation, the hippocampus (Figs. 6.27 and 6.31), formed
Meningeal irritation usually causes a strong head- by invagination of the ventricular wall from the medial
ache. This occurs most dramatically with subarachnoid side by the hippocampal fissure.
hemorrhage, in which an intense headache starts The curved form of the lateral ventricles can be
abruptly the moment the bleeding starts and blood understood on the basis of the embryonic development
flows into the subarachnoid space. In such instances, of the cerebrum (Fig. 7.4). Both the lateral ventricles
the cause is usually spontaneous rupture of an aneu- and the nervous tissue in its walls (such as the caudate
rysm (a sac-like dilatation) on one of the arteries at the nucleus and the hippocampus) eventually obtain a
base of the skull. curved shape.
The Cerebrospinal Fluid Is Produced by Vascular

THE CEREBRAL VENTRICLES AND THE
Plexuses in the Ventricles
CEREBROSPINAL FLUID
All of the ventricles are filled with a clear, watery fluid,
We have mentioned the ventricular system several times the CSF. Most of the fluid is produced by vascular tufts,
in connection with treatment of the various parts of the the choroid plexus.2 This is present in all four ventricles
brain. Here we consider the ventricular system as a (Fig. 7.5), but the largest amount of choroid plexus is in
whole, along with the CSF. the lateral ventricles (Fig. 6.31). The plexuses arise in
early embryonic life by invaginations of the innermost
membrane (the pia mater) at sites where the wall of the
The Location and Form of the Ventricles
neural tube is very thin (Fig. 7.6). An elaborate struc-
The thin central canal of the cord continues upward ture of thin, branching protrusions, or villi, arises here
into the brain stem. There the canal widens to form the (Fig. 7.7). The choroid plexuses attach to the wall
fourth ventricle at the posterior aspect of the medulla of the ventricles with a thin stalk (tela choroidea).
and pons (Figs. 6.1, 7.3, and 7.5). The ventricle has a The surface of the villi is covered by simple cuboid
tentlike form with the apex projecting into the cerebel-
lum and two lateral recesses (recessus lateralis). The 1 There is a thin slit between the septum pellucidum of the two sides that has
diamond-shaped rhomboid fossa at the dorsal aspect of nothing to do with the ventricles. In embryonic development, the slit is continu-
the brain stem (Fig. 6.19) forms the floor of the ous with the room between the two hemispheres but is later closed when the
corpus callosum grows across the two hemispheres. Downward, the fornices
fourth ventricle, while the cerebellar peduncles form close the slit (Fig. 6.29).
the lateral walls. 2 Early observations in experimental animals suggested that the choroid plexus
The third ventricle is a thin slitlike room between the is not solely responsible for CSF production. Thus, removal of the choroid
plexus did not prevent development of hydrocephalus after blocking the CSF
two thalami (see Figs. 6.27, 6.30, 6.31, 7.3, and 7.5). drainage. It is now assumed that in humans 10% to 30% of the CSF is pro-
During embryonic development, the primordia of the duced by brain interstitial uid passing through the ependyma.
Anterior (frontal) Posterior (occipital) Third Interventricular

horn of lateral horn of lateral ventricle foramen
ventricle ventricle
Anterior
horn
Lateral
ventricle
Third ventricle
Inferior (temporal) Inferior horn

horn of lateral Aqueduct
ventricle Aqueduct Fourth ventricle
Fourth ventricle
Interventricular
foramen
Posterior horn
Anterior horn
Third ventricle gure 7.3 The ventricular system

Inferior horn of the brain.
Caudate Lateral ventricle

nucleus
epithelium (which is continuous with the ependyma
4 MONTHS
covering the inside of the ventricles). The epithelial cells
have microvilli that increase their surface in contact
with the CSF. The interior of the villi is composed of
loose connective tissue with numerous capillaries of the
fenestrated type, which are rather leaky. Therefore, the
8 MONTHS hydrostatic pressure inside the capillaries produces a
net flow of water with solutes (and a fair amount of
6 MONTHS
proteins) into the interstitial space of the villi. This pro-
tein-rich fluid cannot leave the villi directly, however,
because the epithelial cells covering the villi attach to
each other with tight junctions (Fig 7.7). The transport
of water through the epithelium is caused by active
transport of sodium. Thus, the pumping of sodium pro-
duces an osmotic gradient so that water diffuses from
the interior of the villi into the ventricles. Other ions,
NEWBORN
such as chloride and bicarbonate, follow the water pas-
gure 7.4 Development of the cerebral hemispheres and the lateral sively. The epithelial cells of the choroid plexus are
ventricles. The characteristic arched shape of the ventricles can be equipped with water channels or aquaporins (AQP1)
explained by the manner in which the hemispheres fold during their on the apical surface (that is, facing the CSF).
growth in embryonic life. The caudate nucleus, located in the wall of
Presumably, the aquaporins are important for the rapid
the lateral ventricle, is indicated in blue. All structures in the wall of the
ventricles attain the curved shape. The gure also shows the develop- transport of water. Indeed, the rate of CSF secretion by
ment of gyri and sulci. Compare the pattern in the newborn and in the the choroid plexus (0.2 mL/min/g tissue) is much higher
adult (Fig. 6.25). (Based on Hamilton, Boyd, and Mossman 1972.) than in other secretory epithelia in the body.
Subarachnoid space with
Superior sagittal sinus cerebrospinal fluid
Arachnoid
Dura granulations Cuboidal epithelium
with microvilli
Septum
ptum Choroid
Ch roi
Cho d plexus
roid
ro p in
pellucidum lateral ventricle
Choroid plexus in
third ventricle
Fenestrated Tight Loose
Loosse
capillary junction connective
connee Cerebrospinal
tissue fluid
Interventricular
foramen
Third ventricle
Tela choroidea
Aqueduct
Fourth ventricle
Opening in fourth Choroid
ventricle plexus
Cisterna gure 7.7 Structure of the choroid plexus, exemplied by one villus
magna (inset). Arrows indicate the ow of uid from the capillaries to the
ventricles.
Central canal
The epithelium of the choroid plexus represents a
barrier between the blood and the CSF, the bloodCSF
barrier. Thus, many substances that can leave the capil-
laries of the choroid plexus cannot enter the CSF. This
is obviously important, because neurons are extremely
sensitive to changes in the composition of their environ-
ment. We will later describe a similar but even more
gure 7.5 The ventricular system, the subarachnoid space, and important barrier between the blood in the brain capil-
the choroid plexus. All ventricles contain choroid plexus. Arrows laries and the brain interstitial fluid.
indicate the ow of the cerebrospinal uid from the ventricles into
the subarachnoid space through openings in the walls of the fourth
ventricle. Composition and Functions of the Cerebrospinal Fluid
The concentration of sodium, potassium, and several
other ions is about the same in the CSF as in the blood
(there are some minor differences, however). The con-
A B centration of glucose is about two-thirds that in the
Cerebral blood. A major difference concerns proteins: there is
hemisphere Lateral ventricle Pia
normally very little protein in the CSF (less than 0.5%
of the plasma protein concentration).
Water and soluble substances are freely exchange-
able between the CSF and the interstitial fluid of the
nervous tissue because the ependyma is freely perme-
able to water and even small protein molecules. It is not
surprising, therefore, that many neurotransmitters,
peptides, and other neuroactive substances occur in the
CSF, and their presence there does not by itself signify
a functional role. Some substances, howevernotably
Choroid plexus Tela choroidea
hormones synthesized in the anterior pituitaryare
apparently actively secreted into the CSF, not simply
gure 7.6 Embryonic development of the choroid plexus. Schematic
of a frontal section through the cerebral hemispheres at an early
accepted by passive diffusion. Some other substances
stage, showing how the choroid plexus is formed by invaginations of appear to use the CSF as a means to reach specific
the pia into the ventricles. receptors close to the ventricles.
The CSF has an important protective function because Circulation and Drainage of the Cerebrospinal Fluid
the brain almost floats in it. Thus, theoretically buoy-
About one-half liter of CSF is produced each day, yet
ancy reduces the weight of the brain to about 50 g,
the total volume of fluid in the ventricles and the suba-
which means less traction on vessels and nerves con-
rachnoid space is only 130 to 140 mL (approximately
nected to the CNS. Further, the effect on the brain of 3
20 mL is in the ventricles). In addition, approximately
blows to the head is dampened because water has to be
75 mL surrounds the spinal cord. Thus, the total
pressed aside before the brain hits its hard surroundings
amount is renewed several times a day. This means that
(the skull).
effective means of drainage must exist.
Another possible functional role of the CSF can be
The fluid produced in the lateral ventricles flows into
deduced from the fact, mentioned above, that water
the third ventricle through the interventricular foramen
and solutes pass freely between it and the extracellular
(of Monro) (Fig. 7.5; see Fig. 6.23). From there the fluid
fluid (interstitium) of the nervous tissue. This means
flows through the narrow cerebral aqueduct to the
that diffusion into the CSF may minimize accumulation
fourth ventricle. The choroid plexuses in the third and
of harmful substances in the nervous tissue (such as
fourth ventricles add more fluid. The fluid leaves the
potassium ions during prolonged periods of intense
ventricular system and enters the subarachnoid space
neuronal activity). This would be of significance, how-
(more specifically, the cisterna magna) through three
ever, only for neurons that are fairly close to the ven-
openings in the fourth ventricle: one in the midline pos-
tricles, as the diffusion of molecules in the labyrinth-like
teriorly (the foramen of Magendie) and two laterally
brain interstitium is slow (much slower than in free
(the lateral recesses or foramina of Luschka) (Fig. 7.5).
water). Thus, after injecting representative substances
The fluid then spreads out over the entire surface of the
in the brain, the concentration is reduced by 90% some
brain and spinal cord. From the base of the brain, there
1 to 3 mm away from the injection site.
is an upward stream along the lateral aspects of the
Regardless of the normal functions of substances in
hemispheres toward the midline (Fig. 7.5). The flow
the CSF, examination of the CSF composition gives
velocity is uneven, however, as shown by following the
valuable information of the extracellular fluid of the
spread of injected substances. After injection into the
brain. This fluid compartment is difficult to examine
lateral ventricles labeled substances are detectable after
directly, but because the ependyma is freely permeable,
a few minutes in the subarachnoid space, but then
one can safely assume that the composition of the CSF
moves very slowly over the cerebral hemispheres (sev-
matches fairly well the environment of the neurons.
eral hours) and down to the lumbar cistern (one hour).
The routes of CSF drainage are not completely
Cerebrospinal Fluid as a Signal Pathway known, although emptying into venous sinuses by way
of arachnoid villi is usually assumed to constitute
The concentration of the hormone melatonin (which
the main route. The arachnoid villi are small evagina-
influences sexual functions and circadian rhythms by
tions of the arachnoid. Several villi together form
binding to receptors in the hypothalamus) is twice as
macroscopically visible protrusions called arachnoid
high in the third ventricle as in the lateral ventricles and
granulations, which are particularly prominent along
100 times higher than in cerebral arteries. This suggests
the superior sagittal sinus (Figs. 7.2 and 7.5). Passage
that melatonin is secreted into the CSF and uses this as
of fluid from the subarachnoid space to the venous
its main transport medium, whereas the bloodstream is
sinuses is presumably caused by a difference in hydro-
of minor importance.
static pressure, the pressure being higher in the suba-
Some studies indicate that substances in the CSF
rachnoid space (about 15 cm of H2O) than in the sinuses
might be of importance for sleep. Thus, by transferring
(78 cm of H2O). Nevertheless, we do not actually
CSF from a sleep-deprived animal, the recipient becomes
know how much of the CSF that is drained in this way.4
sleepy. The responsible substance has not been identi-
fied but interleukin 1 (IL-1) is a likely candidate.
Thus, its concentration in the CSF increases by sleep 3 The total volume of the ventricles has been determined mainly by use of
deprivation and has also been shown to induce sleep. plastic casts in xed brains. The average total volume is probably some less
3
The further signal pathway of IL-1 from CSF to rele- than 20 cm . The individual variations are surprisingly large, however (the
3
normal range is probably from 7 to 30 cm ). Most studies have examined only
vant neurons is not known, but it finally influences the 3
the lateral ventricles, nding an average volume of about 7 cm for each. The
neurons in the reticular formation that are responsible volumes of the third and fourth ventricles appear to be some less than 1 cm for
3
for regulation of sleep and wakefulness. each. Even though the ventricular size increases somewhat with age, this can
explain only a small fraction of the individual variations. In the same individual,
Several growth factors are synthesized and secreted by however, the two lateral ventricles are quite similar in volume.
the choroid plexus. While the choroid plexus epithelium 4 One reason for questioning the role of the arachnoid granulations in CSF
expresses receptors for such growth factorssuggesting drainage is that they are not present prenatally while the choroid plexuses
are well developed by the end of the embryonic period (about 8 weeks after
an autocrine functionthey may also be expected to fertilization). Therefore, in the fetus and newborn other routes seem to be
act on nervous tissue close to the ventricles. responsible for most or all of the CSF drainage.
Another, and perhaps quantitatively more important increased intraventricular pressure due to obstruction
route of drainage, is along cranial and spinal nerve of the drainage of the CSFfor example, by closure of
roots and then into extracranial lymphatic vessels (the the aqueduct (inflammation, tumor, bleeding) or the
nervous tissue contains no lymphatics). Animal experi- outlets from the fourth ventricles. Even if this may be
ments indicate that drainage through the cribriform the cause in some, it cannot explain all cases of hydro-
plate (where the olfactory nerve fibers enter the skull, cephalus. Thus, some persons develop hydrocephalus
see Fig. 8.10) may be of particular significance. in spite of apparently normal intraventricular pressure
and no sign of obstruction (communicating or normal
pressure hydrocephalus).
Brain Edema, Herniation, and Hydrocephalus
If obstruction of CSF flow from the ventricles occurs
Because the CNS and the CSF are located in a closed in an adult, in whom the sutures of the skull have grown
container with rigid walls, the pressure inside the con- firmly together, the intracranial pressure increases
tainer increases if, for some reason, the amount of sub- markedly, with dramatic symptoms. If the condition
stance inside it increases. The intracranial pressure is arises in early childhood before closure of the sutures,
the same for the nervous tissue and the CSF, but it can however, the size of the head grows abnormally, with
be measured most conveniently in the latter. For each the skull yielding to the increased intracranial pressure.
heartbeat, for example, the pressure inside the cerebral This may continue for some time with surprisingly few
ventricles increases slightly because more blood is signs of cerebral dysfunction, but the development of
pumped into the brain. Correspondingly, the pressure the brain will eventually suffer, with results such as
increases on coughing and straining because the drain- mental retardation. Hydrocephalus in children may
age of venous blood from the cranial cavity and the be treated by shunting the CSF directly into a big vein
vertebral canal is reduced. outside the skull.
Regardless of cause, any intracranial expansive pro-
cess leads to increased intracranial pressure. When the
Examination of the Cerebrospinal Fluid
pressure increases, the blood pressure increases to main-
and the Ventricles
tain cerebral blood flow. Thus, abnormally elevated
blood pressure, usually combined with slowing of the Examination of the CSF can provide valuable informa-
heart rate, is one of the signs of severely increased tion about neurological diseases. A sample of the fluid
intracranial pressure. However, an increase above a is usually withdrawn with a thin needle from the suba-
certain level reduces blood flow and the functioning of rachnoid space in the dural sacthat is, below the level
the brain suffers (with signs of confusion and eventu- of the second lumbar vertebra (lumbar cistern). This
ally loss of consciousness). This occurs, for example, in way there is no risk of damaging the spinal cord (see
patients with brain edema. This is a dangerous compli- Fig. 6.3). When the tip of the needle is in the subarach-
cation of acute brain damage caused by, for example, noid space, the intracranial pressure can also be mea-
head injuries. The edema is caused by extravasation of sured. Examination of the fluid, in part under the
fluid from the brain capillaries. Similarly, an intracra- microscope, can give information about possible bleed-
nial hemorrhage, which may arise from vessels inside or ing into the subarachnoid space and about infections
outside the brain substance, can also cause a dangerous and inflammations of the brain itself (encephalitis) or
increase of the intracranial pressure. If the expansion the meninges (meningitis). In the latter case, there are
process is located in the posterior fossa (below the cer- numerous leukocytes in the CSF. The concentration of
ebellar tentorium; see Fig. 8.9), the cerebellar tonsils proteins, normally very low, may increase in certain
(see Figs. 6.13 and 6.32C) may be dislocated downward diseases (e.g., in multiple sclerosis, in which the pro-
into the foramen magnum and thus compress the teins are antibodies against components of the nervous
medulla (tonsillar herniation). If the expansive process tissue).
is located above the tentorium (in the middle or ante- The shape and size of the ventricles can be determined
rior fossa), the uncus of the temporal lobe (see Fig. 6.26) noninvasively in living subjects by use of computer
can be dislocated downward beneath the edge of the tomography (CT) and magnetic resonance imaging
tentorium and compress the brain stem at the level of (MRI) (see Figs. 6.2, 6.28, 23.4, and 32.11). Atrophy of
the mesencephalon (see Figs. 6.29 and 8.9). Both forms the nervous tissue of the brainfor example, atrophy
of herniation may lead to serious brain damage or death. of the cerebral cortex, which occurs in dementialeads
A condition with increased amount of CSF and dila- to dilatation of the ventricles, whereas expansive, space-
tation of the ventricles is called hydrocephalus. It is occupying processes like hemorrhages and tumors may
usually assumed that the condition arises because of distort and compress the ventricles.
8 The Blood Supply of the CNS
OVERVIEW nearest capillary. The total length of all capillaries in
the brain are said to be 400 miles, and their total sur-
Of all cell types in the body, neurons are the most sensi- face area more than 20 m2. To understand the normal
tive to interruption of their supply of oxygen (anoxia). properties and the responses to disease of brain capil-
Only a few minutes stop in the blood flow may cause laries, however, they cannot be studied in isolation. The
neuronal death. The oxygen consumption of the brain term neurovascular unit serves to emphasize the close
is high even at rest. Therefore, the blood supply of the structural and functional relationship between neurons,
central nervous system (CNS) is ample, and the brain glial cells, associated capillary-endothelial cells, basal
receives about 15% of the cardiac output at rest. lamina, and pericytes (Fig. 8.1).
Regulatory mechanisms ensure that the brain gets what
it needsif necessary, at the expense of all other organs.
Regulation of Cerebral Circulation
The arteries of the brain lie within the cranial cavity
and are mostly devoid of anastomoses (connections) Regulation of the blood flow is one among several
with arteries outside the skull. Therefore, other arteries factors governing the composition of the brains extra-
cannot take over if the intracranial ones are narrowed cellular milieuthat is, the concentration of ions,
or occluded. neuroactive substances, nutrients, and water (osmolar-
The cerebral blood flow is largely controlled by the ity). Control of the properties of astrocytes and the
local conditions in the nervous tissue, that is, there is a bloodbrain barrier are other important factors (see
high degree of autoregulation. Local changes in the Chapter 2, under Astroglia and the Control of Neuronal
concentrations of ions, oxygen, carbon dioxide, and Homeostasis).
various signal substances determine the resistance The cerebral circulation exhibits a high degree of
offered by the arterioles. Brain vessels receive sensory autoregulationthat is, conditions in the brain itself
innervation from the trigeminal nerve. determine the blood flow. If the blood pressure falls,
In most organs, small-molecule substances pass the the arteries dilate. This reduces vascular resistance so
capillary wall, and their concentration is therefore simi- that the blood flow is upheld. If the blood pressure
lar in the blood plasma and in the interstitial fluid. In rises, the opposite happens: the arteries constrict. This
contrast, the CNS exerts strict control of what is let in. is an important control mechanism, since increased
The bloodbrain barrier (a similar barrier exists between capillary hydrostatic pressure may cause brain edema.
the blood and the cerebrospinal fluid [CSF]) is due mainly The brain maintains almost constant blood flow as long
to special, selective properties of the brain capillaries. as the systolic pressure is between 60 and 160 mm Hg.
In a few small regions adjoining the ventricles, the If the pressure falls below 60 mm, however, the flow
capillaries are fenestrated and hence let substances from falls steeply and the person becomes unconscious.
the blood pass through easily. At such places, neurons Among the many factors that control cerebral blood
are exposed to substances of the blood that do not enter flow, local changes in the immediate surroundings of
other parts of the brain. These regions are called the the neurons have an important role. These are changes
+
circumventricular organs. in concentrations of ions (among them H ions), CO2
Broadly speaking, the internal carotid artery supplies and O2. Hypoxia (abnormally low concentration of O2)
most of the cerebral hemispheres, whereas the vertebral and hypercapnia (above-normal concentration of CO2)
artery supplies the brain stem and the cerebellum. both cause marked vasodilatation and increased cere-
Communicating arteries at the base of the skull estab- bral blood flow. Increased local blood flow is closely
lish anastomoses between the posterior (vertebral) and coupled to increased neuronal activity, and this phe-
the anterior (internal carotid) cerebral circulations. nomenon is utilized in studies of correlations between
changes in brain activity and behavior (see Regional
Cerebral Blood Flow and Neuronal Activity).
CEREBRAL MICROCIRCULATION AND Autonomic circulatory control seems to play a minor
THE BLOODBRAIN BARRIER part in the brain (in contrast to in most other organs), even
though sympathetic fibers innervate brain vessels. Such
The brain has a very high density of capillaries, fibers release norepinephrine, neuropeptide Y (NPY) and
and neurons are seldom more than 10 m from the possibly ATP, and stimulation causes vasoconstriction.
104
8: THE BLOOD SUPPLY OF THE CNS 105
A B
Astrocyte
Tight junction
Gap junction Endothelial cell

(nexus)
Pericyte
Basal lamina
Astrocytic end feet
gure 8.1 The bloodbrain barrier/neurovascular unit. A: Schematic its relationship to processes of three astrocytes (the processes are
drawing showing the main features. Important elements are tight marked with different colors). The electron micrograph is one among
junctions between the endothelial cells and a continuous layer of many in a true series of ultrathin sections, used for three-dimensional
astrocytic end feet. Gap junctions establish low-resistance connec- reconstruction of the astrocytic processes. This makes it possible to
tions between the astrocytes. The basal lamina also contributes to the decide that the marked processes belong to different astrocytes.
barrier properties of the neurovascular unit. Not shown in the gure, (Courtesy of Drs. Thomas Misje Mathiisen and Ole Petter Ottersen,
although included in the term neurovascular unit, are neurons that Department of Anatomy, Institute of Basic Medical Sciences,
are in contact with processes of the astrocyte (see Figs. 2.3 and 2.5). University of Oslo, Norway.)
B: Electron micrograph showing a brain capillary (hippocampus) and
Nevertheless, under normal conditions, activity of sym- thought to act, at least in part, by preventing release of
pathetic fibers appears to have only marginal effects on neuropeptides from trigeminal vascular nerve endings,
blood flow. Thus, although sympathetic activity can thereby reducing perivascular inflammation.
constrict large brain arteries, peripheral small vessels
dilate (probably because of local control). Brain arteries
Regional Cerebral Blood Flow and Neuronal Activity
are also supplied by serotonergic fibers that arise in the
raphe nuclei of the brain stem and that, on stimulation, Neuroimaging techniques, such as positron emission
mainly cause vasoconstriction. tomography (PET) and functional magnetic resonance
Finally, brain arteries receive sensory innervation imaging (fMRI), permit the visualization of brain
from the trigeminal nerve. These fibers contain subregions activated in conjunction with specific behaviors
stance P, calcitonin generelated peptide (CGRP), and and mental operations (see Chapter 11, under Methods
neurokinin. Electric stimulation of such sensory fibers to Study Neuronal Activity and Connectivity in the
causes vasodilatation, presumably by peripheral release Living Brain: PET and fMRI). This is especially valu-
of neuropeptides. The trigeminal arterial innervation, able for the study of speech, abstract problem solving,
along with the vascular serotonin receptors, is an and other functions that can be studied only in humans.
important factor in the pain of migraine attacks. PET and fMRI are based on the existence of a relation-
Thus, the most effective drugs to prevent the pain of ship between the regional cerebral blood flow (rCBF)
migraine are serotonin-receptor agonists. The drugs are and the neuronal activity in that region. Thus, increased
neuronal activity is regularly followed in a few hundred excitability must be kept out. Many neuroactive
milliseconds by increased local blood flow (hyperemia). substances (such as glutamate, monoamines, and many
The mechanisms responsible for the coupling of neu- neuropeptides) are produced also in peripheral tissues
ronal activity to blood flow are not clear, partly due to and are present in the blood plasma in varying concen-
conflicting data. One important mechanism, however, trations. Neuronal excitability cannot be subject to
appears from animal experiments to be activation of incidental blood plasma variations of neuroactive sub-
astrocytes by synaptic release of glutamate (by binding stances. It should be emphasized, however, that there is
to metabotropic glutamate receptors in the astrocyte not only a barrier intercalated between the blood and
2+
membrane). Thus, elevated Ca in astrocytic end feet the brain but also specific transport mechanisms for
(Fig. 8.1) would produce vasodilatation by release of certain substances that the brain needs.
vasoactive substances. Although there are several pos-
sible mediators (e.g., nitric oxide [NO] and adenosine),
Physiological Properties of the BloodBrain Barrier
in vivo experiments suggest that metabolites of arachi-
donic acid, such as prostaglandins, may be of particular Several factors together constitute the bloodbrain
importance. Nevertheless, signals from astrocytes do barrier, which is more than just a barrier since some
not seem to be responsible for all the hyperemia caused substances are actively transported into the brain:
by synaptic activity. Possibly, NO released from neu-
1. Brain capillaries are much less permeable than
rons may contribute. NO would seem well suited: it is
capillaries in most other tissues so that even many small
produced in many neurons on synaptic activation, it
molecules cannot pass the capillary wall. This results
diffuses freely, and it causes vasodilatation. A further
mainly from very extensive tight junctions between the
question concerns whether the control of regional blood 1
endothelial cells. Substances therefore have to pass
flow is exerted only on the smooth muscle cells of arte-
through the plasma membrane of the capillaries to enter
rioles. Thus, the pericytes (Fig. 8.1) surrounding capil-
the brain interstitium. (In the capillary walls of most
laries are contractile, and may contribute to the change
other organs, there are slitsas a result of less exten-
of blood flow induced by synaptic activity.
sive tight junctions between the endothelial cells
Even though a close relationship between neuronal
where water can flow.) Water-soluble substances are
activity and blood flow seems to be the rule, exceptions
thus effectively prevented from passing (except via spe-
may exist. For example, it was recently shown that
cific uptake mechanisms), whereas small, lipid-soluble
blood flow may increase in anticipation of an event that
molecules can pass the plasma membrane with ease.
is expected to require increased neuronal activity in a
Indeed, all drugs used for treating diseases of the CNS
certain neuronal population. In such cases, the arterial
are of this kind.
dilatation is local and apparently not related to a global
2. There are very few endocytotic (pinocytotic) vesi-
regulation of cerebral blood flow. Although the mecha-
cles in the cytoplasm of endothelial cells in the CNS (in
nism for this anticipatory vascular response is not
contrast to, e.g., muscle capillaries). Such vesicles are
known, it most likely involves the innervation of small
believed to transport small and large molecules through
cerebral vessels. If anticipatory vascular control is a
the endothelial wall.
regularly occurring phenomenon, it represents a source
3. Brain endothelial cells are equipped with trans-
of error to the interpretation of fMRI studies, since
porter molecules (P glycoprotein) that actively expel
these assume that increased local blood flow is a sign of
lipid-soluble moleculesthat is, such that enters by
increased neuronal activity.
passive diffusion through the plasma membrane.
Knockout mice that lack the gene for P glycoprotein
Why do we Need a BloodBrain Barrier? illustrate its importance: they show increased sensitivity
to drugs and toxins in blood plasma. Indeed, P glyco-
In most organs of our body, small-molecule substances
protein transports many drugs out of the brain.
pass the capillary wall with relative ease, and their con-
4. Brain endothelial cells appear to be able to actively
centration is therefore similar in the blood plasma and
pump ions that are present in different concentration in
in the interstitial fluid. In contrast, the CNS exerts strict
immigration control. The bloodbrain barrier (we
have previously mentioned a similar barrier between
the blood and the CSF) is mainly due to special, selec-
1 Brain endothelial tight junctions contain a number of adhesion molecules
tive properties of the brain capillaries. Consequently, (which are transmembrane proteins). Several of these show altered expression
the composition of the interstitial (extracellular) fluid in various neurological diseases. Occludin is one such protein of importance for
of the brain differs from that in most other organs. The tight junction properties. Occludin shows decreased expression in diseases with
breakdown of the blood-brain barrier (e.g., multiple sclerosis). Alterations of
need for such a barrier may seem obvious: substances various claudins have been implicated in disruption of the blood-brain barrier
that would disturb the delicate balance of neuronal caused by epileptic seizures, ischemia, dementia, and HIV-1 infections.
the brain extracellular fluid and in the blood plasma embryonic development, as it occurs before the appear-
+ + 2+ 3
(Na , K , Ca , and others). ance of astrocytes.
5. Organic acids are actively pumped out of the brain
by a specific transporter (primarily expressed in the
Modulation of the BloodBrain Barrier in
choroid plexus).
Health and Disease
6. Water-soluble substances, such as glucose and
some amino acids, are taken up by active transport In cell cultures, a number of physiological and pharma-
after binding to specific receptors in the endothelial cological substances affect the properties of tight junc-
membrane (carrier-mediated transport). Glucose is an tions. Normally, for example, a limited number of
example of a substance with high water solubility that lymphocytes are allowed to enter the brain to patrol
nevertheless reaches high concentrations in the brain the tissue for foreign molecules. This requires specific
(this is necessary because the neurons depend almost receptor-mediated mechanisms that (most likely) tran-
solely on glucose as a source of energy). The glucose siently open tight junctions to let in lymphocytes.
2
transporter GLUT1 is specific to brain capillaries. Unfortunately, also some metastatic cancer cells pass
7. Macromolecules, such as some growth factors and the bloodbrain barrier. Malnutrition alters the blood
cytokines, are to a limited extent carried from blood brain barrier, and substances like histamine and brady-
plasma into the brain, probably by receptor-mediated kinin make brain capillaries leaky (just as they do in
transport. other organs). According to animal experiments, even
conditions with inflammatory pain (due to injection of
The properties of the bloodbrain barrier are of
irritants in the paw) can alter the permeability of the
consequence for whether a drug may gain access to the
bloodbrain barrier, presumably by circulating cytok-
brain; as a rule, only lipid-soluble drugs can reach ther-
ines acting on tight junction proteins. Stress can increase
apeutic concentrations in the brain. Certain drugs such
the permeability of the bloodbrain barrier to drugs,
as barbiturates used for induction of anesthesia are
according to animal experiments. Presumably, this is so
highly lipid-soluble and act rapidly. Other drugs, such
also in humans. For example, pyridostigmine (an ace-
as penicillin, have low lipid solubility and pass the
tylcholinesterase inhibitor used to treat myasthenia
bloodbrain barrier only with difficulty. In serious
gravis) normally acts only in peripheral tissues. During
infections of the CNS, penicillin (or another drug with
the first Gulf War (19901991) soldiers that were given
low lipid solubility) must be injected directly into the
prophylactic pyridostigmine (in case of nerve gas expo-
CSF, usually in the cisterna magna (see Fig. 7.5). The
sure) exhibited much more central side effects than are
drug then easily enters the brain tissue because there is
observed when the drug is given to soldiers in peacetime.
no barrier between the CSF and the brain interstitial
In several different, unrelated neurological diseases,
fluid.
the bloodbrain barrier becomes less effective, mainly
due to disturbed interactions between glia and endothe-
Induction and Maintenance of the BloodBrain Barrier lial cells. At the ultrastructural level, the neurovascular
unit undergoes changes, such as loss of endothelial-cell
The special structural and functional properties of brain
tight junctions, and changes of the astrocytes. In multiple
capillaries depend primarily on influence from sur-
sclerosis, for example, the blood brainbarrier is partly
rounding elements. If peripheral tissue is transplanted
opened during exacerbations of the disease. Furthermore,
into the brain, the in-growing capillaries attain the
the neurovascular unit is altered in neurodegenerative
properties characteristic of the peripheral tissue: that is,
diseases (such as Alzheimers disease and Parkinsons
no bloodbrain barrier forms. The opposite happens if
disease), in infections of the CNS (such as meningitis
brain tissue is transplanted into another organ. The
and septicemia), and in ischemia (due to stroke or trau-
astrocytic processes that surround all brain capillaries
matic brain injury). In the latter case, the disruption of
in the adult (Fig. 8.1; see also Figs. 2.3 and 2.5), are
the bloodbrain barrier contributes to brain edema.
certainly important for maintaining several features of
It is not clear, however, whether alterations of the
the bloodbrain barrier. Their exact roles are not clear,
neurovascular unit are causal to the diseases or are
however, partly due to conflicting data. For example,
experiments show that astrocytes can induce tight junc-
tions in brain endothelial cells. Nevertheless, other cell 3 Growth factors of the Wnt family (Wnt7 and Wnt8) are secreted by the
types (probably neuronal progenitor cells) appear to be neuroepithelial cells in the earliest phases of nervous system development.
responsible for the first formation of tight junctions in Binding of Wnts to specic receptors in endothelial cells induce vessels to grow
into the nervous tissue and develop their characteristic properties, such as the
expression of the glucose transporter GLUT1. Mice lacking the genes for Wnt7
and Wnt8 show abnormal vascular growth, impaired blood brain barrier prop-
2 Mutations of the human GLUT1 gene cause a syndrome with infantile erties, and lack of GLUT1 expression. (Wnt signaling also inuences a number
seizures, delayed development, and microcephaly. of other developmental processes in the brain.)
merely responses to the disease processes (which may bloodstream to the anterior pituitary (see Chapter 30,
nevertheless contribute to the disease manifestations). under The Influence of the Hypothalamus on the
Anterior Pituitary).
The two endocrine glands that are from the brain,
Some Parts of the Brain Lack a BloodBrain Barrier
the posterior pituitary and the pineal body, also lack a
In a few small regions adjoining the ventricles, the cap- bloodbrain barrier. As with the median eminence, this
illaries are fenestrated and hence let substances from is related to their release of hormones directly into the
the blood pass through easily. At such places, neurons bloodstream.
are exposed to substances of the blood that do not enter
other parts of the brain. These regions are called the
ARTERIAL SYSTEM
circumventricular organs (Fig. 8.2). Among these, the
area postrema is found in the lower end of the fourth
The Brain Receives Arterial Blood from the Internal
ventricle, whereas the subfornical organ lies in the roof
Carotid and the Vertebral Arteries
of the third ventricle just underneath the fornix close to
the interventricular foramen. Both the area postrema Broadly speaking, the internal carotid artery supplies
and the subfornical organ contain many neurons that most of the cerebral hemispheres, whereas the vertebral
send their axons to other parts of the CNS and can thus artery supplies the brain stem and the cerebellum.
mediate various specific influences on the nervous sys- The internal carotid artery (arteria carotis interna)
tem. Neurons in the area postrema are involved in the enters the cranial cavity through a canal at the base of
vomiting reflex when this is elicited by toxic substances the skull (the carotid canal in the temporal bone) and
of the blood (see also Chapter 27, under The Vomiting then divides into three branches (Fig. 8.3):
Reflex). Neurons in the subfornical organ monitor the
1. The ophthalmic artery passes to the orbit through
salt concentration of the blood. They send signals to the
the optic canal and thus does not supply the brain itself
hypothalamus that can initiate responses necessary to
(although, strictly speaking, the retina is part of the
maintain the fluid balance of the body. Further, neu-
CNS). The central retinal artery (a. centralis retinae)
rons in the subfornical organ respond to circulating
enters the eye through the optic nerve and supplies the
peptides involved in regulating energy balance (see
retina.
Chapter 30, under Regulation of Digestion and
2. The anterior cerebral artery runs forward over the
Feeding).The subfornical organ and other parts of the
optic nerve and along the medial aspect of the hemi-
circumventricular organs are probably also targets of
sphere (Figs. 8.3 and 8.5). It supplies most of the cortex
substances in the blood that induce fever and other
on the medial aspect of the hemisphere (except the most
symptoms of infections (see Chapter 30, Hypothalamic
posterior parts and the inferior aspect of the temporal
Neurons Are Influenced by Hormones and Fever).
lobe). Its branches reach only a short distance onto the
The median eminence (eminentia mediana) in the
convexity of the hemispheres, supplying the leg repre-
hypothalamus (see Fig. 30.6C) also lacks a bloodbrain
sentations of the motor and somatosensory areas.
barrier. This region does not contain neuronal cell bod-
Shortly after its origin, the anterior cerebral artery gives
ies but receives nerve fibers from other parts of the
off thin branches that penetrate the base of the hemi-
hypothalamus. Hormones released from nerve termi-
sphere to supply anterior portions of the basal ganglia
nals in the median eminence are transported by the
and hypothalamus.
3. The middle cerebral artery is the largest branch.
It curves laterally into the lateral cerebral fissure and
follows this backward and upward (Figs. 8.3, 8.4, and
Subfornical 8.5). On its way, numerous branches are given off that
organ supply most of the cerebral cortex on the convexity of
the hemispheres, notably the motor and somatosensory
Pineal body cortical areas, except for their most medial parts (with
Hypothalamus
neuronal groups concerned with the motor and sensory
functions of the legs; see Figs. 22.5 and 22.9), which are
Posterior supplied by the anterior cerebral artery. The deep parts
pituitary
of the cerebrum, such as most of the basal ganglia and
Area postrema
the internal capsule, receive their own branches from
the middle cerebral artery, lenticulostriate arteries
(Fig. 8.4), and by a separate branch of the internal
gure 8.2 Regions of the brain devoid of bloodbrain barrier. carotid artery, the anterior choroid artery (Fig. 8.3).
Anterior cerebral artery

Anterior communicating artery
Internal carotid artery
Anterior
cerebral artery Anteri
Anterior choroidal artery
Sella turcica (branc
(branches to the internal capsule)
Middle cerebral artery
Midd
Posterior communicating
P
artery
a
Posterior cerebral artery

Superior cerebellar artery
Basilar artery
Anterior inferior
cerebellar artery
Posterior inferior
cerebellar artery
Foramen
magnum
Vertebral Vertebral artery
artery
Anterior spinal artery
gure 8.3 The main arteries of the brain. Anastomoses occur arterial circuit at the base of the brain. Left: Arteries at the base of the
between the branches of the internal carotid artery and the vertebral brain as reconstructed from MRIs. (Courtesy of Dr. S.J. Bakke,
artery and between the two anterior cerebral arteries, forming an Rikshospitalet University Hospital, Oslo, Norway.)
The vertebral artery (Fig. 8.3) enters the posterior oblongata, the pons, the mesencephalon, and the
fossa after ascending through the transverse foramina cerebellum. The largest branches are the posterior
of the cervical vertebrae (see Fig. 27.7). When passing inferior cerebellar, anterior inferior cerebellar, and the
from the atlas through the foramen magnum, the superior cerebellar arteries (Fig. 8.3):
artery is highly convoluted, enabling it to follow the
a. The posterior inferior cerebellar artery supplies
large movements in the upper cervical joints without
the lateral part of the medulla and inferior parts
being overstretched or compressed. Nevertheless,
of the cerebellar hemispheres. It usually originates
extreme movementsparticularly in elderly people
from the extracranial portion of the vertebral artery;
with sclerotic arteriesmay temporarily occlude the
more seldom from the basilar artery.
vertebral artery. This may lead to loss of conscious-
b. The anterior inferior cerebellar artery supplies
ness due to lack of blood supply to the brain stem.
lateral parts of the pons and parts of the cerebellum
Backward bending of the head combined with rotation
(see Chapter 27, under Lateral Pontine Infarction).
is particularly apt to compress the vertebral artery.
c. The superior cerebellar artery supplies the dorsal
Further, the vertebral arteries supply the following
aspect of the cerebellum and parts of the pons and
branches:
the mesencephalon.
1. The basilar artery arises when the vertebral arter- d. The labyrinthine artery is a small branch from
ies of the two sides unite at the lower level of the pons the anterior inferior cerebellar artery (or, less frequently,
to form (Fig. 8.3). from the basilar artery). It supplies the labyrinth in
2. The vertebral arteries and the basilar artery the inner ear (its occlusion will therefore cause deaf-
send off numerous branches to supply the medulla ness on the side of occlusion and vertigo).
e. Several thin branchescalled perforator arteries Communications between the Major Brain Arteries
penetrate the brain stem from the basilar artery
At the base of the brain, there is a connection on each
along its course. Some arise from the dorsal aspect
side between the middle and the posterior cerebral
of the basilar artery and supply midline structures
arteries, the posterior communicating artery (arteria
in the pons and mesencephalon. Others course later-
communicans posterior) (Fig. 8.3). This means that, as
ally for a variable distance before they penetrate the
long as the communicating artery is open, if one of
brain stem.
the two main arterial trunks (the internal carotid or the
3. The posterior cerebral arteries are the two end vertebral artery) is narrowed or even occluded, the
branches of the basilar artery and arise at the upper end other may compensate for the loss. There is also a cor-
of the pons. The posterior cerebral artery curves poste- responding communicating artery between the two
riorly around the mesencephalon and continue at the anterior cerebral arteries, called the anterior communi-
medial side of the hemisphere to the occipital lobe cating artery (Fig. 8.3). In this manner a circle of anas-
(Figs. 8.3 and 8.5). The posterior cerebral artery sup- tomosing arteries is formed at the base of the skull, the
plies large parts of the occipital lobe, notably the visual circle of Willis (circulus arteriosus cerebri), which may
cortex, and the inferior aspect of the temporal lobe con- be of great clinical significance. It explains, for exam-
taining higher visual association areas (e.g., necessary ple, how some people may have a totally occluded
for the recognition of objects). Perforating branches internal carotid artery on one side without any neuro-
leave the first part of the posterior cerebral artery to logical signs. In addition, the communicating arteries
supply the cerebral peduncle (the crus cerebri with can most likely become wider when the occlusion of the
descending tracts as well as nuclei dorsal to the crus, internal carotid artery develops slowly over the years.
such as the oculomotor nucleus). Some branches supply
the dorsal parts of the mesencephalon and posterior
parts of the diencephalon. The Spinal Cord Receives Arteries at Many Levels
In general, the arteries of the cord are arranged with
one artery running in the midline anteriorly, the ante-
rior spinal artery, and one on each side running along
the rows of posterior roots, the posterior spinal arteries
(Fig. 8.6). All three arteries begin cranially as branches
of the vertebral arteries but receive contributions from
the small arteries that enter the vertebral canal along
with the spinal nerves.
Individual Variations in Size and Distribution of

Cerebral Arteries Have Clinical Signicance
The symptoms produced by occlusion of one arterial
Internal capsule branch are variable because of individual differences in
the size and exact distribution of the various arterial
branches. Thus, if one artery is small, another supply-
ing a neighboring territory is usually large. The anterior
and posterior inferior cerebellar arteries are examples
Thalamus of this phenomenon: sometimes one of them supply the
total territory normally supplied by both. Even the two
vertebral arteries often differ markedly in size in one
Basal
ganglia person, explaining why symptoms caused by occlusion
of the artery may vary from minimal to life threatening.
Temporal lobe Middle cerebral Less than 50% of the population appears to have a
artery typical circle of Willis, that is, the communicating
Lenticulostriate arteries arteries are symmetrical and with a certain cross-sec-
(lateral and medial) tional diameter. In some persons the anterior communi-
Arteriae centrales
(anterolaterales)
cating artery is very thin or missing; in others this may
concern the posterior communicating artery on one or
gure 8.4 Course of the middle cerebral artery. In the depth of the
both sides. Therefore, the ability of the carotid artery of
lateral ssure, this artery gives off branches to the internal capsule one side to compensate for the loss of the correspond-
and to the basal ganglia. ing artery of the other side would be expected to vary
Precentral gyrus
Anterior cerebral artery
Leg
Arm
Face

Posterior cerebral artery
Vision
Anterior cerebral
artery
Posterior cerebral
gure 8.5 The parts of the brain supplied with blood
from the main arterial branches. artery
considerably among individuals. Similar individual

variations exist with regard to the ability of the anterior
(carotid) and posterior (vertebral) circulations to com-
pensate each other.
Posterior spinal artery
VENOUS SYSTEM
The Venous Blood Is Collected in Sinuses

The cerebral veins can be divided into deep and super-
ficial types. The latter partly accompany the arteries on
the surface of the brain. All of the veins empty into
large venous sinuses that are formed by folds of the
dura (Figs. 8.78.9).
The superficial veins at the dorsal parts of the hemi-
Anterior spinal artery spheres run upward and medially and empty into the
large superior sagittal sinus in the upper margin of the
gure 8.6 The arterial supply of the spinal cord. falx cerebri. Where the falx cerebri meets the tentorium
Falx cerebri
Cerebellar tentorium
Superior sagittal sinus
Great cerebral vein
Straight sinus
Confluence of sinuses
Transverse sinus
gure 8.7 Folds of the dura and the venous
Sigmoid sinus sinuses. The folds minimize the movements
9th & 10th cranial nerves of the brain and contain venous sinuses (in
blue).
cerebelli, the superior sagittal sinus divides into two Most of the blood in the deep cerebral veins collects
parts, the transverse sinuses, so named because they fol- into the great cerebral vein of Galen (vena cerebri
low a transverse course laterally along where the tento- magna; Fig. 8.7). This comes out from the inferior side
rium is attached to the occipital bone. The sigmoid of the posterior end of the corpus callosum and empties
sinusforming the direct continuation of the transverse into the straight sinus (sinus rectus) in the midline of
sinusempties into the internal jugular vein at the jug- the tentorium. The straight sinus drains into the supe-
ular foramen. The internal jugular vein leaves the skull rior sagittal sinus at the confluence region, from which
and continues downward into the neck. the transverse sinus originates. Unlike the arteries, the
cerebral veins have numerous anastomoses. At some
locations, there are also emissary veins that form con-
nections between intracranial and extracranial veins
(see Fig. 6.34).
Superior sagittal sinus
Bridging Veins
Veins draining into the sinuses from the subarachnoid
Straight sinus spacefor example, along the superior sagittal sinus
are called bridging veins (see Fig. 6.34). They constitute
some of the few attachments that exist between the
convexity of the hemispheres and the skull. Head inju-
ries that lead to sudden displacement of the brain inside
Transverse sinus
the skull may cause bridging veins to tear, with venous
bleeding as a result. This results in a chronic subdural
hematoma, which expands very slowly (due to an
osmotic effect of the decomposing blood of the hema-
toma). The name implies that the blood collects between
Sigmoid sinus the dura and the arachnoid, in the subdural space. The
blood remains localized, in contrast to what happens
when the bleeding occurs in the subarachnoid space.
The symptoms arising from a subdural hematoma
may be due to pressure on the underlying parts of the
gure 8.8 Venous sinuses as visualized via MRI. (Courtesy of brain (e.g., paresis if the hematoma overlies the motor
Dr. S.J. Bakke, Rikshospitalet University Hospital, Oslo, Norway.) cortex), or they may be due to increased intracranial
Cribriform plate
(Olfactory nerve)
Optic nerve
Pituitary
Cavernous sinus
Trochlear nerve
Oculomotor nerve
Trigeminal nerve
Petrous sinus
Abducens nerve
Facial and vestibulo-

cochlear nerves
Glossopharyngeal
and vagal nerves
Hypoglossal nerve
Sigmoid sinus
Great cerebral vein
Transverse sinus
gure 8.9 The large venous sinuses at the base
of the skull. On the right side, the tentorium Straight sinus
cerebelli is partly removed. The cranial nerves
and their sites of exit from the skull are also Superior sagittal sinus
Cerebellar tentorium
shown.
pressure with more unspecific symptoms, such as head- venous anastomoses). In such cases a dramatic and
ache and confusion. life-threatening condition ensues. Symptoms such as
headache, confusion, and loss of consciousness are
caused by elevated intracranial pressure, while double
The Cavernous Sinus Has Relations to the Pituitary and
vision (diplopia), and pain and loss of sensibility in the
Cranial Nerves
face are due to affection of the third, fourth, fifth, and
One of the sinuses at the base of the skull is the cavern- sixth cranial nerves.
ous sinus lateral to the pituitary gland (Fig. 8.9). Blood
from the pituitary (among other structures) flows into
Venous Drainage of the Spinal Cord
the cavernous sinus and continues posteriorly in the
inferior petrous sinus to the internal jugular vein. Some The venous blood is collected in a venous plexus at the
cranial nerves, particularly those moving the eyeball, surface of the cord. This plexus empties into another,
pass through the cavernous sinus on their way to the larger plexus at the surface of the dura, the epidural
orbit. Infections can occasionally spread from the face plexus (see Fig. 6.6). From there the blood is emptied
or the nasal sinuses to the cavernous sinus (by way of into veins outside the vertebral canal.
II DEVELOPMENT, AGING, AND PLASTICITY
T HE fully developed nervous system consists of

incredibly complex networks of connections.
There are billions of neurons in the human brain, and
complicated and precisely organized networks arise
during development of the individual? What roles do
genetic and environmental factors play in the final
each one is probably, on average, connected with sev- structure and performance of the brain? Such questions
eral thousand others. The number of possible combina- are dealt with in Chapter 9. In Chapter 10, we discuss
tions of synaptic contacts is therefore astronomic. the changes taking place in the aging brain and their
Indeed, a section of nervous tissue stained to reveal all consequences for function. A common theme in
neuronal processes might appear as a chaotic jungle. Chapters 9 and 10 is nervous system plasticitythat is,
Nevertheless, we have ample evidence that this is very its ability to adapt structurally and functionally to
far from the case: order exists everywhere, and the altered demands. In Chapter 11, we discuss plastic
mutual connections between neuronal groups are far changes in the nervous system as the basis for recovery
from random. This leads to a number of questions, such of function after damage to the central nervous system.
as: How do the thousands of individual cell groups find We will argue that a common theme in all rehabilitative
their highly specific positions in the brain? How do the efforts is to facilitate learning.
9 Prenatal and Postnatal Development
OVERVIEW branches remain, has been most intensively studied

with regard to the innervation of skeletal muscles.
Development of the nervous system starts by growth of Neuronal activity is necessary for the proper devel-
parts of the cellular layer covering the dorsal aspect of opment of axonal ramifications and for the formation
the embryo. Diffusible substances produced by the of synapses. During this process, certain connections
underlying tissue induce growth of the cells. This phase survive and possibly expand, whereas others are elimi-
of induction is an example of how the cells and tissues nated. Impulse activity alone is not enough for proper
interact during development. Then follows a more pro- development in the central nervous system (CNS), how-
longed period during which the primitive neurons and ever. The pattern of impulses has to be one that occurs
glial precursors divide mitotically. This is called the in an intact, normal animalwhich probably means
phase of cell proliferation. The number of divisions is that it must contain meaningful informationto be of
genetically determined. To get from the site of prolif- consequence for synapse formation. We use the term
eration to their final position in the nervous system, the use-dependent synaptic plasticity to characterize devel-
primitive neurons have to migrate. After reaching their opmental processes that require proper use of the
final location, they start to aggregate into groups, rep- relevant neural networks.
resenting the future nuclei.
For most neurons, differentiation starts with the out-
growth of processes after migration. By differentiation, PRENATAL DEVELOPMENT
we mean the development of structural and functional
features that makes cells different from each other. Very Assembly of neurons into nuclei and establishment of
early in differentiation the dendritic tree starts to their interconnections are largely genetically deter-
develop. Fully grown, this pattern is often highly char- mined. The outer shape of the brain, the position of
acteristic. While the neuronal processes are developing, thousands of neuronal groups (nuclei), and the main
the neuronal membranes undergo changes, and the neural connections arise prenatally: our genes contain
neurotransmitters and other specific synaptic proper- the recipe for the building of the nervous system in
ties of the neurons begin to be expressed. considerable detail. During embryonic development,
The next step in the development of the nervous precursor cells are triggered to differentiatefirst to
system is the outgrowth of axons and establishment of neurons and glial cells, and then to numerous special-
specific synaptic connections. During this phase, the ized subtypes of each. This occurs by modifications of
axons must find their way and recognize the neurons the cells chromatin, for example, by methylation of
with which they are going to establish synaptic contact. specific sites of the DNA, thereby modifying the expres-
Several factors have a role in this process. Neurons can sion of certain genes (without altering the DNA itself).
be equipped with specific recognition molecules, the Largely, our genome possesses the instructions that
target region can produce a diffusible substance that determine final size of neurons, the shape of their den-
attracts the axons, and the time of birth of a neuron dritic trees, and the types of neurotransmitters expressed,
may determine the synaptic contacts to be established. as evidenced by growth of neurons in culture. Nevertheless,
Many more neurons are formed during the prolifera- the full functional development of the brain depends
tion phase than the number present in the mature ner- critically on proper use of the neurons and their inter-
vous system. In fact, many neurons are eliminated at the connections (discussed later in this chapter). Consequently,
time their axons are establishing synaptic contacts. This the normal development and performance of the nervous
is called the phase of selective cell death and has been system depend on interactions of genetic and environ-
observed in many parts of the nervous system. Usually, mental factors.
about half of the neurons are eliminated during this
phase, although there are large regional differences.
The Central Nervous System Develops as a Long Tube
In some systems, the elimination of axon collaterals
occurs at a later stage than selective cell death. This A few days after fertilization of the egg, differentiation
phenomenon, which perhaps may be compared with of the cells of the embryo to the main kinds of tissue has
the pruning of a tree so that only the most viable started. From being a round lump of cells, after about a
117
week, the embryo resembles an elongated disc. In the Neural plate

second week the disc is covered on the upper or dorsal A
Neural crest
side and along the edges by primitive epithelium, the (primordium)
ectoderm, whereas the under or ventral side is covered
by an epitheliumthe endodermwhich later forms Notochordal plate
the intestinal tract and its glands. Between these two Neural groove
epithelial layers develops the mesoderm that later dif- B
ferentiates into the musculoskeletal system. In the third
week (after 18 days) the development of the nervous Ectoderm
system starts, with formation of a thickening, the
neural plate, in the prospective cranial end of the disc
(Figs. 9.1 and 9.2). The thickening is due to growth of Foregut
(endoderm)
the ectodermal cells so that they form a tall, simple,
columnar neuroepithelium. Diffusible substances
1
called morphogens from the underlying mesodermal
Neural crest
cells induce formation of the neural plate (see also C
Neuromeres and Hox Genes later). The differentia- Migrating neural
tion of ectodermal cells to neuroepithelium proceeds in crest cells
a cranial-to-caudal direction. A longitudinal infolding
of the ectoderm occurs by the end of the third week Neural tube
(Fig. 9.1). This neural groove is subsequently closed in
the fourth week; the closing starts in the middle part Notochord
(Fig. 9.2) and forms the neural tube, which is soon cov-
ered by the ectoderm dorsally (Figs. 9.1 and 9.2) The
wall of the tube is formed by primitive neuroepithelial
cells, which proliferate enormously and develop into gure 9.1 Formation of the neural tube and the neural crest.
neurons and glial cells. The lateral edge of the neural Schematic cross sections through embryos at different stages of devel-
opment. A: The formation of the neural tube is induced by substances
plate forms a distinct cell group, the neural crest, which
diffusing from the underlying mesoderm (notochordal plate).
later forms a longitudinal column on each side of the Approximately 17 days. B: The neural tube is formed by growth and
neural tube (Fig. 9.1). The neural crest produces the folding of the neural plate. Approximately 21 days C: The neural
neurons of the peripheral nervous system, among them crest gives origin to spinal ganglion cells and autonomic ganglion
spinal ganglion cells and autonomic ganglion cells. The cells (and some other cell types).The neural crest cells migrate into the
body to form ganglia. Approximately 24 days.
neural crest also produces Schwann cells and satellite
cells (a kind of glia) in the ganglia.
cells of the adrenal medulla, melanocytes of the skin,
and parts of the septum that divides the pulmonal artery
The Neural Crest Produces More Than Neurons
and the aorta.
and Glia
Experiments with labeling of neural crest cells before
Early Development of the Cranial End
they migrate (Fig. 9.1) show that some differentiate
of the Neural Tube
into non-nervous structures. These include the smooth
muscles of the eye (intrinsic eye muscles) and, most Whereas the caudal end of the neural tubewhich devel-
likely, the pia and the arachnoid (the dura mater is ops into the spinal cordretains its simple tubular form,
believed to originate from the mesoderm). Migrated the expanded cranial end undergoes marked changes.
neural crest cells also form the dermis and subcutis of This occurs because different parts grow at different
the face and the cartilaginous skeleton of the visceral rates, and because the tube bends, forming flexures
arches. Finally, neural crest cells produce endocrine (Fig. 9.3). In the fourth week three swellings or primary
vesicles take shape (Figs. 9.3 and 9.4). The cavities inside
1 Morphogens are substances that spread by diffusion from a localized source the primary vesicles are continuous and develop into the
and govern the embryological development and patterning of organs and body ventricular system of the brain (see Fig. 7.3). The most
parts. Their effects depend on their concentrationsoften so that high and low cranial vesicle is called the prosencephalon (forebrain),
concentrations exert opposite effects. Among several morphogens involved in
patterning of the human nervous system, the protein sonic hedgehog plays an the middle one the mesencephalon (the midbrain), and
important role at very early stages. For example, sonic hedgehog is expressed the caudal-most one the rhombencephalon (hindbrain).
by the notochord when the dorsalventral differentiation of the neural tube A ventrally directed bendthe cervical flexurearises
begins. It also acts at later stages to guide axonal growth, attracting outgrowing
axons in low concentrations, and repelling them in high concentrations (as at the junction between the rhombencephalon and the
shown for retinal ganglion cell axons growing from the eye toward the brain). spinal cord (Fig. 9.3). Later, a mesencephalic flexure
9: PRENATAL AND POSTNATAL DEVELOPMENT 119
end of the neural tube, and each segment is called a
neuromere. The segmentation is most obvious in the
rhombencephalon, and we use the term rhombomere in
this region. Although their external signs disappear by
the sixth week, the neuromeres are important because
Brain primordium
they represent the first segregation of neurons that later
differentiate into the various nuclei of the brain stem.
Thus, several cranial nerves and their nuclei are first
Neural tube laid down according to a segmental pattern, like the
spinal nerves, although later development makes the
cranial nerve pattern less regular.
The mesencephalon changes little during further
development, in contrast to the two other primary ves-
Somites icles. The prosencephalon develops into the diencepha-
Neural lon and the cerebral hemispheres, whereas the
groove
rhombencephalon differentiates into the medulla oblon-
gata, the pons, and the cerebellum (Figs. 9.4 and 9.5).
The rostral end of the prosencephalon produces two
more vesicles (one on each side), called the telencepha-
lon (Figs. 9.4 and 9.5), which later forms the cerebral
cortex and basal ganglia. In addition, the olfactory
bulbs (see Fig. 3.13) arise as evaginations from the ven-
gure 9.2 The neural plate and closure of the neural groove. tral aspect of the telencephalon. The remaining caudal
Drawing of a 22-day-old human embryo, approximately 1 mm long. part of the prosencephalon forms the diencephalon,
The central nervous system is shown in pink. (Based on Hamilton,
Boyd, and Mossman 1972.)
which includes the thalamus and hypothalamus. At an
early stage (Fig. 9.3), cuplike evaginationsthe eye
vesiclesare formed from the prosencephalon (the part
arises between the rhombencephalon and the mesen- later to become the diencephalon). The eye vesicles
cephalon. A dorsally directed bendthe pontine develop into the retina and the optic nerve. The rhomb-
flexurelater divides the rhombencephalon into two encephalon develops two parts: the myelencephalon
parts (Fig. 9.5). forming the medulla oblongata, and the metencephalon
Early in the fourth week, the ventral aspect of the forming the pons and most of the cerebellum (the cere-
prospective brain exhibits shallow, transverse grooves. bellum also develops from the mesencephalon, as dis-
These are external signs of segmentation of the cranial cussed next).
Ear 7th and 8th cranial nerves

Trigeminal nerve
Eye
Somites
gure 9.3 Early stages of brain Mesencephalic

development. Left: Drawing of a Cervical flexure
28-day-old human embryo, approxi- Heart flexure
mately 3.5 mm long. Right: Drawings
of the cranial part of the neural tube Eye vesicle
(the brain primordium) isolated and
magnied compared with the draw-
ing of the embryo. Arrows indicate
the exures of the neural tube. The
lower left is cut through (seen from
the dorsal aspect) to show the pri-
Spinal cord
mary vesicles and the ventricular Prosencephalon
space. (Based on Hamilton, Boyd, Mesencephalon
and Mossman 1972.) Rhombencephalon
A B
Lateral ventricle
Telencephalon
Prosencephalon Third ventricle
Diencephalon
Mesencephalon
Metencephalon
Rhombencephalon gure 9.4 Different divisions of the brain primordium.
Fourth ventricle Schematic of the cranial part of the neural tube (straight-
ened out and cut open horizontally). A: Approximately
Myelencephalon
the same stage as in Fig. 4.3. B: The same stage as in
Spinal cord Fig. 4.13A. Note the development of the telencephalon
(the hemispheres) that gradually covers the diencephalon.
and central canal). The innermost layer, the ventricular

Early Phases in the Development of
zone, borders the cavity. In the ventricular zone, the
the Neuroepithelium
cells divide mitotically (Figs. 9.6 and 9.13A). The future
Initially, the wall of the neural tube consists of only one neurons, the neuroblasts, afterward migrate outward to
layer of cylindrical neuroepithelial cells (Figs. 9.1 and form the mantle zone that later becomes the gray mat-
9.2), bounded externally by the external limiting mem- ter. A layer without neurons, the marginal zone, forms
brane (covered by the pia) and internally toward the external to the mantle zone and becomes the white mat-
cavity by the internal limiting membrane. These are ter. The neurons of the mantle zone send axons into the
basal membranes built of extracellular material, which marginal zone. These axons loop back to the mantle
always develop with surface epithelia. Intense prolifera- zone, however, to synapse on neurons there (these are
tion of neuroepithelial cells soon leads to several layers the first association connections to arise). Other axons
of nuclei. The epithelium does not become truly strati- leave the neural tube as motor fibers growing peripher-
fied, however, because all cells retain a thin process ally to contact muscle cells and glands (Fig. 9.7). After
reaching the internal limiting membrane (pseudostrati- neuroblast production ends, various types of glial cells
fied epithelium; Fig. 9.6). The outermost cells move are produced by mitosis of neuroepithelial cells that
toward the cavity of the neural tube (the future ventricles remain in the ventricular zone. The last to be produced
Pontine flexure
Visceral arches Mesencephalo
Mesencephalon Pons
Medulla
oblongata
Diencepha
Eye Hemispher
(telenceph
Heart Spinal cord Optic
Trigeminal nerve
nerve
Lateral ventricle
Umbilical cord
Arm
Third ventricle
gure 9.5 Early development of the brain. Left: Drawing of a cranial part of the neural tube at the same stage. (Based on Hamilton,
36-day-old human embryo, approximately 11 mm long. Right: The Boyd, and Mossman 1972.)
Neural tube
Neuroepithelial cell
Neuroblast Neuron
Pia
MARGINAL ZONE
Glioblast
MANTLE ZONE
gure 9.6 Differentiation of the neuroep- Radial glia

ithelium. Left: Drawing of a section
through the wall of the neural tube at an VENTRICULAR
early stage (cf. Fig. 9.7A). Right: Arrows ZONE
show how the neuroepithelial cells move
while they differentiate into different cell
types. Mitoses Ependymal cell
are the ependymal cells. These retain their internal posi- (the future brain), however, major alterations in the
tion and cover the ventricular face of the neural tube mutual positions of gray and white matter occur. In the
(Fig. 9.6). The cavity is filled with cerebrospinal fluid developing cerebellar and cerebral cortices, for exam-
produced by tufts invaginated from the wall into the ple, neurons migrate from the mantle zone through the
cavity (see Fig. 7.6). These tuftsthe future choroid marginal zone and form a layered sheet of gray matter
plexusare covered by ependymal cells. externally, just under the pia.
The simple layering of the neural tube, with the man-
tle zone (gray matter) inside and the marginal zone
Neuromeres
(white matter) outside, is retained with minor changes
in the spinal cord. In the cranial part of the neural tube We mentioned that the rostral part of the neural tube
shows transient, external signs of segmentationeach
segment constituting a neuromere. Although this phe-
Ventricle nomenon was observed in the nineteenth century, mod-
ern cell biological methods were necessary for closer
Ventricular study of their role in the development of the nervous
zone system. Neuromeres are most convincingly shown in
the rhombencephalon, where they are called rhombom-
Mantle eres. It is assumed that the mesencephalon consists of
zone two neuromeres, whereas the prosencephalon probably
consists of six. The great interest in neuromeres and
Marginal other external signs of segmentation arose because they
zone provide information about the mechanisms that control
the early development from the undifferentiated neural.
Cranial nerve Each rhombomere represents a unit of neurons that
root fibers do not mix with neurons of other rhombomeres during
subsequent development. This neuronal specification
takes place just when the rhombomere boundaries arise.
The rhombomeres arise when adjoining groups of neu-
rons begin to express different surface markers. The
neurons of one rhombomere, among other things, have
gure 9.7 Outgrowth of cranial nerves from the rhombencephalon. a specified future peripheral target (the neurons of the
Photomicrograph of a horizontal section through a chicken embryo
neural crest in the head region are also specified with
at about the same stage as in Figure 4.3. Thin bundles of axons leave
the marginal zone and penetrate the connective tissue that surrounds regard to their peripheral target before they start to
the brain primordium. migrate peripherally). The motor trigeminal nucleus,
for example, is formed in rhombomeres r2 and r3, high concentrations it induces differentiation of poste-
whereas the motor facial nucleus develops in r4 and r5. rior parts. This explains why adequate dietary levels of
The motor and sensory cranial nerve axons already vitamin A are necessary for the normal development of
have a specified target when they start growing out the CNS, but also why too much also may cause mal-
from the neural tube (Fig. 9.7). Thus, when a rhom- formations (as may occur in women treated for acne
bomere is transplanted to another place in the chicken with retinoic acid in early pregnancy).
embryonic brain, it develops as if it were still in its orig- Neuromeric borders, identified with genetic markers,
inal place and not corresponding to its new location. are more reliable indicators of future borders between
Such specification must be caused by the switching on anatomically and functionally different areas than are
of certain geneswhich start to express themselves by borders between brain vesicles. For example, the cere-
production of mRNAwhile probably other genes are bellum, traditionally regarded as arising only from the
switched off. metencephalon, is also formed by neurons in the adjoin-
ing part of the mesencephalon. The rostral border of
neurons forming the cerebellum coincides with a bor-
Hox Genes
der for the expression of the engrailed 2 gene.
Many so-called Hox genes have been identified that are
expressed in a pattern corresponding to neuromeric
Further Development of the Spinal Cord and
boundaries in vertebrates. Most of these genes code for
the Brain Stem
proteins that act as transcription factors. These bind to
DNA of other genes and regulate their transcription. In the fourth week, the proliferation of neuroblasts in
Typically, transcription factors are expressed tempo- the mantle zone produces a large ventral thickening and
rarily during specific phases of development. (Hox a smaller dorsal one on each side of the neural tube.
genes not only control regional development of the ner- These thickenings are called the basal plates and the
vous system but also act in pattern formation in other alar plates, respectively (Figs. 9.8, 9.9, and 9.10).
parts of the body.) When a certain Hox gene is switched A shallow furrow, the sulcus limitans, marks the border
on, a cascade of changes in the expression of other between them. This remains visible in the lower part of
genes is initiated, producing signal molecules that give the brain stem in the adult (see Fig. 3.17), while it
the neuronal groups their identityfor example, disappears early in the spinal cord. The basal plate con-
regarding location and connections. A crucial question tains neuroblasts that later become motor neurons,
is, of course, what controls the regionalized expression whereas many alar plate neuroblasts become sensory
of Hox genes giving rise to the rhombomeres? One neurons. This corresponds to the functional division
important factor is retinoic acid (vitamin A), which between the ventral and dorsal horns of the cord. In the
normally occurs with an anteroposterior (rostrocaudal) adult brain stem, the sulcus limitans marks the border
concentration gradient in the embryo (highest concen- between the motor and the sensory cranial nerve nuclei
tration posteriorly or caudally). The retinoic acid seems (Fig. 9.11). In the open part of the rhombencephalon
to stem from the mesoderm adjacent to the neural tube. later to become parts of the medulla and the ponsthe
In low concentrations, retinoic acid acts on Hox genes motor nuclei lie medially and the sensory nuclei later-
that specify anterior parts of the neural tube, while in ally (see Figs. 27.2 and 27.3). This is caused by lateral
A B
Ectoderm
Ventricular zone
Alar plate
Basal plate
Marginal zone
Spinal ganglion
Notochord
gure 9.8 Early development of the spinal cord. A: Photomicrograph a 6-week-old human embryo; cf. Fig. 9.5). B: Drawing based on a pho-
of a cross section of a chicken embryo (corresponding approximately to tomicrograph of the human spinal cord at about 7 weeks gestation.
Roof
Alar plate
Fourth
ventricle
Basal plate
Alar plate
Sulcus limitans
Ear Sulcus limitans
vesicle
Cranial
nerve Afferent nuclei
Basal plate
Efferent nuclei
Notochord
Somatic efferent Visceral efferent

(general) Visceral afferent
gure 9.9 The rhombencephalon. Early stage of development,
approximately as in Fig. 9.3. Photomicrograph of a cross section of a Somatic afferent
chicken embryo. Inset: A human embryo at a corresponding stage of
development. Note the thin rhombencephalic roof attached to the
edge of the alar plate.
bending of the alar platesaway from each otherso Somatic efferent

(special)
that the roof of the rhombencephalon becomes only a
thin membrane (Figs. 9.9 and 9.10). At a later stage, the
gure 9.10 Development of the cranial nerve nuclei. Schematic.
cerebellum develops from the margins of the alar plates
Three stages are shown to explain the mutual positions of the nuclei.
(the rhombic lip). After their formation, the special somatic efferent nuclei move vent-
At an early stage, several neuronal groups in the rolaterally. See also Figs. 17.2 and 17.3.
brain stem migrate from their birthplace in the alar
or basal plates. In the pons, neuroblasts move from the cranial nerve nuclei that innervate visceral (branchial)
rhombic lip in a ventral direction and form the pontine arch muscles (see Fig. 9.10). These neurons move in a
nuclei (see Fig. 3.18). Similarly, in the medulla the infe- ventral direction during early development after they
rior olive (another nucleus projecting to the cerebellum; have started to send out axons. The course of the root
see Fig. 3.17) is formed by neuroblasts moving ventrally fibers in the brain stem therefore shows the path fol-
from the rhombic lip. Another example is the motor lowed by the migrating neurons (see Fig. 27.11).
L2 L2 L2 L2
Vertebral
bodies
S1 root
S1
S1
S1
S1
Spinal Spinal
cord ganglion S1
gure 9.11 Relationship between the

lengths of the spinal cord and the verte-
bral column. (Based on Hamilton, Boyd,
and Mossman 1972.) 3 months 4 months 5 months 7 months
Until the eighth to ninth week, the spinal cord extends ventral roots. As for the eleventh cranial nerve (the
the full length of the spinal canal of the embryo. After accessory), it is not settled whether the two muscles it
that, however, the vertebral column and the coverings innervates (the sternocleidomastoid and trapezius)
of the cord grow more rapidly than the spinal cord develop from somites or from visceral arches. The latter
itself, producing a gradually increasing length differ- hypothesis is supported by the fact that the accessory
ence (Fig. 9.11). This explains the oblique course of the nerve root fibers, coming from the upper cervical
spinal nerves in the vertebral canal before they leave segments, exit the cord more dorsally than the spinal
through the intervertebral foramina. The lower end of ventral roots (corresponding to the level where visceral
the cord is at the level of the third lumbar vertebra at arch nerves leave the brain stem; see Fig. 27.8).
birth, in contrast to the first lumbar vertebra in adults.
The dural sac, containing spinal nerve roots (the cauda
Further Development of the Diencephalon
equina), continues down to the second sacral vertebra
(see Fig. 3.3). The diencephalon represents the caudal part of the
original prosencephalic vesicle (Figs. 9.4 and 9.5). The
lateral wall in this part becomes thicker at an early stage
Cranial Nerves and Visceral Arches
and develops into the thalamus (Fig. 9.12A). The floor
Cranial nerves 5, 7, 9, and 10 (trigeminal, facial, plate forms the hypothalamus and the posterior pitu-
glossopharyngeal, and vagal; see Figs. 6.15 and 6.19) itary (see Figs. 6.22 and 6.24). The latter arise as an
innervate structures developed from visceral arches (or evagination of the floor plate. The furrow (hypotha-
branchial arches). In fish, the two upper visceral arches lamic sulcus; see Fig. 6.23) marking the border between
are parts of the viscerocranium surrounding the oral the thalamus and the hypothalamus might be a contin-
cavity. They are not equipped with gills, in contrast to uation of the sulcus limitans (Fig. 9.10) It is not settled,
the lower (36) arches that are true respiratory organs. however, whether the arrangement with basal and alar
In mammals, none of the visceral arches has respiratory plates continues rostrally into the diencephalon. The thin
functions. Parts of them are used for new tasks, whereas roof plate of the diencephalon forms by invagination the
other parts have regressed. There are no signs of gill choroid plexus of the third ventricle (see Fig. 7.5).
development at any stage of human embryogenesis. The Further, the roof plate produces the pineal body by
term branchial arch (from Greek brankhion, gill) is evagination (see Fig. 6.23). The eye vesicles occur at an
therefore not quite appropriate. earlier stage (before the further differentiation of the
A visceral arch consists of a skeletal part (cartilage, prosencephalon; Fig. 9.3) but retain connection with
later replaced by bone in some arches), muscles, skin, the diencephalon by the future optic nerve (Fig. 9.5).
mucous membranes, and a nerve of its own. As men-
tioned, neural crest cells give rise to the skeletal part. In
Further Development of the Telencephalon
human embryos, some visceral arches appear as ventral
bulges in the head and cervical region (Figs. 9.3 and In the fifth week, development of the cerebral hemi-
9.5). The first visceral archproducing the upper and spheres starts with the appearance of one vesicle on
lower jaw with attached masticatory muscles, along each side of the prosencephalon (Figs. 9.4 and 9.5).
with the hammer and the anvil of the middle earis These are called the telencephalic (cerebral) vesicles.
innervated by the fifth cranial nerve (the trigeminal). Their cavities form the lateral ventricles, which initially
The second visceral archforming, among other things, have wide openings to the third ventricle (interventricu-
the upper part of the hyoid bone, the stirrup of the lar foramen, Fig. 9.12A). The mantle zone of the basal
middle ear, and the facial musclesis innervated by the part of the telencephalic vesicle thickens rapidly to form
seventh cranial nerve (the facial). The third visceral the corpus striatum of the basal ganglia (Fig. 9.12A).
archforming most of the hyoid bone and the poste- The thinner overlying part, called the pallium, becomes
rior part of the tongueis innervated by the ninth the cerebral cortex. The pallium grows dorsally, rostrally,
cranial nerve (the glossopharyngeal). The fourth, fifth, and caudally in relation to the diencephalon (Fig. 9.4).
and sixth visceral arches form the cartilaginous skeleton The caudal and ventral parts of the hemispheres later
of the larynx and the muscles of the larynx and the fuse with the diencephalon (Fig. 9.12B).
pharynx. These structures are innervated for the most The basal ganglia primordium is later divided into
part by the tenth cranial nerve (the vagus). two partsthe lateral and medial corpus striatumby
Cranial nerves 3, 4, 6, and 12 (the oculomotor, tro- descending axons from the cerebral cortex. These
chlear, abducens, and hypoglossal; see Fig. 3.14) inner- descending axons form the internal capsule (Fig. 9.12B).
vate structures that most likely develop from segmentally As development proceeds, the caudate nucleus and the
arranged somites (somites are paired cubical masses thalamus come to lie medial to the internal capsule
giving rise to muscles, the axial skeleton, and the der- whereas the lentiform nucleus (the putamen and the
mis of the skin). These nerves are homologous to spinal globus pallidus) lies laterally (see Fig. 13.2).
Hippocampal primordium
Hippocampal sulcus
A
Pallium
Lateral ventricle
Choroid plexus
Interventricular
Descending foramen
fibers from
the pallium Medial and lateral
corpus striatum
Thalamus
Third ventricle
B
Corpus callosum
Fornix
Caudate nucleus
gure 9.12 Development of the telencephalon.

A: Early stage, in which the telencephalon is still
separated from the diencephalon. Descending Thalamus
bers have started their growth from the pallium
(primordium of the cerebral cortex) to the brain Internal
stem and the spinal cord. B: The telencephalon capsule Caudate nucleus
is now attached to the diencephalon laterally,
and the medial and lateral striatum have been
separated by the internal capsule. The hip-
pocampus has changed its position, due to the Temporal horn of Hippocampus
growth of the hemispheres (cf. Fig. 3.36). (Based the lateral ventricle
on Hamilton, Boyd, and Mossman 1972.)
In the medial wall of the pallium, just above the hemisphere. At a later stage, we can differentiate a ven-
attachment of the choroid plexus, a thickening arises tricular zone, mantle zone, and marginal zone, just as in
that bulges into the lateral ventricle (Fig. 9.13A). This is other parts of the neural tube (Fig. 9.13A). At the begin-
the beginning of the hippocampus, which is partly sepa- ning of the eighth week, neuroblasts from the mantle
rated from the rest of the pallium by the hippocampal zone migrate into the marginal zone and start establish-
sulcus. As the hemispheres grow, their shape changes so ing the cortical plate (Fig. 9.13B), which in due course
that the temporal lobes come to lie ventrally. This will develop into the mature cerebral cortex by waves of
produces the characteristic curved shape of the lateral cells migrating toward the cortical surface. The peak of
ventricles and the structures in their wall, such as the migratory activity probably occurs between the third and
hippocampus and the caudate nucleus (see Figs. 7.4 and fifth months, while migration ends in the third trimester.
31.2). The hippocampus thus moves from the position By the end of the seventh month the cortex has developed
in Fig. 4.12A to that in Fig. 4.12B. six layers, as in the mature cortex (see Figs. 33.1 and
The choroid plexus of the lateral ventricles is formed 33.2). Synapses begin to occur in the fourth month
by invagination of the thin part of the pallium (together (earliest in the prospective somatosensory cortex).
with the pia) close to the dorsal aspect of the dienceph- The deepest cortical layers are established first; thus,
alon (Fig. 9.12B; see also Fig. 7.6). neurons destined for superficial layers have to pass
through the deep layers. Neuroepithelial cells in the ven-
tricular zone that have ceased dividing are termed post-
Development of the Cerebral Cortex
mitotic. The exact time a neuron becomes postmitoticits
At first, the telencephalic vesicle consists of only one birth dateappears to decide which cortical layer it will
layer of neuroepithelial cells. These proliferate, however, join. Radially oriented glial cells, radial glia (Fig. 9.6),
producing rapid growth of the prospective cerebral with processes extending from the ependyma to the pia,
A B
Pia
Marginal zone
Cortical plate
(primordium of the
cerebral cortex)
Transitory layer
of neurons
Ventricular zone
gure 9.13 Differentiation of the prosencephalic neuroepithelium to of a section through the telencephalon (rat) at a much later stage than
the cerebral cortex. A: Photomicrograph of a cross section through in A, corresponding approximately to the fourth to fth month in human
the neural tube (prosencephalic part) at an early stage (chicken development. The ventricular zone is densely packed with neuroblasts
embryo, corresponding to early fourth week gestation in humans). that will soon migrate toward the cortical plate. In further development,
Mitotic activity occurs in the ventricular zone. B: Photomicrograph the cortical plate develops into the adult six-layered cortex.
guide the migration of postmitotic neurons toward the The differentiation of the cortical plate into distinct
cortex. The phenotype of postmitotic neurons, for areas (see Fig. 33.4)a process called arealization
example, whether they will develop into interneurons or depends on both genetic factors intrinsic to the devel-
projection neurons, appears to be specified at the time oping cortical progenitor cells and extrinsic influences.
they start migrating toward their final destination. In the beginning, local patterning centers in the periph-
Shortly after the establishment of the cortical plate, ery of the ventricular zone produces gradients of mor-
thalamocortical fibers start to invade the telencephalic phogens that define four main, overlapping domains in
wall, although they must wait several weeks below the the cortical plate.3 The morphogens in turn initiate
cortical plate before they find their final destination in more discrete expressions of transcription factors in
the developing cortex. The earliest afferent fibers to cortical progenitor cells. These transcription factors are
arrive, however, are monoaminergic (at about 7 weeks). involved in the further differentiation of the cortical
While probably all progenitors of projection neurons plate into areas with sharp borders (as well as in other
arise in the ventricular zone and migrate radially to their aspects of cortical development).
final destination, many prospective cortical interneu- Among extrinsic influences, thalamocortical afferents
rons arise from subcortical sites in the ventral forebrain. appear to be of particular importance for the mature
They then migrate tangentially along the cortical plate cytoarchitectonic characteristics of an area. For exam-
for varying distances before they change course and ple, the characteristic cytoarchitectonic differences
migrate perpendicularly into the cortex.2 between the primary sensory areas (compare Figs. 33.2
and 33.4) depend on from which specific thalamic
nucleus the areas receive their afferents. For example,
Specication of Cortical Cytoarchitectonic Areas
transplanting a piece of visual cortex to the somatosen-
The adult cerebral cortex consists of many areas sory cortex makes the transplanted tissue acquire the
that differ structurally and functionally (see Fig. 33.4). cytoarchitectonic features that are typical of the soma-
tosensory cortex. Further, immature projection neurons
2 All cortical interneurons are GABAergic but fall into different groups
transplanted from one area to another develop axonal
structurally and with regard to whether they co-express the neuropeptide soma-
tostatin (SST), parvalbumin (PVA), or calretinin (CR). The three main groups
of GABAergic interneurons seem to be specied at the time they migrate from 3 For example, the arealization of the frontal cortex seems to be initiated by
the so-called ventricular (ganglionic) eminences. two broblast growth factors (Fgf8 and Fgf17).
ramifications appropriate for the area to which they are
transplanted. Thus, the local environment contributes Right Left
significantly to the neuronal phenotype.
In addition to the genetically determined development
described here, proper use of cortical areas is critical for
the realization of their functional specialization. This
involves use-dependent plastic processes, stabilizing
useful synaptic connections, and eliminating those that
prove to be superfluous or maladaptive.
Migration and Migration Disorders

We know some of the factors governing neuronal
migration, such as recognition molecules, adhesion
molecules, cytoskeletal components, and others. There
is a complex interplay among them, and the different Lateral
sulcus
factors must be present in the proper concentration at
the proper time and place. For example, the early pres-
ence of certain neurotransmitters influences neuronal
motility by acting on ion channels that increase the
2+
intracellular Ca concentration. The glycoprotein reelin
(among other factors) governs the final positioning
gure 9.14 Neuronal migration disorder. Horizontal T1-weighted
of migrating neurons in the cortex. Because reelin is
MRI. The right frontal cortex is dysplastic: it is thicker than normal
produced by Cajal-Retzius cells in the marginal zone with obliteration of normal sulci (polymicrogyria). Similar alterations
(Fig. 9.6) , it would seem logical that a concentration occur around the lateral sulcus. (Courtesy of Dr. S.J. Bakke,
gradient of reelin between the marginal and ventricular Rikshospitalet University Hospital, Norway.)
layers is critical for normal development. The mecha-
nisms behind the effects of reelin appear to be more
complex, however. Nevertheless, mice with a mutated is epilepsy (which is often difficult to treat pharmaco-
gene for reelin exhibit characteristic malformations of logically). This is compatible with the fact that migra-
layered structures; in the cerebral cortex, the late-arriving tion disorders also are associated with molecular
neurons do not migrate past those that arrived first to abnormalities of cortical neurons. Thus, animal experi-
occupy the outer layers. Although the neurons survive ments suggest that epilepsy can arise in dysplastic
and establish apparently normal connections, the brain cortex because of an imbalance between the expression
does not function normally. Another mutation, shown of excitatory and inhibitory receptors (up-regulation of
in some humans, affects the migration before the neu- amino-methylisoxazole propionic acid [AMPA] recep-
rons enter the cortical plate and is associated with a tors and down-regulation of GABAA receptors).
smooth cortex lacking the normal six-layered structure
(Miller-Dieker lissencephaly). This is just one example
Programmed Cell Death and Competition for
of a large and varied group of malformations in
Trophic Factors
humansmigration disorderscaused by delayed or
deficient migration of postmitotic neurons. As previously mentioned, many more neurons are
Migration disorders affect primarily the cerebral cor- formed during the proliferation phase than are found in
tex and the cerebellum. Many are inherited recessively, the mature nervous system. Cell death usually coincides
although ischemia, radiation, and other influences can in time with the period during which the neurons estab-
cause migration disorders (as shown in animal experi- lish synaptic contacts. For the most intensively studied
ments). In the cerebral cortex, migration disorders typi- neuronal groups, such as spinal motoneurons and reti-
cally are associated with defective development of the nal ganglion cells, the amount of elimination depends
gyri (Fig. 9.14), which may be lacking (lissencephaly), on target size. If the target (e.g., striated muscle cells) is
too small (polymicrogyria), or show other abnormali- experimentally expanded, more motoneurons survive,
ties. Usually, such a cortex is called dysplastic, and whereas reducing the target size increases elimination.
some use the term dysplastic cortex as synonymous This can be explained by the neurons needing a suffi-
with migration disorders. cient supply of a growth-promoting substancea
Migration disorders cause a number of syndromes trophic factorto survive. The target cells produce
characterized by cognitive and behavioral defects (mental limited amounts of this trophic factor; that is, there is
retardation is common). Typical of many such syndromes not enough to keep all neurons alive. The neurons
innervating the target compete for the trophic factor, (BDNF), and several others (neurotrophin NT-3, NT-4,
and only the winners survive. Because a limited number and so forth). Apart from regulating many aspects of
of synapses can be formed on each neuron, the axons neuronal growth and differentiation during prenatal
arriving first have an advantage. The trophic factor is development, they are involved in synaptic plasticity
taken up by the nerve terminals at the synaptic sites and and neuronal survival in the adult nervous system. The
transported retrogradely to the cell body. The elimina- neurotrophins bind to specific tyrosine-kinase receptors
tion of surplus neurons appears to occur rapidly, per- (Trk) and to an unrelated receptor, p75NTR (p75 neu-
5
haps during a few days in some systems. Overall, this rotrophin receptor). The two kinds of receptor may
kind of cell death is believed to ensure optimal numeri- help to explain further why the effects of neurotrophins
cal relationships between, for example, motoneurons are highly complex and not fully understood. Among
and muscle cells. Cell death probably also serves to other differences, the effects mediated via Trk and
eliminate incorrect synaptic connections. p75NTR receptors tend to be opposite. Thus, nerve
Programmed cell death is not uniform throughout growth factor prevents programmed cell death by
the nervous system. In the primordial cerebral cortex binding to TrkA receptors, whereas binding to p75NTR
probably about 90% of the neurons die, whereas in promotes it. Thus, the effects of a neurotrophin on a
the spinal cord few interneurons die. About 50% of certain neuronal population depend on the local expres-
motoneurons die, and a similar rate holds for a type sion of neurotrophin receptors (e.g., the balance
of interneuron in the retina (amacrine cells). We do between expression of Trk and p75 receptors). The
not know the reasons for such differences, and many expression of the neurotrophins and their receptors appear
questions remain unanswered concerning programmed to be dynamically regulated by a complex interaction
6
cell death. For example, the number of cells that die among intrinsic and extrinsic factors. Thus, neurotro-
is not always related to the size of the target. phin effects would differ among neuronal populations,
Cell death as a normal developmental process is and on the same population at different points of time.
termed apoptosis (in contrast to necrosis, which means Among other growth factors acting in the brain are
cell death caused by abnormal, nonphysiological the fibroblast growth factors (FGFs), which influence
influences).4 What triggers this process? When certain differentiation and survival of several kinds of neurons.
nerve cells die without the presence of a growth factor, Several other growth factors that were initially discov-
does it happen because the cell needs the factor for vital ered in the peripheral tissues are also expressed in the
metabolic processes or because the factor inactivates brain.
genes that trigger apoptosis? There is much evidence in
favor of the latter explanationthat is, the existence of
Neurotrophins, Plasticity, and Disease
a genetic death program in each cell. For example,
mutation of certain genes prevents apoptosis that As mentioned, neurotrophins play a role not only dur-
normally would have occurred at a certain stage of ing normal development but also in the adult brain.
development. The finding that expression of neurotrophins can be use
dependent has attracted special interest in their role in
synaptic plasticity. Brain-derived neurotrophic factor
Neurotrophins and Other Growth Factors
(BDNF), for example, is involved in the induction of
The Italian Nobel Prize winner Rita Levi-Montalcini LTP. In the visual cortex, the expression of the receptor
discovered around 1950 a substance that stimulates TrkB parallels the critical period in development, and
axonal growth in the peripheral nervous system. This the synthesis increases with increased use of the visual
substancetermed nerve growth factor (NGF)is a system. Beneficial effects of physical activity on cogni-
protein produced by the cells of the target organ. tive functions and neurogenesis appear at least in part
Antibodies against NGF inhibit the growth of axons to be mediated by increased expression of BDNF (and
from autonomic ganglion cells and sensory cells derived perhaps NGF).
from the neural crest. In cell cultures, axons grow into
an area containing NGF and retract from areas without
it. NGF binds to specific membrane receptors. It is
5 The Trk receptors constitute a family of threeTrkA, TrkB, and TrkC
transported retrogradely to the cell body, enabling each of which can be activated by one or more of the neurotrophins NGF,
effects on gene expressions. After the discovery of NGF, BDNF, NT-3, and NT-4. Overall, NGF seems to exert its main effects via TrkA
several related neuronal growth factors have been iden- receptors, while BDNF acts mainly via TrkB. The p75NTR belongs to the
tumor necrosis factor receptor (TNFR) family (tumor necrosis factor is an
tified. Together they form the neurotrophin family, inammatory cytokine released from leukocytes, inducing apoptosis via its
consisting of NGF, brain-derived neurotrophic factor receptors).
6 For example, while the expression of p75NTR in normal adult brain is min-
imal, it increases after injury. At the same time, Trk receptor expression may be
4 Apoptosis is characterized by the breakdown of DNA to smaller fragments reduced. This would tend to push the effect of neurotrophin receptor activation
and the subsequent dissolution of the cell. from supporting cell survival to inducing cell death.
Neurotrophins are also intensely investigated for Myelination of the cranial nerves starts in the sixth
their possible beneficial effects after brain injury. For fetal month, except for the optic nerve (which is a cen-
example, administration of growth factors at the site of tral tract and not a peripheral nerve). Myelination starts
injured neurons might help them survive. In animal shortly before birth in the optic nerve.
experiments, injection of NGF into the ventricular sys- In the cerebral cortex, myelination begins shortly
tem prevented delayed cell death in the hippocampus before birth, first in motor and sensory areas. The asso-
after a period without blood supply. The role of ciation areas are mainly myelinated during the first
neurotrophins in neurodegenerative diseases has also 4 months after birth, although myelination continues
attracted interest. One theory proposes that the senile after that period. The last regions to become fully
plaques in the brain of Alzheimer patients down-regulate myelinated are the association areas in the frontal lobe
FGF in their environment, thus causing neuronal death. (prefrontal cortex).
In Parkinsons disease and Huntingtons disease as well, Although the myelination largely occurs according to
the level of FGF is apparently reduced. The connection the pattern described in the preceding text, longitudinal
between such changes and the disease process is not magnetic resonance imaging (MRI) studies indicate that
clarified, however. the relative proportion of white matter in the brain
Prolonged stress can cause neuronal death in experi- increases (although slightly) until adult age. For exam-
mental animals. Decreased production of neurotrophins ple, the cross-section of the corpus callosum increases
BDNF in particularmay mediate the effect of stress. from 5 to 18 years of age. Presumably, after the age of
Alterations of growth factors also occur in patients 2 to 3 years the increase in white matter is caused by
with severe depression, and both antidepressant drugs increased myelin-sheath thickness of already myelinated
and electroconvulsive therapy have been reported to axons.
increase expression of BDNF (among other effects).
Malformations of the Nervous System
We discussed migration disorders as a cause of
Myelination
malformations, especially of the cerebral cortex. These
Myelination of axons starts in the fourth month of ges- malformations are special since the development of the
tation and is largely completed 2 to 3 years after birth. cerebral cortex is so protracted, ending late in the
Although many axons in the CNS remain unmyeli- prenatal period. Here we consider other kinds of
nated, the process of myelination is clearly related to malformations that occur before the gross shape of the
functional maturation of neuronal interconnections. CNS has been established.
Full functional capacity cannot be expected before Malformations of the nervous system, as in other
myelination is completed. As for the individual neuron, organs of the body, may be caused by genes or environ-
myelination starts at the soma and proceeds distally. mental factors (or by both). External agents, such as
Different tracts are myelinated at different times. Overall, viruses and drugs, are most likely to cause serious mal-
tracts concerned with basic tasks, necessary for life, are formations or maldevelopment if they act in the period
the first to be myelinated (such as sucking, swallowing, of maximal differentiationthat is, from the third to
retraction from harmful stimuli, emptying of bowel and eighth week after fertilization (most organs are formed
bladder, and so forth). Such connections are also phy- during the embryonic period from the fourth to eighth
logenetically the oldest. week). Harmful influences before this stage usually lead
In the spinal cord, myelination starts in the cervical to early death of the embryo.
region and proceeds in the caudal direction. First to be Among the most common malformations is defective
myelinated are the propriospinal fibers (interconnect- closure of the neural tube, which may be caused by
ing various spinal segments). Ventral root motor fibers various genetic and environmental factors. Normally,
are myelinated earlier than the dorsal root sensory the closure is completed by the end of the fourth week.
fibers. Myelination of ascending spinal tracts starts in Lack of closure may affect the whole length of the neu-
the sixth fetal month, and tracts descending from the ral tube but is most often restricted to either the cranial
brain stem follow (reticulospinal and vestibulospinal or the caudal end. When the neural tube does not
tracts). These tracts need to be functioning at birth. In develop normally, neither do overlying structures such
contrast, the pyramidal tract, which controls the most as the skull, parts of the vertebral column, and the skin.
precise voluntary movements, is fully myelinated only Their normal development depends on induction by
about 2 years after birth. Connections from the cere- diffusible substances (morphogens) from the nervous
bral cortex to the cerebellum (see Fig. 24.7) are myeli- tissue. With defective closure of the cranial end, the
nated at the same time as the pyramidal tract, which brain does not develop, and the remainder of the neural
seems logical because these connections are important plate degenerates. This condition is termed anencephaly.
for coordination of voluntary movements. Such fetuses may sometimes live until birth but always
die shortly after. A defective closure of the spinal cord very complex interplay of simultaneous building up
(most often in the lumbosacral part) is termed spina and tearing down, resembling the work of a sculptor
bifida because the vertebral arch and soft tissue dorsal who adds excess of clay to be able to carve out the fine
to the cord do not develop normally. This condition details.
may vary in severity. In the most serious cases the ver-
tebral arches, muscles, and skin are absent and there is
Distances Are Small in the Early Embryo
herniation of the coverings of the cord that contain
degenerated nervous tissue (meningomyelocele). Less Knowing the complexity of the mature nervous system,
severe cases may involve herniation of the coverings but one might think that most of the human genome must
keep the spinal cord intact, whereas the least affected be devoted to specification of neuronal connections.
have only partial lack of the vertebral arch (spina bifida This is not the case of course. We should bear in mind
occulta). In the most serious cases, the cord does not that the whole embryo is only a few millimeters to a
develop normally, leading to pareses and sensory dis- couple of centimeters during the stages of most intense
turbances of the legs. When the nervous supply is defi- axonal outgrowths. Thus, the distances that axons have
cient, the muscles do not develop to their normal size to grow to reach their targets are usually very short.
and strength. Further, the topography of the nervous system at these
Reduced drainage of the cerebrospinal fluid caused early stages is also much simpler than later, as not all
by, for example, abnormal narrowing or obliteration of nuclear groups develop simultaneously. Our present
the cerebral aqueduct (see Fig. 7.5) leads to hydroceph- knowledge suggests that combined actions of several
alus. If left untreated, this will cause death or seriously mechanisms, each of them relatively simple, can explain
impair brain development (see also Chapter 7, under how the specificity of the nervous system arises.
Brain Edema, Herniation, and Hydrocephalus).
Time of Neuronal Birth
MECHANISMS FOR ESTABLISHMENT OF SPECIFIC The genetically programmed time of neuronal birth can
CONNECTIONS explain the development of specific connections in
many cases (Fig. 9.15). If, at the time of axonal out-
The main morphologic features of the nervous system growth from one neuronal group, only certain neurons
such as its macroscopic form, the positions of major are present in the direction of growth, the axons will hit
nuclei and their interconnectionsarise before birth their correct target without specific recognition mole-
and shortly after. In a sense, this represents the hard wir- cules. In addition, programming of neurons for maxi-
ing of the brain. In this section, we discuss mechanisms mal synapse formation during a limited period ensures
important for forming the brains wiring diagrams. that synapses are established upon arrival of the proper
The growth of axons is often surprisingly goal-directed, axons. The time during which neurons readily produce
indicating the existence of guiding mechanisms. We synapses is usually limited. Axons encountering a par-
will discuss some mechanisms that can aid axons in ticular neuronal group at a later stage cannot establish
selecting their target. The number of known interacting synapses, and therefore they either retract or grow past
players at the cellular and molecular levels is enormous, to other targets.
and many more are probably yet to be identified. It
should therefore not come as a surprise that we cannot
Trophic Factors
fully explain how the amazing connectional specificity
of the mature nervous system arises. Timing of neuronal birth and maturation cannot
explain all aspects of specificity, however. For example,
what decides the direction of axonal outgrowths? For
Trial and Error
some neurons, such as pyramidal cells in the cerebral
Although trial and error cannot explain the overall cortex, the initial growth direction is genetically deter-
development of orderly connections in the nervous sys- mined. After that, however, signals in the environment
tem, it nevertheless plays a role at the local level. Indeed, of the axons determine the growth direction. Thus, cor-
modern imagining methods permitting in vivo observa- tical pyramidal cells are occasionally inverted with
tion of growing neurons show that growth and retrac- their apical dendrite pointing toward the white matter
tion of neuronal processes are highly dynamic processes. instead of toward the cortical surface. In such cases, the
Thus, at the same time as growth cones randomly axons start growing toward the pial surface but soon
explore their immediate environment and new spines reverse direction and grow toward the white matter, as
bud from dendrites, errors are corrected continuously do normal pyramidal cells (see Fig. 33.5). Such findings
by retraction of unsuccessful growth cones and spines. are best explained by the target organs producing
The development of neuronal networks is therefore a growth-promoting substancestrophic factorsthat
A diffuse in the tissue. Axons then grow in the direction

Frontal cortex of increasing concentration of the factor, which binds
to specific receptors, so that only axons expressing the
Occipital receptor are attracted. This may explain why axons
cortex from a neuronal group in some cases grow toward their
correct target even if the neuronal group has been
moved to another site before axonal outgrowth.
Early-growing
axons Late-growing axons
Cell-Adhesion Molecules and Fasciculation
Growth cone
In other instances, neurons or glia along the route
apparently express specific molecules that function as
signposts. When the first pioneer axons have reached
their target, the rest of the axons can get there simply
Early-arriving by following the pioneers. (The pioneers may have a
neurons Pontine nuclei
relatively simple task because, as mentioned, the dis-
tances they grow are very short and the landscape is
simple.) Axons with a common target can express at
their surface neuronal-cell adhesion molecules
B
(N-CAMs) that make them sticky (N-CAMs are pro-
Trophic factor teins related to the immunoglobulins). Axons expressing
(produced by a particular kind of N-CAM are then kept together,
early-arriving
Late-arriving neurons)
whereas others are repelled or inhibited in their growth.
neurons In this way axons with common targets form bundles,
or fascicles, and the phenomenon is termed fascicula-
In-growing
tion. The well-defined tracts of the nervous system arise
collaterals in this way.
C
Growth Cones and Their Interactions with N-CAMs

and Other Molecules
The many trophic factors, signpost molecules, recog-
nition molecules, and N-CAMs governing the establish-
Trophic factor
ment of specific connections mostly act on the axonal
(produced by growth cone. The growth cone is an expanded part of
late-arriving neurons) the tip of a growing axon (Figs. 9.15). It continuously
sends out small extensions, or filopodia, as if exploring
its immediate surroundings (Fig. 9.16). Filopodia
gure 9.15 Development of topographically organized connections:
example from the corticopontine projection (cf. Fig. 14. 7). A: Because
encountering the proper molecules in the tissue are
the axons from the frontal lobe start growing earlier than axons from stabilized, and this determines the direction of further
the occipital lobe, they have reached further down in the brain stem. growth, while other filopodia retract. The stabilization
At this stage, neurons migrate into the ventral pons to form the pon- depends on increased number of actin molecules in the
tine nuclei. B: At a later stage, the early-arriving pontine neurons pro- filopodia and of microtubules in the axon. Several
duce a trophic substance that attracts collaterals from the descending
axons. However, only the axons from the frontal lobe are sufciently
N-CAMS influence the growth of the axon when they
mature to emit collaterals at this stage (2 days elapse from the time the are present near the growth cone. These N-CAMs can
axons arrive in the pons until they can form collaterals). Immature be expressed at the surface of both the growth cone and
neurons continue to invade the ventral pons and form a shell around the nearby cells. Binding of the N-CAM molecules to
the early-arriving neurons. C: Late-arriving pontine neurons are now each other causes stickiness. In other instances, N-CAMs
sufciently mature to produce the trophic factor, whereas the early-
arriving ones have stopped their production. At this later stage, only
bind to specific receptors in the growth cone membrane
the axons from the occipital lobe can emit collaterals. Thus, axons and thus activate intracellular second messengers (by
2+
from different parts of the cerebral cortex end in different parts of the influx of Ca ions). There are also extracellular mole-
pontine nuclei, forming the orderly topographic arrangement seen in cules with actions on the growth cone, such as laminin,
the adult (see Fig. 24.8). In this example, the topographic arrangement which is bound to the basal lamina. Laminin binds to
can be explained by genetically programmed differences in the time of
birth for neurons in various parts of the cerebral cortex and the pon-
receptors in the growth cone membrane. Laminin can
tine nuclei. Other mechanisms may operate as well. (Based on experi- occur transiently along the path of growing axons in
mental studies in the rat by Leergaard, Lakke, and Bjaalie 1995.) the peripheral nervous system, guiding the growth
toward the target organ. Although the action of lami- there are signpost molecules along the route. One
nin is not by itself specific, its time-specific expression example illustrating this is the growth of axons from
ensures that only axons present at the proper time will the retina through the optic chiasm. Figure 16.14 shows
grow. This is another example of the importance of the arrangement of the axons from various parts of the
timingin this case of axonal outgrowthduring retina as they pass through the optic chiasm in the
development. adult. Axons from the nasal retina cross to the other
side, whereas axons from the temporal retina pass
ipsilaterallythat is, without crossing. In the adult,
Examples of Axonal Pathnding
crossing and ipsilateral axons are segregated as they
The inverted pyramidal cells, previously mentioned, approach the optic chiasm. During the first outgrowth,
exemplify that gradients of substances in the environ- however, axons from the nasal and temporal parts of
ment of the axon govern growth direction. Another the retina are mixed. Nevertheless, they take the correct
example concerns the development of descending path when they reach the region of the chiasm, even
connections from the cerebral cortexthat is, the out- when this requires that some have to bend 90 degrees,
growth of axons from projection neurons in the cere- and that some axons must cross each other. Interaction
bral cortex. Many such axons reach the spinal cord between axons from the two eyes is not necessary,
and, in addition, emit collaterals to nuclei in the brain either. Thus, even if one of the eye primordia is removed
stem. Initially, the axons grow toward the cord without before the axons have reached the optic chiasm the
sending out collaterals (Fig. 9.15A). After a certain axons from the remaining eye still find their correct
interval or waiting time, however, collaterals grow out way through. Neither can trophic factors from the
and innervate the pontine nuclei (Fig. 9.15B). The col- target organ of the axons (a thalamic nucleus) play a
laterals to the pontine nuclei arise just when the pontine decisive role because this nucleus is not yet established
neurons have reached a certain stage of maturation at the time the axons grow through the optic chiasm.
(postmitotic age). Most likely, the pontine neurons at this Therefore, local clues in the region of the optic chiasm
stage produce a trophic factor that attracts growing must guide the axonsat least during the first pioneer-
axons. Such a mechanism, depending on diffusion, can ing phase. In the next few weekswhen thousands of
operate only over short distances. Thus, it is less likely axons follow the pioneers through the chiasmcell
that trophic factors produced in the spinal cord are adhesion molecules and fasciculation are important.
responsible for the goal-directed growth of corticospinal Another example of the importance of local signpost
axons. cues for axonal pathfinding is the development of skel-
When the distance to the target is too long for trophic etal muscle nerve supply by spinal motoneurons. Even
factors alone to guide axonal growth, we assume that after removal of the primordial muscle, the axons that
would normally supply it still find their way to the site
of the (removed) muscle.
Bundle of actin
Growth cone filaments
Elimination of Axon Collaterals and Synapses
Filopodium
Meshwork of As mentioned, the terminal area of a group of axons is
actin often more extensive initially than after maturation,
filaments
forming a surplus of synapses. Newborn monkeys, for
example, have higher numbers of synapses on each
Micro- neuron in many parts of the brain than adult monkeys.
tubules
Thus, many collaterals and synapses are eliminated
during further development. When it occurs in early
phases of development (prenatally), elimination is prob-
Axon ably due mainly to programmed cell death. Later on,
competition for growth factors may be more important.
In this way, the axonal ramifications of each neuron are
pruned, thereby increasing the spatial precision of
connections. In other instances, neurons initially send
gure 9.16 The axonal growth cone. A growth cone contains a cen- axon collaterals to two (or more) nuclei, but only one
tral and stable bundle of microtubules. In addition, dynamic microtu- collateral survives while the other disappears during
bules extend toward the lopodia and work together with actin further development.
laments. The lopodia contain bundles of actin laments providing
motility. The lopodia extend or retract depending on the specic
Elimination of axon collaterals is exemplified by the
molecules they meet in their immediate environment. (Based on Kalil development of descending connections from the visual
and Dent 2005.) cortex. Initially, the axons grow down to the spinal
cord, sending off collaterals to the pontine nuclei with relatively less developed cerebral cortex. Most likely,
(among other areas) on their way (Fig. 9.15). After the this is related to the enormous human potential for learn-
pontine collaterals are established, those to the cord ing and adaptation: evolution has favored flexibility and
disappear (in adult animals there are no connections learning capacity at the expense of secure genetic
from the visual cortex to the cord). We do not know preprogramming of brain synaptic interconnections.
how this happens; perhaps trophic factors from the
cord or medulla trick the axons to grow beyond their
The Brain Changes during Adolescence
real targets. We may further assume that once in the
cord, the axons are not able to establish synapses, per- For some unknown reason, the rate of synapse elimina-
haps because they lack specific recognition molecules tion appears to be particularly high just before and dur-
or simply because the spinal neurons are not receptive ing puberty. In the monkey visual cortex, for example,
at the time the axons arrive. the maximum number of synapses occurs around the
A further example concerns descending axons from third postnatal month. Thereafter, the number is fairly
the forelimb region of the motor cortex (of rodents). constant until puberty, when a marked reduction occurs
Initially, such axons reach both the cervical and the (40% loss) to obtain stable adult values. Longitudinal
lumbar parts of the cord (innervating the forelimb and MRI studies in children and adolescents indicate that
the hind limb, respectively). Collaterals enter the spinal the ratio of gray and white matter changes, especially
gray matter only in the cervical region, however, and around pubertyin spite of unaltered total brain vol-
the branch to the lumbar cord disappears without ume. First, there is an increase of gray matter that is
having established synapses. most marked in the frontal lobes. After puberty, gray
matter declines while white matter increases. These
changes appear to continue into the late 20s. Although
Formation and Elimination of Synapses from
their functional meaning is not clear, such data
Newborn to Adult
strengthen the impression that considerable plastic
While the number of neurons in the human cerebral changes occur in the brain during adolescence.
cortex appears to be fairly constant after the twenty-
eighth gestational week, the synaptic densities undergo
Establishment of Topographic Maps
marked changes until the end of puberty. In general, the
synaptic density in the cerebral cortex increases steeply When axons arrive at their target, they usually do not
from before birth to late in the first postnatal year. establish synapses at random among the neurons but,
Thereafter, the density declines slowlypresumably rather, in a restricted part of a neuronal group. Thus,
due to elimination of synapsesuntil reaching adult the incoming axons together form a topographic map so
values between age 10 and 15. There appears to be that, for example, different body parts (see Fig. 14.7) or
large variations among cortical areas, with earlier max- parts of the visual field (see Fig. 16.19) are represented
imum density and a shorter period of synapse elimina- by spatially separate neurons. Most connections in the
tion in primary sensory areas than in association areas. brain exhibit some degree of topographic organization,
In the visual cortex, synaptic density at birth is about and this is not restricted to systems that convey sensory
10% of that at 4 to 8 months after birth, when the information and motor commands. Some topographic
number of synapses per neuron is estimated to be maps are simple, while others may appear highly
15,000. Thereafter, the number declines to about 7500 complex.
at 10 to 12 years of age. This number seems then to be In some parts of the brainfor example, in the supe-
stable for many years. Similarly, in the auditory cortex, rior colliculus where axons from the retina form a map
synaptic density peaks at about 3 months after birth, of the visual fieldthere exist gradients of specific
7
while synapse elimination ends at around age 12. In the receptors along different axes during development.
frontal association areas, maximum synaptic density Genetic programming of neuronal time of birth is
occurs about 15 months postnatally, while elimination another important mechanism. (Time of birth also
ends around age 16. decides the scheduling of axonal outgrowth and the
We can only speculate on the functional meaning of
such changes of synaptic numbers and densities. It 7 In the early development of the superior colliculus, neurons express mem-
seems reasonable, however, that a large surplus of brane-bound ephrins (ephrin A [EphA] and B [EphB]) that form mediolateral
synapses is useful in phases with large plastic changes. and anteroposterior gradients. Axons arising in different parts of the retina dif-
fer with regard to the kind of ephrin (EphA or EphB) receptor they express and
Presumably, there is a large pool of labile (perhaps are thereby specied to establish synapses in certain parts of the colliculus.
silent) synapses, of which only some become stabi- Activation of the Eph receptor requires contact between the axon and the target
lized by proper use. It may be significant that the post- neuron. In general, it appears that activation of EphA receptors leads to axon
repulsionthat is, the growth cone collapseswhile activation of EphB leads
natal overproduction of synapses is particularly marked to attraction with stabilization of the growth cone (partly by actin polymeriza-
in the human cerebral cortex, as compared with animals tion). Ephrins are also involved in neuronal migration and synapse formation.
ability to form and receive synapses, as discussed brain stem (especially important might be those that
above.) Figure 9.15 illustrates how topographic maps contain serotonin). Maturation of the locomotor func-
in the pontine nuclei may arise. In the adult, axons from tion starts with the forelimb and proceeds caudally to
the cerebral cortex end in a precise topographic pattern the hind limb, in parallel with the growth of descending
in the pontine nuclei. Functionally different parts of the axons.
cerebral cortex connect with different parts of the nuclei
(Fig. 24.9). This pattern appears to arise because axons
Postnatal Growth of the Brain
from different parts of the cortex start growing at dif-
ferent times and because subgroups of pontine neurons The weight of the human brain triples during the first
are born at different times. year of life (from 300 to 900 g), and at the same time
Although the basic pattern of topography is geneti- major changes of synaptic density take place, as dis-
cally determined, proper use of the system is necessary cussed in the preceding text. After the first year, the
to obtain maximum precision of spatial arrangements. weight increases more slowly to reach adult values
We return to this next in considering the environmental around the age of 5 to 7 (1400 g for men and 1250 g for
effects of experience on the development of the nervous women). This weight gain is caused by the growth of
system. existing neurons and their processes, the myelination of
axons, and the proliferation of glial cells. The neuronal
growth mainly involves expansion of the dendritic trees
Prenatal Development of a Neuronal Network
and formation of axon collaterals with nerve terminals.
We use as an example the development of the spinal The growth of dendritic arbors is especially marked in
network that controls locomotion. This network arises the human cerebral cortex during the first 2 years of
long before locomotor movements are of any use. In life (Fig. 9.17). There is good evidence that increased
human fetuses, rhythmic movements of the extremities dendritic ramifications relate to an increased number of
(although uncoordinated) occur as early as 10 weeks synapses. Myelination of corticocortical connections
after fertilization. At first, the spinal network initiates takes place during the same period and is a sign of func-
movements without any sensory information or com- tional maturation. Increased conduction velocity
mands from higher levels of the CNS. Gradually the enhances both the precision and the capacity of the
coordination improves to complete locomotor patterns neural networks; that is, their potential for information
(improvement continues after birth when the system is processing increases.
used in a goal-directed manner). The prenatal improve-
ment is probably due to several factors: altered electric
Human Brain Weights
properties of the neurons, expression of novel transmit-
ters and receptors, and development of the connections Typical values of average adult brain weight from large
among the network neurons. These alterations depend autopsy studies are about 1400 g in men and 1250 g in
on the development of descending connections from the women. Usually, such studies are based on brains of
Visual cortex Parietal association cortex
gure 9.17 Postnatal development of

the human cerebral cortex. Drawings
based on Golgi sections from the visual
cortex showing the increase in dendritic
arborizations from birth and until the
age of 2 years. The increase in dendritic
arborization is most likely related to
the increase in the number of synapses
Newborn 2 years Newborn 2 years per neuron. (From Conel 1939.)
adults between the ages of 20 and 40 years. More inter- analog of experiments with enriched environments.
esting than average weight is the range of variation Indeed, wild animals have somewhat larger brains than
among normal individuals. An investigation of brains tame animals of the same species. The responsible influ-
from 200 persons 17 to 40 years of age reported varia- ence must occur quite early, because animals born in
tions from 1120 to 1780 g in men and from 1070 to the wild and later tamed have the same brain size as
1550 g in women. Older autopsy studies indicate that wild animals. The difference is not genetic, however,
adult brain weight (volume) is reached between ages 5 because individuals of the first generation born in
and 10. An MRI study of 85 normal children, aged 5 to captivity have smaller brains than their wild relatives
17, did not find any volume increase after the age of 5. have. Experimental enrichment in the early postnatal
MRI studies show a weak correlation between brain period of rats induced increased synaptic density in the
volume and IQ, both among children and adults. hippocampus and improved performance in certain
learning and memory tasks. Results from experiments
on the motor system further support the association
THE ROLE OF THE ENVIRONMENT IN DEVELOPMENT between synaptic plasticity and learning: Among young
OF THE NERVOUS SYSTEM adult rats doing different motor tasks, some developed
more synapses per neuron in the cerebellar cortex than
Growth and Use-Dependent Plasticity others did. The decisive factor was not the amount of
motor activity but that the activity implied learning of
Although the brains postnatal weight gain is largely
new motor behaviors. Other experiments show that
genetically determined, the final functional state of the
learning of specific skills is associated with synaptic
various neural systems and networks depends critically
changes in cortical areas involved in the task. For exam-
on their proper use during a certain period: they must
ple, as monkeys gradually improved their performance
be used at the proper time and in a meaningful way.
in distinguishing tones of different frequencies, the part
The ensuing use-dependent structural changes occur
of the auditory cortex representing the particular fre-
mainly at the synaptic level, determining the final num-
quencies increased in size. Similar changes occur in the
ber of synapses, their precise distribution, and postsyn-
motor cortex during learning of motor skills.
aptic effects. Both establishment and elimination of
The preceding examples strongly suggest that
synapses occur at high rates during the development
formation and modification of synapses are closely
toward a fully functioning system. As we have discussed,
linked with learning. It is plausible, for example, that
an enormous surplus of synapses arises in infancy, with
life in the wild (or in an artificially enriched environ-
subsequent synaptic elimination as the neuronal net-
ment) requires the acquisition of a broader repertoire of
works mature. Nevertheless, networks that are properly
adaptive behaviors than life in the cage or the bin. In
used appear to end up with a higher number of synapses
8 general, there is good reason to assert that task-specific
than networks not subjected to normal challenges.
networks become operational during childhood because
of learning processes driven by active interactions
Enriched Environments and Synaptic Plasticity between the individual and his or her environment.
Numerous animal experiments have shown robust
effects of environmental conditions on brain structure Information Must Be Meaningful
and biochemistry, as well as on behavior. Early experi-
Nerve impulses are not by themselves sufficient for nor-
ments showed, for example, that dendritic arboriza-
mal development, as shown in many animal experi-
tions were more extensive in the cerebral cortex of rats
ments. For example, in goldfish exposed only to diffuse
raised in an enriched environment (a simulated natural
light (devoid of information) at the time retinal axons
environment with ample space and access to toys) than
form synapses in the optic tectum, the normal ordered
in rats raised in standard laboratory cages.9 Brains of
map of the visual environment does not develop
wild and tame animals represent a naturally occurring
properly. Another example concerns the development
of connections from the retina to the visual cortex. At
first, neurons in the visual cortex are influenced with
8 Kittens that do not use their vision during the phase of maximal synapse
production (sensitive period), end up with about two-third of the normal equal strength from each eye. Soon after birth, how-
number of synapses in the visual cortex. Generalizing from this observation, ever, neurons in the cortex segregate into groups, with
one-third of synapses in the cerebral cortex may depend on proper use of the a dominant input from one eye and a weaker input
functional system in which they participate.
9 It should be emphasized that so-called enriched environments are enriched from the other. This phenomenon is called eye domi-
only as compared with standard laboratory conditions. The latter is a situation nance. When all impulse traffic from the retina is
of deprivation rather than of normality. Both the standard and the enriched- blocked in kittens, eye dominance does not develop:
conditions are therefore highly articial. Nevertheless, when interpreted with
caution, experiments with enriched environments give robust evidence of the each neuron continues to respond equally well to signals
role of environmental factors in brain development and function. from either eye. Artificial electric stimulation of the
optic nerve can nevertheless induce eye dominance even ranging from the molecular to the behavioral level. . .
though the animal is blind, but only if the signals from But, to the great relief of many of us, early experience is
the two eyes arrive with a minute time difference (cor- not necessarily destiny. . . .
responding to what occurs under natural conditions
with light falling on the two retinas). With natural use
Sensitive (Critical) Periods
of the system during development, axon terminals
conveying signals from the two eyes compete for the The term sensitive or critical period pertains to the
available synaptic sites on each neuron. development of a particular function of the nervous
Both of the aforementioned examples from the visual system and refers to the period when the system respon-
system show that, in order to induce the normal synaptic sible for the function is maximally plasticthat is, its
pattern and connectivity, nerve impulses must convey capacity for structural and functional adaptations is at
11
meaningful informationthat is, information that its highest. Further, the full development of a particu-
helps the animal adapt to its environment. lar function requires proper use of the relevant neuronal
networks during the sensitive period. For example, the
ability of the mature brain to process sensory information
Early Social Experience Alters Brain Structure
depends on use of the particular sensory system during
and Function
periods in early postnatal development. The same holds
Human experiences and animal experiments strongly for the development of many skills. Further, we know
suggest that social conditions in early childhood can that later use of a system cannot fully compensate for
influence adult emotional and cognitive behavior, and the lack of use during the sensitive period.
that this is associated with alterations of brain struc- Sensitive periods occur at different times and vary in
ture. For example, rat pups of mothers spending much duration for different systems and behaviors. The
time licking and grooming them develop higher synap- opening of a sensitive period coincides with increased
tic density in the hippocampus than do pups with moth- plasticity and with intense use of the neural networks
ers paying less attention to them. In agreement with responsible for the particular behavior. In normal chil-
alterations of the hippocampus, the pups of high-licking dren, for example, intense training of walking starts at
mothers also show enhanced spatial learning and mem- about 1 year of age, and the vocabulary develops almost
ory. Further, as adults, the offspring of high-licking explosively between ages 2 and 3. We can only speculate
mothers show a different response to stress than what drivesor motivatesa normal child to train so
10
offspring of low-licking mothers. Another example intensely just during the phases of maximum plasticity.
concerns the effects of exposing rat pups to traumatic The phases of system-specific, maximum plasticity
emotional experiences, for example by separating them must coincide with meaningful use of the systems to
from their mothers. Such pups show synaptic altera- ensure optimal development. For example, infant mon-
tions in the anterior cingulate gyrus (see Fig. 6.26), a keys prevented from using their vision until the age of
region that is involved in emotional processing. Further, 3 to 6 months needed several months after regaining
separation was associated with altered development of vision to learn to distinguish a circle from a square.
neural networks that control emotional responses medi- A normal infant monkey learns this simple task in a few
ated by the autonomic nervous system. days. Monkeys deprived of vision during the sensitive
Even though early experiences seem capable of pro- period do not develop the proper synaptic connections
ducing life-long alterations of brain structure, improved in the cortex that enable them to extract the meaning of
environmental conditions at a later stage can reverse visual information. Further, they do not develop the abil-
the changes. For example, exposure to an enriched ity to integrate vision and the other senses (see Chapter 34,
environment around puberty was found to normalize under The Parietal Lobe and the Development of
the structural changes of the rat hippocampus induced the Ability to Integrate Somatosensory and Visual
by early traumatic experiences. As summarized by the Information). There is much evidence that later use
U.S. neuroscientist Robert M. Sapolsky (2004 , p. 792): and extra training cannot fully compensate for the lack
Thus, early experience can have lifelong consequences of use during the sensitive period. For example, although
language may be acquired even if training starts later
than normally, development of the full potential
10 This inuence appears to be mediated by (at least) two intracellular path- requires that training start during the first few years
ways. First, a high-licking mother, as compared with a low-licking one, induces of life.
higher levels of serotonin in the pups brain. This in turn leads to increased
NGF-expression in the hippocampus. In addition, the glucocorticoid receptor
gene in the hippocampus is demethylated. This makes the gene permanently
more accessible to activation by NGF, resulting in permanent high levels of 11 Many researchers now prefer the term sensitive period because critical
glucocorticoid receptors in the hippocampus. The level of glucocorticoid period may give a false impression of an all-or-nothing phenomenon. Thus,
receptors relates to behavioral and endocrine responses to stress in the adult even though the sensitive period undoubtedly is of special importance, most
animal. systems remain plastic also after the end of the sensitive period.
Although the period of intense synaptic proliferation as witnessed by delay of the plasticity increase if use of
is brief and well defined, the sensitive period for func- the system is prevented. In the visual system, the earliest
tional development is usually much longer and need not sensitive period seems to start with a genetically deter-
have a clear-cut endpoint. Moreover, sensitive periods mined proliferation of synapses in a particular neuronal
in humans are generally much longer than in animals network. Figure 9.18 shows the increase of synapses
with a shorter period of postnatal development. In per neuron from birth to adulthood in the cat visual
humans the sensitive period for vision, for example, cortex. The largest increase starts at the time the kittens
probably lasts for the first 2 to 3 years, although the open their eyes at about 8 days and ends after about 1
development is most rapid during the first year. Various month. Further experiments showed that part of this
aspects of vision have different sensitive periods, and at increase takes place only if the visual system is used. In
the cellular level, neurons in different layers of the one group of kittens, the eyelids were sutured in the
visual cortex develop their characteristic properties at first postnatal week, whereas in another group the optic
different times. More complex behaviors have, as one nerves were cut. Both groups had about 30% fewer
would expect, later sensitive periods than simple behav- synapses per neuron in the visual cortex than controls.
iors. For example, in the visual system the sensitive It is worth noting that the effect was the same regard-
periods for development of binocular vision ends long less of whether the visual cortex was completely cut off
before the sensitive period for the analysis of complex from afferent signals from the retina or only lacked a
objects. meaningful sensory input (with sutured eyelids, action
Compared with other phases of development, a sen- potentials still travel in the optic nerve).
sitive period is characterized by both increased plastic- As to what ends a sensitive period, reduced levels of
ity and increased vulnerability of the nervous structures monoamines probably contributes. Another factor
involved. These factors are mutually dependent: one appears to be signal molecules from myelin that reduce
cannot have the one without the other. Thus, lack of plasticity. Further, the development of GABAergic inhi-
proper stimulation, lack of opportunities for practice, bition seems to correlate in time with the end of sensi-
or exposure to harmful environments has effects that tive periods. Indeed, a proper balance between excitation
are more serious during sensitive periods than at other and inhibition is a prerequisite for normal functioning
times. of neuronal networks. In functional terms, the sensitive
period would seem to end when the neuronal networks
have attained the level of structural refinement that
Cellular Mechanisms and Sensitive Periods
enables them to perform the tasks demanded of them. If
We do not fully understand the cellular mechanisms a system is not used at the right time, the start of the
underlying the enhanced plasticity during sensitive sensitive period may be delayed for some time: the
periods. We do know, however, that sensitive periods in
experimental animals correlate with the ease of LTP
induction (long-term potentiation). We also know that
monoamines play an important role. Thus, a sufficient
level of these transmitters must be present in the cerebral
cortex at the time of synaptic proliferation. Monoaminergic 7000
fibers are the first to grow into the cerebral cortex during
SYNAPSES PER NEURON
development, perhaps to prepare the ground for the sen-

sitive period. Through their modulatory actions, mono-
amines may ensure the necessary responsiveness of
neurons to new synapses. Several growth factors and
neurotrophins, known to influence neuronal plasticity,
are expressed during sensitive periods.
Start and End of Sensitive Periods

We do not fully understand which mechanisms start 15 10 Birth +8 +19 +27 +36 +39
and end a sensitive period. In general terms, it seems Adult
DAYS
likely that a sensitive period starts when a genetically
determined development of relevant neuronal networks
reaches a certain stage, so that, as it were, experience gure 9.18 Postnatal increase in number of synapses during a sensi-
tive period. The graph shows the change in the number of synapses
has a substrate to work on. We know that the start of a per neuron in the visual cortex of kittens. The number increases
sensitive period coincides with increased plasticity. In steeply when the kittens open their eyes 8 days after birth. (Based on
addition, experience in itself seems to boost plasticity, Cragg 1972.)
system waits for the right signals. However, if time established the cortical networks needed for integrating
passes without proper use, the networks seem to be visual information with other sensory modalities. Thus,
taken over by other systems. In this way, they become his brain was not capable of using the wealth of infor-
less and less accessible for their proper inputs. One mation provided by his eyes. In contrast, if the visual
example concerns children that are born blind: as system has been used normally during the sensitive
adults, their visual areas are activated by somatosensory period in infancy and early childhood, even many years
stimuli (e.g., during Braille reading). of temporary blindness have no serious effects on visual
capacities.
Another example concerns children who are born
Examples of Sensitive Periods in Humans
deaf and later receive a cochlear implant that supplies
Infants born with opaque lenses in their eyes the brain with information about sounds of different
cataractscan develop normal vision if the lens is frequencies. Experience shows that such children can
removed at a very early stage. The longer the time develop useful language and hearing behavior if the
before operation, the smaller the chances are that the implant is provided earlythat is, during the first 2 to
child will attain normal vision. Persons attaining their 3 years of life. As with vision, access to auditory infor-
sight after puberty (for example, by removal of an mation during the sensitive period is necessary for
opaque lens) have grave difficulties using their sight. proper development of the hearing system. To use
The new sense may cause trouble rather than being sounds as basis for development of language, for exam-
the expected blessing. Some choose to return to life as a ple, numerous specific connections must be formed in
blind person. A boy operated on at the age of 8 illus- the brain between the auditory cortex and other areas
trates this problem. Several months of patient training of the cerebral cortex. Such connections cannot be
were needed before he could recognize objects by sight properly formed after the sensitive period. At least in
(objects he was familiar with from the use of other part, this is due to other systems taking over the parts
senses). The surgeon who treated the boy concluded of the cerebral cortex that are normally engaged in
afterward: To give back his sight to a congenitally auditory functions. Thus, deaf children activate the
blind patient is more the work of an educationalist than auditory cortex when using sign language (this is called
of a surgeon (cited by Zeki, 1993 , 216). The main cross-modal plasticity). Cochlear implants in such chil-
reason for the problems encountered by this boy (and dren do not restore sound-activation of the auditory
others in his situation) is most likely that he had not cortex.
10 The Nervous System and Aging
OVERVIEW a reduction of average brain weight, enlargement of

ventricles (indicative of tissue atrophy), the appearance
Many presumably harmful changes occur in the brain of degenerative patches, and neuronal shrinkage (that
as we grow older. There are, for example, reductions occurs primarily in very old people). Dendritic trees
of average brain weight, synaptic numbers, and neu- and synaptic numbers appear to be reduced in the cere-
rotransmitters. There is also a loss of myelinated nerve bral cortex. Reduced blood flow of the whole brain or
fibers, and together all these changes would be expected certain regions has been found in several studies. Several
to cause less efficient communication in neuronal net- other changes, particularly in neurotransmitters and
works. Age-related changes appear to affect especially their receptors, have been reported. With imaging tech-
networks of the prefrontal cortex and the medial tem- niques, several alterations have been reported, notably
poral loberegions critically involved in memory and changes of both gray and white matter. The relation-
other cognitive functions. Nevertheless, most healthy ship between biologic changes and impairments of
elderly persons function remarkably well in spite of brain performance is still debated, however. This is
biologic alterationswith only a minor reduction of partly because of conflicting evidence on several impor-
recent memory and some slowing of movements and tant points and uncertain interpretations of findings.
mental processes. This is believed to result from com- Interpretations are hampered, for example, because the
pensatory, use-dependent plasticity initiated in response biologic differences usually represent small group aver-
to the biologic changes. Thus, elderly individuals seem ages, while the individual differences within each age
to activate larger parts of the brain when solving men- group may be much larger. Because detailed informa-
tal tasks (often both hemispheres are activated in con- tion of a persons behavioral and cognitive performance
trast to strictly unilateral activation in younger people). is seldom available when examining the brain after
Aging also entails a fairly marked loss of peripheral death, correlations must be tentative. In animal experi-
receptors, which may compromise vision, hearing, and ments, formal testing can be performed before examin-
balance. Such loss of peripheral receptors is often more ing the brain, enabling more affirmative conclusions
bothersome than the changes occurring in the brain. regarding the correlation between behavior and age-
In neurodegenerative diseases, loss of neurons and related brain alterations. Unfortunately, some biologic
their processes usually proceeds for many years before alterations that are well documented in aged rats and
symptoms occur. This is at least partly due to compensa- monkeys are controversial in humans.
tory processes going on in parallel with neuronal loss.
The emerging symptoms depend mainly on which parts Nonuniform Distribution of Changes
of the brain are subject to the neuronal loss. In spite of In spite of the uncertainties just mentioned, one impor-
being caused by different mutations, misfolding of tant point seems clear: Alterations of brain structures
intracellular proteins occurs in many neurodegenerative with advancing age are not uniformly distributed but,
diseases. Misfolding appears to initiate cytotoxicity. rather, are concentrated in specific parts of the brain.
Neurodegenerative diseases with massive loss of neurons Thus, changes in a small part of the cortex may cause
in the cerebral cortex lead to dementia, with Alzheimers functional deficits without significantly affecting over-
disease as the most common. This disease is characterized all numbers of neuronal elements. Most consistently,
byin addition to cortical neuronal lossdegeneration changes have been observed in the hippocampal forma-
of the cholinergic basal nucleus (of Meynert) and marked tion and the prefrontal cortex. In general, psychological
loss of acetylcholine in the cortex. tests show that functions of the brain that are served by
these altered parts of the brain also show the most
AGE-RELATED CHANGES IN THE NORMAL BRAIN marked reductions by normal aging.
AND THEIR CONSEQUENCES
Elderly People Differ Widely with Regard
Biologic Changes and Their Interpretations to Brain Functions
Comparisons of the brains of young and old persons It should be emphasized that individual differences with
have revealed several biologic differences. These include regard to brain functions are as marked among the
139
elderly as among young people. When we characterize during aging. More reliable methods later showed these
persons in general terms according to their age, we numbers to be far too high (an important source of
often forget that persons of the same agebe it 25 or error being different shrinkagedue to different water
80 yearsdiffer widely not only physically but also contentof young and old brains). Indeed, recent stud-
emotionally and cognitively. For example, our person- ies with stereological methods find little or no neuronal
alities are quite stable over the adult life span. While loss in the human cerebral cortex. One study of 90 per-
certain traits are characteristic of elderly people as a sons of both sexes suggested a loss of about 10% of
group (as for adolescents and for middle aged people) cortical neurons from 20 to 90 years, while other stud-
the individual differences are actually more prominent. ies did not find any significant neuronal loss in selected
This even concerns memory for recent events, which is parts of the cortex with advancing age. Relatively few
probably the most constant cognitive sign of aging. brains examined, and different sex and age distribution
Investigations of aged rats, monkeys, and humans with may probably explain some of the differences among
standard tests for recent memory reveal that a relatively studies. The total number of neurons in the cerebral
large minority does as well as young controls. Indeed, a cortex of humans may vary by 100% among individu-
study of more than 1600 persons with a simple memory als, according to studies with stereological methods. As
test (repeat a list of 20 words just presented) showed noted by Alan Peters and coworkers (1998, p. 297):
that the performance of the oldest group (88 years) Such large variations make it virtually impossible to
overlapped that of the youngest (25 years) by 50%. accurately determine if there is a significant loss of neu-
Another characteristic of elderly people is a reduction rons from an individual brain, and raises doubt about
in psychomotor speed. They may speak more slowly, the significance of a loss up to 10% . . .
use more time to consider a question or to recall a name,
and motor responses are less brisk than in young peo-
Loss of Gray and White Matter
ple. For many, however, this reduction is apparent only
when the performance demand is high. Even though few neurons are lost during aging, the
brain nevertheless shrinks, as witnessed by data of brain
weights after death and brain volumes during life (with
Loss of Neurons Does Not Explain Cognitive Decline in
magnetic resonance imaging [MRI]). MRI studies show
Normal Aging
that as we grow older, we lose both gray and white
Reduced mental capacities in older people are often matter and the cerebral ventricles expand correspond-
explained simply by referring to neuronal death (as ingly. The reduction of gray matter is most likely due to
we know, lost neurons are generally not replaced). shrinkage of cell bodies, loss of dendritic branches
However, even though a modest loss of neurons may (especially the smaller ones and spines), loss of thin
occur, there seems to be agreement that this can explain axonal branches and nerve terminals, and loss of water
neither cognitive decline nor the reduction of brain (as in all tissues of the body, the brains water content
weight reported in normal aging. decreases with age). Shrinkage of cell bodies seems to
From a theoretical viewpoint, a modest diffuse neu- occur especially after 80 years. While the exact distribu-
ronal loss would not necessarily cause clear reductions in tion of age-related cortical thinning (that is, gray matter
the performance of the nervous system. As discussed ear- loss) differs somewhat among studies, two findings
lier, large populations of neurons share responsibility for appear to be consistent: first, the distribution is patchy
most specific tasks, especially higher mental functions with regions with marked thinning alternating with
such as abstract thinking, language, and memory. These regions with no thinning, and second, alterations are
are the products of distributed networks that connect most marked the prefrontal cortex.
neuronal groups in many parts of the brain. A diffusely There is good evidence from animal studies that
1
distributed reduction of neurons in these networks would many synapses are lost during aging. For example, in
not be expected to cause functional deficits, except the prefrontal cortex of old monkeys, there are on
perhaps with maximal demands on performance. average 30% fewer synapses in some cortical layers
Animal studies support that neuronal death is not the than in young individuals. Further, there is a clear
cause of normal age-related cognitive decline. Thus, old correlation between the magnitude of the synaptic loss
rats and monkeys showing cognitive impairments do and degree of cognitive decline in the old monkeys.
not have fewer neurons than young animals in the Interestingly, the loss is particularly marked in layers 1,
hippocampal region and the prefrontal cortex. 2, and 3, giving off and receiving the bulk of corticocor-
tical (association) connections. Corresponding to the
How Many Neurons Are Lost?
1 Whether corresponding age-dependent loss of synapses occur in the human
Early studies of postmortem human brains suggested cortex is not clear, however, owing to conicting data from studies using com-
that as much as 20% to 50% of neurons are lost parable methods.
10: THE NERVOUS SYSTEM AND AGING 141
anatomic data, spontaneous excitatory postsynaptic other transmitter systems may prevent that a small
potentials were reduced in the same layers in aged mon- change in density of a certain receptor causes a loss of
keys, suggesting reduced excitability of cortical neurons function.
with aging. Recently, age-related change of dopamine receptors
Age-dependent loss of white matter of the cerebral has attracted special interest. Dopamine plays a role in
hemispheres occurs in humans and in experimental ani- regulating attention (among other actions), and loss of
mals. This appears to be due to loss of (mostly thin) dopaminergic receptorsespecially in the prefrontal
myelinated fibers and alterations of myelin structure, cortexhas been suggested to contribute to the cogni-
presumably leading to degraded corticocortical connective deficits observed in the elderly. Loss of dopamine
tivity. Corticocortical connections that link the prefron- receptors probably reduces the signal-to-noise ratio for
tal cortex with parietal and temporal cortical areas are of cortical neurons, making them less specific and more
special importance for cognitive functions. Accordingly, prone to erroneous responses. Indeed, PET studies have
neuropsychological tests of cognitive functions suggest a shown a relationship among density of dopamine recep-
relationship between loss of white matterespecially in tors, cognition, and age. However, we do not know
the frontal lobesand cognitive decline. whether reduced dopamine transmission is a major
In conclusion, it seems that the aging cortex is factor in cognitive aging.
characterized by loss of synaptic contacts and cortico-
cortical connectivity, affecting the prefrontal cortex to a
Why Is Psychomotor Speed Reduced in the Elderly?
larger degree than other parts of the brain. These altera-
tions would be expected to slow down communication Most likely, the reduction in psychomotor speed mainly
among cortical neurons, and might help to explain the reflects longer time needed for signal transfer and
typical slowing of mental processes in elderly people. information processing in the old brain, caused by
slower axonal conduction in myelinated fibers and loss
of excitatory synapses. A reduced number of excitatory
How Much Does the Brain Shrink during Aging?
synapses on a neuron would prolong the time needed to
A large study comparing average brain weights at 25 reach the threshold for eliciting action potentials.
and 80 years of age found 1400 and 1300 g for men Reduced amounts of available neurotransmitters and
respectively, and 1250 and 1150 g for women. Thus, it receptors would have the same effect. Such alterations
would appear that the brain is on average some less might also explain that the reaction time is longer in
than 10% lighter at age 80 than at age 25. For method- older than in younger persons.
ological reasons, this is probably an underestimate, and
in vivo MRI studies indicate a volume loss of 20% to
Memory Impairment in the Elderly
30% from adolescence to 80 years of age. However, the
shrinkage is not evenly distributed in the brain. A lon- Solid evidence links age-dependent memory loss to
gitudinal study with MRI scanning of each person with changes in specific areas of the brain. Studies of aged rats
an interval of 5 years suggested that the most marked indicate that their memory impairments are due to ana-
cortical shrinkage affects association areas in the fron- tomic and physiological changes in the hippocampal
tal, parietal, and temporal lobes. Marked shrinkage region. The hippocampus and surrounding parts of the
affected also the cerebellar hemispheres, the hippocam- temporal lobe are necessary for the storage and retrieval
pus, and the caudate nucleus. Other longitudinal studies of events, faces, names, and so forth (see Chapter 32). The
have come to largely the same conclusions (although changes occurring in the hippocampus are quite specific
there are differences with regard to specific regions). and affect only certain kinds of neurons and synapses.
Some changes are presumably caused by compensatory
mechanisms. For example, one kind of neuron receives
Neurotransmitters and Receptors
fewer synapses, but each nerve terminal releases more
Reduced age-related levels of several neurotransmitters transmitter. Long-term potentiation (LTP) is more diffi-
and their receptorsincluding glutamate, acetylcholine, cult to produce and does not last as long in aged rats as in
dopamine, and norepinephrinehave been reported. young ones. The memory impairment in aged monkeys
However, most of these findings are difficult to evalu- has the same characteristics as in young monkeys after
ate with regard to their contributions to decline of removal of the medial temporal lobe. Thus, it seems likely
brain functions. For example, alterations of glutamate that age-dependent loss of recent memory is caused pri-
transmission in prefrontal cortex might simply be the marily by specific changes in the hippocampus and sur-
result of loss of excitatory synapses. In other instances, rounding parts of the medial temporal lobe. In addition,
changes in transmitters and receptors may be the result changes of the dorsolateral parts of the prefrontal cortex
of compensatory mechanisms rather than the cause of are associated with reduced working memory (the ability
functional deficits. Further, compensatory changes of to hold a number of items temporarily in memory).
Loss of Peripheral Sensory Receptors with Age explaining age-related decline, but rather in under-
standing the high level of cognitive success that can be
For everyday problems of the elderly, changes in the
maintained by older adults in the face of such signifi-
CNS may be less important than loss of sensory cells
cant neurobiological changes. There is now much
and neurons of the peripheral sensory organs. These
evidence that this seeming paradox arises because the
losses are of sight and hearing in particular, but joint
nervous system remains plastic throughout life (even
sense and sense of equilibrium also deteriorate with
though the plasticity decreases with advancing age).
advancing age. For example, animal experiments show
Thus, even in old age we can learn and thereby upheld
that muscle stretch receptors (muscle spindles) lose
functions that are threatened by loss of neuronal ele-
dynamic sensitivity. This might result in slower reflex
ments. Probably, this process is not principally different
responses to unexpected, sudden movements of the
from what takes place at any age when the brain is
limbs. In general, thick myelinated, fast conducting
challengedbe it by damage or disease, need for new
fibers are more vulnerable during aging than thin fibers.
skills, or novel environments.
Especially, impaired proprioception and cutaneous
Interestingly, brain-imaging studies show that elderly
sensation in the lower extremities may contribute to
and young people have different patterns of cortical
increased risk of falling among the elderly.
activation during cognitive tasks, even when perfor-
Transmission of sensory signals at lower levels of the
mance is equal. In particular, processes that are strongly
CNS is serialthat is, the different links in the chain
lateralized in the young are more evenly divided between
are coupled one after another (see Fig. 14.1). If one link
the two hemispheres in the elderly (Fig. 10.1). Much
is completely broken, all transmission stops, and the
evidence supports that this activation pattern in the
brain cannot compensate for the loss of sensory infor-
elderly is a sign of functional compensation rather than
mation. This contrasts with the high degree of parallel
of faulty processing. For example, the tendency to use
processing taking place at higher levels, particularly in
both hemispheres is associated with higher performance
the cerebral cortex.
compared with other elderly persons using mainly one
hemisphere. Elderly persons show less hippocampal
Dizziness and Loss of Vestibular Receptors activation than young people on certain memory tests,
presumably because of age-related alterations in the
Studies of eye movements show that the vestibuloocu-
hippocampal region. Among the elderly, those showing
lar reflex (VOR) is less accurate in persons older than
increased prefrontal activation (compared with young
the age 75 than in younger persons. This reflex ensures
persons and age-matched controls) performed better on
that the gaze is kept fixed at one point in the environ-
memory tests than those with less prefrontal activation.
ment when the head rotates (to keep the retinal image
This suggests that increased prefrontal activation in the
stable). Further, optokinetic eye movements become
more sluggish in old age. Such eye movements are elic- Young Old
ited when the environment movesfor example, when
looking out of a carso that the gaze is kept fixed.
Suppression of the VOR, which is necessary when the
head rotates in the same direction as the visual scene, is
also impaired in many elderly persons. All these changes
may cause difficulties with vision and orientation while
moving, especially if the movement is rapid. This may
Central
be an important factor in the dizziness bothering many sulcus
elderly people. At the cellular level, a major cause of
impaired equilibrium and eye movements may be loss
of sensory cells in the vestibular apparatus. A 40% loss
has been reported in persons 75 years of age.
Prefrontal activation during a
demanding cognitive task
Plasticity May Compensate for Age-Dependent Losses gure 10.1 Altered brain activation patterns in the elderly.
Comparisons with functional MRI of young and elderly people (older
As we grow older, potentially harmful changes occur in than 65 years) during execution of various cognitive tasks shows
the brain, as discussed in the preceding text. Yet, most clear differences. This gure shows (in a very simplied form) that
elderly people manage remarkably well and show only during a demanding verb-generation task, elderly persons activate the
minor functional deficits, which often become apparent prefrontal cortex on both sides, whereas young people activate only
one side (differences are apparent also in other parts of the brain).
only in situations with high demands. As said by Denise This extra activation most likely is due to compensatory (plastic) pro-
Park and Patricia Reuter-Lorenz (2008, p. 183): The cesses. It would mean that elderly people, while solving the task as
puzzle for cognitive neuroscientists is not so much in well as young people, must allocate more resources to the task.
elderly compensates for reduced performance of the other elements. Further, age-related changes may be
hippocampal region. Disrupting cortical processing by slowed by use-dependent production of growth factors
transcranial magnetic stimulation (TMS) supports that and neurotrophins. Finally, by continuously challenging
the bilateral frontal activation in the elderly is of func- the systems, compensation by recruiting additional neu-
tional significance. Thus, in the young, TMS of the left ronal groups would counteract the inevitable negative
prefrontal region influenced memory performance most effects of aging on the brain.
severely, while in older adults application to either the
left or the right hemisphere reduced their performance
Physical Exercise May Protect the Aging Brain
equally. Also for successful motor performance, larger
parts of the cortex and the cerebellum are recruited in There is evidence from both experimental animals and
elderly than in young persons. humans that physical training (especially cardiovascu-
Together, these and other observations strongly sug- lar conditioning) can improve cognition. This has also
gest that plastic changes occur in the aging brain, and been examined specifically with regard to the aging
that they counteract the detrimental effects of age-related population. For example, a study including more than
loss of neural elements. 5000 women older than 65 years showed that those
with the highest level of physical activity were less likely
to develop cognitive decline during the next 6 to 8 years.
The Benet of Experience
Other studies indicate that aerobic capacityas
Normal aging does not affect everyday activities signifi- expressed in maximal oxygen uptakeis the factor
cantly. Indeed, it appears that all activities (motor or most clearly linked with beneficial effects on cognitive
intellectual) that have become highly automated by long functions. Especially executive cognitive processes
practice are quite resistant to age-dependent decline. such as planning, task coordination, and working mem-
Both speed and precision can then be maintained into oryseem to benefit from aerobic training. Increased
advancing age. We need only think of musicians, such production of BDNF (brain derived neurotrophic
as Rubinstein and Horowitz, performing with excel- factor)known to enhance neuronal plasticitymay
lence after 80. Preserved superior spatial memory in old mediate some of the effects of physical training on the
taxi drivers provides another example of the effect of brain.
experience. Further, a study comparing young and old
bridge and chess players concluded that there was no
clear age-related decline in performance, with prior NEURODEGENERATIVE DISEASES AND DEMENTIA
experience being more important than the players age.
A generally reduced short-term memory in the older Dementia
players is presumably compensated by superior card
Dementia can be defined as an acquired, global impair-
recognition and specific memory for cards. Thus, old
ment of intellect, reason, and personality, but without
experienced players remembered more cards after a
impairment of consciousness. It is uncommon before the
1-second exposure than young untrained ones did, and
age of 60 but occurs with increasing frequency, especially
this difference persisted even if the younger players
after the age of 75. One-third of people older than
were given more time. Another example of the benefi-
85 years of age may exhibit signs of dementia; although
cial effect of experience comes from a study comparing
with varying severity. Dementia can have different causes,
old and young bank employees. Although the older
but all cases share extensive damage to neurons and con-
employees scored on average less on reasoning tests
nections of the cerebral cortex. One cause of dementia is
than the younger ones did, this did not correlate with
loss of brain tissue due to ischemic brain lesions. Usually,
poorer job performance. In conclusion, specific experi-
the patient has suffered from repeated small infarctions
ence and continuous training appears to be more impor-
of the white matter, causing vascular cognitive impair-
tant for performance than normal age-related reductions 3
ment (VCI). Dementia can also be caused by intoxica-
in cognitive functions.
tions (alcohol, solvents, and carbon monoxide), large
Presumably, continuous use of neural systems makes
tumors, or infections (for example, HIV).
them more resistant to age-related impairment. One
Neurodegenerative diseases leading to progressive
reason may be that more neurons are included in task-
2 neuronal loss, however, cause most cases of dementia.
specific networks. This might make the networks more
Most people in the latter group have Alzheimers dis-
robust and less vulnerable to a loss of synapses and
ease (AD). This disease was described just after 1900 as
2 London taxi drivers were found to have larger hippocampi than controls,
and the difference increased with increasing experience (Maguire et al. 2000). 3 Vascular cognitive impairment was formerly termed vascular dementia, and
Presumably, this represents a learning effect caused by their long-term engage- that term is still widely used. Cerebrovascular lesions may be the main cause in
ment in spatial navigation. as many as 15% of all patients with dementia.
a distinct kind of dementia, which characteristically memory is an early sign: the person forgets appoint-
developed before the age of 60 (presenile dementia). ments and names, repeats questions, and may appear
Around 1970 it was realized, however, that the major- confused and helpless. There is typically a loss of inter-
ity of cases of dementia beginning after age 60 also are est and initiative, and a neglect of daily activities. Initial
of the Alzheimer kind. Despite all the research since symptoms are usually vague and hard to distinguish
then, so far, no one theory can explain the complex from normal aging. In some patients, the early signs of
biochemical and pathological aspects of this devastat- dementia may be misdiagnosed as depression. If such
ing disease. Frontotemporal dementia (FTD) is less patients receive antidepressant drugs, their condition
common than Alzheimers disease and affects different can deteriorate dramatically with confusion, loss of
parts of the cerebral cortex. This explains why the bladder control, and other symptoms. This may proba-
symptoms differ in these two forms of dementia. In bly be explained, at least in part, by the anticholinergic
many patients, multiple cerebrovascular lesions may effect of such drugs.
coexist with Alzheimer pathology, aggravating the Microscopically, senile plaques and neurofibrillary
cognitive deficits (mixed type dementia). tangles in the cerebral cortex characterize AD. The lat-
ter consist of thickened, intraneuronal fibrils. The senile
plaques are patchy, degenerative changes with extracel-
Common Molecular Mechanisms in
lular deposits of amyloid and other proteins, in which
Neurodegenerative Diseases
amyloid b-protein (A) is a major component. The
Alzheimers disease, Parkinsons disease, Huntingtons plaques also contain many abnormal axon terminals.
disease, amyotrophic lateral sclerosis (ALS), and other A is formed from a large membrane protein called
neurodegenerative diseases have in common that neu- amyloid precursor protein (APP). We do not know the
rons slowly die in a long period preceding the debut of function of APP, but it is present normally in most neu-
neurologic symptoms. These diseases affect different rons and is transported anterogradely in the axons to
parts of the nervous system, occur in different age the terminals. A is normally secreted from neurons,
groups, and show different heritability. They therefore and we do not know why it precipitates in AD. The
present as separate disease entities. They may neverthe- neurofibrillary tangles consist of a specific kind of fila-
less share basic cellular malfunctions that eventually ment (paired helical filaments; PHF). A major component
cause neuronal death. One common finding is that neu- of PHF is an abnormal kind of the microtubule-associated
rons accumulate large amounts of misfolded proteins, protein tau. The protein lacks its normal ability to
which thereby induce cytotoxicity. Various factors, attach to microtubules, however, and this may explain
such as gene mutations, environmental influences, and why tau aggregates as abnormal filaments.
aging may induce misfolding of proteins. Most likely, a There is a marked loss of synapses in AD, as shown
modest amount of misfolded proteins occurs normally, via electron microscopic observations. Most notable
and cellular processes are disturbed only when the are losses in the layers two and three of the cerebral
amount of misfolded proteins exceeds the cells capac- cortex (see Fig. 33.1) that send out and receive associa-
ity to remove them. Disturbed cellular processes com- tion connections. Figure 10.2 shows the typical distri-
prise transcription, energy handling, axonal transport, bution of early changes in the form of cortical atrophy.
synaptic function, and apoptosis. Apparently, different The pathologic changes are more severe in the associa-
mutations can produce similar clinical pictures, the tion areas of the frontal and temporal lobes than in the
crucial point being which neuronal populations are primary sensory and motor areas. The earliest changes
affected. Thus, dementia will ensue if sufficient num- appear to occur regularly in the entorhinal cortex (part
bers of neurons in certain parts of the cerebral cortex of the hippocampal region in the medial temporal lobe).
die, regardless of the cause of cellular death. It appears that severity of dementia shows a closer cor-
Neurodegenerative diseases are characterized by clumps relation with the degree of synaptic loss than with the
of misfolded proteinsinclusion bodiesin the neu- density of senile plaques and neurofibrillary tangles.
ronal cytoplasm. Most likely, damaging effects of the What causes the cell loss (and loss of synapses) is not
misfolded proteins is exerted before they are collected quite clear, although both A and tau are involved in
in clumps, with the latter representing just the end stage the process. Neither is the relationship between these
in a cascade of molecular events. two actors clear. The so-called amyloid-cascade hypoth-
esis implies that overproduction of A leads to amyloid
precipitation that induces formation of neurofibrillary
Alzheimers Disease
tangles, which then cause neuronal death.
There is now little doubt that Alzheimers disease (AD) Alzheimer patients have a severe neuronal loss in a dif-
represents a distinct disease entity, not just an exagger- fusely distributed cell group at the base of the cerebral hemi-
ated form of normal aging. The disease manifests itself spheres, called the basal nucleus (of Meynert) (Fig. 10.3).
by gradual decline of mental functions. Impaired recent Many neurons in this nucleus are cholinergic and send
Superior excitability and improves the signal-to-noise ratio of corti-

Parietal
frontal cal neurons, enhancing their ability to handle information
rapidly and accurately. These facts form the basis of the
first pharmacological treatment of AD, which aimed at
increasing the amount of acetylcholine available in the
cerebral cortex.
The relationship between the loss of basal nucleus
neurons and the pathological changes in the cerebral
cortex is not clear, however. Thus, not all aspects of the
Inferior functional impairment in AD can be induced by destruc-
frontal
nferior te
Inferior emporal
temporal tion of the basal nucleus in experimental animals.
Temporal pole Further, transmitters other than acetylcholine are also
affected by AD. Many monoaminergic neurons die in
the locus coeruleus and the raphe nuclei, which may
explain why the levels of norepinephrine and serotonin
in the cortex are markedly reduced. Depleting the cere-
bral cortex of acetylcholine, norepinephrine, or sero-
tonin (rats) triggers a rapid rise of APP synthesis. Such
transmitter depletion can be produced by destroying
the basal nucleus, the raphe nuclei, or the locus coer-
uleus. These findings suggest, first, that APP synthesis is
normally controlled by synaptic actions and, second,
that precipitation of amyloid might be caused by loss of
Medial temporal
transmitter actions.
gure 10.2 The distribution of cortical atrophy in early stages of Even though patients with AD are quite similar with
Alzheimers disease. The blue patches show approximate locations of regard to brain pathology and clinical manifestations,
regions with the most marked thinning of the cortex, based on quan- they differ in terms of causal factors. Heritability plays
titative analysis of MRI data. More extensive parts of the cortex a variable role but is especially important in patients
become atrophic as the disease progresses. (Based on data of
with an early onset of symptoms (before 60 years).
Dickerson et al. 2009.)
Many in the latter group inherit the disease dominantly.
These patients have mutations of three genes: two genes
their axons to the cerebral cortex (see Chapter 31, under coding for presenilins (1 and 2) and the APP gene. All
Cholinergic Neurons Projecting to the Cerebral Cortex). three mutations increase A synthesis. The much more
Loss of neurons in the basal nucleus may therefore explain common late-onset AD shows less obvious familial
why Alzheimer patients have severely reduced amounts accumulation of cases. A large number of genes have
of acetylcholine in the cortex. Acetylcholine raises the been implicated as possible risk factors, however.
Internal capsule Putamen Globus pallidus Caudate nucleus
Anterior Posterior
gure 10.3 The basal nucleus (of Meynert). Frontal section

through the left hemisphere (monkey). The cholinergic neurons
of the basal nucleus are indicated with red dots. The basal
nucleus is continuous anteriorly with the septal nuclei and
other cholinergic cell groups of the forebrain. (Redrawn from Septal nuclei Anterior Basal nucleus
Richardson and DeLong 1988.) commissure (Meynert)
For example, persons with the ApoE4 gene (coding for Picks disease. It can be distinguished from AD by the
a apolipoprotein) run a much higher risk of AD than do distribution of degenerative changes, which affect
persons with genes for another variety of apolipopro- primarily frontal and temporal parts of the cerebral
tein. Apolipoproteins normally transport cholesterol in cortex. Further, the initial symptoms are behavioral
the blood. ApoE4, however, also binds to amyloid aberrations, typical for lesions of the affected regions,
-protein and is present in senile plaques and neurofi- rather than loss of memory (patients with FTD are
brillary tangles. Therefore, it may facilitate the precipi- often misdiagnosed as suffering from a psychiatric dis-
tation of amyloid. ease). Both FTD and AD, however, are associated with
abnormal phosphorylation of the microtubule-associated
protein tau.
Frontotemporal Dementia
Perhaps as many of 15% of all patients with dementia
have frontotemporal dementia (FTD), formerly called
11 Restitution of Function after
Brain Damage
OVERVIEW be due to a disturbance of ongoing developmental

processes.
Whatever the nature of the insult, brain damage ulti-
mately leads to loss of neurons and their interconnec-
tions. Although new neurons are produced in limited BRAIN INJURIES AND POSSIBLE REPARATIVE
parts of the adult brain, there is no effective replace- PROCESSES
ment of lost neurons after brain damage. Reduced or
abolished blood supplyischemiainitiates a cascade Ischemic Cell Damage
of cellular events ending in cell death. Excessive release
Abolished or reduced blood supply to an organ is called
of glutamate and ensuing excitation appear to be crucial
ischemia. Regardless of cause, even a few minutes of
steps in a vicious cycle. In a region with focal ischemia
severe brain ischemia can produce massive neuronal
(e.g., caused by occlusion of an artery) there is central
death, but, surprisingly, the neurons often do not die
zone where all cells will die and a peripheral zonethe
until several hours after the ischemic episode. This is so
penumbrawith diminished supply, in which neurons
because the lack of oxygen (hypoxia) and glucose trig-
may silenced but do not die. They may be rescued if
gers a cascade of events, in which each step takes some
circulation is restored within a certain time (e.g., by
time but results eventually in neuronal death. Although
thrombolytic drugs or reduction in edema).
many factors are implied, glutamate and glutamate
The nervous system retains its plasticity throughout
receptors are under particularly strong suspicion as the
life, and this property is a prerequisite for recovery
main villains of this drama. Thus, ischemia leads to
of function after damage of nervous tissue. Yet what
excessive release of glutamate (see later, The Glutamate
changes do occur in the brain when a patient recovers
Hypothesis, and Chapter 5, under NMDA Receptors:
functions after a stroke or other acute brain insults?
Mediators of Both Learning and Neuronal Damage).
Judging from animal experiments and brain imaging
In an ischemic region, whether it is due to edema, bleed-
studies of human stroke patients, recovery is due to a
ing (e.g., after head injuries), or vascular occlusion,
learning process in which remaining parts of the brain
there is usually a central zone where the ischemia is
are modified. We call this process substitution. The
so severe that all neurons die.1 Outside this region,
modification is driven by continuous efforts to perform
however, there is a zonethe penumbra (from Latin
tasks that were made difficult or impossible by the brain
paene = almost, and umbra = shadow)characterized
damage. Crucial factors determining the degree of prog-
by neurons that are nonfunctional (unexcitable) but
ress are motivation, focused attention, and amount of
still viable.
training. Stroke patients who have recovered activate
The discovery of the delay between an ischemic epi-
much larger parts of the cortex than normal persons
sode and irreversible cell damage initiated an enormous
when performing simple movements. In addition, plas-
research activity to find drugs that prevent or reduce
tic changes may be compensatory, in the sense that they
the brain damage. In clinical situations, focal ischemia
do not restore the lost function but reduces disturbing
due to occlusion of a brain artery by thrombosis or
symptoms or enable goal attainment by other means
embolus is more common than global ischemia (shut-
than those enabled by the damaged parts of the brain.
ting down the blood supply to the whole brain, as can
Infants with early brain damage may in some cases
occur in cardiac arrest). In cases of focal ischemia hopes
recover remarkably well, especially if lesions (even very
were raised to reduce the size of the brain infarct by
large ones) are confined to one hemisphere. In other
instances, with bilateral or lesions affecting deeper parts
of the brain (basal ganglia, brain stem), complex func-
1 Cell death in the central region completely devoid of blood supply is due to
tional impairments become stable and may even worsen necrosis, as judged from the electron microscopic appearance. There is some
during the first years of life. This may at least partly evidence that apoptosis may cause cell death in the penumbra.
147
keeping neurons in the penumbra alive until the circula- Blood flow
tion improves (improvement may occur spontaneously
or by use of thrombolytic drugs that dissolve the vascular O2 and glucose
obstruction). So far, however, the results with glutamate- in brain
receptor blockers (especially of the N-methyl-D-aspartate
[NMDA] receptor) have been disappointing in humans ATP
in spite of convincing results in animal experiments. Anaerob glycolyisis
One problem has been intolerable side effects with the
doses that are necessary to obtain protection. This +
Na intracell.
might not be surprising considering that glutamatergic K
+
extracell.

transmission participates in virtually every neuronal Cl intracell.
network. Another reason for the failure of numerous pH
attempts to achieve neuroprotection after stroke may
be that although the activation of NMDA receptors Depolarization
undoubtedly is harmful in the early stages of a stroke, it
Release of
may be necessary for recovery in the delayed phase. glutamate
Opening of
Further, it appears that the cellular events evolving in voltage-gated
the penumbra are much more complex than assumed Ca2+ channels Activation of GluR
with regard to both the number of substances involved (NMDA & AMPA)
and the temporal profile of cellular changes.
Excessive release of glutamate cannot readily explain Ca2+ intracell.
all aspects of ischemic cell death, however. For exam-
Activ. of NO-synthase Activation of:
ple, after global ischemia, the cell death is not diffusely NO Protein kinases
distributed. Especially vulnerable are the neurons in the Phospholipase
CA1 field of the hippocampus (see Fig. 32.10). Regional Endonuclease
differences in glutamate release or glutamate receptors Other enzymes
are probably not the reason. More likely explanations
concern differences among regions regarding the pres- Prod. free radicals
ence and regulation of neurotrophic factors. DNA-damage
Cell death
The Glutamate Hypothesis of Ischemic Cell Damage
According to the glutamate hypothesis, the sequence of gure 11.1 Sequence of cellular changes after focal ischemia leading
events after a temporary stop of blood flow may be as to cell death (hypothetical). (Based on Samdani et al. 1997.)
follows (Fig. 11.1):
enzymes that degrade proteins and nucleic acids and by
1. The loss of energy supply rapidly reduces the
activating nitric oxide (NO) synthases that leads to pro-
activity of the sodiumpotassium pump, leading to
duction of free radicals. In turn this destroys other vital
(among other things)
+ enzymes.
2. Increased extracellular K concentration that
7. Before the strong inflow of calcium there is an
depolarizes the neurons so they fire bursts of action
inflow of Na+ accompanied by Cl and water, which
potentials, which leads to
causes neurons and glia to swell.
3. Steadily worsening imbalances of ion concentra-
tions across the cell membrane that make the neuron That NMDA receptors are involved in ischemic cell
incapable of firing action potentials (electrically silent), death is indirectly supported by animal experiments
while at the same time involving NMDA-receptor blockers. If such drugs are
4. The extracellular glutamate concentration rises given even a few hours after an ischemic episode, they
steeply (because, among other things, the ionic imbal- reduce or prevent the cell damage. Also, blockers of
ances reverse the pumping of glutamate by high-affinity AMPA receptors provide protection against ischemic
transporters), leading to cell death in such experiments.
5. Enormous activation of glutamate receptors,
among them NMDA receptors; this in turn is believed
Neurogenesis: Production of New Neurons in the
to induce
Adult Brain
6. Cell damage, probably because of an uncontrolled
rise in intracellular Ca2+ concentration. This may harm In adult mammals, new neurons are produced continu-
the cell in various ways, for example, by activating ously in parts of the subventricular zone and the dentate
11: RESTITUTION OF FUNCTION AFTER BRAIN DAMAGE 149
gyrus of the hippocampal formation (see Fig. 32.10). neuroscientists for a century, has recently been answered
The neurons produced in the subventricular zone at least partly. Thus, in the adult brain, the growth cone
migrate into the olfactory bulb (claims that some also of an axon trying to regenerate quickly collapses due to
populate the cerebral cortex have not been substanti- the presence of inhibitory substances. Among several
ated). Although only a minority of the newly formed such substances, myelin-associated proteins produced
neurons appears to survive, some are incorporated into by oligodendroglia have been most thoroughly studied.
existing networks. The finding that the number of The proteins bind to receptors in the membrane of the
surviving neurons is use-dependent further strengthens growth cone and activate intracellular pathways that
the assumption that the new neurons are of functional quickly down-regulate protein synthesis. In addition,
significance. Neurogenesis thus seems to represent an scar formation at the site of injury also inhibits axonal
additional but spatially restricted form of plasticity, regeneration.
supplementing the ubiquitous synaptic plasticity discussed Central axons may regenerate under certain condi-
earlier in this book. It remains to be determined, however, tions, however. Thus, the proximal stump of a cut
how much and in what way neurogenesis contributes to central axon can grow into a piece of peripheral nerve
the role of hippocampus in memory formation. if it contains viable Schwann cells. Indeed, growth of
Nevertheless, adult neurogenesis has attracted much central axons for several centimeters has been demon-
interest and raised hopes that it may be induced in strated in nerve transplants in experimental animals.
regions with neuronal loss due to injury or disease. Another special kind of glial cellolfactory ensheathing
Indeed, increased neurogenesis occurred in the subven- cells (OECs)can also induce growth of central axons
tricular zone after ischemic brain injury in rats, and and has been subject to clinical trials. These cells cover
some neurons were incorporated in adjacent parts of the the olfactory-receptor cell axons that extend from the
striatum. The clinical relevance of such observations is nasal mucosa to the olfactory bulb. Interestingly, the
not yet known, however. olfactory receptor cells are renewed throughout life, and
the OECs provide a permissive environment enabling
the axons to grow into the CNS. Local supply of
Why Is Neurogenesis and Regeneration So Restricted in
substances that block the growth-inhibiting proteins
the Human Brain?
combined with transplantation of OECs is now used
Because neurogenesiscontrary to earlier beliefsdoes experimentally in patients with transverse lesions of the
occur in adult mammals, one may ask why it is so limited cord in the hope of inducing axonal regeneration across
in distribution. Thus, in reptiles and birds neurogenesis the lesion. So far, howeverin spite of positive results
occurs in large parts of the nervous system. One reason in experimental animalssuch procedures have not
may be that new neurons might be disturbing rather than provided convincing functional improvement in patients.
beneficial if not properly integrated with existing net- Animal studies (rodents) suggest that a combination of
works, and that the increasing complexity of the mam- regeneration-promoting local measures and active reha-
malian brain has rendered successful integration of new bilitation might give the best results.
neurons less likely. Mutations that diminished neurogen-
esis may therefore have given an evolutionary advantage.
Collateral Sprouting Can Aid Restitution
The situation in the dentate gyrus may be special because
of its specific role in memory acquisitionperhaps Neurons that have lost their afferents may be supplied
ordinary synaptic changes are insufficient or less with new ones from normal axons in the vicinity. This
efficacious than addition of new neurons. is called collateral sprouting. After cutting afferent
Further, it is probably not coincidental that the mature axons to a neuronal group (deafferentation), the axons
CNS produces substances that inhibit axonal growth (such degenerate and glial cells remove their nerve terminals.
substances are not present during early development). An In a relatively short time, however, new nerve terminals
uncontrolled axonal growth in the mature brain might fill the vacant synaptic sites. This probably occurs
cause harm rather than help restitution. Correspondingly, because a trophic substance becomes available from the
although supply of growth promoting factors after brain deafferented neurons. The trophic substance stimulates
damage might rescue sick neurons and promote axonal nearby normal axons to send out sprouts. Obviously,
growth, it might also be expected to disturb the connec- collateral sprouting can only act locally in restoration
tions and functions of the healthy neurons. of neuronal activity. There is no evidence that it can
restore connections between more distant cell groups.
Nor do all systems seem to exhibit collateral sprouting.
Axonal Regeneration in the CNSHope for Spinal
Neither can collateral sprouting restore the original
Cord Repair?
pattern of innervation because the neurons responsible
Why do severed axons regenerate in the peripheral ner- for that pattern are gone. Thus, there will always be a
vous system but not in the CNS? This question, puzzling loss of specificity of connections, compared with the
normal situation. Indeed, restitution of function seen the destroyed neurons. Functional restoration has also
after brain damage usually entails a loss of precision; been demonstrated in some studies. Embryonic neuro-
for example, recovery of movement force is usually blasts are obviously not affected by the myelin-associated
better than recovery of the ability to carry out delicate factors that normally inhibit axonal growth in the mature
movements. CNS.
Although collateral sprouting probably aids recovery Many problems complicate the transplantations of
in many situations, it may not always be beneficial. For embryonic tissue, however. One is the ethical issue of
example, after a stroke that damages the motor path- using brains of early abortions for therapy. Neuroblasts
ways descending from the cerebral cortex, axon collat- grown in culture may replace embryonic cells, however.
erals from sensory neurons may fill the vacant synaptic Such cells may also be genetically modified to, for
sites on motor neurons in the cord. This would not help example, improve survival in the host. Other problems
to improve the voluntary control of the muscles but with neural transplantations are technical, such as the
might, rather, contribute to the abnormally increased necessity for growth over long distances in the human
reactivity of the muscles to sensory stimuli that is char- brain (as compared with the rat) and survival of a suf-
acteristic of such cases (as in spasticity). ficient number of neuroblasts. The chances of success
are best with restoring diffusely organized, fairly short
connections, whereas chances are presumably remote
Can We Help Restitution by Neurotrophic Factors,
with precisely organized, long-ranging connections in
Drugs, or Transplantation?
the human brain.
The well-established effects of neurotrophins and
growth factors on plasticity and neuronal survival raise
the question of whether they can be used therapeuti-
BRAIN PROCESSES UNDERLYING RECOVERY
cally. Thus, one might expect that raising the level of
OF FUNCTION
such substances in the damaged brain might rescue neu-
rons and stimulate the plastic changes necessary for res-
Substitution and Compensation
titution. The application in the CNS of such substances
meets difficulties, however. Because they are proteins, Differentiated neurons are unable to divide mitotically,
the substances do not pass the bloodbrain barrier and the brain does not possess a store of undifferenti-
readily, and even if they are delivered directly into the ated neurons that can multiply and replace lost ones
cerebrospinal fluid, their tissue penetration is restricted. (with some possible exceptions, as discussed earlier).
Also, long-term supply of proteins to the brain may Thus, as a rule, dead neurons are not replaced. We also
have uncontrollable actions and perhaps dangerous know that cut axons do not regenerate in the CNS (the
side effects. Therefore, the hope is to develop drugs that latter in contrast to the peripheral nervous system).
can stimulate the synthesis of specific neurotrophic fac- Therefore, a reparative process in which the damaged
tors in the brain itself or to improve their penetration of structures regenerate or are replaced by new ones can-
the bloodbrain barrier. not explain the recovery of function after brain damage.
Drugs that increase brain levels of monoamines Rather, recovery must be due to changes among the
(e.g., amphetamine) help recovery after brain lesions in remaining undamaged neurons and glial cells. Indeed,
experimental animals, apparently by increasing plastic- there is much evidence to suggest that neural circuits
ity. From a theoretical point of view, it seems likely that reorganize to adapt to a novel situation. We discuss two
the same would apply to humans. Indeed, some studies kinds of adaptation next, both of which can probably
suggest that amphetamine speeds up recovery in stroke best be regarded as learning processes.
patients. Presumably, the effect would be best when In one type of adaptationwhich we call substitution
combined with function-specific training. intact neuronal groups take over and substitute for the
Another means of helping restitution might be to replace damaged parts. The neuronal groups responsible for the
lost neurons by transplantation of neural precursor cells substitution normally carry out tasks similar to those of
neuroblastsinto damaged regions. Embryonic neurons the damaged ones. Thus, after a stroke destroys the cell
can still send out axons, provided the embryo is so young groups that are responsible for initiating certain kinds
that the neuroblasts have not yet sent out axons. Besides of movement, the cells responsible for other kinds of
numerous animal experiments, this approach has been movements may take over to some extent. For example,
tried in a limited number of patients with Parkinsons dis- other cortical areas may partially substitute for func-
ease, giving promising results. Animal experiments show tions lost when a lesion destroys the primary motor cor-
convincingly that neuroblasts can survive and send out tex, and neuronal groups that normally control only one
axons after transplantation to an adult brain. If they are side of the body may expand their activity to the other
transplanted to a site where the adult neurons have been side as well. Substitution can seldom restore a system to
destroyed, the axons may even reach the normal targets of its premorbid functional level, however. After all, an
amateur, who still has to take care of his former duties, For example, an arm that was totally paralyzed the day
has replaced a specialist! after a stroke may in a matter of days be only slightly
The other kind of adaptation, called compensation, weaker and clumsier than before the stroke. However,
implies that any remaining structures change their nor- when the condition deteriorates rapidly after the initial
mal activity to diminish disturbing symptoms produced insult, the reason is usually that the edema worsens and
by the injury. This is relevant when the brain damage compromises the blood supply to more and more of the
not only leads to loss of functions, such as muscular brain.
weakness or sensory loss, but also produces disturbing Certainly, plastic changes occur shortly after an injury
phenomena such as involuntary movements or sensory (hours, days), as witnessed by animal experiments.
confusion. For example, unilateral destruction of the Thus, there is probably no sharp distinction between
vestibular apparatus in the inner ear initially causes the rapid and the slow phases of recoverythe nervous
severe dizziness and disturbances of posture and eye system starts its adaptation to the new circumstances
movements. This is due to a mismatch between the immediately.
vestibular information reaching the brain from the two
sides of the body. The symptoms usually subside quickly,
Methods to Study Neuronal Activity and Connectivity
because the vestibular system compensates by altering
in the Living Brain
its sensitivity and information handling. Although this
does not normalize the sense of equilibrium, it reduces Throughout this book, references are made to studies
disturbing symptoms. By substitution, the brain can using brain imaging techniques, particularly those that
learn to rely on other sources of information to control enable determination of regional cerebral blood flow
posture and movements. Thus, the postural adjustments (see Chapter 8, under Regional Cerebral Blood Flow
necessary for the upright position gradually improve and Neuronal Activity). Because of the link between a
because visual information substitutes for vestibular. change of neuronal activity and local cerebral blood
When denied the use of vision (as in the dark), the person flow, the flow of blood through specific parts of the
becomes very unsteady. brain can be correlated with certain stimuli or specific
Some patients do not recover useful function of a sensory, motor, or mental activities. Computer tomog-
body part after brain injury. To some extent goals can raphy (CT) can be used to visualize the distribution of
still be achieved by using other movement strategies, a radioactive substance in the living brain. This method,
for example, using the (normal) left arm instead of the called positron emission tomography (PET), is based
paralyzed right, using a stick to keep balance, using on the use of isotopes that emit positrons. Positrons
both hands instead of one, and so forth. Also in such fuse immediately with electrons, producing two gamma
cases, the degree of success depends on a learning pro- rays going in opposite directions, thus permitting the
cess, even though the level of performance as a rule will identification of their origin in the brain with the aid of
be severely reduced compared with the normal situation. a powerful computer. PET produces images that show
This may also be regarded as a form of compensation, the distribution of an inhaled or injected radioactively
and should be distinguished from substitution. labeled substance at a given time. By labeling substances
of biological interest, one can determine their distribu-
tion in the body. In the case of blood flow measure-
Restitution after a Stroke Can Be Divided into
ment, radioactively labeled water is injected into the
Two Phases
bloodstream. Functional MRI (fMRI) is the other main
After a person has a stroke, there is usually a first phase method to visualize dynamic changes in the brain. This
of rapid improvement lasting from days to weeks, fol- method is based on the fact that the magnetic proper-
lowed by a second phase of slower progress lasting ties of hemoglobin depend on whether or not it is oxy-
from months to years. Acute damage to neural tissue is genated, and small differences in blood oxyhemoglobin
usually caused by head injuries with crushing of neural concentration can be detected with MRI. For unknown
tissue and bleeding or by vascular occlusion caused by reasons, the oxygen uptake of nerve cells does not
thrombosis or an embolus. Secondary changes occur in increase simultaneously with increased activity. Thus, it
the penumbra (the tissue surrounding the damaged appears that neurons work anaerobically during a brief
area) such as edema (tissue swelling) and disturbed period of increased activity, despite a sufficient oxygen
local circulation. If the edema subsides quickly and the supply. The glucose uptake increases, however, and so
circulation improves in the penumbra, neurons will does the blood flow. When the blood flow increases
regain their normal activity (compare with the transient without increased oxygen uptake, more oxygen remains
weakness and loss of cutaneous sensation produced by in the blood after passing the capillariesthat is, the
pressure on a peripheral nerve). This is probably why arteriovenous O2 difference is reduced. MRI can detect
there is often a marked improvement of the patients this change, and in this way the regions of increased or
condition during the first week or two after the accident. reduced blood flow can be visualized. An advantage
over PET is that the picture of blood flow changes can and between the cerebral cortex and subcortical nuclei.
be compared with the precise MRI picture of the same The method cannot determine the polarity of connec-
persons brain. This permits localization of blood flow tions and the spatial resolution is limited. Provided the
changes to anatomic structures with a spatial resolution results are critically evaluated in conjunction with
down to less than 2 mm. experimental tracing data from primates, the method
A drawback of blood flow measurement as an indi- gives important information.
cator of neuronal activity is its low time resolution
compared with the time scale for signal transmission in
Studies of Recovery after a Stroke in Humans
the brain. In this respect, recording the electrical activ-
ity of the brain is superior. This is usually done by Many stroke patients have muscular weakness (pare-
placing many electrodes on the head and is called ses) in the opposite side of the body as a dominating
electroencephalography (EEG, see Chapter 26, under symptom. This is called hemiplegia (hemi, half; plegia,
Electroencephalography). EEG has been developed from Greek pleg, stroke). The symptoms are caused by
to enable study of topographic patterns of cerebral acti- destruction (due to occlusion of an artery or a bleeding)
vation in relation to the performance of specific tasks, of motor pathways from the cerebral cortex to the brain
and coherence of EEG activity in different cortical areas stem and the cord (see Fig. 22.3). Usually, the injury
suggests that the areas are functionally interconnected. occurs in the internal capsule (see Fig. 22.13) where the
A drawback with EEG is its low spatial resolution, descending fibers from the cerebral cortex are collected.
which means that only a crude correlation is possible When such injuries cause hemiplegia, we use the term
between electrical activity and its origin in the brain. capsular hemiplegia. Because patients with this clinical
A more recent technique, magnetic encephalography condition are so common, and because the site of their
(MEG), records the magnetic fields produced by the injury is usually well localized, they have been the sub-
electric activity of the brain. The spatial resolution is jects for many studies of restitution. Some examples
much better than with EEGat best, down to a few elucidating mechanisms behind restitution in humans
millimeters. (For both methods, however, the spatial are presented here.
resolution becomes poorer the deeper in the brain the Regional cerebral blood flow is closely linked with
source of activity is located.) A further advantage with neuronal activity. Thus, when we find altered blood
the MEG technique is that it can be combined with flowusing PET or fMRI brain imagingin a specific
MRI. This enables precise localization of the brain areas part of the brain after a stroke, it is taken as evidence of
participating in a task, at the same time as the temporal altered activity caused by the stroke. One group of
aspects are analyzed (such as the sequence in which patients with capsular hemiplegia was tested 3 months
various cell groups are activated). after the stroke. They were then completely or substan-
Electric stimulation of the brain through the skull tially recovered; for example, they could all perform
(transcranially) requires an intensity that causes pain, opposition movements with the fingers. The test was
and is therefore seldom used. With transcranial magnetic to touch the thumb sequentially with the fingers, in a
stimulation (TMS; also termed magnetic brain stimula- rhythm determined by a metronome. In normal control
tion), however, neurons in the cerebral cortex can be persons, this task is associated with increased blood
activated painlessly with a short, intense magnetic pulse flow primarily in the opposite motor cortex (and in
applied to the head. The magnetic field penetrates the subcortical motor regions like the cerebellum and the
skull and creates an electric current in the brain, primar- basal ganglia). This fits with the fact that the pyramidal
ily in the outer parts of the cerebral cortex. Magnetic tract, which is necessary for precise finger movements,
brain stimulation also enables study of how disruption originates in the motor cortex and is crossed. The
of normal activity in a specific part of the cortex affects patients differed from the controls by showing increased
behavior and cognitive functions. activity in cortical areas that are not normally activated
Connectivity in the living brain can be studied with in this kind of simple, routine movement, notably in
TMS and with diffusion-weighted imaging (DWI). TMS parts of the, insula, posterior parietal cortex, and cin-
has been used to study the connections between the gulate gyrus. In controls, these areas show increased
motor cortex and the spinal cord in healthy persons activity with complex movements and problem-solving
and in persons with motor dysfunction (e.g., multiple tasks that require extra attention. The regions have in
sclerosis). It can also be used to study whether parts of common that they send association connections to the
the brain are interconnected, and in particular, whether premotor area (PMA; see Fig. 22.10) and by this route
connectivity changes in the course of therapeutic inter- can influence voluntary movements. Indeed, increased
ventions (such as rehabilitative training programs for activity is also present in the premotor area. In addition,
stroke patients). DWI (and further developments of this some of the patients differed from the controls by show-
method) enables visualization of major pathways in the ing increased activity in motor cortical areas on the same
brain, such as connections among various cortical areas, (ipsilateral) side as the affected hand. Such findings
suggest that functional recovery after hemiplegia is of the contralateral hand, as in normal persons. Further,
related to the patients learning to use larger parts of the in some recovered stroke patients, involuntary move-
cerebral cortex for control of simple finger movements ments of the unaffected fingersmirror movements
than before the damage, and their using motor areas on accompany voluntary movements of the paretic fingers.
the same side as the pareses. A large number of studies Finally, a peculiar experiment of nature strongly sug-
confirm the above findings, although the exact distribu- gests that the undamaged hemisphere participates in
tion of activation may vary somewhat among studies. recovery in some patients. Thus, two patients with
Use of transcranial magnetic stimulation (TMS) in res- purely motor symptoms who were in good recovery
tituted stroke patients has furthermore showed that not from capsular hemiplegia suffered a second stroke in the
only are cortical activation differently distributed but internal capsule of the other hemisphere. As expected,
there is also evidence of altered connectivity, as assessed their previously normal side now became paretic, but so
in a resting situation. Further support for structural did also the recovered side. This phenomenon is diffi-
changes during recovery comes from use of MRI-based cult to explain if we do not assume that the restitution
morphometry, suggesting that an intense rehabilitative had involved the use of motor pathways from the nor-
training program is associated with increased cortical mal hemisphere to ipsilateral muscles.
gray matter in the regions most activated by movements. Most patients do not exhibit mirror movements,
The involvement of larger parts of the cerebral cortex however, and several studies found no evidence of con-
may explain why simple, previously effortless move- tribution of descending pathways from the undamaged
ments require so much more attention and mental hemisphere (e.g., with the use TMS).
energy than before the stroke. There is evidence that
descending fibers from various cortical motor areas,
Examples of Substitution from Animal Experiments
such as the primary motor cortex (MI), the supplemen-
tary motor area (SMA), and premotor area (PMA) Substitution implies that neuronal groups and path-
occupy different parts of the internal capsule. Thus, ways that normally participate only marginally gradu-
when a capsular stroke damages the most powerful and ally take over the responsibility for the execution of a
direct pathway from the cortex to the motor neurons task. Clinical recovery after brain damage resembles a
arising in MIother, parallel, descending pathways long-term learning process, involving strengthening of
may be trained to activate motor neurons more pow- specific synaptic connections by repeated use.
erfully than before the stroke. Some redirecting of impulse traffic can occur even
immediately after the damage, however. When the arm
region of the motor cortex in monkeys doing specific
The Contribution of the Undamaged Hemisphere
wrist movements is cooled, the movements immediately
to Recovery
become slower and weaker. This is expected because
Although many observations suggest that the undam- the cooling inactivates many pyramidal tract neurons.
aged hemisphere participates in recovery, the responsi- Activity in the somatosensory cortex increases simulta-
ble mechanism is not clear. In particular, results are neously, however, as if this region were prepared to
conflicting as to whether or not descending motor path- take over immediately. If the somatosensory cortex is
ways from the undamaged hemisphere contributethe then also cooled, the monkey becomes paralytic and is
other possibility being actions via the lesioned hemi- unable to do the movements at all. Cooling of the
sphere and its remaining descending connections. One somatosensory cortex alone has almost no effect on the
should note that most studies involve a small number of movements and is not accompanied by increased activ-
patients with somewhat differently placed lesions, mak- ity in the motor cortex. These data suggest that the
ing it difficult to draw general conclusions. The weight impulse traffic can be switched very rapidly from one
of evidence suggests that different mechanisms may path to another, so that command signals for move-
operate during recovery in patients with a similar func- ments are redirected to the somatosensory cortex. If the
tional and clinical picture. motor cortex were permanently inactivated, we might
Some observations support that use of uncrossed expect that establishment of new synapses would grad-
motor pathways contribute to recovery. For example, a ually strengthen the new impulse routes. Further exper-
group of patients with strokes affecting the pyramidal iments indicate that this is indeed what happens. After
tract in the posterior part of the internal capsule (as the first link of the disynaptic pathway from the cere-
verified with MRI) had initially severe paresis of the bellum to the motor cortex is severed in monkeys
hand contralateral to the stroke, but they gradually (Fig. 11.2A), voluntary movements become jerky and
recovered the ability to perform fractionate finger uncoordinated. In 2 to 3 weeks, however, most symp-
movements. In these patients, transcranial magnetic toms disappear, and movements are carried out almost
stimulation of the motor cortex of the undamaged as before (Fig. 11.2B). Thus, considerable restitution has
hemisphere evoked movements of both handsnot just occurred, despite permanent damage to the connections.
If the somatosensory cortex is then destroyed, however, contradictory information (double vision). Some chil-
the original symptoms recur with full strength (Fig. 11.2C). dren solve the conflict by constantly using one eye and
After this second operation, recovery takes much lon- ignoring information from the other, whereas other
ger and is incomplete. Obviously, during the first phase children use the two eyes interchangeably. It turns out
of recovery, the somatosensory cortex substituted the that in those always using the same eye, vision eventu-
cerebellum regarding information to the motor cortex. ally becomes severely reduced in the eye that is not
This information is presumably carried by the numer- used. Those using their eyes interchangeably, however,
ous association connections from the somatosensory to retain normal vision in both eyes. The images reaching
the motor cortex. This assumption is supported by the the cortex from the two eyeseven with a squintare
electron microscopic demonstration of increased syn- almost identical. The crucial factor is whether or not
aptic density in the motor cortex after recovery. These the information receives attention. In anesthetized
experiments thus suggest that new synapses can be animals, cells in the visual cortex can change their prop-
established in the adult after brain damage, even in a erties after exposure to light stimuli if they are coupled
neuronal group far removed from the site of injury. with stimulation of cell groups that are normally active
during focused attention. Thus, the learning effect
appears to require that two kinds of synaptic input
Restitution Is a Learning Process
converge at a neuron: one kind provides specific infor-
Regardless of whether long-term restitution is caused mation; the other tells the neuron that this is relevant
by other neuronal groups taking over a function or by information that should be stored (see Fig. 4.10). As
collateral sprouting (or both), there is good reason to discussed earlier, the release of monoamines is probably
believe that the improvement is a result of a learning a factor in such plastic changes.
process, subject to the same rules that underlie learning During restitution, skills are re-learned more or less
in an intact nervous system. All learning is likely to completely. Of course, the degree of recovery depends
involve changes in the properties of existing synapses, on the localization and size of the damaged region and
formation of new ones, and removal of inappropriate on whether the neuronal loss occurs acutely or chroni-
ones. Such use-dependent plasticity continues through- cally (due to a degenerative process). With otherwise
out life and is the nervous systems means of adapting identical lesions, however, the recovery depends on
to new and changing conditions, in both the body itself well-known factors that contribute to successful learn-
and the environment. The process is bound to take time ing in normal people. Among these, motivation and
and is probably slower in a brain deprived of many amount of training are of fundamental importance.
neurons. We know, from our own experience and from Other factors, such as encouragement, feedback, and
cognitive psychology, the importance of motivation the learners perception of progress, are crucial for
and focused, selective attention for effective learning. maintaining a high motivation and would be especially
An example of the importance of focused attention con- important in patients with brain damage. Further, the
cerns infants and children with a squint (strabismus). prospects of recovery seem to be better when training
Because the retinal images are different in the two eyes, starts very early after a stroke. This agrees with animal
the child attends to signals from one eye only to avoid experiments showing that the plasticity is highest in a
Motor Somatosensory
cortex (MI) cortex (SI)
Thalamus
Pyramidal tract
gure 11.2 Example of recovery due to substitution.

Cerebellum
Recovery of coordinated movements after loss of
connections from the cerebellum to the cerebral cortex
Incoordination due Recovery aided Incoordination is aided by strengthening of connections from the
to interruption of by strengthened returns after somatosensory cortex to the motor cortex. (Based on
cerebello-cerebral connections destruction SI experiments in monkeys and cats by Mackel 1987,
pathway from SI to MI and Keller and coworkers 1990.)
limited period after the infliction of a brain lesion. widespread connections might probably aid restitution.
Finally, although the learning curve (rate of recovery) is As long as the damage is restricted to one hemisphere,
usually steepest during the first few months after a size of the lesion does not seem to matter for success of
stroke, improvement can continue for several years if restitution. The most crucial negative factor in children
training is continued. One study even showed that a with such lesions is the occurrence of seizures, which
specific training program started 4 years after a stroke inhibits cognitive development. Presumably, ongoing
led to rapid improvement in hand function in patients epileptic activity disturbs the use-dependent development
with a deficit that had been stable for several years. of brain networks.
These results were obtained by combining carefully
planned training of the disabled arm with preventing
The Limits of Plasticity: Cerebral Palsy
use of the normal arm (by a sling). This method, called
constraint-induced movement therapy (CI therapy), is Although recovery is remarkably good in some cases of
based on results from experiments with constraining early unilateral brain damage, this appears not to be the
the normal arm in monkeys with unilateral lesions of most common outcome after early brain damage.
the motor system. Apart from constraining the normal Indeed, prenatal and perinatal (at the time of birth)
arm, the crucial factors for success seem to be a highly brain damage often gives more serious functional defi-
motivated patient, gradually increasing complexity of cits than similar injuries acquired later in life. Thus, the
the training tasks so that the patient experiences prog- child with early brain damage often presents with a
ress regularly, and several hours of daily training. mixture of symptoms, such as pareses, postural abnor-
malities, and involuntary movements. This is the case
3
for children with cerebral palsy, suffering from the
RESTITUTION AFTER DAMAGE IN EARLY CHILDHOOD effects of lesionssuch as birth-associated hypoxia,
intrauterine infections, or genetic aberrationsthat
The brain is certainly more plastic prenatally and dur- may have occurred at different developmental stages.
ing infancy than in adulthood. Thus, one might expect Some children with cerebral palsy have additional cog-
restitution to be more complete after early than after nitive impairments. We have discussed that during sen-
late brain damage. This holds only for some cases of sitive periods of development the brain is not only more
early brain damage, however. In other cases, the conse- plastic but also more vulnerable than later. Thus, a
quences are in fact more severe. lesion acquired pre- or perinatally might interfere with
a number of developmental processes. In addition, col-
lateral sprouting at early stages may not necessarily be
Successful Restitution after Large Lesions of
helpful. Thus, sprouts from nearby neurons may fill
One Hemisphere
vacant synaptic sites, regardless of whether this is func-
The most clear-cut examples of successful recovery after tionally meaningful or not. For example, in the cord
early brain damage concern infants with lesionseven sprouts from sensory fibers may innervate motor neu-
2
very large onesof one hemisphere. In such cases, rons that have lost their input from the cerebral cortex.
although the child remains hemiplegic, cognitive devel- Such blind sprouting in various parts of the brain
opment may be virtually normal. The reason restitution and cord may perhaps contribute to the involuntary
is so successful is probably only partly that the individual movements typical of many children with cerebral
neurons are more apt to send out new collaterals and palsy. Further, long tracts that are already established
remove others. Another factor could be as important: are apparently not replaced if damaged. Thus, if the left
because in the young brain various regions, particularly motor cortex (sending fibers to the right spinal cord) is
of the cerebral cortex, are not yet fully engaged in the removed in monkeys shortly after birth, these monkeys
tasks for which they are destined, they are recruited more never learn (with their right hand) the kinds of move-
easily for other purposes if necessary. Thus, the right ments that depend on direct connections from the cere-
hemisphere of the brain may take over the processing of bral cortex to the cord. This is because these connections
language if the left hemisphere (which normally does are already established at birth in monkeys (and in
this) is damaged at an early age. In addition, prenatally humans). Reports of apparent reestablishment of long
and in infancy many connections are more widespread fiber tracts after early injury are probably based on
than later. During further development, synapses in some experiments in which the injury was inflicted before the
targets strengthen while synapses in other targets weaken axons from the relevant cell groups had reached their
or disappear. This is at least partly a use-dependent pro- targets. In such instances, the outgrowing axons may
cess, and in case of brain damage, persistence of the
3 Cerebral palsy is used as an umbrella term for a number of clinically different
2 The situation appears to be less favorable when the lesions affect both hemi- neurological disorders that appear in infancy or early childhood and are domi-
spheres (even when the lesions are relatively small). nated by disturbances of bodily movements and posture.
also innervate other cell groups than they normally do. relevant corticospinal fibers do all cross (in the medulla).
This may be due to a lack of normal competition among This development is at least partly use-dependent and
outgrowing fiber tracts. governed by the childs efforts to learn new skills.
Finally, we will mention one other possible factor A frequent kind of cerebral palsy is hemiplegia caused
although speculativethat may help to explain unsuc- by a perinatal stroke. Typically, disturbed movement
cessful restitution after early brain damage. Prenatal control and posture in these children appear not imme-
brain damage occurs in a brain that is not yet geared to diately but during the first 3 years of life, and often
motivated, goal-directed behavior; establishment of skills acquired early are later lost. This is probably
functional networks is still mainly under genetic con- due to plastic processes that are detrimental to normal
trol. Thus, when emerging neuronal networks are dis- motor development. Thus, it appears that any remain-
turbed there is presumably little pressure on functional ing corticospinal fibers from the damaged hemisphere
restitution, in contrast to what is usually the case when are prevented from establishing synaptic connections
damage occurs postnatally. This may allow haphazard in the cord by competition from the much stronger
plastic changes that are not tempered by a pressure to connections of the undamaged hemisphere. Indeed, the
re-establish connectivity that is necessary for certain undamaged hemisphere retains and strengthens its ipsi-
behaviors. lateral connections to the cord, rather than being weak-
ened as would normally occur (this is shown in animal
experiments and indirectly by use of TMS in human
Early Damage of the Corticospinal (Pyramidal) Tract
infants). Children with cerebral palsy doing mirror
Direct connections from the cerebral cortex to the spinal movements express this: that is, voluntary movements
cord are necessary for the acquisition and performance with one hand are always accompanied by the same
of most skilled movements. Although corticospinal movement with the other hand. Why this abnormal
fibers reach the cord at the seventh gestational month, innervation pattern is associated with poor function is
the development of synaptic connections in the cord not so obvious, however. In any case, animal experiments
and myelination of the corticospinal fibers go on at show that stimulation of the damaged hemisphere can
least until the child is 2 to 3 years old. Some connec- rescue the remaining fibers and prevent the poor func-
tions are strengthened and others are removed during tional outcome. Further, it appears that in infants with
this period. Presumably, this represents a sensitive cerebral palsy early specific training (constraint-induced
period for establishment of specific corticospinal con- movement therapy) of the impaired arm can improve
nections. Initially, connections from each hemisphere the functional outcome. Probably, in such cases use-
are bilateral, but at the age of 2 the hand is controlled dependent plasticity serves to prevent the gradual loss
exclusively from the contralateral hemisphere; that is, the of connections from the damaged hemisphere.
III SENSORY SYSTEMS
T HE first chapter in this part covers the basic fea-

tures that are common to all sensory receptors,
or sense organs. Such knowledge will make reading the
fullness of the bladder. We also use the term system
for the parts of the nervous system that deal with tasks
other than sensory ones. The motor system, for exam-
following chapters easier. The next three chapters treat ple, initiates appropriate movements and maintains
various aspects of the somatosensory system, which is bodily postures.
primarily concerned with sensory information from the We use the term system rather loosely here: we do
skin, joints, and muscles. Chapter 13 deals with the not imply that each system can be understood indepen-
peripheral parts of the somatosensory system; that is, dently of the rest of the nervous system. Further, it is
the sense organs and their connections into the central often arbitrary as to which system a particular neuronal
nervous system. Chapter 14 deals with the central path- group is said to belong. Thus, usually a cell group is
ways and neuronal groups concerned with processing of used in the operations of several systems. Especially at
somatosensory information, while Chapter 15 discusses higher levels of the brain, information from various sys-
pain in some more depth. (Sensory information from the tems converges. Cortical neuronal groups, for example,
internal organsvisceral sensationis dealt with mainly may be devoted to both sensory processing and motor
in Chapter 29.) In Chapter 16, we describe the visual preparation. Convergence of information from several
system, from the peripheral receptors in the eye to the sensory systems seems necessary for us to perceive that
higher association areas of the cerebral cortex. Chapter the different kinds of information actually concern the
17 deals with the auditory system (hearing); Chapter 18 same phenomenon, whether it is in our own body or in
with the vestibular system (sense of equilibrium); and the environment. How do we know, for example, that
finally Chapter 19 discusses olfaction and taste. the round object with a rough surface we hold in the
We use the term system to indicate that each of these hand is the same as the orange we see with our eyes?
senses is mediated, at least in part, in different regions Sometimes the term system is misused, so that it confuses
of the nervous system. In neurobiology, a system usu- rather than clarifies; this happens when we lump struc-
ally means a set of interconnected neuronal groups that tures about which we know too little, or cell groups that
share either one specific task, or several closely related have such widespread connections that they do not belong
tasks. Sensory systems are designed to capture, transmit, to a particular system. The wish to simplify a complex
and process information about events in the body and realityand the nervous system is indeed overwhelm-
in the environment, such as light hitting the eye or the ingly complexcan sometimes become too strong.
12 Sensory Receptors in General
OVERVIEW receptors adapt rapidly, and partly because sensory

information is heavily censored on its way to the cere-
Sensory signals from nearly all parts of the body are bral cortex.
transmitted to the central nervous system (CNS), bring-
ing information about conditions in the various tissues
and organs and in our surroundings. The structures SENSORY UNITS AND THEIR RECEPTIVE FIELDS
where sensory signals originate are called sense organs,
or receptors. The receptors are formed either by the Regardless of the structure of the receptor, a sensory
terminal branches of an axon (the skin, joints, muscles, neuron transmits the signal to the CNS. We use the
and internal organs) or by specialized sensory cells (the term sensory unit for a sensory neuron with all its ram-
retina, taste buds, and inner ear) that transmit the ifications in the periphery and in the CNS (Figs. 12.1
message to nerve terminals. We are using the word recep- and 12.2). Such primary sensory neurons have their cell
tor differently here than in earlier chapters where we bodies in ganglia close to the cord or the brain stem
applied it to molecules with specific binding properties. (similar neurons are found in the retina). The receptive
A sensory unit is a sensory neuron with all its ramifica- field of the sensory neuron is the part of the body or the
tions in the periphery and in the CNS. The receptive environment from which it samples information. The
field of the sensory neuron is the part of the body or the receptive field of a cutaneous sensory unit is a spot on
environment from which it samples information. These the skin (Fig. 12.1; see also Fig. 13.10). For a sensory
terms are applied to neurons at all levels of the sensory neuron in the retina, the receptive field is a particular
pathways, from the spinal ganglia to the cerebral cortex. spot on the retina, receiving light from a corresponding
Because of convergence, the receptive fields are larger part of the visual field. We can determine the receptive
at higher than at lower levels of the CNS. field of a sensory unit by recording with a thin electrode
Sensory receptors are built to respond preferentially the action potentials produced in an axon or a cell
to certain kinds of stimulus energy, which is called their body, and then we can systematically explore the area
adequate stimulus (mechanical, chemical, electromag- from which it can be activated.
netic, and so forth). Regardless of the nature of the stim-
ulus, it is translated into electric discharges conducted in
axons; that is, the language of the nervous system. This
process is called transduction and involves direct or Sensory
indirect activation of specific cation channels. Activation unit A Skin
produces a receptor potential, which is a graded depo-
larization of the receptor membrane (similar to a syn-
aptic potential). We classify receptors by their adequate Receptive fields
stimulus (e.g., mechanoreceptor, photoreceptor, and so Sensory A
forth), by their degree of adaptation, and by the site unit B
from which they collect information. For example,
many receptors are rapidly adapting, meaning that the B
respond mainly to start and stop of a stimulus. Others
are slowly adapting, and continue to signal a stationary
stimulus. Receptors in the muscles and connective tissue gure 12.1 Sensory units and receptive elds. Simplied representa-
are termed proprioceptors, while exteroceptors capture tion of two sensory units (A and B), which in this case are spinal
information from our surroundings (e.g., light, some- ganglion cells. The peripheral process of each unit (bers) ramies in an
thing touching the skin, and so on). Enteroceptors area of the skin, which is the receptive eld of this particular unit, and
(interoceptors) inform about stimuli arising in the vis- the receptive elds of the two units overlap. The density of terminal
nerve ber branchesendowed with receptor propertiesis highest
ceral organs. In general, contrasts and brief, unexpected in the central part of the receptive eld. Therefore, the threshold for
stimuli and are perceived much more easily than steady eliciting action potentials is lower centrally than peripherally in the
and familiar ones. This is partly because the majority of receptive eld.
159
A B
Transmitter release
CENTRAL NERVOUS
SYSTEM
gure 12.2 Two main kinds of sen-

sory receptor. Left: The most com-
mon kind, found in most parts of the
Sensory
Action potentials body. The receptor properties are in
neuron
conducted along the the terminal ramications of a sen-
axon sory axon that belongs to a pseudouni-
polar ganglion cell. Right: The kind of
receptor found in the sense organs for
Chemical taste, equilibrium, and hearing. The
transmission receptor properties are located on a
from the sensory cell that transmits the signal
Threshold receptor cell to to a ganglion cell. In both kinds of
the sensory receptor, a stimulus produces a graded
neuron receptor potential. An action poten-
tial results in the ganglion cell to the
Receptor left if the graded potential reaches the
potential
threshold. The sensory cell to the right
does not produce an action potential
Stimulus Stimulus but releases a chemical substance that
depolarizes the terminals of the ganglion
PERIPHERAL NERVOUS SYSTEM cell. In the CNS the signal is transmitted
chemically to central sensory neurons.
Convergence Makes Receptive Fields Larger

rapid changes of properties are largely due to specific
We will come back to the sensory unit and receptive activation of inhibitory interneurons (see Fig. 13.3).
field and exemplify them in the following chapters. Further, receptive fields can change because of specific
Here it is important to note that these terms apply to training (learning) and of lesions that alter the sensory
sensory neurons at any level of the pathways that lead inputs to the CNS.
from the receptors to the cerebral cortex. A neuron in
the visual cortex, for example, reacts to light hitting
only one particular part of the retina, which represents TRANSDUCTION: THE TRANSLATION OF STIMULI
the receptive field of the neuron (see Fig. 7.8). At the TO ACTION POTENTIALS
cortical level the receptive field depends on convergence
from several sensory units at lower levels (retina and The task of the receptors is to respond to stimuli.
thalamus, for example). Thus, receptive fields are usu- Regardless of the nature of the stimulus, the receptor
ally larger for cortical sensory units than for those translates the stimulus to the language spoken by the
closer to the sense organ. nervous systemthat is, electrical signals in the form of
action potentials. We discuss in Chapter 4 how summa-
tion of many synaptic inputs evokes an action potential
Receptive Fields Are Dynamic and Context-Dependent
(depolarization to threshold) that is propagated along
One might perhaps expect that the receptive field of the axon.
a sensory neuron would be a constant, hard-wired
property. This is not the case, however; there is ample
Receptor Potentials
experimental evidence that receptive fields are dynamic.
The size of a receptive field depends on the context of a In receptors, the action potential arises near the terminal
stimulus; for example, focused attention reduces the branches of the sensory neuron. This is true regardless
receptive fields of neurons in the visual cortex. Such of whether the stimulus acts directly on the terminal
12: SENSORY RECEPTORS IN GENERAL 161
branches (as in the skin; Fig. 12.1; see also Fig. 13.1) or proteins via the rigid cytoskeleton (or similar structures
indirectly via receptor cells (as in the retina and the outside the nerve terminal), which in turn either opens
inner ear; see Figs. 16.4 and 17.5). The stimulus alters ion channels mechanically (Fig. 12.3B) or chemically
the permeability of the receptor membrane, thus depo- via intracellular second messengers (Fig. 12.3C). Actions
larizing the receptor. The effect of the stimulus on ion of external mechanical forces on membrane proteins
channel openings is graded like a synaptic potential (see have been particularly well elucidated in the sense
Fig. 4.4). This graded change in the membrane poten- organs for hearing and equilibrium (see Fig. 17.8).
tial is called a receptor potential (Fig. 12.2). The recep- Other receptors are particularly sensitive to the
tor potential that arises in the terminal branches spreads temperature in their surroundings. Change in tempera-
electrotonically in the proximal direction (toward the ture appears to alter the voltage sensitivity of specific
CNS, as in Fig. 12.2; see also Fig. 13.2) to the site where subsets of TRP channels, thereby producing a receptor
+
an action potential arises by opening voltage-gated Na potential. Substances producing a cooling sensation
channels (provided the receptor potential is strong when applied to the skin, like menthol, activate a TRP
enough). The process is similar to synaptic activation of channel expressed in cold-sensitive receptors.
a neuron (in which the action potential usually arises Finally, it should be noted that many receptors are
where the axon leaves the cell body). In sensory cells, sensitive to several kinds of stimuli; for example, mech-
the stimulus does not evoke an action potential but leads anoreceptors may be sensitive to temperature.2 Many
to graded release of a neurotransmitter that depolarizes receptors evoking pain when activated express various
the terminals of the sensory cell (Fig. 12.2, right). kinds of TRP channels, thus combining sensitivities to
mechanical, thermal, and chemical stimuli.
Transduction and TRP Channels
The mechanisms behind translation, or transduction, PROPERTIES AND CLASSIFICATION OF RECEPTORS
of a stimulus to a receptor potential are only partly
known. Modality and Quality of Sensation
Although dozens of receptors and ion channels are
When a particular kind of receptor is stimulated with
involved, receptor potentials in a variety of receptors
sufficient intensity to cause a consciously perceived
depend on activation of members of a large family of
sensation, we always get the same kind or modality of
cation channels, collectively termed transient receptor
sensory experiencefor example, light, touch, pres-
potential (TRP) channels (mammals have more than
sure, warmth, pain, or sound. The words modality and
30 genes coding for TRP channels). Together, TRP
quality are both used to describe aspects of sensation
channels exhibit a great variety of activation mecha-
but unfortunately somewhat differently by various
nisms and kinds of stimuli to which they respond.1
authors. We use quality here to describe further the nature
Many receptors are depolarized by binding of a
of a sensory modality; for example, pain is a sensory
specific chemical substance to the membrane. The
modality that may have a burning quality. That stimu-
chemical acts either directly on TRP channel proteins
lation of a particular receptor always evokes a sensation
(or other channels) or indirectly via G proteincoupled
of the same modality does not mean that the receptor
receptors. The latter can then alter the opening state of
necessarily has been subjected to its adequate stimulus.
ion channels via intracellular second messengers (such
Thus, most receptors can respond to stimuli of other
as cyclic AMP or GMP). For example, light hitting the
kinds (inadequate stimuli), although the threshold then
photoreceptors in the retina changes the photopigment,
is much higher for evoking a response. As an example,
which leads to breakdown of cyclic GMP. Cyclic GMP
we can mention the perception of light upon a blow to
keeps Na+ channels open, so this breakdown leads to
the eye (mechanical stimulus of the photoreceptors rather
closure of Na+ channels. Thus, unlike other receptors,
than the normal light stimulus), and perception of sound
the photoreceptors are hyperpolarized by their proper
upon chemical, rather than the normal mechanical, irri-
stimulus.
tation of the receptors for hearing. The kind of perceived
Many receptors are most easily activated by mechan-
sensationthe modality or quality of sensationis thus
ical forces. Typical examples are receptors detecting
characteristic for each type of receptor (Mllers law of
pressure on the skin or rotation of a joint. Mechanical
specific nerve energies). Irritation of the axon leading
forces can most likely evoke a receptor potential in dif-
from the receptor will also evoke the same sensory
ferent ways. Stretching of the cell membrane may open
TRP channels directly (Fig. 12.3A). More commonly,
the mechanical force transmits to membrane-receptor 2 This is most likely the explanation why a cold object feels heavier than a warm
(The Weber deception or silver Thaler illusion). Thus, some mechanosensi-
tive skin receptors increase their ring when the temperature drops. These recep-
1 TRP channels are not restricted to sensory neurons but are expressed in tors appears to express both mechanosensitive and thermosensitive TRP channels.
virtually all tissues of the body. The biologic meaningif anyof this dual sensitivity is unknown.
Ion channel
A Outside
ACTIVATION BY
STRETCH OF THE
CELL MEMBRANE
Inside
Cytoskeleton
B
ACTIVATION BY
STRETCH OF
STRUCTURAL
PROTEINS
C
ACTIVATION BY
STRETCH OF
STRUCTURAL
PROTEINS AND
SECOND MESSEN-
GERS
gure 12.3 Possible means for mechanical stimuli to evoke receptor potentials via TRP ion channels. (Based on Christensen and Corey 2007.)
modality as when the receptor is stimulated by its chemoreceptors, responds primarily to certain chemical
adequate stimulus. substances in the interstitial fluid surrounding the
receptor. Many chemoreceptors respond to substances
produced by or released from cells as a result of tissue
Adequate Stimulus
damage and inflammation, regardless of the cause
Most receptors are built to respond only or preferably mechanical trauma, burns, infection, and so forth. Other
to one kind of stimulus energy: mechanical, chemical, kinds of chemoreceptors are the receptors for taste and
thermal, and so forth. The kind of stimulus to which smell. Receptors in the retina responding to visible light
the receptor responds most easilythat is, with the are called photoreceptors. Thermoreceptors respond
lowest thresholdis called the adequate stimulus for most easily to warming or cooling of the tissue in which
the receptor. We also say that the receptor is specific for they lie.
this type of stimulus, whether it is mechanical, chemi-
cal, electromagnetic (light), or thermal (warmth, cold).
Threshold
As we shall see, each of these broad groups of stimuli is
registered by receptors with different properties. Even when stimulated by their adequate stimulus,
Receptors are classified according to the nature of receptors vary enormously with regard to the strength
their adequate stimulus, that is, their stimulus specific- of the stimulus needed to activate them; that is, they
ity. A large group of receptors, the mechanoreceptors, have different thresholds for activation. For example,
responds primarily to distortion of the tissue in which in the retina, the rods are much more sensitive (have
they lie and thus inform the CNS about mechanical lower threshold) to light than the cones. Another exam-
stimuli. Such receptors are numerous in the skin, in ple concerns mechanoreceptors, many of which have a
deep tissues such as muscles and joint capsules, and low threshold and send signals even on the slightest
in internal organs. Another large group of receptors, touch of the skin or a just barely perceptible movement
12: SENSORY RECEPTORS IN GENERAL 163
of a joint. Other mechanoreceptors have a high thres- Origin of Stimulus
hold and require very strong stimulation to respond; we
Receptor classification can be based on the origin of
usually perceive such stimuli as painful.
the stimuli the receptors capture. For example, mecha-
noreceptors maydepending on their locationgive
Adaptation information of very different events (even though all
are mechanical). A low-threshold mechanoreceptor in
Receptors differ in other ways, too. Many receptors send
the wall of the urinary bladder provides information
action potentials only when a stimulus starts (or stops).
about its degree of distension, mechanoreceptors in
If the stimulus is continuous, this kind of receptor ceases
the inner ear inform us about sound (movement of air
to respond and thus provides information about changes
molecules), whereas mechanoreceptors around the root
in stimulation only. Such receptors are called rapidly
of a hair respond to the slightest bending of the hair.
adapting. When after a short time we cease noticing that
We usually distinguish between exteroceptors, prop-
something touches the skin, this is partly because so
rioceptors, and enteroceptors. Exteroceptive signals
many of the receptors in the skin are rapidly adapting.
reach the body from the outside, from our environment.
Other receptors, however, continue responding (and
Most exteroceptors are located in the skin, whereas the
thus sending action potentials) as long as the stimulus
receptors in the eye and the internal ear represent impor-
continues. Such receptors are called slowly adapting (or
tant special kinds of exteroceptors that respond to tele-
nonadapting). Receptors responsible for the sensation of
ceptive signals. Proprioceptive signals originate in the
pain exemplify slowly adapting receptors. It would not
body itself. The term is, however, restricted mostly to
be appropriate if the body were to adapt to painful stim-
signals arising in the musculoskeletal system, including
uli because these usually signal danger and threat of
the joints. Enteroceptive signals arise from the internal
tissue damage. Receptors that signal the position of the
(visceral) organs, such as the intestinal tract, lungs, and
body in space and the position of our bodily parts in
the heart.
relation to each other must also be slowly adapting; if
not, we would lose this kind of information after a few
seconds if no movement took place. That adaptation is a Comprehensive Classication of a Receptor
property of the receptors themselves can be verified by
By the descriptions discussed in the preceding text, we
recording the action potentials from the sensory fibers
can classify receptors by the characteristics we want to
supplying various kinds of receptors. For example, affer-
emphasize. We can also give a complete description of
ent fibers from receptors excited by warming of the skin
the receptor by mentioning all the characteristic prop-
stop sending signals if the same stimulus is maintained
erties: for example, a proprioceptive, fast-adapting,
for some time, whereas afferent nerve fibers from sense
low-threshold mechanoreceptor (informing about joint
organs in a muscle continue to send signals as long as the
rotation), or an enteroceptive, slowly adapting chemore-
muscle is held in a stretched position.
ceptor (in the wall of an artery informing about the
oxygen tension of the blood).
Dynamic and Static Sensitivity
Many receptors respond more vigorously to rapid
RECEPTORS AND SUBJECTIVE SENSORY EXPERIENCE
changes in the stimulus than to slow ones (they adapt
rapidly). For example, rapid stretch of a muscle pro-
Receptor Type and Quality of Sensation: An Uncertain
duces much higher firing frequency in the sensory nerve
Connection
fibers leading from the muscle than when the same
stretch is applied slowly (see Fig. 13.8). Such a receptor The kind of conscious sensory experience it evokes is
can therefore inform about the velocity of stretching, perhaps the most interesting among a receptors many
not just its magnitude. This property of a receptor is characteristics. How do I describe what I feel when a par-
called dynamic sensitivity. A receptor that continues to ticular kind of receptor sends signals to the brain? We
produce action potentials with a constant frequency as use the term pain receptor or nociceptor to describe
long as the stimulus is constant (slowly adapting or receptors that, when stimulated, produce pain. Stimulation
nonadapting) is said to have static sensitivity. Often, of cold receptors causes a feeling of coldness, stimulation
one receptor has both kinds of sensitivity (see Figs. 13.8 of warm receptors gives a feeling of warmth, and so
and 16.8). The majority of receptors, however, have on. Only exceptionally is it possible, however, to know
dynamic sensitivity and are rapidly adapting. This helps whether a sensory experience is evoked by stimulation of
to explain the everyday experience that we are much one receptor type only, or by the simultaneous activation
more aware of changing stimuli than those that are of several kinds. The connection between the conscious
constantsuch as an insect moving on the skin or a sensory experience and the responsible receptors is there-
moving light, as opposed to stationary ones. fore often uncertain. Because only human beings can
inform the observer directly of what they feel, animal movements from signals that arise from external per-
experiments alone cannot resolve the question of the turbations. As rule, our self-produced sensory signals
relationship between receptors and conscious sensations. are inhibited while the unforeseen external ones are
Moreover, the very same receptors that can be exam- enhanced.
ined physiologically cannot be examined anatomically
in human beings. Important insight has nevertheless
Central Analysis
emerged from correlation of observations obtained in
animals with psychophysical observation in humans We cannot explain how it happens that action poten-
(see Chapter 13, under Microneurographic Studies of tials, which are of the same kind in all nerve fibers,
Human Skin Receptors). evoke entirely different conscious sensations, depend-
In most cases, our conscious sensory experiences are ing on where the stimulus arises. One prerequisite is
due to signals from several kinds of receptor. The brain that different kinds of sensory information are analyzed
interprets a barrage of signals and the context in which by different neurons (i.e., neurons located in anatomi-
they arise, and provides us with a unitary sensation. cally distinct parts of the CNS). A complete mixing of
The sensation of taste is an example: it depends not information from different receptor types would not be
only on signals from taste receptors (on the tongue) but compatible with our discriminative abilities. It is equally,
also on signals from olfactory receptors (with some clear, however, that there must be ways in which the
contribution from mechanoreceptors and thermorecep- brain can bring the different kinds of information
tors in the mouth). together, making meaning and unity out of the innu-
merable bits and pieces of sensory information. Such a
synthesis may not necessarily be due to convergence of
The Brain Does Not Receive True Information
all relevant information onto a single cell group. Rather,
Not all signals reaching the CNS from the receptors are we now believe the final processing to depend on exten-
consciously perceived. In particular, enteroceptive sig- sive interconnections among cortical areas dealing with
nals are mostly processed only at a subconscious level. different aspects of sensory information (these aspects
For signals from all kinds of receptors, however, a are treated further in Chapter 16, under How Are Data
considerable selection and suppression of signals take from Different Visual Areas Integrated? and Chapter
place at all levels of the sensory pathways in the spinal 34, under Parietal Association Areas).
cord and the brain, to leave out irrelevant information. In an elegant study, de Lafuente and Romo (2005)
At the same time, relevant signals are usually enhanced trained monkeys to respond to cutaneous stimuli that
in the CNS (see also Chapter 13, under Inhibitory were barely detectable, while at the same time recording
Interneurons Improve the Discriminative Sensation). neuronal activity in the cerebral cortex. In turned out
We mentioned that receptive fields of sensory cells that whenever the monkey responded to the stimulus
expand or shrink in a context-dependent manner, and (as a sign of perception), there was activity among neu-
that most receptors respond more strongly to changing rons in the premotor cortex of frontal lobe as well as in
than to constant stimuli. Therefore, sensory informa- the somatosensory cortex. Activity in the somatosensory
tion is censored and does not provide the brain with cortex alone was apparently not sufficient for perception.
an objective representation of the physical world (see On the other hand, there was frontal activation in
Fig. 16.9). Usually, such weighting of sensory signals instances when the monkey (erroneously) responded
is advantageous because it ensures that the most without the stimulus being strong enough to evoke activ-
behaviorally relevant information is prioritized while ity in the somatosensory cortex. This example serves
irrelevant or less important signals are suppressed. An further to emphasize that our conscious sensations are
example concerns our need to be able to distinguish not hard-wired to the signals from sensory receptors,
sensory signals that we produce ourselves by voluntary but depends critically on central analysis.
13 Peripheral Parts of the
Somatosensory System
OVERVIEW or muscle fibersdetermine the kind of stimulus they

respond to with the lowest threshold. Further, capsular
The term somatosensory includes, strictly speaking, all elements and membrane receptor proteins determine
sensations pertaining to the body (soma). It is therefore whether the receptor is rapidly or slowly adapting.
more comprehensive than the significance commonly Cutaneous low-threshold mechanoreceptors are of
assigned to itnamely, sensory information specifically four types: Meissner corpuscles reside in the dermal
from skin, joints, and muscles only. In this chapter, we papillae of glabrous skin (e.g., on fingertips) and
discuss receptors (sense organs) located in the skin and respond to the slightest impression on the skin. They
in the musculoskeletal system and the neurons leading are rapidly adapting, thus signaling only when some-
from them into the central nervous system (CNS). thing touches (or leaves) the skinnot when the skin
Receptors in the skin and in deep tissues are either free remains impressed. Like Meissner corpuscles, Merkel
or encapsulated. The terminal ramifications in encapsu- disks respond to small impressions of the skin but are
lated receptors are surrounded by connective tissue cells, slowly adapting. Ruffini corpuscles are located in the
serving as a filter ensuring that only certain kinds of dermis and respond to stretching of the skin. They are
stimuli reach the axon terminal. We distinguish between slowly adapting, and probably signal the steady tension
exteroceptors, located in the skin, and proprioceptors in (important, e.g., when holding objects). Pacinian
muscles and connective tissue around the joints. corpuscles are large, lamellate structures located on the
Regardless of their location, somatosensory receptors transition between the dermis and the subcutaneous tis-
can be classified by their adequate stimulus as mechano- sue. They are extremely rapidly adapting and are well
receptors, thermoreceptors, and chemoreceptors. suited to signal vibration (>100 Hz). The receptive
High-threshold receptors usually signal impending fields of Meissner corpuscles and Merkel disks are small
tissue damage, and are termed nociceptors. They are all (especially on distal parts of the extremities), making
free nerve endings, but differ with regard to stimulus these receptors of crucial importance for discriminative
specificity. Some respond only to intense mechanical sensation.
stimuli, others to chemical (inflammatory) substances, Among proprioceptive low-threshold mechanorecep-
while others detect extreme heat or coldness. Many tors, the muscle spindles are the most elaborate. They
nociceptors respond to several kinds of stimuli (poly- consist of a small bundle of thin, so-called intrafusal
modal nociceptors), while others do not respond to muscle fibers encircled by sensory nerve endings. Although
normal pain-provoking stimuli but require prolonged each muscle spindle is much shorter than the muscle in
stimulation to become active (silent nociceptors). In which it lies, it is connected with connective tissue strands
addition to signaling impending acute tissue damage, to both tendons of the muscle. Thus, when the muscle
nociceptors probably play an important role in moni- elongates, the muscle spindle is stretched and the sensory
toring the composition of the tissue fluid and thus con- endings are depolarized. The muscle-spindle sensory
tribute to bodily homeostasis. endings have both dynamic and static sensitivity, mak-
Thermoreceptors respond to even very small changes ing them suited to record the actual muscle length at any
of the temperature of their surroundings (especially in time, length change, and direction and velocity of change.
the skin). They are much less sensitive to steady-state Signals from muscle spindles contribute to reflex control
temperature. Cold receptors detect cooling below the of movements and to kinesthesiathat is, our conscious
normal skin temperature, while warm receptors detect perception of joint positions and movements. Tendon
a rise in temperature. organs are located at the musculotendinous junction,
Low-threshold mechanoreceptors in the skin and in and measure the force of muscle contraction. Joint recep-
the deep tissues share many physiological properties. In tors are located in the fibrous joint capsule and in liga-
general, they signal deformation of the tissue in which ments around the joints. They can signal movements and
they reside. Their capsular elements and relation to steady positions but their contributions to movement
surrounding tissue componentssuch as collagen fibrils control and kinesthesia are not well understood.
165
Dorsal root fibers conducting from somatosensory Free and Encapsulated Receptors
receptors are classified according to conduction velocity
We conveniently subdivide receptors in the skin (and in
into myelinated A fibers and unmyelinated C fibers. The
deep tissues) on a structural basis into free and encapsu-
thickest A fibers conduct from low-threshold mechano-
lated, although there are numerous transitional forms.
receptors, whereas thin A fibers (A) and C fibers conduct
In encapsulated receptors, the terminal ramifications of
from nociceptors and thermoreceptors. The thin (A
the sensory axon are surrounded by a specialized capsule-
and C) and thick dorsal root fibers end almost completely
like structure of connective tissue cells (Fig. 13.1A, C,
separated in the cord. Probably all primary sensory
and D), whereas such a structure is lacking around the
neurons release a classical transmitter with fast synaptic
free receptors or endings (Fig. 13.1E). The encapsulation
actions in the spinal cord. Probably all primary sensory
serves as a filter, so that only certain kinds of stimuli
neurons release a classical neurotransmitter with fast
reach the axon terminal inside. Schwann cells cover the
synaptic actions in the spinal cord. In addition, many
axonal ramifications of the free receptors, except at
contain several neuropeptides, such as substance P and
their tips (Fig. 13.1E), where their receptor properties
others. Apparently, release of neuropeptides from the
presumably reside. Free receptors are the most numerous
peripheral branches of sensory neurons contributes to
and widespread, being present in virtually all parts of the
local inflammation in several diseases (e.g., arthritis,
body. In the skin, free receptors are particularly numer-
asthma, and migraine).
ous in the upper parts of the dermis, and they even
The ventral branches of the spinal nerves form plexuses
extend for a short distance between the cells of the deeper
supplying the arms and the legs. Each nerve emerging
layers of the epidermis.
from these plexuses contains sensory and motor fibers
Free receptors that are structurally indistinguishable can
arising from several segments of the spinal cord. In the
nevertheless have different adequate stimuli. The cornea of
peripheral distribution of the fibers, however, the seg-
the eye, for example, contains only free nerve endings but
mental origin of the fibers is retained. Thus, sensory
functionally there are at least four different receptors.
fibers of one dorsal root supply a distinct part of the
Thus, anatomically identical receptors can differ function-
skin. The area of the skin supplied with sensory fibers
ally as a result of their expression of different repertoires of
from one spinal segment is called a dermatome.
membrane channels and receptor molecules.
EXTEROCEPTORS: CUTANEOUS SENSATION Nociceptors

Receptors that on activation evoke a sensation of pain
The skin and the subcutaneous tissue contain receptors
are termed nociceptors. A more precise, physiological
that respond to stimuli from our surroundings. Among
definition would be: a receptor that is activated by
the almost indefinitely varied sensory experiences that
stimuli that produce tissue damage, or would do so if
can be evoked from the skin, we usually distinguish only
the stimulus continued. In Chapter 15, we discuss the
a few, regarded as the basic modalities: touch, pressure,
relationship between nociceptor stimulation and the
heat, cold, and pain. There is indirect evidence that each
experience of pain. In the skin and, as far as we know,
of these sensations can be evoked by stimulation of one
in all other tissues from which painful sensations can be
receptor type. Yet it is important to realize that terms
evoked, nociceptors are free nerve endings. It is charac-
such as pain, cold, and touch refer to the quality
teristic that most stimuli we experience as painful are so
of our subjective sensory experience evoked by certain
intense that they produce tissue damage or will do so if
kinds of stimuli. Thus, a classification of sensations on
the stimulus is continued. Functionally, skin nocicep-
this basis does not enable us to conclude that for each
tors are of three main types. One type responds to
subjective quality of sensation there exists one particular
intense mechanical stimulation only (such as pinching,
kind of receptor.
cutting, and stretching), and is therefore termed a high-
Sensationssuch as itch, tickle, dampness, or dryness;
threshold mechanoreceptor. The other is also activated
the texture of surfaces; and the firmness or softness of
by intense mechanical stimuli but in addition, by intense
objectsare thought to arise from the simultaneous 1
warming of the skin (above 45C) and by chemical
stimulation of several kinds of receptors in the skin and
also in deeper tissues. As discussed in Chapter 12, our
conscious sensory experience is the result of an inter- 1 Heat activates nociceptors by opening the nonselective cation channel
pretation in the brain of information from a multitude TRPV1 (and apparently also other varieties of the TRPV channel). Interestingly,
capsaicin, responsible for the pungency of hot peppers, activates the heat-
of receptors. sensitive channel. On continued presence, however, capsaicin desensitizes the
Functionally, skin receptorslike receptors in other receptor thus alleviating ongoing pain. Drugs that selectively block the TRPV1
parts of the bodycan be classified by their adequate channel have been tested in animals and found effective in alleviating inamma-
tory pain but also causing a rise in body temperature. Thus, the TRPV1 channel
stimulus as mechanoreceptors, thermoreceptors, and apparently contributes not only to thermal and chemical nociception but also
chemoreceptors. to control of body temperature.
13: PERIPHERAL PARTS OF THE SOMATOSENSORY SYSTEM 167
Meissner
corpuscle Merkel cell Free endings
EPIDERMIS
DERMIS
SUBCUTIS
Axon Ruffini corpuscle

A B Hair root
Pacininian corpuscle
Naked part of free

nerve ending
Merkel cell
Axon
Myelin
Schwann cell
Collagen
Axon fibers
C D E
gure 13.1 Cutaneous receptors. Schematic of receptors as they a tortuous course between at, specialized connective tissue cells. The
appear in sections through the skin. Sensory nerve bers and recep- whole sense organ is anchored to the epidermis with thin collagen
tors in (A) glabrous skin (palms of the hands and soles of the feet) and bers. D: A disk of Merkel (present in both glabrous and hairy skin).
(B) hairy skin. Nerve endings in hairy skin wind around the hair The axonal terminal is closely apposed to a Merkel cell in the epider-
follicles and are activated by the slightest bending of the hair. mal cell layer. E: Free nerve endings are covered by Schwann cells
C: Meissner corpuscle (from glabrous skin). The axon (red) follows except at their tips, where the receptor properties reside.
substances that are liberated by tissue damage and suited to communicate about disease processes in the
inflammation. Because such receptors can be activated tissues, and are probably important for communication
by different sensory modalities, they are termed poly- between the immune system and the brain.
modal nociceptors. In addition, recent studies indicate Many substances can excite nociceptors, and specific
that many nociceptors are purely sensitive to chemical membrane receptors and ion channels have been identi-
substances released in inflamed tissue. Since such recep- fied for some. ATP, for example, excites nociceptors by
tors are unresponsive to most nociceptive stimuli used in binding to purinoceptors (Fig. 13.2). Because ATP is
animal experiments, they are termed silent nociceptors. normally present only intracellularly, its extracellular
Silent nociceptors typically require stimulation for 10 to occurrence is an unequivocal sign of cellular damage.
20 minutes to become active; thereafter, however, they The peptide bradykinin, which is produced by the release
may continue firing for hours. They are present in skin, of proteolytic enzymes from damaged cells, acts on
muscles, and visceral organs and may constitute about specific membrane receptors in nociceptors. Several other
one-third of all nociceptors. They appear particularly mediators of inflammationsuch as prostaglandins,
Cell injury conduction. Ten voltage-gated sodium channels have

been identified, sharing a basic structure but with some-
ATP
ATP
what different properties and distribution. Sensory
ATP
ATP Receptor potential neurons express several kinds, and some of these occur
primarily in small nociceptive spinal ganglion cells.
ATP Purinoceptors
Nerve injury as well as inflammation cause rapid changes
Voltage-gated in the expression of several voltage-gated sodium chan-
sodium channels
Other factors acting nels, thus rendering the ganglion cells hyperexcitable (as
on nociceptors:
Heat mentioned earlier in relation to hyperalgesia).
Cold
Prostaglandins
One channelNaV1.7appears to be particularly
Bradykinin important for the generation of action potentials in
Cytokines
Nerve growth factors axons leading from nociceptors. Rare inherited diseases
Serotonin
Histamine
Action potential caused by mutations of the gene (SCN9A) coding for
H+ NaV1.7 shed light on the function of this channel. Two
gain-of-function mutations cause attacks of intense
gure 13.2 Nociceptor activation. ATP is one among many sub- pain but with different mechanisms. Patients with par-
stances that activate nociceptors. Because the extracellular ATP con-
oxysmal extreme pain disorder suffer from attacks of
centration is extremely low normally, ATP is a very sensitive signal of
impending cell damage. Binding of ATP to specic receptors depolar- pain in the eyes, jaw, and rectum, apparently caused by
izes the nerve terminal (receptor potential). If the receptor potential incomplete inactivation of the NaV1.7 channel. Patients
reaches threshold an action potential arises due to opening of voltage- with erythromelalgia (primary erythermalgia) experi-
gated sodium channels. The action potential is conducted to the CNS. ence burning pain and redness in the hands and feet.
Some other means of activating nociceptors are listed.
The mutation in the latter patients cause the channel to
open to easily (lowered threshold). A third variety of
inherited NaV1.7 channelopathy was quite recently
histamine, serotonin, substance P, and adenosinemay found among members of a Pakistani family. Those
contribute to nociceptor activation and sensitization. afflicted show complete absence of pain sensitivity and
H + ions (pH < 6) activate nociceptors effectively and, in suffer serious injuries as they grow up. The mutation in
addition, seem to increase their responses to inflamma- these patients appears to cause a loss of function of the
tory substances. NaV1.7 channel, resulting in abolished impulse traffic
A characteristic feature of nociceptors is their ten- from nociceptors.
dency to be sensitized by prolonged stimulation (this is Other voltage-gated sodium channels, expressed in
the opposite phenomenon of adaptation). Sensitization nociceptive ganglion cells, also appear to be involved in
is due to accumulation of inflammatory products that clinical pain conditions. Great efforts are now being
up-regulate voltage-gated Na+ channels and transient made to develop drugs that can block specific voltage-
receptor potential (TRP) channels expressed in sensory gated sodium channels. Nonspecific blockers, such as
neurons. Sensitization partly explains why even normally lidocaine, have long been used for local anesthesia.
non-noxious stimuli (such as touching the skin) may be
felt as painful when the skin is inflamed. A condition of
Silent Nociceptors, the Immune System, Homeostasis,
abnormal intensity of pain compared to the strength of
and Sickness Behavior
the stimulus is called hyperalgesia. As discussed later in
this chapter, hyperalgesia may also be caused by altered Since mediators released in inflamed tissues activate them,
properties of neurons in the CNS, especially in the spinal silent nociceptors most likely contribute to the pain that
dorsal horn. The term allodynia is used when innocuous follows tissue damage. Nevertheless, in contrast to other
stimuli, such as light touch, evoke intense pain. nociceptors they may not function primarily as a warn-
Signals from nociceptors are conducted in thin myeli- ing system for impending tissue damage but, rather,
nated (A) and unmyelinated (C) fibers. This is further play a long-term role in evaluating the status of the
discussed later in this chapter, under Classification of tissue microenvironment. Thus, they would play a role in
Dorsal Root Fibers in Accordance with Their Thickness. bodily homeostasis. Signals from silent nociceptors may
be particularly important to modulate the activity of the
immune system. Thus, we know that the nervous system
Nociceptors, Voltage-Gated Sodium Channels, and
can influence the properties of the cells of the immune
Inherited Channelopathies
system, as we shall return to in Chapter 30. To do this,
Sensory neurons express a multitude of ion channels and the nervous system needs information from the battle-
receptors, among them several kinds of voltage-gated field of the immune system. Silent nociceptors seem
sodium (Na+) channels. Such channels are expressed in well suited to carry out this task, as substances released
all neurons and are necessary for excitability and impulse from leukocytes activate them. We know, for example,
that cytokines released in the gastric mucosa stimulate them, we know most about the low-threshold mechano-
nerve fibers in the vagus nerve. This produces sickness receptors. The following account mainly deals with low-
behavior in rats: they move less around, lose appetite, are threshold mechanoreceptors of the skin. High-threshold
uninterested in their surroundings, and so forth. In addi- mechanoreceptors in the skin are nociceptors and do
tion, cytokines in the bloodstream can reach neurons not differ significantly from such receptors in muscles
in certain parts of the brain, either by passing the and around joints. As far as we know, they are always
bloodbrain barrier or by acting on places devoid of a free nerve endings (Fig. 13.1E).
bloodbrain barrier. It seems likely that signals from silent There are several kinds of low-threshold mechano-
nociceptorsnot only in the skin but also in deep tissues receptors in the skin, ranging from free receptors to
and visceral organscontribute to how we feel, or the those with an elaborate capsule. Some adapt slowly or
subjective feeling of the physiological state of the body. not at all; others adapt very rapidly. For example,
receptors found close to the roots of hairs (Fig. 13.1B)
are rapidly adapting. They are activated by even the
Thermoreceptors
slightest bending of a hair, as can easily be verified by
Free endings of thin sensory nerve fibers are responsible touching the hairs on the back of ones own hand. If the
for the perception of heat and cold. Although warm hair is held in the new position, however, the sensation
and cold receptors look the same, they express different disappears immediately. Unmyelinated afferent fibers
kinds of TRP channels. Cold receptors respond with an from hairy skin that signal light touch may be of special
increase of firing frequency to cooling of the skin below importance for mediating emotional aspects of touch
2
the normal temperature (about 32C). They stop (rather than precise, discriminative information).
responding, however, at very low skin temperatures. Although the thick, glabrous skin on the palm of the
Surprisingly, cold receptors can also be excited by skin hand and on the sole of the foot lacks hair, the elabo-
temperatures above 45C. This explains why a hot rate encapsulated receptors are particularly abundant at
shower may feel cold at the beginning (until we feel these locations and are obviously related to the superior
pain, as mentioned previously, temperatures above sensory abilities of these partsthe fingers, in particular
45C excite polymodal nociceptors). This phenomenon (Table 13.1). One such receptor is the Meissner corpuscle,
is called paradoxical cold (sensation). Signals from cold which mediates information about touch. Meissner
receptors are conducted in thin myelinated (A) fibers. corpuscles are small oval bodies located in the dermal
Warm receptors respond to warming of the skin above papillae just beneath the epidermisin fact, as close to
the normal temperature up to about 45C. The signals the surface of the skin as possible without being directly
are conducted in unmyelinated (C) fibers. exposed (Fig. 13.1A and C). Several axons approach
The adequate stimulus for thermoreceptors is the the corpuscle and follow a tortuous course inside the
temperature of the tissue surrounding them or, rather, capsule between the lamellae formed by connective tissue
changes in the temperature. The receptors send action cells.3 Meissner corpuscles respond by sending action
potentials with a relatively low frequency at a steady potentials even when indenting only a few micrometers
temperature, whereas a small change in the temperature the skin overlying the receptor. If the skin is kept indented,
elicits a marked change in the firing frequency. A heat however, the receptor stops sending action potentials.
receptor, for example, fires at constant room tempera- On release of the pressure, a few action potentials are
ture with a low frequency, but warming the skin even again elicited. Meissner corpuscles are thus rapidly
slightly increases in the firing rate. The response is par- adapting and obviously have a low threshold for their
ticularly brisk if the warming happens rapidly (thus, we adequate stimulus. These corpuscles are presumably
perceive lukewarm water as hot if the hand is cold when well suited to, among other things, signal direction and
put into it). A change in skin temperature of 0.2C is velocity of objects moving on the skin.
sufficient to cause a marked change in firing rate from a
thermoreceptor. Thus, the thermoreceptors do not give
an objective measure of the actual skin temperature but,
rather, signal changes that may be significant in our 2 A woman with selective loss of large-diameter myelinated sensory bers
adjustment to the environment (to keep the body tem- provided an opportunity to study the properties of low-threshold C-bers
(Olausson et al. 2002). Light touch (stroking with a soft brush) applied to the
perature constant). Thus, they are important for the back of the hand was felt as a very faint and diffuse but pleasant pressure (no
maintenance of bodily homeostasis. sensation was evoked by brushing the palm of the hand, corresponding to the
lack of unmyelinated low-threshold afferents from glabrous skin). Interestingly,
functional magnetic resonance imaging (fMRI) showed activation of the insu-
Mechanoreceptors of the Skin laknown to be related to affective aspects of sensationbut not in SI that is
responsible for the discriminative aspects.
The study of receptors for pain and temperature sensa- 3 In addition to a thick myelinated axon, the Meissner corpuscle receives thin
unmyelinated axons. The latter contain neuropeptides and express receptors
tion is more difficult than the study of mechanoreceptors. typical of nociceptors. So far, however, there is no direct evidence of a contribu-
These are particularly well studied, therefore, and among tion from Meissner corpuscles in nociceptive signaling.
table 13.1 is put in contact with the skin, the frequency of action
RECEPTIVE ADAPTATION
potentials in the afferent fiber follows closely the frequency
FIELDS of vibration. Vibration with a frequency below 100 Hz
Rapid Slow appears to be signaled by Meissner corpuscles.
Meissner corpuscles: Merkel disks: Itch and Tickle

Glabrous skin, in Close to the
Small dermal papillae epithelium Itching is a peculiar, unpleasant sensation evoked by
Touch: moving stimuli Touch (judging form stimulation of free nerve endings in superficial parts
Vibration < 100 Hz & surface of objects)
of the skin and mucous membranes. The signals are
conducted in unmyelinated sensory fibers to the spinal
Pacinian corpuscles: Ruffini corpuscles:
cord. From the cord to higher levels, the signals follow
Large Border dermis- Dermis, parallel to
subcutis; the skin surface; the pathways for pain, because cutting these also abol-
Vibration > 100 Hz stretch of the skin ishes the sensation of itching. (In fact, we know that
(friction) weakly painful stimuli, such as scratching the skin,
suppress the sensation of itching.) Further, liberation of
histamine in the skin, for example, from mast cells in
allergic reactions, evokes itching. The leaves of stinging
Ruffini corpuscles are also low-threshold mechano- nettle (Urtica dioica) provoke intense itching because
receptors and are slowly adapting. They consist of a they contain histamine. Microneurographic studies in
bundle of collagen fibrils with a sensory axon branching humans have identified a subgroup of peripheral sensory
between the fibrils (Fig. 13.1A). The collagen fibrils units (with unmyelinated fibers) that react vigorously
connect with those in the dermis, and stretching of the to histamine and produce itching when stimulated.
skin in the direction of the fibrils is the adequate stimulus These units have been regarded as itch-specific (even
for the receptor. Stretching the skin tightens the fibrils, though capsaicin and inflammatory substances such as
which, in turn, leads to deformation and depolarization prostaglandin E and bradykinin also activate them).
of the axonal ramifications, thus producing action Further, some units in the dorsal horn (lamina 1) respond
potentials in the afferent fiber. It is therefore assumed primarily when histamine is applied in their receptive
that Ruffini corpuscles function as low-threshold stretch fields. Histamine appears to evoke activity in the same
receptors of the skin, informing us about the magnitude parts of the cerebral cortex as painful stimuli do, as
and direction of stretch. shown via functional magnetic resonance imaging (fMRI).
Another kind of slowly adapting, low-threshold Nevertheless, animal experiments suggest that itch
mechanoreceptor in the skin is the Merkel disk involves neuronal groupsfrom the cord to the cortex
(Fig. 13.1A and D), present particularly on the distal that are at least partly separate from those treating
parts of the extremities, the lips, and the external genitals. noxious stimuli. Thus, the sensation of itch may be
An axon ends in close contact with a large epithelial cell served by a specific subdivision of the neural system
in the basal layer of the epidermis. Even after several for pain. Itching is a symptom in several diseases (can-
minutes of constant pressure on the skin overlying the cer, metabolic disorders, skin diseases, and others).
Merkel disks, the receptor continue to send action Histamine does not seem to be involved in such cases,
potentials at about the same rate. however.
A final type of low-threshold mechanoreceptor, Tickling is another peculiar sensory phenomenon. It
Pacinian corpuscles (Fig. 13.1A), are found at the is evoked by stimulation of low-threshold mechanore-
junction between the dermis and the subcutaneous ceptors, but we do not know which subgroup is involved.
layer; they are also present at other locations, such as in The sensation of tickling is strongly influenced by the
the mesenteries, vessel walls, joint capsules, and in the context in which it is evoked: the same stimulus may be
periosteum. Pacinian corpuscles are large (up to 4 mm experienced as tickling in one situation and merely as
long) ovoid bodies, which can be seen macroscopically at light touch in another. For example, we know that we
dissection. A thick axon is surrounded by numerous are unable to tickle ourselves, probably because the
lamellae, which are formed by a special kind of connective brain can easily distinguish sensory signals produced by
tissue cell. Between the cellular lamellae there are fluid- our own actions and those coming from other sources.
filled spaces. Pacinian corpuscles are very rapidly adapt- We also know that our emotional state influences whether
ing, eliciting only one or two action potentials in the or not a stimulus is felt as tickling. This example may
afferent fiber at the onset of indentation of the skin. The serve to emphasize a point we will return to repeatedly:
adequate stimulus is therefore extremely rapid indenta- the sensory messages sent from the receptors are subject
tion of the skin. In practice, this is achieved by vibration to extensive processing before a conscious sensation is
with a frequency of 100 to 400 Hz. If a vibrating probe produced.
What Information Is Signaled by Low-Threshold units that most likely end in Meissner corpuscles pro-
Cutaneous Mechanoreceptors? duces a feeling of light touch, like a tap on the skin with
the point of a pencil. As a rule, the person localizes the
Together, the four types of low-threshold mechanore-
feeling to exactly the point on the skin previously found
ceptors described in the preceding text are thought to
to be the receptive field of the sensory unit. Activating a
mediate the different qualities of our sense of touch and
sensory unit that presumably leads off from Merkel disks
pressure, which are so well developed in glabrous skin
evokes a sensation of light, steady pressure (as long as
(fingers, toes, and lips). One important aspect is the
the stimulus lasts). Stimulating axons that appear to
ability to judge the speed and direction of a moving object
end in Pacinian corpuscles gives a feeling of vibration.
in contact with the skin, as well as the friction between
them. Thus, we may perceive quickly that an object is
slipping from our grip and judge from the friction the Receptive Fields of Cutaneous Sensory Units
force needed to stop the movement. Two of the receptor
It has been known for a long time that cutaneous sensa-
types, Merkel disks and Ruffini corpuscles, are slowly
tion is punctate; that is, there are distinct tiny spots on
adapting and, as long as the stimulus lasts, continue to
the skin that are sensitive to different sensory modalities.
provide information about slight pressure and stretch-
We therefore use the terms cold, warm, touch, and
ing of the skin, respectively (Table 13.1). The other two,
pain spots. Cold spots are most easily demonstrated.
Meissner and Pacinian corpuscles, are rapidly adapting
Between the spots sensitive to cooling of the skin, there
and signal only the start and stop of stimuli. It seems
are others where contact with a cold object is felt only
likely that Meissner corpuscles would be particularly
as pressure. This is so because each sensory unit distrib-
well suited to signal the direction and speed of a moving
utes all its peripheral ramifications within a limited area
stimulus. It should be noted that low-threshold mecha-
of the skin. Thus, the sensory unit can be activated only
noreceptors in the skin also contribute to joint sense (see
from this part of the skin, which constitutes its receptive
later), and control of posture and movements (see
field (Fig. 13.3; see Fig. 12.1). Certain parts of the skin
Chapter 18, under Receptors of Importance for Upright
lack ramifications belonging to cold sensory units;
Posture, and Chapter 21, under Cutaneous Receptors
consequently, sensations of cold cannot be evoked from
and the Precision Grip).
such areas. Correspondingly, many small spots on prox-
imal parts of the bodyfor example, on the abdomen
and the upper armlack nociceptors; therefore, inser-
Microneurographic Studies of Human Skin Receptors
tion of a sharp needle at such places is felt only as touch.
Studies with techniques that enable recording from and The receptive fields of nociceptive sensory units are so
stimulation of peripheral nerves in conscious human closely spaced, however, that one has to make a thorough
beings have provided important information with regard search to find painless spots.
to the functional properties of receptors (Fig. 13.3). The The size of the receptive field depends on the area of
Swedish neurophysiologists Hagbarth and Vallbo pio- the skin receiving axonal branches from the sensory
neered this technique around 1970. With the use of neuron. In general, the density of sensory unitsthat is,
2
very thin needle electrodes, one records the activity of the number of units innervating; for example, 1 cm of
single sensory axons within a nerve, such as the median the skinis highest in distal parts of the body (fingers,
nerve at the forearm. Thus, it is possible to determine toes, and lips), and the receptive fields are smaller dis-
the receptive field of this particular sensory unit, along tally than proximally (Fig. 13.3). This explains why the
with its adequate stimulus. In glabrous skin of the fingers stimulus threshold is lower and the ability to localize a
and palms, four types of low-threshold mechano- stimulus is more precise in the palm of the hand than at,
receptors have been so characterized. Most likely, they for example, the upper arm.
correspond to the four encapsulated types described
earlier (Table 13.1). Thus, there are two types of rapidly
Discriminative Sensation
adapting sensory units: one with a small receptive field
(most likely the Meissner corpuscle), and the other with The punctate arrangement of the cutaneous sensation is
a large and indistinct receptive field (Pacinian corpuscle). important for our ability to localize stimuli. Being able
The two other types of sensory units are slowly adapt- to determine that two pointed objects (such as the legs
ing; again, one has a small receptive field (Merkel disk) of a compass) touch the skin rather than one must mean
and the other a large but direction-specific receptive that separate units innervate the two spots. Not surpris-
field (most likely the Ruffini corpuscle). ingly, the distance between two points on the skin that,
Stimulation of the axons of the sensory units that have when touched, can be identified as two is shortest where
just been recorded enables correlations to be made between the density of sensory units is highest, and the receptive
the conscious sensory experiences evoked by stimulation fields are smallestthat is, on the fingertips (Fig. 13.3A
of only one sensory unit. Stimulation of single sensory and B). Determining this distance gives a measure of what
A B C gure 13.3 Receptive elds. A: Size and location of

the receptive elds of 15 sensory units, determined by
recording from the median nerve. All of these sensory
units were rapidly adapting and were most likely con-
ducting from Meissner corpuscles. Within each recep-
tive eld there are many Meissner corpuscles, all
supplied by the same axon. B: Relative density of sen-
sory units conducting from Meissner corpuscles (i.e.,
number of sensory units supplying 1 cm2). The density
increases distally and is highest at the volar aspect of
the ngertips. C: Two-point discrimination. The num-
bers give the shortest distance between two points
touching the skin that can be identied by the experi-
mental subject as two (reducing the distance further
makes the person experience only one point touching
Receptive fields Density of Two-point threshold the skin). Average of 10 subjects. (Based on microneu-
sensory units rographic studies by Vallbo and Johansson 1978.)
we call two-point discrimination and is often used clin- stimulated area is reduced, and we perceive the stimu-
ically. The smallest distance at which two stimuli can lated area as smaller as and more sharply delimited
be discriminated is the two-point threshold (Fig. 13.3C). than it really is. In this way, the CNS receives distorted
A useful test for this kind of discriminative sensation is sensory information.
the writing of letters or figures on the skin (with the
subjects eyes closed). The figures that can be interpreted
are quite small on the fingertips, somewhat larger on the
palms, much larger on the upper arm, and even larger on
the trunk. As one might expect, the pathways conduct-
ing the sensory signals from the spots on the skin are
arranged topographically so that signals from different Real stimulus
parts of the skin are kept separate at all levels up to the
cerebral cortex.
Lateral Inhibition: Inhibitory Interneurons Improve the

Discriminative Sensation
The two-point threshold (Fig. 13.3C) does not depend
solely on the size and density of the cutaneous receptive
fields. Inhibitory interneurons in the cord (and at higher Peripheral sensory
neurons (units)
levels) restrict the signal traffic from the periphery of a
stimulated spot, thereby improving the discriminative
Central sensory
ability compared with what might be expected from the neurons (in the
anatomic arrangement of receptive fields (Fig. 13.4). cord)
The cutaneous sensory units (neurons) send off collat-
Inhibitory
erals in the CNS that activate inhibitory interneurons interneurons
that, in turn, inhibit sensory neurons in the vicinity.
This phenomenon is called lateral inhibition, and occurs
at all levels of the sensory pathways and in all sensory
systems. Figure 13.4 shows an example with a pencil
pressed lightly onto the skin. The sensory units with
receptive fields in the center of the stimulated spot
receive the most intense stimulation. Therefore, they
excite the inhibitory interneurons strongly, with conse- Perceived stimulus
quent strong inhibition of sensory units leading from
the periphery of the spot. Sensory units with receptive
fields in the periphery are less strongly stimulated but
receive strong inhibition. Thus, they cannot inhibit the gure 13.4 Lateral inhibition. Simplied presentation of how inhib-
transmission of signals from the center of the spot. itory interneurons in the CNS can improve the precision of the
Together, the impulse traffic from the periphery of the sensory information reaching consciousness.
PROPRIOCEPTORS: DEEP SENSATION shows that almost 40% of all the axons are either thin
myelinated or unmyelinated sensory fibers, terminating in
As mentioned, the term proprioceptive is used for free endings (Fig. 13.5). Manyprobably the majority
sensations pertaining to the musculoskeletal system of the unmyelinated and thin myelinated axons lead
the muscles, tendons, joint capsules, and ligaments. from nociceptors in the muscle. This has been shown by
There are many similarities between proprioceptors and recording the activity of single sensory units that innervate
cutaneous receptors. For example, numerous free recep- a muscle while systematically exploring their adequate
tors (belonging to thin myelinated and unmyelinated stimuli. Such units were excited by both strong mechani-
axons) occur in the muscles, the muscle fascia, and the cal stimuli and substances liberated in inflamed tissue
dense connective tissue of joint capsules and ligaments. (such as bradykinin, known to provoke pain in humans).
Many of these are nociceptors as in the skin. Inflammation also sensitizes the nociceptive sensory units;
Here we are dealing primarily with specialized sense making them respond to normal movements (this may
organs in muscles and around joints, which are of cru- partly explain the muscle soreness after heavy exercise).
cial importance for control of posture and goal-directed Like cutaneous nociceptors, those in muscle are also
movements. These are low-threshold mechanorecep- sensitized by prolonged stimulation, and some sensory
tors, and the signals from them are conducted centrally units are activated by ischemia. For example, muscle
in thick, myelinated axons. The adequate stimulus of ischemia caused by a thrombotic artery, produces pain in
these receptors is stretching of the tissue in which they humans.4
lie. Whether the receptors are located in a muscle or in Microneurographic studies have identified sensory
a joint capsule, joint movement is the natural stimulus units in human muscle nerves that have nociceptor-like
that leads to their activation. properties similar to those described in the preceding
We first discuss specialized sense organs in muscles text in experimental animals. Thus, human units are
muscle spindles and tendon organsand then discuss slowly adapting, have a high threshold for mechanical
receptors in joint capsules and ligaments. In Chapters 18 stimuli, and can be activated by inflammatory sub-
and 21, we treat the role of proprioceptors in control of stances. Electrical stimulation of small nerve fascicles in
movements. human muscle nerves produces pain as the only sensory
experience. The pain is felt to be deep (not in the skin)
and has a cramp-like quality. The subject localizes the
Classication of Muscle Sensory Fibers
pain to the muscle supplied by the nerve, not to the site
Muscle afferents, that is, sensory fibers leading from mus- of nerve stimulation that is at a distance from the mus-
cles, are classified according to size into groups I to IV cle (recording and stimulation of single sensory fibers
(size or thickness is closely related to conduction velocity). have confirmed these findings). If the stimulation con-
Group I muscle afferents contain fast conducting, thick tinues, or its intensity is increased, the pain radiates to
myelinated fibers, while group II contain medium- other regions than the muscle itself (this phenomenon is
sized myelinated fibers, and group III comprises the called referred pain; see later, Spinothalamic Cells
thinnest myelinated fibers. Group IV contains the slowly Receive Signals from Both Somatic and Visceral
conducting unmyelinated fibers. Group I is further Structures: Referred Pain).
divided into Ia and Ib fibers, with Ib fibers conducting A small number of axons from nociceptors in a mus-
slightly more slowly than Ia fibers. Signals from low- cle tendon have been investigated with microneurogra-
threshold mechanoreceptors in musclesthat is, from phy. Stimulation of such a sensory unit produced a
muscle spindlesare conducted in group I and II fibers, sharp pain, different from the muscle pain described
while the tendon organs are supplied with Ib fibers. above. The subject localized the pain to the tendon.
Unfortunately, other terms are used for classification of
cutaneous sensory fibers and efferent (motor) fibers.
Ergoreceptors and Other Kinds of Free Receptors in
Broadly, group I and II fibers correspond with regard to
Muscles
conduction velocity to A and A fibers, while group
III and IV correspond to A and C fibers, respectively Not all of the thin, slowly conducting sensory fibers in
(see later in this chapter under Classification of Dorsal a muscle nerve are nociceptors. Thus, in experimental
Root Fibers in Accordance with Their Thickness). animals, some of these fibers have a low mechanical
threshold; that is, ordinary muscle contraction or gentle
Nociceptors in Muscle and Tendon
4 Animal experiments using cultured dorsal root ganglion cells indicate that
As mentioned, muscles are supplied with numerous free the adequate stimulus for many muscle nociceptors is a combination of
nerve endings of thin myelinated and unmyelinated axons protons, ATP, and lactate, acting on ASICs (acid sensing ion channels), P2X
(purinergic type 2), and TRPV receptors, respectively. Increased levels of these
(i.e., the most slowly conducting fibers). Microscopic metabolites would presumably mediate the pain provoked by heavy muscular
examination of muscle nerves in experimental animals exercise (causing ischemia).
Tendon
Thin nerve fibers

with free endings
Muscle Connective
nerve tissue capsule
of the muscle
spindle
IIntrafusal
Ia muscle fibers
II
Ib Extrafusal
muscle fibers
Muscle fascia
Tendon
gure 13.5 Sensory innervation of skeletal muscles.
Tendon organ The size of the receptors relative to the muscle is exag-
gerated. Because the muscle spindle attaches to the
tendons via connective tissue bers, the muscle spindle
is stretched whenever the whole muscle is stretched.
Many of the free nerve endings are nociceptors.
stretching of the muscle activates them. Their maximal intrafusal fibers show cross-striation only at their ends.
firing rate is reached by stimuli much weaker than the This means that they are able to contract only these
stimuli producing pain. Such receptors may be respon- parts and not their middle portions. There are two main
sible for circulatory and respiratory reflex effects known types of intrafusal fibers (Fig. 13.6). One type is called
to occur at the start of muscular activity. Thus, there is the nuclear bag fiber because the nuclei are all collected
a slight increase of pulse and breathing rate that occurs in the middle part of the muscle fiber. In the other type,
too early to be caused by a rise in blood CO2 or lowered the nuclear chain fiber, the nuclei are evenly distributed
pH. Although the receptors responsible for such reflex along the muscle fiber.
effects have not been identified with certainty, they are The nerve supply of the muscle spindles is highly
called ergoreceptors (ergoceptors). complex, and only the main features will be treated
here (Figs. 13.513.7). A thick afferent fiber ends with
a spiraling course around the middle portion of the
The Structure and Innervation of the Muscle Spindle
nuclear bag and to a lesser extent nuclear chain fibers,
The name muscle spindle is derived from the oblong shape forming the primary sensory ending of the muscle
of this sense organ. The muscle spindles are located spindle. In addition, a thinner afferent fiber ends mainly
within the muscle, among the striated muscle cells, and in relation to the nuclear chain fibers, forming the
consist of a few (214) specialized muscle cells enclosed secondary sensory ending. Afferent nerve fibers from
in a connective tissue capsule. The capsule is approxi- muscles are classified with regard to thickness (and thus
mately 0.2 to 0.3 mm in diameter and up to 5 mm long. to conduction velocity) in groups I to IV, with group I
The muscle fibers (or muscle cells) of the spindle are fibers comprising thick myelinated axons, and group IV
called intrafusal and are much thinner and shorter unmyelinated ones. Group I is further divided into Ia and
(710 mm long) than the ordinary, extrafusal, muscle Ib, the former being the thickest. The primary sensory
fibers. In contrast to the extrafusal muscle fibers, the ending belongs to a group Ia afferent fiber, whereas the
fibers Ia fiber II fiber Primary afferent fiber (group Ia)
Muscle spindle
A
Nuclear bag
Nuclear chain
Primary ending Secondary ending Alfa () motoneuron

Interneurons
gure 13.6 The muscle spindle. Schematic of the two kinds of intra-
fusal muscle bers and their innervation. (Modied from Matthews Secondary afferent fiber (group II)
1964.) B
secondary sensory ending originates from a group II

afferent fiber (Figs. 13.7A and B). Both types of sensory
neuron have their cell bodies in the spinal ganglia.The
adequate stimulus for the primary and secondary sen-
sory endings is stretching of the intrafusal muscle fibers.
This deforms the spiraling axonal branches and thus
elicits depolarization and (if the depolarization is strong
enough) action potentials in the group Ia and II sensory
fibers. Gamma () motoneuron
The muscle spindle is also supplied with motor axons, Gamma () fiber
C
called fusimotor, or , fibers, coming from moto-
neurons located in the ventral horn (Fig. 13.7C). The
fibers end in the distal cross-striated parts of the intra-
fusal fibers and make them contract (Fig. 13.6). The
contraction leads to stretching of the noncontractile
middle part of the intrafusal fibers, where the sensory
endings are located, increasing the sensitivity of the
intrafusal fibers to stretch. It should be emphasized that
because the intrafusal fibers are so few and thin, their
contraction does not contribute to the tension or short-
ening of the whole muscle. gure 13.7 Innervation of the muscle spindle. A: The fast-conducting
group Ia bers end monosynaptically on motoneurons in the ventral
horn. This is the reex arc that mediates the brief muscle contraction
Number and Density of Muscle Spindles elicited by a tendon tap (monosynaptic or phasic stretch reex). In
addition, Ia afferents end on interneurons and send ascending and
The number of muscle spindles has been determined in descending collaterals into the dorsal columns. B: The group II bers
approximately 200 human muscles, and varies greatly end on interneurons in the intermediate zone and the ventral horn.
C: The small motoneurons lie scattered among the larger motoneu-
from muscle to muscle. The functional significance of
rons in the ventral horn.
such variations is not clear, and has been subject to
different interpretations. In large muscles such as the
latissimus dorsi the total number of muscle spindles is of the hand contain 12 spindles per gram of muscle with
about 400, whereas the small abductor pollicis brevis a total count of only 18 muscle spindles. The corre-
contains about 80. The largest absolute number, close to sponding numbers for the soleus and the EDL are 0.4
1300, was found in the quadriceps muscle. The soleus and 3.7, respectively.
muscle contains approximately 400 muscle spindles, the When comparing the number of muscle spindles with the
medial gastrocnemius 150, and the extensor digitorum number of motor units of the muscle, however, the ratio is
longus muscle (EDL) 190. Although the absolute number not necessarily higher in small than in large muscles. (A
is low in small muscles, the density of muscle spindles motor unit is a motoneuron and all the extrafusal mus-
may be very high. For example, the tiny lumbrical muscles cle fibers it supplies, and is the basic functional unit of
a muscle. Motor units are larger; that is, there are more action potentials) as the length of the muscle increases
muscle fibers per motoneuron, in large than in small (Fig. 13.8). If the muscle shortens, the firing rate
muscles; see Chapter 21.) Thus, the ratio for the first decreases (if the muscle is sufficiently shortened, no
dorsal interosseus muscle is 0.29, the first lumbrical action potentials can be recorded; see Fig. 13.9). When
muscle 0.54, the biceps muscle 0.41, and the tibialis the length of the muscle is kept constant, the firing rate
anterior muscle 0.64. is also constant (static phase in Fig. 13.8); the muscle
Another relationship exists between density of muscle spindle afferents are thus slowly adapting. This property
spindles and kind of extrafusal muscle fibers. In general, of the muscle spindle is called static sensitivity. Because
it appears that muscle spindles are most abundant in red the firing rate of both group Ia and group II fibers
parts of a muscle (Type 1 muscle fibers, see Chapter 21). depends on the length of the muscle, both inform the
CNS about the length of the muscle at any time (or the
static length).
Functional Properties of the Muscle Spindle
During the phase in which the muscle length is
To understand how the muscle spindle functions, one changed, however, group Ia and group II afferent fibers
must know that it is arranged in parallel with the extra- behave differently (dynamic phase in Fig. 13.8). The
fusal muscle fibers. Thus, both ends of the spindle are firing rate of the group Ia fiber is much higher during
attached to the connective tissue within the muscle and stretching than when the length is kept stationary in the
are thereby indirectly anchored to the muscle tendons stretched position, but the group II fiber does not show
(Fig. 13.5). From this structure one may deduce that this same change in firing rate. During the shortening
when the whole muscle shortens as a result of contrac- phase, the Ia fiber becomes completely silent.
tion of the extrafusal fibers, the intrafusal fibers will be Although not shown in Fig. 13.8, the firing rate of
shortened passively. Conversely, stretching of the whole the group Ia fiber also depends on the velocity of the
muscle will stretch the intrafusal muscle fibers. The rate length change. Thus, the Ia fiber signals that the length
of shortening or lengthening will be the same for the of the muscle is changing, as well as the velocity with
muscle spindle as for the whole muscle. which it is occurring. This property is called dynamic
Action potentials can be recorded from single group sensitivity.
Ia and II afferent fibers in the dorsal roots of anesthe- These facts indicate that the primary sensory ending
tized animals. It is then possible to study how the primary of the muscle spindle has both static and dynamic sen-
and secondary sensory endings behave in response to sitivity: this ending is capable of informing about the
various stimuli. As expected from the anatomic facts actual length of the muscle (position of a joint), whether
described in the preceding text, both types of afferent the length is constant or changing ( joint movement),
fibers increase their firing rate (i.e., the frequency of and the velocity of change (velocity of the movement).
II fiber
Ia fiber
gure 13.8 Functional properties of the
muscle spindle. Both the primary and
the secondary sensory endings signal the
static length of the muscle (static sensi-
tivity), whereas only the primary ending
Static phase signals the length changes (movements)
and their velocity (dynamic sensitivity).
Dynamic phase Dynamic phase The diagram is based on recordings from
(lengthening) (shortening) single dorsal root bers of anesthetized
Static phase Static phase cats. The change of ring frequency of
MUSCLE LENGTH
group Ia and group II bers can then be
related to static muscle length (static
phase) and to both stretching and short-
PRIMARY ENDING Ia ening of the muscle (dynamic phases).
The density of the vertical lines on the
two lower rows indicates the frequency
of action potentials in the dorsal root
SECONDARY ENDING II
bers. (The muscle spindle is not under
the inuence of motoneurons in this
Action potentials Time experiment.)
Ia fiber the properties of the muscle spindle are markedly influ-
enced by the activity of the motoneurons. To under-
stand the functioning of the muscle spindle in an intact
organism, we must therefore also know the actions of
the innervation.
fiber
Effects of Innervation on the Properties of the
Muscle Spindle
Static phase
Lengthening
As mentioned, signals in fibers elicit contraction of the
distal, cross-striated parts of the intrafusal muscle
MUSCLE LENGTH Static phase fibers. This stretches the midportion of the intrafusal
fibers with the sensory endings (Fig. 13.6). In addition,
NO ACTIVITY
it also alters the stiffness of the intrafusal fibers so that
their reaction to stretch is altered. In general, the
motoneurons and their fibers enable the brain to con-
STIMULATION STATIC trol the sensitivity of the muscle spindle to length and
changes in length.
In animal experiments, single fibers in the ventral
STIMULATION DYNAMIC roots have been stimulated while, at the same time, the
Action potentials in Ia fiber Time activity of group Ia and group II afferent fibers in the
dorsal roots were recorded. It has thus been shown that
gure 13.9 Action of motoneurons on the muscle spindle. The there are two types of motoneurons (Fig. 13.9). One
experimental setup is as in Fig. 13.8, except that in addition to record-
ing the activity of group Ia bers in the dorsal root, axons are iso-
type increases the dynamic sensitivity of the muscle
lated in the ventral roots so they can be electrically stimulated. In this spindle and is therefore called D (gamma dynamic). On
example, there is no ring of the Ia ber at the resting length of the a fairly rapid stretch of the muscle, the firing rate of a
muscle when the bers are not stimulated. Stimulation of a static group Ia fiber increases more when the muscle spindle
ber (innervating the same spindle that the Ia ber conducts from) receives signals from D motoneurons than without such
makes the Ia ber re even at the static resting length; stretching the
muscle to a new static length increases the ring frequency to a new
influence, but the firing rate during static length is not
stable level. Stimulation of a dynamic ber increases the ring fre- significantly altered (Fig. 13.9). The muscle spindles
quency of the Ia ber mainly during the stretching phase. increased sensitivity to stretch enables the CNS to react
more rapidly and forcefully to any unwanted change in
muscle length (imposed, e.g., by external forces that
Because the secondary sensory ending almost totally upset body balance or ongoing movements).
lacks dynamic sensitivity, it should be able to inform Signals from the other type of motoneurons increase
primarily about the static length of the muscle. the static sensitivity of the muscle spindle and are therefore
There is much evidence to suggest that the nuclear called S (gamma static). The activity of S motoneurons
bag fibers are responsible for the dynamic sensitivity of increases the firing rate of muscle spindle afferent fibers
the primary sensory ending, whereas the nuclear chain during constant length, as compared with a situation
fibers are responsible for the static sensitivity of both without activity. Although not shown in Fig. 13.9, the
the primary and secondary sensory endings. That the firing rate of both group Ia and group II afferents
primary and secondary sensory endings (and their affer- increases. This influence of the system may be impor-
ent nerve fibers) have different properties is most likely tant to prevent the muscle spindles from becoming
due to differences in viscoelastic properties of the nuclear silentthat is, sending no action potentialsduring
bag and nuclear chain intrafusal muscle fibers.5 the shortening of the muscle. In other words, the length
The preceding description of the properties of the sensitivity of the muscle spindle increases. Thus, the
muscle spindle derives from experiments in which there muscle spindle may signal the length of the muscle in its
was no impulse traffic in the fusimotor axons (because entire range of movements, which is for precise move-
the ventral roots were cut before recording from the ment control and for our awareness of joint positions.6
dorsal roots). As discussed in the next section, however, (Figure 13.7 shows that stimulation of S in fact reduces
5 In reality, the conditions are even more complex. Among other things, there 6 The innervation poses a problem for the brain when judging joint positions
are two types of nuclear bag bers that differ ultrastructurally and histochemi- and movements, however, since the signals from muscle spindles depend not
cally: Only one of them, called bag1, appears to be responsible for the dynamic only on the absolute length of the muscle but also on the degree of activity.
sensitivity of the primary sensory ending. The other one, called bag2, behaves Since muscle spindles are crucial for our perception of joint positions and
more like a nuclear chain ber and contributes presumably only to the static movements, the brain must in some way be able to account for the activity
sensitivity. and end up with a true measure of muscle length.
the dynamic sensitivity of the primary sensory ending, it appears that the sensitivity of the muscle spindle has
since there is no extra increase in firing rate of the Ia been increased by selective activation of motoneurons.
fiber during the stretch phase. Under the influence of S, It is also difficult to understand why the elaborate
the primary sensory ending behaves more like a second- system has developed if its activity were always to
reflect that of the system. In fact, there are collaterals
7
ary one.)
Even though this description of the properties of mus- of axons, so-called axons, that innervate some
cle spindles is based on experiments in animals, there is intrafusal muscle fibers, and in submammalian species
evidence that it applies to the human muscle spindle. (e.g., in the frog) there are only fibers. During evolu-
Certainly, however, results from anesthetized animals, tion, the system appeared first.
often with the spinal cord isolated from the rest of the
brain, do not enable us to draw conclusions as to the
Signals from Muscle Spindles Reach Consciousness
functions of the muscle spindle in intact organisms, for
example, in human voluntary movements and in prop- There is good evidence that signals from muscle spindles
rioception. It may seem paradoxical that the muscle contribute to our conscious awareness of joint angle
spindle is among the most studied sense organs, yet its and movement (discussed further later in this chapter).
functional roles remain only partially understood. Signals from a single muscle spindle are not sufficient to
produce a conscious sensation, however (in contrast to
some cutaneous and joint low-threshold mechanorecep-
Muscle Spindles in Humans and Coactivation
tors), so that microneurographic stimulation of single
The activity of group Ia afferent fibers in the nerves of spindle afferents from human intrinsic hand muscles
the arm and the leg has been recorded in conscious does not evoke any sensation. Many muscle spindles
human subjects via microneurographic techniques. It must obviously be activated simultaneously for the sig-
appears (unexpectedly, based on animal experiments) nals to be consciously perceived, and presumably this
that in a resting muscle there is little or no impulse traffic always happens when a muscle is stretched. Therefore, it
from the muscle spindle. Indirectly, this shows that there seems unnecessary and perhaps also disturbing (noise)
is no fusimotor () activity, either. But if the muscle to the brain if every muscle spindle were to evoke a
contracts isometrically (i.e., without change of length), sensation on its own.
there is a sharp increase of the firing frequency of Ia Especially in weak contractions, different parts of a
fibers, which must be caused by increased fusimotor muscle undergo different length changes; consequently,
activity that occurs simultaneously with the increase in the muscle spindles would fire with different frequen-
-motoneuron activity (which evokes the contraction cies. In this way the signals from single muscle spindles
of the extrafusal fibers). This phenomenon of simulta- may provide useful feedback to the motor control
neous activation of and motoneurons is called machinery in the cord about smaller parts of the muscle.
coactivation. This ensures that the sensitivity of the The cerebral cortex is presumably concerned only with
muscle spindle is increased whenever the muscle is being the muscle as a whole and extracts necessary informa-
used. In fact, the firing rate of the Ia fiber is maintained tion by integrating the signals from the numerous muscle
or increased even if the muscle is shortened during spindles.
active contraction. This must mean that the fusimotor
activity (firing rate of the motoneurons) increases
The Tendon Organ
during active shortening of the muscle.
The preceding example of coactivation does not The other kind of proprioceptive receptor we describe
mean that the motoneurons are activated only in con- here is the tendon organ, also called the Golgi tendon
junction with the motoneurons, even though direct organ. It is built more simply than the muscle spindle and
proof of separate activation is scarce. There are situa- consists of a sensory nerve fiber that follows a convoluted
tions in which it would be desirable to have increased course among collagen fibrils of the tendon, close to the
sensitivity of the muscle spindle without simultaneous musculotendinous junction (Fig. 13.5). The number of
muscle contraction. One piece of indirect evidence tendon organs in a muscle appears to be only slightly
comes from studies of stretch reflexes during mental lower than the number of muscle spindles. The thick,
imagery. In such a situationwhen the subject imag- myelinated fiber leading from the tendon organ belongs
ines the performance of a movementthe stretch reflex to group I and is called a group Ib fiber. There is no effer-
response of the relevant muscles is increased without ent innervation of the tendon organ (in contrast to the
concomitant increase of -motoneuron excitability, so muscle spindle): its sensitivity cannot be controlled from
the CNS.
The adequate stimulus of the tendon organ is stretch-
7 Because the bag bers appear to be solely responsible for the dynamic sensitiv-
ity of the muscle spindle, it has been assumed that dynamic bers end on bag ing the part of the tendon in which it lies. Stretching
bers and static bers end on chain bers. This is not fully claried, however. tightens the collagen fibers, and thus the axonal branches
between them are deformed (probably stretched, similar Why Tendon Organs Are More Sensitive to Contraction
to the group Ia afferents). This depolarizes the receptor than to Passive Stretch
and, if the stimulus is of sufficient intensity, evokes
Structural details may explain why the tendon organ is
action potentials in the afferent Ib fiber. Recording the
more sensitive to active contraction than to passive stretch.
activity of Ib fibers shows that the receptor is slowly
Each tendon organ is directly attached to a small bundle
adapting. It is important to realize that the tendon
of extrafusal muscle fibers. If one or a few of these con-
organ, in contrast to the muscle spindle, is coupled in
tract, the tension set up in this particular small part of
series with the extrafusal muscle fibers. Both passive
the tendon is much higher than the tension measured for
stretch and active contraction of the muscle increase the
the whole muscle. To obtain the same tension in this
tension of the tendon and thus activate the tendon
particular tendon organ by passive stretch, higher over-
organ receptor. The tendon organ, consequently, can
all tension of the muscle would have to be produced.
inform the CNS about the muscle tension. In contrast,
The muscle fibers attached to one tendon organ appear
the activity of the muscle spindle depends on the muscle
to belong to several motor units (see Chapter 21, under
length and not on the tension.
Motor Units). Because each tendon organ probably
Recording from single group Ib fibers in the dorsal
monitors the tension produced by only a few motor
root of anesthetized cats (Fig. 13.10) confirms what
units, the CNS is informed not only of the overall tension
was expected on the basis of the structure of the tendon
produced by the muscle but also of how the workload
organ. In addition, however, such experiments have
is distributed among the different motor units.
shown that the tendon organ is much more sensitive to
tension produced by active contraction than to that
produced by passive stretch. The tendon organ there- The Actions of Ib Afferents on Spinal Motoneurons
fore appears to be primarily concerned with signaling
how hard the muscle is contracting rather than with Activation of the group Ib afferents from tendon organs
how hard it is passively stretched. was shown a long time ago to inhibit (via interneurons)
motoneurons of the muscle in which the tendon organs
lie (homonymous inhibition). Although these experiments
were performed on anesthetized animals, and therefore
should be interpreted with caution, the task of the tendon
Ib fiber
organ was said to be to prevent contractions from being
Relaxed Passive Active too strong. More recent studies have shown that the
muscle stretch contraction
effects of the Ib afferents in the cord are not limited to
homonymous inhibition. In awake animals, the effect on
the motoneurons depends on the locomotor phase, and
the effect is reversed from inhibition to excitation when
moving from the swing phase to the standing phase.
Thus, tendon organs in hind limb extensors excite exten-
Tendon organ sor motoneurons when the leg is in the standing phase
(via excitatory interneurons). In this case the signals
from the tendon organ serve to amplify the contraction
of the extensor muscles that keep the upright position.
This is an example of how higher motor centers (in the
MUSCLE brain stem and cerebral cortex) can switch the impulse
LENGTH
traffic from one route to another in the cord, depending
on the motor task. Further examples of this phenome-
Ib FIBER
non are provided in Chapter 21.
Perception of Muscle Force

Ia FIBER
Our conscious perception of how hard the muscles con-
Action potentials Time
tract may depend on two sources of information. One is
gure 13.10 Functional properties of the tendon organ. The experi- the total activity of neurons in the motor cortex that send
mental setup is as in Fig. 13.8. Action potentials are recorded from commands to the muscles that contract. This requires
isolated Ib bers in the dorsal roots. Vertical lines on the lower rows that other parts of the brainfor example, the soma-
indicate the ring frequency. Both passive stretching and active con-
tosensory cortexreceive a copy of the motor commands
traction of the muscle increase the ring frequency of the Ib ber, but
active contraction produces the greatest increase. The ring frequency sent to the muscles. This is called efference copy, or
of a Ia ber during the same experiment is shown for comparison. corollary discharge. Based on previous experience, the
somatosensory cortex (in cooperation with other cortical glabrous skin. The encapsulated joint receptors are
regions) may estimate the muscle force that corresponds low-threshold mechanoreceptors and have been divided
to the motor command. The other source of informa- into four groups. The type 1 joint receptor resembles
tion is the proprioceptors that inform about the tension the Ruffini corpuscle in the dermis (Fig. 13.1A). A
in the muscles themselves and in connective tissue that is myelinated axon ramifies among collagen fibrils, within
stretched by muscle contraction. As discussed, tendon a thin connective tissue capsule. They are found almost
organs are particularly suited to informing about the exclusively in the fibrous part of the joint capsules. The
tension in a contracting muscle, but because muscles adequate stimulus of these Ruffini-like receptors is
often insert in the joint capsule, joint receptors may also increased tension in the part of the capsule in which
contribute to communication of information. they lie. The higher the capsular tension is, the higher is
That the motor cortex output plays a part is witnessed the firing rate in the afferent sensory fiber from the
by the fact that persons with pareses due to muscle disease receptor. Like the Ruffini corpuscle in the skin, this joint
judge objects to be heavier than they actually are. To receptor is slowly adapting. Because the tension in vari-
compensate for the weakened muscle, the motor cortex ous parts of the capsule depends on the joint position,
output is presumably higher than normal while the type 1 receptors would appear suited to signal the posi-
proprioceptive feedback is correct (informing about the tion of the joint. For example, receptors in the posterior
real muscle tension). Nevertheless, the proprioceptive part of the elbow joint capsule would be highly active
information seems to be necessary also, since patients in a flexed position of the joint, which stretches the
with neuropathies may experience difficulties with capsule, and less active in an extended position, which
holding a steady force and judging the weight of relaxes the capsule. The receptor also has dynamic
objects. sensitivity, giving a stronger response (higher firing rate)
to a rapid movement than to a slow one. The type 1 or
Ruffini-like receptor thus seems capable of signaling
Low-Threshold Mechanoreceptors around the Joints
static joint position, joint movements, and direction
Not only receptors in muscles and tendons but also recep- and speed of movements. As discussed later, however,
tors in the connective tissue around the joints provide the ability of the type 1 receptor to signal static joint
information important for our awareness of movements position appears to be limited.
and for motor control. While the relative importance of The type 2 joint receptor structurally and functionally
information from joint and muscle receptors is not resembles the Pacinian corpuscle but is considerably
clear, the prevailing view is that the contribution from smaller (it is also called Paciniform receptor). Type 2
joint receptors to proprioception is less important than receptors are present only in the fibrous part of the joint
that of the muscle spindles. capsules. They are rapidly adapting, and their adequate
Many sensory nerve fibers end in the joint capsules stimulus is stretching of the part of the capsule in which
and in the ligaments around the joints (Fig. 13.11). they lie. Owing to their rapid adaptation, they can inform
Many are free-ending receptors; others are encapsulated only on joint movements, not of static position. They
endings that correspond anatomically and with regard appear particularly suited to signal movement velocity
to response properties to encapsulated receptors in and have also been called acceleration receptors.
Type 1 Type 3
Type 2 Type 4 gure 13.11 Joint innervation. Drawing of a

knee joint, showing the distribution of the vari-
ous kinds of joint receptors. The morphology of
the four main receptor types is shown in more
detail in the side panels. Type 1, 2, and 3 are low-
threshold mechanoreceptors responding to small
changes in joint-capsule tension. Type 4 are free
nerve endings (most of them nociceptors).
A third kind of encapsulated receptor (type 3) resembles typical of primary sensory neurons (substance P, CGRP,
the tendon organ and is present in ligaments only. It is and others). Due to the low density of such fibers, doubt
slowly adapting (like the tendon organ), but its func- nevertheless exists as to their functional significance.
tional role is unknown. A protective role in signaling Studies in humans using various ways of stimulating the
overstretching of joints has been proposed but has not synovial membrane (during surgery under local anesthesia)
gained experimental support. have given conflicting evidence: some report that pain
Microneurographic studies in humans with stimulation sensations were evoked from the synovial membrane,
of single afferent fibers from finger joints show that others not. In probably the most careful study, however,
signals from low-threshold joint receptors can reach pain (or any other sensation) was only occasionally
consciousness. Thus, when a fiber leading from a pre- evoked from the synovial membrane of the knee joint
sumed type 1 receptor was stimulated, the subject with mechanical and chemical stimuli. This contrasted
reported the feeling of a movement of the relevant joint with the ease with which pain was evoked from the
(the location and adequate stimulus of the receptor fibrous capsule and ligaments, as described earlier.
were determined before stimulation). In other instances In contrast to the sparse sensory innervation, the
of single-unit stimulation, the subject reported only a synovial vessels possess a rich efferent (autonomic) inner-
nonpainful, punctate feeling at the joint. vation. These fibers contain norepinephrine and usually
also neuropeptide Y (NPY). Release of norepinephrine
can induce the release of substance P from sensory nerve
Joint Nociceptors
fibers in the vicinity, and substance P may be involved
The fibrous part of the joint capsule and the ligaments are in producing inflammation in arthritis. Indeed, by remov-
richly supplied with thin myelinated and unmyelinated ing the autonomic innervation of the joint, arthritic inflam-
axons ending in free receptors. These have been termed mation can be reduced in animal models of arthritis. It
type 4 joint receptors. Many of these, like free endings in should be emphasized, however, that norepinephrine and
other tissues, are nociceptors. The joint capsules and liga- substance P are present also in the fibrous capsule.
ments contain high-threshold mechanoreceptors, poly- Therefore, sensory fibers in the synovial membrane may
modal nociceptors, and silent nociceptors. Stimulation not necessarily be responsible for the inflammatory
of the fibrous capsule and the ligaments during surgery response.
of the knee joint confirms that pain can be evoked
from both the capsule and ligaments. The sensation is
Kinesthesia
punctateas in the skinso that certain spots when
probed with a needle evoke pain while other spots The term kinesthesia (sometimes used synonymously with
evoke a feeling of pressure or no sensation at all. joint sensation and proprioceptive sensation) is commonly
Many of the thin fibers ending in the joint capsule con- used to refer to the perception of joint position, joint move-
tain neuropeptides, such as substance P and calcitonin ments, and the direction and velocity of joint movements.
gene-related peptide (CGRP). Release of such peptides is Strictly speaking, the word kinesthesia (Greek: kinesis,
believed to have a role in the development of inflamma- movement) encompasses only the dynamic and not the
tory arthritis in humans (especially rheumatoid arthritis). static aspect of sensation. The term joint sensation is not
Thus, the severity of induced inflammatory arthritis in a good alternative, however, because it may give the
experimental animals is reduced after depleting the joint false impression that kinesthesia depends only on joint
sensory fibers of substance P (see later in this chapter receptors. Some also include in the term kinesthesia
under Inflammatory diseases and release of neuropep- the perception of force, effort, and heaviness in relation
tides from peripheral branches of sensory neurons). to muscle contractions.
Other free joint receptors appear to be ergoreceptors Our ability to judge the position of a joint (without
that is, they play a part in circulatory and respiratory seeing it), even after a long period without movement, is
reflexes that are elicited by passive joint movements. usually fairly precise, as can be verified by trying to
match the position of the joint to be tested with the joint
of the other side (e.g., finger or elbow joints). This is the
Innervation of the Synovial Membrane
static part of kinesthesia. Nevertheless, the precision of
While autonomic efferent fibers have been traced to the our judgment is increased considerably if movements
synovial membrane, innervation by sensory fibers has are allowed, particularly active movements.
been a matter of dispute. Thus, such fibers were not iden- The static aspect of kinesthesia depends on slowly
tified by use of heavy metal impregnation, which reliably adapting receptors that change their firing rate with chang-
showed nerve fibers in the fibrous capsule. Nevertheless, ing joint position. The dynamic aspect of kinesthesiathe
recent immunocytochemical studies in humans showed ability to perceive that a movement is taking place and
the presence of thin nerve fibers that end freely in the to judge the direction and velocity of the movement
synovial membrane. These fibers contain neuropeptides depends on receptors with dynamic sensitivity, many of
them rapidly adapting. Receptors with such properties, presumably all afferent signals from the joint capsule
which are influenced by joint movements, are found in and the overlying skin by local anesthesia does not
muscles, around the joints, and in the skin. The accumu- impair kinesthesia appreciably. Local anesthesia of
lated evidence today indicates that muscle spindles, joint finger joint capsules and the skin of the fingers provides
receptors, and skin receptors all contribute to kinesthesia. more marked reduction of kinesthesia, but even in such
Muscle spindles appear to contribute most importantly cases the loss of kinesthesia is not complete.
to kinesthesia with regard to large joints, such as the
hip and knee joints, whereas joint receptors and skin
Proprioceptors, Balance, and Voluntary Movements
receptors may have more significant contributions with
regard to finger and toe joints. Patients with neuropathies causing loss of thick myelinated
fibers in their peripheral nerves have problems with
voluntary movements, especially when they cannot see
Signicance of Various Receptors for Kinesthesia
the moving parts. They also depend on visual informa-
The views on which receptor types are responsible for tion to keep upright and perceiving the position of their
kinesthesia have undergone considerable changes. At body parts. Their problems must be caused by the loss
the beginning of the past century, the newly discovered of information from low-threshold mechanoreceptors,
muscle spindle was held solely responsible but during presumably mainly proprioceptors. Most disturbed are
the 1950s and early 1960s investigations indicated that movements requiring coordination of several joints, such
joint receptors had the necessary properties to signal all as slicing bread, hitting a nail with a hammer, unlocking
the information needed for kinesthesia. It was also a door, and so forth. The regulation of muscular force
argued that the muscle spindle cannot give the neces- is inaccurate, and they have particular problems with
sary information, since the firing rate of its afferent maintaining a constant force for some time. Presumably,
nerve fibers depends not only on the actual position information from proprioceptors is necessary for a con-
and movements of a joint but also on whether the tinuous upgrading of the central motor program, so
motoneurons are active. While it was held that signals that the commands issued to the muscles are adapted to
from the muscle spindles do not reach consciousness, it the actual position of the body parts. Thus, the influence
has now been convincingly demonstrated that signals of gravity changes continuously during a movement, and
from the muscle spindles can reach consciousness and so do the mutual forces exerted by the parts (e.g., between
that they contribute to our kinesthetic sense. A simple the arm and the forearm). The movements become inac-
demonstration to this effect was performed by vibrat- curate and insecure if the force of muscle contraction is
ing the biceps muscle in a normal subject. Vibration is not adapted to these changes, which may differ slightly
known to stimulate the primary sensory endings of every time we, for example, raise a glass of water. Such
muscle spindles (the stimulus consists of brief stretches proprioceptive feedback is particularly important for
of the muscle). The subject, who is blindfolded, feels small, precise movements, when unforeseen disturbances
that the forearm is moving downward even though occur during the movement, and when we learn new
no such movement is occurringthat is, there is an movements. Vision can only partially compensate for
illusory extension movement at the elbow joint. This the loss of proprioceptive information.
corresponds to a lengthening of the biceps muscle, and As mentioned, kinesthesia does not depend solely on
under normal circumstances would be the normal cause information from proprioceptors; cutaneous receptors
of an increased firing rate in muscle spindle afferents. also contribute. Patients with peripheral neuropathies
Reexamination of the properties of joint receptors and loss of proprioceptive information usually also have
showed a striking paucity of slowly adapting joint reduced cutaneous sensation that may contribute to
receptors (type 1) that are active in midrange positions their disturbances of posture. Thus, specifying the indi-
of the joint, the range in which the precision of kines- vidual contribution of muscle spindles, tendon organs,
thesia is best. Because most type 1 receptors appear to joint receptors, and cutaneous receptors to the control of
reach their maximal firing rate only toward extreme voluntary movements is difficult. Further, when informa-
joint positions, it seems unlikely that joint receptors tion of one kind is reduced, the patient will learn to rely
alone can provide all the necessary information. Further, more on information from other kinds of receptors. In
examination of patients with artificial joints who lack addition, the analysis is complicated by the fact that the
joint capsules (and thus, presumably, most of their joint various proprioceptors differ regarding their contribu-
receptors) show that their kinesthesia is only slightly tion to kinesthesia in different joints, and this probably
reduced, at least with regard to the hip joint and the is true for control of voluntary movements as well. The
metacarpophalangeal joints. Presumably, muscle spindles brain extracts what it needs for motor control from the
(not tendon organs) are responsible for the remaining collective information provided by all these receptors.
kinesthesia in such cases, even though skin receptors may Nevertheless, it is striking that loss of proprioceptive
contribute as well (particularly for the metacarpophalan- information is poorly compensated: the person becomes
geal joints). For the knee joint, however, elimination of permanently dependent upon the cumbersome use of
visual information to control posture and voluntary Collateral
movements. Terminal ramifications Ascending
branch
We return to proprioceptors and their central actions
in Chapter 14, and discuss their relation to motor control Descending
in Chapters 18 and 21. branch
Dorsal
column
Clinical Examples of Loss of Somatosensory Dorsal root fiber
Information
In his book The Man Who Mistook His Wife for a Hat,
the neurologist Oliver Sacks gives a vivid description of Skin
a young woman, Christina, who completely lost kines-
thetic sensation. A sensory neuropathy of unknown origin
deprived her suddenly of virtually all kinds of proprio-
ceptive information. Her cutaneous sensation was only
Merkel disks
slightly reduced, and motor axons were essentially
spared. Nevertheless, at first she could not stand without gure 13.12 Terminal pattern of a dorsal root ber. A dorsal root
continuously watching her feet. She could not hold any- ber (in this case conducting from Merkel disks) divides into an
thing in her hands, and they wandered around without ascending and a descending branch after entering the cord. These
her awareness. When stretching out to grasp an object branches give off several collaterals that end in the dorsal horn. The
piece of the cord shown is about 1 cm long, but the axon continues
she usually missed itthe movement stopped too soon beyond this in both directions. Corresponding reconstructions have
or too late. Something awfuls happened, I cant feel my been made for sensory units leading from several other kinds of recep-
body. I feel weirddisembodied, she said, and I may tors, and each sensory unit has a characteristic terminal pattern in the
lose my arms. I think theyre one place and I find dorsal horn. (Based on Brown 1981.)
theyre another. After having proprioception explained,
she said: This proprioception is like the eyes of the
body, the way the body sees itself. And if it goes, as its The sensory fibers of the spinal nerves have their cell
gone with me, its like the body is blind . . . so I have to bodies in the dorsal root ganglia (see Figs. 6.5 and 6.9).
watch itbe its eyes. Right? Likewise, the sensory fibers in the cranial nerves have
Another example concerns a 36-year-old man who their cell bodies in ganglia close to the brain stem (see
gradually lost both cutaneous and kinesthetic sensation Fig. 27.5).
of the extremities due to a sensory neuropathy (described As mentioned, the spinal ganglion cells are pseudouni-
by Rothwell and coworkers 1982). His muscle power polar (see Figs. 1.5 and 12.2) and send one long process
was hardly reduced, and he did surprisingly well on peripherally, ending freely or in encapsulated sense
several routine tests of motor function. He performed, organs. Functionally and structurally, both the periph-
for example, various finger movements that require eral and the central processes are axons. The central
cooperation between muscles in the forearm and the process enters the cord and then divides into an ascend-
hand. He could move his thumb with fair precision over ing and a descending branch (Fig. 13.12). These branches
three different distances and with three different velocities, give off several collaterals ventrally to the gray matter of
and he could judge reasonably well the resistance to a the cord. One sensory neuron, entering the cord through
movement. In spite of this, his hands were almost use- one dorsal root, can therefore influence spinal neurons
less in daily life. He could not hold a cup with one hand, at several segmental levels of the cord.
hold a pen and write, or button his shirt. Most likely, this
can be explained by lack of automatic adjustment of
Classication of Dorsal Root Fibers in Accordance with
ongoing movements and by an inability to maintain con-
Their Thickness
stant muscle force for more than a few seconds (without
seeing the part). The problems seemed to arise also because The dorsal root fibers vary in thickness, from the thick-
he was unable to do longer sequences of simple move- est myelinated ones, with a diameter of 20 m and
ments without constantly watching what he was doing. conduction velocity of 120 m/sec, to the thinnest unmy-
elinated fibers, with a diameter of less than 1 m and
conduction velocity of less than 1 m/sec. The thick fibers
THE SENSORY FIBERS AND THE DORSAL ROOTS belong to the ganglion cells with large cell bodies, and
the thin fibers belong to those with small cell bodies
Afferent (sensory) fibers from the receptors follow the (Fig. 13.13). We have previously in this chapter described
peripheral nerves toward the CNS. Close to the spinal classification of sensory axons from muscle by their
cord, the sensory fibers are collected in the dorsal roots thickness (conduction velocity) into groups I to IV (see
and enter the cord through these (see Fig. 6.5 and 13.12). under Classification of Muscle Sensory Fibers).
With retrograde transport methods, their cell bodies

have been shown to lie in the dorsal root ganglia. Some
ventral root sensory fibers leave the ventral root to inner-
vate the pia at the ventral aspect of the cord; others
reverse direction before they enter the cord. Some of
these then enter the cord through the dorsal root, whereas
the further course of the others is unknown. Neither do
we know whether these peculiar arrangements have a
special biological meaning.
Fiber Categories and Conscious Sensations

Relationships between signals conducted in sensory fibers
of various size (thickness) and conscious sensations have
been investigated primarily via graded electrical stimu-
gure 13.13 Spinal ganglion. Photomicrograph of a section from lation of peripheral nerves and selective blockage of
a human spinal ganglion. The cell bodies of the pseudounipolar
neurons are of different size. The cell bodies are surrounded by satel-
axonal conduction. By electrical stimulation of peripheral
lite cells. Inset: Photomicrograph of section treated with a silver nerves, the weakest stimulation evokes activity only in
impregnation method showing axons. Arrow points to the axon the thickest myelinated fibers, and with increasing inten-
leaving the cell body of the ganglion cell. sity, the thinner fibers are recruited progressively. Thus,
the thickest fibers have the lowest electrical threshold
for activation. In human subjects, pain is evoked by
Another classification of sensory fibers is used mainly such stimulation only if the stimulus is strong enough
for cutaneous afferents. Myelinated fibers fall within to activate A fibers. The person then typically reports
group A, and group C contains the unmyelinated fibers. that the pain is of a sharp, pricking quality. If the stim-
In the A group, the fastest conducting (thickest) fibers ulus strength is increased to recruit C fibers as well, the
are termed A, somewhat slower conducting fibers person experiences an intense, often burning pain that
are A, and the thinnest of the myelinated fibers are continues after the stimulus stops. These experiments
called A. are in agreement with the common experience that one
The different kinds of sensory receptors are supplied usually can distinguish two phases of pain after an
with axons of characteristic thickness. Signals from acute injury. The first phase, or fast pain, is experienced
low-threshold mechanoreceptors are conducted in thick immediately after the stimulus, is well localized, and
myelinated fibers (A and A); signals from cold recep- not very intense; the second phase, or slow pain, occurs
tors are conducted in thin myelinated fibers (A), while with a longer latency and is more unpleasant, is not well
unmyelinated (C) fibers conduct from heat receptors. localized, and usually continues after the end of the
Signals from nociceptors are conducted in A and C stimulus. The slow pain is delayed because it depends on
fibers. In the spinal cord, the terminations of the A being conducted in C fibers with a conduction velocity
and C fibers are almost completely separated from of less than 1 m/sec. The difference in conduction velocity
those of the A and A fibers (Fig. 13.16). between fibers that give rise to fast and slow pain is most
easily observed when something hits the foot hard enough
to cause painfor example, when a toe is bumped against
Are There Sensory Fibers in the Ventral Roots?
a hard object. The pathway from the toe to the cerebral
We now know that there are exceptions to the rule that cortex is longer than from any other part of the body, so
sensory fibers enter the cord through the dorsal roots the time lag between the signals conducted in thick and
and that motor fibers enter through the ventral roots thin fibers is greatest. In fact, the very first sensation is
(the law of Magendie). The fact that cutting the dorsal only that something touched the foot, due to activation of
rootsdorsal rhizotomydoes not always abolish pain low-threshold mechanoreceptors. Almost simultaneously,
indicates that not all sensory information passes through the sharp and well-localized fast pain is perceived, and we
the dorsal roots. Electron microscopic investigations have then know that the pain will soon be worsethe diffuse,
proved the presence of many unmyelinated fibers in the burning, and intensely unpleasant slow pain continuing
ventral roots of several species, including humans. Many for some time.
of these are efferent, preganglionic autonomic fibers, but Injection of local anesthetics around a peripheral
physiological data show that others (30% in the rat) are nerve blocks the thinnest (C) fibers first and the thickest
sensory and react to stimulation of nociceptors. However, myelinated ones last. Accordingly, with local anesthetics
few, if any, of these unmyelinated fibers have been proved the pain disappears first, whereas the tactile sensation
actually to enter the cord through the ventral root. remains considerably longer, and some sensations may
remain throughout the period of anesthesia. When supplied with sensory fibers from one spinal segment is
peripheral nerves are subjected to pressure, conduction called a dermatome. In the thorax and abdomen, der-
in thick fibers is blocked first, and, accordingly, there matomes form circular belts; in the extremities, however,
first occurs a reduction of the ability to perceive light conditions are more complicated (Figs. 13.14 and 6.15).
touch and to judge the position of joints, but pain Knowledge of the segmental innervation of the skin
8
perception is still present. (and also of the segmental innervation of muscles and
viscera, dealt with in Chapters 21 and 27) is of great
practical value in clinical neurology. For example, if a
The Segmental Innervation: The Dermatomes
dorsal root is interrupted, the skin sensation is reduced
The ventral branches (rami) of the spinal nerves form or abolished in the corresponding dermatome.
plexuses supplying the arms (see Fig. 21.1) and the legs. Because the dermatomes overlap, each spot on the skin
Each nerve emerging from these plexuses contains is innervated by sensory fibers from at least two dorsal
9
sensory and motor fibers arising from several segments. roots. Interruption of a single dorsal root therefore may
In the peripheral distribution of the fibers, however, the not produce a clear-cut sensory deficit. Nevertheless,
segmental origin of the fibers is retained. Thus, sensory careful examination usually shows a narrow zone (cen-
fibers of one spinal segmentthat is, of one dorsal root trally in the dermatome) where the cutaneous sensation
supply a distinct part of the skin. The area of the skin
9 Animal experiments indicate that the dermatomes are about twice as large as
what appears from ordinary testing conditions, and the overlap is correspond-
+
8 For local anesthetics, which act by blocking voltage-gated Na channels in ingly larger. Inhibitory propriospinal bers in the tract of Lissauer (Fig. 6.15)
the axonal membrane, access to the channels is more direct in unmyelinated seem to inhibit weak sensory inputs from the peripheral parts of the dermatome,
bers than in thick, myelinated ones. Pressure affects primarily thick myeli- so that only signals from its central parts evoke a sensation. Under pathological
nated bers, presumably because of their high oxygen demand that make them conditions, however, the spinal neurons may become hyperexcitable and there-
more vulnerable than unmyelinated bers to ischemia. fore respond to sensory inputs that normally are too weak to activate them.
A C2
C2
C3 C3
C4
C4 C7
C5
T1
T1
T4
T11
L1
C5 T1 C7
T10 L5
T10
S1
S2
C6 T12 C6
C7 C8 C8
S2
Ventral axial line

C4
C5
C7
C6 T1 gure 13.14 Dermatomes of
C8
C5 the trunk and the upper extremity.
Dermatomes not supplied by
neighboring spinal segments meet
C6 at the ventral axial line (C5 and T1).
C7 The map gives a false impression
T1
C8 of the borders between the der-
matomes; in reality neighboring
dermatomes overlap considerably.
(From Keegan and Garrett 1948.)
to touch is slightly reduced and that for pain is abol- sporadic observations based on the method of remaining
ished (analgesia). The usually more marked reduction sensibility in patients in whom the dorsal roots were cut
in pain than in touch sensation is due to less extensive to relieve pain.
overlapping of fibers coming from nociceptors than of The dermatomal map presented here (Figs. 13.14 and
fibers coming from low-threshold mechanoreceptors. 13.15; reproduced from Keegan and Garrett 1948) is
When a dorsal root is subjected to irritation, as may based on observations of a large number of patients with
occur by compression or stretching in connection with root compressions (usually due to a herniated interverte-
growth of an intraspinal tumor or protrusion of an inter- bral disk) and, in addition, on examination of the distri-
vertebral disk, this can cause pain and other sensory bution of reduced sensation in volunteers who had been
phenomena (numbness, pricking, tingling, and so forth) subjected to local anesthesia of dorsal roots. The skin
in the vicinity of the dermatome. Often the symptoms regions with reduced sensation (hypoesthesia) were care-
are felt only in smaller parts of the dermatome. With a fully mapped out before operation and during operation
protruding (herniated) intervertebral disk in the lumbar it was determined which root was affected. Local anes-
spine, for example, most often the roots of the fifth thesia of a dorsal root also produces a sensory loss that
lumbar or first sacral nerves are affected, and the pain is much less extensive than the total distribution of
is felt in the leg (sciatica). sensory fibers of the root. Thus, the borders between
All dermatomal maps are composites of many single dermatomes as presented in Figs. 13.14 and 13.15 are
observations; no more than one or a few dermatomes imaginary. They ignore, for example, the great overlap
have been determined in any single person. For this between neighboring dermatomes, as well as the fact
reason, all maps showing dermatomes for the whole that the dermatomes are much wider than the zones of
body are approximations, not taking into account, for hypoesthesia occurring after damage to one dorsal root.
example, the considerable individual variations that
exist. This, together with the fact that different methods
Fibers from Different Receptors End in Different Parts
have been used, probably explains why the dermatomal
of the Dorsal Horn
maps of different authors vary so much. For the student
the main emphasis should therefore be on learning the The thin (A and C) and thick (A and A) dorsal
main features of the dermatomal distribution rather root fibers end almost completely separated in the cord
than the artificial (and falsely defined) borders indicated (Fig. 13.16). This indicates that afferents from nociceptors
on the maps. and low-threshold mechanoreceptors make monosynaptic
contacts on different neuronal populations, as confirmed
by recordings from single units in the dorsal horn.
How the Dermatomes Have Been Determined
Nevertheless, the extensive dendrites of spinal neurons
The oldest method for determining the dermatome is to (see Fig. 6.12) and numerous interneurons enable con-
follow the distribution of the nerves by dissection. To fol- vergence of signals from different receptor types. Thus,
low the course of fibers from a root through the plexuses in the dorsal horn, some neurons are modality specific,
is, of course, far from easy. Certain diseases may affect whereas others integrate signals from different kinds of
single dorsal roots and produce changes restricted to receptors.
the dermatome. Shingles (herpes zoster), for example, is Thin A and C fibers conducting signals from noci-
a viral infection of the spinal ganglion cells that produces ceptors end almost exclusively in the dorsalmost parts of
skin eruptions in the dermatome of the affected dorsal the dorsal horn, in laminae I and II (substantia gelati-
roots. Examination of many patients with this disease nosa), but to some extent the A fibers also terminate in
served as a basis for maps showing the dermatome lamina V. Low-threshold receptors around the joints
(Head 1920). Electrical stimulation of dorsal roots during send signals mainly to lamina VI. Signals from cutaneous
operations (Foerster 1933) and comparison of observa- low-threshold mechanoreceptors activate mostly neurons
tions during operations for herniated intervertebral disks in deep parts of the dorsal hornthat is, in laminae III
10
with the information given previously by the patient of to V. Signals from low-threshold mechanoreceptors
where the pain and sensory loss were localized also help
determine the location of dermatomes. Local anesthesia 10 Combination of physiological and anatomic techniques veried the differ-
of single or several dorsal roots in healthy volunteers has ential terminal patterns of dorsal-root bers. Further, such experiments made it
also been of value. The best method is to eliminate possible to study in detail the termination of individual sensory units, as exem-
plied in Fig. 13.12. Single axons in the dorsal root were penetrated with thin
impulse conduction in several dorsal roots on each side of glass microelectrodes (pipettes). After determination of the receptive eld and
one that is left intact (method of remaining sensibility). adequate stimulus of the sensory unit, a tracer substance was injected in the
Sherrington (1898) did this experimentally in monkeys axon with same pipette. The axon and its ramications were subsequently
traced in serial sections of the spinal cord. A remarkable degree of specicity
but the results are not directly applicable to humans. exists in the pattern of termination of bers that belong to functionally different
The German neurosurgeon Foerster (1933) made more receptors.
L1
L2
L2 L3
L4
L5
S1
L1 S3
L3
S2 S2 S4
S2 S5
L2
L4
L3 L1
L5 S2 L1
L4 L2 S1 S2
S1
Ventral
axial line L3
L5
L4
L5
S2
S1 S2
S1 L5
L4 L5
S1 L5
gure 13.15 Dermatomes of the lower L4
extremity. (From Keegan and Garrett
1948.)
Dorsal columns Tract of Lissauer Lamina I Lamina II

A
A
A
I C
II
III
gure 13.16 Terminal regions of the
IV
dorsal root bers in the cord. Left:
Photomicrograph of myelin stained
transverse section through the cervical V
cord. Right: Schematic drawing. The
thickest myelinated bers (A, from VI
muscle spindles and tendon organs) end
in the deep parts of the dorsal horn and
partly also in the ventral horn. Thick, VII
myelinated bers from cutaneous
mechanoreceptors (A) end in laminae IX
IIIVI. The thinnest myelinated and
VIII
unmyelinated dorsal root bers (A
and C)many of them leading from IX
IX
nociceptorsend in laminae I, II, and Collaterals of A and IX
parts of V. Based on experiments with A fibers IX
axonal transport of tracer substances.
and from nociceptors (and thermoreceptors) follow the highest concentration in the dorsalmost laminae
different routes from the dorsal horn to the cerebral (I and especially II). NMDA receptors have attracted
cortex, as we will discuss in Chapter 14. much interest because of their possible role in develop-
ment of central sensitization in chronic pain. There is
also evidence that some primary sensory fibers release
Thin Sensory Fibers from Muscles, Joints, and Viscera:
ATP (probably together with glutamate), exerting fast,
Nociception and Homeostasis
excitatory synaptic actions.
Whereas the thin afferent fibers (the majority coming Several neuropeptides are present in the central and
from nociceptors and thermoreceptors) from the skin peripheral terminals and in the cell bodies of spinal ganglion
end mainly in laminae I and II, corresponding fibers cells, as shown with immunocytochemical techniques.
from the viscera appear to end almost exclusively in These include substance P (SP), vasoactive intestinal
laminae I (and, to some extent, lamina V), thus avoiding polypeptide (VIP), cholecystokinin (CCK), somatostatin,
the substantia gelatinosa. Thin muscle and joint affer- calcitonin gene-related peptide (CGRP), galanin, and
ents appear to terminate in the same parts of the dorsal others. Many ganglion cells contain more than one
horn as the fibers from viscera (although there are some neuropeptide; for example, 80% of all SP-containing
conflicting data). Another feature of afferents from cells contain CGRP as well. The neuropeptides proba-
muscles and joints is their extensive rostrocaudal distri- bly always colocalize with a classical transmitter with a
bution in the cord. For example, afferent fibers from a fast, excitatory action. The peptides appear to mediate
single facet joint of the back terminate in seven to eight slow, modulatory synaptic actions in the dorsal horn,
segments of the cord (cat). It is a common experience probably largely by acting on extrasynaptic receptors
that pain of visceral origin has different qualities than (see Fig. 5.1). When applied locally in the dorsal horn,
pain evoked from the skin; visceral pain is much more SP and CGRP increase the release of glutamate. Further,
diffuse and difficult to localize. In addition, pain that SP receptors (neurokinin receptors) and N-methyl-D-
arises in muscles and joints is less precisely localized aspartate (NMDA) receptors (glutamate) interact, mak-
than cutaneous pain and radiates out from the site of the ing the NMDA receptors more sensitive to glutamate.
noxious stimulus. We also mentioned that muscle pain Release of SP in the dorsal horn might therefore enhance
has a cramp-like quality. Presumably, the anatomic and prolong the excitation produced by incoming
arrangements in the dorsal horn may contribute to such signals from sensory receptors. We return in Chapter 15
differences. to how this phenomenon may relate to increased pain
Lamina I of the dorsal horn has attracted interest sensitivity.
because of its possible role in homeostasis. Due to the A relationship seems to exist between the kind of
unique convergence of thin sensory fibers (especially C tissue a neuron innervates and its neuropeptide content.
fibers) from virtually all tissues of the bodymany of For example, many more of the ganglion cells innervat-
them chemoreceptorslamina I neurons may monitor ing viscera contain SP and CGRP than do those cells
the metabolic status of the organism (such as the con- innervating the skin. About two-thirds of the ganglion
centration of lactic acid and other metabolites produced cells supplying joints contain SP and CGRP. The evidence
in working muscles). At higher levels of the CNS, so far is too limited, however, to draw conclusions regard-
information from lamina I neurons most likely elicits ing relations between neuropeptides, sensory modalities,
appropriate autonomic and endocrine adjustments, while and tissue or organ specificity.
increasing afferent activity is perceived as discomfort
and pain. The latter feelings are, of course, strong rec-
Neuropeptides in Spinal Ganglion Cells and
ommendations to the brain to change behavior (so
Nociceptors
that homeostasis is reestablished).
Most of the neuropeptides are found only in small
ganglion cells (Fig. 13.13) which have thin axons; these
Primary Sensory Fibers and Neurotransmitters
are probably mainly C fibers but also some A fibers.
Probably all primary sensory neurons release a classical Substance P, for example, is present in most of the small
transmitter with fast synaptic actions in the spinal cord. ganglion cells (in about 20% of all, large and small
Among other evidence, this is based on the observation together). The neuropeptide receptors are concentrated
that boutons originating from dorsal root afferents con- in laminae I and II (with the exception of CGRP receptors).
tain small, clear vesicles, which have been shown in These data suggest that the neuropeptides are particu-
other parts of the nervous system to contain this kind of larly involved in transmission from nociceptors and
neurotransmitter. It has been estimated that at least thermoreceptors. Correspondingly, several neuropeptides
70% of all dorsal root fibers release an excitatory amino and their receptors in the dorsal horn are up- or down-
acid transmitter. Both ionotropic and metabotropic regulated in conjunction with inflammation, nerve injury,
glutamate receptors are present in the dorsal horn, with and enduring pain. Especially SP and its receptors
(neurokinin 1, or NK-1) are likely to be involved in from leukocytes. Such substances may contribute to the
processing of signals from nociceptors. Thus, SP is damage of the joint cartilage in arthritis. Blocking the
released from dorsal root fibers in the dorsal horn on SP receptors (NK-1) or depleting the nerves of SP with
nociceptor activation, and microinjection of SP in the capsaicin reduces the inflammatory reaction. Therefore,
dorsal horn make neurons more susceptible to sensory peripheral release of neuropeptides is now believed to
stimulation. Blocking NK-1 receptors prevents this play a role in several human diseases, including rheu-
11
effect. matoid arthritis, asthma, inflammatory bowel disease,
and migraine.
Inammatory Diseases and Release of Neuropeptides
from Peripheral Branches of Sensory Neurons Sensory Fibers Are Links in Reex Arcs: Spinal
The function of neuropeptides present in the peripheral Interneurons
ramifications of primary sensory neurons is less under- Sensory information reaching the spinal cord through
stood than their functions in the central terminals. We the dorsal roots is further conveyed to higher levels of
do not know, for example, whether these peptides are the CNS. In addition, many of the spinal neurons that
released under normal circumstances and take part in are contacted by dorsal root fibers are not links in
the normal homeostatic control. We know, however, ascending sensory pathways but have axons that ramify
that the peptides can be released in the peripheral tissue within the cordthat is, they are spinal interneurons.
by noxious stimuli and by antidromic activation of the The axons of these interneurons establish synaptic con-
axon (see Chapter 29, under Antidrome Signals and tacts with other spinal neurons, among them motoneurons
the Axonal Reflex). Several of these peptides, when (see Fig. 6.6) and sympathetic neurons in the interme-
released in the tissues, have profound effects on vessels, diolateral cell column (see Fig. 3.8), giving origin to
as shown in the skin and mucous membranes. SP and efferent fibers to smooth muscles and glands. In this
VIP both produce vasodilation, and thereby increased manner, reflex arcs (see Fig. 21.9) for several important
blood flow and extravasation of fluid from the capillar- somatic (skeletal muscle) and autonomic (visceral)
ies leading to edema. Furthermore, SP can activate cells reflexes are established. Most, if not all, spinal interneu-
of the immune system, resulting in phagocytosis and rons also establish connections between neurons at
release of inflammatory mediators. Inhalation of irri- different segmental levels (propriospinal fibers). Each
tating gases may provoke release of SP from peripheral
spinal interneuron thus establishes synaptic contacts
sensory fibers in the airways, and the same takes place
with a large number of other neurons in the spinal cord.
in the skin upon strong mechanical stimulation, such as
Signals entering the cord through one dorsal root may
scratching. The liberation of SP in such cases is proba-
influence neurons at several segmental levels, by both
bly due to an axonal reflex because afferent signals
their own ascending and descending collaterals and their
from the receptors are transmitted not only toward the
influence on interneurons with propriospinal collaterals
spinal cord but also distally in branches of the sensory
(Fig. 13.12; see also Fig. 21.10).
fibers (that is, distally in the branches that were not
How far the signals from one dorsal root fiber spread
stimulated).
from interneuron to interneuron depends on the other
Injury to the nerve or the innervated tissue changes
synaptic influences these interneurons receive. For exam-
the neuropeptide content of the ganglion cells. For
ple, descending connections from the brain can selectively
example, experimental arthritis leads to a marked
facilitate or inhibit spinal interneurons. This enables the
increase of SP and CGRP in the cell bodies of the gan-
impulse traffic from dorsal root fibers to be directed so
glion cells that innervate the affected joint (the arthritis
that certain reflex arcs are used, whereas others are
is produced in animals by injecting the joint with a local
switched off, in accordance with the need of the organ-
irritant). SP enters the synovial fluid, and induces release
ism as a whole. Presynaptic inhibition is an important
of such substances as prostaglandins and collagenase
mechanism in this respect (see Fig. 4.7). For example,
separate groups of interneurons mediate presynaptic
11 Although SP is clearly associated with nociception, the correlation is not inhibition of group I muscle afferents, group II muscle
absolute (as judged from studies combining physiological and immunocytochemical
characterization of single spinal ganglion cells). Thus, an SP-containing ganglion cell
afferents, and group Ib tendon organ afferents. Spinal
is not necessarily nociceptive, and many nociceptive neurons do not contain SP. reflexes are treated in more detail in Chapter 21.
14 Central Parts of the Somatosensory
System
OVERVIEW for perception of touch, pressure, vibration, and kinesthesia,

but it is of primary importance for the discriminatory
There are two major somatosensory pathways, both aspects of sensationthat is, the ability to distinguish
consisting of three neurons forming a chain from the differently placed and different kinds of stimuli. The path-
receptors to the cerebral cortex (Fig. 14.1). The first, the way appears not to be necessary for the mere perception
primary sensory neuron, has its cell body in a spinal of, for example, light touch or movement of a joint.
ganglion or in a cranial nerve ganglion; the next, the The central pathway followed by signals conducted
secondary sensory neuron, has its cell body in the gray in the thin dorsal root fibers differs from that followed
matter of the spinal cord or in the brain stem; and the by the thick fibers. The thin fibers make synaptic contacts
third, the tertiary sensory neuron, has its cell body in the in the gray matter of the dorsal horn, where most of the
thalamus. Both somatosensory pathways are crossed, so secondary sensory neurons of this pathway are located.
that signals from one side of the body are brought to the The axons of the secondary neurons cross to the other
cerebral hemisphere of the other side. The actual cross- side of the spinal cord and form the spinothalamic tract.
ing over takes place at different levels for the two path- As the name implies, the fibers of this tract terminate
ways, however (Fig. 14.1). Another important point is in the thalamus. The spinothalamic tract is primarily
that the pathways are somatotopically organized, which important for the perception of pain and temperature,
implies that neurons that conduct signals from different which is consistent with the observation that it transmits
parts of the body are kept separate. information mainly from A and C dorsal root afferents.
Whereas axons conducting from different kinds of (There are also some other, less specialized, pathways
receptors lie intermingled in the peripheral nerves and capable of transmitting somatosensory information.)
the dorsal roots, they are grouped according to their As mentioned, the sensory signals conducted in the
thickness as soon as they enter the spinal cord. The thick medial lemniscus and the spinothalamic tract finally
dorsal root fibers (A and A) pass medially, whereas reach the somatosensory cortex (SI). Here, the body is
the thin ones (A and C) follow a more lateral course represented somatotopically with the face most laterally
into the dorsal horn. Largely, then, neurons conveying on the convexity and the foot on the medial side of the
signals related to low-threshold mechanoreceptors and hemisphere. In addition, the spinothalamic tract sends
nociceptors (and thermoreceptors) are kept separate in signals to several other parts of the cerebral cortex (nota-
the spinal cord, as previously discussed. This segregation bly the anterior cingulate gyrus and the insula). Sensory
is maintained in the pathways that lead from the cord to information reaching the SI is subject to some process-
higher levels. ing before being forwarded to the posterior parietal
The medially located, thick dorsal root fibers continue cortex for further analysis and integration with other
without synaptic interruption rostrally in the dorsal sensory modalities. In addition, many fibers pass from
columns (dorsal funiculus), without synaptic interrup- SI to the precentral motor cortex, contributing to control
tion in the cord. The first synaptic interruption occurs in of voluntary movements.
the dorsal column nuclei, which contain the cell bodies
of the secondary neurons in this pathway. The secondary
axons cross in the medulla to end in the thalamus on CENTRAL SOMATOSENSORY PATHWAYS
the opposite side, forming the so-called medial lemniscus.
From the thalamus, the tertiary neurons send their axons Chapter 13 dealt with the peripheral parts of the soma-
to the primary somatosensory cortex (SI) in the post- tosensory systemthe receptors and the primary sensory
central gyrus. Together, these three links constitute the neurons. We now turn to the tracts and nuclei conveying
so-called dorsal columnmedial lemniscus pathway. and processing somatosensory information within the
From the prevalence of thick fibers conducting from central nervous system (CNS). The term somatosensory
low-threshold mechanoreceptors, it follows that the pathways is not entirely appropriate, however, because
dorsal columnmedial lemniscus pathway is important these pathways transmit signals not only from somatic
190
14: CENTRAL PARTS OF THE SOMATOSENSORY SYSTEM 191
SOMATOSENSORY Examples of lesion experiments in animals and obser-
CORTEX vations in humans with brain damage are mentioned
throughout this book. The interpretation of the associ-
ation between the normal function of the structures and
the symptoms that ensue after lesions is often far from
straightforward, however. For example, a lesion may
destroy not only a certain group of neurons but also fibers
passing through the area. In such cases, dysfunction of
THALAMUS
neuronal groups distant from the lesion may produce the
symptoms. The interpretation is generally least problem-
Medial atic when lesions are confined to large, well-delimited
lemniscus
tracts, whereas symptoms after lesions of the cerebral
MEDULLA cortex may be much more difficult to interpret. A funda-
Dorsal column nuclei
mental problem remains, however, in all such experi-
ments: to what extent can normal function of a part of
Dorsal
columns Skin the brain be deduced from the deficits and disturbances
Spinothalamic resulting from its removal? In many instances, the symp-
tract Touch and
joint sense toms occurring are generally a consequence of dysfunc-
tion and compensations of cell groups not damaged by
SPINAL CORD the lesion.
Pain and Electrical stimulation of tracts and specific cell groups
temperature can elucidate their functions, assuming that the physio-
Dorsal horn logical and behavioral effects are closely related to their
normal function. One example is electrical stimulation
gure 14.1 Somatosensory pathways. Highly simplied to show the of the motor cortex in the precentral gyrus, which elic-
main features of the two major pathways: the medial lemniscusdorsal its more or less isolated muscle contractions in the
column pathway and the spinothalamic tract. The two pathways cross opposite side of the body. This example also illustrates
at different levels and differ in the sensory modalities they mediate. the limitations of such methods: the experiments tell
us that the motor cortex is important for the start of
movements, but they tell us very little about how the
structures, such as skin, muscles, and joints, but also from complicated pattern of activity in many muscleswhich
internal (visceral) organs. Most signals from internal is characteristic of our voluntary movementscomes
organs are not consciously perceived, and visceral sensory about. The difficulties of interpretation become much
processes have been less intensively investigated than greater when regions with multifarious connections
somatosensory ones. We treat sensory information from with other parts of the brain are stimulated (this may
the internal organs in Chapter 29. be particularly obvious for stimulation experiments
Before we describe the somatosensory pathways in of the so-called limbic system; see Chapter 31, under
more depth, a few basic features of the thalamus need Behavioral Effects after Damage or Stimulation of the
to be emphasized. Amygdala).
Stimulation experiments often have to be performed
on anesthetized animals, so this further limits the con-
Lesion and Stimulation Experiments Are Used to
clusions about normal cell function. Many cell groups
Determine the Functions of Cell Groups
are much less excitable during general anesthesia. This
A fundamental approach to the study of the function of problem can be overcome by the use of chronically
specific parts of the nervous system is to make circum- implanted electrodes, which enable stimulation to be
scribed lesions in animals and to observe the functional performed in conscious animals. Such electrodes are
disturbances that ensue. Such a lesion may constitute inter- inserted in the brain under general anesthesia and are
ruption of fiber tracts, destruction of neurons within a fixed to the skull to remain in place (the electrodes
nucleus, or removal of large parts, such as a whole lobe of cause no pain because the nervous tissue is devoid of
the cerebral hemisphere. It is also possible to cool circum- nociceptors). The behavioral effects of stimulation of
scribed regions reversibly, so that neurons are silenced specific parts can then be observed repeatedly. After the
only temporarily. Corresponding reversible effects can be experiments, the exact location of the electrode can be
obtained with the use of local anesthetics. To study the verified histologically. Such experiments also entail
functional and behavioral changes, highly sophisticated problems of interpretation. After all, the evoked activity
test methods may be necessary. Also, control experiments is artificial, and one usually cannot know whether iden-
with lesions of other parts are usually crucial. tical patterns of activity occur naturally.
The Thalamus: Relay Station for Sensory Pathways and contact motoneurons (primary afferents from
muscle spindles).
All pathways conducting sensory information from the
The fibers occupying the medial part of the dorsal
receptors to the cerebral cortex (except the olfactory
columnsthe gracile fascicleconduct signals from the
pathways) are synaptically interrupted in the thalamus.
lower part of the trunk and the legs. These fibers end in
In addition, the thalamus has a decisive influence on
the gracile nucleus (Fig. 14.2). Signals from the upper
the general level of neuronal activity of the cerebral
part of the trunk and the arms are conducted in the
cortex and thus on the level of consciousness and atten-
lateral part of the dorsal columns, the cuneate fascicle.
tion. The macroscopic appearance of the thalamus
The fibers of the cuneate fascicle terminate in the cuneate
is described and illustrated in Chapter 6 (see Figs. 6.22,
nucleus. Why the longest fibers of the dorsal columns lie
6.24, and 6.27). Three major subdivisions, delimited
most medially is explained by the simple fact that they
by the Y-shaped internal medullary lamina, can be
enter the cord at the lowermost level, where no other
identified macroscopically (Fig. 14.6; see also Fig. 6.24):
long ascending fibers are present. At higher levels, fibers
an anterior nuclear group (or complex), a medial
entering from the dorsal root occupy positions lateral to
nuclear group, and a lateral region or part made up of
those that have entered at more caudal levels. Initially
a dorsal and a ventral nuclear group (Fig. 14.6; see also
the fibers of the dorsal columns are arranged segmen-
Fig. 33.7). Within and close to the internal medullary
tally, but as they ascend, the fibers rearrange themselves
laminae are several less clearly defined groups of neu-
so that they are organized somatotopicallythat is,
rons, called the intralaminar thalamic nuclei.1 These are
of particular interest because of their relation to the
thalamic influence on consciousness and sleep (this is
further described in Chapter 26). The intralaminar Leg POSTCENTRAL GYRUS (SI)
nuclei are probably also important for the perception Arm
of pain.
Each of the three major thalamic subdivisions can be THALAMUS
further subdivided into smaller nuclei based on cyto- (ventral nucleus)
architectural differences. These are called the specific Face
thalamic nuclei, because most of them are relays in pre-
cisely organized, major pathways that reach only certain
parts of the cerebral cortex. The various specific nuclei
have different functional tasks, and they receive fiber Internal
capsule
connections from the somatosensory nuclei, the retina, VPL
the nuclei of the auditory pathways, the cerebellum, the
VPM
basal ganglia, and some other cell groups. As a rule,
each nucleus receives afferents from only one of these Trigeminal MESENCEPHALON
nucleus (face)
sources. The somatosensory pathways terminate in the
ventral nuclear group, as is dealt with in more detail
later in this chapter.
PONS
The Dorsal Columns and the Medial Lemniscus Trigeminal nerve

Gracile nucleus
The thick, myelinated fibers in the medial portion of the (leg) Medial lemniscus
dorsal roots curve rostrally within the dorsal columns
(funiculi) just after entering the cord. Many of these Cuenate
nucleus (arm) MEDULLA
fibers ascend to the dorsal column nuclei in the medulla
(see Figs. 6.16 and 6.19), where they terminate and
establish synaptic contacts (Fig. 14.1). As the fibers Dorsal root Cuneate fascicle
ascend in the dorsal columns, they send off collaterals Spinal
nerve Gracile fascicle
ventrally to the spinal gray matter (see Fig. 13.12).
Most of these collaterals establish synaptic contact with
SPINAL CORD
interneurons, but some reach as far as the ventral horn
1 The intralaminar thalamic nuclei were formerly called the unspecic

thalamic nuclei because their connections with the cerebral cortex were gure 14.2 The dorsal columnmedial lemniscus pathway. This is
thought to be diffusely distributed, in contrast to the connections of the specic the main pathway for transmission of signals from low-threshold
thalamic nuclei. More recent studies have questioned the nonspecic nature of mechanoreceptors. Fibers leading signals from mechanoreceptors in
the intralaminar nuclei, however. the face join the medial lemniscus in the brain stem.
fibers conducting from the hand lie together, separated
from those of the forearm, and so on (Fig. 14.2). Thus,
fibers from different dorsal roots are mixed at higher Spinothalamic
levels of the dorsal columns. tract PAG
The primary afferent fibers ascending in the dorsal
columns end in a particular cytoarchitectonic subdivi- Medial
sionthe cluster regionof the dorsal column nuclei. lemniscus Red nucleus
The morphology and arrangement of the neurons in the
cluster regions ensure a particularly precise topographic
arrangement of the afferent and efferent connections.
The neurons of the cluster regions of the dorsal column
nuclei send their axons rostrally to the thalamus, forming
the medial lemniscus. The fibers first course anteriorly Spinal trigeminal
and cross the midline to occupy a position just dorsal to nucleus
the pyramid (Fig. 14.3; see also Fig. 6.17). In the pons
and the mesencephalon, the medial lemniscus is placed Spino-
thalamic
more laterally (Fig. 14.3; see also Figs. 6.18 and 6.20). tract
The medial lemniscus ends in the ventral posterolat-
eral nucleus, VPL (Figs. 14.2 and 14.6). The fibers of Arm Medial
the medial lemniscus are somatotopically organized,2 Leg lemniscus
and this pattern is maintained as the fibers terminate in Arm
the VPL. Fibers from the gracile nucleus (sensory sig- Leg
nals from the leg) terminate most laterally, with fibers
from the cuneate nucleus (arm) terminating more medi-
ally. Most medially, in a separate nucleus, the ventral Pyramid
posteromedial nucleus (VPM) ends the fibers from the
Gracile fascicle
sensory trigeminal nucleus (relaying signals from the Cuneate
face; Fig. 14.6). fascicle
S L
Neurons of the dorsal column nuclei that send their Th
C
axons in the medial lemniscus most likely use glutamate
as transmitter (like most other long, precisely organized
tracts in the CNS).
The Dorsal Columns Contain More than Primary

S L Th C
Afferent Fibers
Spinothalamic and
Many of the primary afferent fibers in the dorsal columns spinoreticular tracts
do not reach the dorsal column nuclei, even though
gure 14.3 Somatosensory pathways. Position and segmental arrange-
they may pass through many segmentsfor example, ment in the cord, medulla, and mesencephalon. The spinal cord is
from the lumbar to the cervical levels. Further, not all disproportionally large. Termination of collaterals of spinothalamic
fibers of the dorsal columns are primary afferents. bers in the brain stem are not shown (see Fig. 15.2).
Thus, the dorsal columns contain a large number of
axons from neurons located in the spinal gray matter.
Most of these are propriospinal fibers extending just
for one or a few segments to end in the cord (proprio- Lemniscus System and Additional Pathways from
spinal fibers). Others, however, end in the dorsal column Nociceptors).
nuclei and are called postsynaptic dorsal column neurons. The dorsal columns also contain some descending
The possible relationship of these fibers to transmission axons making synaptic contacts in the dorsal horn
of nociceptive signals is discussed later in this chapter (especially in lamina V, containing neurons excited by
(Single-Unit Properties in the Dorsal ColumnMedial signals from nociceptors). These descending fibers come
from neurons in a subdivision of the dorsal column
nuclei (the reticular zone) that receives afferents from
2 That bers carrying signals from the leg are located more anteriorly within the cerebral cortex and the reticular formation. Thus,
the medial lemniscus than are those related to the arm (Fig. 14.3) is simply the dorsal column nuclei are part of a neuronal network
because the gracile nucleus is situated more caudally than the cuneate nucleus.
When bers from the cuneate nucleus join those from the gracile nucleus, the
thatby way of descending connectionscontrol the
anterior position is already occupied. flow of sensory information from the cord (see later in
this chapter under Transmission of Sensory Signals Is parts of the extremities. Recordings from neurons in the
Controlled from the Brain). cluster regions of the dorsal column nuclei show that
many neurons are activated by only one kind of receptor.
Some are activated only by joint movements, others
Thalamocortical Pathway to SI and SII
only by light touch of the skin, others only by vibration,
The neurons of the VPL and the VPM send their axons and so forth. These neurons are called modality specific
into the internal capsule (Fig. 14.2) and further through (because they only react to one kind of stimulus) and
this to the postcentral gyrus. This part of the cortex, place specific (because they are activated only from one
made up of cytoarchitectonic fields 3, 1, and 2 (after restricted part of the body).
Brodmann; see Fig. 34.3), constitutes the primary soma- Neurons in the VPL and SI also have the same char-
tosensory area, SI (Figs. 14.2 and 14.6). In addition, some acteristic response properties as those described for the
fibers from the VPL and the VPM end in the secondary neurons of the dorsal column nuclei, even though an
somatosensory area, SII, situated in the upper wall of the increasing number of neurons are activated by more
lateral cerebral fissure (Fig. 14.6). On electrical stimula- than one kind of receptor. In addition, the receptive
tion of SI or SII, conscious human subjects report sensory field tends to be somewhat larger for neurons in SI than,
phenomena such as tingling, itching, numbness, and so for example, in the dorsal column nuclei.
forth. Just as the somatosensory pathways are somato- Some of the axons that end in the dorsal column
topically organized, this is also the case within SI and nuclei do not belong to primary sensory units but to
SII (Figs. 14.2 and 14.7). Fibers conducting signals from neurons with their cell bodies in the dorsal horn (post-
the leg end most medially within the postcentral gyrus, synaptic dorsal column neurons). Unexpectedly, these
then follow fibers conveying signals from the trunk, postsynaptic neurons are activated not only from cuta-
arm, and face successively in the lateral direction. neous low-threshold receptors but also from visceral
nociceptors. We return later in this Chapter to these
special dorsal-column sensory units and their possible
Epileptic Seizures Demonstrate the Cortical
role in nociception (see under Additional Pathways
Somatotopic Pattern
from Nociceptors).
On irritation of the cortex within the postcentral gyrus
for example, by a chip of bone from a skull fracture
Functions of the Dorsal ColumnMedial Lemniscus
the patient may experience fits of abnormal sensations.
System
In the same person, the fits have the same characteristic
pattern each time: The sensations are felt in one particu- Most of the axons at all levels of the dorsal column
lar part of the body and then spread gradually to other medial lemniscus system are thick and rapidly conducting.
parts. The spreading follows the known somatotopic This, together with the data from single-unit recordings
pattern within SI (see Fig. 14.8). For example, the patient mentioned above, enable us to conclude that the dorsal
may first experience a tingling sensation in the thumb; columnmedial lemniscus system is particularly well
then it moves to the index finger and the other fingers; suited to bring fast and precise information from the skin
then to the forearm, upper arm, shoulder, and even fur- and musculoskeletal system about the type of stimulus,
ther. Such epileptic seizures are called Jacksonian fits the exact site of the stimulus, and when the stimulus
(after the famous British neurologist, Hughlings Jackson). starts and stops. Thus, it provides information about the
They signify the presence of a local disease process of the sensory quality and the spatial and temporal character-
brain, and the starting point of the abnormal sensations istics of any stimulus of low intensity (what, where,
indicates the focus of the disease. Often the sensory phe- and when). The next question is then: how is this
nomena are followed by muscle spasms (convulsions) information used by the CNS? Unfortunately, on this
due to spreading of the abnormal cortical electrical activ- point conclusions are largely based on the deficits observed
ity to the motor cortex of the precentral gyrus. when the system is not working. Further, because of the
adaptive changes taking place after an injury, we have to
distinguish between the acute and long-term functional
Single-Unit Properties in the Dorsal ColumnMedial
deficits. Other problems of interpretation arise because
Lemniscus System
with incomplete lesions, functional deficits may be
3
As mentioned, the dorsal columns contain primarily revealed only by tests that require full use of the system.
fibers coming from low-threshold mechanoreceptors in
the skin, muscles, and joints. Recording the activity of
single units in the dorsal columns has confirmed this and
has shown that there is a predominance of rapidly adapt- 3 For example, experiments in cats show that sparing as little as 10% of
the bers of the dorsal columnsas compared with a lesion comprising all
ing sensory units; relatively few are slowly adapting. bersmarkedly reduces the sensory decits with regard to, for example, the
They have small receptive fields, mostly at the distal discrimination of surfaces with different roughness.
Most studies (with some exceptions) indicate that in In fact, after damage to the system, the motor deficits
monkeys, as in humans, acute damage to the dorsal col- may be more disturbing than the purely sensory ones.
umns produces severe ataxia (insecure and incoordinate
movements), which recedes partly or completely within
The Dorsal Columns and Kinesthesia
weeks to months after the damage. In some patients,
the ataxia may be so severe that they cannot walk with- Observations in humans have provided conflicting
out support. Observations some time after the damage results as to whether lesions of the dorsal column
indicate, however, that the dorsal columnmedial lemnis- medial lemniscus system give impaired kinesthesia. A
cus system is not necessary for all aspects of cutaneous thorough clinical study by Nathan and coworkers (1986,
sensation and kinesthesia. First, temperature and pain p. 1032), however, concluded that complete lesions of
perception are unaltered by lesioning the dorsal columns; the dorsal columns do produce clear-cut and enduring
second, light touch of the skin can easily be felt, as can kinesthetic deficits. But they emphasize that: routine
passive joint movements. Two-point discrimination may examination of tactile sensibility does not show up
not be appreciably reduced, and some reports even indi- these defects as well as everyday activities of living. The
cate that the ability to recognize objects by manipulation further one gets away from this testing situation, the
may be retained (clinical observations do not support easier it is to see the effects of these disturbances of
the latter point, however). What appears to be consis- sensibility. One example may illustrate this point: a
tently impaired is the ability to solve tasks that require patient with damage to the dorsal columns was aware of
spatially and, in particular, temporally very accurate a toe being passively moved by the examiner; neverthe-
sensory information. Thus, a coin pressed into the palm less, his shoe would easily slip off his foot without his
of the hand may perhaps be recognized, but the patient noticing, and he was unable to roll over in bed because
is unable to decide which is the larger of two coins. The he did not realize that one leg was hanging off the bed.
patient may also correctly identify that something is In monkeys, Vierck and Cooper (1998) described defi-
moving on the skin, but not the direction of the move- cient kinesthetic sensation of the hands after cutting the
ment. To ask the patient to identify figures written on cuneate fasciculus, although only specific and detailed
the skin, for example, is one sensitive test of the function testing revealed the problems. Thus, the perception of
of the dorsal columnmedial lemniscus system. Further, passive finger movements was impaired only if the move-
some careful clinical observations indicate that the per- ments were small or slow. This is indeed what you would
ception of joint position and movement is abnormal expect when eliminating a system devoted to very precise
after lesions of the dorsal columns. sensory information. It is furthermore worth noticing
The above-described sensory deficits occurring after that the monkeys had more obvious problems with pre-
4
lesions of the dorsal columns have in common that they cise hand movements than with kinesthesia.
concern spatial and temporal comparisons of stimuli,
or what we call discriminative sensation. Such sensory
Clinical Examination of the Dorsal ColumnMedial
information is crucially important for the performance
Lemniscus System
of many voluntary movements; indeed, disturbances of
voluntary movements are characteristic of the lesions Many of the deficits that occur after damage to the dor-
that affect the dorsal columnmedial lemniscus system. sal columnmedial lemniscus system may not be revealed
After the acute phase, the movement deficits first con- by a routine neurological examination. Nevertheless,
cern movements that require fast and reliable feedback they may render the patient severely handicapped in daily
information from the moving parts. For example, the life. We described earlier in this chapter similar symp-
ability to adjust the grip when an object is slipping is toms occurring after loss of thick myelinated nerve fibers
clearly reduced. Delicate movements, such as writing in the peripheral nerves. This is not surprising because
and buttoning, are performed only with difficulty after many of these fibers continue into the dorsal columns.
lesions of the dorsal columns. It is not possible to throw The deficits may be more severe with peripheral loss,
an object accurately or to perform a precise jump, pre- however, because reflex effects from low-threshold
sumably because such activities require feedback infor-
mation from skin receptors to judge the pressure exerted
4 In the legs, however, no defect of joint sense occurred in monkeys after
on the hand by the object or by the ground against the lesions of the dorsal columns at thoracic or cervical levels. This can perhaps be
sole of the foot. explained by less rigorous testing of the legs than of the hands. Another expla-
In conclusion, the dorsal columnmedial lemniscus nation is possible however. Thus, primary afferent bers conveying signals from
slowly adapting low-threshold mechanoreceptors in leg muscles and joints leave
system is of primary importance for complex sensory the gracile fasciculus at the low thoracic level (in monkeys). Then they enter the
tasks, such as determination (comparison) of direction dorsal horn, where they synapse on second-order sensory neurons. The axons
and speed of moving stimuli. Further, many precise vol- of the latter continue in the dorsal part of the lateral funiculus, not in the dorsal
columns. Thus, a lesion of the dorsal columns at cervical levels would not inter-
untary movementsespecially of the handdepend on rupt signals from leg proprioceptors. We do not know, however, whether this
the fast sensory feedback provided only by this system. arrangement pertains also to humans.
mechanoreceptors (among other things) are also lost. Leg POSTCENTRAL GYRUS (SI)
Based on these considerations, a routine examination Arm
of kinesthesia (asking the patient to indicate the direc-
tion of movement in a joint being passively moved)
would not provide definite information because such a THALAMUS
(ventral nucleus)
test may be negative (i.e., normal performance) in spite Face
of damage to the dorsal columns or the medial lemniscus.
Neither is testing the sense of vibration a reliable source
of information; several clinical studies show that vibra-
tion is not always reduced after damage to the dorsal
columns. A routine testing of cutaneous sensation would
not necessarily reveal the lesion. The most reliable infor- Internal
capsule
mation is presumably obtained by testing the ability to
judge the direction of a stimulus to the skin and to
examine the patients ability to identify numbers written MESENCEPHALON
on the skin.
The Spinothalamic Tract PONS
As mentioned, the fibers in the lateral portion of the Trigeminal

dorsal roots are predominantly thin (A and C fibers). nerve (face)
Immediately after entering the cord, such fibers divide
into short ascending and descending branches, passing Trigeminal
nucleus
only for one or two segments in each direction. The (spinal
MEDULLA
collaterals and terminal branches of these fibers pass subdivision)
ventrally to end in the gray substance of the dorsal
horn, where they establish synaptic contacts with other Spinal Dorsal root Spinothalamic
neurons (Figs. 14.4 and 14.5). The thinnest (largely C nerve tract
fibers) among the ascending and descending branches
of the dorsal root fibers form a small bundle immedi-
SPINAL CORD
ately dorsal to the dorsal horn, called the tract of
5
Lissauer, or the zona terminalis (see Fig. 13.16).
Many neurons in the dorsal horn send off long
Anterolateral funiculus
ascending axons. Most of these first course almost hor-
izontally and somewhat ventrally across the midline
through the gray substance (Figs. 14.1 and 14.4). After gure 14.4 The spinothalamic tract. This is the main pathway for
having entered the lateral funiculus on the opposite transmission of signals from nociceptors and thermoreceptors.
side, the fibers curve sharply in the rostral direction. As Nociceptive and thermoceptive signals from the face join the spinotha-
mentioned, some of these fibers ascend without inter- lamic tract in the brain stem (the spinal trigeminal nucleus).
ruption as far as the thalamus, thus forming the spino-
thalamic tract. Many of the spinothalamic fibers give
off collaterals in the brain stem to nuclei involved in auto- fibers terminating in the brain stem. In the brain stem,
nomic control (circulation, respiration) and in behavioral the spinothalamic tract lies laterally and fairly super-
responses to signals from nociceptors. The majority of ficially (Fig. 14.3).
spinothalamic tract fibers are located in the anterolateral
quadrant (funiculus), that is, anteriorly within the lateral
Synaptic Coupling between Dorsal Root Fibers and
funiculus (Fig. 14.3). Here the spinothalamic fibers
Spinothalamic Neurons
intermingle with numerous propriospinal fibers and
The location and properties of spinothalamic neurons
have been determined by use of axonal transport methods
5 There has been a long-standing controversy with regard to the ber composi-
tion of the tract of Lissauer, largely because of difculties in tracing unmyeli- combined with physiological studies of anatomically
nated bers. Investigations with improved methods indicate that about 80% of identified neurons (Fig. 14.5). Particularly, conditions
the bers of the tract of Lissauer are primary afferent (dorsal root) bers. The in monkeys may be expected to correspond closely to
other bers are propriospinal bers ensuring cooperation between neighboring
segments. This concerns in particular Rexeds laminae I and II, which also those in humans. The major group of spinothalamic
receive most of the thin primary afferents. cells is located in lamina V, particularly in those parts
I A the signals from nociceptors are processed. For exam-

C ple, hardly any of the neurons in lamina II (substantia
II gelatinosa) send fibers into the spinothalamic tract, yet
III
C
they receive a large proportion of the dorsal root C
Spinothalamic fibers. Generally, the interneurons of the dorsal horn
neurons IV and those of substantia gelatinosa in particularwill
have a decisive influence on whether the signals from
V
nociceptors will be transmitted to higher levels of the
nervous system. These interneurons can both inhibit
VI and facilitate the signal traffic that will ascend in the
spinothalamic tract. Thus, they will strongly influence
how intense the experience of pain will be on a certain
stimulation of nociceptors. As we discuss later in this
VII
chapter, the CNS can control signal transmission from
receptors to higher levels by descending fibers acting on
IX
the dorsal horn interneurons.
VIII
IX IX Properties of Spinothalamic Tract Units

IX
Physiological studies of single spinothalamic cells and of
IX
thalamic cells in the terminal regions of spinothalamic
fibers are in accord with their preferential activation
gure 14.5 Signal transmission from nociceptors in the spinal cord. from thin (A and C) dorsal root fibers.
The gure shows the terminal regions of thin dorsal root bers leading
from nociceptors and the position of neurons sending their axons to
The spinothalamic cells in the cord are classified by
the opposite thalamus (spinothalamic neurons). Lamina II (substantia their response properties:
gelatinosa) receives many C bers, but the neurons of this lamina do
not send their axons to the thalamus.
1. Low-threshold unitsneurons that react only to
light mechanical stimuli (e.g., light touch of the skin)
2. Wide dynamic range units (WDR)neurons that
that receive A fibers from the dorsal roots. The other
react to stimuli of high intensity (activating nocicep-
major population of spinothalamic cells are located
tors) and to light stimuli; the impulse frequency of these
in lamina I. When we recall that most of the A and C
cells increases with increasing stimulus intensity
fibers establish synapses in lamina I and V (Fig. 14.5),
3. High-threshold units (HT)neurons that respond
the relationship between the spinothalamic tract and
only to stimuli of an intensity sufficient to activate
perception of pain becomes understandable. In addi-
nociceptors
tion, scattered spinothalamic cells are found more
4. Thermosensitive unitsneurons that respond
ventrally in laminae VII and VIII (Fig. 14.5).
only to either warming or cooling of the skin, indicating
The anatomic data indicate that many thin dorsal root
that they are activated by thermoreceptors.
fibers do not synapse directly (monosynaptically) onto
the spinothalamic cells but influence them indirectly via These properties, determined in animal experiments,
spinal interneurons. The numerous small neurons in agree well with clinical observations in patients who have
lamina II, which are contacted by dorsal root C fibers, been subjected to therapeutic interruption of the antero-
send their axons in part dorsally into lamina Iwhere lateral funiculus (containing the spinothalamic tract and
spinothalamic cells can be influencedand in part ven- other fibers). This operation, called cordotomy, is some-
trally in the dorsal horn to contact other interneurons, times applied to alleviate intense pain that cannot be
which in their turn form synapses on spinothalamic overcome in any other way. After such an operation,
cells in laminae V, VII, and VIII. In addition, many of sensations of pain and temperature are almost totally
the neurons in lamina II send axon collaterals to spinal abolished in the opposite side of the body in the parts
segments above and below their own (passing in the supplied by sensory fibers from the spinal segments below
tract of Lissauer). the level of interruption (although only temporarily; see
The synaptic arrangements underlying further transfer under Additional Pathways from Nociceptors).
of signals transmitted in thin dorsal root afferents, many Although both lamina I and lamina V contain a mixture
coming from nociceptors, must be complex. The large of WDR and HT neurons, it appears that lamina I con-
number of very small interneurons and the numerous tains a majority of HT (nociceptive specific) neurons,
neuroactive substances (e.g., numerous neuropeptides) whereas WDR-neurons dominate in the deeper parts of
in the dorsal horn make it a difficult task to clarify how the dorsal horn.
Terminations of the Spinothalamic Tract and Further under Which Parts of the Cerebral Cortex Process
Projections to the Cortex Nociceptive Information?).
The thalamic termination site of the spinothalamic tract
is more extensive than that of the medial lemniscus, and Does the Spinothalamic Tract Consist of Distinct
the same holds for the further signal transmission to the Discriminative and Affective Parts?
cerebral cortex. Many of the spinothalamic fibers end The spinothalamic tract has been proposed to consist of
in the VPL with a somatotopic pattern (Fig. 14.4), but two anatomically and functionally different components.
not in exactly the same parts as the fibers of the medial One partending in the lateral thalamus (mainly in VPL
lemniscus (corresponding fibers from the spinal trigeminal and VPM) with further transmission to SIwould be
nucleus end in the VPM). The terminal ramifications are responsible for the discriminative aspects of pain percep-
also different for the two pathways, and nociceptor- tion; that is, our ability to localize a painful stimulus and
activation of VPL neurons requires more summation to judge its quality (sticking, burning, cramp-like, and so
than activation from low-threshold mechanoreceptors. forth). The other partconsisting of fibers ending in the
In addition, many of the spinothalamic fibers arising in medial thalamus (especially in the intralaminar nuclei)
lamina I end more posteriorly in the ventromedial nucleus and projecting on to the insulawould be responsible
(VM). Spinothalamic fibers also end in parts of the intra- for the affective, emotional aspects of pain. There is much
laminar nuclei (e.g., the central lateral nucleus, CL), in the evidence, however, that this division is at least an over-
mediodorsal nucleus (MD), and some other nuclei. simplification. For example, many spinothalamic fibers
The multiple terminations of spinothalamic fibers send collaterals to both lateral and medial thalamic nuclei
probably explain how signals from nociceptors, by way (and to parts of the reticular formation in the brain stem).
of thalamocortical fibers, can reach several regions of Furthermore, microstimulation of the lateral thalamus in
the cortex in addition to SI and SII. Recordings of single- humans (presumably in the ventromedial nucleus) evoked
unit activity in monkey SI indicate that neurons activated pain that could be precisely localized and at the same
by high-intensity (presumably noxious) cutaneous stimuli time evoked strong emotions (anxiety, discomfort).
are concentrated in a narrow zone at the transition
between Brodmanns areas 3 and 1 (Fig. 14.6). This may
Spinothalamic Cells Receive Signals from Both Somatic
primarily concern signals relayed through the VPL, whereas
and Visceral Structures
signals from other parts of the thalamus receiving spino-
thalamic fibers may directly and indirectly influence Recording from spinothalamic cells in the spinal cord has
other cortical areas, such as the anterior cingulate gyrus shown that many can be activated by nociceptive stimuli
and the insula (this is further treated later in this chapter, applied to visceral organs and to the skin. Signals from
Central Postcentral gyrus (SI)

sulcus
Posterior parietal cortex
Area 5
Central
sulcus Postcentral gyrus (SI)
1
3b
4 2
SII 5
3a gure 14. 6 The somatosensory cortex
(SI) and its thalamic afferent nucleus.
Upper left: The location of the SI and
SII and parts of the posterior parietal
Thalamus cortex in the left hemisphere. Upper
right: The extension of the various
cytoarchitectonic areas of the central
A Intralaminar nuclei region. Below: The VPLsupplying
the SI and SII with somatosensory
VA signalsis marked on a schematic
VL drawing of the left thalamus. The main
afferent pathways to the VPL are also
VPL
VPM indicated. A, anterior thalamic nucleus;
LG, lateral geniculate body; MG, med-
CGM
CGL ical geniculate body; VA, ventral ante-
rior nucleus; VL, ventral lateral nucleus;
Medial lemniscus and From sensory VPM, ventral posteromedial nucleus;
spinothalamic tract trigeminal nucleus
VPL, ventral posterolateral nucleus.
the skin and viscera converge onto the same neuron, which blood pressure, heart rate, sweating, breathing, muscle
then conveys the information to the thalamus. Nociceptive tone, bladder and bowel function, and so forth. Parts of
signals from muscles and skin can also converge onto the the reticular formation, the PAG (periaqueductal gray),
same spinothalamic neuron. Sensory convergence of this and the parabrachial nucleus all receive signals from noci-
kind pertains to regions of the skin and deep tissues and ceptors and participate in automatic behavioral responses
to visceral organs that receive sensory innervation from to nociceptor activation. Among these, the parabrachial
the same segments of the cord. The primary sensory fibers nucleus is special since it receives spinal afferents mainly
can activate the spinothalamic cells monosynaptically from lamina I, which contains many neurons specifically
6
or through one or more interneurons (polysynaptically). activated from nociceptors. In addition, these brain stem
In addition, in some spinal ganglion cells the peripheral nuclei send fibers rostrally to end in the amygdala, hypo-
process divides, with one branch innervating the skin thalamus, and thalamus. Such connections are probably
and the other a visceral organ or a muscle. involved in the varied affective, autonomic, endocrine,
The observations of convergence on spinothalamic and behavioral responses to noxious stimuli but may also
cells and branching of sensory fibers may help explain gain access to the cortical network responsible for pain
why pain arising from a visceral organ is often felt as if perception. Whereas the spinothalamic tract is mainly
it comes from the skin. This phenomenon is called crossed, these other pathways are bilateral. Thus, unilateral
referred pain and is discussed further in Chapter 29. stimuli would reach the thalamus (and cerebral cortex) of
both sides.
We know that nociceptive neurons are easily sensitized
What Tracts in the Anterolateral Funiculus Can
by prolonged stimulation. For example, recordings during
Mediate Alone: A Case History
brain surgery in humans with chronic pain syndromes
A woman with a knife-stab partly severing the cord at revealed neurons in the reticular formation and thalamus
the Th3 level illustrates what the anterolateral funiculus that responded to noxious stimuli; while such responses
alone can mediate of somatic sensations (Danzinger and were not found in the same regions in pain-free controls
coworkers 1996). The lesion, which was verified during (the patients were undergoing brain surgery for move-
open surgery, severed the cord completely except for the ment disorders). These and other data strongly suggest
anterolateral fascicle and adjoining parts of the lateral that various cell groups and pathwaysin addition to the
funicle on the left side. Shortly after the accident, with spinothalamic tractare recruited under special, poorly
some difficulty, she was able to perceive and localize understood circumstances.
light touch on both sides of the body below the lesion. After interruption of the spinothalamic tract by cor-
She was able to perceive passive joint movements on dotomy, pain usually returns in some months to a year.
the left side, but not vibration. Eighteen years after the This probably depends, at least partly, on transmission
lesion her sensibility was virtually unchanged. The lesion of nociceptive signals in pathways other than the spino-
did not abolish control of the bladder and the rectum, thalamic tract (nociceptor-activated postsynaptic units
and she retained some voluntary control of movements in the dorsal columns, spinoparabrachialamygdala
of the left leg (whereas the right leg was paralytic, she connections, and others). Presumably, after severance of
was, for example, able to lift the left leg 30 in the the dominant spinothalamic pathway, other minor path-
supine position). ways, which normally do not contribute significantly to
our pain perception, take over.
Additional Pathways from Nociceptors
Homeostatic Surveillance: A Task of Ascending Tracts
Other pathways than the spinothalamic tract may
from Lamina I?
transmit signals from nociceptors to consciousness,
even if their contribution may be minor under normal As mentioned, perception of pain and temperature are
conditions. It should be emphasized that nociceptive particularly dependent on the spinothalamic tract,
signals reach numerous subcortical nuclei (in the rat although, as witnessed by clinical observations, this
apparently more than 20), many of which have ascend- tract can also mediate a relatively crude sense of touch
ing projections. Concerning transmission from visceral and pressure. In a broad perspective, pathways leading
nociceptors, postsynaptic fibers in the dorsal columns from nociceptors constitute an alarm system: they
seem to contribute in addition to the spinothalamic report that something is wrong in the body and a change
tract. There is also evidence that signals in the dorsal
columns may contribute to chronic pain in some instances
(this is further discussed in Chapter 29, under Visceral 6 In the cat, the majority of lamina I neurons with an ascending axon terminate
Pain). Further, many nociceptor-activated spinal neurons in the parabrachial nucleus and the PAG (twice as many in the parabrachial
nucleus as in PAG). Only about one sixth appears to terminate in the thalamus.
send their axons to brain stem nuclei that mediate auto- If this is so also in humans, it would underscore the role of lamina I in homeo-
matic responses to noxious stimuli, such as changes of static control.
of behavior is required to avoid damage. Especially in this particular situation. During walking, signals from
many neurons in lamina Iresponding to a variety of mechanoreceptors in the sole of the foot are let through
potentially harmful tissue substances and to heat and to the motor cortex immediately before heel strike, while
coldseem suited for this task. The system notifies the traffic is inhibited during most of the stance phase.
impending cell damage regardless of cause (metabolites, We know from daily life that we have the ability to
inflammatory mediators, extreme temperatures, or leave out sensory signals that are irrelevant at the moment.
mechanical forces), and is an integral part of the defense Without such filtering mechanisms, we would be flooded
systems of the body. Pain elicits a stress response consist- by sensory information. The sensory information finally
ing of autonomic, somatic, and endocrine components reaching the cerebral cortex is therefore censored
aiming at restoring homeostasis. Activation of brain stem and distorted compared with the stimuli received by the
nuclei (parabrachial nucleus, PAG), the hypothalamus, receptors.
and the amygdala elicits the stress response, either by Later in this chapter we deal specifically with descend-
ascending tracts carrying signals from nociceptors or by ing control of transmission in the pain pathways.
descending signals from the cortical pain network (or
both). In daily life, most of the signals conveyed through
Why We Cannot Tickle Ourselves
A and C fibers do not reach consciousness: small adjust-
ments prevent the sum of stimulation to reach a level The fact that we are unable to tickle ourselves is an
sufficient to cause pain. We alter position, change clothing, interesting special case of sensory-information control.
or protect ourselves in other ways without needing to Identical signals from cutaneous low-threshold mechan-
pay attention. Persons born without the ability to feel oreceptors can be perceived as tickling if they are caused
pain illustrate the importance of the alarm system: they by another person stroking our skin but as mere touch
incur frequent and serious injuries of various kinds such if a self-initiated movement causes them. In the latter
as burns, wounds, infections, overstretched joints, and situation, the activation of SI is reduced. Apparently,
fractures. only signals that are unexpected or unpredictable are let
through to SI without suppression. Presumably, experi-
ence has provided us with (subconscious) knowledge of
The Brain Controls the Transmission of Sensory Signals
the sensory signals that a certain motor command will
Descending fibers from the cerebral cortex and the brain produce. The cerebellum may have a role in such situations
stem end in the relay nuclei of the somatosensory path- by informing the cerebral cortex about which somatosen-
ways. One important group of such connections arises sory signals might be expected. Probably, the cerebellum
in SI (the primary somatosensory area) and terminates in receives a copy of the motor command issued from the
the thalamus (VPL and other nuclei), the dorsal column motor cortex (efference copy).
nuclei, the sensory trigeminal nucleus, and the dorsal
horn of the cord (see Fig. 22.8). These connections are
somatotopically organized and enable selective control of THE SOMATOSENSORY CORTICAL REGIONS
sensory signal transmission from particular parts of the
body and from particular receptor types. Physiological As mentioned, the sensory signals conducted in the medial
studies indicate that descending connections from the lemniscus finally reach the two somatosensory areas,
SI sometimes can facilitate signal transmission through SI and SII. In addition, the spinothalamic tract sends
the sensory relay nuclei, but inhibitory effects appear to signals to several other parts of the cerebral cortex.
be most common. The latter effects are mediated via Both SI and SII receive somatotopically-organized pro-
inhibitory interneurons. Generally, it appears that signals jections from the VPL and VPM (Figs. 14.7 and 14.8),
from somatosensory receptors are continuously regu- transmitting signals primarily from low-threshold mech-
lated to adapt to changing needsfor example, whether anoreceptors and, to a lesser extent, from nociceptors.
sensory information is received passively or actively Somatosensory signals also reach other cortical regions,
sought, whether it is needed for movement control, or however, such as the motor cortex (MI) in the precen-
just arise as a trivial result of self-initiated movements tral gyrus. Not unexpectedly, primarily signals from
(see later, Why We Cannot Tickle Ourselves). proprioceptors are conveyed to the motor cortex.
Recordings from single units of the medial lemniscus in The parts of SI receiving sensory signals from the feet,
conscious monkeys have shown reduced impulse traffic hands, and face are much larger than those receiving
from cutaneous receptors immediately before a voluntary signals from other parts of the body (Fig. 14.8). Further,
movement. There is indirect evidence of the same phenom- the region devoted to the thumb is larger than that
enon in humans: the threshold for perceiving a vibratory devoted to the palm of the hand, which, in turn, is larger
stimulus is elevated immediately before a voluntary than that devoted to the forearm, and so on. This is
movement. Perhaps this happens because proprioceptive mainly a reflection of the much higher density of sensory
signals are of greater importance than cutaneous ones units that supply the skin at distal parts of the extremities
Supplementary of the cortical representation of certain body parts.
motor area (SMA) Similar overrepresentations exist within the visual and
auditory systems.
Various brain-imagining techniques, such as fMRI
and PET, have brought a wealth of information on the
Foot contribution of specific cortical areas in motor, sensory,
Primary motor Primary somatosensory
area (MI) area (SI) and cognitive processes. We refer to results from such
studies throughout this book. A brief description of
these and other methods for study of the living human
Central sulcus brain are found in Chapter 11 (see under Methods to
Hand Study Neuronal Activity and Connectivity in the Living
Brain).
Face
The Primary Somatosensory Area (SI)

The primary somatosensory area, in particular, has been
the subject of intense anatomic and physiologic investi-
Secondary somatosensory gations. The subdivision of SI into different cytoarchi-
area (SII)
tectonic areas3, 1, and 2 of Brodmann (see Figs. 22.4
and 33.2)corresponds to functional differences. These
gure 14.7 The somatosensory regions SI and SII and their somato-
areas extend as narrow strips from the midline laterally
topic organization (monkey). Motor areas (MI and SMA) are also
shown. (After Woolsey 1958.) along the postcentral gyrus: that is, perpendicular to the
somatotopic arrangement (Fig. 14.6; see also Fig. 33.3).
Animal experiments, particularly by the American neuro-
physiologist Mountcastle, show that the cytoarchitec-
tonic subdivisions differ with regard to the kinds of
receptor from which they receive information. Area 3a,
on the transition to the MI (see Fig. 22.4), receives sensory
7
signals from muscle spindles in particular. Neurons in
area 3b are mainly activated by stimulation of cutaneous
receptors (predominantly by low-threshold mechanore-
ceptors). Neurons receiving information from rapidly
adapting receptors appear to be separated from those
receiving from slowly adapting receptors. Area 2 is influ-
enced by proprioceptors to a larger extent than area 3b is;
for example, many neurons are most easily activated by
bending of a joint. Within each of the cytoarchitectonic
subdivisions it appears that the whole body has its repre-
sentation; thus there are probably three body maps within
SI. The map in Fig. 14.7 therefore gives a somewhat mis-
leadingly simplified presentation.
Figure 14.8 shows the representation of body parts
based on electric stimulation of the cortical surface in
conscious patients (during neurosurgery for therapeutic
gure 14.8 Relative size of the cortical regions representing various reasons). The patient tells where she feels something
body parts. Schematic section through the postcentral gyrus (SI) of when a certain cortical site is stimulated. Although later
the human brain. Based on electrical stimulation during brain surgery studies overall agree with the findings of Penfield and
under local anesthesia. (After Peneld and Rasmussen 1950.)
Rasmussen (Fig. 14.8), an exception seems to concern
the representation of the genitals, that most likely are
represented on the convexity near the lower part of the
(and parts of the face) than more proximal parts of the
trunk. To use this very detailed information from the 7 Some have argued that area 3a should be considered a part of the MI rather
most densely innervated parts of the body, a large vol- than of SI. In certain respects, anatomically and physiologically, area 3a repre-
ume of cortical gray matterthat is, many neurons sents at least a transitional zone. Like the other subdivision of SI, area 3a
receives thalamic afferents from VPL, whereas MI (area 4) receives them from
has to be available for information processing. A VL. The afferents from other parts of the cortex are more like those of MI than
magnification factor gives a numerical representation of the other parts of SI, however.
abdomen (and not on the medial aspect of the hemi- respond to complex combinations of stimuli, as shown in
sphere close to the foot, as originally indicated by Penfield monkeys. Their activity depends not only on what is occur-
8
and Rasmussen). ring in the periphery but also on whether the attention
Even though many neurons in SI are activated only of the monkey is directed toward the stimulus. The pos-
or most easily from one receptor typethat is, they are terior parietal cortex sends efferent connections to motor
modality-specificthere are other neurons in SI with areas in the frontal lobe, thereby linking sensory infor-
more complex properties. For example, many neurons mation with goal-directed movements. Accordingly,
have large receptive fields, indicating that they receive some neurons are active in conjunction with the monkey
convergent inputs from many primary sensory neurons. stretching its arm toward something it wants.
Further, movement of just one joint in one direction In addition to the posterior parietal cortex, SII (Fig. 14.6)
activates some neurons, while other neurons are activated and adjoining areas in the insula (Fig. 14.9; see also
by several joints. Still other neurons in SI require specific Fig. 6.29) also process information from SI. The anterior
combinations of receptor inputs to be activated. Thus, part of insula integrates somatosensory information with
processing of the raw sensory information already other sensory modalities (taste and smell, and signals from
begins at the first cortical stage; SI is not merely a simple vestibular receptors). Sensory units in these areas typi-
receiver of sensory information. cally have large receptive fields and are activated from
Efferent association connections from SI pass poste- both sides of the body. Insula is, however, more strongly
riorly to the posterior parietal cortex, which processes linked with processing of visceral sensory information
the sensory information (see below), and anteriorly to and pain (see below, and Chapter 34, under Insula).
the motor cortex (MI). The latter connections appear to
be of particular importance while learning new move-
Symptoms after Lesions of the Somatosensory Areas
ments, whereas they are not crucial for the performance
of well-rehearsed movements (as judging from lesion Lesions of SI in humans entail reduced sensation in the
experiments in monkeys). This may be explained by an opposite half of the body. A localized destruction of the
extra need for fast and precise feedback from the moving SI, or of the fibers reaching it from the thalamus, may
parts during learning. The connections from SI to MI, produce loss of sensation in a restricted area (corre-
furthermore, are necessary for motor recovery after sponding to the somatotopic localization within SI).
cutting the connections from the cerebellum to MI, as Not all sensory qualities are affected equally, however.
discussed in Chapter 11 (see under Examples of Discriminative cutaneous sensation and kinesthesia are
Substitution from Animal Experiments). This may also particularly disturbed; much less reduced (if at all) is
be regarded as a learning situation. pain sensation. As is the case with lesions of the dorsal
columns, the sensory deficits gradually diminish after
the time of the lesion. The least improvement with time
Further Processing of Sensory Information Outside SI
is seen in the discriminative aspects of sensation, whereas
Although processing somatic sensory information starts pain sensation improves considerably. This can perhaps
in SI, clinical and experimental observations show that be explained by the fact that the pathways for signals
the cortex posterior to SI is necessary for comprehen- from nociceptors are to a larger extent bilateral than are
sive utilization. The posterior parietal cortex comprises the pathways from low-threshold mechanoreceptors.
area 5 and area 7 (Fig. 14.6; see also Fig. 33.7) and
belongs to the association areas of the cerebral cortex
(these will be further discussed in Chapters 33 and 34).
Areas 5 and 7 do not receive direct sensory information SI Posterior parietal cortex Anterior
from the large somatosensory pathways but via numer- Prefrontal cingulate gyrus
cortex
ous association fibers from SI and SII. They also receive
numerous connections from other parts of the cortex.
Broadly speaking, in areas 5 and 7 the bits of information
reaching SI are put together and compared with other
inputs, such as visual information and information
about the salience of a stimulus and about intentions.
Neurons in area 5 often have large receptive fields and
SII
Insula
8 Representation of the genitals on the medial aspect of the hemisphere would
be in conict with the principle of continuous representation of body parts
(Fig. 14.7). Indeed, a recent study using natural peripheral stimulation and
fMRI (rather than stimulation of the cortical surface) concluded that the gure 14.9 Regions of the cerebral cortex showing increased activity
penis is represented on the convexity in the transition zone between the lower during pain perception. (Based on data from a meta-analysis pub-
abdomen and the thighs (Kell et al. 2005). lished by Peyron et al. 2000.)
It might also be explained by signals from nociceptors regions are the insula, SII, and the anterior cingulate
being distributed to areas outside the SI. gyrus (Fig. 14.9). In addition, most studies show activa-
Whereas lesions of the posterior parietal cortex pro- tion in SI, the premotor area, and the thalamus. Often
duce difficulties with the use of objects (apraxia), lesions the prefrontal cortex and the posterior parietal cortex
of SII and neighboring regions in the insula impair the (area 7b) are activated as well.
ability to recognize objects by touch (tactile agnosia). Most experimental studies evoked activation of the
Similar problems with the visual recognition of objects anterior cingulate gyrus (and other areas) via stimula-
occur after lesions of dorsal and ventral divisions of the tion of skin nociceptors (injecting irritating substances
extrastriatal visual areas, respectively. or radiation heat). In fact, surgical ablation of the ante-
rior cingulate gyrus has been used to alleviate chronic
pain. Afterward, some patients report that the pain is
Which Parts of the Cerebral Cortex Process Nociceptive
still there, but it is less bothersome: it seems as if the
Information?
affective component of the pain has been reduced (this
Animal experiments show that noxious stimuli activate is similar to pain perception after large lesions of the
neuronal groups in many parts of the brain, both sub- frontal lobe). This may perhaps be explained by other
cortically (in the amygdala, hypothalamus, PAG, basal mental processes that involve the cingulate gyrus. For
ganglia, and cerebellum) and in the cerebral cortex. SI example, activation of the anterior cingulate gyrus is
does not appear to play a central role in pain perception, associated with the person directing his attention
however, in contrast to its crucial role in other aspects toward a stimulus. Further, activation of the anterior
of somatosensory sensation. Although they have been cingulate gyrus is associated with monitoring of cogni-
elicited by electrical stimulation of SI in humans, pain tive and bodily processes: there is a change of activity in
sensations are an infrequent effect of such stimulation. relation to errors. Indeed, signals from nociceptors are
Curiously, stimulation of other parts of the cortex did strong warnings that something is wrong in the body, and
not evoke pain, either. Ablations of SI do not necessar- they forcefully direct our attention to the painful site.
ily reduce pain perception, and only occasionally has it The cortical pattern of activation upon nociceptor
been reported to relieve chronic pain. Some even ques- stimulation, as revealed by PET and fMRI, depends less
tioned the importance of the cerebral cortex for pain on the mode of stimulation than on the context and the
perception. However, recent studies in humans, using subjects state of mind (anxiety, expectations, feeling of
PET and fMRI, have demonstrated robust activation of control, and so forth). Many of the areas activated by
the cerebral cortex on stimulation of nociceptors and, painful stimuli may be activated in conjunction with
further, that this activation is associated with the subjec- other kinds of sensory processing and mental activities.
9
tive experience of pain. The most consistently activated Therefore, most likely no cortical regions are specific to
pain processing. It seems, rather, that we experience
pain when a distributed network of cortical and sub-
9 The interpretation of such data is not straightforward, however. For exam- cortical regions reaches a certain level and pattern of
ple, it is not always clear whether a change of cortical activity is an expression activity. This pain network (pain matrix) overlaps
of altered sensory, affective, or cognitive processing. Furthermore, change of
activity may be due to facilitation or inhibition of movements in response to a other cortical networks, such as networks for attention,
painful stimulus rather than to the experience of pain as such. emotional processing, and body image.
15 Pain
OVERVIEW be completely abolished or greatly enhanced, depending

on the situation.
While the previous chapter dealt with the basic neuro- The placebo effect is prominent in relation to pain.
biological aspects of pain, we here discuss pain in a That is, pain is often reduced when the person expects
broader context. that a treatment will help. This is not a matter of belief
First we emphasize that the ability to feel pain is of only, but relates to biologic processes in the brain. For
vital importance; without it we do not get the necessary example, the placebo effect is associated with altered
warnings to protect ourselves and maintain bodily activity in the pain networks and with release of
homeostasis. Nevertheless, in a clinical setting long- endorphins in key, pain-related neuronal groups. The
lasting pain is a major problem. The pain system has opposite phenomenon is called nocebo, and means that
several characteristic properties. One is its pronounced expectation of a harmful treatment worsens pain.
plasticity, considering that with ongoing pain neuronal
properties are quickly changed in the direction of hyper-
excitability. This helps explain the phenomenon of SOME DISTINCTIVE FEATURES OF PAIN
hyperalgesia (stronger than normal experience of pain
upon nociceptor activation). Pain is furthermore a Due to the great clinical importance of pain, we will
strong learning signal; we cannot afford to forget poten- treat this subject in some more depth. In several ways
tially harmful stimuli. such as cortical processing and its strong affective
Another notable characteristic is that the association coloringpain differs from other kinds of somatic
between nociceptor activity and pain perception is clear sensation and has proved much more difficult to study
cut only in case of acute exposure to noxious stimuli. In scientifically. In the previous chapter, we dealt with the
pain of longer duration, it may be experienced more or neurobiological aspects of pain. Here, we will discuss
less independent of nociceptor activity. This is most some of the characteristics that make pain systems so
obvious in cases of deafferentation pain where intense special, such as the tendency of pain to outlast its initial
pain is felt in a body part in spite of complete (or incom- cause, the complex control mechanisms of the brain,
plete) loss of sensory information from that part. We and the strong dependence of pain perception on context
use the term pathologic pain about conditions in which and expectation. The latter underscores that the experi-
pain occurs without any nociceptor activation (or ence of paineven more than other sensory modalities
peripheral tissue pathology)that is, pain that has no depends on an interpretation of available information
obvious biologic function (in contrast to normal or from various external and internal sources. As phrased
physiological pain). by Ramachandran and Blakeslee in their book Phantoms
Signals from nociceptors are transmitted to the cerebral in the Brain (1998, p. 54): . . . pain is an opinion on
cortex but also many other parts of the central nervous the organisms state of health rather than a mere reflex-
system (CNS). These include the PAG (periaqueductal ive response to an injury.
gray) and other nuclei in the brain stem, as well as the
hypothalamus and the amygdala. These nuclei are impor-
Pain Is of Vital Importance
tant for coordination of autonomic, endocrine, somatic,
and emotional responses that optimize our total response In the clinical situation, where pain is often the main
to physical and mental challenges. presenting complaint of patients, it is easy to forget the
The transmission of nociceptive signals from the cord to good sides of pain perception. Children born without
higher levels is subject to descending control. The respon- the ability to feel pain have severely reduced quality of
sible systems are complex, involving networks intercon- life, and often die young. The following description in
necting parts of the brain. Among transmitters, serotonin, the book, Pain: the gift nobody wants (Brand and Yancey
norepinephrine, and endorphins (opioid peptides) appear 1993 p. 3), tells us why: Tanya, now eleven, was living a
to be of special importance. Depending on, among other pathetic existence in an institution. She had lost both legs
factors, the emotional state and expectations of the subject, to amputation . . . her failure to limp or shift weight when
descending systems may inhibit or facilitate transmission standing (because she felt no discomfort) had eventually
at spinal and higher levels. Thus, perception of pain may put intolerable pressure on her joints. Tanya had also
204
15: PAIN 205
lost most of her fingers. Her elbows were constantly to be crucial. For example, even a relatively short train
dislocated. She suffered the effects of chronic sepsis from of signals from nociceptors alters the properties of the
ulcers . . . Her tongue was lacerated and badly scarred receiving dorsal horn neurons. Presumably, this prop-
from her nervous habit of chewing it. The ability to erty is necessary for proper functioning of the pain
feel pain is indeed necessary for us to be able to prevent system, for example, to ensure the necessary high level
injuries from innumerable small (and occasional large) of sensitivity. Nevertheless, plasticity too often seems to
physical threats. Also lowered pain threshold and spon- go awry causing pathologic pain, that is, pain that can-
taneous pain in conjunction with tissue damage are bio- not be explained by adequate nociceptor activation and
logically meaningful, because they ensure protection has no protective or reparative function. In cases of
and optimal conditions for healing. In a wider context, pathologic pain, plastic changes occur at all levels of
the pain system constitutes an integral part of the bodily the pain system, from the dorsal horn to the cerebral
systems for defense and homeostatic control, as dis- cortex.
cussed in Chapter 14, under Homeostatic Surveillance:
A Task of Ascending Tracts from Lamina I?.
Nociceptors and the Perception of Pain
The vital importance of the pain system might perhaps
give us a clue to why it so often goes awry. In the inevi- It is important to realize that pain perception and
table balance between sensitivity and specificity, the nociceptor activity are not synonymous terms. Thus,
system is biased heavily in favor of sensitivity: we can- nociceptor activity and the feeling of pain may occur
not afford to miss alarms of potential life-threatening independently of each other. The usual definition of a
events. Thus, the specificity would be correspondingly nociceptor is purely physiological: a receptor that is
low, leaving the system open to false alarms. Indeed, activated by stimuli that produce tissue damage, or
some poorly understood pain conditions, such as fibro- would do so if the stimulus continued. In contrast, pain
myalgia, might perhaps be understood in such terms. is a subjective experience with a psychological defini-
tion: an unpleasant sensory and emotional experience,
which occurs together with actual or threatening tissue
Change Behavior and Remember What Happened!
damage, or is described as if it were caused by tissue
The above example of a child born without the ability to damage. Usually, of course, nociceptor activation causes
feel pain also exemplifies that the feeling of pain is as a the pain, and when we feel pain, we more or less auto-
strong signal to change behavior. The lack of adaptation matically ascribe it to something that harms our body.
in the pain systemon the contrary, it easily sensitizes Indeed, pain is always felt somewhere in our body, even
is meaningful: it might be disastrous if we stop paying if it is caused solely by abnormal activity of neurons in
attention to a steady stream of signals from nociceptors. the brain. Thus, on the one hand, a person may suffer the
This is very different from the situation for other sensory most intense pain, yet there may be no evidence of noci-
systems where adaptation is a characteristic property. ceptor stimulation; on the other hand, there are many
Further, pain is a forceful stimulus to learning: we quickly examples of persons exposed to massive nociceptor stim-
learn to avoid everything that previously led to tissue ulation who feel no pain. Examples of the latter situation
injury or threatened to do so. When the childmostly are seen in serious accidents in which the injured person
by learning by doingdevelops mastering and control may experience no pain immediately afterward, in spite
1
of its environment, experience of pain is a central guide. of considerable tissue damage. This is most likely
In this sense, physical pain is just one aspect of discom- explained by mechanisms of the brain preventing nocice-
fort and suffering and belongs perhaps conceptually more ptive signals from reaching consciousness (this is dis-
under brain systems handling punishment and reward cussed further later in this chapter). In certain situations,
(suffering and pleasure) than under sensory systems. such mechanisms may be necessary to survive.
Interestingly, functional magnetic resonance imaging
fMRI studies show overlap between brain regions that
are activated when we feel pleasure and pain. Overlap WHEN THE PAIN SYSTEM GETS OUT OF CONTROL
also exists between the brain activity related to physical
and social pain (e.g., when social relationships are Acute and Enduring (Chronic) Pain
threatened or lost). Especially the anterior cingulate
Many observations suggest that acute, ordinary pain
gyrus, the orbitofrontal cortex, and the insula are sites
differs from pain of longer duration (chronic) regarding
where pain and emotions meet.
Plasticity of the Pain System 1 Of patients admitted to an emergency ward, 40% reported no pain at the
time of injury, 40% reported pain that was judged (by the doctors) as stronger
For the development of various maladaptive pain condi- than expected on the basis of the injury, but only 20% reported pain that was
tions, the pain systems well-developed plasticity seems judged as adequate (Hardcastle 1999).
2
central mechanisms. The former is clearly related to (among others) spinothalamic neurons in the segments
nociceptor activation; it ends when (or shortly after) above and below the dorsal roots leading from the
the stimulus ends. The threshold for eliciting acute pain inflamed region (as mentioned, the dorsal root fibers
is high (see the preceding definition of a nociceptor). divide in an ascending and a descending branch that
There is good correspondence between the intensity of may pass for several segments).
nociceptor stimulation and the experience of pain. In Glial cells seem to be implicated in development and
such instances, pain is a homeostatic factor, serving as a maintenance of chronic pain. Thus, in the cord astro-
signal to change behavior to avoid tissue damage. Chronic cytes and activated microglia release neuroactive sub-
pain, in contrast, is characterized by a weak or absent stances (interleukins, tumor necrosis factor, nitric oxide
correlation between stimulus and experience of pain. For [NO], ATP, and others). These substances may increase
example, hyperalgesiathe experience of pain on noci- transmitter release from central terminals of nocicep-
ceptor stimulationis more intense than normalis tive dorsal root fibers. Further, activated glial cells can
3
often present. Thus, the somatosensory system is abnor- sensitize dorsal horn neurons, among them spinotha-
mally sensitive. We all experience this altered state of the lamic ones. Activation of glial cells occurs with infec-
somatosensory system with, for example, a sprained tions in the CNS, but also in response to release of
ankle or a local infection, that is, in situations with substance P and amino acid transmitters from nocicep-
inflammation. Even slight movement or touching of the tive dorsal root fibers.
injured part evokes intense pain, or it may be painful also
at rest. In this situation the pain can be seen as biologi-
Plastic Changes and Altered Brain Networks
cally meaningful, as it ensures that the injured part gets
the necessary rest; moreover, the pain subsides in parallel Hyperalgesia, allodynia, and radiating pain are at least
with the inflammation as the tissue heals. Hyperalgesia is partly due to altered synaptic transmission in the CNS:
due to sensitization of both the nociceptors (primary chronic pain is associated with plastic changes that
hyperalgesia) and of neurons in the dorsal horn and at make neurons in many parts of the somatosensory
higher levels (secondary hyperalgesia). Experimentally, system hyperexcitable. This is best documented in the
dorsal horn neurons can be made hyperexcitable by dorsal horn but occurs also at higher levels. As with plastic
inducing inflammation in a joint or in the skin. changes in other systems, N-methyl-D-aspartate (NMDA)
Some, but not all, chronic pain patients have a low- receptors have a crucial role. Substance P increases
ered threshold, so that normal innoxious stimuli (such the sensitivity of NMDA receptors to glutamate, so
as touching the skin) can elicit intense and long-lasting that wide-dynamic range spinothalamic neurons might
pain. This phenomenon is called allodynia and appears react more vigorously to inputs from low-threshold
to be caused by (abnormal) activation of nociceptive mechanoreceptors.
neurons in the cord by dorsal root fibers (A) leading Intense pain of some duration may leave memory
from low-threshold mechanoreceptors. Change of pre- traces in the brain, so that later, minimal provocation
synaptic inhibition is probably instrumental in causing may suffice to revive the pain. For example, a man who
such a switch in the signal traffic. (The normal situation had a painful spine fracture reexperienced the pain when,
is that activity in thick myelinated dorsal root fibers many years later, he suffered a myocardial infarction.
inhibits nociceptive neurons, as discussed later under Electric stimulation during brain surgery indicates that
Analgesia Can Be Produced by Nerve Stimulation and part of the somatosensory thalamus becomes hyper-
Acupuncture). excitable in patients with chronic pain syndromes. For
Another characteristic of long-lasting pain is the ten- example, patients with panic attacks accompanied by
dency to radiatethe pain spreads out from the original chest pain and patients with deafferentation pain
painful site. This is most likely due to sensitization of reported their usual pain on thalamic stimulation. In
contrast, patients undergoing surgery for movement
disorders reported no pain on stimulation at the same
2 The indiscriminate use of the term chronic pain has been criticized because
it lacks precision and encompasses a variety of conditions with different causes, thalamic sites.
courses, and prognoses. Indeed, denitions of chronic pain differ widely. It appears from morphometric studies that chronic
Some dene it as pain that persists longer than the course of natural healing, pain conditions may cause gray and white matter altera-
others that it lasts longer than three, alternatively six months. Some even use
as a criterion that the pain has not responded to available (drug) treatment. tions in pain-related networks. Although findings differ
The International Association for the Study of Pain denes chronic pain as: somewhat among studies, most report gray-matter
. . . pain which persists past the normal time of healing . . . With non-malignant reductions in the anterior cingulate cortex, the insula, and
pain, three months is the most convenient point of division between acute
and chronic pain, but for research purposes six months will often be the orbitofrontal cortex (the specific cellular changes that
preferred. underlie these findings are unknown, however). Further,
3 The International Association for the Study of Pain has proposed that fMRI studies show altered activation of networks related
hyperalgesia be used as an umbrella term for all conditions of increased pain
sensitivity (Loeser and Treede 2008). Allodynia would then be a special case of to attention in chronic pain patients. Finally, in patients
hyperalgesia. with complex regional pain syndrome (CRPS), the
15: PAIN 207
somatosensory-cortex representation of the painful part Complex Regional Pain Syndromes (CRPS): A Special
seems to shrink but normalizes during successful therapy. Type of Pathologic Pain
Curiously, in chronic back pain patients, an enlarged
In some patients, pain continues in spite of complete
back representation appears to occur. It seems, there-
healing of an injury (most often in the extremities). What
fore, fair to say that while cortical reorganization in
started as a normal, nociceptor-driven pain continues
chronic pain states is well documented, its functional
for unknown reasons as a pathologic pain. For example,
significance is less than clear.
an apparently trivial fracture of the radius is sometimes
followed by pain for years after the fracture has healed.
Pathologic Pain Similar persistence of pain can occur after partial lesions
of peripheral nerves (neuropathic pain).Usually, such
Chronic pain can occur not only on increased nocicep-
patients also suffer from hyperalgesia and allodynia, and
tor activity but also after loss of sensory information,
even light touch may provoke excruciating pain. Often
either from nociceptors or from low-threshold mecha-
they also show signs of autonomic dysfunction, such as
noreceptors. We use the term pathologic pain here rather
abnormal sweating and circulatory disturbances. This
loosely to describe conditions in which pain occurs
condition used to be called reflex sympathetic dystrophy
without any nociceptor activation (or peripheral tissue
(RSD), reflex dystrophy, or sympathetically mediated
pathology)that is, pain that has no obvious biologic
pain. It is especially unfortunate, however, that names
function (in contrast to normal or physiological pain).
of poorly understood diseases implicate an etiology, like
Pathologic pain may have quite different causes, such
reflex and sympathetic. In some cases, especially
as partial damage to peripheral nerves or destruction of
after nerve injury, the pain has a peculiar burning qual-
central somatosensory pathways, for example, in the
ity, and the name causalgia refers to this condition
cord or in the thalamus (usually termed neuropathic
(Greek: kausos, heat; algos, pain).
pain). Deafferentation pain is pain that, paradoxically,
The term complex regional pain syndrome (CRPS)
occurs after loss of sensory information from a body
was introduced in an attempt to avoid the many confus-
part. A striking example of the latter is patients with
ing terms for these kinds of pathologic pain conditions.
avulsion of dorsal roots (this occurs sometimes with the
CRPS is a purely descriptive term, reflecting that we do
roots of the brachial plexus upon a violent pull of the
not know the pathophysiological mechanisms leading
arm). In spite of no sensory nerves entering the cord,
to the various symptoms. It has two subgroups, with
such patients often develop excruciating pain in the
reasonably precise definitions, corresponding largely to
denervated arm. Pathologic pain also occurs in some
reflex dystrophy (CRPS type I) and causalgia (CRPS
patients below a transverse lesion of the cord, even
type II), respectively.
though all ascending sensory pathways are interrupted.
Pathologic pain may also be felt in an area of the skin
with reduced sensibility in patients who have had shin-
CRPS and the Sympathetic System
gles (postherpetic neuralgia). A stroke destroying parts
of the thalamus leading to reduced sensibility in a body As mentioned, patients with complex regional pain syn-
part is sometimes associated with chronic pain (thalamic dromes often show evidence of autonomic dysfunction
pain). Phantom pain, often occurring for shorter or longer in the painful partmainly hyperactivity of the sympa-
periods after amputations, refers to pain felt in the thetic system. The often-used term reflex sympathetic
missing body part. Clinical evidence indicates that this dystrophy (RSD) implies that sympathetic dysfunction
peculiar phenomenon is associated with plastic changes causes the syndrome. The pain relief achieved in some
in the brain (especially in the somatosensory cortex). It patients by a sympathetic block (e.g., of the stellate gan-
is not due to abnormal activity in peripheral nerves or glion in case of pain in the hand) would seem to support
ascending sensory pathways. Often, the pain occurs this assumption. Nevertheless, microneurographic and
together with a vivid experience of abnormal movements other kinds of studies have not confirmed abnormally
or postures of the missing limb. Probably, the brain increased activity of sympathetic postganglionic fibers
misinterprets the lack of sensory information from the in such patients, even in those with obvious signs of sym-
missing body, drawing the conclusion that something is pathetic hyperactivity such as profuse sweating and
seriously wrong out there. extreme cutaneous vasoconstriction. This seeming para-
It is fair to say that our understanding of pathologic dox may perhaps be explained by adrenergic receptors
pain syndromes is far from satisfactory. It is particularly starting to be expressed by spinal ganglion cells (Fig. 15.1).
enigmatic why apparently identical injuries cause chronic Thus, normal levels circulating catecholamines may acti-
pain in some patients but not in others (the majority). vate sensory neurons. There is furthermore evidence that
An association between pathologic pain syndromes and in some CRPS patients neuropeptides (substance P and
certain personality traits has not been convincingly cholecystokinin [CCK] in particular) are released from
demonstrated. sensory nerve endings in the skin of the painful parts.
Spinal ganglion cells

Norepinephrine CENTRAL CONTROL OF TRANSMISSION FROM
Epinephrine NOCICEPTORS AND PAIN SENSATION
Adrenergic receptor
We now realize that a complex networkstretching
from the spinal cord to the cerebral cortexmodulates
transmission of signals from nociceptors and pain per-
ception. As mentioned, both the context of the nocicep-
tive signals and how the brain interprets the situation
Capillary determine how we perceive signals from nociceptors. In
the modulatory network, serotonin, norepinephrine,
and opioid peptides seem to play crucial roles, although
several other neurotransmitters also participate.
Descending Control from the Brain Stem

Postganglionic A dramatic observation by Reynolds (1969) was the
sympathetic neuron starting point for much later research on central control
of nociception. He showed that by electrical stimulation
gure 15.1 Sensory neurons (spinal ganglion cells) express adrenergic of a mesencephalic region, the periaqueductal gray matter
receptors in certain chronic pain conditions. Receptors are located on (PAG; Fig. 15.2; see also Fig. 6.20), conscious rats could
the cell body and the peripheral branches. be subjected to major surgery without apparently feeling
any pain (as judged from their behavior and other obser-
vations). The stimulation produced analgesia (no experi-
This causes so-called neurogenic inflammation, which ence of pain on noxious stimuli). Subsequent research
may produce some (but not all) of the autonomic signs indicates that the effect of PAG stimulation can be
in CRPS. The relationship between neurogenic inflam- explained, at least in part, by activation of descending
mation and pain in CRPS is not clear, however. connections to the dorsal horn. Although a sparse direct
Anterior cingulate
cortex
Somatosensory cortex
(SI, SII)
Insula
Thalamus Hypothalamus
Amygdala
(central nucleus)
Brain stem PAG

gure 15.2 Descending systems for modula-
Rostral ventromedial tion of nociceptive signal transmission. Left:
medulla (RVM; includes Ascending pain pathways. Right: Green neu-
Ascending nucleus raphe magnus) rons mediate inhibition of ascending transmis-
pain pathways Serotonin neurons sion whereas red neurons mediate facilitation.
Spinothalamic
tract PAG has a pivotal position in the network for
Thin myelinated (A) pain modulation. The anterior cingulate cor-
og unmyelinated (C) tex, the prefrontal cortex, amygdala, and the
Spinal cord sensory fibers hypothalamus send instructions to PAG depend-
ing on the emotional state and the expectations
of the individual. Opioids inuence the trans-
Dorsal horn mission at all levels of the network. Simplied.
(Laminae I and II) (Based on Fields 2004.)
15: PAIN 209
pathway from the PAG to the spinal cord exists, the Although descending systems that inhibit signal traf-
main pathway appears to be synaptically interrupted in fic from nociceptors have attracted most attention, there
cell groups in the medulla, especially the raphe magnus are also connections with facilitating effects (Fig. 15.2).
nucleus (NRM) (Fig. 15.2; see also Figs. 26.5 and 26.6) Animal experiments suggest that descending connec-
and other nearby cell groups in the medullary reticular tions from the brain stem can contribute to the develop-
formation. The descending fibers from these nuclei ment of hyperalgesia in cases of peripheral inflammation.
(raphespinal fibers) lie in the dorsolateral funiculus of Further, descending connections may contribute to the
the cord, and cutting the latter abolishes the effects of maintenance of pain in some chronic conditions.
PAG stimulation almost completely. Further, electrical
stimulation of NRM inhibits spinothalamic cells.
PAG Coordinates Stress Responses
We do not know in detail the synaptic arrangements
in the spinal cord that mediate these effects from the Studies of the PAG suggest that this nuclear complex
brain stem, but it is of interest that fibers from the NRM plays a pivotal role in coordinating bodily reactions to
establish synapses in the dorsalmost part of the dorsal painful and potentially harmful somatosensory stimuli
horn (laminae I and II), which receives most dorsal root that is, endocrine, autonomic, and somatic responses with
fibers conveying signals from nociceptors (Fig. 15.3). the common goal to reestablish or maintain homeostasis.
Many of the NRM neurons contain serotonin, and this Interestingly, different parts of the PAG mediate different
is apparently a transmitter at synapses established by kinds of responses to painful and other stressful stimuli.
raphespinal fibers in the cord. The actions of serotonin Stimulation of the ventral part of the PAG elicits an active,
in the dorsal horn are complex, but experiments with defensive behavior, whereas stimulation of dorsal part
microinjections indicate that it inhibits nociceptive spi- causes an immobility (freezing) reaction. Further, the ven-
nothalamic cells. Probably, the inhibitory effects are tral part mediates opioid-dependent analgesia, as judged
mediated partly by direct synapses on spinothalamic from abolition of the effect by injections of naloxone
cells and partly by synapses on dorsal horn interneurons. (which prevents binding of some endorphins to their
Transmitters other than serotoninnorepinephrine receptors). Stimulation of the dorsal part, in contrast,
and opioid peptides in particularcontribute to the produces an analgesia that cannot be reversed by nalox-
effects on pain transmission obtained by stimulation of one, suggesting that transmitters other than endorphins
NRM and nearby structures. Indeed, the effects of the are responsible. This dual response pattern elicited from
neurotransmitters used in the descending control systems the PAG in experimental animals corresponds to typi-
are not fixed: depending on the cause of the pain and cal human reactions to pain originating from skin and
the context in which it occurs, the same transmitter from the viscera, respectively. Pain of cutaneous origin
may have opposite effects. typically produces movements and increased heart rate
and respiration, whereas immobility, lowered heart rate,
sweating, and nausea often accompany pain arising in
deep structures.
From brain stem
(Rostral ventromedial medulla
and dorsolateral pons)
Ascending Connections that Modulate Pain Perception
The effects of PAG stimulation on pain sensation are
probably mediated not only by descending connections
Substantia to the cord. There are also ascending connections from
gelatinosa
I _ the PAG and the parabrachial nucleus, which may
_ influence signal transmission at the thalamic level
II (intralaminar thalamic nuclei) and in other cell groups
+
Serotonin, related to pain sensation. Nociceptive signals reaching
III Enkephalin norepinephrine the amygdala are relayed in PAG and some other brain
stem nuclei. Together with the cerebral cortex, the
amygdala integrates nociceptive signals and other infor-
IV mation about the stimulus and its context. In this way,
the significance of a stimulus is interpreted in relation
to the needs of the whole organism. The amygdala send
To thalamus efferent fibers to PAG that may initiate appropriate
responsesamong them, suppression (or facilitation) of
gure 15.3 The substantia gelatinosa. One of several possible wiring
transmission from nociceptors. The nucleus accumbens
patterns in the dorsal horn, which can contribute to inhibition of in the forebrain (see Fig. 23.15)involved in control of
spinothalamic cells. reward-dependent behaviorplays a part in analgesia
4
evoked by painful stimuli. In pain-induced analgesia, Analgesia Can Be Produced by Nerve Stimulation
pain in one part of the body seems to be rewarded by and Acupuncture
analgesia in other parts.
Analgesia may also be produced therapeutically by
stimulation of peripheral nerves. When done with sur-
Opiates, Opioids, and Endorphins face electrodes, the procedure is called transcutaneous
nerve stimulation (TNS). One kind of analgesia occurs
Some of the dorsal horn interneurons contain opioid
immediately and is mediated by activity of thick myeli-
peptides. These neuropeptides, found in many parts of
nated fibers in the stimulated nerves (i.e., fibers leading
the brain, got their name because they have actions that
from low-threshold mechanoreceptors). Selective stim-
resemble closely those of the opiate-type drugs, such as
ulation of such fibers is elicited by electrical stimulation
morphine. The naturally occurring (endogenous) peptides
with high frequency and low intensity or by natural
of this kind are also called endorphins, that is, endoge-
stimuli such as vibration, light touch, or pressure. The
nous morphine. Opioids, when injected locally in the
analgesia is restricted to parts of the body innervated by
dorsal horn, have inhibitory effects on spinothalamic cells,
the peripheral nerves, and it usually disappears when the
but it is not known whether the inhibition is caused by
stimulation stops. It is mediated by activity in collaterals
a direct action or is mediated by interneurons (or both).
of the thick dorsal root fibers that inhibit impulse trans-
Three main groups of endorphins have so far been dis-
mission from the thin (A and C) fibers in the dorsal
covered, each with its characteristic distribution in the
horn, via inhibitory interneurons and presynaptic inhi-
brain and spinal cord. Best characterized are endorphin,
bition. Melzack and Wall (1965) proposed such interac-
two varieties of enkephalin, and dynorphin. Whereas
tion between thick and thin dorsal root fibers in their
endorphin is restricted to one neuronal group in the
gate-control theory. It is presumably the basis of the
hypothalamus (the arcuate nucleus), the enkephalins and
everyday observation that it helps to blow at a finger
dynorphin are present in interneurons in many parts of
that hurts, that it may help to move the part that has
the CNS (among them, parts that are not concerned
received an acute injury, that labor pains may be allevi-
with aspects of pain sensation).
ated by rubbing over the lower back, and so forth.
That morphine and other opiates can alleviate severe
Another kind of stimulation-induced analgesia requires
pain has been known for hundreds of years. Today we
that thin sensory fibers be activated. This can be achieved
know that there are receptors in the brain to which
by electrical stimulation of low frequency with relative
opiates can bind and exert their effects. These receptors
high intensity. Classical acupuncture probably obtains
are actually receptors for the endorphins, and at least
the same effect by rotation of thin needles in the tissue.
five different receptors, each with affinity for a certain
The analgesia produced by this kind of stimulation
subgroup of endorphins, have so far been identified.
occurs with latency but may last for hours after termi-
Opiate receptors (binding morphine) are present in,
nation of the stimulation. Analgesia is not limited to the
among other places, the PAG, the NRM, and parts of
parts of the body that were stimulated. This kind of
the spinal dorsal horn (especially laminae I, II, and V).
stimulation-induced analgesia is most likely due, at least
Microinjection of morphine in the PAG can produce
in part, to activation of the descending connections
analgesia in experimental animals that depend at least
from the brain stem. The activation may happen by
in part on connections from the NRM to the spinal
way of collaterals from spinothalamic and spinoreticu-
cord. The actions of morphine appear thus to be exerted
lar cells to the PAG and adjacent parts of the reticular
both in the spinal cord and in the PAG. In the cord,
formation. The analgesia can be reversed or prevented
binding of morphine to opiate receptors on inhibitory
by intravenous injection of naloxone. Further, in animal
interneurons in the substantia gelatinosa and, presum-
experiments it has been blocked by sectioning the
ably, on primary afferent terminals, leads to inhibition
dorsolateral fascicle. The results of such control experi-
of spinothalamic cells. The action in the PAG occurs
ments are in part contradictory, however, and indicate
most likely by activation of the descending pathway
that not all aspects of stimulation-induced analgesia
from NRM and probably also by activation of ascend-
can be explained by liberation of endorphins.
ing connections from the PAG acting on higher levels of
the CNS. Binding of morphine in other parts of the
brain, such as the amygdala and other limbic structures,
Functional Role of Pain-Modulating Systems
is probably also important in explaining the actions of
morphine. A dominating view today is that modulation of pain is
just one among several bodily adjustmentscontrolled
by the nervous systemto physical and mental chal-
4 Both dopamine and opioid peptides in the nucleus accumbens appear to be lenges. The mental set and the individuals interpre-
necessary for pain-induced analgesia. The nucleus accumbens probably exerts
its effects by indirect connections to NRM or nearby regions. The PAG and the tation of the situation determine the choice of responses.
hypothalamus may be intercalated in the pathway. In other words, expectation of what a stimulus will
15: PAIN 211
cause is more decisive for the response than the stimu- transmission, depending on the situation (Fig. 15.2).
lus itself. Nevertheless, we do not fully understand the Such mechanisms are most likely involved in the placebo
functional role of the pain-modulating systems, nor and nocebo effects on pain. One likely pathway goes from
under which conditions they are activated. It is reason- the amygdala to the PAG. At the cortical level, expecta-
able to assume, however, that inhibiting systems are tion of pain relief reduces the activity of the pain network
active in situations with severe injuries and no experi- (Fig. 15.4A). Further, during the expectation phase corti-
ence of pain (as, e.g., in war and major civil accidents). cal regions usually involved in cognitive and evaluative
In such situations, suppression of pain may enable con- processes show enhanced activity (Figure 15.4B).
tinuation of intense physical activity, which may be of A common misconception is that the placebo effect
vital importance. Markedly reduced pain sensitivity may works only with moderate pains and only in comparison
also occur in more peaceful situations, such as sport with weak drugs. However, if the patient believes that
competitions. Further, pain-suppressing systems (at sev- the drug she gets is morphine, the placebo effect is much
eral levels) appear to be active in expectation-dependent greater than if the patient believes it to be aspirin. Indeed,
analgesia, although expectation may also increase pain postoperative, intravenous administration of placebo
perception (see next section, Placebo and Nocebo). (saline) in full view of the patient had the same analgesic
Animal experiments indicate that analgesia can occur effect as 6 to 8 mg of morphine given covertly.
in stressful situations characterized by the inability to The question remains, however, how expectancy
escape (stress-induced analgesia). However, the mental controls the pain network and pain-suppressing sys-
state of the animal seems to decide whether analgesia tems. Put more broadly: how do thoughts and feelings
occurs. Thus, in one study analgesia occurred only if express themselves through the body? We discuss this
the animal was calm at the start of the period of stress, theme further in Chapters 31 and 32 although, admit-
whereas anxious animals became hyperalgesic. This tedly, we are far from a full understanding of the mind
resembles the well-known effect of anxiety on the expe- body problem.
rience of pain in humans.
Placebo
PLACEBO AND NOCEBO The word placebo (literally: I shall please) has been
used for a long time about mock medicinethat is, drugs
The placebo effect is probably best understood as one and procedures that the doctor knows have no effect. In
part of a repertoire of responses to challenges that clinical trials, for example, inert tablets are given as a
threaten our mental or physical stability (see also placebo to decide whether a drug has a specific effect on
Chapter 30, under Psychosomatic Relations, and a disease. Thus, it is well known that a treatment with-
Chapter 31, under Amygdala and Conditioned Fear). out any specific effect may influence the disease and the
Although it has attracted most attention in connection experience of pain. We know that the effect is only
with the treatment of pain, we now know that placebo present if the patient expects the treatment to work.
effects concern several physiological processes. The Further, surgery produces a larger placebo effect than
beneficial placebo effect depends on the patients posi- drugs, and injection of a drug is more efficient than oral
tive expectations, but negative expectations may evoke administration.
increased pain and harmful physiological alterations. An operation introduced in the 1950s to cure angina
This is called the nocebo effect. However, placebo (and pectoris exemplifies the placebo effect of surgery. On a
nocebo) effects may in addition involve conditioned dubious theoretical basis, the internal mammary arteries
responses, for example elicited by the taste of a drug that were ligated to improve the blood supply to the ailing
5
previously was experienced as effective (e.g., a painkiller). heart. Many patients noted improvement in their condi-
In this respect, the placebo response is learned, depend- tion after the surgery. Later pathological examinations
ing on prior experience. Even the observation of another showed, however, that no improvement of the blood
person receiving a beneficial treatment induces a placebo supply had occurred. Therefore, a study was initiated to
response in the observer. compare two groups of patients with angina pectoris:
As discussed, descending connections from the one group underwent ligation of the artery, the other
brain stem can inhibit or enhance nociceptive signal group underwent the same procedure but without liga-
tion (a sham operation). Many of the patients in both
groups noted improvement, and the improvement lasted
5 In one study, patients received the immunosuppressant cyclosporine in asso-
ciation with a avored drink. After a number of repetitions of the association, for the observation period of 6 months. Remarkably, the
the avored drink alone induced immunosuppression. Several other studies in improvement concerned not only reduction of pain but
experimental animals and in humans have shown similar conditioning of also objectively measurable variables, such as walking
immune responses. The endocrine system is also subject to placebo condition-
ing. The conditioned immune and endocrine responses do not require conscious distance, drug consumption, and (in some) even the
expectations. electrocardiogram. Several later studies have shown
Cingulate gyrus
Medial Cingulate gyru
C gyrus
prefrontal
cortex
Pons (PAG?
Thalamus PAG (?)
Parabrachial nucleus?)
Medulla
Dorsolateral Posterior
prefrontal parietal cortex
cortex
Insula Orbitofrontal Insula

cortex
Regions with decreased activity Regions with increased activity in the Regions activated both by placebo
during placebo analgesia expectation phase of placebo and by opioids
gure 15.4 Brain regions involved in placebo analgesia. The size and The regions shown in B are activated by cognitive and evaluative
position of the relevant regions are only approximations, and other processes, as shown in other fMRI studies. (Based on fMRI data
regions than those shown here are involved in placebo analgesia. published by Petrovic et al. 2005 and Wager et al. 2004.)
similar results. For example, in one study the effect of certain parts of the body. In a recent study, pain was
ultrasound on pain after tooth extractions was com- evoked at different locations by injections of capsaicin.
pared with placebo. Not only did the patients receiving A placebo creamsaid to have a strong anesthetic
the probe without any ultrasound (the placebo group) effectwas applied at one of the painful sites. At this
feel less pain, they also experienced less local edema site, but not at the others, the persons reported a marked
and could open their mouths wider than patients in the reduction of pain, which was prevented by naloxone.
placebo group. Thus, the placebo effect is not limited to This fits with the fact that the PAG is somatotopically
subjective experiences related to disease but can also organized and that electric stimulation of different parts
affect physiological processes. Obviously, the placebo produce analgesia restricted to certain body parts. Thus,
effect is not merely a question of imagination, and its the placebo effect is probably not mediated by diffuse
presence in a patient is not related to whether the disease release of opioids but by activation of specific neuronal
is organic or functional. Interestingly, fMRI studies groups, some of them containing opioid peptides.
indicate that analgesia obtained by an opioid drug and
by placebo activate the same brain sites (Fig. 15.4C).
Nocebo
As discussed in the preceding text, expectation of a posi-
The Endorphin Hypothesis and Somatotopic
tive effect influences markedly how the brain modulates
Placebo Effects
pain and several physiological processes. Thus, the pla-
The endorphin hypothesis became popular when it cebo effect depends on whether the patient believes that
was reported that naloxone (an opiate antagonist) the treatment can help. As mentioned, the opposite
could prevent the placebo effect. However, as empha- effect, called nocebo, can occur if the patient expects no
sized by Wall (1993, p. 197), . . . it is not clear what help or believes that the treatment may be harmful. In
insight into the overall placebo phenomenon is pro- such instances, a neutral substance may worsen the
vided by showing that some link in the machinery pain and produce unwanted biologic effects. The neu-
involves endorphins. We now know that the placebo robiological basis of nocebo effects is so far largely
effect, rather than being mediated by a diffuse release of unknown. However, while placebo responses are asso-
endorphins, is associated with altered opioid transmis- ciated with increased opioid and dopaminergic activity
sion in specific brain sites. Further, the placebo effect in several cortical and subcortical sites (e.g., the nucleus
can apparently be rather specific and restricted to only accumbens), nocebo responses seems to be associated
15: PAIN 213
with decreased activity in the same sites. Further, nocebo Attention, memories,
seems to be associated with increased cholecystokinin interpretations,
(CCK) activity, as a CCK antagonist (proglumide) expectations...
blocks nocebo-induced hyperalgesia. Interestingly, CCK

acts as a neuromodulator in the brain sites that show Cortical
Other cortical
increased opioid activity during placebo analgesia. A networks pain
close link seems to exist between anxiety and nocebo networks
hyperalgesia. It may seem that, . . . verbal suggestions
of a positive outcome (pain decrease) activate endoge- Fear, anxiety, Thalamus
nous -opioid neurotransmission, while suggestions of associations, Amygdala
depression
a negative outcome (pain increase) activate CCK-A and/
or CCK-B receptors (Benedetti et al. 2007, p. 265). PAG Dorsal horn
In any case, the fact that verbal instructions alone can
induce improvement or worsening of a patients condi-
tion will influence every therapeutic situation. Besides Nociceptors
the specific therapeutic effect of the treatment initiated
Injury, disease
by the doctor, the outcome for the patient depends on
whether placebo or nocebo effects are evoked.
gure 15.5 The cortical pain network and modes of activation.
Schematic to show how quite different inputs can activate the pain
MODERN VIEWS ON PAIN AND PAIN TREATMENT networkfrom peripheral nociceptors triggered by tissue injury to
purely mental processes.
Recent years of intensive interdisciplinary research have

led to important new insights in pain mechanisms, along
with improved pain therapy. Some aspects have been Both forms are expressions of dynamic interactions
mentioned in this chapter. We now realize that many between many brain systems. For example, depression
more parts of the brain are involved in pain processing and anxiety strongly influence pain perception, while
than was formerly believed. Although we are still far chronic pain by itself can cause the same symptoms.
from a complete understanding, we know many of the Psychological reward mechanisms can in some instances
pieces that form the basis of subjective pain experience suppress pain, in others contribute to its maintenance.
and the physical and mental reactions to pain. Some For the brain to interpret the multitude of signals
pain conditions, previously rejected as imaginations arising in the body correctly, a proper balance among
or ignored because they were incomprehensiblesuch the various somatosensory modalities seems necessary.
as deafferentation paincan now be at least partly Thus, loss of sensory informationregardless of
explained in a neurobiological context. The pain is whether it concerns low-threshold mechanoreceptors
equally real to the individual, regardless of whether its or nociceptorscan cause long-lasting pain. The brain
cause is a stroke, a nerve injury, a panic attack, or a apparently misinterprets what is going on out there.
broken leg, and it is always felt as arising somewhere in Probably, the same occurs when a patient experiences
the body. bizarre distortions of the body image after an amputa-
We also know that the experience of pain is associated tion or even when an extremity is immobilized (Oliver
with activity in a distributed cortical and subcortical Sacks describes in the book A Leg to Stand On [1994]
networknot a specific pain center. Conceivably, his own experiences of this kind after a knee injury with
when this network enters a state of synchronized activity immobilization). Interestingly, attempts to correct with
we experience the unpleasant emotional and bodily state mirrors the experience of abnormal postures in amputees
we call pain. Complex neural networks are typically led to immediate pain relief as soon as the body image
densely interconnected, so that a specific neuronal group was normalized. The basic problem may probably be
may take part in different tasks, depending on the situa- not so much loss of sensory information per se, but
tion. Thus, many other networks can presumably access rather a mismatch between the motor commands and
the pain network and contribute to its activation the sensory feedback. Thus, when the sensory feedback
(Fig. 15.5). This implies that the feeling of pain can be does not match the expectations (based on previous
evoked not only by signals from nociceptors but also by experience), the alarm goes.
activity in neuronal groups related to motivation, atten- We also have learned that the central pain system is
tion, expectations, emotions, memories, and so forth. plastic, so that its behavior can change quickly. This has
Rather than making sharp distinctions between organic led to a better understanding of the differences between
and psychological pain, we realize that all pain encom- acute and chronic pain. Pain can obviously leave perma-
passes both aspects, albeit in varying proportions. nent traces in the brain, even though, mercifully, most
pains are forgotten very quickly. Plastic changes may therapy is to prevent the occurrence of the plastic
produce chronic pain in some persons, while in others changes in the dorsal horn and elsewhere. Thus, analge-
they may enable reactivation of a long-forgotten pain in sic drugs are often administered before surgery, and
a certain body part. afterward the dosage is individualized according to the
Advances in basic pain research have influenced need of the patient rather than to a fixed scheme. In
clinical practice; for example, new drugs are designed to addition, the importance of early and efficient pain relief
attack the central synaptic changes in chronic pain in patients with injuries that are apt to produce persist-
directly. Further, an important aim for modern pain ing pain is being realized.
16 The Visual System
OVERVIEW ensuring fixation of our gaze on the object we want to

examine and follows it if it moves, and those ensuring
Humans are visual animals. Like in other primates, that the visual images formed at the retina are always in
our visual system is highly developed, and accordingly focus. Such visual reflexes, however, are only briefly
large parts of the cerebral cortex are devoted to pro- mentioned in this chapter. They are discussed more thor-
cessing of visual information. There are approximately oughly in Chapter 25, under Central Control of Eye
1 million axons in the optic nerve, constituting almost Movements, and in Chapter 27, under The Light
40% of the total number of axons in the cranial nerves. Reflex and the Accommodation Reflex.
The receptors for sight, photoreceptors, are the rods
and cones of the retina. Their adequate stimulus is elec-
tromagnetic waves with a wavelength between 400 and
THE EYEBALL AND THE REFRACTING MEDIA
700 nm. The photoreceptors do not react to light with
shorter (ultraviolet light) or longer (infrared light) wave-
The Eye and a Camera Have Certain Features
lengths. The photoreceptors transform light energy to
in Common
graded changes of the membrane potential with ensuing
release of glutamate. From the photoreceptors, the signals The eyeball (bulbus oculi) (Figs. 16.1 and 16.2) has a
pass to bipolar cells and from these to retinal ganglion firm outer wall of dense connective tissue covered on
cells. Several kinds of interneurons enable considerable the inside by the light-sensitive retina. Between these
information processing in the retina. The rods are respon- two layers is a vascular layer, the choroid, that is highly
sible for vision in dim light, whereas the cones require pigmented, thus ensuring that light enters the eye only
daylight and are necessary for perception of visual details through the pupil and preventing reflection of light
and colors. (compare with the dull black inside a camera). The
The visual pathways start with the retinal ganglion diameter of the pupil (the shutter) controls the amount
cells sending their axons to the lateral geniculate body of light allowed into the eye. Refraction of the light
of the thalamus. The ganglion cell axons leave the eye in takes place on its way through the cornea and the lens.
the optic nerve and pass through the optic chiasm, where The curvature of the lens can be varied by the use of the
axons from nasal half of the retina cross while axons from ciliary muscles, so that the retinal image is always
the temporal half pass through uncrossed. The axons con- sharply focused (in a camera, the focusing is brought
tinue in the optic tract to the lateral geniculate body. about by varying the distance between the lens and the
Axons from neurons in the lateral geniculate form the light-sensitive film). Extraocular muscles (external eye
optic radiation, and end in the primary visual cortex muscles) attach to the eyeballs and can move them to
the striate areain the occipital lobe of the same side. coordinate their positions, so that the visual images hit
In this way, stimuli from the left visual field reach the corresponding points of the two retinas (Fig. 16.3).
right occipital lobe. The visual pathways show a precise, This is a prerequisite for our perception of one image,
retinotopical organization at all levels. The area striata and not two (two slightly different images are formed in
performs the first analysis of the visual information, the eyes, however). We discuss the extraocular muscles
while further processing takes place in extrastriate visual more comprehensively in Chapter 25.
areas in the occipital, temporal, and parietal lobes. The
processing is largely segregated, so that, for example,
Structural Features of the Eye
different areas deal with color and motion. Visual infor-
mation from the extrastriate areas is integrated with The wall of the eye consists of three layers. Outermost
other sensory modalities, and finally reaches the frontal is the sclera; then follows the choroid, and the retina is
lobe where visual information contributes to the control the innermost layer. The eye keeps its spherical shape
of behavior. because the sclera has some stiffness, but mainly because
To understand the visual system, it is not sufficient to the pressure inside the eye is higher than outside
know the conscious use of visual information; the many (approximately 15 cm H2O).
reflex effects elicited by visual stimuli must also be Anteriorly, the sclera has a circular opening, in which
taken into account. Among the reflex effects are those the transparent cornea is positioned like a glass of
215
The choroid (the vascular coat) is rich in vessels that

nourish the cells of the outer parts of the retina. In addi-
Cornea tion, the connective tissue of the choroid contains
numerous highly pigmented cells. Anteriorly, close to
Iris
the opening in the sclera, the choroid is thickened and
forms a ring (Figs. 16.1 and 16.2) called the ciliary body.
Optic nerve This contains the smooth ciliary muscle, which controls
the curvature of the lens. From the anterior edge of the
ciliary body, approximately at the junction between the
Fovea
centralis
sclera and the cornea, the choroid continues as the iris.
Papilla
This is a circular disk with a central opening, the pupil.
The iris contains smooth musculature that serves to
Central retinal regulate the size of the pupil. Smooth muscle fibers
artery arranged circularly form the pupillary sphincter muscle
Lens
(m. sphincter pupillae), which, when it contracts, makes
the pupil smaller so that less light enters the interior of
the eye. Radially arranged smooth muscle fibers in the
gure 16.1 The left eye. The eye is divided in two along the visual iris, forming the pupillary dilatator muscle (m. dilatator
axis (cf. Fig. 16.2). pupillae) widen the pupil when they contract.
The space inside the eye in front of the lens and the
iris is called the anterior chamber. It is filled with a clear
a wristwatch. The cornea consists of a special kind of
watery fluid that is produced by small processes of the
connective tissue with densely packed collagen fibrils
ciliary body. The space behind the lens is filled with a
arranged strictly geometrically. This arrangement is a
clear jellylike substance called the vitreous body (corpus
prerequisite for the transparency of the cornea, as is
viteum).
also its lack of blood vessels. The cornea is nourished by
The eyeball is moved inside the orbit by six small
the tear fluid and by the fluid inside the eye. The cornea
striated muscles, the extraocular muscles (see Figs. 25.1
contains numerous unmyelinated sensory nerve fibers,
and 27.16). The muscles originate in the wall of the
providing information about even the slightest touch. A
orbit, and their tendons insert in the sclera. The extra-
stratified squamous epithelium that is only a few cells
ocular muscles are innervated by the third, fourth, and
thick covers the outside of the cornea.
sixth cranial nerves. They cooperate very precisely to
produce the movements of the eyes that ensure that the
visual axes (Fig. 16.2) of the eyes are always directed
Visual axis of the eye toward the point of fixation (Fig. 16.3C).
Cornea Anterior chamber
The Visual Field
Iris
Ciliary body The visual field is the part of our surroundings from
which the eyes can perceive light (without movement of
Zonula fibers
the eyes or the head). Together, the two eyes cover a
Lens Sclera large area (Fig. 16.3A and B). Light from a particular
point in the visual field falls on a particular point on the
retina. Because of the refraction of the light when it
Vitreal body
passes the optic media of the eye, the image on the retina
External eye
is upside down. For convenience, we divide the retina
muscle and the visual field vertically in two halves: the tempo-
Fovea
ral partsthat is, lateral parts, toward the templeand
Sclera
Papilla centralis the nasal parts (Fig. 16.3C). The nasal halves of the ret-
Choroidea ina receive light from the temporal halves of the visual
field, and the temporal halves of the retina receive light
Retina from the nasal visual field. The situation is the same for
the upper and lower halves of the retina and the corre-
sponding parts of the visual field. Thus, light from the
Optic nerve
lower half of the visual field reaches the upper half of
gure 16.2 Transverse (horizontal) section through the right eye, as the retina. The lateral 30 degrees of the visual field is
viewed from above. viewed by one eye only, because the nose prevents light
16: THE VISUAL SYSTEM 217
from reaching the anterior part of the temporal retina borders of the visual field by moving an object (e.g., the
(Fig. 16.3C), and is therefore called the monocular finger of the examiner) from well outside the visual
zone. Both eyes view the rest of the visual field, the bin- field toward its center. A systematic examination cover-
ocular zone. ing all parts of the visual field for each eye is done by
Damage to parts of the nasal retina in one eye pro- so-called perimetry.
duces a blind spot in the temporal visual field; damage
in the upper half of the retina in one eye produces a
The Lens and the Far and Near Points of the Eye:
blind spot in the lower visual field; and so forth. Damage
Accommodation
that affects the binocular zone usually goes unnoticed
by the patient. Therefore, the visual field must be exam- The lens is transparent and built of cells that form long
ined for each eye separately. This is done with the per- fibers. It is elastic and, when loosened from the ciliary
son fixating the gaze at a target straight ahead while body to which it is attached with thin zonular fibers
one eye is covered. Often it suffices to test the outer (Figs. 16.1 and 2), it becomes rounder. Contraction of
A Visual field
both eyes
Point of
fixation
Monocular
Monocular zone
zone
Binocular zone
B Visual field Visual field

left eye right eye
C Binocular zone
Point of fixation
Left Right
monocular monocular
zone zone
gure 16.3 The visual eld. A: The visual Left temporal Right temporal
Nasal
elds of both eyes when the gaze is directed retina retina
retina
straight ahead. B: The visual eld as deter- Fovea
mined for each eye separately. C: The posi-
tions of the eyes ensure that the images fall Corresponding
on corresponding parts of the two retinas. points on retina
the ciliary muscle reduces the diameter of the ring THE RETINA
formed by the ciliary body. This slackens the zonular
fibers and enables the lens to become rounder; that is, The retina forms the innermost layer of the eye (Fig. 16.2).
its curvature (convexity) and thus also the refraction of The outer part of the retina, which adjoins the choroid,
the light increase. Contraction of the ciliary muscle is is the pigmented epithelium consisting of one layer of
required sharply to see objects that are closer to the eye cuboid cells with large amounts of pigmented granules
than approximately 6 m. This distance is called the far in their cytoplasm. Internal to the pigmented epithelium
point of the eye. In a normalemmetropiceye, the follows a layer with photoreceptors, and then two further
length of the eyeball is accurately adjusted to the refrac- layers with neurons (Fig. 16.4). The processes of the
tion of the cornea and the lens in the relaxed state. photoreceptors contact the bipolar cells, which, in turn,
When viewing objects at distances greater than about 6 transmit signals to the retinal ganglion cells. The axons
m, the lens maintains the same convexity, and yet the of the ganglion cells leave the eye in the optic nerve to end
image is always focused on the retina. This is because in nuclei in the diencephalon and the mesencephalon.
the light rays entering the eye from points at such dis- The pigmented epithelium extends forward to the edge
tances are all virtually parallel and are therefore col- of the pupil (Fig. 16.2), whereas the photoreceptors,
lected in the plane of the retina (like a camera focused bipolars, and ganglion cells are present only in the parts
at infinite distance). If the length of the eyeball differs of the retina situated posterior to the ciliary body (pars
from the normal (even by only a few hundred microns), nervosa retinae).
the light rays are not collected in the plane of the eye Unlike many other receptors, the photoreceptors are
and the sight is blurred. If the eyeball is too long, the not of peripheral origin but belong to the central ner-
light rays are collected in front of the retina. This condi- vous system (CNS). The retina develops in embryonic
tion is called myopia and is corrected by concave () life as an evagination of the diencephalon (see Fig. 9.3).
glasses.1 If the eyeball is too short, the light rays meet
behind the retina. Convex (+) glasses correct this hyper-
metropia (in children, because of their elastic lenses, the
error is easily corrected by constant accommodation). Light
The closer an object comes within the far point of the
eye, the more the convexity of the lens must be increased
by contraction of the ciliary muscle. Such adjustment of
the lens for near sight is called accommodation. The Axon
closest distance from the eye at which we can see an
object sharply is called the near point of the eye. Ones Ganglion cell
own near point can be easily determined by fixing the Amacrine cell
eyes on an object (e.g., a finger) that is gradually moved
closer to the eye, until it no longer can be viewed
Bipolar cell
sharply.
The far point of the eye depends on the curvature of Horizontal cell
the lens in its relaxed statethat is, with no contrac-
tion of the ciliary muscleand remains stable through-
out life. The near point, however, depends on the ability
of the lens to increase its curvature and moves gradu-
ally away from the eye from birth until about the age of
60. This happens because the lens becomes gradually
stiffer and less elastic, so that the ability to increase its Photoreceptor cell
convexity declines steadily. At about the age of 45 so
much accommodation is lostor, in other words, the
near point is so far awaythat it is difficult to read fine Outer segment
print. This condition, called presbyopia, is corrected by
the use of convex (+) glasses of appropriate strength.
Pigment epithelium
Pigmented
fibroblast in
1 A correlation exists between much reading (i.e., accommodating for long choroid
periods) and development of myopia in adolescents. Animal experiments con-
rm that how the eye is used inuences the growth of the eyeball. Thus, when
3-month-old monkeys were equipped with +3 glasses, the length of the eye gure 16.4 The retina. The main cell types and their interconnec-
changed to compensate for the refraction error. tions (highly simplied).
Strictly speaking, the term retinal ganglion cell is mostly intracellularly, whereas in the cones they are
therefore not correct, but it is nevertheless maintained. partly invaginations of the surface membrane. The pho-
Because the photoreceptors are located external to toreceptors constantly remove and resynthesize the
the two other neuronal layers, the light has to pass membrane folds.
through the latter to reach the photoreceptors. Because The rods and the cones contain different kinds of
there are no myelinated axons in the retina, however, photopigment. The rods contain rhodopsin, which has
the layers internal to the photoreceptors are sufficiently been the most studied. It consists of a protein part,
translucent. opsin, and retinal, which is an aldehyde of the vitamin
In addition to the aforementioned neuronal types, A molecule. Retinal is light absorbing and is changed
the retina also contains many interneurons, the ama- by light (absorption of photons). Simultaneously, the
crine cells, and the horizontal cells (Fig. 16.4; these neu- opsin part is changed, and this leads to alteration of the
rons are treated in more detail later in this chapter, membrane potential of the photoreceptor (hyperpolar-
+
under Interneurons in the Retina). The horizontal ization by closure of Na channels). The transduction
cells are responsible for lateral inhibition (see Fig. 13.4), mechanism involves activation of G proteins and intra-
among other things. More processing of sensory infor- cellular signal molecules, and structurally the photo-
mation takes place in the retina than in any other sense pigments resemble closely other G proteincoupled
organ. Thus, the visual information transmitted to receptors (e.g., muscarinic receptors, and receptors for
higher centers of the brain from the retina is already smell). The hyperpolarization of the photoreceptors by
distorted by enhancement of the contrast between light stimuli affects the bipolar cells (and retinal
light and darkness and by preference for signals caused interneurons), which then act on the ganglion cells to
by light from moving objects. alter the frequency of action potentials conducted in the
optic nerve to the visual centers of the brain.
The photopigment of the cones differs slightly from
The Retina Has a Layered Structure
rhodopsin in the structure of the opsin molecules.
Under the microscope, several distinct layers of the Further, there are three varieties of cone opsin mole-
retina can be identified in sections cut perpendicular to cules, which explain why we have three kinds of cones
its surface (Figs. 16.5 and 16.12). Externally, toward absorbing light of different wavelengths (Fig. 16.6).
the pigmented epithelium, lie the light-sensitive parts of The opsin of the cones is also bound to retinal, but the
the photoreceptorstheir external segments. The two opsin molecule determines the wavelength sensitivity of
types of photoreceptors, the rods and the cones, can be retinal.
distinguished because the external segments of the
cones are thicker and usually somewhat shorter than
Dark Adaptation and Light Adaptation
those of the rods. Internal to the layer of the external
segments, there are three distinct layers with cell nuclei. When looking into the eye (e.g., through an ophthal-
The outer nuclear layer consists of the nuclei of the moscope), the color of the retina is a deep purple
photoreceptors. The nuclei of the bipolar cells (and because of the content of rhodopsin. The reflection of
many of the interneurons) form the inner nuclear layer. light from the retina produces the red eyes of flash pho-
The innermost layer of nuclei belongs to the ganglion tography. The color bleaches quickly on illumination of
cellsthe ganglion cell layer. Between the nuclear layers the retina, but it returns slowly in the dark. The light
lie processes of the neurons and their synapses, conse- has broken down the rhodopsin, and it takes some time
quently termed the outer and inner synaptic layers (or to resynthesize it. We experience the time needed for
plexiform layers). In the outer synaptic layer, the processes this process of dark adaptation when entering a dark
of the bipolar cells end in depressions in the processes of room from strong sunlight. In the beginning, we can
the photoreceptors (Fig. 16.4). The photoreceptor pro- hardly see anything, but gradually the ability to see
cesses contain synaptic vesicles close to the presynaptic returns. This happens in two stages; first, there is a
membrane. rapid stage of improvement of about 10 minutes, and
A special kind of glial cellthe Mller cellsextends thereafter a slower stage of almost 1 hour until full light
through the retina from the pigmented epithelium to the sensitivity has been restored (if the initial illumination
vitreous body. They are most likely a form of astrocyte. was very intense). Because the rods are responsible for
vision in dim light (scotopic vision), the dark adapta-
tion depends on resynthesis of rhodopsin in the rods.
Photoreceptors and the Photopigment
We experience the opposite phenomenon of dark
Electron microscopy reveals that the outer segments of adaptation, light adaptation, when moving from dark-
the rods and cones are packed with folded membrane, ness into strong light. Also then, after first seeing noth-
forming a large surface containing the light-sensitive ing, vision gradually returns. The strong light bleaches
photopigment. In the rods, the folds of membrane lie the photopigment massivelythat is, there is an intense,
Axons of ganglion
cells
Ganglion cell layer
Inner synaptic
(plexiform) layer
Inner nuclear layer

(bipolars)
Outer synaptic
(plexiform) layer
Outer nuclear layer

(photoreceptors)
Outer segments of
rods and cones
Pigment epithelium
Choroid
gure 16.5 The retina. Photomicrograph of a microscopic section here than in Fig. 16.12). The outer segment of a cone is marked with
showing the various layers (monkey). The section is from the periph- an asterisk. Magnication, 175.
eral part of the retina (this explains the lower density of ganglion cells
brief stimulation of many receptors, producing the

almost painful sensation of blinding light. The rhodop-
sin of the rods remains bleached as long as it is exposed
to strong light and the rods cannot contribute to vision
Relative absorption %
under these conditions. The cones are first maximally
hyperpolarized and are therefore unable to respond.
100 This explains why we cannot discriminate forms and
colors at first. However, during a few seconds the outer
segments of the cones depolarize to a level where they
again can respond to changes of illumination. Change
2+
60 of intracellular Ca concentration is of crucial impor-
tance for this depolarization. Light adaptation, then,
depends on change of the cone-membrane potential.
Additional adaptations occur when passing from dark-
20
ness to light, such as constriction of the pupils to reduce
light entering the eye (anyone having tried to enter a
400 500 600 700 sunlit street after widening the pupils by atropine has
experienced the importance of this adaptation).
Wavelength (nm)
gure 16.6 The three different kinds of visual pigment. The diagram Rods and Cones Have Different Properties
shows the efciency with which the three kinds of cones absorb light
of different wavelengths. Note the marked overlapping of the absorp- The rods are much more sensitive than the cones and
tion curves. react to extremely small amounts of light, whereas the
cones need strong light to react. This is partly because information than when the cones are responsible. This
the outer (external) segment of the rod is longer and explains our inability to perceive visual details, such as
contains more photopigment than that of the cone. The small letters, in dim light. Therefore, the cones are
rods are thus responsible for vision when the light is responsible not only for color vision but also for our
dim, called scotopic vision, whereas the cones are respon- ability to perceive visual details: they are responsible
2
sible for vision in good lightphotopic vision. (That for precise perception of patterns and form.
vitamin A is necessary for the synthesis of rhodopsin
explains why vitamin A deficiency causes night blind-
Color Blindness
ness.) The distribution of light sensitivity for different
wavelengths of light is the same for all the rods (maximal In most cases color blindness is an inheritable condition,
sensitivity for wavelengths around 500 nm); hence, they due to either lack of one kind of cones or an error affect-
cannot help us discriminate between light of different ing one of the three cone photopigments. Green or red
wavelengths, which is a prerequisite for color vision. blindness (or weakness) are the most common forms,
The cones, in contrast, are as mentioned of three kinds, affecting about 3% of the male population, whereas blue
each with a particular variety of photopigment with blindness is very rare. Genes at the X chromosome code
maximal light sensitivity to different wavelengths. One the photopigments of the red- and green-sensitive cones,
kind of cone responds best to light with wavelengths in whereas the genes for the blue-sensitive photopigment
the blue part of the spectrum, another in the red part, and for rhodopsin are at autosomal chromosomes.
and the other in the green part (considerably fewer Since the condition is recessively heritable, it is under-
cones react to blue than to red and to green). One kind standable that almost only men are color blind.
of cone alone cannot inform about color, however. This Rarely are two kinds of cones lacking, or even all
is so because each photopigment is bleached not only three. Finally, deficient or absent color vision can some-
by light with wavelengths to which it is maximally sen- times be caused by disease of the retina or a lesion of
sitive but also by stronger light with shorter and longer the visual cortex.
wavelengths (Fig. 16.6). Only by comparing the degree
of activation of the different kinds of cones can the neu-
Signal Transmission in the Retina
rons receiving signals from them extract information
about the distribution of wavelengths in the light falling The photoreceptors do not behave like other receptors
on the retina. Together, the three kinds of cones are when exposed to their adequate stimulus: as mentioned,
responsible for color vision. As mentioned, however, they are hyperpolarized instead of depolarized. Here
the cones are not very sensitive to light; from daily expe- we briefly discuss how hyperpolarization of the receptors
rience, we know that we need good light to perceive the can elicit action potentials in the neurons conducting
color of objects. In poor light, everything appears as a the signals to the brain.
variation of gray. One important point is that the photoreceptors are
Other important differences between rods and cones unusual also in another respect: they are in a depolar-
concern their interconnections with other neurons in ized state in the dark, with a membrane potential around
+
the retina. Notably, many rods connect to each bipolar 30 mV. Na channels that are open in darkness prob-
cellthat is, there is a high degree of convergence. For ably cause this. Like other receptors, the photoreceptors
the cones, on the other hand, there is typically much (and the bipolar cells) do not produce action potentials
less convergence, with a few cones connected to one but produce only graded changes of the membrane
bipolar cell. This also helps us understand why less light potential. Because the distance is very short from the
is required to convey signals through the optic nerve outer segmentwhere the membrane potential changes
from the rods than from the cones. The difference in ariseto the synapses between the photoreceptors and
convergence means that the cones provide information the bipolar cells, even small membrane-potential fluctu-
with a higher spatial resolution than the rodsthat is, ations cause alterations of the transmitter release from
two points must be farther apart to be perceived as two the photoreceptors. (There is thus no need for the pro-
when the rods are responsible for transmitting the duction of action potentials, which are necessary only
when signals are to be propagated over long distances.)
Light falling on the retina causes closure of the photo-
2 Two kinds of photoreceptors with different sensitivities to light enable the receptor-Na+ channels by degradation of the photo-
visual system to give meaningful information even with being exposed to pigment and cyclic GMP. Closing of Na+ channels
extreme variations of light intensities. Release of dopamine from one kind of
amacrines seems actively to support the change from scotopic (rods) to photo- hyperpolarizes the cell. Transmitter release from the
pic (cones) vision. Light induces release of dopamine that enhances the signal photoreceptors (as from other neurons) is caused by
transmission from the cones compared with the rods. Further, dopamine membrane depolarization without any definite threshold
uncouples electric synapses between amacrines and a certain kind of bipolars,
so that signals are less widely distributed horizontally in the retina. This pre- that has to be exceeded. Thus, in the dark, the photo-
sumably contributes to the enhanced spatial resolution with photopic vision. receptors release transmitter continuously, whereas the
release is reduced by light (as if darkness were the The bipolar cells have depolarizing (excitatory)
adequate stimulus). Recording from bipolar cells has effects on the retinal ganglion cells (and on amacrine
shown that they are of two kinds: one is depolarized by cells), and we can then understand why there are also
light, and the other is hyperpolarized. Glutamatewhich two kinds of ganglion cells: one that is excited, and one
is the transmitter released from the photoreceptors that is inhibited by light hitting the photoreceptors to
has a depolarizing (and therefore excitatory) effect on which they are coupled. We therefore use the terms ON
neurons in other parts of the CNS. With regard to the and OFF bipolars and ganglion cells. In contrast to the
bipolars, however, one kind is hyperpolarized by gluta- photoreceptors and the bipolars, the ganglion cells pro-
mate, whereas another is depolarized. This is presumably duce action potentials (conducted in the optic nerve to
due to the existence of two different kinds of postsyn- the higher visual centers).
aptic glutamate receptor.
We can summarize the events as follows. When light
Couplings from Rods and Cones Are Different
hyperpolarizes the photoreceptors, the release of gluta-
mate is reduced, as mentioned. This leads to less hyperpo- Figure 16.7 shows that there are two parallel signal
larization, which is the same as depolarization, of one pathways from the cones. The ON ganglion cells increase
kind of bipolar; thus, some of the bipolars are depolarized their firing frequency with increasing intensity of light
and therefore increase their own transmitter release. This hitting the cones with which they are connected,
is an example of disinhibition. The opposite happens with whereas the OFF ganglion cells increase their firing fre-
the other kind of bipolar cell, which is hyperpolarized quency with increasing darkness. These two channels
(receives less depolarization) and therefore reduces its enable the ganglion cells to inform of a much wider
transmitter release. Thus, one kind of bipolar reacts with range of light intensities than if there were only one
increased transmitter release when light is turned on, the channel. However, the bipolars and the ganglion cells
other kind when the light is turned off (Fig. 16.7). do not inform about the absolute light intensity but the
intensity in a small spot on the retina in comparison to
the surroundings. This is caused by lateral inhibition
produced by horizontal cells (Fig. 16.7), which are elec-
trically coupled.
The coupling from the rods to the ganglion cells is
more complicated than from the cones. Thus, bipolars
ON-ganglion cell OFF- ganglion excited by rods do not influence ganglion cells directly
cell
but via a special kind of amacrine cells (Fig. 16.7).
These amacrines excite ON bipolars and inhibit OFF
Amacrine cell bipolars. It should be noticed that the rods and cones
are coupled to the same ganglion cells. Consequently, a
ganglion cell transmitting signals from cones in daylight
OFF bipolar transmits from rods in the dusk.
ON bipolar
Interneurons in the Retina

As mentioned, the retina contains interneurons in addi-
Horizontal
cell tion to the photoreceptors, bipolars, and ganglion cells
(Fig. 16.4). The horizontal cells send their processes in
the plane of the retinathat is, perpendicular to the
orientation of the photoreceptors and the bipolars (Fig.
16.7). The horizontal cell processes establish contact
with the inner segments of the photoreceptors and with
Cone the dendrites of the bipolars. They therefore regulate
the transmission from the photoreceptors to the bipo-
lars. There is good evidence that the horizontal cells are
Rod responsible for the typical receptive fields of the bipo-
lars and ganglion cells with central excitation and
gure 16.7 ON and OFF bipolar and ganglion cells in the retina. peripheral inhibition (or vice versa). This involves com-
Simplied diagram showing the coupling of a cone to two different plex and unusual synaptic mechanisms that are not
bipolar cells, and further coupling of the bipolars to ganglion cells
fully understood. The horizontal cells are intercon-
that increase or decrease their activity, respectively, when light falls
on their receptive elds. Amacrine cells are intercalated in the cou- nected with electric synapses, probably enabling trans-
pling of rods to ganglion cells. mission for several millimeters in the plane of the retina.
They release -aminobutyric acid (GABA) in their effer- glion cells that are activated and inhibited, respectively,
ent synapses onto the inner segments of the photorecep- by light hitting the central zone of the receptive field.
tors. Each horizontal cell is depolarized by glutamate These correspond to ON and OFF ganglion cells, described
released from many photoreceptors. Thus, light hitting above with reference to the center of their receptive
the photoreceptors leads to hyperpolarization of the fields (Fig. 16.7). Thus, as mentioned, illumination of a
horizontal cells; that is, they release less GABA so that small spot on the retina can lead to increased activity in
the photoreceptors are disinhibited. Conversely, the one chain of neuronsforming, as it were, a channel
horizontal cells hyperpolarize the photoreceptors in for signal transmission to the higher visual centers
darkness. and reduced activity in another. (The arrangement of a
The other kind of retinal interneuron, the amacrine central excitatory field and a peripheral inhibitory zone
cell, is located with its cell body in the inner nuclear is also found in the somatosensory system.) For recep-
layer and establishes contact with both the axons of the tive fields of the retinal ganglion cells, the central excit-
bipolar cells and the dendrites of the ganglion cells (Fig. atory or inhibitory part of the receptive field can be
16.7). Amacrine cells are thus intercalated between explained by direct coupling from photoreceptors to
bipolar cells and ganglion cells, and many bipolar cells bipolars and further to ganglion cells, whereas the
exert their effect on ganglion cells only or mainly via peripheral zone with opposite effects must involve hor-
amacrine cells. As mentioned, this is the rule for rod izontal cells producing lateral inhibition (Fig. 16.7). As
bipolars (bipolars connected with rods). Such amacrines expected, illumination of the complete receptive field
(AII) form electric synapses with ON (depolarizing) the central and peripheral zones simultaneouslygives
bipolars and chemical glycinergic synapses with OFF a much weaker response from the ganglion cells than
(hyperpolarizing) bipolars. Some of the processes of the illumination of the central zone only (Fig. 16.8).
amacrine cells also extend horizontally for considerable In conclusion, each ganglion cell brings information
distances. The actions of the amacrine cells are varied to higher visual centers about a particular small, round
and complex, and there are numerous morphological area in a definite position on the retina, and thus in the
varieties. They are also heterogeneous with regard to visual field. Together, the receptive fields of all ganglion
their transmitter content, and, as mentioned, some cells cover the whole visual field with the same type of
establish both chemical and electric synapses. One concentrically arranged receptive fields. Ganglion cells
subgroup of amacrines contains GABA, for example; that lie side by side in the retina have overlapping, but
others contain acetylcholine or dopamine. At least not identical, receptive fields.
seven different neuropeptides have been associated with
amacrine cells. Twenty different kinds of amacrine cells
Retinal Ganglion Cells Exaggerate Contours
have so far been identified, considering differences in
both synaptic connectivity and transmitter content. The Recording of ganglion cell activity under different light-
amacrines play an important role in influencing the ing conditions show that the retinal ganglion cells do
activity of many ganglion cells with properties that cannot give information about absolute light intensity.
not be explained by transmission directly from bipolars Rather, their activity depends on the contrast of inten-
to ganglion cells. For example, amacrine cells appear to sity between the light falling on the central and the
be partly responsible for making certain ganglion cells peripheral parts of the receptive field. For example, for
sensitive to light stimuli (contrasts) with a specific an on-center cell, a narrow beam of strong light hitting
orientation. precisely the center of the receptive field while the
peripheral zone is in darkness evokes maximal firing
frequency.
Receptive Fields of Retinal Ganglion Cells
This preference of the visual system for contrast in
Most retinal ganglion cells have in common that they light intensity can be demonstrated, for example, by
are excited most effectively by shining light on small looking at a gray circular spot surrounded by black
circular spots on the retina. These are the receptive (Fig. 16.9A). Exchanging the black surrounding with a
fields of the ganglion cells and can be defined as the light gray makes the gray spot appear darker (even
area of the retina from which a ganglion cell can be though the amount of light the eye receives from the
influenced. The receptive field can of course be deter- central gray area is unchanged). This property of the
mined not only for ganglion cells but also for neurons visual system makes it particularly suited to detect con-
at all levels of the visual pathways. The ganglion cells tours, which are especially important for analysis of
are typically excited from a small central circle and form. Our ability to judge contrasts of light intensities
inhibited from a peripheral circular zone, or vice versa does not just depend on retinal mechanisms, however.
(Fig. 16.8A). The American neurophysiologist Stephen For example, the brightness of an area compared with
Kuffler first demonstrated this in the early 1950s. He its neighbors depends on our (subconscious) judgment
introduced the terms on-center and off-center for gan- of how the light fallsthat is, whether we assume that
A B
RETINAL GANGLION CELLS LATERAL GENICULATE BODY STRIATE AREA

Receptive field Receptive field Receptive field (simple cell)
_ _ _
_ _ _ _ _ _ _ _
_ + _ _ + _ +
_ + + _+
_ _ _ _
Light Light
Light
Central
illumination +
_ _
_ +
_ + _
_
_ + _
_ +
Peripheral
illumination
Orientation of
stripe of light
Diffuse light 0 0,5 1,0 1,5 sec 0 1,0 2,0 3,0 sec
(illumination both
centrally and
peripherally)
gure 16.8 Receptive elds of cells at various levels of the visual eld and excitation from the peripheryalso exist (off-center eld).
pathways. A: Retinal ganglion cells and cells of the lateral geniculate B: The receptive elds of simple cells of the striate area are typically
body have similar receptive elds. The ring frequencies of the neu- oblong with an excitatory and an inhibitory zone. The cells are called
rons when subjected to different kinds of light stimuli are shown in orientation-specic because they respond preferentially to a stripe of
the graphs. Only cells that are excited by shining light on the central light with a specic orientation. The gure shows only one orienta-
part of the receptive eld are shown here (on-center eld), but cells tion of the receptive elds, but all orientations are represented among
with the opposite propertiesthat is, inhibition from the central cells of the striate area. (Based on Kufer et al. 1984.)
the area is in direct light or in shadow. Processes at the

A B cortical level must cause this, since it requires assump-
tions of the three-dimensional form of the object and
from where the light comes. If we misinterpret such
conditions, we make false judgments about relative
light intensities. Figure 16.7B shows that also our judg-
ment of the color of a field depends on its context.
Visual Acuity and the Size of Receptive Fields

We know from everyday experience that in order to
perceive visual details, we must direct the eyes toward
an object. The visual axes have to be oriented so that
light from the object falls on a small region of the retina
gure 16.9 Perceived light intensity and color depend on contrast in the back of the eye, the macula lutea (macula, spot;
and context. A: The central circle reects the same amount of light in lutea, yellow). The macula is about 2 mm in diameter and
both examples; yet we perceive the upper one as darker than the lower.
has a yellowish color when viewed through an ophthal-
B: Perceived color intensity differs dramatically with the context. The
small colored rectangles are copied from the central and peripheral moscope, distinguishing it from the purple color of the
rings, respectively. surrounding retina. Here the visual acuity is greatest,
and it decreases steeply when moving peripherally on of the retina, however, the convergence is much greater
the retina. The visual acuity is expressed as the distance than 100:1, whereas it is much smaller in central parts
(in degrees) two points in the visual field have to be (Fig. 16.12). In the central parts of the fovea (foveola;
apart to be perceived as two and not one. In clinical Fig. 16.10), there are even 1:1 connectionsthat is, one
work, visual acuity is usually determined by viewing photoreceptor connects to one bipolar, which is con-
letters of different sizes at a fixed distance (at the far nected to only one ganglion cell. As mentioned, the rods
point of the eye). The center of the macula has a small show a much greater convergence than the cones, which
depression, the fovea centralis (Figs. 16.1, 16.2, and is in accordance with the distribution of the rods and
16.10). The depression exists because the bipolars and cones: the macula contains almost only cones, whereas
the ganglion cells are pushed aside to enable maximal the most peripheral parts contain almost only rods. The
access for light to the photoreceptors. The small region relative absence of cones in the peripheral parts of the
is also devoid of capillaries. In the central part of the retina (receiving light from peripheral parts of the visual
macula, only cones are present, and only in the macular field) can be demonstrated by how far out in the visual
part of the retina is the visual acuity sufficient to enable field the color of an object can be perceived. It then
us to read ordinary print (e.g., a newspaper). The farther appears that the visual field for color is considerably
we move peripherally from the macula, the lower the smaller than for moving objects. Another factor that
visual acuity. One can demonstrate this easily by trying contributes to the higher visual acuity in the central
to determine how far out in the visual field one can parts of the retinaparticularly in the region of the
recognize a face. Closely linked with these differences in fovea, is that the density of photoreceptors is higher
visual acuity are differences in the size of the receptive there than more peripherally. Figure 16.13 illustrates a
fields of ganglion cells in the central and peripheral third contributing factor: the dendritic arborizations of
parts of the retina. the ganglion cells are more restricted in central than in
Where the optic nerve leaves the eye, there is a circular peripheral parts of the retina, which is also important
area devoid of photoreceptors, appropriately called the for the degree of convergence on each ganglion cell.
blind spot (Figs. 16.1, 16.2, and 16.11. We do not notice Finally, differences between the retinal interneurons in
these blind areas of the two retinas, however, because central and peripheral parts of the retina also play an
3
they are not located at corresponding points (Fig. 16.3). important role.
Differences between the Central and Peripheral Parts

of the Retina
What is the basis for the striking differences in receptive-
field size of ganglion cells in central and peripheral parts
of the retina? One important factor is that the degree of
convergence varies dramatically. There are about 100 Optic papilla
million photoreceptors in the human retina and only Retina
Sclera
1 million ganglion cells; on the average, 100 photore-
ceptors connect to one ganglion cell. In peripheral parts
3 Even when using only one eye we usually do not notice the blind spot, how-
ever. This is due to the capacity of the visual system to ll inn missing parts of
a visual scene (if the size of the missing part is not too big).
Layer of nerve
Foveola fibers
Ganglion cell
layer
Inner nuclear
layer (bipolars)
Outer nuclear Dura
Optic
layer
(photoreceptors) nerve
Pigment epithelium
gure 16.11 The optic nerve and the optic papillae. Photomicrograph
gure 16.10 The fovea centralis. Schematized drawing of micro- of section through the posterior pole of the eye at the exit of the optic
scopic section through the posterior pole of the eye. The bipolar and nerve (the blind spot). The optic nerve swells immediately outside the
the ganglion cells are pushed aside in the most central part of the eye because the axons become myelinated. The ganglion cell axons
fovea (the foveola), whereas the density of photoreceptors is at its are unmyelinated as long as they course through the innermost layer
highest in this same area. of the retina.
CENTRAL RETINA PERIPHERAL RETINA
Ganglion cell layer
Inner synaptic
(plexiform) layer
Inner nuclear layer

Outer synaptic
(plexiform) layer
Outer nuclear layer
Outer segments
of rods and cones
Choroid
gure 16.12 Central and peripheral parts of the retina. Photo- when moving from the central to the peripheral parts of the retina. The
micrographs illustrating how the various retinal layers differ in thickness density of ganglion cells is quite different in the two areas.
There Are Two Main Kinds of Retinal Ganglion Cell

DISTANCE FROM FOVEA
1 mm 8 mm We described two kinds of retinal ganglion cell that differ
according to whether they signal light or darkness (ON
and OFF ganglion cells). There are, however, further spe-
cializations among ganglion cells that we should know
to understand the information sent from the retina to
higher visual centers.
M cells Anatomic studies showed many years ago that the
retinal ganglion cells differ greatly in size. One tendency,
mentioned above, is that the dendrites of the ganglion
cells are longer peripherally than centrally (Fig. 16.13).
This relates to differences in the size of their receptive
fields. However, ganglion cells with the same placement
with regard to eccentricity on the retina also vary in
size. It is now customary to recognize two main kinds
of retinal ganglion cell, together constituting about
90% of all cells: the M cells and the P cells. As seen in
P cells Fig. 16.13, the P cells are tiny compared with the
M cells, but both types are much smaller centrally than
peripherally. Physiological studies of their properties
indicate that the M cells primarily signal movement and
contrasts of illumination, whereas the P cells are respon-
sible for providing information about fine features (high
gure 16.13 Two main kinds of retinal ganglion cells (monkey). visual acuity) and color. Both kinds can have either
Both types increase in size in the peripheral direction (distance from
ON or OFF properties and can be activated under both
the fovea). The extension of the dendritic tree is related to the size of
the receptive elds of the ganglion cells. The cells have been visualized scotopic and photopic light conditions. This is what
by intracellular injection of HRP. (Based on Shapley and Perry 1986.) one would expect, because signals from rods and cones
converge on the same ganglion cells (Fig. 16.7). It is mesencephalon. It gives some insight into the develop-
nevertheless possible that the M cells play a more ment of the visual system to compare the proportion of
important role than P cells in scotopic vision. retinal ganglion cells that sends axons to the mesen-
Next, we discuss the organization of the pathways cephalon in various species. Thus, in the cat, about
followed by the signals from the retina, and we will see 50% of the axons in the optic nerve pass to the mesen-
that information from the two main types of ganglion cephalon, and the proportion is most likely even higher
cells is kept separateat least to some extentup to in lower mammals like the rat. In humans, it is probable
the cortical level. that even less than 10% pass to the mesencephalon.
With increasing development of the cerebral cortex,
more and more of the analysis of visual information
More about Retinal Ganglion Cells
takes place at the cortical level rather than in the brain
The functional properties of the two main morphologi- stem visual centers.
cal types of ganglion cells have been clarified by intra-
cellular staining of cells that first have been characterized
by their response to various kinds of light stimuli.
ORGANIZATION OF THE VISUAL PATHWAYS
Particularly the cats and the monkeys retinal ganglion
cells have been studied in depth. Even though cat and
The Visual Pathways
monkey (and presumably human) ganglion cells have
several features in commonfor example, with regard The axons of the retinal ganglion cells constitute the
to the organization of their receptive fieldsthere are first link in the central visual pathways. All ganglion
also important differences (notably that cats lack ability cell axons run toward the posterior pole of the eye,
to differentiate colors, and their visual acuity is much where they pass through the wall of the eyeball at the
lower than in monkeys and man).What follows here is optic papilla (Figs. 16.1 and 16.11). They then form the
based on findings in the monkey. The M cells (called optic nerve, which passes through the orbit and enters
A cells by some authors) have a large cell body and a the cranial cavity. Here the two optic nerves unite to
fairly extensive dendritic tree (Fig. 16.13). The axon is form the optic chiasm (Fig. 16.14; see also Fig. 6.13). In
relatively thick. The P cells (or B cells) have smaller cell the optic chiasm some of the axons cross, and crossed
bodies, a less extensive dendritic tree, and a thinner and uncrossed fibers continue in the optic tract, which
axon than the M cells. The P cells are most numerous curves around the crus cerebri to end in the lateral
and probably constitute about 80% of all of the gan- geniculate body (corpus geniculatum laterale) of the
glion cells. A major difference is that many of the P cells thalamus (Fig. 16.15; see also Figs. 6.21 and 6.27).
respond preferentially to light with a particular wave- Here the axon terminals of the retinal ganglion cells
lengththat is, they are color-specificwhereas M cells establish synaptic contact with neurons that send their
do not have such specificity. The M cells are more sensitive axons posteriorly into the occipital lobe. These efferent
than the P cells to contrasts in intensity of illumination, fibers of the lateral geniculate body form the optic radi-
however. ation (radiatio optica) (Fig. 16.16). The optic radiation
A further difference is that the M cells appear to curves anteriorly and laterally to the posterior horn of
respond better than the P cells to moving stimuli. In the lateral ventricle and ends in the primary visual cor-
general, the M cells tend to respond especially when a tical area, which is situated around the calcarine sulcus
stimulus starts and stops, whereas the P cells tend to give (see Fig. 6.26). Some of the fibers of the optic radiation
a signal as long as the stimulus lasts. In spite of anatomic lie in the posterior part of the internal capsule, where they
differences between M and P cells, however, each group can be damaged together with the fibers of the pyramidal
contains a wide variety of properties. For most proper- tractfor example, by bleeding or infarctionthus
ties, the two groups overlap, so that some M cells are producing a combination of weakness (paresis) of the
more like typical P cells with regard to certain func- muscles of the opposite side of the body and blind areas
tional properties, and vice versa. in the opposite visual hemifield. The primary visual area
A third kind of retinal ganglion cell does not fit into is area 17 of Brodmann, which is also called the striate
the M and P groups described so far. In the monkey, they area. The latter name (which we will use here) refers to a
constitute about 10% of all ganglion cells. Both anatom- white stripe in the cortex, running parallel to the cortical
ically and physiologically, this group is heterogeneous, surface. The stripe consists of myelinated fibers and is
but the cells are usually smaller than the P cells and have therefore whitish in a cut brain (Fig. 16.17).
thinner axons. The common feature of this group is Not all fibers of the optic nerve terminate in the lat-
that the cells send their axons to the mesencephalon eral geniculate body. Some (about 10% in the monkey)
rather than to the thalamus, like the M and P cells. A terminate in the mesencephalon, especially in the supe-
small fraction of the M cells sends an axon (most likely rior colliculus and the pretectal nuclei. These fibers are
a collateral of the axon going to the thalamus) to the of importance primarily for reflex adjustments of the
Visual field left eye Visual field right eye position of the head and the eyes. Some fibers of the optic
nerve pass to the hypothalamus where they contribute to
regulation of circadian rhythms (see Chapter 30, under
Nasal
visual field
Nasal visual Hypothalamus and Circadian Rhythms).
field
Temporal Temporal
visual field visual field
Axons from the M and P Cells Terminate in Different
Layers of the Lateral Geniculate Body
The human lateral geniculate body (and that of other
primates, like monkeys) consists of six cell layers
Nasal retina
(Figs. 16.18 and 16.19). The two ventral-most laminas
(1 and 2) are composed of large cells and are therefore
called the magnocellular layers, whereas the dorsal
four are composed of small cells and are called the
Temporal parvocellular layers (Fig. 16.16). Anatomic and physio-
retina Optic nerve logical studies have shown that the large retinal ganglion
cells, the M cells, send their axons to the magnocellular
Optic tract layers of the lateral geniculate body, whereas the small
Optic chiasm
Lateral
ganglion cells, the P cells, send their axons (at least
geniculate preferentially) to the parvocellular layers (Fig. 16.18).
body There is thus a division of the lateral geniculate body
that largely corresponds to the functional division
among retinal ganglion cells. It is now usual to speak of
Optic
the two parallel pathwaysM and Pfrom the retina
radiation to the lateral geniculate and further to the visual cortex.
The significance of this will be discussed in connection
with the visual cortex.
Signal Processing in the Lateral Geniculate Body:

Corticothalamic Connections
Although the receptive fields of neurons in the lateral
geniculate body are closely similar to those of retinal
ganglion cells, the lateral geniculate is not merely a sim-
ple relay station. Signals from the retina are subject to
Left striate area (primary Right striate area modification before being forwarded to the striate area.
visual area, V1)
Of special importance are strong, retinotopically orga-
gure 16.14 The visual pathways. For didactic reasons, the visual nized corticothalamic projections from the visual cor-
eld of each eye is shown separately (cf. Fig. 16.3). tex to the lateral geniculate. These connections most
likely can control the signal traffic from the retina
through the lateral geniculate and have been shown
physiologically to influence the properties of the neu-
rons. This modulation probably relates to mental states
Lateral
Internal capsule geniculate
(posterior part) body
Temporal lobe
gure 16.15 The lateral geniculate body.

Hippocampus
Drawing and photograph of frontal section
Mesencephalon through the right hemisphere. The whitish bands
separating the lamellae are partly visible.
Lateral ventricle Corresponding

points on the retina
Striate area
1 Optic chiasm
Striate area 2
Optic radiation 3
Lateral
4
Optic nerve geniculate
5
Optic chiasm body
6
gure 16.16 The optic radiation. The course of the bers from the
lateral geniculate body to the striate area shows how the bers bend Lateral geniculate body
around the lateral ventricle and extend partly into the temporal lobe.
gure 16.19 Fusion of the visual images. The signals from corre-
sponding points on the two retinae end in different layers of the
Calcarine sulcus geniculatethat is, signals from the two eyes are kept separate at this
level. The convergence of signals takes place in the striate area.
such as motivation, alertness, expectation, and stimulus

context. Corticothalamic fibers may contribute to the
suppression of vision of one eye in patients with strabis-
mus (squint, cross-eyed); this has the obvious advantage
of avoiding double vision. In addition, the lateral genic-
ulate receives fibers from other sources, notably from
cholinergic cell groups of the pontine reticular formation;
these connections probably regulate the signal transmis-
sion through the lateral geniculate to the striate area, in
accordance with the level of consciousness and attention.
Finally, a large number of GABAergic interneurons
and numerous dendrodendritic synapses in the lateral
geniculate presumably enable neurons with somewhat
different receptive fields to influence each other.
gure 16.17 The striate area. Photograph of a section through the
human occipital lobe showing the characteristic whitish stripe in
layer 4 (the line of Gennari) of the striate area. Arrows mark the Visual Signals from One Side of the Visual Field Reach
border between the striate area and neighboring extrastriate areas. the Hemisphere of the Other Side
See Fig. 33.5 for photomicrographs of a thionine-stained and myelin-
stained sections from the striate area. Figure 16.14 shows how the fibers are arranged in the
optic chiasm. The fibers coming from the nasal halves of
LATERAL GENICULATE BODY the two retinas cross, whereas the fibers from the tem-
Parvocellular layer poral halves pass through without crossing. In this way,
the left lateral geniculate body receives fibers from the
RETINA
temporal retina of the left eye and from the nasal retina
Magnocellular layer
of the right eye. The lateral geniculate body thus receives
light from the contralateral half of the visual field. In
functional terms, the crossing of signals corresponds to
that taking place in the somatosensory system.
P cell Optic nerve fibers from the two eyes are kept sepa-
M cell rate at the level of the lateral geniculate body, since
three of the six layers receive fibers from the ipsilateral
gure 16.18 The lateral geniculate body. The two main kinds of
eye, and the three others receive fibers from the contra-
retinal ganglion cells end in different layers of the lateral geniculate. lateral eye (Fig. 16.19). After cutting one optic nerve,
(Based on Shapley and Perry 1986.) almost all cells in three of the layers degenerate
(transneuronal degeneration), whereas the other three localization ensuring that signals from different parts of
layers remain normal. Physiological experiments also the visual field are kept separate (compare with somato-
show that neurons within each layer of the lateral topic localization within the somatosensory pathways).
geniculate body are influenced from one eye only: these But the retinotopic localization is much more fine-grained
cells are monocular. We first encounter cells that are than what appears in Fig. 16.20. Although many fiber sys-
influenced from both eyesbinocular cellsat the level tems of the brain are topographically organized, no one is
of the striate area. as sharply localized as the visual pathways, which show a
true point-to-point localization.
In the lateral geniculate body, fibers from differently
Fusion of Visual Images
placed tiny parts of the retina end differently. Each
Normally, we perceive one image of the objects we look small spot in the retinaand thus in the visual fieldis
at, even though two (slightly different) images are formed represented in its own part of the lateral geniculate
on the retina. The two images are perceived as one, and (Fig. 16.19). The retinotopic localization in the lateral
the phenomenon is called fusion. Fusion requires that the geniculate is such that neurons influenced from the
visual axes of the two eyes be properly aligned, so that same part of the visual field (that is, from correspond-
the images fall on corresponding points on the retina ing points on the retina) lie stacked in a column perpen-
(Fig. 16.3). The two maculae are obviously corresponding dicular to the layers. This has been demonstrated with
points, and the images fall on them when we fix the gaze various anatomic techniques, and physiologically by
on a point to see it as sharply as possible. As mentioned, inserting microelectrodes perpendicular to the layers
the signals from the two eyes are kept separate in the lat- and determining the receptive fields of the cells that
eral geniculate body, but at the cortical level many cells are encountered. The receptive fields of neurons in the
are influenced from both eyesthat is, they are binocular lateral geniculate are quite similar to those of retinal
(Fig. 16.19). Convergence in the cortex of signals from ganglion cells (Fig. 16.8A).
corresponding points in the two eyes is a prerequisite for The thalamocortical connections from the lateral
fusion. Fusion is not present from birth but develops grad- geniculate body to the striate area are also organized
ually from about the age of 3 to 7 months. During this with a precise retinotopic arrangement. This has been
period, the movements of the eyes become coordinated, demonstrated, for example, by injection of a small
so that all movements are conjugated and the images fall amount of horseradish peroxidase in the striate area:
on corresponding points when the gaze is fixed. retrogradely labeled cells are then confined to a narrow
column that extends through all six layers of the lateral
geniculate.
Strabismus (Squint)
That all links of the visual pathways are retinotopically
Strabismus (squint, cross-eyed) means that the visual organized can be verified by shining light on a small spot
axes of the eyes are not properly aligned, and, accord- on the retina. This evokes increased neuronal activity in a
ingly, the images do not fall on corresponding points. small region of the striate area, and when the light is shone
This may be due to problems with the extraocular mus- on other parts of the retina, the evoked cortical activity
cles or their nervous control, or the pressure on the changes position systematically. This kind of experiment
brain to produce fusion may be too weak. The reason has clarified how the visual field is represented in the cere-
for weak pressure may be reduced vision on one or both bral cortex of animals. Careful examination of patients
eyes (e.g., due to retinal disease or a cataract). The lack with circumscribed cortical lesions (often gunshot wounds)
of fusion in children with a squint leads to underdevel- provides the basis for maps of the human visual cortex, as
opment or suppression of vision for the eye not used for shown in Fig. 16.20. Electrical stimulation of the human
fixation. In this manner, bothersome double vision is occipital lobe confirms the retinotopic arrangement within
avoided, but even a relatively brief period of strabismus the striate area. Stimulation with a needle electrode usually
in early childhood may lead to permanently reduced evokes the sensation of a flash of light in a certain part of
visual acuity. It has been shown in monkeys that stra- the visual field. When the electrode is placed close to the
bismus (produced experimentally) leads to a reduced occipital pole of the cerebral hemisphere, the person reports
number of cells in the striate area that is influenced by that the flash is located straight ahead, in agreement with
both eyes. In one kind of squint, the child uses the two the fact that fibers carrying signals from the macula end
eyes alternatively for fixation, and in such patients, the near the occipital pole. As the electrode is moved forward
visual acuity is usually conserved for both eyes. along the calcarine sulcus, the light flash is perceived as
occurring progressively more peripherally in the visual field
(at the opposite side of the stimulated hemisphere). If the
The Visual Pathways Are Retinotopically Organized
electrode is placed above (dorsal to) the calcarine sulcus,
The arrangement of the visual pathways just described the light occurs in the lower visual field, whereas stimula-
concerns merely retinal halvesthat is, a crude retinotopic tion below the calcarine sulcus elicits a sensation of light
Visual field (left)
Retina
Lateral
geniculate
body
Optic radiation
Calcarine
Striate area sulcus
Calcarine
sulcus
gure 16.20 Retinotopic localization of the visual pathways. Left: peripheral parts most anteriorly in the striate area. Right: The exten-
The striate area has been unfolded. Note that information from the sion of the striate area on the surface of the occipital lobe; most of it
upper half of the visual eld reaches the part of the striate area below is buried in the calcarine sulcus. The striate area is similarly oriented
the calcarine sulcus, whereas the lower visual eld projects above. in the left and the right gures.
Central parts of the visual eld are represented most posteriorly and
in the upper visual field. Studies in healthy humans with nuclei, these send their efferents to the cortex, notably
positron emission tomography (PET) and functional to the extrastriate visual areas (cortical areas processing
magnetic resonance imaging (fMRI) have confirmed the information from the striate area). Thus visual infor-
main features of the retinotopic organization of the striate mation may reach the cortex even when the optic radia-
area. tion or the striate area is damaged. Even though these
Disease processes (e.g., a tumor) involving the visual visual pathwayswhich circumvent the lateral geniculate
cortex may also at times elicit sensations of light because bodyare retinotopically organized, they are apparently
the neurons are abnormally irritated. Epileptic seizures capable only of giving crude information about move-
originating in the visual cortex often start with a visual ment in the visual field. Thus, after bilateral damage of the
aurathat is, the muscular convulsions are preceded striate area in monkeys, the animals react easily to mov-
by bizarre patterns of light in the visual field opposite ing stimuli, even though in other respects they behave
the diseased hemisphere. as if they were blind. Studies of patients with damage at
various levels of the visual pathways and of the visual
cortex (localized with the use of MRI) indicate that, as
Visual Information Can Reach the Cortex via the
long as parts of the extrastriate visual areas on the con-
Superior Colliculus and the Pulvinar
vexity are intact, the patients retain some capacity to
Not all fibers in the optic nerve end in the lateral genicu- recognize movements in the visual field. When sitting in
late body, as mentioned. About 10% (in the monkey) front of a large screen with a random pattern of moving
leave the optic tract to terminate in the pretectal nuclei dots, patients with damage of the striate area (and sur-
and in the superior colliculus (see Fig. 27.19). Some rounding areas on the medial aspect of the hemisphere)
fibers end in the pulvinar (see Figs. 6.21 and 6.22), and reacted with movements of the eyes, apparently follow-
this nucleus (together with another thalamic nucleus, the ing the moving objects. They reported that they felt
lateral posterior nucleus, LP; see Fig. 33.7) also receives something moving in front of them, and they had some
afferents from the superior colliculus. Like other thalamic ability to identify the movement direction. They had no
feeling of seeing anything, however, and when tested provided with a higher density of receptors than other
with perimetry, they were completely blind. This pecu- parts, and, further, a much larger number of neurons at
liar conditiontermed blindsightis of considerable higher levels are devoted to the analysis of information
theoretical interest in the search for the neurobiological from these parts. A disproportionately large part of the
basis of consciousness (see later, Consciousness and striate area treats information from the small macular
Visual Experience). region (Fig. 16.20). The magnification factor quantifies
The visual connections of the superior colliculus are the relation between the cortical area devoted to differ-
primarily concerned with reflex movements of the eyes ent parts of the visual field. If information from all parts
and the head, as already mentioned. Thus, most of the of the retina were to be treated with similar accuracy,
efferent connections from the superior colliculus pass the cerebral cortex would have to be several times
to premotor cell groups in the brain stem concerned larger. Precise control of eye movements, however,
with control of such movements. The pretectal nuclei ensures that light from the most interesting part of the
constitute a link in the pathway for the light reflex visual field always falls on the macula.
(Fig. 27.19).
Interruption of the Visual Pathways
Central Parts of the Visual Field Are Overrepresented
Partial damage to the visual pathways produces symp-
In addition to the extremely precise retinotopic arrange- toms that confirm the arrangement of the cells and
ment of the visual pathways, another important feature fibers at various levels of the optic system (Fig. 16.21).
must be mentioned. We have described that the density Interruption of the optic nerve prevents any visual signals
of retinal ganglion cells is considerably higher in central from reaching the brain from that eye. If only the cross-
than in peripheral parts of the retina (particularly high ing fibers are damaged at the level of the optic chiasm,
in the macula). This corresponds to conditions in the signals from the two nasal halves of the retinas are
somatosensory system, where the density of receptors is interrupted, and the patient is blind in the temporal
highest at the fingertips (the somatosensory macula). parts of the visual field on both sides. This is called
Figure 16.20 illustrates that axons from central parts of bitemporal hemianopsia. The patient may not notice
the retina end in a disproportionally large part of the this, however, because the blind part of the visual field
lateral geniculate body and that this overrepresentation is not experienced as darkness but rather as nothing.
of the central parts of the retina becomes even more The visual defect may be discovered incidentally by a
marked in the striate area. Again, conditions are similar tendency to bump into objects located a little to the side
to those in the somatosensory system (see Fig. 14.8). and perhaps by being hit by a car coming from the side
Thus, the parts of the body and the visual field in which when driving. This kind of visual defect may be caused
we have the best somatosensory and visual abilities are by a tumor of the pituitary (located just below the
BITEMPORAL HEMIANOPSIA HOMONYMOUS HEMIANOPSIA SCOTOMA
Optic Optic chiasm

nerve Optic tract
Striate
area
gure 16.21 Visual eld defects after lesions of the visual pathways. elds of the two eyes are shown separately for didactic reasons.
The black areas indicate the blind parts of the visual eld. The visual
Rather, there are temporally and spatially specific pat-
terns of neuronal activity that represent the patterns of
Lateral light falling on the retina. So far, however, we have
ventricle only vague ideas about how the activity of the neuronal
populations engaged in visual processing at the cortical
Optic level is related to our subjective visual experiences.
chiasm
We will now look at certain fundamental features of
Tumor of the functional organization of the striate area and also
the pituitary mention the regions surrounding it, the so-called extras-
triate visual areas. These take part in the further process-
Sphenoidal ing of visual information. Thus, the visual cortex consists
sinus
of much more than just the primary visual cortex (V1),
the striate area, even though most of the fibers from the
gure 16.22 Tumor of the pituitary compressing the chiasma. lateral geniculate body terminate there. Schematically,
Frontal MRI. The right part of the chiasma is outlined in yellow.
Note how the tumor preferentially hits the middle part of the
the signals from the retina first reach the striate area
chiasma, damaging the crossing axons (cf. Fig. 16.21). (Courtesy of and are then forwarded to other cortical areas. Different
Dr. S.J. Bakke, Rikshospitalet University Hospital, Norway.) aspects of visual processing such as analysis of color,
form, and movement take place in at least partly differ-
ent subdivisions of the extrastriate areas. Thus, damage
to the striate area produces complete blindness in a part
optic chiasm). When the tumor grows, it has to expand of the visual field, whereas damage restricted to extras-
upward because it is located in a bony excavation (the triate areas produces defects of restricted aspects of visual
sella turcica) and thus first compresses the middle part analysis. Some of the extrastriate areas receive only indi-
of the chiasm (Fig. 16.22). Damage to the optic tract rect projections from the striate area (see Figs. 33.11
produces a different clinical picture. If the damage is on and 33.13).
the right side, visual signals from the temporal half of
the right retina and the nasal half of the left retina are
Properties of Neurons in the Striate Area
prevented from reaching the cortex: that is, the patient
is blind in the left half of the visual field. This is called The retinal ganglion cells and cells of the lateral genicu-
homonymous hemianopsia. The same visual defect occurs late body have relatively simple, round receptive fields
when the optic radiation, or the striate area, is totally with a central zone that elicits excitation or inhibition
destroyed. More frequently, however, there are incomplete when they are illuminated, as well as a peripheral zone
lesions of the optic radiation (note its position in the with the opposite effect (Fig. 16.8B). But round spots of
posterior part of the internal capsule) or of the striate light are not an effective stimulus for the neurons of the
area, producing blind spots or scotoma in the opposite visual cortex. What constituted the adequate stimulus
visual field (at corresponding points). Because of the for the cortical cells remained a mystery for a long time.
accurate retinotopic arrangement within the visual path- Diffuse light was not found to be effective, and neither
ways, mapping of such blind spots enables a precise was the kind of stimulus that so effectively affected the
determination of the site of the lesion. cells of the lateral geniculate. In 1962, however, the
Nobel laureates (1981) David Hubel and Torsten Wiesel
from the United States were able to show that many cells
THE VISUAL CORTEX AND THE FINAL PROCESSING in the striate area respond briskly to elongated fields of
OF VISUAL INFORMATION light or elongated contrasts between light and darkness.
It was furthermore striking that many cells required
The retinotopic localization within the visual pathways that the light stimulus be oriented in a specific direction:
may make it appear that a copy of the two retinal images turning a bar of light some degrees reduced the response
is formed in the striate area. Indeed, the striate area was markedly. This property was termed orientation selectiv-
formerly sometimes called the cortical retina. We now ity. Some cells required a bar of light or a straight light/
know, however, that such a view represents an undue darkness transition of a specific orientation in a specific
oversimplification; considerable processing and integra- part of the visual field to respond, whereas other cells
tion of the visual information take place in the striate responded to a properly oriented stimulus within a larger
area. Thus, most neurons have properties that are differ- area. Such cells thus appear to detect contours with a
ent from those encountered at lower levels of the visual certain orientation regardless of their position within a
pathways. Therefore, when we use the term visual larger part of the visual field. Hubel and Wiesel called
images, we do not mean images or pictures in the the first type simple cells (Fig. 16.8B) and the latter type
usual sense, either in the retina or in the visual cortex. complex cells. Within each group there are several
subtypes according to details of their properties. Why

the properties of the complex cells are more complex
than those of the simple ones may not be obvious, but
presumably the terms were used because Hubel and
Wiesel assumed that the properties of the complex cells
could be explained by several simple cells acting on one
complex cell. The properties of the simple cells, Hubel
and Wiesel suggested, could be explained if several neu-
rons in the lateral geniculate with round receptive fields
in a row (together forming a stripe) converge on one
cortical cell. It is, however, not yet entirely clear which
neuronal interconnections underlie the properties of
cells in the striate cortex.
Hubel and Wiesel also discovered other fundamental
properties of cells in the striate area. Among other
things, cells generally respond much better to a moving
than to a stationary stimulus. Many cells respond pref-
gure 16.23 Ocular dominance columns. Photomicrograph of a
erentially to a line or contour that is moving in a spe- section cut tangentially to the cortical surface of the striate area and
cific direction. Such direction-selective cells thus can stained to reveal differences in cytochrome oxidase activity. The
detect not only the orientation of a contour but also in section is from a monkey that was blind in one eye, causing reduced
which direction it is moving. Other kinds of specificities cytochrome oxidase activity in the regions (light stripes) of the striate
area connected mainly with the blind eye. The dark stripes receive
have also been described for cells in the striate area. For
their main input from the normal eye. Magnication, 25. (Courtesy
example, many binocular cells (cells that require input of Dr. J.G. Bjaalie, Department of Anatomy, Institute of Basic Medical
from both eyes) are sensitive to disparity of the images: Sciences, University of Oslo.)
that is, they require that the images from the two eyes
are slightly different (disparate). This is always the case
for images falling on corresponding points of the retina
because the angle of view is different for the two eyes
(except in the center of the macula) and also for images
of objects that are nearer or farther from the fixation
point. The ability to detect binocular disparity is impor-
tant for perception of depth and for stereoscopic vision.
In addition to single cells being specific or selective
with regard to their adequate stimulus, there is also a
strong tendency for cells with similar properties in this
respect to be located together, more or less clearly sepa-
rated from cells with other properties. This is called gure 16.24 Color-specic blobs in the striate area. Photomicro-
modular organization (Figs. 16.23 and 16.24) and con- graph of a section cut tangentially to the surface of the striate area
cerns properties such as orientation selectivity, wave- of a normal monkey and stained to show differences in cytochrome
length (color) selectivity, and ocular dominance (i.e., oxidase activity. The section passes through laminas 2 to 3 and shows
which eye has the strongest influence). Such segregation numerous small, darkly stained patches or blobs, which correspond
to regions with color-specic neurons. Magnication, 25. (Courtesy
of neurons in the striate area requires that fibers carry- of Dr. J. G. Bjaalie, Department of Anatomy, Institute of Basic
ing different aspects of visual information from the lat- Medical Sciences, University of Oslo.)
eral geniculate end at least to some extent differentially
in the cortex. In agreement with this, fibers from the
parvocellular layers of the lateral geniculate (Fig. 16.18)
terminate deeper in lamina 4 than fibers from the mag- viewing it from above, the groups of cells with similar
nocellular layers. orientation selectivity are located in an irregular pat-
tern of curving bands. This has been demonstrated with
the deoxyglucose method, which demonstrates the neu-
Modular Organization of the Visual Cortex
rons that are most active at a certain time. When an
The first example of modular organization discovered experimental animal is exposed for some time to paral-
by Hubel and Wiesel was the tendency for cells with lel stripes of light, increased glucose uptake takes place
similar orientation selectivity to be grouped together in in cells distributed in bands in the striate area. Another
columns perpendicular to the cortical surface. If we modular organization concerns ocular dominance. As
imagine that the striate area is unfolded and we are mentioned, many cells in the striate area respond to
light from corresponding points in the two retinas, but stimuli. Nevertheless, what is taking place in the striate
for most cells the influence is strongest from one of area appears to be mainly a first analysis and sorting of
the eyes. The use of various tracer techniques and the raw data, which must be further processed elsewhere to
deoxyglucose method has shown that neurons sharing form the basis for our conscious visual experiences.
ocular dominance are also distributed in bands within There is now much evidence of separate, or segregated,
the striate area. Such ocular dominance columns can treatment of the various features of visual images (such
also be demonstrated in animals with monocular blind- as form, color, movement, and location in the visual
ness (Fig. 16.23). A final example of modular organiza- field) outside the striate area, and we discuss a few exam-
tion concerns color-specific cells (strictly speaking: ples in the next section. At some stage in the processing,
wavelength specific). They are not aggregated in bands however, different features of the visual image must be
but in clumps or blobs in laminas 2 to 3 of the striate area brought together and integrated. We return to this later
of monkeys. For some unknown reason, these blobs have in this chapter.
a higher cytochrome oxidase activity than the surrounding
tissue and can thus be easily identified in sections with a
Segregation: Dorsal and Ventral Pathways (Streams)
simple histochemical procedure (Fig. 16.24).
Out of the Striate Area
It has been proposed that a ventral stream of informa-
Extrastriate Visual Areas
tion concerning object identification (what) passes
As mentioned, several areas around the striate area take downward from the occipital lobe to the temporal lobe,
part in visual processing. These are collectively called whereas another, dorsal stream concerned with spatial
the extrastriate visual areas and consist mainly of features and movement (where) passes upward to the
Brodmanns areas 18 and 19, which in the monkey each parietal lobe (see Fig. 16.25). This concept is partly based
consist of several subdivisions. Whereas V1 is often on results from experiments in monkeys with lesions that
used for area 17 (the striate area), parts of the extrastri- have been restricted to visual parts of either the tem-
ate areas are termed V2 to V5. Other parts have specific poral lobe or the posterior parietal cortex. Monkeys
names. In total, about 30 visual areas have been charac- with bilateral lesions of temporal visual areas have
terized so far in the monkey, and each is in some way reduced ability to identify objects; for example, they
involved in the processing of visual information. Many can no longer distinguish between a pyramid and a
have a more or less complete representation of the cube. In contrast, lesions of visual parts of the posterior
visual field and are retinotopically organized, although parietal cortex reduce the ability to localize an object in
with different degrees of precision. Together, the visual space and in relation to other objects; among other
areas occupy more than half of all of the cerebral cortex symptoms, such monkeys have difficulties with perform-
in the monkey. The interconnections between the striate ing goal-directed movements. It suffices with a unilat-
area and the extrastriate areas, and among the extras- eral lesion of the parietal lobe to produce deficits in
triate areas, are numerous and as a rule reciprocal. The the contralateral half of the visual field. This resembles
complete scheme of visual association connections is
therefore extremely complex and explains why it is dif-
ficult to determine the contribution of each individual
4
area to the processing of visual information.
Parietal cortex
Further Processing of Visual Information: Segregation (area 7)
and Integration
Prefrontal
The properties of single neurons in the striate area sug- cortex MT
V4 V2
gest that these neurons together are the basis for the V1
cortical analysis of form, depth, movement, and color.

Their properties, for example, fit predictions made on
the basis of psychophysical experiments in humans,
such as the preference for contours and for moving
Extrastriatal cortex
(inferotemporal)
4 It is not immediately clear why the cerebral cortex is organized so that the
gure 16.25 Dorsal and ventral pathways out of striate area (V1).
visual eld is represented repeatedly in different parts. It may be a result of the
Monkey. The ventral pathway is especially important for conscious
adoption of novel functions by the visual cortex during evolution, and because
this probably occurs more easily by adding new areas (or duplicating an old object identication, whereas the dorsal pathway is crucial for per-
one) than by already existing areas taking up new functions. It is presumably ception of movement and space. Note convergence of information
also a simpler solution to have several separate areas than one large area with from the two pathways in the prefrontal cortex. (Based on data pub-
regard to arrangement of the necessary ber connections. lished by Deco and Rolls 2005.)
the symptoms occurring in humans after damage to the This pathway presumably signals forms and patterns and
posterior parietal cortex, such as reduced ability to judge would seem particularly important for our ability to dis-
movements in the visual field and disturbed eye move- cern visual details. A third parvocellular pathway orig-
ments (see Chapter 34, under More about Symptoms inates in striate neurons that are, at least to a large extent,
after Lesions of the Posterior Parietal Cortex). The wavelength-specific, signaling information about color.
pathways taken by the signals from the striate area to These three pathways from the striate area appear
the temporal and posterior parietal visual regions are to be kept separate, at least partly, also at the next
not known in detail, but several visual areas are interca- stationthat is, in area V2, which is adjacent to the
lated in the pathways (Fig. 16.25). striate area. From V2, information about movement
It is often stated without reservation that the ventral is channeled to area V5 (also called MT, the middle
(temporal) and dorsal (parietal) streams out of the striate temporal visual area), whereas information about color
area segregate information from P and M cells, respec- is channeled primarily to area V4. The major outflow
tively. This is an oversimplification, however. For exam- from V5 has been traced to the posterior parietal
ple, some convergence of information from M and P cells cortex. Information about forms and patterns is chan-
takes place already in the striate area (besides the more neled primarily from V2 to inferotemporal visual areas
prominent segregation). The sum of evidence suggests (i.e., situated inferiorly in the temporal lobe). How far
that the subcortical pathways from the retina to the the specialization goes within each of these areas is
striate area are specialized for signaling simple stimulus not clear, however. The numerous interconnections
features, whereas the further pathways do more advanced among the extrastriate areas suggest that they cooper-
processing using as, a rule, information from both M and ate extensively. Accordingly, single neurons in area V5,
P cells.5 for example, are sensitive not only to movement but
also to certain other visual features. Similarly, neurons
in area V4 are not purely color-specific.
More about Segregated Information Processing in the
Extrastriate Visual Areas
Color Vision and Color Opponency
While there is no doubt that different aspects of visual
information are to some degree segregated in the striate We discussed parts of the elements responsible for color
area and in the extrastriate areas, how far the segrega- visionnamely, the three kinds of cones with sensitivi-
tion goes is a contentious issue. One striking example ties for light of different wavelengths (Fig. 16.6). We
of anatomic segregation is the termination in patches also emphasized that the brain must compare the degree
and bands of projections from the striate area to other of stimulation of three kinds of cone to know the
visual areas. Closer examination of such patterns and wavelength composition of the light (and therefore the
correlation with the physiological properties of cells color of an object). Figure 16.6 shows the large overlap
within the patches and bands indicate the existence between the sensitivity curves of the three kinds of cone,
functionally different information channels out of the especially between those with sensitivities in the red
striate area, as described in the preceding text with regard and green parts of the spectrum, respectively. How can
to a dorsal and a ventral pathway or stream. More detailed we then perceive so many nuances of each color? Part of
analysis revealed a pathway from cells in the striate area the explanation is found in how the cones are coupled
that are predominantly influenced by the magnocellular to the next links in the pathway to the cortex. Thus,
layers of the lateral geniculate. The properties of these retinal ganglion cells and neurons in the lateral geniculate
striate cells indicate that they signal movement and body have narrower sensitivity curves than the cones,
depth cues. Another pathway comes from cells that making them better at discriminating wavelengths.
appear to be influenced by the parvocellular layers of Many ganglion cells and lateral geniculate cells respond
the lateral geniculate. Accordingly, these striate cells to light of different wavelengths but with opposite
have small receptive fields and are orientation-selective. signsone wavelength exciting the cell, the other inhib-
iting it. This phenomenon is called color opponency
and must be due to convergence on one ganglion cell
5 Although behavioral studies suggest that the parietal pathway be made
nonfunctional by destruction of the magnocellular layers of the lateral geniculate
(or lateral geniculate cell) of signals from cones with
nucleus, the temporal pathway is not correspondingly affected by destruction different wavelength sensitivities. Some neurons are
of the parvocellular layers. Thus, whereas selective lesions of the parvocellular excited (ON response) by red light in the central zone of
layers affect color vision, acuity, and contrast sensitivity, destruction of the
temporal visual areas primarily affects form recognition and discrimination.
the receptive field (Fig. 16.8) and inhibited (OFF response)
Selective lesions of the magnocellular layers produce reduced perception of by green light in the peripheral zone; others are inhibited
contrasts with fast-moving stimuli, while this defect does not occur after lesions by red light centrally and excited by green peripherally,
of the parietal visual areas. Further, experiments with lesions of the magnocel-
lular layers suggest that depth perception does not depend on information from
and so forth. Such combinations improve the ability to
M cells alone. discriminate wavelengths in the redgreen part of the
spectrum. Some neurons exhibit color opponency to Afterimages
blue and yellow light (a combination of red and green),
If we look at a red surface for a few seconds and then
others to white light (stimulation of all three kinds of
move to a white, we see a green surface where we just
cones) and darkness.
saw the red. This is called an afterimage. The afterimage
Even more complex kinds of color opponency are
of yellow is blue, and for white it is black. This phenom-
found among neurons in the visual cortex. For exam-
enon can be partly explained by selective bleaching of a
ple, a neuron may respond with an ON response to red
particular kind of cone. For example, a red light bleaches
light and an OFF response to green light in the center of
mainly the cones with wavelength sensitivity in the red
its receptive field, whereas the reverse responses are
part of the spectrum. When the eye then receives white
evoked from the peripheral zone (double opponency).
light, the red cones are, for a short while, less sensi-
Such neurons are found in the cytochrome-rich patches
tive than the others. This creates a relative dominance of
in laminas 23 of the striate area (Fig. 16.24). Together,
signals from green cones, and the surface is perceived
all the color opponency neurons provide accurate infor-
as green. What we have said so far might suggest that
mation of the wavelength composition of the light
the color of the afterimage depends only on the light
hitting a spot on the retina.
first hitting the retina. It is not that simple, however.
The afterimage depends on the color perceived by the
Color Constancy subject, not the absolute wavelength compositionthat
is, color constancy occurs also for after images. The
We are used to, and take for granted, that an object has
afterimage effect can also occur when looking for a while
a certain color, regardless of whether we see it in direct
at a moving object and then at a stationary one. We then
sunlight, in the shadow, or in artificial light. For exam-
perceive an illusory movement of the stationary object in
ple, we consistently identify a banana as yellow, an
the opposite direction.
apple as red, the grass as green, and so forth (although
we perceive differences in nuances). This property of
our visual system, called color constancy, is by no means What Is Color?
self-evident. Thus, the wavelength composition of the
light reflected from an object depends not only on the Even this fragmentary discussion of color vision may
physical properties of the surface but also on the light give some thoughts as to the real meaning of the term
shining on the object. Different light sources produce color. Color is, strictly speaking, not a property of an
light with quite different wavelength composition. The object but a subjective experience of a person seeing
light received by the eye from an object thus differs the object. The experience is based on how the brain
markedly under different lighting conditions. processes information about the wavelength composi-
Color constancy is obviously of great biologic impor- tion of the light reflected from the object (and from all
tance. The color of an object gives us essential informa- other objects in the same visual scene). That we also
tion as to its nature, but only if the color is an invariant, can imagine colors raises the question of where and
typical property. For example, we know that a yellow how colors (as percepts) are represented in our mem-
banana is edible, whereas green or brown ones are not. ory. Now we can only give fragmentary answers to this
Even under quite different illuminations, we easily and other questions about how the brain creates colors
make this kind of choice based on color. or even visual images at all. Nevertheless, the consider-
We do not fully understand how the brain accom- ations discussed here might serve to emphasize that
plishes this remarkable task, although it must depend on there is no absolute correlation between a visual stimu-
processing at the cortical level. Color constancy occurs lus and the perception it evokes. Of course, this is not
only if the object we look at is part of a complex, specific to seeing but pertains to the other senses as well.
multicolored scene. Experiments with patterned, multi- Fortunately, relationships between certain patterns of
colored surfaces show that the composition of the light stimuli and external events are reasonably constant.
reflected from one part of the visual scene may be changed Therefore, we usually take the right decisions by relying
considerably without changing the color perceived by on our brains interpretation (our percept) of the stimuli
an observer. If the same square is seen against an evenly (the color of a traffic light, the movements of a snake,
dark background, however, the perceived color changes the contours of a horse, and so forth).
according to the composition of the reflected lightfor
example, from green to white. This must mean that
Lesions of the Extrastriate Areas: Visual Agnosia
under natural conditions the brain determines the color
of an object by comparing the wavelength composition Humans with lesions of the temporal extrastriate areas
of the light from its surface with the composition of show various forms of reduced ability to recognize
light from all other surfaces in the visual field. objects (agnosia). A patient may be unable to recognize
faces, another may have no problem with faces but can- however, he could easily describe their form and color,
not recognize fingers (finger agnosia), and so on (see and he could judge depth in the visual scene.
Chapter 34, under Lesions of the Association Areas: Patients with selective loss of depth perception after
Agnosia and Apraxia). High-resolution fMRI in cortical damage have been described. To such patients
humans and recording from single neurons in monkeys other people look completely flat, as made from card-
indicate that a small region in the fusiform gyrus board; patients can recognize their color, contours, and
contains a particularly high proportion of face-specific shading, however. The exact site of the lesion in such
neurons (Fig. 16.26). Nevertheless, recordings with mul- patients has not been determined, but PET studies indicate
tiple surface electrodes in patients (to localize epileptic that tasks requiring depth perception activate several
foci) suggest that several, separate small areas in the areas in the cerebral cortex (and in the cerebellar hemi-
inferior temporal cortex participate in face recognition. spheres), and that these areas overlap with areas
These areas appear to be parts of a mosaic of areas with involved in other visual tasks.
different specializations. This agrees with observations
after lesions of extensive parts of the inferotemporal
Integration of Visual Information: One Final Area?
extrastriate areas: such patients are deficient in several
specific kinds of object recognition and suffer from not The fact that there is much evidence of separate pro-
only prosopagnosia (inability to recognize faces; from cessing in the visual cortex of different aspects of visual
Greek, prosopon = face). Selective loss of color vision information must not make us forget that at some level
(achromatopsia) after lesions restricted to a region below a synthesis has to occur. Information about form, posi-
the calcarine sulcus (in the lingual gyrus) has been con- tion, movement, and color must in some way be linked
vincingly documented (Fig. 16.26). This corresponds together. After all, the color belongs to a certain object,
most likely to area V4 in monkeys. Patients with unilat- with a certain form and position and with a certain speed
eral lesions in this region are reported to see everything and direction of movement. Our percept is unitary,
in the opposite half of the visual field in black and white, although the brain first has dissected out and analyzed
whereas the other half has normal colors. the bits and pieces of information in the light falling on
Damage at the junction between the occipital and the the retina. What does integration of information mean
parietal lobes can produce selective impairment of the in the context of sensory processing? One might think
ability to recognize movements (akinetopsia). One that there must exist one final, site (area) in which all
patient with a bilateral lesion of this region could not see aspects of visual information are brought together, but
moving objects; when the same objects were stationary, anatomic data do not favor the existence of such corti-
cal areas. Even in the prefrontal cortex, visual informa-
tion about what and where is treated separately
(in conjunction with coupling of visual features of
objects to voluntary movements).
There are also theoretical problems with the notion
of a final integrative area. Thus, although our conscious
experience is unitary, it consists of components to
which we have separate, conscious access. For example,
Parahippocampal a car may be characterized by its color, by its shape, or
gyrus by its movements. The components are kept separate
yet linked in such a way that we perceive them as
Striate area (V1)
belonging together. Another theoretical problem with a
final integrative area is where to place awareness of
the visual image. As expressed by the British neurobi-
ologist Semir Zeki (1993): If all the visual areas report
to a single master cortical area, who or what does that
Lingual gyrus single area report to? Put more visually, who is look-
Fusiform gyrus ing at the visual image provided by that master area?
Area selective
for faces Area selective for
human bodies
Role of the Striate Area in Visual Awareness and
gure 16.26 Subdivisions of the extrastriate visual areas that are
Visual Imagery
selective for recognition of human faces and human bodies, respec- We mentioned patients with blindsight above (under
tively. Surface marking is based on high-resolution fMRI from nor-
mal persons. These two areas could not be discerned with standard
Visual Information Can Reach the Cortex via the
fMRI with lower resolution. (Based on data published by Schwarzlose Superior Colliculus and the Pulvinar). Such patients
et al. 2005.) have no awareness of having seen anything, yet they
can respond to movement in the visual field. In such with visual awareness. A possible common denomina-
cases, visual information reaches the extrastriate areas tor for awareness of sensory information in general,
that are specialized for analysis of movements without was formulated as follows by Zeman (2004, p. 324):
going through the striate area. We may then ask whether . . . awareness occurs as the result of physiologically
conscious visual experience requires that visual infor- appropriate interactions between neural systems which
mation first go through the striate areain other words, serve sensation, memory, and action; activity which
that activation of the striate area is necessary for visual remains within a single system . . . can influence behav-
awareness. One approach to this question is to study ior but will not enter awareness.
brain activity with the PET technique while subjects In conclusion, both clinical and brain imaging studies
imagine visual scenes, such as a red car or their home clearly show that extensive parts of the cerebral cortex
street. In such situations, the subject has retrieved the are involved in conscious visual experience. It should
information from memory and sees the scene with be noted, however, that visual information that is not
closed eyes. Which parts of the brain are then specifi- consciously perceived can nevertheless be used for
cally activated? It appears that largely the same extras- preparation of voluntary (conscious) movements.
triate areas are activated during visual imagery as when
seeing. The PET data are conflicting as to whether the
Subconscious Use of Visual Information
striate area is activated with visual imagery, but the
fact that patients with cortical blindness (damage to A striking example was published by Goodale and
the striate area) are able to imagine visual scenes strongly Milner in 1992. A woman suffered damage to parts of
suggests that the striate area is not necessary for visual her occipital lobes (with sparing of the striate cortex)
imagery. Also, clinical observations suggest that visual because of carbon monoxide poisoning. Afterward she
imagery and seeing may not use identical cortical struc- was unable to recognize objects (visual agnosia). For
tures. Thus, a few patients have been reported who example, she could not decide whether an object was
could recognize objects when seeing them but could not oriented vertically or horizontally, nor could she show
imagine the same objects. The reverse situation has also the size of the object with her fingers. When asked to
been described. grasp it, however, she accomplished this easily and with
normal preparatory adjustment of the fingers. Thus,
she could adapt her grip to specific visual features, yet
Visual Awareness and Synchronized Network Activity
she had no awareness of these features. Obviously, the
We have treated integration at early stages of the visual parts of the brain preparing voluntary, goal-directed
processing, such as cells in the striate area responding movements have access to information about shape,
to contours with a certain orientation regardless where size, and orientation, no matter whether these features
it occurs within a larger part of the visual field. Further are consciously perceived or not.
integration produces more complex properties, so that
cells respond only when several characteristics coincide
Development of Normal Vision Requires Proper Use
(such as a contour with a specific orientation moving in
a certain direction). Such and more complex integration There may be other causes than a squint for lack of
of data need not occur on single cells, however; it may normal visual development. For example, if the eye
also occur by coordinated activity in separate neurons does not receive proper stimulation because errors of
that are synaptically linked (neuronal networks). As refraction produce a retinal image that is out of focus
mentioned, it is noteworthy that the many visual areas or because light for some reason does not reach the
are so extensively interconnected. For example, the striate retina, vision is not developed normally. In humans, the
area receives connections from most of the areas to which first 2 to 3 years (in particular the first year) are espe-
it projects, and the same holds for many extrastriate areas cially important in this respect; lack of meaningful use
and their relations to other cortical areas. Presumably, of the eye even for a short period may then give perma-
our conscious visual image is a product of the total pat- nently reduced visual acuity (as discussed in Chapter 9).
tern of impulses in many, interconnected cortical areas at Animal experiments furthermore show that, contrary
any moment. Synchronized activity of neuronal groups to what might be expected, vision is better preserved if
receiving the same kind of information (e.g., about the both eyes are covered for a period than if only one is
direction of movement) may play an important part, and covered. This is so because the two eyes compete
has been shown to occur in cortical areas. during the early development of the visual system. If
fMRI studies suggest that an extended network con- only one eye is used, it acquires an advantage and takes
necting ventral (temporal) visual areas and parts of pari- over neurons in the visual cortex that normally would
etal and prefrontal areas is especially active in conjunction have been used by the other eye.
17 The Auditory System
OVERVIEW signals from both ears with a time difference are crucial
for our ability to localize sounds.
The sense of hearing is of great importance in higher
animalsnot least in humans, for whom speech is
the most important means of communication. The
THE COCHLEA
adequate stimulus for the auditory receptors is sound
waves with frequencies between 20 and about 20,000 Hz.
The Cochlea Is Part of the Labyrinth
The sensitivity is greatest, however, between 1000 and
4000 Hz and declines steeply toward the highest and The labyrinth consists of an outer bony part surround-
the lowest frequencies; that is, a tone of 15,000 Hz ing an irregular canal in the temporal bone, and an
must be much stronger than a sound of 1000 Hz to be inner membranous part following and partly filling the
perceived. The range of frequencies to which the ear is canal (Figs. 17.1, 17.2, and 17.3). The membranous
most sensitive corresponds fairly well to the range of canal is filled with a fluid called the endolymph
frequencies for human speech. The frequency of sound (Figs. 17.1 and 17.4). Between the membranous and
waves determines the pitch, whereas the amplitude of the bony parts is a space filled with a fluid called the
the waves determines the intensity. Many animals can perilymph. The composition of the endolymph and of
perceive sound over a much wider range of frequencies the perilymph differs: the concentrations of sodium and
than humans can. For example, dogs can hear a whistle potassium ions in the perilymph are similar to those in
hardly noticed by humans, and bats use extremely high- the cerebrospinal fluid (i.e., similar to those in the extra-
pitched sounds for echolocation. Sound waves pass cellular fluid), whereas the concentrations of these ions
through the air to the tympanic membrane, which trans- in the endolymph are like those found intracellularly.
mits them via a chain of three tiny bones to the cochlea. Thus, the cilia of the sensory cellssurrounded by the
The sensory cellsthe hair cellsof the cochlea are endolymph (Fig. 17.5)are embedded in an unusual
low-threshold mechanoreceptors sensitive to the bend- extracellular fluid with K+ as the dominating cation.
ing of stereocilia on their surface. From the cochlea, the The protein concentration, however, is much higher in
signals are conducted to the cochlear nuclei in the brain the perilymph than in the endolymph and the cerebro-
stem through the eighth cranial nerve, the vestibuloco- spinal fluid. The high K+ concentration creates a poten-
chlear nerve. This nerve also carries signals from the tial of about 90 mV between the endolymph and the
sense organ for equilibriumthe vestibular apparatus perilymph, called the endocochlear potential (the endo-
that anatomically and evolutionarily is closely related lymph is positive in relation to the perilymph). The spe-
to the cochlea. Functionally, however, these two parts cial composition of the endolymph and the endocochlear
have little in common, and we describe the sense of potential are of crucial importance for the transduction
equilibrium together with other aspects of vestibular mechanism of the hair cells, as discussed later in this
function in Chapter 18. chapter.
From the cochlear nuclei, the auditory pathways The labyrinth has two main parts. One is the cochlea
carry signals to the inferior colliculus (and some other and the other is the vestibular apparatus consisting of
brain stem nuclei). Neurons in the inferior colliculus three semicircular ducts and two round dilatations
send their axons to the medial geniculate body of the (Fig. 17.2). Here we consider only the organ of hearing,
thalamus. Thalamocortical axons reach the primary the cochlea. The membranous part of the cochleathe
auditory area (A1) situated on the upper face of the cochlear ductforms a thin-walled tube with a trian-
temporal lobe (buried in the lateral sulcus). The audi- gular shape (in cross section), surrounded by the bony
tory pathways from one ear reach both hemispheres, in part of the cochlea. The duct forms a spiral with two
contrast to the almost complete crossing of somatosen- and a half to three turns (Figs. 17.2, 17.3, and 17.4).
sory pathways. Further processing of auditory informa- The lowermost wall of the cochlear duct is formed by
tion takes place in cortical areas surrounding A1 in the the basilar membrane (membrana basilaris), which is
temporal lobe. Outward connections from these areas suspended between the two facing sides of the bony
ensure integration of auditory information with other canal (Figs. 17.4 and 17.5). At the inner side of the
sensory modalities. Nuclei in the brain stem receiving turns, the basilar membrane is attached to a bony
240
17: THE AUDITORY SYSTEM 241
Utriculus Perilymph
Semicircular Vestibular
Vestibu nerve
External meatus Malleus Incus
s Stapes
ducts Cochlear nerve
gure 17.1 The ear. The middle ear

has three ear ossicles, and the inner
ear has the membranous labyrinth
(located in the temporal bone). The Cochlear Internal
Tympanic membrane Sacculus
eustachian tube connects the middle duct meatus
Middle ear Eustachian tube
ear with the pharynx.
A Semicircular ducts B
Ampulla
Utriculus
Ut i lus
Utriculu
Oval
Ovaal window
w Cochlea
Sac
S
Saccule
Round window
gure 17.2 A: The membranous labyrinth with its vestibular B: The uid in the labyrinth visualized via three dimensional recon-
part (the semicircular ducts, the saccule, and the utricle) and the audi- struction of MRIs. (Courtesy of Dr. Einar Hopp, Rikshospitalet
tory part (the cochlea). The stapes is attached in the oval window. University Hospital, Oslo, Norway.)
prominencethe bony spiral lamina (lamina spiralis epithelial cells. The vascular stria is responsible for the
+
ossea)which follows the cochlea in its spiraling course high K of the endolymph and the positive electric
(Figs. 17.4 and 17.5). The sensory epithelium, forming potential between the endolymph and the perilymph.1
the organ of Corti, rests on the basilar membrane (Figs. The room outside the cochlear duct consists of
17.4, 17.5, and 17.6). The length of the cochlear duct, two parallel canals. The one situated below the basilar
and thus of the basilar membrane, is about 3.5 cm (Fig. membrane is the scala tympani; the one above the
17.7). The thin vestibular membrane forms the upper
wall of the cochlear duct (Figs. 17.4 and 17.5). The
third, lateral, or outer wall of the cochlear duct lies on 1 In experimental animals, atrophy of the vascular stria causes hearing loss,
the bony wall of the canal and is formed by a special- and the severity seems to be proportional to reduction of the endocochlear
potential. There is evidence thatin addition to loss of hair cellsatrophy of
ized, stratified epithelium, the vascular stria (Fig. 17.6). the vascular stria can contribute to presbyacusis (age-related hearing loss) in
As the name implies, there are capillaries among the humans.
Temporal
lobe
Pons gure 17.3 The labyrinth. Two closely spaced,
frontal MRIs. The uid-lled cochlea (left) and
semicircular canals (right) are clearly seen just
Semicircular below the temporal lobe (the image is weighted so
Cochlea ducts that water appears white).
Temporal bone
Helicotrema
Bony labyrinth
Endolymph
Figure
Perilymph 17.5
Scala vestibuli
Vestibular
membrane
Cochlear duct
(scala media)
Modiolus Organ of Corti
Scala tympani
Figure 17.6
Bony spiral
Cochlear lamina
nerve
gure 17.4 Section through the cochlea.
Scala vestibuli
Vestibular
membrane
Vascular stria
Cochlear duct
Tectorial
membrane
Spiral
ganglion
Organ of Corti
Basilar
membrane
Scala tympani
gure 17.5 Section through the cochlea.

Photomicrograph. Cf. Fig. 17.4.
A B
Tectorial membrane Tectorial membrane
Inner hair cell
Outer hair cells
Sensory Pillar cell Basilar

nerve fibers membrane
Pillar cell Tunnel Ganglion cells
Inner hair cells of Corti Outer hair cells Basilar (Spiral ganglion)
(single row) (three rows) membrane
Bony spiral
lamina
gure 17.6 The organ of Corti. A: Three-dimensional representa- appear to change their form in relation to loud sounds, possibly to
tion of a short segment of the organ of Corti (the whole organ extends prevent damage of hair cells. B: Cf. Fig. 17.4. Note that only the tall-
the full length of the cochlear duct). The inner hair cells are in a single est stereocilia of the outer hair cells are in contact with the tectorial
row, and the outer hair cells are in three parallel rows. The pillar cells membrane.
Tympanic membrane
Stapes
Scala vestibuli
hitting the skull can also be transmitted through the
Cochlear duct Helicotrema bone directly to the receptors. This kind of transmis-
sion, however, is very inefficient with regard to airborne
sound waves and therefore plays no role in normal
hearing (bone conduction of sound waves is used for
20 kHz 2 kHz 0.2 kHz testing the function of the cochlea and also for certain
Basilar
hearing aid devices).
Round
window membrane Sound waves hit the eardrum or tympanic membrane
Scala tympani located at the bottom of the external meatus (Fig. 17.1).
The eardrum consists of a thin, tense connective tissue
gure 17.7 The middle ear and the cochlea. The cochlear duct is membrane covered by a thin layer of epithelium on
pictured as if straightened (length about 3.5 cm). The oscillations of both sides; it is richly supplied with nociceptors, like
the stapes are transmitted to the uid in the scala vestibuli and from
the tight skin of the inner part of the external meatus.
there to the cochlear duct. Different tone frequencies set different
parts of the basilar membrane in motion. Note that the highest frequen- The three ossicles form a chain through the middle
cies stimulate the hair cells near the base of the cochlea, whereas the ear and connect the eardrum with the oval window
lowest frequencies stimulate hair cells near the apex (near helico- (Figs. 17.1, 17.2, and 17.7). The malleus (the hammer)
trema). (Based on Fettiplace and Hackney 2006.) has a shaft that is attached to the inner side of the eardrum.
The head of the malleus connects to the incus (the anvil)
vestibular membrane is the scala vestibuli (Figs. 17.4 by a joint, and the incus is further connected to the stapes
and 17.5). Both have openings or windows in the bone (the stirrup) by a joint. The basal plate of the stapes
facing the middle ear (Figs. 17.2 and 17.7). The oval inserts in the oval window, thus closing the scala vestibuli
window ( fenestra vestibuli) is situated at the end of the (Fig. 17.7). The sound waves make the eardrum and the
scala vestibuli, whereas the round window ( fenestra ossicles vibrate with the frequency of the waves, and
cochleae) is at the end of the scala tympani. The stapes thus the movement transmits to the fluid in the cochlea.
and a thin membrane of connective tissue close the Because the area of the eardrum is so much larger than
windows, respectively (Fig. 17.7). that of the basal plate of the stapes, the pressure per
square unit increases 20 times. This amplification mech-
anism increases the sensitivity for sound dramatically,
How Sound Waves Are Transmitted to the
compared to a situation without the ossicles. Normally,
Sensory Cells in the Cochlea
even the slightest movement of the eardrum is sufficient
Conduction of sound waves from the air to the receptor to cause stimulation of the receptors in the cochlea:
cells in the cochlea occurs through the external ear (the sound waves with amplitude of only 0.01 nm suffice to
auricle and the external auditory meatus) and the mid- produce the weakest perceptible sound with the frequency
dle ear or tympanic cavity (Fig. 17.1). Sound waves to which the ear is most sensitive. If the sound waves
were to be transmitted directly from the air to the fluid Chapter 18, under More about the Vestibular Hair
in the cochlea, a large proportion would be reflected Cells). Along the basilar membrane, there are two pop-
without reaching the sensory cells of the cochlea. The ulations of receptor cells: one formed by the outer hair
sound would have to be much stronger to be perceived cells, the other by the inner hair cells (Fig. 17.5). The
in such a situation. This is the case when diseases of the inner hair cells, closest to the bony spiral lamina, form a
middle ear destroy the ossicles or stiffen their joints and single row, while the outer hair cells form three parallel
thus eliminate the amplification mechanism. The ensu- rows. There are approximately 3500 inner and 15,000
ing hearing loss is called conduction deafness. A prereq- outer hair cells in the human cochlea. The two kinds of
uisite for the free movement of the eardrum is that the cells differ in both morphology and innervation. Many
pressure be equal on the two sides. This is ensured by more sensory nerve fibers contact the inner than the
the eustachian tube (tuba auditoria), which connects outer hair cells, whereas the reverse situation exists for
the middle ear cavity with the pharynx (Fig. 17.1). the efferent innervation. There is good evidence that the
When the stapes is pressed (slightly) into the oval inner hair cells are responsible for signaling sound,
window, the pressure of the sound waves is transmitted whereas the outer hair cells regulate the sensitivity of the
directly to the fluid (the perilymph) in the scala vestibuli. sense organ.
Because water is incompressible, the sound waves can Supporting cells surround the hair cells. Two rows of
2
cause movement of the fluid only because the room can especially large supporting cells, the pillar cells, sepa-
expand at some other point. The thin, compliant mem- rate the inner and outer hair cells and form the tunnel of
brane that covers the round window allows such expan- Corti. Above the hair cells lies a thick plate, the tectorial
sion. The membrane is pressed outward (into the middle membrane, which is indirectly attached to the bony wall
ear) each time the stapes is pressed into the oval window. of the cochlea (Figs. 17.5 and 17.6). Sensory (afferent)
Movement of the perilymph in the scala vestibuli trans- nerve fibers of the eighth cranial nerve contact the basal
mits immediately to the endolymph in the cochlear duct parts of the hair cells (Figs. 17.6 and 17.8). The cell
through the thin vestibular membrane. The movement bodies of the sensory neurons are located in the bony
thus propagates to the basilar membrane, which is spiral lamina close to the midportion of the cochlea (the
pressed downward, and transmits the movement to the modiolus, Figs. 17.4, 17.5, and 17.6). Efferent nerve
perilymph in the scala tympani. In short, movements of fibers also contact the hair cells (Fig. 17.8), enabling the
the stapes in and out of the oval windowin pace with central nervous system (CNS) to control the sensitivity
the sound wavesproduce corresponding movements of the auditory receptors.
of the basilar membrane. Movements of the basilar Deflection of the stereocilia, caused by movement of
membrane stimulate the receptor (hair) cells. the basilar membrane, produces receptor potentials in
Next, we describe how the receptor cells are arranged both inner and outer hair cells. The further events differ,
in the organ of Corti and the mechanism by which however: in the inner hair cells, depolarization facilitates
movements of the basilar membrane lead to excitation transmitter release, whereas depolarization stimulates
of the receptor cells. contractile activity in the outer hair cells.
Sound Pressure Is Measured in Decibels The Inner Hair Cells and Mechanoelectric Transduction
The amplitude of the sound waves determines the sound Unlike the stereocilia of the outer hair cells, those of the
pressurethat is, the pressure of air molecules on the inner hair cells are not in direct contact with the tecto-
tympanic membrane. The most intense sound that the rial membrane (Fig. 17.6B). How can then the sound
12
human ear can perceive is about 10 times stronger waves lead to deflection of the stereocilia of the inner
than the weakest. A logarithmic scale is used for sound hair cells? Most likely, movement of the fluid surround-
pressure. One decibel (dB) represents the pressure nec- ing the stereocilia is sufficient, causing the stereocilia to
essary to produce the weakest perceptible sound, whereas move back and forth, in pace with the vibrations of the
just below 130 dB represents the strongest (the pain basilar membrane. The stereocilia are stiff, due to their
threshold is at 130140 dB). Ordinary speech produces content of actin filaments. Thus, each cilium moves like
a sound pressure between 30 and 70 dB. This scale a rod around its point of insertion in the top plate of the
gives relative measures of intensity because the sensitiv- hair cell (Fig. 17.8). Further, the stereocilia are coupled
ity of the ear differs for different frequencies. so that they all move together. Thereby, the sensitivity
The Organ of Corti

2 The pillar cells and other supporting cells in the organ of Corti appear to
The receptor cells in the cochlea are called hair cells contribute to control of cochlear sound sensitivity. In animals exposed to loud
sounds, the form and mutual positions of the supporting cells change in pace
because they are equipped with sensory hairs, or stereo- with changes in cochlear sensitivity. This may be a mechanism to protect the
cilia, on their apical surface (Figs. 17.6 and 17.8; see also hair cells.
Stereocilia
Top link Movement of stereocilia
Top link
Ion channel
gure 17.8 Inner hair cell. Left: Compare

with Fig. 17.5. Right: The most likely mech-
anism of sensory transduction in hair cells.
The tip link pulls open the ion channel when
the stereocilia are deected. The tip link is
thought to act like a spring that gates the Afferent nerve fiber
opening of the channel. (Based on Pickles
and Corey 1992.) Efferent nerve fiber
of each hair cell becomes much higher than if the Release of sufficient amounts of the transmitter elicits
stereocilia moved independently. action potentials in the sensory nerve fibers, and the
The stereocilia are of unequal length and orderly signals are transmitted to the brain stem (see Fig. 12.1).
arranged from the shortest to the longest (Fig. 17.8).3 When the stereocilia move back and forth, the ensuing
This structural polarization corresponds to a functional receptor potential of the hair cell follows a sinus curve;
one: bending of the stereocilia toward the longest cilium that is, the membrane potential oscillates in pace with
depolarizes the hair cell, whereas the opposite move- the vibrations of the basilar membrane. Because the
ment hyperpolarizes it. The depolarization produces a receptor potential modulates the transmitter release,
graded receptor potential. Thus, bending the stereocilia the action potentials conducted in the sensory fibers
one way increases the frequency of firing in the afferent follow the frequency of the sound waves.
nerve fibers. Depolarization of the hair cell is most likely
caused by opening of mechanosensitive ion channels
The Outer Hair Cells Amplify Sound Waves
near the tip of the stereocilia.
The mechanism for channel opening appears to be as The motion of the basilar membrane differs from that
follows. The stereocilia are interconnected near their expected of a passive mechanical structure. There must
tips by a thin protein thread called a tip link (Fig. 17.8). be mechanisms intrinsic to the cochlea that can amplify
The tip links attach to the channel proteins and opens the vibrations of the basilar membrane almost 100 times.
the channels by a direct pull when the stereocilia are Much evidence points to the outer hair cells as the motors
deflected. The depolarization is presumably mediated of the amplification; that is, they can rapidly transmit
by K+ ions entering the hair cell, since the endolymph mechanical energy to a very narrow strip of the basilar
that surrounds the stereocilia contains a very high con- membrane.
centration of K+ and low Na+. In addition, the endoco- Because the stereocilia of the outer hair cells are
chlear potential speeds the flow of cations because it attached to tectorial membrane, their deflection by
adds to the membrane potential of the stereocilia. The basilar membrane vibration seems easy to explain.4
required movement of the stereocilia is minimal: a When the basilar membrane vibrates, the hair cells are
barely perceptible sound moves the tip of each stereo- displaced relative to the tectorial membrane, which is
cilium about 1 nm (1/100,000,000 mm), whereas the relatively immobile because it is anchored to the bony
strongest perceptible sound moves the stereocilia about wall. Thus, the stereocilia are moved back and forth, in
1 mthat is, corresponding to the thickness of the pace with the frequency of the sound waves. The recep-
stereocilium. tor potential initiates contractile activity, changing the
Depolarization leads to release of glutamate from form of the cell.5 The ensuing fast contractions of the
the basal part of the inner hair cells. This transmits the
signal to the sensory nerve endings (acting on amino-
methylisoxazole propionic acid [AMPA] receptors). 4 Although only the tallest stereocilia attach to the tectorial membrane, the
linking of the stereocilia to each other make them move together as a unity.
5 The voltage-sensitive contractile protein prestin expands or compresses the
cell body in response to changes of the membrane potential. The effects of
3 Vestibular hair cells have an extra tall kinocilium (non-motile) marking the manipulating the prestin gene (e.g., studying the effects on hearing of making
highest point in the row of stereocilia (see Fig. 18.6). This disappears from the the gene nonfunctional in knockout mice) suggest that this protein is of critical
cochlear hair cells shortly after birth, however. importance for the amplication mechanism.
outer hair cells move the basilar membrane, producing Each hair cell is best activated by tones within a very
both an amplification of the vibrations and a narrow- narrow range of frequencies. Together, the hair cells
ing of the vibrating part, which sharpens the tuning of and the sensory fibers leading from them cover the total
the frequency curve. Together, these changes ensure range of frequencies we can perceive.
more precise signal transmission. Whether the amplifi- The tonotopic localization is such that the tones with
cation is due solely to deformation of the outer hair cell the highest pitch (highest frequencies) are registered by
body (elongation and shortening) or whether move- the hair cells closest to the oval window (i.e., on the
ments of the cilia also contribute, is not settled. basal part of the basilar membrane), whereas the lowest
The efferent fibers ending on the outer hair cells frequencies are registered at the top of the cochlea (i.e.,
release acetylcholine (and most likely ATP) that hyper- at the apical part of the basilar membrane). This can be
polarizes the cells by binding to muscarinic receptors. explained, at least partly, by the physical properties of
This reduces the active movements of the stereocilia the basilar membrane, as proposed by the German
leading to less amplification and broader tuning of the physicist Hermann Helmholtz in the nineteenth century.
frequency curve. The basilar membrane is most narrow basally and
becomes progressively wider in the apical direction.
The fibers of the basilar membrane are oriented trans-
Otoacoustic Emissions
versely to the long axis of the basilar membrane (Fig. 17.6)
The ear actually emits faint soundsotoacoustic and are therefore longer apically than basally. In anal-
emissionsthat appear to be produced by the contrac- ogy with the strings of an instrument (e.g., a piano),
tions of the outer hair cells. A microphone in the exter- basal parts would be expected to vibrate with a higher
nal meatus can record such sounds, which can occur frequency than apical parts. This is the main basis of
spontaneously or be evoked by a click. The hearing sys- the resonance theory of Helmholtz, which postulates
tem works in reverse, as it were: the outer hair cells that each position along the basilar membrane corre-
move the basilar membrane, which in turn moves the sponds to a certain frequency. Although later research
fluid in the cochlea; this moves the ossicles, which then has shown that even a pure tone makes large parts of
move the tympanic membrane that produces the sound. the basilar membrane vibrate, the region in which the
The phenomenon is used diagnosticallyfor example, maximal amplitude occurs is very narrow. This appears
in infantsto decide whether the cochlea functions to be caused by the amplification produced by contrac-
normally. tions of the outer hair cells, as discussed in the preced-
ing text. Thus, the hair cells differ in accordance with
their position on the basilar membrane, so that their
Different Frequencies are Registered at Different Sites
thresholds are lower for certain frequencies than for
along the Basilar Membrane: Tonotopic Localization
others.
The ordered arrangement of neurons and nerve fibers
signaling different pitches of sound (frequencies) is
Cochlear and Brain Stem Implants to Restore Hearing
called tonotopic localization (compare with somato-
topic localization in the somatosensory system and reti- When deafness is due to loss of hair cells without affec-
notopic localization in the visual system). As discussed tion of the afferent nerve fibers, hearing can be restored
later, the auditory pathways are tonotopically orga- by a so-called cochlear implant. During surgery, a thin,
nized all the way from the cochlea to the cerebral cor- isolated electrode is inserted along the basilar mem-
tex. The tonotopic localization in the cochlea has been brane. The isolation is removed at around 20 points,
demonstrated in several ways. After receiving lesions enabling electric stimulation of the cochlear nerve fibers
restricted to a small part of the organ of Corti (which at these sites. Hence, a range of frequencies can be
extends along the full length of the basilar membrane), transmitted to the brain; in accordance with the tono-
experimental animals no longer react to sound in a topic localization along the basilar membrane (the fre-
certain, narrow range of frequencies (pitches), whereas quency resolution is of course inferior to what is possible
they react normally to sounds of other frequencies. In with a normal number of hair cells). A microphone and
humans, similar selective deafness may occur after pro- microprocessor transform the sound waves to electric
longed exposure to noise, for example, in factories. signals that are sent to the electrode.
Anatomic examination of the cochlea after death in In children who are born deaf, a cochlear implant
such persons has shown that the hair cells have disap- can enable development of speech and speech compre-
peared in a restricted region on the basilar membrane, hension. Most of the children are able to attend normal
the position of the region differing with the frequency school classes. However, the implant must be inserted
to which the person was deaf. The tonotopic localization as early as possible, and not later than 3 to 4 years of
has been determined in detail by recording the response age. If the cortical networks necessary for analysis and
of single hair cells to sounds of different frequencies. use of sounds are not developed before this age, they
cannot develop later, probably because the auditory auditory pathways cause hearing loss; this kind, called
cortex has been taken over by other systems. Indeed, central deafness, is considered later in this chapter.
there is evidence from functional magnetic resonance To distinguish between conductive and sensorineural
imaging (fMRI) studies that visual stimuli may activate deafness, one can compare the threshold for sounds
the auditory cortex in congenitally blind persons. This conducted through the air with sound conducted
corresponds to the situation in children who are born through the bones of the skull. In the Rinne test, a
blind and later regain sight (e.g., by removing a cataract), vibrating tuning fork is first applied to the mastoid pro-
as discussed in Chapter 9. In deaf adults, who have had cess and then a little away from the external ear.
normal hearing earlier, a cochlear implant can restore Normally, the sound is heard much better when it is
hearing so they can comprehend speech. In this situation, conducted through the air than through the bone; how-
the networks responsible for sound processing were ever, in conductive deafness, caused by destruction of
presumably established in early childhood and remained the eardrum or the ossicles, the bone-conducted sound
essentially intact even after a period without hearing. is heard best. In the Weber test, the vibrating tuning
However, intense training is required after surgery, in fork is applied to the forehead in the midline. Normally,
order to make sense of the foreign sounds provided by the sound is heard equally in both ears; in conductive
the implant. Further, the longer the time from loss of deafness, it is heard best in the deaf ear, whereas in
hearing to implantation, the poorer is the prospect of a sensorineural deafness it is heard best in the normal
satisfactory result. ear. The reason for the lateralization to the deaf ear in
When deafness is due to destruction of the cochlear conduction deafness is not clear. It is possible that the
nerve, a cochlear implant will of course have no effect. airborne sound masks the bone-conducted sound on
In some such patients, restoration of hearing has been the normal side.
attempted by implanting an array of electrodes over the Destruction of the cochlear nerve or the cochlear hair
ventral cochlear nucleus. Otherwise, the strategy is sim- cells, that is, peripheral lesions, produces hearing loss
ilar to that used in cochlear implants. The success so far of the ear on the same side (the same happens, of course,
has been much more limited than with cochlear implants, with a lesion of the cochlear nuclei). The hair cells may
however. be damaged by noise and by certain drugs. There is
also a steady loss of hair cells with aging, particularly
near the base of the cochlear duct (high frequencies).
THE AUDITORY PATHWAYS
Destruction of the cochlear nerve may be caused by a
tumor in the internal auditory meatus (Fig. 17.1, called
Distinctive Features of the Central Auditory System
acoustic neuroma (arising from the Schwann cells of
The anatomic organization of the central auditory path- the eighth cranial nerve). As the tumor grows, it com-
ways has some unusual features, different from other presses the cochlear, the vestibular, and the facial nerves
sensory systems we have dealt with. More nuclei are (all passing through the internal meatus). Symptoms
intercalated in the auditory pathways, and these nuclei may therefore be caused by irritation (in the early phase)
have extensive and complicated interconnections. In or destruction of all of these nerves. Thus, the first
addition, some fibers cross the midline at several levels symptoms may be due to irritation of the cochlear nerve,
of the auditory pathways. These features have made the causing ringing in the ear (tinnitus) and sometimes ver-
auditory pathways more difficult to study than other tigo due to irritation of the vestibular nerve, but gradu-
sensory pathways. The crossing at several levels also ally deafness develops. As the tumor grows, it compresses
renders hearing examinations of limited practical value the brain stem with additional symptoms from the
for determining the site of lesions in the CNS. trigeminal nerve and ascending and descending long
tracts. The cochlear nerve may also be compressed or
torn by skull fractures passing through the temporal bone.
Conduction Deafness and Sensorineural Hearing Loss
Peripheral lesions of the auditory system, in addition to
The most common causes of hearing loss are diseases of causing unilateral deafness, also reduce or eliminate the
the middle ear, either because they compromise the ability to localize the source of a sound.
conduction of sounds to the cochlea or because they
destroy the neural elements of the cochlea or the eighth
The Cochlear Nerve and the Cochlear Nuclei
nerve. The first kind is called conductive deafness, the
second sensorineural (or nerve) deafness. Transmission The part of the eighth cranial nerve conducting signals
of sound to the cochlea can be reduced or abolished by from the cochlea is called the cochlear nerve. Most of the
middle ear infections that damage the eardrum or the fibers are afferent and have their cell bodies in the spiral
ossicles. In otosclerosis, the basal plate of the stapes ganglion, which is located in the bony spiral lamina (Figs.
becomes fixed in the oval window and therefore cannot 17.417.6). From the spiral ganglion the fibers pass
transmit sounds. Less frequently, lesions of the central through the midportion of the cochlea (the modiolus,
Fig. 17.4) and through the internal acoustic meatus

(internal auditory canal) to the cerebellopontine angle A
(Fig. 17.9). There the nerve enters the two cochlear AI
nuclei the dorsal and the ventrallocated laterally on
the medulla (Figs. 17.9 and 17.10; see also Fig. 27.2),
external to the inferior cerebellar peduncle (see Fig. 24.1).
After entering the nuclei, the cochlear nerve fibers divide
and end in precise tonotopic order in several parts of the
nuclei. The tonotopic localization has been demon- Medial
strated, for example, with microelectrode recordings geniculate
body
that make it possible to determine the response of single
fibers and neurons to tones of different frequencies.
The efferent fibers of the cochlear nerve arise in the
superior olivary complex, located in the rostral part of
the medulla (Fig. 17.10). The fibers end, as mentioned,
Inferior
predominantly around the outer hair cells. Stimulation colliculus
of the efferent fibers reduces the signal frequency of the Lateral
Acoustic stria
afferent fibers from the inner hair cells. Thus, the CNS lemniscus
can influence the flow of auditory signals at the level of Dorsal
cochlear
the receptors, not just centrally. Cochlear nucleus
nerve
Ascending Pathways from the Cochlear Nuclei

Ventral
From the cochlear nuclei, the auditory signals are trans- cochlear
nucleus
mitted to the inferior colliculus (mainly of the opposite
Cochlea Superior olive
side). The pathway formed by the ascending fibers from
the cochlear nuclei is called the lateral lemniscus (Figs. Trapezoid body
17.9 and 17.10). Many of the fibers end in other B
nucleisuch as the superior olivary complexthat
Lateral lemniscus Ventral
send fibers to the inferior colliculus. Neurons in the cochlear
Lateral nucleus
Medial
Superior
olive
gure 17.10 Parallel ascending auditory pathways. Schematic based

on experimental studies of the cat. A: The connections are bilateral,
so that AI on one side receives signals from the cochleae of both sides.
Thalamus B: Some main connections of the superior olive. Note that signals
from both ears reach the medial part of the superior olive. This
arrangement is of importance for localization of sound.
Medial
geniculate body
Inferior inferior colliculus send their axons to the medial genic-
colliculus ulate body of the thalamus (Figs. 17.9 and 17.10; see
Cochlear nerve also Figs. 6.21 and 6.22). The fibers form an oblong
Lateral
lemniscus elevation at the dorsal side of the mesencephalon, the
7th nerve inferior collicular brachium (brachium quadrigeminum
8th nerve
(facial) inferius). The efferent fibers from the medial geniculate
body end in the auditory cortex located in the temporal
Dorsal cochlear Acoustic stria
lobe (in the superior temporal gyrus; Figs. 17.10 and
nucleus
17.11). The ascending fibers from the medial geniculate
body are located in the posterior part of the internal
gure 17.9 Nuclei of the auditory pathways. Signals from the
capsule. At all levels, the auditory pathway is precisely
cochlea of one side reach the medial geniculate bodies of both sides organized, with cells responding to sounds of different
(although not shown in the gure). frequencies arranged in parallel lamellae.
Central Inferior parietal
sulcus lobulus Temporal plane
AI (area 41)
Prefrontal
cortex Auditory
belt
gure 17.11 The human auditory cortex. The Area 22
gure shows in a simplied form the concentric
arrangement of the auditory areas, and how the
Superior
connections spread out from AI, nally reach- temporal
ing the prefrontal cortex (there are reciprocal gyrus
connections at all levels, although not shown
here). Dorsal and ventral pathways from audi-
tory areas to the frontal lobe are indicated. The
ventral pathway is thought to deal with identi-
cation of sounds and their meaning, whereas
the dorsal pathway primarily deals with aspects
of sound localization and movements. The inset Lateral sulcus
shows a frontal section through the temporal Superior temporal
lobe, and the distribution of the auditory areas. gyrus
Even though the central auditory pathways are pre- Experimentally, two components of the ascending
dominantly crossed, there is a significant uncrossed auditory pathways have been identified. One is called
component. Therefore, unilateral damage to the path- the core projection and is a pathway for auditory signals
ways does not produce a clear-cut hearing deficit. The only. It is precisely tonotopically localized at all levels
ability to localize from where a sound comes may be and terminates in the primary auditory cortex, AI. The
reduced, however. core projection is synaptically interrupted in the central
parts of the inferior colliculus and specific parts of the
medial geniculate body. The other component is called
The Auditory Pathways Consist of Functionally
the belt projection. It is synaptically interrupted in the
Different Components
peripheral parts of the inferior colliculus and terminates
Efferent fibers from the cochlear nuclei take different in the cortex surrounding the AI. The cells of this path-
routes (Fig. 17.10A). Fibers from the dorsal cochlear way are influenced by visual and somatosensory stimuli
nucleus pass in the acoustic stria dorsal to the inferior in addition to auditory ones. The belt projection is
cerebellar peduncle and then cross through the reticular thought to be important for integrating of auditory
formation and join the lateral lemniscus (Figs. 17.9 and information with other kinds of sensory information.
17.10). Most fibers from the ventral cochlear nucleus Generalizations to conditions in humans on the basis
pass ventrally and cross to the other side in the trape- of studies done in other species must be made with par-
zoid body in the lowermost part of the pons (Fig. 17 ticular caution, however. Thus, species differences appear
10A). Some of these fibers end in the superior olivary to be greater for the auditory system than for other
complex of both sides, whereas others continue ros- sensory systems. This may presumably be related to the
trally in the lateral lemniscus to the inferior colliculus. great differences that exist among species with regard
The functional significance of these parallel paths out of to how sound is used as a source of information. For
the cochlear nuclei is not fully understood, but animal example, certain nuclei that are large in the cat are very
experiments (especially in the cat) show that single cells small in humans, and vice versa.
in the dorsal and ventral nuclei have different proper-
ties. Schematically, many cells in the ventral nucleus
Sound Localization
respond to sound stimuli much like the primary afferent
fibers of the cochlear nerve, whereas cells in the dorsal It is not enough that the CNS analyzes the sound fre-
nucleus have more complex response properties. For quencies and on this basis interprets the meaning of the
example, cells in the dorsal nucleus are often excited by sound (e.g., who or what produced the sound). Locating
sound with one particular frequency and inhibited by the source of a sound is another important but difficult
another frequency. It has been suggested that the dorsal task of the auditory system. To be able to judge the
nucleus forwards signals that are important for direct- distance and direction to a sound source (potential prey
ing attention toward a sound, whereas information or a danger) is obviously of vital importance to most
from the ventral nucleus is important for, among other animal species. The precision of our ability to localize
things, localizing a sound. sound is formidable: humans can distinguish sounds
separated by no more than 2 degrees. To do this, cen- cell has two long dendrites oriented transversely. One
tral parts of the auditory system must be able to detect dendrite receives signals from the right ear, the other
temporal differences of 11 sec (microseconds) between from the left. These cells are very sensitive to small time
sounds reaching the two ears. differences in synaptic inputs to the two dendrites and
Unilateral damage to the auditory cortex reduces are most sensitive to sounds with low frequencies. The
the ability of experimental animals to locate sounds efferent fibers of the medial part pass to the central
coming from the opposite side. Thus, a cat with such a nucleus of the inferior colliculus on the same side.
lesion does not move toward its prey sending out a brief
sound (e.g., a mouse). The head and eyes, however,
Descending Control of the Auditory Pathways
move toward the preyeven after bilateral damage
of the auditory cortexshowing that nuclei at lower There are descending fibers at all levels of the auditory
levels of the auditory pathways can locate the sound pathways. Numerous fibers pass from the auditory
and elicit appropriate reflex movements. cortex to the medial geniculate body (like other thal-
Concerning location of sounds in the horizontal amic nuclei) and to the inferior colliculus. Other fibers
planethat is, to the right or left of the midsagittal descend from the inferior colliculus to the nuclei at
planebasic computations occur in the first synaptic lower levels. As mentioned, efferent fibers in the cochlear
relay after the cochlear nuclei, the superior olive (Fig. nerve end in contact primarily with the outer hair cells
17.10). We are less certain regarding mechanisms for of the cochlea; such fibers come from the superior
location of sounds in the vertical plane, although the olivary complex and form the olivocochlear bundle.
dorsal cochlear nucleus is probably involved. Neurons The descending connections are, at least in part, precisely
in the inferior colliculus respond specifically to sound organized and can therefore be expected to selectively
from a certain direction, and the inferior colliculus control subgroups of neurons in the auditory pathways
probably contains a map of our auditory space. (e.g., neurons transmitting information about a certain
frequency).
There are many inhibitory interneurons in the nuclei
The Superior Olive and Sound Localization
of the auditory pathways, and both -aminobutyric acid
The superior olivary complex (superior olive) is located (GABA) and glycine are used as transmitters for such
in the lower part of the pons, in the trapezoid body interneurons. Physiological experiments show that the
(Fig. 17.10). A striking feature is that most neurons are central transmission of auditory signals can be inhib-
influenced from both ears, which led to the assumption ited, probably at all levels from the cochlea to the cere-
that the superior olive is particularly important in local- bral cortex. The censoring of the sensory information
izing the origin of a sound. When a sound hits the head that is allowed to reach consciousness is perhaps even
from the right side, it will reach the right ear slightly more pronounced in the auditory system than in other
before it reaches the left, because the head is in the way. sensory systems. Selective suppression of auditory infor-
The sound will also be slightly weakened before reaching mation is necessary if we are to select the relevant sounds
the left ear. Psychophysical experiments in humans indi- among numerous irrelevant ones. Such mechanisms are
cate that side differences in both time and intensity are most likely at work when, for example, at a cocktail
used by the auditory system to localize sounds. The time party with numerous voices we nevertheless are able to
difference is most important for localizing sounds of low select and pay attention to only one of them.
frequencies, whereas intensity differences are most impor- The brain must be able to distinguish between sounds
tant for sounds of higher frequencies (above 4000 Hz). that are generated externally and sounds we produce
The superior olivary complex consists of several, ourselves. Indeed, auditory neurons are inhibited dur-
tonotopically organized subdivisions. The lateral part ing vocalization. Although the exact mechanisms are
receives afferents from the cochlear nuclei of both sides unknown, this most likely involves interpretation of
and projects bilaterally to the inferior colliculi. Most corollary dischargethat is, copies of the motor commands
cells in the lateral part are excited by signals from the producing the sounds are sent to (most likely) the audi-
ear of the same side and inhibited by signals from the tory cortex. Descending connections may ensure specific
contralateral ear (via interneurons). The cells respond inhibition at several levels of the auditory pathways.
best when the sounds hitting the two ears are of differ-
ent intensities. Consequently, the lateral part of the
Auditory Reexes
superior olive is assumed to use intensity differences for
the analysis of sound localization. The ascending auditory pathways convey signals that
The medial part of the superior olive appears to be enable the conscious perception of sounds. Auditory
particularly important in localizing low-frequency sounds. information is also used at a subconscious level to elicit
It receives afferents from a particular subdivision of the reflex responses. The reticular formation receives col-
ventral cochlear nucleus of both sides (Fig. 17.10B). Each laterals from the ascending auditory pathways, and such
connections mediate the sudden muscle activity pro- AI is situated on the upper face of the temporal lobe in
voked by a strong, unexpected soundthat is, a startle a region called the temporal plane (Fig. 17.11). In
response. Other auditory signals pass to the nuclei of humans, Brodmanns area 41 is thought to correspond
the facial and trigeminal nerves, which innervate two to area AI of monkeys and other animals. Several other
small muscles in the middle ear: the stapedius and ten- auditory areas are arranged concentrically around AI
sor tympani muscles. Contraction of these muscles (in monkey about 15 such areas have been identified;
dampens the movements of the middle ear ossicles and cf. organization of extrastriatal visual areas). The areas
thereby protects the cochlea against sounds of high closest to AI form a belt-like region, and have therefore
intensity. Paresis of the facial nerve often is accompa- been termed the auditory belt. The belt region receives
nied by hypersensitivity to sounds, or hyperacusis. thalamocortical afferents from other parts of the medial
Other, more complex, reflex arcs mediate automatic geniculate body than AI, while its main afferents appear
movements of the head and eyes, and even the body, in to come from AI. Outside the auditory belt, we find
the direction of an unexpected sound. The centers for additional auditory areas that receive processed audi-
such reflexes are probably located in the inferior and tory information from the auditory belt, but no affer-
superior colliculi. The inferior colliculus sends fibers to ents from the medial geniculate body. Here starts
the superior colliculus, which has connections with the integration of auditory and other sensory modalities.
relevant motor nuclei in the brain stem and spinal cord. These areas are probably located within area 22 of
Further, in the superior colliculus integration of audi- Brodmann (Fig. 17.11; see also Fig. 33.3). There appears
tory, visual, and somatosensory information takes place, to be several parallel channels from the core region to
so that the final motor response is appropriate for the the belt region, and further on to area 22 (similar to the
organism as a whole. organization of parallel pathways out of the striate
area)each conveying different aspects of auditory
information. There are, however, numerous intercon-
THE AUDITORY CORTEX nections among areas suggesting that the functional
segregation cannot be absolute.
The cortical auditory areas are less studied than the
visual areas, and important aspects of human hearing
Properties of Neurons in Primary Auditory Cortex
are still poorly understood. While the auditory cortical
areas are organized according to the same general prin- Fibers from the medial geniculate body end with precise
ciples as the other sensory areas, notable differences exist. tonotopic localization in the AI (Figs. 17.10 and 17.11).
Thus, the auditory system shows a more pronounced Accordingly, single neurons in AI respond to sounds
parallel organization than, for example, the visual sys- with a narrower frequency range than neurons in other
tem. This is particularly evident in the auditory pathways auditory areas (sharper tuning). Although many neu-
and intercalated nuclei but concerns also the cortical rons in AI depict simple, physical features of sounds
areas. Further, more information processing takes place (such as pitch and amplitude), others have surprisingly
at lower levels in the auditory than in other sensory complex properties. Some respond, for example, best to
systems. While the auditory cortex is not crucial for the a sound when the frequency is increasing or decreasing.
ability to identify single sounds, it is required when dif- Other cells are influenced from both ears, but often
ferent sounds are to be out together to a meaningful such that they are excited by signals from one ear and
whole. inhibited from the other. Further, the response of many
neurons (as in other primary visual areas) depends on
the context of a stimulus. It even seems that the object
Core and Belt Areas
with which a sound is associated modulates the activity
The primary auditory area (AI, core region) appears to of many AI neurons.
consist of several tonotopically organized subdivisions
(in contrast to the striate area that consists of one reti-
6 Asymmetrical Organization of the Auditory Cortex in
notopically organized representation of visual field).
the Temporal Plane
6 In monkeys, three areas in the superior temporal gyrus receive tonotopically The auditory cortical areas appear to be asymmetrical
organized projections from the ventral part of the medial geniculate body. One in most humans. Thus, according to several MRI and
is the classical AI area, the two others adjoin AI rostrally (termed R and RT). postmortem studies the so-called Heschls gyruscon-
The reason to include them in the term primary auditory cortex is that all
three show structural features typical of primary sensory areas, such as a well- taining the AIis larger on the left than on the right
developed lamina 4 consisting of densely packed, small neurons (see Fig. 33.4), side, and the same holds for regions (area 22) adjacent
and dense afferent projections from a specic thalamic nucleus. The tonotopic to AI in the temporal plane (some studies did not find
arrangement in AI is such that the highest frequencies are represented caudally
and the lowest rostrally, whereas the opposite arrangement appears to exist such asymmetries, however). Intrinsic (horizontal) con-
in area R. nections in area 22 show a higher number of separate
clusters of terminal fibers on the left than on the right there is evidence from both experimental animals and
side, which presumably enables a more fine-grained humans that the further projections to the frontal lobe
analysis. It has furthermore been reported that fibers are divided into a ventral pathway for what and a
in the white matter are more heavily myelinated in the dorsal pathway for where (Fig. 17.11). This seems to
left than in the right temporal plane, enabling faster correspond to the organization of visual corticocortical
processing. Such anatomic differences are compatible connections into dorsal and ventral pathways or streams
with evidence that the left auditory cortex has a higher (see Fig. 16.24). Projections to the prefrontal cortex
degree of temporal sensitivity needed for optimal speech enable transformation of auditory information into
discrimination. The right auditory cortex appears to actions. How far the subdivision of tasks between a
be better than the left in the discrimination of pitch, ventral and a dorsal pathway goes is nevertheless not
melody, and sound intensity. clear. Thus, many neurons in posterior parts of the
auditory cortex, supposed to be specialized for spatial
tasks, respond to various aspects of speech.
Further Treatment Outside the Primary Auditory Cortex
As mentioned, the auditory belt receives it main affer-
Damage to Central Parts of the Auditory System and
ents from AI. The tonotopic localization is less sharp
Acoustic Agnosia
than in AI. Many neurons appear to respond best to
species-specific sounds (sounds of speech in humans). Restricted lesions of the auditory pathways or the
Other neurons seem to code the localization of a sound auditory cortexcentral lesionsusually produce no
source, while others combine information about speech clear-cut symptoms. As mentioned, this is because the
sounds and their source (wherefrom and from what). connections from the cochlear nuclei to the cerebral
With regard to perception of voices and music, the anal- cortex are bilateral (although with a contralateral pre-
ysis of temporal patterns is of particular importance. ponderance). Patients with bilateral damage of the audi-
The areas outside AI show functional specializations. tory cortex are reported to be able to perceive sounds
Thus, at least partly different subregions of the auditory and even discriminate tones with different pitches and
belt deal with whatthat is, the frequency composi- intensities (even though not necessarily with normal
tion of the soundsand wherethat is, the localiza- speed and precision). This corresponds to findings made
tion in space of the sound source. fMRI studies show, in monkeys. The ability to recognize and interpret tones
for example, that especially caudal parts of the auditory in particular patterns, however, is reduced or abolished.
cortex are activated by moving sounds, while speech- Such patients are unable to recognize familiar sounds
7
relevant sounds primarily activate rostral parts. Further, such as laughter, a bell that tolls, sounds of various
animals, and so forth. They are furthermore unable to
7 Clinical observations in humans also support specializations among the audi- understand the speech of other people, even though
tory areas outside AI. For example, in some patients after bilateral, partial they can speak and read themselves. This is called
lesions of the superior temporal gyrus, speech comprehension may be preserved acoustic agnosia.
while the perception of speech melody (prosody) and music may be impaired.
18 The Sense of Equilibrium
OVERVIEW Postural control and the role of vestibular signals in

the control of eye movements are also discussed in
The sense of equilibrium, narrowly defined, depends on Chapter 22 and Chapter 25, respectively.
signals from sense organs that record the position and
movements of the head. Such receptors are found in the
STRUCTURE AND FUNCTION OF THE VESTIBULAR
vestibular apparatus in the inner ear. Together with the
APPARATUS
cochlea they form the labyrinth. As the cochlear duct,
the vestibular labyrinth is filled with endolymph. The
The Vestibular Part of the Labyrinth
vestibular labyrinth consists of three semicircular ducts
(canals) and two small expansions, the saccule and the Unlike the cochlea, the vestibular apparatus does not
utricle. Cristae equipped with hair cells are found in depend on the external ear and the tympanic cavity to
expansions of the ducts, and respond to movements of function. Like the cochlear duct with the organ of Corti
the endolymph. Movements of the endolymph arise (see Figs. 17.4 and 17.6), the membranous labyrinth
when the head rotates, and the hair cells thus signal containing the vestibular receptors is embedded in the
angular acceleration. The semicircular ducts are oriented temporal bone and surrounded by a space containing
in three, mutually perpendicular planes. Hair cells in perilymph. The membranous labyrinth is filled with
the saccule and utricle are found on flat surfaces called endolymph (Figs. 18.2 and 18.3).
saccular and utricular maculae. The stereocilia of the The vestibular part of the labyrinth consists of two
hair cells are embedded in a gelatinous substance con- small vesicles, the utricle and the saccule, and three circu-
taining otoliths. These tiny stones ensure that the hair lar tubes connected to the utricle, the semicircular ducts
cells respond to gravitational forces and thus record the (see Fig. 17.2). Each of the semicircular ducts has a swell-
position of the head in space. ing, the ampulla, in the end close to the utriculus. The
Afferents from the vestibular apparatus end in the ves- ducts are oriented in three planes perpendicular to each
tibular nuclei in the upper medulla and lower pons. From other. In the erect position and with the head in a neutral
there, signals flow in three main directions: to the spinal position, the lateral semicircular duct lies approximately
cord, to neuronal groups controlling eye movements, in the horizontal plane, whereas the posterior and the
and to the cerebellum. These connections mainly control anterior ducts are oriented vertically (Fig. 18.1).
automatic responses aimed at maintaining the upright Sensory epithelium with hair cells (Figs. 18.2 and
position (postural reflexes) and fixation of visual targets 18.3) is found at five locations in the vestibular laby-
(vestibulo-ocular reflexes). In addition, vestibular signals rinth. The hair cells are similar to those in the cochlea,
reach several small areas in the cerebral cortex. Thereby, except that they are equipped with a long kinocilium
signals from vestibular receptors contribute to our con- not present on cochlear hair cells (compare Figs. 18.6
scious awareness of the position of the body in space. and 17.8). In each of the ampullae of the semicircular
The vestibular apparatus is not the only source of ducts, there is a transversely oriented elevation, the
sensory information for maintaining equilibrium, how- ampullar crista (Fig. 18.3). Hair cells with long cilia
ever, and neither does it provide all necessary informa- (Fig. 18.4) are present between the epithelial cells that
tion. Visual information and signals from somatosensory form the crista. The cilia project into a jellylike mass,
receptors (proprioceptors and cutaneous receptors) also the cupula. In the utricle and the saccule there are small
contribute. To control the upright, bipedal position of patches of hair cells like those in the ampullae, the
the human body, the brain needs information not only utricular and saccular maculae (Figs. 18.2 and 9.5).
of the position of the head in space (provided by the The macular hair cells are also covered by a jellylike
vestibular receptors) but also the heads position in rela- mass, which is special because of its content of small
tion to the body and the mutual positions of the major stones, the otoliths (Figs. 18.2, right, and 18.5). The
body parts. Indeed, the experience of dizziness and dis- otoliths are crystals of calcium salts. The utricular mac-
equilibrium can have many causes other than dysfunc- ula lies in approximately the same plane as the lateral
tion of the vestibular apparatus. To analyze such semicircular duct (i.e., horizontally in the neutral posi-
problems one must take into account all factors that tion), whereas the saccular macula is oriented almost
contribute to maintenance of our upright position. vertically (Fig. 18.1).
253
A B C
Pyramid of
temporal bone
Anterior (vertical)
semicirc. duct Saccular macula
Utricular macula
Posterior (vertical)
semicirc. duct
Sacculus and
utriculus
Vestibular part of the Lateral (horizontal)

labyrinth (enlarged) semicircular duct
Internal meatus Foramen
magnum
External meatus
gure 18.1 The vestibular apparatus. A: The position of the laby- body. C: The base of the skull, as viewed from above, with the ves-
rinth in the temporal bone. B: The vestibular part of the labyrinth is tibular apparatus projected to the surface of the pyramid of the tem-
colored more darkly than the auditory part. Note the orientation of poral bone. Note the orientation of the saccular and utricular
the semicircular ducts in relation to the conventional planes of the maculae.
More about Vestibular Hair Cells cells in the maculae are arranged differently with regard
to the orientation of the polarization axes, so that all
The vestibular and cochlear hair cells have the same
the cells together cover 360 degrees (Fig. 18.6B). This
basic properties (see Chapter 17, under The Inner Hair
ensures that the information received by the brain about
Cells and Mechanoelectric Transduction), although
head position in space is unambiguous. This requires,
there are some structural differences. On the apical end
of course, that the brain is able to compare the magni-
of the cells there are 50 to 110 stereocilia and one lon-
tude of the signals from various parts of the maculae to
ger and thicker kinocilium (Fig. 18.6). The stereocilia
reach a conclusion.
are unusually long microvilli and contain actin fila-
Electron microscopic studies showed more than 50
ments like other microvilli. The kinocilium contains
years ago that there are two kinds of vestibular receptor
microtubuli (like cilia of the respiratory epithelial cells).
cells, which are found both in the cristae of the semicir-
The stereocilia are arranged regularly in accordance
cular ducts and in the maculae of the saccule and utricle
with their height (Figs. 18.2, 18.4, and 18.6; see also
(Fig. 18.6A). One kind, the type 1 cell, is bottle-shaped,
Fig. 17.8). This structural polarization of the receptor
whereas the type 2 cell is slender. The sensory fibers
cells corresponds with the functional polarization men-
(the peripheral process of the vestibular ganglion cells)
tioned above. Thus, bending of the stereocilia toward
end differently on the two cell types (Fig. 18.6A). The
the kinocilium increases the firing frequency of the sen-
functional significance of the two types of hair cells is
sory fibers in contact with the cell, whereas bending in
still unknown.
the opposite direction reduces the firing frequency. This
is because the receptor cell is depolarized or hyperpo- The Adequate Stimulus for the Semicircular Ducts Is
larized by bending of the cilia. The receptor potentials Rotation of the Head
of the hair cells induce release of glutamate, which
depolarizes the afferent nerve fibers. Deflection of the Flow of the fluid (the endolymph) inside the semicircu-
cilia perpendicular to the direction of the polarization lar ducts displaces the cupula, thereby bending the cilia
produces no response, whereas oblique displacements (Fig. 18.3). This activates or inhibits the sensory cells,
give a reduced response compared with a stimulus that depending on the direction of bending. Rotational
is properly aligned with the polarization. This means movements of the head produce flow of the endolymph
that a given firing frequency of an afferent fiber is in the semicircular ducts. This is explained by the iner-
ambiguous ; it can be caused by a weak stimulus in the tia of the fluid: when the head starts to rotate, the fluid
direction of the polarization or a stronger obliquely ori- lags behind, and when the rotation stops, the fluid
ented one. Further, a given firing frequency may be continues to flow for a moment (like the water in a
caused by moving the head forward (e.g., walking) or bowl that is rotated rapidly for a couple of turns). If the
tilting the head backwards. This may be why the hair head rotation continues at even velocity, the fluid and
18: THE SENSE OF EQUILIBRIUM 255
A The orientation of the semicircular ducts ensures that

UTRICULAR MACULA
rotation of the head in any conceivable plane produces
Otolith membrane change of activity of the receptors in one or more of the
ducts. The brain monitors the rotational movements of
the head by reading the pattern of activity produced by
all the receptors. The semicircular ducts of both sides
must function normally to supply the brain with the
necessary information. A pair of ducts (e.g., the right
Otoliths and left lateral ones) gives complementary signals to a
given rotationthat is, increased signal frequency from
Cilia the one and reduced from the other.
Sacculus and Utriculus Signal the Position of the

Head and Linear Acceleration
The small otoliths have higher specific weight than the
Vestibular
endolymph and the substance in which they are embed-
nerve fibers Hair cell ded and are therefore more influenced by gravitational
forces. Taking as an example the utricular macula, which
in the neutral head position is oriented horizontally (Fig.
B
18.1), a change of head position tilts the macula, and the
otoliths pull the cilia in that direction. Different angles of
Endolymph Otoliths tilt produce different patterns of activity of the macular
Hair cells
hair cells. Owing to their different orientations in space,
the utricular and saccular hair cells together provide
information about all possible head positions. The utri-
cle records especially lateral tilt (i.e., head positions that
vary around a sagittal axis), whereas the saccule proba-
Vestibular
nerve
bly records mainly flexionextension of the head (i.e.,
movement in the cervical joints around a transverse axis).
Its ability to provide information about the position of
the head at any one time (in the absence of movement)
shows that the vestibular apparatus has static sensitivity.
gure 18.2 The utricular and saccular maculae. A: The utricular This property depends on the presence of receptors that
macula. Note the polarization of the hair cells. The otoliths are
embedded in a gelatinous substance that covers the hair cells (otolith
adapt slowly or not at all, so that they give a constant
membrane). (Based on Lindeman 1973.) B: Photomicrograph of a signal as long as a certain position is maintained. The
section through the sacculus with the macula. static sensitivity of the vestibular apparatus depends, as
we have seen, on the force of gravity and disappears in a
state of weightlessness (such as in space travel). Because
the head will after a short time move with the same the static sensitivity is a property of the utricle and the
speed and in the same direction, which means that the saccule, these parts of the vestibular apparatus are called
cilia are not bent. Thus, it is clear that not every rota- the static labyrinth. We will see, however, that this part
tional movement is recorded by the receptors of the of the labyrinth also has dynamic properties.
semicircular ducts: alteration of the velocity of the rota- The dynamic sensitivity of the utricle and the saccule
tional movementthat is, positive or negative angular is seen when their activity is recorded during linear
accelerationis the adequate stimulus for the semicir- acceleration. The response increases (i.e., the firing fre-
cular duct receptors. Thus, these receptors have dynamic quency of the afferent fibers) with increasing accelera-
sensitivity. Linear acceleration does not affect (or affects tion. This is again explained by the inertia of the
only slightly) the semicircular ducts. By linear displace- otoliths. On linear displacement of the head with chang-
ment of the head (a translatory movement) without ing velocity, as in a car that is accelerating, the otoliths
concomitant rotation, there is no stimulation of the lag behind and thereby bend the cilia backward (in rela-
semicircular duct receptors. An example of linear accel- tion to the direction of the movement). The opposite
eration is a car that starts or brakes on a flat, straight happens when the car slows down; the otoliths con-
road. If the road goes up and down and is curved, rota- tinue to move for a moment and bend the cilia forward
tional accelerations of the car (and the heads of its pas- (compare with the forces acting on a loose object in a
sengers) are superimposed on the linear ones. car when the car speeds up or slows down).
A B C
Cupula
Cilia
Hair cells Ampulla
Bending of the cupula

Endolymph movement
Semcircular
ducts
Vestibular nerve fibers
Head movement
gure 18.3 The ampullar crista. A: Three-dimensional drawing of the crista in the horizontal semicircular duct. C: Movement of the
showing the relationship between the crista, the hair cells, and the endolymph deects the cupula and the stereocilia of the hair cells. See
cupula. (Based on Wersll 1956.) B: The labyrinth with the position text for further details.
gure 18.5 Otoliths from the utricular macula. Scanning electron

gure 18.4 Sensory (hair) cells of the utricular macula. Scanning elec- micrograph. Magnication, 2100. (Courtesy of Dr. H. Lindeman,
tron micrograph. The apical surface of one sensory cell is indicated. Rikshospitalet National Hospital, Norway.)
Magnication, 10,000. Compare with Fig. 9.2B. (Courtesy of
Dr. H. Lindeman, Rikshospitalet National Hospital, Norway.)
CONNECTIONS OF THE VESTIBULAR NUCLEI visual, proprioceptive, and vestibular signals occurs at all
levelsfrom the first synapses of the primary afferent
The vestibular system differs from other systems in its fibers in the brain stem to the cerebral cortex. This is
high degree of multisensory integration. Thus, signals obviously necessary because the vestibular signalsless
from the semicircular ducts and from the saccular and than other sensory signalsare behaviorally useful on
utricular maculae, that is, information about move- their own. The position and movements of the head must
ments and head positions, converge in the vestibular continuously be related to the positions and movements
nuclei and in the cerebellum. Further, integration of of the eyes and of the body. Accordingly, vestibular
A Depolarization B stimulation does not evoke a conscious vestibular

sensation that can be easily distinguished from other
Hyperpolarization sensory modalities.
Kinocilium
The Vestibular Nuclei and Primary Afferent Fibers
Stereocilia
The primary afferent fibers of the eight cranial nerve end
Supporting cell 1
in various parts of the vestibular nuclei. The collection
of large and small vestibular nuclei is collectively called
the vestibular complex. It covers a large area in the
floor of the fourth ventricle and consists of four large
nuclei and several small cell groups. (Not all cell groups
within the vestibular complex receive primary vestibu-
lar fibers, however, and are therefore not vestibular,
strictly speaking.) Figure 18.7 shows the location of the
Utricular macula
Afferent nerve fibers
Terminal of
efferent nerve fiber
1 There are also efferent cholinergic bers in the vestibular nerve, ending in
gure 18.6 Sensory cells of the vestibular apparatus. A: Two types
contact with the vestibular receptors (Fig. 18.6A). The efferent bers come
of hair cells with different shapes and relations to the afferent nerves. from a small cell group in the lower pons just lateral to the abducens nucleus.
Note the polarization of the cilia. B: The utricular macula, as viewed The projection is bilateral and ends diffusely. Rotational head movements
from above. Arrows indicate the direction of polarization of the evoke efferent activity, with mainly excitatory effects on the vestibular primary
sensory cells in the various parts, which altogether cover all directions afferents. Although its functional role is still unknown, one possibility is that
of deection of the sensory hairs. the efferent innervation increases regularity of afferent ring.
A B Cerebral
cortex
Thalamus Superior colliculus

and eye muscle nuclei
Thalamus
Medial cerebellar
nucleus (fastigial)
Medial Anterior
longitudinal lobe
fascicle
Superior vestibular
nucleus
Medial vestibular
nucleus
Lateral vestibular
nucleus (Deiters)
Vestibulocochlear
nerve
Flocculonodular lobe
Descending
vestibular nucleus Reticular
formation
Labyrinth
Vestibulospinal
tract
Spinal cord
gure 18.7 The vestibular nuclei. A: Location of the nuclei in a dor- muscles and other visually related nuclei of the mesencephalon. Note
sal view of the brain stem. B: The main afferent and efferent connec- also ascending connections to the thalamus (and from there to the cere-
tions. Note reciprocal connections with the spinal cord, the bral cortex), and descending connections from the cerebral cortex to
cerebellum, the reticular formation, and the nuclei of the extraocular the vestibular nuclei.
four major nuclei: the superior, the lateral (or nucleus of is concerned with spatial orientation and goal-directed
Deiters), the medial, and the descending (or inferior). movements. Presumably, these cortical regions are impor-
Primary afferent vestibular fibers divide into an ascend- tant for building internal representations of the position
ing and a descending branch when entering the brain stem. and movements of the body, necessary for the control of
Together, they end in large parts of the vestibular complex movements. Accordingly, physiological experiments show
and in parts of the cerebellum (see Fig. 24.4). Although that vestibular reflexesthe vestibulospinal ones in par-
terminations of fibers from the ampullar cristae and the ticularare modulated in conjunction with voluntary
maculae overlap in the vestibular nuclei, they also show movements. In this way, the reflex responses are subordi-
notable differences in distribution. Thus, afferents from nated to the overall plan for the movements, presumably
the cristae (that is, from the semicircular ducts) end in by way of corticovestibular connections (among others).
the superior nucleus and the rostral part of the medial
nucleus but not in the lateral nucleus, whereas the fibers
Efferent Connections of the Vestibular Nuclei
from the utricular and saccular maculae end in the lateral
nucleus but not (or only sparsely) in the superior nucleus. Schematically, the vestibular nuclei (and therefore also
In agreement with the distribution of primary afferents, the vestibular receptors) act on three main regions (Figs.
neurons in the superior nucleus respond best to rota- 18.7 and 18.8), namely motoneurons in the spinal cord,
tional head movements (angular acceleration), whereas motoneurons in the nuclei of the extraocular muscles,
the cells in the lateral nucleus are particularly sensitive and the cerebellum. Accordingly, information from the
to static head position. Nevertheless, physiological studies vestibular apparatus is used primarily to influence muscles
show that a substantial proportion of neurons in the that maintain our upright position (equilibrium) and
vestibular nuclei integrate information about angular muscles that produce eye movements. The latter move-
acceleration and static position/linear acceleration.2 ments ensure that the retinal image is kept stationary
when the head moves.
Most of the fibers to the spinal cord come from the
The Vestibular Nuclei Receive Afferents from Regions
lateral vestibular nucleus and form the lateral vestibu-
Other than the Labyrinth
lospinal tract. The fibers descend in the ventral funiculus
The physiological properties of neurons in the vestibular on the same side as the nuclei from which they come. In
nuclei are not copies of those of the primary afferent fibers. the ventral horn they endin part monosynaptically
This is due to convergence on the cells of various kinds on and motoneurons (Fig. 18.8A). The tract is
of afferents (such as fibers from the semicircular ducts somatotopically organized, so that various body parts
and the utricle) and by interconnections between the can be selectively controlled. The vestibulospinal tract
nuclei (e.g., commissural fibers linking the two sides). has strong effects on the muscles that contribute to
Further, the vestibular complex receives afferents from equilibrium and posture (see also Chapter 22, under
other parts of the central nervous system (CNS), especially Vestibulospinal Tracts). As mentioned, the lateral
the spinal cord, the reticular formation, certain mesen- nucleus receives afferents from the utricular macula;
cephalic nuclei, and the cerebellum. Afferents from these provide information about the static position of
the mesencephalon arise, for example, in the superior the head in space and thereby indirectly about the posi-
colliculus, and the cerebellar fibers come from both the tion of the body. Change of body position also changes
flocculonodular lobe and the anterior lobe (Fig. 18.7; its center of gravity, with a resulting need to adjust
see also Fig. 24.4), and contribute to adaptation of muscle tone to maintain equilibrium.
vestibular reflexes to changed conditions for example A smaller, medial vestibulospinal tract arises in the
during growth of the head, wearing of glasses, and medial vestibular nucleus. It also descends in the ventral
so forth. funiculus and acts on motoneurons. The fibers do not
The vestibular nuclei receive signals from the cerebral reach below the upper thoracic segments, however, and
cortex (mainly indirectly via the reticular formation but are thought to be of importance primarily for head
also some direct fibers). The corticovestibular fibers arise movements elicited by the vestibular receptors. The
in parts of the cortex, such as the SI (areas 2 and 3a) and so-called vestibulocollic reflex serves to stabilize the
the insula, which receive converging information from the position of the head in space.
labyrinth and proprioceptors. The vestibular nuclei are Fibers to the nuclei of the extraocular muscles arise
also influenced from the posterior parietal cortex, which mainly in the superior and medial nuclei, which receive
many primary afferent fibers from the semicircular
ducts (Fig. 18.8B). The fibers leave the nuclei medially
2 For example, a study in the cat with electric stimulation of separate divisions and join to form a distinct fiber bundle, the medial lon-
of the vestibular nerve found that about one-third of all neurons received con- gitudinal fasciculus, which is located close to the midline
vergent inputs from the vertical semicircular canal and sacculus/utriculus.
Another one-third received convergent input from sacculus and utriculus, and below the floor of the fourth ventricle (Figs. 18.7 and
one fth from the horizontal canal and sacculus/utriculus. 18.8; see also Fig. 6.18). Some of the fibers cross to the
A other side as they ascend. They end in the abducent, the

Lateral vestibular nucleus trochlear, and the oculomotor nuclei and are precisely
(Deiters)
Medial vestibular
Ampulla of organized. In addition to the direct connections in the
semicircular
nucleus duct
medial longitudinal fasciculus, there are indirect path-
Lateral vestibulo- ways from the vestibular nuclei to the eye muscle nuclei
spinal tract via the reticular formation (Fig. 18.8B). We return to
this below when discussing vestibular reflexes.
Utricular macula Vestibulocerebellar fibers (arising in the medial and
Medial
descending vestibular nuclei) end primarily in the ves-
vestibulo- Vestibular nerve tibulocerebellum (Fig. 18.7; see also Fig. 24.4). Fibers
spinal tract from the vestibulocerebellum to the vestibular nuclei
motoneuron can adjust the gain (sensitivity) of the vestibulo-ocular
Muscle reflex, as will be discussed next (see also Fig. 25.4).
Connections to the thalamus from the vestibular
Muscle spindle nuclei have been demonstrated anatomically and end in
the VPL and nearby nuclei. Physiologically, scattered
neurons in a fairly large regions respond to signals from
motoneuron the vestibular apparatus. This probably explains why
Spinal cord vestibular signals reach several, discrete regions of the
cerebral cortex.
B
VESTIBULAR REFLEXES: CONTROL OF EYE
MOVEMENTS AND BODILY POSTURE
The special problems encountered in space journeys

aroused great interest in the mechanisms that underlie
Eye muscle nucleus vestibular reflexes. As with other parts of the brain being
comprehensively investigated, conditions turn out to be
more complex than initially thought. We will discuss
only a few salient points. There are two kinds of reflexes
Medial longitudinal that are elicited from the vestibular apparatus: vestibulo-
fascicle
ocular reflexes that control eye movements and so-called
labyrinthine reflexes mediated by the vestibulospinal
tracts controlling bodily postures (especially the upright
Premotor neuronal group position). In general, signals from the utricle and the
(in reticular formation)
saccule elicit tonic reflex effects, whereas phasic reflex
responses are caused by signals from the semicircular
Superior vestibular ducts when the stimulus is rotation of the head (angular
nucleus acceleration) and from the utricle or saccule when the
Ampulla stimulus is linear acceleration. Because the vestibular
receptors inform only about the head, other receptors
must inform about the movements and positions of other
Medial vestibular
nucleus
bodily parts. To control our upright position, the brain
must integrate these various sources of information and
Utricular macula issue commands that are appropriate for the whole
body. Therefore, the labyrinthine reflexes must operate
in concert with other postural reflexes, and we will
treat these together below.
gure 18.8 Main features of vestibular connections. A: Descending
connections acting on and motoneurons in the spinal cord. The Vestibulo-Ocular Reexes
medial vestibulospinal tract reach only cervical levels. B: Ascending
connections controlling eye movements. There are several vestibulo-ocular reflexes, mediated by
reflex arcs of various complexities. This topic is also
discussed in Chapter 25 dealing with the control of eye
movements. In general, the vestibulo-ocular reflexes
ensure that the image is kept stationary on the retina vestibular information about movements of the head,
when the head moves (rotates). visual signals about movements of the image on the
The simplest vestibulo-ocular reflex is mediated by a retina, and proprioceptive signals about movements of
chain of three neurons (Fig. 18.8; see also Fig. 25.4): the eyes relative to the head.
1. Primary afferent fibers from the cristae of the
semicircular ducts Vestibular Stimulation Produces Nystagmus and Falling
2. Neurons in the vestibular nuclei that send their Tendency
axons to the nuclei of the extraocular muscles (passing
When an upright person rotates fairly rapidly a few
in the medial longitudinal fasciculus)
times around his axis and then stops, the eyes can be
3. Motoneurons in these nuclei, which send their
seen to move rapidly one way (saccade) and slowly the
axons to the extraocular muscles
other for some seconds afterward. Obviously, the rota-
In addition, there are other pathways from the vestibu- tion has induced nystagmus. By using special instru-
lar nuclei to the nuclei of the extraocular muscles that ments, it can be seen that there is nystagmus also at the
are synaptically interrupted in the reticular formation start of the rotation, but in the opposite direction of
and some other brain stem nuclei (Fig. 18.8B). that occurring after the rotation has stopped. When the
A movement of the head in any direction is accompanied person rotates to the right, the saccade movement is to
by a compensatory movement of the eyes in the opposite the right and the slow movement is to the left, as if the
direction and with the same velocity as the head move- person fixes her gaze on a stationary point and then
ment. Rotation of the head produces movement of the moves the eyes rapidly when this point is slipping out of
endolymph inside the semicircular ducts. Taking a rota- the visual field. The eyes then move to a new fixation
tion in the horizontal plane (turning the head from one point, and the same sequence of events is repeated. This
side to the other) as an example, mainly the lateral postrotatory nystagmus is caused by stimulation of the
semicircular duct records the movement and elicits a receptors in the semicircular ducts. As mentioned, at
compensatory eye movement in the horizontal plane. the start of the movement the inertia of the endolymph
When the head movement is relatively small, the eyes makes it lag behind, thereby bending the cilia of the
move with exactly the same velocity as and in the oppo- receptor cells, whereas the endolymph continues to flow
site direction of the head, and the image is kept in the for a moment after the rotation has stopped. The person
same position on the retina all the time. When the head who had just stopped rotating feels as if he were still rotat-
movement becomes larger, so that it becomes impossi- ing, but now in the opposite direction. The direction of
ble to keep the image stationary even with maximal the nystagmus corresponds to the illusion of such a rota-
excursion of the eyes, a fast, or saccadic, movement tionthat is, with the saccade phase to the left after a
occurs in the same direction as the head movement. rotation to the right. If the rotation of the body continues
Then the gaze is fixed again on the object, and another for some time, the nystagmus disappears and the person
slow movement follows (as long as the head continues gets dizzy (compare with ballet dancers who deliberately
to move in the same direction). Such an alternation ensure that the head does not move with even velocity
between slow and fast, saccadic eye movements is called during pirouettes; this way they have sufficient time for
nystagmus. In this case, the nystagmus was produced by fixation so that the brain gets information to determine
stimulation of the semicircular ducts (rotation of the the orientation of the body in space).
head) and is therefore called vestibular nystagmus. After stopping the rotation, the person is also
Movement of the surroundings can also elicit nystagmus unsteady and tends to fall to one side, especially if he is
when the head is stationary. This optokinetic nystagmus asked to keep his eyes closed. Further, the arm deviates
occurs, for example, in a train-passenger watching the to the right if the person is asked to point straight ahead
landscape pass by. (with his eyes closed). This is called postrotational past
pointing. After the rotation stops, the illusion of the
opposite movement (i.e., the person feels he is turning
Vestibular Signals Must Be Integrated with Other
to the left) causes the past pointing to the right: the
Sensory Modalities for Control of Eye Movements
person feels that the room is moving to the right.
As mentioned, the vestibular nuclei receive afferents The postrotational effects on postural muscles are
from sources other than the labyrinth, such as nuclei in mediated via the vestibulospinal tracts (Fig. 18.8A) and
the mesencephalon, the reticular formation, and the show that the receptors of the semicircular ducts also
cerebellum. Some of these sources mediate visual infor- influence the spinal cord and the postural muscles, not
mation that can modify the vestibular reflex responses. just the cranial nerve nuclei and the extraocular muscles.
This convergence of various inputs seems logical. Thus, Nystagmus, falling tendency, and past pointing can
to achieve optimal control of the eye movements, the also be produced by irrigation of the external auditory
responsible neural cell groups must receive and integrate meatus with hot or cold water. The change of temperature
makes the endolymph flow in the semicircular ducts center of the neck reflexes is located in the medulla, and
and thus produces stimulation of the receptors. Such a the effects on the motoneurons are most likely mediated
caloric test is used clinically to examine the function of by both the reticulospinal and vestibulospinal tracts.
the vestibular labyrinth and the conduction of signals
to the brain stem.
More about the Neck and Labyrinthine Reexes
Various diseases affecting the vestibular receptors or
the signal pathways to the motoneurons of the extraoc- Studies of decerebrate, four-legged animals have eluci-
ular muscles (the vestibular nerve, the vestibular nuclei, dated the neck and labyrinthine reflexes (the brain stem
the medial longitudinal fasciculus, and the cerebellum) is transected just below the red nucleus in the mesen-
can produce nystagmus in the absence of vestibular or cephalon). To demonstrate clearly the neck reflexes in
visual stimulation. This is called spontaneous nystagmus. decerebrate animals (mostly cats have been studied),
In certain cases, the nystagmus may be present only in the vestibular receptors must have been eliminated.
certain positions of the head (positional nystagmus). When then the head is bent backward (extension of the
neck), the muscle tension is increased in the extensor
muscles of the forelimbs and decreased in the extensors
Neck and Labyrinthine Reexes
of the hind limbs. Forward bending of the head (flexion)
The vestibular receptors inform about the position and induces the opposite pattern of changes (extension of
movements of the head in space, whereas neck proprio- the hind limbs and flexion of the forelimbs). Tilting the
ceptors can inform about the position and movements head sideways increases the extensor tone on the same
of the body in relation to the head. Based on informa- side and reduces it on the other side, as does turning the
tion from both kinds of receptors, the brain can decide head sideways. These changes of the muscle tone aim at
whether the head is moving in isolation or whether it reestablishing the position of the body relative to the
moves together with the rest of the body. Obviously, head. The receptors for these reflexes are located near the
different kinds of postural responses are needed in these upper cervical joints, because they disappear after transec-
two situations. The labyrinthine reflexes are elicited by tion of the upper three cervical dorsal roots. Muscle
stimulation of the sensory receptors of the semicircular spindles are the most likely candidates, but joint recep-
ducts and the utriculus of the labyrinth. In the neck tors may also contribute. As mentioned, the functional
reflexes, the response is a change of muscle tension, role of the neck reflexes cannot be understood when
especially in the extremities supporting upright stance, observed in isolation, however. Only in conjunction
induced by a change in the position of the head relative with the labyrinthine reflexes are their effects appropri-
to the body (such movements take place primarily in the ate for the whole body.
upper cervical joints). The labyrinthine reflexes when To demonstrate clearly the labyrinthine reflexes, the
operating alone produce muscle contractions in the trunk neck reflexes must have been eliminated by cutting the
and extremities that serve to keep the position of the upper dorsal roots (in a decerebrate animal). It then
head constant. The neck reflexes, as mentioned, serve appears that the effects produced by the labyrinthine
to keep the position of the body constant in relation to reflexes are the opposite of those of the neck reflexes
the head. The latter is a prerequisite for the labyrinthine when the latter act alone. Thus, bending the head back-
reflexes to function properly; the vestibular apparatus ward elicits flexion of the forelimbs and extension of
can provide information only about the position of the the hind limbs, and vice versa when the head is bent
head in space and not about its position in relation to forward. The purpose of these changes of muscle tone
the body. Thus, the labyrinthine reflexes work on the is to bring the head back to the position held before the
assumption that the head has a constant position rela- movementthat is, to keep the position of the head in
tive to the body, and the neck reflexes ensure that this space constant. Provided the neck reflexes ensure that
position is constant. the body stays in a constant position relative to the
The reflexes may be either tonic or phasic. A phasic head, the labyrinthine reflexes will serve to maintain
neck or labyrinthine reflex consists of a rapid, transient both the position of the head in space and the upright
change of muscle tension in postural muscles as a position of the whole body. The labyrinthine reflexes
response to a change of posture (usually a disturbance are shown clearly when the experimental animal stands
of the equilibrium). We experience phasic labyrinthine on a platform that can be tilted in various directions.
reflexes when we trip over and a coordinated set of Tilting the platform forward increases the extensor
compensatory movements occur before we consciously tone in the forelimbs and decreases the tone in the hind
perceive what is going on. In a tonic reflex, the change limbs. Tilting the platform sideways increases the mus-
of muscle tension lasts as long as the new position is cle tone in the extensors on the side to which the tilt is
maintained. directed. Both responses are obviously appropriate for
Vestibulospinal tracts are the most likely candidates the maintenance of body balance. When the platform is
for mediation of the labyrinthine reflexes. The reflex moved quickly in one direction and then back, the
reflex response is transient (phasic reflex). When the even. Further, visual information may be unreliable if
platform is maintained in the new position, the altered we are in an environment with moving objects, because
muscle tone is upheld (tonic reflex). it may be difficult to distinguish own movements from
When both reflexes work together in an intact organ- those of the surrounds. Persons with loss of vestibular
ism, backward bending of the head, for example (with function manage well as long as they can see but they
movement taking place only in the upper cervical joints have serious problems in maintaining the bodys equi-
and no change of body position), produces no change librium in the dark. If one source is unreliable, its con-
in muscle tension of the extremities. The tendency of tribution tends to be ignored, and information from
the labyrinthine reflexes to produce forelimb flexion other sources becomes more important. We also treat
and hind limb extension is canceled by the opposite postural reflexes in Chapter 22 in conjunction with the
tendency of the neck reflexes. In contrast, when the control of automatic movements.
same movement of the head is produced by a backward
movement of the whole body (with no movement of the
More about Receptor Types and Their Contribution to
head relative to the body, like a horse that is rearing),
Postural Control
the labyrinthine reflexes act alone to produce extension
of the hind limbs and flexion of the forelimbs. Another Persons standing on a platform that can be tilted or
example is an animal standing on a platform tilting moved forward or backward have been much used in
forward with no movement of the head relative to the studies of postural control. In this situation, the experi-
body. In that case, the labyrinthine reflexes produce menter can control the direction, speed, and amplitude of
forelimb extension and hind limb flexion. This is an perturbations, and specific kinds of sensory information
appropriate response to maintain balance when standing can be removed temporarily. In addition, patients with
on a downhill slope. However, if the position of the head loss of one or the other kind of receptor have been much
in space is kept constant and the body is moved in rela- studied.
tion to the head, the neck reflexes act alone. An example Signals from muscle spindlesproviding rapid inform-
is a cat jumping down from a table: the neck is extended ing about joint position and movementsare important
(keeping the head position constant), producing exten- for postural control. This is, for example, evident from
sion of the forelimbs, which is appropriate for landing. persons who lose the proprioceptive sense (cf. Chapter 13,
under Clinical Examples of Loss of Somatosensory
Information). Further evidence that muscle spindles
Postural Reexes: Various Receptors Contribute
play a role for posture comes from experiments with
In order to control posture and balance, the CNS must vibration (activating Ia afferents) of leg muscles and neck
receive sufficient information about positions and move- muscles. Such vibration elicits postural adjustments, which
ments in various body parts as well as the nature of the are appropriate, considering that the brain believes
support surface. This information enables the brain to that the muscles are being stretched. The signals are
compute the position of the center of gravity and the obviously interpreted as if the center of gravity were
movements needed to keep it in the right position relative moving. In this case, the muscle spindle information is
to our supporting base. Many sense organs can provide not primarily used at the segmental level for quick pos-
relevant information (visual, proprioceptive, cutaneous, tural responses but is integrated with other inputs at
and vestibular). The signals are analyzed in the CNS, higher levels. Platform experiments further support that
which in response initiates postural reflexes, that is, the contribution of muscle spindles to postural control
automatic, coordinated contractions of muscles that does not depend mainly on simple, spinal reflexes (i.e.,
maintain our upright position. Postural reflexes can be reflex contractions in response to muscle stretch that do
elicited from the labyrinth, from proprioceptors and by not depend on higher levels). When the platform is sud-
vision. The contribution of various receptors to control denly displaced backward (without tilting), the body
of the upright position is not static, however. This is first sways forward with movement primarily at the
because the contribution of each receptor type varies ankle joints. The balance is regained mainly because the
with the nature, magnitude, and context of a postural calf muscles at the back of the leg contract (muscles of
3
perturbation. For example, somatosensory informa- the hip, the back, and in the neck also contribute, espe-
tion from the sole of the foot is less reliable when the cially if the displacement is large). The first part of the
support surface is slippery than when it is firm and contraction of the leg muscles occurs so early after the
perturbation that a reflex must mediate it. (Somewhat
3 There furthermore seems to be individual variation among normal subjects later there is also a voluntary contraction, which con-
with regard to which kind of information they rely on for the reex adjustments tributes to the final outcome of the postural adjust-
in quiet standing. In a study of healthy volunteers, only half of the subjects ment.) In this case, a reflex elicited by stretch of muscle
increased their body sway when the eyes were closed. This suggests that persons
differ with regard to how much they rely on visual information to stabilize the spindles in the calf muscles would seem appropriate. In
quiet standing position. another situation, however, such a reflex would worsen
the balance: if the platform is suddenly tilted backward, the landing. The contraction begins about 75 msec after
the calf muscles are stretched (as in the former example) start of the fall and can therefore occur before landing
but the center of gravity is now displaced backward (and thus before a stretch reflex can be elicited). The
instead of forward. Consequently, a contraction of the latency is also too short for the contraction to be volun-
calf muscles would worsen the imbalance. To regain tary. Animal experiments indicate that the receptors of
balance, the muscles at the front of the leg have to con- this reflex are located in the labyrinth (probably in the
tract as rapidly as possible, in spite of being shortened saccular macula).
by the tilting of the platform, and this is what happens.
Thus, whether a segmental, spinal reflex is elicited depends
Postural Reexes Are under Central Control
on the situation, and inappropriate reflex responses to
stretch are generally suppressed. Indeed, for the func- Reflex responses occur too early after a balance pertur-
tionally important reflex response in the leg muscles bation to be caused by conscious, high-level decisions.
(starting about 90 msec after the balance perturbation), Indeed, the main advantage of a reflex response is
signals from proprioceptors around the vertebral column that it occurs so rapidly. Nevertheless, even automatic
may be more important than signals from leg muscle movements are subject to central control. The response
spindles. Thus, the contraction of the leg muscles cor- to a perturbation challenging our upright position is
relates less with their own length change than with the strongly modulated by expectation and the context in
displacement of the trunk. which the perturbation occurs. For example, a contrac-
Signals from cutaneous low-threshold mechanore- tion of the triceps surae muscle in response to dorsiflex-
ceptors in the sole of the foot seem to contribute to the ion in the ankle joint may restore balance in one situation
reflex contractions of the leg muscles in platform exper- while worsen it in another. In general, the individual
iments. The dorsal columnmedial lemniscus pathway reflex responses are subordinate an overall, coordinated
transmits such signals very rapidly. Presumably, the motor plan designed to attain a certain goal.
brain determines the center of pressure by calculating In infants, comprehensive, high-level motor programs
the difference between the pressure applied to the heel have not yet developed and accordingly, some postural
and the forefoot. The center of pressure informs about reflexes operate on their own. This concerns some
the position of the body center of mass. Patients with vestibular reflexes, the grasp reflex, and others. In coma-
neuropathies who have reduced sensibility in the sole tose patients with lesions of the upper brain stem, exag-
of the foot witness the importance of this input for gerated postural reflexes may appear spontaneously
postural control and for normal gait. usually with a strong dominance of extensor tone. This
Vision also contributes to adjustment of muscle tone condition is called decerebrate rigidity.
with the purpose of maintaining body equilibrium.
Platform experiments indicate that the muscle contrac-
tions in response to a movement of the platform depend CORTICAL PROCESSING OF VESTIBULAR SIGNALS
on whether the subject can see that the body moves in
relation to the surroundings. If the experimental setup is Several Areas Receive Vestibular Signals
such that it appears as though the surroundings do not
Vestibular signals reach several small areas in the
move (i.e., they are made to move in the same direction as
cortex, as shown electrophysiologically in monkeys and
the head), the earliest reflex contractions of the legs are
with imaging methods in humans (Fig. 18.9). The pari-
weaker than when the sense of vision also informs about
etal insular vestibular cortexPIVCis of particular
the movement. We do not fully know the pathways
interest (as the name implies, it lies at the junction
involved, but the final commands are probably sent from 4
between the parietal lobe and the insula). The PIVC
the vestibular nuclei in the vestibulospinal tract.
contains neurons that are activated by signals from
In platform experiments with moderate postural per-
both the semicircular canals (head rotation) and from
turbations, signals from vestibular receptors seem not to
proprioceptors around the upper cervical joints.
be essential for the corrective contractions of leg muscles
Because, in addition, the neurons are influenced by
(ankle strategy). With larger perturbations, however,
visual signals it seems likely that they integrate all kinds
vestibular information contributes to contractions of
hip muscles (hip strategy). When visual information is
eliminated, signals from the utricle and the saccule are
indeed necessary for the proper orientation of the body 4 Imaging studies in humans place the PIVC and other presumptive vestibular-
activated areas somewhat differently. For example, some nd that PIVC
in space, as can be shown in animals whose otoliths have includes posterior parts of the insula, while others limit it to a region just pos-
been removed. Unexpected fall from some height elicits terior to the insula. Such discrepancies are most likely due to differences in
a postural reflex that depends on information from the experimental conditions. It is very difcult to rule out that cortical activation
evoked by caloric, galvanic, or optokinetic stimuliapplied to stimulate ves-
vestibular apparatus. The fall initiates a contraction of tibular receptorsare due to concomitant stimulation of somatosensory or
the muscles of the leg as an appropriate preparation to visual systems.
Area 3a:
Convergence with signals
from muscle spindles
Posterior parietal cortex: Cingulate gyrus:
Premotor areas: Convergence with visual A
Activity associated with
Planning of moveme
movements
ents and
a d somatosensoryy signals
g pain, attention,
p
motivation, and emotio
m emotions
gure 18.9 Cortical areas receiving sig-

nals from the vestibular apparatus. The
locations of regions are only approxima- PIVC:
tions, based on extrapolation from fMRI Convergence e of vestibular
and proprioceptive
eptive signals.
data published by Bottini et al. 2001.
of movement-related information. Signals from the in the occipital lobeextrastriatal body area (EBA)
labyrinth would thus contribute to the awareness of responds especially to body parts (e.g., when the person
bodily posture and movements in space. Interestingly, looks at an arm or a hand). Active movement of the body
clinical observations suggest that lesions in this region part modulates the EBA activity, and this may enable
result in denial of ownership of the contralateral hand. this region to help decide whether the hand belongs to
Neurons in other parts of the cortex that are activated me or someone else (body ownership).
from the labyrinth have properties similar to those in Together, these multiple, interconnected regions
PIVC. This concerns neurons in area 3a (muscle spindle enable us to be aware of our bodies; they provide us
input), in area 2 (joint receptor inputs), and in the cin- with a feeling of ownership, and a sense of agency (i.e.,
gulate gyrus. An area close to the PIVC in the posterior the experience that I am moving my hand, not someone
parietal cortex integrates vestibular and optokinetic else). They also, presumably, form the basis of internal
information. Vestibular activation furthermore occurs models representing stored information of the neuronal
in the premotor cortex (and in some other areas). The processes needed for specific actions (grasping a glass
various vestibular cortical areas are interconnected and of water, descending a staircase, and so forth). Body
send efferent fibers to the vestibular nuclei, as mentioned image and body scheme are terms often used about two
earlier. different aspects of internal bodily representations. The
body image concerns our conscious perception of the
appearance of our body, with regard to its form, size,
Distributed Networks, Body Image, and Body Scheme
and other characteristics. The body scheme concerns
Vestibular information seems to be processed in a distrib- spatial representations of our body parts that do not
uted cortical network, not in a single center. This network enter awareness. The body scheme provides a basis for
integrates several kinds of sensory information related actions, and is continuously updated during movements.
to extrapersonal space and the body. It is connected Putting it simply, the body image concerns what
with and overlaps other networksnotably those that whereas the body scheme concerns how. At least
control movements but also networks related to atten- superficially, the distinction between body image and
tion, emotions, and pain. By feeding into this network, body scheme resembles the distinction between the
vestibular receptors contribute to, but are not solely ventral and dorsal pathways of the visual system: the
responsible for our awareness of body orientation and ventral pathway processes explicit, conscious knowl-
movements in space. Other specialized regions of the edge about objects, whereas the dorsal pathway deals
cortex process other aspects of body-related informa- with implicit knowledge about the objects spatial char-
tion. For example, two extrastriatal visual areas appear acteristics and its relation to action.
to be specialized for recognition and analysis of human Normally, ownership and agency are self-evident:
bodies and body parts. We mentioned the fusiform I do not doubt the hand is mine, and that I am moving
body area (FBA) in Chapter 16 (see Fig. 16.26), which it. The transformation of intention into action is effortless
is particularly activated by recognition of whole human and requires no knowledge of the internal operations
bodies (rather than body parts). Another similar area underlying it. Further, I always experience my body
as a unity: I have a natural sense of coherence. disorders, and it is a transient reaction in certain
Nevertheless, these self-evident facts of life depend situations, as with strong emotions. In such cases, mal-
on a complex interplay among numerous specialized functioning receptors are hardly responsible. Rather,
regions of the brain. There is no single area responsible the cortical networks for spatial orientation may have a
for our sense of unity, ownership, or agency. Indeed, reduced ability to integrate the various sensory inputs
there are numerous clinical examples that the body perhaps because inputs from networks related to emo-
image and body scheme are more fragile than we usually tions and memories disturb them.
assume. Thus, after a stroke, the patient may deny own- Unilateral destruction of the vestibular apparatus in
ership of an arm, or not recognize that the arm is para- humans usually gives very disturbing symptoms, domi-
lyzed or even experience that someone else is moving the nated by dizziness, spontaneous nystagmus, nausea, and
arm. In addition, strong emotions and mental illnesses disequilibrium. The symptoms generally vanish with time,
(e.g., schizophrenia) may disturb the body image or body mainly due to central excitability changes that level out
scheme. Immobilization of jointspresumably produc- the unequal inputs from the two sides. The normalization
ing a mismatch between motor commands and sensory of eye movements seems to be due, at least partly, to the
feedbackmay cause bizarre experiences of positions and patient learning to use proprioceptive signals instead of
movements of the extremity. vestibular ones. Thus, in monkeys with unilateral dam-
age of the labyrinth, signals from neck muscle spindles
initiate an almost normal vestibulo-ocular reflex
Disequilibrium, Dizziness, and Vertigo
when the head rotates.
Berthoz and Viaud-Delmond (1999, p. 709) give a concise
yet comprehensive description of dizziness; Dizziness
Motion Sickness
is characterised by a marked distortion of self-world
relations and reflects a discrepancy between internal Many people suffer from this condition characterized by
sensation and external reality. Spatial disorientation, as nausea, vomiting, dizziness, and autonomic disturbances
well as dizziness, can be due to a peripheral problem in like cold sweat and low blood pressure. Presumably, the
any of the sensory modalities; or, it may be due to a symptoms arise because of conflict between motor com-
central problem, involving not one particular sensory mands and sensory information (from the semicircular
modality but rather the integration and weighting of the ducts, the maculae, the proprioceptors, and vision); that
different modalities and their relation with memory. is, there is a mismatch between the sensory information
Certainly, disequilibrium and dizziness can arise because and what was expected based on prior experience. Usually,
one of the usual channels of sensory information is lost our own movements produce sensory signals, whereas
or malfunctioningthat is, dizziness of peripheral origin. when sitting in a car signals from vestibular receptors are
Vertigowith the very distinctive illusion of movements passively produced and are not accompanied by the
(usually rotation), either of the body in relation to the expected pattern of proprioceptive signals. Such theories
surroundings or vice versashould be distinguished do not explain all aspects of motion sickness, however.
from other kinds of dizziness. True vertigo is usually The symptoms of motion sickness resemble those
caused by labyrinthine disease, whereas dizziness without evoked by ingestion of certain poisons (see Chapter 27,
vertigo may have various causes. For example, consider- under The Vomiting Reflex) and involve some of the
able loss of proprioceptors and vestibular receptors is same central structures (indeed, labyrinthectomized dogs
common in elderly people and may contribute to dizzi- show decreased susceptibility to many emetic drugs).
ness. Abnormal stimulation of certain receptors may This concerns the solitary nucleus in the medulla, as well
also provoke dizziness and imbalance. Perhaps the prob- as the pathways that control the preganglionic autonomic
lems arise not so much because of lack of information as neurons and motoneurons responsible for emptying the
from a conflict between the various sensory inputs: the stomach. Animal experiments confirm that stimulation
internal model expects a certain relationship between of vestibular receptors can produce several autonomic
them so that if the composition of inputs is altered, it effects, by connections from the vestibular nuclei to the
takes some time to update the internal model. The updat- reticular formation and then to preganglionic autonomic
ing presumably depends on use, as do plastic changes in neurons. Signals from the sacculus and utriculus are
generalthat is, improvement depends on specific train- probably particularly important for the occurrence of
ing of the impaired functions. Elderly people suffering motion sickness, judging from studies of persons exposed
from dizziness may easily enter a vicious circle: they need to weightlessness during space travels. The cerebellum
increased amount of balance training because of reduced (especially the nodulus and uvula in the posterior ver-
sensory inputs or central processing capacity, yet they mis) also seems to play a role. Thus, after removal of
move less than before because they are afraid of falling. the posterior vermis in animals, provocations must be
Dizziness is also a common symptom in many psychiatric much stronger to produce motion sickness.
19 Olfaction and Taste
OVERVIEW THE OLFACTORY SYSTEM
The chemical senses of smell and taste enable us to rec- The sense of smell does not play the same important
ognize a vast number of different molecules in our sur- role for adult humans as the senses of hearing and
roundings. Obviously, this gives us information of great vision. This does not mean that the sense of smell is
importance that triggers a range of responsesfrom insignificant in daily life. The perception of odors is
avoiding poisonous food to enjoying the fragrance of a special by its close association with memories and with
rose. Both senses depend on binding of molecules to emotions and moods. Presumably, this explains why
specific chemoreceptors. These receptors are very sensi- we usually remember odors so well. An enormous
tive, thus permitting recognition and discrimination of industry devoted to producing perfumes and other fra-
molecules in extremely low concentrations (in air or in grances shows that for humans the sense of smell has an
fluids). Stereospecificitythat is, the shape of the ligand important role in interpersonal communication.
determines which receptor it binds tois another com- Going back in the evolution of the species, we find
mon property of the chemoreceptors for taste and smell. that smell is the most primitive of the senses. It is
The transduction mechanismsthat is, how the stimuli also the most important one at the early stages of
translate to graded receptor potentialsare similar for evolution. To understand the evolution of the brain,
receptors for taste and smell because they (with some knowledge of the olfactory brain or rhinencephalon
exceptions) are coupled to G proteins (as are photore- has been important because in the early, primitive ver-
ceptors and many neurotransmitter receptors). tebrates almost the whole cerebrum is devoted to the
The olfactory system differs from other sensory sys- processing of olfactory signals. In higher vertebrates,
tems in certain respects: the sensory cellslocated in new parts of the cerebrum emerge that gradually and
the upper nasal cavityare neurons with an axon going completely overshadow the phylogenetically old parts.
directly to the olfactory bulb (part of the central ner- The organization of the central pathways and nuclei
vous system (CNS). Further, the signals in the olfactory that process olfactory information reflects the fact
tract destined for the cerebral cortex are not synapti- that this system developed earlier than the parts of the
cally interrupted in the thalamus but goes directly to cortex (the neocortex) that treat other sensory modali-
the primary olfactory cortex the medial temporal lobe ties. The term olfactory brain for these old parts is
near the uncus. unfortunate, however. In higher vertebrates, large parts
The taste (gustatory) receptor cells are found in taste of the regions corresponding to the rhinencephalon in
buds scattered over most of the tongue. The sensory lower animals have nothing to do with the sense of
cells are equipped with receptors identifying four basic smell but have taken on other important functions, the
taste qualities (sweet, salty, sour, and bitter). In addi- hippocampus (Chapter 32) being the most striking
tion a fifth quality called umami (Japanese: savory, example. This is a common occurrence during evolu-
meaty) is evoked by glutamate binding to specific reception: structures that are no longer used for one func-
tors. Signals from the taste buds are transmitted in the tion may form the basis for the development of new
facial (intermediate) and glossopharyngeal nerves to capacities. Thus, the parts treating olfactory signals
the solitary nucleus in the upper medulla. From there have not developed in pace with the rest of the brain
signals are distributed to other brain stem nuclei impor- during evolution and are therefore relatively much
tant for food intake and digestion, and to higher levels smaller in humans than in, for example, cats and dogs.
such as the hypothalamus, the amygdala, and the pri- In absolute terms, however, the differences are not so
mary taste area in the anterior part of the insula. marked.
Integration of olfactory and gustatory information
takes place in the orbitofrontal cortex (and some other
Receptor Cells for Smell
places). Here, information from the chemical senses is
processed in a broader context with the aim to facilitate The special receptor cells for smell are located in the
appropriate behavior. mucous membrane of the upper part of the nasal cavity,
266
19: OLFACTION AND TASTE 267
Mitral cells odorous substances are hydrophobic, however; that is,
they do not dissolve easily in water. Therefore, we
Glomerulus assume that there exist mechanismssuch as transport
proteinsto bring hydrophobic odorants through the
Olfactory bulb mucus. Several families of odorant-binding proteins
(OBPs) have in fact been identified in the mucus. It is
probable that each protein binds specifically to certain
Skull odorants and may serve to concentrate the odorant in
the proper part of the olfactory epithelium (i.e., the part
containing the receptors specific for the particular odor-
Receptor cells ant). The odorant-binding proteins may also help
of olfactory remove the odorant so that the receptors quickly regain
epithelium
their sensitivity. Specialized glands produce the mucus,
Mucous layer which consists of several layers.
Nasal cavity
Transduction Mechanism
Experiments with a large number of odorants suggest
that the shape of the molecule, rather than its chemical
gure 19.1 The olfactory epithelium and connections to the olfac- composition, determines how it smells (stereospecific-
tory bulb. Neurons (receptor cells) in the olfactory epithelium have ity). This stereochemical theory of smell proposes that
cilia embedded in mucus. The central process (axon) of the receptor the receptor sites on the receptor cells have different
cells end on mitral cells in the glomeruli of the olfactory bulb. The
shapes and that only molecules with a complementary
axons from neurons sharing odorant specicity tend to converge on
one or a few glomeruli in the olfactory bulb. Thus, the glomeruli shape fit into the receptor site. Binding of the molecules
show some odorant specicity. (Based on Mombaerts 1996.) (odorants) to specific odorant receptor proteins (ORs)
in the membrane of the cilia evokes a receptor poten-
tial. This involves activation of G proteins and cyclic
the olfactory epithelium.1 The total number of receptor AMP. Increased intracellular cyclic AMP opens
cells has been estimated to about 10 million in humans, Na+-selective cation channels and thus depolarizes the
and the cells are constantly renewed. Because they are cell. The ORs share structural features with photore-
in fact primitive neurons, they are exceptions to the rule ceptors and adrenergic receptors. In contrast to
that neurons that die are not replaced. The olfactory photoreceptors, however, the olfactory receptors pro-
epithelium is pseudostratified and consists of support- duce action potentials. The action potential arises in the
ing cells and so-called basal cells besides the receptor initial segment of the axon and is transmitted to the
cells (Fig. 19.1). The supporting cells probably insulate olfactory bulb.
the receptor cells electrically, so that signals are not
propagated from one cell to another. The basal cells
divide mitotically and probably give rise to the receptor The Olfactory Receptor Cells Express an Enormous
cells. The receptor cells are bipolar and send a dendrite- Repertoire of Receptor Molecules
like branch toward the epithelial surface, and an axon
through the base of the skull to the olfactory bulb. The What is the basis of our ability to discriminate several
dendrite ends with an expansion densely covered with thousand different odors? The olfactory system is spe-
cilia (Fig. 19.1). Because the cilia are embedded in the cial by the expression of a large number of specific
mucus that covers the epithelium, only substances dis- odorant receptor proteins (ORs), coded by the largest
solved in the mucus can act on the receptor cells. Many vertebrate gene family comprising around 1000 genes
(only the immune system can recognize more different
molecules). Human ORs express only about 350 dif-
1 The area of the olfactory epithelium is obviously not easy to determine in ferent ORs on the surface of the cilia, while rodents and
2
humans. Thus, gures in the literature vary from 1 to 5 cm . This variation may lower primates express many more, probably because a
at least partly be due to a patchy distribution of the epithelium and age-related large fraction (60%70%) of the human odorant-
loss. Thus, while in the fetus the epithelium is continuous and covering a large
proportion of the nasal cavity, it is gradually replaced by respiratory epithelium receptor genes appears to be pseudogenes (genes that
in a patchy fashion. Further, the epithelium may be more anteriorly located are not expressed). In rodents, the proportion of pseudo-
than formerly believed. A combined histological (biopsies) and electrophysio- genes is only about 5%. Presumably, this evolutionary
logical study located the anterior border of the olfactory epithelium at the level
of the anterior end of the middle turbinate1 to 2 cm anterior to what was increase in the number of pseudogenes may reflect
formerly believed (Leopold et al. 2000). diminished importance of olfaction in higher primates.
Although each olfactory receptor cell appears to skull close to the midline in the anterior cranial fossa
express only one kind of OR, electrophysiological record- through the lamina cribrosa of the ethmoid bone.
ings show that the individual olfactory cell responds The olfactory nerve enters the olfactory bulb (Figs. 19.1
to several odorants. This is because each OR can bind and 19.2; see also Fig. 6.13), located just above the
several odorants, and each odorant can bind to multiple nasal cavity under the frontal lobe. In the olfactory
ORs. Thus, each odorant will evoke a complex pattern bulb, the unmyelinated olfactory nerve fibers establish
of activity among the odorant receptor cells. synaptic contacts with the mitral cells (Fig. 19.1),
which, in turn, send axons to the brain through the
olfactory tract (Fig. 19.2). The mitral cells are collected
Central Pathways for Olfactory Signals
in small, round aggregates, called glomeruli (Latin:
Like other sensory cellsfor example, those in the inner glomerulus, small ball of thread). Each glomerulus
ear and in the taste budsthe olfactory receptor cells forms a functional unit.
are surrounded by supporting cells. In other respects, In view of the enormous repertoire of specific ORs,
however, the olfactory receptor cells are different from it is natural to ask to what degree the specificity is
other sensory receptors, showing a more primitive maintained in the further projection from the olfactory
arrangement. Thus, the olfactory cells themselves send epithelium. There seems to be some topography within
a process (an axon) centrally, whereas in the inner ear, the sheet of olfactory epithelium. Thus, different receptor
for example, a peripheral process of a ganglion cell genes are expressed in somewhat different parts of the
contacts the receptor cell. The unmyelinated axons of olfactory epithelium, as shown with the in situ hybrid-
the olfactory cells form many small bundles, together ization technique. Four zones differing with regard to
constituting the olfactory nerve (the first cranial nerve; receptorgene expressions exist in rodents. Further,
Fig. 19.2). The bundles pass through the base of the anatomic studies with axonal transport methods show
that axons from these four zones end differentially
in the olfactory bulb (Fig. 19.2). A more pronounced
Olfactory
epithelium Olfactory nerve
segregation occurs in the glomeruli, however, as each
glomerulus receives afferents from receptor cells with
Olfactory bulb closely similar specificity. This implies that axons from
receptor cells with quite different positions in the olfac-
tory epithelium converge in one glomerulus. This glom-
erular specificity appears not to be inborn, however,
but results from use-dependent plasticity. Thus, in neo-
natal mice each glomerulus receives axons with differ-
ent specificities. This condition persists if use of the
Olfactory tract
olfactory system is prevented by closure of the nostrils
Anterior shortly after birth.
Olfactory commissure
tubercle
The Olfactory Bulb
The structure of the olfactory bulb is complex. It is
Septal nuclei not a simple relay station but, rather, a small brain
in itself, carrying out substantial processing of the sen-
Uncus sory information reaching it. In this sense, there are
Hypothalamus similarities with the retina, and both are parts of the
CNS that have been moved outside the brain. There
is some evidence that the olfactory bulb is of decisive
Entorhinal area
importance for the discriminative aspect of olfaction,
or the ability to distinguish different odors. Thus,
lesions of nuclei in which the fibers from the olfactory
Parahippocampal
gyrus
bulb terminate do not appear to impair simple olfac-
Amygdala tory discrimination.
As mentioned, the axons from the receptor cells syn-
apse with the dendrites of the mitral cells. The glomer-
gure 19.2 The olfactory pathways. Schematic illustration of some uli form complex arrangements involving several
main connections. In the upper left are the olfactory receptors in the
nasal mucosa, sending their central processes to the olfactory bulb.
dendrites and processes of local neurons. The number
The neurons of the olfactory bulb send their axons to the cortex and of glomeruli in the olfactory bulb declines with age,
various nuclei in the vicinity of the tip of the temporal lobe. and only a few are said to remain in very old persons.
Besides mitral cells, the olfactory bulb contains numer- terminate mainly in deeper layers. Most of the efferent
ous small granule cells, forming a separate layer. They fibers from the olfactory bulb end at the medial aspect of
are local neurons that interconnect mitral cells by way the temporal lobepartly in the cortex and partly in the
of dendrodendritic synapses (the granule cells lack amygdala (Figs. 19.2 and 10.3). The amygdala is located
axons). The granule cells are believed to mediate lateral just below the cortex in the tip of the temporal lobe
inhibition in the olfactory bulb, and this is analogous to (Fig. 19.1; see also Figs. 31.1 and 31.3). In the cortex,
the horizontal cells of the retina. Like the horizontal fibers terminate both in the so-called piriform cortex in
cells, the granule cells are electrically coupled. the uncus and in the adjoining parts of the entorhinal area
Many neurotransmitters are found in the olfactory (Figs. 19.2 and 19.3). The fibers to the amygdala end
bulb. The mitral cells most likely use glutamate, whereas only in the corticomedial nucleus, which sends efferent
the granule cells release -aminobutyric acid (GABA). fibers to the hypothalamus. (The amygdala are discussed
Other interneurons are believed to be dopaminergic. In further in Chapter 32.) The cortical regions in the tempo-
addition, norepinephrine and glycine are present in ral lobe that receive direct fibers from the olfactory bulb
some neuronal processes. are called the primary olfactory cortex (Fig. 19.3). It is
There are also efferent fibers in the olfactory tract, believed that olfactory signals come to consciousness in
as shown anatomically. Accordingly, electrical stimula- these and nearby cortical areas.
tion of the olfactory cortex can influence (primarily
inhibit) the signal transmission through the olfactory
Uncinate Fits and Dj Vu
bulb. Some of the efferent fibers release norepinephrine
and are involved in synaptic changes in the olfactory Lesions affecting the uncus and the immediately surround-
bulb related to a certain kind of learning (see later). ing cortex can be accompanied by subjective olfactory
experiences (often unpleasant). Such sensations often
occur as so-called uncinate fits, which frequently also
The Terminal Areas of the Olfactory Tract
include a peculiar feeling of experiencing the events in a
The fibers in the olfactory tract eventually take various dreamdreamy state. Often the patients feel that they
directions, ending in different nuclei, most of which are have experienced the event before (dj vu). Such unci-
located close to the tip of the temporal lobe (Figs. 19.2 nate fits may develop into an epileptic seizure, and the
and 19.3). In contrast to pathways for other sensory condition is regarded as a form of epilepsy.
modalities, which are synaptically interrupted in the thal-
amus, fibers from the olfactory bulb pass directly to the
Further Processing Outside the Primary Olfactory Cortex
cortex. Another difference concerns the cortical lamina in
which the fibers terminate: olfactory fibers terminate The olfactory cortex and the amygdala forward olfactory
in the outermost layers, whereas thalamocortical fibers signals to other parts of the brain. Connections to other
parts of the cortex serve to integrate olfactory with other
kinds of sensory information, leading to the analysis of
Anterior commissure
its meaning. From the primary olfactory cortex, direct
fibers reach nearby areas on the underside of the frontal
lobe, the orbitofrontal cortex. In addition, this part of the
cortex might receive olfactory information indirectly by
way of connections from the mediodorsal thalamic
nucleus, which receives fibers from the amygdala. The
orbitofrontal cortex receives converging projections from
many cortical areas, such as visual and somatosensory
association areas, parts of the insula in receipt of taste
information, and areas related to emotions, motivation,
and memory. Such connections are generally reciprocal;
Su
Su that is, the sending areas receive information from the
Olfactory
bulb Uncu
Unc
Hippocampal sulcus orbitofrontal cortex, which presumably concerns the
Primary Parahippocampal gyrus broader meaning of the olfactory information.
olfactory area Entorhinal Uncus One important pathway for olfactory signals reaches
area Rhinal
sulcus parts of the hypothalamus. These hypothalamic parts
are involved in control of appetite, digestion, and feed-
gure 19.3 The olfactory cortex. The medial aspect of the cerebral
ing behavior (among other functions). Since also the
hemisphere. The primary olfactory cortex is located in the uncus orbitofrontal cortex sends efferents to the hypothala-
(dark green). The olfactory cortex in humans most likely also encom- mus (among other areas), this part of the brain receives
passes parts of the entorhinal area (light green). both relatively pure olfactory information from the
amygdala and highly processed information that has received by a second individual of the same species, in
been analyzed regarding its meaning for the organism. which they release a specific reaction, for example, a
The olfactory nuclei (not the olfactory bulb) on the definite behaviour or a developmental process. Now
two sides are interconnected by fibers running through the term is often used more broadly about all kinds of
the anterior commissure (Fig. 19.2). Thus, olfactory inborn, chemical communication between individuals
information from both sides of the nasal cavity is treated of the same species. In animalsrodents have been
in each hemisphere. most studiedseveral substances in body fluids (such
as urine and saliva) have pheromone activity and
influence a wide range of social interactions, such as
Olfactory Signals and Behavior
sexual behavior, aggression, recognition of other indi-
Olfactory connections to the hypothalamusboth viduals, and so forth. After destruction of the sense
direct and indirect ones via the amygdalaare impor- organ for pheromone recognition, rodents show, for
tant for eating and for behavior directed at acquiring example, reduced sexual activity and territorial defense.
food. Sexual reflexes and sexually related behavior are Pheromones may be volatile substances (small mole-
also influenced by olfactory signals, although more so cules) that move easily with the air, or they may be
in lower mammals than in humans. The structural basis heavier molecules (peptides) that are exchanged among
for such reflexes and behavior is very complex and not individuals only by close contact. In general, it seems
known in detail. Olfactory connections to the amygdala that the volatile pheromones act as signals for sexual
are most likely of importance, not only because the attraction or warning impending danger, whereas the
amygdala acts on the hypothalamus but also because peptide pheromones are of special importance for
it acts on parts of the prefrontal cortex involved in recognition among individuals.
control of emotions and emotional behavior. The vomeronasal organ is a tubular structure in the
nasal septum with an anterior opening. It is well devel-
oped in rodents, whereas it seems to disappear before
Olfaction and Learning
birth in humans. It contains sensory cells like those in
Olfactory sensations in certain sensitive (critical) peri- the olfactory epithelium, expressing a distinct class of
ods of development can induce lasting changes of receptor molecules (In higher primates, the genes
behavior; that is, learning. This phenomenon is called coding for these receptors have become nonfunctional).
olfactory imprinting. One example concerns sheep that In rodents, the sensory cells send their axons to the
establish a strong bond to the lamb shortly after the accessory olfactory bulb and from there connections
birth. This depends on odors of the lamb that are pres- to cortical structures that partly overlap those treating
ent in the amniotic fluid. The mother must be exposed signals from the olfactory epithelium.
to the odor(s) during the first 4 to 12 hours for the Even though the vomeronasal organ is lacking, there
bond to develop. The migration of salmons for thou- is evidence of pheromone-like actions in humans, where
sands of miles is an almost incredible example of how pheromones presumably act via receptors in the olfac-
memory of odors can control behavior. At 2 years of tory epithelium (in rodents pheromones act via both the
age, the salmon is imprinted by odors at its birthplace, vomeronasal organ and the olfactory epithelium).
and these odors guide it when returning home sev- Synchronization of the menstrual cycle in women living
eral years later. Imprinting by smell or taste can occur close together is believed to be mediated by phero-
also before birth. If pregnant rabbits are fed a diet with mones. Especially volatile substances present in armpit
certain aromatic substances, their offspring prefer foods sweat seem to act as pheromones in humans. For exam-
containing these substances. This happens even if they ple, some studies suggest that male armpit sweat may
grow up with a substitute mother on a different diet. influence female menstrual cycle and mood. Mothers
Olfactory imprinting is related to synaptic changes in (but not fathers) seem to be able to recognize their
the olfactory bulb (and most likely other places as well). babies by smell.
Simultaneous arrival of olfactory signals and signals in The significance of pheromones for human social
norepinephrine-containing afferents seems to be neces- behavior and development is controversial. It is safe to
sary for lasting synaptic changes to occur. In the exam- say, however, that they would play a minor role com-
ple with sheep mentioned above, more mitral cells pared with their effects in rodents and other animals. In
responded to odors from the lamb after imprinting. a broader context, pheromones are just one means of
social communication. As concluded by Swaney and
Keverne (2009, p. 239): . . . the evolution of trichro-
Pheromones
macy [color vision] as well as huge increases in social
The term pheromone was introduced by Karlson and complexity have minimised the role of pheromones in
Lscher in 1959 (p. 55), and defined as . . . substances the lives of primates, leading to the total inactivation
which are secreted to the outside by an individual and of the vomeronasal organ . . . while the brain increased
in size and the behavior became emancipated from papilla lies along a transverse line posteriorly on the
2
hormonal regulation. tongue (Fig. 19.5). The taste buds are composed of
approximately 100 elongated sensory cells and support-
ing cells (Fig. 19.4). The sensory cells of the taste buds
GUSTATORY SYSTEM (THE SENSE OF TASTE) are constantly renewed; each cell lives probably only
about 10 days. They have long microvilli at their apical
The sense of taste is not among the most important of surface, protruding into a small opening in the epithe-
the special senses in humans, and much of what we usu- lium, the taste pore. Here, substances that are dissolved
ally call taste experience is in reality brought about by in the saliva contact the membrane of the sensory cell.
stimulation of olfactory receptors. This happens primar- Terminal endings of sensory (afferent) axons contact the
ily by expiratory airflow through the nose while eating basal ends of the sensory cells. Binding of the tasty sub-
(compare the reduced sense of taste during a common stances to receptors in the membrane of the sensory cells
cold). We nevertheless interpret this olfactory stimula- depolarizes the cell and thus produces a receptor poten-
3
tion as taste (a further example of the importance of tial (as in other sensory cells). ATP released from the
central interpretations of sensory signals for our con- basal aspect of the sensory cell binds to ionotropic puri-
scious perception). In addition, signals from oral ther- noceptors (P2x) in the sensory nerve endings and produces
moreceptors and mechanoreceptors contribute to what action potentials.
we experience as a unitary sensory phenomenon. Finally,
nociceptors activated by spicy food (such as chili
peppers) contribute to taste perception. 2 There are also some taste buds on the soft palate, which are innervated by the
intermediate nerve. The few taste buds present on the most posterior part of the
tongue and on the upper side of the epiglottis are innervated by the vagus nerve.
The Taste Receptors and Taste Qualities Extralingual taste receptors are believed to protect the airways from aspiration
of uids.
The true taste signals come from chemoreceptors in the 3 There are two kinds of receptor cell in the taste buds. Unexpectedly, it seems
that the kind that expresses taste receptors in high concentrations do not con-
taste buds that are located primarily in the epithelium of tact sensory bers, whereas the other kind, expressing fewer taste receptors,
the tongue (Fig. 19.4). The taste buds are concentrated makes direct contact. Therefore, several taste cells probably work together as a
along the lateral margins of the tongue and the root of unit with some cells being responsible for transduction while others transmit
signals to the sensory bers. Indeed, the taste cells seem capable of mutual com-
the tongue and are found in small elevations of the munication by way of gap junctions and release of neurotransmitters (ATP,
mucous membrane called papillae. The largest (vallate) serotonin, and others).
Epithelial Sensory cell

cells Taste pore Supporting
cell
Somatosensory area (SI)
and anterior insula
Thalamus
Foliate
Fungiform papilla
Vallate Solitary
papilla papilla VPM nucleus
Facial nerve
(Intermediate)
Chorda
tympani
Sensory
nerve fiber
Glossopharyn-
Lingual nerve geal nerve
gure 19.5 Pathways for taste signals. The various kinds of papilla
gure 19.4 Taste bud. Semischematic drawing based on electron contain taste buds. In the solitary nucleus, taste information is inte-
micrographs. The receptor molecules for taste substances sit in the grated with somatosensory signals from the oral cavity. The solitary
membrane of the receptor cell cilia. In the taste pore, the receptors are nucleus receives addition input from the viscera via the vagus nerve
exposed to substances dissolved in uids. (not shown in the gure).
We usually distinguish four elementary taste quali- particularly high at the apical membrane, whereas the
ties: salty, sour, sweet, and bitter. In addition, umami other kinds of channels are evenly distributed. Sour
+
taste is now often included as a fifth quality. The recep- substances will therefore close many K channels but
tors evoking the umami quality detects amino acids and only a few other channels. Salty substances act primar-
+
L-glutamate in particular. Indeed, the sodium salt of ily on passive Na channels in the apical membrane.
+
glutamate is widely used as a flavor enhancer. There are When the concentration of Na increases in the fluid in
+
probably many more specific receptors than basic taste contact with the apical membrane, Na ions enter the
qualities. Especially bitter tasting substances appear to cell and depolarize it.
be detected by several specific receptors. This seems Sweet substances and umami act on members of the
reasonable, as bitter taste often is associated with poi- same family of G proteincoupled receptors (T1R),
sonous foods and their recognition would give special which also includes metabotropic glutamate receptors
survival value. and GABAB receptors. One kind of the T1R receptor
Each of the basic taste qualities is most easily per- binds several different sweet substances, while another
ceived (have the lowest threshold for identification) in binds amino acids. In humans, this receptor is selective
a particular region of the tongue: sweet at the tip of for glutamate (in rodents it binds several kinds of amino
the tongue, then salty, sour, and bitter more posteri- acids).
orly, in that order. Such differences are only relative, Bitter substances another G proteincoupled recep-
however, and humans are able to perceive all qualities tor family than sweet and umami (T2R). Whereas only
from either the anterior and posterior part of the tongue. three genes code for T1R, about 30 code for T2R. Each
Accordingly, receptors for all taste qualities have been variety of T2R recognizes only a few bitter substances
identified in all parts of the tongue equipped with but each sensory cell expresses several kinds of the T2R.
taste buds. Thus, each cell can recognize a wide variety of bitter
Fat is very important for the tastiness of foods. It substances.
therefore seemed a paradox that no specific receptors
were known, even though the texture of fatdetected
Why Cats Dont Like Sweets
by low-threshold mechanoreceptors in the oral cavity
appears to play a role for taste perception. However, Cats do not express the gene coding for one of the sweet
now binding of long-chain fatty acids to the apical receptors (T1R2). This may probably explain why cats
membrane of taste cells have been demonstrated, and show little interest in sweet foods: they probably get no
furthermore, we know that fatty acids act on taste-cell taste perception from it. In an evolutionary perspective,
ion channels. sweet receptors are much more important for primates
that feed on fruits and berries than for carnivores feed-
ing primarily on meat. Aspartame, used as an artificial
Flavors Act on Ion Channels and on G ProteinCoupled
sweetener, binds in humans to the T1R2 receptor and
Receptors in the Apical Membrane
therefore gives a sweet sensation. In mice, this receptor
Salty and sour substances depolarize taste cells by direct is slightly different and unable to bind aspartame.
binding to ion channels, whereas sweet and bitter sub- Consequently, mice are unable to detect aspartame in
stances and glutamate act mainly or only on G protein their food. Similar genetic polymorphisms may perhaps
coupled receptors. A number of genes code for sweet, explain why humans differ concerning their propensity
bitter, and umami receptors. for sweets.
No specific receptors are required for salty and bitter
+ +
substances, because they act on ubiquitous H and Na
Modulation of Taste-Cell Sensitivity
ion channels. The specificity of the sensory cell depends
on the fact that the cell is exposed to the stimulus only Various factors, such as hormones and neurotransmit-
at the apical membrane. The cells of the taste bud are ters, and neuropeptides modulate the sensitivity of the
interconnected with tight junctions (zonula occludens) sensory cells. These substances can be released from
that seal the lateral membranes off from the taste pore. basal cells in the taste buds or enter from the blood.
Thus, fluid in the mouth cannot penetrate between the The basal cells of the taste buds contain serotonin
cells. Sour substances appear to act primarily by virtue (among other substances). Although its function is not
of their concentration of hydrogen ions, which act by clear, serotonin increases the sensitivity of the sensory
closing K+ channels in the apical membrane. This depo- cells to taste stimuli. Depression and anxiety are com-
larizes the cell. Hydrogen ions, however, act on several monly associated with reduced taste sensation. One
kinds of channels, such as channels for Na+ and Ca2+; study found reduced sensitivity for all taste qualities
one might think that closure of such channels would (but especially sweet) in deeply depressed patients. The
counteract the effect on K+ channels. Specificity is sense of taste returns when the depression resolves.
achieved because the concentration of K+ channels is Low levels of monoamines in the taste buds may explain
these findings, as suggested also by the finding that been changed from, for example, sweet to bitter. This
selective serotonin-reuptake inhibitors (SSRIs) reduces implies the existence of mechanisms ensuring that,
the threshold for detecting flavors by 20% to 30% in when the sensory cells are renewed, they retain their
normal persons. line to the brain. On the other hand, each sensory
Vasopressin (the antidiuretic hormone) and aldoster- fiber must be able to recognize its kind of sensory
oneboth protecting the blood volume by acting on cell, because each sensory fiber branches and supply
ionic transport across the renal tubular epithelium several taste buds and several sensory cells in each
increase the response of the taste cells to sodium chlo- taste bud.
+
ride (by acting on Na channels).
Pathways for Taste Signals and the Primary Taste Area
Specicity of Taste Cells and Primary Afferent Units
The intermediate nerve (accompanying the facial nerve)
Each sensory cell in the taste buds appears to respond contains the taste fibers from the anterior two-thirds of
rather specifically to one kind of taste substance (sweet, the tongue, whereas the fibers from the posterior third
sour, bitter, or umami). The further transmission of follow the glossopharyngeal nerve (Fig. 19.5). All taste
signals in the primary afferent fibers is less specific fibers end in the rostral part of the solitary nucleus. The
but retains some segregation. Thus, primary taste neurons in the solitary nucleus send their axons to sev-
afferents (sensory units) fall into two broad categories, eral areas, thus mediating reflex effects, coordination of
specialists or generalists, depending on degree of the activity of visceral organs, and perception of taste.
specificity. The specialist sensory units respond best to Fibers pass to the visceral efferent nuclei of the salivary
stimulation with one category of substances, whereas glands and to the dorsal motor nucleus of the vagus.
the generalists respond to several with about the same Such connections mediate reflex secretion of saliva and
threshold. This conclusion is based on recordings from gastric juice (and other digestive fluids). Some of the
single afferent fibers in several animal species. In agree- cells in the solitary nucleus send their axons to the
ment with the existence of specific primary afferents, hypothalamus. This enables taste signals to influence
stimulation of one kind of sensory unit (e.g., sweet the higher autonomic centers. Taste information reaches
specific) evokes behavior in agreement with the nature the amygdala. Finally, direct fibers from the solitary
of the stimulus. The specific response to electric stimu- nucleus end in the thalamus, enabling taste signals to
lation of the sensory units remains even though their reach the cerebral cortex. The synaptic interruption in
properties are changed (by genetic manipulation) so the thalamus is in the VPM nucleus (Fig. 19.5; see also
that they no more express the appropriate receptor. Fig. 14.6), which serves as a relay for signals from the
Thus, the central connections of the sensory unit deter- face in general.
mine the behavioral response evoked upon stimulation Taste signals are transmitted from the thalamus to
of a sensory unit, even if its receptor expression has the face region of the SI, close to the representation of
Cingulate gyrus
Scattered units activated by
olfactory, gustatory, and oral
som
somato
atosensory
osensory stimuli
somatosensory
Central sulcus
SI
SI
gure 19.6 Cortical regions processing

information from taste receptors. These
regions may constitute a avor network
responsible for our experience and discrimina-
tion of avors. The density of taste-responsive Insula
Orbitofrontal cortexx
units is low in all regions. In contrast to pri- Integration with smell and
andd
mary visual and auditory cortices that contain ies,
other sensory modalities,
only modality-specic units, the primary taste and with emotions and d
context information Primary taste area
area contains neurons integrating several sen- Units responding to
sory modalities, notably olfactory and oral olfactory and gustatory
stimuli
somatosensory stimuli.
the tongue (see Fig. 14.8) and the anterior part of the way of descending fibers from the hypothalamus). The
insula. Together, these areas comprise the primary solitary nucleus receives descending fibers from the
taste area (Fig. 19.6). Sensory units responding to the amygdala, probably mediating conditioned aversion to
elementary taste qualities are, as mentioned, to some certain flavors. Finally, the cortical taste area sends
degree segregated in the first link of the taste pathways. fibers to the rostral part of the solitary nucleus, enabling
However, a considerable convergence occurs in the that the signal traffic is modulated by context and
solitary nucleus. Most neurons respond to several taste expectation already at the brain-stem level.
qualities, although a few respond specifically to sweet
or bitter substances. In the primary taste area, even
Further Cortical Processing
fewer neurons appear to be specific. Further, many
neurons receive convergent inputs of taste and other Our conscious experience of taste is due not just to
sensory modalities, so that integration of taste and, for stimulation of taste receptors, as mentioned.
example, olfaction starts at the first cortical station. Furthermore, numerous taste cells with different speci-
For example, chemotopic localization in the primary ficities are presumably always stimulated while eating
taste area (topographically organized representation of or drinking. The synthesis in the cerebral cortex of all
different flavors) has not been documented in neuro- these varied signals forms the basis of our subjective
physiologic studies of primates. Nevertheless, we have experience of taste. Convergence of olfactory and taste
no problems discriminating the basic taste qualities and signals takes place in the anterior part of the insula.
innumerable other nuances of taste. How can a high A higher level of integration occurs in the orbitofrontal
level of discrimination be achieved if there are no cortex where taste, smell, and other sensory modalities
labeled lines keeping apart signals from different meet (Fig. 19.6). Thus, responses of neurons in the
kinds of receptor (as in the somatosensory system)? orbitofrontal cortex to flavors depend on whether the
One view is that discrimination occurs by simultaneous animal is hungry or not. This may be caused by connec-
analysis of the activity pattern in many sensory tions from cortical areas related to motivationthat is,
unitsso-called population coding. The temporal areas that may inform about the significance of a sen-
pattern of signals from different receptors is crucial, not sory stimulus. That our subjective sensory experience
their spatial segregation. Nevertheless, the labeled is determined not only by the stimulus holds for all
line view received support recently from evidence of sensory systems. Nevertheless, the emotional influence
chemotopic localization in the primary taste area of on the sensory experience is probably more marked for
rodents. This was shown by transsynaptic transport to taste and smell than for other modalities. We know
the cortex from bitter and sweet receptors in the taste from everyday experience, for example, how the same
4
buds. Possibly, there may be elements of both mecha- smell or taste may be experienced as pleasant in one
nismsthat is, labeled lines and population codingin situation and nauseating in another.
the central processing of gustatory signals. It is fair to
say, however, that the mechanisms responsible for taste
Conditioned Taste Aversion
discrimination are not fully understood.
Taste is an important learning signal; it may be of vital
importance to learn rapidly the association between a
Signal Transmission from Taste Buds Is Modulated in
taste and its significancethat is, whether it signals
the Brain Stem
something edible or poisonous. Survival of wild animals
The response of neurons in the solitary nucleus to depends upon their ability to learn such association at
signals from taste buds depends on several other inputs the first trial, establishing a stable conditioned taste
to the solitary nucleus. For example, the response is aversion to dangerous foods. Nausea is a very efficient
inhibited by distension of the stomach. This is mediated learning signal when evoked by food intake. By just
by signals transmitted from the stomach by the vagus trying a small portion of the food, the animal usually
nerve. Further, solitary neurons respond to alterations can survive and learn to never again try the same poten-
in blood levels of insulin and glucose (presumably by tial food. The close coupling in the solitary nucleus of
gustatory information with signals from the stomach
most likely is involved in establishing the associations
4 An functional magnetic resonance imaging (fMRI) study of six persons between flavors and their significance. Other neuronal
reported slightly different locations of cortical responses to different avors. groups believed to participate in conditioned taste
The interpretation of such data is uncertain, however, because the distribution aversion are found in the parabrachial area (pons), the
of response may have been inuenced by other factors than taste that varied
during the experimental sessions. amygdala, and the orbitofrontal cortex.
IV MOTOR SYSTEMS
T HE cell groups and tracts in the central nervous

system that control the activity of the skeletal
muscles compose the motor systems. We may also use
involved in mediating the commands from the motor
centers to the muscles, and are necessary for the initia-
tion of voluntary movements; paralysis ensues when
the term somatic motor systems to distinguish them they are damaged. Then we treat the basal ganglia
from the systems that control smooth muscles and (Chapter 23) and the cerebellum (Chapter 24), which
glands. have their main connections with the central motor
Although the motor systems consists of several inter- nuclei and are necessary for the proper execution of
connected parts,we first discuss some general aspects movements rather than for their initiation. Finally, in
(Chapter 20). Then we treat the peripheral (lower) Chapter 25 the control of eye movements is treated
motor neurons (Chapter 21) and the central (upper) separately due to the distinctive features of this system.
motor neurons (Chapter 22). These parts are directly
20 Motor Systems and Movements
in General
OVERVIEW which are usually classified as cognitive, are never-

theless indispensable for performance of purposeful
This chapter discusses the close interdependence of movements (e.g., parts of the prefrontal cortex involved
what we, somewhat arbitrarily, term the motor system in the early stages of movement planning and in the
and other systems of the brain. For example, normal mediation of motivated behavior). On the other hand,
motor control and especially motor learning depend parts that we here include in the motor systems, nota-
heavily on sensory information. Large parts of the cere- bly the basal ganglia and the cerebellum, participate in
bral cortex in the parietal and frontal lobes are engaged nonmotor tasks. The basal ganglia, for example, play
in transformation of sensory information into action. prominent roles in emotional and cognitive functions.
Further, the purpose of movements is often not move- Likewise, recent research, for example, functional
ment per se but movements performed to collect sen- magnetic resonance imaging (fMRI) studies in humans,
sory information. Without precise control of our fingers, strongly suggest that the cerebellum participates in
lips, tongue, and eyes, sensory information would be sensory and cognitive functions.
severely degraded. This also concerns the chemical We may conclude that, at the higher levels of the
senses (olfaction and taste). For example, sniffing is a CNS, it becomes arbitrary whether we classify regions
prerequisite for optimal detection of smells. We fur- as sensory, motor, or cognitive: these concepts are too
thermore need to be able to scan our environments with narrow to encompass the complex tasks undertaken by
our eyes, and our fingers move swiftly and accurately large parts of the cerebral cortex and many related
back and forth over objects we need to identify. We fur- subcortical nuclei.
ther discuss movements differing with regard to velocity
and to whether they aim at stabilizing or moving parts
of the body. Finally, we discuss how we can classify Sensory Feedback
movements according to degree of voluntary control, Although for didactic reasons we treat the motor and
from fully automatic reflex movements to the most con- sensory systems as independent entities, this is an over-
sciously controlled skilled movements of the fingers. simplification. For the motor systems to function, they
must cooperate closely with the sensory systems. For
example, during most movements, the motor centers
MOTOR AND OTHER SYSTEMS ARE MUTUALLY need constant information from receptors in muscles,
DEPENDENT around joints, and in the skin about whether the
movement is progressing in accordance with the plan.
The Term Motor System Lacks Precision Further, visual information is often crucial for the
Although we include only restricted parts of the ner- proper execution of movements. Such sensory feedback
vous system in the term motor system, nevertheless sig- information enables the CNS to adjust and correct the
nals from parts of the brain not usually considered command signals issued to the muscles either during
motor are necessary for proper movement. Thus, many the movement or during the next time the movement is
parts of the central nervous system (CNS) may be con- performed. Learning of new skills especially depends
sidered motor in the sense that they contribute to the critically on reliable sensory feedback. Indeed, we per-
activity of the more narrowly defined motor systems. form unfamiliar movements slowly to allow sufficient
Some of these regions are usually considered part of the time for sensory feedback.
sensory systems, as they are crucial for the processing
of sensory information (e.g., the posterior parietal asso-
Movements in the Service of Sensation
ciation areas, discussed in Chapter 14, which process
visual and somatosensory information but also issue Many movementsnotably of the hands, mouth, and
commands to motor areas). Other parts of the brain, tongueare executed to collect sensory information.
277
Indeed, the hand is a sensory organ in its own right. For external force is smaller than the muscle force, the
example, we use delicate, exploratory finger movements muscle shortens and a movement occurs; this is called
to judge the form, surface, consistency, and so forth of concentric or isotonic contraction. When the external
objects. Losses of muscle coordination or of hand sen- forces equal the force of the muscle contraction, no
sation have equally devastating consequences for hand movement occurs; this is called isometric contraction.
function. In addition, eye movements are entirely When the external force is greater than the opposing
devoted to assist the brain in the acquisition of visual force produced by the muscle contraction, the muscle
information, and head movements aid the auditory sys- lengthens; this is called eccentric contraction. Eccentric
tem. As aptly formulated by the Israeli neuroscientist contraction occurs, for example, with the thigh muscles
Ehud Ahissar (2008, p. 1370) Without eye movement, when we walk down a staircase, as the muscles brake
the world becomes uniformly gray; without sniffing, the movement produced by the weight of the body.
only the initial changes in the odor environment are
sensed; and without finger or whisker motion, objects
Ramp and Ballistic Movements
cannot be identified.
Movements may be classified by the speed with which
they are performed. Ramp movements are performed
Motor Systems and SelfRecognition relatively slowly. The crucial point is that the move-
Movements play an important role in the experience ment is slow enough to enable sensory feedback infor-
and ownership of our bodies. For example, experiments mation to influence the movement during its execution.
in human volunteers show that self-recognition (e.g., Ballistic movements are very rapid, and their character-
the hand belongs to me) is significantly better during a istic feature is that they are too fast to enable feedback
self-generated movement than when depending on pro- control: the name derives from analogy with a bullet shot
prioceptive and visual information alone. Our body out of a gun.
scheme and body image (cf. Chapter 18) depend on
regular updating by sensory information provided by Automatic and Voluntary Movements
our own, purposeful movements. If there is a mismatch
between movement commands and sensory feedback, Movements may also be classified according to whether
misconceptions of the body regularly occur (e.g., after they are voluntary or automatic ; automatic movements
amputation, deafferentation, immobilization of joints, take place without our conscious participation. In real-
and so forth). ity, this is much too crude a distinction: there is a grad-
ual transition from what Hughlings Jackson in the past
century termed the most automatic to the least auto-
CLASSIFICATION OF MOVEMENTS matic movements. The most automatic movements are
basic, simple reflexes, such as the retraction of the arm
Stabilizing and Moving from a noxious stimulus. Locomotion is an example of
a semiautomatic movementthat is, the basic pattern
Before we describe the motor systems, some comments is automatic, but starting and stopping and necessary
on movements in general are pertinent. First, muscle con- adjustments may require conscious (voluntary) control.
traction may not necessarily elicit movement (i.e., alter The least automatic movements are precision grips with
the position of one or more joints); just as often, muscle the fingers and delicate manipulatory or exploratory
activity is used to prevent movementfor example, mus- movements such as writing, drawing, playing a musical
cles maintain our posture by counteracting the force of instrument, and so forth. Equally precise voluntary
gravity. In preventing movement, the muscles may be control exists for the muscles of the larynx, the tongue,
said to stabilize a joint (against external forces) and to and some of the facial muscles. We know that the degree
have a postural function. Further, movement in one to which a movement is automatic changes with learn-
part of the bodyfor example, in an armrequires ing: in the beginning a new movement requires full
that muscles in other parts contract to prevent the body voluntary control, and in the process of learning the
balance from being upset. Therfore, a muscle in one movement becomes more automatic. When playing a
situation may be used as a mover and in another situation well-rehearsed musical piece on the piano, for example,
as a stabilizer. we do not need to pay attention to the fingers and their
movements.
As a rule, the most automatic movements require only
Contractions: Concentric, Isometric, and Eccentric
the use of relatively simple reflex arcs at the spinal level;
Whether or not a movement is to occur depends on the participation of higher motor centers is not necessary.
magnitude of the force produced by the muscle contrac- Somewhat less automatic and more complex movements
tion and the external forces acting on the joint. When the such as ventilation, locomotion, and postural control
20: MOTOR SYSTEMS AND MOVEMENTS IN GENERAL 279
depend, in addition, on the participation of neuronal repertoire of voluntary movements. Also, these features
groups in the brain stem. Such movements do not ensure great flexibility in how motor tasks are solved.
require our attention directed toward them but can be The same task may be solved in different ways, and we
subjected to voluntary control. The least automatic can continuously adapt to novel challenges. The great
movements depend on the participation of the highest adaptability and flexibility of movements distinguish
levelthe cerebral cortexto coordinate and control humans from most animals. Most animals are highly
the activity of motor centers in the brain stem and spi- specialized for a limited number of motor tasks, con-
nal cord. The vast number of neurons and the plasticity trolled by stereotyped motor programs that develop
of the human brain enable learning of an almost infinite according to a fixed pattern.
21 The Peripheral Motor Neurons
and Reexes
OVERVIEW cranial nerve nuclei. There are two kinds: motoneu-

rons innervate the extrafusal muscle fibers, whereas the
The peripheral or lower motor neurons (motoneurons) g motoneurons innervate the intrafusal muscle fibers of
constitute the final and only connection between the the muscle spindle (see Figs. 13.6 and 13.7).
central nervous system (CNS) and the muscles. If they The motoneurons of the ventral horn (Fig. 21.1) and
are destroyed, paralyses of the muscles ensue. There are in the cranial nerve nuclei are easily recognized in
two types of lower motor neuronsa motoneurons microscopic sections because of their large size and the
innervating the extrafusal muscle fibers and g motoneu- big clumps of rough endoplasmic reticulum (rER) in the
rons supplying the muscle spindles. The motoneurons cytoplasm of their cell bodies (see Fig. 1.2). The rich
are arranged in columns in the spinal cord; each col- content of rER indicates that the neurons have a high
umn supplying one or a few muscles with synergetic protein synthesis. These proteins are, for example,
actions. Each column extends through two or more enzymes for transmitter synthesis and metabolism and
segments, so that each muscled receives fibers from at various kinds of membrane proteins. The vast surface
least two spinal segments. An motoneuron and all the of the motoneurons with their large dendritic tree and
muscle fibers it innervates is called a motor unit. Large long axons presumably explains why motoneurons
muscles consist of a few hundred to more than a thou- contain more rER than most other neuronal types.
sand motor units. Muscle fibers are classified according
to ATPase activity into type 1 and type 2 fibers. In gen-
eral, type 1 fibers have the highest endurance whereas Ventral Roots and Plexuses
the type 2 fibers contract with the highest velocity and The axons of the motoneurons leave the spinal cord
force. The muscle fibers of one motor unit are all of the through the ventral roots and continue into the ventral
same fiber type. and dorsal branches (rami) of the spinal nerves to inner-
A reflex is an involuntary response to a stimulus, vate skeletal muscles of the trunk and the extremities
which is mediated by the nervous system. The motoneu- (see Figs. 6.5 and 6.7). Correspondingly, the axons
rons are parts of reflex arcs, consisting of receptors that from the cranial nerve motor nuclei supply the muscles
capture the stimulus, sensory neurons conducting signals of the tongue, pharynx, palate, larynx, and face, as well
to the CNS, a reflex centrum (e.g., in the spinal cord), as the extraocular muscles. The axons of all the
and an effector (muscle or glandular cells). In this chap- motoneurons located in one spinal segment leave the
ter, we discuss the flexion reflex and stretch reflexes in cord through one ventral root and continue into one
particular. Stretch reflexes are of two main kinds: the spinal nerve. The ventral branches of the spinal nerves
monosynaptic stretch reflex (routinely tested by a tendon form plexuses so that the motor axons from one spinal
tap) and the polysynaptic, long-latency stretch reflex. segment are distributed to several peripheral nerves
Both consist of a muscle contraction in response to (Fig. 21.2).
muscle stretch (the muscle spindle is receptor). We also
discuss the resting tone of muscles (muscle tone), and how
it may vary in health and disease. Finally, we treat the The Final Common Path and Synaptic Contacts
ability of peripheral nerves to regenerate after severance. on Motoneurons
Contraction of skeletal muscles can be elicited only by
MOTONEURONS AND MUSCLES signals conducted in the axons of motoneurons. If these
axons are interrupted, the muscles become paralyzed.
The peripheral motor neurons are nerve cells that send The peripheral motor neurons thus constitute the final
their axons to skeletal muscles. Another term is lower common path for all signals from the CNS to skeletal
motor neurons. These are the motoneurons in the ven- muscles (the term final common path was introduced
tral horn of the spinal cord and in the somatic motor by the British neurophysiologist and Nobel laureate
280
21: THE PERIPHERAL MOTOR NEURONS AND REFLEXES 281
A B
Ventral horn
gure 21.1 Motoneurons. A: Photo-

micrograph and drawing of a Ventral root
transverse section of the (lumbar) fibers
spinal cord. The motoneurons
are collected in groups (columns) Lamina IX
that together form the lamina IX
of Rexed (outlined in orange).
C Motoneuron
B: Photomicrograph of a transverse
section through the human lumbar
enlargement, Bodians silver
impregnation method. Cell bodies
and axons are black. Due to shrink-
Axon
age, the cell bodies are surrounded
by a light zone. Bundles of motor
axons can be seen penetrating the
white matter. C: Higher magnica-
tion of a motoneuron and the rst
part of its axon; from the framed
area in B.
Sir Charles Sherrington). The motoneurons may be Each motoneuron probably receives about 30,000
compared with the keys of a piano on which higher nerve terminalssome forming excitatory synapses, oth-
levels of the CNS can play. As we describe later in this ers inhibitory; some with fast synaptic actions, others with
chapter, many parts of the CNS cooperate in determin- slow modulatory ones. The sum of these influences deter-
ing the activity of the motoneurons and thus the con- mines whether and with what frequency the motoneurons
traction of our muscles. will send action potentials to the muscles. That we can
Dorsalis scapulae nerve

Levator scapulae m.
Rhomboid m.
C5
Suprascapular nerve
Supraspinatus m. C6
Infraspinatus m.
Axillary nerve
Deltoid m.
Teres minor m.
Musculocutaneus nerve
Biceps brachii m. Thoracicus longus nerve
Brachial muscle Serratus anterior m.
Subscapular nerves
Teres major m.
Subscapular m.
gure 21.2 The brachial plexus. Axons of motoneu- Anterior lateral thoracic
rons in one spinal segment (C5 is used as an example) nerve
are distributed to several peripheral nerves to supply Pectoralis major m.
Radial nerve
various muscles of the arm. Each muscle also receives M. brachioradialis
motor bers from other segments, although they are M. supinator
not shown here.
perform such a wide variety of movements is due to the nerve onlyfor example, by disk protrusion in sciatica
ability of the CNS to select precisely, by way of the or by a tumor growing in the spinal canalwill not
motoneurons, the combinations of muscles to be used produce paralysis of a muscle but only a more or less
and to determine the speed and force with which they pronounced paresis (weakness).
are to contract. The anatomic organization of motoneurons has been
studied via transsection of muscle nerves in experimen-
tal animals. A retrograde reaction, which is easily seen
Neurotransmitters
through a microscope, occurs in the cell bodies of the
The motoneurons use acetylcholine as transmitter, motoneurons. Studies using retrograde transport of
and the synthesizing enzyme choline acetyltransferase tracer substances have detailed the picture consider-
(ChAT) can be demonstrated immunohistochemically ably. Study of patients with poliomyelitis has provided
in the motoneurons and in their terminals. Motoneurons information about conditions in the human cord (the
also contain the neuropeptide calcitonin gene-related poliovirus infects and kills motoneurons). Because the
peptide (CGRP). The level of CGRP in the motoneu- distribution of paralyzed muscles usually has been
rons is under the influence of descending connections determined before death, it can be compared with the
from higher levels of the CNS; when such connections distribution of cell loss among the motoneuron groups
are transected, the level of CGRP drops. There is exper- in the cord and brain stem.
imental evidence that CGRP influences the synthesis of
acetylcholine receptors of the muscle cells. If so, this
Motoneuron Columns Are Somatotopically
may be one (of several) means by which the CNS can
Distributed in the Ventral Horn
influence the properties of muscle cells.
Groups of motoneurons that supply axial musclesthat
is, muscles of the back, neck, abdomen, and pelvisare
Motoneurons Are Collected in Columns
located most medially within the ventral horn, whereas
The motoneurons are collected in groups, which form motoneurons supplying muscles of the extremities lie
Rexeds lamina IX in the spinal cord (Fig. 21.1; see also
Fig. 6.10). The dendrites of the motoneurons do not
respect the boundaries of lamina IX, however, and
extend far in the transverse and in the rostrocaudal Columns of
motoneurons
directionsfor example, into lamina VII, where many
interneurons are located (see Fig. 6.12). The rostrocau-
dal (longitudinal) extension of the dendrites enables
dorsal root fibers from several segments to act on each
motoneuron. The dendritic tree increases the surface of
the motoneurons enormously, and, not surprisingly,
the vast majority of the nerve terminals contacting
motoneurons are axodendritic.
Three-dimensionally, the motoneurons are collected
in longitudinally oriented columns (Fig. 21.3). Each col-
umn contains the and motoneurons to one muscle C5
or a few functionally very similar (synergistic) muscles. C6
Within a column supplying more than one muscle, the
motoneurons to each muscle are at least partly segre- C7
gated. As a rule, each column extends through more than C8
one segment of the cord. Consequently, each muscle
receives motor fibers through more than one ventral T1
1
root and spinal nerve. Destruction of one root or spinal
1 About 20 Hox genes control the specication of motoneurons with regard to

their peripheral target (muscle). In addition, expression of recognition mole-
cules and guidance receptors in the peripheral tissues is required for axons to
nd their target. When looking at the intricate trajectory of branches from
motoneurons in one segment (Fig. 21.2) the task of creating a precise topo-
gure 21.3 Columnar arrangement of motoneurons. Schematic of
graphic relationship between spinal cord motoneurons and muscles seems
daunting. It should be recalled, however, that at the time of outgrowth in early the somatotopic localization of the motoneuronal columns innervat-
embryonic life, the distances are small and trajectories of axonal growth are ing the arm, located in the spinal segments C5T1. Motoneurons sup-
usually fairly straight. The complicated structure of the plexuses (Fig. 21.2) plying the intrinsic muscles of the hand are located most caudally
arises later in development. (C8T1) and most dorsally in the ventral horn.
more laterally. This explains why the ventral horn is from nerve to muscle takes place (Figs. 21.4 and 21.5).
broader (extends more laterally) in the segments of the Within the end-plate region, the axonal branch divides
cord that send fibers to the extremities (i.e., C5T1 and further and forms up to about 50 nerve terminals (bou-
L1S2; compare Figs. 6.8, 6.10, and 6.11). There is also tons), each establishing synaptic contact with the muscle
a further somatotopic organization: motoneurons sup- cell. The postsynaptic side at this neuromuscular junc-
plying proximal muscles of the extremities (the shoul- tion is somewhat special compared with synapses in the
der and hip) are located more ventrally than those CNS, as junctional folds and a thin basal lamina are
supplying the distal muscles (the hand and foot). This is intercalated between the presynaptic and postsynaptic
shown in Figure 21.3, which also shows that the proxi- membranes (Fig. 21.5B). The boutons contain acetyl-
mal muscles are supplied from motoneurons located choline, and the postsynaptic membrane contains ace-
more rostrally than those supplying the distal muscles. tylcholine receptors of the nicotinic type. The density of
For example, the shoulder muscles are mainly inner- acetylcholine receptors is much higher in the end-plate
vated by the upper parts of the brachial plexus (C5C6), region than elsewhere on the muscle cell surface, which
whereas the lowermost segments (C8T1) innervate the is appropriate because only at the end plate is the muscle
intrinsic muscles of the hand. cell normally exposed to acetylcholine. During embry-
onic development, howeverbefore the nerve fibers
growing out from the cord have reached the muscle
Motoneurons Are of Functionally Different Kinds
cellsthe acetylcholine receptors are evenly distributed
As mentioned, the and motoneurons supplying one all over the muscle membrane. Only after establishment
muscle lie together within one column in the ventral of properly functioning synaptic contacts are the recep-
horn. In a microscopic section of the cord it can be seen tors redistributed to attain the mature pattern. During
that the motoneuron cell bodies vary in size (Fig. 21.1; development, spinal motoneurons transiently express
see also Fig. 1.2). As in other parts of the nervous sys- the neuropeptide galanin, which presumably influences
tem, the neurons with the largest cell bodies have the the synapse formation at the motor end plate.
thickest (and thus the fastest conducting) axons. The g
motoneurons are the smallest within a group, while the a
motoneuronsalthough larger than the motoneurons
vary considerably in size. Such size differences are Motor
related to differences among the muscle cells supplied end plate
by the motoneurons. Briefly stated, the smallest
motoneurons control delicate movements with little
force, whereas the largest motoneurons come into play
only when a movement requires great force. The large
Axon
motoneurons also have a much higher maximal firing
frequency than the small ones, and the large ones tend
to fire in brief bursts with a high frequency, whereas the
small motoneurons tend to go on firing for a long
time with a low frequency. These differences in firing
pattern reflect that the large motoneurons are used for
Muscle cell
forceful, rapid movements of short duration, whereas (extrafusal)
the small motoneurons can uphold a moderate muscu-
lar tension for a long time. For these reasons, we apply
the term phasic motoneurons to the large ones, and
tonic motoneurons to the small ones. The properties Small nerve
of the motoneurons are discussed further when we
deal with the motor units.
The Motor End Plate and Neuromuscular Transmission

After entering the muscle, the -motoneuron axon
divides into many thin branches or collaterals. Each of
these terminal branches contacts one muscle cell only.
Each muscle cell is thus contacted by only one branch gure 21.4 Motor end plates. Photomicrograph of skeletal muscle
cells and a small bundle of nerve bers innervating the cells. The tis-
from one motoneuron. Such a branch ends on the sue is stained with gold chloride to darken the nerve bers and their
muscle cell approximately midway between its ends, terminal boutons. Each motor end plate consists of numerous small
forming the motor end plate, where the signal transfer boutons. Four end plates are seen here. Magnication, 500.
A B The disease myasthenia gravis is characterized by

Schwann cell excessive fatigability of striated muscles, which is
Nerve terminal Synaptic
Myelin vesicles caused by autoantibodies binding to the acetylcholine
Basal receptors. Thus, there are fewer than normal acetylcho-
Motor lamina
end plate line receptors available at the neuromuscular junction
and release of acetylcholine opens fewer ion channels,
leading to less than normal depolarization. The proba-
B
bility of evoking an action potential in the muscle cell
membrane is consequently reduced. Drugs that inhibit
Muscle cell the acetylcholine esterase (neostigmine, physostigmine)
Synaptic cleft Junctional folds
may lessen the symptoms. With this inhibition, the
transmitter gets a longer time to act, and the probabil-
gure 21.5 The motor end plate. A: Schematic showing how the ity of evoking an action potential is increased. Typically,
myelinated nerve ber loses the myelin sheath before it ramies in the most severely affected are the muscles of the head, pro-
end-plate area, each terminal branch ending in a nerve terminal. Each ducing symptoms such as double vision (due to paresis
muscle cell has only one end plate. B: Section through one of the
nerve terminals in A, based on electron microscopic observations.
of extraocular muscles) and involuntary lowering of the
The synaptic cleft contains a thin basal lamina, and the postsynaptic upper eyelids (ptosis). The voice becomes weaker while
membrane is thrown into deep folds (junctional folds). speaking and swallowing may become difficult. In addi-
tion, the respiratory muscles are usually affected.
An action potential propagated along the axon of the
motoneuron depolarizes all the boutons and elicits
The Force of Muscle Contraction Is Controlled
release of acetylcholine. The transmitter binds to the
by the Motoneurons
acetylcholine receptors, and, as at other excitatory syn-
apses, this depolarizes the postsynaptic membrane. This A single presynaptic action potential at the motor end
change in the membrane potential is called the end- plate elicits only a brief contraction, a twitch, of the
plate potential. Because of the large number of nerve muscle cell (Fig. 21.6). The twitch lasts only for about
terminals formed by one terminal fiber, enough trans- one-tenth of a second. However, if another action
mitter is released by a single nerve impulse to depolar- potential follows shortly after the first onethat is,
ize the muscle cell membrane to the threshold for an before the tension produced by the first twitch is over
action potential. The action potential is propagated the tension produced by the muscle is upheld and,
over the whole surface of the muscle cell and elicits a furthermore, may increase considerably. This is called
brief contraction. The enzyme acetylcholinesterase rap- summation. Up to a limit, the tension produced by the
idly terminates the action of acetylcholine by degrading muscle cell increases with increasing frequency of action
it. The enzyme is present in the synaptic cleft and the potentials; that is, the force produced by the muscle cell
junctional folds. is determined by the firing frequency of the motoneu-
ron. Whereas the twitch is the response of the muscle
cell to a single nerve signal, tetanic contraction is the
Neuromuscular Transmission Can Be Disturbed
term used of the muscle response to a train of signals
by Poison and Disease
with the highest frequency to which the muscle cell can
Various drugs and naturally occurring poisonous sub- respond (Fig. 21.6). The tetanic tension is thus the
stances can influence the signal transmission at the neu- maximal force the muscle cell can produce. (One may,
romuscular junction and produce involuntary muscle as shown in Fig. 21.6, differentiate between unfused or
contractions or muscle paralysis. The South American incomplete tetanus at submaximal firing frequencies
Indian poison curare and similar synthetic substances and fused or complete tetanus at the maximal firing
paralyze the muscle cells by blocking the acetylcholine frequency. The term tetanus, as used here, refers to
receptors. Such drugs are often used during abdominal the complete tetanus.)
surgery to obtain sufficient muscle relaxation. Several
kinds of snake poisons act by blocking acetylcholine
There Are Functionally Different Kinds of Striated
receptors and thereby paralyze the victim. The botuli-
Muscle Fiber Types
num toxin (produced by a microorganism growing in
certain kinds of spoiled food) paralyzes the muscles by In both animals and humans, the skeletal muscles are
preventing the release of acetylcholine from the nerve composed of different kinds of muscle cells or muscle
terminals at the motor end plate. A similar mechanism fibers (these terms are used interchangeably). The most
sometimes produces muscle weakness in patients with clear-cut evidence is provided by the fact that in some
cancer; apparently, substances preventing release of species certain muscles have a dark color (red muscles),
acetylcholine are produced in the body. whereas other muscles are light (white muscles)for
Muscle tension
Complete tetanus
Twitch Incomplete tetanus
Nerve
gure 21.6 Muscle contraction. The muscle ten- impulses
sion increases with increasing ring frequency of the
motoneurons innervating the muscle cell. (Redrawn 0.5 sec.
from Kandel and Schwartz 1985.)
example, the almost white breast muscles and the dark

leg muscles of the chicken. Such muscles are composed A
of muscle fibers of only one (or predominantly one)
kind, and we classify the muscle cells as either white or
red. The color difference is due to differences in the
content of myoglobin, which is red (closely related to
hemoglobin) and transports oxygen within the muscle
cell. Further study showed that white and red muscle
cells differ with regard to endurancethat is, how long
they can maintain tension. This is mainly due to differ-
ences in the capacity to take up oxygen and to aerobic
ATP production (oxidative phosphorylation). As one
would expect, the red muscles have the highest endur-
ance. In addition to containing more myoglobin than
the white muscle fibers (cells), the red ones also contain
more mitochondria, which are responsible for the aero-
bic ATP production. There are also other important
differences: the white muscle fibers contract more rap- B
idly and develop greater force than the red fibers. With
physiological methods, muscle cells can be classified as
fast twitch (FT), corresponding largely to white fibers,
and slow twitch (ST), corresponding to the red fibers.
The differences with regard to contraction velocity and
maximal force development are related to differences in
the amount and type of myosin ATPase (enzymes cleav-
ing ATP, thus providing the energy for the muscle con-
traction). With histochemical staining methods, muscle
fibers are classified in accordance with their ATPase
activity (Fig. 21.7). On the basis of ATPase staining,
human muscle fibers are classified as type 1, corre-
sponding largely to the red and the ST fibers mentioned
above, and type 2 fibers, corresponding largely to the
white and FT fibers. The type 2 group is heterogeneous, gure 21.7 Muscle ber types. Photomicrographs of cross sections
however, and consists of type 2A fibers, which resemble of skeletal muscle (human). The sections are treated so that the color
the type 1 fibers in having a relatively high oxidative intensity of the muscle bers depends on their myosin-ATPase activ-
capacity, and the type 2B fibers, which are the most ity. With this particular treatment, the type 1 bers are light and the
typical white fibers with low oxidative capacity. type 2 bers are dark. A: From the quadriceps muscle of a normal
person. B: From the same muscle of a weight lifter. Note the differ-
The CNS thus can select muscle fibers in accordance ence in muscle ber thickness. Magnication, 200. (Courtesy of
with the requirement of the task: one fiber type is best Dr. H.A. Dahl, Norwegian University of Physical Education and
suited for contractions of moderate force that last for a Sport, Oslo.)
long time, whereas the other type is used particularly stretching, found no change of the viscoelastic properties
for contractions with high force but short duration. of muscle and tendon in spite of increased range of motion.
The muscle tension was higher in extreme joint positions,
however, suggesting that the increased range is due to
Muscle Fiber Types in Humans
increased tolerance to high tensile forces rather than to
With few exceptions, human skeletal muscles are com- changes in the muscle.
posed of a mixture of type 1 and type 2 muscle fibers.
However, the thickness difference between type 1 and
Motor Units
type 2 fibers is much less marked than in experimental
animals. Type 2 fibers are as a rule only slightly thicker As mentioned, the axon of the motoneuron divides into
than type 2 in males, while in females the reverse situa- numerous branches when entering the muscle, and each
tion appears to be the rule. terminal branch makes synaptic contact with one mus-
Histochemical examination of many different muscle cell. Further, each muscle cell is innervated by one
cles in several individuals has indicated that the compo- motoneuron only. When an motoneuron sends action
sition of fiber types is fairly constant when comparing potentials to a muscle, all muscle cells innervated by
muscles from one individual, whereas the individual that motoneuron contract simultaneously. Therefore,
differences are great. Thus, some persons have a high in a sense, an motoneuron and all the muscle cells
percentage of type 1 in most of their muscles, whereas that it innervates constitute the smallest functional unit
others have a strong preponderance of type 2 fibers. of the motor system and were called a motor unit by
Studies of fiber composition in successful athletes have Sherrington (Fig. 21.8). (Compare with the term sensory
shown that those engaged in endurance sports (such as unit, introduced in Chapter 12.) The size of a motor
marathons and cross-country skiing) usually have a unitthat is, the number of muscle cells supplied by
high percentage of type 1 fibers, whereas a high per- one motoneuronvaries greatly. This has been studied
centage of type 2 fibers is found in those engaged in by counting the axons in the muscle nerve (after destruc-
sports requiring explosive force (such as ice hockey and tion of the dorsal roots, to let the sensory axons degen-
weight lifting). erate) and counting the muscle cells. An average seems
Recent studies suggest that the relationship between to be around 150 muscle cells per motoneuron, with a
histochemical classification (ATPase) and functional range of from less than 10 to more than 1000. As might
properties is less clear-cut than formerly believed. Thus, be expected, the smallest motor units are found in
muscle fibers belonging to the same fiber type histochem- muscles that are used for delicate movements, which we
ically can nevertheless have quite different contractile must be able to control very precisely. Examples are the
properties in different muscles. For example, the human intrinsic muscles of the hand, the muscles of the larynx,
adductor pollicis and soleus muscles both consist of the facial muscles, and the extraocular muscles. The
about 80% type 1 fibers; yet the contraction velocity of largest motor units occur in large muscles used for
is about the double in adductor pollicis. movements of considerable force and with less precise
control, such as the muscles of the back, the abdomen,
and the thigh. Within one muscle, however, the motor
Muscles Also Contain Connective Tissue:
units also vary in size.
Stretching of Muscles
There is also a relationship between the size of a
A muscle consists of a large number of muscle cells, motor unit (in terms of number of muscle fibers) and
stretching from tendon to tendon (usually at an angle to the size of its motoneuron. Thus, the motoneurons with
the longitudinal axis of the muscle). Bundles of muscle the largest cell bodies and the thickest axons as a rule
fibers are surrounded by connective tissue that contains belong to the largest motor units. This fits with the use
the vessels and nerves. The whole muscle is wrapped in of large motor units for fast and forceful movements:
a connective tissue sheath, the muscle fascia. In some the large motoneurons have the highest maximal firing
muscles the fascia is thick and fairly tight; in others it is frequencies, and their axons conduct the signals to the
2
thin and loose. The connective tissue of the fascia and muscles with a minimal delay.
within the muscle is continuous with the tendons. Muscle cells belonging to different motor units lie inter-
Therefore, the passive properties of a musclethat is, its mingled in the muscle, as is obvious in sections stained to
consistency and resistance to being stretcheddepend identify fiber types (Fig. 21.7). Correspondingly, muscle
on both properties of the muscle cells and on the amount
and arrangement of the connective tissue. 2 The relationship between motoneuron size and motor unit properties is not
Passive stretching of muscles to maintain or increase absolute, however. Motoneurons of the same size may have different maximal
joint mobility is used therapeutically and in sports. The ring frequencies. Further, motoneurons of the same size may innervate muscle
cells with different contractile properties. The latter is probably because the
reasons for increased mobility after regular stretching are motoneuron ring frequency (and ring pattern) inuences the contractile
not entirely clear. One study, with 3 weeks of intensive properties of the muscle cells.
Electromyography
As mentioned, muscle contraction is elicited by an
action potential that is propagated along the muscle cell
membrane. Like action potentials of nerve cells, the
muscle cell action potential can be recorded with an
electrode. This is called electromyography (EMG) and
is performed either with an electrode placed on the skin
overlying the musclesurface EMGor with a thin
needle electrode inserted into the muscle. The surface
method gives an impression of the total electrical activ-
ity of the muscle, whereas needle electrodes sample the
activity of a small part of the muscle. Because the EMG
is a measure of the electrical activity and not of the
motoneuron Muscle cells mechanical activity of the muscle, it is not well suited to
measure muscle-force production. In some instances of
gure 21.8 A motor unit. Schematic of a motoneuron in the ventral prolonged activity, the muscle force may be declining in
horn and its axon, which branches to supply many muscle bers. The
spite of constant or even increasing EMG activitythe
muscle cells belonging to one unit (red) lie intermingled with muscle
cells belonging to other motor units (brown). declining force being caused by changed conditions in
the muscle itselfwhereas muscle action potentials are
evoked normally by the nerve to the muscle.
cells belonging to one motor unit spread over a consider- When recording from a normal muscle at the start of
able part of the total cross-sectional area of the muscle. a very weak, voluntary contraction, the EMG shows
regular, single potentials due, presumably, to the activ-
ity of only one motor unit. As the force increases, more
Motor Units and Fiber Types
potentials occur in the EMG, reflecting the recruitment
Muscle cells belonging to the same motor unit are all of of more motor units. At a certain level of force, the
the same fiber type. Thus, they not only contract simul- potentials are so frequent that the picture becomes
taneously but also share properties with regard to con- unclearthat is, it is impossible to recognize a further
traction velocity, maximal force, and endurance. In increase of the EMG activity. This occurs not only
general, the smallest motor units consist of type 1 fibers, because of recruitment but also because of the increase in
whereas the largest ones consist of type 2B fibers. This the frequency of action potentials for each motor unit.
further increases the difference between large and small EMG is a valuable tool for studying the participation
motor units with regard to their maximal force; not of various muscles in normal movements: for example,
only are there more muscle cells in the large units, but to determine the timing of contraction in muscles of the
each cell also develops more force. Recruitment of one leg during walking. EMG also aids in the diagnosis of
extra motor unit with type 1 fibers adds just a little diseases of the peripheral motor neurons and of the
extra to the total tension of the muscle, which thus can muscles themselves, as in determining whether a disease
be graded finely (like an electrical switch with many affects the motoneurons or the muscle. If the motoneu-
small steps to vary the heat of a stove). As one might rons are put out of action, the EMG activity will be
expect, such motor units are used for precisely con- reduced or absent, whereas in a disease that affects the
trolled movements of small force. Recruitment of a large contractile apparatus of the muscle, the EMG may be
motor unit consisting of type 2 fibers, in contrast, gives normal. In addition, in cases of injury to peripheral
a comparatively large increase in the total tension of the nerves, it can be ascertained whether the lesion is com-
muscle (the switch has large steps). Such motor units plete (no EMG activity) or incomplete (even though
are recruited only when large force production is needed. there may be no visible movements).
Often this concerns fast movements because high accel-
eration requires a large force.3
Gradation of Muscle Force: Recruitment and Frequency
3 The ber type used for a particular kind of movement has been studied by the As we all know, the force of muscular contraction can
so-called glycogen-depletion technique. By prolonged use, all of the muscle be finely graded within very wide limits, from a barely
bers of a motor unit deplete their stores of glycogen, as evident in histochemi-
cally treated frozen sections of a small piece of muscle tissue (obtained by perceptible contraction to a tension that is high enough
biopsy). The type 1 muscle bers are depleted rst when the force exerted is to tear the muscle loose from its insertion. This depends
lowthat is, no type 2 bers are recruited. When the force is very high, how- on the ability of the CNS to control the activity (the
ever, the type 2 bers are depleted rst; although type 1 bers are also recruited,
because of their high endurance, they are not depleted during the short period level of excitation) of the motoneurons. There are two
in which a maximal force can be maintained. means by which the force of muscle contraction can be
gradually increased. One means is to bring more and recruited at the beginning of the contraction (judging
more motoneurons to send action potentials to the
5
from animal experiments). Because a relatively large
muscle. This is called recruitment, because more and fraction of the motor units is recruited, the required
more motor unitsand thus muscle fibersare called force is achieved with a low firing frequency, so that the
into action. The other means is by increasing the firing motor units can work for a long time without fatigue. If
frequency of the motoneurons already recruited and the contraction continues, however, some motor units
thereby increasing the force developed by each motor fatigue and fresh ones are recruited to maintain con-
unit. Thus, the force exerted by each motor unit (as by stant force. Finally, so many small or medium large
each muscle cell) can be graded from the small and brief motor units are fatigued that the largest motor units
tension produced by a single twitch to full tetanic tension must be recruited to prevent a drop of force. This
(Fig. 21.6). recruitment pattern is only valid, however, when the
When a muscle contraction is initiated, the small contraction force is so low that the blood flow is not
motoneurons are always recruited first, and with increas- impeded (even at 25% of maximal voluntary contrac-
ing force the larger ones are recruited successively. This is tion force the blood flow is significantly reduced).
called the size principle of recruitment and was demon-
strated by the American neurophysiologist E. Henneman
in the 1960s. The excitability of the motoneurons is REFLEXES
inversely related to their size; thus, the small motoneurons
are more easily excited to the threshold for initiation of When a response to a stimulus is automatic (involuntary),
action potentials than are the large ones. This is presum- and the response is mediated by the nervous system, we
ably related to differences both in membrane properties of call it a reflex. Many of the tasks of the nervous
the motoneurons and in the density of excitatory synapses. system are carried out automatically or reflexlythat
The size principle ensures selection of the motor units that is, independent of conscious interaction. This, of course,
are best suited for a particular kind of movement.4 frees the higher levels of the brain from handling numer-
ous trivial everyday tasks. The distinction between
reflex movements and those initiated voluntarily are
Recruitment during Movements with Different
not always as clear-cut as it might seem from this defi-
Force Requirements
nition, however. We discussed in Chapter 20 that move-
The number of motor units that are recruited at the ments are best classified on a continuous scale from the
beginning of a voluntary contraction depends on the most automatic to the least automatic. In the text that
force requirement. If maximal force is needed (as with follows we discuss mainly some spinal reflexes that are
a movement of maximal speed), most or all-motor units examples of the most automatic movements. Chapters
are recruited almost simultaneously. Nevertheless, the 18 and 22 discuss somewhat less automatic movements,
small ones are activated slightly before the large ones such as postural reflexes and locomotion. Reflexes involv-
because the small motoneurons reach the threshold ing cranial nerve nuclei are discussed in Chapter 27, and
for eliciting action potentials first. Thus, the order of some visceral reflexes are treated in Chapter 29.
recruitment is maintained (according to the size princi- Even though reflexes differ in many respects, they nev-
ple) when maximal force is required. To produce the ertheless share some fundamental properties. Reflexes
maximal force, besides recruiting as many motor units are stereotyped and constant because the same stimulus
as possible, the central motor centers must increase the always gives the same kind of response. With increasing
firing frequencies of the motoneurons to the maximal: strength of the stimulus, however, the response usually
a muscle develops maximal force when all motor units increases in strength or magnitude. The reflexes are
are recruited and contract tetanically (complete teta- inborn: we do not need to learn them from experience.
nus). Such a contraction, however, can be maintained (One example that illustrates the need for inborn motor
for only a short period before the muscle fatigues. The behavior is the sucking reflex in the newborn child.)
situation is different when a movement requires low Many reflexes occur in large groups of animal species;
force. Consider, for example, an isometric contraction all mammals, for example, have several reflexes in com-
that should last as long as possible (i.e., the force must be mon. In general, the reflexes are appropriate and useful
kept constant). Here, more than half the motor units are and ensure that the individual adapts to the environ-
ment. Reflexes are also fundamental for reproduction.
4 In spite of the general validity of the size principle for recruitment of motoneu-
rons, experiments with the use of biofeedback (EMG) during voluntary move- 5 There are, however, large differences among human muscles with regard to
ments indicate that humans can to some degree select among the low-threshold the proportion of motor units that are recruited early. In intrinsic hand muscles,
motor units, probably depending on the ability of higher motor centers to focus for example, most of the units are recruited even at low forces, whereas in the
excitation among motoneurons with presumably the same size. biceps brachii new units are recruited until maximal force.
Some reflexes are simple with regard to both the stimu- The Reex Arc and Basic Features of Reexes
lus and the response, like the blink reflex (closing of the
The structural basis of a reflex is a reflex arc (Fig. 21.9),
eye when something touches the cornea). Others are
which consists of the following links:
much more complex and require cooperation of many
structures, like the swallowing reflex. Some reflexes 1. A receptor, which records the stimulus and
involve lower parts of the CNS only (spinal cord and translates it to action potentials
brain stem), whereas others involve the higher parts 2. An afferent link (a primary sensory neuron),
(even the cerebral cortex). Some reflexes are mediated which conducts the action potentials to the CNS
by a chain of only two or three neurons, others by com- 3. A reflex center, in which the signals from the
plicated and extensive neuronal networks. receptor may be modified (increased or decreased) by
Even though reflexes are independent of our will, signals from other receptors and other parts of the CNS,
some of them can be suppressed voluntarily (e.g., the where aftersignals are issued to effectors
reflexes for emptying the bladder and the rectum). 4. An efferent link (neurons with axons passing out
Other reflexes take place without our being aware of of the CNS), which conducts action potentials to the
them, and with no possibility of influencing them vol- organ producing the response
untarily (like most of the reflexes related to the control 5. An effector, which may be skeletal (striated)
of visceral functions). muscle, cardiac muscle, smooth muscle (in the wall of
vessels and visceral organs), or glands
Conditioned Responses (Reexes) Reflexes with their reflex center in the spinal cord are
called spinal reflexes. Brain stem reflexes, as the name
True reflexes should not be confused with another kind implies, have their center in the medulla, pons, or mes-
of automatic behavior, conditioned reflexes or, better, encephalon; cortical reflexes have a reflex center that
conditioned responses. In conditioned responses the involves parts of the cerebral cortex. Some reflex arcs
stimulus evoking a true reflex response (the uncondi- are simple, while others that involve coactivation of
tioned stimulus) has been replacedby learningby several muscle groups may be highly complexwith
another stimulus. This learning occurs when the uncon- reflex centers that include neurons in the brain stem
ditioned stimulus (e.g., a puff of air on the cornea which and in the cord. Most reflex centers include links of
elicits a blink reflex) is regularly preceded by another several synaptically coupled neurons; such reflexes are
kind of stimulus (e.g., a tone; the conditioning stimu- called polysynaptic. If only one synapse is intercalated
lus). After some time, the conditioning stimulus will between the afferent and the efferent link, the reflex is
elicit the reflex response even when it is not followed by called monosynaptic.
the unconditioned stimulus. The classical examples are
the experiments of the Russian physiologist Pavlov, in
which gastric secretion was produced by ringing a bell
(conditioned stimulus). During the learning phase, the Afferent link
bell was always followed by food being presented (sensory neuron)
(unconditioned stimulus). There are many examples Receptor
from daily life of such conditioned behavioral responses,
and conditioning is an important kind of learning. The
cerebellum appears to be important for conditioning of
movements, such as the blink reflex but also movements
that involve skeletal muscles.
Interneuron Effector (muscle)
Some Reexes Disappear during Development
Some reflexes are present only during certain phases of
development, such as the sucking reflex and the grasp-
ing reflex in infants. When the reflexes disappear, they
Efferent link (motor
are no longer needed and would only disturb voluntary, neuron)
goal-directed movements. The reflex arcs do not disap- Reflex center
pear, but the reflex response is suppressed by higher
gure 21.9 Reex arc. Schematic. All reex arcs contain the same
levels of the CNS. That the nervous apparatus persists elements. The gure shows a spinal reex arc, with cutaneous nerve
is witnessed by the persistence or reappearance of prim- endings as receptors and a skeletal muscle as effector. The reex cen-
itive reflexes in brain-damaged children and adults. ter has in this example two synapses (a disynaptic reex).
Although a reflex response is mediated each time by the skin, whereas the response involves a complex array
the same set of neurons, the excitability of these neu- of muscles (such as extensors of the ankle, flexors of
rons can be modified from higher levels of the CNS. the knee and the hip; Fig. 21.10). Contraction of the
This is necessary to adapt individual reflexes to the muscles in the leg that is withdrawn, however, is not
overall plan for bodily movements. Reflex movements sufficient. Muscles of the other leg must also contract
that operate on their own would disturb normal volun- (primarily extensor muscles) to prevent loss of balance.
tary movements. Modulation of the excitability of the Thus, the stimulus must be distributed to motoneurons
reflex center can be exerted by presynaptic inhibition of in many segments of the cord. This happens by way of
primary afferent fibers, by postsynaptic excitatory of ascending and descending collaterals of the primary sen-
inhibitory actions on interneurons and motoneurons, sory fibers and by way of spinal interneurons (Fig. 21.10).
and by efferent control of the sensitivity of some kinds In response to a simple stimulus, a purposeful, harmo-
of receptor (cf. motoneurons). nious movement occurs, requiring that all the muscles
We first discuss two different spinal reflexes with contract at the right time and with the right force. The
skeletal muscles as effectors. The firstthe flexion or synaptic couplings in the cord underlying this response
withdrawal reflexserves to protect the body; the sec- must be both complex and precise.
ond, so-called stretch reflex (or rather stretch reflexes
since there are several varieties), automatically adjusts
A Flexion Reex Can Be Evoked from
muscle tension during postural tasks and voluntary
Low-Threshold Receptors
movements.
Under certain circumstances, several kinds of receptor
in the skin, around the joints, or in muscles can elicit
The Flexion Reex
a flexion reflex. Common to these receptors is that
This reflex is evoked by activation of nociceptors in the their signals converge on interneurons that excite flexor
skin and underlying tissues. For example, when a foot motoneurons. The sensory fibers from such receptors
hits a sharp object while walking, the whole leg is imme- were therefore termed flexor reflex afferents (FRAs).
diately withdrawn away from the object (Fig. 21.10). In Their effects have been most studied in so-called spinal
this case, one or more interneurons are intercalated animals (the cord is transected and isolated from the
between the terminals of the afferent sensory fiber and rest of the CNS). Many FRAs lead from low-threshold
the motoneurons producing the responsethat is, the mechanoreceptors (e.g., group II muscle afferents),
reflex is polysynaptic. That this is a reflex is clear from, while others lead from nociceptors. Normally, the con-
among other things, the fact that it may be elicited even vergence of FRAs on interneurons is believed to ensure
when the spinal cord is transected above the reflex cen- necessary feedback during ongoing movements
ter. The flexion reflex disappears in deep unconscious- perhaps rhythmic movements in particular. The term
ness. For surgery, anesthesia has to be sufficiently deep flexor reflex afferents is therefore not quite appropri-
to abolish flexion reflexes. ate because many of the FRAs do not normally evoke
As mentioned, the receptors for the flexion reflex are the protective flexion reflex. In patients with transverse
nociceptors. The stimulus usually hits a small spot on lesions of the cord the situation is different, however.
L3 motoneuron
gure 21.10 The exion (withdrawal) reex. The

Muscles diagram is highly simplied. In this case, several
Efferent link synapses are intercalated between the afferent and
L5
the efferent links of the reex arc. Here nociceptors
in the sole of the foot are activated (by walking on
a sharp object). The signals are conducted centrally
in a sensory ber (red), which sends out several col-
S1 Afferent link laterals and, via interneurons and propriospinal
bers, activates motoneurons at several segmen-
tal levels of the cord. In turn, the motoneurons
Efferent link make many muscles contract to lift the foot off
the ground (away from the painful stimulus). At
Receptors the same time, extensor muscles are activated in the
(in sole of the foot) other leg to maintain balance.
Reflex changes occur in body parts that have been clarified, however, concerning the role of the stretch
innervated from the cord below the lesion, including reflexes in movement control.
forceful and long-lasting contractions of flexor muscles.
Such contractions are elicited by innocuous stimuli,
The Monosynaptic Stretch Reex
including stimulation of low-threshold mechanorecep-
tors and thermoreceptors. Most likely, this is due to The patellar reflex (Fig. 21.11)tested routinely as part
abnormal excitability of interneurons in receipt of FRA of a clinical examinationis probably the best-known
inputs produced by the lack of supraspinal control (see example of a stretch reflex. The stimulus is a tap on the
also Chapter 22, under Mechanisms Responsible for patellar ligament (the tendon of the quadriceps muscle).
Development of Spasticity). The response is a contraction of the quadriceps muscle,
thus producing a brief extension movement at the
knee joint. The reflex arc is shown schematically in
Stretch Reexes
Fig. 21.11, and it can be seen that only one synapse is
Under certain circumstances a muscle responds with a intercalated in the reflex centerthat is, the reflex is
contraction when it is being stretched. (It is easy to find monosynaptic. The receptors are the muscle spindles in
out by oneself that stretching a muscle does not always the quadriceps muscle that is stretched; the afferent link
produce a contraction.) When the latency of the contrac- is constituted by the Ia fibers, which end in the spinal
tion is too short to be voluntary, we call this a stretch cord with some collaterals ending directly (monosynap-
reflex. The most obvious purpose of such a reflex might tically) on the motoneurons supplying the quadriceps
be to keep the muscle length constant. Receptors for muscle. The axons of the motoneurons constitute the
stretch reflexes are the muscle spindles. Stretch reflexes efferent link, which at the motor end plate activates the
have been much studied due to their relation to move- extrafusal fibers of the quadriceps muscle (the effector).
ment control. For the patellar reflex, the latency between the stimulus
We speak of different stretch reflexes because muscle and the start of the contraction (as recorded with EMG)
contraction occurring as a result of muscle stretching is about 30 msec, and a slightly shorter latency pertains
usually consists of several phases of contractions, each
with a different latency as recorded by EMG. The reflex
latency is the time between the stimulus and the response L4
Muscle spindle
(between stretch and contraction). It results from the Ia fiber
M. quadriceps
conduction time from the muscle spindles to the spinal
cord; the delay at the synapse(s) intercalated between
the muscle spindle afferent fibers and the motoneu-
rons; the conduction time from the motoneurons to the
muscle; and, finally, the synaptic delay at the motor end
motoneuron
plate. Measurement of the latency between the stimulus
and the response makes it possible to decide whether a
muscle contraction is the result of a monosynaptic stretch Tendon
reflex, or whether otherpolysynapticpathways are
involved. The monosynaptic stretch reflex, with only Ia fiber
Interneuron
one synapse intercalated between the afferent and the
efferent link, is the simplest reflex with the shortest
latency (Fig. 21.11). Each intercalated synapse increases
the latency with a few milliseconds. Thus, muscle con-
tractions occurring with longer latencies after stretching
the muscle indicate that there are more neurons interca-
lated between the afferent link (the sensory fibers) and
the motoneurons. That some stretch reflex responses motoneuron
have longer latency than others may not only be due to
gure 21.11 Stretch reex. The patellar reex is used here as an
more synapses intercalated in the reflex center, how- example of a monosynaptic reexthat is, with only one synapse
ever. Thus, while the fast monosynaptic reflex depends intercalated between the afferent and the efferent link. The stimulus
on signals in the thick group Ia fibers (see Figs. 13.6 is a tap on the patellar ligament below the patella, which stretches the
and 13.7), slower conducting group II muscle spindle muscle. The response is a brief muscle contraction. Bottom right: The
afferents may contribute to reflex responses with longer Ia ber from the muscle spindle contacts the motoneurons monosyn-
aptically, but it also contacts many interneurons. Some of these are
latencies. excitatory, mediating a polysynaptic activation of some motoneu-
We discuss the monosynaptic and the polysynaptic rons; other interneurons are inhibitory, mediating inhibition of other
stretch reflexes separately next. Much remains to be motoneurons.
to reflexes in the upper arm muscles because of a shorter

Pyramidal tract neuron
peripheral pathwayfor example, the biceps reflex has
a latency of about 25 msec.
To evoke a muscle contraction through this simple Ia fiber (from muscle spindle)
reflex arc, the muscle must be stretched rapidlythat
is, by phasic stretching. The actual lengthening pro-
duced by the stimulus may be very little; the salient
point is the velocity of stretching. As discussed in
Chapter 13, the group Ia afferents of the muscle spin-
dles are especially sensitive to the velocity of stretching,
+
so that even a brief stimulus, stretching the muscle only
a fraction of a millimeter, produces a brisk response. Inhibitory

A tap on a tendon with a reflex hammer produces this interneurons
kind of stimulus, although it is far from being a natural
+
stimulus. Because both the stimulus and the response
last only for a very short time, we also use the term Presynaptic
nerve terminal
phasic stretch reflex. The monosynaptic stretch reflex
can be elicited in most skeletal muscles but much more
gure 21.12 Strengthening of the stretch reex by the Jendrssik
easily in some muscles than in others. There are also maneuver. Possible mechanism, in which descending commands
individual differences: in some healthy persons, phasic reduce presynaptic inhibition of Ia afferents from the muscle spindles.
stretch reflexes cannot be elicited. (Based on electrophysiological studies in humans by Zehr and Stein
1999.) See text for further discussion.
The Jendrssik Maneuver and Strengthening of the

contribute to the response. The reflex center is not
Monosynaptic Stretch Reex
restricted to one spinal segment. Thus, motoneurons
As mentioned, in some healthy persons the monosynap- supplying the quadriceps muscle are present in several
tic reflex cannot be elicited by ordinary tendon taps lumbar segments (L2L4). Further, the strength of the
with a reflex hammer. Absent stretch reflexes may also responseeven when the stimulus (the tendon tap) is
be due to lesions of the reflex arc, however. To help kept constantmay vary considerably from person to
decide whether the reflex is merely weak or absent, person and even from time to time for one person
there are means to strengthen the reflex response in depending on, for example, the level of anxiety. This
healthy people. The person forcefully contracts a mus- can be understood when considering that the motoneu-
cle of the arm (especially the forearm) or the jaws while rons receive influences not only from the muscle spindle
the examiner tries to evoke a reflex in the lower extrem- afferents but also from other kinds of receptors and
ities. It takes about 300 msec from start of the maneu- higher levels of the CNS (compare the effect of
ver to maximal facilitation of the reflex. The facilitation motoneurons on the excitability of the muscle spin-
of the monosynaptic stretch reflex by such maneuvers dles). Further, the terminals of the Ia afferents are
must be due to descending signals (pyramidal tract?) subject to presynaptic inhibition, which reduces the
that increase the excitability of the reflex center. One excitation that impinges on the motoneurons.
possibility with some experimental support is shown in Altogether, this means that the gain of the reflex is
Fig. 21.12. The descending fibers act on the interneu- modulated in accordance with the overall need of the
rons that inhibit the interneurons that are producing organism. It also explains whyduring learning of a
presynaptic inhibition of the Ia terminals. Other possi- motor taskthe strength of the monosynaptic reflex
ble explanations have also some experimental support, response can be strengthened or weakened according to
for example, that increased activity may play a role. what is functionally appropriate. We return to modula-
Whatever the mechanism, the effect is obviously not tion of reflex responses.
restricted to increased reflex gain for the working mus-
cles but also for muscles in other parts of the body.
Reciprocal Inhibition
Stretching a muscle does not only lead to excitation of
The Monosynaptic Stretch Reex Is Not as Simple
the motoneurons innervating the muscle (homony-
as It Appears
mous excitation); at the same time, the motoneurons of
Even a monosynaptic reflex is not quite as simple the antagonists are inhibited. This phenomenon is called
as Fig. 21.11 indicates, however. Stretching of the reciprocal inhibition and is obviously functionally
muscle activates not one but presumably, most of the appropriate: it prevents a stretch reflex from being elic-
muscle spindles of the muscle so that many motor units ited in the antagonists when they are stretched by the
reflex contraction of the agonists (which, in turn, would Muscle spindle L4
elicit a new stretch reflex of the agonists, and so on). M. quadriceps Ia fiber
The reciprocal inhibition thus prevents unwanted oscil-
latory movements. Indeed, after damage to descending
motor pathways, repetitive alternate contractions of +
agonists and antagonists can occur. This phenomenon,
called clonus, is most likely due to disturbed function- motoneuron S1
ing of spinal inhibitory interneurons. Reciprocal inhibi-
tion also reduces the tension of the antagonist muscles,
Hamstrings
which otherwise would brake the desired movement. In Tendon
+
the case of the patellar reflex, the motoneurons of the _
knee flexors are inhibited (Fig. 21.13). The inhibition
of the motoneurons of the antagonist is mediated by
so-called Ia-inhibitory interneurons, which are excited motoneuron Inhibitory
6 interneuron
by Ia afferents from the agonist muscles.
Motoneurons Can Inhibit Their Own Activity: gure 21.13 Reciprocal inhibition. Schematic of how the stretching
of one muscleproducing a reex contractionelicits inhibition of
Renshaw Cells
the antagonistic muscles via inhibitory interneurons.
Together, the many inputs to the motoneurons determine
their level of excitabilitythat is, these inputs also
determine the activity of the skeletal muscles. Besides the motoneuronal activity is required), descending connec-
inhibition of motoneurons by primary afferent fibers (via tions from the brain stem and the cerebral cortex may
interneurons) described in the preceding text, the inhibit the Renshaw cells that are supplying the work-
motoneurons can also inhibit their own activity. Thus, ing muscles. Thus, the activity of the Renshaw cells, as
the -motoneuron axons send off collaterals before they that of many other kinds of spinal interneurons, is
leave the ventral horn (Fig. 21.14). Because they turn modulated in accordance with the overall plan for the
back, they are called recurrent collaterals. The recurrent movements.
collaterals end primarily on a group of inhibitory interneu-
rons, the Renshaw cells, located ventromedially in the The Long-Latency (Polysynaptic) Stretch Reex
ventral horn. The axons of the Renshaw cells ramify
extensively and contact primarily the motoneurons (but As mentioned, stretching of a muscle may elicit reflex
also certain kinds of inhibitory interneurons). In this man- contraction via routes other than the monosynaptic reflex
ner, the activity of the motoneurons excites the Renshaw arc. The muscle spindle afferent fibers (Ia and II) contact
cells, which, in turn, inhibit the same motoneurons and not only motoneurons but also many interneurons
other motoneurons that supply muscles with similar
action (agonists). Further, the Renshaw cells inhibit the
inhibitory interneurons mediating the reciprocal inhibi-
tion (Fig. 21.10)that is, the inhibition of the motoneu- Renshaw cell
rons supplying the antagonists is reduced (disinhibition).
In case of a stretch reflex, the activity of the Renshaw cells
shortens the reflex contraction of the agonists and, at the
same time, shortens the reciprocal inhibition of the antag-
onists. In general, recurrent inhibition appears to be more
+
important in proximal than in distal muscles.
The Renshaw system seems important to prevent
the motoneurons from sending long trains of action
potentials as a response to a brief stimulus. In situations
motoneuron
(such as during voluntary movements, when prolonged
Recurrent
collateral
6 The termination of Ia afferents in the spinal cord are differentiated, so that

gure 21.14 Recurrent inhibition. The motoneurons inhibit their
some collaterals end in contact with interneurons that inhibit the muscle in
which the muscle spindles lie. Although this inhibitory inuence is not notice- own activity by sending recurrent collaterals ending on the inhibitory
able when testing the monosynaptic stretch reex, it may have a role in perfor- Renshaw cells. The Renshaw cells are also inuenced by other spinal
mance of natural movements when the eliciting of stretch reexes may be neurons and from higher levels, which determine how strongly they
unwanted. will respond to a certain input from the motoneurons.
(Fig. 21.11), establishing polysynaptic routes from the lesions of the descending motor pathways or by lesions
muscle spindle afferents to the motoneurons. Rapid of the dorsal columns (presumably carrying the signals
stretching of the biceps muscle may elicit two or three from the muscle spindles to the cerebral cortex). Further,
reflex responses, as determined with EMG in human the reflex is often weakened after lesions of the cerebel-
subjects. In addition to an early EMG activity with a lum. But such findings may also be explained by a
latency of about 25 msec (the monosynaptic stretch purely spinal reflex that is under strong supraspinal
reflex, or M1 response), another reflex contraction (M2) control.
starts at about 50 msec and sometimes a new phase of More decisive evidence of a transcortical route for
contraction (M3) at about 70 to 80 msec. These are not the long-latency stretch reflexat least regarding cer-
voluntary responses, since the earliest voluntary muscle tain muscle groupscomes from observations in a few
contractions occur at about 100 msec after the stretch patients with a peculiar inborn abnormality of the pyra-
(in the upper arm). These reflex responses constitute the midal tract. These persons always perform mirror
long-latency stretch reflex (other names are the func- movements of the hands; asked to flex the index finger
tional stretch reflex, the polysynaptic stretch reflex, and of the left hand, they always flex the right index finger
the long-loop stretch reflex). as well (more proximal movements, e.g., of the shoul-
A striking property of the long-latency stretch reflex ders, are performed normally). This behavior appears
is that the strength of the response depends to such a from electrophysiological studies to be caused by
high degree on whether the muscle is relaxed or active branching of individual pyramidal tract axons to sup-
at the time of stretching. If the muscle is relaxed or only ply motoneurons of both sides of the spinal cord. Thus,
slightly active when stretched, there is usually no long- stimulation of the hand region of the motor cortex of
latency reflex response at all. Further, the strength of one hemisphere causes symmetrical movements of both
the response depends on prior instruction to the subject hands (unlike the normal situation, in which such stim-
with regard to whether to resist the imposed stretch or ulation always cause movements of the opposite hand
to let go. When the person is asked to let go when an only). When eliciting stretch reflexes in such subjects,
imposed movement (at an unpredictable time) stretches the monosynaptic reflex occurs only on the same side as
the muscle (e.g., an imposed extension at the elbow that the stretch is applied (as normal), whereas the long-latency
stretches the biceps muscle), the reflex response is much stretch reflex occurs in both hands after a unilateral
smaller than when the person is asked to resist the stimulus. The latter observation is hard to explain unless
imposed movement. Thus, the magnitude of the reflex the reflex arc of the long-latency reflex involves the
response can be adapted to what is functionally appro- pyramidal tract.
priate in a particular situation. These findings may not pertain to long-latency stretch
A further characteristic of the long-latency stretch reflexes in all muscle groups. For example, the long-
reflex is that the strength of the response may change latency stretch reflexes appear to be transcortical for
during learning of a motor task. Thus, by repeated distal arm muscles but not (or to a lesser degree) for
trials, the reflex response becomes weaker in muscles in proximal arm muscles and muscles in the foot. For these
which a contraction in response to stretching is func- latter muscles, the long-latency reflex may be elicited by
tionally inappropriate and stronger in muscles in which group II muscle afferents, which conduct with about
a contraction is appropriate. This learning effect, or half the velocity of group Ia fibers.
adaptation of the stretch reflex, occurs only in connec-
tion with the particular learned movement; in connec-
The Function of Stretch Reexes
tion with other movements, the reflex response of the
muscle is unaltered. As mentioned, the monosynaptic One might think that the stretch reflexeswhich, after
stretch reflex is also subject to similar learned, task- all, are relatively simpleare well understood with
related modulation, but the changes appear to be smaller regard to their functional roles. For example, the mus-
than those obtained with the long-latency reflex. cle spindles and the motoneurons are among the best-
characterized receptors and central neurons, respectively.
Nevertheless, we still do not fully understand the role
Is the Long-Latency Stretch Reex Mediated
of the stretch reflexes in the control of voluntary move-
by the Cerebral Cortex?
ments and in the control of posture and muscle tone.
The exact central pathway followed by the impulses We discuss here only some possible functions.
mediating the long-latency stretch reflex has been much As mentioned, one likely task of the stretch reflex is
debated. Indirect data indicate that the reflex pathway to ensure that the length of a muscle is kept constant. In
may involve the motor cortex of the cerebral cortex many situations, this is of obvious importancefor
(therefore, the term long-loop stretch reflex is often example, in the upright position when some external
used). In support of a transcortical route are the obser- perturbation threatens the body balance. The sudden
vations that the reflex is weakened or abolished by displacement of the center of gravity forward stretches
the extensor muscles of the back and thus might elicit a When the opposing external force is suddenly reduced,
stretch reflex tending to resume the former position. It the opposite events take place. The speed of the flexion
is furthermore an obvious advantage that such a correc- movement of the thumb increases, and the firing fre-
tive contraction occurs as quickly as possible. Making quency of the spindle afferents decreases for a moment,
such an adjustment depend only on voluntary contrac- thus reducing the firing of the motoneurons and the
tion would lengthen the latency fourfold, with the force of contraction. The speed of movement is adjusted.
danger of the corrections occurring too late. Also while It is probable that the stretch reflex functions in this
walkingwhen external perturbations may disturb the manner especially during slow precision movements
programmed pattern of muscular activitystretch when we cannot accurately predict the external force at
reflexes may contribute to rapid adjustments. Nevertheless, all times. The sensitivity of the muscle spindles is kept
it is not clear to what extent stretch reflexes really at a high level, so that they may record even the slight-
participate in such adjustments. (See also Chapter 18, est perturbations and ensure that the activity of the
under More about Receptor Types and Their motoneurons is adjusted appropriately.
Contribution to Postural Control.)
Another situation in which stretch reflexes may be of
Cutaneous Receptors and the Precision Grip
importance is during slow, precise voluntary movements
when the external opposing forces change unpredictably. In some situations, stimulation of low-threshold skin
Again, the advantage would be that the adjustment of mechanoreceptors causes reflex muscular contraction.
muscle tension occurs much earlier than can be achieved For example, when (during a precision grip with the
by voluntary action alone. (See also Chapter 13, under fingers) the object slips, a reflex increase of the grip
Proprioceptors and Voluntary Movements.) force occurs. The latency from the start of the slip to
the muscular response is only 60 to 80 msecthat is,
too short to be mediated by a voluntary command.
Stretch Reexes May Correct for Change in External
Examination of patients with reduced cutaneous sensa-
Resistance during Precision Movements
tion but normal motor apparatus suggests that loss of
Studies of slow movements of the thumb by the British such rapid, reflex adjustment of the grip force is partly
neurologist David Marsden have shed light on the responsible for their difficulties with precision move-
contribution of stretch reflexes during precision movements (see Chapter 13, under Clinical Examples of
ments. The subject is asked to flex the thumb with a Loss of Somatosensory Information).
constant speed against an external opposing force of
constant magnitude. The EMG of the flexor pollicis
Central Modulation of Reexes
longus muscle is recorded continuously. The external
force is then changed suddenly at unpredictable times It should be clear from the preceding discussing that
during the movementeither increased or reduced. stretching of a muscle does not necessarily elicit a reflex
When the external force is increased, the movement is contraction. Many factors influence whether there will
immediately slowed down. Because of the ag coactiva- be a response, such as the velocity of stretching and
tion (see Chapter 13, under Muscle Spindles in Humans whether the muscle is active when being stretched.
and Coactivation), the frequency of signals from Further, the response depends heavily on whether a
the muscle spindle increases. The - coactivation reflex contraction is functionally appropriate. Such
ensures that, as the muscle shortens owing to the acti- gain modulation of the stretch reflex is mediated by
vation of the motoneurons, the spindle midportion is descending connections from higher levels of the CNS
stretched. This upholds the firing of muscle spindle (e.g., from the motor cortex). It appears to be exerted
afferents in spite of the shortening, which otherwise would mostly by a precise control of the excitability of specific
have led to reduced firing. To keep up with the steadily sets of spinal interneurons, which are intercalated
shortening muscle, the firing of the motoneurons must in particular reflex arcs. In addition, presynaptic inhibi-
also increase steadily. When the movement is suddenly tion may very selectively switch off the input
halted or slowed down, the firing frequency of the from specific sets of receptors. Thus, reflex arcs may be
motoneurons continues increasing, in anticipation of opened or closed in accordance with the need of
further shortening of the muscle. Thus, for a moment, the overall plan for movements (Fig. 21.15). Obviously,
the firing of the muscle spindle afferents increases more the motor programs in the cerebral cortex and the brain
than what is appropriate with regard to the actual stem specify not only the muscular activity but also the
length of the muscle. This increases the excitation of the gain of spinal reflex arcs at any moment.
motoneurons, and their firing increases, thus increas- Reflex modulation has been studied most during
ing the force of the muscle contraction. The result is locomotion in humans and is found in several muscle
that the increased external force is rapidly compensated groups. Thus, the strength of reflex contractions in
for, and the original speed of the movement is resumed. many leg muscles depends on whether the leg is in the
A Pyramidal tract: B
Commands from motor cortex
Sensory
+ information: joint
position (ankle)
+ +
+ Excitatory interneuron +

Inhibitory interneuron
+ + +
motoneuron +
STOP
STOP
Triceps surae
Tibialis
anterior
Plantar flexion Dorsal flexion
gure 21.15 Spinal interneurons and switching of signal pathways. B: The position in the ankle joint has changed, giving a different sen-
Synaptic couplings (highly schematic) may explain how the position sory input (from muscle spindles) than in A. The sensory signals
in the ankle joint can determine whether a central command facili- excite the interneurons that inhibit triceps motoneurons. Thus, the
tates a exion or an extension movement. A: The central command same command from the motor cortex as in A produces in B contrac-
produces contraction of ankle exors (triceps surae) because the sig- tion of the tibialis anterior muscle rather than the triceps. (Based on
nal pathway to the extensors is shut off by inhibitory interneurons. McCrea 1992.)
swing or in the stance phase. In the ankle flexors relaxed muscle; a more precise term is therefore resting
(m. triceps surae), for example, stretch reflexes are tone. In pathological conditions, the resting tone may be
weak or absent in the swing phase, whereas they are either increased or decreased. The term muscle tone is
brisk in the stance phase. This seems appropriate, ambiguous, however, as witnessed by its use by various
because in the stance phase the reflex contraction would authors. (Some authors have suggested that the term
strengthen the desired plantar flexion, whereas in the should be abandoned because its lack of precision.)
swing phase the appropriate movement is dorsal flex- Muscle tone is usually determined by palpation
ion of the foot to enable free swing of the leg. ( judging the consistency and stiffness of the tissue by
Arm muscles also show marked reflex modulation in pressing the muscle belly between the fingers) and by
persons catching a ball. In a certain phase of the move- stretching ( judging the resistance offered to passive
ment, even the reciprocal inhibition is absentthat is, a stretch). Some authors use the term only about the tone
stretch reflex can be elicited in a muscle without inhibi- as judged by stretching. Palpation and stretching do not
tion of its antagonists. This is functionally appropriate test identical properties of the muscle, however. For
when agonists and antagonists are required to co-contract example, after a stroke giving central pareses (as in cap-
to stabilize the joint. sular hemiplegia), the muscle tone is commonly reduced
In addition, the gain of the flexion reflex is under when judged by palpation (the consistency is reduced),
some degree of supraspinal control. This is evident whereas the resistance offered to passive stretching is
during walking, when a flexion reflex may cause a fall. increased (spasticity). Because examination of muscle
Thus, noxious stimulation of the sole of the foot elicits tone is important for the diagnosis of diseases that
a brisk flexion reflex if the leg is in the swing phase, affect the motor system, it is regrettable that we do not
whereas the response is weak or absent when the foot is have a clear understanding of the basis of normal
used for support. Interestingly, this kind of modulation muscle tone and of the mechanisms behind changes of
appears not to be present in four-legged animals, muscle tone in disease states.
presumably because their balance is less vulnerable to
changing the support of one leg only.
Muscle Tone Is an Expression of Tissue Stiffness
The confusion about the exact meaning of the term
MUSCLE TONE muscle tone stems partly from the fact that words
like firmness, tension, stiffness, and elasticity
The term muscle tone refers to the tension in muscles. are often used without definition. Different persons
Usually, it means the slight tension that can be felt in a may therefore use them with different meanings.
Unfortunately, this is often the case even when observa- muscle tone. So far, however, these factors are only
tions made by different examiners are compared. hypothetical.
Stiffness and tension can be defined in mathematical Nevertheless, many healthy persons are unable to relax
terms, however, and can also be objectively recorded their muscles completely, at least during an examination.
and measured. The definition of stiffness (K) is K = T/L; Thus, EMG would show a modest electric activity when
that is, K expresses how much the muscles are stretched the examiner handles the muscles. The contraction is
(L) by a certain increase in tension (T). The greater probably not of a reflex nature but is produced by volun-
the stiffness, the higher the tension necessary to stretch tary commands (i.e., by signals issued from the cerebral
the muscle. Note that this definition applies only to the cortex). Thus, in such persons there is usually muscle
component of muscle tension determined by passive activity also in muscles that are shortened passively as the
stretching and not to the consistency (firmness, elastic- examiner produces a joint movement (the person helps
ity) as judged by palpation. Consistency can hardly be the examiner).
measured objectively and depends on the subjective In conclusion, individual differences in resting muscle
assessment of the examiner. tone among healthy persons may in some cases be
caused by differences in the degree of relaxation. In
addition, there are most likely also individual differ-
What Determines Muscle Tone?
ences with regard to the passive viscoelastic properties
From everyday experience, we know that contraction of the muscles.
of a muscle (caused by actinmyosin interactions) is the
one factor that most markedly alters the muscle tone, as
Is Muscle Tone Due to Reex Contraction?
judged by both palpation and stretching. The purpose
of the contraction, of course, is to increase the tension It was formerly assumed that even relaxed muscle was
of the muscle. The tone felt in a fully relaxed muscle in a state of slight contractile activity, and that this
(showing no EMG activity), however, must depend on activity was maintained by a steady flow of signals from
passive properties of the muscle. Small contributions to the muscle spindles driving motoneuron firing. This
the tension of the muscle stem from the viscoelastic was based primarily on observations in animals with
properties of the muscle cells and the connective tissue transsection of the brain stem (decerebration), in which
of the muscle and its tendons. There is evidence that the activity of the motoneurons is enhanced. This
even among persons who are able to relax their muscles increases the signal traffic from the muscle spindles,
completely (as judged by EMG), the muscle tone (as and thereby the muscles are in a state of tonic contrac-
judged by palpation) may vary. What are the bases of tion. In accordance with these observations, muscle
such differences? The elastic properties of the muscle tone in normal human subjects was assumed to be
explain why, when the muscle is stretched passively maintained by the long-latency stretch reflex (tonic
beyond a certain length, the tension increases steeply stretch reflex). This view cannot be upheld in light of
(the slack is taken out of the elastic, as it were). This is more recent data, however. In the first place, several
experienced when a relaxed muscle becomes firmer on EMG studies show that in persons who are able to
palpation and offers increasing resistance to stretching relax properly, there is no electrical activity in their
toward extreme joint positions (therefore, such posi- muscles (and, therefore, no contractile activity). Further,
tions should be avoided when examining muscle tone). microneurographic studies have not confirmed that
Even in a relaxed muscle of medium length, however, there is signal traffic in the muscle spindle afferents that
properties of the muscle cells themselves can influence conduct from relaxed muscles in human subjects. In
the muscle stiffness. Elastic titin (connectin) molecules relaxed subjects, the resistance against even rapid pas-
of the cytoskeleton connect the Z discs with the myosin sive stretching of a muscle is very low (except when the
filaments. They extend from the Z disc to the middle of monosynaptic stretch reflex is elicited by a tendon tap).
the A band of the sarcomere and contribute to the resis- There is thus no evidence of a reflex tone in relaxed
tance to stretch offered by a relaxed muscle cell. The muscles.
titins exist in several varieties (isoforms). For example,
there are different isoforms in the soleus and the psoas
Muscle Cramps and Plateau Potentials
muscles, and the resting tone differs greatly in these
muscles (highest in the psoas). Further, even in relaxed Cramps are sudden, involuntary, and painful muscle
muscle a few crossbridges between actin and myosin contractions. The person notices that a part of the mus-
filaments can exist, judging from experiments with iso- cle becomes tight. Cramps may occur in healthy people
lated muscle cells. If the number of such crossbridges during sleep, in pregnancy, and after fatiguing muscu-
varies among muscles, it might contribute to differences lar exercise. Cramps may also occur in diseases such as
in resting tone. Further, differences in the amount and neuropathies, amyotrophic lateral sclerosis (ALS), and
composition of connective tissue and the extracellu- vascular diseases. Stretching the muscle is often the
lar fluid may contribute to individual differences in most efficient way to stop the contraction. It was shown
many years ago that the kinds of cramp mentioned here decision as to whether a muscle has abnormally low
are caused by high-frequency firing of a motoneurons tone is more difficult. As mentioned, a normal, fully
(other kinds of cramp may be caused by altered relaxed muscle will have a very low tension when tested
conditions in the muscle itself). An interesting possibil- by stretching. Some authors believe that when paretic
ity is that cramps arise because of the motoneurons or paralytic muscles feel softer and more flaccid than
ability to form plateau potentials, as characterized by a normal muscle, it is because of lack of voluntary con-
stable depolarized state (see also Chapter 22, under traction, which probably occurs to some extent during
Monoaminergic Pathways from the Brain Stem to the passive movements and palpation. Indeed, experiments
Spinal Cord, and Mechanism Responsible for the measuring the resistance to passive stretching of normal
Development of Spasticity). In this state, a brief excit- and alleged hypotonic muscles did not show consistent
atory input can trigger a train of action potential lasting differences. The experiments were performed by mea-
for many seconds or even minutes. Experimentally, a suring the falling time of the leg (passive flexion of the
brief train of signals in Ia fibers from the muscle spin- knee) in healthy persons with the ability to relax fully
dles can cause sustained motoneuron firing and cramps, (determined with EMG) and in patients with pareses of
possibly because of induction of plateau potentials, but the quadriceps muscle (clinically judged as hypotonic).
any excitatory input would presumably have the same On the other hand, the individual differences in falling
effect. The plateau potential can be terminated by a timethat is, muscle toneamong the normal subjects
brief hyperpolarizing synaptic input. Whether plateau were fairly large, presumably because of differences in
potentials occur in muscle cramps in humans is the passive viscoelastic properties. Nevertheless, with
unknown, but if they do, why they are induced at peripheral pareses, rapid changes of the passive viscoelas-
rest in some healthy persons needs nevertheless to be tic properties of the muscles may occur, which may help
explained. Conceivably, increased extracellular K+ due explain why the paretic muscles feel softer on palpation.
to intense motoneuronal firing during endurance After damage to peripheral motoneurons, the muscles
exercise may elicit plateau potentials. Another possibil- waste rapidly, reducing the muscle volume to sometimes
ity is that plateau potentials are triggered by altered only 20% to 30% of normal in about 3 months. The
inputs to motoneurons during muscular fatiguefor metabolism of muscle cells is obviously dramatically
example, by increased muscle spindle afferent activity altered by loss of contact between nerve and muscle.
and reduced presynaptic inhibition. That stretching and Abnormally increased muscle tone, hypertonia, would
sometimes massage terminate cramps might be due to imply that the muscles continuously have an increased
stimulation of afferent inputs that inhibit motoneurons tone, in spite of attempts to relax. As mentioned, many
(via interneurons). Ia afferents are unlikely to be acti- healthy persons are not able to relax completely, at least
vated in this situation, as they respond poorly to slow not in an examination situation, and the border between
stretching of the muscle. Electrical stimulation of the normal and pathologically increased muscle tone may not
tendon inhibits experimentally evoked muscle cramp, be easy to draw. Fairly characteristic disturbances of mus-
suggesting that stretching of the cramped muscle works cle tone do occur in certain diseases of the CNS, however.
by activation of 1b afferents from the tendon organ.
So-called writers cramp is a task-specific focal dysto-
Spasticity and Rigidity
nia of the hand. The cramp usually occurs when trying
to do a task that requires fine-motor movements. In this The term spasticity is used in clinical neurology of a
case, it is believed that basal-ganglia dysfunction lies condition in which there is increased resistance against
behind the abnormal motoneuronal firing. rapid stretching of muscles. By palpation, the muscles
may feel normal or hypotonic, and there may not be
increased resistance against slow, passive movements.
Changes of Muscle Tone in Disease
Spasticity occurs after damage to the descending motor
Pathologically changed muscle tone is called hypotonia pathways from the cerebral cortex to the motoneurons
when it is lower than normal and hypertonia when and is probably due primarily to changed spinal-in-
higher than normal. Of course, to recognize abnormal terneuron excitability. The increased resistance to rapid
muscle tone one must first be able to decide what is stretch is most likely caused by abnormally brisk mono-
normal, but from the preceding discussion, it should be synaptic stretch reflexes, whereas the long-latency stretch
clear that normal muscle tone is not a precise, well- reflexes are weaker than normal.
defined concept. The decision as to whether a muscle Rigidity is the term used to characterize the increased
has a normal tone is based largely on the subjective muscle tone occurring in Parkinsons disease (Chapter 23).
judgment of the examiner. This judgment, of course, Even with very slow, passive movements, an increased,
depends on experience. Whereas hypertonia may be cogwheel-like resistance is felt by the examiner. This
identified with reasonable certainty and even measured may be caused by increased long-latency stretch reflexes
in semiquantitative terms by stretching the muscles, the that are elicited by abnormally slow movements.
Also with rigidity and spasticity, there is evidence of Pyramidal tract
Lesion causing
changed passive viscoelastic properties (in addition to central paresis
the changed stretch reflexes). Thus, in patients with
Muscle spindle
moderately severe Parkinsons disease, increased resis-
tance to slow elbow extension was found, even though
there was no EMG activity of the biceps muscle (which
was being stretched). In some spastic patients, increased
resistance even to slow stretching of relaxed leg muscles
was present, but only when the spasticity had lasted for
more than a year. Thus, it seems as though an altered
pattern of signals from the motoneuronslike those
occurring in diseases with rigidity or spasticitymay
change the passive, viscoelastic properties of the muscles.
INJURY OF PERIPHERAL MOTOR NEURONS motoneuron

Lesion causing
AND REGENERATION peripheral paresis
When all motoneurons (or their axons) supplying a mus-

cle are destroyed, the muscle cannot be made to contract: gure 21.16 Peripheral and central pareses. Lesions of the motoneu-
it is paralyzed. Both voluntary and reflex movements are rons produce peripheral pareses, characterized by loss of both volun-
tary and reex contractions. Central paresescharacterized by loss
abolished. If not all of the motoneurons (or their axons) of voluntary movements but retained reex contractionsensue when
supplying a muscle are destroyed (Fig. 21.16), the mus- descending corticospinal pathways are interrupted.
cle can still contract, although with less speed and force
than normal. This is called a partial paralysis, or pare-
sis. Typically, the paretic muscle feels soft and flaccid, its ventral root (e.g., the C5 root as in Fig. 21.2) produces
and there is a marked reduction in the muscle mass. only a paresis, not a complete paralysis of a muscle.
This is called muscle atrophy or wasting and is more Alternatively, several muscles become paretic because
marked with more complete destruction of the motoneu- each segment contains motoneurons supplying several
rons. The muscle cells that no longer receive signals muscles, but if the peripheral nerve (e.g., the thoracicus
from the motoneurons become thinner and eventually longus nerve in Fig. 21.2) supplying a muscle (the serra-
disappear if no reinnervation takes place (see later). tus anterior) is severed, the muscle becomes paralytic.
Peripheral and Central Pareses Peripheral Axons Can Regenerate

The muscle weakness caused by the loss of the When a peripheral nerve is injured so that the axons are
motoneurons or their axons (lower motor neurons) is interrupted, the distal parts of the axons degenerate
called a peripheral paralysis (paresis), to distinguish it and are gradually removed (by macrophages). The cell
from a central paralysis caused by interruption of the bodies (of the motoneurons and the spinal ganglion
central motor pathways (the upper motor neurons). cells) show retrograde changes and, even though some
Central pareses are discussed in Chapter 22. Suffice it of the cells die, many survive. The proximal parts of the
here to mention that in central pareses the spinal reflex axons of the surviving neurons start to grow (in con-
arcs are intact (Fig. 21.16). Characteristic of peripheral trast to what happens in the CNS; see Chapter 11,
paresesapart from the weakened or abolished volun- under Can We Help Restitution?). When possible,
tary contractionsis that the muscles are flaccid, reflex the growing axons follow the canals in the nerve left by
movements are weakened or abolished, and muscle the degenerated axons. The Schwann cells do not die
wasting progresses rapidly and becomes marked. and form a lining of the canals for the growing axons.
In cases of peripheral pareses, the distribution of The axons grow 1 to 2 mm per day, although the
affected muscles may tell us where the disease process is growth gets slower the farther peripherally the axon
located. For example, the distribution will differ, grows.
depending on whether the lesion is located in the spinal
cord, in the plexuses formed by the spinal nerves, or in Factors that Inuence Regeneration
the peripheral nerves more peripherally (Fig. 21.2). As a
rule, one muscle is supplied with motor fibers from two The outcome of this regeneration of the axons depends
or more spinal segments, as discussed above (Fig. 21.3). on several factors, among them the conditions at the
Therefore, damage restricted to one spinal segment or site of injury and the age of the person. If the continuity
of the nerve is not lostas when the nerve is crushed or control of the muscle may become less precise than
damaged by compressionthe growing axons have a before the injury. Animal experiments suggest that the
fair chance of finding the right track and reaching the remaining motor units may increase their size four to
target they innervated formerly. If the nerve is com- six times.
pletely severed (e.g., by tearing or a cut), many axons After suturing a cut muscle nerve, reflex contractions
will follow a wrong path even though the cut ends are often show less recovery than voluntary contractions.
meticulously stitched together. Thus, motor axons may This is probably because the sensory fibers (innervating
innervate different muscles than previously, and, like- muscle spindles and tendon organs) have greater diffi-
wise, sensory axons may innervate different regions of culties in reaching their correct target than the motor
the skin than before the injury. For example, motoneu- axons. Thus, after crushing a nervewhen the regener-
rons formerly supplying an extensor muscle may after ating axons more easily find the right paththe reflex
the regeneration supply a flexor; sensory nerve fibers contractions show better recovery.
formerly supplying the thumb may innervate the index
finger; and so forth. The longer the distance an axon
Regeneration of Motor Axons after Avulsion
has to grow after the damage, the poorer the chances
of Spinal Roots
that it will reach its target. Thus, one cannot expect full
functional recovery after suture of a cut peripheral Severed axons of motoneurons can, in fact, grow for
nerve. The results are better in children than in adults, short distances in the spinal cord. This has been shown
however. This may be because children have a greater in animal experiments after avulsion of the nerve roots
regenerative capacity, but presumably also because of the brachial plexus (Fig. 21.1). In this kind of lesion
their brains adapt more easily to a novel pattern of occurring in humans exposed to forceful traction and
innervation in the periphery. depression of the shoulder and armthe roots are liter-
In cases of incomplete severance of a nerve, the ally torn loose from the cord. If the roots are surgically
remaining motor axons usually send out new branches attached to their former sites of attachment, the motor
within the muscle (collateral sprouting). The sprouts axons first grow through the ventral hornthat is, the
grow into and make synaptic contacts at the empty central nervous territory devoid of Schwann cellsand
motor end plates left by the degenerated axons. In this then into the roots and, finally, the muscles. In animals
case, many of the muscle cells, which shortly after the and in humans muscle function has been regained after
injury were paralyzed, become reinnervated and some root avulsions by this technique, even though the inner-
of the muscle power is regained. The remaining motor vation is less precise than before. The reason for this
units of the muscle become larger, and therefore the unusual central regeneration is so far unknown.
22 The Motor Cortical Areas and
Descending Pathways
OVERVIEW We also discuss motor cortical areasthat is, areas

that participate in planning and organizing movements.
This chapter deals with the control of complex, pur- Many parts of the cortex are motor in this respect, but
poseful movementsfrom such that are largely auto- we usually restrict the term to the primary motor area
matic to those that require our full attention. The most (MI) in the precentral gyrus, the premotor area (PMA)
direct control is exerted by upper motor neurons in the just in front of MI, and the supplementary motor area
cerebral cortex and the brain stem that send fibers to (SMA) on the medial aspect of the hemisphere. The MI
end in direct synaptic contact with the lower motor gives origin to a large part of the pyramidal tract fibers,
neurons (motoneurons) or with interneurons that, in and has monosynaptic connections with the motoneu-
turn, contact the motoneurons. (The basal ganglia and rons in the brain stem and spinal cord. PMA and SMA
the cerebellumboth necessary for proper motor act largely by instructing the MI what to do. Whereas
control without being responsible for movement initia- lesions of MI produce pareses, lesions of PMA and
tionwill be treated in the next two chapters.) The SMA give difficulties with initiation of movements and
pyramidal tract is the only direct pathway from the with purposeful movements that require coordinated
cerebral cortex to lower motor neurons in the brain sequences of muscle contractions. Posterior parietal
stem and the spinal cord. The pyramidal tract is indis- areas and regions in the prefrontal cortex are necessary
pensable for the ability to perform precise, voluntary for transforming sensory information into action, and for
movements of the hands (requiring fractionate finger selection of actions that are behaviorally appropriate.
movements), whereas more proximal movements can The final part of the chapter deals with symptoms
be performed although with less speed and precision in resulting from damage to the central motor pathways.
the absence of the pyramidal tract. For the latter kind The main characteristics of central paresessuch as
of movement, several indirect pathwayssynaptically hyperreflexia (spasticity) and loss of dexterityare
interrupted in the brain stemare especially important. described and some tentative explanations are offered.
The corticoreticulospinal pathways are important for Customarily, a division has been made between the
maintaining the upright position (posture), for orient- pyramidal (corticospinal) tract and other nuclei and
ing movements of the body toward external events, and tracts involved in motor control. The latter have often
for fairly crude, stereotyped voluntary movements of been collectively called the extrapyramidal system.
the extremities. Nevertheless, both the direct and the So many parts of the brain contribute in different ways
indirect pathways participate, to a varying degree, in to motor control, however, that lumping them together
virtually all voluntary movements. The sharing of tasks in a system confuses more than it clarifies. Therefore,
among them is such that cell groups in the brain stem we will not use the term extrapyramidal here but
can largely on their own control many automatic move- rather describe what we regard as the most important
ments, whereas the participation of the cortex increases components in control of voluntary movements.
with increasing degree of voluntary control.
Reticulospinal and vestibulospinal pathways are of
special importance for the more automatic movements, THE PYRAMIDAL TRACT (THE CORTICOSPINAL TRACT)
such as postural adjustments and locomotion. Rhythmic
movements, such as locomotion and respiration, depend The pyramidal tract is of crucial importance for our
on the activity of rhythm generators in the spinal cord ability to perform precise, voluntary movements. The
and the brain stem. With regard to locomotion, there is tract consists of axons of neurons with their cell bodies
most likely one spinal rhythm generator for each in the cerebral cortex, as indicated by its other name,
extremity. Supraspinal control of locomotion depends the corticospinal tract. The axons descend through the
on a mesencephalic locomotor region (MLR). A contri- internal capsule, the crus cerebri (cerebral peduncle), the
bution from the motor cortex is necessary if the ground pons, and the medulla (Figs. 22.2, 22.3, and 22.7). Most
is uneven and unpredictable. of the fibers cross to the other side in the lowermost part
301
Motor cortex Somatosensory

cortex
A B
Red nucleus
Pyramidal tract
act
Cranial nerve
nucleus
Corticobulbar Pontine
fibers reticular formation
Motor cranial
nerves
Medullary reticular
formation
Reticulospinal
Corticospinal fibers fibers
(pyramidal tract)
gure 22.1 Direct and indirect motor pathways to the spinal cord. cord (corticospinal bers). B: Nuclei in the brain stem with efferent
A: The pyramidal tract passes directly from the cerebral cortex to the connections acting on motoneurons. Indirect corticospinal pathways
motoneurons in the brain stem (corticobulbar bers) and in the spinal are established by corticofugal connections to the brain stem nuclei.
of the medulla and continue downward in the lateral formation, the colliculi, the dorsal column nuclei, and
funicle of the cord, to finally establish synaptic contacts other nuclei).
in the spinal gray matter. The pyramidal tract derives its name from the pyra-
Fibers also leave the pyramidal tract on their way mid of the medulla, which is formed by the fibers of the
through the brain stem, to reach cranial nerve motor corticospinal tract (see Figs. 6.15 and 6.16). Strictly
nuclei (Figs. 22.1 and 22.3). Such fibers form part speaking, therefore, the term pyramidal tract encom-
of the corticobulbar tract (other corticobulbar fibers passes only the fibers destined for the spinal cord and
reach the red nucleus, the pontine nuclei, the reticular not those destined for the cranial nerve motor nuclei.
Corpus callosum
Caudate nucleus
Thalamus
Internal capsule
Putamen
Red nucleus
Lateral geniculate body
Substantia nigra
Hippocampus
Crus cerebri
Pons
Medulla oblongata gure 22.2 Course of the pyramidal

tract through the internal capsule and
Pyramid
the brain stem. Longitudinal bundles
Pyramidal decussation of myelinated bers are evident in the
crus, the pons, and the medullary pyra-
mid. Compare with Fig. 22.13.
22: THE MOTOR CORTICAL AREAS AND DESCENDING PATHWAYS 303
Motor area
Precentral gyrus Postcentral sulcus
Central sulcus
Thalamus
Internal
capsule 3b
4
Cranial nerve
motor nuclei
3a
Medullary
pyramid
Pyramidal gure 22.4 The central region with MI (primary motor area) and SI
decussation (somatosensory area). Photomicrograph of a section perpendicular to
Lateral corticospinal the central sulcus (monkey). There is a notable difference in thickness
tract between the MI and the SI. The dark dots in the deep parts of the
cortex (in layer 5) are the cell bodies of pyramidal tract cells that have
Motoneurons been retrogradely labeled by an injection of a tracer substance (horse-
radish peroxidase) in the spinal cord. There are more labeled cells in
the MI than in the SI.
gure 22.3 Direct corticobulbar and corticospinal pathways (the
pyramidal tract). The corticospinal tract is mainly crossed, whereas
many of the cranial nerve nuclei receive crossed and uncrossed corti- It was originally thought that all fibers of the pyrami-
cobulbar bers. Note the crossing of the corticospinal tract in the dal tract came from area 4 and, furthermore, only from
lower medulla. the cells with the largest cell bodies, the giant cells of
Betz. The number of Betz cells, however, is much too
Nevertheless, for practical reasons both groups are low to account for the number of axons in the pyramidal
usually included in the term. tract (about 1 million in humans). More recent studies
with retrograde transport of tracer substances (Fig. 22.4)
have largely clarified the origin of the pyramidal tract
Origin of the Pyramidal Tract
in various animals. In the monkey, numerous cells in
A large proportion of the fibers of the pyramidal tract area 4, in addition to the Betz cells, contribute to the
comes from neurons with their cell bodies in the pre- pyramidal tract, as do also many cells in areas outside
central gyrusthat is, area 4 of Brodmann (Figs. 22.4, area 4. Although the relative contribution from various
and 22.5; see also Fig. 33.3). This region was called the areas differ among authors, it seems that about two-
primary motor area (MI), because muscle contractions thirds of all fibers arise in front of the central sulcus
could most easily (with the weakest current) be elicited that is, in area 4 and area 6 (PMA and SMA in Fig. 22.6),
from this part of the cerebral cortex. The somatotopical whereas the rest comes from SI (areas 3, 1, 2), SII, and
organization of MI (Fig. 22.5) has been verified in parts of the posterior parietal cortex (area 5). A consid-
humans with various kinds of stimulation and imaging erable fraction of the fibers from SI arise in area
techniques (electric and magnetic stimulation, positron 3athat is, the part of SI adjacent to area 4 (Fig. 22.4)
emission tomography [PET], functional magnetic reso- that receives an input from muscle spindles. Muscle
nance imaging [fMRI]). It corresponds roughly to the contractions can also be elicited from the areas outside
somatotopical pattern in SI (see Fig. 14.8). We return to MI, like SI, by electrical stimulation, but the stimula-
MI later in this chapter. tion has to be more intense than in area MI. This reflects
Hand Forearm The cell bodies of all neurons of the pyramidal tract lie
Arm
5. -2. finger
Thumb
Thorax in the cortical fifth layer (lamina V; compare Figs. 22.4
Abdomen
Neck Thigh and 33.2) and are called pyramidal cells. The name
Face Leg
Tongue refers to the shape of the cell body (see Figs. 1.1, 33.1,
Jaw
Pharynx and 33.5).
Larynx
Course and Crossing of the Pyramidal Tract

As mentioned, the pyramidal tract passes downward
through the internal capsule. It occupies a posterior
position (Fig. 22.7A), as judged from observations after
small lesions (see Fig. 22.13) and stimulation during
brain surgery of the internal capsule in humans. (It was
formerly assumed that the pyramidal tract fibers were
spread over a large part of the posterior leg of the
internal capsule.) Fibers governing the muscles of the
face are believed to lie most anteriorly, the leg most
Foot
Toes posteriorly. Experimental studies in monkeys indicate
Rectum that descending fibers from the PMA and SMA lie in
Bladder
the knee region (genu) and the anterior leg of the
internal capsule, respectively. The internal capsule con-
tains many other fibers than those of the pyramidal
tract; the latter constitute only a minority. For example,
sensory fibers ascend from the thalamus to the cortex,
gure 22.5 Somatotopic organization of the motor cortex. The
points indicate the sites from which muscle contraction in a particular and descending fibers from the cortex reach the thala-
body part was produced by weak electrical stimulation. (Based on mus, the reticular formation, and other cell groups of
Foerster 1936). the brain stem. Further, in the anterior part of the inter-
nal capsule lie the pallidothalamic fibers (related to
motor functions of the basal ganglia), and posteriorly
that the pyramidal tract fibers from SI and the other (in the lower part) the optic radiation passes through
regions outside area 4 have less direct access to the on its way to the occipital lobe. Therefore, damage of
motoneurons than the neurons in area 4. The pyrami- the internal capsulesuch as an infarction caused by
dal tract fibers coming from SI and area 5 are probably occlusion of an arterymay produce sensory and other
more concerned with the control of sensory signal deficits in addition to pareses of the muscles of the
transmission than with the initiation of movements. opposite body half (capsular hemiplegia).
In the mesencephalon, the pyramidal tract fibers
Primary motor
Somatosensory area (SI) distribute over the middle two-thirds of the crus and
area (MI)
Supplementary
mix with other descending fibers (Fig. 22.7B). As men-
Posterior parietal tioned, all of the corticospinal fibers are collected within
motor area Leg cortex (area 5)
the medullary pyramid (Fig. 22.6D; see Fig. 6.17). At
Arm the caudalmost level of the medulla, most of the corti-
cospinal fibers cross the midline and continue in the
lateral funicle of the cord as the lateral corticospinal
Face tract (Figs. 22.7E and 22.8). A small contingent contin-
ues, without crossing, downward in the ventral funicle
as the ventral corticospinal tract. Some uncrossed fibers
may also pass in the lateral funicle (Fig. 22.8).
Premotor
area Pyramidal-tract actions on the muscles of the distal
extremities are mediated almost exclusively by fibers
that cross in the lower medulla. This is supported by
studies in humans with transcranial magnetic stimula-
tion (TMS) of the motor cortex. The small contingent
gure 22.6 Cortical regions giving origin to the pyramidal tract. of uncrossed (and doubly crossed) fibers mentioned
Based on experimental studies in monkeys with retrograde transport above can influence mainly axial musclesthat is, mus-
of tracer substances (cf. Fig. 22.4). The primary motor cortex (MI) has
the highest density of pyramidal tract neurons; that is, neurons that are
cles of the back, the thorax, and the abdomen. This is
retrogradely labeled from the spinal cord. Lower densities of labeled in accordance with their termination medially in the
neurons occur in SI, SMA, PMA, and the posterior parietal cortex. ventral horn (Fig. 22.8; see Fig. 21.3).
A B
LEFT
MESENCEPHALON
Frontal Crus cerebri
Caudate Leg
nucleus Face Arm
C
Internal
capsule
PONS
LEFT
Face A
Arm
Leg
B
D
Thalamus MEDULLA
C
D
E
Occipital E Medullary
pyramid
SPINAL
CORD
Lateral Ventral
corticospinal corticospinal
tract tract
gure 22.7 Position and somatotopic pattern of the pyramidal tract sections. Compare with Figs. 14.2, 14.3, and 14.4 showing the posi-
at various levels. A: Horizontal section (cf. Fig. 6.30). BE: Transverse tions of the somatosensory tracts at the same levels.
The pyramidal tract fibers that control the muscles the central canal (Fig. 22.7E is probably reasonably
of the head (the face, tongue, pharynx, and larynx) accurate in this respect). Equally important for the
leave the corticospinal fibers in the brain stem to end in interpretation of symptoms in patients with spinal cord
or close to the motor and sensory cranial nerve nuclei injuries is that the anteroposterior location of the lat-
(Fig. 22.3). Apart from most of the facial muscles, other eral tract shows considerable individual variations.
muscles of the head generally receive both crossed and The majority of the corticospinal fibers cross in most
uncrossed pyramidal tract fibers. Thus, when the pyra- individuals, and it is customary to say that there are
midal tract fibers are interrupted in the internal capsule, about 15% uncrossed fibers. The great individual vari-
there are seldom clear-cut pareses of the muscles of the ations emphasize that this is only an average number,
tongue, the pharynx, and the larynx, whereas the corner however. Indeed, in a few individuals the pyramidal
of the mouth hangs down on the opposite side of the tract is completely crossed with all fibers located dor-
lesion. sally in the lateral funicle, or it is completely uncrossed
with all fibers in the ventral funicle. As a rule, most of
the uncrossed fibers continue in the ventral funicle as
Individual Variations in the Position and Crossing of
the ventral corticospinal tract (Fig. 22.5), whereas some
the Pyramidal Tract
join the crossed fibers from the other side in the lateral
There are considerable individual variations in both the funicle (Fig. 22.8). Some fibers cross twice, and many
distribution of the pyramidal tract fibers in the spinal individuals have a small crossed, ventral component.
white matter and the percentage of uncrossed fibers. The division of uncrossed fibers between the lateral and
Nathan and coworkers (1990) reexamined these clini- the ventral funicles varies among individuals.
cally important matters and found, for example, that Finally, although usually not acknowledged, in about
the corticospinal fibers are more widely distributed in 75% of the population the pyramidal tract is asymmetric:
the lateral funicle than is depicted in textbooks. Thus, the lateral and the ventral components are both larger on
such fibers are usually found also ventral to the level of one side than on the other (most often on the right side).
Motor Somatosensory between 5 and 30 m/sec. Corticospinal neurons are

area(MI) area (SI) glutamatergic, exerting excitatory effects. In general,
the thickest (and thus fastest conducting) fibers come
from MI.
In accordance with the somatotopic pattern within
MI (Fig. 22.5), fibers from the medial parts of the pre-
central gyrus (leg representation) end in the lumbosacral
part of the cord, whereas fibers from more lateral parts
(arm representation) end in the cervical and upper tho-
racic cord. Fibers from MI and SI also terminate differ-
ently in the cord (Fig. 22.8). Thus, fibers from SI end
predominantly in the dorsal horn, whereas fibers from
MI end in the intermediate zone and the ventral horn
(laminae VIIIX).
Pyramidal tract
Monosynaptic Cortico-Motoneuronal Connections

II Anatomic and physiologic data show that some of the
pyramidal tract fibers coming from MI end monosyn-
V aptically on the motoneurons. This concerns primarily
VII motoneuron groups that control the distal muscles of
the extremitiesin particular, the intrinsic muscles of
IX the hand. During evolution, the pyramidal tract has
increased in size and with regard to monosynaptic con-
nections with the motoneurons. This change has taken
place in parallel with increased versatility and precision
of the movements of the hand (which, in turn, depend
gure 22.8 Terminal regions of the pyramidal tract. Based on exper- on increased brain volume). In the rat and the rabbit,
iments in monkeys with anterograde transport of radioactively
labeled amino acids after injections in various parts of the motor cor-
for example, the pyramidal tract is only slightly devel-
tex (MI) and the somatosensory cortex (SI). Corticospinal bers from oped. It is more prominent in the cat, but there are no
the MI end more anteriorly in the gray matter of the cord than those monosynaptic connections between pyramidal tract
from the SI. The uncrossed bers end predominantly medially in the neurons in the motor cortex and motoneurons in the
ventral hornthat is, in contact with the motoneurons that supply cordall connections are with spinal interneurons. In
axial and proximal muscles. (Based on Ralston and Ralston 1985.)
monkeys, there is a modest proportion of monosynaptic
connections, but the proportion is larger in the anthro-
This asymmetry presumably arises because a larger poid apes (e.g., the chimpanzee) and still larger in
proportion of the fibers from (usually) the left hemi- humans. Even some shoulder muscles, like the deltoid,
sphere cross than from the right hemisphere. Thus, the receive some monosynaptic connections in humans.
lateral (crossed) tract becomes larger on the right side The monosynaptic connections are of particular impor-
than on the left, whereas the ventral (uncrossed) tract tance for the movements that require the highest degree
becomes smaller on the left side. of voluntary controlthe least automatic movements
Such individual variations would influence the sever- such as independent or fractionated finger movements.
ity of motor symptoms after damage to the brain or This relationship is witnessed by the fact that in certain
spinal cord and may help explain why symptoms vary subprimate mammals with an exceptional manual dex-
so much among patients with very similar lesions. Thus, terity (and the ability to use the fingers individually), some
occasionally an infarct of the internal capsule produces monosynaptic motoneuronal connections are present.
most severe ipsilateral pareses (on the same side), and
lesions of the cord may give motor symptoms that are
Distribution and Actions of Single Corticospinal Fibers
unexpected from their location.
A corticospinal neuron in MI usually has strong excit-
atory actions on some motoneurons and weaker excit-
Conduction Velocity and Termination of the
atory actions or inhibitory actions (via interneurons) on
Pyramidal Tract
many others. Accordingly, anatomic data from tracing
The pyramidal tract fibers vary considerably in thick- of single fibers show widespread ramifications of a sin-
ness, from the thickest myelinated kind to unmyelinated gle pyramidal tract axon, enabling it to contact numer-
ones. Most are rather thin; with conduction velocities ous motoneurons in different segments of the cord that
supply several muscles. This may appear surprising in cutaneous low-threshold mechanoreceptorssends
light of the very discrete and precise movements the fibers primarily to laminae III and IV, which receive the
pyramidal tract is capable of producing. However, as a same kind of sensory input (through the dorsal roots).
rule, the various muscles contacted from one corticospi- Fibers from area 3a end deeper in the dorsal horn, where
nal neuron have similar actionsthat is, they are syner- primary afferents from proprioceptors end. Physiological
gists. Further, the strength of the influence of one experiments confirm that SI influences sensory cells in
pyramidal tract cell probably varies greatly among the the dorsal horn. Most often, SI inhibits neurons that are
motoneurons it contacts, depending on the number and excited from low-threshold mechanoreceptors. As dis-
location of synaptic contacts. For example, corticospi- cussed in Chapter 14 (under The Transmission of
nal fibers terminate on both proximal and distal parts Sensory Signals Can Be Controlled from the Brain),
of the dendrites. Contacts with inhibitory interneurons suppression of certain kinds of sensory information may
further increase the specificity of actions. In many vol- be important, for example, during movements.
untary movements, commands from the motor cortex
elicit reciprocal inhibition in the cord. Such varied effects
The Pyramidal Tract Fibers Open and Close Spinal
of the pyramidal tract fibers fit with the motor cortex
Reex Arcs
being organized to initiate purposeful movements, requir-
ing coordinated activity of multiple muscles around Even in humans, a large proportion of the pyramidal
several joints (rather than the contraction of muscles tract fibers end in synaptic contact with interneurons in
in isolation). This topic is discussed further under laminae VII and VIII (Fig. 22.8; see also Fig. 6.12).
Functional Organization of the Primary Motor Area. Manyperhaps mostof these interneurons make
synaptic contacts either on motoneurons or on other
interneurons, which, in turn, contact motoneurons. In
The Pyramidal Tract Controls Flexors More
this manner, the pyramidal tract may mediate varied
than Extensors
effects on the motoneurons. This is true of both the
Experiments with transcranial magnetic stimulation motoneurons and the motoneurons, so that the
(TMS) of the motor cortex show that flexors of the pyramidal tract can control the sensitivity of the muscle
thumb have a lower threshold for activation than the spindle. Because many of the interneurons contacted by
extensors. Corresponding findings pertain to the biceps pyramidal tract fibers are intercalated in reflex arcs, the
muscle (flexor) and the triceps muscle (extensor) of the motor cortex can ensure that the various spinal reflexes
upper arm. At least concerning finger movements, it are adapted to the overall aim of the movements. For
seems reasonable that the flexors require somewhat example (as described in Chapter 21), the strength of
more precise control than the extensors, although both the long-latency stretch reflex can be increased or
certainly are necessary for manual dexterity (e.g., hold- decreased, depending on what is appropriate during
ing and manipulating small objects). Interestingly, fMRI motor learning. The interneurons mediating reciprocal
studies indicate that a smaller part of MI is activated inhibition during stretch reflexes (see Fig. 21.13) are
during simple finger flexions than during finger exten- also controlled by the pyramidal tract. Likewise, the
sions. Presumably, this may be due to more monosynaptic Renshaw cells (see Fig. 21.14) are subject to supraspi-
connections to the flexor motoneurons. nal control, so that the strength of the recurrent inhibi-
The functional flexors of the ankle joint (the tibialis tion can be increased or decreased selectively in various
anterior muscle and others that dorsiflex the ankle) are motoneuronal groups. A final example is the interneu-
more influenced by the pyramidal tract than are the rons that mediate inhibition of motoneurons evoked by
plantar flexors (the triceps surae and others). This stimulation of tendon organs (in the same muscle as
would seem to fit with clinical observations in patients supplied by the motoneurons). This reflex arc can also be
with hemiplegia: ankle dorsiflexion is more reduced in opened or closed by the pyramidal tract. Thus, the
power than plantar flexion (the foot droops). However, autogenic inhibition elicited by stimulation of tendon
the typical posture of the hemiplegic arm (Fig. 22.11) organs can be reversed to excitation during voluntary
with tonic flexion at the elbowcan obviously not be contraction of the muscle (whereas at the same time the
explained in this way. inhibition of other muscles may be enhanced).
The Pyramidal Tract Controls Sensory Neurons in the Function of the Pyramidal Tract as Judged from
Spinal Cord Functional Decits after Lesions
The effects of SI (via fibers traveling in the pyramidal To clarify the function of a tract, two approaches have
tract) on neurons in the dorsal horn are quite specific. mainly been used: studying (1) the properties of single
Thus, projections differ from individual cytoarchitectonic neurons and (2) the deficits that ensue when the entire
subdivisions within SI: area 3breceiving input from tract is eliminated. We discussed in the preceding text
some properties of single pyramidal tract neurons. system to the motoneurons in the cranial nerve nuclei
Their strong (partly monosynaptic) connections with and the spinal cord. The nuclei giving origin to these
distal muscles suggest that the pyramidal tract is par- other tracts (often included in the extrapyramidal sys-
ticularly important for delicate movementsfor exam- tem) are located in the brain stem, but several of them
ple, of the fingers. We discuss further the properties of receive afferents from the cerebral cortexin particu-
pyramidal tract neurons under Functional Organization lar, from the motor cortex (Fig. 22.1). Thus, several
of the Primary Motor Area. Here we restrict ourselves indirect pathwayssynaptically interrupted in the
to what we have learned from lesion experiments in brain stemtransmit signals from the cortex to the
animals and from humans with diseases that affect the motoneurons. In addition, some other brain stem nuclei
pyramidal tract. with descending connections to motoneurons do not
Shortly after unilateral transection of the pyramid, receive fibers from the motor cortex. The latter nuclei
1
a monkey can move around apparently normally. are primarily involved in control of highly automatic
Nevertheless, to use the hand to pick up a morsel of food, muscle contractions, such as those aiming at maintain-
for example, is almost impossible for some time, even ing body balance and the movements of respiration.
though the hand can be used effectively for climbing. Broadly speaking, the pyramidal tract is important
Initially, the monkey is unable to move the hand indepen- primarily for the least automatic movementsthat is,
dently of the arm. Gradually, over some weeks, the those requiring a high degree of conscious, voluntary
monkey regains the ability to use the hand for grasping attention. The other pathways are important for move-
objects, but the movements are clumsy and consist only ments that are more automatic. This dichotomy agrees
of simultaneous flexion of all fingers (a sort of scraping with the fact that the pyramidal tract is primarily
movement). However, the ability to move the fingers important for the movements of the distal parts of the
independently of each otherfractionated movements extremities, whereas the other pathways are more con-
does not return (even after 5 years). The precision grip, in cerned with movements of the proximal parts of the
which the thumb opposes the index finger, is permanently extremities and of the trunk. Such a task division does
lost. Monkeys in which the pyramid is cut shortly after not imply, however, that these two systemsthe
birth never develop the precision grip. Thus, no other direct and the indirect corticospinal pathwaysoperate
tracts can take over this task from the pyramidal tract. independently. Most movements, even delicate finger
In humans (as in monkeys) with damage of the motor movements, require that the hand is moved to the right
cortex or the pyramidal tract (often in the internal cap- position and is kept in a specific posture. Further, even
sule), the most enduring symptom is difficulty with small movements of the arm displace the center of gravity,
tasks that require precise, fractionated finger move- requiring postural adjustments by many other muscles.
ments, such as writing, tying shoelaces, buttoning a Figure 22.9 shows the main brain stem nuclei send-
3
shirt, and picking up small objects (like a needle). Less ing fibers to the spinal cord, while Fig. 22.1B shows
precise movements involving larger muscle groups are connections from the motor and somatosensory areas
usually less severely affected. In addition, lesions of the to the reticular formation and some other nuclei. In
upper motor neurons in humans produce characteristic addition, monoaminergic spinal pathways from the
changes of muscle tone and reflexes (spasticity), which locus coeruleus and the raphe nuclei are included in
do not occur in monkeys with lesions restricted to the Fig. 22.9. The latter pathways do not participate in
pyramidal tract.2 We return to the symptoms produced control of specific movements but modulate the excit-
by lesions of the descending motor pathways in humans ability in spinal neuronal networks.
at the end of this chapter.
Corticoreticulospinal Pathways
INDIRECT CORTICOSPINAL PATHWAYS The reticular formation is an important source of
descending fibers that can influence the motoneurons.
In addition to the pyramidal tract, several pathways The reticular formation is discussed more completely in
mediate signals from higher levels of the central nervous Chapter 26 (its functions are not restricted to motor con-
trol). Reticulospinal fibers arise primarily from the retic-
1 Certainly, the pyramidal tract is more developed in humans than in monkeys. ular formation of the pons and the medulla (Fig. 22.9;
Thus, the possibility cannot be excluded that symptoms would be somewhat see also Figs. 26.1 and 26.8). These regions receive
more pronounced in humans after a corresponding lesion (as they are far more corticoreticular fibers from the cerebral cortex, and
pronounced in a monkey than in a cat).
2 In humans with lesions of the pyramidal tract, there is usually damage to especially from the motor areas (areas 4 and 6). Thus,
other structures as well. As is well known, the bers of the pyramidal tract are there is a corticoreticulospinal pathway that can mediate
isolated only in the pyramid (only a few patients have been described with
infarcts limited to the medullary pyramid). In the internal capsule, the mesen-
cephalon (crus), the pons, and in the cord, it either is mixed with or lies in close 3 Sensitive tracing techniques have demonstrated several minor spinal projec-
apposition to other tracts. tions from the brain stem in addition to the major ones described here.
formation and somewhat different sites of termination
in the cord.
Superior
S
ccolliculus Fibers from the pontine and medullary parts of the
reticular formation (Fig. 22.9) run in different parts of
Red nucleus the white matter: the pontine fibers are located in the
Tectospinal tract
ventral funicle (see Fig. 16.8), whereas the medullary
Locus coeruleus fibers are in the ventral part of the lateral funicle.
Vestibular
Pontine reticular nuclei Together, reticulospinal fibers terminate in large parts
formation of the ventral horn but primarily in medial parts, where
Medullary reticular
formation
Vestibulospinal the motoneurons to the axial muscles and the proximal
tracts
Raphe nuclei muscles of the extremities are located. Connections are
Reticulospinal
tracts particularly ample to the motoneurons that innervate
neck muscles, which are important for movements of
gure 22.9 The major brain stem nuclei sending bers to the spinal the head. The medullary fibers terminate somewhat
cord. Some of the nuclei receive afferents from the cerebral cortex more laterally in the ventral horn (particularly in lamina
(cf. Fig. 22.1). The monoaminergic nuclei are yellow. VII but to some extent also in lamina IX) than the pon-
tine fibers. The latter terminate mostly more medially in
laminae VII and VIII. The medullary reticulospinal tract
signals from the cortical motor areas to the spinal may thus be expected to have access to motoneurons
motoneurons (see Fig. 26.8). innervating muscles of the extremities, whereas the
It is impossible to transect the reticulospinal tracts in pontine reticulospinal tract reaches mostly motoneu-
the white matter of the spinal cord without at the same rons of axial muscles (neck, back, and abdomen).
time involving other tracts. This has made it difficult to Many of the reticulospinal fibers send collaterals to
clarify the role of the reticulospinal tracts in motor con- both cervical and lumbar segments of the spinal cord
trol. Nevertheless, experiments with relatively selective and often to the ventral horns of both sides. Thus, such
lesions of the reticular formation indicate that the neurons are capable of influencing numerous muscles
reticulospinal tracts are important for maintaining the at the same time. This may be functionally meaningful
upright position (posture), for orienting movements of in relation to adjustment of posture and body balance.
the body toward external events, and for fairly crude, Nevertheless, there is also some degree of somatotopic
stereotyped voluntary movements of the extremities organization among reticulospinal neurons, as demon-
(such as extending the arm toward an object). At least strated with retrograde axonal transport methods. Also,
in monkeys, the pyramidal tract is not necessary for electrical stimulation of the reticular formation can
such movements, as described earlier. The crude move- elicit muscle contractions restricted to smaller parts of
ments of the extremities are most likely mediated by the body. Together, these data indicate that the reticu-
pathways from the motor cortex via the reticular for- lospinal fibers can mediate both rather diffuse effects
mation and the reticulospinal tracts (see Fig. 26.8). on many muscle groups and more focused influences
Because reticulospinal neurons receive inputs from related to specific, goal-directed movements.
sources besides the motor cortexsuch as the vestibu- Both excitatory and inhibitory effects on the motoneu-
lar nuclei, the basal ganglia, and the cerebellummany rons can be elicited by electrical stimulation of the retic-
cell groups cooperate to produce the final activity of ular formation. Inhibition of reflex and voluntary
reticulospinal neurons. movements can be produced by stimulation of a region
in the lower part of the medulla (see Fig. 26.10), whereas
increased reflex movements and muscle tone can be
More about Reticulospinal Tracts
elicited from a more rostral region. The reticulospinal
The actions in the cord of the reticulospinal fibers are fibers act on both the and motoneurons. Thus, the
multifarious. In Chapter 15, we described reticulospi- reticular formation also controls the sensitivity of the
nal fibers descending in the dorsolateral fascicle and muscle spindles, and in certain situations it is probable
ending dorsally in the spinal gray matter (see Figs. 15.2 that it acts only on the motoneurons and not the
and 15.3), with powerful effects on the central trans- motoneurons. There is even some evidence that the
mission of signals from nociceptors. The reticulospinal reticular formation may act selectively on either static
fibers that are of interest in relation to motor control or dynamic motoneurons.
terminate more ventrally in the spinal gray matter, with
monosynaptic and polysynaptic effects on the motoneu-
The Tectospinal Tract
rons. These fibers descend in the ventral part of the lateral
funicle and in the ventral funicle. They belong to at least Several mesencephalic cell groups send axons to the spi-
two tracts with different sites of origin in the reticular nal cord. A large number of fibers arise in the superior
colliculus and form the tectospinal tract. The descend- In contrast to the other cell groups in the brain stem
ing fibers cross the midline shortly below the superior sending fibers to the cord, the vestibular nuclei receive
colliculus, and most terminate at cervical levels of the few afferents from the cerebral cortex. The vestibu-
cord. The superior colliculus receives numerous fibers lospinal neurons are therefore more independent of the
from the retina, the visual cortex, and from the so-called cerebral cortex than, for example, the reticulospinal
frontal eye field (area 8 in Fig. 25.7), which are of par- neurons. The vestibular nuclei mediate primarily auto-
ticular importance for control of conjugate eye move- matic, reflex movements and adjustments of muscle
ments. Efferent fibers from the superior colliculus do tone. Nevertheless, the activity of the vestibular nuclei
not act solely on the cord; motoneurons in the brain may be influenced indirectly from the cortex, as they
stem innervating extraocular muscles are also influenced receive afferents from the reticular formation. For
(although indirectly via the reticular formation). In example, the influence of vision on automatic adjust-
agreement with these anatomic data, electrical stimula- ments of posture appears to be mediated via the ves-
tion of the superior colliculus in experimental animals tibular nuclei.
produces coordinated movements of the eyes and the
head. The tectospinal tract is of particular importance
The Red Nucleus and the Rubrospinal Tract
for movements of the head and the eyes as parts of optic
reflexes: that is, the head and the eyes are directed The red nucleus (nucleus ruber) in the mesencephalon
toward something in the visual field. (Auditory signals (see Figs. 6.20 and 6.21) consists of a caudal magnocel-
also reach the superior colliculus via the inferior colliculus lular part (large, motoneuron-like neurons) and a
and can thus elicit head movements.) rostral parvocellular (small-celled) part. In monkeys the
The superior colliculus also receives afferents from magnocellular part is quite small, and in humans it con-
nonvisual parts of the cortex, like the SI and MI. Thus, tains even fewer neurons. The large parvocellular part
a corticotectospinal pathway may perhaps play a part receives its main afferents from the cerebellum (espe-
in voluntary movements. cially from the dentate nucleus, receiving its main affer-
ents from the cerebellar hemispheres). Many (most?) of
the efferents from the parvocellular part goes to the
Vestibulospinal Tracts
inferior olive (which sends its efferent fiber to the cere-
Primary sensory fibers from the vestibular apparatus bellum). By way of cerebellar pathways to the motor
terminate in the vestibular nuclei, which is located in cortex, it appears that the parvocellular red nucleus
the pons and medulla (see Fig. 9.7). Vestibular signals influences movements primarily through its interplay
about the position and movements of the head also with the cerebellum and the motor cortex, not by sending
indirectly provide information about the position of the fibers to the spinal cord.
body and about disturbances in balance. Two tracts, The magnocellular red nucleus sends fibers to the
issued from the vestibular nuclei to the spinal cord, can spinal cord, forming the rubrospinal tract. The tract
contribute to the maintenance of body balance and crosses the midline just below the red nucleus and
posture. The largest is the lateral vestibulospinal tract, descends in the lateral funicle, mixed with the fibers of
which comes from the lateral vestibular (Deiters) the pyramidal tract. The rubrospinal tract is somatoto-
nucleus and reaches all levels of the cord. The tract lies pically organized. In the cat and the monkey, the fibers
in the ventral funicle. The fibers exert an excitatory terminate in largely the same parts of the spinal gray
action on both and motoneurons. Like the reticu- matter as the pyramidal tract and have their most
lospinal fibers, the vestibulospinal ones act primarily marked effect on flexor motoneurons of distal muscles
on motoneurons in the medial parts of the ventral (also like the pyramidal tract). The red nucleus receives
hornthat is, axial muscles and proximal muscles of fibers from the motor cortex of the same side. A corti-
the extremities. Thus, the lateral vestibulospinal tract corubrospinal pathway is thus established from the
can adjust the contraction of muscles that oppose the cerebral cortex to the spinal motoneurons. In the cat
force of gravity (antigravity muscles). and monkey this pathway supplements the pyramidal
The other vestibulospinal tract is much smaller and tract in the control of voluntary movements (although
reaches only the cervical and upper thoracic segments it is of greater functional importance in the cat than in
of the cord. This medial vestibulospinal tract is there- the monkey). Whether it plays such a role in humans
fore primarily important for mediation of reflex head seems unlikely because the magnocellular part is so
movements in response to vestibular stimuli. This con- small, and the parvocellular part does not appear to
clusion is also supported by physiological experiments. project to the spinal cord (in monkey and humans). In
Unlike the lateral vestibulospinal tract, many of the monkeys, the ratio of rubrospinal to corticospinal fibers
neurons of the medial tract are inhibitory (probably has been estimated to about 1:100, and this ratio is
using glycine as a transmitter). most likely even lower in humans.
Monoaminergic Pathways from the Brain Stem to the were treated in more depth in Chapter 18 in conjunction
Spinal Cord with the control of body balance.
Although they are often included among the reticu-
lospinal pathways, descending monoaminergic fibers The Cerebral Cortex Coordinates Brain Stem
to the cord from the raphe nuclei (Fig. 22.9; see also and Spinal Networks
Figs. 26.6 and 26.7), the locus coeruleus (see Fig. 15.6),
Brain stem and spinal networks can on their own con-
and scattered cell groups in their vicinity have distinct
trol quite complex movement sequences; the contribu-
properties. Such monoaminergic fibers terminate in the
tion of the cerebral cortex being restricted to start and
ventral horn (in addition to in the dorsal horn). Many
stop signals. In general, however, the cerebral cortex,
of the raphespinal fibers contain serotonin, whereas the
the basal ganglia, and the cerebellum are needed to
coeruleospinal fibers contain norepinephrine. In addi-
incorporate the activity of the lower networks in an
tion, several neuropeptides coexist with the monoam-
overall plan. To achieve this, the indirect corticospinal
ines. Both these tracts end rather diffusely in the spinal
pathways are instrumental in coordinating the various
gray matter and can hardly mediate information related
automatic responses initiated from the lower levels.
to specific movements. More likely, they exert general,
This happens mainly by modulating the excitability of
widespread facilitatory influences on the motoneurons,
brain stem and spinal interneurons. Further, most pur-
as judged from the effects on spinal motoneurons of
poseful movements challenge our balance by moving
microinjections of serotonin and norepinephrine. Thus,
the center of gravity. When learning a sequence of move-
the excitability of most motoneurons may be enhanced,
ments, the higher levels make internal models that,
so that they react more vigorously to an input from the
among other things, anticipate the postural perturba-
pathways that mediate specific motor commands (such
tions caused by the desired movements. Thus, such
as the pyramidal tract). At the same time, the descending
anticipatory control is an important characteristic of
monoaminergic connections to the dorsal horn may pre-
skilled and of harmonious movements.
vent disturbing signals from nociceptors from reaching
consciousness. In deep sleep (REM sleep), all movements
are suppressed, and the descending monoaminergic Postural Reexes
neurons show their lowest activity.
To maintain equilibrium we need rapid corrections of
It is possible that these monoaminergic pathways
muscle tension in various parts of the body. Postural
contribute to the effects of motivation on the perfor-
reflexes produce the automatic movements that help
mance of voluntary movements when the muscle
us regain equilibrium quicklyfor example, when slip-
contractions occur with increased speed and force. This
ping on ice. It is a common experience that these
may be related to the ability of the monoamines (sero-
compensatory movements happen so rapidly that only
tonin in particular) to alter the excitability of the
afterward are we aware of which movements we per-
motoneurons by inducing a so-called plateau potential
formed. The tasks of the postural reflexes are to main-
(see Chapter 21, under Muscle Cramps and Plateau
tain an appropriate posture of the body, to help regain
Potentials). Thus, serotonin (and other transmitters)
equilibrium when it is disturbed, and to ensure optimal
can bring the motoneuron from a state of stable hyper-
starting positions for the execution of specific move-
polarization with low excitability to stable depolariza-
ments. Large perturbations may require additional vol-
tion (plateau potential). In this state, a brief excitatory
untary movements (coming later than the automatic
input elicits tonic firing from seconds to minutes. Plateau
ones). To issue the right motor commands, the brain
potentials may also be an efficient means to control the
must receive immediate and reliable information as
activity of muscles used for postural tasks because they
soon as something threatens our upright positionthat
exhibit long periods of tonic contractions (at least in
is, information from receptors that detect joint move-
experimental animals). A brief inhibitory input suffices
ments and movements of the whole body. Because our
to terminate the tonic firing.
upright position is labilewith a small supporting area
and a high center of gravityconstant corrections are
CONTROL OF AUTOMATIC MOVEMENTS necessary. For example, we sway a little back and forth
in quiet standing, as an expression of imperceptible
In this section, we treat the control of two kinds of auto- postural corrections (reflex responses).
matic movement: the postural reflexes and locomotion. Receptors that provide information used for postural
Postural control and control of movements, either auto- control are proprioceptors in the legs, the spine, and the
matic or voluntary, are not independent, however, since neck; cutaneous receptors on the sole of the foot; ves-
postural control is a prerequisite for proper execution of tibular receptors in the inner ear; and photoreceptors in
virtually every purposeful movement. Postural reflexes the retina. The more demanding the challenge to the
balance becomes, the more important becomes the ability object that touches the palm. After damage of the fron-
to use several kinds of sensory information. The signals tal lobes (presumably, in particular, the supplementary
from the various receptors are integrated at the brain motor area, SMA), the reflex may reappear in adults.
stem level (in the vestibular nuclei and the reticular for- The strength of the grasp reflex depends on the position
mation) and in the cerebral cortex. Presumably, the of the body, reflecting that its purpose is to cling to the
sensory information is compared with an internal model mother when she moves about (thus, the reflex is of less
of the motor task facing us. The sensory information functional importance in humans than in monkeys).
serves to update the internal representations so they fit
the present situation. Internal models are thought to serve
Control of Locomotion and Rhythm Generators
as frames of reference for the continuous monitoring and
adjustment of our posture. Selection of an overall motor The upright locomotion of humans requires somewhat
response is done on the basis of the central processing different movements than in animals walking on four
of the sensory information. However, the final motor legs; not the least are that the demands on postural con-
command depends not only on the sensory signals but trol are quite different. Certainly, the large size of the
also on the context in which they arise. Therefore, a human brain has enabled many processeswhich in
certain sensory input can elicit very different postural lower animals are controlled from the spinal cord and
responses in different situations. Mainly reticulospinal the brain stemto be controlled from the cerebral cortex.
and vestibulospinal fiber tracts mediate the final postural Nevertheless, with regard to basic mechanisms, the neural
commands. control of locomotion is probably very similar in humans
The postural reflexes operate on a feedback basis: and in other mammals. The following account is largely
they are responses to movements that have already based on data obtained from animal experiments.
started. In conjunction with voluntary movements, Fairly normal locomotion can be produced in animals
however, commands about postural adjustments are (such as cats) even when the spinal cord is isolated from
issued in advance. From prior experience, the brain has the brain stem and the brain. This can be observed on a
determined which adjustments will be needed to keep treadmill when the paws touch the moving ground (the
balance during, for example, an arm movement. This is animal has to be supported since there are no postural
called feedforward or anticipatory control and is pre- reflexes). Central rhythm generators must, therefore,
sumably based on the presence of internal models for exist in the cord, able to produce rhythmic, alternating
well-rehearsed movements. leg movements in the absence of any command signals
from higher levels. The rhythm generators consist of
fairly complicated spinal networks of interneurons with
Development of Postural Control
excitatory and inhibitory interconnections, eventually
Postural control is developed during childhood, start- controlling the activity of the motoneurons. Some of the
ing as soon as the balance is challenged by the upright neurons within the network appear to have pacemaker
position. Although anticipatory control probably starts properties; that is, they fire brief trains of action poten-
to develop very early, the first attempts at postural tials with silent periods between, without receiving a
corrections depend heavily on feedback information. rhythmically alternating input.
The corrections are large and inaccurate (ballistic). By The rhythm generator does not depend on sensory
constantly challenging the limits of its balance, the child input from the moving parts to produce the motoneu-
improves both its use of feedback information and ron activity typical of locomotion. Thus, the rhythmic
anticipatory controlimproving skills by experimenta- motoneuronal activity continues even after complete
tion. This presumably goes together with establishing paralysis of the muscles (e.g., after cutting the ventral
and refining the internal models of various skills. The roots). This is called fictive locomotion, and the pattern
development is not monotonous; there appear to be of motoneuronal activity is strikingly similar to that
alternating periods with overreliance on one or the observed during normal walking in intact animals. This
other strategy until the adult pattern is established does not mean that sensory inputs are without signifi-
around age 10 to 12. The adult pattern is characterized cance for locomotor control, however. The activity of
by flexible postural responses based on a full integra- the rhythm generators can indeed be modified by sen-
tion of feedback and anticipatory control strategies. sory signals from the peripheral receptors providing
information about how the movements are proceeding.
Inhibitory interneurons can contribute to the rhythmic
The Grasp Reex
pattern of activity by inhibiting the antagonists when
The grasp reflex is usually regarded as one of the the agonists have reached their maximal activity.
postural reflexes. It is normally expressed only in infants Renshaw cells (see Fig. 21.14) can probably contribute
during the first 6 months and has disappeared at by shortening impulse trains from the motoneurons
12 months. It consists of the fingers firmly grasping an and at the same time increasing the excitability of
antagonist motoneurons. There is probably one rhythm (fastigial) cerebellar nucleus to the medullary reticular
generator for each extremity. Long propriospinal fibers formation (see Fig. 24.6). Connections from the motor
that interconnect the forelimb and hindlimb generators cortex (especially the pyramidal tract) are of increasing
ensure that their activities are coordinated. importance for the control of locomotion as the ground
The presence of rhythm generators in the human spi- becomes more uneven and unpredictablethat is, as
nal cord is indicated by the occurrence of locomotion- each step has to be controlled individually. Thus, after
like movements in anencephalic infants (born without destruction of the motor cortex, cats can still walk fairly
most of the brain). In normal infants, walking move- normally on an even surface but are helpless when they
ments of the legs can be elicited in the first few months are required to walk along a ladder or a narrow bar.
(if the infant is held under the arms and the feet are
made to touch the floor). This ability usually disap-
pears, to reappear when the infant starts to crawl at MOTOR CORTICAL AREAS AND CONTROL OF
about 8 months. Locomotor movements can be elicited VOLUNTARY MOVEMENTS
in patients with complete transverse lesions of the cord
if the body is supported and the feet hit a treadmill. The Motor Networks
locomotor pattern is more normal with high than with
low spinal lesions, suggesting that the network control- We do not fully understand how the appropriate corti-
ling human walking is not restricted to the lumbosacral cospinal neurons are selected to produce a purposeful
cord. Presumably, the lumbosacral rhythm generators movement. The decision to initiate a particular move-
depend on cooperation with similar networks in the ment is certainly not made in the MI, and it is not likely
cervical cord (as in four-legged animals). to be caused by activity in one particular cell group.
Cognitive processes are expressions of activity in dis-
tributed networks of cortical neurons. Likewise, many
Central Control of Locomotor Movements parts of the cerebral cortex and interconnected subcor-
Several parts of the brain contribute to the control of tical nuclei are responsible for motor control. While the
the spinal rhythm generators. The most direct influence final movement command issues from the primary
comes from parts of the reticular formation, but also motor cortex (M1), the decision to move is mediated to
the basal ganglia, the cerebellum, and the cerebral cor- M1 from other parts of the cortex. Accordingly, brain-
tex contribute. Electric stimulation of a region in the imaging methods such as PET and fMRI have shown
mesencephalic reticular formation produces rhythmic that large parts of the cortex are activated in relation to
4
locomotor movements in animals. This mesencephalic voluntary movements. Further, when sensitive methods
locomotor region (MLR) is situated just ventral to the are used to record the electrical activity over the brain
inferior colliculus on the pontomesencephalic junction. of a person asked to perform a simple flexionextension
The pedunculopontine nucleus (PPN) is another name movement of a finger, changes of activity over large
applied to this part of the mesencephalon (although the parts of both hemispheres first occur. This is a slowly
MLR and PPN are probably overlapping but not identi- rising negative wavea so-called readiness potential
cal). Most likely, the effects on spinal motoneurons starting about 850 msec before the movement.
from the MLR are mediated by reticulospinal fibers, Approximately 60 msec before the movement, the activ-
since they are abolished by cutting the ventral and ventro- ity is concentrated over the arm region of the motor
lateral funicles. Further, many reticulospinal neurons are cortex (on the side opposite the moving fingers). Studies
rhythmically active in pace with walking movements. of monkeys with implanted microelectrodes show that
The basal ganglia have reciprocal connections with not only is the cerebral cortex activated before a volun-
the PPN and appear to modulate locomotor movements tary movement; there is also increased neuronal activity
without initiating them. The characteristic gait distur- in the cerebellum, the basal ganglia, the thalamus, and
bances in Parkinsons disease may possibly be explained parts of the limbic structures.
by dysfunction of these connections (see Chapter 23,
under The Efferent Connections of the Basal Ganglia).
Hierarchical Organization of Motor Areas
In addition, the cerebellum (particularly the vermis)
influences locomotor movements, and cerebellar lesions The regions defined today as motor in a strict sense are
may produce an ataxic gait. The cerebellar effects are largely confined to the cytoarchitectonic areas 4 and 6
probably mediated by connections from the medial of the frontal lobe (Fig. 22.10; see also Fig. 33.3). The
MI (area 4) in the precentral gyrus has a special posi-
tion because it exerts the most direct and powerful
4 Rhythmic locomotor movements can be elicited by stimulation of the so- effects on the motoneurons. Further, lesions of the MI
called subthalamic region, which is close to the posterior hypothalamus. It is
not clear, however, whether the effect is due to stimulation of passing bers produce clear-cut pareses, in contrast to lesions of other
rather than neurons in the subthalamic region itself. cortical regions. Within area 6, two main subdivisions
are usually recognized: the medially situated supple- symptoms are difficulties with coordination of bilateral
mentary motor area (SMA), and the lateral premotor movements, such as swinging the arms in opposite
area (PMA). Besides sending fibers to the spinal cord, directions.
thus contributing to the corticospinal tract, both the The posterior parietal cortex and the prefrontal
SMA and the PMA send many fibers to the MI. They cortex are also concerned with motor control, although
can therefore act on motoneurons in two fairly direct less directly than the MI, SMA, and PMA. In certain
ways. Usually, however, the effect on MI has been con- respects, the parietal and prefrontal areas are higher up
sidered most important, and, consequently, the SMA in the hierarchy of motor areas. The posterior parietal
and PMA are often placed above the MI in a hierarchy cortex is important for the transformation of soma-
of motor areas. The SMA and PMAsometimes termed tosensory and visual information into appropriate motor
supramotor areasare believed to instruct the MI in what commands. The prefrontal cortex shows increased activ-
to do. Several observations support this assumption ity before self-initiated movements (i.e., movements that
for example, that the SMA and PMA usually become are not a response to external stimuli). The functions
active in advance of MI during voluntary movements. of these cortical regions are multifarious, however, and
Clinical observations of patients with complete or par- certainly not restricted to motor control. They are dis-
tial lesions suggest that SMA and PMA are important cussed more fully in Chapter 21.
for sequential movements, especially performance of During execution of well-rehearsed, routine move-
rhythmic sequences (there are no pareses). A pianist suf- ments, only relevant parts of the MI increases its activ-
fering from such a lesion could no longer play because ity, as judged from fMRI studies (Fig. 22.11). Apparently,
he was unable to keep even intervals between the key- higher motor areas are only minimally engaged; their
strokes. The great Russian neuropsychologist Alexander contribution restricted to mediating the intention to
R. Luria used the term loss of movement melodies to move. Presumably, motor program is located in the
describe symptoms after lesions of area 6. Among typical motor cortex, the basal ganglia, and the cerebellum.
SUPPLEMENTARY MOTOR AREA (SMA)

Organizing and planning sequential
Central sulcus movements; rhythm; use of both arms
simultanenously.
SI M1 SMA
5
7
Central sulcus
PREMOTOR AREA (dorsal part)
Visual guidance of arm
movements. 5
Response selection based on POSTERIOR PARIETAL
sensory information.
PMAd M1 SI CORTEX:
7 Transformation of sensory
information to action; goal-directed
hand movements; use of tools
PMAv
PREMOTOR AREA (ventral part)

Interpretation of other persons
actions (mirror neurons)
Use of tools
gure 22.10 Areas of special importance for the control of volun- PET and fMRI studies. Areas in the prefrontal cortex are engaged in
tary movements. The borders of the various areas are not exact. They cognitive aspects of motor control (selection of goal, choice of strat-
are partly based on cytoarchitectonic maps (Brodmann), partly on egy, and so forth), but are not shown.
(via the pontine nuclei), the red nucleus, the reticular
formation, and the motor thalamus. This means that
a copy of the motor commands that are issued to the
Right Left motoneuronsan efference copyreaches the basal
ganglia and the cerebellum. Such information helps
them to assist in the control of ongoing movements and
in learning new ones. Efference copies also reach corti-
cal regions that are responsible for the sense of effort
(see Chapter 13, under Perception of Muscle Force),
and regions that enable us to distinguish sensory infor-
mation that arises as a result of our own movements
from such that is due to external events. Efference copies
are also important for updating the body scheme and for
our perception of bodily ownership (see Chapter 18,
under Distributed Networks, Body Image, and Body
Scheme). Consequently, damage to the motor cortex
is not identical to damage of the pyramidal tractmany
neuronal groups besides the motoneurons lose crucial
information.
Most if not all pyramidal tract fibers ending mono-
synaptically on the motoneurons come from MI, which
gure 22.11 Parts of the motor cortex activated by nger tapping. explains why the threshold for eliciting movements by
T1-weighted fMRI. Areas with increased blood ow are colored (red: electrical stimulation is lower here than in any other
left motor cortex, activated by tapping the right index nger, green: part of the cortex.6 Accordingly, the movements evoked
right motor cortex activated by tapping the left index nger).
by very weak electrical stimulation of the motor cortex
Movements that are more complex activate addition areas. (Courtesy
of Dr. S.J. Bakke, Rikshospitalet University Hospital, Norway.) are mediated by the pyramidal tract. Such movements
occur in the opposite body half and can be limited to a
few muscles in distal parts of the extremities and the
face. Increasing stimulus strength recruits more mus-
cles, and ones that are more proximal. These effects are
The Connections of MI
most likely mediated by polysynaptic pyramidal tract
The physiologically defined MI corresponds fairly connections (via spinal interneurons) and by corticore-
closely to Brodmanns area 4.5 It receives main afferents ticulospinal pathways. Muscles that are often used
from SI, SII, SMA, PMA, and the posterior parietal cor- simultaneously on both sides of the body, like the mus-
tex, in addition to afferents from motor parts of the cles of the back and the abdomen, can be relatively eas-
thalamus (the ventrolateral nucleus, VL; see Figs. 6.21 ily activated on both sides (bilaterally) by stimulation
and 14.16). The cerebellum, especially, sends important of the MI of one side. Movements of the fingers, how-
information about movement performance to MI via ever, can be evoked only from the opposite (contralat-
VL (the basal ganglia mainly influence the MI via con- eral) MI, which reflects that the fingers are used
nections to area 6). independently and usually differently on the two sides.
Although a large fraction of the pyramidal tract The anatomic basis of this is the complete crossing of
fibers arise in MI, these nevertheless constitute only a the pyramidal tract fibers that control distal muscles, as
minority of all efferents from MI. The motor cortex mentioned earlier. Similar conditions pertain to the
sends, for example, feedback connections to the corti- commissural fibers that interconnect the MI of the two
cal areas from which it receives afferents. Further, hemispheres: only parts of the MI representing the
numerous fibers pass to subcortical regions involved in trunk and the proximal parts of the extremities are
motor control, such as the basal ganglia, the cerebellum interconnected. The large areas representing the distal
muscles are devoid of commissural connections, pre-
sumably as an expression of the independent use of the
5 It is not clear whether there is complete coincidence between the physiologi- two hands (see Fig. 33.12).
cally dened MI and area 4, which is dened cytoarchitectonically. Some
authors maintain that the MI extends anteriorly somewhat into area 6 with the
representation of axial and proximal muscles. Such disagreement may be
caused by lack of clear-cut cytoarchitectonic changes when moving anteriorly
from area 4 into area 6. Cytoarchitectonic borders, as depicted so condently 6 Near the end of the nineteenth century, electrical stimulation of area 4 in
in maps like that in Fig. 33.3, are in reality seldom unequivocal. The consider- dogs produced the rst rm evidence of specializations within the cerebral cor-
able differences between maps published by different authors witness this tex. Before that, the existence of functional localization in the cerebral cortex
point. was hotly debated.
Epileptic Seizures Starting in MI spread over a relatively large cortical area (although
respecting the rough somatotopic pattern shown in
The so-called Jackson epileptic seizures (described in
Fig. 22.5). For example, within the motor hand region,
Chapter 14) illustrate the somatotopic pattern within
pyramidal tract neurons that control different joints of
the MI (Figs. 22.11 and 22.12). The abnormal dis-
the hand are intermingled. Thus, every small patch of
charges of the neurons start at one site in the MI and
the motor cortex would contain neurons that control
spread out in a regular manner. Thus, the muscular
several different muscles. We also know that each
cramps start in one part of the bodyfor example, the
pyramidal tract axon acts on more than one muscle
footand spread to the lower leg, then to the thigh, the
(although with a stronger action on some than on oth-
abdomen, the shoulder, and so forth. Nearly always,
ers). Therefore, the explanation why we can do isolated
the fits start around the mouth, in the tongue, the thumb,
movements of single joints cannot be that each pyrami-
or the big toe. This is best explained by the fact that the
dal tract neuron is specified for one movement only.
cortical neurons controlling these parts occupy the larg-
A particular movement is specified by the collective
est volume of the MI and have the largest proportion of
activity of a large neuronal population rather than by a
monosynaptic corticomotoneuronal connections.
narrow tuning of a few neurons. Further, such popula-
tions appear to be related to initiation of purposeful
Functional Organization of the Primary Motor Area movements involving several joints, rather than to iso-
lated, single-joint movements (consider how seldom
As with SI, a disproportionally large part of the MI is
our movements involve one joint only). This conclusion
devoted to control of the hand (especially the thumb
received recent support from experiments with micro-
and the index finger) and the lips and the tongue
stimulation of the monkey motor cortex. In contrast to
(Fig. 22.12). In comparison, very small parts of the MI
most previous studies, long trains of stimuli lasting for
contain neurons that control muscles of the back and
about 500 msec were used, similar to the time scale of
the abdomen. How many cortical neurons that are con-
normal reaching movements. Such stimulation evoked
cerned with the motor control of a particular body part
coordinated movements and postures that involved
depends on the variety and precision of the movements
many joints. Notably, the movements resembled pur-
rather than on the size of the part.
poseful movementssuch as opening the mouth and,
Focusing on the properties of single cells led to the
at the same time, shaping the hand and moving it to the
view that pyramidal tract neurons were collected in
mouth. In other words, the motor cortex is organized
groups controlling muscles around single joints (some-
to optimize task performance, not to control individual
what like the arrangement in the spinal cord where
muscles or joints. As an example, destruction of the
motoneurons are collected in groups related to single
cats motor cortex does not affect single-joint move-
muscles; see Fig. 21.3). However, further studies have
ments but complex, multijoint movements, such as
not supported this interpretation. Thus, pyramidal tract
stretching the paw toward a goal.
neurons controlling motoneurons of one muscle usually
Several observations show that the selection of corti-
cospinal neurons can be extremely precise and varied.
First, one corticospinal neuron can be active when a
certain hand muscle is used for a precision grip, whereas
it is much less active or inactive when the muscle is used
Trunk for a more crude grasping movement. Other corticospi-
nal neurons must therefore be responsible for produc-
Hand Foot ing the required force from the muscle in the latter
situation. Second, human subjects can quickly learn to
recruit one specific motor unit among many others
when given biofeedback (seeing the EMG pattern of the
Face muscle). This suggests an almost incredible ability to
focus excitation from the motor cortex on certain spinal
motoneurons. Considering the precision of movements
Tongue required of a violinist, a watchmaker, or a neurosurgeon,
the above observations become perhaps less surprising,
however.
Lateral sulcus
Properties of Single Neurons in MI

gure 22.12 Relative size of the regions of the MI representing vari-
ous body parts, as revealed by electrical stimulation of the exposed Many cells in the MI become active (or increase their fir-
human MI. (Based on Peneld and Rasmussen 1950.) ing frequency) immediately before a voluntary movement
starts, as shown with microelectrode recordings. In the performance of a complex movement. Observations
contrast, most cells in the SI become active after move- of the kinds discussed above have led to the suggestion
ment onset, indicating that they are activated by sen- that the SMA is important for organizing and planning
sory signals from the moving parts but do not contribute complex movements and for mediating an appropriate
to the initiation of the movement. Some pyramidal tract motor response to sensory stimuli.
neurons (corticospinal neurons) increase their activity Damage of the SMA in humans usually produces
only in relation to the start of a movement, whereas severe motor impairments. Typically, the spontaneous
others are active during the whole movement. The fir- use of the contralateral hand is abolished for weeks to
ing frequency of some neurons correlates with the force some months; this condition is sometimes termed motor
8
of muscular contraction. In the MI of a monkey sitting neglect. Another and more enduring problem is diffi-
quietly waiting for a signal to move, some corticospinal culty with the simultaneous use of both hands to solve
neurons fire continuously. This probably means that a task. Monkeys with a lesion of SMA show similar
the motor cortex not only initiates and controls move- symptoms. For example, when a piece of food is stuck
ments but also determines the readiness of selected in a hole in a Plexiglas plate, a normal monkey easily
motoneuronal groups by keeping them slightly depolar- retrieves it by pushing with one finger from above and
ized (below the threshold for initiation of action poten- collecting the piece with the other hand from below.
tials). This enables the motoneurons to respond more After damage to the SMA, the monkey pushes from
quickly to a go signal from the motor cortex or from above with both hands. That the grasp reflex is disturbed
subcortical levels, such as the reticular formation, the for some time after damage to the SMA may presum-
vestibular nuclei, and sensory signals through the dorsal ably be due to a disruption of normal integration of
roots (e.g., from muscle spindles). At the same time as a somatosensory stimuli and motor responses.
corticospinal neuron excites motoneurons of synergistic
muscles, motoneurons of antagonistic muscles are inhib-
Additional Motor Areas on the Medial Wall of
ited (via inhibitory interneurons mediating reciprocal
the Hemisphere
inhibition).
Several smaller motor areas have been identified
adjacent to SMA on the medial wall. This concerns the
The Supplementary Motor Area
so-called presupplementary motor area (preSMA) and
The SMA is located in front of the MI on the medial side the cingulate motor area (consisting of three small areas
of the hemisphere (Fig. 22.10). It sends fibers to both the buried in the cingulate sulcus). These areas differ from
spinal cord and the reticular formation. Thus, the SMA the SMA with regard to connectivity and by being
contributes to both direct and indirect corticospinal associated with somewhat different aspects of motor
7
pathways. The SMA also sends many fibers to the MI, control. The pre-SMA seems to be particularly active in
and this pathway is probably most important for its relation to the performance of novel movement
influence on motor control. This assumption is primarily sequences but less in relation to well-rehearsed move-
based on results obtained by microelectrode recordings ments. The cingulate motor area may be involved in
in monkeys and on brain imaging in humans. Afferents reward-based movement control.
to the SMA come fromamong other sourcesthe
prefrontal association areas (see Fig. 34.3).
The Premotor Area
The neuronal activity in the SMA of humans appears
to increase especially in relation to somewhat complex The PMA occupies the largest part of area 6 on the con-
movements. As mentioned, a series of simple flexion vexity of the hemisphere (Fig. 22.10).9 Like the SMA,
extension movements of a finger increases the activity the PMA receives its most important afferents from the
mainly in the MI hand area, not in the SMA (Fig. 22.11). prefrontal cortex, although not from identical parts.
When the task is to perform a series of different move- The PMA probably sends fewer efferent fibers to the
ments in a specified sequence, however, there is also spinal cord than the SMA but has strong connections
increased activity in the SMA. It appears that the activ-
ity increases first in the SMA and then in the MI.
8 Some patients with lesions of SMA show the so-called alien (anarchic) limb
Increased activity in the SMA is not related to the move- syndrome. The arm makes purposeful movements, for example grasping an
ment itself, as it is sufficient that the person imagines object, without the patients intention. The person recognizes the limb as his
own but has apparently no control over its actions. In some patients, there is an
irresistible urge to grasp and use nearby objects, even if they have no intention
to do so (utilization behavior). It is unclear, however, whether some aspects of
7 Spinal projections from SMA and PMA end primarily on interneurons in these symptoms depend on simultaneous lesions of the corpus callosum.
the intermediate part of the spinal gray matterthat is, relatively far from the 9 Assuming that area 6 of humans corresponds functionally to area 6 in mon-
motoneurons. These spinal projections may therefore serve to prepare the keys, the SMA and PMA have increased in size during evolution. Thus, areas 4
spinal networks for the motor commands from MI, rather than initiating move- and 6 are of approximately the same size in monkeys (Fig. 22.8), whereas area
ments on their own. 6 is much larger than area 4 in humans (see Fig. 33.3).
with the reticular formation, the red nucleus, the basal It is believed that the perceived action of the other
ganglia, and the cerebellum. As with the SMA, how- person is automatically simulated by the mirror system
ever, the connections from the PMA to the MI are prob- without being actually carried out. The system of
ably those most directly related to the motor functions mirror neurons is probably involved in learning by imi-
of the PMA. As indicated in Fig. 22.10, the PMA con- tation and in the reading of other persons motor
sists of a dorsal (PMd) and a ventral (PMv) subdivision intentions. Some argue that the mirror system also is
that differ with regard to connectivity and functional responsible for mind reading in a wider sense, that is,
properties. Experiments in monkeys indicate that the perception of others intentions and the communicative
PMA is important for the control of visually guided content of movements (called social cognition). Others
movements, such as the proper orientation of the hand question this so-called motor theory of social cogni-
and fingers when they approach an object to be grasped. tion. As said by Jacob and Jeannerod (2005, p. 22)
The PMA thus performs visuomotor transformations . . . we grant that simulating an agents movements
of signals coming especially from the posterior parietal might be sufficient for understanding his motor inten-
cortex. In monkeys, many cells in the PMA change their tion, but we . . . argue that it is not sufficient for under-
activity about 60 msec after a light signal that the mon- standing the agents prior intention, his social intention,
key is trained to respond to with a certain movement. and communicative intention. Certainly, identical
The activity of the PMA neurons continues until just movements may result from very different intentions
before the movement starts, even when the monkey is and for different purposes. Another system, collecting
trained to wait for many seconds after the signal before much more varied information than the mirror system
actually performing the movement. Thus, the PMA does, seems necessary for social cognition (notably
appears to hold the intention to move and the motor association areas in the superior temporal sulcus, the
plan in standby until it is appropriate to start. amygdala, and the orbitofrontal cortex).
Monkeys with lesions of the PMA also have difficul-
ties with moving the hand around a transparent obsta-
Motor Imagery
cle to reach an object: They persistently use the direct
approach, bumping into the obstacle. After damage to Do we use the same parts of the brain when we imagine
the MI, the handling of an object is clumsy and inse- a movement as when we perform it? Many studies with
cure, but the ability to avoid an obstacle is not lost. brain-imaging methods, such as PET and fMRI have
Connections from the extrastriate areas in the occipital addressed this question. Most agree that largely the
lobe to the PMA are necessary for the ability to same cortical networks are activated in both situations.
perform such circumventive goal-directed movements. This holds for the PMA, parts of the prefrontal cortex,
Obviously, the PMA is important for the ability to the basal ganglia, lateral parts of the cerebellum, and
adapt a goal-directed movement to altered external the posterior parietal cortex. Some studies also show
conditions. increased activity in MI, although considerably less
Damage of the PMA often produces a peculiar than in relation to movement execution. In agreement
tendency to continue a certain movement when first with such data, magnetic stimulation of MI most easily
started, even though the movement is unsuccessful in evokes contraction of the muscles involved in the imag-
achieving its goal. Thus, when the hand in one of the ined movement (data are conflicting, however, whether
examples mentioned above bumps into an obstacle (in spinal motoneurons also show similar facilitation
this case, a transparent plate), the monkey nevertheless during motor imagery). Dissimilarities concern SMA,
repeats the same movement repeatedly. This phenome- where somewhat different subregions are active in
non is called perseveration and occurs in humans after motor imagery than in real movements. Further, infe-
damage to the frontal lobes. rior parts of the prefrontal cortex are active only during
imagery, so perhaps this region is responsible for the
suppression of movements. The same neuronal pro-
Mirror Neurons
cesses seem to underlie imagined and real movements,
In the ventral part of the PMA (PMv) and in the poste- as indicated by the fact that they take equal time from
rior parietal cortex certain neurons are active not only start to end. Patients with lesions of the motor cortex
when the person performs a certain movement but also can still imagine movements in the paretic side, but just
when she watches another person performing the same as the real movements the imagined ones are slower
movement. Such mirror neurons respond particularly than normal. Patients with Parkinsons disease likewise
well to use of tools, and they may respond to the sound exhibit similar slowing and reduced amplitude of real
produced by an action. Although identified with cer- and imagined movements. After lesions of the posterior
tainty only in monkeys, mirror neurons probably exist parietal cortex, however, the imagination of movements
also in the human brain, as judged from fMRI studies. seems to be more affected than their execution.
Learning and the Motor Cortex Indeed, damage to the posterior parietal cortex also
produces motor disturbances. There are no pareses,
Brain-imaging studies show that higher association
however, but rather difficulties with the execution of
areas in the prefrontal and posterior parietal cortices
more complex movements. Patients with such lesions
are active during learning of new motor skills. As move-
may be unable to open a door or to handle previously
ments become more automatic, the activity decreases in
familiar tools like a screwdriver or a can opener. They
these areas, presumably because of use-dependent
also have difficulties with proper orientation of the
plastic changes. We mentioned that the pre-SMA might
hand in relation to an object, and they easily miss an
be particularly engaged in learning new sequential
object even though they see it clearly. This kind of
movements. Further, animal experiments and human
symptom is called apraxia (see also Chapter 34).
brain-imaging data indicate that plastic changes occur
Interestingly, similar symptoms may occur after lesions
also in the MI during motor learning. Both LTP and
of the frontal lobes in front of the MI, presumably
LTD can be induced in the cerebral cortex, and motor
reflecting the intimate connections between the poste-
learning appears to be associated with strengthening of
rior parietal cortex and the frontal lobes.
horizontal connections within MI thereby coupling
functionally related neurons. Thus, pyramidal cells in
laminas II and III strengthen their synaptic couplings
SYMPTOMS CAUSED BY INTERRUPTION OF CENTRAL
with neurons in other parts of the motor cortex during
MOTOR PATHWAYS (UPPER MOTOR NEURONS)
skill learning in rats. Further, the connections are
specific for the body parts that are used in the motor
The term central paresis is used for a muscle weakness
performance.
that is caused by interruption of the central motor
In humans, the finger representation in MI increases
pathways that conduct signals from the cerebral cortex
during 1 week of intense piano training of a specific
(especially the MI) to the motoneurons. Only the
sequence, as judged from threshold changes to mag-
pyramidal tract goes directly; the other pathways are
netic stimulation of various parts of the motor cortex.
indirect, with synaptic interruption in the brain stem.
Changes were obtained both with real movements and
We have discussed that the various pathways take care
with mental training (motor imagery), although the
of somewhat different aspects of motor control. The
effect was largest with real movements. In a group of
term upper motor syndrome is often used for the clini-
right-handed elite badminton players, the stimulation
cal picture resulting from interruption of the central
threshold was lower and the hand area was larger in the
motor pathways, to differentiate it from the lower
left than in the right motor cortex (such differences
motor syndrome (peripheral pareses) resulting from
were not found in a group of recreational players).
destruction of the motoneurons (including their axons;
see Fig. 21.16).
The Posterior Parietal Cortex and Voluntary
Mechanisms underlying recovery after damage to the
Movements
upper motor neurons was discussed in Chapter 11,
Area 5 is of particular importance for processing soma- under Studies of Recovery after a Stroke in Humans.
tosensory information (received from SI), whereas area
7 also receives information from visual cortical areas
Negative and Positive Symptoms
(see Figs. 21.9 and 21.10). Many neurons in these areas
are active in relation to movements, as shown by Vernon Although pareses are present in both, peripheral and
Mountcastle (1975) and others. One kind of neuron is central pareses differ in other respects. In peripheral
active before goal-directed, reaching movements, such pareses, the symptoms are all negative, in the sense that
as when a monkey stretches its hand toward a banana. they represent loss of function, like reduced or abol-
Such neurons do not become active, however, in rela- ished muscle power, resting tone, and reflex contrac-
tion to a movement in the same direction but without a tions. There is also marked and rapid wasting. In central
specific aim, or in relation to a passive movement. pareses positive symptoms also occurthat is, there are
Other kinds of neurons increase their activity in rela- symptoms caused by hyperactivity of neurons, such as
tion to exploratory hand movements, such as when a increased reflex responses and resting muscle tone. Such
monkey studies a foreign object. In area 7, some neu- differences are understandable when considering that
rons increase their activity only when the monkey the peripheral motor neurons are still functioning in
stretches the hand toward an object that it also looks central paresis (see Fig. 21.16). The motoneurons can
at. As there are ample connections from the posterior be activated by signals from various receptors through
parietal cortex to the SMA and PMA), it is likely that the dorsal roots, from spinal interneurons, and from
the posterior parietal cortex in part determines the any remaining descending pathways, even though they
behavior of cells in these motor areas. cannot be brought into action voluntarily. Because the
motoneurons still send signals to the muscles in a patient differ among spastic patients with similar lesions.
with central pareses, muscle wasting is modest, in con- A priori, it seems likely that the loss of descending cor-
trast to that in peripheral pareses. Generally speaking, ticospinal fibers results in decreased activity of inhibi-
the positive symptoms occurring after damage to upper tory interneurons and many studies have been performed
motoneurons are due to hyperexcitability of neuronal in humans to determine the excitability of specific kinds
groups in the spinal cord, thus producing abnormal of interneurons. As discussed earlier in this chapter, the
muscle contractions (e.g., on innocuous stimuli like pyramidal tract modulates reflex responses by specific
moving or touching a limb). Because the reflex arc is actions on several kinds of spinal interneurons.
intact, reflexes like the stretch reflex and the flexion Several studies have shown reduced activity of
reflex can still be elicited, and typically, the reflex the interneurons mediating reciprocal inhibition (see
responses are stronger than normal in patients with Fig. 21.13) in spastic patients, both after spinal cord
central pareses (hyperreflexia). Although the reflex lesions and in capsular hemiplegia. This would help
responses are weak or absent shortly after a stroke, and explain the occurrence of hyperreflexia. For example,
especially after a transverse lesion of the cord (spinal when testing the Achilles reflex with a tap on the tendon,
shock), they recover in some days or weeks. Especially a monosynaptic stretch reflex is elicited in the calf mus-
the monosynaptic stretch reflex (as tested with a tendon cles (ankle plantar flexors). Normally, the reciprocal
tap) becomes hyperactive on the affected side.10 In addi- inhibition prevents a stretch reflex from being elicited
tion, most patients develop an increased reflex response also in the antagoniststhat is, the ankle dorsiflexors.
to passive movements of the affected limbsthat is, to If the reciprocal inhibition is reduced, however, a reflex
stretching of the paretic muscles. The reflex contraction contraction of the ankle dorsiflexors can occur; in turn,
depends on the velocity of stretch, so that slow move- this may produce a new reflex contraction in the plantar
ments typically do not elicit any contraction. In some flexors, and so forth. When a single tap on the tendon
patients, however, especially in those with spinal trans- elicits repeated contractions, it is termed clonus.
section or multiple sclerosis, even slow movements or Another possible factor in spastic patients may
innocuous cutaneous stimuli may provoke prolonged be reduced recurrent inhibition of motoneurons by
and painful muscle spasms. Renshaw cells (see Fig. 21.14). When ankle dorsiflexors
The term spasticity refers to the positive symptoms in contract, for example, Renshaw cells inhibit the
patients with upper motor neuron lesions. Some use the motoneurons to the ankle plantar flexors so there is less
term to include all positive symptomsthat is, hyper- chance of eliciting an unwanted stretch reflex. Reduced
reflexia, increased muscle tone, and muscle spasms. activity of the Renshaw cells in such situations would
Others define spasticity more narrowly, restricting it to contribute to the occurrence of clonus in spastic patients.
the velocity-dependent increase of resistance to muscle Reduced recurrent inhibition has indeed been found in
stretch.11 some spastic patients with spinal lesions, although not
in hemiplegic patients. Conversely, reduced activity in
inhibitory interneurons activated from tendon organs
Mechanisms Responsible for Development of Spasticity
(Ib afferents) has been found in hemiplegic patients but
The development of spasticitywidely defined as the not in patients with spinal lesions.
positive symptoms that occur after a lesion of the upper There is also evidence of reduced activity of interneu-
motor neuronsis due mainly or solely to excitability rons mediating presynaptic inhibition of Ia afferent
changes in the cord leading to exaggerated motor terminals. This would lead to a stronger than normal
responses to signals from receptors, from other parts of excitatory effect of muscle stretch (particularly rapid
the cord, and remaining supraspinal pathways. It is stretch) on the motoneurons. This appears not always
highly likely that plastic processes, for example, in the to be present in spastic patients, however. For example,
form of accidental collateral sprouting, contribute to one study found reduced presynaptic inhibition in the
excitability changes. The more precise mechanisms arm but not in the leg of hemiplegic patients. Reduced
underlying spasticity are not known, however. To com- postactivation depression has been observed in patients
plicate matters, there is evidence that the mechanisms with spasticity due to various causes. Postactivation
depression means that the postsynaptic effect diminishes
when action potentials in muscle spindle primary affer-
10 The long-latency stretch reex appears to be weaker than normal in spastic ents follow each other with brief intervals. It is probably
patients, as judged from the EMG response to carefully graded muscle stretch due to less transmitter being released. Obviously, reduc-
and vibratory stimuli. This ts with other data suggesting a transcortical route
for the long-latency stretch reex, as discussed in Chapter 21. tion of this phenomenon might contribute to increased
11 As dened by J. W. Lance (cited by Landau 1987, p. 722), Spasticity is a motoneuron excitation to a given muscle stretch.
motor disorder characterized by a velocity-dependent increase in tonic stretch A permanently increased excitability of the motoneu-
reexes (muscle tone) with exaggerated tendon jerks, resulting from hyperexcit-
ability of the stretch reex, as one component of the upper motor neuron rons themselves has not been found in patients with
syndrome. spasticity. The intrinsic properties of the motoneurons
might nevertheless be changed, because plateau poten- mechanisms, perhaps combined with abnormally low
tials may be more easily induced, as judged from animal threshold for eliciting plateau potential, produce symp-
experiments. We mentioned above (Monoaminergic toms that are indistinguishable clinically. Yet, to select
Pathways from the Brain Stem to the Spinal Cord) the right treatment, it would be crucial to know which
that when a plateau potential is induced in a motoneu- mechanisms are disturbed in each patient.
ron it goes on firing for seconds to minutes without
further stimulation. After a spinal transection in rats,
Other Features of the Upper Motor Syndrome
plateau potentials disappear but return in the course of
some months. Interestingly, when plateau potentials Even though central pareses can be produced by lesions
reappear, they can be induced by a variety of innocuous located anywhere between the motor cortex and the
stimuli and appear to be closely related to the degree of motoneurons, the most common cause is interruption
spasticity. Whether lowered threshold for inducing pla- of the descending fibers by a thrombosis or bleeding in
teau potentials plays a part in humans with spasticity the internal capsule (Fig. 22.13). The pareses then affect
remains to be determined, however. the muscles of the opposite half of the body (hemipare-
It was formerly assumed that increased signal traffic ses, hemiplegia). The term capsular hemiplegia is com-
from the muscle spindlesdue to increased motoneu- monly used for this condition. In such patientsin
ron firingexplained the increased stretch reflex responses contrast to those who suffer a transverse lesion of the
in spasticity. Microneurographic recordings have not cordfibers descending from cell groups in the brain
verified this, however, as the firing frequency of Ia stem (the reticular formation and the vestibular nuclei)
afferent fibers was not found to be increased in spastic can still activate the motoneurons. This may explain
patients compared with normal controls. why resting muscle tone is typically increased in some
In conclusion, the reflex hyperexcitability and muscle groups in patients with capsular hemiplegia
increased muscle tone in patients with the upper motor (Fig. 22.14). Thus, in the arm the increased tone affects
neuron syndrome may arise from changes of several the flexors so that the arm is kept flexed at the elbow,
inhibitory mechanisms in the spinal cord, although few whereas the extensors of the leg are affected (interrup-
if any of the changes seem to be present in all patients. tion of motor pathways in the cord result in increased
Possibly, varying combinations of disturbed inhibitory resting tone of flexors also in the leg). An important
A B
gure 22.13 Infarction in the internal capsule with degeneration of the right side, most marked for nger movements. He recovered com-
the pyramidal tract. The patient, a 19-year-old man, suddenly became pletely. PET studies in this patient after recovery showed that nger
hemiplegic, probably due to occlusion of a brain artery by an embolus movements of the right hand were associated with increased activity
from the heart. A: Drawing of a horizontal CT showing the localiza- in the left motor cortex and PMA, and bilaterally in the SMA, cingu-
tion of the infarction (red) in the posterior limb of the internal capsule late gyrus, and the insula (in normal controls only the motor cortex
(cf. Fig. 6.30). Seven months after the stroke, the lesion measured 5 show increased activity with isolated nger movements; cf. Fig. 22.11).
16 mm. B: Frontal MRI 4 months after the stroke, with the degener- The patient made involuntary mirror movements of the left ngers
ated pyramidal tract (arrowheads) shown as whitish (cf. Fig. 22.2). It when using the right ones. (From Danek et al. 1990. Reproduced
can be followed from the internal capsule through the pons and into with permission from Oxford University Press.)
the medulla. Immediately after the stroke, the patient had pareses on
feature of pareses in hemiplegia is that the velocity with viscoelastic properties of muscles can change gradually
which voluntary movements can be performed is after damage to the upper motor neurons. That is, resis-
reduced more than the isometric force (i.e., speed of tance to stretch may be increased without concomitant
movements is reduced more than strength). This is muscle contraction, and the range of joint motion may
called retardation and concerns particularly fine finger be restricted. The latter phenomenon is called contrac-
movements and movements of the lips and tongue, ture and is due to change of connective tissue elements
whereas larger movements are less severely affected. in muscle, tendons, and joint capsules that are kept in a
Writing, tying, buttoning, and similar delicate move- shortened position. Drugs used to treat spasticity such
ments may be impossible for a patient with capsular as baclofen (reducing the excitability of motoneurons)
hemiplegia, or the movements are performed only very or botulinum toxin (paralyzes muscles) cannot treat
slowly and clumsily. This loss of dexterity is due to the this kind of reduced joint mobility.
loss of direct corticospinal fibers (the pyramidal tract),
which are necessary for independent finger movements.
The Plantar Reex and Other Reexes that Are
Movements lose their rhythm and fluency. The fatiga-
Changed in Upper Motor Neuron Lesions
bility is also abnormally greatthat is, the muscular
force drops quickly when a voluntary movement is Interruption of descending central motor pathways, as
repeated several times. The patient experiences a drain capsular hemiplegia, also produces changes of
matic increase in the mental effort needed for voluntary reflexes other than the stretch reflexes. The so-called
movements: movements that before the stroke required plantar reflex, elicited by stroking with a pointed object
no mental effort can afterward be performed only with in a forward direction along the sole of the foot
the utmost concentration and strain. (especially the lateral margin), is inverted (Fig. 22.15).
Changes in the contractile properties of the paretic Instead of the normal response, which is a flexion move-
muscles also occur in hemiplegic patients. Thus, in the ment of the great toe (and the other toes), the great toe
intrinsic muscles of the hand, the fatigability of type 1 extends (moves upward). This phenomenon, with
muscle cells is increased and the contraction velocity of extension instead of flexion of the great toe, is called
the type 2 fibers is reduced. Such changes will presum- the sign of Babinski and is a sensitive indicator of dam-
ably contribute to the slowness and increased fatigabil- age of corticospinal pathways.12 For example, increased
ity in patients with central pareses. Further, the passive, intracranial pressure and unilateral herniation with
compression of the descending motor fibers in the mes-
encephalon may invert the plantar reflex at an early
stage (this will occur with the foot contralateral to the
herniation, owing to the crossing of the pyramidal tract
in the lower medulla). An inverted plantar reflex may
also occur during general anesthesia and in other condi-
tions with reduced cerebral activity. In patients with
central pareses, the threshold for eliciting the plantar
reflex is lowered and it can be elicited from a wider area
than normally. Further, the response may include a
complete flexion reflex of the lower extremity with flex-
ion in the hip and knee and dorsiflexion in the ankle.13
In newborn children, the plantar reflex is inverted
and can remain so until the age of 2 (although most
infants respond with plantar flexion of the big toe by
12 months). This is most likely due to the dependence
of the normal reflex on the integrity of the pyramidal
tract, which is not fully myelinated until between 12
and 24 months after birth.
12 Studies of patients subject to cordotomy (cutting parts of the lateral funicle

to achieve analgesia) indicate that the sign of Babinski occurs only if the lesion
affects the pyramidal tract.
13 Electrophysiological studies indicate that Babinskis sign is due to hyperex-
gure 22.14 Hemiplegia of the left side. Note the characteristic citability of the reex center in the cord, so that the extensor hallucis longus
position of the arm with exion in the elbow and wrist. The paretic muscle is recruited together with the ankle extensors. EMG recordings and
leg is moved laterally in a semicircle during the swing phase to keep experiments with nerve blocks show that the exors of the great toe are still
the foot off the ground (circumduction). active but that they are overcome by the greater force exerted by the extensors.
A B
gure 22.15 Inverted plantar reex in central pareses

(sign of Babinski). A: The normal plantar reex is plantar
exion of all the toes when a pointed instrument is moved
along the sole of the foot (from the heel to the toes). B: In
a patient with central pareses (damage of the pyramidal
tract) the big toe moves upward (dorsiexion).
Reduction or absence of the so-called abdominal lesions of the motor and premotor cortex but not after
reflex is also typical of upper motor neuron lesions. The complete lesions of the medullary pyramid. To compli-
normal reflex response is a unilateral contraction of cate matters, however, hyperreflexia and spasticity have
abdominal muscles upon stroking the skin with a been reported in a few patients with (most likely) pure
pointed object. The so-called clasp-knife reflex or phe- lesions of the pyramid. Nevertheless, the weight of
nomenon occurs in some patients: when the patient evidence favor the view that in capsular hemiplegia
contracts a muscle isometrically against resistance for motor symptoms other than loss of dexterity arise from
some time, it suddenly yields. The involuntary stop of destruction of other corticofugal pathways than the
contraction is due to stimulation of high-threshold mus- pyramidal tract. It seems likely that interruption of
cle afferents that inhibit the motoneurons (signals from the corticoreticulospinal pathways is important for the
tendon organs were formerly believed to be responsible, more severe symptoms after a capsular lesion than after
but this was not confirmed in animal experiments). one limited to the medullary pyramid, including the
development of spasticity.
We should also keep in mind that a lesion of the
The Pyramidal Tract Syndrome
internal capsule might interrupt tracts of importance
Formerly, all of the motor symptoms occurring in cap- for motor control other than the corticospinal and cor-
sular hemiplegia were thought to be caused by damage ticoreticular ones. Thus, many fibers acting (directly or
to the pyramidal tract, and the term pyramidal tract indirectly) on the cerebellum and on the basal ganglia
syndrome is still widely used. Closer study suggests, will usually be destroyed, and this probably contributes
however, that not all symptoms can be explained by to the clumsiness of voluntary movements. Further,
damage to the pyramidal tract. Both in monkeys and many patients with capsular hemiplegia have sensory
humans with lesions restricted to the medullary pyra- symptoms in addition to the motor ones, either because
mid, difficulty with fractionate finger movements is the the thalamus itself is affected or because the ascending
only constantly remaining symptom after some time. fiber tracts conveying sensory signals from the thala-
Otherwise, the recovery is almost completea patient mus to the cortex are interrupted (e.g., visual field
with an infarction limited to the right medullary pyra- defects). Reduced or altered cutaneous sensation and
mid even learned to play the cello afterward (see cap- kinesthesia may therefore also contribute to the motor
tion to Fig. 22.13). In monkeys, spasticity ensues after symptoms.
23 The Basal Ganglia
OVERVIEW release a brake on voluntary movements, facilitating

switching from one movement (or mental task) to
In Chapter 22, we discussed descending pathways from another. In addition, the basal ganglia are important
the cerebral cortex, which (directly and indirectly) for the establishment of habits and learning of auto-
influence the motoneurons and thereby are crucial for matic movement sequences. The tasks of the basal gan-
the initiation and control of movements. As mentioned, glia are not restricted to motor control, however. Even
the basal ganglia form a side loop to the descending though the most obvious symptoms in diseases of the
motor pathways, and diseases affecting the basal gan- basal ganglia are related to the motor system, both clin-
glia lead to characteristic disturbances of voluntary ical and experimental evidence indicates that the basal
movements and of muscle tone but no pareses. ganglia also play a role in cognitive functions. Further,
Broadly speaking, the basal ganglia are intercalated the most ventral parts of the basal gangliatermed the
in a loop of fiber connections from the cerebral cortex ventral striatopallidumcontribute to control of moti-
and back to the cerebral cortex through the thalamus. vation and emotions.
In this respect, the basal ganglia resemble the cerebel- The multifarious connections and tasks of the basal
lum. The basal ganglia process information from large ganglia serve to remind us that classification of parts of
parts of the cerebral cortex before answers are sent the brain into rigid functional categories such as motor,
back to the cortex. Different parts of the basal ganglia sensory, and cognitive must not be taken literally
assist different subdivisions of the cerebral cortex in their but rather as a didactic oversimplification.
specific tasks. In this way, the basal ganglia are orga-
nized in several anatomically and functionally different,
parallel circuits. STRUCTURE AND CONNECTIONS OF
Striatum, composed of the putamen and the caudate THE BASAL GANGLIA
nucleus, is the receiving part of the basal ganglia. The
striatum receives excitatory (glutamate) connections Figure 23.1 gives a simplified account of the how the
from not only motor parts of the cortex but also from basal ganglia are intercalated in a side loop of the direct
association areas and so-called limbic parts of the cor- and indirect descending motor pathways. It also shows
tex (e.g., orbitofrontal cortex). In addition, the striatum that the basal ganglia connect with motor centers in the
receives strong connections from the thalamus. Among brain stem. Figure 23.2 gives a schematic presentation
striatal afferents, the nigrostriatal pathway has a special of the main connections of the basal ganglia, emphasizing
position; it is dopaminergic and exerts strong modulatory the circuit cortexstriatumglobus pallidus/substantia
control of striatal activity. Most of the striatal neurons nigrathalamuscortex.
are GABAergic, and send their axons to the globus On an anatomic basis the term basal ganglia usu-
pallidus and the substantia nigra. These nuclei send their ally includes the caudate nucleus, the putamen, and the
GABAergic efferent connections to the thalamus and globus pallidus (Figs. 23.323.5; see also Fig. 6.29).1
certain cell groups in the brain stem. From the thala- Here we use the term basal ganglia of a set of func-
mus, excitatory (glutamate) connections reach especially tionally related cell groups rather than in a strictly
motor and prefrontal parts of the cortex, whereas the topographic sense. Therefore, we also include the sub-
brain stem nuclei (especially the pedunculopontine stantia nigra and the subthalamic nucleus because both
nucleus [PPN]) influence reticulospinal pathways engaged are intimately connected with the anatomically defined
in control of posture and locomotion. basal ganglia (Figs. 23.3 and 23.4). Because of their
It is noteworthy that the pathway from the striatum to
the thalamus contains two inhibitory neurons in a row.
1 The claustrum (Fig. 23.4) and the amygdala (amygdaloid nucleus) were also
Thus, increased activity of striatal projection neurons included in the term basal ganglia by the early anatomists. The function of
(driven from the cortex) leads to disinhibition in the the claustrum is still largely unknown, even though it is known to receive its
thalamus, and hence increased excitation in the cortical main afferents from the cerebral cortex and to send efferents directly back to
the cortex. The amygdala differs with regard to both connections and functions
areas receiving the thalamic input. This has led to the from the other parts of the basal ganglia, and is now usually considered a part
suggestion that the basal ganglia serve, as it were, to of the so-called limbic structures (Chapter 31).
324
23: THE BASAL GANGLIA 325
MAIN CONNECTIONS
Cerebral cortex
Cerebral cortex
Thalamus
Direct and Striatum Thalamus
indirect
motor
Brain
Basal ganglia
pathways Globus pallidus Subthalamic n.
stem
Substantia nigra
Spinal cord
gure 23.2
gure 23.1
macroscopic shape, the putamen and globus pallidus The globus pallidus has a different internal structure
together are called the lentiform nucleus. The caudate than the striatum, with larger, more motoneuron-like
nucleus and the putamen are similarly built, with pre- cells, and is also called the paleostriatum or pallidum. It
dominantly small neurons. They are also functionally consists of two parts, an internal segment (GPi) and an
related and are collectively termed the striatum or neo- external segment (GPe) (Figs. 23.3 and 23.4). The term
striatum. The neostriatum contains several neuronal corpus striatum includes both the pallidum and the
types that differ with regard to where they send their neostriatum. Phylogenetically, the caudate nucleus and
axons and to which neurotransmitters they use. Most of the putamen developed together and are younger than
the neurons, however, send their axons out of the stria- the pallidum (thus the names neostriatum and paleo-
tum (projection neurons); only a minority is interneu- striatum). As we will see, these two main divisions of the
rons with axons ramifying locally within the striatum. basal ganglia differ also with regard to connections.
The presence of several kinds of interneuron is consis- Cell groups that join the corpus striatum ventrally
tent with the fact that the striatum is not simply a relay without sharp transitionssuch as the nucleus accum-
station but also performs considerable processing of bens and the olfactory tubercleare now collectively
information. termed the ventral striatum, and thus included in the
A B
Lateral ventricle
(frontal horn)
Caudate
nucleus
(caput) A
Putamen
Globus pallidus
external segment GPe
internal segment GPi
Internal capsule
Thalamus C Thalamus
Caudate nucleus
(cauda)
Lateral ventricle
(occipital horn)
gure 23.3 Shape and position of the basal
ganglia. A: Part of a horizontal section through Caudate Caudate
the hemisphere, as shown (B) with a line in nucleus nucleus
drawing of the hemisphere (cf. Fig. 6.30 show- (caput) Putamen (cauda)
ing the whole section). C: Left putamen and cau-
date nucleus; lateral aspect.
Cerebral cortex
Caudate nucleus
(caput)
Internal
capsule
Putamen
Globus
pallidus
GPe
GPi
Claustrum
Caudate
nucleus
(cauda)
Pons
Subthalamic nucleus
gure 23.4 The basal ganglia seen in the
Substantia nigra frontal plane.
basal-ganglia concept. There is also a ventral exten-

The Striatum Is the Receiving Part of the Basal Ganglia
sion of the globus pallidus, called the ventral pal-
lidum. The ventral striatum differs in some respects Most of the information to be processed in the basal
from the restthat is, from the dorsal striatumand ganglia first reaches the striatum. It is characterized by
is treated separately in this chapter. The connections three major sources of afferents: the cerebral cortex, the
of the ventral striatopallidum correlate with its intralaminar thalamic nuclei, and dopamine-containing
importance for behavior governed by emotions. cell groups in the mesencephalon (Fig. 23.6).
Amygdala Putamen Globus Caudate 3d ventricle Internal

Amygdala Caudate Putamen Thalamus Lateral ventricle
pallidus nucleus capsule
nucleus
A B
gure 23.5 Magnetic resonance images (MRI) of the basal ganglia. the section. B: Parasagittal plane. (Courtesy of Dr. S. J. Bakke,
A: Frontal plane; red line in B shows approximate position of Rikshospitalet University Hospital, Oslo, Norway.)
The putamen is dominated by somatotopically orga-
Cerebral cortex nized inputs from the SI and MI. The caudate nucleus,
in contrast, receives fibers predominantly from the
Corticostriatal
tract association areasthat is, regions that are less directly
GLUTAMATE concerned with motor control than with cognitive func-
tions and emotions. Whereas the putamen receives rela-
Caudate nucleus tively raw, or unprocessed, information from sensory
receptors via the SI and from upper motor neurons in
the MI, the caudate nucleus receives information that is
Putamen
a result of integration of signals from many sources.
Such information reaching the caudate nucleus may
Thalamostriatal concern, for example, earlier stages in the chains of
tract
neural events leading to a decision about which move-
GLUTAMATE
ments are appropriate in the situation.
Thalamus
(intralaminar The striatal afferents from the intralaminar thalamic
nuclei) nuclei (Fig. 23.6; see Fig. 6.22) are numerous and are
believed to transmit information to the striatum about
Nigrostriatal tract stimuli that need special attention.
DOPAMINE
Caudate nucleus Dopaminergic striatal afferents to the dorsal striatum
Substantia nigra arise in the pars compacta of the substantia nigra,
(pars compacta) whereas the ventral striatum receive such fibers from
more scattered dopaminergic cells in the ventral
gure 23.6 The main afferent connections of the striatum.
tegmental area (VTA) dorsal to the substantia nigra
(Fig. 23.8). VTA also sends dopaminergic fibers to the
The largest contingent of afferents comes from the prefrontal cortex.
cerebral cortex. Almost all areas of the cortex send Additional, quantitatively minor afferent contingents
fibers to the striatum, but the caudate nucleus and to the striatum come from the serotonergic raphe nuclei
the putamen receive from different parts (Fig. 23.7). in the brain stem, among several other sources.
MI and SI
Association SMA
areas PMA
Prefrontal
cortex
Caudate
nucleus
VA, MD Thalamus
Putamen
Putamen
VL
gure 23.7 Parallel circuits cortexbasal ganglia
thalamuscortex. Highly simplied. The putamen
receives bers primarily from the motor and soma-
tosensory areas (red), whereas the caudate nucleus is
dominated by inputs from the association areas in
the frontal, parietal, and temporal lobes (blue). The
gure further shows that sensorimotor information, Substantia nigra
after processing in the basal ganglia, ends primarily Globus pallidus
in the SMA, whereas information from the association Internal segment
areas reaches large parts of the prefrontal cortex.
A B
Thalamus
Pars compacta
Red nucleus
Pars reticulata
Crus
cerebri
Substantia nigra
C D
To striatum To ventral striatum To thalamus, From striatum &
DOPAMINE & prefrontal cortex superior collic. , globus pallidus
DOPAMINE & PPN GABA
GABA gure 23.8 The substantia nigra.
A: Photomicrograph of transverse
section through the mesencephalon
(myelin stain). Inset (D) shows
plane and position of the section.
The photomicrograph is from the
VTA section shown in Fig. 6.21. B: Higher
magnication of framed area. The
cells of the pars compacta are clearly
Pars compacta seen as dark dots. The dark color is
Mesencephalon due to their content of pigment.
C: The two parts of the substantia
nigra differ structurally and with
regard to connections. Afferent
bers to the pars reticulata contact
Pars reticulata the dendrites of the dopaminergic
neurons in the pars compacta.
Thalamostriatal Connections ending in the specific thalamic nuclei. Thus, the thalam-
ostriatal projection seems to be part of a side loop in
The thalamostriatal projections have marked effects on
the pathway from the basal ganglia to the cortexhan-
striatal-neuron excitability, yet their functional role is
dling a copy of the pallidal output and sending
poorly understood. The main sources of thalamostri-
answers back to the striatum.
atal fibers are the centromedian (CM) and parafascicu-
lar (Pf) nuclei. In addition, projections arise in the
specific thalamic nuclei. Thus, while the VL and VA Efferent Connections of the Basal Ganglia: Striatal
send their main efferents to the cerebral cortex, they Projection Neurons
also send many fibers back to the striatum. The projec-
More than 70% of the striatal neurons have relatively
tion from the intralaminar nuclei has been most studied
small cell bodies and dendrites with numerous spines
and might provide the striatum with information about
(Fig. 23.9A) and are called medium spiny neurons.2
events that requires special attention. Thus, neurons in
This cell type contains -aminobutyric acid (GABA)
CM integrate various kinds of sensory information and
and sends its axon out of the striatum to the globus
increase their activity when a person switches from a
relaxed waking state to an attention-demanding task.
A major input to the CM and Pf comes from the globus 2 The percentage of projection neurons is higher in subprimate species (90%).
This agrees with an evolutionary trend with increasing proportion of interneu-
pallidus (internal segment) and the substantia nigra rons in general (e.g., in the cerebral cortex, the thalamus, and several brain stem
(pars reticulata) in the form of collaterals of fibers nuclei).
pallidus and the substantia nigra. There are two main A B
subtypes of this medium spiny neuron (Fig. 23.9A).
One kind contains substance P (and usually also dynor- Glutamate
Glutamate Dopamine
phin) in addition to GABA; the other contains enkepha- From cortex
lin in addition to GABA (a third, less characterized kind
of projection neuron contains neurokinin B in addition STRIATUM
to substance P and enkephalin). Physiological studies
suggest that the two kinds of medium spiny neurons GABA
+
project to different targets (Fig. 23.9A): GABA + Substance P
substance P neurons projects primarily to the GPi and/
Acetylcholine
or to the substantia nigra, whereas GABA + enkephalin PALLIDUM
3
neurons projects mainly to the GPe.
The two kinds of medium spiny neurons differ
also with regard to expression of dopamine receptors:
GABA + substance P neurons express predominantly D1
receptors, whereas GABA + enkephalin neurons express
mainly D2 receptors. Because these two kinds of recep- GABA
tor have opposite effects, the two kinds of medium spiny +
Enkephalin
neurons respond differently to dopamine. We return to
this point when discussion dopamine actions in the Dopamine
striatum. antia nigra)
(from substantia
gure 23.9 Three important kinds of neuron in the striatum, and the
Striatal Interneurons: Cholinergic and GABAergic termination of dopaminergic bers. A: The striatal projection neu-
rons are relatively small and their dendrites have many spines
The striatum has a complex intrinsic organization, even (medium spiny neurons). All striatal projection neurons are
though the majority of neurons are simple projection GABAergic but two kinds can be distinguished based on their content
neurons. For example, the axons of the medium spiny of neuropeptides (substance P and enkephalin). Note the large,
cholinergic interneurons. GABAergic interneurons are not shown.
neurons give off recurrent collaterals in the striatum
B: Dopaminergic synapses are often situated on spines that are con-
(Fig. 23.9A). Further, a number of different interneu- tacted by glutamatergic nerve terminals from the cortex. In addition,
rons exist (i.e., their axonal arborizations remain within dopaminergic bers end without forming synapses. Therefore,
the striatum). dopamine presumably acts via both specic synapses and volume
One conspicuous kind of interneuron, which consti- transmission.
tutes about 1% of all striatal neurons, has a large cell
body and smooth dendrites and contains acetylcholine GABAergic inhibition plays an important role in the
(Fig. 23.9A). These interneurons receive excitatory syn- functioning of the striatum, even though about 80% of
aptic influences from the cerebral cortex and the intra- all synapses are glutamatergic (mainly from the cortex
laminar thalamic nuclei (glutamatergic), as well as and the thalamus). Thus, by blocking GABAA receptors
inhibitory influences by the recurrent collaterals from in the striatum, the spontaneous firing rate of the pro-
GABAergic projection neurons. Acetylcholine acts via jection neurons triples. The inhibition is partly due to
muscarinic receptors (indirectly linked with K+ channels) the recurrent collaterals of the medium spiny neurons,
on striatal projection neurons with slow, modulatory partly to several types of fast-spiking GABAergic
effects. The overall effect of acetylcholine on the projec- interneurons, which receive excitation from the cere-
tion neurons is to ensure that they react with bursts of bral cortex and in turn inhibit the medium spiny neu-
action potentials to excitatory inputs from the cerebral rons. The recurrent inhibition has been assumed to
cortex: that is, the efficiency of signal transmission is produce lateral inhibition (see Fig. 13.4), whereas the
enhanced. The cholinergic interneurons contributein function of the inhibitory interneurons may to regulate
a yet unknown wayto the symptoms in Parkinsons overall excitability in a feedforward manner, in con-
disease, since anticholinergic drugs can improve the trast to the feedback action of the projection-neuron
symptoms. recurrent collaterals.4
4 The effects of GABA in the striatum are more complex than just producing
3 In at least apparent contradiction to such a dichotomy, tracing of single inhibition by binding to GABAA receptors, however. This is because the projec-
axons indicate that the majority of medium spiny neurons send collaterals to tion neurons have a strongly polarized resting potential (80 to 90 mV). That
GPe, GPi, and the nigra. If the innervation density differs among the targets, means that GABA depolarizes the projection neurons in the resting state. Only
however, a functional dichotomy may nevertheless be compatible with the when the membrane potential has been reduced to about 60 mV (by excitatory
observed branching of axons to several targets. inputs) does GABA produces hyperpolarization (inhibition).
Dopaminergic terminals of nigrostriatal neurons con- actions, not merely isolated movements. Thus, the
tact the projection neurons and the cholinergic interneu- effects exerted by the basal ganglia on other parts of the
rons (Fig. 23.9). In agreement with this, both cell types nervous system are mediated primarily by efferent fibers
express mRNA for dopamine receptors. from the pallidum and the substantia nigra. These
nuclei receive their main afferents from the striatum
(Figs. 23.7 and 23.10). In this manner, the pallidum
Compartments in the Striatum: Islands, Striosomes,
and nigra process information from the striatum before
and Matrix
it is sent to premotor networks. The efferents from the
The various cell types, neurotransmitters and afferent striatum are topographically organized, so that subdivi-
connections are not evenly distributed throughout the sions of the striatum are connected with specific parts
striatum. First, the striatal neurons form clusters, called of the pallidum and the nigra.
islands. Further, a mosaic pattern appears after staining
to demonstrate acetylcholine esterase. Poorly stained
The Substantia Nigra
patches called striosomes are embedded in a heavily
stained matrix. The matrix can be further subdivided The substantia nigra and some of its connections have
by visualization of various transmitters and their recep- been mentioned several times, and we will also return
tors. Cholinergic interneurons and GABAergic projec- to it when dealing with Parkinsons disease, in which
tion neurons are found within both the matrix and the the nigra plays a crucial role. A collective treatment of
striosomes, and the two main kinds of projection neu- the main features of the substantia nigra may therefore
rons do not appear to be clearly segregated, either. be pertinent at this stage
However, corticostriatal fibers terminating in the strio- The substantia nigra can be divided anatomically into
somes and in the matrix come from deep and superficial two parts, the pars compacta and the pars reticulata
parts of layer 5, respectively. Thus, cortical information (Figs. 23.8A and 13.11A). The compacta is richer in
to neurons in the two compartments would be expected cells than the reticulata, whereas the latter (as the name
to differ slightly, even when coming from the same cor- implies) is dominated by dendritic arborizations. The
tical area. Further, the further projections also appear reticulata also contains numerous neurons, however.
to differ with regard to exact termination and patterns The compacta neurons contain pigment (neuromela-
of arborizations. Finally, striatal afferent connections nin), which makes the nigra visible as a dark band in
terminate in patches within the matrix. Each small part the cut human mesencephalon (see Fig. 23.4). The pars
of the cortex, for example, projects divergently in many
patches. These data have been taken as evidence that the
striatum is organized in numerous minor compartments
or modules, each presumably representing a functional Cerebral
unit. It is fair to say, however, that in spite of a wealth cortex
of data, the functional significance of striatal compart-
mentalization is still a matter of speculation (and the
interpretation of data is made more difficult by the
existence of species differences).
Striatum
Efferent Connections of the Basal Ganglia: Acting on Internal

capsule
Premotor Networks in Thalamus and Brain Stem
Pallido-
The efferent connections of the basal ganglia may be thalamic
summarized as follows. The internal segment of the tract
globus pallidus and the substantia nigra send the infor- Thalamus
(VL, VA)
mation processed in the basal ganglia to premotor
Globus
networks in the thalamus, the mesencephalon, and the pallidus
superior colliculus. Here we use the terms premotor Substantia
and premotor networks in a rather loose sense about nigra
neuronal groups acting either directly on motoneurons
Glutamatergic neurons
or on the motor cortex. Such premotor networks are
found in the spinal cord, the reticular formation, and GABAergic neurons
the thalamus. Neurons of the thalamic VL nucleus, for
gure 23.10 The loop cortexbasal gangliathalamuscortex con-
example, are considered premotor due to their direct tains two inhibitory neurons in series. This means that increased
projection to the motor cortex. Premotor networks orga- signal trafc out of the striatum leads to less inhibition in the thalamus
nize the activity of motoneurons to produce purposeful (disinhibition). Cf. text.
reticulata, located ventral to the compacta, is lighter. inhibitory effects on the cells in the nigra. Excitatory
The dopaminergic nigrostriatal neurons are located in afferents to the nigra arise in the subthalamic nucleus
the pars compacta, whereas the GABAergic nigrotha- and the pedunculopontine nucleus (PPN) in the mesen-
lamic neurons are located primarily in the pars reticu- cephalon (glutamate). Afferents with modulatory effects
lata (Fig. 23.8C). come from the locus coeruleus (norepinephrine) and
The efferent connections of the pars compacta (Fig. the raphe nuclei (serotonin). Additional afferents arise
23.11A) pass primarily to the striatum (with a smaller in the ventral striatum and the bed nucleus of the stria
contingents to the subthalamic nucleus and some other terminalis (BST), presumably mediating signals related
nuclei). This is the largest dopaminergic pathway in the to motivation, attention, and mood. An important link
brain, and nigra is the largest collection of dopamine- in the latter pathways is the habenula (especially the
containing neurons. Pars reticulata send GABAergic lateral nucleus). Electric stimulation of the lateral habe-
fibers to the thalamus (VA, MD). In addition, it projects nula effectively suppresses activity of dopaminergic neu-
to the superior colliculus (Fig. 23.11A), which control rons, presumably by activating inhibitory interneurons.
coordinated eye and head movements, and to the
pedunculopontine nucleus (PPN) involved control of gait
Pathways from the Globus Pallidus and the Substantia
and posture. The nigral neurons sending their axons to
Nigra to the Cerebral Cortex
the thalamus and the superior colliculus are found in
largely separate parts of the pars reticulata. As mentioned, the globus pallidus consists of two
The afferent fiber connections of the nigra (Fig. 23.11B) parts, an external (GPe) and an internal (GPi) segment
arise in numerous cell groups, but quantitatively the (Figs. 23.3 and 23.4). Both segments receive their main
most important input comes from the striatum. This afferents from the striatum, with additional inputs from
projection shows some topographic organization; for the subthalamic nucleus. Whereas the fibers from the
example, afferents from the putamen and caudate striatum exert inhibitory actions in the GPi, the subtha-
nucleus end differently. Even though most striatonigral lamic afferents are excitatory. The balance between
fibers terminate in the pars reticulata, cells in the com- these two inputs therefore to a large extent determines
pacta can also be influenced because their long den- the activity of the GPi neurons. The main part of the
drites extend into the reticulata (Fig. 23.8). GABA is efferents from GPi goes to the thalamus and the sub-
the transmitter for the striatonigral fibers, exerting stantia nigra (pars reticulata), whereas the GPe projects
Caudate
nucleus
Striatum
Striatum
GABA
Putamen
Thalamus
(VA, MD)
Subthalamic
nucleus
GLUTAMATE
Substantia nigra
pars compacta
DOPAMINE
Substantia nigra PPN
pars reticulata GLUTAMATE
GABA
Superior
Locus coeruleus
colliculus PPN NOREPINEPH- Raphe nuclei
RINE SEROTONIN
gure 23.11 Main connections of the substantia nigra. A: Efferents. (GABAergic) afferents come from the striatum, whereas excitatory
Dopaminergic neurons in the pars compacta send bers to the stria- (glutamate) bers com from the subthalamic nucleus and the PPN.
tum, whereas GABAergic neurons in the reticulata act on premotor Modulatory afferents arise in the raphe nuclei (serotonin) and the
neurons in the thalamus and the brain stem. B: Afferents. Inhibitory locus coeruleus (norepinephrine).
mainly to the subthalamic nucleus. Many of the palli- (PPN) have attracted special interest. Thus, this region
dothalamic fibers pass through the internal capsule overlaps with the mesencephalic locomotor region (elec-
(Fig. 23.10) and can therefore be damaged by lesions in trical stimulation of this region elicits walking
6
this region (this should be kept in mind when analyzing movements). Conceivably, these connections are of rel-
the symptoms occurring after capsular infarctions, as evance for the characteristic disturbances of muscle tone
5
discussed in Chapter 22). In the thalamus the pallidal (rigidity) and locomotion seen in Parkinsons disease (in
fibers end in the ventral anterior nucleus (VA) and in which there is marked cell loss in the substantia nigra
parts of the ventrolateral nucleus (VL) (Figs. 23.3 and but also in the PPN). Some observations furthermore
13.4; see also Fig. 14.6). The VL and VA send their indicate that the characteristic poverty of movement
main efferents to the cerebral cortex but also many akinesiain Parkinsons disease might be due to increased
fibers back to the striatum. In more detail, the VA sends inhibition of the PPN from the globus pallidus. For
efferent fibers to the premotor area (PMA) and the pre- example, destruction of the PPN in monkeys has been
7
frontal cortex, whereas the parts of the VL that receive reported to produce akinesia.
fibers from the pallidum and the nigra project primarily Connections from the substantia nigra to the supe-
to the supplementary motor area (SMA; see Fig. 24.16). rior colliculus (Fig. 23.11A) participate in the control
The substantia nigra sends fibers to the thalamus, end- of coordinated head and eye movements.
ing in partly different nuclei than the pallidal fibers.
Thus, the efferents from pars reticulata of the substantia
The Basal Ganglia Are Arranged in Parallel Circuits
nigra end in parts of the VA and the mediodorsal nucleus
(MD; Figs. 23.7 and 23.11A). From there, signals travel Studies with axonal tracing techniques indicate that
primarily to parts of the PMA and the prefrontal cortex. there are four (or more) loops or circuits through the
Summing up, much of the information flow from the basal ganglia, in which the flow of information is kept
basal ganglia is directed toward the motor cortical at least largely segregated. This localization goes fur-
areas. Physiological studies also indicate that the influ- ther than depicted in Fig. 23.7, which shows only the
ence of the basal ganglia on motor control involves the main differences between projections from association
corticospinal tract and indirect descending pathways areas and the pericentral (motor and somatosensory
from the cerebral cortex to the motoneurons (Fig. 23.1). areas) region. Four circuits are now well established:
It should be kept in mind, however, that the caudate one originating in sensorimotor areas, one in associa-
nucleus receives afferents mainly from cortical association areas, one in so-called limbic cortex, and one in
tion areas and acts primarily on the prefrontal cortex oculomotor cortical areas. Via the basal ganglia and the
(Fig. 23.7), which is not directly involved in motor thalamus, signals are funneled back to largely separate
control but in cognitive functions, such as memory and parts of the cortex. Thus, the basal ganglia appear, at
planning of behavior. Accordingly, lesions of the cau- least as a general rule, to process different kinds of
date nucleus in monkeys produce symptoms similar to information in parallel.
those seen after damage to the prefrontal cortexamong One circuit arises in the SMA, MI, and SI; passes
other things, reduced performance in tests requiring through the putamen; and, via the pallidum and the
spatial memory (such as to recall where an object is thalamus, ends mainly in the SMA. This circuit is prob-
located when it is out of sight). ably the one most directly involved in control of move-
ments. Recordings of single-cell activity in the putamen
support this assumption. Each circuit thereby seems to
Basal Ganglia Efferents to the Brain Stem:
be specialized for certain tasks. It should be empha-
Pedunculopontine Nucleus and
sized, however, that although there probably is modest
Superior Colliculus
integration among the various circuits, each circuit
In addition to the massive connections from the basal integrates information from anatomically separated,
ganglia to the thalamus, there are also efferents reaching although functionally related, cortical areas. A second
the reticular formation in the mesencephalon (Fig. circuit arises in different parts of the prefrontal cortex
23.11A). This enables the basal ganglia to influence and passes through the caudate nucleus, the substantia
muscle tone and movements via reticulospinal tracts.
Connections from the pars reticulata of the substantia 6 Most bers from the GPi to the PPN are collaterals of pallidothalamic bers,
nigra and from the GPi to a part of the mesencephalic suggesting that the thalamus and the PPN receive the same kind of information
reticular formation called the pedunculopontine nucleus from GPi. The PPN projects back to the pallidum and also to the subthalamic
nucleus. Obviously, the PPN not only is an output channel from the basal gan-
glia to brain stem premotor cell groups but also acts back on the basal ganglia,
inuencing their internal information processing.
5 The efferent bers from the pallidum form two bundles, the ansa lenticularis 7 That connections from the globus pallidus to the PPN are involved in akine-
and the fasciculus lenticularis. They arise from somewhat different parts of the sia is further supported by the effects of stereotaxic surgery in patients with
internal pallidal segment and fuse to form the fasciculus thalamicus after having Parkinsons disease. Thus, lesions of the GPi often improve the akinesia,
traversed the internal capsule. whereas lesions of the thalamus do not have this effect.
nigra (to a lesser degree the pallidum), the VA, and the
mediodorsal thalamic nucleus (MD in Fig. 23.3; see Disinhibition of Premotor Neurons
also Figs. 21.7 and 21.8) and back to prefrontal cortical
areas. The third arises in limbic parts of the cortex Cerebral Cortex
(the cingulate gyrus, orbitofrontal areas of the prefron- Glutamate+
tal cortex, and parts of the temporal lobe cortex, which Glutamate+
are parts of or closely connected with the limbic struc- Striatum Thalamus
tures). This limbic circuit passes through the ventral GABA
striatum, ventral pallidum, and the MD of the thalamus GABA
and back to the cortical areas from which the circuit Globus pallidus
started. These connections are believed to be involved & nigra
in regulation of mood and emotions, and to behavior GABA
directed to satisfy basal needs (such as eating and drink- Brain stem (PPN)
ing), and to obtain rewards (see The Ventral Striatum,
Psychosis, and Drug Addiction, later). In addition, a
gure 23.12
fourth circuit in parts of the frontal and parietal lobes
concerned with oculomotor controlthat is, area 8
immediately in front of area 6 (the frontal eye field) and
area 7 (see Fig. 25.7). After synaptic interruption in spe- GABAergicthat is, the pallidothalamic fibers from
cific parts of the caudate nucleus, this circuit ends primar- the GPi and the pallidosubthalamic fibers from the GPe
ily in area 8. This prefrontal circuit presumably enables are inhibitory. The nigrothalamic fibers, arising in the
the basal ganglia to influence cognitive functions. pars reticulata, are also GABAergic and thus inhibitory.
While the principle of parallel processing in the basal The thalamocortical fibers (from the VL and VA, as from
ganglia seems well established, there is evidence that other thalamic nuclei) are excitatory (glutamate).
there is also considerable crosstalk among the circuits. The flow of information from the cerebral cortex
Tracing experiments in animals and DWI (diffusion through the basal ganglia and back is obviously less
weighted imaging) studies humans suggest that the thal- straightforward than if all involved synapses were excit-
amus might be a main site for integration in the basal atory. Notably, there is a chain of two inhibitory neu-
ganglia circuits. rons from the striatum to the premotor neurons in the
All the circuits are influenced by the subthalamic thalamus and the brain stem (Fig. 23.12). Increased
nucleus (Fig. 23.4). Indeed, subdivisions of this small cortical input to the striatum would lead to decreased
nucleus project with topographic order to the dorsal activity of the pallidal neurons, because excitation of
and ventral pallidum. This might explain why electric striatal neurons produces increased inhibition in the
stimulation of the subthalamic nucleus (deep brain pallidum. In turn, this would increase the activity of
stimulation) aimed at improving motor symptoms in thalamocortical neurons (because they would receive
Parkinsons disease can give side effects such as mood less inhibition from the pallidum). Thus, excitatory
changes (depression or mania), cognitive decline, and impulses from the cortex would eventually produce
personality changes. Affections of circuits involving the disinhibition of the thalamocortical neurons (and other
prefrontal cortex are especially likely to produce such premotor neurons in the reticular formation and the
side effects. superior colliculus receiving fibers from the substantia
nigra).
Transmitters and Synaptic Actions in the CortexBasal
GangliaCortex Loop: Disinhibition Functional Signicance of Disinhibition in Premotor
To understand the processing going on within the basal Neuronal Groups
ganglia and their effects on other parts of the brain, we Recordings of single-cell activity in the basal ganglia
need to know the transmitters and the synaptic actions in awake monkeys are compatible with the aforemen-
of all the neurons involved. The conditions turn out to be tioned considerations. At rest, most striatal neurons are
extremely complex. Numerous neuroactive substances silentthat is, they do not produce action poten-
have been found in the striatum, although only a few tialswhereas the pallidal neurons and neurons in the
can be correlated with anatomic and physiologic data. pars reticulata of the substantia nigra fire with a high,
The corticostriatal and thalamostriatal fibers are regular frequency.8 This would presumably keep the
excitatory due to release of glutamate (Fig. 23.12). As
discussed in the preceding text, the striatopallidal and
8 This is not quite true for the GPe neurons, however, because they re with a
striatonigral fibers contain GABA and have inhibitory somewhat lower and more uneven frequency than GPi neurons, and further-
effects. The neurons in the globus pallidus are also more tend to re in bursts.
premotor neurons in the thalamus and the brain stem in Motor cortex
a state of inhibition when the animal is not moving.
Commands from the cortex to the basal ganglia in rela-
tion to the preparation or execution of movements
would release the premotor neurons from this inhibi-
tion. Indeed, electrophysiological experiments show that
increased striatal activity reduces the activity of many
pallidal and nigral neurons, followed by increased firing
of thalamocortical neurons.
GPe
It has been proposed that the disinhibition of premo-
GPi
tor neurons by the basal ganglia is a gating mechanism
to control the access of other inputs (e.g., sensory) to the
motor cortex. As the connections of the basal ganglia
are topographically organized at all levels, this would Subthalamic
be a specific and focused gating rather than a diffuse nucleus
one, varying with the nature of the motor task. Such
focused effects might serve to reinforce wanted move-
ments while suppressing unwanted ones. Substantia nigra
(pars reticulata)
The Subthalamic Nucleus Regulates Pallidal GABAergic neurons

and Nigral Activity Glutamatergic neurons
While efferents of the internal pallidal segment (GPi)
gure 23.13 Main connections of the subthalamic nucleus. Inhibitory
end primarily in the thalamus (and the nigra), the
afferents arise in the globus pallidus and substantia nigra, whereas
GABAergic fibers from the GPe are directed toward the excitatory connections come from (among other sources) the motor
subthalamic nucleus (Fig. 23.13). The subthalamic cortex. Glutamatergic neurons in the subthalamic nucleus excite the
nucleus also receives excitatory afferents from the GABAergic neurons in the globus pallidus and the substantia nigra.
motor cortex, thus constituting a cortical input to the Especially the connections from GPe to the subthalamic nucleus and
from there to GPi have been postulated to be of special signicance
basal ganglia in addition to the major corticostriatal
for the symptoms in Parkinsons disease.
pathway. Most of the efferents from the subthalamic
nucleus go back to both segments of the pallidum and
to the pars reticulata of the substantia nigra. As men-
tioned, the subthalamopallidal fibers exert excitatory Thus, the violent involuntary movements of the oppo-
actions. site body half after destruction of the subthalamic
The efferents of the subthalamic nucleus are topo- nucleushemiballismusmight be caused by hyperac-
graphically organized, as shown with axonal transport tivity among the thalamocortical neurons. In a yet
methods. Thus, different neuronal populations project unknown way, disturbed activity of subthalamic neu-
to the substantia nigra and the pallidum, and there are rons (abnormal high-frequency firing and oscillatory
differences with the regard to projections to minor parts activity) appears to be crucial to the symptoms in
of the pallidum. Fibers from the subthalamic nucleus Parkinsons disease. Indeed, switching off the sub-
and the striatum converge on the same neurons in the thalamic nucleus by lesion or by electric stimulation has
GPi. These data suggest that the activity of the produced marked symptomatic relief in many patients.
GABAergic neurons in GPi are determined largely by
the sum of synaptic influences from the striatum () and
Actions of Dopamine in the Striatum
the subthalamic nucleus (+). Because GPi neurons inhibit
thalamocortical neurons, increased subthalamic activity The connections and transmitters described so far are
would be expected to produce reduced excitation of the concerned with fast transmission of specific informa-
motor cortexthat is, inhibition of voluntary move- tion, mediated by glutamate and GABA. In addition,
ments. Thus, the subthalamic nucleus is believed to con- modulatory transmitters have important roles in the
trol or stop ongoing movements, rather than to select functioning of the basal ganglia. This concerns dop-
and initiate movements. Considering the somatotopical amine in particular. Indeed, the most studied basal gan-
organization of its connections, the subthalamic nucleus glia connection is the dopaminergic nigrostriatal
presumably exerts specific actions rather than a diffuse pathway, which is the most massive dopaminergic
inhibition of all motor activity. pathway in the central nervous system (CNS). Many
Loss of influence from the subthalamic nucleus dopaminergic nerve terminals are strategically placed
would produce disinhibition of thalamocortical neurons. on spines close to the corticostriatal nerve terminals
9
(Fig. 23.9B). This is a pathway of great clinical interest stabilize the membrane potential, perhaps to avoid
because several diseases are related to disturbed dopamine- excessive activation by glutamate from the cortex.
mediated synaptic transmission (Parkinsons disease, In conclusion, dopamine probably serves to keep the
schizophrenia, Tourettes syndrome, and others). membrane potential in the range where the postsynap-
Striatal neurons express, not unexpectedly, dopamine tic neuron is apt to fire in burststhat is, in a state
receptors. Dopamine alters the response of striatal neu- suited for efficient signal transmission. Some data sug-
rons to specific inputs from the cerebral cortex and the gest that D1 receptor activation enhances the activity of
thalamus. In more detail, however, actions of dopamine neurons that receive a strong and focused excitatory
on neuronal excitability in the striatum are multifarious input (from the cerebral cortex), while reducing the
and not fully understood. activity of neurons receiving weak inputs. This would
There are two main kinds of dopamine receptorD1 help in focusing striatal activity, in accordance with
and D2, with subtypes of each. Common to the D1-like other data indicating that the basal ganglia assists in the
receptors (D1 and D5) is that they increase the synthesis selection of behavior, such as the choice of specific
of intracellular cyclic AMP, whereas D2-like receptors movements.
(D2D4) have the opposite effect. Dopamine receptors
are present both pre- and postsynaptically in the striatum, The Indirect Pathway, the Subthalamic Nucleus,
and dopamine influences, among other things, several and Parkinsons Disease
kinds of ion channel. The actions of the D1 receptor is
The signal pathway we described abovecortex-striatum-
most studied, whereas more remains to be known about
GPi-thalamus-cortexare often said to establish a
the D2 receptor.
Although there is, as mentioned previously, physio-
logical evidence that the major effect on striatal projec- Cerebral cortex
tion neurons of D1-receptor activation is excitatory and + GLUTAMATE
that of D2-receptor activation is inhibitory, the actions
of dopamine is not properly described by this simple
dichotomy. One factor complicating the analysis is that
dopaminergic neurons fire in two characteristic modes,
tonic and phasic, with either a sustained or transitory
rise in dopamine concentrations. There is some evidence
that phasic release of dopamine acts on D1 receptors Thalamus
(excitatory, LTP induction) whereas tonic release acti-
vates D2 receptors (inhibitory, LTD induction). Because
the two main types of medium spiny neurons express
_
different dopamine receptors (Fig. 23.14), this would GLUTAMATE GABA
GABA+SP DIRECT
imply the neuronal target of dopamine depends on the PATHWAY
firing mode of the nigrostriatal neurons. Another factor +
making it difficult to generalize dopamine actions is D1
that the effect of dopamine depends on the state of the +
postsynaptic neuron. For example, D1 receptors may D2
GABA
produce depolarization or hyperpolarization, depend- _
ing on the membrane potential of the postsynaptic
GABA+Enk
_ _
neuron. In one state, the neuron is depolarized and fire + GLUTAMATE
bursts of action potentials; in the other state it is hyper-
polarized and inactive. In the inactive state, activation Striatum GPe GPi GABA
of D1 receptors depolarizes the cell (by closure of K+ _
channels) so that it reacts more easily with burst to an INDIRECT
excitatory input from the cortex. If the neuron is in the PATHWAY Subthalamic nucleus
active state, however, D1 receptor activation closes a
gure 23.14 Direct and indirect pathways through the basal
Na+ channel that keeps the neuron depolarized by leak- ganglia. One pathway goes directly from the globus pallidus to the
age of cations into the cell. Closing this channel would thalamus; the other goes indirectly via the subthalamic nucleus.
Excitation of striatal projection neurons from the cerebral cortex
would produce disinhibition in the thalamus via the direct pathway,
while producing inhibition via the indirect pathway. Disturbance of
9 Dopamine depletion in the striatum is associated with loss of dendritic
arborizations and spines (in Parkinsons disease and in animal experiments). the balance between these two pathways is postulated to explain
Therefore, dopamine probably has a direct growth-promoting effect on neurons, some of the symptoms in Parkinsons disease. However, anatomic
or it protects against the harmful effects of strong glutamatergic excitation (or data speak against that the division between the direct and indirect
both). pathway is as sharp as shown in this gure.
direct signal pathway to distinguish it from an indirect What Activates the Nigrostriatal Neurons?
pathway (Fig. 23.14). The latter involves a side-loop
In light of the dominating effects of dopamine in the
connecting the GPe to the subthalamic nucleus, which
striatum, it is of particular interest to know under which
projects back to the GPi. Findings of increased activity
conditions the nigrostriatal neurons are activated. Clues
in the subthalamic nucleus in animal models of
may come from the fact that many of the nuclei sending
Parkinsons disease led to great interest in the indirect
fibers to the nigra change their activity in relation to
pathway because it offered a possible explanation of
arousal, motivation, and emotionally driven behavior.
how loss of striatal dopamine can lead to subthalamic
This concerns the PPN, the locus coeruleus, the raphe
hyperactivity. As described in the preceding text, it has
nuclei, and the ventral striatum and other cell groups in
been assumed that striatal medium spiny neurons con- 10
the basal forebrain. Accordingly, physiological stud-
taining GABA and substance P project mainly to the
ies show that striatonigral neurons do not change their
GPi and express D1 receptors, whereas neurons contain-
firing in relation to movements but in relation to stimuli
ing GABA and enkephalin project mainly to GPe and
that are unexpected or are judged to be of particular
express D2 receptors (Fig. 23.9). These assumptions led
salience for the behavior of the animal at the moment.
to the postulation of two parallel signal pathways out
This may concern stimuli signaling reward or punish-
of the striatum: the direct and the indirect. In conjunc-
ment, although they must have a fairly high intensity to
tion with data showing that D1 receptors excite striatal
activate dopaminergic neurons.
projection neurons whereas D2 receptors inhibit them,
In general, dopamine assists in establishing associa-
this could explain the subthalamic hyperactivity. The
tions between stimuli and their reward value. This kind
model predicts that release of dopamine in the striatum
of learning underlies motivated behavior based on prior
excites striatal neurons that project to the GPi while
experience. As mentioned, dopaminergic neurons in the
inhibiting neurons projecting to the GPe. This would
midbrain fire either in bursts or tonically. Selective
increase inhibition in the GPi but reduce it in the GPe,
reduction of burst firing in mice (by genetic manipula-
thereby evoking increased inhibition of subthalamic
tions), support the idea that a brief release of dopamine
neurons. Because of reduced firing, the subthalamic
acts as a signal for associative learning, especially related
excitatory influence on the GPi would be diminished.
to potentially rewarding or dangerous events.
Thus, release of dopamine in the striatum wouldvia
both the direct and the indirect pathwaysreduce exci-
tation in the GPi. Thus would give less inhibition (disin-
THE VENTRAL STRIATUM
hibition) of thalamic and nigral neurons from GPithat
is, the excitation of cortical motor areas would increase.
The term ventral striatum is used for rather diffusely
In this way, dopamine would facilitate movements via
distributed cell groups in the basal part of the hemi-
both pathways. In case of dopamine depletion in the
spheres (the basal forebrain; see Chapter 31, under
striatum, the GPe would receive stronger inhibition
The Basal Forebrain, for a discussion of its constitut-
from the striatum (because the GABA + enkephalin
ing parts). The ventral striatum merges with the dorsal
neurons are no longer inhibited by dopamine), and this
striatum without sharp boundaries. The nucleus accum-
was postulated to explain the increased subthalamic
bens represents a fairly distinct part of the ventral stria-
activity.
tum, and connects the caudate nucleus and the putamen
Even though subthalamic dysfunction undeniably is
ventrally (Fig. 23.15). A similar diffuse cell group, the
of crucial importance in Parkinsons disease, the clear
ventral pallidum, merges with the dorsal well-defined
division between a direct and an indirect pathway may
parts of the globus pallidus (see Fig. 31.8). The ventral
not be tenable. One problem is, as mentioned, that
striatopallidum is used as a collective term.
many striatal neurons send branches to several targets
(not only to GPi or GPe). Moreover, the scheme in
Fig. 13.14 is highly simplified because it leaves out sev- Connections of the Ventral Striatum
eral fiber connections. For example, the subthalamic
Although the ventral striatopallidum has no sharp bound-
nucleus does not only project to the GPi but also to the
aries toward other cell groups in the basal forebrain, its
GPe. Finally, the segregation of D1 and D2 receptors in
the striatum may not be as sharp as depicted in
Fig. 13.14. Thus, studies with sensitive techniques indi- 10 The habenula receives afferents from these nuclei and the hypothalamus
cate that many striatal projection neurons express both and projects to the substantia nigra pars compacta and the VTA. It seems to
play a particular role in controlling the activity of dopaminergic neurons (and
D1 and D2 receptors, although apparently the expres- other monoaminergic neurons). Signals from the habenula appear to occur
sion of one receptor type dominates. Finally, experi- especially in situations when an expected reward is not given. It has therefore
mental studies in Parkinsonian monkeys have not been been suggested to constitute a pivotal link in a circuit of disappointment
(Fritz A. Henn, personal communication). Indeed, the lateral habenula shows
able to confirm the postulated reduced activity in GPe altered activity in depression and is the target of deep brain stimulation for
neurons (explaining the subthalamic hyperactivity). depressive disorders.
Internal
capsule
Dorsal striatum
Insula Claustrum
Septal nuclei
Anterior commissure
Ventral striatum
(nucleus accumbens)
Optic nerve
Temporal lobe
gure 23.15 The ventral striatum with the nucleus accumbens. The Photo of a frontal section through the brain at the level of the anterior
septal nuclei, which belong to the basal forebrain, are also indicated. commissure (cf. Fig. 6.26).
relationship to the basal ganglia is witnessed by the and that the pleasurable feelings evoked by, for exam-
similarities of their connections. We mentioned one of ple, narcotic drugs are caused by release of dopamine in
the circuits through the basal ganglia: from parts of the the nucleus accumbens. Indeed, much evidence points
prefrontal cortex and cingulate gyrus to the ventral to dopamine as the neurotransmitter most directly
striatum, from there to the ventral pallidum, then to the involved in the pleasurable effects of drugs of abuse.
mediodorsal thalamic nucleus (MD), and finally back Nevertheless, many other parts of the brain than the
to the prefrontal cortex. There is probably a further dif- nucleus accumbens are activated by stimuli evoking
ferentiation of connections through the ventral striatum reward-motivated behavior, and there are substances
(several circuits). Thus, it receives afferents with some top- that produce reward behavior without activating the
ographic localization from the hippocampal formation, mesolimbic dopaminergic neurons. Today, several
the amygdala, the orbitofrontal cortex, and parts of the other transmitters than dopamine are under intense
temporal lobe (all these sources are either parts of the lim- scrutiny in addiction researchsuch as glutamate, ace-
bic structures or closely connected with them). The nucleus tylcholine, serotonin, and several neuropeptides. As
accumbens also send efferent fibers to the hypothalamus said by the American neuropharmacologist Ann Kelley
and the mesencephalic reticular formation (PPN). (2002, p. 448) in connection with nicotine addiction:
Like the dorsal striatum, the ventral striatum receives Thus, repeated exposure of the brain to drugs with
many dopaminergic fibers; those projecting to the ven- abuse potential sets in motion a cascade of activity
tral striatum are located mainly dorsomedially to the involving dopamine, glutamate and acetylcholine sig-
substantia nigra, in the ventral tegmental area (VTA). naling. Further, opinions on what drives the mesen-
Since the dopaminergic neurons in VTA project primar- cephalic dopaminergic neurons has changed from solely
ily to the ventral striatum, the prefrontal cortex and focusing on reward to a more general activation by
other cell groups that are closely linked with limbic unexpected or highly salient stimuli requiring a change
structures, the term the mesolimbic dopaminergic sys- of behavior, as discussed above.
tem is now widely used. To use the word system for
this is hardly justified, however, as there is little reason
The Ventral Striatum, Psychosis, and Drug Addiction
to assume that these widespread dopaminergic projec-
tions are functionally homogeneous. Afferents to the The dopaminergic projection to the ventral striatum
VTA have been traced from the prefrontal cortex, the (especially to the nucleus accumbens) has attracted
nucleus accumbens, and the PPN (and other nuclei). much interest, because antipsychotic drugs appear to
bind with particularly high density in the ventral stria-
tum. Such drugs are dopamine antagonists with pre-
The Mesolimbic Reward System
ferred binding to D2 receptors. Neurons in the nucleus
A popular theory suggests that the dopaminergic accumbens of experimental animals change their pat-
mesolimbic connections constitute a reward pathway tern of activity during development of drug addiction,
no matter whether the drug is amphetamine, cocaine, normal, whereas the manner in which the task is per-
or morphine. The addictive behavior is reduced by formed is not significantly altered. Therefore, neither
lesions of the nucleus accumbens or by removing its the movement command nor the movement program
dopaminergic innervation. Thus, after giving a dop- appears to be located within the basal ganglia them-
amine antagonist, the experimental animals stop self- selves. There is also evidence that the basal ganglia par-
administration of cocaine (they could easily obtain an ticipate when movements are learned by repetition and
intravenous dose by a movement). Further, dopaminer- not by gaining insight into the nature of the task and,
gic activity is increased in paranoid psychoses elicited furthermore, that the basal ganglia enable automatic
by amphetamines or cocaine (see also Chapter 5, under performance of well-rehearsed movements by the use of
GABA Receptors Are Influenced by Drugs, Alcohol, motor programs located elsewhere in the CNS. We also
and Anesthetics, Nicotinic Addiction, and Drugs discussed earlier the role of the basal ganglia (and dop-
Altering Monoamine Activity in the Brain). amine in particular) with regard to associative learning.
However interesting these observations are, they
provide only limited insight. By focusing on one trans-
Motivation
mitter and one part of the brain, one may even give the
impression that there is a simple biologic explanation Some experimental evidence shows that the basal
to complex mental phenomena. Indeed, many parts of the ganglia contribute to the linking of motivation and
brain other than the nucleus accumbens show altered emotions to the execution of movements. Thus, record-
activity in the conditions discussed here (see Chapter 34 ing the activity of single cells in the striatum indicates
for some comments on mental illness and the cerebral that many respond best when a stimulus is linked with
cortex). In drug addiction, for example, changes of neu- memory of an event that has a particular significance
ronal activity occur in the locus coeruleus (norepineph- for the animal. For example, certain cells in the sub-
rine) and in the intralaminar thalamic nuclei, amygdala, stantia nigra are active just before a rapid eye move-
and parts of the basal forebrain adjoining the nucleus ment, but only when the movement is directed toward
accumbens. It is not clear whether the nucleus accum- a target whose location the animal must remember in
bens or the ventral tegmental area is the primary target order to obtain a reward. As mentioned, the nigrostri-
of narcotic drugs in the brain; neither is it known how atal dopaminergic fibers appear to provide information
such drugs alter the properties of dopaminergic neu- about the relevance of a stimulus. Further, motivation
rotransmission. (expectation of reward) influences strongly how sen-
sory information is processed in the striatum.
FUNCTIONS OF THE BASAL GANGLIA

Shift of Behavior
In spite of enormous research activity during recent A central theory, trying to unite several lines of investi-
years, the functions of the basal ganglia are still far from gation, proposes that the basal ganglia are important
fully understood. One reason is that recent research for the selection and shift of behavior in particular. This
has made us realize that the basal ganglia participate in appears to concern both movements and cognitive func-
much more than just motor control; they also provide tions. In response to unexpected changes in the envi-
important contributions to cognitive and emotional ronment, it is often necessary to switch attention quickly
processing. Further, their role in various aspects of from one target to another. At the same time, the behav-
learning attracts increasing interest. ior might need to be shifted on the basis of a decision of
what is appropriate in the new situation. Thus, a new
behavior is selected, and the current behavior must
Movement Planning and Learning 11
therefore be stopped. The evaluation (giving priority
Taking the connections of the basal ganglia as a start- to a certain behavior) probably requires cooperation
ing point (leaving out the ventral striatum for the time between the prefrontal cortex and limbic structures,
being), it is noteworthy that their major output goes to while the execution of the behavioral switching may
the SMA, PMA, and the prefrontal cortical areas. The depend on the basal ganglia (regardless of whether it
properties of these areas suggest that the basal ganglia concerns change of movements or thoughts).
would be important in the planning phase of a move-
ment, such as when several single-joint movements have
to be put together to produce a complex movement, or
when sensory stimuli or stored information has to be 11 Because the activity of most GPi neurons increases in relation to a
translated into an adequate motor response. Observations movement (thus increasing inhibition of thalamocortical neurons), one
would think that the basal ganglia were concerned primarily with stopping
of symptoms in monkeys with lesions of the globus pal- ongoing movements rather than helping to initiate new ones. Such stopping
lidus indicate that learned movements are slower than is of course a prerequisite for starting anew.
Interval Timing the relationships between certain symptoms and the
elements responsible within the basal ganglia.
Finally, the basal ganglia seem to be involved in interval
As mentioned, the most obvious symptoms in dis-
timing, underlying the ability to judge intervals and
eases of the basal ganglia are motor ones. As a rule,
duration. This is the basis of our ability to form tempo-
there is a mixture of symptoms due to loss of neuronal
ral expectations and predictions about ongoing and
activity (compare with pareses after destruction of cen-
future events (the expected time of movement sequences
tral motor pathways) and symptoms due to abnormally
and cognitive processes). Striatal neurons may monitor
increased neuronal activity (compare with spasticity
oscillatory patterns in large areas of the cortex. Thus,
occurring after lesions of central motor pathways). The
human functional magnetic resonance imaging (fMRI)
most frequent diseases of the basal ganglia impede the
studies of persons performing timing tasks show altered
initiation of movement and lead to akinesia. When
activity in the striatum and the substantia nigra, in
started, the movements are slower and of smaller ampli-
addition to in areas such as the prefrontal cortex, the
tude than normal (bradykinesia). Because movements
cingulate gyrus, SMA, parietal cortex, and the insula.
are difficult to initiate, there is also a conspicuous pau-
There is some evidence that these regions functions as a
city of movements, usually implied in the term akinesia
network in relation to interval timing. However, also
but sometimes termed hypokinesia. In addition, there
other parts of the brain may be of importance in this
are more or less pronounced involuntary movements
respect, notably the cerebellum (see Chapter 24, under
(dyskinesia).
The Timing Theory: Does the Cerebellum Perform a
The diseases of the basal ganglia fall into two broad
Basic Operation Used in All Its Functions?). It should
groups: those characterized by akinesia and rigidity
be emphasized, however, that it is not settled whether
(Parkinsons disease is the most common example), and
the sense of time is represented by specific modules
those dominated by dyskinesia (e.g., Huntingtons dis-
and networks, or whether it is an ubiquitous property
ease). The first group is also characterized by loss of
of neuronal activity in itself.
dopamine effects in the basal ganglia, whereas the sec-
ond group shows signs of dopaminergic hyperactivity.
Symptoms after Focal Lesions of the Basal Some authors use the terms hyperkinetic and hypoki-
Ganglia in Humans netic disorders to distinguish the two main kinds of
basal ganglia diseases. The hypokinetic disorders are
Studies of patients with destruction (vascular lesions in usually combined with rigidity and tremor (i.e., signs of
particular) confined to parts of the basal ganglia have neuronal hyperactivity), whereas the hyperkinetic dis-
given limited insight in their normal functions. A meta- orders are often combined with muscular hypotonia.
analysis of 240 such patients found that dystonias The most frequent disease affecting the basal ganglia
that is, abnormal positions of body parts due to is Parkinsons disease, mentioned several times already
persistently increased muscle tonewere most frequently in this chapter. Typically, voluntary movements are
encountered. Parkinsonism or choreatic movements hard to initiate (akinesia) and they are slower and
occurred in only very few patients. Motor symptoms smaller than normal (bradykinesia). In addition, there
were most frequent, after lesions comprising the puta- is an increased muscular resting tone in the form of
men and the globus pallidus, which is in agreement rigidity (cf. Chapter 21) and resting tremorthat is,
with the connections of these parts. Most frequent involuntary, rhythmic, alternating movements. Patients
among behavioral changes was apathy, with loss of with Parkinsons disease have regularly been found to
initiative, spontaneous thought, and emotional responses have a pronounced neuronal loss in the substantia
(abulia). Such symptoms were most frequent after nigra and a corresponding decrease of dopamine in the
lesions affecting the caudate nucleus, in agreement with striatum.
its extensive connections with the prefrontal cortex. In Huntingtons disease, in which there is a marked
Nevertheless, on further analysis, many observations cell loss in the striatum, the most pronounced symptom
could not be fitted into the current theories of basal is involuntary, jerky, often dance-like movements
ganglia functions, and the symptoms varied consider- (chorea).
ably, even among patients with very similar localization Violent, large involuntary movements of one side of
of their lesions. the body, called hemiballismus, occur typically after
damage to the subthalamic nucleus of the opposite side.
Other diseases are also dominated by sudden, involun-
DISEASES OF THE BASAL GANGLIA tary muscular contractions, occurring with uneven inter-
vals, called tics. One example is Tourettes syndrome,
As the functions and internal operations of the basal believed to be caused by dysfunction of the basal ganglia.
ganglia are still incompletely known, it should come as The symptoms can be partially relieved by dopamine
no surprise that we have only partial explanations of antagonists.
the dopamine-containing neurons. As a consequence of

Parkinsons Disease
the loss of dopaminergic nigrostriatal fibers, the dop-
This disease of unknown etiology usually starts during amine content of the striatum is reduced. Symptoms
the fifth or sixth decade of life. The syndrome includes, first appear, however, when the dopamine content of
as mentioned, akinesia, bradykinesia, tremor, and rigid- the striatum is reduced by 80% to 90%. Another strik-
ity. In addition, there are disturbances of postural ing change is loss of 20% to 30% of the spines on stri-
reflexes. Notably, the body balance during walking is atal projection neurons. As mentioned, this may be due
disturbed, so that the patient appears to be running to loss of a possible growth-promoting effect of dop-
after his center of gravity. The steps are typically very amine. Another possibility is that spine loss is due to
short, which is due to the bradykinesia (the movements glutamatergic overactivity in corticostriatal synapses.
are not only slower than normal but also reduced in The latter explanation is suggested by the observation
amplitude). When being pushed from behind, the that loss of dopamine indeed increases activity in gluta-
patient has difficulty stopping and continues to move matergic synapses, and by the close proximity of dop-
forward. The normal pendulum movements of the arms aminergic and glutamatergic synapses on the spines
during walking are absent. There is also a conspicuous (Fig. 23.9B).
loss of facial expression (the face becomes like a mask).
There are disturbances of the autonomic nervous
Can We Explain the Symptoms in
system, such as increased salivation and secretion from
Parkinsons Disease?
sebaceous glands of the skin. We do not know how the
basal ganglia would influence the autonomic nervous Increased firing of neurons in the subthalamic nucleus
system, and the autonomic symptoms perhaps may be is the most striking electrophysiological finding in
caused by a more general disturbance of monoamine Parkinsons disease. There is also increased activity in
metabolism (not only dopaminergic cell groups are the GPi, presumably due to the increased excitatory
affected in Parkinsons disease). input from the subthalamic nucleus. As discussed earlier
The tremor is typical, with its frequency of 3 to 6 (The Indirect Pathway, the Subthalamic Nucleus,
per second, and it is most pronounced at rest. When and Parkinsons Disease), it is not clear how loss of
the patient uses the hand, the tremor disappears or is dopamine in the striatum leads to subthalamic hyperac-
reduced in amplitude. The increased muscle tone, the tivity. Even if we ignore that problem, the relationship
rigidity, is different from the spasticity that occurs between the subthalamic hyperactivity and the symp-
after lesions of central motor pathways. The resis- toms is not obvious. True enough, increased GPi activ-
tance to passive movements is equal in extensors and ity would increase thalamic inhibition and thus reduce
flexors and is independent of whether the muscle is excitation in the motor cortical areas, and this fits with
stretched slowly or rapidly. There is no clear-cut positron emission tomography (PET) studies that show
increase in the strength of the monosynaptic stretch reduced blood flow in the SMA in Parkinsonian patients.
reflex (such as the patellar reflex), whereas the long- Although reduced thalamocortical activation of motor
latency stretch reflexes are increased, and this may areas thus helps to explain bradykinesia/akinesia, it is
perhaps contribute to the difficulties with balance nevertheless puzzling that thalamotomy (a stereotaxic
and locomotion. The rigidity is apparently not caused lesion of VL/VA) mainly improves rigidity and tremor
by hyperactivity of motoneurons but by descending with less effect on the akinesia and bradykinesia, and
influences that increase the excitability of the neither is voluntary movement made more difficult by
motoneurons so that they fire continuouslyperhaps the surgery. Further, thalamic infarcts affecting the VL/
like the situation in a nervous person who is unable VA do not produce Parkinson-like symptoms, even
to relax his muscles. The plantar reflex is normal in though thalamocortical activation of motor areas must
patients with Parkinsons disease, indicating that there be severely reduced. Like thalamotomy, pallidotomy
is no damage to the central motor pathways. It is indeed improves rigidity and tremor; in addition, it improves
an old clinical observation that the tremor and rigidity the akinesia. Because loss of dopamine in the striatum
disappear if a patient with Parkinsons disease has a produces such devastating motor disturbances, it seems
capsular hemiplegia, and corresponding observations paradoxical that thalamotomy and pallidotomy
are made in experimental animals. The last central link which eliminate the major effects of the basal ganglia
in the pathways mediating the tremor and rigidity must on other parts of the braindo not worsen control of
therefore be pathways from the cerebral cortex to the voluntary movements. It may be mistaken, however, to
motoneurons. try to explain the symptoms simply in terms of more or
The most pronounced structural change in the brain less excitation or inhibition at stations in the cortex
of patients with Parkinsons disease is a profound loss basal gangliacortex loop. There is evidence, for exam-
of pigmented (melanin-containing) neurons in the pars ple, that thalamic neurons (both in the lateral nucleus
compacta of the substantia nigra (Fig. 23.8). These are and in the intralaminar nuclei) in Parkinsonian patients
show various forms of abnormal, partly rhythmic firing. For example, altered dopamine functioning in the hypo-
Further, their activityin contrast to that in normal thalamus might explain side effects such as nausea, loss
personsshows no modulation in relation to move- of appetite, and reduced control of blood pressure.
ments. In addition, the hyperactivity in the subthalamic Other side effects are sleep disturbances and changes of
nucleus takes the form of high-frequency oscillations mood. In some cases, the treatment can precipitate a
(which appear to be reduced by dopaminergic medica- psychosis that might be due to actions of dopamine on
tion). We furthermore know that hyperpolarization of the prefrontal cortex limbic structures. Long-term treat-
thalamocortical neurons can induce oscillatory activity ment may provoke motor symptoms that are different
under certain circumstances (cf. Chapter 26, under from those caused by the disease, such as chorea-like
Thalamocortical Neurons and EEG). Perhaps the and athetoid dyskinesias (athetosis is used of slow,
abnormal inhibition from the GPi in some way releases wormlike, involuntary movements of the fingers and
the thalamic neurons from normal control. As proposed toes).
by Marsden and Obeso (1994), the Parkinsonian symp- Stereotaxic surgery has now been replaced by deep
toms may arise mainly because the basal ganglia out- brain stimulation (DBS) of the subthalamic nucleus or
puts become noisy and thus disrupt the activity of the GPi. Such treatment gives considerable improve-
their targets. Some neurons fire rhythmically while ment to many patients (the effect is better on positive
others become very difficult to activate. The oscillatory than on negative symptoms). It appears that improve-
(20 Hz) firing of large populations of neurons may be ment occurs regardless of whether the subthalamic
abnormally synchronized. Presumably, such states are nucleus is destroyed or stimulated electrically. Although
labile, with rapid shifts between oscillatory activity and this might seem to support the hypothesis that DBS
inactivity. Neuronal networks might shift from one removes a disturbing influence (rather than normaliz-
functional state to another in milliseconds. Conceivably, ing basal ganglia functioning), the mechanism whereby
such shifts produce the rapid fluctuations in symptoms DBS achieves its effect is poorly understood.
sometimes observed in Parkinsons disease. The motor Replacement of lost dopaminergic neurons by trans-
system may be better off when the disruptive basal gan- plantation has now been tried for some years in patients
glia outputs are removed (be it by thalamotomy, pallido- with Parkinsons disease, with marked improvement in
tomy, or deep brain stimulation)leaving it in peace at least some patients. The basis for this approach is
to compensate for the loss of basal ganglia inputs. animal experimentspioneered by, among others, the
Swedish neurobiologist Anders Bjrklundshowing
that transplantation can eliminate virtually all symp-
Therapeutic Approaches to Parkinsons Disease
toms produced by lesions of the substantia nigra in
The finding of reduced striatal dopamine led to attempts adult rats. The transplanted cells must be embryonic
to alleviate the symptoms by giving the patients dop- or transformed stem cells to avoid rejection, and are
amine, to substitute for the loss of dopaminergic neurons. injected into the striatum of the recipient. The surviving
For various reasons, a precursor of dopaminelevodopa cells synthesize and release dopamine. Neurons for
(L-dopa)has to be used. This is converted to dopamine transplantation can be developed from stem cells in cul-
in the brain. This treatment has a beneficial effect on ture, and this approach might be used in the future
the symptoms, particularly on the very troublesome (thus avoiding ethical and practical problems with the
bradykinesia. Even though L-dopa has proved to be a use of human embryos).
very helpful drug, the first hopes turned out to be unre-
alistic. The drug does not affect the course of the dis-
Huntingtons Disease
ease, and the therapeutic effect decreases as the disease
progresses. There probably must be a certain number of This disease is dominantly inherited and usually starts
remaining dopaminergic neurons in the nigra for L-dopa in the fourth decade of life. It is caused by expansion of
to be converted to dopamine in the striatal dopaminer- trinucleotide (CAG) repeats in the huntingtin gene (for
gic boutons. More profound changes of the striatal mechanisms of neuronal death in neurodegenerative
neurons and their ability to react to dopamine may also diseases, see Chapter 10, under Common Molecular
occur. One might think that when the brain is unable to Mechanisms in Neurodegenerative Diseases). The dis-
produce enough dopamine itself, it would not be able ease has a steadily progressing course, and is character-
to produce dopamine from a supplied precursor, either. ized by rapid, jerky, involuntary movements of the face,
However, enzymes converting L-dopa to dopamine are arms, and legs. In advanced stages, the patient is never
present not only in dopaminergic neurons in the nigra at rest. The dance-like quality of the movements led to
but also in glial cells and in other types of neurons. the terms chorea and choreatic movements (Greek: cho-
The L-dopa treatment has side effects, as one might rea, dance). The most prominent pathological change
expect when giving a drug that acts not only in the involves the striatum, with a marked loss of GABAergic
striatum but also in many cell groups in the brain. projection neurons.
Observations suggest that in early stages of the dis- heritable component but responsible genes have not
ease, mostly neurons projecting to the GPe degenerate been identified. The condition is probably caused by a
(the indirect pathway; see earlier). This would pro- functional disturbance of the basal ganglia and the pre-
duce reduced inhibition of GPe neurons and, by that, frontal cortex, although the mechanisms are not known.
increased inhibition of the subthalamic nucleus. (Animal Volumetric studies with MRI indicate that the caudate
models support that reduced activity of the subthalamic nucleus is smaller than normal, and fMRI studies show
nucleus may be crucial for development of choreatic altered activity in the striatum and related cortical
movements.) This in turn leads to reduced excitation regions. It has been postulated that the tics are caused
of GPi, and thereby to less inhibition (disinhibition) of by abnormal activity in small groups of striatal projec-
thalamocortical neurons in VL and VA. Thus, the cho- tion neurons (cf. striosomes and matrix discussed in the
reatic movements might be causally related to increased preceding text). Involvement of both motor and limbic
excitatory input to motor cortical areas. circuits has been proposed to explain both the motor
In later stages of the disease, the striatal neurons pro- and associated behavioral and emotional symptoms.
jecting to the GPi also die (as do many neurons in other Dopaminergic hyperactivity may play a role in the dis-
parts of the brain). This leads to reduced inhibition of ease, but other transmitters, such as serotonin and
GPi, with subsequent increased inhibition of thalamo- GABA, have also been implicated.
cortical neurons (as in Parkinsons disease). This is taken The disease starts during childhood, usually between
to explain why bradykinesia develops in later stages of the ages of 5 and 10 years, and it affects boys more
Huntingtons disease, while the choreatic movements frequently than girls. Often the symptoms diminish
continue. This is not obviously logical, however, if the before or during adolescence. Many patients have a
effects of both the direct and indirect pathways are repertoire of repetitive behavior, such as touching oth-
mediated by the GPi. Another explanatory model ers, repeating their own words, or echoing the words or
focuses on dopaminergic hyperactivity in the striatum, movements of others. Vocalizations (vocal tics) com-
caused by loss of GABAergic inhibition in the substan- monly include explosive cursing or compulsive utter-
tia nigra. Although there are problems also with this ance of obscenities, which interrupt normal speech.
model, it fits with the observation that l-dopa worsens Many patients describe that an inner tension builds up,
the choreatic movements of patients with Huntingtons and this is temporarily relieved by the tic. Some people
disease. The disease also leads to mental deterioration with Tourettes syndrome appear to have unusual
with dementia, which probably may be explained by energy and creativity. As children, they often show
cell loss occurring also in the cerebral cortex (particu- hyperactive behavior. This may lead to serious social
larly the frontal lobes). problems, especially when, as often happens, the dis-
The genetic defect is located on the short arm of ease is misdiagnosed as a behavioral disorder of social
chromosome 4, and this makes it possible to decide origin.
whether a person is a carrier of the disease long before Treatment with dopamine antagonists (especially
the symptoms occur. This is of importance regarding haloperidol, a D2-receptor antagonist) may reduce the
the choice whether or not to have children. However, involuntary movements and other troublesome symp-
to provide individuals with such knowledge as long as toms. However, the patients mental energy and self-
there is no effective treatment poses obvious ethical perception may be severely affected by the treatment.
questions. As vividly described by Oliver Sacks in The Man Who
Mistook His Wife for a Hat, this may be experienced by
some patients as worse than the symptoms. Since 1999,
Tourettes Syndrome
deep-brain stimulation has been used in some patients
This is a peculiar and multifarious condition with mul- with severe symptoms and poor response to conven-
tiple tics (quick involuntary movements that are repeti- tional treatments. Beneficial results have been reported
tive at irregular intervals) associated with involuntary with different sites of stimulation (the GPi, the accum-
vocalization as central manifestations. It has a strong bens, and the intralaminar thalamic nuclei).
24 The Cerebellum
OVERVIEW receives afferents. In contrast to the cerebral cortex, the

cerebellar cortex has no association and commissural
The cerebellum and the basal ganglia have in common connections: different parts of the cerebellum do not
that they are involved in motor control without being talk to each other. Consequently, the cerebellum con-
responsible for the initiation of move ments, and both sists of many functional units or modules, each carrying
are built into side loops of the motor cortical areas out a specific task. The cerebellum can be subdivided in
and the central motor pathways. Both contribute to three main parts based on connections: vestibulocere-
motor learning, although in different ways. Although bellum, spinocerebellum, and cerebrocerebellum. Within
the major fiber connections of the cerebellum suggest a each of these major divisions numerous small modules
motor function, some connections are compatible with have been identified. The cerebrocerebellumreceiving
a cerebellar contribution to cognitive functions. A brief large number of afferents from the cerebral cortex via
account of the cerebellum was given in Chapter 6. the pontine nucleicomprise about 90% of the human
Damage to the cerebellum produces characteristic cerebellar volume. The spinocerebellum receives affer-
symptoms primarily with respect to the execution of vol- ents from the spinal cord informing about sensory
untary movements. Our normal movements are always events and the state of premotor networks and act back
coordinatedthat is, the various muscles participating by way of reticulospinal and vestibulospinal pathways.
contract at the proper time and with the proper force. Owing to the structural homogeneity of the cerebel-
This is a prerequisite for our ability to hit a nail with a lar cortex, all modules have the same kind of machinery
hammer, for writing even and rounded letters, for the and, presumably, perform the same kind of information
words to follow each other with proper loudness and processing. Among several possibilities, the cerebellum
rhythm during speech, and so forth. After cerebellar may be specially designed for accurate timing of events,
damage, such coordination is lacking, and the move- not only for movements but also for certain cognitive
ments become uncertain and jerky. tasks carried out by the cerebral cortex. Further, the
The cerebellum receives information from many cerebellum is involved in aspects of motor learning.
sources. Sensory signals come from the skin, joints, mus-
cles, vestibular apparatus, and eye. In most instances,
this sensory information appears to be related to aspects SUBDIVISIONS AND AFFERENT CONNECTIONS
of movement, such as signals from muscle and joint OF THE CEREBELLUM
receptors about positions and ongoing movements.
Information is also coming from other parts of the cen- The macroscopic anatomy of the cerebellum is described
tral nervous system (CNS), especially from the cerebral in Chapter 6 (see Figs. 6.1, 6.13, and 6.32), but some
cortexprimarily from cortical areas treating informa- points bear repetition here. Figure 24.1 shows how the
tion about movements or involved in planning or initia- cerebellum resides in a side loop of the motor corti-
tion of movements. The cerebellum sends information cal areas and the central motor pathways. Figure 24.2
primarily to cell groups that give origin to the central shows how all afferent and efferent connections pass
motor pathways, like the motor cortical areas and the through the cerebellar peduncles. The thickness of the
reticular formation of the brain stem. arrows indicates the relative number of afferent and
A striking feature of cerebellar organization is that efferent fibers. The external part of the cerebellum is a
the number of fibers leading to the cerebellum is much thin, highly convoluted sheet of gray matter, the cere-
larger than the number of fibers leading out; the rela- bellar cortex (Fig. 24.3). The folds are arranged trans-
tionship is about 40:1 in humans. The high degree of versely and form numerous folia. If the cerebellum were
convergence shows that considerable integration and unfolded completely in the anteroposterior direction, it
processing of information takes place in the cerebellum would measure 2 m! The cerebellar cortex is thinner
before an answer is issued. and of a simpler build than the cerebral cortex, consist-
The afferent fibers end in segregated regions of the ing only of three layers (Fig. 24.2). The total number of
cerebellar cortex, and the efferents from these regions neurons is nevertheless much higher than in the cere-
are also largely segregated. As a general rule, the cerebral cortex due to the dense packing of tiny neurons in
bellum sends signals to same regions from which it the granular layer. All signaling out of the cerebellum is
343
Thalamus
Cerebral cortex
Thalamus
Direct and
indirect Mesencephalon
motor Superior cerebellar
pathways Brain peduncle
Stem Brachium conjunctivum
Cerebellum
Pons Middle cerebellar
peduncle
Brachium pontis
Spinal cord
Inferior cerebellar
peduncle
Medulla Corpus restiforme
gure 24.1
gure 24.2 The cerebellar peduncles contain the afferent and effer-
ent connections of the cerebellum. The brain stem, as viewed from the
mediated by the axons of the Purkinje cells (Figs. 24.2 left. Arrows indicate the peduncle used by the main afferent and effer-
and 24.12). The underlying white matter contains the ent connections on entering or leaving the cerebellum. The thickness
afferent and efferent fibers of the cerebellar cortex. In of the arrows indicates the magnitude of the various connections.
Note the massive afferent pathway from the pontine nuclei that enter
addition, masses of gray matter, the intracerebellar
through the middle cerebellar peduncle (the brachium pontis). The
nuclei, are embedded in the white matter in the central largest number of efferent bers leaves the cerebellum through the
parts of the cerebellum (Fig. 24.3). These nuclei are superior cerebellar peduncle (the brachium conjunctivum).
relay stations in the efferent connections of the cerebel-
lar cortexthat is, the majority of the Purkinje cell
axons terminate in the intracerebellar nuclei.
A B C
Pia
Cerebral
hemisphere Molecular
layer
Purkinje cell
layer
White matter
Vermis
Cerebellar
hemisphere Cerebellar Granular layer
cortex
Cerebellar
nucleus Dentate
(Dentate) nucleus
White
matter
gure 24.3 The cerebellum, the cerebellar cortex, and an intracere- area corresponding to the frame in A. Thionine staining.
bellar nucleus. A: Frontal section through the cerebrum and the pos- C: Higher magnication of framed area in B, showing the three layers
terior fossa with the cerebellum. Note the folding of the cerebellar of the cerebellar cortex. Cf. Fig. 24.12 showing the structural ele-
surface to form thin folia. Cf. Fig. 6.32. B: Photomicrograph from the ments of the cerebellar cortex in detail.
24: THE CEREBELLUM 345
The Cerebellum Consists of Three Functionally
hemispheres, bordering the vermis medially, is called the
Different Parts
intermediate zone (Fig. 24.4). This zone cannot be dis-
The structure of the cortex is the same all over the cer- tinguished from the rest of the cerebellum on a macro-
ebellum. Therefore, various parts of the cerebellum dif- scopic basis but only on the basis of fiber connections.
fer in function because of differences in fiber connections: A deep, transversely oriented cleft, the primary fissure,
the subdivisions of the cerebellum receive afferents from divides the corpus cerebelli. The parts of the corpus
and act on different parts of the nervous system. Indeed, cerebelli in front of and behind the primary fissure are
a subdivision of the cerebellum based on functional dif- called the anterior lobe and the posterior lobe, respec-
ferences corresponds closely with a subdivision based on tively. The anterior and posterior parts of the vermis
differences in afferent connections (Fig. 24.4). Further, constitute the phylogenetically oldest parts of the corpus
such a subdivision corresponds also with one based on cerebelli. The midportion of the vermis and the hemi-
the cerebellar phylogenetic development from lower to spheres are younger and are therefore called the neocer-
higher animals. ebellum. The anterior and posterior portions of the vermis
The most primitive part of the cerebellumthe part and the adjoining parts of the intermediate zone of the
occurring first during phylogenyis the small floccu- corpus cerebelli receive afferents primarily from the spi-
lonodular lobe (Fig. 24.4; see Figs. 6.13 and 6.32). It nal cord and are therefore also termed the spinocerebel-
consists of the nodulus in the midline (a part of the ver- lum. The hemispheres receive their main input from the
mis) connected laterally with a thin stalk to the floccu- cerebral cortex (synaptically interrupted in the pontine
lus. The size of this part of the cerebellum varies little nuclei) and are therefore termed the cerebrocerebellum
among mammals. The flocculonodular lobe receives or the pontocerebellum.
afferents primarily from the vestibular apparatus and With regard to the efferent connections, the three
the vestibular nuclei and is therefore called the vestibu- main subdivisions of the cerebellum act on the parts of
locerebellum. The rest of the cerebellum is called the the CNS from which they receive their afferents; that is,
corpus cerebelli. This comprises all of the vermis (except the vestibulocerebellum sends fibers mainly to the ves-
the nodulus), which forms a narrow zone on both sides tibular nuclei, the spinocerebellum influences the spinal
of the midline, and the large lateral parts called the cord, and the cerebrocerebellum acts on the cerebral
cerebellar hemispheres. The medialmost part of the cortex.
Vermis
Intermediate zone
ANTERIOR LOBE
ANTERIOR LOBE
Primary fissure Primary fissure
Hemisphere
(neocerebellum)
POSTERIOR LOBE
Flocculus
FLOCCULONODULAR LOBE Nodulus
Spino- Vestibulo- Cerebro-

cerebellum cerebellum cerebellum
gure 24.4 Main cerebellar subdivisions. Left: A sagittal section Fig. 6.32. The right half shows the terminal regions of the three major
through the cerebellum and the brain stem. Right: The human cere- afferent contingents to the cerebellum (vestibular, spinal, and cere-
bellum unfolded and seen from the dorsal aspect. The left half shows brocortical). Because the intermediate zone receives information from
the macroscopic subdivisions of the cerebellum into lobes, as well as both the spinal cord and the cerebral cortex, there is no sharp border
the border between the vermis and the hemisphere. Compare with between the spinocerebellum and the cerebrocerebellum.
Afferents from the Labyrinth and the Vestibular Nuclei therefore termed indirect spinocerebellar tracts (not
shown in Fig. 24.6). The spinocerebellar tracts origi-
Primary vestibular afferents bring sensory signals from
nate from neurons with their cell bodies located in
the vestibular apparatus in the inner ear. They enter the
different lamina of the spinal cord (Fig. 24.7). They are
cerebellum through the inferior cerebellar peduncle
therefore influenced by different kinds of sensory recep-
(Fig. 24.1) and end in the flocculonodular lobe and
tors and spinal interneurons and bring different kinds
adjoining parts of the vermis (Fig. 24.5). Although most
of information to the cerebellum. The spinocerebellar
of the primary vestibular afferents end in the vestibular
axons end mostly in the spinocerebellum of the same
nuclei, many neurons in the latter send axons to the
side (as their cell bodies). Some pass uncrossed; other
cerebellum. In this manner, the cerebellum receives ves-
fibers cross twice (first in the spinal cord and then back
tibular information also via secondary vestibular affer-
again in the brain stem). The fibers are located in the
ents. The vestibular input provides the cerebellum with
lateral funicle as they ascend (Fig. 24.7). The tracts are
information about the position and movements of the
somatotopically organized, so that signals from differ-
head. Efferents from the flocculonodular lobe end in
ent body parts are kept segregated. The somatotopic
the vestibular nuclei and can thereby influence the body
pattern is maintained within the cerebellum (Fig. 24.8)
equilibrium (via the vestibulospinal tracts) and eye move-
so that the leg is represented anteriorly within the
ments via the medial longitudinal fascicle (Fig. 24.5 and
anterior lobe, with the arm and the face represented
see Fig. 18.9).
successively more posteriorly. In the posterior lobe, the
arrangement is the reverse, with the face represented
Afferents from the Spinal Cord anteriorly.
Several pathways bring signals from the spinal cord to
the cerebellum (Fig. 24.6). Some of these pathways Direct Spinocerebellar Tracts
go uninterrupted from the cord to the cerebellum and
Functionally, the direct spinocerebellar tracts consist of
are called direct spinocerebellar tracts, whereas others
two main groups. One group of tracts conveys informa-
are synaptically interrupted in brain stem nuclei and are
tion from muscle spindles, tendon organs, and cutaneous
low-threshold mechanoreceptors. Physiological studies
show that many of the neurons of the direct spinocere-
VESTIBULOCEREBELLUM bellar tracts are activated monosynaptically by primary
Eye muscle nuclei SPINOCEREBELLUM

Anterior lobe
ANTERIOR LOBE
Medial cerebellar
nucleus (fastigial)
Vestibular Flocculonodular
nuclei lobe
Vestibular
apparatus
Reticular
Vestibulospinal formation Vestibular nuclei
tracts
Spinocerebellar
tracts (direct)
Reticulospinal &
gure 24.5 Main connections of the vestibulocerebellum. Afferents vestibulospinal
are shown in black and efferents in blue in a schematic of a sagittal tracts
section through the brain stem. Also shown are primary and second-
ary vestibulocerebellar bers and the projection back to the vestibular
nuclei. In addition to afferents from the vestibulocerebellum, the ves- gure 24.6 Main connections of the spinocerebellum. The spinocer-
tibular nuclei receive cerebellar afferents from the anterior lobe ver- ebellum can inuence spinal motoneurons by both the reticulospinal
mis and from the fastigial nucleus (not shown). and vestibulospinal pathways.
Dorsal commands issued to the motoneurons and the move-
Clarkes column spinocerebellar ments they produce. The cerebellum can probably judge
tract
whether the command led to the desired result. When,
for example, an unexpected increase of external resis-
tance to a movement reduces the velocity compared
with what was intended, the cerebellum would be
informed immediately. By means of its connections to
the spinal cord, the cerebellum can then help to adjust
the firing of the motoneurons to the new situation, so
that the correct velocity is regained.
Indirect Spinocerebellar Tracts

Ventral
spinocerebellar There are several indirect spinocerebellar tracts, but
tract
here we will only mention the largest one, which is syn-
gure 24.7 The dorsal and ventral spinocerebellar tracts. Transverse aptically interrupted in the inferior olive in the medulla
section through the thoracic cord, showing the position of the cell
(see Fig. 6.17). Neurons at all levels of the cord send
bodies in the gray spinal matter and the tracts in the white matter.
Most of the bers of the ventral spinocerebellar tract cross twice fibers to the inferior olive of the opposite side. The
(once in the cord and once in the brain stem), so that most spinocer- spino-olivary fibers end in parts of the inferior olive
ebellar signals reach the cerebellar half on the same side as the cell that project to the spinocerebellum of the opposite side;
bodies are located. thus, like the direct spinocerebellar tracts, the spino-
olivocerebellar tract conveys information mainly from
one side of the cord to the cerebellar half of the same
afferent (sensory) fibers. The tracts conduct very rapidly
side. This pathway, too, is precisely somatotopically
and appear to give precisely timed information about
organized. The kind of information conveyed by the
movements.
spino-olivocerebellar tract appears to be different from
Another group of direct spinocerebellar tracts does
that conveyed by the other spinocerebellar tracts. We
not convey signals from receptors but provides informa-
return to the inferior olive later in this chapter, because
tion about the level of activity among specific groups of
it has a unique role among the cell groups that send
spinal interneurons. As a rule, such interneurons are
fibers to the cerebellum.
intercalated in spinal reflex arcs and between descending
motor pathways and motoneurons forming premotor
networks. Information about their activity is therefore The Dorsal, Ventral, and Some Other
presumably highly relevant for cerebellar operations. Spinocerebellar Tracts
Together, the direct spinocerebellar tracts provide
Originally, two direct spinocerebellar tracts were
the cerebellum with information about the activity both
described, differing with regard to the position of their
before and after the motoneuronsthat is, about the
fibers in the lateral funicle of the cord. The fibers of one
of the tracts are located dorsally, and the tract was
ANTERIOR LOBE
called the dorsal spinocerebellar tract; the fibers of the
Primary fissure
ventral spinocerebellar tract are located more ventrally
Foot (Fig. 24.7).
The dorsal spinocerebellar tract comes from a distinct
Arm cell group with fairly large cells at the base of the dorsal
horn, forming the column of Clarke located in the spi-
Face
nal segments from T1 to L2 only. The axons of the cells
in the column of Clarke ascend on the same side and
Face Face
enter the cerebellum through the inferior cerebellar
peduncle (Fig. 24.1). Primary afferent fibers entering
Arm Arm
the cord through spinal nerves below the L2 ascend in
Foot Foot
POSTERIOR the dorsal columns before entering the lowermost part
LOBE
of the column of Clarke. The dorsal spinocerebellar
tract conveys information only from the trunk and the
Vermis lower extremities and ends in the corresponding parts
gure 24.8 Somatotopic localization of the cerebellar cortex. Based
of the spinocerebellum. Another cell group, the exter-
on experiments with electrical stimulation of peripheral nerves and of nal cuneate nucleus, located laterally in the medulla
somatotopic subdivisions of the SI and the MI. oblongata, mediates the same kind of information from
the upper extremities. Functionally, this nucleus corre- nucleus also receives afferents from sources other than
sponds to the column of Clarke, and primary afferents the spinal cord, notably the red nucleus, the vestibular
from the arms ascend in the dorsal columns to end in nuclei, and the motor cortex. Many cells, for example,
the nucleus. The cells of the external cuneate nucleus are strongly influenced by tilting of the head, which
send their axons to the arm regions of the spinocerebel- stimulates vestibular receptors.
lum of the same side (Fig. 24.8), forming the cuneocer- Finally, information from sensory receptors can reach
ebellar tract. As mentioned, primary afferent fibers the cerebellum not only through some of the spinocere-
from muscle spindles and tendon organs end monosyn- bellar tracts but also through fibers sent to the spinocer-
aptically on the neurons of the column of Clarke (and ebellum from the dorsal column nuclei and the trigeminal
the external cuneate nucleus). In addition, the column nuclei.
of Clarke receives polysynaptic information from the
same kind of receptors, as well as from joint and cuta-
Afferent Connections from the Cerebral Cortex
neous receptors. Indeed, recent physiological studies
show that most of the column-of-Clarke neurons inte- In humans, by far the largest number of cerebellar
grate information from various receptor types activated afferent fibers arises in the pontine nuclei (Fig. 24.9; see
by a specific movement. Thus, the dorsal spinocerebel- Fig. 6.18). The pontocerebellar tract ends primarily in
lar tract appears to inform primarily about complex the cerebellar hemispheres, which constitute the major
joint movements, for example, those that involve the part (90%) of the cerebellum in humans. The vast major-
whole extremity. This is another example that sensory ity of afferents to the pontine nuclei arises in the cerebral
1
relay nuclei do not merely transmit signals unchanged cortex and forms the corticopontine tract (Fig. 24.8).
from receptors; they always process information in The main task of the pontine nuclei therefore is to pro-
some way. cess information from the cerebral cortex and forward
The ventral spinocerebellar tract originates from cells it to the cerebellar cortex. The corticopontine tract is
located mainly laterally in lamina VII (Fig. 24.7; see uncrossed, whereas most of the pontocerebellar fibers
Fig. 6.14)that is, in the lamina containing the largest cross; thus, the cerebral cortex of one side acts mainly
number of interneurons. Most of the axons cross at the on the cerebellar hemisphere of the opposite side.
segmental level in the cord to the lateral funicle of the The corticopontine tract runs in the internal capsule
opposite side. However, after having reached the cerebel- and then in the crus cerebri (see Fig. 6.20), where it
lum through the superior cerebellar peduncle (Fig. 24.1), occupies a large part; of the approximately 19 million
many of the fibers cross once more. The cell bodies of fibers in the crus of the human brain, the corticopon-
the neurons giving origin to the ventral spinocerebellar tine fibers constitute the majority (the pyramidal tract,
neurons are found only below the midthoracic level of in comparison, contains only about 1 million fibers).
the cord and have a rostral counterpart conveying A large fraction of the corticopontine fibers arise in
information from higher levels of the cord, the rostral the MI and SI. There are also substantial contributions
spinocerebellar tract. These tracts convey information from the supplementary motor cortex (SMA) and pre-
about the activity of the spinal interneurons, as men- motor cortex (PMA) and from areas 5 and 7 of the pos-
tioned above. Physiological experiments indicate that terior parietal cortex (Fig. 24.9). Contributions that are
they inform primarily about the activity of inhibitory more modest come from parts of the prefrontal cortex.
interneurons. In various ways, all of these areas are active during or
In addition to the spinocerebellar tracts mentioned so before movements. Presumably, the cerebellum thus
far, other cell groups in the spinal cord also send fibers receives information about movement planning and
to the cerebellum. Among such cell groups is the central about the motor commands that are sent out from the
cervical nucleus, located in the upper cervical segments. cortex; in response, it can modulate the activity of the
The fibers end in the anterior folia of the anterior lobe motor cortex so that the movements are performed
and transmit signals primarily from receptors around smoothly and accurately. The pontine nuclei also receive
the cervical joints. afferents from the visual cortex (mainly extrastriate
An additional indirect spinocerebellar pathway is areas), and physiological experiments indicate that
relayed in the lateral reticular nucleus, located in the these fibers inform primarily about moving objects in
medulla just lateral to the inferior olive. This spinore- the visual field. Such connections may be important for
ticulocerebellar pathway, too, is mainly uncrossed and
appears to convey information about the activity of cer-
tain groups of spinal interneurons. Because most of the 1 Other precerebellar nuclei that is, brain stem nuclei that send their effer-
spinal interneurons are strongly influenced by descend- ents to the cerebellumalso receive afferents from the cerebral cortex. This
ing motor pathways (e.g., the pyramidal tract), the concerns mainly the reticular tegmental nucleus, located just dorsal to the pon-
tine nuclei (participating in the control of eye movements, see Chapter 25), and
ascending tract to the lateral reticular nucleus probably the lateral reticular nucleus. In quantitative terms, these pathways play minor
informs about their activity as well. The lateral reticular roles compared with the corticopontocerebellar pathway.
CEREBROCEREBELLUM a topographic organizationfor example, upholding
Cerebral cortex the somatotopic pattern in the connections from MI
and SI (Fig. 24.7). The connections from the cerebral
cortex to the pontine nuclei exhibit an extreme diver-
Thalamus gence : that is, a small part of, let us say MI, influences
small clusters of neurons in widespread parts of the
pontine nuclei. Presumably, each pontine neuron
VL Cerebellothalamic
tract receives converging inputs from specific combinations
of cortical cell groups, thus integrating various kinds of
Lateral cerebellar nucleus
(Dentate) information before forwarding messages to the cerebel-
Corticopontine lum. The next linkthe pontocerebellar tractshows
tract a marked convergence (as well as divergence). In this
Pontine nuclei way, the corticopontocerebellar pathway seems to pro-
duce numerous specific combinations of cerebrocorti-
cal inputs in the cerebellar cortex. These and other data
indicate that there is a functional localization within
the cerebellar hemispheres, so that smaller parts take
Pontocerebellar care of specific tasks.
tract
MI SI Posterior
PMA, parietal cortex
gure 24.9 Main connections of the cerebrocerebellum. The ascend-
SMA
ing connections to the cerebral cortex are synaptically interrupted in Prefrontal
the dentate nucleus and in the thalamus. The projection from the cortex Visual
cerebellar cortex to the cerebellar nuclei is GABAergic and inhibitory, cortex
whereas the other links in the cerebrocerebellar pathway are excit-
atory. Compare Fig. 24.17 showing the crossing of the cerebrocere-
bellar connections.
the execution of visually guided movements.2 The pon-

tine nuclei also receive connections from parts of the
hypothalamus and limbic structures, notably the mam-
millary bodies and the cingulate gyrus. The information
conveyed from these regions is probably not directly
related to movement. The cingulate gyrus is concerned,
for example, with attention and with error-detection
during motor, sensory, and cognitive processes. These
connections and those from the prefrontal cortex may
form the basis of cerebellar contributions to certain cogni-
tive tasks (see later in this chapter, The Cerebellum and
Cognitive Functions). In addition, limbic cortico-
Pontine
pontine connections might contribute to the well-known nuclei
influence of motivation and emotions on movements.
Topographic Organization of the

Cerebrocerebellar Pathway
The corticopontine projection is topographically orga-
nized, so that different cortical regions project to largely
different parts of the pontine nuclei (Fig. 24.10). The
fibers coming from the MI and SI are somatotopically
organized. Further, the pontocerebellar projection shows
gure 24.10 The corticopontine pathway. Areas of the cerebral cor-
2 There are modest connections to the pontine nuclei from the frontal eye eld, tex that are connected with the cerebellar hemispheres by means of
involved in control of rapid eye movements, and from area 9 in the dorsolateral the pontine nuclei are shown in different colors. In the pontine nuclei,
part of the prefrontal cortex. Some bers arise in parts of the auditory cortex, bers from each cortical region terminate in its own territory. Note
whereas few if any pontine bers come from the rest of the temporal lobe. the lamellar arrangement, resembling the skins of an onion.
The Intermediate Zone Is a Meeting Place for Signals cortex. Here, the vast amount of information provided
from the Cord and the Cerebral Cortex by all of the afferents is processed. To some extent,
different kinds of information are integrated, and then
The intermediate zone (Fig. 24.4) is mainly defined on
answers are issued to various motor centers of the
the basis of its efferent connections (projecting to the
brain and spinal cord. As mentioned, the cerebellar
interposed intracerebellar nuclei; Fig. 24.11). It also has
cortex has the same structure all over (it cannot be
special features with regard to afferents, however (Fig.
subdivided into cytoarchitectonic areas, differing also
24.11). Whereas the lateral parts of the hemispheres are
in this respect from the cerebral cortex), and it lacks
strongly dominated by inputs from the cerebral cortex,
association fibers that interconnect different regions.
and the vermis is dominated by spinal inputs, the inter-
The structural arrangement of the neuronal elements is
mediate zone receives connections from both the cere-
strictly geometric, so the individual elements can be dis-
bral cortex and the spinal cord (Fig. 24.4). Animal
tinguished fairly easily. This helps explain why the
experiments indicate that the cortical input to the inter-
structure and internal connections of the cerebellar cor-
mediate zone comes primarily from the MI and SI. Single
tex are much better known than that of the cerebral
neurons in the intermediate zone can be activated from
cortex.
both the cerebral cortex and the spinal cord. For example,
in the arm region of the anterior lobe, intermediate-
zone neurons receive converging input from the arm The Cerebellar Cortex Consists of Three Layers
region of the MI and SI and from sensory receptors in the
The superficial, outermost layer is the molecular layer
arm. Perhaps the cerebellum in this case compares copies
(Figs. 24.2 and 24.12). It contains mainly dendrites and
of the motor commands sent from the cerebral cortex
axons from cells in the deeper layers and only a few cell
with the signals from the periphery providing informa-
bodies. The middle layer is dominated by the large
tion about the actual movement that was produced by the
Purkinje cells, arranged in a monolayer, and is called
command (signaled by the spinocerebellar tracts).
the Purkinje cell layer. The deepest, lowermost layer is
the granular layer, named so because it is packed with
THE CEREBELLAR CORTEX AND THE MOSSY AND tiny granule cells. The axons of the granule cells ascend
CLIMBING FIBERS through the Purkinje cell layer into the molecular layer,
where they divide at a right angle into two branches run-
Before discussing the efferent connections of the cerebel- ning parallel with the surface of the cortex (Figs. 24.12
lum, we need to know something about the cerebellar and 14.13). These branches are called parallel fibers
and run in the direction of the long axis of the folia.
INTERMEDIATE ZONE The parallel fibers form numerous synapses with the
Motor (MI) & Purkinje cell dendrites. The Purkinje cell dendritic tree
somatosensory (SI) is unusual: first, it has an enormously rich branching
areas pattern; second, the dendritic tree is compressed into
one plane, forming an espalier oriented perpendicular
to the long axis of the folia and the parallel fibers. This
Thalamus
arrangement ensures that each parallel fiber forms syn-
apses with many Purkinje cells (the parallel fibers can
VL be several millimeters long). At the same time, an enor-
mous number of parallel fibers contact each Purkinje
Interposed cell: it has been estimated that each Purkinje cell receives
nucleus
about 200,000 synapses. Considering that there are
Red nucleus
approximately 100 billion granule cells but only 30 mil-
Pontine nuclei lion Purkinje cells, each Purkinje cell would integrate
signals from about 3000 granule cells.3
In addition to granule cells and Purkinje cells, the
cerebellar cortex contains inhibitory interneurons
(Fig. 24.13) that serve to limit the activity of the Purkinje
Rubrospinal tract cells and probably increase the spatial precision of the
Spinocerebellar
tracts
3 Although older quantitative studies agreed that the number of Purkinje cells
in the human cerebellum is about 15 million, a study with an improved stereo-
gure 24.11 Main connections of the intermediate zone. Both the logical method estimated the number to about 30 10 million (Andersen et al.
6
spinal cord (via the red nucleus) and the cerebral cortex (via the thal- 1992). The same study estimated the number of granule cells to about 100 10 ,
9
while the number of neurons in the dentate nucleus was 5 10 .

6
amus) can be inuenced by the intermediate zone.
Parallel fiber
(glutamate) Purkinje cell
Granule cell
Purkinje cell
(GABA) MOLECULAR
LAYER
Climbing fiber
PURKINJE CELL
ramifications
LAYER
(glutamate)
GRANULAR
LAYER
Climbing fiber
gure 24.12 Structure of the cerebellar

cortex. The three layers and the main cell Purkinje cell axon
types are shown schematically in a piece of
cerebellar folium. The Purkinje cell dendrites
are arranged perpendicular to the long axis
of the folium and the parallel bers. The Mossy fiber (glutamate)
two main kinds of afferent bers (mossy and
climbing bers) are also shown. The mossy Climbing fiber (glutamate)
bers end on the granule cells, whereas the Intracerebellar nucleus
climbing bers enter the molecular layer to
end on the Purkinje cell dendrites.
incoming signals (cf. inhibitory interneurons in sensory contain -aminobutyric acid (GABA), and they inhibit
systems; see Fig. 13.4). their target cells, as shown physiologically. The granule
As mentioned, the Purkinje cells are the only ones cells have an excitatory action on the Purkinje cells,
that send their axons out of the cerebellar cortex and releasing glutamate.
thus constitute the efferent channel. The Purkinje cells
The Cerebellar Cortex Contains Three Kinds of
Purkinje cell
Inhibitory Interneurons
Stellate cell
All cerebellar interneurons contain GABA (some may
+ + + + also contain glycine, another inhibitory neurotransmit-
ter). One main type of interneuron is the stellate cell,
+ Parallel fiber
located in the molecular layer (Fig. 24.13). It receives
_
afferent excitatory input from the granule cells (parallel
fibers), and its axons form synapses with the Purkinje cell
dendrites. Another kind of interneuron, the basket
Basket cell _ cell, is located close to the Purkinje cell layer. Basket
_ cells are also contacted by parallel fibers, whereas their
axons end with synapses around the initial segment of
+ Golgi cell the Purkinje cell axonsa location that enables the
Granule cell basket cells to inhibit the Purkinje cells very efficiently.
The axonal branches of the basket cells are arranged
perpendicular to the long axis of the folia, so that they
_ inhibit Purkinje cells lateral to those that are being acti-
vated by parallel fiber excitation. Activation of a group
Cerebellar + of granule cells would lead to a narrow band of excita-
nuclear neuron Mossy fiber
+ tion of the Purkinje cells along the folium, flanked by a
zone of basket-cell mediated inhibition on each side.
Thus, it appears to be a kind of lateral inhibition, which
Climbing fiber
is common in sensory systems to increase the spatial
gure 24.13 The cerebellar cortex. Schematic of the main cell types
precision. Correspondingly, the extent of the cerebellar
and their synaptic arrangements. The three types of GABAergic cortical region activated by each mossy fiber is reduced.
interneurons are colored green. (Redrawn from Eccles et al. 1967.) The third kind of inhibitory interneuron, the Golgi cell,
is located in the granular layer. The dendrites of the In contrast to mossy fibers, the firing frequency of
Golgi cells extend upward into the molecular layer and the climbing fibers is very low under natural conditions
are therefore contacted by parallel fibers (like the stel- (often less than one signal per second). Even maximal
late cells and the basket cells). The axonal branches stimulation does not bring the firing frequency above
form synapses with the dendrites of the granule cells 10/sec. Accordingly, recordings of Purkinje cell activity
and thus reduce the excitation received by the Purkinje in an animal at rest shows continuous firing of simple
cells from the granule cells. spikes with high frequency, interrupted now and then
by complex spikes.
Acute destruction or inactivation of the inferior olive
Afferents to the Cerebellar Cortex Are of Two Main
demonstrates its importance for motor control. Movements
Kinds: Mossy and Climbing Fibers
become uncoordinated, similar to the effect of removing
The afferent fibers to the cerebellar cortex fall into two the whole cerebellum. Accordingly, physiologic studies
categories, which differ in how the fibers end in the show that inactivation of the olive (by injection of a
cerebellar cortex. Both kinds have an excitatory synap- local anesthetic) produces a marked disinhibition of the
tic action, most likely mediated by glutamate. The Purkinje cells. This increases the inhibition of the intrac-
climbing fibers all come from the inferior olive, whereas erebellar nuclear cells so that the cerebellar output to
afferents from nearly all other nuclei end as mossy fibers other parts of the brain is virtually eliminated.
(such as the vestibulocerebellar, the spinocerebellar, and In conclusion, the Purkinje cells receive excitation
the pontocerebellar fibers).4 from both mossy and climbing fiber afferent inputs but
The mossy fibers conduct signals relatively rapidly with very different spatial and temporal characteristics
and end in the granular layer, establishing synapses of their actions.
with the granule cell dendrites (Figs. 24.12 and 24.13).
One mossy fiber branches extensively and contacts a
Connections of the Inferior Olive
large number of granule cells, each of which, in turn,
contacts many Purkinje cells. Thus, each mossy fiber The climbing fibers cross and end in the cerebellar
influences many Purkinje cells, but the excitatory effect nuclei and the cerebellar cortex with an extremely pre-
on each is weak, so that many mossy fibers must be cise topographic order. One subdivision of the olive
active together to provide sufficient excitation (via the receives afferents primarily from the cord via several
parallel fibers) to fire a Purkinje cell (as mentioned, precisely organized spino-olivary tracts, and project to
the parallel fibers excite the Purkinje cells). A typical the spinocerebellum. Another part receives afferents
feature of the mossy fibers is that they transmit action from the superior colliculus and project to the midpor-
potentials with a high frequency and make the Purkinje tion of vermis (the oculomotor vermis). The superior
cells fire so-called simple spikes with a frequency of 50 to colliculus receives signals from the retina, from the
100 per second. visual cortex, and the SI. These parts of the olive contrib-
All the climbing fibers cross to the opposite side and ute to the control of eye and head movements. A small
end very differently from the mossy fibers: the fibers olivary subdivision receives afferents from the pretectal
ascend directly to the molecular layer and divide into nuclei (see Fig. 27.19) and project to the flocculonodu-
several branches, each climbing along a Purkinje cell lar lobe. The pretectal nuclei receive signals from the
dendrite (Figs. 24.12 and 24.13). As they climb, they form retina, and its projection to the olive is of importance for
numerous synapses with the dendrites. Each Purkinje adaptation of the vestibuloocular reflex (see Fig. 25.4;
cell receives branches from only one climbing fiber see also later, Examples of the Cerebellar Role in
(i.e., from only one cell in the inferior olive). Each oli- Motor Learning).
vary cell, however, innervates more than one Purkinje The main part of the human inferior olive (the princi-
cell, as the number of Purkinje cells is higher than the pal nucleus) projects to the cerebellar hemispheres and
number of olivary cells. Because each climbing fiber receives afferents from various mesencephalic nuclei,
forms so many synapses with a Purkinje cell, the total notably the parvocellular red nucleus. These mesen-
excitatory action is strong. Thus, even a single action cephalic nuclei receive afferents from the cerebral cor-
potential in a climbing fiber elicits a burst of action tex (especially M1, SMA, and PMA) and can therefore
potentials in the Purkinje cellscalled complex spikes. mediate cortical information to the cerebellar hemi-
spheres. In addition, the mesencephalic nuclei receive
strong connections from the cerebellar nuclei, thereby
4 In addition to the climbing bers and mossy bers, demonstrated with the
Golgi method a long time ago, a third type of cerebellar afferent has been dem- establishing a loop: cerebellumred nucleusinferior
onstrated by using the histouorescence method (visualizing bers containing olivecerebellum. The functional role of this rather
catecholamines). Such bers come from the raphe nuclei and from the locus massive pathway is unknown. Finally, the inferior olive
coeruleus and contain serotonin and norepinephrine, respectively. They appear
to end rather diffusely in both the granular and molecular layers. Direct bers receives GABAergic fibers from the cerebellar nuclei (of
from the hypothalamus also end in this manner. the opposite side).
long-term depression (LTD, see Chapter 4, under
Mossy and Climbing Fibers Mediate Different
Different Kinds of Synaptic Plasticity) depends on a
Kinds of Information 2+
rise in Ca concentration in the Purkinje cell dendrites,
The great differences between the mossy and climbing which is produced by the binding of glutamate to
fibers with regard to both structural and physiological amino-methylisoxazole propionic acid (AMPA) and
properties strongly suggest that they convey different metabotropic glutamate receptors. Most likely, how-
kinds of information and thus play different parts in ever, several cellular mechanisms underlie cerebellar
5
cerebellar functions. Because of their ability to vary their plasticity.
signal frequency over a wide range, the mossy fibers are
presumably well suited for providing precisely graded
The Inferior Olive and Rhythmic Movements
information about movements (the muscles involved,
as well as the direction, speed, and force of movements), As mentioned, the climbing fibers arise in the inferior
localization and characteristics of skin stimuli, details olivea large, folded nucleus in the ventral medulla
concerning motor commands issued from the cerebral (see Fig. 6.17). A characteristic property of olivary neu-
cortex, and so forth. Such assumptions also fit with the rons is that their membrane potential shows spontane-
physiological properties of spinocerebellar fibers, known ous fluctuations that facilitate rhythmic firing with a
to end as mossy fibers (less is known about the cortico- frequency of 5 to 10 Hz. Llins and Sugimori (1992)
pontocerebellar pathway in this respect). propose that that the inferior olive functions as a pace-
The climbing fibers, because of their low range of fir- maker for movements, by alerting specific combina-
ing frequency, are less likely to provide precisely graded tions of premotor neurons in the cord. Indeed, making
information. Recordings of the firing of the Purkinje the olivary neurons to fire rhythmically by systemic
cells in response to climbing fiber activity also suggest administration of the alkaloid harmaline produces
that the climbing fibers have a unique functional role. rhythmic muscular contractionstremorin large parts
Thus, as mentioned, a single action potential in a climb- of the body with a frequency of 10 Hz. Further, olivary
ing fiber is sufficient to trigger a burst of Purkinje cell neurons fire rhythmically in pace with licking movements
action potentials (complex spikes). This would suggest in the rat, which occur with a frequency of 6 to 8 Hz.
an all-or-none action rather than a graded one. Several Another peculiarity of olivary neurons is that they are
theories of cerebellar functions postulate that the climb- electrically coupled (nexus). This enables large assemblies
ing fibers inform about errors in the execution of a of neurons to fire synchronously. The GABAergic fibers
movement (giving an error signal) when the move- from the cerebellar nuclei, mentioned earlier, can switch
ment does not correspond to what was intended, and off the electric coupling so that the synchronously firing
there is some experimental support for this hypothesis. neuronal assemblies become much smaller. Conceivably,
Some studies show that the firing frequency of climbing this relates to how the cerebellum organizes the activa-
fibers increases in relation to a perturbation of an ongo- tion of muscle groups at specific moments during a
ing movement, whereas the firing frequency is unrelated movement.
to, for example, the direction and velocity of the move-
ment. In experiments with walking cats, the firing fre-
The Mossy Fibers and Fractured Somatotopy in the
quency of climbing fibers leading from the forelimb
Cerebellar Cortex
increases when the foot meets an obstacle, so that the
walking pattern has to be changed. In monkeys learn- The American neurophysiologist Welker (1987) using
ing a new movement, there is increased climbing-fiber very precise, micromapping methods, described a novel
activity from the relevant body parts. When the move- aspect of the somatotopic localization within the cere-
ment is well rehearsedthat is, the learning phase is bellum. The mossy fibers, formerly thought to end with
overthe climbing fiber firing frequency does not a fairly diffuse somatotopic pattern, were shown to end
increase during execution of the movement (no more in numerous, discrete patches in the cortex, each patch
error signals?). being defined by its sensory input from a specific minor
A specific role of the climbing fibers during motor part of the body. Each patch is usually less than 1 mm
learning has been postulated based on this and other in diameter (in the rat and cat). Thus, the leg region
kinds of experiments. The climbing fiber input is within the posterior lobe consists in reality of a mosaic
thought to alter for a long time (days, perhaps years) of patches. A salient feature is that adjacent patches can
the responsiveness of the Purkinje cells to mossy fiber receive inputs from body parts that are widely separated.
inputs. This appears to happen only on simultaneous
activation of a Purkinje cell by specific sets of climbing
and mossy fibers, leading to a change of Purkinje cell 5 The hypothesis that LTD is the cellular basis of cerebellar plasticity (and thus
learning) is not supported by all available data, however. For example, knock-
excitability, so that the following mossy fiber signals out mice lacking certain glutamate receptors exhibited reduced motor learning
have less effect than previously. This phenomenon, in spite of retained ability to produce LTD in the cerebellar cortex.
Further, the same body part is usually represented in The corticonuclear connections are precisely, topo-
several widely separated patches. This arrangement of graphically organized, so that, as a rule, fibers from the
the mossy fibers was termed fractured somatotopy by anterior parts of the cerebellar cortex end in anterior
Welker. It presumably is a means to integrate various parts of the nuclei, fibers from medial parts of the cor-
inputs sharing relevance for a certain movement. How tex end medially, and so forth. There is in addition a
this pattern of mossy fiber inputs is coordinated with marked longitudinal localization, with the vermis send-
the climbing fiber inputs is not clear. As discussed later ing fibers to the fastigial nucleus, the intermediate zone
(Fig. 24.18), the climbing fibers terminate in narrow to the interposed nuclei, and the hemispheres to the
sagittal strips or zones, and one such strip is often dentate nucleus (Fig. 24.15). There is also somatotopic
related to one body part only. localization within each of the nuclei so that different
parts influence movements in different parts of the
body. Overall, signals from different parts of the cere-
EFFERENT CONNECTIONS OF THE CEREBELLUM bellum are kept segregated through the nuclei and fur-
ther on to other parts of the brain. Thus, each of the
As previously mentioned, the three main subdivisions nuclei sends efferent fibers to a separate target region,
of the cerebellum act largely on the parts of the nervous as shown in a very simplified manner in Figs. 24.6,
system from which they receive afferent inputs. The vast 24.9, and 24.11.
majority of the Purkinje cell axons end in the cerebellar
nuclei (corticonuclear fibers). The neurons of these
Direct Projections from the Cerebellum to the Vestibular
nuclei forward the information to the various targets of
Nuclei
the cerebellum.
Parts of the vestibular nuclei correspond in certain
respects to the cerebellar nuclei. Thus, the Purkinje cells
The Cerebellar Nuclei and the Corticonuclear
of the vestibulocerebellum send their axons directly to the
Connections
vestibular nuclei as corticovestibular fibers (Fig. 24.5).
The cerebellar nuclei are located in the deep white mat- These fibers end primarily in vestibular nuclei that send
ter of the cerebellum, just above the roof of the fourth ascending connections to the nuclei of the external
ventricle (Figs. 24.2 and 24.14). In humans, there are ocular muscles (the medial longitudinal fasciculus; see
four nuclei on each side. Close to the midline, under the Fig. 18.8) and, to a lesser extent, in parts of the nuclei
vermis, lies the fastigial nucleus (medial cerebellar sending fibers to the spinal cord. The vestibular nuclei
nucleus); then follow two small nuclei; and most later- also receive direct projections from Purkinje cells of the
ally lies the large, folded dentate nucleus (lateral cere- vermis of the anterior and the posterior lobesthat is,
bellar nucleus). The two small nuclei have specific outside the vestibulocerebellum as defined here. These
names in humans (the globose and the emboliform fibers end primarily in the lateral vestibular nucleus
nuclei) and correspond to the anterior and posterior (nucleus of Deiters; see Figs. 18.7 and 18.8), which
interposed nuclei in animals. projects to the spinal cord. Thus, the cerebellar vermis
Mesencephalon
Fastigial nucleus
Interposed nucleus
Dentate nucleus
Vermis Hemisphere
gure 24.14 The cerebellar nuclei. Left: Drawing of an oblique dorsally than the drawing. Therefore, only the dentate and the inter-
section through the cerebellum and the brain stem. Right: posed nuclei are seen in the photomicrograph.
Photomicrograph of a myelin-stained section placed slightly more
Vermis Increase or decrease in the firing frequency of the
Intermediate zone
Purkinje cells immediately causes change in the activity
ANTERIOR LOBE
of the nuclear cells. A prerequisite for this is synchro-
Primary fissure
nous firing of many Purkinje cells with axons converg-
Hemisphere
(neocerebellum)
ing on a few nuclear cells. Then even minute changes of
the activity of each Purkinje cell changes the signals
issued from the cerebellum to its target nuclei. Indeed,
there is evidence that synchronous firing of assemblies
of functionally related Purkinje cells is a fundamental
feature in cerebellar functioning.
In conclusion, the outputs of the cerebellar nuclei
reflect with high temporal precision even very weak
inputs to the cerebellar cortex. This is presumably impor-
tant for, among other tasks, the cerebellar role in con-
POSTERIOR LOBE
trol of rhythm, as we discuss later in this chapter.
Organization of Efferent Connections from the

Cerebellar Nuclei
The fibers from the dentate nucleus leave the cerebellum
through the superior cerebellar peduncle (Fig. 24.2).
They cross the midline in the mesencephalon, and some
Dentate Interposed Fastigial
nucleus nucleus nucleus
fibers end in the red nucleus of the opposite side. Most
fibers continue rostrally, however, to end in the thalamus.
gure 24.15 Sagittal arrangement of corticonuclear connections. Here, the dentate fibers end primarily in the ventrolat-
Purkinje cells in the hemispheres project to the dentate nucleus, eral nucleus, VL (some also reach the VA) (Fig. 24.16).
whereas Purkinje cells in the intermediate zone and the vermis project These nuclei also receive fibers from the basal ganglia,
to the interposed and fastigial nucleus, respectively. In addition,
but they end in different parts than the cerebellar fibers
Purkinje cells in the anterior and posterior vermis project to the ves-
tibular nuclei. (as shown schematically in Fig. 24.16), in agreement
with physiological studies showing that the basal gan-
glia and the cerebellum do not influence identical parts
can influence spinal motoneurons via the lateral vestib- of the cortex. Signals from the cerebellar hemispheres
ulospinal tract, besides its effects mediated by means of pass primarily to the MI, whereas the basal ganglia via
the fastigial nucleus to the reticular formation and the the thalamus act mainly on premotor areas and the pre-
lateral vestibular nucleus. The vestibulocerebellum thus frontal cortex. In addition, the cerebellum influences
contributes to the control of eye movements, whereas parts of the SMA and PMA that apparently differ from
the vermis via the vestibular nuclei primarily controls the parts influenced from the basal ganglia. There is also
posture and equilibrium. anatomic and physiological evidence of connections
from the dentate nucleus (via the thalamus) to area 9 in
the dorsolateral prefrontal cortex. Even though such
Cerebellar Nuclear Neurons Are Spontaneously Active
connections most likely are modest compared to those
The nuclear cells fire with a high frequency even in an reaching the motor areas, they are suggested to be of
animal sitting quietly. When neurons fire without any decisive importance for the cerebellar influence on cog-
obvious excitatory input, they are said to be spontane- nitive tasks.
ously active. Indeed, in vitro studies of cerebellar slices As mentioned, the efferents from the intermediate
show that the nuclear neurons have intrinsic properties zone reach the interposed nuclei. These send their effer-
that depolarize the membrane even in the absence of an ents both to the contralateral thalamus (to the VL
excitatory input (pacemaker properties). Because all mainly, like the dentate) and the red nucleus (Fig. 24.11).
Purkinje cells are inhibitory (GABA), a continuous firing This enables the interposed nuclei to influence motoneu-
of the nuclear cells is a prerequisite for the information rons via both the rubrospinal tract and the pyramidal
from the cerebellar cortex to be passed on (increased tract. Because the rubrospinal tract is crossed, the inter-
Purkinje cell activity leads to reduced nuclear cell firing). posed nucleus (and the intermediate zone) acts on the
In addition to their tendency for spontaneous depolar- body half of the same side. The human rubrospinal
ization, the nuclear cells receive some excitatory inputs, tract is, however, most likely too small to be of much
namely the spinocerebellar and olivocerebellar projec- functional significance (cf. Chapter 22, under The Red
tions that give off collaterals to the cerebellar nuclei. Nucleus and the Rubrospinal Tract).
SI MI SMA
PMA Prefrontal in the 1940s. But the localization within the cerebellum
cortex is far more sophisticated than what could be revealed
by the fairly primitive methods 70 years ago. Each of
the three longitudinal zones of Jansen and Brodal can
thus be further subdivided, as shown by the Dutch neuro-
anatomist J. Voogd and coworkers. Figure 24.17 shows
the zones of the intermediate zone as an example.
The zonal pattern is especially sharp within the olivo-
cerebellar and corticonuclear projections. The neurons
located within a particular small part of the olive send
their fibers to a narrow longitudinal zone, whereas the
neighboring zones receive climbing fibers from other
parts of the olive (Fig. 24.17). The Purkinje cells of the
zones also send their axons to different parts of the cer-
ebellar nuclei. The parcellation of the cortex into sagittal
zones in fact goes further than shown in Fig. 24.17.
Physiological studies show that within the anterior lobe
each zone consists of several microzones, which differ
in the information they receive. Apart from the parallel
VA
VL
VPL Intermediate zone
From basal ganglia C3 C2 C1
Pallidothalamic tract
From cerebellum
Medial lemniscus Cerebellothalamic tract
gure 24.16 Thalamocortical connections. Schematic of the arrange-

ment within the ventral thalamic nucleus of afferents from the
somatosensory pathways, the cerebellum, and the basal ganglia and
their further projections to the SI, MI, and the premotor cortex.
The fastigial nucleus (receiving Purkinje cell axons

from the vermis) sends its efferents to both the vestibu-
lar nuclei and the reticular formation (Fig. 24.6). Thus,
motoneurons can be influenced via the vestibulospinal
and the reticulospinal tracts. On the basis of what we
discussed in Chapter 22, the cerebellum via the fastigial
nucleus can influence posture and relatively automatic
movements like locomotion. This is supported by the Interposed
nucleus
results of animal experiments and by clinical observations.
In addition, connections from the fastigial nucleus to
the reticular formation mediate cerebellar influences on
autonomic functions, as shown in animal experiments. Dentate Fastigial
nucleus nucleus
Sagittal Zones and Modules in the Cerebellum

Inferior olive
We have so far described that the main subdivisions of
the cerebellumsuch as the flocculonodular lobe, the
gure 24.17 Zonal organization of the cerebellar cortex. Very sim-
vermis, and the hemispheresdiffer with regard to plied illustration of the precise topographic pattern of cerebellar
connectivity. Further, we have seen that the lateral parts efferent and afferent connections. The cortex can be divided into lon-
of the hemispheres, the intermediate zone, and the gitudinal zones projecting to different parts of the cerebellar nuclei
vermis differ with regard to their efferent connections and receiving afferents from different parts of the inferior olive. Here,
(Fig. 24.15). This organization of the cerebellum into the intermediate zone is shown as an example. The intermediate zone
is divided into three zones termed C1C3 differing with regard to
three longitudinal zones, each projecting to separate olivary afferents and nuclear target region. Each zone, or rather parts
parts of the cerebellar nuclei, was first described by the of a zone, control certain muscular groups and their coordination in
Norwegian neuroanatomists Jan Jansen and Alf Brodal goal-directed movements.
fibers, extending for a few millimeters perpendicular to Motor cortex
the longitudinal zones, there are no association fibers
interconnecting different parts of the cerebellar cortex.
Thus, the cerebellar cortex and the cerebellar nuclei
consist of numerous compartments, or modules, that
function (at least largely) independently of each other.
Some data suggest that each module takes care of a spe- Thalamus (VL) Internal
cific motor task. As mentioned, in this respect the cer- capsule
ebellar cortex differs from the cerebral cortex, which is
characterized by extensive association connections and
cooperation among different regions.
CEREBELLAR FUNCTIONS AND SYMPTOMS Cerebellar

IN DISEASE hemisphere
We finally discuss the function of the cerebellum, with

special reference to the motor disturbances that occur
in humans and experimental animals after damage to Dentate Pyramidal tract
the cerebellum. (To some extent, the function of an nucleus
organ is easier to discover when it does not work prop- Purkinje cell
Decussation
erly.) Because both the ascending fibers from the cere-
bellum to the cerebral cortex and the descending fibers
from the cerebral cortex to the spinal cord are crossed, gure 24.18 Unilateral lesions of the cerebellum produce symptoms
the cerebellar hemisphere exerts its influence on the on the same side. Ascending connections from the dentate nucleus
cross in the mesencephalon on their way to the thalamus. The next
body half of the same side (Fig. 24.18). Consequently, link passes to the motor cortex, where pyramidal tract neurons are
with diseases of the cerebellum, the symptoms occur on inuenced. Since the pyramidal tract crosses (in the lower medulla), the
the same side as the lesion. cerebellar hemispheres control muscles in the ipsilateral body half.
Clinically, only certain motor symptoms can with
certainty be referred to cerebellar lesions, even though the subdivisions give different symptoms. On this basis,
a multitude of symptoms have been produced in exper- one usually distinguishes three cerebellar syndromes:7
6
imental animals after lesions of the cerebellum. Modern the flocculonodular syndrome, the anterior lobe syn-
neuroimaging techniques, however, provide the oppor- drome, and the neocerebellar syndrome. The existence
tunity to localize accurately even fairly small lesions in of three distinct syndromes is most clear-cut in experi-
living subjects and, furthermore, to study cerebellar mental animals. In humans, the neocerebellar syndrome
neuronal activity (indirectly) in healthy and diseased is most often seen, which is not surprising because the
subjects performing specific tasks. Such studies have hemispheres (the neocerebellum) make up the major
demonstrated change of cerebellar activity in relation part of the human cerebellum.
to performance of tasks that were unexpected on the basis
of clinical observations. We return to this below when
considering the cerebellar role in cognitive functions. The Flocculonodular and Anterior Lobe Syndromes
To judge from the cerebellar connections as we have Isolated damage to the flocculonodular lobe in mon-
discussed them here, it is clear that the cerebellum influ- keys produces disturbances of the equilibriumthat is,
ences movements by acting on the neuronal groups that unsteadiness in standing and walking. When the body
give origin to the central motor pathways (the pyramidal is supported, movements of the extremities can be per-
tract, the reticulospinal tracts, and the vestibulospinal formed normally, however. Sometimes, similar symp-
tracts). These pathways, of course, control the activity of toms occur in humans with a special kind of tumor
spinal and cranial nerve motoneurons. The three main in the posterior cranial fossa, most often a so-called
subdivisions of the cerebellum (Fig. 24.4) act on differ- medulloblastoma arising from the nodulus. The ani-
ent neuronal groups, and lesions restricted to each of mals also exhibit nystagmus with the quick phase to the
side of the lesion. (Nystagmus is movements in which
6 This is probably explained by the fact that in humans the lesions that give the eyes move slowly in one directionas when track-
clear-cut symptoms most often are large and not conned to particular func- ing a moving object with the gazeand rapidly back.)
tional or anatomic cerebellar subdivisions. Further, they are usually combined
with lesions in other parts of the CNS (e.g., in parts of the brain stem). It is
therefore often difcult to decide whether a particular symptom is caused by
the cerebellar lesion. 7 A syndrome is a constellation of symptoms that occur together.
Eye movements may also be disturbed in humans with the rapid eye movements overshoot the target and are
cerebellar lesions that affect the vestibulocerebellum. followed by several correcting movements before the
Damage to the anterior lobe in experimental animals gaze is finally fixed. The role of the cerebellum in the
primarily produces a change of muscle tone. In decere- control of eye movements is further discussed in Chapter
brate animals, the decerebrate rigidity increases, as do 25, under The Cerebellum Controls Both Saccades
the postural reflexes. This fits with the observation that and Pursuit Movements.
electrical stimulation of the anterior lobe reduces the
decerebrate rigidity (as mentioned, the Purkinje cells
The Neocerebellar Syndrome
inhibit the cells of the cerebellar nuclei, whereas the
nuclear cells have excitatory actions on reticulospinal The neocerebellum plays a different functional role
8
and vestibulospinal neurons). In addition, some than the phylogenetically older parts of the cerebellum:
Purkinje cells in the anterior lobe vermis send axons it is primarily concerned with the coordination of the
directly to the vestibular nuclei, and removal of this (least automatic) voluntary movements. This stands to
inhibitory action would also tend to increase the activ- reason, since the cerebellar hemispheres send their main
ity of the vestibulospinal neurons and thus the decere- output to the MI (via the dentate nucleus and the thala-
brate rigidity. In humans, it is doubtful whether lesions mus) and thus influence the neurons of the pyramidal
of the anterior lobe produce increased muscle tone. tract (Figs. 24.9 and 24.18). After removal of one cer-
More marked is gait ataxia (unsteadiness of walking) in ebellar hemisphere in a monkey, the voluntary move-
patients with damage that mainly affects the anterior ments become uncertain on the same side of the body:
lobe vermis and the intermediate zone (this occurs in they become uncoordinated or ataxic. The same effect
cerebellar degeneration caused by alcohol abuse). The can be produced by cooling the dentate nucleus (by the
anterior lobe vermis, by means of its efferent connec- use of a cooling electrode) in a monkey that is perform-
tions to the fastigial nucleus and from there to the retic- ing a well-rehearsed movement (as soon as the cooling
ular formation, must therefore be assumed to have a is reversed, the movements again become normal).
role in coordination of the half-automatic movements Movements that were performed quickly and smoothly
of walking and postural adjustments. Similarly, selec- become unsteady and jerky by the cooling. The monkey
tive lesions of the fastigial nucleus in monkeys cause misses repeatedly when trying to grasp an object, even
difficulties with walking, sitting, and maintaining the though it knows perfectly well where it is and what is
upright position. demanded. Sometimes the hand is moved too far in
relation to the object, sometimes too short. The move-
ments tend to be decomposed; that is, instead of occur-
Cerebellar Lesions and Eye Movements
ring simultaneously in several joints, they take place in
As mentioned, lesions of the flocculonodular lobe can one joint at a time, and the velocity is unevensome-
cause nystagmus. This may manifest itself as spontane- times too high and sometimes too low. Selective dam-
ous nystagmus (i.e., nystagmus occurring in a person at age or transient uncoupling of the dentate nucleus in
rest with no kind of stimulation) or only when the monkeys indicates that the cerebellar hemispheres are
patient tries to keep the gaze in an eccentric position particularly important when movements must take
(paralysis of gaze nystagmus). Conceivably, these symp- place in several joints at the same time. Picking up a
toms are due to the loss of Purkinje cells that normally raisin, for example, became impossible because the
inhibit the vestibular nuclei (especially the medial monkey could no longer coordinate the movements of
nucleus) sending fibers to the nuclei of the extrinsic eye the joints of the wrist, thumb, and index finger. Precise
muscles (see Fig. 18.8). In addition, the patients with movements of one finger at the time could be done nor-
lesions of the flocculonodular lobe may have difficulties mally, however. Difficulties with hitting an object when
with slow pursuit movements (tracking a moving object trying to grasp it with the hand can probably be attrib-
with the gaze). Pursuit movements may also be impaired uted to the same basic defect; that is, difficulties with
after lesions restricted to lateral parts of the pontine coordinating the movements of the wrist, shoulder, and
nuclei or the cerebellar hemispheres (impaired to the elbow joints.
side of the lesion). Finally, lesions of the cerebellar hemi- Ataxia of this kind is also the most prominent symptom
sphere may cause so-called saccadic dysmetriathat is, in humans with damage to the cerebellar hemispheres.
For example, difficulty with the precision grip similar
to that described in monkeys has recently been observed
8 Electrical stimulation with electrodes surgically implanted at the cerebellar
surface has been used in patients with neurological disorders such as epilepsy in patients with unilateral infarcts of the cerebellar
and cerebral palsy. The theoretical basis is the inhibitory action of the Purkinje hemispheres. The increase of force when grasping an
cells with subsequent reduction of abnormally increased neuronal excitability object is slower than normal and the adjustment of the
and muscle tone. Even though some report favorable results with such stimula-
tion, there is no agreement as to whether the effect is due to the cerebellar grip force is deficient when grasping and lifting at the
stimulation or to some other factor. same time. In clinical neurology, the various elements
of ataxia have particular names, such as dysmetria The German neuroscientist Valentin Braitenberg pro-
(movement is not stopped in time), asynergia (decomposed more than 50 years ago that the cerebellum func-
position of complex movements), dysdiadochokinesia tions as a kind of clock, measuring temporal intervals
(reduced ability to perform rapidly alternating move- with great accuracy. The theory was subsequently mod-
ments of, for example, the hand), and intentional tremor ified to emphasize the cerebellar role in the control of
(tremor arising when trying to perform a movement, movement sequences and perhaps other sequential
such as grasping an object). Speech is also often dis- behaviors. The theory is based on, among other things,
turbed in cerebellar diseases. It has been called speech the regular arrangement of the parallel fibers (Figs. 24. 12
ataxia, to emphasize that it also appears to be caused and 24.13). Action potentials conducted along the
by incoordination (in the respiratory muscles, the mus- parallel fibers will excite the Purkinje cells in a fixed
cles of the larynx, and others), making the strength and temporal sequence. We discussed that a timing function
velocity of the speech uneven. might be crucial in the cerebellar contribution to motor
All the elements of ataxia have been attributed to a control, and recent data suggest that the cerebellar tim-
fundamental defect in control of the force and of the ing function may also be used in nonmotor tasks. Thus,
9
exact timing of the starting and stopping of movements. patients with cerebellar damage were impaired not only
As mentioned, the temporal aspect appears to be cen- in their ability to reproduce a certain rhythm by tap-
tral to the cerebellar contribution to motor control. ping their fingers but also in discriminating different
This is evidenced by patients with cerebellar damage sound rhythmsthat is, not only impaired execution
who are unable to perform sequences of finger move- but also perception of rhythm. They had no problems
ments in a particular rhythm. The movements are done with discriminating sounds of different intensities, how-
by each finger without a fixed temporal relation to ever, which suggest that the defect is specific to discrim-
movements of the other fingers. ination of temporal intervals. Reduced ability to judge
In acute damage to the cerebellar hemispheres in the velocity of visual stimuli has also been reported in
humans, the muscle tone often appears to be reduced patients with cerebellar lesions.
when tested by passive stretch (the symptom is transient). The inferior olive and the climbing fibers may have a
This is called cerebellar hypotonia. The underlying crucial role in the timing function of the cerebellum.
mechanism is not clear, although experiments in anes- Thus, the olivary neurons fire rhythmically, and neu-
thetized animals suggested that it is caused by reduced rons that activate Purkinje cells within a narrow sagittal
motoneuron activity. Recent experiments in awake zone fire synchronously. Further, there is experimental
animals and in humans, however, show that the muscle- evidence that the firing rhythm of olivary neurons and
spindle sensitivity to stretch is not significantly altered the rhythm of certain movements is correlated (see also
by cerebellar lesions (even when they include the dentate the earlier section, The Inferior Olive).
and interposed nuclei). Another aspect of timing is the judgment of duration,
for example, how long time has passed since I started a
particular action (mental or physical)? Whether the cer-
The Timing Theory: Does the Cerebellum Perform a
ebellum plays a role for this time function as well is not
Basic Operation Used in All Its Functions?
clear (see also Chapter 23, under Interval Timing).
Even though the study of cerebellar symptoms provides
reasonable insight into the functions of the cerebellum,
The Cerebellum and Motor Learning
we are far from understanding how the cerebellum
performs its tasks. The striking uniformity and strictly Animal experiments indicate that long-lasting changes
geometric structure of the cerebellar cortex has led to in synaptic efficacy may take place in the cerebellar cor-
comparison with a computer, which can perform the tex during motor learning. Much interest is devoted to
same kinds of computations on various kinds of infor- theories that consider the cerebellum to be a learning
mation. The subdivision of the cerebellum into numer- machine. The cerebellum may help automation of move-
ous, apparently independent units or modules may fit ments and perhaps also of certain cognitive functions.
such a concept. Several theories have been put forward There is considerable evidence that plastic changes occur
to explain how the cerebellum operates. None of them in the cerebellum during motor learning. For example,
has so far been universally accepted, however, and there the activation of the cerebellar hemispheres (as mea-
is disagreement with regard to interpretation of some sured with fMRI) is higher when a new sequence of
experiments said to support one theory or the other. movements is learned than when the automated move-
ment is performed afterward. We discussed the possible
role of the climbing fibers in motor learning, and LTD
9 It is not certain, however, that this sufces to explain why the symptoms are as a likely cellular mechanism (see the earlier section,
most marked when movements in two or more joints must be coordinated
(such as moving the index nger quickly to the tip of the nose from a position Mossy and Climbing Fibers Mediate Different Kinds
with the arm stretched out). of Information). Recent studies found that patients
with cerebellar lesions have impaired ability to learn Information about head movements from the vestibular
conditioned responses (shown for the blink reflex and apparatus is provided by mossy fibers, which also end
the withdrawal reflex in the leg). It has not been directly in the flocculus. The sensitivity of the vestibulo-ocular
shown, however, that LTD is induced in the cerebellum reflex can be altered experimentally in a short time,
during motor learning. as shown by making experimental animals wear pris-
Because learning takes place in the cerebellum in con- matic glasses that displace the image on the retina. The
ditioned responses, it is tempting to assume that corre- most drastic experiment is when the movement of the
sponding changes occur in the cerebellar hemispheres surroundings appears to be the opposite of the real
when humans learn complex voluntary movements movement, leading to a complete reversal of the reflex
(such as playing a musical instrument). Indeed, some response. Destruction of the cerebellar flocculus pre-
experiments support this assumption. Thus, patients vents adaptation of the reflex. (It is disputed, however,
with cerebellar lesions (or lesions of the inferior olive) whether the change in synaptic efficacythat is, the
show reduced motor learning capacity when wearing learningis caused by changes in the cerebellum or
prismatic glasses while throwing darts. Both patients elsewhere.)
and controls missed systematically to one side of the tar- Certain conditioned responses are examples of pos-
get immediately after putting on the prisms (because the sible cerebellar participation during motor learning.
aiming follows the direction of the gaze). During subse- Especially the so-called nictitating membrane reflex (a
quent repetitions, the control persons improved their part of the blink reflex) in rabbits has been investigated.
performance, while no improvement occurred in the cer- When a jet of air hits the eye the nictitating membrane
ebellar patients. Conversely, the controls overshot the moves together with the eyelid. This is an unconditioned
target after removal of the prisms, although this did not reflex, in which the trigeminal nerve is the afferent link;
occur in the cerebellar patients. the reflex center is in the brain stem involving the sen-
Although there is a strong case for a cerebellar role in sory trigeminal nucleus, the reticular formation, and the
motor learning, this should not be taken to imply that facial nucleus; and the efferent link is the facial nerve to
motor learning involves only the cerebellum. Indeed, there the muscles around the eye. If the jet of air is regularly
is good evidence that motor learning involves synaptic preceded by a tone (conditioning stimulus), the rabbit
changes in distributed networks, including at least motor will eventually react with a nictitating membrane move-
cortical areas and the basal ganglia (cf. Chapter 22, under ment even when the tone is presented alone. The signal
Learning and the Motor Cortex, and Chapter 23, pathway for the conditioned response is much more
under Movement Planning and Learning). complicated than that for the unconditioned reflex
(e.g., the auditory pathways and parts of the cerebral
cortex are involved). What is interesting in this connec-
More about the Cerebellum and Motor Learning
tion, however, is that after destruction of the cerebel-
Structural changes of the cerebellum during motor lum, the reflex can no longer be conditioned (i.e., only
learning have been found in rats that were trained in the unconditioned response occurs, and the animal can
an acrobatic task. After 30 days, the trained rats had no longer be trained to react to the tone only). Damage
significantly more synapses in the molecular layer than to the cerebellum after having made the response condi-
the untrained controls had. The increase was in both tioned abolishes the conditioned (but not the uncondi-
parallel fiber synapses and climbing fiber synapses with tioned) response. It is sufficient to remove a small part
Purkinje cells. of the cerebellar face area of the intermediate zone to
A much-studied example of cerebellar plasticity is adap- get these effects (this is a further example of the cerebel-
tation of the vestibulo-ocular reflex (VOR) (see Fig. 25.4), lar functional localization). After establishing the con-
as first shown by the Japanese neurophysiologist Masao ditioned response, it can be evoked by electric stimulation
Ito. The VOR ensures that when the head moves in one of pontocerebellar mossy fibers.
direction, the eyes move in the opposite direction with
exactly the same speed. This makes it possible to keep
The Cerebellum and Cognitive Functions
the gaze fixed on a stationary object even though the
head moves. The magnitude of the reflex response to a Many observations now suggest that the cerebellar
certain head movement (that is, the gain of the reflex) functions are not restricted to motor ones. While this
needs to be adjusted when, for example, the head grows topic has attracted much interest, and numerous
and alters its proportions. By means of relay stations neuroimaging studies have been performed in normal
(see Fig. 25.4), signals from the retina provide informa- persons and cerebellar patients, findings are partly con-
tion about retinal slip (the image is not kept stationary tradictory. It is therefore too early to draw conclusions
on the retina but moves). Climbing fibers ending in the as to the importance of the cerebellum for mental tasks
flocculus provide such signals and thus tell the cerebel- that are usually considered the domain of the cerebral
lum that the velocity of the eye movement is incorrect. cortex.
We mentioned that the cerebellum might be impor- cerebellum may also participate in other kinds of learn-
tant for the perception of rhythm, not only the proper ing than learning of movements. Thus, measurements
execution of rhythmic movements. Further, reduced of regional cerebral oxidative metabolism with PET in
ability to rapidly shift the attention from one kind of humans show that the posterior parts of the cerebellar
stimulus to another was found in six patients with hemispheres increase their neuronal activity when
lesions of the cerebellar hemispheres. The patients abil- learning a tactile recognition task (more than during
ity to maintain focused attention was not reduced, and just tactile recognition of an object).
neither was their perception of the stimuli. These and As mentioned, interpretation of associations between
other studies have been taken as evidence that the cer- cerebellar change of activity and the performance of
ebellum participates in a purely cognitive taskthat is, cognitive tasks is not straightforward. For example, it is
10
the switching of attention. Many neuroimaging stud- difficult to eliminate the possibility that the cerebellar
ies demonstrate (indirectly) that blood flow increases contribution concerns aspects of execution rather than
(or decreases) in parts of the cerebellum during the per- earlier stages in the processing. When trying to assess
formance of various cognitive tasks. For example, per- the importance of the cerebellum for cognitive func-
sons trying to solve a pegboard puzzle showed increased tions, we should remember that rather sophisticated
blood flow in the dentate nucleus. In such studies, one tests are required to reveal cognitive defects in cerebel-
seeks to eliminate the possibility that the increase is lar patients while their motor impairments are obvious
caused by the movements alone (e.g., moving the pegs). and incapacitating. This might be illustrated by a study
Another study reported increased blood flow in the of children who had their cerebellum partly removed
cerebellar hemispheres in persons trying to find verbs before the age of 3 (because of tumors). These children
going with nouns. Further, increased blood flow in the showed no significant signs of disturbed cognitive
hemispheres was observed in persons playing imaginary development, even though their motor acquisition of
tennis, and in persons counting silently. Finally, the motor skills was clearly subnormal. The problems with
interpreting clinical data become obvious, however,
when adding that among the children, those who had
10 An fMRI study of normal persons challenged this interpretation, however.
Thus, altered cerebellar activity occurred only in relation to a motor response received radiation therapy scored below normal on
associated with the shift of attention. both cognitive and motor tests.
25 Control of Eye Movements
networks in the brain stem. At least two regions of the

OVERVIEW
cerebral cortex are closely involved in the control of eye
movements (Fig. 15.7): the frontal eye field is primarily
For the eye to provide useful information to higher
related to initiation of saccadic movements, whereas
visual centers, the picture must be held stationary on the
several smaller areas in the parietotemporal region are
retina. Further, the eyes must be positioned so that the
mainly involved in the control of pursuit movements.
most salient part of a visual scene falls on the central
The third, fourth, and sixth cranial nerves and their
part of the retina with the highest visual acuity. Finally,
nuclei are treated in Chapter 27, together with the light
to sample enough information, the eyes must be moved
reflex and accommodation reflex mediated by the
quickly from one point of salience to another. The control
intrinsic eye muscles. Chapter 16 gives a brief account
system must therefore be able to move the eyes quickly
of the structure of the eye.
and precisely to make the image fall on the macula;
such movements are called saccades (or saccadic move-
ments). In addition, the control system must move the
MOVEMENTS OF THE EYES AND THE EYE MUSCLES
eyes so the retinal image is stationary even if the head or
the object is moving. The latter are called slow-pursuit
Horizontal, Vertical, and Rotatory Movements of the Eye
movements. The extraocular muscles responsible for
moving the eyes receive their nerve supply from the The eye is a sphere, lying in the orbit, surrounded by
nuclei of the third, fourth, and sixth cranial nerves. fat. It can rotate freely in any direction around its cen-
The control system coordinates the activity of the ter, whereas translatory movements are prevented. To
motoneurons in these nuclei. Premotor networks inter- describe the rotatory movements of a sphere, we define
connecting areas in the cerebral cortex, the brain stem, three axes, passing through the center and oriented per-
and the cerebellum carry out this task. To enable coor- pendicular to each other. For convenience, we describe
dinated activity, the nuclei of the extraocular muscles are the movements as taking place in three planes: a frontal,
interconnected by numerous fibers forming the medial sagittal, and a transverse or horizontal plane. A move-
longitudinal fascicle. The control system uses sensory ment in the horizontal plane takes place around a verti-
information from the retina, which informs about cal axis, and the anterior part of the eyeand therefore
whether the retinal image is stationary or slipping, from the gazemoves from side to side. We perform hori-
the vestibular apparatus about the movements of the zontal eye movements when looking to one side; when
head, and from proprioceptors in the eye muscles about looking to the left, the left eye rotates laterally and the
the movements of the eyes in the orbit. All this sensory right eye rotates medially. A movement in the sagittal
information is integrated and transformed into a motor plane takes place around a transverse axis, and the ante-
signal specifying the total activity of the extraocular rior part of the eye moves up and down. Such movements,
muscles at any time. For control of horizontal eye directing the gaze up and down, are called vertical eye
movementsespecially saccadesthe most important movements. Movements in the frontal plane take place
premotor area, the paramedian pontine reticular forma- around a sagittal axis, and the eye rotates without any
tion (PPRF), lies close to the abducens nucleus on each horizontal or vertical movement. For practical reasons
side. The PPRF sends fibers to the abducens and oculo- only, such movements around a sagittal axis are called
motor nuclei and coordinates their activities. A corre- rotatory eye movements (strictly speaking, all eye move-
sponding premotor area for vertical eye movements is ments are rotations around the center of the eyeball).
found in the mesencephalic reticular formation close to
the oculomotor nucleus.
The Extraocular Muscles and Their Actions
There is an important difference between the control
of eye muscles and of other muscles subjected to precise The six extraocular (extrinsic) muscles (Fig. 25.1) ensure
voluntary control (e.g., intrinsic hand muscles): the that the visual axes of the eyes (see Fig. 16.2) can be
nuclei of the extraocular musclesin contrast to spinal directed precisely toward any point in the visual field.
motoneuronsreceive no direct fibers from the cere- The scheme in Fig. 15.2 shows the main movements
bral cortex. The central control is exerted via premotor produced by each of the extraocular muscles if they
362
25: CONTROL OF EYE MOVEMENTS 363
were acting alone (this is a theoretical situation, because superior rectus muscle pulls the eye (the cornea) upward,
in reality they always work in concert). Most of the whereas the inferior rectus muscle pulls it downward.
muscles produce combinations of vertical, horizontal, These two therefore produce vertical movements.
and rotatory movements. Further, the actions of each Because the superior and inferior rectus muscles run
of the muscles change with the position of the eye anteriorly in a lateral direction, however, they do not
because this changes the position and direction of the only produce vertical movements but also some hori-
line of pull. The extraocular muscles (Fig. 15.1; see also zontal movement (in the medial direction). Thus, when
Fig. 27.16) all attach to the sclera and originate from the superior rectus muscle acts alone, it produces an
the wall of the orbit (a brief account of the structure of upward movement combined with a (smaller) medial
the eye bulb is given in Chapter 16). We analyze the that is, an oblique movement. In addition, the muscle
actions of the extraocular muscles in relation to the produces a small medial rotation of the eye (around the
above-defined three axes through the center of the eye- sagittal axis). The superior oblique muscle has a more
ball. We then need to know the direction of the force complicated course than the other extraocular muscles
exerted by the muscles in relation to the axis. We must (Fig. 15.1; see also Fig. 27.16). It originates posteriorly
furthermore know whether the muscle insertion in the in the orbit and runs forward medially. Just behind the
sclera is anterior or posterior to the equatorial plane of anterior margin of the orbit, it bends sharply around a
the eye, a frontal plane dividing the eye in an anterior small hook of connective tissue and continues in a pos-
and a posterior half. terolateral direction to insert posterior to the equatorial
There are four straight and two oblique extraocular plane. The muscle has actions around all three axes: it
muscles (Fig. 25.1, see also Fig. 27.16). Figure 25.2 shows rotates the eye around the sagittal axis so that the upper
schematically the actions of each muscle if it acted part moves medially and furthermore directs the gaze
alone. Most muscle produce movements that are com- downward and laterally (Fig. 15.2). The inferior oblique
posed of horizontal, vertical, and rotatory components. muscle originates from the bottom of the orbit in its
We can nevertheless simplify their functions by stating anteromedial part and runs, like the superior oblique,
that two muscles produce predominantly horizontal posterolaterally to insert behind the equator (Fig. 15.1).
movements (the medial and lateral rectus muscles), two It directs the gaze laterally and upward and rotates the
produce predominantly vertical movements (the supe- eye around the sagittal axis with its upper part laterally.
rior and inferior rectus muscles), whereas two muscles These considerations and the scheme in Fig. 15.2
produce mainly rotatory movements (the superior and concern movements starting from a neutral position of
inferior oblique muscles). The straight ones (the rectus the eyethat is, when viewing a distant object straight
muscles) come from the posterior end of the orbit and ahead. Changing the position of the eye in the orbit also
run forward to insert in front of the equatorial plane. changes the action of the muscles (for some muscles the
This means that the lateral rectus muscle pulls the front of change is small, for others quite marked). For example,
the eye (the cornea) laterally, whereas the medial rectus the superior rectus is a pure elevator when the eye is
muscle pulls it medially (these two muscles thus produce 23 degrees abducted. The oblique muscles perform pure
pure horizontal movements). Correspondingly, the vertical movements when the eye is about 50 degrees
abducted (cf. Fig. 27.16 showing the line of action of
the superior oblique). This is basis for the test of the
Superior oblique muscle extraocular muscles in Fig. 25.3, designed to test each
Superior rectus muscle muscle in isolation (as far as possible).
Levator palpebrae
muscle
Natural Eye Movements Are Conjugated
Virtually every natural eye movement is a combination
of the various movement directions described in the
preceding text. By combining proper amounts of verti-
cal and horizontal movements, any oblique movement
can be produced. Further, all natural eye movements
are conjugatedthat is, the two eyes move together to
Inferior rectus muscle Lateral rectus ensure that the image always falls on corresponding
muscle
Inferior oblique muscle points of the two retinas (see Fig. 16.3). Double vision
(diplopia) results if the eye movements do not occur in
gure 25.1 The extraocular muscles seen from the lateral aspect. conjugation. This is a typical symptom of pareses of the
The lateral wall of the orbit is removed. The straight muscles insert in
front of the equatorial plane of the eye, whereas the oblique muscles
extraocular muscles.
insert behind it (see also Fig. 27.16, which shows the orbit and the eye Almost all eye movements require a complicated coop-
muscles from above). eration of numerous muscles, with activation of synergists
Inferior Superior Inferior

oblique rectus oblique
(3) (3) (3)
gure 25.2 Actions of the extraocular
muscles. These are as observed when
Medial Lateral movements start from a neutral position
Lateral
rectus rectus rectus of the eye. Arrows indicate direction of
(6) (3) (6) the action (but not the force). Except for
the medial and lateral recti, all muscles
rotate the eye, in addition to their other
actions. Starting positions away from
Inferior the neutral may alter the actions of the
Superior rectus Superior muscles. For example, the superior rec-
oblique (3) oblique tus is a pure elevator when the eye is
(4) (4) 23 degrees abducted (cf. Fig. 15.3).
and inhibition of antagonists. When, for example, we with ordinary skeletal muscle fibers, and the motor units
look to the left, we activate the left lateral rectus and are among the smallest in the body (only 510 muscle
inhibit the left medial rectus, whereas we activate the fibers per motoneuron). Consequently, the nerves to
right medial rectus and inhibit the right lateral rectus. the extraocular muscles contain many nerve fibers: the
This is the simplest possible example, with a purely abducens nerve in humans (supplying only one muscle)
horizontal movement. In most other situations, the contains around 6000 axons.
cooperation between various muscles becomes much The extraocular muscles are required both to hold a
more complicated and requires an extensive, sophisti- certain tension for a long time (static position holding)
cated neural network for control. Electromyographic and to produce extremely fast movements. Accordingly,
(EMG) recordings in awake human subjects with their the maximal speed of contraction is high in comparison
eyes open show that there is some activity in virtually all with other skeletal muscle fibers. Further, the maximal
of the extraocular muscles. The tension produced by each firing frequency of the motoneuronsoccurring during
muscle varies, of course, with the position of the eyes. saccadic movementsis unusually high. Patients with a
paralysis of the lateral rectus muscle demonstrate that
there is constant activity in extraocular muscles. Even
The Eye Muscles Are Built for Precise Control
though the only muscle capable of active abduction is
The structure of the extraocular muscles reflects their paralyzed, a small abduction nevertheless occurs when
use in extremely delicate and precisely controlled move- the patient attempts to look to the affected side. This
ments. The muscle fibers are very thin in comparison abduction is caused by the relaxation of muscles that
adduct the eye, primarily the medial rectus (an example
of reciprocal inhibition).
Inferior
rior oblique
obliqu
ue The extraocular muscles are composed of a mixture
of fibers with fast and with slow twitch contractions. In
addition, there are muscle fibers that do not produce
Medial twitches but only a slow graded contraction (they receive
rectus
multiple end plates along the length of the muscle and
occur only in eye muscles). Their function is unknown, but
erior obliqu
Superior obl
bliqu
ique
q e
oblique presumably, they contribute to static position holding.
Eye Muscles, Proprioception, and Efference Copy

ectus
Superior rectus
There are muscle spindles in the extraocular muscles
(100150 altogether in the six human extraocular mus-
Lateral cles). Apart from the general rule that muscles subject
rectus
to precise control have a high density of muscle spin-
dles, their functional role in the extraocular muscles is
ctus
Inferior rectus not clear. Thus, signals from extraocular muscle spin-
dles are apparently not consciously perceivedthat is,
gure 25.3 Scheme for testing the eye muscles. Based on testing in
they do not contribute to the awareness of eye position
extreme positions in which the muscles produce relatively pure verti- and movements (in this respect differing from muscle
cal or horizontal movements. See text for further discussion. spindles elsewhere). Nor do signals from extraocular
muscle spindles evoke stretch reflexes. There is evidence landscape and fix the gaze at one point for a moment
that muscle-spindle signals, providing information and then move on (with a saccade) to another point of
about the length and the change of length of the extraoc- fixation. They can also occur reflexly, as part of ves-
ular muscles, are integrated in the cerebral cortex with tibular or optokinetic nystagmus. When awake, we
signals providing information about movements of the perform saccades all the time, often several per second.
head from the labyrinth and with signals from the ret- In this way, we constantly scan the visual scene to pro-
ina. Experiments in monkeys with transection of the vide maximal information. Because the visual acuity
ophthalmic nerve (assumed to contain most of the mus- declines so rapidly outward from the macula, scanning
cle spindle afferents from the extraocular muscles) did is necessary to use the full analyzing capacity of the
not disturb saccadic and pursuit movements, although visual system.
they did produce instability of the eyes and slow pendu- 2. Smooth-pursuit movements are performed when
lar movements in darkness. It seems that the control we follow a small moving object to keep the image sta-
system receives enough information from the efference tionary on the central part of the retina. As a rule, we
copy (i.e., the copy of the motor commands sent to the use pursuit movements both of the eyes and of the head
extraocular muscles). when looking at a moving object. One might think that
Presumably, information from the eye muscle prop- the movements of the head would elicit conjugated eye
rioceptors contributes to the long-term calibration movements in the opposite direction of the head because
of the efference copy. When there is a mismatch between of the vestibulo-ocular reflex. This does not occur, how-
the command and the feedback (informing about the ever, because the vestibulo-ocular reflex is suppressed
true movement of the eye) this may be used to change during such smooth-pursuit movements. This kind of
the motor program. Such mismatch arises, for example, smooth movement is voluntary in the sense that it requires
when the dimensions of the eye and the eye muscles that our attention be directed to something in the visual
change as we grow. Thus, proprioceptive information field; that is, the gaze is voluntarily fixed. Vestibular
is presumably necessary to ensure fusion of the retinal and optokinetic stimuli can also elicit reflex slow move-
images (avoid strabismus with double vision). ments that stabilize the retinal image. These are invol-
untary in the sense that they occur also without paying
attention to something in the visual field.
BRAIN STEM AND CEREBELLAR CONTROL OF 3. Optokinetic reflex movements are movements
EYE MOVEMENTS intended to stabilize the retinal image when the whole
visual field moves relative to the head. The stimulus is
Kinds of Eye Movement movement of the image on the retina (retinal slip).
When looking out from a train this kind of movement
As mentioned, the control system for eye movements
occur. Then a slow movement (following the scene
must ensure that the gaze can be moved quickly from
moving outside the window) is interrupted by a quick,
one point of fixation to another by saccadic move-
opposite movementresetting the eyes to their original
ments, but also that the gaze can be kept stationary on
positionwhen the eyes cannot follow the scene any-
an object when the object or the head moves by pursuit
more. This movement pattern is called optokinetic
movements. The eye movements may be either volun-
nystagmus. The optokinetic reflex can be suppressed
tary, as when we follow a moving object with the eyes,
voluntarily only by fixating on an object that is station-
or reflex, as when the head moves (a vestibulo-ocular
ary (or moves with a different speed) in relation to the
reflex) or the surroundings move (an optokinetic reflex).
movement of the rest of the visual scene.
The vestibulo-ocular reflex and nystagmus are discussed
4. Vestibulo-ocular reflex movements (VORs) are eye
in Chapter 18.
movements elicited by movements of the head (Fig. 25.4).
The following is a highly schematic description of eye
The eyes move with the same velocity as the head but in
movements. Different premotor networks control each
the opposite direction, thereby ensuring that the retinal
of the kinds of movement, although they all converge
image is stationary. When the eye cannot move further,
on the motoneurons of the extraocular muscles. The
a fast movement occurs in the opposite direction, reset-
separation of the different central networks is less clear-
ting the position of the eye; then the slow movement
cut than formerly believed, however. Thus, recent stud-
starts again. These alternate movements are called ves-
ies show that several regions, for example in the cerebral
tibular nystagmus. The quick phase of vestibular nys-
cortex and the cerebellum, participate in the control of
tagmus and saccades share many characteristics, but
both saccadic and pursuit movements.
are not identical. The VOR enables us to see an object
1. Saccades are conjugated movements that change the sharply even when we move around. When the head
visual axis of the eyes from one point of fixation to another rotates, the stimulus originates in the semicircular ducts.
with maximal speed. Saccades can (at least in a certain Even though the VOR has been most studied in relation
sense) be voluntary, as when we look at a stationary to rotations in the horizontal plane (Fig. 15.4), the
Flocculus
Purkinje cell
Inferior olive
gure 25.4 Main structural elements of the
Pretectal nuclei vestibulo-ocular reex. Only excitatory connec-
tions are shown, even though there are inhibitory
neurons in the vestibular nuclei that inuence the
motoneurons of the antagonists. The reex arc
consists of three neurons from the semicircular
duct to the extraocular muscles. The cerebellar
occulus receives signals from the labyrinth and
from the retina, and the output of the Purkinje cells
can adjust the sensitivity of the vestibular neurons,
Labyrinth Vestibular Eye muscle if necessary, to avoid retinal slip. (Based on Ito
(semicircular ducts) nucleus nucleus 1984.)
reflex is three-dimensional in the sense that all direc- functional words. Native readers of English perceive
tions of head rotation elicit specific compensatory eye about 4 letters to the left and 15 to the right of the point
movements.1 of fixation.
5. Vergence movements change the visual axes of the A woman with inborn ophthalmoplegia (inability to
eyes in relation to each other when the point of fixation move the eyes) had surprisingly small problems and was
moves away from or toward the eyes. This is necessary able to live a normal life. She apparently used quick head
to keep the image on corresponding points of the retina. movements to compensate for the lack of saccadic eye
Vergence movements are a prerequisite for fusion of the movements (Gilchrist 1997), and was thereby able to
two images and for stereoscopic vision. Convergence of scan the visual scene with sufficient speed and accuracy.
the visual axes, which takes place when an object is
approaching the eyes, depends primarily on the activity
The Cerebellum Can Adjust the Vestibulo-Ocular
of the medial rectus muscles, with some contribution
Reex to Changing External Conditions
also from the superior and inferior recti (Fig. 15.2).
Accommodation and pupillary constriction accompany The magnitude of the reflex response (not the response
convergence movements.2 itself) to a certain rotational stimulus depends on signals
to the vestibular nuclei from the cerebellum (Fig. 25.4).
The Purkinje cells of the vestibulocerebellum receive
More about Voluntary Saccades and Scanning
primary vestibular fibers (ending as mossy fibers) that
When reading we fixate a point on the line for an aver- provide information about direction and velocity of the
age of 250 msec (60500) before the gaze is moved on head movement. In addition, the same Purkinje cells
by a saccade. How far the gaze moves before reaching a receive information, via the inferior olive and climbing
new point of fixation varies greatly. There is a tendency fibers, about whether the image is stationary or slips on
to fixate on long content words rather than on short the retina. A retinal slip indicates that the velocity of
the compensatory head movement is too high or too
1 The VOR described herethe rotational VOR or RVORis not the only low. The cerebellum is then capable of adjusting the
vestibulo-ocular reex. Translatory (linear) accelerations of the head (stimulat- excitability (the gain) of the neurons in the vestibular
ing the sacculus and utriculus) also elicit compensatory eye movements (trans- nucleithat is, in the reflex center of the vestibulo-
lational VOR, or TVOR; otolith-OR, or OOR). In real life, both kinds of head
movement occur, and the different sensory inputs from the labyrinth must be ocular reflex. Such adaptive change of gain of the reflex
integrated centrally to yield a motor command that ensures a stable retinal is presumably needed continuously during growth and
image. in situations of muscular fatigue. Experiments in which
2 Gaze holding is sometimes included among the kinds of eye movement. It is
the ability to stabilize the eye position (and the image on the retina) after a shift animals wear optic prisms that deflect the light so that
of gaze. Premotor neurons controlling gaze holding appear to rely on a partly it appears to come from another direction than it really
separate premotor network, although located close to the paramedian pontine does, show the remarkable capacity for adaptation
reticular formation (PPRF) and the rostral interstitial nucleus of the medial
longitudinal fasciculus (riMLF). (learning) in this system.
Brain Stem Centers for Control of Eye Movements
Signals informing about desired eye position, actual
position, retinal slip, and position of the head are inte-
grated in the reticular formation close to the eye muscle Medial
rectus m.
nuclei. From these premotor neuronal groups com- Lateral
mands are sent to the motoneurons. By combining rectus m.
anatomic data on the fiber connections with physiologi-
cal results (obtained by single-cell recordings, electrical Oculomotor
and natural stimulation, and lesions) the preoculomotor nerve (3)
networks have been described in detail.
Oculomotor
A center for horizontal eye movements has been nucleus
identified in the paramedian pontine reticular forma- Abducens
tion (PPRF). PPRF lies close to, and sends fibers to, the nerve (6)
Medial longitudinal
abducens nucleus (Fig. 25.5). It also sends fibers to fasciculus
the parts of the oculomotor nucleus that contains the
motoneurons of the medial rectus muscle. Together with PPRF
the lateral rectus (innervated by the abducens nucleus),
the medial rectus participates in horizontal movements. Abducens
In addition, there are so-called internuclear neurons in nucleus
the abducens nucleus that send axons to the medial rec-
tus motoneurons of the opposite side (Fig. 25.6). This
premotor network ensures simultaneous activation of gure 25.6 Control of horizontal conjugate eye movements. Highly
the lateral rectus on one side and the medial rectus on simplied scheme to show some of the connections responsible. Only
the other, along with inhibition of the antagonists. excitatory connections are included. The gure also shows how inter-
A lesion in the region of the PPRF reduces horizontal ruption of the medial longitudinal fascicle produces a paralysis of the
gaze in the medial direction (internuclear ophthalmoplegia).
conjugate movements to the side of the lesion. Especially
marked is the reduction in saccadic movements. A unilat-
eral lesion of the medial longitudinal fasciculus between
so-called internuclear ophthalmoplegia with abolished
the abducens and the oculomotor nucleus produces
ability to adduct the eye on the same side (the medial
rectus muscle). This may be understood based on the
diagram in Fig. 25.6. However, vergence movements
Center for vertical eye
movements (RI)
are possible even though the medial rectus is responsi-
Superior
colliculus ble also in that case. Thus, pathways other than the
medial longitudinal fasciculus are responsible for the
Oculomotor nucleus activation of the medial rectus muscle during vergence
Trochlear nucleus movements.
Oculomotor nerve
A center for vertical and rotatory eye movements has
been identified in the reticular formation close to the
oculomotor nucleus. This region includes a nucleus
Medial
called the rostral interstitial nucleus of the medial lon-
longitudinal gitudinal fasciculus (riMLF or RI) and probably another
fasciculus
Pons small cell group (the interstitial nucleus of Cajal). This
region receives afferents from the vestibular nuclei, the
pretectum (and thereby indirectly from the superior
colliculus), and the frontal eye field. Physiologic studies
Center for horizontal indicate that there are monosynaptic connections from
eye movements (PPRF)
the region of the riMLF to the trochlear nucleus and to
Abducens nerve Abducens nucleu the motoneuron groups within the oculomotor nucleus
that produce vertical eye movements.
The PPRF and the region of the RI are interconnected,
indicating that they do not operate independently of
gure 25.5 Centers for vertical and horizontal eye movements.
each other. The fact that most natural eye movements
Sagittal section through the monkey brain stem. (Based on Bttner- are neither purely horizontal not purely vertical but
Ennever 1988.) combinations of both strongly suggests that the centers
for horizontal and vertical movements must coordinate Precentral

gyrus Central
their activity. sulcus
Frontal eye field
Parietal eye
e field
Properties of Neurons in the PPRF
The PPRF receives signals directly and indirectly from
the vestibular nuclei, the superior colliculus, and the
frontal eye field. It appears to function as the last pre-
motor station for the initiation of conjugate horizontal
saccadic movements. In agreement with this, there are
neurons in the PPRF that are active immediately before
and during a saccade to the same side, whereas they are
inactive during slow-pursuit movements and fixation.
Lateral sulcus Area MT & MST
These so-called excitatory burst neurons establish
excitatory connections with the motoneurons respon- Middle temporal
gyrus
sible for the saccade. There are also inhibitory burst
neurons, located close to the PPRF, with a pattern of gure 25.7 Cortical areas involved in control of eye movements.
activity similar to that of the excitatory burst neurons. Areas on the medial wall of the hemisphere are not shown. Size and
Monosynaptically they inhibit the motoneurons in the position of the areas are only approximate. (Based on Mri 2006.)
abducens nucleus of the opposite side. The activity of
both kinds of burst neurons appears to be controlled by
a third kind of neuron in the PPRF, which is tonically
active. Such omnipause neurons probably inhibit the We have previously mentioned connections from the
burst neurons tonically, except in relation to saccades. vestibular nuclei, which, by means of the medial longi-
Thus, the omnipause neurons are silent immediately tudinal fasciculus, reach all the cranial nerve nuclei of
before and during saccades, regardless of the direction the eye muscles (see Fig. 18.8A). These connections are
and amplitude of the movement. Recent studies indi- both crossed and uncrossed. Some of the vestibular
cate that the omnipause neurons receive direct connec- neurons sending their axons into the medial longitudi-
tions from both the superior colliculus and the frontal nal fasciculus are excitatory; other neurons are inhibi-
eye field. tory (GABA). The connections are precisely organized,
enabling the activation of specific synergists and the
inhibition of their antagonists (with regard to the
Afferent Connections of the Ocular Premotor Networks
intended eye movement). Other efferent fibers from
Many kinds of information must be integrated and the vestibular nuclei end in cell groups situated near the
translated into motor commands to achieve the extremely eye muscle nuclei, which send their axons to the latter.
precise control of eye movements. Visual signals do The perihypoglossal nuclei are examples of such preoc-
not pass directly from the retina to the eye muscle nuclei ulomotor cell groups. These nuclei (the most prominent
but are mediated by several brain stem nuclei, which one is the prepositus hypoglossus nucleus) lie around
also receive impulses other than visual information. the hypoglossal nucleus in the medulla. In addition to
This concerns the superior colliculus and the pretectal afferents from the vestibular nuclei, the perihypoglossal
nuclei (situated rostral and ventral to the superior col- nuclei receive afferents from other structures involved
liculus; see Fig. 27.19). These nuclei receive afferents in eye movement control, such as parts of the reticular
from the retina and from the parts of the cerebral cor- formation and the cerebellum. The direct and indirect
tex that are involved in control of eye movements (the impulse pathways from the vestibular nuclei to the
frontal eye field, the posterior parietal cortex, and parts eye muscle nuclei mediate the vestibulo-ocular reflexes
of the extrastriate visual areas; Fig. 25.7). Many neurons (Fig. 15.4) and are probably involved also in optoki-
in the superior colliculus are active immediately before netic reflexes. In the latter case, signals from the retina
a saccade and most likely have an important role in the reaching the vestibular nuclei (synaptically interrupted
organization of conjugated saccades. This is mediated in several nuclei) must be involved rather than signals
by connections from the superior colliculus to the retic- from the labyrinth.
ular formation and from there to the eye muscle nuclei. Proprioceptive signals from muscle spindles of the
In addition, the superior colliculus is important for extraocular muscles reach the eye muscle nuclei from
integration of somatosensory and visual information. the mesencephalic trigeminal nucleus (see Fig. 27.13).
This is needed, for example, to rapidly direct the gaze As mentioned, proprioceptive signals are probably nec-
to a somatosensory stimulus (involving simultaneous essary for the long-term correction and adaptation of
and coordinated movements of the eyes and the head). the mutual position of the eyes in fixation.
The Cerebellum Controls Both Saccades and among them the premotor gaze centers discussed in the
Pursuit Movements preceding text. Recent functional magnetic resonance
imaging (fMRI) and positron emission tomography
Cerebellar lesions can impair both saccadic and slow-
(PET) studies in humans indicate that a distributed
pursuit movements. The middle part of the vermis (lob-
cortical network controls eye movements. This network
ules VIVII, vermal oculomotor region) is particularly
includes discrete regions in the frontal and parietal
concerned with the performance of saccades, while the
lobes, and at the temporo-occipital junction. While
flocculus and adjoining parts of the posterior lobe (the
each area appears to be most important for one kind of
paraflocculus) seem most important for pursuit move-
movement, all areas alter their activity in relation to
ments. After cerebellectomy, monkeys are unable to
both saccades and pursuit movements (based on human
perform pursuit movements, whereas saccades can be
fMRI studies). Interestingly, areas for control of eye
performed although with reduced precision and velocity.
movements (especially saccades) overlap areas related
Clinical observations support the role of the cerebellum
to shift of attention. This seems logical because a volun-
in control of pursuit movements also in humans (the def-
tary saccade is a motor expression of a shift of atten-
icits observed in patients with cerebellar lesions resemble
tional focus.
the dose-dependent effects of alcohol on pursuit move-
ments). The distinction between the vermal oculomotor
region and flocculus/paraflocculus is not absolute, Saccades
however, because both contain neurons related to either
With regard to specializations among cortical areas,
saccades or pursuit movements. In accordance with
clinical observations indicate that the frontal eye field
this, animal experiments and observations in humans
(FEF, or area 8 of Brodmann; Fig. 25.7, see also Fig. 33.3)
indicate that the vermal oculomotor region controls
is of particular importance for voluntary saccades.
both precision of saccades and the velocity of pursuit
Electrical stimulation of the frontal eye field elicits con-
movements.
jugated eye movements to the opposite side. The effect
Recent studies strongly suggest that lateral parts
is mediated by fibers descending in the internal capsule
of the pontine nuclei are necessary for voluntary pur-
to brain stem premotor cell groups, such as the superior
suit movements and for the slow phase of optokinetic
colliculus, the pretectal nuclei, and the PPRF, which, in
nystagmus.3 This is based on recordings of single-cell
turn, activate motoneurons in the eye muscle nuclei.
activity and lesion experiments in monkeys, as well as
A unilateral lesion of the frontal eye field makes the
in a few patients with small brain-stem infarctions. The
patient unable to move the gaze voluntarily to the side
relevant parts of the pontine nuclei send efferents to
opposite the lesion (e.g., when asked by the examiner to
both oculomotor-related cerebellar regions, and they
move the gaze). This is called a gaze paralysis.
receive afferents from (among other areas) the middle
Correspondingly, the activity in the FEF increases more
superior temporal area (MST), which is related to visual
during voluntary than during reflex-evoked saccades.
analysis of moving objects. Parallel pathways seem to
Indeed, the ability to move the gaze laterally is not
exist for the control of pursuit movements, however
completely lost after a lesion of the FEF. Thus, smooth-
for example, the pontine reticulotegmental nucleus
pursuit movements occur when an object is brought
(PRN), located immediately dorsal to the pontine nuclei,
into the visual field and then moved slowly laterally
also relays signals from cortical oculomotor areas to
that is, the patient is able to follow the object with her
the cerebellum. The fact that the PRN is involved also
gaze. Imaging studies show additional activation of the
in saccadic movements underscores that the networks
SMA, dorsolateral prefrontal cortex, and posterior
controlling different kinds of eye movement are not
parietal cortex (see Fig. 21.13) in relation to voluntary
entirely separate.
saccades. An area close to the frontal eye field, the
supplementary eye field (SEF) is particularly active
when saccades are coordinated with hand movements
CORTICAL CONTROL OF EYE MOVEMENTS (based on single-unit recording in behaving monkeys).
It is also active when saccades are made to a remem-
There are no direct connections from the cerebral cortex bered target locationthat is, in the absence of visual
to the eye muscle nuclei. Activation of the extraocular or other information about where the target is.
muscles from the cortex in conjunction with voluntary eye The superior colliculus and the vermal oculomotor
movements is mediated via other brain stem cell groups, area of the cerebellum both receive information from
the frontal eye field and the posterior parietal cortex,
and both are necessary for proper execution of sacca-
3 Voluntary pursuit movements and the slow phase of optokinetic nystagmus des. They are not necessary for their initiation, how-
appear to be controlled by largely the same neuronal groups because both kinds
of movement are disturbed after lesions of the middle superior temporal area ever, because lesions of neither the cerebellum nor the
(MST), the pontine nuclei, or the occulus/paraocculus. superior colliculus abolish saccadic movements.
neurons that change their activity in relation to gaze

Pursuit Movements
fixation are present in the frontal eye field and in the
With regard to cortical control of smooth-pursuit move- posterior parietal cortex. PET studies in humans, how-
ments, several small areas in the parietal lobe, and at the ever, indicate that frontal lobes are particularly impor-
temporo-occipital junction are of particular importance tant for the ability actively to fix the gaze. This includes
(Fig. 15.7; see also Figs. 16.25 and 34.2). This notion is the frontal eye field, the anterior cingulate gyrus, and
based on, among other things, single-cell recordings. parts of the prefrontal cortex. In general, these regions
The middle temporal area (area MT, V5) is important become active in conjunction with directed attention,
for perception of movement. Neurons in MT respond and lesions in humans produce an impaired ability to
to movement of the image on the retina (retinal slip), fix the gaze.
which is a strong stimulus to elicit pursuit movements Often the tendency to fix the gaze on an object is not
of the eyes. The middle superior temporal area (area voluntary (cf. the term fixation reflex), at least not in
MST) lies close to area MT and is of special interest the strict sense (even though fixation depends on the
because it contains many neurons that respond prefer- person being conscious). Optokinetic nystagmus is an
entially to moving visual stimuli in a specific direction. expression of the strong tendency to fix the gaze. When
The subcortical cell groups intercalated between these a screen with alternating black and white vertical stripes
cortical regions and the eye muscle nuclei are not fully is moved horizontally in front of a person, nystagmus
clarified. One important pathway seems to go from the occurs. The gaze is fixed automatically on one of the
cortex to the pontine nuclei (see Fig. 24.10), then to stripes and follows it until it leaves the visual field. Then
the cerebellum, further to the vestibular nuclei and the a quick movement resets the eyes to the starting posi-
reticular formation, and thence to the eye muscle nuclei. tion, and the gaze is fixed again on another stripe. This
In addition to in the parietal and temporal areas, neu- sequence repeats itself as long as the screen moves.
rons with activity related to pursuit movements occur
in the frontal eye field and the supplementary eye field.
Miniature Eye Movements
Accordingly, impairment of pursuit movements has
been reported in humans with frontal lesions including Closer study shows that even during active fixation, the
the supplementary eye field. eyes are not completely still. Several kinds of miniature
movement occur, such as a slow drift of the eyes, min-
iature saccades, and tremor. The amplitudes of these
Gaze Fixation
movements are very small, however, and are not nor-
The ability to fix the gaze is a prerequisite for voluntary mally perceived. Nevertheless, the phenomenon can be
slow-pursuit movements. A specific fixation center in demonstrated by fixating a square pattern for about
the cerebral cortex has not been found; as with most 20 seconds and then move the gaze to a white surface.
other tasks carried out by the cerebral cortex the task is The afterimage of the square pattern is then seen to move,
solved in a distributed network. In monkeys, single because the eyes are not completely still (Ilg 1997).
V THE BRAIN STEM AND THE CRANIAL
NERVES
T HE definition of the term brain stem varies. The

widest definitionused in Chapter 6includes
the medulla oblongata, the pons, the mesencephalon,
the cranial nerves and their nuclei represent the spinal
cord of the head. On the other hand, many neuronal
groups in the brain stem represent a superior level of
and the diencephalon. In this part of the book, and most control over the spinal cord and the cranial nerve nuclei.
often in clinical contexts, we restrict it to the medulla, Examples are the vestibular nuclei and various premo-
the pons, and the mesencephalon, which together form tor nuclei in the reticular formation. In addition, other
a macroscopically distinct part of the brain. Which neuronal groupsusually included in the reticular
definition is used is of no great importance because the formationexert ascending influences on the thalamus
brain stem is a topographically and embryologically and the cerebral cortex related to consciousness,
defined unit; it does not represent a functional system. arousal, and sleep. This section deals with both levels of
Neuronal groups within the brain stem take part in organization. Chapter 26 deals with the reticular for-
virtually all the tasks of the central nervous system. mation, which represents the superior level of control.
Functionally, the brain stem may be said to have Chapter 27 describes most of the cranial nerves and
two levels of organization. On the one hand, most of their nuclei.
26 The Reticular Formation:
Premotor Networks,
Consciousness, and Sleep
OVERVIEW STRUCTURE AND CONNECTIONS OF THE

RETICULAR FORMATION
The reticular formation extends from the lower end of
the medulla to the upper end of the mesencephalon. At Structure and Subdivisions
all levels, it occupies the central parts and fills the ter-
The reticular formation extends from the lower end of
ritories not occupied by cranial nerve nuclei and other
the medulla to the upper end of the mesencephalon,
distinct nuclei and by the large fiber tracts. The raphe
where it gradually fuses with certain thalamic cell
nuclei (serotonin) and the locus coeruleus (norepineph- 1
groups (Fig. 26.1). At all levels it occupies the central
rine) are often included in the reticular formation, and
parts and fills the territories not occupied by cranial
are treated in this chapter. Although the reticular
nerve nuclei and other distinct nuclei (such as the dorsal
formation consists of many functionally diverse subdi-
column nuclei, the pontine nuclei, and the colliculi) and
visions, they all share some anatomic features. Thus,
by the large fiber tracts (such as the medial lemniscus
the neurons have wide dendritic arborizations and their
and the pyramidal tract). The reticular formation
long axons give off numerous collaterals. The afferent
received its name from the early anatomists because
and efferent connections show only a rough topo-
of its network-like appearance in microscopic sections
graphic order. Efferent connections reach most parts of
(Figs. 26.2 and 26.3). It is built of cells of various forms
the central nervous system (CNS, from the cord to the
and sizes that appear to be rather randomly mixed.
cerebral cortex), while afferents bring all kinds of sen-
Between the cells, there is a wickerwork of fibers pass-
sory information. These features show that the reticular
ing in many directions (Fig. 26.2). These fibers are
formation is built for integration. Accordingly, the
partly axons and dendrites of the neurons of the reticu-
reticular formation attends primarily to tasks involving
lar formation and partly afferent axons from other sec-
the nervous system and the organism as a whole.
tions of the CNS. The reticular neurons have typically
Subdivisions of the reticular formation form premotor
very long and straight dendrites, so that they cover a
networks that organize several complex behaviors.
large volume of tissue (Fig. 26.3). This distinguishes the
These behaviors include control of body posture, orien-
reticular neurons from those found in specific nuclei of
tation of the head and body toward external stimuli,
the brain stem, such as the cranial nerve nuclei (see the
control of eye movements, and coordination of the
hypoglossal nucleus in Fig. 26.3).
activity of the visceral organs. These tasks fit with the
reticular formation being phylogenetically old and
present even in lower vertebrates. In addition, parts of Medial Parts Are Afferent and Lateral Parts Are Efferent
the reticular formation (especially in the upper pons
A more detailed analysis of the reticular formation
and mesencephalon) send ascending connections to the
makes clear, however, that it consists of several subdi-
thalamus and the cerebral cortex. These connections
visions, among which the cells differ in shape, size, and
form the activating system of the brain stem. The integ-
arrangement even though the borders between such
rity of this system is a prerequisite for consciousness,
subdivisions are not sharp (Fig. 26.1). It is especially
and is closely linked to control of awareness and atten-
tion. Further, parts of the reticular formation, including
cholinergic cell groups in the upper pons, are concerned 1 Some authors include certain thalamic cell groupsespecially the intralami-
with regulation of sleep. nar nucleiin the term the reticular formation of the brain stem.
373
MESENCEPHALON parts, such as the thalamus, and lower parts, such as

Superior colliculus
Sup the spinal cord.
The Reticular Formation Is Built for Integration

Periaqueductal gray Studies with the Golgi method and with intracellular
(PAG) tracers give evidence of how complexly the reticular
formation is organized. The long ascending and
Raphe nuclei descending efferent fibers give off numerous collaterals
on their way through the brain stem (Fig. 26.4). As can
Substantia nigra
be seen in Fig. 26.3, the collaterals run primarily in the
transverse plane. Most dendrites of reticular cells have
the same preferential orientation, so the reticular for-
mation appears to consist of numerous transversely ori-
Superior cerebellar
PONS peduncle
ented disks (Fig. 26.3). The numerous collaterals of the
axons from the cells in the medial parts ensure that sig-
nals from each reticular cell may reach many function-
ally diverse cell groups (such as other parts of the
reticular formation, cranial nerve nuclei, dorsal column
Raphe nuclei
R nuclei, colliculi, spinal cord, certain thalamic nuclei,
and hypothalamus).
Pontine nuclei
P
The Raphe Nuclei and the Locus Coeruleus:
Common Features
MEDULLA
Trigeminal nucleus The raphe nuclei (raphe, seam) together form a narrow,
sagittally oriented plate of neurons in the midline of the
medulla, pons, and mesencephalon (Figs. 26.1, 26.5,
and 26.6). In many ways, these nuclei have similarities
Gigantocellular part of with the reticular formation proper and are often con-
the reticular formation sidered part of it. The locus coeruleus is small group of
only about 15,000 strongly pigmented neurons located
Raphe magnus nucleus
under the floor of the fourth ventricle (Fig. 26.7). It has
clear borders except ventrally where it merges gradu-
ally with the adjoining reticular formation, which also
contains many norepinephric neurons. This is one rea-
gure 26.1 The reticular formation. Transverse sections through
various levels of the brain stem (cat) showing the position of the retic-
son the locus coeruleus is often included in the reticular
ular formation. The size of the red dots indicates the size of the neu- formation.
rons, which varies considerably among subdivisions of the reticular A characteristic feature of these two nuclei is that
formation. (Based on Brodal 1957.) they contain only a small number of neurons, while
their axons have extremely widespread ramifications,
reaching virtually all parts of the brain and the spinal
important that such cytoarchitectonically defined sub- cord. Their synaptic actions are modulatory, although
divisions also differ with regard to fiber connections, the effects vary among different targets due to different
neurotransmitters, and functions. In the pons and the distribution of receptors. The raphe nuclei contain
medulla, approximately the medial two-thirds of the mainly serotonergic neurons, whereas the locus coer-
reticular formation consists of many large cells, in part uleus neurons contain norepinephrine (cf. Chapter 5,
so-called giant cells (Figs. 26.1 and 26.2). The lateral under Biogenic Amines). Another special feature is
one-third contains almost exclusively small cells. Tract- that they send fibers directly to the cerebral cortex, that
tracing methods have shown that the medial part sends is, without synaptic interruption in the thalamus, as is
out many long, ascending and descending fibers, whereas typical of most cortical afferent pathways from lower
the lateral small-celled part receives most of the afferents levels. These features are shared with other cell groups,
coming to the reticular formation. In general, therefore, notably the dopaminergic neurons in the mesencepha-
we may say that the lateral part is receiving, whereas lon and the cholinergic cell groups in the pons and the
the medial part is efferent (executive). The efferents basal forebrain (cf. Chapter 5, under Modulatory
convey the influence of the reticular formation to higher Transmitter Systems).
26: THE RETICULAR FORMATION: PREMOTOR NETWORKS, CONSCIOUSNESS, AND SLEEP 375
Medial reticular Lateral reticular

formation formation
gure 26.2 The reticular formation. Photomicrograph of section of The photomicrograph shows the transition between the large-
the medulla, stained to show myelinated bers (blue) and cell bodies celled medial division and the small-celled lateral division.
(red). The cell bodies are distributed diffusely without clear nuclear Magnication, 300.
borders and with small ber bundles coursing in various directions.
Gigantocellular reticular formation
Hypoglossal nucleus
Axon
a
R.gc.
Inferior olive
Pons
MEDULLA Pyramidal tract

Orientation of dendritic OBLONGATA
trees in reticular formation
gure 26.3 Orientation of dendrites in the reticular formation. brain stem nuclei. A long axon with numerous collaterals extending
Sagittal section through the medulla (rat). The long, straight dendrites ventrally in the transverse plane is also shown. Collaterals of the
are typical of the neurons of the reticular formation, in contrast to the pyramidal tract bers enter the reticular formation. (Modied from
neurons of a cranial nerve nucleus (the hypoglossal) and other specic Scheibel and Scheibel 1958.)
In other chapters, we discuss the effects of the mono-

amines serotonin and epinephrine on sensory-information
processing (see Chapter 15, under Central Control of
Transmission from Nociceptors and Pain Sensation, and
Chapter 19, under Modulation of Taste Cell Sensitivity)
and on movements (Chapter 22, under Monoaminergic
Pathways from the Brain Stem to the Spinal Cord). We
Collateral
give examples of the importance of these monoamines
for emotions and motivation in Chapter 5 (Monoamine
Oxidase, Serotonin Transporters, and Behavior). They
are of crucial importance for brain plasticity and learning,
and influence cardiovascular control and other functions
Collateral governed by the autonomic nervous system. Finally,
serotonin and norepinephrine participate in regulation
of attention and sleep. The serotonergic raphe neurons
Axon and the norepinephric locus coeruleus neurons have in
common that they are active during wakefulness and less
active during sleep (we return to this, under Neuronal
Collateral
Groups and Transmitters Controlling Sleep). They
differ, however, in their response to sensory stimuli:
only the norepinephric neurons increase their activity in
relation to salient stimuli (like the dopaminergic neurons
in the substantia nigra).
The Raphe Nuclei

Based on cytoarchitectonic and connectional differences,
several raphe nuclei have been identified (Fig. 26.6) even
gure 26.4 Neurons in the medial part of the reticular formation though their borders are far from sharp. Together, the
with long ascending and descending axons. Right: Example of a neu- raphe nuclei receive afferents from many sources, such
ron with a bifurcating axon, with one ascending and one descending
as the cerebral cortex, the hypothalamus, and other
branch. Both branches give off collaterals as they course through the
reticular formation. Left: Two neurons with ascending and descend-
ing axons, respectively. In this way, neurons with ascending axons
can inuence the activity of neurons with descending axons.
A B
Spinal
trigeminal
nucleus
Raphe
nuclei
Inferior olive
Medial
lemniscus
Pyramid
gure 26.5 The raphe nuclei. A: Transverse section of the upper of the midline. B: Larger magnication from framed area in A. The
medulla, stained to visualize neuronal cell bodies and myelinated cell bodies of raphe neurons are seen as small dots.
axons. The raphe nuclei are seen as narrow light stripes on each side
parts of the reticular formation. In spite of the extensive
distribution of the efferent fibers, the different raphe
Frontal lobe nuclei have largely different targets. Thus, the caudal
Amygdala raphe nuclei send their efferents to the spinal cord, whereas
Striatum
Septal Hippocampus the rostral nuclei send fibers upstream (Fig. 26.6). The
nuclei actions of serotonin depend on the kinds of receptor
that are present postsynaptically in the target nuclei (see
Thalamus
Chapter 5, under Monoamine Receptors). In addition,
Hypothalamus PAG Locus most raphe neurons contain neuropeptides (substance P
coeruleus and thyrotropin-releasing hormone, [TRH]), which
presumably contribute to the synaptic effects of efferent
fibers from the raphe nuclei. Serotonin also influences
the cerebral circulation. A final peculiarity of the raphe
RAPHE NUCLEI nuclei is that they send fibers ending in close relation to
Cerebellum
the ependymal cells (which cover the interior aspect of
the brain ventricles). Presumably, such fibers contribute
to the regulation of transport processes through the
ependyma.
Spinal cord Various kinds of behavioral changes have been reported
after lesions of the raphe nuclei, such as aggression and
gure 26.6 The raphe nuclei and their efferent connections. increased motor activity (to destroy the raphe nuclei in
Schematic midsagittal section through the brain, showing the various
isolation, however, is, virtually impossible).
subdivisions of the raphe nuclei and some main connections. The
most rostral nuclei send their bers rostrally to the thalamus, cortex,
and other cell groups, whereas the caudal nuclei project to the spinal
The Locus Coeruleus
cord. Together, the raphe nuclei supply large parts of the central ner-
vous system with serotonergic bers. In spite of containing so few neurons, the efferent fibers
of the locus coeruleus reach virtually all parts of the cen-
tral nervous system. It sends, for example, direct fibers to
the cerebral cortex, the hypothalamus, the basal ganglia,
A 4th ventricle B
4th ventricle
Trigeminal root fibers &
Superior mesencephalic trigemi-
cerebellar nal nucleus
Locus
coeruleus peduncle
Locus coeruleus
Pontine reticular Medial (pigmented neurons)
formation lemniscus
Pontine nuclei
gure 26.7 The locus coeruleus. A: Transverse section of the upper neurons in the locus coeruleus are heavily pigmented. This nucleus
pons (approximately the same level as in Fig. 3.18). The locus coer- and other norepinephric cell groups in the vicinity have neurons with
uleus is positioned just below the oor of the fourth ventricle. B: Larger highly branched axons that end rather diffusely in most parts of the
magnication from framed area in A. The norepinephrine-containing central nervous system.
the hippocampus, and other limbic structures. Direct on pain transmission might be viewed in the perspective
fibers also reach the spinal cord but only parts of the of pain as part of a homeostatic response, as discussed
brain stem (especially sensory nuclei). The dense norepi- in Chapter 15. Further, chemosensitive neurons in the
nephric innervation of the reticular formation and the rostral raphe nuclei can increase wakefulness and alter
motor nuclei must therefore originate from the scattered cerebral circulation. They also seem to mediate signals
norepinephric neurons outside the locus coeruleus. that evoke anxiety associated with high blood CO2 lev-
The afferent connections come mainly from a few els (a single inhalation of air with 35% CO2 provokes
regions. The locus coeruleus receives direct connections acute anxiety).
from the cingulate gyrus and the orbitofrontal cortex An overarching function of the locus coeruleus may
(in monkeys and presumably in humans as well). be to increase arousal and attention in response to
Subcortical afferents seem from recent studies to arise salient sensory information. However, the task may be
in the medullary part the reticular formation and in the more specific than this, according to a theory put for-
amygdala. The medullary connections probably pro- ward by Aston-Jones and Cohen (2005). During wake-
vide the locus coeruleus with integrated sensory infor- fulness, the locus coeruleus neurons alternate between
mation, while fibers from the amygdala might signal phasic and tonic firing. The phasic state is proposed to
the emotional value of sensory information. Single optimize ongoing actions (help to maintain the focus on
neurons in the locus coeruleus respond preferentially the present task). Tonic activity, on the other hand,
to novel, exciting sensory stimuli. Because norepineph- allows shift of attention away from the ongoing activity
rine increases the response to specific stimuli and improves to enable exploratory behavior to select a new (and
the signal-to-noise ratio of postsynaptic neurons, the more rewarding) behavior. Instruction to shift behavior
locus coeruleus is believed to play a particular role in appears to reach the locus coeruleus from parts of the
mediating arousal and shifts of behavior. One example prefrontal cortex (the cingulate and the orbitofrontal
is the facilitatory effect of norepinephrine on spinal cortex). The gyrus cinguli, for example, seems to moni-
motoneurons (see Chapter 22, under Monoaminergic tor errors during execution, and helps decide whether
Pathway from the Brain Stem to the Spinal Cord). actions produce the expected results.
Norepinephrine also has a special role in relation to
synaptic plasticity. For example, it is especially concen-
The Efferent Connections of the Reticular Formation
trated in the cerebral cortex during sensitive periods of
development. The reticular formation sends fibers to (and thereby
acts on) four main regions: the thalamus, the spinal
cord, brain stem nuclei, and the cerebellum. The cell
Possible Tasks of the Raphe Nuclei and the
groups giving off ascending axons are located some-
Locus Coeruleus
what more caudally than those emitting descending
The modulatory neurotransmittersincluding sero- axons (Fig. 26.8). By means of the numerous collaterals
tonin and norepinephrineinfluence virtually all brain of both the ascending and descending fibers in the retic-
functions. This is not surprising, considering the widely ular formation (Figs. 26.3 and 26.4), the two kinds of
branching axons of the neurons containing these neu- cell groups can influence each other. Further, there
rotransmitters. In view of the small and relatively are also many interneurons connecting different parts
homogeneous nuclei giving origin to the axons, it seems of the reticular formation. Thus, a close cooperation is
nevertheless possible that the multifarious actions are possible between the parts of the reticular formation
subject to a common aim or plan. However, in spite that act on the cerebral cortex and those that act on the
of several unifying theories, none has obtained general spinal cord. Collaterals of ascending and descending
acceptance. We here present just a few possible unify- axons mediate actions on brain stem nuclei.
ing concepts. One of the theories concerning serotonin Parts of the reticular formation form premotor net-
views the raphe nuclei as especially important for works. Chapter 25 deals with premotor networks in the
homeostatic control (another theory tries to collect all pons and mesencephalon controlling and coordinating
serotonin actions under the heading of motor control). the activity of the eye muscle nuclei. Other premotor
One of the facts favoring homeostatic control as a com- networks in the reticular formation control rhythmic
mon theme is that many raphe neurons are chemosensi- movements such as locomotion (Chapter 22) and respi-
tive and measure the CO2 level in the blood (thus ration. Further, premotor networks coordinate the activ-
indirectly monitoring the pH of the nervous tissue). ity of the widely separated motoneurons responsible for
Chemosensitive neurons in the medulla participate in the cough reflex and the vomiting reflex.
control of respiration (normalization of CO2). Actions The descending fibers run in the ventral part of the
of serotonin on spinal motoneurons can perhaps have lateral funicle and in the ventral funicle (Fig. 26.9), and
something to do with the fact that muscular activity is are related to motor control. Such reticulospinal fibers
a major source of CO2 production. Serotonergic actions end primarily on interneurons, which, in turn, can
Cerebral cortex
Pontine
nuclei Intralaminar
thalamic nuclei
Pontine reticular
formation
Superior
Medullary reticular colliculs PAG
formation Basal ganglia
Inferior
olive Mesencephalic
reticular formation
Dorsal
column
nuclei
Pontine reticular
gure 26.8 Position of efferent reticular cell groups. Drawing of formation
sagittal section through the brain stem (cat). Neurons sending axons Vestibular Cranial nerve
to higher levels (the thalamus) are red, while neurons with descending nuclei nuclei
axons are green. The cell groups sending descending bers are located
somewhat more rostrally than the regions sending ascending bers, Medullary
providing opportunity for mutual inuences by collaterals (as shown reticular
in Fig. 26.4). formation
Reticulospinal
tracts
influence motoneurons. The ventral reticulospinal tracts
are discussed in Chapter 22 (More About Reticulo-
spinal Tracts). The ventral reticulospinal tracts are
both crossed and uncrossed and mediate both inhibi-
tory and excitatory effects on spinal motoneurons. The
reticulospinal neurons are further characterized by their
axonal branching pattern, with collaterals given off at
several levels of the spinal cord. Thus, each neuron can gure 26.9 Efferent connections of the reticular formation. Various
influence muscles in different parts of the body. As dis- subdivisions of the reticular formation send bers to higher levels,
such the thalamus, the basal ganglia, and the cerebral cortex.
cussed in Chapter 22, the ventral reticulospinal tracts
Descending bers end in the spinal cord. In addition, the reticular
are of particular importance for postural control, for formation sends bers to the cranial nerve nuclei and other brain
the orientation of the head and body toward external stem nuclei, such as PAG and the superior colliculus, and the vestibu-
stimuli, and for voluntary movements of proximal body lar nuclei. Most of the long connections are both crossed and
parts. Connections from the superior colliculusthat uncrossed, although this is not shown in the gure. Numerous shorter
bers interconnecting subdivisions of the reticular formation are not
mediate sensory information to the reticular formation
shown.
are crucial for orienting movements toward novel stim-
uli. Combined anatomic and physiologic studies of single
cells have shown the importance of a tecto-reticulospinal reticular connections later in this chapter; suffice it to
pathway for such movements. The dorsal reticulospinal say here that they are of particular importance for the
fibers concern primarily control of sensory informa- general level of activity of the cerebral cortex, which, in
tion. Many of these fibers are monoaminergic and arise turn, concerns consciousness and attention.
partly in the raphe nuclei and adjoining parts of the
reticular formation (see Fig. 15.3).
The Reticular Formation Receives All Kinds of
The ascending fibers from the reticular formation end
Sensory Information
in the intralaminar thalamic nuclei (Fig. 26.9), unlike
the specific sensory tracts that end in the lateral thal- Various cell groups send fibers to the reticular forma-
amic nucleus. Some fibers also end in the hypothalamus. tion (Fig. 26.10). Spinoreticular fibers are discussed in
We discuss the functional significance of the ascending Chapter 14. These fibers ascend in the ventral part of
the lateral funicle together with the spinothalamic tract, which, presumably, mediate nociceptive and thermo-
but diverge in the lower medulla. Among other destina- ceptive signals to the reticular formation. Collaterals of
tions, the fibers end in the parts of the reticular forma- ascending axons from the sensory (spinal) trigeminal
tion that give off long ascending axons to the thalamus. nucleus supply the same kind of information from the
2
This provides a spino-reticulothalamic pathway that is face. Visceral sensory signals reach the reticular forma-
anatomically and functionally different from the major tion by collaterals of ascending fibers from the solitary
sensory pathways. Some of the spinoreticular fibers end nucleus (which receives afferents from the vagus nerve,
in areas containing neurons that send axons back to the for example).
spinal cord, thus establishing feedback loops between The superior colliculus sends fibers to parts of the
the reticular formation and the cord. reticular formation, as mentioned. These connections
In addition to spinal neurons that send their axons make it possible for visual signals to influence the reticu-
only to the reticular formation, many secondary sensory lar formation because the superior colliculus receives
neurons send collaterals to the reticular formation. This visual information directly from the retina and from the
concerns many of the fibers of the spinothalamic tract, visual cortex. In addition, the superior colliculus receives
somatosensory information from the cortex and inte-
grates visual and somatosensory stimuli enabling orien-
Cerebral cortex tation toward external stimuli.
Auditory signals reach the reticular formation by
collaterals of ascending fibers in the auditory pathways.
Corticoreticular
tract Vestibular signals come from the vestibular nuclei.
The preceding description of afferents indicates that
signals from virtually all kinds of receptors can influence
neurons of the reticular formation. This is verified by
physiological experiments. Electrodes placed in the reticu-
lar formation can record potentials evoked by stimulation
Internal of receptors for light, sound, smell, and taste. Furthermore,
capsule stimulation of peripheral nerves carrying signals from
Superior
colliculus cutaneous receptors and proprioceptors and of visceral
Basal ganglia
PAG
nerves evokes activity. Whenever a receptor is stimulated,
Trigeminal Mesencephalic the signals reach not only the cortical areas important
nerve reticular formation for the perception of the stimulus but also the reticular
Pontine
ret. form.
formation.
Afferents from Subcortical Nuclei and the

Cerebral Cortex
Sensorisk
trigeminuskjerne Corticoreticular fibers arise mainly in the cortical
Vestibular Fastigial nucleus areas that give origin to the pyramidal tract (Fig. 26.10).
nuclei (medial cerebellar n.) They end preponderantly in the regions of the reticular
Solitary
nucleus formation that send axons to the spinal cord. As dis-
cussed in Chapter 22, the corticoreticulospinal pathway
Medullary is of special importance for the control of voluntary
reticular formation
and automatic movements.
Vagus nerve As discussed in Chapter 23, the basal ganglia (the sub-
Spinoreticular stantia nigra) send efferents to the mesencephalic reticu-
tracts lar formation (the locomotor region, or PPN). Fibers
from the hypothalamus ending in parts of the reticular
formation serve to coordinate the activity of different
peripheral parts of the autonomic system. Limbic struc-
tures, notably the amygdala, also send fibers to the
gure 26.10 Afferent connections of the reticular formation. Several reticular formation. Such connections probably mediate
spinoreticular tracts mediate various kinds of sensory information. In emotional effects on autonomic and somatic motor
addition, the reticular formation is inuenced from sensory cranial
nerve nuclei and other brain stem nuclei, such as the PAG, the supe-
rior colliculus, and the vestibular nuclei (not shown). The descending 2 The medial lemniscus does not give off collaterals to the reticular formation.
bers from the cerebral cortex are links in indirect corticospinal path- Information from low-threshold mechanoreceptors must therefore reach the
ways (cf. Fig. 22.1). reticular formation by means of spinoreticular neurons.
functions. The periaqueductal gray (PAG) is discussed catches our attention, this is mediated by the reticular
in Chapter 15 in relation to suppression of nociceptive formation. At the same time, premotor networks in the
signals, but this mesencephalic complex of smaller reticular formation produces the motor responses that
nuclei has a wider specter of functions; for example, it ensure automatic orientation of the head and the body
helps initiate defensive reactions to external threats or toward the source of the stimulus. The motor appara-
other kinds of stress. This happens by way of its effer- tus is mobilized, together with alterations of respiration
ent connections to premotor networks in the reticular and circulation.
formation. The reticular formation receives afferents
from the cerebellum (primarily the fastigial nucleus; see
Actions on Skeletal Muscles
Fig. 24.6). This is an important pathway for the cere-
bellar influence on and motoneurons. In addition, Animal experiments during the 1940s led to the identifi-
this pathway presumably mediates cerebellar influence cation of two regions within the reticular formation that
of the autonomic nervous system. Thus, electric stimu- influence muscle tone. Stimulation of a region in the
lation of the vermis can elicit changes in autonomic medulla that sends particularly strong connections to
functions. the spinal cord (Fig. 26.9) could inhibit stretch reflexes
and movements induced by stimulation of the motor
cortex. This region was therefore called the inhibitory
FUNCTIONS OF THE RETICULAR FORMATION region (Fig. 26.11). A region with opposite effects, the
facilitatory region, was found rostral to the inhibitory
It follows from the preceding discussion of its efferent one. It extends rostrally into the mesencephalon and is
connections that the reticular formation can act on located somewhat more laterally than the inhibitory
virtually all other parts of the CNS. We considered its region. The distinction between inhibitory and facili-
effects on the spinal cord in Chapters 14 and 22, and tatory regions is less sharp than originally believed,
we add more here on this point. In addition, we discuss however. In several places, single neurons with inhibi-
the effects on the cerebral cortex, which are of particu- tory or facilitatory actions on muscles are intermingled.
lar importance. Parts of the reticular formation that are The actions in the cord concern not only but also
involved in the control of eye movements are discussed in motoneurons, so that the reticular formation can con-
Chapter 25, whereas the parts involved in the control of trol the sensitivity of the muscle spindles. The activity
autonomic functions are described briefly in Chapter 28.
The Activating System

Electrical stimulation of parts of the reticular formation
alters several functions mediated by the spinal cord,
such as muscle tone, respiration, and blood pressure. In
addition, the general activity of the cerebral cortex,
which is closely related to the level of consciousness,
can be altered by stimulation of the reticular formation.
The activating system of the brain stem was therefore _
Facilitatory
F
_
introduced as another name for the reticular formation. region
Pons
Pons
It should be emphasized, however, that these wide-
spread effects are not served by the reticular formation Medulla
Med.obl. Inhibitory
region I
as a whole but by relatively specific subregions. Further,
stimulation of the reticular formation can also produce
inhibitory effects on several processes. Therefore, the
term activating system is not synonymous with the
reticular formation but pertains to effects obtained
from specific subregions only (to be discussed further Inhibition Facilitation
I F
later in this chapter).
There is continuous activity in the reticular forma- gure 26.11 Facilitatory and inhibitory regions of the reticular
tion maintained by a constant inflow of signals from formation. Schematic sagittal section through the brain stem (cat).
various sources. The level of consciousness reflects the The diagram at the bottom shows the amplitude of the patellar reex
tonic activity in specific parts of the reticular forma- (measured with EMG). In the period marked Inhibition, the inhib-
itory region was stimulated electrically and the reex response is
tion. In particular, such activity is essential for the con- almost abolished. In the period marked Facilitation, the facilitatory
scious awareness of sensory stimuli and for adequate region was stimulated and the patellar reex response is markedly
behavioral responses to them. When a novel stimulus enhanced. (Modied from Kaada 1950.)
of the motoneurons is increased by stimulation of the rhythm generatorse.g., those producing locomotor
facilitatory region and inhibited by the inhibitory movements). Normally, however, a much wider network
region. The muscle tone can therefore be up- and down- participates in respiratory control, including neurons in
regulated by altering the balance between the influences the pontine reticular formation. The VRG receives sen-
from the two regions. Since the cerebral cortex, the cer- sory signals from the thoracic cage and the lungs about
ebellum, the basal ganglia, and other regions send fibers the degree of expansion, and from chemoreceptors
to the reticular formation, it follows that muscle tone about blood pH and CO2 content. Such information
can be influenced from these parts as well. It should be modulates the activity of the rhythm generator, without
recalled, however, that cell groups other than the retic- being necessary for the maintenance of breathing.
ular formation also have direct access to the motoneu- The respiratory rhythm generator is unstable shortly
rons, notably the vestibular nuclei with their strong after birth in rats (but not in pigs and cats). A theory
facilitatory effects on the tone of muscles maintaining proposes that similar immaturityso that the breath-
the upright position (see Chapter 21 for a discussion of ing rhythm is easily disturbed or abolishedlies behind
muscle tone). sudden infant death syndrome.
In addition to the rather diffuse effects on muscle tone Parts of the reticular formation also receive all neces-
obtained by electrical stimulation of the reticular forma- sary information for cardiovascular control. Thus, these
tion, its role in the control of certain kinds of voluntary regions control blood pressure, the blood volume distri-
and reflex movements were discussed in Chapter 22. bution among the organs, the stroke volume, and the
No principal difference exists, however, between the heart rate. Rather extensive networks in the rostral
influence of motoneurons in eliciting a movement and ventrolateral medulla (RVLM) are responsible for coor-
in maintaining a (static) posture. Based on the present dinating the necessary adjustments of vascular resis-
state of knowledge of the organization of the reticular tance and cardiac output. The effects are mediated by
formation, the emphasis is more on its control of spe- reticulospinal fibers acting on preganglionic sympa-
cific motor tasks than on its diffuse effects on the mus- thetic neurons and fibers to brain stem preganglionic
cle system as a whole. For example, certain subregions parasympathetic neurons (with fibers passing in the
have a particular role in controlling the rhythmic loco- vagus nerve).
motor movements, whereas other regions are devoted
to controlling eye movements, and some are concerned
The Reticular Formation and the Relationship
primarily with orienting movements of the head and
between Mental and Bodily Processes
the body in response to optic and vestibular stimuli. In
such functions, parts of the reticular formationoften Variations in the activity of the reticular formation are
consisting of extensive premotor networkscollect the reflected in virtually all aspects of the nervous processes
relevant information about, for example, the position and in the activity of the endocrine organs controlled by
of the head and body, and ensure through their output the hypothalamus. Such interactions may help explain
signals the coordinated activity of all the muscles that the intimate correlation of mental and bodily processes.
are necessary to produce a proper response. Common There is much evidence to suggest that our mental state
to premotor networks is their control of the activity of influences the activity of parts of the reticular forma-
large groups of muscles. tion. The thought of a forthcoming, unpleasant event or
the memory of an embarrassing or agonizing situation
may suddenly make a drowsy person alert and tense
Effects on Respiration and Circulation
(increased muscle tone), produce sweating, increase the
Microelectrode studies have shown that neurons with heart rate, and so forth. Every doctor who routinely
respiratory movement-related activity lie in several tests reflexes knows that apprehension and anxiousness
regions of the reticular formation, even though they are is accompanied by increased reflex responses and
concentrated in the ventrolateral medullary reticular increased muscular tone. An exaggerated patellar reflex
formation, which is often termed the ventral respiratory at the start of a consultation becomes normal as the
group (VRG). This region contains many premotor patient relaxes. Another everyday example is the diffi-
neurons that control (monosynaptically and polysynap- culty in falling asleep when one is preoccupied with dis-
tically) the rhythmic activity of motoneurons innervat- tressing thoughts.
ing the diaphragm and other respiratory muscles. The All of the above-mentioned effects covary with altered
rhythm generator itself consists most likely of a small activity in parts of the reticular formation that is closely
neuronal network in the rostral part of the VRG, the linked with neuronal activity in the thalamus, cerebral
so-called pre-Btzinger complex. Thus, animal experi- cortex, limbic structures, and the hypothalamus. Thus,
ments indicate that this small region is both necessary stimulation of certain cortical areas can increase the activ-
and sufficient to elicit rhythmic respiratory movements ity of reticular neurons followed by desynchronization
(this network has properties in common with other of the EEG (unanesthetized animals become attentive).
These effects are mediated by direct and indirect connec- ascending activating system, and probably specific
tions from the cortex to the brain stem. There are also activity patterns in the thalamocortical system. As put
connections from the hypothalamus and limbic structures by Searle (2000, p. 574): Only the already conscious
(such as the amygdala) to the reticular formation, which subject can have visual experiences.
may be of particular importance because emotions are Most people would accept that consciousness is a
most effective in causing activation. That insomnia is product of neuronal activity and, as such, an emergent
related to increased activity in the reticular formation property of the brain. It cannot be singled out as a sep-
is suggested by the fact that most drugs used against arate part; rather, consciousness represents a partic-
insomnia reduce the activity of certain groups of reticular ular state of the brain. This in itself does not explain the
neurons. General anesthesia abolishes the transmission phenomenon, and consciousness cannot be fully under-
through central parts of the reticular formation (resulting stood by a reductionistic approach, studying in ever more
in lack of activation of the EEG and unconsciousness), detail the constituent parts of the brain. The brain
whereas the transmission in the specific sensory pathways consisting of billions of neuronsproduces something
is less affected. that is more than the sum of its parts, and even the most
We also know that bodily processes influence our detailed knowledge of synaptic couplings, transmitters,
mental state. For example, a treatment that leads to and receptors does not suffice to explain consciousness
muscle relaxation usually also reduces mental tension. and other mental phenomena. A consciousness center
Again, the effects are probably mediated by a reduction or module somewhere in the brain is incompatible with
of the activity of the reticular formation. At the same our present knowledge about the brain. That uncon-
time, there are alterations of respiration, blood pres- sciousness follows interruption of the ascending acti-
sure, heart rate, and other autonomic functions such as vating system in the mesencephalon does not imply
sweat secretion, peristaltic movements of the bowel, that the locus of consciousness is somewhere in the
and secretion of gastric juice. There is evidence that mesencephalon (similarly, the fact that a car cannot run
some of the autonomic expressions of anxiety (e.g. pal- without a battery does not imply that the battery is
pitations) may by themselves serve to maintain and the car).
increase the anxiety.
We return to the interactions between the mind and the
Neurobiological Basis of Consciousness
body in Chapters 30 (under Hypothalamus and Mental
Functions) and 32 (under Amygdala and Emotions). For higher mental functions, the cerebral cortex is
essential, and the cerebral cortex is certainly necessary
for consciousness. It would nevertheless be misleading
to state that the cerebral cortex alone owns the prop-
CONSCIOUSNESS
erty of consciousness. In general, consciousness depends
on coordinated activity in a network comprising the
What Is Consciousness?
brain stem, the thalamus, and the cerebral cortex.
Consciousness eludes attempts at precise scientific Isolated activity in any one of the parts of the network
definitions. Yet, we all know what it is to be conscious. is not sufficient. For example, activity in specific corti-
The American philosopher John Searle (2000, p. 559) cal areas responsible for (conscious) analysis of sensory
gives this definition: Consciousness consists of inner, information or control of cognitive processes cannot
qualitative, subjective states and processes of sentience produce conscious experience on their own. We do not
or awareness. Consciousness, so defined, begins when know the neurobiological mechanisms producing the
we wake in the morning from a dreamless sleep and conscious state.
continues until we fall asleep again, die, go into a coma, In Chapter 16, we discuss whether specific parts
or otherwise become unconscious. A salient feature of the cortex can be linked to conscious visual experi-
of consciousness is unity or wholeness: we perceive our- ences (How Are Data from Different Visual Areas
selves as a whole, and all the different bits and pieces of Integrated?). A building block theory of conscious-
information analyzed by specialized brain systems are ness has some experimental support (e.g., from the
incorporated into a unitary experience. (Certain brain study of persons with blindsight) but seems unable to
lesions, however, can dramatically change this; e.g., a explain important aspects. Much recent research has
stroke patient can deny that his paralyzed leg is a part focused on what has been termed the hypothesis of
of his body.) Further, consciousness cannot be sepa- unified field consciousness. This implies that con-
rated from its content, including subjective sensations, sciousness might not be separable into different
moods, motives, inner images, and thoughts. Yet, we domainsas visual, auditory, somatosensory, emo-
know that specific sensory information is not sufficient tional, and so forth. Much information now points to
for conscious experiences to arise: the brain must be in synchronized activitybinding vast assemblies of
a conscious state that depends on the integrity of the neurons in a coherent stateas a prerequisite for
from to waves is called desynchronization, or acti-

3
conscious experience. In particular, synchronization
within an extensive frontoparietal network may be vation of the EEG. During sleep, other wave forms and
characteristic of a conscious state. Indeed, conditions patterns occur that are typical of specific stages of sleep.
with unconsciousness (such as coma, deep sleep, gen- Various neurological diseases can be diagnosed because
eral anesthesia, and the vegetative state) show reduced they are associated with characteristic changes of the
metabolic activity in the frontoparietal network. EEG. To some extent, the EEG can also help localize
Only few of our mental processesin spite of their the disease process. An EEG is particularly important in
dependence on the integrity of the cerebral cortex the diagnosis of epilepsy.
take place in the searchlight of consciousness. There The EEG varies considerably with age; most marked
is in fact much experimental evidence suggesting that of are the changes during the first couple of years. There
our conscious or voluntary behavior often reflects are also individual variations. Further, the EEG pattern
4
processes that do not come to full awareness. changes during sleep and during general anesthesia.
Hyperventilation, which leads to a reduced carbon diox-
ide concentration in the blood, changes the excitability
The Study of Consciousness: Electroencephalography
of cortical neurons, and this is reflected in the EEG.
Direct recording from the surface of the cerebral cortex Finally, several drugs affect the EEG.
of animals shows that the patterns of electrical waves
differ among parts of the hemispheres. In humans, too,
Thalamocortical Neurons Have Two States
direct recordings from the exposed cortex can be done
of Activity
during brain surgery (electrocorticography). The elec-
trical waves are conducted through the skull and the We do not fully know how the various waveforms in
soft tissues of the scalp and can therefore be recorded the normal EEG arise, but it is clear that they depend in
with electrodes placed on the skin of the head. With large measure on different activity states in thalamocor-
this method, electroencephalography (EEG), the electri- tical neurons. Thalamocortical neurons (functioning as
cal signals are dispersed and attenuated on their way relay cells for transmission of sensory and other signals
through the skull and soft tissues, so that the origin of to the cortex) have unique membrane properties owing
the signals within the hemisphere can be only roughly to the presence of a special kind of Ca2+ channel that
determined. Nevertheless, the method has been of great opens only when the cell is hyperpolarized to a certain
importance both for research and diagnostically since level. In addition, massive connections from the cerebral
its introduction around 1930. cortex to the thalamuscorticothalamic connections
When analyzing the EEG, one can discern various play an important part in the rhythmic firing of thalamo-
waveforms and patterns. The waves are relatively slow, cortical neurons.
with a frequency of 8 to 12/sec (Fig. 26.12). They occur Thalamocortical neurons generate action potential in
typically in an awake person who is relaxed and resting two different patterns or modes: they may fire in bursts
with her eyes closed. When the person opens her eyes or (that is, they fire 2 to 8 action potentials with a high
starts to think about a mental task (Fig. 26.12), the EEG frequency followed by a pause), or they fire single spikes
immediately changes to a pattern with more irregular with a varying overall frequency. The bursting pattern
waves with a higher frequency and lower amplitude. is associated with synchronization of the EEG (in states
These are called waves. The change of wave pattern of drowsiness and so-called slow-wave sleep), whereas
the single-spike firing occurs together with desynchro-
nization (during attentiveness and during rapid-eye-
3 EEG recordings in humans during watching of ambiguous pictures support movement sleep). It appears that these different
the relevance of synchronization for conscious experience. The picture could be
interpreted either as meaningless or representing a face. When persons reported functional states of the thalamocortical (relay) neurons
that they saw a face the EEG showed synchronization of widely separated corti- determine whether they transmit signals to the cortex.
cal areas, whereas synchronization did not occur when they saw no meaning in Only in the single-spike mode do the cells transmit to
the picture.
4 A woman suffering a stroke that damaged the midportion of the corpus cal- the cortex the information they receive from, for exam-
losum was asked to identify objects with the right and left hand (without ple, peripheral receptors.
vision). The damaged part of the corpus callosum connects the somatosensory Switching between bursting and single-spike firing can
areas. Therefore, in this case somatosensory information could not be trans-
ferred between the hemispheres. When holding a rubber in her right hand she be produced by modulatory influences from the reticular
was able to name it correctly. This is as expected, because the sensory informa- formation (see later, Multiple Pathways and Transmitters
tion passes from the right hand to the left hemisphere that is responsible for Are Responsible for Cortical Activation). Further, the
speech in most people. When she held the rubber in her left hand, however, she
did not notice anything or she did not know what it was. In this case, the infor- reticular thalamic nucleus (see Fig. 33.8)consisting of
mation went to the mute right hemisphere. Nevertheless, she was afterwards GABAergic neurons with local actions in the thalamus
able to pick out a rubber from a bag with her left hand when asked to nd the has a central role in the switching (cf. Chapter 33, under
same object she just held. Thus, the right hemisphere was able to identify the
object, remember it, and use the hidden information in conscious behavior Inhibition in the Thalamus: Interneurons and the
(Gazzaniga 1993). Reticular Thalamic Nucleus).
waves (synchronization)
A
gure 26.12 Electroencephalography Opening the eyes

(EEG). Three traces are shown, all of
them recorded over the occipital lobes. B waves (desynchronization)
A: The person is in a relaxed state, with
his eyes closed. There are waves typical
of synchronization. B: At the arrow, the
person opens his eyes, and the waves C Calculation Answer
are replaced by faster, irregular waves with
smaller amplitude, called waves. The
13 x 9 117
EEG is desynchronized. C: Desynchro-
nization produced by solving a mental
task. The person is asked to make a
calculation (13 9). After the calcula- 1 sec.
tion is completed (at 117), the slower
waves return.
A Prerequisite for Consciousness: Effects of the Reticular

rate and with lower amplitude. Together with this
Formation on the Cerebral Cortex
desynchronization of the EEG occur signs of increased
The effect of the reticular formation on the cerebral attention and alertnessthat is, an arousal is produced.
cortex was brought into focus by a paper published by Such an arousal can also be produced in unanesthetized
the neurophysiologists G. Moruzzi (Italian) and H.W. animals with implanted electrodes. For example, a cat
Magoun (American) in 1949. Suddenly, new perspec- lying still with no obvious interest in its surroundings
tives were opened on important aspects of brain func- becomes suddenly alert and attentive when the reticular
tioning, especially consciousness, sleep, and wakefulness. formation is stimulated with a high-frequency train of
Based on their animal experiments, Moruzzi and impulses. Marked reduction of the activity of the retic-
Magoun formulated a new concept: the ascending acti- ular formation is associated with unconsciousness, as
vating system of the brain stem. Later studies confirmed shown experimentally in animals with selective lesions.
their hypothesis that (parts of) the reticular formation As mentioned, the reticular formation can have either
is necessary for maintenance of normal wakeful con- activating or inhibiting effects on functions mediated
sciousness. The reticular formation determines the level by the spinal cord, depending on which region is stimu-
of consciousness, with its many variations from tense lated (Fig. 26.11). Similar findings were made with
alertness to drowsiness and sleep. regard to the ascending effects on the cerebral cortex,
Electrical stimulation of the reticular formation in even though so far we have discussed only the activat-
anesthetized animals produces certain changes of the ing effects. It appears that inhibitionthat is, synchro-
electrical activity in the cortex, as recorded by EEG. nization of the EEG is evoked most easily from the
Under anesthesia (without stimulation), relatively slow caudal parts, whereas activation or desynchronization
waves dominate (Fig. 26.13). On electric stimulation is evoked from the rostral parts (corresponding to the
of the reticular formation, the slow waves of the EEG effects on skeletal muscles). We return to this below
are replaced by waves with a faster and more irregular when discussing sleep.
waves (synchronization) waves (desynchronization) waves

gure 26.13 Electroencephalographic
(EEG) recordings from the classic stud-
ies of Moruzzi and Magoun (1949). The
four tracings are recorded over different
parts of the cerebral cortex of a cat. The
thick line at the bottom shows the period
of electrical stimulation of the reticular
formation. The stimulation produces
desynchronization of the EEG (activa- Stimulation of reticular formation
tion), which returns to a synchronized 1 sec
pattern when the stimulation stops.
In humans with prolonged periods of unconscious- most importantly, they are unable to arouse the animal.
ness after head injuries, there is often damage of the Pathways other than the major sensory ones must there-
mesencephalic reticular formation. The lesion can be fore be responsible when the reticular formation activates
surprisingly small and yet produce deep unconscious- the EEG over major parts of the cerebral hemisphere
ness. This fits with animal experiments showing that and produces behavioral changes indicating increased
interruption of the ascending reticular connections in attention.
the mesencephalon produces loss of consciousness, in Connections from the reticular formation to the
spite of normal conduction in the large sensory path- intralaminar thalamic nuclei are likely candidates.
ways (medial lemniscus, spinothalamic tract, and visual Thus, electrical stimulation of these nuclei can produce
and auditory pathways). activation of the EEG similar to that seen after stimula-
tion of the reticular formation itself. The intralaminar
thalamic nuclei send widespread efferents to the cere-
Control of Sensory Information and
bral cortex (cf. Chapter 33, under The Intralaminar
Focusing of Attention
Thalamic Nuclei). Therefore, a reticulothalamocorti-
The main task of the ascending activating system is cal pathway probably is important for the actions of
probably to focus our attention on certain stimuli or the reticular formation on the cerebral cortex. Many of
internal events, rather than to produce a diffuse aware- the reticulothalamic fibers to the intralaminar nuclei
ness (if such a state is conceivable). To achieve this, it is are cholinergic and come from a few small cell groups
5
necessary to prevent irrelevant stimuli from entering in the dorsal part of the pons. In addition to this indi-
consciousness. Together with other mechanisms, inhi- rect reticulothalamocortical pathway, there are direct
bition from the reticular formation can ensure that, for projections to the cerebral cortex from monoaminergic
example, we do not notice that someone is talking to us cell groups in the brain stemusually considered parts
while we are absorbed in a book. In Chapters 14 and of the reticular formationsuch as the raphe nuclei
15, we discussed how the central transmission of sen- (serotonin), the locus coeruleus (norepinephrine), and
sory signals is controlled from higher levels of the CNS, the ventral tegmental area in the mesencephalon (dop-
usually so that signals from certain kinds of receptor or amine). These nuclei also project to the thalamus, how-
parts of the body are inhibited. For example, descending ever. Stimulation of each of these cell groups can
connections to the spinal cord from the raphe nuclei and produce synchronization of the EEG, even though they
various (other) parts of the reticular formation suppress behave differently in other respects. For example, their
the central conduction of signals from nociceptors. activities differ with regard to sleep, as discussed below.
Further, the central transmission of visual, auditory, Norepinephric neurons increase their firing rate shortly
and other sensory impulses is controlled by the reticular before and during periods with cortical activation and
formation. Thus, even though it is not alone in this focused attention. Similarly, serotonergic raphe neu-
capacity, the reticular formation plays an important part rons and histaminergic neurons in the hypothalamus
in eliminating sensory signals that are considered irrel- (tuberomammillary nucleus) are more active during
evant, so that our attention can be focused on salient wakefulness than during sleep.6 As with the other mod-
signals. ulatory inputs, activation of histaminergic fibers can
bring thalamocortical neurons from a state of burst
firing to single-spike firing.
Pathways and Transmitters Responsible for
Experiments in rats with selective elimination of
Cortical Activation
various neurotransmitter systems suggest the following
What are the pathways used by the reticular formation (very simplified) specializations with regard to tasks
to influence consciousness, attention, and sleep? All of requiring focused attention: the cholinergic connections
the major specific sensory pathways (the spinothalamic increase the precision of the performance, the norepi-
tract, the medial lemniscus, and the visual and auditory nephric ones reduce the effect of distracting stimuli, the
pathways) can be interrupted without affecting con- dopaminergic ones increase the speed of execution,
sciousness or the activation of the EEG produced by and the serotonergic ones limit the frequency of impul-
stimulation of the reticular formation. If these sensory sive response errors (see also Possible Tasks of the
pathways are left intact but the ascending connections
of the reticular formation are interrupted by a cut in the
mesencephalon, the animal becomes unconscious. 5 The largest pontine cholinergic cell groups are the pedunculopontine nucleus
(PPN) and the lateral dorsal tegmental nucleus (LDT). The PPN consists of
Electrical stimulation of the reticular formation can no several subdivisions, however, and many neurons are glutamatergic; moreover,
longer activate the EEG, even though stimulation of a part of the PPN has important connections with the basal ganglia and other
peripheral receptors evokes potentials in the cortical parts of the brain stem.
6 Histamine-receptor antagonists, commonly used for allergy and motion sick-
sensory regions. Thus, the sensory signals reach the cor- ness, block the activating effect of histamine, and this might explain why they
tex, but they are restricted to the sensory regions, and, have sleepiness as a side effect.
Raphe Nuclei and the Locus Coeruleus earlier in this system. This condition is called the locked-in syndrome.
chapter). The patient is unable to move or talk but is otherwise
To summarize, at least five cell groups, using as many fully conscious and mentally intact.
transmitters, cooperate in the control of consciousness
and attention. They exert their effects partly in the thal-
amus and partly in the cerebral cortex. Most likely, SLEEP
each of the cell groups and transmitters influence differ-
ent aspects of wakefulness. The necessity of sleep and its contribution to mental
and physical health may seem self-evident. Yet, the
more specific functions of sleep and its neurobiological
Coma, Vegetative State, and the Locked-in Syndrome
basis are not fully understood. Indeed, control of sleep
For clinical purposes, the definition of consciousness and its various phases has turned out be very complex,
is practical: a condition of wakefulness in which the involving many neuronal groups and neurotransmitters.
person responds appropriately to stimuli and, by his Here we provide only a brief and simplified treatment
behavior, demonstrates awareness of himself and his of this topic.
surroundings. Patients with diseases or damage of the
brain can exhibit states of consciousness ranging from
Sleep Phases
full awareness to coma. A person in a coma appears to
be sleeping, but cannot be awakened by any kinds of sen- Sleep consists of several phases that can be distinguished
sory stimulus. Purely reflex movements may be evoked, based on differences in the EEG. The transition from
however (e.g., the withdrawal reflex). A coma may have alertness to drowsiness changes the EEG in the direc-
several different causes but it is always a serious condition of synchronization. When a subject is falling into a
tion. The prognosis is poorer the longer a comatose deep, quiet sleep, the waves disappear altogether and
state lasts. After acute head trauma, persistent uncon- are replaced by irregular slow waves with greater ampli-
sciousness suggests brain stem involvement, typically of tude (slow-wave sleep). After an initial light phase I, the
the mesencephalic reticular formation. sleep becomes gradually deeper, until phase IV. To
After a few weeks, some comatose patients enter waken a person in sleep phase IV requires relatively
a persistent vegetative state in which they show some strong stimuli, whereas only weak stimuli are necessary
signs of wakefulness: they may open their eyes upon in phase I. Phase V is special because the EEG is desyn-
strong stimulation and after some time even spontane- chronized, and there are conjugated movements of the
ously. They may briefly fix the gaze on a person or eyes, much like a person looking at moving objects.
an object. They show no other signs of being aware of Because of these rapid eye movements (REM), this
their surroundings, however, and they do not talk. phase is called REM sleep or paradoxical sleep. The eye
Functional magnetic resonance imaging (fMRI) studies movements appear to relate to the content of the dream.
in such patients show activity patterns compatible with Thus, patients suffering from neglect of the left visual
unconsciousness. For example, in 15 patients noxious hemifield (after damage to the right hemisphere) have
stimuli activated expected parts of the brain stem, thal- conjugated eye movements during REM sleep only to
amus, and SI but not the rest of the pain network, the right side; that is, the visual field they attend to
including the insula, the cingulate gyrus, and the SII. when awake. Muscle tone is generally reduced, with
Nevertheless, doubt exists as to whether some patients occasional muscular twitches, and there are changes of
in the vegetative state can perceive and respond ade- blood pressure and heart rate. Dreaming occursat
quately to external events. Thus, a patient showed acti- least mainlyduring REM sleep. The various phases of
vation (measured via fMRI) of relevant motor networks sleep follow each other with the same order throughout
when asked to imagine playing tennis. Further, speech the night. Usually, the first REM phase occurs after
areas were activated when the patient was presented about 1.5 hours of sleep and lasts for about 10 minutes.
with spoken sentences. It is not clear, however, whether Thereafter the REM phases return at intervals of 1 to
these observations mean that the patient was in fact 2 hours, and become gradually longer up to about
conscious, or whether it just shows how much of cere- 30 minutes. When waking up (or being wakened) just
bral processing that can occur without entering con- after a REM phase, a person remembers the content of
sciousness. the dream vividly.
On rare occasions, a patient may appear unconscious The cerebral cortex is as active during REM sleep as
yet be fully awake. This occurs typically after brain when awake, but is partly uncoupled from the thala-
stem infarctions that damage the ventral parts of the mus, which in the awake state delivers a constant stream
pons with the pyramidal tract and corticobulbar tracts of information about the external world. The EEG pat-
on both sides. The sensory pathways located more tern during sleep is produced by complex interactions
dorsally are spared, as is also the ascending activating between neuronal firing patterns in the thalamus and
the cortex. Inhibitory interneurons in both places have by EEG desynchronization. The yawning movement
important roles in producing the synchronized firing of evokes sensory inputs via (among others) the trigeminal
thalamocortical neurons characteristic of sleep. nerve.
Contagious yawningthat is, yawning elicited by
the sight or the sound of someone else yawningmay
Why Do We Sleep?
be an expression of our ability to imagine the state of
One hypothesis assigns a homeostatic function to sleep. mind of other people. It does not occur in animals that
The energy stores of the brain need rebuilding, the syn- are unable to recognize their own mirror image, and
aptic vesicles need refilling with neurotransmitters, and not in children younger than the age of 2. An fMRI
so forth. Another theory emphasize that sleep is neces- study showed change of activity in parts of the parietal
sary for the sake of plasticity. Growth of neurons and cortex and the cingulate gyrus in contagious yawning
establishment (and pruning) of synaptic contacts pro- (regions otherwise implicated in empathy). Regions
ceed presumably better when the neurons are not thought to contain mirror neurons were not activated,
required to participate in task solving and production however.
of goal-directed behavior. Useful connections need con- Pathologic yawning occurs in various diseases, for
solidation while other should be weakened or removed. example in migraine. It also occurs as a side effect of
The plasticity hypothesis would imply that sleep is dopaminergic drugs and serotonin-reuptake inhibitors.
important for learning and memory, a notion that has The importance of dopamine is supported by the obser-
received experimental support. Thus, there is evidence vation that yawning is reduced in patients with Parkinsons
that brain plasticity is increased during sleep. In agree- disease (with loss of dopamine). Increased yawning has
ment with this, even a brief nap immediately after a learn- been described as an early sign in infarctions of the
ing session can improve the subsequent performance. upper pons, and in patients with amyotrophic lateral
Animal experiments suggest that the consolidation of sclerosis (ALS). In both cases, it may be due to loss of
newly learned material take place predominantly in descending inhibitory control of brain stem yawning
specific sleep phases. The earliest studies focused on the centers.
phases with dreaming (REM-sleep), while the phases
with slow-wave sleep now seem to be equally impor-
Neuronal Groups and Transmitters Controlling Sleep
tant.7 For example, human EEG studies found increase
in slow waves over cortical regions involved in a pre- As mentioned, the neural basis of sleep and its various
ceding learning session (e.g., over the posterior parietal phases is not fully understood and has turned out to be
cortex after a spatial-task training session). Further, very complex. Several brain regions and neurotransmit-
slow-wave increases were associated with improved ters are important. Lesions of the hypothalamus, for
performance when tested afterwards. Consolidation of example, can lead to increased or reduced amounts of
newly learned material is believed to depend on a dialog sleep (see Chapter 30, under Hypothalamus and Sleep),
between the hippocampus and the cortex, and this pro- but it is evident from animal experiments that the
cess appears to go on during slow-wave sleep (but not neuronal groups most directly involved in sleep control
during REM sleep), as witnessed by correlated firing are located in the brain stem, especially in the pons. In
in the hippocampus and the prefrontal cortex during agreement with this, fMRI in humans shows increased
slow-wave sleep. blood flow in the dorsal pons during REM sleep.
Initially, after the discovery of the activating system, it
was assumed that sleep was simply the result of reduced
Yawning
activity of the activating systemthat is, a purely passive
Most mammals yawn but we are not sure why. The process. Further studies showed, however, that sleep
hypothalamus, the basal ganglia, and the reticular for- could be induced by electrical stimulation of the lower
mation have been implicated in the control of yawning parts of the reticular formation and that lesions of the
(in addition, a number of cranial nerves and spinal same region prevented sleep (insomnia).
nerves are responsible for the execution). One hypoth- For induction of sleep, activity in cholinergic neurons
esis proposes that yawning serves to increase alertness in the dorsolateral pons is crucial (the pedunculopon-
in situations where we are passive but need to pay atten- tine nucleus, and some smaller cell groups). These neu-
tion (lectures may be an example). This assumption is rons project to the thalamus to influence the activity of
based on the observation that yawning activates parts the large sensory relay nuclei (the geniculate nuclei and
of the reticular formation and is immediately followed the VPL). In addition, they project to neurons in the
nearby reticular formation, which, in turn, project to cho-
linergic neurons in the hypothalamus and the basal
7 There is some evidence that REM sleep may be most important for consoli-
dation of emotional and procedural memories, whereas slow-wave sleep is nucleus (among other targets). The effects of acetylcholine
more involved in spatial and declarative memories. in the thalamus are mediated by muscarinic receptors.
The pontine cholinergic neurons fire in bursts (bursting daytime, whereas night sleep is fragmented. The disease
neurons) ahead of the eye movements in REM sleep. seems to be due to degeneration of a cell group in the lateral
Their close relation to REM sleep is further shown by the hypothalamus. The neurons of this group have wide-
observation that microinjection of acetylcholine in the spread axonal ramifications and release neuropeptides
dorsolateral pons increases REM sleep for several days. called hypocretins (orexins). Hypocretin-containing neu-
The roles of serotonin and norepinephrine in control of rons appear especially to target modulatory cell groups,
sleep are less clear, probably because they are difficult to such as the locus coeruleus, raphe nuclei, dopaminergic
study in isolation. Thus, cholinergic and monoaminergic neurons in the mesencephalon, and the tuberomammil-
neurons lie partly intermingled in the dorsolateral pons. It lary nucleus (histamine). Because hypocretins seem to
seems established, however, that the monoamines exert be excitatory, they would increase arousal by increasing
their main effect on sleep by modulating the activity of the norepinephrine release from the locus coeruleus neurons,
pontine cholinergic neurons. Mostly, the monoamines as confirmed in animal experiments.
inhibit the cholinergic neurons, thus increasing wakeful- Patients with narcolepsy also have increased concen-
ness. This conclusion is based on the fact that, among tration of muscarinic receptors within the brain stem
other things, the monoaminergic neurons fire during (cf. the increased REM sleep caused by injection of ace-
8
wakefulness and are silent during REM sleep. Further, tylcholine in the dorsolateral pons, mentioned above).
microinjection of serotonin hyperpolarizes (inhibits) the Further, there is evidence that monoamine metabolism
bursting neurons in the dorsolateral pons. Finally, drugs is deficient. Both drugs that block muscarinic receptors
that enhance the synaptic effect of serotonin (such as and drugs that increase synaptic concentration of
reuptake inhibitors) reduce REM sleep in humans. monoamines (such as amphetamine and tricyclic antide-
Spinal motoneurons are strongly inhibited from the pressants) are reported to reduce the narcoleptic attacks.
brain stem during REM sleep. This prevents the execu- Possible connections between the loss of hypocretin
tion of movements that are part of the dream (small, neurons in the hypothalamus and the alterations of
miniature movements nevertheless occur during dream- muscarinic receptors and monoamine metabolism in the
ing). The inhibition is partly initiated by the pontine cho- brain stem are unknown.
linergic neurons, although the major control most likely is
exerted by norepinephric neurons close to the locus coer-
Dreaming
uleus (the subcoeruleus nucleus). Reticulospinal neurons
in the medial medullary reticular formation mediate the Why we dream has been the subject of much specula-
effects on the motoneurons. After destruction of descend- tion and many theories. REM sleep appears to occur in
ing norepinephrine-containing fibers, animals still have all mammals, even in the earliest species that developed
REM sleep but behave as if they were acting out their about 140 million years ago.9 This fact alone suggests
dreams with orienting movements, more complex explor- that REM sleep has an important function. Further
atory behavior, and attack or flight. support for its biological significance comes from
Other neurotransmittersGABA, dopamine, and other observations. Thus, the proportion of REM sleep
several neuropeptidesare involved in control of sleep increases after a period with REM-sleep deprivation,
by influencing the activity of the pontine cholinergic and it is much more difficult to prevent the occurrence
neurons. In addition, glutamate and glycine act by way of REM sleep than the other phases of sleep. Newborn
of pathways that are more indirect. Thus, many drugs infants have approximately 8 hours of REM sleep per
acting on the brain would be expected to influence sleep day and a special sleep rhythm. It consists of periods of
and wakefulness. 50 to 60 minutes of sleep usually starting with REM
sleep rather than slow-wave sleep. By the age of 2, REM
sleep lasts only about 3 hours, and the sleep pattern is
Narcolepsy
largely as it is in adults. The reason that REM sleep
Narcolepsy is a genetically linked disease with sudden, is so dominating during infancy (and before birth) is
irresistible attacks of REM sleep (or components of unknown. One possibility is that REM sleep is neces-
REM sleep). Starting usually between the ages of 10 and sary for neuronal growth and development of connec-
30, the disease affects equally often men and women. tions, as discussed earlier. The dominating view today
The patients experience increased sleepiness during is that dreams contribute to the processing and consoli-
dation of newly learned material, along with the inte-
gration of new experiences with older ones. Animal
8 Raphe neurons increase their activity and serotonin release during wakeful-
ness, and reduce their activity during sleep. Yet, destruction of the raphe nuclei experiments indicate that storage of new material is
or blockage of the serotonin synthesis produces insomnia. To reconcile these at
least apparently conicting observations, it has been postulated that serotonin
released during waking gradually activates sleep-promoting neurons in the 9 Whales (Cetacea) appear not to have REM sleep. In these mammals, the two
anterior hypothalamus (by acting at the gene level). This might serve as a hemispheres alternate to exhibit slow-wave sleep. Perhaps constant vigilance is
homeostatic mechanism to initiate sleep after some time of wakefulness. a necessity for adaptation and survival.
reduced by prevention of REM sleep a certain period psychoanalysis since Freud. Rather than emphasizing
after the learning situation. During REM sleep in cer- the role of dreams in learning, psychoanalytic tradition
tain animals, a particular pattern of electrical activity would stress their importance for the elaboration of
theta rhythmoccurs in the hippocampus. Since the inner conflicts that are not consciously accessible. These
hippocampus plays a crucial role in learning, this has two possibilities might not be mutually exclusive, how-
been taken to support the relationship between REM ever. Perhaps a common purpose for all dreams is to
sleep and learning. help the individual develop coping strategies, as this
The view that dreams are psychologically meaning- requires the integration of new with old experiences, as
ful, relating in a disguised form to inner conflicts and well as ensuring that inner conflicts do not block learn-
life events, is the basis for their central place in the ing and appropriate behavior.
27 The Cranial Nerves
OVERVIEW GENERAL ORGANIZATION OF THE CRANIAL NERVES
W e usually count 12 cranial nerves, even though neither Before dealing with specifics for each of the cranial
the first (the olfactory nerve) nor the second (the optic nerves (Fig. 27.1), we discuss some features that are
nerve) are true nerves. These two and, in addition, the common to them all. Like the spinal nerves that con-
cochlear nerve and the vestibular nerve are dealt with in nect the spinal cord with the body, the cranial nerves
Chapters 16 to 19. connect the brain stem with the peripheral organs.
A brief survey of the cranial nerves is given in Chapter 6. Several structural features are shared by the spinal cord
The prenatal development of the cranial nerve nuclei is and the brain stem, and thus also by the spinal and cra-
treated in Chapter 9 (see under Cranial Nerves and nial nerves. Nevertheless, the brain stem is less regularly
Visceral Arches). built and more complex in its organization than the spi-
The cranial nerves connect the brain stem with struc- nal cord and the cranial nerves are not as schematic in
tures in the head, neck, and in the thoracic and abdominal their composition as the spinal nerves. Most of the cra-
cavities. The cranial nerves are not as regularly built as the nial nerves, for example, lack a distinct ventral (motor)
spinal nerves because some are purely motor, others are root and a dorsal (sensory) root. Some of the cranial
purely sensory, and some are mixed (like the spinal nerves). nerves are purely sensory, others are purely motor, and
The cranial nerves contain four main fiber types. Somatic others are mixed. Like the spinal nerves, several of the
efferent fibers supply skeletal (striated) muscles, while vis- cranial nerves contain autonomic (preganglionic) fibers
ceral efferent fibers supply smooth muscles and glands supplying smooth muscles and glands. Finally, some
and belong to the parasympathetic part of the autonomic also contain afferent fibers from visceral organs.
nervous system. Somatic afferent fibers conduct sensory
signals from the skin and mucous membranes of the face,
The Cranial Nerves Can Contain Four Different
from muscles and joints, and from the vestibular appara-
Kinds of Nerve Fibers
tus and the cochlea, while visceral afferent fibers bring
sensory signals from the visceral organs. In early embryo- The cranial nerves can contain the following kinds of
logical development, the cranial nerve nuclei form longitu- fibers:
dinal columns (cf. columnar arrangement of motoneurons
1. Somatic efferent fibers innervating skeletal (stri-
in the cord), each column giving origin to only one of the
ated) muscles
four kinds of fiber. The columns are arranged so that, in
2. Visceral efferent fibers supplying smooth muscles
general, motor cranial nuclei (somatic and visceral effer-
and glands and belonging to the parasympathetic part
ent) lie medially in the brain stem while sensory nuclei
of the autonomic nervous system
(somatic and visceral afferent) lie laterally. Later in devel-
3. Somatic afferent fibers with sensory signals from
opment, the columns break up into discrete smaller nuclei
the skin and mucous membranes of the face, from mus-
but their mediolateral position and fiber composition
cles and joints, and from the vestibular apparatus and
remain the same (with some exceptions). The cranial nerve
the cochlea
nuclei and the cranial nerves are links in various brain
4. Visceral afferent fibers with sensory signals from
stem reflexes (e.g. the blink reflex and the vomiting reflex).
the visceral organs
The somatic motor nuclei receive innervation from the
motor cortical areas, partly as collaterals of pyramidal The efferent fibers of the cranial nerves have their
tract fibers, partly as corticobulbar fibers destined only for cell bodies in brain stem nuclei corresponding to the
the brain stem. Somatic sensory nuclei convey signals to columns of spinal motoneurons (see Fig. 21.3) and the
the sensory areas of the cerebral cortex by joining the large intermediolateral cell column of the cord. We use
ascending sensory tracts (e.g. the spinothalamic tract and the terms somatic efferent and visceral efferent cranial
the medial lemniscus). nerve nuclei of these cell groups (Figs. 27.2 and 27.3).
A fair knowledge of the position of the various cranial The afferent fibers have their cell bodies in ganglia close
nerve nuclei, the course of the nerves, and their main func- to the brain stem, corresponding to the spinal ganglia.
tions serve as a necessary basis for a topographic diagnosis The central process of the ganglion cells enters the brain
of brain stem lesions. stem and ends on neurons in nuclei corresponding to
391
the spinal dorsal horn and the dorsal column nuclei

(Figs. 27.3 and 27.4). We use the terms somatic afferent
and visceral afferent cranial nerve nuclei for such
groups. From such afferent (sensory) nuclei, signals are
conducted centrally to the thalamus and the cortex, and
via brain stem interneurons to the somatic and visceral
efferent (motor) cranial nerve nuclei (as links of brain
Optic n.(2) stem reflex arcs; Fig. 27.4).
Oculomotor n. (3)
Trigeminal n. (5) Trochlear A Broad View on the Position of the Cranial

nerve (4) Nerve Nuclei
In early embryonic life, all neurons giving origin to a
particular kind of fiber lie together in one longitudinal
Vestibulo- column in the brain stem. During further development,
Abducens n. (6) cochlear n. (8) these columns break up into smaller groups, and some of
Glossopharyngeal n. (9) Intermediate n. (7) them move away from the original column. Nevertheless,
Facial n. (7)
Vagus nerve (10) the tendency for cranial nerve nuclei of the same cate-
Hypoglossal n. (12) gory to form columns can be recognized also in the
adult brain (Fig. 27.2). The demonstration of this regu-
Accessory n. (11) lar pattern has been of value in understanding the
functions of the cranial nerves. Further, knowledge of
gure 27.1 The brain stem and the cranial nerves, as viewed from this pattern aids us in learning about the cranial nerves
the left side. See also Figs. 6.14 and 6.15.
A B
MOTOR NUCLEI SENSORY NUCLEI
Visceral efferent
oculomotor nucleus
(Edinger-Westphal)
Oculomotor nucleus
(somatic efferent) Mesencephalic
trigeminal
Trochlear nucleus nucleus MESEN-
CEPHALON
Principal
Motor trigeminal trigeminal
nucleus nucleus
Abducens
nucleus PONS
Facial
nucleus
Cochlear
Superior & inferior nuclei
salivatory nuclei
Ambiguus nucleus Vestibular nuclei
Hypoglossal nucleus Solitary nucleus

(visceral afferent) MEDULLA
Motor vagus nucleus
(visceral efferent) Spinal trigeminal
nucleus
Accessory nucleus
gure 27.2 Position of the columns of the cranial nerve nuclei. are shown in the same color. They form more or less continuous
A: Schematic of the brain stem, as viewed from the dorsal side. The columns. B: The position in the brain stem of some nuclei as seen from
nuclei belonging to the same kind (e.g., somatic efferent, visceral afferent) the left side. The positions of the various nuclei are only approximate.
27: THE CRANIAL NERVES 393
Special somatic afferent
(hearing, equilibrium)
8
COLUMNS OF CRANIAL NERVE NUCLEI
Visceral
Somatic afferent
Visceral
afferent General somatic afferent
efferent
(skin)
Somatic 5
efferent
Visceral afferent
(taste) 7, 9
Visceral afferent
(airways, gut) 10
gure 27.3 Position of the columns of the cranial

nerve nuclei. Schematic cross section of the medulla
(cf. Figs. 27.2 and 27.5). As a rule, the motor
nuclei are located medial to the sensory nuclei, as
shown schematically on the left side. The right half Visceral efferent
shows how the various kinds of bers are distrib- (smooth muscles, glands)
Somatic efferent
uted among the cranial nerves. Note that one kind (myotome muscles) 3, 7, 9, 10
of ber usually distributes to several cranial nerves. 3, 4, 6, 11, 12 Special somatic efferent
Some of the peripheral organs innervated by the (visceral arch muscles)
nerves are also shown to the right. 5, 7, 9, 10
A B
Cerebral cortex (SI) Cerebral cortex (MI)
Thalamus
Reticular
formation
Pyramidal tract
Afferent
(sensory)
cranial nerve
nucleus
Efferent (motor)
cranial nerve
nucleus
gure 27.4 Main features of the organization of the cranial nerve reex arc with reex center in the brain stem is established. Descending
nuclei. A: Sensory nucleus (e.g., the trigeminal nucleus). The efferent bers from the cerebral cortex inuences the sensory nucleus.
bers of the nucleus ascend to the thalamus of the opposite side, and B: Motor nucleus (e.g., the facial nucleus) sending its efferent bers
from there the next neuron projects to the cerebral cortex. The bers out of the brain stem to striated muscles. The neurons of the nucleus
destined for the thalamus give off collaterals on their course through are inuenced by the cerebral cortex, by the reticular formation, and
the reticular formation and the motor cranial nerve nuclei. Thus, a by collaterals of the ascending bers from the sensory nuclei.
and their nuclei. It is helpful at the outset to remember Most laterally, we find the somatic afferent nuclei.
the following general rule, evident from Figs. 27.2 This group comprises the sensory trigeminal nucleus (5),
and 27.3: the efferent (motor) nerve nuclei lie medially the vestibular nuclei (8), and the cochlear nuclei (8). The
in the brain stem, whereas the afferent (sensory) nuclei sensory trigeminal nucleus consists of three function-
are located laterally. Further, in most cases the nuclei ally different parts (the spinal, the principal, and the
are located at about the same rostrocaudal level as their mesencephalic nuclei). Together, the three parts form
nerves leave the brain stem. In clinical neurology it is one continuous column, which extends from the upper
important to know the approximate mediolateral and cervical segments of the cord into the mesencephalon
rostrocaudal level of each nucleus (Fig. 27.5). (Fig. 27.2).
The fibers of the vestibulocochlear nerve are often
classified as special somatic afferent because they origi-
Further on the Position of the Cranial Nerve Nuclei
nate from special sense organs; the trigeminal fibers are
The somatic efferent nuclei are in early embryonic life then termed general somatic afferent.
all arranged in a column close to the midline, but later Figure 27.4 and the discussion here show that fibers
some move away in a ventrolateral direction (Figs. 27.3 of one kind all come from one of the columns of nuclei
and 27.5). The nuclei remaining in the medialmost col- only, even though the fibers peripherally may follow
umn are termed general somatic efferent and comprise several of the cranial nerves. Thus, all (general) somatic
(from caudal to rostral) the nucleus of the accessory afferent fibers end in the sensory trigeminal nucleus,
nerve (11), the nucleus of the hypoglossal nerve (12), the whereas the fibers peripherally follow not only the
nucleus of the abducens nerve (6), and the nucleus of the trigeminal nerve but also the glossopharyngeal and the
oculomotor nerve (3). (In the following, for practical vagus nerves.
reasons we use abbreviated names, such as the acces-
sory nucleus and the hypoglossal nucleus.) All of these
Brain Stem Reexes
nuclei innervate myotome musclesthe muscles that
are developed from the segmentally arranged somites of Like the spinal nerves that are links in spinal reflex arcs,
early embryonic life. The somatic efferent nuclei that the cranial nerves constitute afferent and efferent links
have moved away from the medial column all innervate of reflex arcs with reflex centers in the brain stem
branchial musclesthe striated muscles developed from (Fig. 27.4). Some brain stem reflexes are simple, such as
the branchial (visceral) arches (facial and masticatory the monosynaptic stretch reflexthe masseter reflex
muscles, and muscles of the pharynx and larynx). We that can be elicited of the masticatory muscles. Often,
call these nuclei special somatic efferent (although they however, the reflex centers are more complex, compris-
1
most commonly are termed special visceral efferent). ing neurons at several levels of the brain stem (for some,
This group comprises the ambiguus nucleus (9, 10), the even at the cortical level). Thus, the afferent fibers may
facial nucleus (7), and the motor trigeminal nucleus (5). enter the brain stem at one level, whereas the efferent
The visceral efferent (parasympathetic) column of fibers leave at another. One example is the corneal
cranial nerve nuclei is located immediately lateral to reflex (touching of the cornea elicits an eye wink), in
the somatic efferent column (Figs. 27.2, 27.3, and 27.5) which the afferent fibers of the trigeminal nerve, enter-
and comprises the (dorsal) motor nucleus of the vagus ing at the midpontine level, descend in the brain stem
(10), the small inferior and superior salivatory nuclei and form synapses in the lower medulla (the spinal
(9, 7), and the parasympathetic oculomotor nucleus of trigeminal nucleus). From the medulla, the signals travel
Edinger-Westphal (3). The visceral afferent fibers all end by interneurons to the facial nucleus on both sides,
in one long nucleus, the solitary nucleus, which is located located in the lower pons. The reflex center is in this
lateral to the visceral afferent column (Figs. 27.2, 27.3, case rather extensive; consequently, lesions at various
and 27.5). levels of the brain stem may produce a weakened or
abolished corneal reflex. Depending on the location of
the lesion, however, the change of the corneal reflex
1 Both anatomically and functionally, however, the special visceral efferent will be accompanied by various other symptoms, which
neurons are more similar to the somatic efferents. First, branchial (visceral) helps in determining the exact site of the lesion.
arch striated muscles are among those subject to the most precise voluntary
control (the mimetic muscles of the face and the muscles of the larynx) and Several other brain stem reflexes are treated below in
should therefore not be mixed up with visceral (smooth) muscles. Second, the conjunction with the cranial nerves that mediate them.
neurons are structurally like motoneurons; that is, they are larger than the
preganglionic, parasympathetic neurons. In addition, the visceral arch neurons
contain the neuropeptide CGRP that occurs in spinal motoneurons but not in The Cranial Nerve Nuclei Are Connected with Central
preganglionic parasympathetic neurons. Therefore, we nd it preferable to use
the term special somatic efferent. Otherwise, it is of no great importance which Sensory and Motor Tracts
terms are used to group the neurons of the cranial nerves; the important thing
is to know where the cell bodies of the various cranial nerves are located, the As mentioned, the cranial nerves and their nuclei are
course of their bers, and their functions. organized in accordance with the same general rules as
A Oculomotor nucleus
(somatic efferent)
B
Visceral efferent
C oculomotor nucleus
(Edinger -Westphal)
Oculomotor nerve Crus cerebri

(root fibers)
B
Abducens nucleus
Principal trigeminal nucleus

Motor trigeminal nucleus
Facial nerve (root fibers)

Abducens nerve (root fibers)
Hypoglossal nucleus
Motor vagus nucleus
(visceral efferent)
Vestibular nuclei
C
Solitary nucleus
Inferior cerebellar peduncle
Spinal trigeminal nucleus
Ambiguus nucleus
Hypoglossal nerve (root fibers)

gure 27.5 Position of the cranial nerve
nuclei at three levels of the brain stem. Medial lemniscus
A: Mesencephalon. B: Pons. C: Medulla
Pyramid
oblongata. Compare with Fig. 27.2.
the spinal nerves (with some exceptions). This means by the cranial nerves (most marked in the mimetic
2
that the cranial nerves are the first links in sensory muscles).
pathways corresponding to the dorsal columnmedial Examination of the cranial nerves is of great impor-
lemniscus system and the spinothalamic pathway (Fig. 27.4; tance in clinical neurology because it can provide exact
see also Figs. 14.2 and 14.4). Further, as the nuclei information about the site of a disease process. A pre-
involved in the sensory pathways conducting from the requisite is that the examiner has reasonably precise
spinal cord, those of the brain stem are subjected to knowledge of where the cranial nerves exit from the
descending control of the sensory transmission. This brain stem (Fig. 27.1; see also Fig. 6.16) and the position
concerns influences from parts of the reticular forma- of their nuclei both rostrocaudally and mediolaterally
tion and from the cerebral cortex. (Figs. 27.2 and 27.5). Further, the functions of the var-
Several of the somatic efferent (motor) cranial nerve ious nerves must be known in sufficient detail as a basis
nuclei are influenced by the pyramidal tractthat is, by for the necessary tests. On the basis of such knowledge,
fibers forming the corticobulbar tract (Fig. 27.4; see together with knowledge of the positions of the long
also Fig. 22.1). An important difference between the motor and sensory tracts passing through the brain
corticospinal and corticobulbar fibers is that several of
the cranial nerve nuclei receive both crossed and
uncrossed fibers. Unilateral damage to the descending 2 The accessory, the hypoglossal, and the part of the facial nucleus supplying
fibers (e.g., in the internal capsule) produces clear-cut the lower part of the faceand often also the motor trigeminal nucleus
receive only crossed bers, as judged from clinical observations (Monrad-
pareses only in some of the muscle groups innervated Krohn 1954).
stem, the clinician can make a fairly precise topographi- posterior inferior cerebellar artery (see Fig. 8.3), even
cal diagnosis in most cases (Fig. 27.6; see also Fig. 14.3). though the occlusion often sits in the vertebral artery.
Figures 6.166.18 and 6.20 show the location of the The German neurologist Adolf Wallenberg described
cranial nerve nuclei in cross sections of the brain stem. the clinical picture of such infarctions in 1895, and it
has since been known as Wallenbergs syndrome.
Typical cases present with dizziness and vertigo (ves-
Brain Stem Lesions Can Produce Symptoms from
tibular nuclei), gait ataxia (spinocerebellar and olivo-
Several Cranial Nerves and Long Tracts
cerebellar tracts in the inferior cerebellar peduncle),
Many disease processes can cause brain stem lesions. difficulties with swallowing and hoarseness (ambiguus
Often, brain stem symptoms are caused by diseases that nucleus and root fibers of the vagus and glossopharyn-
produce symptoms also from other parts of the central geal nerves). A characteristic symptom constellation is
nervous system (CNS; e.g., multiple sclerosis, amyo- reduced pain and temperature sensation in the face on
trophic lateral sclerosis, metastatic brain disease). the side of the lesion and in the body of the opposite
Lesions limited to the brain stem are most often due to side (face: spinal trigeminal nucleus and descending
vascular occlusions of arterial branches causing infarc- trigeminal root fibers; body: spinothalamic tract). Most
tions (see Figs. 8.38.5). Any branch can be affected cases also present Horners syndrome (loss of sympa-
(although some more often than others), and the result- thetic innervation of the face on same side as the lesion,
ing symptoms depend on which structures are supplied see Fig. 28.10) due to interruption of descending fibers
by the occluded branch. There are, however, large indi- to the preganglionic sympathetic neurons in the cord.
vidual variations regarding the area supplied by a par- Individual cases may present only some of these symp-
ticular artery, and between the right and left side in the toms or other symptoms in addition, depending on the
same individual. Thus, symptoms will vary after occlu- exact site and extension of the lesion.
sion of a particular artery. Memorizing detailed lists of
symptoms typical for each arterial branch has therefore
limited value. A fairly precise localization of the lesion THE HYPOGLOSSAL NERVE
can usually be made on the basis of a thorough clinical
examination of the cranial nerves and the long ascending The twelfth cranial nerve, the hypoglossal nerve (Fig. 27.1),
and descending tracts (the dorsal columnmedial lemnis- is the motor nerve of the tongue. It is composed of only
cus, the spinothalamic tract, and the pyramidal tract). somatic efferent fibers. The fibers come from the hypo-
Figure 27.6 gives an overview of the structures that glossal nucleus, which forms a slender, longitudinal
can be damaged by lesions in the medulla. Most com- column close to the midline in the medulla (Figs. 27.2
mon are lateral infarctions in the area supplied by the and 27.5). The nucleus produces an elongated elevation
A B
Inferior cerebellar peduncle Medial longitudinal fascicle Motor (visceral)
(spinocerebellar & Spinal tract of (eye movements, balance) vagus nucleus
olivocerebellar tracts; Hypoglossal nucleus
trigeminal nerve Solitary nucleus (muscles of the tongue,
coordination gait) (pain, face same side) Dorsal column nuclei (sensory viscera, taste) same side )
Spinal trigeminal
nucleus
Spinothalamic Vagus nerve

tract (pain, body
opposite side)
Medial lemniscus
(low-threshold
Ambiguus
mechanoreceptors
nucleus
(larynx & pharynx;
opposite side;
voice, swallowing)
discriminative
sensation)
Pyramid
(pyramidal tract; Hypoglossal
voluntary movements, nerve
opposite side)
gure 27.6 Position of cranial nerve nuclei, some other nuclei, and infarction in a case of Wallenbergs syndrome is indicated with a stip-
the main tracts in the medulla. A: Major tracts and typical symptoms pled line. The gure helps identify the symptoms that are likely to occur
produced by their interruption. B: Cranial nerve nuclei. The area of after lesions of lateral or medial parts of the medulla, respectively.
in the floor of the fourth ventricle (the hypoglossal trig- action when acting unilaterally is to draw the tongue
one; see Fig. 6.19). The root fibers of the nerve pass forward and to the opposite side.
ventrally and leave the medulla just lateral to the pyra-
mid (Figs. 27.1, 27.5, and 27.6). Several small fiber
The Ansa Cervicalis
bundles join to form the nerve, which leaves the skull
through the hypoglossal canal in the occipital bone. Some of the motor fibers from the first cervical spinal
The nerve then forms an arc as it courses downward segment join the hypoglossal nerve and follow it for
and forward in the upper neckexternal to the carotid some distance before leaving it and descending in the
arteryto the root of the tongue. The fibers innervate neck. The descending fibers join other motor fibers
the striated muscle cells of the tongue. from the second and third cervical segments and thereaf-
The muscles of the tongue are used voluntarily dur- ter form an arc external to the internal jugular vein, called
ing speech and eating. In such activities, the neurons of the ansa cervicalis (ansa, handle). The fibers of the ansa
the hypoglossal nucleus are influenced by fibers of the cervicalis innervate the infrahyoid muscles and are not
pyramidal tract coming from the face region of the related to the hypoglossal nucleus or the muscles of the
motor cortex of the opposite hemisphere. The descend- tongue. Damage to the hypoglossal nucleus or the proxi-
ing fibers cross in the medulla just above the nucleus. mal part of the nerve (before the fibers from C1 join it)
A central motor lesion above the nucleus (e.g., in the therefore produces no pareses of the infrahyoid muscles.
internal capsule) can produce pareses of the opposite
half of the tongue, together with the more obvious
pareses of the extremities. No clear-cut atrophy of the THE ACCESSORY NERVE
tongue occurs in cases of central motor lesions.
Reflex movements of the tongue occur in swallowing The eleventh cranial nerve, the accessory nerve, brings
(and vomiting). The hypoglossal motoneurons are then somatic efferent fibers to two muscles in the neckthe
activated from the brain stem reflex centers located in sternocleidomastoid and the trapezius. The accessory
the reticular formation. Various kinds of stimuli can nucleus is located in a column in the upper part of the
activate the reflex center for swallowing, notably touch- cervical cord (Fig. 27.2) and contains neurons that are of
and pressure receptors at the back of the tongue. the ordinary motoneuron type. The root fibers leave the
A unilateral lesion of the hypoglossal nerve or nucleus cord and ascend to enter the posterior fossa through
produces paralysis of the tongue on the same side. As the foramen magnum (Fig. 27.8). The nerve then leaves
this is a peripheral paresis, a pronounced atrophy of the the skull through the jugular foramen together with the
tongue muscles ensues. This is witnessed by a wrinkled vagus and the glossopharyngeal nerves. Outside the
surface of the tongue because the mucous membrane skull, the nerve passes internal to the sternocleidomas-
becomes too big for the reduced volume (Fig. 27.7). toid muscle and superficially through the upper part of
When stretching out the tongue, it deviates to the paretic the lateral triangle of the neck before continuing under
side, because of paresis of the genioglossus muscle. This the upper part of the trapezius muscle.
muscle passes backward and laterally into the tongue Some fibers from the nucleus ambiguus join the
from its origin at the inside of the mandible; its normal accessory nerve for a short distance intracranially. These
fibers leave the nerve just outside the jugular foramen
and follow the vagus nerve in their further course. They
should therefore be considered a part of the vagus with
a somewhat aberrant course rather than a part of the
accessory nerve.
In central motor lesions (of the corticobulbar compo-
nent of the pyramidal tract), pareses of the contralat-
eral sternocleidomastoid and the trapezius are usually
observed. Because of its superficial position, the nerve
may be damaged in the lateral triangle of the neck,
producing a peripheral paresis. In such a case only the
trapezius is paretic because the fibers innervating the
sternocleidomastoid leave the nerve higher up. Further,
the upper part of the trapezius muscle is usually most
seriously affected, the lower part being supplied also
from the cervical plexus. Paresis of the trapezius muscle
gure 27.7 Peripheral paralysis of the hypoglossal nerve on the left
side. The tongue deviates to the side of the lesion when the patient
makes it difficult to elevate the arm, because the trape-
tries to stretch it out. Atrophy of the intrinsic muscles of the tongue zius is necessary for the rotation of the shoulder blade
makes the surface wrinkled. around its anteroposterior axis.
THE VAGUS NERVE in the (dorsal) motor nucleus of the vagus (Figs. 27.2
and 27.6; see Fig. 6.17).3 The fibers do not pass directly
The vagus nerve is the tenth cranial nerve and is charac- to the organs but end on a second set of neurons in
terized by containing fibers of all four kinds described parasympathetic ganglia close to or in the walls of the
above. Correspondingly, it is connected with four differ- organs (Fig. 27.9), as is the case for all parasympathetic
ent nuclei in the medulla. The root fibers emerge in a nerves. The neurons leading from the CNS to the gan-
row at the lateral aspect of the medulla (Figs. 27.1 and glia are called preganglionic, and those leading from
27.3) and join to form one nerve, which leaves the skull the ganglion to the organ are called postganglionic (see
through the jugular foramen (Fig. 27.8). Embryologically, Fig. 28.1).
the vagus nerve belongs to the fourth, fifth, and sixth The vagus gives off visceral efferent fibers descending
branchial arches, and this explains the peculiar course of to the heart in the neck (Fig. 27.9). The cell bodies
some of its branches. In the jugular foramen and imme- of the postganglionic neurons are located in the wall of
diately below, the nerve has two swellingsthe jugular the heart and around the great vessels near the heart,
and the nodose ganglia (Fig. 27.9)that contain the and the postganglionic fibers end among the muscle
pseudounipolar cell bodies of the sensory vagus fibers. cells of the heart, especially those of the sinus node,
As implied by the name (Latin: vagus, wandering), the which determines the heart rate.
vagus nerve sends branches to widespread regions of the Other branches from the vagus supply the esophagus
body. After leaving the skull, the nerve passes as a fairly and the trachea and, further down in the thorax, the
thick cord downward in the neck together with the com- bronchi of the lung. The postganglionic fibers innervate
mon carotid artery, further through the thorax, and into smooth muscles and glands in these structures.
the abdomen through the diaphragm. It gives off branches
in the neck, in the thorax, and in the abdomen.
3 Experiments with tracing techniques show that the neurons supplying the
heart (and probably also the lungs) have their cell bodies in an external, distinct
Visceral Efferent (Parasympathetic) Vagus Fibers part of the nucleus ambiguus. The cell bodies are morphologically like those of
the dorsal motor vagus nucleus, but they differ from the larger motoneurons in
The visceral efferent neurons belong to the parasympa- the main nucleus ambiguus, which innervate striated muscles (of the pharynx
thetic part of the autonomic system. The cell bodies lie and larynx).
Cerebellar peduncles
Facial & cestibulo-

cochlear nerves
Internal acoustic
meatus
Vagus and glosso-
pharyngeal nerves
Jugular foramen
Medulla
Accessory nerve
Foramen magnum
Vertebral artery
Second cervical nerve

(dorsal root)
gure 27.8 The accessory nerve. The lower

part of the brain stem and the upper cervical
cord, as viewed from behind. The cerebellum
is removed. The bers of the accessory nerve
proper emerge from the three upper cervical seg-
ments and exit the cord between the ventral and
dorsal roots (the ventral roots are not visible in
the gure). Compare with the emergence of the
vagus bers in Fig. 27.1.
Jugular foramen Visceral Afferent Vagus Fibers

All branches of the vagus with visceral efferent fibers
Jugular ganglion also contain afferent (sensory) fibers. These neurons
Nodose ganglion have their pseudounipolar cell bodies in the large
nodose ganglion (Fig. 27.9). When the fibers enter the
Superior laryngeal brain stem, they form a small bundle that passes cau-
nerve
dally: the solitary tract (this is not a true tract, however,
Right vagus
nerve but the central course of a nerve). The fibers establish
synapses in the solitary nucleus (Figs. 27.2 and 27.6;
see Fig. 6.17). The efferent fibers from this nucleus pass
to the reticular formation and other cranial nerve nuclei
in the vicinity and to higher levels such as the thalamus
Larynx and the hypothalamus (Fig. 27.4).
All of the sensory fibers from the larynx and some
Trachea
from the pharynx follow the vagus. The sensory fibers
Esophagus from the larynx follow the superior laryngeal nerve
Recurrent (from the part above the vocal cords) and the recurrent
laryngeal nerve
Lung laryngeal nerve (from the lower part of the larynx). On
Aorta
an embryological basis, all sensory fibers from the phar-
ynx (and the posterior part of the tongue) should be clas-
Heart
sified as visceral afferent. There is evidence, however,
that such fibers end in the somatic afferent trigeminal
nucleus and not in the visceral afferent solitary nucleus.
Left vagus Functionally, they may therefore be considered somatic
nerve
afferent rather than visceral afferent. Vagus may also
Liver carry nociceptive signals from parts of the heart (see
Stomach Chapter 29, under Central Pathways for Visceral
Afferent Signals).
Visceral afferent signals in the vagus nerve most likely
Pancreas contribute to conscious feelings like hunger or satiety.
Gall bladder
There is also evidence that signals in the vagus nerve
Large
intestine contribute to the feelings associated with infections (loss
of appetite, tiredness, somnolence, and so forth) and the
induction of sickness behavior. Together with other vis-
Small intestine
ceral afferent fibers, the vagus contributes to our general
bodily feelingalso called the sense of the physiological
condition of the body (Craig 2002). This is discussed
further in Chapter 30, under The Hypothalamus and
the Immune System.
gure 27.9 Course and distribution of the vagus nerve.
Visceral Reexes
The visceral afferents in the vagus nerve are links in
In the abdomen, the vagus sends fibers to the stomach, reflex arcs that control secretion and peristaltic move-
the small intestine, and the first half of the large intes- ments of the gastrointestinal tract (and vomiting). Such
tine. The vagus also supplies the liver, the gallbladder, reflexes also mediate alterations of airway secretion
and the pancreas with parasympathetic fibers. To reach and of the airway resistance by changing the tone of the
the various organs, the fibers follow the arteries and bronchial smooth muscles. The reflex centers of all
form plexuses around them together with sympathetic these reflexes are located in the medulla, and the effer-
fibers. ent links are visceral efferent fibers coming from the
Functionally, signals in the vagus nerve reduce the dorsal motor nucleus of the vagus.
heart rate, constrict the bronchi, and increase bronchial Visceral afferents from baroreceptors in the wall of the
secretion, whereas the peristaltic movements and secre- large vessels provide information about the blood pres-
tion are increased in the stomach and intestine. The sure in the aorta. Increased blood pressure gives rise to
secretion of the pancreas is also increased. increased firing frequency of the afferent fibers. In turn,
this produces increased firing of visceral efferent vagus special somatic efferent nuclei. The fibers supply all
fibers, which reduces the heart rate. The reflex center must striated muscles of the larynx and parts of the muscles
involve connections from the solitary nucleus to the motor of the pharynx. The fibers to the pharynx take off from
nucleus of the vagus (these two nuclei are close neighbors, the vagus as several small branches, whereas most of
as can be seen in Fig. 27.2). the fibers to the larynx are collected in the recurrent
The motor nucleus of the vagus can be influenced also laryngeal nerve (Fig. 27.9). This nerve takes off from
by signals other than those coming from the viscera. For the main vagus trunk at the level of the aortic arch
example, the sight, the smell, or even the thought of on the left side and the subclavian artery on the right. It
food can produce increased secretion of gastric juice. then arches behind the vessels and ascends in the fur-
These are examples of conditioned responses, whereas row between the trachea and the esophagus, to reach
the stimulation of taste receptors produces an uncondi- the larynx. One of the laryngeal muscles located on the
tioned (true reflex) response. outside, the cricothyroid muscle, receives motor fibers
Other examples of visceral reflexes are discussed in in the superior laryngeal nerve (which is a predomi-
Chapter 29, under Visceral Reflexes. nantly sensory nerve, as mentioned earlier). The vagus
also innervates one of the muscles of the soft palate, the
levator veli palatini muscle.
The Vomiting Reex
A lesion of the vagus nerve above the exit of the
Vomiting is usually caused by marked dilatation of the motor branches to the pharynx and the soft palate pro-
stomach or irritation of its mucosa. The biologic signifi- duces deviation of the uvula and the posterior pharyn-
cance of the reflex is presumably to rid the stomach of geal wall to the normal side (as can be seen, e.g., when
potentially harmful contents. As we all know, however, a patient is asked to say aah; Fig. 27.10). Pareses of
vomiting can also be provoked by irritation of the phar- the soft palate and the pharynx cause fluid and food to
ynx (putting a finger in the throat) and by foul odors, enter the nasal cavity when swallowing (owing to inad-
strong emotions, and travel sickness. Several different equate closure of the nasopharynx). Further, the voice
afferent links to the reflex center must therefore exist. becomes hoarse because the vocal cords cannot be
The emptying of the stomach is caused by coordinated properly adducted. Such a symptom will obviously also
contractions of the smooth muscles in the stomach wall occur after a lesion of the recurrent laryngeal nerve
and striated muscles in the diaphragm and the abdomi- anywhere along its course. In case of a unilateral lesion,
nal wall. In addition, laryngeal muscles (closing the air- the voice hoarseness will gradually disappear, because
ways) and muscles of the pharynx, the soft palate, and the muscles of the normal side adapt to the changed
the tongue also participate. Thus, the reflex center must conditions.
activate visceral efferent neurons and motoneurons at The neurons of the nucleus ambiguus are influenced
several levels of the brain stem and the spinal cord in a by, among other sources, the pyramidal tract during
specific sequence. The reflex center is actually quite speech. They can also be activated involuntarily in the
widespread, but usually matters are simplified by restrict- cough reflex by irritating stimuli of the respiratory tract.
ing it to the medulla, including the solitary nucleus. This
receives the visceral afferent fibers from the stomach,
Somatic Afferent Vagus Fibers
forming the afferent link when the reflex is elicited from
the stomach itself. From the reflex center in the medulla, This is the smallest contingent of fibers in the vagus
signals pass to the motor nuclei via synaptic interrup- nerve. They have their cell bodies in the small jugular
tion in the reticular formation and reticulospinal fibers.
In addition, there are direct spinal projections from the Uvula
solitary nucleus to the motoneurons of the diaphragm
and abdominal wall.
Substances in the bloodstream cause vomiting by
direct action at the area postrema of the medulla (see
Chapter 8, under Some Parts of the Brain Lack a
BloodBrain Barrier). Neurons in the area postrema
project to the solitary nucleus. Apomorphine and other Posterior Tongue
alkaloids are given orally or subcutaneously to provoke pharyngeal wall
vomiting.
NORMAL RIGHT VAGUS
PARALYSIS
Somatic Efferent Vagus Fibers
gure 27.10 Paralysis of the right vagus nerve. The uvula and the
The somatic efferent vagus fibers come from the ambig- posterior pharyngeal wall are pulled toward the normal side when the
uus nucleus (Figs. 27.2 and 27.5), which belongs to the patient says aah. (Redrawn from Mumenthaler 1979.)
ganglion and come from a small region of the skin of the The Sinus Nerve and Baroreceptors
external earthe auricular ramus (Fig. 27.9). The fibers
A special contingent of visceral afferent fibers in the
terminate in the trigeminal sensory nucleus. Touching
glossopharyngeal nerve comes from the wall of the
the innervated area, for example, by an otoscope in the
carotid sinus (the thin-walled, dilated part of the inter-
external meatus may evoke a cough reflex and in some
nal carotid artery). The fibers conduct signals from
individuals even a vomiting reflex. The causes of these
mechanoreceptors recording the tension of the arterial
phenomena are unknown. They might be due to connec-
wall; that is, the receptors monitor the blood pressure
tions from the trigeminal nucleus to the solitary nucleus
and are therefore called baroreceptors (cf. the same
or by abnormal signal transmission between sensory
kind of afferents from the aorta running with the vagus
fibers of the vagus nerve (ephaptic transmission).
nerve). The afferent fibers end in the solitary nucleus,
and from there the signals are conveyed to the motor
nucleus of the vagus. Increased signal frequency of the
THE GLOSSOPHARYNGEAL NERVE
cardiac vagus fibers reduces the heart rate, and thereby
the blood pressure is reduced. When the blood pressure
The ninth cranial nerve, the glossopharyngeal, resem-
falls, there will be reduced firing of the cardiac vagus
bles the vagus but is smaller and innervates a more
fibers, with increased heart rate and blood pressure.
restricted region. The root fibers leave the medulla
This is one of several mechanisms to keep the blood
immediately rostral to the vagus fibers (Fig. 27.1). The
pressure within certain limits and that the cerebral blood
root fibers fuse to form one trunk that leaves the cranial
flow is sufficient at all times.
cavity through the jugular foramen (together with the
vagus and the accessory nerves). The nerve follows an
arched course (ventrally) lateral to the pharynx, which The Nuclei of the Glossopharyngeal Nerve
it penetrates to reach the base of the tongue. Close to
The somatic efferent fibers to the striated pharynx
the jugular foramen, the nerve contains two small sen-
muscles come from the ambiguus nucleus, whereas the
sory ganglia with pseudounipolar ganglion cells, the
visceral efferent fibers have their cell bodies in the small
superior and petrous ganglia.
inferior salivatory nucleus (Fig. 27.2). The signals from
Of the peripheral branches, some innervate the mus-
this nucleus follow a somewhat complicated course to
cles and the mucous membrane of the pharynx (together
reach the parotid gland (as is the case for several of
with the vagus, which appears to be the most important
the parasympathetic fiber components of the cranial
quantitatively); other sensory fibers reach the posterior
nerves). The preganglionic parasympathetic fibers from
part of the tongue, to innervate taste buds, and the
the inferior salivatory nucleus end in the small otic gan-
mucous membrane (and also the mucous membrane of
glion just outside the cranial cavity. The postganglionic
the soft palate and the tonsillar region). The glossopha-
fibers from the ganglion cells join one of the trigeminal
ryngeal nerve also contains visceral efferent (parasym-
branchesthe auriculotemporal nerve that passes close
pathetic) fibers to the parotid gland and to the salivary
to the ganglionto reach gland (see Fig. 28.11).
glands in the posterior part of the tongue (see Fig. 28.11
The visceral afferent fibers carrying signals from the
for the course of the parasympathetic fibers).
taste buds in the posterior third of the tongue end in the
solitary nucleus. From there, the signals pass to the thal-
Abducens nucleus Genu of amus and further on to the cerebral cortex. The sensory
facial nerve fibers from the posterior part of the tongue, the tonsils,
the soft palate, and the pharynx end in the sensory
Facial nucleus
trigeminal nucleus.
THE VESTIBULOCOCHLEAR NERVE
The eighth cranial nerve, although consisting of only

one trunk, is in reality two functionally different nerves:
PONS
the cochlear nerve (see Chapter 17) and the vestibular
Facial nerve
nerve (described with the sense of equilibrium in
Chapter 18). The nerves fuse after leaving the labyrinth
(the cochlea and the vestibular apparatus) and follow
Abducens nerve
the internal acoustic meatus. At the lower end of the
gure 27.11 Course of the facial nerve and its relation to the pons, in the cerebellopontine angle, the nerve enters the
abducens nucleus. Schematic cross section through the lower pons. brain stem. Most of the fibers in the vestibular nerve
end in the vestibular nuclei; some end in the cerebellum. small elevation; the facial colliculus (see Fig. 6.19).
The cochlear nerve ends in the cochlear nuclei (Fig. 27.2). Owing to the course of the nerve, symptoms of a periph-
The cell bodies of the primary afferent fibers are located eral facial paresis may occur in lesions that are located
at the bottom of the internal meatus, forming the ves- considerably more medial and dorsal than the nucleus
tibular ganglion and the spiral ganglion. The main itself. Figure 27.11 shows that damage to the abducens
structural features of the labyrinth are described in nucleus (affecting the lateral rectus muscle of the eye) is
Chapters 17 and 18. also likely to be accompanied by signs of pareses of the
facial muscles of the same side.
THE FACIAL AND INTERMEDIATE NERVES

The Mimetic Muscles
The seventh cranial nerve belongs to the second bran- The facial or mimetic muscles originate from the facial
chial (visceral) arch and innervates structures developed skeleton and insert with elastic tendons in the dermis.
from this. The facial nerve is the motor nerve of the facial There are many small muscles, with the majority located
(mimetic) muscles, supplying them with special somatic around the mouth and the eyes. Of particular practical
efferent fibers. The small intermediate nerve follows the value are the muscles responsible for blinking and
facial nerve and is usually considered to belong to it. closure of the eye (the orbicularis oculi muscle) and the
Thus, parts of the intermediate nerve might be regarded muscles around the mouth (the orbicularis oris and sev-
as a sensory root of the facial nerve with its visceral affer- eral other muscles that move the lips). The buccinator
ent fibers. The intermediate nerve also contains visceral muscle prevents the cheeks from being pressed out
efferent (parasympathetic) fibers, however. when the intraoral pressure is increased and, perhaps
The facial nerve and the intermediate nerve leave the more importantly, prevents the cheeks from being
brain stem together laterally at the lower border of the sucked in between the teeth.
pons, just ventral to the eighth nerve (Fig. 27.1). They
then follow the eighth nerve to the bottom of the inter-
Central and Peripheral Facial Pareses
nal auditory meatus, where the intermediate nerve
leaves the facial nerve. The facial nerve proper (with the Signals from the facial nucleus evoke contractions of
somatic efferent fibers) then arches first posterolaterally the mimetic muscles and are therefore responsible for
and thereafter downward in the facial canal. It leaves our facial expressions. These muscles function also in
the skull through the stylomastoid foramen immedi- conjunction with speech, eating, blinking, and so forth.
ately medial and anterior to the mastoid process. The The pyramidal tract (corticobulbar fibers) conveys
nerve then passes forward through the parotid gland signals for voluntary movements of the facial muscles.
and divides into several branches, spreading out like a The fibers arise from the face region of the MI in the
fan to all the facial muscles. precentral gyrus (see Fig. 22.5).
The visceral efferent (parasympathetic preganglionic) The part of the facial nucleus supplying the muscles
fibers in the intermediate nerve bring secretory signals in the forehead and around the eyes receive both
to the lacrimal gland and the submandibular and the uncrossed and crossed pyramidal tract fibers, whereas the
sublingual salivary glands (see Fig. 28.11 for the com- muscles in the lower part of the face receive purely crossed
plicated route followed by the fibers). The visceral fibers. A lesion of the pyramidal tract (e.g., in the internal
afferent fibers of the intermediate nerve come from capsule) therefore produces clear-cut pareses only in the
taste buds in the anterior two-thirds of the tongue. lower part of the face on the opposite side. Most obvious
is the sagging corner of the mouth. The patient can still
wrinkle the forehead and close the eyes voluntarily. A
The Facial Nerve
peripheral lesion (of the facial nucleus or the nerve), how-
The motor fibers of the facial nerve have their cell bod- ever, produces pareses of all the facial muscles on the
ies in the facial nucleus, located in the lower pons. It same side as the lesion (Fig. 27.12). For example, the eye
belongs to the column of special somatic efferent nuclei cannot be closed, so there is danger of drying and ulcer-
(Figs. 27.2 and 27.3). The nucleus consists of several ation of the cornea (and permanent loss of vision).
subdivisions, each supplying small groups of muscles. Peripheral lesions of the facial nerve may be caused
The root fibers of the facial nerve have a peculiar course by hemorrhage, infarctions, or tumors in the pons, by
before they leave the brain stem (Fig. 27.11). First, the infections of the middle ear (to which the nerve passes
fibers pass medially and lie dorsal to the abducens nucleus, in close proximity), or by damage to the branches in the
forming the genu of the facial nerve, before they bend in face. Most often, however, the cause of peripheral facial
the lateral and ventral direction. The facial fibers pass paresis is unknown (Bells palsy). In such cases, the
just beneath the floor of the fourth ventricle and form a muscle power usually returns after some time.
spinal trigeminal nucleus (Fig. 27.13). From there the
signals pass via interneurons in the reticular formation
to the facial nucleus of both sides, and a contraction of
the muscles of the eyelid is produced. The corneal reflex
can be weakened or abolished by a lesion anywhere
along the course of the afferent and efferent links or in
the rather extensive reflex center.
Another reflex mediated by the facial nerve is the sta-
pedius reflex, in which the response is contraction of the
tiny stapedius muscle in the middle ear. The stimulus is
an intense sound conducted centrally in the cochlear
(acoustic) nerve to the cochlear nuclei. Most likely,
interneurons in the reticular formation transfer the sig-
nals to the facial nucleus. The stapedius muscle pulls the
stapes a little out of the oval window (see Fig. 17.7) and
thereby dampens the transmission of sound waves to
the cochlear duct. Accordingly, peripheral facial paresis
can produce hypersensitivity to sounds, or hyperacusis.
gure 27.12 Peripheral facial paralysis (right side). The patient is Secretion of Tears and Saliva
asked to close her eyes and to retract the corners of the mouth. (Based
on Monrad-Krohn 1954.) The preganglionic parasympathetic fibers of the interme-
diate nerveacting on the lacrimal, the submandibular,
and the sublingual glandshave their cell bodies in the
Facial Expressions of Emotion Do Not Depend on the
small superior salivatory nucleus. This nucleus belongs
Pyramidal Tract
to the column of visceral efferent nuclei (Fig. 27.2). As
Whereas signals mediated by the pyramidal tract acti- mentioned, preganglionic parasympathetic fibers acting
vate the motoneurons of the facial nucleus in voluntary on the parotid gland have their cell bodies in the infe-
movements (such as speech and eating), other descend- rior salivatory nucleus and leave the brain stem in the
ing pathways are responsible for facial expressions of glossopharyngeal nerve.
emotions, such as sorrow and pleasure. As most of us The secretion of saliva is brought about primarily by
know from personal experience, a genuine smile cannot stimulation of the taste receptors but also by signals
be produced on command but arises independent of any from higher levels of the brain (such as the thought of
conscious will. Indeed, our facial expressions often reveal tasty food; it is especially effective to imagine that one
emotions we would rather have concealed. A voluntary
effort is required to suppress spontaneous facial expres-
sions, which most likely are controlled by descending Mesencephalic
connections from the hypothalamus and possibly the trigeminal nucleus
basal ganglia. Thus, lesions of the pyramidal tract do Motor trigeminal
not abolish spontaneous facial expressions. The patient Ophthalmic nerve (1) nucleus
smiles and laughs when told a good joke but cannot Principal trigeminal
Maxillary nucleus
present a polite social smile. In central pareses (such as nerve (2)
capsular hemiplegia) emotional facial expressions are in
fact often exaggerated, and the patient cannot suppress
a smile or prevent crying. Diseases of the basal ganglia, Mandibular
such as Parkinsons disease, present the opposite picture: nerve (3) Semilunar Spinal trigeminal
the emotional, spontaneous expressions are lacking, ganglion nucleus
whereas a voluntary, social smile is possible.
1
2
3
The Facial Nerve and Reexes
The facial nucleus is also a link in some important reflex
arcs. One is the corneal or blink reflex. It is elicited by gure 27.13 The trigeminal nuclei. In addition, the gure shows the
touch or irritation of the cornea, and the sensory signals topographic arrangement in the spinal trigeminal nucleus of the bers
are conducted centrally in the trigeminal nerve to the from the three main trigeminal branches.
is eating a lemon). Strong emotions, for example, anxi- it contains a small portion with special somatic efferent
ety before a performance, can inhibit the secretion of fibers to the masticatory muscles. The trigeminal nerve
saliva, as experienced by mouth dryness. is the nerve of the first branchial (visceral) arch and
The secretion of tears, even more than the salivary innervates structures that are developed from this arch.
secretion, is an example of how visceral functions can The nerve leaves the brain stem laterally on the pons
be influenced from higher levels of the brain. The con- (Fig. 27.1) with a small (medial) motor root and a large
tinuous secretion of tears is of course primarily a physi- (lateral) sensory root. Shortly after leaving the pons, the
ological protection of the eyes and increases in response nerve expands to form the large semilunar ganglion,
to any irritation of the cornea or the conjunctiva; nev- which contains the cell bodies of the pseudounipolar
ertheless, the most profuse tear production occurs when (sensory) ganglion cells. Three large branches continue
we express strong emotions by crying. The signals to anteriorly from the ganglion: the ophthalmic, the max-
the superior salivatory nucleus producing the flow of illary, and the mandibular nerves (Fig. 27.13).
tears when crying are not mediated by the pyramidal The ophthalmic nerve enters the orbit and supplies
tract or other efferent cortical fibers descending in the the eye bulb (including the cornea), the upper eyelid,
internal capsule, in correspondence with the fact that the back of the nose, and the skin of the forehead
tears cannot be produced voluntarily nor can the secre- with sensory fibers (Fig. 27.14). It also sends fibers to
tion of tears be suppressed. Most likely, fibers from the the mucous membranes of the anterior part of the
hypothalamus are responsible for the activation of the nasal cavity. The maxillary nerve runs forward in a
visceral efferent neurons during crying. Nevertheless, sulcus in the bottom of the orbit and sends fibers to
the hypothalamus is under the influence of higher lev- the lower eyelid, the skin above the mouth, the upper
els, such as parts of the cerebral cortex and the limbic teeth and the gingiva, and, finally, the hard palate
structures. Thus, the conscious experience of the emo- and the posterior (major) part of the nasal cavity.
tions (such as sorrow or pity) starts the train of neural The mandibular nerve innervates the lower teeth and
events leading to tear secretion. gingiva, the tongue, and the skin of the lower jaw and
upward, well into the temporal region (Fig. 27.14).
The branch of the mandibular nerve supplying the
The Intermediate Nerve
tongue with somatic sensory afferent fibers is called
The small geniculate ganglion, containing the cell bod- the lingual nerve. This nerve receives visceral afferent
ies of the sensory fibers of the intermediate nerve, is (taste) fibers from the chorda tympani, destined for
found where the facial nerve bends posteriorly in the the anterior two-thirds of the tongue.
temporal bone. Here a branch of the intermediate nerve, The motor fibers of the trigeminal nerve follow the
the greater petrosal nerve, leaves the main trunk of the mandibular nerve but leave this in several smaller twigs
facial nerve to course anteriorly. It contains visceral
efferent (parasympathetic) fibers that end in the small
parasympathetic pterygopalatine ganglion located
behind the orbit. From there postganglionic fibers fol-
low trigeminal branches to the lacrimal gland and glands
in the nasal cavity (see Fig. 28.11). The rest of the inter-
mediate nerve fibers leave the facial nerve as it passes
downward posterior to the middle ear. This branch is Supraor-
C2
bital nerve
bital ner
erve
ve
e
called the chorda tympani because it passes through the OPHTHALMIC
ALMIC
NERVE
middle ear (tympanic cavity) on its way forward to join Auriculo-
Auu
te
temporal
the lingual nerve (a trigeminal branch) outside the skull. ne
nerve
The chorda tympani contains visceral afferent fibers
from taste buds in the anterior two-thirds of the tongue.
In
nfrao
orbital
Infraorbital
These fibers have their cell bodies in the geniculate gan- nerve
nervee
glion. In addition, the chorda tympani carries visceral
MAXILLARY
efferent (parasympathetic) fibers that end in the small NERVE C2, C3
submandibular ganglion. From this ganglion, postgan-
glionic parasympathetic fibers pass to the submandibu-
lar and the sublingual (salivary) glands. C4
MANDIBULAR C5
NERVE
THE TRIGEMINAL NERVE
gure 27.14 Distribution in the facial skin of the three main trigem-
inal branches. The names of some further branches and the segmental
The fifth cranial nerve is primarily the sensory nerve of origins of sensory bers to the rest of the head and the neck are
the face, with mainly somatic afferent fibers. In addition, indicated.
to the masticatory muscles (and some other muscles signals are transmitted to the face region of the SI in the
with relation to the lower jaw and the soft palate). postcentral gyrus.
The Sensory Trigeminal Nucleus More about the Subdivisions of the Sensory
Trigeminal Nucleus
With regard to function and fiber composition, the sensory
part of the trigeminal nerve corresponds to the spinal dor- The thinnest fibers of the trigeminal nerve (A and C
sal roots. The trigeminal nerve, therefore, belongs to the fibers)conducting primarily from nociceptors and ther-
somatosensory system and conducts signals from low- moreceptorsbend caudally after entering the pons
threshold mechanoreceptors, thermoreceptors, and noci- (Fig. 27.13). They continue as a small bundle, the spinal
ceptors in the face and in the mucous membranes of the tract of the trigeminal nerve, located just beneath the
face. As with other spinal nerves, fibers leading from dif- medullary surface. It is joined by somatic afferent fibers
ferent kinds of receptors are intermingled in the nerve but that have followed the glossopharyngeal and the vagus
are arranged by receptor type when entering the CNS. nerves peripherally. Just like the solitary tract, the spinal
Then the fibers distribute to the three subdivisions of the tract, strictly speaking, is not a tract, as it consists of the
long sensory trigeminal nucleus (Figs. 27.2 and 27.13). central process of the pseudounipolar ganglion cells. The
Fibers from proprioceptors (muscle spindles, joint recep- spinal tract continues down into the upper cervical seg-
tors) end in the mesencephalic nucleus, fibers from low- ments and corresponds to the zona terminalis (bundle of
threshold mechanoreceptors end in the main or principal Lissauer) in the cord (see Fig. 13.16). The fibers enter the
nucleus, whereas signals from nociceptors end in the spinal trigeminal nucleus (nucleus of the spinal trigeminal
4
spinal trigeminal nucleus. tract), which corresponds largely to the dorsalmost lami-
nae of the cord. For example, a layer very similar to the
substantia gelatinosa is present. The spinal trigeminal
Central Transmission of Signals from the
nucleus can be further subdivided in a rostrocaudal
Trigeminal Nucleus
sequence. The caudal subnucleus appears to be especially
Functionally, the spinal trigeminal nucleus (especially involved in pain mechanisms and corresponds most
its caudal part) corresponds to the dorsalmost laminae closely with the dorsal laminas of the cord. It also receives
of the cord, whereas the principal sensory nucleus cor- dorsal root fibers from the upper cervical segments. This
responds to the dorsal column nuclei. These similarities may perhaps explain why a certain condition with parox-
are evident also in the central pathways. The secondary ysms of facial pain of unknown origintrigeminal neural-
sensory fibers from the cells in the spinal nucleus join giamay sometimes irradiate outside the area innervated
the spinothalamic tract (see Fig. 14.4) and end in the by the trigeminal nerve. The spinal trigeminal nucleus fur-
thalamus. Fibers from the main nucleus join the medial thermore shows a dorsoventral topographic localization.
lemniscus (see Fig. 14.2). The somatotopic pattern Thus the main trigeminal branches end sequentially, with
within the thalamic terminal region is such that the the ophthalmic nerve ending most ventrally and the man-
fibers from the trigeminal nucleuscarrying signals dibular nerve most dorsally (Fig. 27.13).
from the faceend most medially, in the VPM (see Thick myelinated fibers (A) in the trigeminal nerve
Fig. 14.6). The ascending fibers from the trigeminal from the skin end mostly in the principal sensory
nucleus cross to the opposite side before they join the trigeminal nucleus (Fig. 27.13) with a precise somato-
large sensory tracts. As discussed (under Brain Stem topic pattern.
Lesions Can Produce Symptoms from Several Cranial The mesencephalic trigeminal nucleus stretches as a
Nerves and Long Tracts), a lesion affecting lateral slender column from the upper part of the pons and into
parts of the medulla is likely to interrupt the spinotha- the mesencephalon. This is a very unusual nucleus, as its
lamic tract and the spinal trigeminal nucleus. This will neurons look like pseudounipolar ganglion cells and,
usually cause reduced or abolished pain and tempera- indeed, send one process peripherally into the trigemi-
ture sensation in the opposite body half but on the same nal nerve. Afferent fibers from the muscle spindles of
side of the face (Fig. 27.6).5 From the thalamus, the the masticatory muscles follow the mandibular nerve,
whereas those from the extraocular muscles follow the
ophthalmic and perhaps the oculomotor nerve. Signals
from mechanoreceptors in the root sheaths of the teeth
4 The separation of bers of different types is not quite as sharp as this account end in the mesencephalic nucleus.
may indicate. Many trigeminal bers divide after entering the brain stem into
an ascending and a descending branch (just like the sensory bers entering the
cord). In this manner, single ganglion cells may end in more than one nuclear Reexes Involving the Trigeminal Nerve
subdivision.
5 If the lesion is situated high in the medulla or in the lower pons the ascending Like the spinal dorsal root fibers, the trigeminal nerve
(secondary sensory) bers from the spinal trigeminal nucleus have crossed and
joined the spinothalamic tract. In such cases, loss of pain and temperature sen-
constitutes the afferent link of several reflex arcs. The
sation in the face occurs on the opposite side of the lesion. trigeminal nucleus, especially the spinal subdivision,
has numerous connections with the reticular formation. Voluntary movements of the jaws during speech and
This is partly by means of reflex arcs involving the chewing depend on the pyramidal tract (corticobulbar
trigeminal nerve as the afferent link but also as links in fibers). The fibers from the MI to the motor trigeminal
ascending pathways to the thalamus with signals from nucleus are often both crossed and uncrossed (bilat-
nociceptors. eral), but in some persons, they appear to be purely
We described the corneal reflex earlier, in conjunc- crossed. Only in the latter case, will there be clear-cut
tion with the facial nerve that constitutes the efferent signs of pareses of the masticatory muscles after a lesion
link of this reflex. Other reflexes are the sneeze reflex, of the internal capsule (capsular hemiplegia). There
elicited from the mucous membrane of the nasal cavity, may also be other signs of a central paresis, such as an
and the sucking reflex, elicited in the newborn from increased masseter reflex on the paretic side.
mechanoreceptors of the lips. A brief tap downward on Reflex movements of the masticatory muscles occur
the chin can produce a stretch reflex, stretching the mas- during swallowing, sucking, and vomiting. The afferent
ticatory muscles (among them, the masseter muscle). fibers of such reflexes are sensory trigeminal fibers from
This masseter reflex is monosynaptic and involves the the oral cavity and sensory fibers passing in the vagus
mesencephalic trigeminal nucleus. The peripheral pro- and the glossopharyngeal nerves.
cesses of the neurons of this nucleus innervate the mus-
cle spindles, and the central processes reach the motor
Lateral Pontine Infarction
trigeminal nucleus in the pons. This reflex, with its
reflex center in the mesencephalon and pons, is one of Infarction in the lateral part of the pons is usually due
those routinely tested in clinical neurology. to occlusion of the anterior inferior cerebellar artery,
which leaves the basilar artery in the lower third of the
pons (see Fig. 8.3). Besides the pons, the artery often
The Motor Trigeminal Nucleus
supplies the brachium pontis, the flocculus, and middle
The special somatic efferent fibers in the trigeminal parts of the cerebellar hemispheres. The most common
nerve come from the motor trigeminal nucleus, located symptoms are due to damage of the root fibers and the
in the pons at the level of the main sensory nucleus nuclei of the trigeminal, the facial, and the vestibuloco-
(Fig. 27.13, see also Fig. 27.2). All of the motor fibers chlear nerves (Fig. 27.1). Cerebellar symptoms and
follow the mandibular nerve. A peripheral paresis of the symptoms due to damage to the long ascending and
motor fibers of the trigeminal nerve (or the nucleus) descending tracts are more variable, presumably due to
leads to atrophy of the masticatory muscles and reduced individual variations in the area supplied by the artery.
force of biting on the side of the lesion. A unilateral pare- A lateral pontine infarction will usually produce ipsilat-
sis of the masticatory muscles is most easily detected by eral peripheral facial paresis (the root fibers leave later-
asking the patient to open his mouth widely; the lower ally in the lower pons), ipsilateral sensory loss in the
jaw then deviates toward the side of the paretic muscles face (all sensory qualities due to interruption of trigemi-
(Fig. 27.15). This is caused by paresis of the lateral ptery- nal root fibers), deafness and dizziness (the vestibuloco-
goid muscle, which normally pulls the mandible forward chlear nerve, vestibular nuclei), and in some gaze paralysis
in conjunction with opening of the mouth. to the side (ascending connections from the vestibular
nuclei; see Fig. 25.6). In addition, there is usually
ipsilateral ataxia (the cerebellar hemispheres) and occa-
sionally contralateral central pareses and an inverted
plantar reflex (pyramidal tract) or contralateral reduced
pain and temperature sensibility (the spinothalamic
tract). Horners syndrome is often present as well (see
Chapter 28, under Interruption of the Sympathetic
Innervation of the Head).
THE ABDUCENS, TROCHLEAR, AND

OCULOMOTOR NERVES
These three cranial nervesthe sixth, fourth, and

thirdsupply the extraocular muscles with somatic
gure 27.15 Deviation of the jaw as a sign of peripheral trigeminal efferent fibers (Fig. 27.16). In addition, the oculomotor
pareses. Paresis of the right trigeminal nerve. Normally, the two lat-
eral pterygoid muscles pull the jaw forward when opening the mouth.
nerve contains visceral efferent (parasympathetic) fibers
When unopposed by the paretic right pterygoid, the left (normal one) to the smooth, intrinsic eye muscles. Simplified, we may
moves the jaw to the right when the patient opens her mouth. say that by moving the eye in the orbit, the extraocular
muscles ensure that the images we look at fall on the The Abducens Nerve
central part of the retina (the macula). The intrinsic
The abducens nerve leaves the brain stem close to the
muscles control the amount of light that reaches the
midline at the junction of the medulla and the pons
retina and adjust the curvature of the lens so that the
(Fig. 27.1; see Fig. 6.15). Figure 27.11 shows the loca-
retinal image is always in focus. Most of these tasks are
tion of the abducens nucleus and its relation to the
performed reflexly, and usually eye position, light access,
facial nerve. The abducens nerve runs forward intracra-
and lens curvature are controlled simultaneously. In
nially and passes through the cavernous sinus before
Chapter 25, we discussed the extraocular muscles and
entering the orbit through the superior orbital fissure
the control of eye movements.
(Fig. 27.16). It supplies only one muscle, the lateral
Typical symptoms resulting from lesions of the extraoc-
rectus. The muscle pulls the eye so the cornea faces
ular muscles or their nerves are strabismus (squint),
laterally (abducts the eye; see Fig. 25.2). Even though
double vision, and dizziness (probably due to double
other muscles can abduct the eye somewhat (the supe-
vision). In addition, the patient usually keeps his head a
rior and the inferior oblique muscles), the lateral rectus
little bent or turned in order to reduce the double vision
is necessary for more than a slight lateral movement
(that is, trying to keep a position in which the paretic
(Fig. 27.17). A person with a unilateral lesion of the
muscle(s) is used as little as possible). Figure 25.3 shows
abducens nerve usually keeps the head turned some-
a simple scheme for examination of the six extraocular
what to the side of the lesion to compensate for the loss
muscles.
of lateral motion of the eye.
The Trochlear Nerve

Superior oblique This is the only one of the cranial nerves to leave the
muscle brain stem on the dorsal side ( just below the inferior col-
6
liculus) (Fig. 27.1; see Fig. 6.19). The trochlear nucleus
lies a little ventrally to the aqueduct in the mesencepha-
lon (Fig. 27.2). Like the abducens nerve, the trochlear
traverses the cavernous sinus and enters the orbit through
the superior orbital fissure. It innervates the superior
oblique muscle (Fig. 27.16; see Fig. 25.1), which directs
the gaze downward and laterally (see Fig. 25.2).
Medial
rectus
muscle Lateral
rectus The Oculomotor Nerve
muscle
Inferior
rectus The nerve emerges from the ventral aspect of the mes-
muscle Ciliary
C encephalon, in the interpeduncular fossa (Fig. 27.1; see
ganglion
g
Fig. 6.20). This is the largest of the three nerves supply-
Levator
palpebrae ing the extraocular muscles; as mentioned, it contains
muscle Ab
Abducens nerve somatic efferent and visceral efferent fibers. The somatic
Maxillary nerve efferent fibers come from the large oculomotor nucleus
(nucleus of the oculomotor nerve) situated close to the
Ophthalmic nerve
Optic nerve Mandibular

nerve
Internal
carotid
artery Semilunar
ganglion
Optic (trigeminal)
chiasm
Oculomotor nerve
Trochlear nerve gure 27.17 Paresis of the right abducens nerve. When the patient
looks to his right, the right eye does not follow the left, because the
gure 27.16 The right eye with muscles and nerves, as viewed from right rectus muscle is paralyzed.
above. Three cranial nerves innervate the muscles of the eye. Some of
the extraocular muscles and the optic nerve have been cut. The exter-
nal layers of the eye bulb have been partly removed to expose the 6 Another peculiarity of the trochlear nerve is that it crosses the midline before
postganglionic bers from the ciliary ganglion on their way to the leaving the brain stem, so that the left trochlear nucleus innervates the right
intrinsic eye muscles. Note the position of the trigeminal ganglion superior oblique muscle, and vice versa. Some of the bers of the oculomotor
and the internal carotid artery. nerve also cross before leaving the brain stem.
midline in the mesencephalon, ventral to the aqueduct muscle). As in lesions of the abducens or the trochlear
(Figs. 27.2 and 27.5). The medial longitudinal fascicu- nerves, the patient will have double vision. In addition,
lus, with ascending fibers from the vestibular nuclei, the upper eyelid droopsptosisbecause of paralysis
lies close to the oculomotor nucleus (and to the abducens of the levator palpebrae (Fig. 27.18). The interruption
and trochlear nuclei as well). The visceral efferent of the parasympathetic fibers makes the pupil larger
(preganglionic parasympathetic) fibers come from the (due to loss of action of the pupillary sphincter), and
small nucleus of Edinger-Westphal located near the ocul- the light reflex is absent (in an incomplete lesion of
omotor nucleus. Often the term oculomotor complex the nerve, the pupil may be slightly larger and the reac-
is used for the somatic efferent and visceral efferent tion to light more sluggish than on the normal side).
nuclei together. Accommodation of the lens is abolished, making it
The oculomotor nerve passes forward to the orbit impossible to see near objects sharply. The intracranial
through the cavernous sinus together with the other course of the oculomotor nerve makes it especially vul-
nerves to the eye (entering through the superior orbital nerable in cases of temporal herniation caused by increased
fissure). The somatic efferent and parasympathetic intracranial pressure (see Chapter 3). Thus, examination
fibers part in the orbit (Fig. 27.16). The somatic effer- of the size of the pupils, and their reaction to light, is of
ent fibers innervate the following extraocular muscles: great practical value in patients who are unconscious
the superior and inferior rectus, the medial rectus, and after head trauma.
the inferior oblique. These muscles can move the eye
medially, upward, and downward and rotate it around
The Light Reex and the Accommodation Reex
the sagittal axis (see Fig. 25.2). In addition, the oculo-
motor nerve supplies the levator palpebrae muscle, The oculomotor nerve is the efferent link of both of
which serves to lift the upper eyelid. these reflexes, even though they are quite different in
The visceral efferent oculomotor fibers end in the other respects. The light reflex is relatively simple, with
small ciliary ganglion situated behind the eye (Fig. 27.16). its reflex center in the brain stem (Fig. 27.19). Increased
Here the fibers establish synapses with the postgangli- amount of light hitting the retina elicits a contraction of
onic neurons, which send their axons anteriorly in the the pupillary sphincter muscle. Both pupils constrict
wall of the eye to innervate the intrinsic (smooth) mus- even when the light hits only one eye. The afferent link
cles of the eye: the pupillary sphincter and the ciliary consists of fibers of the optic nerve that leave the optic
muscle (see Fig. 16.2). Contraction of the ciliary muscle tract before it reaches the lateral geniculate body. The
increases the lens curvature when looking at near objects fibers end in the pretectal nuclei on both sides. From
(see Chapter 16, under The Lens and the Far and Near these nuclei, the signals pass to the Edinger-Westphal
Points of the Eye: Accommodation). The sphincter nuclei on both sides, and by means of the ciliary gan-
constricts the pupil to reduce the amount of light reach- glion, the signals reach the sphincter. The bilaterality of
ing the retina. the connections explains why a unilateral stimulus pro-
A lesion of the oculomotor nerve produces, among duces a bilateral response.
other symptoms, an abnormal position of the eye, which Unilateral interruption of the oculomotor nerve
is directed laterally (due to the unopposed pull of the abolishes the light reflex in the eye on the side of the
lateral rectus) and downward (due to the superior oblique lesion, but the reflex is present in the other eye. In case
gure 27.18 Paresis of the oculomotor nerve

(right side). Left: The upper eyelid droops (pto-
sis) due to paresis of the levator palpebrae
muscle. Right: The examiner lifts the eyelid and
reveals that the right eye is abducted and low-
ered due to the unopposed actions of the lateral
rectus and the superior oblique muscles.
Pupillary sphincter muscle Ciliary muscle
Retina
Retina
Optic nerve
Optic nerve
Optic chiasm
Ciliary
Ciliary ganglion
ganglion
Optic tract
Optic tract Oculomotor nerve
Oculomotor nerve Lateral
geniculate
Parasympathetic body
oculomotor nucleus Parasympathetic
oculomotor nucleus
(Edinger-Westphal) (Edinger-Westphal)
Pretectal nuclei Pretectal nuclei

Optic
Superior colliculus radiation Superior
colliculus
gure 27.19 The reex arc for the light reex.
of interruption of the afferent link on one side (damage

to the retina or the optic nerve), the light reflex is absent
in both eyes when light is shone into the eye on the Extrastriatal
visual areas
lesioned side but is present in both sides when the other
eye is illuminated. Thus, examination of the light reflex
can provide valuable information with regard to the
site of a lesion. gure 27.20 The reex arc for the accommodation reex.
The accommodation reflex is a cortical reflex: the
reflex arc passes through the cerebral cortex. The affer-
ent link is fibers passing in the optic nerve from the as shown in Fig. 27.18) and from there to the nearby
retina, and the efferent link consists of parasympathetic reticular formation. Neurons in the reticular formation
fibers in the oculomotor nerve to the ciliary ganglion mediate the signals to the Edinger-Westphal nucleus.
(Fig. 27.20). From there the postganglionic fibers pass The accommodation reflex is elicited only when we fix
to the ciliary muscle. The reflex center is not known in the gaze on an object that is moving toward us. Together
detail, but recent studies indicate that the cortical fibers with the accommodation, a pupillary constriction
pass to the superior colliculus (not the pretectal nuclei, occurs as the object comes closer.
VI THE AUTONOMIC NERVOUS SYSTEM
T HE autonomic nervous system (or visceral sys-

tem) is not a term that can be defined precisely,
either anatomically or functionally. The old belief that
while Chapter 29 describes the characteristic features
of visceral afferent neuronsthat is, the sensory inner-
vation of visceral organs. Even though visceral afferent
the somatic and the autonomic parts of the nervous neurons do not differ structurally from somatic afferent
system are completely independent is not tenable. The neurons, there are nevertheless physiological differences
more we have learned about the nervous system, the that are important in a clinical contextin particular,
clearer it has become that simplistic divisions like this in relation to pain arising in the visceral organs. Although
are arbitrary. Some authors therefore maintain that the Chapter 29 contains discussion of some visceral reflexes
term autonomic nervous system should be abandoned and their central control, main topics concerning the
and replaced by simply referring to visceral neurons central control of the autonomic system, notably the
that is, the neurons that innervate visceral organs. For hypothalamus, are discussed in Chapter 30.
practical reasons, it is nevertheless helpful to use the The autonomic system can also be divided into a sym-
term autonomic nervous system and to define it very pathetic and a parasympathetic part, differing anatomi-
broadly as the neuronal groups and fiber connections cally and functionally (again, the separation is most
that control the activity of visceral organs, vessels, and obvious in the peripheral nervous system). The actions of
glands (also the vessels and glands that are not parts of the two parts of the autonomic system are often antago-
visceral organs). Visceral organs contain smooth-muscle nistic: where the sympathetic system activates, the para-
cells and glandular cells. We can therefore also define sympathetic reduces the activity, and vice versa. In
the autonomic system as the parts of the nervous system addition, the enteric nervous system is now regarded as a
that control the activity of smooth muscles and glands, distinct part of the autonomic nervous system. It consists
regardless of their location in the body (in contrast to of some million neurons and an extensive network in the
the somatic or cerebrospinal system, which controls wall of the digestive tract. The enteric system is influ-
striated skeletal muscles). Mostly, we are not aware of enced by both the sympathetic and the parasympathetic
the processes going on in the organs controlled by the systems but functions independently as well.
autonomic nervous system, and their activities are not In a superior perspective, a major function of the auto-
subject to voluntary, conscious control. nomic system is to contribute to bodily homeostasis,
The autonomic system can be subdivided in different that is, the maintenance of a relatively constant internal
ways. As with the somatic system, we distinguish milieu. The autonomic nervous system is not the only
peripheral and central parts. Whereas the peripheral means by which the central nervous system can control
parts of the autonomic and somatic systems can be sep- homeostasis, however. In addition, the endocrine system,
arated fairly well, the division becomes much less clear which is controlled from the central nervous system via
within the central nervous system. The peripheral parts the pituitary gland, serves this purpose. Further, homeo-
of the autonomic system are described in Chapters 28 stasis requires appropriate somatic motor activity to
and 29. Although the nerves to visceral organs contain secure, for example, the supply of water and nutrients.
both efferent (motor) and afferent (sensory) fibers, the The role of the hypothalamus is to organize the auto-
anatomic differences between the autonomic and the nomic, endocrine, and somatic-motor processes into
somatic systems concern primarily the efferent side. behavior that is appropriate for the immediate and
Chapter 28 deals with the visceral efferent neurons, long-term needs of the organism.
28 Visceral Efferent Neurons:
The Sympathetic and
Parasympathetic Divisions
OVERVIEW somatic structures of the trunk. Preganglionic sympa-

thetic fibers destined for visceral organs pass through
In general, the actions of the sympathetic system sug- the ganglia and leave the sympathetic trunk in separate
gest that it is of special importance in situations of splanchnic nerves. These end in prevertebral ganglia,
stress, requiring mobilization of bodily resources. The and from there postganglionic fibers follow arteries to
parasympathetic system, in contrast, contributes pri- the target organs.
marily to processes of maintenance, such as digestion The enteric system consists of some million neurons
and reproductive behavior. Such generalized statements in the wall of the gastrointestinal tract, controlling
are useful only as rules of thumb, however, because the peristaltic movements, secretion, and absorption. While
actions of the two systems are much more varied than it operates to a large extent independently of the CNS,
this. Table 28.1 gives an overview of the main actions this mini-brain of the gut integrates local information
of the two systems in various organs. from the gut with central commands through the sym-
The sympathetic and parasympathetic system both pathetic and parasympathetic systems.
consist of two consecutive neurons leading from the
central nervous system (CNS) to the target organs. The
preganglionic neuron has its cell body in the cord or in
GENERAL ORGANIZATION
the brain stem and the axon terminates in a ganglion.
Postganglionic neurons have their cell bodies in the
Two Succeeding Neurons Constitute the
ganglia while their axons terminate close to smooth
Efferent Pathway
muscle cells and glandular cells. The preganglionic sym-
pathetic neurons are found in the intermediolateral Despite their different actions, the sympathetic and
column of the cord, stretching from T1 to L2, whereas the parasympathetic systems have certain features of
the preganglionic parasympathetic cell bodies reside in peripheral organization in common that should be
the brain stem and in the sacral cord. All preganglionic known before discussing the differences between them.
neurons use acetylcholine as transmitter in the ganglia, In contrast to the somatic efferent fibers (leading from
where they act on nicotinic receptors. Most sympathetic motoneurons to skeletal muscles), the visceral efferent
neurons use norepinephrine (and various neuropeptides) fibers do not pass nonstop to the organs. The transmis-
as transmitter, while parasympathetic neurons use ace- sion of signals is synaptically interrupted in autonomic
tylcholine binding to muscarinic receptors. ganglia (Figs. 28.1 and 28.2). The multipolar neurons
Preganglionic sympathetic and parasympathetic in the ganglia send their axons to the effectors (smooth-
fibers leave the cord and the brain stem through ventral muscle cells and glands) in the visceral organs. The
roots and motor cranial nerves. Their further course neurons conducting signals to the ganglia are called
differs, however. The parasympathetic fibers pass preganglionic, whereas the ganglion cells and their
directly to ganglia that lie close to or in the wall of the axons are called postganglionic. The cell bodies of the
target organ. The sympathetic fibers leave the spinal preganglionic neurons are located in the spinal cord and
nerves just outside the intervertebral foramen and enter the brain stem. The preganglionic neurons, both the
the sympathetic trunk, which stretches from the base of sympathetic and the parasympathetic ones, use acetyl-
the skull to the lower end of the cord. The sympathetic choline as a neurotransmitter.
trunk forms a chain of interconnected sympathetic gan- Another typical feature of the visceral efferent neurons
glia. From these ganglia, sympathetic postganglionic is that, as a rule, the postganglionic fibers form extensive
fibers follow the spinal nerves to the extremities and plexuses around the organs they innervate.
413
CNS PNS than those of skeletal muscle cells do. Further, smooth-
muscle cells (e.g., in the wall of the gastrointestinal
tract) can be made to contract by stimuli other than
Ganglion
nervous ones, such as by stretching and by the actions
of hormones. The autonomic system therefore contrib-
utes to the regulation of the contraction of smooth-
SYMPATHETIC
muscle cells in the gastrointestinal tract and in the walls
Preganglionic Postganglionic
of the vessels, but it is not alone in this capacity (again
neurons neurons in contrast to the control of skeletal muscle cells by the
motoneurons).
Some Organs Are Subject to More Precise Autonomic

PARA- Control than Others
SYMPATHETIC Ganglion
There are, nevertheless, great differences between
different organs with regard to the precision of their
gure 28.1 Basic organization of the peripheral part of the auto-
nomic system. Two consecutive neurons conduct the signals from the autonomic innervation. Some visceral organs require
central nervous system to the effectors. Note the difference in length much faster and more accurate control than others. The
between the pre- and postganglionic bers in the sympathetic and the smooth muscles of the eye (the ciliary muscle and the
parasympathetic systems. Effectors may be glandular cells and not pupillary sphincter, regulating the curvature of the lens
only smooth-muscle cells, as shown here.
and the diameter of the pupil) must be subject to very
precise control. The same holds for the muscles of the
ductus deferens, in which the propulsive contractions
Postganglionic Fibers Do Not Establish
must be fast and well coordinated. Such demands are
Typical Synapses
not made of the smooth muscles of the gastrointestinal
The thin, unmyelinated postganglionic fibers do not tract and the vessels. Corresponding to different func-
form typical synapses with the effector cells; in contrast tional requirements, the pattern of autonomic innerva-
to the somatic efferent fibers innervating skeletal muscle tion varies in different organs. The intrinsic eye muscles,
cells (see Fig. 21.5). When the postganglionic fibers for example, receive a large number of nerve fibers so
reach the vicinity of the effector cells, they branch exten- that all muscle cells come in close contact with vari-
sively, and there are small swellingsvaricosities cosities of nerve fibers. This is called multiunit arrange-
along the branches (Fig. 28.1). In each varicosity, there ment, because it is similar to the conditions in the
are vesicles with neurotransmitters. The varicosities do somatic system with many precisely controlled motor
not form synapses but can be located fairly close to the units. In places with few nerve fibers to supply a large
effector cells. In some places, the distance is only 50 nm, number of smooth-muscle cells, so that only a few cells
thus permitting very direct and precise control of the are close to nerve varicosities, we use the term single-
effector cell. Most often, however, the distance between unit arrangement. Thus, numerous muscle cells behave
the varicosities and the effectors is so great that the neu- as a unit when one or a few of them are activated.
rotransmitter, after being released, must diffuse over a
considerable distance to reach its target. This means
Autonomic Ganglia and Plexuses
that the neurotransmitter acts on several effector cells
within a certain distance. When the diffusion distance is The autonomic ganglia contain multipolar neurons of
great, the transmitter acts slowly, with a long latency various sizes (Fig. 28.3) with long, branching dendrites.
and a prolonged action (compared with the fast action The axons are mostly unmyelinated and very thin. The
at the neuromuscular junction). Often, only a few of cell bodies of the ganglion cells are embedded in a mesh-
the smooth-muscle cells in the wall of a hollow organ work of fibers consisting of afferent fibers, ganglion cell
(such as a vessel) are close enough to the varicosities to dendrites, and axons of the ganglion cells. At least some
be directly influenced by the transmitter. In such cases, of the ganglia receive sensory fibers from visceral
the action potential elicited in some smooth-muscle organs. There are also interneurons in the autonomic
cells is propagated from cell to cell via gap junctions ganglia. Such features, and other data, indicate that the
between them (electric coupling). In general, therefore, ganglia are not just simple synaptic interruptions of
the actions of the autonomic nervous system are more purely motor (efferent) pathways but can serve as reflex
diffusely distributed, both spatially and temporally, centers for some visceral reflexes.
than is the case in the somatic system. The properties of When an organ is innervated by both sympathetic
the smooth-muscle cells contribute to increase this dif- and parasympathetic fibers, these two components
ference, because their action potentials last much longer intermingle and form autonomic plexuses just outside
28: VISCERAL EFFERENT NEURONS: THE SYMPATHETIC AND PARASYMPATHETIC DIVISIONS 415
Parasympathetic
ganglion
Accommodation
Pupillary
constriction
PARASYMPATHETIC
Lacrimal gland Preganglionic neurons
in the brain stem
Salivary glands
SYMPATHETIC
Preganglionic neurons in T1 L2
Head (sympathetic)
Pupillary dilatation Control of
Circulatory control circulation in skin
Sweat secretion and muscles
Heart
gure 28.2 Main anatomic features Lungs

of the autonomic nervous system. Sweat secretion
The preganglionic sympathetic neu-
rons have their cell bodies in the
Gastrointesti- Goose skin
intermediolateral column, whereas
nal tract
the corresponding parasympathetic
Adrenal medulla
neurons are located in the brain stem
and the sacral cord. The cell bodies
of sympathetic postganglionic neu-
Bladder
rons in ganglia lie close to the verte- Rectum
bral column (paravertebral and Bladder
Genitals
Rectum
prevertebral ganglia), whereas those Genitals
of parasympathetic postganglionic
neurons lie in ganglia close to the PARASYMPATHETIC
Preganglionic neurons in S2S4
organ. The sympathetic bers reach
all parts of the body, but the parasym-
pathetic bers have a more restricted
distribution. (After Pick 1970.)
A B
gure 28.3 Autonomic ganglion. Photomi-

crograph of section through the celiac gan-
glion impregnated with heavy metals to
show nerve bers (black) and neurons (red).
A: The multipolar postganglionic neurons lie
in a wickerwork of preganglionic and post-
ganglionic nerve bers. Thus, the autonomic
ganglia consist of groups of postganglionic
neurons embedded in a plexus. B: Higher
magnication of postganglionic neurons.
or in the wall of the organs. At many places, cell bodies of are mostly restricted to the true visceral organs. The
postganglionic cells form small clumps intermingled with body wall and the extremities (skin, muscles, joints) do
the fibers of the plexuses. Thus, ganglia and plexuses often not receive parasympathetic fibers.
coexist, and the ganglia then have the same prefix as the Table 28.1 gives a broad overview of the functions of
plexuses. For example, the cardiac plexus on the outside the two systems; a more comprehensive discussion is
of the heart contains both kinds of fibers and, in addition, provided later in this chapter.
the cell bodies of the postganglionic parasympathetic neu-
rons. Especially well developed plexuses are found around
The Parasympathetic Innervation Is Usually More
the large vessels in the upper abdomen, where parasym-
Precise than the Sympathetic
pathetic vagus fibers intermingle with sympathetic fibers.
These prevertebral plexuses get their names from the As a rule (with notable exceptions), the sympathetic sys-
arteries they surround and follow peripherally: the celiac tem is more diffusely organized than the parasympa-
plexus, the superior and inferior mesenteric plexus, and thetic. This is evident, for example, in the relation between
the renal plexus. The prevertebral plexuses continue into the number of preganglionic and postganglionic fibers.
the pelvis as the hypogastric plexus. In the parasympathetic ciliary ganglion (see Fig. 27.16),
two postganglionic fibers leave the ganglion for each
preganglionic fiber reaching itthat is, a 2:1 relation-
Differences between the Sympathetic and the
ship (in the cat). For the sympathetic superior cervical
Parasympathetic Systems
ganglion (Fig. 28.7), the relationship is 30:1 in the cat
The two systems differ in several respects. The location and 60 to 190:1 in humans (this ganglion contains more
of preganglionic neurons differs: the sympathetic ones than 1 million neurons in humans). Further, the para-
are found in the T1L2 spinal segments, whereas the sympathetic innervation is in several places arranged
parasympathetic preganglionic neurons lie in the brain with multiunitsthat is, small motor units with the
stem and the S2S4 spinal segments (Fig. 28.2). Further, possibility of precise control. This concerns, for example,
the ganglia are located differently: sympathetic ones lie the innervation of the intrinsic eye muscles. The sympa-
close to the CNS, whereas the parasympathetic ganglia thetic innervation is often (but not always) arranged with
are located close to the target organs. Thus, the sympa- single unitsthat is, a large number of smooth muscle
thetic preganglionic fibers are short, and the parasym- cells are activated from one postganglionic fiber and
pathetic ones are long (Figs. 28.1 and 28.2). behave as a functional unit.
Another difference between the two systems is the Another difference concerns the topographic arrange-
neurotransmitters used by the postganglionic neurons: ment of the preganglionic neurons. Whereas the sympa-
the sympathetic fibers release norepinephrine, whereas thetic neurons show only a fairly rough topography within
the parasympathetic fibers release acetylcholine from the intermediolateral column in relation to the location of
their varicosities. the target (Fig. 28.7; Table 28.2), the parasympathetic
Finally, the distribution of postganglionic fibers is neurons are as a rule collected in distinct nuclei (Figs. 28.2
different. Thus, virtually all parts of the body receive and 28.11) or subdivisions of a nucleus (like the motor
sympathetic fibers, whereas the parasympathetic fibers nucleus of the vagus), each related to one target organ.
table 28.1 Summary of Some Main Actions of the Autonomic System

Organ Sympathetic System Parasympathetic System
Arteries (arterioles) Vasoconstriction Vasodilatation in glands and genital organs
Skin Vasoconstriction; sweat secretion; goose skin No innervation
Skeletal muscles Vasoconstriction No innervation
Heart Increased rate and stroke volume Reduced heart rate
Airways Relaxation of bronchial smooth muscle (reduced Contraction of bronchial smooth muscle; secretion from
airway resistance) mucous glands
Gastrointestinal tract Reduced blood ow and peristaltic movements Increased peristaltic movements; secretion of gastric juice,
bile, and pancreatic juice
Urinary bladder Relaxation of muscle for emptying (detrusor) Contraction of detrusor; relaxation of urethral sphincter
Rectum Relaxation of muscle for emptying; closure of internal Contraction of muscle for emptying; relaxation of internal
sphincter (smooth muscle) sphincter
Genital organs Contraction of the ductus deferens (ejaculation) Erection (penis, clitoris)
Eye Pupillary dilatation Pupillary constriction; accommodation; secretion of tears
see Table 28.2 for further details.
table 28.2 Principal Features of Autonomic Innervation
Sympathetic Parasympathetic
Preganglionic Postganglionic Preganglionic Postganglionic
Organ Neuron Neuron Action Neuron Neuron Action
Eye T1T2 Superior cervical Pupillary Parasympathetic Ciliary ganglion Pupillary
ganglion dilatation oculomotor constriction
nucleus (Edinger accommodation
Westphal)
Lacrimal gland T1T2 Superior cervical ? Superior salivatory Pterygopalatine Secretion ganglion
ganglion nucleus
Submandibular T1T2 Superior cervical Vasoconstriction Superior salivatory Submandibular Secretion,

and sublingual ganglion nucleus ganglion vasodilatation
glands
Parotid gland Vasoconstriction Inferior salivatory Otic ganglion Secretion,
nucleus vasodilatation
Heart T1T4(5) Superior, middle, Increased rate and Dorsal motor Cardiac plexus Reduced heart rate
and inferior stroke volume vagus nucleus
cervical 1 upper
thoracic ganglia
Bronchi, lungs T1T34 Inferior cervical 1 Bronchial Dorsal motor Pulmonary Bronchial
upper thoracic dilatation vagus nucleus plexus constriction and
ganglia secretion
Stomach T6T10 (greater Celiac ganglion Inhibition of Dorsal motor Gastric plexus Peristaltic
splanchnic peristaltic vagus nucleus movement and
nerve) movement and secretion
secretion;
contraction of
pyloric sphincter
Pancreas T6T10 (greater Celiac ganglion ? Dorsal motor Periarterial Secretion
splanchnic vagus nucleus plexus
nerve)
Small intestine, T6T10 (greater Celiac ganglion Inhibition of Dorsal motor Myenteric and Peristaltic
ascending and splanchnic 1 superior peristaltic vagus nucleus submucous movement and
transverse nerve) and inferior movement and plexus secretion
large intestine mesenteric secretion (ganglion)
ganglia
Descending large T10L2 Inferior Inhibition of Sacral cord S3S4 Myenteric and Peristaltic
intestine, mesenteric, peristaltic submucous movement and
sigmoid and hypogastric, movement and plexus secretion
rectum and pelvic secretion (ganglion)
ganglia
(plexuses)
Ureter, bladder T10L2 Hypogastric and Inhibition of Sacral cord S3S4 Pelvic plexus Contraction of
pelvic ganglia detrusor detrusor
(plexuses)
Head and neck T1T24 Superior cervical Vasoconstriction

(skin and ganglion sweat secretion,
skeletal muscles) and piloerection
Upper extremity T3T6 Stellate ganglion, Vasoconstriction

upper thoracic sweat secretion,
and piloerection
Lower extremity T10L2 Lower lumbar Vasoconstriction,

and upper sweat secretion,
sacral ganglia and piloerection
The difference in innervation precision between the

sympathetic and the parasympathetic systems men-
tioned above have several exceptions, however. One
example is the ductus deferens, in which the rhythmic
contractions are elicited by sympathetic fibers. A multi-
unit arrangement is required to ensure the necessary Intermediolateral
precision and speed of the contractile wave moving the cell column
sperm during ejaculation. Another example is that the
parasympathetic innervation of the gastrointestinal
Motoneurons
tract is rather diffuse (single-unit arrangement).
gure 28.4 The intermediolateral cell column contains the cell

PERIPHERAL PARTS OF THE SYMPATHETIC SYSTEM bodies of the preganglionic sympathetic neurons. Cross section of the
thoracic cord.
Preganglionic Fibers and the Sympathetic Trunk
The peripheral parts of the sympathetic system consist in only the T1L2 segments, only the ventral roots of
of both neurons conveying signals to visceral organs these segments contain preganglionic sympathetic fibers
and sensory fibers leading in the opposite direction. (the sympathetic system is also called the thoracolum-
The efferent, preganglionic sympathetic neurons have bar system). The sympathetic fibers follow the somatic
their cell bodies in the intermediolateral column in the ones for a short distance, however. Just after the ventral
spinal cord (Fig. 28.4). The preganglionic fibers leave and the dorsal roots fuse, the sympathetic preganglionic
the cord (like other efferent fibers) through the ventral fibers leave the spinal nerve to end in a sympathetic gan-
roots, but because the intermediolateral column is present glion (Fig. 28.5). In early embryonic life, one ganglion is
Preganglionic neurons
Gray communicating
ramus
W
White communicating Skin
ra
ramus
Postgang
Postganglionic
neuron
Sweat gland
Paravertebral ganglion
Sympathetic trunk
Prevertebral
ganglion
gure 28.5 The sympathetic system. Post-

Artery ganglionic neurons are located in the ganglia of
the sympathetic trunk and in the prevertebral
ganglia. Sympathetic bers to the trunk and the
extremities follow the spinal nerves, whereas
Visceral organ
bers to the visceral organs form separate nerves
and follow the main vessels to the organs.
produced on each side for every spinal segment, but The preganglionic sympathetic fibers leave the spinal
during further development, some ganglia fuse, so the nerve as a small bundle called the white communicating
final number is smaller than the number of segments. ramus (branch), which connects the nerve with the
This reduction is most marked in the cervical region. sympathetic trunk (Figs. 28.5 and 28.6). The whitish
The ganglia are located just outside the intervertebral color arises because the preganglionic fibers are myeli-
foramen, laterally on the vertebral column (Fig. 28.6). nated. Because of the restricted extension of the inter-
The row of such paravertebral ganglia extends from the mediolateral column, only the thoracic and the upper
base of the skull to the coccygeal bone in the pelvis two lumbar spinal nerves give off white communicating
minor. Because fiber bundles interconnect the ganglia, rami.
a continuous string called the sympathetic trunk is When reaching the ganglia of the sympathetic trunk,
formed (Figs. 28.5 and 28.6). The ganglia form small some preganglionic fibers establish synapses with post-
swellings along the trunk. There is usually one ganglion ganglionic neurons in that ganglion, whereas others
for each pair of spinal nerves, except in the cervical continue uninterrupted through the ganglion (Fig. 28.5).
region, where there are only three: the superior, middle, In the upper part of the trunk, the fibers continue ros-
and inferior cervical ganglia. The middle ganglion can trally, in the lower part caudally, to establish synapses
be missing, and the inferior cervical ganglion is usually with ganglion cells in ganglia at levels above and below
fused with the uppermost thoracic ganglion to form the the intermediolateral column (Figs. 28.7, 28.8, and 28.9).
large stellate ganglion (Fig. 28.6). Some cross connec- This arrangement ensures that preganglionic fibers
tions are present in the lumbar and sacral parts of the reach all the ganglia of the sympathetic trunk (the para-
sympathetic trunks. vertebral ganglia).
Some of the preganglionic fibers pass directly through
the ganglia and form separate nervessplanchnic
nervesdestined for prevertebral sympathetic ganglia
Middle cervical
ganglion (Figs. 28.5 and 28.7). We return to this point later in
Cardiac nerves this chapter.
Common carotid
artery
Brachial plexus Postganglionic Sympathetic Fibers
Stellate ganglion
Suclavian artery The postganglionic fibers from the ganglia of the sym-
pathetic trunk take different routes. From all of the
ganglia, some fibers pass back to the spinal nerve as the
Intercostal
nerves
Pulmonary thin gray communicating ramus (Figs. 28.5 and 28.6).
branch
This ramus is more grayish than the white ramus
because most of the postganglionic fibers are unmyeli-
1
Sympathetic nated. All of the spinal nerves receive postganglionic
trunk fibers through the communicating rami (Fig. 28.6). The
Communicating postganglionic fibers follow the spinal nerves out into
rami all their branches (Figs. 28.8 and 28.9). Some postgan-
glionic fibers leave the trunk, pass to larger arteries in
the vicinity, and innervate the smooth-muscle cells of
the artery. Many of the postganglionic sympathetic
Ribs fibers that follow the spinal nerves leave them peripher-
ally to innervate small vessels. Other fibers from the
spinal nerves innervate the sweat glands and the smooth
Greater muscles attached to hair follicles (Fig. 28.5).
splanchinc nerve
Lesser splanchinc Sympathetic Innervation of the Head and Extremities

nerve
The head, neck, and upper extremity receive pregangli-
Diaphragm
onic sympathetic fibers from the upper thoracic segments
(Table 28.2). The fibers enter the sympathetic trunk
1 White and gray rami often fuse into one, so that even at the levels T1L2 there
gure 28.6 The sympathetic trunk. Part of the thoracic vertebral col- may be only one communicating ramus on each side. This contains, as will be
umn and the ribs, as viewed from the right. Note the communicating understood, both the pre- and postganglionic bers. In the case of two rami, the
rami and the splanchnic nerves. (Redrawn from Spalteholz 1933.) color difference between them is not very marked.
Internal carotid artery

(carotid plexus)
Superior cervical Head

ganglion
Gray communicating
ramus Cranial nerves
Cardiac
Preganglionic plexus Heart
neuron
Gray communi- Bronchi

cating ramus Stellate
White communi- ganglion
T1 cating ramus
Lungs
Postganglionic
Ventral ramus neuron
of spinal nerve
Celiac plexus &
ganglion
Esophagus
Stomach
Splanchnic
nerves Spleen
Small intestine
Mesenteric Large intestine
plexus & (upper)
ganglion Liver
Pancreas
Large intestine
L2 (lower)
Rectum
Bladder
Genital
organs
Pelvic plexus
Sympathetic trunk
gure 28.7 The sympathetic system. The sympathetic trunk with are shown. The organs innervated from the various ganglia are also
the paravertebral ganglia, and the prevertebral ganglia and plexuses specied.
through the communicating rami. Some establish syn- The head receives postganglionic fibers from the
aptic contacts with postganglionic neurons in the upper superior cervical ganglion. From the ganglion, the
thoracic ganglia, whereas other fibers pass through fibers follow arteries and cranial nerves to the skin,
these ganglia to end in the cervical ganglia (Figs. 28.7 the eye, the lacrimal gland, and the salivary glands
and 28.8). From these ganglia, postganglionic fibers (Table 28.2).
enter the spinal nerves to the neck (C1C4) and the With regard to the lower extremities, the arrangement
upper extremity (C5T1). corresponds to that described for the upper extremity,
smooth tarsal muscle. This constellation of symptoms
Superior cervical red and dry skin, miosis, and ptosisaffecting half of
ganglion the face is called Horners syndrome (Fig. 28.10).
Horners syndrome can also be caused by lesions in
Ventral root
C5
the brain stem, interrupting the descending fibers to the
Postganglionic C intermediolateral column (cf. Chapter 27, under Brain
sympathetic fibers 5 Middle
cervical Stem Lesions Can Produce Symptoms from Several
ganglion Cranial Nerves and Long Tracts and Lateral Pontine
Infarctions).
C7
C8 Sympathetic Innervation of the Viscera

Stellate T1
Brachial As mentioned, the postganglionic sympathetic fibers to
ganglion
plexus
T2 the extremities and the body wall follow mainly the spi-
T1 nal nerves. The visceral organs of the thorax and the
abdomen do not receive branches from the spinal
nerves, however. Therefore, the sympathetic fibers des-
tined for these organs have to form separate nerves.
Such splanchnic nerves are thin twigs that leave the
sympathetic trunk at various levels.
The sympathetic fibers to the heart follow the supe-
Preganglionic rior, middle, and inferior cardiac nerves leaving the
sympathetic fibers
corresponding cervical ganglia. The cell bodies of the
postganglionic neurons lie in the cervical ganglia. In
addition, some smaller branches to the heart take off
Sympathetic trunk Spinal cord from the upper thoracic sympathetic ganglia.
Most sympathetic fibers to the abdominal viscera
gure 28.8 Sympathetic innervation of the upper extremity. The form the greater and lesser splanchnic nerves (Fig. 28.6).
preganglionic bers come from the upper thoracic segments of the cord These nerves consist mainly of preganglionic fibers
and synapse in the ganglia of the sympathetic trunk up to the middle
cervical ganglion. The postganglionic bers follow the spinal nerves
from spinal segments T6T11, which pass uninterrupted
to the arm. (Redrawn from Haymaker and Woodhall 1945.) through the ganglia of the sympathetic trunk (Figs. 28.5
and 28.7). The nerves penetrate the diaphragm and end
in ganglia located on the ventral side of the abdominal
with postganglionic fibers following the spinal the spi- aorta in the upper abdomen. As mentioned, these are
nal nerves (Fig. 28.9). called prevertebral ganglia, to distinguish them from
the paravertebral ganglia of the sympathetic trunk.
Interruption of the Sympathetic Innervation of the The largest among the prevertebral ganglia is the
Head: Horners Syndrome celiac ganglion, located where the celiac artery emerges
from the aorta. Smaller prevertebral ganglia occur where
A lesion of the sympathetic trunk in the neck is the most the superior and inferior mesenteric arteries emerge. The
common cause of sympathetic denervation of the head. postganglionic fibers follow the arteries to the various
Because all preganglionic fibers enter the trunk below organs.
the inferior cervical ganglion (Fig. 28.8), a lesion any- The greater and lesser splanchnic nerves and the
where above the level of the thoracic outlet can inter- corresponding prevertebral ganglia supply the visceral
rupt the sympathetic innervation of the head. It may be organs in the upper and middle part of the abdomen,
caused, for example, by a tumor in the apex of the lung, such as the stomach, pancreas, gallbladder, small intes-
in the thyroid gland, or in any of the numerous lymph tine, and the large intestine to the descending part. The
nodes in the neck. The ensuing symptoms can be under- adrenal medulla, which also receives preganglionic
stood based on the effects of sympathetic fibers on the fibers from the splanchnic nerves, is special. The medul-
skin and the eye (Table 28.1). In the case of a unilateral lary endocrine cells (chromaffin cells)which are trans-
lesion, the facial skin on the side of the lesion becomes formed postganglionic neuronsrelease epinephrine
redder (warmer) and drier than that on the other side (and small amounts of norepinephrine) into the blood-
(caused by vasodilatation and lack of sweat secretion). stream on sympathetic stimulation.
The pupil is miotic (smaller) on the side of the lesion The visceral organs of the lower abdomen and the pel-
(paralysis of the pupillary sphincter), and there is slight vis receive their sympathetic innervation from the interme-
ptosis (the eyelid droops) owing to paralysis of the diolateral column in the lower thoracic and upper two
Sympathetic trunk Spinal cord
Preganglionic T10
sympathetic fibers
L1
Spinal nerve (L1)
L5 Preganglionic
parasympathetic
S1 fibers
Femoral nerve
(L2 L4)
Postganglionic
parasympathetic
fibers
Bladder
Postganglionic Rectum
sympathetic fibers Genital organs
gure 28.9 Sympathetic innervation of the lower

extremity. On the right side, pre- and postganglionic
parasympathetic bers from the sacral cord are also
Ischiadic nerve shown. (Redrawn from Haymaker and Woodhall
(L4 S3) 1945.)
lumbar segments (Table 28.2). These fibers also leave the from the lower part of the abdominal aorta into the
sympathetic trunk as separate nerves (lumbar splanchnic pelvis minor as the hypogastric plexus. In the pelvis, the
nerves) to reach prevertebral ganglia. The postganglionic hypogastric plexus mixes with parasympathetic fibers
fibers follow the arteries to the organs (Fig. 28.6). from the pelvic nerves and forms the pelvic plexus
The prevertebral ganglia are embedded in a mesh- around the pelvic organs, as mentioned earlier.
work of fibers, forming prevertebral plexuses, with names
corresponding to those of the ganglia (Fig. 28.7). The
plexuses formed mainly by sympathetic fibers continue PERIPHERAL PARTS OF THE PARASYMPATHETIC
SYSTEM
As mentioned, the preganglionic parasympathetic (vis-

ceral efferent) neurons have their cell bodies in the brain
stem and in the sacral cord. The neurons look like the
sympathetic preganglionic neurons of the intermedio-
lateral column.
The Cranial Nerves Contain Preganglionic

gure 28.10 Horners syndrome. The left half of the face shows the Parasympathetic Fibers
characteristic symptoms of loss of sympathetic innervation: red and
dry skin, constricted pupil (miosis), and drooping of the upper eyelid The preganglionic fibers of the cranial part of the para-
(ptosis). sympathetic system follow the oculomotor, the facial
(intermediate), the glossopharyngeal, and the vagus pterygopalatine, the otic, and the submandibular gan-
nerves. The fibers come from the visceral efferent col- glia. From these ganglia, the postganglionic fibers pass
umn of cranial nerve nuclei (see Figs. 27.2 and 27.3). to the effector organs (the intrinsic muscles of the eye,
The preganglionic fibers of the cranial nerves supplying the lacrimal gland, and the salivary glands).
structures in the head end in several parasympathetic The preganglionic fibers of the vagus nerve do not
ganglia, located outside the skull close to large cranial end in well-defined ganglia but in more diffusely dis-
nerve trunks (Fig. 28.11). These are the ciliary, the tributed collections of postganglionic neurons in the
Parasympathetic
oculomotor nucleus
(Edinger- Westphal)
MESENCEPHALON
Ciliary ganglion
Pupillary sphincter
muscle
Ciliary muscle
Oculomotor nerve Superior salivatory

nucleus
Lacrimal gland
Maxillary nerve
Intermediate nerve
MEDULLA
(UPPER) Greater
petrosal nerve Pterygopalatine
ganglion Nasal & palatal
glands
Chorda Lingual nerve
tympani
Facial nerve
Inferior Submandibular
salivatory Motor vagus Submandibular gland
nucleus nucleus ganglion Sublingual gland
Middle meningeal
Mandibular nerve artery
Glosso-
pharyngeal Parotid gland
nerve
Auriculotemporal
Lesser nerve
petrosal nerve
MEDULLA
(LOWER) Otic
Tympanic nerve ganglion
Pharynx
Esophagus
Vagus nerve Bronchi
Lungs
Heart
Thoracic & abdominal Stomach
ganglia & plexuses Small intestine
Large intestine (upper)
SPINAL CORD Liver & gall bladder
S 3 S4 Pancreas
Large intestine (lower)

Rectum
Pelvic splanchnic Bladder

nerves
Genital organs
gure 28.11 The parasympathetic system. The cell bodies of the quite complicated because they jump from one cranial nerve to
preganglionic neurons are located in the brain stem and in the sacral another on their way to the target.
cord. The peripheral course of the parasympathetic bers is often
walls of (or just outside) the thoracic and abdominal Spinal cord
Sympathetic
organs. These postganglionic neurons have short axons trunk
running in the wall of the organ and innervate smooth- T11
muscle cells and glands. As mentioned in Chapter 27, the
vagus nerve sends parasympathetic fibers to the heart,
the lungs, the gastrointestinal tract down to the descend-
Sensory
ing colon, the gallbladder, the liver, and the pancreas L4
neuron
(see Fig. 17.9). With postganglionic sympathetic fibers,
the vagus nerve forms the cardiac plexus, which lies
around the aortal arch and extends down onto the heart. Preganglionic Sensory
The cardiac plexus also contains scattered groups of post- parasympathetic neuron
neurons
ganglionic parasympathetic cell bodies, with the largest
S3 S4
group just underneath the aorta. The sinus node and the
atrioventricular node receive the densest innervation of
parasympathetic postganglionic (vagus) fibers, whereas
the ventricles receive few such fibers (they receive a dense
sympathetic postganglionic innervation, however). In the Bladder
airways, the vagus participates in plexuses around the (fundus)
trachea and the bronchithe tracheobronchial plexus
containing scattered postganglionic neurons.
The Sacral Part of the Parasympathetic System

Supplies the Genitals, Bladder, and Rectum
The cell bodies of the preganglionic neurons in the sacral
Postganglionic
cord are located in the (S2) S3S4 segments, with a posi- parasympathetic
tion corresponding to the intermediolateral column neuron
Bladder
External
of the sympathetic system (Figs. 28.11 and 28.12). The sphincter
(neck)
parasympathetic preganglionic fibers leave the cord
through the ventral roots and follow the spinal nerves for gure 28.12 Innervation of the bladder. Left: The parasympathetic
innervation of the smooth muscles that are responsible for emptying
a short distance. Then they leave the spinal nerves as
the bladder. The preganglionic neurons are located in the spinal
separate, small pelvic splanchnic nerves. In contrast to segments S3S4, whereas the postganglionic cell bodies are found just
the sympathetic preganglionic fibers, the parasympathetic outside or in the wall of the bladder. Right side: The course of the
ones do not pass to the sympathetic trunk but join post- sensory bers from the bladder. From the lower part, the sensory
ganglionic sympathetic fibers in the pelvic plexus, located bers follow the efferent parasympathetic bers, whereas the sensory
bers from the upper part (the fundus) follow the sympathetic bers
immediately lateral to the rectum, the bladder, the pros-
(via the sympathetic trunk). The striated, external sphincter muscle is
tate gland (in the male), and the cervix (in the female). innervated by motoneurons in the sacral segments S3S4 (not shown).
Many of the postganglionic parasympathetic neurons are
located in the pelvic plexus (the pelvic ganglion).
Postganglionic parasympathetic fibers innervate all circular and the longitudinal external smooth-muscle lay-
the organs of the pelvis and, in addition, the corpora ers; the smaller submucous plexus is situated below the
cavernosa (erectile tissue) of the penis and the clitoris. mucous membrane. The plexuses are formed by the axons
The descending and sigmoid colon and the rectum are of the enteric neurons, together with postganglionic sym-
innervated from the sacral parasympathetic division. pathetic fibers (with their cell bodies in the prevertebral
Of particular practical importance is the parasympa- ganglia). The neurons of the enteric system monitor the
thetic innervation of the rectum and the bladder, which tension in the intestinal wall and the chemical milieu of
is responsible for emptying these organs (Fig. 28.12). the mucosa, and they control the peristaltic movements
We treat the emptying reflex of the bladder later in this of the bowel, moving the content toward the anus. In
chapter. addition, they influence blood flow, the secretion from
mucosal glands, and the absorption of nutrients.
It was formerly believed that the enteric neurons were
THE ENTERIC NERVOUS SYSTEM
parasympathetic postganglionic. Only a minority con-
tains acetylcholine, the classic transmitter of postgangli-
The Mini-Brain of the Gut
onic parasympathetic neurons, however. It has become
As mentioned, the digestive tract contains millions of increasingly clear that these plexuses and ganglia repre-
neurons embedded in two plexuses in the wall. Largest sent a part of the peripheral nervous system that is, to a
is the myenteric plexus, which is located between the large extent, independent of the rest of the nervous
system. Some even use the term the mini-brain of the The parasympathetic system controls primarily pro-
gut. Thus, the neurons in the myenteric and submucous cesses that are necessary for the maintenance of the
ganglia are able to function even after the sympathetic organism over the long term. The parasympathetic sys-
and parasympathetic nerves to the gastrointestinal tract tem thus activates the digestive processes, ensures that
have been cut. The number of neurons in the enteric waste products are expelled by contraction of the blad-
system is large, and only a few of these are under direct der and rectum, protects the eye against strong light,
control from the CNS (by means of parasympathetic ensures focused vision, reduces the activity of the heart,
preganglionic fibers). reduces the diameter of the airways, and increases bron-
Broadly speaking, the enteric system integrates infor- chial secretion. The sympathetic system as a whole is
mation about the local conditions with central commands more concerned with mobilizing the resources of the
through sympathetic and parasympathetic postganglionic body when an extra effort is required. In situations of
fibers. fear and anger, there are usually signs indicating increased
sympathetic activity, such as increased blood pressure,
increased heart rate, and dilatation of the pupils. At the
Neuronal Types and Neurotransmitters
same time, stored energy is mobilized by epinephrine
The enteric plexuses contain not only motor neurons secreted into the bloodstream from the adrenal medulla
innervating smooth-muscle cells and glandsbut also (increased blood level of glucose and fatty acids).
interneurons and most likely sensory neurons. Numerous Epinephrine also activates the heart and dilates the bron-
neurotransmittersin particular, many neuropeptides chi (relaxation of smooth-muscle cells). The activity of
have been found in the enteric ganglion cells. With few the gastrointestinal tract is inhibited. In general, such
exceptions, however, they are not yet functionally char- responses are adequate in flight-or-fight situations.
acterized. Different kinds of neurons contain different
combinations of neuropeptides and classic transmitters
A More Nuanced View
(acetylcholine, GABA, and serotonin). Excitatory neu-
rons, sending their axons upward (toward the mouth), The simple dichotomy presented in the preceding text
ensure constriction of the bowel above a bolus of intes- disregards that, in addition, the sympathetic system
tinal contents. Such neurons typically contain acetyl- takes part in daily maintenance and is active not just in
choline and substance P. Inhibitory neurons send their stressful situations. For example, the sympathetic sys-
axons downward (toward the anus) and inhibit the tem is crucial for the temperature-regulating functions
circular muscle layer in front of a bolus, thus easing its of the skin, and sympathetic activity is required every
propulsion. Such neurons may contain ATP, vasoactive time we rise from the sitting position to avoid fall in
intestinal peptide (VIP), or nitric oxide (NO). Neurons blood pressure and fainting. Further, the sympathetic
acting on epithelial cells to increase the transport of water system cooperates with the parasympathetic system in
and electrolytes may contain either VIP or acetylcholine control of reproductive functions. Moreover, the sym-
(with a variety of peptides, such as galanin, neuropeptide pathetic system is not activated in an all-or-none fash-
Y, cholecystokinin [CCK], or calcitonin gene-related ion: some parts may be active, while others are not.
peptide [CGRP]). Thus, the sympathetic output to an organ may be regu-
A special kind of neuron contains the gastrin-releasing lated up and down independently of sympathetic out-
peptide (GRP). A group of such neurons are found in the puts to other organs. Finally, both systems may send
wall of the stomach and send processes to the gastrin- signals at the same time to an organ (the heart, e.g.,
producing cells in its distal part (the antrum). Stimulation receives both kinds of signals at the same time). The
of the vagus causes release of GRP, which then induces traditional scheme with reciprocal autonomic innerva-
release of gastrin to the bloodstream. It affects acid- tionwith autonomic tone determined by a point on
producing cells (parietal cells) in the upper part of the a continuum from sympathetic to parasympatheticis
stomach. therefore not tenable.
Finally, some enteric neurons are most likely sensory
and send their central process to prevertebral ganglia.
Actions of Sympathetic Fibers on the Circulatory
Thus, local reflex arcs not involving the CNS may exist.
and Respiratory Organs
The postganglionic sympathetic fibers innervate vessels
in all parts of the body. In general, the sympathetic
FUNCTIONAL ASPECTS OF THE AUTONOMIC
innervation of the circulatory system ensures that the
NERVOUS SYSTEM
cardiac output can be increased, that the blood pressure
can be maintained, and that the blood flow is directed
Defense and Maintenance
to the organs needing it the most.
When the autonomic system is considered as a whole, The sympathetic system increases the heart rate by
certain main functional features emerge (Table 28.1). acting on pacemaker cells in the sinus node. Further, the
stroke volume increases. Cardiac muscle cells with a musculature in humans, even though such innervation
lower spontaneous firing frequency than the cells of the is present in several animal species. Thus, using histo-
sinus node are activated by spread of the signal from fluorescence techniques, which visualize catecholamin-
the sinus node before the spontaneous depolarization ergic nerve fibers in tissue sections, studies in humans
has reached the threshold for an action potential. At have shown the presence of such fibers around the ves-
rest, the heart is under a certain dominance of the para- sels but not around the bronchi. Epinephrine, however,
sympathetic system (the vagus nerve), which restrains has a powerful inhibitory effect on the bronchial mus-
the cardiac activity. Actions on the stroke volume by culature; that is, it produces bronchial dilation. Most
the autonomic system are mediated by fibers ending likely, therefore, the sympathetic system acts on the
near the muscle cells of the ventricles. resistance of the airways by its stimulation of the adre-
Because the vascular smooth-muscle cells are arranged nal medulla.
circularly, contraction reduces the diameter and increases
the vascular resistance. Such vasoconstriction is most
Control of Blood Pressure and Blood-Flow Distribution
marked in the smallest arteries, the arterioles, which are
especially concerned with the regulation of blood flow Normally, the sympathetic neurons are activated
to the organs. Action potentials in the sympathetic fibers reflexly, and many of them are links in arcs for so-called
ending in the vessel walls produce vasoconstriction and, vasomotor reflexes, the reflexes in which the response
thus, reduced blood flow. By varying the signal fre- is a change of vascular diameter (and thus resistance).
quency of the sympathetic nerves, the CNS can vary the The reflex arcs go through the cord or higher levels (the
diameter of the vessels.2 When there are no signals in reticular formation or the hypothalamus). The superior
the sympathetic fibers innervating the vessel (and no aim of the control of blood pressure is to ensure that
other substances act to produce contraction), the arteri- the brain (and the heart) always has a sufficient blood
oles are maximally widened by the internal blood pres- flow. Baroreceptors in the large arteries in the neck and
sure. This is called vasodilatation (vasodilation). the aortal arch record the slightest fall in blood pressure
In many situations, the task of the sympathetic sys- and produce an automatic increase of the signal fre-
tem is to ensure that there is a sufficient blood flow quency of sympathetic fibers. This is most marked for
through high-priority organs, primarily the brain and the skeletal muscles, but, if necessary, the heart rate is
the heart. When the blood flow through these organs also increased. In this manner, vasoconstriction of the
diminishes, sympathetic neurons to vessels in other skeletal muscle arterioles is produced, thus increasing
parts of the body increase their firing rate. Thus, the the vascular resistance and elevating the blood pressure,
blood flow through skeletal muscles and the visceral with the end result that the blood flow to the brain is
organs is reduced. Sudden vasodilatation in large parts increased to an adequate level.
of the body leads to a fall in blood pressure and faint- Vasomotor reflexes have been studied with the
ing, because the cerebral blood flow is reduced. microneurographic technique, enabling the recording
Sympathetic innervation of the large veins is also of the activity of small groups of postganglionic sympa-
important for the maintenance of adequate blood pres- thetic fibers in humans. This makes it possible to study
sure. Constriction of such capacity vessels distributes the relationship between the sympathetic signal fre-
more of the blood volume to the arterial sidethat is, quency and, for example, blood pressure. The postgan-
the effective blood volume increases. This mechanism is glionic sympathetic fibers to muscle arterioles fire in
important in case blood volume is reduced (on bleeding bursts in pace with the pulse. The bursts are evoked by
or dehydration). baroreceptor activation during the diastole of the heart.
Signals in sympathetic fibers to arterioles in skeletal The overall firing frequency changes in association with
muscles produce (as their main effect) vasoconstriction. changes of blood pressure. Considering the enormous
Whether some sympathetic fibers may have the opposite blood flow that can pass through working muscles, we
effect in humans is not settled. Epinephrinereleased must obviously have central control of this part of the
from the adrenal medulla on sympathetic stimulation vascular system. Only if the heart increases its output and
may, however, inhibit the vascular smooth-muscle cells other vascular beds are constricted (e.g., in the abdomi-
and thereby produce vasodilatation. nal organs) can the sympathetic throttling of the mus-
The vessels of the lungs receive sympathetic fibers pro- cles be relieved without fall in the blood pressure.
ducing vasodilatation. It is doubtful whether postgangli-
onic sympathetic fibers act on the bronchial smooth
Individual Differences in Sympathetic Activity
There are striking differences among persons with regard
2 The degree of vasoconstriction is inuenced not only by the nervous system to the level of activity of sympathetic fibers under identi-
but also by circulating hormones, in particular, epinephrine. Further, sub-
stances produced by the local metabolism in the tissue inuence the degree of cal circumstances, as shown with the microneurographic
contraction of the vascular smooth-muscle cells. technique. Postganglionic fibers to skeletal muscles,
which constitute a large fraction of all postganglionic Irritation of Peripheral Nerves Can Produce Changes
fibers in peripheral nerves, have been studied in partic- in the Skin
ular. As mentioned, the activity of these fibers changes
The effects of sympathetic fibers to the skinthat is,
in close correlation with changes of the central blood
sweat secretion, vasoconstriction, and piloerection
pressure. Comparison of persons with normal blood
can be reproduced by electrical stimulation of the ven-
pressure shows that the resting activity of sympathetic
tral roots or the peripheral branches of the spinal nerves.
fibers varies by a factor of 10 from person to person.
The sympathetic fibers can be irritated by infections or
Thus, each person appears to have his own characteris-
by compression or traction of the nerves. In such cases,
tic pattern, which is unchanged over a long time. From
there is abnormal sweat secretion from pale and cold
this baseline value, the signal frequency is up- or
areas of the skin. Destruction of the sympathetic fibers
down-regulated in response to alterations in blood
(by, e.g., prolonged compression) leads to abolished
pressure caused by, for example, the change of body
sweat secretion and vasodilatation, resulting in areas of
position from sitting to standing. No clear correlation
the skin that are abnormally warm and red and at the
has been found between the level of activity in sympa-
same time dry. Observations of such local changes of
thetic fibers to muscles and elevated blood pressure
the skin can be helpful in the diagnosis of diseases that
(hypertension).
affect the peripheral nerves.
Effects of Sympathetic Fibers in the Skin

Effects of Sympathetic Fibers in the Gastrointestinal
The sympathetic innervation of the skin serves first and
Tract, the Genital Organs, and the Eyes
foremost the control of body temperature. The activity
of the postganglionic sympathetic fibers to the skin In the abdominal viscera, signals in sympathetic fibers
appears not to be clearly related to the blood pressure, produce vasoconstriction and reduced contractile activ-
in contrast to the activity of fibers supplying vessels in ity of the smooth muscles of the walls of hollow organs
skeletal muscles, but skin sympathetic fiber activity is (i.e., reducing the amplitude and frequency of the peri-
closely correlated with the ambient temperature. staltic movements). At the same time, the secretion of
The sweat glands of the skin are innervated by sym- the glands of the digestive tract is reduced. In sum, these
pathetic fibers, producing sweat secretion. Increased effects result in a marked reduction of the digestive
activity of fibers innervating the sweat glands occurs processes. The sympathetic system also inhibits the
together with reduced activity of fibers to the small ves- emptying of the rectum, both by inhibition of the smooth
sels. This produces vasodilatation and sweat secretion muscles of the wall and by activating the smooth
with increased loss of heat. A special feature of the muscles of the internal anal sphincter. The sympathetic
innervation of sweat glands is that the neurotransmitter system seems to play a minor role in the control of the
released from the postganglionic fibers is acetylcholine bladder in humans (see later, Normal Emptying of the
3
(and not norepinephrine). Bladder).
Sweat secretion may also occur in extreme situations The sympathetic innervation of the genital organs
with a large drop in blood pressure or with strong pain. concerns vessels and the smooth musculature. The inner-
In such situations, the skin vessels are maximally con- vation of the ductus deferens is of particular importance
stricted and the skin is, consequently, pale and cold because signals in sympathetic fibers are responsible for
(cold sweat). the rhythmic contractions during ejaculation. The
Signals in sympathetic fibers also activate the small uterus receives sympathetic fibers but their functional
smooth muscles attached to the hair roots, which make role is not clear. Thus, even after complete denervation,
the hairs stand up. This is called piloerection (piloarrec- the uterus may function normally in pregnancy and in
tion). At the same time, the muscles compress the seba- parturition.
ceous glands, so that they empty their product into the The sympathetic fibers to the eye have their cell bod-
hair follicle. In humans, the sympathetic control of hair ies in the superior cervical ganglion. They produce dila-
position is of minor importance, whereas in animals it is tion of the pupil by activating the pupillary dilatator
of great significance for control of body temperature. muscle and by causing contraction of the radially ori-
ented vessels of the iris (the latter effect is probably most
important for pupillary dilation). A small smooth mus-
cle attached to the upper eyelid, the tarsal muscle, is
3 Human hairy skin (but not glabrous skin) receives sympathetic bers of two
kinds: the ordinary noradrenergic vasoconstrictor bers innervating vessels in also innervated by sympathetic fibers. The tonic activity
all parts of the body, and cholinergic vasodilator bers. The latter bers medi- of this muscle helps to keep the eyelid up while we are
ate reex responses to rise in core temperature (whole body heating) when the awake (the paresis of the tarsal muscle is responsible for
need to dissipate heat is great. The cholinergic vasodilator bers co-release neu-
ropeptides (e.g., VIP). In addition, local NO production contributes to vasodi- the slight drooping of the eyelid occurring in Horners
latation. syndrome).
Orthostatic and Postprandial Hypotension copy). The other possibility is that a purely spinal reflex
inhibits the preganglionic neurons that control blood
Some people have poor control of the blood-flow distri-
flow to the working muscles.
bution in situations with change of body position from
supine to standing (orthostatic hypotension). This is
believed to be due to a failure of the sympathetic sys-
The Effects of Parasympathetic Fibers
tem. Such persons also often feel limp and uncomfort-
able after a meal, because of a fall in the blood pressure As mentioned, the sympathetic and the parasympathetic
(postprandial hypotension). Microneurographic studies systems have mostly antagonistic effects (on the organs
suggest that this is caused by a lack of sympathetic innervated by both; Tables 28.1 and 28.2). Because the
activity. Normally after a meal, the sympathetic signal postganglionic fibers usually contain neuropeptides in
activity increases in nerves to the lower extremities, addition to acetylcholine, however, their actions may
whereas in the patients with postprandial hypotension no be more complex than either stimulation or inhibition
such increase occurs. (To maintain the blood pressure, of the organ.
the blood flow to the lower part of the body must be The parasympathetic postganglionic fibers produce
reduced when that to the digestive tract increases.) glandular secretion (e.g., from the lacrimal gland, sali-
vary glands, and glands of the respiratory and gastroin-
testinal tracts). Parasympathetic fibers are furthermore
Function-Specic Sympathetic Control
responsible for increased strength and frequency of peri-
The preceding discussion showed that various catego- staltic contractions in the gastrointestinal tract and the
ries of sympathetic fibers can be controlled indepen- bladder. The parasympathetic innervation is particularly
dently. There is not a uniform sympathetic tone for important for the emptying of the bladder (Fig. 28.12)
all parts of the sympathetic system. High activity in and the rectum (control of micturition is treated in
some parts must coexist with low activity in others if Chapter 29 in connection with visceral reflexes).
the sympathetic system is to fulfill its tasks in control- As mentioned, the heart receives parasympathetic
ling blood pressure and body temperature, in reproduc- preganglionic fibers through the vagus nerve. The sinus
tion, and so forth. Accordingly, recent anatomic studies node and the atrioventricular node receive particularly
show that sympathetic neurons innervating different tar- dense innervation of postganglionic (cholinergic) fibers.
gets are more clearly segregated than formerly believed. Lowering of the heart rateby affecting the sinus
For example, double labeling with retrograde tracers nodeis the most marked effect of vagus stimulation.
show that, in the intermediolateral column, neurons In addition, the vagus exerts more complex effects on
supplying the superior cervical ganglion and the stellate the ventricles. Most likely, this happens by presynaptic
ganglion are largely segregated (although they are found inhibition of sympathetic postganglionic fibers, thus
mainly in the same spinal segments, with 90% in T1T6). reducing the contractile force of the heart muscle. Some
Thus, higher levels of the CNS (such as the hypothala- effects of vagus stimulation are not mediated by acetyl-
mus) can selectively control subdivisions of the sympa- choline but, most likely, by neuropeptides such as
thetic system. somatostatin and VIP. In the resting situation the heart
Microneurographic observations further support that receives parasympathetic signals with a low frequency
selective control takes place. Recording During rest, the (higher in endurance-trained than in untrained per-
firing frequency is uniform to different muscles. In this sons). During work, the influence of the vagus dimin-
situation, a common signal (probably from the brain ishes with the need for increased cardiac output. The
stem) commands all sympathetic neurons controlling effect of the vagus on the coronary arteries in humans is
muscle blood flow. As soon as a muscle starts working, believed to be constrictive. In the airways, the vagus
however, the sympathetic signal frequency drops in the produces bronchial constriction and secretion.
nerve to this muscle, while it remains unaltered to the Most of the vessels of the body do not receive para-
resting muscles. In this situation, the sympathetic sys- sympathetic innervation. Exceptions are vessels of glands
tem exerts a differential control of the muscles; that is, and of the external genitals, in which parasympathetic
the signal frequencies depend on their individual needs. signals cause vasodilation (i.e., they inhibit the smooth-
The specificity of sympathetic control of muscle muscle cells). Increased activity of the parasympathetic
blood flow can presumably arise in two ways. One pos- fibers to the penis (and the clitoris) produces erection
sibility is lowered central drive (from the brain stem) to (see Chapter 29, under Control of the Erection and
the preganglionic neurons that control specific muscles. In Ejaculation Reflexes).
turn, this may be due to sensory signals from ergorecep- In the eye, parasympathetic fibers of the oculomotor
tors in the working muscle, or that the motor cortex nerve reduce the diameter of the pupil and produce
informs higher levels of the autonomic system about which accommodation of the lens (see Chapter 27, under The
muscles are being selected for a motor task (efference Light Reflex and the Accommodation Reflex).
Emotions and the Autonomic Nervous System ganglion cells. The functional significance of these
neuropeptides, which coexist with acetylcholine in
The autonomic system is not independent of higher
preganglionic neurons, is so far not clear, but the two
mental processes, even though its processes are not
substances are most likely released together.
under conscious control or are as a rule not consciously
perceived. The activity of sympathetic fibers to the skin,
for example, are strongly influenced by emotions, as Postganglionic Neurons
witnessed by blushing when having made a fool of
Most postganglionic parasympathetic neurons release
oneself and paleness when frightened. Further, the
acetylcholine. In the peripheral organs, acetylcholine
effect of emotions on the circulatory system may mani-
binds to muscarinic receptors in the membrane of cardiac,
fest itself as palpitations, hypertension, or bradycardia
smooth-muscle, and glandular cells.
and peripheral vasodilatation, leading to a fall in blood
Most postganglionic sympathetic neurons release
pressure and perhaps fainting. In fainting, there are
norepinephrine and are noradrenergic (norepinephric).
marked changes of both sympathetic and parasympa-
The effects on the effector cells are mediated by two
thetic activity. The control of the gastrointestinal tract
kinds of receptors, - and the -adrenergic receptors,
may be altered by emotionsfor example, with increased
which are distributed differently and have different
peristaltic movements and secretions leading to diar-
effects on the postsynaptic cells. In the heart, norepi-
rhea. Also, bladder emptying is under emotional influ-
nephrine produces increased heart rate by its binding to
ence, as witnessed by the frequent urge to void when
receptors. By binding to receptors, norepinephrine
nervousfor example, before an exam or an athletic con-
produces contraction of smooth-muscle cells in most
test. In case of very strong fear, involuntary emptying of
blood vessels, in the ductus deferens, and in the pupil-
the bladder and rectum may occur. Emotional influence
lary dilatator muscle of the eye. Binding to -receptors
on erection is another example: sensory stimuli and sim-
elicits relaxation of smooth-muscle cells in the wall of
ple reflexes alone do not determine the parasympathetic
the bladder, the uterus, and the airways.
actions on the vessels in the penis and the clitoris.
Epinephrine, which is released from the chromaffin
Pathways and nuclei mediating the effects of emo-
cells of the adrenal medulla by sympathetic stimulation,
tions on preganglionic autonomic neurons (and thus on
has largely the same effects as norepinephrine. Thus,
visceral organs) involve parts of the cerebral cortex, the
epinephrine binds to - and -adrenergic receptors of
hypothalamus, the amygdala, the periaqueductal gray
the heart, vessels, and the respiratory tract. In addition,
(PAG), and the reticular formation. For example, elec-
epinephrine stimulates the release of free fatty acids from
trical stimulation of the amygdala can produce empty-
adipose tissue and the breakdown of glycogen to glu-
ing of the bladder and rectum in experimental animals.
cose. These metabolic effects are mediated by receptors
Probably, the pathway goes via the PAG (see also
in fat and liver cells.
Chapter 31, under Amygdala and Conditioned Fear
and Cortical Control of Autonomic Functions and
Emotions). Subgroups of Adrenergic Receptors
Each of the two main kinds- and -adrenergic
receptorshas several subtypes with different distribu-
NEUROTRANSMITTERS IN THE AUTONOMIC
tions and actions. When norepinephrine binds to the 1
NERVOUS SYSTEM
receptor, it produces opening of Ca2+ channels, which
leads to depolarization and, in turn, elicits contraction
Preganglionic Neurons
or secretion. The action of the 1 receptor is not directly
The signal transmission between neurons of the auto- on the Ca2+ channel but indirectly via intracellular sec-
nomic system is mediated by neurotransmitters, as else- ond messengers (diacylglycerol and activation of pro-
where in the nervous system. The preganglionic fibers tein-kinase C). The 2 receptor is mostly localized
end with typical synapses on the dendrites of the post- presynaptically and modulates the transmitter release.
ganglionic neurons. As mentioned, all (or the vast major- The 1 receptor is mostly localized postsynaptically in
ity of) preganglionic neurons use acetylcholine; that is, the heart, on adipose cells, and in the CNS. It acts through
they are cholinergic. The released acetylcholine binds to cyclic AMP as a second messenger. The 2 receptor has a
nicotinic receptors in the membrane of the postgangli- different distribution than the 1 receptor, being pri-
onic neurons in the autonomic ganglia. marily found in smooth-muscle cells of the respiratory
Many (perhaps all) preganglionic neurons contain in tract. Binding of epinephrine (or drugs with similar
addition neuropeptides (enkephalin, somatostatin, neu- action) to 2 receptors relaxes the smooth-muscle cells,
rotensin, and others), as demonstrated with immunocy- notably in the walls of the bronchi. This relaxation pro-
tochemical techniques. The various neuropeptides appear duces dilatation of the bronchi and reduces airway
to be expressed differentially in subgroups of autonomic resistance.
Noncholinergic and Nonadrenergic Transmission The sympathetic inhibiting effect on the peristaltic con-
in the Autonomic System tractions of the gastrointestinal tract is mediated, at
least partly, by binding of norepinephrine to recep-
In addition to the classical neurotransmitters acetylcho-
tors on the parasympathetic, cholinergic terminals: that
line and norepinephrine, several other neuroactive
is, the release of acetylcholine is inhibited.
substances have been demonstrated in the autonomic
nervous system. As mentioned, many preganglionic and
postganglionic neurons contain neuropeptides, as well Sensitization
as acetylcholine or norepinephrine. Further, some auto-
When the postganglionic autonomic fibers to an organ
nomic neuronsnotably in the enteric systemcontain
are interrupted, the sensitivity of the organ to the
neither acetylcholine nor norepinephrine. Such noncho-
transmitter (which is no longer released) is increased.
linergic and nonadrenergic (NANC) autonomic fibers
Epinephrine and norepinephrine in the bloodstream, for
are also found in the respiratory tract, the gastrointesti-
example, have a more powerful action after an organ
nal tract, the bladder, and the external genitals. Some of
has lost its sympathetic innervation, and the same holds
them release ATP or NO as a neurotransmitter; others
for adrenergic drugs. This phenomenon, called sensiti-
contain neuropeptides such as somatostatin, substance P,
zation, is not restricted to the autonomic system, how-
VIP, and CCK.
ever. It occurs, presumably, after denervation of any
The coexistence of norepinephrine and other trans-
neuron. For example, skeletal muscle cells have increased
mitters was first suggested by the observation that
sensitivity to acetylcholine after having lost their nerve
blocking the receptors for norepinephrine did not pre-
supply. The underlying mechanism is probably increased
vent all effects of sympathetic nerve stimulation. In the
postsynaptic density of receptors, as though the neuron
ductus deferens, which receives a very dense sympa-
attempts to maintain normal synaptic activity.
thetic innervation, stimulation of the nerves produces,
first, a fast contraction caused by release of ATP and,
subsequently, a slow contraction produced by norepi- Drugs with Actions on the Autonomic
nephrine. In the salivary glands, the parasympathetic Nervous System
postganglionic fibers release both acetylcholine and VIP.
Several drugs influence the synaptic transmission in the
The acetylcholine produces secretion from the glandular
autonomic nervous system. Atropine blocks the action
cells, whereas the VIP produces vasodilatation. Another
of acetylcholine (released from postganglionic parasym-
example concerns the arteries of the penis and the clito-
pathetic fibers) on muscarinic receptors. Other drugs
ris, which dilate to cause erection. This vasodilatation
have similar anticholinergic effects, often as a side effect.
is caused by parasympathetic postganglionic fibers that
This is the case for several psychopharmaceuticals.
release NO (but not acetylcholine).
The peripheral actions of the parasympathetic system
Some parasympathetic postganglionic fibers in the
are inhibited, causing symptoms such as dilated pupils
heart release somatostatin and probably VIP, thus increas-
(mydriasis) and reduced accommodation of the lens
ing the heart rate. In the stomach, vagus stimulation
(causing difficulties in seeing close objects clearly). The
can produce release of VIP in addition to acetylcholine.
heart rate increases, and the secretory activity is reduced
Stimulation of nerves to the human airways can pro-
in several glands. The reduced salivary secretion causes
duce bronchial dilatation, although not by release of
dryness of the mouth, a very bothersome side effect of
norepinephrine or acetylcholine. The effect appears to
anticholinergic drugs. Atropine, for example, is used to
be mediated by release of VIP from postganglionic
reduce secretion of glands in the respiratory tract dur-
nerve varicosities.
ing surgical anesthesia. The peristaltic contractions of
the bowel are reduced, causing constipation. The blad-
Presynaptic Receptors Modulate the Transmitter
der contractility is reduced, with danger of incomplete
Release from Postganglionic Nerve Terminals
emptying (especially in cases of prostatic enlargement
Neurotransmitters released from the postganglionic neu- causing increased urethral resistance, the danger of
rons bind not only to postsynaptic receptors in the mem- urinary retention should be kept in mind). Because the
brane of smooth-muscle and glandular cells but also to sweat glands receive a cholinergic innervation, their
presynaptic receptors in the membrane of the varicosi- secretion may also be reduced (most antiperspirants
ties along the fibers (see Fig. 5.1). Thus, for example, contain substances with an anticholinergic action).
norepinephrine that is released from sympathetic fibers Pilocarpine is an example of a drug with a parasym-
can bind presynaptically and inhibit further release of pathicomimetic action: that is, a cholinergic drug.
norepinephrine or bind to parasympathetic cholinergic Administration of pilocarpine causes increased salivation
terminals in the vicinity. In the heart, sympathetic fibers and tear flow, reduced heart rate, and increased secretion
inhibit the release of acetylcholine in this manner. from, and peristaltic movements of, the gastrointestinal
tract. The pupil is small (miotic), causing reduced vision to treat patients with bronchial obstruction (as asth-
in dim light. matics) without such side effects as increased cardiac
Many drugs activate adrenergic receptorsthat is, activity and hypertension.
they have sympathicomimetic effects. Some act on both Drugs can also influence the signal transmission in
and receptors; others act preferentially on one or the the autonomic ganglia. As mentioned, acetylcholine is
other receptor type (or on subtypes). Isoprenaline (iso- the main transmitter in both sympathetic and parasym-
proterenol) acts selectively on receptors and produces pathetic ganglia. The nicotinic receptors in the ganglia
increased heart rate and bronchial dilatation. Metaraminol are nevertheless somewhat different from those present
acts preferentially on receptors and causes peripheral at the neuromuscular junction. This makes it possible
vasoconstriction and, thereby, increased blood pressure. to influence one of these targets without affecting the
Drugs that block receptors (such as phentolamine) other.
produce peripheral vasodilatation and a fall in blood All neurotransmitters present in the peripheral parts
pressure, whereas drugs that block receptors mainly of the autonomic system are also found in the CNS,
cause reduced heart rate and stroke volume, and bron- together with adrenergic and cholinergic receptors.
chial constriction. The development of more selective Therefore, drugs designed to act on peripheral parts of
blockers, acting selectively on 1 receptors present in the autonomic nervous system may produce side effects
the heart, has made it possible to treat hypertension through actions in the CNSthat is, in case they pass
without unwanted bronchial constriction (2 receptors the blood-brain barrier. Beta () blockers, for example,
are found primarily in the lungs). In contrast, the devel- which are used extensively to treat hypertension, can
opment of adrenergic drugs acting selectively on 2 give central side effects, such as dizziness, disturbed
receptors (and not on 1 receptors) has made it possible sleep, and depression.
29 Sensory Visceral Neurons and
Visceral Reexes
OVERVIEW Under abnormal conditions, however, sensory sig-

nals from the viscera can produce the sensations of
Afferent fibers conveying sensory information from the intense pain and feeling of sickness. We discuss the spe-
viscera to the central nervous system (CNS) go together cial features of visceral pain and the phenomenon of
with the visceral efferent (sympathetic and parasympa- referred pain in particular.
thetic) fibers. Sensory fibers follow the sympathetic
splanchnic nerves, leaving the sympathetic trunk at
various levels, the parasympathetic cranial nerves (the VISCERAL RECEPTORS AND AFFERENT PATHWAYS
oculomotor, the intermediate, the glossopharyngeal,
and the vagus nerves), and, finally, the parasympathetic Visceral Receptors
pelvic nerves leaving the sacral spinal nerves to inner-
Morphologically, most of the visceral receptors are free
vate pelvic organs. As a general rule, fibers conducting
nerve endings (see Fig. 13.1).1 They respond to various
signals from visceral nociceptors follow sympathetic
kinds of stimuli, even though they are structurally iden-
nerves, whereas the parasympathetic nerves contain
tical. A large group consists of mechanoreceptors
fibers conducting from other kinds of receptors.
recording the tension of the tissue in which they are
The visceral afferent neurons are structurally indis-
located. Such receptors are found, for example, in the
tinguishable from the somatic afferent onesthat is,
heart, lungs, and the walls of hollow abdominal organs.
they have their pseudounipolar cell bodies in ganglia of
They provide information about the degree of filling of
the spinal and cranial nerves. The peripheral process
hollow organs and can elicit reflex contractions aimed
follows the sympathetic or parasympathetic nerves to
at emptying the organ or moving the content. Some
the organs, whereas the central process enters the dor-
stretch receptors may give rise to sensations of pain by
sal horn or the brain stem sensory nuclei (the solitary
responding to strong dilatation of a hollow organ and
nucleus). The vast majority of the visceral afferent fibers
to forceful contractions of the smooth musculature, but
are thin A and C fibers.
most visceral nociceptors are believed to be chemore-
The normal function of the sensory innervation of
ceptors sensitive to substances in the tissue produced by
the internal organs is primarily related to their media-
inflammation or ischemia.
tion of visceral reflexes, such as coughing, vomiting,
Other chemoreceptors, strategically placed in the
swallowing, circulatory and respiratory reflexes, emp-
vascular system (at the aortic arch and at the bifurca-
tying of the rectum and bladder, and so forth. These
tion of the common carotid artery), react to the carbon
reflexes have their reflex centers in the spinal cord or in
dioxide and oxygen concentration in the blood.
the reticular formation. In addition, silent nocicep-
Typically, visceral receptors have large receptive
tors may mediate information about the local milieu
fields, with a low density of nerve endings. These fea-
of the internal organs, contributing to homeostasis.
tures fit with the observations that visceral receptors
Visceral afferents also mediate information from the
exhibit marked spatial summationthat is, the thresh-
immune system to the brain, evoking fever and other
old for eliciting action potentials becomes lower as the
aspects of sickness behavior during infections and other
area of stimulation increases. This may explain why
inflammatory diseases. With some exceptions, such as
strong but spatially very restricted stimuli (such as knife
taste and fairly diffuse sensations of hunger, fullness,
cuts) usually do not evoke pain from visceral organs.
and so forth, the sensory signals from the viscera are
not consciously perceived.
The control of micturition is discussed, including not
only the spinal reflex mechanisms involved but also the
1 There are some encapsulated nerve endings in the visceral organs. Thus,
necessary contributions from the pontine micturition Pacinian corpuscles are present in the pancreas, the mesenteries, and the vessel
center and the cerebral cortex. walls. Their functional role at these sites is unknown.
432
29: SENSORY VISCERAL NEURONS AND VISCERAL REFLEXES 433
Peripheral Routes for Nociceptive Signals lamina I
As mentioned, most visceral afferents leading from

Spinal ganglion
nociceptors follow the sympathetic nerves (Fig. 29.1).
Exceptions to this rule are nociceptors in the neck
of the bladder, the prostate, the cervix uteri, and the
rectum. Pain fibers from these organs follow the
parasympathetic pelvic nerves to the sacral spinal nerves
(see Fig. 28.12). Signals from nociceptors in the fundus
of the uterus and of the bladder, however, follow the
Communicating
sympathetic nerves of the hypogastric plexus, ending in ramus
segments T11L2. Although nociceptive signals from the
heart were assumed to follow exclusively the sympa-
thetic nerves, some observations indicate that this may
hold only for signals from the anterior wall of the heart,
while signals from the posterior wall and the lower sur-
face may be conducted in the vagus nerve.2
Fibers carrying nociceptive signals from the arteries
in the extremities and the body wall follow the spinal
nerves, together with the sympathetic efferent fibers. Sympathetic trunk
Splanchnic nerve
Central Pathways for Visceral Afferent Signals

The sensory signals from the visceral organs pass through Prevertebral
plexus
the dorsal roots and end primarily in the dorsalmost
parts of the dorsal hornthat is, lamina I (Fig. 29.1;
see Fig. 13.16). Notably, the visceral afferents avoid the
substantia gelatinosa (lamina II, which receives numer-
ous C fibers from somatic structures). The sensory fibers
Intestinal organ
following the cranial nerves end in the solitary nucleus
in the medulla (see Fig. 27.2). From these receiving cell
groups in the spinal cord and in the brain stem, the sig-
gure 29.1 Sensory bers follow sympathetic nerves to the visceral
nals are transmitted to motor nucleiespecially those organs. The bers pass through the prevertebral plexuses and ganglia
consisting of preganglionic autonomic neuronsto the before they enter the spinal nerves via the communicating rami.
reticular formation, and to the hypothalamus and the
thalamus. For the most part, the visceral afferent sig-
nals that arrive through the dorsal roots are transmitted The Dorsal Columns Carry Signals from
centrally through the spinothalamic and spinoreticular Visceral Nociceptors
tracts (see Figs. 14.4 and 26.10). Details are not known, Surprisingly, in addition to constituting a major path-
however, with regard to the central transmission of way for signals from somatic low-threshold mechano-
visceral afferent signals. receptors, the dorsal columns have also been shown to
carry sensory signals from visceral organs. This con-
cerns postsynaptic dorsal column sensory units, many
of which are activated by noxious stimuli. In the gracile
2 Observations after surgical interventions to relieve pains of angina were
nucleus, some neurons receive converging inputs from
taken as evidence that all nociceptive bers from the heart follow the sympa- cutaneous low-threshold mechanoreceptors and high-
thetic nerves. These are the middle and lower cardiac nerves arising from the threshold receptors in the pelvic viscera. Corresponding
cervical sympathetic trunk, and some smaller twigs leaving the sympathetic
trunk below the stellate ganglion (45 upper thoracic ganglia). Although most
convergence occurs in the next link, in the VPL of the
patients reported complete relief of angina pains after cutting of the dorsal thalamus. Signals from cutaneous low-threshold mech-
roots in the upper thoracic and lower cervical segments (or removing the cor- anoreceptors on the arms and chest and from nocicep-
responding ganglia), some patients were not helped. However, some patients
reported pain relief after cutting of the vagus nerve, and electric stimulation of
tors in the heart converge on neurons in the cuneate
the vagus nerve has been reported to evoke burning pain deep in the chest. nucleus and the thalamus. Thus, the dorsal column
Perhaps these ndings may be explained if the nociceptive signals follow differ- medial lemniscus pathway can obviously contribute to
ent nerves from the anterior and posterior cardiac walls. Indeed, animal exper-
iments indicate that sympathectomy does not relieve pain arising in the posterior
signaling from visceral nociceptors, although this is not
cardiac wall. usually apparent from studies of its functions or the
effects of lesions. Nevertheless, there is evidence that J receptors produces rapid and shallow breathing but
signals in the dorsal columns can contribute to the may probably also cause bronchial constriction (this
experience of pain in humans. For example, a patient is known to occur in patients with heart failure and
with intense pain due to cancer of the large bowel was increased pulmonary capillary pressure). It is further-
made pain free by bilateral sectioning of the gracile fas- more believed that signals from the J receptors can reach
cicles at the T10 level (the effect lasted until his death consciousness and cause a feeling of shortness of breath,
three months later). Animal experiments confirm that or dyspnea. J receptors are also believed to elicit the dry
nociceptive signals from the lower abdomen and the cough typical of lunge edema, as occurring in patients
pelvis cease to activate the cerebral cortex after transec- with congestive heart failure or persons suffering from
tion of the gracile fascicle. Finally, the convergence altitude sickness.
mediated by the dorsal columns may also contribute to
referred pain (discussed later).
The Emptying Reex of the Bladder
As mentioned, the bladder emptying reflex is evoked by
VISCERAL REFLEXES stimulation of stretch receptors in the wall of the bladder,
which record filling. The signals are conducted in myeli-
Many of the visceral reflexes elicited by signals from nated afferent fibers to the lumbosacral cord (Fig. 29.2;
visceral receptors and receptors in the walls of vessels see Fig. 28.12). Many sensory units that lead from the
have their reflex centers in the spinal cord. The more bladder are slowly adapting with dynamic sensitivity;
complex reflexes, however, requiring coordination of that is, they respond more upon rapid than upon slow
activity in several parts of the body, have reflex centers distension of the bladder. No signals are sent when the
in the brain stem or in the hypothalamus. We return to bladder is empty, but when urine starts to accumulate
this in Chapter 30. Vasomotor reflexes were discussed the sensory units start firing. Normal adult bladder capac-
earlier in this chapter. Other important visceral reflexes ity is about 500 mL. The pressure in the human bladder
are produced by stimulation of receptors in the lungs during filling is typically between 5 and 15 mm Hg,
and the airways, such as coughing and respiratory whereas emptying is normally elicited at 25 to 30 mm Hg.
adjustments (see later). The vomiting reflex can be elic- At night (during sleep), the bladder fills to about the
ited by irritation of the mucosa of the stomach but also double of daytime volume before evoking an urge to
in various other ways (see Chapter 27, under The void. This is a prerequisite for 8 hours uninterrupted
Vomiting Reflex). The emptying reflexes of the rectum sleep.3 Urine does not leak out in the filling phase because
and the bladder are elicited by stimulation of stretch the intraurethral pressure is kept higher than the intra-
receptors in their walls and have reflex centers partly in vesical pressure. The intraurethral pressure is maintained
spinal segments (S2) S3S4 and partly in the brain stem. by several factors, among them smooth muscles and
These visceral reflexes are unusual because they can be elastic tissue in the urethral wall. In the filling phase,
suppressed voluntarily. The emptying reflex of the blad- the smooth muscle of the bladder wallthe detrusor
der is discussed further later. muscleis relaxed, while the striated external sphinc-
ter in the pelvic floor is tonically active. When the intra-
vesical pressure reaches the critical level, brisk activity
Reexes Elicited from Receptors of the Lungs
of parasympathetic neurons makes the detrusor muscle
Signals from stretch receptors in the bronchial walls contract. In addition, the striated sphincter muscle and
contribute to inhibition of inspiratory movements when other muscles in the pelvic floor must relax. Normal
the lungs have been inflated to a certain extent (the emptying of the bladder thus requires coordinated
Hering-Breuer reflex). Receptors producing coughing control of parasympathetic preganglionic neurons in
are probably free endings between the epithelial cells of the S3S4 segments and of motoneurons in the S1S3
the airways, in part located very close to the epithelial segments.
surface (irritation receptors). Such free nerve endings The parasympathetic control of the detrusor muscle
contain substance P (as do many other sensory neu- is mediated by acetylcholine. In addition, vasoactive
rons), which is released by exposure to irritant gases. intestinal peptide (VIP) released from parasympathetic
A special kind of receptorthe J, or juxtapulmonary, fibers might contribute to inhibition of the smooth
receptoris located close to the lung alveoli. It responds muscles surrounding the urethra.
to increased pulmonary capillary pressure. Increased
pressure in the left atrium (which receives the blood
from the lungs) immediately leads to increased pulmo- 3 One or more of the centers of the micturition reex must therefore be inhib-
nary capillary pressure, with the danger of developing ited during sleep. This inhibition develops between the ages of three and ve. In
children with enuresis (bedwetting), this inhibition seems to be lacking, as
lung edema. Thus, it seems reasonable that the capillary about the same bladder lling volume elicits emptying during night and during
pressure must be monitored closely. Stimulation of the daytime.
conversely, selective antagonists are used to improve
bladder outflow in such patients. Alpha ()-adrenergic
receptors are present at many levels of the reflex path-
PAG Pontine micturition waycentrally in the cord and at higher levels, in the
center autonomic ganglia, and in the smooth-muscle cell mem-
brane; further, they are located both pre- and postsyn-
aptically and are activated by both norepinephrine
Prefrontal cortex released from postganglionic sympathetic fibers and by
Hypothalamus
circulating epinephrine. Thus, deciding the site of action
of a certain adrenergic drug is not straightforward.
Central Control of Micturition

Normal emptying of the bladder requires more than
intact spinal reflex arches. This is evident in patients
with transsection of the cord above the sacral level. If
Bladder
the lesion is complete, all descending connections act-
ing on the sacral reflex centers are interrupted. The
S3 S4
patients experience great difficulties with emptying the
bladder because, among other problems, the activities
of the detrusor muscle and the internal sphincter are
not coordinated. This is called dyssynergia. (In addi-
External sphincter tion, the bladder often becomes hyperactivei.e., the
(striated)
emptying reflex is elicited at a lower pressure than
gure 29.2 Pathways and nuclei involved in control of micturition. before.) Patients with lesions of the brain stem above
The reex center for the emptying reex is located in the sacral cord the pons do not have dyssynergia. Further observations
but is controlled by descending connections from the pontine micturi- show that the dorsolateral pons (near the locus coer-
tion center. This is under control of higher centers, like the PAG, the uleus) contains a neuronal network that coordinate the
hypothalamus, and the cerebral cortex.
spinal reflexes involved in micturitionthe pontine
micturition center (Fig. 29.2). Ascending spinoreticular
fibers, which inform about the filling pressure, join the
The Role of the Sympathetic System in Bladder
spinothalamic tract ventrolaterally in the cord. The
Control Is Not Clear
fibers end in the PAG, which is assumed to send signals
Evidence in experimental animals (cats and dogs) indi- to the micturition center. The marked emotional influence
cates that sympathetic activity increases during the filling on micturition, such as frequent urination in association
phase, inhibiting the detrusor and activating smooth- with nervousness and fear, is probably mediated by con-
muscle cells around the urethra in the bladder neck (inter- nections from the amygdala to the PAG (see Fig. 31.6).
nal sphincter). Few noradrenergic fibers are found in the Animal experiments indicate that the descending (retic-
human detrusor region (fundus), however, and sympa- ulospinal) fibers from the pontine micturition center lie
thetic stimulation does not seem to inhibit the detrusor in dispersed in the lateral funiculus, with the majority in
the filling phase. (Because many noradrenergic fibers are its dorsal part. Clinical observations, however, indicate
found in the pelvic plexus and associated small parasym- that in humans the fibers might lie more ventrally, close
pathetic ganglia, sympathetic inhibition of the detrusor to the pyramidal tract in the lateral funicle. Thus, damage
muscle might theoretically occur by inhibition of the of the pyramidal tract in the spinal cord is often associ-
postganglionic parasympathetic neurons.) There is a ated with urge incontinence (inability to inhibit the
richer noradrenergic innervation acting on 1-adrenergic emptying reflex) as a sign of impaired central bladder
receptors to produce contraction of smooth-muscle cells control.
in the bladder neck and trigonal area. These smooth mus- Although lesions above the pons do not disturb the
cles function as a genital sphincter that prevents back- normal emptying of the bladder, patients with such
flow of semen to the bladder during ejaculation. The role lesions may have problems with controlling of the initia-
of sympathetic innervation of the bladder neck for main- tion of micturition (inhibition in particular). The cell
taining the urethral pressure during the bladder-filling groups responsible for the voluntary control of micturi-
phase is not equally clear, however. Nevertheless, drugs tion are not known in detail, although medial parts of the
acting on adrenergic receptors affect bladder emptying. frontal lobe and the hypothalamus appear to be involved
Thus, -adrenergic agonists may worsen urinary reten- (Fig. 29.2). Clinical observations indicate that damage to
tion in patients with an enlarged prostatic gland and, the frontal lobes may cause urge incontinence.
Cortical Activity and Bladder Control reflex centers for erection and ejaculation. They are not
necessary for erection and ejaculation, however. Thus,
Positron emission tomography (PET) and functional
provided the lesion is above the midthoracic level, both
magnetic resonance imaging (fMRI) studies indicate
erection and expulsion of the semen can occur after
that neurons in the dorsolateral pons and the prefrontal
transection of the cord. In such patients, erection is
cortex increase their activity during micturition. The
evoked by sensory stimuli from the penis (the patient
activity is largest on the right side in both men and
has no conscious sensations, however, because the
women. In persons trying to void without succeeding, the
ascending sensory tracts are interrupted). The hypotha-
activity increases in the frontal lobe but not in the dorso-
lamic cell groups are influenced, among other areas,
lateral pons. There is sign of increased activity, however,
from the cerebral cortex and the amygdala. Normally,
in a slightly more ventral pontine region; in animals, this
of course, descending connections from these higher
region controls the pelvic muscles (presumably including
levels are involved in the induction of erection, more or
the external urethral sphincter) by descending reticu-
less independently of the sensory signals that act through
lospinal fibers. When trying to inhibit voiding when the
the spinal reflex arc. The spinal reflex centers of erec-
bladder was full, activity increases in the anterior
tion and ejaculation are inhibited from an area in the
cingulate gyrus and the insula. This fits with data show-
ventral part of the upper medulla by way of descending
ing that the insula receives visceral sensory inputs (see
connections that act on parasympathetic and sympa-
Chapter 34, under The Insula). Both the insula and
thetic preganglionic neurons and motoneurons. The
the anterior cingulate gyrus are furthermore known to
lack of such inhibitory connections may explain why
influence the autonomic system. In addition, the ante-
some patients with transection of the cord above the
rior cingulate gyrus is active during focused attention
sacral level suffer from priapismthat is, a hyperactive
and when selecting appropriate behavior. The insula
erection reflex.
may be responsible for sending descending commands
eventually inhibiting the detrusorwhen micturition
should be postponed.
VISCERAL PAIN
The Erection and Ejaculation Reexes Salient Features

As mentioned, erection depends on parasympathetic Visceral pain differs in many respects from pain origi-
signals to the vessels of the penis or the clitoris, whereas nating in somatic structures; it is usually more diffuse,
ejaculation is due mainly to sympathetic signals to the less precisely graded, and of a different quality than
smooth muscles of the ductus deferens and the prostate. pain arising in the skin. Visceral disease processes, such
The preganglionic neurons of these functions have their as appendicitis, initially cause a vague discomfort, with
cell bodies in the lumbosacral cord (see Figs. 28.7 and nausea rather than pain. Also, a feeling of fainting may
28.11). In addition, successful expulsion of the semen occur, probably due to lowered blood pressure. The ini-
requires coordination of smooth muscles closing the tial discomfort or pain is typically felt deep in the mid-
upper urethra (the genital sphincter, mentioned above) line in the thorax or the abdomen, regardless of the
and striated muscles of the pelvic floorthat is, sphinc- organ involved. This first phase usually lasts for min-
ter muscles and muscles around the penile cavernous utes to some hours. Thereafter, the pain moves to sites
bodies, especially the bulbospongiosus (bulbocaverno- more specific to the diseased organ, but not necessarily
sus) muscle. The motoneurons of the latter muscles where the organ is located. The pain is typically felt
are found in the sacral cord. In male rats, these groups in the body wall or the extremities innervated from
of motoneurons are three times larger than in female the same spinal segments as the diseased organ. This
rats. This sexual dimorphism arises early in the prena- referred paindescribed in more detail lateris easier
tal development and depends on the presence of minute to localize and describe than the initial discomfort or
amounts of androgens. pain. Skin areas with referred pain may become hyper-
Evidently, erection and ejaculation require precise esthetic (increased sensitivity for touch) or hyperalgesic
temporal coordination of several muscles. The coordi- (increased pain upon nociceptor activation). The hype-
nation is carried out in the spinal cord by a complex ralgesia is usually most marked in muscles and can be
premotor network. For example, the activity of sympa- accompanied by tonic contractions. Appendicitis, for
thetic preganglionic neurons in the lower thoracic example, usually leads to a bandlike hyperesthetic
upper lumbar cord must be coordinated with the activity region of the skin corresponding to the dermatomes
of parasympathetic preganglionic neurons and T1T11 (see Fig. 13.14) on the right side. In addition,
motoneurons in the sacral cord. Cell groups in the retic- circulatory changes may occur in the same area, pre-
ular formation of the pons, close to those controlling sumably caused by reflex actions on preganglionic sym-
micturition, and in the hypothalamus control the spinal pathetic neurons. Thus, looking for such sensory and
circulatory changes may provide valuable diagnostic (angina pectoris) or occluded (heart infarction). Pain
clues when suspecting diseases of visceral organs. may also be felt when viscera are inflamed and when
Typically, visceral pain is accompanied by slow pulse, irritating substances come in contact with the perito-
lowered blood pressure, and cold sweatthat is, effects neum, as in cases of perforation of a gastric ulcer or an
mediated by the autonomic nervous system. Nausea inflamed gallbladder. The spread of bile, gastric con-
and vomiting, and a tendency to keep still are also fre- tent, or blood to the peritoneal cavity causes extreme
4
quent in patients with visceral pains. Many of these pain and shock. Sensory units leading from the bladder
effects are probably orchestrated by the periaqueductal change their behavior when the mucosa is inflamed.
gray (PAG). The PAG receives nociceptive signals and First, mechanoreceptors recording stretching of the
coordinates a varied specter of autonomic and somatic wall become more sensitive (lowered thresholds); sec-
reactions to stressful stimuli (see Chapter 15, under ond, many silent nociceptors (see Chapter 13, under
The Functional Role of the Pain-Suppressing Systems). Not All Nociceptors May Signal Tissue Damage)
Several factors might contribute to the diffuseness of start firing. Under normal conditions, even marked
visceral pain. As mentioned, the density of sensory stretching of the wall does not activate such receptors,
innervation is generally low in visceral organs with, whereas in inflammation they respond to even moder-
consequently, very large receptive fields of the sensory ate distension of the bladder. This may explain the fre-
units. In addition, the central branches of the visceral quent voiding in patients with cystitis and the urge to
spinal ganglion cells run for a long distance, both ros- void even when the bladder is almost empty.
trally and caudally in the cord. Thus, signals entering in The arteries are also sensitive to painful stimuli. An
one dorsal root can activate spinothalamic cells at many arterial puncture (e.g., to draw a blood sample) is painful.
segmental levels. Further, spasmodic contractions or strong dilatation
of arteries are also painful. For example, the pain of
migraine is most likely due to dilatation of extracranial
Stimuli that Activate Visceral Nociceptors
arteries and subsequent inflammation.
The adequate stimuli for visceral nociceptors differ
from those of somatic nociceptors. This may be so Sympathectomy
because visceral organs are not normally subject to
Knowledge of the special features of visceral pain and
stimuli that are potentially tissue damaging and thus
of the segmental innervation of visceral organs (see
require a change of behavior. In fact, stimuli that harm
Table 28.2) is of importance for surgical interventions
the visceral tissue may not provoke pain, while appar-
of the autonomic nervous system. Such operations are
ently innocuous stimuli may cause intense pain. Surgery
performed most often on the sympathetic system (sym-
of visceral organs (e.g., of the abdomen) can be per-
pathectomy). Indications are chronic pain conditions,
formed without the patient feeling pain as long as the
especially complex regional pain syndromes (CRPS; see
abdominal wall is anesthetized. Pain is felt only when
Chapter 15, under Complex Regional Pain Syndromes
the mesenteries or the peritoneum is pulled. Cutting
(CRPS)Special Type of Pathologic Pain) but sym-
with a sharp knife, for example, is not painful, and nei-
pathectomies are also performed to increase the blood
ther is tearing or pinching. Indeed, cancer of the lungs,
flow of the extremities (to interrupt vasoconstrictor
kidneys, the liver, and the gut may cause considerable
fibers) and to reduce excessive sweating (hyperhidrosis).
tissue destruction without evoking pain. Still, abnormal
For example, interruption of the lumbar sympathetic
distension of a hollow organ or forceful contraction of
trunk interrupts the sympathetic outflow to the lower
smooth muscles in its wall produces intense pain. This
extremities (see Fig. 28.9). The use of sympathectomies
occurs when a stone blocks the ureter or the gall ducts,
for these conditions is controversial, due to unwanted
or when something obstructs the intestine. The wall of
side effects and lack of convincing documentation of
the organ is distended above the obstruction, and force-
effects.
ful contractions of the smooth musculature are pro-
Sympathectomy or sympathetic block is also per-
duced in an attempt to overcome the obstruction. Such
formed occasionally to interrupt the pathways for pain
spasmodic contractions usually occur with regular
signals from visceral organs. For example, in some
intervals, explaining the typical bouts of pain experi-
patients with intractable pain arising in the upper abdo-
enced in such cases. Another cause of visceral pain is
men (usually because of terminal cancer of the pancreas
ischemia, which can occur when an artery is narrowed
or the stomach), the transmission of sensory signals can
by thrombosis or embolism. The most common exam-
be blocked by alcohol injections into the celiac plexus.
ple is the pain felt when a coronary artery is narrowed
Because this procedure also blocks the efferent sympa-
thetic signals, the patients experience transitory orthos-
4 The bouts of pain due to obstruction of a hollow visceral organ (the ureter or tatic hypotension due to vasodilatation in the abdominal
the intestine) are usually accompanied by an intense urge to move. organs.
Referred Pain Diaphragm

Heart
As mentioned, pain of visceral origin is often not felt Gall
bladder
where the organ is located but in some other place,
often in the body wall or the extremities (Fig. 29.3).
This phenomenon is called referred pain. The referred
painfor example, in the left arm in the case of angina,
and under the right scapula in the case of a gallstone Ureter
(stone)
can be localized fairly precisely by the patient. At the Small
site of the diseased organ, however, there is usually only intestine
a diffuse pain, difficult both to localize and to describe. Uterus
Rectum
As mentioned, it typically takes some time for referred
pain to develop. Appendix
The most widely accepted explanation of referred Large
pain is based on the observed convergence of signals intestine Ureter (stone)
from somatic structures (especially the skin) and
gure 29.3 Referred pain. Examples of typical sites of pain in
viscera.5 Such convergence occurs in the dorsal horn, in diseases affecting various visceral organs. (Based on Cope 1968.)
the dorsal column nuclei, and in the thalamus, as dis-
cussed above and in Chapter 14 (under Spinothalamic
going to a visceral organ or a muscle. For example, one
Neurons Receive Signals from Both Somatic and Visceral
study found that about one-fifth of the fibers in the
Structures). As a rule, the diseased organ and the site
splanchnic nerve could be activated by electric stimula-
of referred pain receive sensory innervation from the
tion of a somatic nerve. This may also contribute to the
same spinal segments. Conceivably, the signals coming
occurrence of referred pain. In such instances, an axon
from the visceral organs are interpreted as arising in the
reflex (see later) may cause cutaneous hyperesthesia and
skin and not in the visceral organ because signals from
vascular changes, as sensory signals from the visceral
the visceral organs are never consciously perceived
organ are conducted not only into the cord but also
under normal circumstances (e.g., nociceptors of the
peripherally in the branch into the skin. There sensory
heart are not normally stimulated). The referred pain
fibers may release neuropeptides such as substance P and
usually takes some time to develop, and the occurrence
VIP, which cause changes of blood flow and sensitize
of (referred) hyperesthesia and hyperalgesia is presum-
sensory nerve endings (see Chapter 13, under Primary
ably explained by sensitization of central neurons receiv-
Sensory Fibers and Neurotransmitters).
ing convergent inputs, leading to hyperexcitability and
even spontaneous firing (i.e., independent of signals from
the periphery). The importance of central sensitization is Examples of Referred Pain
supported by the observation that the referred pain is felt
The pain arising in the heart is usually referred to the
even after blocking the sensory nerve fibers that lead
ulnar aspect of the left arm or the upper part of the
from the area of referred pain. Further, the expansion of
chest (Fig. 29.3). These regions of the skin and the heart
the painful area after some time is best explained by cen-
both receive sensory innervation from the upper tho-
tral sensitization of propriospinal neuronstransmitting
racic segments of the cord. The gallbladder and the skin
signals to segments above and below those innervating
in the region of the lower end of the scapula are both
the diseased organ. Indeed, animal experiments show
innervated from the eighth thoracic segment. The shoul-
that the receptive fields of dorsal horn neurons expand
der pain on irritation of the diaphragm is explained by
dramatically when the tissue from which they receive
the common innervation from the fourth and fifth
sensory signals is chronically inflamed.
cervical segments. Pain from the urinary bladder can be
Another peculiarity is that referred pain shows a
referred to two areas of the skin: one innervated by the
tendency to localize to parts of the body that previously
spinal segments S2-S3 and one higher up on the back
have been the site of a painful process. For example, a
innervated by the lower thoracic and upper lumbar seg-
patient felt the pain of angina in a part of the spine that
ments (see Fig. 13.15). This fits with the segments of
had been fractured many years ago. It seems as if a pain
the cord innervating the bladder (see Fig. 28.12).
can be remembered as a persistent central sensitization
(plasticity).
The peripheral axon of some spinal ganglion cells Antidromic Signals and the Axonal Reex
divides, with one branch going to the skin and another
Electrical stimulation of dorsal roots can produce vaso-
dilatation in the dermatome of the root concerned. This
5 That local anesthesia of the diseased organ prevents the development of
is caused by signals conducted in the peripheral direc-
referred pain proves that it depends on the nervous system. tion by the sensory fibers. Signals conducted in the
direction opposite the normal direction are called innervate the stimulated skin stripe. These branches
antidromic. Of course, the action potentials are end in the skin outside the stripe, where they liberate
exactly the same as those conducted in the normal substance P and cause vasodilatation. The process is
orthodromicdirection. Antidromic signals in C fibers called a reflex, and because it uses only the peripheral
appear to release substance P from the peripheral process of a pseudounipolar ganglion cell, it is called an
branches. Substance P probably causes the release of axon reflex. The reflex cannot be elicited in an area of
histamine (presumably from mast cells). Histamine the skin that has been deprived of its sensory innerva-
causes vasodilatation, especially of the capillaries, and tion, proving that the phenomenon is mediated by nerve
at the same time the capillaries become leaky. Thus, a fibers.
local edema is produced. Under normal conditions, the antidromic signals in sen-
Various phenomena can probably be explained by sory fibers hardly play any role, but they may help explain
this phenomenon. When the skin is stroked with a fairly certain pathological phenomena. An example from the
sharp object, it reddens (vasodilatation) after a few sec- airways can be mentioned. In disposed individuals, irritat-
onds on both sides of the stripe. This can be explained ing gases can produce a marked edema of the mucous
as follows: the stroking of the skin stimulates C fiber membranes. The edema is caused apparently by histamine
nociceptors, and action potentials are conducted to the release, which, in turn, is caused by substance P released
CNS (and we experience a sharp pain). At the same by an axon reflex from the sensory fibers that innervate
time, however, the action potential is also conducted the mucous membrane (partly coming close to the surface
peripherally in the branches of the C fiber that do not of the epithelium).
30 The Central Autonomic System:
The Hypothalamus
OVERVIEW blood pressure, noxious stimuli, and skin temperature;

and the intensity of ambient light. Afferents from lim-
Sympathetic and parasympathetic parts cannot be bic structures inform about emotional and motivational
clearly separated in the higher centers that control auto- aspects. Hypothalamic efferent connections are also
nomic functions. This is not unexpected, as there is a widespread and have three main targets: the pituitary,
constant need for coordination of the activity of pregan- autonomic preganglionic neurons, somatic-efferent cell
glionic sympathetic and parasympathetic neurons. As groups, and higher levels of the brain (limbic structures
discussed in Chapter 28, it is not so that either the sym- and the cerebral cortex).
pathetic or the parasympathetic system is active. Further, The role of the amygdala (and some other nuclei) and
higher levels can select specific subgroups of pregangli- the cerebral cortex in the control of autonomic functions
onic neurons for a certain task. We have also mentioned is discussed in Chapter 31.
regions in the brain stemin the reticular formation in
particularthat initiate various automatic behaviors,
such as stereotyped, purposeful movement patterns and CENTERS IN THE BRAIN STEM FOR
effects mediated by the autonomic nervous system. Such COORDINATION OF BEHAVIOR
brain stem centers do not operate independently,
however; in most instances their activity is modulated Physiological experiments have localized several regions
and controlled from higher levels of the brain, among of the brain stem involved in the control of autonomic
which the hypothalamus has a prominent role. In addi- processes (see Chapter 26, under Control of Circulation
tion, the hypothalamus plays a unique roleby means and Respiration, and Chapter 29, under Visceral
of the pituitary glandin the superior control of the Reflexes). Electrical stimulation and lesions of restricted
endocrine system. parts of the reticular formation of the pons and medulla
Even though the hypothalamus is the part of the brain produce changes in blood pressure, cardiac activity,
most closely linked with control of the autonomic ner- respiration, sweat secretion, gastrointestinal activity,
vous system, its functional role is wider. Thus, a central and other processes. Such higher-level centers exert
task of the hypothalamus is to coordinate autonomic, control of the lower autonomic reflex centers of the spi-
endocrine, and somatic motor responses to behavior nal cord and coordinate their activities. The anatomic
that is appropriate for the immediate needs of the body, substrates of the brain stem centers are groups of neu-
such as feeding, drinking, and reproduction. The overall rons in the medullary and pontine reticular formation;
aim is to maintain bodily homeostasis in a wide sense. as a rule, the centers are not well-defined nuclei but are
The hypothalamus is also connected with higher parts formed by extensive networks of interconnected neu-
of the central nervous system (CNS), however, including rons. Visceral afferent fibers ending in the solitary
the cerebral cortex and the amygdala. These connections nucleus inform the networks of the state of the body.
are important links in the interactions between bodily From there, signals pass to various premotor groups in
and mental processes (psychosomatic interrelations), the reticular formation, which, in turn, send efferents to
which play a role in both health and disease. Especially, motor nuclei (autonomic and somatic) in the brain stem
interactions between the nervous system and the immune and the cord. The brain stem centers thus ensure, for
system may help explain how mental states influence example, that the segmental vasomotor reflexes operate
health and disease, and how bodily processes influence together to serve the needs of the whole organism, not
our mental states. only its individual parts. We discussed in Chapter 28
The afferent connections of the hypothalamus are how the blood supply of other organs is subordinate to
multifarious, reflecting its integrative role. The hypo- the needs of the brain and how the micturition center in
thalamus receives information about olfactory and taste the pons coordinates the activity of several smooth and
stimuli; the conditions in the gastrointestinal tract; the striated muscles. Further, cell groups in the reticular
440
30: THE CENTRAL AUTONOMIC SYSTEM: THE HYPOTHALAMUS 441
formation initiate movements and postural adjustments STRUCTURE AND CONNECTIONS OF THE
as parts of complex behaviors in response to thirst, HYPOTHALAMUS
hunger, external dangers, sexual arousal, and so forth.
Several such behaviors are coordinated from the supe- This small part of the brain, weighing only 4 to 5 g in
rior colliculus and the periaqueductal gray (PAG) in the humans, is a mosaic of minor nuclei that can be distin-
mesencephalon by way of their efferent connections to guished on the basis of their cytoarchitectonics, connec-
the reticular formation. Connections from the PAG ini- tions, cytochemistry, and physiological properties. Only
tiate coordinated alterations of circulation and respira- the main features are discussed here.
tion, pain perception, and automatic movements in
response to threatening or novel stimuli. Pain, for exam-
Hypothalamic Nuclei
ple, might be understood not merely as signal of tissue
damage but as signaling the need to change behavior. In the wall of the third ventricle, below the hypotha-
A perfect coordination cannot be performed by the lamic sulcus, some identifiable nuclei are embedded in a
brain stem autonomic centers, however. This is witnessed more diffuse mass of neurons (Figs. 30.130.3); together
by the poor control of autonomic functions such as blood these constitute the hypothalamus. The borders between
pressure and body temperature in decerebrate animals. the hypothalamic nuclei and the neighboring regions are
Optimal autonomic control, and coordination of auto- not sharply demarcated. This explains why different
nomic with endocrine and somatic processes, requires authors have drawn the borders differently. Figure 30.3
that the brain stem and spinal centers be supplied with shows the classic subdivisions of the British neuroanato-
afferent fibers from higher centers, especially in the hypo- mist Le Gros Clark. It is now common to distinguish a
thalamus but also in the amygdala (which acts on the medial part of the hypothalamus, containing several
brain stem partly through the hypothalamus). discernible nuclei, and a lateral hypothalamic area (or
nucleus) with a diffuse structure. Numerous longitudi-
nally running fibers traverse the lateral hypothalamic
PAG Coordinates Behavior in Response
area. These fibers are often collectively termed the medial
to Threatening Stimuli
forebrain bundle, though this is not a single tract ana-
The PAG is not a unit, either anatomically or function- tomically or functionally and has no sharp borders (see
ally. It consists of several columnar groups of neurons, Chapter 31, under The Medial Forebrain Bundle).
each differing with regard to connections. Stimulation Within the medial part, one can distinguish anterior,
of a dorsolateral column elicits arousal, tachycardia, middle (tuberal), and posterior (mammillary) nuclear
rise in blood pressure, and increased respiration, and it groups. Particularly well defined are two anterior large
facilitates orienting responses. At the same time, a non- nucleithe paraventricular nucleus and the supraoptic
opioid analgesia is produced. The actions are mediated nucleus (Fig. 30.3). The first is located close to the wall
by, among others, connections to the locus coeruleus, of the third ventricle; the latter is just above the optic
the ambiguus nucleus, the solitary nucleus, and parts of chiasm (Fig. 30.1). In the same region lies the suprachi-
the reticular formation but also by ascending connec- asmatic nucleus (SCN) that functions as a biologic
1
tions to the anterior hypothalamus and the intralaminar clock (see later, Circadian Rhythms). In the middle,
thalamic nuclei. Together, this part of the PAG initiates or tuberal, nuclear group we find the ventromedial, the
defensive behavior in response to strong emotions or dorsomedial, and the arcuate (infundibular) nuclei. The
aversive external stimuli. Stimulation of a ventrolateral latter nucleus is located in the bottom of the third
column in the PAG elicits inhibition of movements, like ventricle (Figs. 30.1 and 30.3; see Fig. 6.24), below the
the freezing response to sudden fear (e.g., when a rat ventromedial nucleus. In the posterior part of the hypo-
sees a cat). In addition, the PAG probably mediates the thalamus we find the posterior nucleus close to the
immobility typical of conditions with strong visceral ventricular wall, whereas the characteristic mammillary
pain. The immobility is accompanied by fall in blood nucleus (consisting of several subnuclei) is located in
pressure, bradycardia, and opioid-dependent analgesia. the bottom of the ventricle (Fig. 30.3; see also Fig. 33.8)
These effects are mediated by efferent connections to The term mammillary body is used for the macroscopi-
the nucleus raphe magnus (NRM) and the reticular for- cally visible part of the mammillary nuclei (see Fig. 6.13).
mation in the ventrolateral medulla, and to the lateral In general, short intrahypothalamic fibers mediate a high
hypothalamus and the basal forebrain. degree of cooperation among the hypothalamic nuclei.
How the brain chooses between the two kinds of Notably, there are numerous reciprocal connections
behavior that can be elicited from the PAG is not quite
clear. Presumably, descending commands from higher
levels (probably routed through the hypothalamus and 1 The suprachiasmatic nucleus cannot be identied in ordinary thionine-
stained sections in contrast to the supraoptic and paraventricular nuclei. It is
the amygdala) differ, depending on the nature of the clearly visible, however, by use of immunocytochemical identication of several
stimuli and their context. neuropeptides (vasopressin, VIP, neuropeptide Y, and neurotensin).
Corpus callosum
Caudate nucleus
Fornix
Anterior thalamic
nucleus
Third ventricle
Globus pallidus
Paraventricular nucleus
Lateral hypothalamic
area
Supraoptic nucleus
Optic tract
Arcuate nucleus
Amygdala
gure 30.1 The hypothalamus.
Frontal section through the hemi-
sphere.
between the medial nuclei and the lateral area (nucleus)

Fornix
of the hypothalamus.
The Hypothalamus Contains Many Neurotransmitters

Thalamus
Numerous neurotransmitters are present in the hypo-
thalamus, as demonstrated with immunocytochemical
and biochemical methods. Acetylcholine, norepineph- Hypothalamus
rine, dopamine, serotonin, histamine, and many neuro-
peptides occur with a differential distribution among Infundibulum
the hypothalamic nuclei. Norepinephrine is among the (Pituitary stalk)
neurotransmitters found in highest concentration (some Pituitary
of the norepinephrine is related to terminals of fibers gland Mammillary
body
from the locus coeruleus). Some of the neuropeptides
are involved in the hypothalamic control of the pitu-
itary gland or are released to the bloodstream in the Paraventricular
ventricular Ventromedial Posterior
Nucleus
nucleus
eu
us nucleus
nucleu
euss paraventricularis
nucleus
pituitary. We return to some of the neuropeptides and
Corpus callosum
Fornix
Lamina
Thalamus terminalis
Supraoptic
Hypothalamus nucleus
Mammillary body
Optic Mammillary
chiasm Arcuate
Optic nerve nucleus body
Pituitary stalk Tuber
Adenohypophysis Infundibulum cinereum
Neurohypophysis
gure 30.3 The hypothalamus. Median section through the third
gure 30.2 The hypothalamus and the pituitary as seen in a midsag- ventricle. Some of the major hypothalamic nuclei are shown with col-
ittal MRI scan. (Courtesy of Dr. S.J. Bakke, Rikshospitalet University ored dots. The size of the dots indicates the relative size of the neurons
Hospital, Oslo, Norway.) of the various nuclei. (Redrawn after Le Gros Clark et al. 1936.)
their possible functions later in this chapter. Here we note The many groups of afferents end in at least partially
that each neuropeptide takes part in different functional different parts of the hypothalamus, which fits with
tasks, even though only one is mentioned in this discus- physiological evidence that the hypothalamus consists
sion. The functional role of the various neurotransmitters of many functionally different parts (we discuss some
in the hypothalamus is still incompletely known. of these later in this chapter). Nevertheless, both the
many intrinsic connections and the properties of single
cells show that the various afferent signals are consider-
Afferent Connections and Other Kinds of Input
ably processed and integrated before commands are
to the Hypothalamus
sent out to various targets.
Figure 30.4 shows diagrammatically the main afferent
connections of the hypothalamus. It is immediately
The Connections and Functions of the Hypothalamic
clear that manyperhaps mostparts of the brain are
Nuclei Have Been Difcult to Clarify
able to influence the hypothalamus! (The mammillary
nucleus is in several aspects different from the other Determining the exact connections and functional roles
hypothalamic nuclei and is treated separately later in of the various nuclei has proved more difficult in the
this chapter.) In addition, the hypothalamus is special hypothalamus than in most other parts of the brain.
because it receives information by hormones acting on This is partly because the nuclei are so small and are
specific receptors, and that it contains special sensory located in a part of the brain that is difficult to reach
neurons that record blood temperature (thermorecep- with experimental manipulations and partly because
tors) and salt concentration (osmoreceptors). In addi- most of the afferent and efferent fibers are unmyeli-
tion, information about temperature and water balance nated and mixed with fibers destined for other parts of
is brought to the hypothalamus from peripheral recep- the brain. In particular, lesions or stimulations of the
tors in the body. These features reflect the functions of lateral hypothalamic area are bound to affect the medial
the hypothalamus in homeostatic control. forebrain bundle and, thereby, fibers destined for other
Hypothalamic afferent nerve fibers bring signals regions than the hypothalamus. Further, the rich net-
from most kinds of sense organ and from higher levels work of intrahypothalamic connections means that a
of the brain, such as the cerebral cortex and the limbic lesion of one nucleus will interfere with the functioning
structures. Thus, the hypothalamus receives informa- of several others as well. Modern methods using toxic
tion about olfactory and taste stimuli; the conditions in agents that destroy the cell bodies without affecting
the gastrointestinal tract; the blood pressure, noxious fibers of passage have helped to settle some controver-
stimuli, and skin temperature; and the intensity of sies, however. Finally, there are notable differences in
ambient light. The afferent fibers from limbic struc- both connections and neurotransmitters in various spe-
tures, such as the amygdala, inform about emotional cies, and most experimental data have been obtained in
and motivational aspects. rats or cats.
Cingulate
gyrus
Fornix
Septal nuclei
Stria
terminalis
Orbitofrontal
cortex
PAG
Olfactory PAG
bulb Locus
coeruleus
Raphe
Amygdala nuclei
Retina
Olfactory Solitary
cortex Hippocampal nucleus
formation Reticular
formation
gure 30.4 Main afferent connections of the hypothala- From the
mus. Arrows indicate direction of impulse conduction. spinal cord
Efferent Connections and temporal association areas. Some of these direct

hypothalamocortical fibers are GABAergic. In addition, a
The efferent connections of the hypothalamus are wide-
diffusely organized histaminergic projection to large parts
spread (Fig. 30.5), enabling this tiny part of the brain
of the cortex arises in the small tuberomammillary nucleus.
to influence the pituitary, autonomic preganglionic neu-
This projection may be involved with other ascending
rons, somatic-efferent cell groups, and higher levels of
connections in cortical activation (see Chapter 26).
the brain. The hypothalamus sends fibers to most of the
cell groups from which it receives afferents, such as the
amygdala, the septal nuclei, nuclei of the reticular for- More about Hypothalamic Afferent Connections
mation, the PAG, some of the cranial nerve nuclei, and
A retinohypothalamic tract supplies the hypothalamus
the spinal cord. The hypothalamus can also influence
with visual information about the total amount of light
the prefrontal cortex.
(not patterned vision). This information helps control
Hypothalamic influences on autonomic processes
bodily functions with daily variations (see later, The
such as blood pressure, heart rate, temperature regula-
Hypothalamus and Circadian Rhythms). In addition
tion, and digestion are mediated by direct and indirect
to direct projections from the olfactory bulb, olfactory
descending connections to the preganglionic sympa-
information reaches the hypothalamus indirectly from
thetic and parasympathetic neurons. Many hypotha-
regions receiving fibers from the olfactory bulb, such as
lamic neurons send axons to parasympathetic cell groups
the amygdala and the olfactory cortex (Fig. 30.4). This
of the brain stem (such as the motor nucleus of the
information is important for sexual behavior (shown in
vagus) and to the sympathetic neurons of the interme-
rats) and for autonomic control of digestion. Physiological
diolateral column of the cord. In addition, the reticular
studies show that auditory information can reach the
formation receives many afferents from the hypothala-
hypothalamus, and the same holds for signals from
mus and mediates effects on brain stem nuclei.
cutaneous receptors. Anatomically, direct fibers have
Hypothalamic effects on the cerebral cortex occur
been traced from the spinal cord to the hypothalamus.
through direct projections and indirectly via the thala-
Many such direct fibers arise in lamina I and convey
mus (the latter route concerns especially the mammillary
nociceptive and other kinds of information needed for
nucleus; see later). Although the mediodorsal thalamic
homeostatic control (see Chapter 29, under Central
nucleus (MD) is unlikely to receive direct hypothalamic
Pathways for Visceral Afferent Signals). They may
afferents, several nuclei mentioned above that receive
also contribute to autonomic and endocrine responses
fibers from the hypothalamus project to the MD (such as
to noxious stimuli. Most information from the spinal
the amygdala and the septal nuclei). The MD projects to
cord reaches the hypothalamus indirectly via the reticu-
the prefrontal cortex (see Fig. 33.7). Direct connections
lar formation, however. In that case, the sensory infor-
from the hypothalamus pass to the orbitofrontal cortex
mation is presumably highly integratedthat is, not
providing specific information about stimulus features.
Sensory signals from visceral organs reach the hypothal-
amus after synaptic interruption in the solitary nucleus
Fornix
and, most likely, a further synaptic relay in the reticular
Stria formation. Such signals, for example, may inform about
terminalis
the filling of the stomach, which influences the feeling
Thalamus of hunger or satiety.
(MD) As mentioned, fibers from the amygdala may convey
olfactory information, but they also provide signals
PAG
related to emotions and motivation. The hippocampal
Orbitofrontal
Locus formation in the medial part of the temporal lobe
coeruleus (another of the limbic structures) sends many fibers in
cortex
the fornix to end in the hypothalamus. We do not know
Septal nuclei Motor vagus
nucleus
what information these fibers transmit. Presumably, it
Amygdala is a synthesis of several sensory modalities. The ventral
Hippocampal striatum sends fibers to the lateral hypothalamus, and
formation Reticular the cingulate gyrus can act via the septal nuclei. Part of
formation
the orbitofrontal cortex has direct connections to the
Spinal cord (preganglionic hypothalamus, presumably mediating processed infor-
sympathetic neurons) mation about taste and smell; that is, information that
gure 30.5 Main efferent connections of the hypothalamus. The
has been evaluated regarding its significance. Sensory
connections to the pituitary (Fig. 30.7) gland are not included, nor signals linked to motivation may also be conveyed to
are the connections of the mammillary nucleus (see Fig. 30.6). the hypothalamus from the orbitofrontal cortex.
The Mammillary Nucleus Hormones that Act on Hypothalamic Neurons
Situated most posteriorly in the hypothalamus, the In addition to receptors for the endogenous neurotrans-
mammillary nucleus differs in several respects from the mitters, many hypothalamic cells contain receptors for
other nuclei. It consists of several subnuclei and forms various hormones, such as for the steroid sex hormones,
the characteristically shaped mammillary bodies (one thyroid hormones, hormones of the adrenal cortex, and
on each side) at the ventral aspect of the diencephalon hormones released from the anterior pituitary. Often
(Fig. 30.3; see Figs. 6.13 and 6.15). The subnuclei differ these hormones act on the brain as part of feedback
to some extent with regard to connections, although we loops to regulate the production of hormones from the
will disregard such differences here. The mammillary pituitary. Hormones also influence other functions of
nucleus appears to be an important link in the signal the brain, however.
transmission from structures in the temporal lobe to the The lipid-soluble steroid hormones (sex hormones
cingulate gyrus. These connections, and thus the mam- and the hormones of the adrenal cortex) and thyroid
millary nucleus, are most likely concerned with spatial hormones pass the bloodbrain barrier easily. The
memory and orientation in space (see Chapter 32, under steroid hormones bind to intracellular receptors and
Amnesia Caused by Lesions outside the Medial Temporal thereby influence the activity of hypothalamic cells (and
Lobe). cells in other parts of the brain, particularly in certain
Among the efferent mammillary connections (Fig. 30.6), limbic structures). The binding of sex hormones in the
the mammillothalamic tract (the bundle of Vicq dAzyr) brain influences reproductive behavior, as shown in
is most conspicuous. These fibers, forming a thick animal experiments. Glucocorticoids (from the adrenal
bundle, run anteriorly and upward in the wall of the cortex) bind to specific receptors in the paraventricular
third ventricle to end in the anterior thalamic nucleus nucleus, among other places. Binding of glucocorticoids
(see Figs. 6.24 and 33.7), and this nucleus projects to elicits behavior with the aim of increasing carbohydrate
the cingulate gyrus (Fig. 30.6). Thus, a major target of intake in experimental animals.
the mammillary nucleus is the cerebral cortex. Another Some hormones that do not pass the bloodbrain
large efferent fiber tract descends in the brain stem as barrier can nevertheless act on the hypothalamus and
the mammillotegmental tract. These fibers end primarily certain other brain regions. This is possible because
in certain nuclei of the mesencephalic and pontine retic- certain regions of the brain close to the ventricles lack a
ular formation. Fibers also pass to the pontine nuclei, bloodbrain barrier (see Chapter 7, under Some Parts
enabling signals from the mammillary nucleus to reach of the Brain Lack a BloodBrain Barrier), and the
the cerebellum. neurons in such regions send axons to other parts of the
Most of the afferent fibers to the mammillary nucleus brain. One example is the subfornical organ, located
originate in the hippocampal formation and pass in the below the fornix close to the wall of the third ventricle.
fornix (Fig. 30.6; see Figs. 6.23 and 32.2). In humans, The hormone angiotensin II, which is produced in
the fornix contains more than 1 million axons. In addi- response to a blood-volume reduction, binds to specific
tion, the mammillary nucleus receives afferents from the receptors in the subfornical organ. The latter sends axons
septal nuclei and some brain stem nuclei. to the supraoptic and paraventricular hypothalamic
nuclei (which produce the antidiuretic hormone). This
exemplifies that hormones acting on the hypothalamus
Cingulate (directly or indirectly) provide feedback information of
gyrus
importance for the hypothalamic control of the pitu-
Fornix
itary gland. We mention other hormonal actions on the
Thalamus hypothalamus and other parts of the brain later in this
(anterior
nucleus)
chapter.
Mammillothalamic
tract
Mammillotegmental THE HYPOTHALAMUS AND THE ENDOCRINE SYSTEM

PAG
tract
Direct and indirect connections to the preganglionic sym-
Reticular
formation pathetic and parasympathetic neurons explain the effects
of the hypothalamus on organs innervated by the auto-
nomic nervous system. In addition, the hypothalamus
MAMMILLARY acts on the endocrine organs by controlling the superior
BODY Hippocampal endocrine organ, the pituitary. Accordingly, diseases or
formation
lesions of the hypothalamus can disturb functions con-
gure 30.6 Main connections of the mammillary nucleus. trolled by the endocrine system, such as sexual functions,
growth, and metabolism. The pituitary gland (the hypo- and chromophobes. The acidophils produce GH and
physis) consists of an anterior lobe, the adenohypophy- prolactin, whereas the basophils probably produce the
sis, which develops from the epithelium of the primitive rest. The chromophobes may represent precursors to
foregut and consists of clusters of epithelial cells with a the acidophils and basophils. It follows that both the
rich supply of wide capillaries (sinusoids). The poste- basophils and the acidophils are heterogeneous groups,
rior lobe of the pituitary, the neurohypophysis, devel- as indeed has been shown with immunocytochemical
ops from the neural tube and consists of nerve terminals techniques with antibodies raised against the various
of fibers from the hypothalamus and a special kind of hormones.
glial cell, the pituicytes.
Hypothalamic control concerns both the anterior
Relationship between the Hypothalamus and
and posterior parts of the pituitary (Fig. 30.7). Two
the Posterior Pituitary
different pathways exert the hypothalamopituitary
interactions. The posterior pituitary receives a direct Two peptide hormones are released to the bloodstream
neural tractoften referred to as the supraopticohypo- in the posterior pituitary: vasopressin or antidiuretic
physial or the hypothalamohypophysial tractwhereas hormone (ADH) and oxytocin. Both hormones consist
the so-called tuberoinfundibular tract and a special portal of nine amino acids, are synthesized in the hypothalamus,
vascular system reach the anterior pituitary (Fig. 30.6C). and are brought to the pituitary by axonal transport. The
We return to this later. thin, unmyelinated axons reaching the posterior lobe
(in humans, about 100,000) come from two nuclei in
the anterior part of the hypothalamus: the supraoptic
The Anterior Pituitary Produces Several Hormones
nucleus and the paraventricular nucleus (Figs. 30.1,
The epithelial cells of he adenohypophysis produce and 30.3, and 30.7A). Most of the hormone-producing cells
secrete the following hormones: are large, with large vesicles in their cytoplasm that
contain precursor molecules of the final hormones. The
1. Growth hormone (GH) or somatotropic hormone,
neurons are collectively termed the magnocellular
which stimulates body growth, particularly growth of
neuroendocrine system (to distinguish them from the
long bones
parvocellular neuroendocrine system that is discussed
2. Thyroid-stimulating hormone (TSH)
later). Even though vasopressin and oxytocin are pro-
3. Adrenocorticotropic hormone (ACTH), which stim-
duced in both cell groups, vasopressin is produced
ulates the production of steroid hormones, such as cor-
2 predominantly in the supraoptic nucleus and oxytocin
tisol, in the adrenal cortex
mainly in the paraventricular nucleus. The hormones
4. Two gonadotropic hormonesone follicle-stimu-
can also be demonstrated within the axons, which end
lating hormone (FSH) that promotes the growth of the
with large nerve terminals in close contact with the
oocyte and its surrounding follicle cells and one luteiniz-
fenestrated capillaries of the posterior lobe (Fig. 30.7B).
ing hormone (LH) that is necessary for the ovulation
Action potentials invading the nerve terminals consti-
and formation of the corpus luteum from the follicular
tute the signal for release of the hormone ( just as for
cells
the release of neurotransmitter in ordinary nerve cells).
5. Prolactin (or lactogenic hormone), which stimu-
The cells of the supraoptic and the paraventricular
lates growth of the mammary gland during pregnancy
nucleus are called neurosecretory because they have all
and maintains the milk production during the nursing
the characteristic features of neurons but, at the same
period
time, release their product to the bloodstream.
Various observations indicate that, as a rule, a specific
cell type produces each hormone. The cells are named
Vasopressin: Control of Osmolarity
for the hormone they produce, and are called soma-
totrophs (GH), thyrotrophs (TSH), mammotrophs (pro- Vasopressin (ADH) was extracted from the posterior
lactin), and so forth. In routine histological sections, lobe quite early, before the neural connection between
however, only three kinds of epithelial cell can be recog- the hypothalamus and the posterior lobe had been ascer-
nized in the anterior pituitary: acidophils, basophils, tained. The hormone acts by increasing the water reab-
sorption in the kidneys by acting on aquaporins (water
channels)that is, it reduces the urine secretion (the
2 The hormone ACTH is synthesized from a large precursor protein called pro- hormone also elicits contraction of vascular smooth-
opiomelanocortin or pro-ACTH/endorphin. This precursor molecule is cleaved
into other peptides, notably lipotropin (-LPH) with a yet-unsettled function, muscle cells, which explains why it is also called vaso-
and endorphin, which is a potent opioid peptide with inhibitory actions on pressin). It was known that destruction of the posterior
pain transmission. The functional role of the endorphin secreted from the pitu- lobe leads to a condition called diabetes insipidus, which
itary is not clear, however. Beta () endorphin is also found in a hypothalamic
nucleus (the arcuate nucleus) with projections to brain stem nuclei of importance is characterized by daily urine volume of 10 to 15 liters;
for pain transmission (see Chapter 15, under Opiates and Endorphins). diabetes insipidus also occurs as an inherited disease.
Patients with this disease have pronounced cell loss in interactions, and anxiety reduction (and several other
the supraoptic and paraventricular nuclei. Later it was effects). These effects are produced by binding of vaso-
discovered that the disease could also be produced by pressin and oxytocin to specific receptors, modulating
cutting the pituitary stalk. This was the beginning of a the activity of task-specific networks in several parts of
full understanding of the nature of the relationship the brain.
between the hypothalamus and the pituitary. The pro- How the peptides reach their many central targets
duction of ADH varies in accordance with the osmolar- is less clear, however, because both peptides are mainly
3
ity of the blood. Most likely, the cells of the supraoptic synthesized in the magnocellular neurons of the supraop-
nucleus (and in some other nuclei) function as osmore- tic and paraventricular nuclei that send their axons to
ceptors. When the osmotic pressure of the blood increases the posterior lobe of the pituitary. However, some small
because of extraordinary loss or reduced intake of fluid (parvocellular) neurons in the paraventricular nucleus
(e.g., by heavy sweating, diarrhea, or vomiting), the produce the peptides and send their axons to various
cells of the supraoptic nucleus are excited and increase central nuclei. Further, at least in some species, neurons
the frequency of their action potentials, thus releasing in the suprachiasmatic nucleus, the amygdala, and in
more ADH into the bloodstream. This results in reduced the basal forebrain also express vasopressin and oxyto-
urine volume (the urine becomes more concentrated). At cin. Finally, the neurons of the magnocellular nuclei
the same time, the synthesis of the hormone is increased. release peptides from the soma and the dendrites
Even a salty meal is enough to stimulate the osmorecep- (Fig. 30.7B). Dendritic release probably enables vaso-
tors. Therefore, the hypothalamus is a control center for pressin and oxytocin to act by volume transmission on
the bodys housekeeping of water. neurons expressing the appropriate receptors near the
paraventricular and supraoptic nuclei. While both pep-
tides enter the cerebrospinal fluid (where their concen-
Oxytocin: Parturition and Milk Ejection
trations are usually higher than in the blood) it is not
Oxytocin elicits contraction of the smooth-muscle cells known whether this plays a functional role.
in the wall of the uterus and thus has a role during
parturition. It also produces contraction of the smooth-
Inuence of the Hypothalamus on the Anterior Pituitary:
muscle cells (myoepithelial cells) of the mammary gland,
The Hypophyseal Portal System
thereby assisting in emptying the breast of milk. When
the infant suckles, sensory impulses travel from the nip- It has long been known that altered growth, metabo-
ple (through the spinal nerves) to the cord and further lism, and sexual functionsprocesses that are controlled
to the hypothalamus, where the neurons of the para- by hormones produced in the anterior pituitarycan
ventricular nucleus are influenced. Increased firing fre- accompany diseases affecting the hypothalamus. There
quency leads to increased secretion of oxytocin to the are no axonal connections from the thalamus to the
bloodstream, and the hormone reaches the mammary anterior pituitary, however, and mechanisms other than
gland in seconds. This is called the milk ejection reflex. those concerning the posterior lobe must be responsible
It is special in that only the afferent link is neural; the for the influence of the hypothalamus on the anterior
efferent link is humoral. Although oxytocin is present lobe. The discovery of a special vascular arrangement in
in males, its function is so far unknown. the infundibulum (stalk) of the pituitarythe hypophy-
seal portal systemwas a breakthrough in this respect
(Fig. 30.7C). Most of the arteries reaching the anterior
Vasopressin and Oxytocin Act in the Brain
pituitary do not branch into capillaries among the epi-
as Well as Peripherally
thelial cells but continue upward into the stalk (some
Although the peripheral actions of vasopressin and oxy- arteries enter the stalk directly). In the upper part of the
tocin have received most attention, both peptides exert stalk, the vessels form wide capillaries (sinusoids) that
effects on central neurons, influencing many aspects of finally collect into large veins. These hypophyseal portal
behavior and cognition. For example, central infusion veins course back to the anterior lobe, where they form
of oxytocin induces maternal behavior in rats, and oxy- a new set of sinusoids among the epithelial cells. From
tocin furthermore facilitates pair bonding (preference these sinusoids, the blood collects in veins that leave the
for a particular mate) in monogamous species. Central pituitary. Because the blood in the sinusoids of the ante-
actions of vasopressin include sexual behavior, social rior lobe has first been through a capillary net in the
stalk, substances can be transported from there to the
3 The ADH secretion is also inuenced by other factors, although in primates anterior lobe. Numerous thin axons from the hypothal-
these appear to be much less potent than changes of osmolarity. For example, amus end in the uppermost part of the hypophyseal
reduced blood volume leads to concentration of angiotensin II in the blood- stalk, forming the tuberoinfundibular tract. This region
stream, which, in turn, affects the supraoptic and paraventricular nuclei by
means of the subfornical organ. Ethanol reduces the secretion of ADH, thereby is called the median eminence (Fig. 30.7C). The axons
increasing urine production. that end in contact with the capillaries in the median
eminence transport peptides by axonal transport and the brain. Thus, the interplay between the hypothala-
release them into the hypophyseal portal system. From mus and the endocrine system is complex.
the capillaries in the median eminence, the blood brings Releasing hormones are present also in the hypotha-
the peptides to the second capillary network among the lamic neurons that send axons to other parts of the
epithelial cells of the anterior lobe. brain, where they act at conventional synapses. Examples
The neurons that send axons to the median eminence are somatostatin (inhibits the release of GH), thyrotropin-
lie mainly close to the wall of the third ventricle (periven- releasing hormone (TRH), and corticotropin-releasing
tricularly). Because the neurons are relatively small, hormone (CRH). Thus, these peptides function as releas-
they are collectively termed the parvocellular neuroen- ing hormones at one site and as neurotransmitters at
docrine system (to distinguish them from the magnocel- another. This emphasizes the futility of assigning one
lular system). Many of the neurons are found in the function to each peptide. We return to the central actions
arcuate nucleus (Figs. 30.1 and 30.2). of some of these peptides in Chapter 31.
Most of the peptides transported by the portal sys-
tem cause hormonal secretion from the epithelial cells
More about Some Releasing Hormones
of the anterior lobe and are therefore called releasing
hormones or factors. A single releasing hormone acts In humans, neurons producing CRH (corticotrophin-
preferentially (but not only) on a specific kind of cells in releasing hormone or factor, CRF) are mainly found in
the anterior pituitary and thus produces secretion of a particular small-celled subdivision of the paraventric-
mainly one hormone. Some peptides transported in the ular nucleus. ACTH stimulates the secretion of gluco-
tuberoinfundibular tract have an inhibitory effect on corticoids from the adrenal cortex, and such secretion
the secretion of anterior lobe hormones and are called is an important response to stress (see below). Besides
inhibitory hormones or factors. Most of the neurons of multifarious metabolic effects, the glucocorticoids act
the parvocellular system release more than one peptide, on the anterior pituitary and the hypothalamus to
however. The neurons may therefore have several dif- inhibit the synthesis and release of ACTH and CRH
ferent actions on the anterior pituitary. Which releasing (negative feedback). CRH is also involved in emotional
(peptide) hormone that is preferentially released from a responses (see Chapter 31, under The Amygdala,
parvocellular neuron depends both on the level of the Anxiety, and Neurotransmitters). The neurons contain-
anterior pituitary hormone in the bloodstream (feeding CRH also express several other peptides (among
back) and on afferent connections from other parts of them vasopressin and enkephalin).
A B C
Paraventricular Neurosecretory Arcuate nucleus
nucleus neuron (and other nuclei)
Supraoptic
nucleus
Median
Infundibulum eminence
Hypothalamo-
hypophyseal Capillary
Anterior lobe tract Artery network 1
Capillary
network 2
Posterior lobe
Vein
Fenestrated capillary
gure 30.7 Relationship between the hypothalamus and the pitu- pituitary stalk ensure that releasing hormones (factors) are trans-
itary gland. A: Connections from the hypothalamus to the posterior ported from the median eminence in the upper part of the stalk to the
lobe. B: Axonal transport of peptide hormones (neuropeptides) from epithelial cells of the anterior lobe.
the hypothalamus to the pituitary. C: The portal vessels of the
GRH (Growth hormonereleasing hormone) is found from other nuclei, in addition to parts of the hypothal-
mainly in the arcuate nucleus, which, as mentioned, amuslead to incorrect identification of hypothalamic
sends its efferents to the median eminence. The peptide centers and misconceptions about the independence of
somatostatin, which inhibits the release of the growth hypothalamic control functions. The altered view on
hormone, is present in neurons of the arcuate nucleus hypothalamic centers parallels the change of view
but also appears in many other cell groups that do not during the last 30 to 40 years on the existence of func-
project to the median eminence. Prolactin is also con- tional centers of the brain in general. Rather than focus-
trolled by two hypothalamic peptides, the stimulating ing on individual cell groups as responsible (centers) for
prolactin-releasing hormone (PRH) and dopamine (also complex functions, we now emphasize how many cell
called prolactin releaseinhibiting hormone, PIH). groups contribute to execution of most tasks. When we
Hypothalamic neurons containing dopamine are mainly nevertheless sometimes use the term center for con-
found in two small paraventricular cell groups and in venience, the reader should realize its limited explana-
the supraoptic nucleus. tory value. For example, we have not explained how
We do not know why some pituitary hormones are the CNS controls micturition by placing a micturition
controlled by two hypothalamic peptides with opposite center in the pons.
effects, while others are controlled by only one. A rough functional subdivision of the hypothalamus
emerged from the pioneer lesion experiments: The ante-
rior parts of the hypothalamus are particularly con-
FUNCTIONAL ASPECTS cerned with effects mediated by the parasympathetic
system while the posterior part controls functions in
The preceding account of its connections suggests that which the sympathetic system has a dominant role.
the hypothalamus functions as a coordinator of informa-
tion of many different kinds, particularly pertaining to
Control of Body Temperature
homeostasis and bodily maintenance. The hypothala-
mus contains networks of neurons that serve as control The hypothalamus receives information about ambient
centers for several functions, such as blood pressure, temperature from thermoreceptors in the skin. It initi-
body temperature, water balance, metabolism, digestion, ates peripheral responses to increase heat production or
reproduction, and defensive responses. Further, the heat loss. Information from the skin is not sufficient,
hypothalamus governs the rhythmic variations of several however, because the superior goal is to keep the core
bodily processes. For each of the mentioned broad func- temperature constant (i.e., in deep parts of the body)
tional categories, the hypothalamus serves to coordinate not the skin temperature that may vary considerably, as
endocrine, autonomic, and somatic motor responses into we know from everyday experience. To be able to con-
appropriate behavior. trol the core temperature, the hypothalamus must also
Early lesion experiments indicate that the anterior be informed about the blood temperature in central parts
parts of the hypothalamus are concerned with predom- of the body. As mentioned, some neurons in the anterior
inantly parasympathetic effects, whereas the posterior hypothalamus are temperature-sensitive. Accordingly,
parts are more involved in functions carried out by the when the blood flowing through the anterior part of the
sympathetic system. This should serve only as a rough hypothalamus is warmed, an experimental animal shows
rule of thumb, because further studies show that, as a signs of increased heat loss. Cats, for example, pant and
rule, it is not possible to localize functions to specific sweat through the paws. In humans, skin vasodilata-
hypothalamic nuclei. tion (redness and warmth) and sweating occur. If these
parts of the hypothalamus are destroyed (on both sides),
the animal no longer reacts to a rise in ambient tem-
Hypothalamic Centers
perature. The body temperature therefore rises. In con-
Hypothalamic centers are in fact extensive networks trast, when the posterior parts of the hypothalamus are
of mutually interconnected hypothalamic cell groups. destroyed, the animal no longer reacts with shivering
This agrees with the observation that many of the auto- and vasoconstriction to a fall in ambient temperature.
nomic processes influenced by the hypothalamus are Therefore, the body temperature drops (the vasocon-
not controlled independently. Some factors, such as the striction reduces heat loss, and the shivering increases heat
diameter of the vessels, are of importance in several dif- production). This exemplifies how the hypothalamus
ferent processes, including temperature regulation and coordinates autonomic (vasoconstriction) and somatic
control of blood pressure. Complex behavior, such as (shivering) responses. These and other observations
that necessary for feeding and drinking, depends on the suggest that neuronal groups in the anterior part of the
integrity of both medial and lateral hypothalamic areas, hypothalamus are necessary for the coordination of the
even though subregions play different roles. Early studies processes ensuring that the body temperature does not
with crude methodsoften destroying passing fibers rise above normal levels (increasing heat loss), whereas
the posterior parts contain neurons necessary for heat IL1 in the peritoneal cavity (mimicking a local inflam-
conservation. Together, these parts function as a ther- mation) do not induce fever after cutting of the vagus
mostat that tries to keep the body temperature as close nerve.
as possible to a set point of 37C. If the temperature drops Whatever the cause of their presence, cytokines in the
below the set point, the heater is turned onthat is, hypothalamus induce the synthesis of prostaglandins
measures are initiated to conserve heat (skin vasocon- (among other substances), which increase the activity of
striction or putting on more clothes) and, if necessary, cold-sensitive neurons and reduce the activity of heat-
to increase heat production (shivering or voluntary sensitive ones. That antipyretic (reduce fever) drugs, such
muscular activity). as aspirin, inhibit the synthesis of prostaglandins supports
In humans, abnormal rise in the body temperature, a crucial role of prostaglandins in fever production.
hyperthermia, can occur in diseases that affect the hypo- Local adaptations in the hypothalamus ensure that
thalamus or by an inadvertent lesion during surgery. the fever does not reach dangerous levels (antipyresis).
The rise can also occur as a side effect of certain drugs Cytokines activate neurons in the paraventricular
acting on the brain (e.g., antipsychotics). Occasionally, nucleus producing CRH and vasopressin. As discussed,
hyperthermia occurs during general anesthesia. CRH release leads to increased blood levels of cortisol.
This would reduce the peripheral production of cytok-
ines and, by that, reduce the fever. Further, fibers from
Fever
the paraventricular nucleus release vasopressin in the
Fever is part of the so-called acute-phase response elic- septal nuclei. Experimental infusion of vasopressin in
ited by immune system activation (see below, Effects the septal nuclei suppresses almost completely the febrile
of the Immune System on the Nervous System). Fever response to intravenous injection of pyrogens. It appears
arises when the set point of the hypothalamic thermo- most likely that the septal nuclei act back via septohy-
stat is altered. Especially neurons in the preoptic area pothalamic fibers to cancel the effect of cytokines on the
(POA) in the anterior hypothalamus appear to be cru- thermostat.
cial, as judged from microinjections of fever-producing
substances. If the set point is changed to, for example,
The Hypothalamus, Sleep, and Hypocretins
39C, the normal body temperature is judged to be too
low and measures to conserve and produce heat are Sleep disturbances often accompany lesions of the
started (skin vasoconstriction, shivering, curling up, hypothalamus in experimental animals and in humans,
putting on more clothes). The person feels cold while sometimes as an abnormal amount of sleep and some-
the temperature is below the new set point. Fever has times as insomnia or disturbed sleep rhythm. Animal
most likely evolved as a defensive response, improving experiments in the 1940s demonstrated that lesions in
survival from infections (although fever is sometimes the preoptic area in the anterior hypothalamus caused
harmful). insomnia, and later studies identified single neurons
Fever can be caused (indirectly) by lipopolysaccha- with their maximal activity during sleep in the same
rides (called pyrogens) from bacterial membranes or by region. Later studies have identified two neuronal
simple tissue injury that leads to inflammation (e.g., groups in the posterior hypothalamus of importance
4
fever after severe sunburn). The pyrogens or other tis- for wakefulness.
sue changes make leukocytes release cytokines. The The first is the tuberomammillary nucleus that con-
cytokines interleukin 1 (IL-1), and tumor-necrotic tains histaminergic neurons with widespread axonal
factor (TNF) have been detected in the tissue fluid from ramifications. Histamine binds to histamine receptors
the anterior hypothalamus in experimental animals (H1H3) in many brain regions. With regard to the his-
with fever. IL-1, which is the most potent fever-induc- taminergic effect on wakefulness, the projections to the
ing substance, appears to act via interleukin 6 (IL-6). cerebral cortex, the locus coeruleus, and the raphe nuclei
Thus, IL-1 does not induce fever in knockout mice are probably most important (histamine has several
that lack the IL-6 gene. It is not quite clear, however, additional actions, for example on learning and mem-
how the cytokines accumulate in the hypothalamus. ory). GABAergic neurons in the preoptic area project to
Blood borne cytokines can bind specifically at sites the (histaminergic) tuberomammillary nucleus, and may
without the bloodbrain barriersuch as the subforni- therefore contribute to sleep by inhibiting wake-active
cal organwhere the neurons express IL-1 and IL-6 neurons.
receptors. In turn, these might induce synthesis of The second group consists of diffusely spread neurons
cytokines in the hypothalamus. It is also possible that (about 7000 in humans) in the posterior and lateral
cytokines are brought through the bloodbrain barrier
by specific transporters. Finally, there is evidence that
4 The epidemic in the early twentieth century of a presumed viral disease causing
sensory impulses in the vagus nerve may induce cytokine (among other complications) extreme somnolenceencephalitis lethargica
production in the hypothalamus. Thus, injections of pointed to the posterior hypothalamus as important for waking.
hypothalamus that release two varieties of the neuro- in the environment. For example, in humans it seems
peptide hypocretin (orexin). The hypocretins bind to appropriate that most bodily functions are at their low-
specific receptors and exert a wake-promoting effect est level during the night, whereas animals hunting at
when infused in animals. Further support for the impor- night would need a different activity profile. Persons
tance of hypocretins came from the observation that staying in environments without any information about
patients with narcolepsy have reduced levels of hypocre- the time of the day develop a rhythm with cycles slightly
tins in the cerebrospinal fluid and loss of hypocretiner- longer than 24 hours. The capacity to produce circa-
gic neurons (see Chapter 26, under Narcolepsy). The dian rhythms is inborn, and cyclic activity appears in
hypocretins exert effects several places but projections the hypothalamus (rat) late in intrauterine life. The
to the tuberomammillary nucleus may be of particular SCN functions as a pacemaker or biologic clock, pro-
importance. Thus, hypocretins increase release of hista- ducing a certain rhythm even in the absence of external
mine and wakefulness but not in knockout mice lacking inputs. Nevertheless, the exact rhythmthat is, at what
expression of the H1 receptor. In addition, hypocretiner- time of the day the highest and lowest values occuris
gic fibers pass to the locus coeruleus and the raphe nuclei, modulated by sensory information. Light stimuli from
both related to control of arousal (see Chapter 26, under the retina (Fig. 30.4), varying with length of the light/
Multiple Pathways and Transmitters Are Responsible dark cycle, appear to be particularly important for the
for Cortical Activation). Interestingly, the suprachias- set of such circadian rhythms. Other factors also seem
matic nucleus, which is responsible for the control of to contribute, however, such as activity level.
circadian rhythms, projects to regions with hypocretin- The retinohypothalamic fibers, which arise from
5
expressing neurons. retinal ganglion cells, end in the SCN. They inform only
The hypocretins are yet another example that each of about the amount of light but do not provide specific
the brains many signal substances influences several information about patterns, movements, and so forth.
different processes. Indeed, the hypocretins were dis- In addition, the SCN receives afferents from a small
covered because of their ability to induce feeding behav- part of the lateral geniculate nucleus and from the raphe
ior in experimental animals. Later, their importance for nuclei (serotonin).
wakefulness was revealed, and now they are implicated The SCN has efferent connections with several other
in a number of other functions as well. parts of the hypothalamus, which enable it to synchro-
It should be emphasized that many more neuronal nize the various functions mentioned above (and other
groups and neurotransmitters than those mentioned functions as well). This concerns, for example, the
here are implicated in the control of wakefulness and CRH-containing neurons in the paraventricular nucleus
sleep (see Chapter 26). that control the blood level of corticosteroids. Other
connections reach the thalamus and cell groups in the
basal forebrain (see Chapter 31, under The Basal
The Hypothalamus and Circadian Rhythms
Forebrain). Such connections might influence diurnal
The hypothalamus plays a role as a pacemaker for sev- variations in motivation and memory. With regard to
eral functions showing a cyclic, diurnal variation. Such hypothalamic control of the sleepwake cycle, newly dis-
circadian rhythms are governed from the small supra- covered (polysynaptic) connections from the SCN to the
chiasmatic nucleus (SCN), situated just above the optic locus coeruleus (norepinephrine) are of particular inter-
chiasm. -Aminobutyric acid (GABA) is the transmitter est (see The Hypothalamus, Sleep, and Hypocretins).
for most of the neurons in the SCN, colocalized with A special polysynaptic efferent pathway from the SCN
neuropeptides (either vasopressin or VIP). Lesions of to the pineal gland controls secretion of the hormone
the SCN disturb (but do not necessarily abolish) the melatonin. Melatonin binds to high-affinity receptors
cyclic variations of bodily functions. Therefore, SCN is in parts of the hypothalamus, among them the SCN,
not alone in determining the circadian rhythms, even if and modulates circadian rhythms. Light can influence
it plays the leading part. the SCN pacemaker via variations in the melatonin
Several physiologic parameterssuch as hormonal level (in addition to by the retinohypothalamic fibers).
levels, blood pressure, body temperature, wakefulness, Melatonin is secreted in response to low levels of light
and sleepare subject to circadian alterations. The same and can therefore be said to signal darkness.
holds for several mental functions, such as reaction time
and mood. The biologic significance of the cyclic varia-
Melatonin
tions of bodily functions is presumably to adapt the level
of activity to the most stable and predictable variations The pineal body or gland (see Chapter 6, under
The Epithalamus and the Pineal Body) produces a
number of neuroactive substances, among them several
5 Hypocretinergic connections to dopaminergic neurons in the mesencephalon
(in the substantia nigra and the VTA) may explain why hypocretins also inu- neuropeptides and large amounts of serotonin. The hor-
ence motivation and reward behavior. mone melatonin has attracted most interest, however.
Melatonin (N-acetylmethoxytryptamine) is synthesized intestine. Stimulation of the anterior hypothalamus, in

from serotonin in two enzymatic steps. No nerve fibers particular, can elicit increased secretion of gastric juice
leave the pineal body, which therefore is assumed to and strengthening of peristaltic movements.
function only as an endocrine gland. The only known Not only the digestive processes but also feeding
afferent nerve fibers arise in the upper cervical sympa- behavior is controlled from the hypothalamus. Early
thetic ganglion (postganglionic fibers). Ambient light stimulation and lesion experiments indicated that the
influences the secretion of melatonin; increased light lateral hypothalamic area could induce increased eating
(longer days) inhibits secretion. In humans, as in exper- (or behavior directed at acquiring food), whereas the
imental animals, the level of melatonin varies with the medial parts (especially the ventromedial nucleus) reduce
lightdarkness cycle, with the highest level occurring at eating (induce satiety). Further studies have shown that,
night. The influence of light is mediated through a tor- although essentially correct, this scheme is too simple.
tuous route: as mentioned, signals from the retina reach A complex network within the hypothalamus and
the SCN directly; neurons there forward signals directly between the hypothalamus and other parts of the brain
or indirectly to the preganglionic sympathetic neurons controls food intake and body weight.
in the upper thoracic cord, and their axons reach the The inputs to the hypothalamic feeding centers are
upper cervical ganglion by means of the sympathetic multifarious, as witnessed by data from animal experi-
trunk (see Fig. 28.7). ments and by everyday experiences of the numerous
Melatonin acts by binding to G proteincoupled factors that influence human feeding behavior. It is nev-
receptors, which occur with the highest concentrations ertheless remarkable how most people maintain their
in the SCN, the paraventricular nucleus, and parts of body weight over many years, although even the small-
the anterior pituitary. The dominating effect of recep- est daily surplus of food would cause a steady weight
tor activation seems to be reduced synthesis of cyclic gain (a surplus of 10 calories a day would increase body
AMP. Melatonin appears to inhibit the secretion of weight by about 1 kg in a year). The hypothalamic cen-
gonadotropic hormones (the effect seems to depend on ters governing food intake are thought to operate as a
the time of the day, however). In experimental animals, homeostat (a system maintaining a steady state by inter-
melatonin also have a number of other actionsfor nal processes.) We also use the term lipostat, because
example, influencing sleep, arousal, body temperature, the control of body fat is so central to maintaining con-
and blood level of cortisol. These effects are believed to stant body weight. Feedback loops ensure that the food
be mediated mainly by the SCN. intake oscillates around a set point. Reduced consump-
Intake of melatonin in humans alters the phase of tion automatically follows overeating.
such rhythms, probably by setting the circadian clock The protein leptin, produced in fat cells, appears to be
in the SCN. Indeed, melatonin is now widely used to the single most important factor ensuring negative feed-
alleviate the unpleasant psychological and physiologi- back from adipose tissue to the hypothalamus (insulin is
cal effects of jet lag (even though its effect in this respect another factor). The function of leptin is probably to
has not yet been convincingly documented). It has also inform about whether the energy reserves (fat) are suf-
been used to normalize sleepwake patterns in blind ficient. The so-called ob gene (ob for obesity) codes for
people. The production of melatonin declines with age, leptin, while the db gene codes for the leptin receptor.
and this has been taken to explain sleep disturbances in Mice lacking either the ob or the db gene develop
elderly people. Because melatonin counteracts the accu- extreme obesity due to increased food intake and reduced
mulation of cytotoxic free radicals, it has been suggested metabolism (in addition, they develop diabetes and
as a drug to halt the progression of degenerative brain increased cortisol levels). Although leptin binds several
diseases (Parkinsons disease, Alzheimers disease, and places in the hypothalamus, a major effect is to inhibit
6
others). The many reported beneficial effects of mela- the release of neuropeptide Y (NPY). NPY reduces
tonin in humans lack documentation, however. It is fair food intake, as shown by injections in certain parts of
to say that its normal role in humans is not yet clear, the hypothalamus in experimental animals.
especially because most of what we know comes from
experiments on rodents.
Loss of Feeding Control
Of course, psychological factorsor, occasionally,
Control of Digestion and Feeding
hypothalamic diseasemay disturb this finely tuned
The hypothalamus controls various metabolic processes.
For example, lesions of certain parts can produce abnor- 6 NPY is involved in other hypothalamic tasks, such as control of circadian
mal fat deposition, both in experimental animals and in rhythms, and secretion of releasing hormones. It is often colocalized with cat-
humans. The gastrointestinal tract is influenced by the echolamines, GABA, or somatostatin. Finally, NPY is also found in the
amygdala where it is involved in stress reactions (having an anxiolytic effect).
hypothalamus. Lesions can produce ulcers of the mucous Obviously, each of the numerous transmitters present in the hypothalamus may
membranes and bleeding in the stomach and the small be expected to participate in quite diverse functions.
control mechanism. Studies of obese people indicate projections from the paraventricular nucleus to sympa-
7
that they have normal leptin production. A hypotha- thetic preganglionic cell groups. In addition to leptin, the
lamic leptin resistance has been proposed, however, to hormone insulin act as one of several feedback signals to
account for the development of obesity (analogous to the arcuate nucleus from the periphery, informing about
insulin resistance in some cases of diabetes). If so, the the energy status of the body. Thus, hypothalamic injec-
question remains how the resistance arises: is it due to a tion of insulin reduces the food intake in normal rats
genetic abnormality, or is the lipostat altered by psycho- (but not in rats with genetically determined obesity).
logical and other factors? Only in about 35% of over- Several other factors contribute in the regulation of
weight people is there evidence of a genetic disposition. food intake. For example, glucose-sensitive hypotha-
Focusing on single actors like leptin, NPY, and hypo- lamic neurons are likely to be involved in the control of
thalamic nuclei should not make us forget that the appetite (for instance, the feeling of hunger when the
hypothalamus does not operate in isolation. The many blood glucose is low). The hormone ghrelinproduced
connections between the hypothalamus and the cerebral in the stomachmay also contribute to regulation of
cortex, the amygdala, and other limbic structures tell us hunger and food intake by acting on neurons in the
that the hypothalamus may be overruled by the higher arcuate nucleus. Indeed, ghrelin activates NPY neurons
parts of the brain engaged in cognitive and emotional and inhibit POMC neurons, as one might expect from
processing. Thus, while the hypothalamus undoubtedly a signal informing about empty energy stores. (As other
is the organizer for motivated behavior related to diges- neuropeptides, ghrelin has diverse actions; it increases,
tion and feeding, other regions than the hypothalamus for example, plasticity in the hippocampus.) Gut hor-
determine whether such behavior occurs. Although we mones, such as cholecystokinin, do not cross the blood
do not fully understand the causes of eating disorders brain barrier, but can act on neurons in the solitary
such as anorexia and bulimia, it is unlikely that the pri- nucleus via the area postrema (lacking a bloodbrain
mary cause is to be found in the hypothalamus.8 barrier). The vagus nerve provides the solitary nucleus
with information about the filling of the stomach and
probably about the levels of glucose and lipids in the
The Arcuate Nucleus, Neuropeptides, and
liver. From the solitary nucleus, signals travel to the
Energy Metabolism
hypothalamus and notably the arcuate nucleus.
Several transmitters (especially many neuropeptides) are
involved in the hypothalamic control of feeding behav-
Hypothalamus, Sexual Functions, and Sex Differences
ior, although much remains before their mutual roles
are clarified. Special interest attaches to NPY, which is The efferent connections of the hypothalamus also
found in high concentration in nerve terminals in the enable it to influence sexual behaviorthat is, to start
paraventricular nucleus. Most of the NPY-containing and coordinate the autonomic, endocrine, and somatic
terminals come from the arcuate nucleus. Two groups motor components. This is verified by many animal
of neurons in the arcuate nucleus have opposite effects: experiments. For example, injection of the female sex
NPY neurons increase food intake while POMC neu- hormone estradiol in the ventromedial hypothalamic
rons (pro-opiomelanocortin) reduce it. For example, nucleus in castrated male rats elicits copulatory behav-
injection of NPY near the paraventricular nucleus ior. Lesions of the ventromedial hypothalamic nucleus
increases food intake in experimental animals. Further, in female rats reduce their sexual activity. We have little
it decreases the metabolism in brown fat and increases precise knowledge of how the hypothalamus controls
fat storage in ordinary (white) fat tissue. This leads to a sexual functions, however. Neither do we understand
larger weight gain than expected from the food intake. fully the structural basis in the hypothalamus for behav-
The NPY-containing connections to the paraventricular ioral sex differences, in spite of numerous findings of sex
nucleus might therefore regulate the energy balance of differences among hypothalamic nuclei.
the body by controlling both appetite and metabolism. In rodents a nucleus in the anterior hypothalamus
How NPY release in the hypothalamus produces this is the sexually dimorphic nucleus of the preoptic area,
not known, although some effects may be mediated by SDN-POis three to eight times larger in males than in
females. While several studies in humans have described
sex differences in the corresponding region, it is remark-
7 A small minority of persons with extreme obesity have mutations of the ob able that they do not agree on which one among three
or db genes. Such persons develop overweight very early. They also suffer from small nuclei that show such sexual dimorphism (neither
low levels of growth hormone and thyroid hormone, and they lack normal
pubertal development. is there agreement with regard to hypothalamic differ-
8 A review of 54 patients with eating disorders occurring in conjunction with ences between heterosexual and homosexual men).
a brain lesion showed that the majority had lesions in the right fronto-temporal Several hypothalamic pathways are likely to be sexu-
region. Lesions of the hypothalamus were associated with reduced or increased
appetite but not with more complex eating disorders (Uher and Treasure ally dimorphic. One among many relevant pathways
2005). passes from the paraventricular nucleus directly to the
spinal motoneurons that innervate the bulbospongiosus stress with increased ACTH secretion might cause
(bulbocavernosus) muscle. This muscle, which is impor- increased vulnerability to infections, allergy, autoimmu-
tant during ejaculation, is large in male rats but tiny in nity, and other diseases.
females. Correspondingly, the descending pathway The bone marrow, thymus, spleen, lymph nodes, and
mentioned above is absent in female rats. The motoneu- gut-associated lymphoid tissue all receive innervation
ron group in the sacral cord that innervates the bulbos- by postganglionic sympathetic fibers. The innervation
pongiosus muscle is three times larger in male than in density is highest in T-lymphocyte areas. Lymphocytes
female rats. The early presence of testosterone prevents express -adrenergic receptors, and varicosities of
programmed cell death among the motoneurons, thereby sympathetic fibers are found close to lymphocytes.
establishing the sex difference. Chemical denervation of lymphoid organs causes reduced
As discussed, the hypothalamus controls sexual func- T-lymphocyte activity, among other effects (B lympho-
tions also by its actions on the pituitary and its secre- cytes appear also to be affected). Modulation of immune
tion of gonadotropic hormones. The sex hormones act responses by efferent parasympathetic fibers in the
on the hypothalamus and other parts of the brain and vagus nerve was recently demonstrated. This seems to
can therefore influence sexual behavior. As shown in happen primarily by acetylcholine binding to periph-
rats and monkeys, transient exposure to small amounts eral nicotinic receptors (in contrast to other parasym-
of sex hormones during early development determines pathetic effects that are mediated by muscarinic
later sexual identity and behavior. Structural differ- receptors). One effect of vagus stimulation is inhibition
ences that depend on circulating sex hormones have of cytokine release from immune cells.
been described in the ventrolateral hypothalamus and In conclusion, the autonomic system is able to modu-
in the amygdala of adult animals. The presence of tes- late the properties of the immune system by endocrine
tosterone seems to be crucial: it initiates structural sex and autonomic pathways, although we have little pre-
difference in the brain, promotes masculine behavior, cise knowledge of the functional significance of such
and suppresses feminine behavior. (See Chapter 34, under modulation.
Cognitive Sex Differences and Lateralization and
Psychological Sex Differences and Biology.)
Sickness behavior
THE HYPOTHALAMUS AND THE IMMUNE SYSTEM
Effects of the Nervous System on the Immune System

The relationship between the nervous system and the Hypothalamus
Regions without
immune system has attracted increasing attention bloodbrain barrier
recently. This topic is important in several respects
for example, regarding the interactions between mental
CRH
and bodily processes. Besides many anecdotal reports
of somatic diseases that start at times of mental stress Motor vagus
and imbalance, there is growing experimental evidence nucleus
Pituitary
of hypothalamic influence on the immune system. This Solitary
nucleus ACTH
concerns, for example, the activity of natural-killer cells
(NK cells) and lymphocytes. Further, antigen stimula- Adrenal Vagus
tion appears to increase activity among certain hypotha- cortex nerve
lamic cell groups. This also suggests that the hypothalamus Vagus
Cortisol
nerve
is in some way involved in the defense against infections.
Other studies show altered T-lymphocyte numbers in
deeply depressed patients. How these interactions come Cytokines
about is not fully understood, and some findings in this Sympathic
field are contradictory. postganglionic
Immune cells fibers
The nervous system can influence the immune system
in two ways: one by the endocrine system, the other by gure 30.8 Interactions between the nervous system and the immune
autonomic innervation of the lymphoid organs (Fig. 30.8). system. Schematic. Cytokines released during immune responses can
ACTH and secretion of glucocorticoids from the adrenal inuence hypothalamic neurons in two ways (left part of the gure).
The middle part shows how the hypothalamus can inuence the
cortex primarily mediate the endocrine influence. The immune system via the pituitary and the adrenal gland. The right part
inhibiting effects of the glucocorticoids on inflammation shows how sympathetic and parasympathetic nerves can mediate
and resistance to infections are well known. Long-lasting hypothalamic effects on the cells of the immune system.
Effects of the Immune System on the Nervous System groups of the reticular formation (see Chapter 31, under
The Amygdala and Emotions).
We deal with immune reactions in the CNS in Chapter
We describe in this section just a few examples of psy-
1, as part of defense mechanisms (under The Reaction
chosomatic interrelations. Women may lose their men-
of Nervous Tissue to Injury and Inflammation).
struation for some time after psychic stress (loss of a
However, the immune system can also influence nor-
close person, dissatisfaction, depression, and so forth).
mal nervous processes (Fig. 30.8). One example is that
The mechanism is apparently reduced secretion of
cytokines from leukocytes cause fever as one compo-
gonadotropic hormones from the pituitary, caused by
nent of the acute-phase response, as discussed above.
reduced production of the relevant releasing hormone.
Further, it seems highly likely that typical symptoms in
When subjected to bodily stress (such as infections,
infectious diseases like drowsiness, loss of appetite
trauma, intoxications, and major surgery), the organism
(anorexia), social withdrawal, listlessness, and aversion
responds by, among other things, increasing the secre-
to certain tastes are caused by action of cytokines in the
tion of corticosteroids. Mental stress can produce the
brain. As mentioned, effects are believed to be mediated
same response by causing increased secretion of releas-
by binding of cytokines to neurons in regions lacking a
ing hormones from the hypothalamus, which, in turn,
bloodbrain barrier and perhaps by direct entrance into
increases the secretion of ACTH from the anterior pitu-
the hypothalamus. In addition, the vagus nerve (and
itary (see Fig. 31.6). In experimental animals, transec-
perhaps other nerves) mediates similar effects on the
tion of the stalk of the pituitary prevents the hormonal
hypothalamus from peripheral tissues with active
response to mental stress. Our mental state influences
immune responses (cutting the vagus nerve reduces sick-
functions controlled by the posterior pituitary (such as
ness behavior in animals with abdominal infections).
urinary volume). A particularly striking example of a
Lymphatic dendritic cells and macrophages release
psychosomatic interrelation is that of a woman breast-
IL-1 that binds to peripheral branches of the vagus.
feeding her baby, who can cause the milk to trickle from
Afferent vagus fibers end in the solitary tract, most
the nipples just by thinking of the child. The inner image
likely releasing glutamate. The solitary nucleus projects
of the child in some way influences the hypothalamus,
to several parts of the hypothalamus that may mediate
with an increase of oxytocin secretion as the result. This
the sickness behavior. In addition, the ACTH secretion
reaches the mammary glands and makes the smooth
from the pituitary (and thus the blood cortisol level) can
muscles contract (milk ejection reflex).
be influenced by signals in the vagus nerve. Thus, fibers
from the solitary nucleus end in the paraventricular
nucleus and modulate the release of corticotropin-releas- Expectation and Health
ing hormone (CRH). Signals in the vagus nerve to the
The relation between expectation and disease has
brain stem and the hypothalamus may also participate
attracted much interest. For example, several studies
when hyperalgesia develops in patients with infections.
address how optimism as a personality trait influences
psychological adaptation, handling of stress (like major
surgery), and self-reported health. Altogether, there are
THE HYPOTHALAMUS AND MENTAL FUNCTIONS
clear positive correlations; that is, an optimistic attitude is
associated with better self-reported health, fewer psychi-
Psychosomatic Interrelations
atric symptoms, lower blood pressure, and so forth.
The relationship between the hypothalamus and the While a causal relationship remains to be established,
pituitary discussed above helps explain why diseases there is solid evidence that our mental state (via the hypo-
affecting the hypothalamus can produce alterations of thalamus) influences several physiological processes in
hormonal secretion from the pituitary itself, the thyroid, the body. Further, studies of the placebo and nocebo phe-
the adrenal cortex, and the gonads. However, it also nomena strongly support the importance of expectations
helps in explaining the relationship between mental and for handling of stressful situations (see Chapter 15).
bodily processescalled psychosomatic interrelations. There are exceptions, however, from a positive cor-
Thus, the hypothalamus receives afferents from many relation between optimism and health (or indirect mea-
parts of the brain, among them the cerebral cortex and sures, like immunity). Thus, some studies find a negative
the limbic structures, which are closely related to what correlation between optimism and immunity when
we term mental or psychic functions. In short, our stressors are complex, long lasting, and unpredictable
mental stateby acting on the hypothalamuscan pro- (Segerstrom 2005). Perhaps, in such situations inevita-
duce alterations of endocrine organs, of organs inner- ble frustrations and disappointments might be less
vated by the autonomic system, and of skeletal muscles. adaptive than resignation (as would be chosen by a less
Not all such effects are mediated via the hypothalamus, optimistic person).
however. Thus, fibers from the cerebral cortex and lim- Another question is why people differ so much with
bic structures access the autonomic and somatic cell regard to how they cope with stressful situations.
Presumably, genetically determined vulnerability factors heterogeneous and poorly understood group of disor-
both psychological and molecularvary considerably ders. There is probably no sharp border between condi-
among people. If vulnerable persons are exposed to tions in which purely psychic factors cause or contribute
many stressful life events in early childhood, they seem to somatic disease (e.g., coronary disease) and those in
at risk to express dysfunctional responses to stress in which clear-cut signs of somatic disease cannot be
later life. found (e.g., fibromyalgia). As discussed earlier and in
Other aspects of the interaction between the mind and relation to the placebo phenomenon (Chapter 15), all
the body are discussed in Chapter 31, under Amygdala disease processes are more or less influenced by the
and Emotions. mental attitude and expectations of the patient, while
any somatic disease will lead to psychological reactions.
In some conditionssuch as irritable bowel syndrome,
Actions of Hormones on Psychic Functions
fibromyalgia, chronic fatigue syndrome, dyspepsia
Bodily processes may influence psychic ones, as discussed without an ulcer, and noncardiac chest painthe influ-
earlier in this chapter. Such interactions are especially ences of psychic factors are thought to be important
clear with regard to the hormonal effects on the brain. and sometimes decisive, although we cannot explain
For example, increased production of thyroid hormones the causative relationships. In other diseaseslike
changes the mental state toward excitement, increased gastric ulcers, coronary disease, asthma, and diabetes
initiative, and lively associations, whereas reduced there is good evidence that psychic stress can increase
production leads to apathy, fatigue, and increased need the vulnerability (i.e., the risk of developing the dis-
for sleep. Many patients with a thyroid disease have ease), without being a main causative factor. Further, in
been misdiagnosed as suffering from a mental disorder. such diseases, which are typically due to the interaction
Treatment with corticosteroids (as used, e.g., with cer- of many risk factors, individuals probably vary as to the
tain kinds of cancer) often elevates the mood (eupho- importance of each risk factor (see Chapter 31, under
ria), making the patient appear unduly cheerful and Amygdala, Anxiety, and Transmitters).
unconcerned. Effects of female sex hormones on the
brain probably cause the changes of mood often associ-
Stress
ated with the menstrual cycle in women (premenstrual
syndrome). Thus, a high density of receptors for sex Used in the present context, stress can be physical or
hormones has been demonstrated in various parts of psychological. A common definition is something per-
the brain. This concerns, in particular, certain cell ceived by the individual as a threat to the homeostasis of
groups in the hypothalamus and the amygdala; neurons the organism. Except for cases of extreme physical stress,
in other parts, such as the cerebral cortex, can also bind the crucial point in stress is how the challenge or extra
sex hormones. It seems likely, therefore, that circulat- demand is perceived, not the stress by itself. Although
ing hormones influence the excitability of many neu- the word stress in common language denotes some-
ronal groups (steroid hormones cross the bloodbrain thing that is bad for the health, extra demands on our
barrier easily). In cats, implantation of female sex physical or mental performance are inevitable and usu-
hormones in the posterior part of the hypothalamus ally not harmful. On the contrary, without challenges to
produces heat behavior. Many other experiments give the status quo, there would be no development, no
further evidence that circulating hormones, presumably learning, and no improvement of adaptive behavior.
by their actions on the brain, can be influenced animal The coordinated sum of endocrine, autonomic, and
behavior. The male sex hormone testosterone can pro- somatic responses to stress is termed a stress reaction.
duce male sexual identification and behavior when The function of the stress reaction is to maintain homeo-
given to monkeys at an early stage of their development, stasis in a wide sense, and the stressful event itself or the
regardless of the sex of the monkey. Thus, a female expectation of it can initiate the reaction. The hypothal-
monkey may later behave like a male if given a small amus obviously plays a central role in our ability to cope
amount of testosterone for a period shortly after birth. with stressful events; that is, the stress reactions are
expressed though the hypothalamic influences on the
endocrine, autonomic, and somatic effector systems.
Psychosomatic Disorders
Stress reactions are commonly assessed by measuring
A psychosomatic disorder (syndrome) is usually defined the blood level of epinephrine (activation of the sympa-
a condition in which psychological processes play a sub- thetic system) and of cortisol (activation of the hypo-
stantial role for the production of the somatic symptoms. thalamicpituitaryadrenal axis). The bodily response
The term somatoform disorder often implies absence of to stress is of course much wider than just these hor-
physical signs that can explain the somatic symptoms. monal changes, however, as discussed earlier in this
However, the definitions of these terms differ among chapter. Indeed, the stress reaction should not be seen
authors, presumably because the terms embrace a as an isolated phenomenon but, rather, as a part of
bodily expressions of arousal (arousal was discussed in reactions can be defined as behavior in response to stim-
Chapter 26). In this perspective, stress is a stimulus that uli producing sensations with an emotional coloring).
increases arousal (with changes of the EEG, attention, This agrees well with the fact that the hypothalamus
muscle tone, respiration, selective autonomic activation, functions as a superior center for control of autonomic
and activation of the CRHACTHglucocorticoid reac- processes. Emotions are expressed, as we know from
tion chain). everyday experience, to a large extent through changes
The purposefulness of the stress reaction is most of the functions of autonomically innervated organs,
obvious with physical stress, such as situations demand- such as palpitations, dryness of the mouth, fainting,
ing extreme endurance or force, or with injuries causing blushing, paling, alterations of the digestive tract, sweat-
rapid blood loss. However, stress reactions are also ing, frequent micturition, and so forth. In addition, auto-
adaptive and beneficial before and during extra mental matic movements, such as rapid, superficial breathing,
demands such as examinations, performances, or novel facial expressions, and postures, witness emotions. Such
situations. Overall, stress reactions are adaptive when movementsorganized by brain stem premotor net-
they improve our ability to cope with the extra demands. worksare probably influenced from the hypothalamus
Lack of corticosteroid hormones due to disease of the (see the discussion of emotional smile and facial palsy in
adrenals (Addisons disease), for example, greatly reduces Chapter 27, under Facial Expressions of Emotion Do
the ability to tackle even minor challenges to homeostasis. Not Depend on the Integrity of the Pyramidal Tract).
The stress reaction becomes potentially disease provoking The role of the hypothalamus in emotional reactions
only when it by far outlasts the actual stressful situation has been studied in cats and dogs in which the whole
(with, among other things, a persistently elevated level of cerebral cortex, the basal ganglia, and large parts of the
stress hormones). thalamus have been removed. So-called sham rage can
be provoked in such animals. Because only the hypo-
thalamus is connected with the brain stem in such ani-
Stress and Disease
mals, their expression of rage must depend on the
When talking of stress causing disease, we usually mean hypothalamus. Such animals react much like normal
psychic stress, and such that lasts for months or years. animals to painful stimuli, with biting, scratching,
Whereas serious physical stress produces a stress reac- snarling, and increased ventilation. Because the whole
tion that is uniform among individuals, the individual cortex is removed, it is unlikely that true emotions are
variations are larger to psychic stress. Thus, the decisive experienced, however. It seems reasonable to conclude
factor is the subjective perception and interpretation of that the hypothalamus contains cell groups that coordi-
the situation. This depends on many conditions, such as nate and put into action the behavior expressing the
prior experiences and how they were tackled (especially rage. In contrast to normal animals, the rage of such
during early childhood). Among psychological stress hypothalamic animals is not directed toward any-
factors (stressors), the feeling of loss of control is prob- thing in particular; they lack the ability to know the
ably the most important. Closely related to this is unpre- nature and the location of the stimulus provoking the
dictability of a situation. Animal experiments show that pain (as one might expect in an animal lacking the cere-
stress reactions to painful stimuli are reduced if the bral cortex and most of the thalamus). Further, the
stimulus is preceded by a warning signal. Presumably, expression of the rage dies out very quickly after the
this is because not knowing when the stimulus occurs stimulus is over, whereas the reactions continue for a
requires constant arousal, whereas the warning enables while in normal animals (as in humans). This observa-
the animal to relax (reduce arousal) between the stress- tion suggests that other parts of the brain normally act
ful events. The importance of the feeling of control is on the hypothalamus to produce emotional reactions,
exemplified by the fact that humans with chronic pain as we discuss in Chapter 31, under The Amygdala and
reduce their consumption of analgesic drugs if they can Emotions.
decide themselves when to take the drug, rather than The preceding account indicates that to regard the
having to ask another person. Another important factor hypothalamus as the locus of the emotions would be an
determining the level of psychic stress is the possibility impermissible oversimplification. Rather, the hypothal-
of obtaining an outlet for frustrationfor example, amus is a superior center for the coordination of emo-
with physical exercise. Finally, animal experiments sup- tional reactions. Observations in humans during brain
port that social attachments reduce psychic stress. surgery with local anesthesia support this conclusion.
Pressure on or traction of the hypothalamic region can
elicit reactions of panic, crying, laughter, or profuse
The Hypothalamus and Emotions
talking. The patients sometimes report a change of
The hypothalamus is among the parts of the brain most mood, such as depression or euphoria. It thus appears
directly involved in the expression of emotions or emo- that the activity of the hypothalamus is significant not
tional reactions (in an experimental context, emotional only for emotional reactions but also for the emotions
themselves. Conceivably, the emotions are evoked by but emotional reactions can be directly observed and
feedback connections from the hypothalamus to the are often more reliable in animals than in humans.
limbic structures and the cerebral cortexstructures Factors such as upbringing, social conventions, and
that are necessary for the experience of emotions (as conscious considerations determine to a large extent
distinct from emotional reactions). The higher regions the emotional reactions in humans. That emotions in
presumably interpret the hypothalamic activity as evi- animals can only be inferred indirectly from their
dence of external or internal stimuli that normally behavior explains why it is not quite clear how many
evoke strong emotions. basic emotions animals have. Commonly, however,
only three basic emotions are identified (in cats, dogs, and
monkeys): rage, fear, and pleasure (love). Even though
Emotions and Emotional Reactions
the emotions of animals certainly are less schematic than
When discussing the relations between the hypothala- this, there is no doubt that the emotions of humans have
mus and emotions, one must distinguish the emotions much more variation and nuances. This should be kept in
themselves from the emotional reactionsthat is, the mind when drawing conclusions with regard to emotions
behavior expressing our emotions. We can experience and psychosomatic interactions in humans on the basis of
the feelings or emotions only subjectively. Of course, animal experiments. The anthropologist Paul Ekman
we may learn that certain external stimuli or situations (1984) identifies seven basic emotions in humans, based
usually produce certain emotions in other people, but on their relation to culture-independent facial expres-
such correlations can only be tentative because so many sions: happiness, sadness, anger, fear, disgust, surprise,
psychological individual variations play a role. We cannot and contempt.
obtain information from animals about their emotions,
VII LIMBIC STRUCTURES
T HIS part of the book deals with parts of the fore-

brain that are closely associated with the cerebral
cortex with regard to development and connections.
nuclei (in contrast to the neocortex that is closely con-
nected with the thalamus). Together, these subcortical
nuclei and the allocortex are commonly said to comprise
The cerebral cortex is divided into two parts (without the so-called limbic system (gyrus limbicus is another
definite delimitations) on the basis of phylogenetic name for the cingulate gyrus). The cell groups compris-
development: the neocortex, which is the most recent ing the limbic system coincide in part with what was
part and comprises most of the cortex in higher mam- formerly called the rhinencephalon, although this term,
mals, and the allocortex, which is the oldest part. The strictly speaking, comprises only the parts of the brain
neocortex is treated in Chapters 33 and 34, while this that receive olfactory fibers. There are wide variations
chapter deals with the allocortex and closely related among authors, however, with regard to which neuronal
subcortical nuclei. The nomenclature used for the old- groups are included in the limbic system, indicating
est part of the cortex varies, but usually the term allo- that the term lacks reasonable precision. Indeed, the
cortex is used for the parts of the cortical mantle with a term system becomes misleading when used to lump
simple, often only three-layered structure instead of the rather arbitrarilyneuronal groups with major func-
six layers that are typical of the neocortex. In reptiles, tional differences. In this book we therefore use the
the allocortex constitutes what little cortex there is. The neutral term limbic structures to avoid giving a mislead-
allocortex receives afferents from adjacent subcortical ing impression of functional unity.
31 The Amygdala, the Basal
Forebrain, and Emotions
OVERVIEW many cholinergic neurons, and is involved in regulation of

in attention, motivation, and memory.
This chapter deals primarily with structures that are of
special importance for emotions, motivation, and affec-
tive behavior. We include in the discussion the cingu- WHAT IS THE LIMBIC SYSTEM?
late gyrus, the septal nuclei, the amygdala, and neuronal
groups in the basal forebrain. In addition, we discuss The structures included in the term the limbic system
neocortical regions involved in emotional processing, are often regarded as the substrate of emotions and
notably parts of the prefrontal cortex and the insula. subconscious processes, in contrast with the cognitive,
The amygdala is located in the tip of the temporal conscious processes that are assumed to be located in the
lobe and consists of several distinct nuclei with differ- neocortex. Sometimes terms such as the emotional
ent connections. It plays an important role in social brain or even the reptile brain have been used to
behavior and in emotional learning and memory. In describe these regions. Each of the cell groups of the lim-
particular, a central task of the amygdala is the estab- bic system participates in various functional domains,
lishment of links between stimuli and their emotional however, and confining them to a single conceptual
value. The amygdala has connections with brain stem framework only hampers understanding. To avoid the
nuclei (e.g., the periaqueductal gray [PAG]) and influ- propagation of simplistic concepts is even more impor-
ences somatic and autonomic responses to strong emo- tant because so much remains before we have a satis-
tions (e.g., mediating conditioned fear responses). It also factory understanding of the functional roles of the
can influence the endocrine system. Amygdaloid con- pertinent structures. The decision as to which structures
nections with the cingulate gyrus, the prefrontal cortex, should be included in the term the limbic system has
and the hippocampus mediate influences on cognitive become more and more arbitrary, as new methods have
processes, affective behavior, and memory. shown that many more parts of the brain participate in
Wide areas of the cerebral cortex influence the activ- emotional processing than believed when the term was
ity of the autonomic nervous system. This influence is coined.1 For example, parts of the neocortex (not only
exerted mainly via the amygdala, the hippocampal for- the allocortex) are strongly implicated in processing of
mation, and the septal nuclei, which in turn, influence emotionsthe prefrontal cortex and the insula, in par-
the hypothalamus and brain stem nuclei. In addition, ticular. Further, cell groups in the basal parts of the
there are some direct connections from the insula and hemispheresthe so-called basal forebrain (including
the orbitofrontal cortex to the hypothalamus. Further, the nucleus accumbens, discussed in Chapter 23)are
neocortical areas in the frontal and temporal lobes proj- densely interconnected with both limbic structures and
ect to the amygdala and can therefore influence the the neocortex, and these cell groups participate in both
hypothalamus indirectly. emotional and cognitive processing. We therefore include
Extensive cortical areas show altered activity in a description of the basal forebrain in this chapter, while
relation to emotions. On the other hand, no area is con- the prefrontal cortex is discussed mainly in Chapters 33
cerned solely with emotional processing. The cingulate and 34. Our present knowledge indicates that all com-
gyrus is, among other tasks, important for the choice of plex behavioral reactions engage the amygdala, the septal
behavior in response to conflicting stimuli. The orbito- nuclei, the hippocampal region, the reticular formation,
frontal and medial parts of the frontal lobes are also the hypothalamus, and large parts of the cerebral cortex.
closely linked with processing of emotions and their
integration with cognitive processes.
The term the basal forebrain (substantia innominata) is 1 Some authors include in the limbic system the mammillary body, the ante-
rior thalamic nucleus, the ventral striatum, and the hypothalamus. Some even
used with reference to diffuse neuronal populations below include brain stem cell groups such as the ventral tegmental area (VTA), the
and medial to the well-defined basal ganglia. It contains raphe nuclei, the PAG, and certain cholinergic neuronal groups.
461
As witnessed by their numerous interconnections, all of the olfactory cortex (see Fig. 19.3). To simplify, we may
these regions cooperate to exert an integrated influence say that the corticomedial nuclei are connected primar-
on the peripheral somatic and autonomic effectors. ily with the olfactory bulb, the hypothalamus, and the
What the American psychologist S.P. Grossman (1976, visceral nuclei of the brain stem, whereas the basolat-
p. 361) said about the septal nuclei probably holds for eral nuclei are mainly connected with the thalamus and
the rest of the limbic structures, too: Just about every prefrontal cortex. In addition, the basolateral nuclei
behavior and/or psychological function which has been send fibers to the ventral striatum and the basal nucleus.
investigated to date has been shown to be affected in This would suggest that the corticomedial part of the
some way by septal lesions. amygdala is concerned primarily with autonomic func-
In conclusion, the limbic system does not represent tions, whereas the basolateral parts are more involved
a unity that can be defined with a reasonable degree of in conscious processes related to the frontal and tempo-
precision. As stated by the American neurologist Antonio ral lobes. The many intrinsic connections among the
Damasio (1995, p. 20), the bizarre distinction between various nuclei show that they must cooperate extensively,
cognition and emotion, as if somehow one could have however.
thoughts without emotion, a mind without affect . . . The amygdala (or its many components) participates
The rift between emotion and cognition acquired a neu- in several higher mental functions, each of which is
roanatomical counterpart in the duality between limbic highly complex. Its functions are correspondingly
system and neocortex. complex and hard to define. Nevertheless, some salient
features are clear. Thus, a central task of the amygdala
is the establishment of links between stimuli and their
The Circuit of Papez
emotional value (put very simply, whether something is
In 1937, Papez described what he considered a closed good or bad). Most of our memories have someoften
circuit of connections starting and ending in the hip- quite strongemotional coloring, which is crucial for
pocampus. From the hippocampus, the flow of signals our ability to react appropriately to a stimulus. Think
was postulated to pass to the mammillary nucleus, from of the importance of being able to judge the facial
this nucleus to the anterior thalamic nucleus, from there expressions of other people, the emotional aspects of
to the cingulate gyrus, and then finally back to the hip- their speech, and so forth. As we discuss in this chapter,
pocampus. This circuit of interconnected cell groups was damage to the amygdala in monkeys leads to, among
hypothesized to form the anatomic basis of emotional other things, difficulties in social interactions.
reactions and expressions. These suggestions formed the
basis for the concept of the limbic system, which was
Afferent Connections of the Amygdala
introduced in the early 1950s by Paul MacLean.
The corticomedial nuclei receive afferents from the
olfactory bulb, the hypothalamus, the intralaminar
THE AMYGDALA thalamic nuclei, and the septal nuclei (Fig. 31.4). They
also receive dopaminergic fibers from the ventral teg-
Main Anatomic and Functional Subdivisions mental area in the mesencephalon, as well as fibers from
The amygdala (the amygdaloid nucleus) is located in the
temporal lobe, underneath the uncus (Figs. 31.1, 31.2,
Cingulate
and 31.3; see Fig. 6.29). In humans, the amygdala is a gyrus
complex of subnuclei, each with a distinctive internal
2
structure, neurotransmitters, and connections. Here Fornix
we restrict ourselves to distinguishing between a small
corticomedial (including a central nucleus) and a large
basolateral nuclear group (including the lateral nucleus).
The basolateral group increases in size from lower to
higher mammals and is particularly well developed in
humans. The corticomedial nuclear group lies close to
Septal
nuclei
2 The amygdala as we describe it here is structurally and functionally hetero-
geneous, and we lump the various nuclei under one name purely for conve- Entorhinal Parahippocampal gyrus
nience. Indeed, in a critical review Larry Swanson and Gorica Petrovich (1998) area Hippocampus
concluded it is necessary to ask whether the concept of a structurally and Amygdala
Uncus
functionally dened amygdala is indeed valid, or whether the concept is hinder-
ing attempts to understand general principles of telencephalic architecture by gure 31.1 The limbic structures. The right hemisphere, as viewed
imposing an arbitrary classication on heterogeneous structures that belong to from the medial aspect. The regions and cell groups indicated in red
different functional systems. are usually included in the term limbic system.
31: THE AMYGDALA, THE BASAL FOREBRAIN, AND EMOTIONS 463
A Fornix B
Mammillary
body
Amygdala
Hippocampus
Subiculum
Dentate gyrus
Mammillary Fimbria
body
Amygdala
Fornix
Hippocampus
gure 31.2 The hippocampus, fornix, mammillary nucleus, and the amygdala. A: Viewed obliquely from behind. B: Viewed from above.
the parabrachial area (in the dorsolateral pons). The lobe, and the cingulate gyrus (Fig. 31.4). Together, the
latter projection may convey information about taste basolateral nucleithe lateral nucleus in particular
and, in addition, about painful stimuli. Thus, ascending receive all kinds of sensory information. This may be
fibers of spinal lamina I nociceptive neurons end in emotionally neutral information from cortical associa-
parts of the parabrachial area that project to the central tion areas and emotionally laden information about
amygdaloid nucleus (among other targets). The sensory unpleasant and threatening stimuli from the reticular
units of this pathway have very large receptive fields formation, the intralaminar thalamic nuclei, and per-
and receive convergent inputs from the skin and viscera. haps parts of the cortex (the insula). Thus, the amygdala
It seems likely that this lamina Iparabrachialamygdaloid receives, for example, information about fear-provoking
pathway contributes to the emotional aspects of pain. stimuli and their context. Efferents from the lateral
The basolateral nuclei receive fibers from several thal- nucleus reach other amygdaloid nuclei that may influ-
amic nuclei, the prefrontal cortex, parts of the temporal ence the cortex (conscious experience of emotions) and
AMYGDALA
Globus pallidus
Third ventricle
Basal nucleus (part of substantia

innominata)
Hypothalamus
Optic tract
Central nucleus CORTICOMEDIAL
}
Cortical nucleus GROUP
Basal nuclei
Lateral nucleus } BASOLATERAL GROUP
gure 31.3 The amygdala. Frontal section through the left hemi- stippled line. The amygdala and the cerebral cortex of the temporal
sphere (cf. Fig. 31.1). Some of the amygdaloid nuclei are marked with lobe are closely connected. The section is placed more posteriorly
orange stippled lines. The basal nucleus is indicated with green than the one in Fig. 31.9.
Cingulate Stria
Thalamus (MD)
gyrus terminalis
Thalamus
Prefrontal Prefrontal
cortex cortex
Septal
nuclei
Hypothalamus Septal
Olfactory nuclei
bulb
Hypothalamus
LA
AMYGDALA
AMYGDALA
PAG
Temporal Temporal
association cortex Parabrachial association PAG
nucleus cortex Hippocampal Locus
formation coeruleus
gure 31.4 Afferent connections of the amygdala. Note the connec-
tions with the hypothalamus, cortical areas in the temporal and the
gure 31.5 Efferent connections of the amygdala. Note connections
frontal lobes, and brain stem nuclei. Not all known connections are
to the hypothalamus, the PAG, the hippocampus, and cortical areas
shown.
in the temporal and frontal lobes. See also Fig. 31.6.
brain stem cell groups (behavioral reactions, including learning effects on neurons in the auditory cortex depend
autonomic responses associated with emotions). on inputs from the amygdala (and the basal nucleus)
besides the specific auditory information via the medial
geniculate body. It seems likely that this is related to the
Efferent Connections of the Amygdala
well-known effects of motivation on learning: we remem-
The efferent connections of the amygdala are mostly ber better the material that has emotional coloring. The
reciprocal to the afferent ones. One major efferent amygdala
pathway goes to the hypothalamus. Most of these fibers Finally, there are connections from the amygdala
are collected in the macroscopically visible stria termi- (especially from the central nucleus) to various brain
nalis, which arches over the thalamus (Fig. 31.5). The stem nuclei, such as the PAG (Fig. 31.6), parts of the
fibers end primarily in the ventromedial hypothalamic reticular formation, and parasympathetic cranial nerve
nucleus (compare with the efferents from the hippocam- nuclei. These connectionstogether with those to the
pal formation, which run in the fornix and end in the hypothalamusare important for the autonomic and
mammillary nucleus). Other efferents pass to the thala- somatic expressions of emotions. The connections to the
mus (especially to the mediodorsal nucleus [MD]), PAG are involved in eliciting conditioned fear behavior.
enabling signals from the amygdala to reach the pre- The PAG sends fibers to various brain stem premotor
frontal cortex (Fig. 31.5). As mentioned, these connec- networks (Fig. 31.6). In rats, conditioned fear includes
tions may be important for the conscious experience of so-called freezing; that is, the animal becomes completely
emotions, such as fear and anxiety. In particular, the still. The freezing reaction, which includes suppressed
amygdalaprefrontal connections might ensure that we pain transmission, occurs typically when a rat meets a
spend our limited attentional resources on the most predator, such as a cat. When exposed to a sudden threat,
important stimuli (those with emotional coloring), and humans also experience a similar halt of all movements,
further, that emotional and cognitive information is until an appropriate behavioral response is selected
integrated prior to decisions and actions. (flight, fight, or continued immobility).
Parts of the allocortex receive fibers from the Many behavioral changes have been produced by
amygdala, especially the hippocampal formation (the electrical stimulation of the amygdala in animals with
entorhinal area and the subiculum) and the septal nuclei. implanted electrodes. (In such experiments, the electrodes
Fibers to the ventral striatum (including the nucleus accum- have been inserted and fixed to the skull under general
bens; see Fig. 23.15) and the basal nucleus (Figs. 31.3 anesthesia. Afterward the electrodes cause the animal no
and 31.8; see Fig. 10.1) arise in the basolateral nuclei of pain or obvious discomfort.) Stimulation produces a var-
the amygdala. The projections to the basal nucleus can ied pattern of somatic and autonomic responses, which
induce activation of the EEG (arousal and increased appear to be parts of more complex behavioral reactions.
attention). There is experimental evidence that synaptic As would be expected from the anatomic data discussed
Sensory association areas Higher association
Primary sensory areas (perirhinal cortex)
CEREBRAL Hippocampal
CORTEX formation
Lateral
THALAMUS AMYGDALA
Central
Substantia innominata
(Bed nucleus of stria
PAG terminalis)
Lateral hypothalamus
EMOTIONAL Hypothalamus (PVN)

BEHAVIOR Medulla
gure 31.6 The amygdala and conditioned fear.
Median eminence
The neural substrate of the autonomic, endocrine,
and somatic responses elicited by a conditioned
AUTONOMIC
stimulus (sound) associated with an electric foot
RESPONSE Anterior lobe of pituitary
shock. The connections of the amygdala with the
sensory association areas are necessary for discrimi-
native aspects of stimulus analysis, while connec-
tions with the hippocampus mediate contextual ENDOCRINE RESPONSE
conditioning. (Based on LeDoux 1995.)
in the preceding text, stimulation of medial and lateral Situations with purely mental stress can produce a
parts of the amygdala gives different responses. Stimulation conditioned-fear reaction in rats as in humans. In rats,
of the corticomedial nuclear group produces smacking, the conditioning may be established by letting a tone be
salivation, and licking and chewing movements. Emptying followed repeatedly by a painful stimulus (e.g., an elec-
of the rectum and the bladder may occur, together with tric shock to the foot). After a while, the tone alone
inhibition of voluntary movements. Stimulation of the elicits fear-related behaviorthat is, behavior that nor-
basolateral nuclear group often produces arousal and mally occurs in threatening or dangerous situations
signs of increased attention: the animal lifts its head, its (such as the sight of a cat). As discussed earlier, the fear
pupils are dilated, and it looks around (especially toward reaction of a rat includes autonomic, somatic, and
the side opposite of the stimulating electrode). The atten- endocrine responses, such as freezing and increased
tion of the animal appears to be directed toward some- secretion of cortisol. When a tone is the conditioning
thing in the surroundings. As might be expected, activation stimulus, the necessary information about the sound is
of the EEG occurs along with these behavioral changes. transmitted directly from the thalamus to the lateral
Strong stimulation can produce dramatic effects, such as amygdaloid nucleus. The auditory cortex is necessary
signs of fear or rage. for the occurrence of the fear reaction only if the animal
has to discriminate two tones with different frequencies.
The hippocampus is not necessary for the tone condi-
Amygdala and Conditioned Fear
tioning. It is necessary, however, for a weaker contex-
As mentioned, the amygdala has a role in a variety of tual conditioning; that is, the fear reaction can also be
emotions and emotionally related behaviors. This, with elicited by clues in the environment of the experimental
its anatomic heterogeneity, strongly suggests that the situation (such as objects, sounds, or odors). Signals are
amygdala is not a functional unit. In the search for the relayed (directly and indirectly) from the lateral nucleus
biologic substrate of specific behaviors, conditioned to the central nucleus. Efferents from the central nucleus
fear has been intensively studied (Fig. 31.6), and crucial to autonomic and somatic cell groups in the brain stem
links in the pathways that underlie this phenomenon (among them the PAG) probably mediate main compo-
have been dissected out in experimental animals. nents of the fear reaction. Thus, destruction of the cen-
Such detailed data may help us understand how the tral nucleus abolishes both the freezing and autonomic
amygdala participates in other kinds of tasks. responses in conditioned fear.
Main Tasks of the Amygdala evaluates very rapidly a stimulus for its threatening
value, and initiates appropriate behavior. However,
The tasks performed by the amygdala have been clari-
selective lesions of the amygdala in monkeys produce
fied by lesion and stimulation experiments in animals,
fewer behavioral changes than reported in early experi-
and recently by numerous functional magnetic resonance
ments with lesions that included adjoining parts of the
imaging (fMRI) studies in humans. Further, important
temporal lobe (see Chapter 34, under Symptoms after
information comes from examination of a few persons
Lesions of the Temporal Cortex). For example, no
who lack the amygdala (usually after surgical treatment
signs of abnormal social development were observed the
of epilepsy). While the connection between the amygdala
first 6 months after bilateral lesions of the amygdala in
and emotions is firmly established, much investigation
infant monkeys, in relationships with either the mother
remains before we understand its specific contributions
or other infants in the group. However, the infants did
to emotional processing and human behavior.
not exhibit the normal signs of distress to separation
Animal experiments show that a central task for the
from the mother, presumably owing to a reduced ability
amygdala is to establish associations between sensory
to perceive danger and threatening situations.
stimuli and their emotional coloring. It is crucial that
we can decide quicklybefore slower conscious delib-
erationswhether a stimulus (or a situation) is threat- Is the Amygdala Concerned Only with
ening or safe (punishment or reward). Accordingly, Negative Emotions?
fMRI studies in humans show activation of the amygdala
Whereas most studies have focused on a correlation
when viewing pictures with an emotional content.
between amygdala activity and negative emotions such
Further, bilateral lesions of the amygdala in monkeys
as fear and anger, recent studies suggest that the amygdala
reduce behavior elicited by emotions. For example, the
plays a role for the recognition of positive emotions as
animals show no fear of snakes (monkeys have an
well. For example, a meta-analysis of human positron
inborn fear of snakes). This can probably be explained
emission tomography (PET) and fMRI studies found
by the removal of amygdaloid effects on the hypothala-
that both negative and positive stimuli were associated
mus and on the brain stem autonomic and somatic
with higher amygdala activity compared with neutral
motor centers (among them the PAG; Fig. 31.6). Sensory
stimuli. Indeed, single-unit studies in monkeys identified
stimuli (such as the sight of a snake), although reaching
distinct populations of amygdaloid neurons responding
consciousness, would not be able to elicit the normal
to positive and negative stimulus valence, respectively
behavioral reactions.
(the two kinds of neuron were not spatially segregated in
The sight of faces expressing anger or fear causes a
the basolateral amygdala, however).
robust activation of the human amygdala, as shown via
fMRI. Correspondingly, patients with amygdaloid
lesions have difficulties with recognizing facial expres- Electric Stimulation of the Human Amygdala
sions. Interestingly, such patients do not show the nor-
In humans, the amygdala has been stimulated in con-
mal tendency to remember events or stimuli that have
junction with brain surgery of the temporal lobe under
an emotional coloring better than they remember neu-
local anesthesia. A wide spectrum of autonomic and
tral ones. This has been demonstrated, for example, by
emotional reactions has been produced in such cases,
showing films containing emotionally neutral material
but most pronounced is a feeling of anxiety. Memory-
and scenes that evoke strong emotions.
like hallucinations and dj vu experiences (the feeling
Selective lesions in adult monkeys produce a pattern
3 of having experienced the same situation before) have
of behavior characterized by social disinhibition. For
also been reported. This is called a dreamy state and
example, they initiate more physical contact, suggesting
can occur in epileptic seizures that start in the temporal
. . .that heightened affiliative social interactions follow-
lobe. Similar effectsthat is, fear and various kinds of
ing amygdala lesions stems from a more general inability
hallucinationshave been produced by stimulation of
to properly perceive danger or threat in the environment
the anterior portion of the hippocampus and the lateral
and use such information to modulate social behavior
cortex of the temporal lobe (in the superior temporal
adaptively (Machado et al. 2008, p. 263). This would
gyrus). This relationship can presumably be explained
fit with the amygdala working as a sort of alarmit
by the close connections between these regions and the
amygdala, all being parts of a more widespread network
3 Hypersexuality was one of the behavioral changes reported in the early stud- for handling of emotions and memories.
ies with large bilateral lesions of the amygdala in monkeys. However, this may
be related to damage to allocortical areas near the amygdala rather than to the
amygdala itself. Nevertheless, it is conspicuous that the amygdala is among the
brain regions with the highest density of receptors for sex hormones. Is Amygdala Necessary for the Experience of Emotions?
Conceivably, the level of sex hormones in the blood inuences the activity of
neurons in parts of the amygdala (the sex hormones are lipid-soluble and pass The finding that the amygdala is necessary for expression
the bloodbrain barrier easily). of emotions (at least some aspects) raises the question of
whether the amygdala is necessary also for the subjec- Connections from medial parts of the prefrontal cor-
tive experience of emotions (such as fear or anger). tex appear to be necessary for unlearningextinctionof
A patient with bilateral destruction of the amygdala, the conditioned fear response. Extinction occurs when
described by the British psychiatrist R. Jacobson (1986), the conditioned stimulus regularly occurs without a
illustrates this point. She appeared calm and relaxed subsequent unconditioned stimulus, but not in rats after
outwardly and had normal heart rate in situations in removal of the medial prefrontal cortex. Other data
which she experienced great anxiety and wanted to run also indicate that extinction depends on an active inhi-
away. Presumably, the coupling between the emotions bition of the amygdala from the prefrontal cortexnot
and the emotional reactions was disrupted in this patient on the disappearance of the synaptic changes underlying
(see Chapter 30, under Emotions and Emotional the associations.
Reactions). Further, 20 patients with amygdaloid
lesions after epilepsy surgery described their daily emo-
Amygdala, Anxiety, and Neurotransmitters
tionspositive and negativein the same manner as
4
normal controls (Anderson and Phelps 2002). The amygdala contains many neurotransmitters, and to
sort out the functional role of each is a formidable task.
For practical reasons, therefore, scientists concentrate
The Amygdala, Learning, and Unlearning
on studying one or a few at a time, with the danger of
The conditioned-fear reaction discussed in the next overlooking the contributions of other transmitters. We
subsection requires a learning process: the rat learns to restrict ourselves here to the transmitters involved in
associate an innocuous stimulus with something pain- conditioned fear and psychic stress. As mentioned, sig-
ful. Destruction of the amygdala prevents establishing nals pass from the lateral to the central nucleus through
the conditioned response. Indeed, induction of LTP both direct and indirect routes.
occurs in certain parts of the amygdala in conjunction Electrical stimulation of the lateral nucleus evokes
with development of a conditioned fear response. Thus, primarily -aminobutyric acid (GABA)-mediated inhi-
experiments with monkeys after a lesion restricted as bition in the central nucleus (acting at both GABAA and
far as possible to the amygdala show that they have dif- GABAB receptors). Some inhibition occurs presynapti-
ficulties in learning the association between objects and cally by reducing the release of glutamate. Drugs that
their meanings. They can recognize objects but cannot reduce anxiety (anxiolytics) may function by interfering
relate them to other kinds of information, such as whether at this level. The benzodiazepines (Valium and others)
the object was associated with a reward or something bind to specific sites on the GABA receptor (benzodiaz-
unpleasant. Many other observations support that the epine receptors) and potentiate the effect of GABA. The
amygdala is necessary for the learning of associations density of benzodiazepine receptors is high in the
between stimuli and their significance in terms of amygdala and particularly high in the lateral nucleus
reward or punishment. We may say that the amygdala (and one other subnucleus of the basolateral complex).
is crucial for the emotional coloring of experiences and Local infusion of benzodiazepines in these nuclei reduces
sensations, and that associations are remembered. The expressions of conditioned fear in experimental animals.
amygdala is not alone in this respect, however. Both the Corticotrophin-releasing hormone (CRH) may also
amygdala and parts of the prefrontal cortex are neces- be an important transmitter in the amygdala in relation
sary in monkeys for the learning and later retrieval of to anxiety and stress. Besides containing CRH-positive
associations between visual stimuli and food rewards. cell bodies, the central nucleus receives many CRH-
The connections involved are partly direct fibers from containing fibers (neurons in the parabrachial area and
the amygdala to the ventromedial prefrontal cortex and the locus coeruleus contain CRH, for example). Injection
partly a pathway interrupted in the mediodorsal thal- of CRH into the cerebral ventricles increases stress
amic nucleus (MD). Experiments in rats suggest that reactions and fear-related behavior, presumably by act-
connections between the basolateral amygdala and the ing in the amygdala but also in other areas. For exam-
ventral striatum are also necessary for establishing ple, noradrenergic neurons in the locus coeruleus are
stimulusreward associations. activated, which may contribute to arousal as part of a
stress reaction. Because acute and chronic stress increases
CRH in the amygdala, microinjections of CRH antago-
4 Not all patients with bilateral damage of the amygdala exhibit a dissociation nists in the central nucleus abolish some stress reactions.
of the experienced emotion and the emotional expressions, however. Indeed, The expectation of pain evokes an endocrine response,
there are surprisingly large individual variations in symptoms among patients
with amygdaloid lesions. Conceivably, the age at which the lesion occurred as one part of a stress reaction (see Chapter 30, under
plays a decisive part: with early lesions, other parts of the brain would be Psychosomatic Disorders). This may be mediated by
expected to at least partly take over the tasks of the amygdala. Further, prior neurons in the central nucleus, which project to the
experiences and subtle difference in context may strongly inuence how differ-
ent subjects with lesions of the amygdala experience and respond to identical paraventricular hypothalamic nucleus. CRH-containing
stimuli. neurons in the paraventricular nucleus project to the
median eminence. There CRH is released and reaches the bear in mind that our simplifying concepts have limited
anterior pituitary via the portal system (see Fig. 30.7). explanatory power. All cortical areas we mention here
CRH increases the secretion of ACTH, thus increasing with focus on autonomic functions and emotions are
cortisol in the bloodstream. also involved in other tasks (participate in other net-
Several transmitters other than CRH show changes in works). For example, most of the cortical areas regulat-
relation to anxiety and stress. Neuropeptide Y (NPY) ing autonomic functions also participate in processing
has attracted much interest. Thus, microinjection of NPY of emotions. This is not unexpected, as the autonomic
in the amygdala evokes largely the opposite effects of adjustments are an integral part of complex behavioral
CRH on stress and fear-related behavior. NPY is pres- responses.
ent in many neurons in the amygdala (colocalized with
norepinephrine, GABA, or somatostatin) and in termi-
Autonomic Functions
nals of afferent axons. Animal experiments suggest that,
whereas CRH is crucial in eliciting a stress reaction, NPY Experimental and clinical data show that wide areas of
that is released after the reaction has started protects the cerebral cortex influence the activity of structures
against overshooting. innervated by the autonomic nervous system. This
influence is mainly exerted via the amygdala, the hip-
pocampal formation, and the septal nuclei, which in
The Amygdala and Depression
turn, influence the hypothalamus and brain stem nuclei.
As mentioned, CRH is one likely transmitter (among In addition, there are some direct connections from the
several) for evoking fear-related behavior and stress insula and the orbitofrontal cortex to the hypothala-
reactions, and the amygdala is an important site of mus. Further, neocortical areas in the frontal and tem-
action. CRH also appears to be related to mood. Thus, poral lobes project to the amygdala and can therefore
the concentration of CRH in the cerebrospinal fluid is influence the hypothalamus indirectly.
increased in many deeply depressed patients and vic- The cingulate gyrusone of the limbic structures
tims of suicide. In the latter group, lowered density of appears to be involved in organization and initiation of
5
the CRH receptor occurred in the frontal lobe (down- various kinds of goal-directed behavior. It projects to
regulation due to constantly increased CRH available?). the hippocampal formation, to the septal nuclei, and to
A transgenic mouse strain overproducing CRH has the amygdalaall of which have connections to vari-
increased levels of ACTH and cortisol in the blood as ous parts of the hypothalamus (Fig. 31.7). Electrical
expected. In addition, mice from this strain show behav- stimulation of the cingulate gyrus elicits a combination
ior indicative of anxiety (e.g., the way they behave in of autonomic (visceral) and somatic effects. Autonomic
novel situations). This behavioral pattern is normalized effects include, for example, alterations of respiration
by supply of CRH antagonists. and circulation (reduced rate of breathing, heart rate,
Measurement of regional cerebral blood flow sup- and blood pressure), of the digestive tract (altered peri-
ports the fact that the function of the amygdala is altered staltic movements and secretory activity), and pupillary
in seriously depressed patients. Thus, compared with a dilatation. Somatic effects are expressed mainly as
control group, depressed patients had increased blood changes of muscle tone and often inhibition of ongoing
flow in the left prefrontal cortex and amygdala. This movements.
observation does not tell us how the amygdala is involved Alterations of functions controlled by the autonomic
in depression, howeverfor example, whether the blood system can be produced by stimulation of parts of the
flow changes are secondary to a change of mood, or cortex other than the cingulate gyrus. Stimulation of
whether changes in the amygdala come first. the orbitofrontal cortex, the insula, and the pole of the
temporal lobe produces effects similar to those obtained
from the cingulate gyrusthat is, combined behavioral,
SOME ASPECTS OF CORTICAL CONTROL OF emotional, and autonomic responses. Stimulation of
AUTONOMIC FUNCTIONS AND EMOTIONS the aforementioned neocortical regions not only pro-
duces effects on autonomic functions; somatic functions
Assigning specific functions to cortical regions builds on are altered as well. In contrast, alterations of autonomic
methods that can only provide indirect answers (func- functions can occur after stimulation of cortical regions
tional deficits after lesions, blood flow changes associ- that one might believe to be purely somatic, such as the
ated with certain behaviors, EEG, single neurons motor and the premotor cortical areas. Thus, stimulation
recordings, and so forth). Because distributed networks
not single areasare responsible for the execution of
complex tasks, assigning functions to specific regions 5 While minor parts of the cingulate gyrus belong to the allocortex, most of it
probably belongs to the oldest parts of the neocortex. The terms limbic or
must be imprecise and simplistic. Although we need paralimbic cortex are often used of cortical regions that have intimate connec-
pigeon holes and labels to aid our thinking, we should tions with limbic structures, such as the amygdala and the hippocampus.
A B
Prefrontal cortex Parietal and temporal Thalamus (MD, NA) CINGULATE GYRUS
association areas
Striatum
Cerebellum
Septal (via pontine
nuclei nuclei)
Subiculum Amygdala
Mammillary
body
Entorhinal area
gure 31.7 Main connections of the cingulate gyrus. A: Afferent con- connections with neocortical association areas and with limbic struc-
nections B: Efferent connections. The cingulate gyrus has reciprocal tures and may act as a mediator between them.
6
of the motor cortex produces vasomotor changes (i.e., special focus on the detection of errors and conflicts.
changes of the blood vessel diameter and, therefore, of For this monitoring, emotions provide important infor-
blood flow) of the opposite body half. On damage to mation about values of different signals. Parts of the cin-
these cortical areas (as seen in patients with a cerebral gulate gyrus (both anterior and posterior parts) and the
stroke), vasomotor changes often occur in the paralyzed anterior insula (Fig. 31.8) also alter their activity in rela-
parts of the body. Even alterations of the heart rate and tion to emotions such as admiration and compassion.
blood pressure and of the digestive tract can occur. As Several parts of the prefrontal cortex show altered
a final example of combined somatic and autonomic activity in relation to emotions in humans, and accord-
effects, stimulation of the frontal eye field (see Fig. 25.7) ingly, lesions often produce emotional disturbances (see
produces pupillary dilatation in addition to the more Chapter 34, under Symptoms after Prefrontal Lesions).
obvious conjugated eye movements. Especially the orbitofrontal and ventromedial parts
seems important for emotional regulation (Fig. 31.8). As
mentioned, these parts have reciprocal connections
Emotions and the Neocortex
with the amygdala. The orbitofrontal cortex may inte-
As mentioned, cortical areas that show altered activity grate competing, emotionally colored signals to provide
(as measured with PET and fMRI) in relation to emo- an appropriate response. For example, a study com-
tions are more extensive that those initially included in pared the behavior of normal and orbitofrontal-lesioned
the limbic system (Fig. 31.8). On the other hand, no monkeys in a situation where a snake occurred between
area is solely concerned with emotional processing. The the monkey and a piece of food. Presumably, amygdala
cingulate gyrus is a pertinent example. Even if it con- informs about the values of the signals (snake and food),
sists of several smaller subdivisions that differ with whereas the orbitofrontal cortex is necessary for evalua-
regard to connections, they all seem to be involved in tion and appropriate action. Such studies strongly suggest
both cognitive and emotional processing, albeit to a that the orbitofrontal cortex is important for behavioral
varying degree. The anterior part of the cingulate gyrus flexibilitythat is, the ability to alter behavior when
(anterior cingulate cortex [ACC]) consists of rostral needed and to choose among conflicting choices.
part that is more concerned with affect regulation and
a caudal part more concerned with cognitive task. In
general, the ACC appears to be important for the choice 6 Stimulation of the ACC in monkeys produces, for example, aggressive
reactions, whereas bilateral removal makes the animals tamer. They may also
of behavior in response to conflicting stimuli. The ACC become socially indifferent that is, they appear to have lost interest in other
also seems to monitor mental and bodily processes with members of their group and do not try to make contact.
presumably reflecting that nothing was known about

its connections and functions. The basal forebrain
(basal prosencephalon) is usually used synonymously
with the substantia innominata. Only recently are its
connections, cytochemistry, and functions being clari-
fied, showing that the basal forebrain is not an ana-
tomic or functional unity. It is now commonly accepted
to divide the basal forebrain into three overlapping
regions, differing regarding neurotransmitters and con-
cingulate Orbitofrontal and nections: the ventral striatopallidum, the extended
cortex medial prefrontal amygdala, and the basal nucleus (Figs. 31.3 and 31.9;
cortex see Fig. 10.1). The ventral striatopallidum was discussed
in Chapter 23. We discuss here only certain aspects of
the basal forebrain, starting with a large group of cho-
linergic neurons that are found in the basal nucleus and
some adjacent cell groups.
Cholinergic Neurons Projecting to the Cerebral Cortex

Orbitofrontal Cholinergic neurons of the basal forebrain form a thin
cortex disc close to the basal surface of the hemispherethe
Insula basal nucleusand are furthermore found in the septal
nuclei and the diagonal band of Broca that extend dor-
gure 31.8 Parts of the cerebral cortex involved in processing of
sally close to the midline (Figs. 10.1, 31.9, and 31.10).
emotions.
The septal nuclei form the most well-defined anatomic
entity among these cell groups, and lie just in front of
Finally, an interesting hypothesis proposes that a net- the anterior commissure (Fig. 31.1; see Fig. 23.15).7
work comprising the amygdala, the nucleus accumbens, The diagonal band of Broca forms a transition between
the orbitofrontal cortex, the insula, and the anterior the basal nucleus and the septal nuclei.
cingulate cortex monitors the energetic demands The cholinergic neurons of the basal forebrain project
involved in performing a task (Boksem and Tops 2008). to the cerebral cortex (both to the allocortex, including
In so doing, the network would need to weigh the the hippocampus, and the neocortex).8 The septal nuclei
potential reward against the energetic cost of a task to and the diagonal band send fibers mainly to the hip-
reach a decision on whether to go on with it or not. pocampal formation, whereas the basal nucleus projects
Presumably, this process would require integration of to the neocortex with a rough topographic order.
emotional (motivational), and cognitive signals. The Although the afferent connections of the cholinergic
authors furthermore suggest that mental fatigue . . .can cell groups of the basal forebrain are incompletely
best be considered as an adaptive signal that the present known, important inputs arise in the brain stem, notably
behavioural strategy may no longer be the most appro- in the locus coeruleus and in cholinergic cell groups in
priate . . . fatigue may present the cognitive system with the dorsolateral pons (such connections are involved in
a signal that encourages the organism to lower present the ascending activating system discussed in Chapter 26).
goals . . . (p. 133). Further, afferents come from the hypothalamus, the cin-
Neocortex and emotions are discussed further in gulate gyrus, and the nucleus accumbens of the ventral
Chapter 34. striatum.
NEURONAL GROUPS IN THE BASAL PARTS OF THE 7 The region containing the septal nuclei is called the precommissural part of
HEMISPHERES: THE BASAL FOREBRAIN the septum (located anterior to the anterior commissure, see Fig. 6.26). The
postcommissural part is the septum pellucidum, which contains no neurons (see
Fig. 6.29).
Below and medial to the well-defined basal ganglia many 8 Not all neurons in the basal forebrain projecting to the cortex are cholinergic.
neurons are spread out rather diffusely. Unfortunately, Some neurons, mingled with the cholinergic ones, are GABAergic. Some con-
tain the neuropeptide galanin, partly colocalized with acetylcholine. In humans
the nomenclature for this region is not consistent among the diagonal band of Broca has many somatostatin-containing neurons,
authors. Thus, different names are often applied to the although it is not known whether they project to the cortex. Thus, although
region or parts of it without attempting to describe more apparently the majority of the neurons in the basal forebrain projecting to the
cortex are cholinergic, it is not a transmitter-specic system. This is of relevance
precisely what is meant. The old anatomists named it when trying to explain the symptoms of diseases with loss of neurons in the
the substantia innominata (the region without a name), basal forebrain (notably Alzheimers disease, discussed in Chapter 10).
Fornix
Caudate
nucleus
Extended
amygdala
(Bed nucleus of
stria terminalis)
Putamen
Globus
pallidus
Insula
Claustrum
Ventral
pallidum
Basal nucleus
gure 31.9 Main components of
Uncus
the basal forebrain. Photograph
of a frontal section through the
right hemisphere. Compare with Amygdala
Fig. 31.10 showing the nucleus
accumbens (ventral striatum) to
advantage.
Among the cholinergic cell groups, the septal nuclei Functional Roles of the Basal Forebrain
first attracted interest because early lesion and stimula- Cholinergic Neurons
tion experiments showed that they influence autonomic
Later studies turned to the role of the cholinergic neu-
functions, emotions, and behavioral reactions. For
rons in attention and memory mechanisms. Particularly
example, lesions of the septal nuclei in animals alter sex-
seminal in this respect was the discovery of cell loss in
ual and foraging behavior: aggressive behavior appears
the basal nucleus in patients with Alzheimers disease.
to be reduced (as stimulation of the septal nuclei can
Some studies in monkeys suggested that the septal
produce aggression). The effects are similar to those
nuclei, the diagonal band of Broca, and the basal nucleus
produced by lesions of the amygdala and the anterior
all must be destroyed to produce memory impairments.
parts of the cingulate gyrus and presumably can be
More detailed experimental studies with injection of
explained by the connections of the septal nuclei with
substances that destroy the cell bodies (but not passing
these parts and the hypothalamus. Symptoms specific
fibers) suggest that the septal nuclei and the diagonal
to the septal nuclei, constituting the so-called septal
band of Broca are especially important for memory
syndrome, have not been proved convincingly.
(presumably because of their connections with the
hippocampus), whereas the basal nucleus is more con-
Corpus
callosum cerned with maintaining and perhaps focusing attention.
Further, there are several reports of patients with small
Caudate
nucleus lesions in the anterior parts of the cholinergic cell
Fornix groups who exhibited clear-cut memory loss (both for
Septal recent and past events). One such patient, for example,
nuclei
had a lesion affecting primarily the diagonal band of
Extended
amygdala Broca, as judged via MRI. The difficulties with the
Anterior exact localization of the damage in such patients warn
commissure against firm conclusions, however.
Nucleus
accumbens
Other Components of the Basal Forebrain: The Ventral
Striatopallidum and the Extended Amygdala
The ventral striatopallidumdiscussed in Chapter
gure 31.10 The basal forebrain. The positions of three main
nuclear components are indicated with different colors in the photo- 26consists of the ventral striatum (including the nucleus
graph of a frontal section through the hemisphere (cf. Fig. 23.15). accumbens) and the ventral pallidum. These parts of the
basal forebrain show similarities with the basal ganglia of the basal forebrain is lumped with the amygdala, it is
(dorsal striatum and dorsal pallidum) regarding cyto- because they share many transmitters and connections.
architectonics, cytochemistry, and connections (e.g., a The anatomic distinction between the extended amygdala
dense dopaminergic innervation from the mesencepha- and the nucleus accumbens is not sharp, however, and
lon). In contrast to the dorsal striatum (the caudate both receive, for example, dopaminergic fibers from the
nucleus and the putamen), which receives the main affer- mesencephalon.
ent input from the neocortex, the ventral striatum receives
main inputs from the allocortex and the amygdala.
The Medial Forebrain Bundle
A further characteristic of the ventral striatum is that it
projects to the hypothalamus and brain stem nuclei, Many fibers interconnecting the various limbic struc-
such as the periaqueductal gray (PAG) and the motor tures are located in a diffusely delimited, parasagittal
vagus nucleus. The ventral pallidum projects to the fiber mass in the basal part of the hemisphere. This ill-
mediodorsal thalamic nucleus (MD) that sends fibers to defined structure is called the medial forebrain bundle
the prefrontal cortex (cf. the projection of the dorsal and passes through the lateral parts of the hypothala-
pallidum to the VL/VA thalamic nuclei that project mus. It extends from the region of the anterior commis-
mainly to the premotor areas). sure anteriorly and into the mesencephalon posteriorly.
Another rather diffuse cell group in the basal fore- Most of the fibers are short, interconnecting nuclei found
brain, continuous with the ventral pallidum, is called close to each other, such as the septal nuclei, other nuclei
the extended amygdala because it forms a rostral exten- in the basal forebrain, various hypothalamic nuclei,
sion of the medial amygdala (Figs. 31.9 and 31.10). and the PAG in the mesencephalon (see Fig. 31.4).
Most of it is made up of the bed nucleus of the stria Fibers from the monoaminergic cell groups of the brain
terminalis (Figs. 31.6 and 36.9). The stria terminalis is stem pass through the medial forebrain bundle on their
a bundle of efferent fibers from the amygdala to the way to forebrain structures, such as the cortex (includ-
septal nuclei and the hypothalamus (Fig. 31.5). The bed ing the hippocampal formation). Functionally, the
nucleus lies medial to the pallidum at the same anteromedial forebrain bundle is heterogeneous, and lesions
posterior level and further anterior to the anterior com- of it cannot be expected to reveal the function of any
missure (i.e., close to the septal nuclei). When this part particular cell group or fiber tract.
32 The Hippocampal Formation:
Learning and Memory
OVERVIEW not usually abolish recall of older memories, although it

prevents the learning of new material. This is probably
The hippocampus and nearby areas in the parahip- because, after a certain time, the memory traces are stored
pocampal gyrus (the dentate gyrus and the entorhinal in many parts of the cerebral cortex.
area) comprise the hippocampal formation, which plays
a crucial role for certain kinds of learning and memory.
THE HIPPOCAMPAL FORMATION
The quantitatively dominating afferent inputs to the
dentate gyrus and the hippocampus arise in the entorhi-
Macroscopic Appearance and Constituent Parts
nal area. The entorhinal area receives afferents from
both nearby areas in the temporal lobe and cortical The hippocampal formation consists of the hippocam-
association areas. Thereby, it receives highly processed pus and nearby regions in the temporal lobe: the dentate
sensory informationthat is, about all important events. gyrus, the subiculum, and the entorhinal area (located
The hippocampal projection neurons send signals via in the parahippocampal gyrus; Figs. 32.1 and 32.2).
intermediaries to several areas, notably back to the ento- Whereas the interest formerly was directed mainly to the
rhinal area and to the mammillary nucleus. Thus, the hippocampus itself, it is now realized that the function
hippocampus acts largely back onto the areas from which of the hippocampus can be understood only in conjunc-
it receives information. tion with the nearby structures in the parahippocampal
Bilateral damage of the hippocampal formation leads gyrus, which are closely interconnected with each other
to amnesiaimpaired memory without intellectual reduc- and with the hippocampus. Although hippocampus is
tion. Lesions restricted to the hippocampus proper pro- included among the limbic structures (see Fig. 31.1), its
duce amnesia, although it is much less severe than when functional role is distinct from that of the amygdala,
the whole hippocampal formation has been damaged. the septal nuclei, and the cingulate gyrus. The amygdala
We can roughly distinguish two kinds of memory: and the hippocampal formation are, for example, both
one kind concerns the memory of events and facts and is crucial for learning and memory, but for different kinds.
called declarative or explicit memory; the other concerns The hippocampus (Figs. 32.1 and 32.3; see Figs. 6.31
skills and habits and is called nondeclarative or implicit and 31.2) forms an elongated bulge medially in the
memory. Only declarative memory depends critically on temporal horn of the lateral ventricle, produced during
the integrity of medial parts of the temporal lobe. For early development by invagination of the ventricular
nondeclarative memory, the basal ganglia, cerebellum, wall by the hippocampal sulcus (see Fig. 9.12). The hip-
and parts of the neocortex appear to be most important. pocampus is easily recognized in thionine-stained micro-
Certainly, the hippocampal formation is not the only scopic sections by its conspicuous layer of pyramidal
part of the brain that is important for memory. Parts of cells (Fig. 32.2). Along the medial aspect of the hip-
the parahippocampal gyrus outside the hippocampal pocampus, the dentate gyrus forms a narrow, notched
formation appear to play an independent role in mem- band (Fig. 32.1; see Fig. 31.2). Microscopically, the
ory formation and retrieval. Further, amnesia has also narrow, dark layer of small granule cells is characteris-
been reported after lesions of the medial thalamus, and tic (Fig. 32.2). The hippocampus and the dentate gyrus
cholinergic cell groups of the basal forebrain also have belong to the allocortex and have a simplified laminar
a role (presumably by way of their connections with the pattern compared with the neocortex. Nevertheless,
hippocampus). Finally, amygdala is crucial for learning they are far from simply built, with several different cell
of associations between stimuli and their emotional types and precisely organized, complex patterns of con-
value. nections. Figure 32.2 shows that the hippocampus (the
The hippocampal formation appears to be important CA1 field) continues into the subiculum but with a
for memory only for a certain time after an event. Thus, marked change in the thickness and organization of
isolated damage of the hippocampal formation does layers (both have three neuronal layers). The transition
473
Thalamus
Internal
capsule
Putamen
Lateral
geniculate
Thalamus body
Hippocampus
Fimbria
Hippocampus Dentate
gyrus
Entorhinal
area
Pons
gure 32.1 The hippocampus. Photograph of a frontal section lateral ventricle. Figure 22.2 shows the whole section. Compare
through the left hemisphere. The hippocampus forms a continuation Figs. 31.1 and 31.2.
of the temporal cortex, as an invagination of the temporal horn of the
between the subiculum and the entorhinal cortex is cingulate gyrus, and septal nuclei (Fig. 32.4). As for neo-
marked with the appearance of a six-layered cortex. cortical connections, the hippocampus obviously pro-
cesses large amounts of information. The parallel
increase in the size of the hippocampus and the neocor-
Two Main Sets of Connections
tex during evolution furthermore indicates that its main
Two aspects of the connections of the hippocampal for- functions are related to the neocortex. A large number of
mation are, presumably, crucial for the understanding of commissural fibers connect the hippocampus of the two
its functional roles: first, the extensive, two-way connec- sides, indicating a close cooperation between them.
tions with various cortical association areas and, second,
the direct and indirect connections with the amygdala,
Afferent Connections of the Hippocampal Formation
Corpus geniculatum The main afferents to the dentate gyrus arise in the
laterale
Mesencephalon entorhinal area Figs. 32.4 and 32.5). Because the den-
tate gyrus sends its efferents to the hippocampus, the
Fimbria entorhinal area is the quantitatively dominating deliv-
Dentate erer of information to the hippocampus. Smaller but
gyrus CA3 Pyramidal
cells functionally important contingents to the hippocampal
formation come from the septal nuclei and monoaminer-
gic cell groups in the brain stem (the locus coeruleus and
CA1 the raphe nuclei). In addition, some fibers come from
Subiculum
Granule the hypothalamus and several thalamic nuclei. Finally, the
cells
amygdala projects to the subiculum and the entorhinal
Entorhinal
area area. The latter connections most likely contribute
to the well-known effect of emotions on learning, as dis-
cussed in Chapter 31 (see Amygdala, Learning, and
Unlearning).
To understand the nature of the information pro-
gure 32.2 The hippocampal formation. Photomicrograph of thion- cessed by the hippocampus, we must know the afferent
ine-stained frontal section through the human temporal lobe. The connections of the entorhinal area. Recent studies with
temporal horn of the lateral ventricle with some of the choroid plexus
is seen above and to the right of the hippocampus. The mesencepha-
retrograde transport in monkeys have shown that most
lon with the crus and the substantia nigra is seen to the left. Compare association areas of the neocortex are likely to influ-
with Fig. 32.1. ence the entorhinal area. Signals reach the entorhinal
32: THE HIPPOCAMPAL FORMATION: LEARNING AND MEMORY 475
A B
Hippocampus Lateral
ventricle
Uncus
R L
gure 32.3 Magnetic resonance images (MRIs) showing the hip- the plane of sectioning. B: Parasagittal plane through the medial part
pocampus. A: Frontal plane. The hippocampus is positioned medially of the temporal lobe. (Courtesy of Dr. S. J. Bakke, Rikshospitalet
in the temporal lobe (stippled outline on one side). Inset shows University Hospital, Oslo, Norway.)
approximate position of the hippocampus in the temporal lobe and
area directly, or indirectly by means of fibers to other information from polysensory association areasthat
areas in the parahippocampal gyrus, which, in turn, is, areas that integrate several sensory modalities.
project to the entorhinal area. Thus, the majority of Finally, afferents arrive from the cingulate gyrus, the
direct entorhinal afferents arise in adjacent parts of the insula, and the prefrontal cortex. Together, the entorhi-
parahippocampal gyrus (see Figs. 6.26 and 31.1) and in nal area receives highly processed sensory information.
the perirhinal cortex (located around the rhinal sulcus; We assume, for example, that information about words
see Fig. 19.3). These areas form a continuous cortical comes to the hippocampus regardless of whether we see
region, although different parts are not identical regard- (read), hear, or read by touch (Braille writing).
ing connections. Together, the region receives visual The cortical areas that provide the entorhinal area
information from extrastriate areas in the inferior part (and thus the hippocampus) with its main inputs project
of the temporal lobe, auditory information from the to other areas as well. For example, both the perirhinal
superior part of the temporal lobe, somatosensory cortex and the subiculum project to the mediodorsal
information from the posterior parietal cortex, and thalamic nucleus (MD), which projects to the prefron-
tal cortex and parts of the cingulate gyrus. This might
explain why amnesia (memory loss) is more severe after
damage of the perirhinal cortex and the areas neighbor-
ing the entorhinal area than after a lesion restricted to
the entorhinal area and the hippocampus (we return to
this point later).
Fornix
Modulatory Afferents Increase Hippocampal Plasticity

Although hippocampal afferents from the septal nuclei
(Fig. 32.4) are not numerous, they have an important
functional role. Many of the septohippocampal neu-
rons release acetylcholine as a modulatory transmitter,
increasing the excitability of the hippocampal pyrami-
dal cells. The hippocampal afferents from the raphe
nuclei (serotonin) and the locus coeruleus (norepineph-
Hippocampus
Septal rine) have modulatory effects on the hippocampal cells.
nuclei
Subiculum Thus, there is evidence that hippocampal long-term
Entorhinal area potentiation (LTP; see later) is reduced after pharmaco-
logic removal of monoamines from the hippocampus.
gure 32.4 Some main connections of the hippocampus. The con-
nections with the entorhinal area mediate specic, highly processed
These modulatory pathways may mediate the effects of
sensory information, whereas the connections with the septal nuclei attention and motivation, which we know have profound
are modulatory. influences on both learning and memory.
Efferent Connections of the Hippocampal Formation Hippocampal Architecture and Intrinsic Connections
Comparison of the efferent connections with the affer- Most of the neurons of the dentate gyrus are the small
ent ones shows that the hippocampal formation has granule cells, whereas the only well-defined hippocam-
largely reciprocal connections with subcortical and pal cell layer consists of large pyramidal cells (Fig. 32.5).
cortical areas. Thus, we must assume that whatever the Above and below the pyramidal cell layer are layers
hippocampus is doing, it requires a constant exchange that contain the pyramidal cell dendrites and incoming
of information with many other areas. The parallel evo- axons. There are also various kinds of interneurons,
lutionary increase of the hippocampus and the cerebral notably the GABAergic basket cells, which inhibit the
hemispheres also suggests that hippocampal functions pyramidal cells. The hippocampus can be divided into
are most closely related to the neocortex. three longitudinal zones, named CA1 to CA3 (Figs. 32.2
There are three parallel pathways out of the hip- and 32.4). The granule cell axons contact the pyramidal
pocampal formation to cortical areas but they all even- cell dendrites, and the pyramidal cells send axons out of
tually reach primarily association areas in the temporal the hippocampus.
and frontal lobes. The major pathway goes from the Even though the internal architecture of the hip-
entorhinal area to adjacent areas in the parahippocam- pocampus is rather complicated, with several neuronal
pal gyrus and the perirhinal cortex, and from there to types with complex interconnections, a relatively simple
more distant areas, notably the tip of the temporal lobe, main transmission route from input to output appears
medial and orbital parts of the prefrontal cortex (includ- to exist (Fig. 32.5). This pathway starts in the entorhi-
ing the cingulate gyrus), and polysensory areas in the nal area and has three synaptic interruptions. Neurons
superior temporal gyrus. A parallel pathway goes directly in the entorhinal area send their axons, forming the so-
from the entorhinal area to the same areas that receive called perforant path, to the hippocampus, where many
the indirect connections, while a third pathway goes end in the dentate gyrus. The axons of the granule cells
directly from the CA1 and the subiculum. of the dentate gyrus, called mossy fibers, end primarily
In addition to these neocortical projections, the subic- on the apical dendrites of the pyramidal cells of CA3.
ulum sends many fibers to the mammillary body (pass- The CA3 pyramidal cells send so-called Schaffer col-
ing in the fornix), which then influences the cingulate laterals to the apical dendrite of the CA1 pyramidal
gyrus via the anterior thalamic nucleus (see Fig. 31.6).1 cells. From CA1 a significant part of the signal traffic
Some fibers in the fornix pass to the nucleus accumbens goes to the subiculum and from there to the entorhinal
and the ventromedial hypothalamus. The subiculum area, thus closing the circuit that passes from the ento-
also sends fibers to the amygdala. Thus, signals from the rhinal area through the hippocampus and back to the
hippocampus can influence neuronal groups that are entorhinal area. All links in this pathway are excitatory,
related to emotions and motivation. using glutamate as neurotransmitter. Figure 32.5 gives
The connections from the hippocampus to the subic- the impression that signal transmission is confined to a
ulum, and from the subiculum to other areas, are plane perpendicular to the long axis of the hippocam-
topographically organized. For example, a longitudinal pus. Thus, the hippocampus would seem to be organized
subicular zone close to the dentate gyrus projects to in numerous lamellas, each lamella presumably repre-
allocortex and nucleus accumbens, whereas a longitu- senting a functional unit.
dinal zone farther from the dentate gyrus projects to While the signal pathway shown in Figure 32.5 appears
the cingulate gyrus. Thus, as different parts have differ- to be central to hippocampal information processing,
ent connections, symptoms after lesions may be expected the conditions are more complex. For example, the fibers
to vary with their exact localization within the of the perforant path not only contact granule cells of
hippocampal formation. Some controversies among the dentate gyrus but also end directly on the hippocam-
authors regarding the effects of hippocampal lesions on pal pyramidal cells. Thus, several parallel pathways enter
memory are probably due to disregard of such anatomic the hippocampus. Further, anatomic investigations per-
facts. formed in monkeys show that the efferent fibers from a
narrow transverse zone of the entorhinal area extend for a
considerable distance longitudinally in the hippocampus.
Thus, each entorhinal efferent neuron can presumably
1 Until the mid-1970s it was believed that most efferents from the hippocam- contact neurons in many hippocampal lamellas. Further,
pus were directed to the mammillary body, passing in the fornix (bers destined the collaterals of the hippocampal pyramidal neurons
for the mammillary nucleus comprise the majority of the fornix bers). This
was based on the erroneous assumption that all axons in the fornix came from
extend not only in the plane of the lamellae (as shown in
hippocampal pyramidal cells. Papez and the postulated circuit interconnecting Fig. 32.5) but also longitudinally. In fact, it is still not clear
the limbic structures presumably inuenced this view on hippocampal efferents what should be regarded as a functional unit within the
(see Chapter 31, under The Circuit of Papez). With the introduction of meth-
ods using axonal transport of radioactively labeled amino acids, however, it
hippocampus and the degree of functional localization
was shown that the fornix bers originate in the subiculum. present.
A B
Hippocampus
Fimbria Schaffer
CA3 collateral
Pyramidal cell
CA2 (CA3)
Temporal horn of
lateral ventricle Mossy fiber
Granule cells
Dentate
gyrus CA1 Pyramidal cell
(CA1)
Perforant path
Subiculum Entorhinal
area
gure 32.5 Signal pathways through the hippocampus. Schematics of widespread connections with cortical association areas. B: Major
a frontal slice through the hippocampus, as shown in C (cf. Fig. 31.2). kinds of neuron in the hippocampus and the course of their axons
A: The ow of signals through the hippocampal formation. The path- (not all collaterals are shown).
way emanates from and returns to the entorhinal area, which has
FUNCTIONAL ASPECTS or nondeclarative memory. Declarative memory depends

on the integrity of the medial temporal lobe (including
2
Different Kinds of Learning and Memory the hippocampus) whereas nondeclarative memory
depends primarily on the basal ganglia, the cerebellum,
Before discussing further the functions of the hippocam-
and parts of the cerebral cortex (see Chapter 22, under
pal formation, some words about learning and memory
The Motor Cortex and Learning, Chapter 23, under
may be useful. The following is a very superficial treat-
What Activates the Nigrostriatal Neurons? and
ment of a large and important field in psychology.
Functions of the Basal Ganglia, and Chapter 24,
Other classifications than those used here exist, and the
under Mossy and Climbing Fibers Mediate Different
different forms of memory may not be as independent
Kinds of Information and The Cerebellum and Motor
as this presentation may suggest.
Learning).
Much of our learning is associative: we learn from
experience that two phenomena occur together. This
holds for classic conditioning (learning of a conditioned Episodic, Semantic, and Autobiographic Memory
response) when one stimulus always follows another,
Declarative memory is of two main kinds. Episodic
and for operant conditioning in which we learn that a
memory concerns episodes and events from ones own
certain behavior produces a certain response. An exam-
life (Where did I put the scissors?). Afterward we can
ple of operant conditioning is a hungry rat that learns
recall the episode, often in the form of pictures, which
by trial and error to press a lever to obtain food. In the
may be described verbally (memory of what). Semantic
same situation later, the rat knows what the appropri-
memory concerns general knowledge about the world
ate behavior is. Not all learning is associative, however.
we live in (the capital of Italy, the first president of the
With constant exposure to a stimulus, the response is
United States, the location of the post office, the letters
alteredfor example, by ceasing to notice a loud sound
of the alphabet, and so forth). Autobiographic memory
we have heard many times. This is called habituation.
that is, the ability to remember events from ones own
The response may also increase with repeated exposure,
lifeusually combines episodic and semantic memory
as with painful stimuli (sensitization). Other, more
but also involves memory processes dependent on the
complex, kinds of learning are nonassociative, such as
learning by imitation elements of language and move-
ment patterns. Often, however, learning includes several
2 One striking piece of evidence comes from patients with Alzheimers disease
of these forms at the same time. (affecting medial parts of the temporal lobe early in the disease process) who
Another way to characterize learning and memory have markedly impaired declarative memory whereas the ability to learn new
relates to what is learned, rather than to how it takes place. skills is relatively preserved. Also, observations of patients with memory decits
after lesions of the medial temporal lobe (without dementia) indicate that they
We can then distinguish two main kinds of memory: learn and remember new movements better than new faces, words, places, and
explicit or declarative memory and implicit, procedural, so forth.
amygdala (emotional coloring) and several parts of the relationship between LTP and learning is difficult, how-
cortex (Fig. 32.6). Common to declarative memories is ever. For example, only specific subsets of synapses in
that we as a rule must consciously search our minds widely distributed networks are likely to show LTP in a
to recall them. In contrast, nondeclarative memory is natural learning situation. To look for such altered
needed to learn and perform skills (riding a bicycle, synapses would seem like looking for a needle in a
dress, use a knife and fork, etc.). Habits and attitudes haystack. Nevertheless, much indirect evidence sup-
also largely fall in this category. The learning leads to ports that hippocampal LTP is related to learning and
altered behavior, but not so that the stored material can memory. Increased synaptic efficacy has been found in
be subject to a conscious analysis. With skills like play- the hippocampus in rats housed in an environment rich
ing an instrument or arithmetic, the stored information in stimuli and challenges (assuming that more learning
becomes accessible only by performing the skill (mem- takes place in this situation than in a standard cage).
ory of how). In ordinary teaching situations, much of LTP-like phenomena have also been observed in the
the learning is implicitfor example, the acquisition of hippocampus after specific training situations. Another
attitudes of which both the teacher and the student are piece of evidence is that N-methyl-D-aspartate (NMDA)-
unaware. receptor antagonists both prevent induction of LTP and
reduce learning and memory in experimental animals.
Gene-technological manipulations have produced
Relationship between Memory and
strains of mice in which hippocampal LTP cannot be
Long-Term Potentiation
induced, and these animals also show reduced learning
The cellular basis of brain plasticity is discussed in ability. Finally, structural synaptic changes have been
Chapter 4, under Synaptic Plasticity). Because the observed in the hippocampus in conjunction with the
hippocampus is involved in learning and memory, it is induction of LTP. Even more compelling, structural
of special interest that the synapses are plastic at several synaptic changes (formation of new synapses and split-
steps in the circuit shown in Figure 31.4. Thus, their ting of spines into two) have also been reported in the
efficacy can be increased for a long time after intensive hippocampus in rats at the time they improve their
stimulation. Indeed, long-term potentiation (LTP) was performance in a learning situation.
first discovered in the hippocampus, although it was
later found in many other areas of the brain, among
Medial Parts of the Temporal Lobe Is Necessary for
them the cerebral cortex and the amygdala. LTP is pro-
Declarative Memory
duced whenever the hippocampal pyramidal cells are
subjected to excitatory inputsfor example, from the The belief that the hippocampus is of importance for
Schaffer collateralswhile they are in a depolarized state memory goes back to the end of the nineteenth century
(i.e., caused by another excitatory input). Thus, simulta- and was based on careful examination of patients with
neous synaptic activation of the cell from two sources amnesia (loss of memory) as a result of brain damage
can make it remember, in the sense that the next time (Fig. 32.7). In particular, the importance of the medial
the cell is activated by the same fibers the postsynaptic temporal lobe for declarative memory was strikingly
effects are stronger than earlier. To demonstrate a direct demonstrated in the 1950s by observations of the
patient H.M. with bilateral removal of the hippocam-
pus and surrounding regions. During the past few years,
refined studies in monkeys with selective lesions, and
observations with magnetic resonance imaging (MRI)
and positron emission tomography (PET) in humans,
PREFRONTAL CORTEX: EXTRASTRIATE have helped clarify the mutual roles of the hippocampus
Memory search AREAS 3
Visual imagery
and other subregions of the medial temporal lobe.
Self-referencing
Monitoring (correct?
appropriate?)
3 Various memory tests are used in experiments with monkeys to study the
relationship between brain structures and memory. One common test is the
so-called delayed nonmatching-to-sample test. The monkey is briey shown an
AMYGDALA: object. After a certain time, the same object is shown with a new one. To receive
Emotional HIPPOCAMPAL
FORMATION: a reward (e.g., orange juice) the monkey must move the new object, thus show-
coloring
Recollection ing that it remembers which one was seen before. The experiment goes on with
continually new pairs of items. With a brief interval between the rst and second
presentation, the performance is independent of the integrity of medial temporal
gure 32.6 Network serving autobiographical memory. Some of the structures. With intervals above 10 sec, however, the frequency of errors
regions showing increased activity in relation to retrieval of autobio- increases in monkeys with such lesions as a sign of failing memory. With more
graphic memories, as revealed by fMRI. (Based on Cabeza and than 2 min intervals, the performance is no better than chance, whereas normal
Jacques 2007.) monkeys reduce their performance to about 80% with intervals of 3 min.
R L and surrounding areas can produce an amnesia that

comprises all prior material without any gradation.
Further, other evidence suggests the participation of the
hippocampal formation in the retrieval of remote mem-
ories. For example, most functional MRI (fMRI) stud-
ies agree that the hippocampus increases its activity in
relation to recollection of autobiographic memories,
independent of how remote they are. As usually in sci-
ence, the disagreements among authors may depend more
on how questions are posed to nature (e.g., different tests
and contexts) than on erroneous results.
The Contribution of the Perirhinal Cortex

Hippocampus Hippocampus
(normal) (atrophic) The most pronounced memory loss occurs when the
hippocampal formation, the perirhinal cortex, and
gure 32.7 MRI in the frontal plane showing hippocampal atrophy
on the left side. A nearby focus of epileptic activity is most likely the areas outside the entorhinal area in the parahippocam-
cause of hippocampal cell loss, causing so-called mesial temporal scle- pal gyrus are destroyed on both sides. Especially, the
rosis. (Courtesy of Dr. S.J. Bakke, Rikshospitalet University Hospital, inclusion of the perirhinal cortex appears to increase
Oslo, Norway.) the severity of amnesia as compared with what occurs
after lesions restricted to the hippocampal formation.
Patients with severe amnesia that is not accompanied Thus, the perirhinal cortex and the adjoining cortex of
by intellectual reduction (dementia) typically have the parahippocampal gyrus appear to contribute to
lesions that affect the medial parts of the temporal lobe memory not only by their connections with the hip-
(and often also the medial parts of the thalamus). Such pocampal formation but also by their connections to
lesions include the hippocampal formation as the other parts of the brain. For example, the perirhinal
most constant finding. Further, testing of patients with cortex projects to the thalamus (MD), amygdala, mam-
restricted lesions of the medial temporal lobe suggested millary body, and parts of the prefrontal cortex. The
that memory impairments concerned long-term mem- perirhinal cortex may be uniquely involved in stimulus
ory, whereas short-term memory was virtually unim- recognition memory.
paired (i.e., the ability to remember, e.g., numbers or
words for up to a minute). Nevertheless, these conclu-
Amnesia: The Famous Case of H.M.
sions may not be generally valid. Thus, conclusions
were generally based on tests requiring the patients to Patients with bilateral damage to medial aspects of the
retain simple motor sequences or short strings of digits temporal lobe have pronounced anterograde (and often
or letters. Indeed, when using more natural test situa- less severe retrograde) amnesia, as described previously.
tions, requiring short-term memory of faces or locations, Scoville and Milner (1957) described the most famous
patients with restricted medial temporal lobe lesions case of this kind in the 1950s. This patient, called H.M.
show reduce performance. in the voluminous literature that deals with the results
The amnesia is anterogradethat is, the memory is of tests to which he had been subjected, underwent sur-
lost for events that take place after the time of the brain gery to remove bilaterally the medial aspects of his tem-
damage. There are also varying degrees of retrograde poral lobes (the purpose was to cure his severe epilepsy).
amnesiathat is, the patient is unable to recall events His lesion most likely comprised the hippocampal for-
that took place before the damage. Retrograde amnesia mation, additional parts of the parahippocampal gyrus,
usually occurs together with anterograde amnesia (but the uncus, and the amygdala. The epileptic seizures
some cases have been reported with relatively pure ret- became less frequent, but, unfortunately, he acquired
rograde amnesia alone). Retrograde amnesia is usually severe, permanent anterograde amnesia. Initially, he
graded, that is, is extends from the time of injury and a also had considerable retrograde amnesia that gradu-
certain time backwards. Observations of patients with ally improved to just 1 year before the operation. He
lesions restricted to medial temporal lobe indicate that remembered well the address of the place he lived before
the retrograde amnesia extends from about one year up the operation, but he never learned the new address
to about 20 years. If the amnesia extends further back when moving afterward. He could easily recall songs he
and include childhood memories, most studies suggest had learned before the operation but not those he heard
that there is damage also outside the medial temporal for the first time afterward. He never learned where the
lobe. Not all researchers agree with this view, however, lawn mower was kept in his new house. Shortly after
and maintain that lesions of the hippocampal formation eating dinner, he could start on a new meal without
remembering that he had just eaten. Nevertheless, his Making Memory Traces Permanent:
intelligence, as measured with various tests, was unal- The HippocampalCortical Dialogue
tered, compared with what it was before the operation,
As mentioned, the amnesia after lesions of the hip-
and his capacity for abstract reasoning was normal.
pocampus and surrounding structures is predominantly
Interestingly, his ability to learn new movements was
anterograde (although retrograde amnesia for several
much better than that for learning new faces, words,
years may occur). This has been taken as evidence that
and so forth. The memory deficits described all concern
representations of events are only temporarily stored in
events that took place some time agothat is, long-term
the hippocampus, before permanent storage in other
memory. His short-term memory was not correspond-
parts of the brain. Other clinical observations of patients
ingly impaired, however. For example, he could recog-
with damage in various parts of the brain indicate that
nize a word among nine presented to him 40 sec earlier.
there is no specific memory center, but well-consoli-
Once H.M. described his life as follows: Every day is
dated information is stored in a distributed fashion.
alone, regardless of the pleasures I have had or the sor-
When a memory is consolidatedpresumably as long-
rows I have had. Without long-term memory, we lose
term synaptic changesthe hippocampal formation no
the continuity in our lives.
longer seems necessary for storage and recall. The time
required to reach this stage is not known, but based on
Can Destruction of the Hippocampus Alone Produce observations of patients with damage to medial parts of
Anterograde Amnesia? the temporal lobe it probably takes a year or more.
During this period, we imagine a gradual consolidation
Lesions restricted to the hippocampus (in contrast to
of the memory traces in the relevant parts of the cortex
the hippocampal formation) are difficult to obtain.
(and probably in subcortical structures). It seems
Nevertheless, recent experiments in monkeys with ste-
unlikely that the information is first held in the hip-
reotaxic lesions, or with controlled global ischemia,
pocampus for a certain period and then transmitted out
come close to the ideal situation. Thus, global ischemia
to the permanent stores in a finally processed form.
of limited duration may kill hippocampal pyramidal
More likely, the consolidation takes place by a continu-
cells selectively. Such experiments show that selective
ous dialogue between the hippocampus and other parts
hippocampal lesions produce impaired memory in
of the cortex. Sleep may be of special importance for
monkeys, although the impairment is much less severe
the dialogue, as witnessed by specific patterns of syn-
than when other parts of the hippocampal formation
chronized activity in the hippocampus and in cortical
are included. The following observations, published by
areas that were particularly active during the learning
Zola-Morgan and coworkers in 1986, strongly suggest
phase (see Chapter 26, under Dreaming). Further, it
that isolated hippocampal damage produces amnesia in
appears that every time a memory is recalled it becomes
humans, too. The patient, called R.B., had an episode
labile and can be modified before renewed consolida-
of brain ischemia during cardiac surgery. Afterward, he
tion occurs.
had moderate anterograde amnesia that lasted until his
As discussed previously, however, it is not quite clear
death some years later. He was not appreciably reduced
whether the hippocampus ever ceases entirely to par-
intellectually. Even though his amnesia was much less
ticipate in storage and retrieval of episodic memories
severe than that of H.M., he had grave problems
(most would agree that retrieval of semantic knowl-
remembering the events of the day before. During his
edgemuch of it acquired during childhoodbecomes
visits to his doctor, he would repeat the same story at
independent of the hippocampus and nearby regions).
short intervals. Histological examination of the brain
after his death showed that the most pronounced alter-
ations were in the hippocampus and, most interestingly,
Amnesia Caused by Lesions Outside the Medial
restricted to CA1 on both sides. Within the CA1, there
Temporal Lobe, and Korsakoffs Syndrome
was an almost total loss of pyramidal cells. That the CA1
field of the hippocampus is particularly vulnerable (to Clinical observations suggest that amnesia can arise
ischemia) was suggested in the nineteenth century based after lesions of the medial thalamus, the mammillary
on observations of patients with epilepsy. The mechanism body, and the connections from the latter to the thala-
in such cases may be excessive release of glutamate that mus (the mammillothalamic tract). Loss of memory
activates the NMDA receptors (see Chapter 11, under also has been reported after lesions of cholinergic cell
Ischemic Cell Damage and the Glutamate Hypothesis). groups in the basal forebrain. Whether isolated damage
As a possible explanation of the marked symptoms of to any one of these structures causes amnesia is not
R.B. caused by a seemingly minor damage to the hip- finally settled, however. As to the relation between the
pocampus, Zola-Morgan et al. suggest that destruction of site of a lesion and ensuing functional disturbances,
the CA1 field (in its entire length) effectively interrupts PET studies of glucose uptake in a group of patients
signal transmission through the hippocampus and thus with severe amnesia are illuminating. These patients all
isolates it from the rest of the brain. showed altered glucose uptake in the hippocampus,
thalamus, cingulate gyrus, and ventral parts of the pre- (usually caused by a ruptured aneurysm of the anterior
frontal cortex, although their lesions as identified with cerebral artery). The often-bizarre stories can usually
MRI were differently placed. It seems reasonable to be traced back to real events, although they consist of
conclude that declarative memory, as usually tested, various, unrelated fragments from memory. It seems
depends on the integrity of several cell groups that are that the patient is unable to suppress irrelevant associa-
mutually interconnected. When one part of the network tions and cannot check them against reality. These are
is damaged, it has consequences for the functioning of faculties usually associated with the prefrontal cortex.
the other parts. This illustrates the problems inherent in
assessing the functional role of a cell group or a tract
What Is the Unique Contribution of the Hippocampus
only from the symptoms caused by their destruction.
to Learning and Memory?
As to thalamic lesions, inclusion of the MD nucleus
(see Fig. 33.8) seems necessary to cause amnesia, There is little doubt that the hippocampus is of crucial
although destruction of the anterior nucleus and the importance for certain kinds of learning and memory,
internal medullary lamina close to the MD may contrib- as discussed earlier. Nevertheless, its specific contribu-
ute (perhaps due to interruption of fibers to and from tion is not entirely clear, and neither is the division of
MD). Severe amnesia was described in a patient who, as labor between the hippocampus and the other compo-
judged from a computed tomography (CT) scan of the nents of the hippocampal formation.4 One central task
brain, had a small lesion confined to the anterior and of the hippocampusin animals and humansseems
medial parts of the thalamus on the left side. (In this to be spatial orientation and navigation. Indeed, imag-
particular case, the verbal memory was more severely ing studies of London taxi drivers suggested correlation
affected than the visual. The patient could with some between the size of the hippocampus and duration of
difficulty remember objects he had seen some time ago, navigational training (animal experiments have found
whereas words heard were completely forgotten.) The the same effect). Properties of single hippocampal cells,
MD sends efferents to the prefrontal cortex, and this is as first described by OKeefe and Nadel (1978), are of
involved in various aspects of memory (cf. Chapter 34, particular interest in this connection. Thus, the firing
under Frontal Association Areas). of single hippocampal neuronscalled place cells
The role of the mammillary body in amnesia has changes with the position of the animal in relation to its
attracted much interest because of its involvement in surroundings: for example, the firing pattern changes
Korsakoffs syndrome, in which the patient suffers from with the location of the animal in different corners of
severe anterograde and retrograde amnesia (among the cage. The hippocampus obviously receives informa-
other cognitive impairments). Cell loss is also found tion about starting position, the direction of movement,
regularly in the medial thalamus, however. Accurate and the distance moved. Based on such experiments,
testing of patients with Korsakoffs syndrome shows OKeefe and coworkers proposed that the hippocampal
that they also have symptoms suggestive of prefrontal neurons together form a cognitive map of our surround-
dysfunction. The disease is usually due to chronic alco- ings. Necessary information may be integrated in the
hol abuse. The retrograde amnesia may be very pro- entorhinal cortex, where neurons are topographically
nouncedfor example, more than 25 years. This in arranged according to their spatial receptive fields.
itself suggests that the pathology in these patients does Together, such grid neurons produce a systematic map
more than interrupt connections between the medial of the surroundings. Indeed, the activity of a few neu-
temporal lobe and other parts of the cerebral cortex. rons can code for the position of a rat with a few centi-
Whether a lesion of the mammillary bodies alone causes meters accuracy. Accordingly, lesions of the hippocampus
amnesia has been a matter of controversy. In monkeys, in rats severely reduce their ability to find their way back
however, bilateral destruction of the mammillary bod- to previous locations. Further, monkeys with lesions of
ies produces a moderate memory loss. Further, amnesia the hippocampal formation have difficulties with remem-
has been reported after bilateral interruption of the bering where an object was locatedthe association
fornix in epileptic patients (cutting the pathway from between objects and space.
the hippocampal formation to the mammillary body).
In any case, it seems unlikely that the memory traces
are stored in the thalamus or the mammillary body.
4 Studies of the development in children with early damage to the hippocampus
shed some light on these questions. Three children suffered hippocampal lesions
without signs of damage to the surrounding cortical regions at birth, and at the
Amnesia with Confabulation age of four and nine, respectively. They were examined at the age of 14, 19, and
22 years. As expected, they suffered from anterograde amnesia. However, the
A peculiar form of amnesia occurs together with con- amnesia was much more severe for episodic than for semantic memory. Their
fabulation: that is, the patient invents stories (without language, reading abilities, and general knowledge were a little below average
knowing that they are not real). Most of these patients for their age groups but they followed ordinary school with normal progression
(Vargha-Khadem et al. 1997). This suggests that the hippocampus is necessary
have a lesion involving the substantia innominata, the for episodic memory, whereas areas around the hippocampus can take care of
medial hypothalamus, and the orbitofrontal cortex semantic memory in the absence of the hippocampus.
One of the great challenges in understanding the hip- successfully to it. Not all this knowledge is accessible
pocampus is to combine its role in spatial navigation for conscious inspection and analysis (nondeclara-
and spatial memory with its undeniable importance for tive or implicit memory, as described). Nevertheless, all
declarative memory. Recent animal experiments sug- memories presumably have as their substrate synaptic
gest that both tasks may be carried out simultaneously: changes in specific parts of the central nervous system.
neuronal populations may at the same time signal where Damasio and Tranel (1992) use the term knowledge
something happens and what is going on. Such a double systems of the brain about the widespread networks
role mightloosely consideredfit with the everyday dedicated to specific tasks. Examples are knowledge
experience that recall depends strongly on context. For systems dealing with social interactions, faces, objects,
example, experiments with divers show that a series of language, or ourselves. Although a part of the temporal
numbers learned under water is better recalled under lobe cortex is particularly important for recognition of
water than on dry land. Similarly, when unable to recall faces, this does not necessarily mean that all informa-
why we went into a room, it may help to go back to the tion about faces is stored there. More likely, this part is
place where we first got the idea to go into the room. unique because it has access to face-related information
stored in many other areas. Presumably, the memory of
faces fails after a stroke in the temporal lobe because
Knowledge Systems of the Brain
there is no one to retrieve and process all the relevant
In a wide sense, memories represent our knowledge of information, not because the storehouse is empty.
the world and the actions that are necessary to relate
VIII THE CEREBRAL CORTEX
T HE human cerebral cortex consists of about

20 billion neurons and constitutes more than half
of all gray matter of the central nervous system. This
cortex in higher mammals, and this part deals only with
the neocortex. In Chapter 33, we deal mainly with the
structure and connections of the cerebral cortex from a
gives a rough impression of its functional importance. functional perspective. In Chapter 34 we discuss the
In lower vertebrates, there are only very modest pri- complex tasks attended to by the cortical association
mordia of the cerebral cortex (allocortex), and it is first areas, which make up the bulk of the human cerebral
in mammals, particularly anthropoid apes and humans, cortex. In previous chapters we treated the role of the
that the cerebral cortex comes to dominate the rest of cerebral cortex in sensory processes (Chapters 1419),
the nervous system quantitatively. This enormous control of body and eye movements (Chapters 22 and
increase in the volume of the cortex has necessitated a 25), autonomic functions and emotions (Chapter 31),
marked folding of the surface of the hemisphere. The and memory (Chapter 32). The role of the cerebral
outer layer of the human cerebral cortex is around cortex in relation to sleep and consciousness is briefly
0.2 m2, but only one-third of this is exposed on the discussed in Chapter 26.
surface. The neocortex constitutes most of the cerebral
33 The Cerebral Cortex: Intrinsic
Organization and Connections
OVERVIEW and several other subcortical nuclei (releasing modula-

tory transmitters). The two final groupsmaking up
In this chapter, we address two levels of organization. the majority of all cortical connectionsconsist of
The first concerns information processing in a small corticocortical fibers; that is, association fibers and
volume of cortex; the second level concerns the inter- commissural fibers. Association fibers are precisely
connection of functionally different cortical units with organized connections linking cortical areas within the
long association and commissural fibers. These connec- same hemisphere, while commissural fibers pass in the
tions are essential parts of distributed, task-specific corpus callosum and connect areas in the two hemi-
cortical networks. spheres. The efferent connections of the cerebral cortex
The neurons of the neocortex are arranged in six can also be divided into subcortical and corticocortical
layers parallel to the cortical surface. The layers differ ones (association and commissural connections).
with regard to afferent and efferent connections. In The subcortical fibers are destined for the thalamus, the
general, layers 2 and 4 are receiving, whereas layers 3 striatum, various brain stem nuclei (among them the
and 5 are mainly efferent. The bulk of afferents from pontine nuclei projecting to the cerebellum), and
the thalamus end in lamina 4, whereas layer 5 gives the spinal cord. The corticocortical connections are for
origin to subcortical tracts to the cord, brain stem, and the most part reciprocalthat is, an area receives fibers
basal ganglia. Layers 2 and 3 receive and send out most from the same areas to which it sends fibers.
of the corticocortical fibers, interconnecting various
parts of the cortex.
The cortex is divided into numerous cytoarchitec-
STRUCTURE OF THE CEREBRAL CORTEX
tonic areas that differ with regard to connections and
functional specializations. At a microstructural level,
Levels of Organization
the cortical neurons are arranged in smaller modules,
often in the form of columns perpendicular to the corti- To understand the relationship between the perfor-
cal surface. Each column, containing some thousand mance of the cerebral cortex and the underlying neural
neurons, represents a computational unit. The neurons processes, we need to address two levels of organiza-
of the columns communicate with each other and with tion. The first concerns information processing in a
neurons in neighboring and distant columns. small volume of cortex; we may term this intracortical
There are two main kinds of cortical neuron: the synaptic organization. The second level concerns the
pyramidal cells with long axons destined for other parts interconnection of functionally different cortical units
of the cortex or subcortical targets, and interneurons with long association and commissural fibers, which
(with numerous subtypes) with short axons remaining we term interareal synaptic organization. How are sig-
in the cortical gray matter. The pyramidal cells are nals arriving in a small bit of the cortex treated before
glutamatergic; whereas all interneurons are GABAergic answers are sent to other parts of the cortex or sub-
(-aminobutyric acid [GABA] is colocalized with differ- cortical nuclei? How are the many different cortical
ent combinations of neuropeptides). In addition, modu- areas interconnected to form networks designed for
latory transmitters, such as dopamine and acetylcholine, solving specific tasks? The enormous number of neu-
regulate the cortical excitability level and the signal-to- rons and synaptic couplings in the human cerebral cor-
noise ratio of cortical neurons. tex explain why we do not have complete answers to
Cortical connections fall into four groups. One group such questions. For example, about 100,000 neurons
of afferents consists of precise, topographically orga- reside below 1 mm2 of cortical surface (rodent SI), and
nized connections from the specific thalamic nuclei; each neuron receives synaptic contacts from at least
each thalamic nucleus supplies one particular part of some hundred other neurons. Further, the tasks of the
the cortex. Another group consists of diffusely orga- cerebral cortex are the most complex of all. To under-
nized connections from the intralaminar thalamic nuclei stand the relationship between the machinery of the
485
brain and mental functions such as personality, mem- layer in which the cell body is located (see Fig. 1.1). The
ory, thought, and feelings is indeed the most formidable large pyramidal cells lie in layers 3 and 5, but many of
and exciting challenge of modern neuroscience. the smaller cells in the other layers are also pyramidal.
The large number of dendritic spines further character-
izes the pyramidal cells (see Fig. 1.1). The rest of the
The Neocortex Consists of Six Layers
cortical neurons constitute a heterogeneous group
All parts of the neocortex have a common basic struc- whose neurons have in common that their cell bodies
ture, with the neurons arranged in six layers, or lami- are not pyramidal; such neurons are therefore lumped
nae, oriented parallel to the surface of the cortex together as nonpyramidal cells. Their shape and size
(Figs. 33.1 and 33.2). Another general feature is the vary considerably, but all of them are most likely
1
arrangement of the neurons in rows or columns ori- interneurons.
ented perpendicular to the cortical surface (Fig. 33.2). The most superficial cortical layer, layer 1, the molec-
Both kinds of cellular aggregation relate to functional ular layer, is rich in fibers but has few neurons (Figs. 33.1
specializations among the neurons, as we discuss below. and 33.2). Apart from axons, it contains the apical den-
Figure 33.1 shows the main features of the layering. drites of pyramidal cells in the deeper layers. Layer 2,
It can be seen that the laminar pattern arises because the external granular layer, contains densely packed,
cells of similar shape and size are collected in more small cell bodies.2 Layer 4, the internal granular layer,
or less distinct layers. The density of cell bodies also
differs among the layers.
About two-thirds of the neurons are cortical pyrami- 1 Some of the nonpyramidal cells are multipolar and are called stellate cells.
Others are called basket cells because their axonal branches form a wickerwork
dal cells (the name refers to the triangular shape of their around the cell bodies of pyramidal cells. In addition, several other varieties of
cell bodies). A typical pyramidal cell has a long axon interneurons are given names that, as a rule, reect the shape of the neuron.
arising from the base of the pyramid and a long apical 2 Formerly, the term granule cell was used of the small cortical neurons,
explaining the names of layers 2 and 4, which contain mainly small cell bodies.
dendrite that extends toward the cortical surface; it Many of the so-called granule cells are, in fact, small pyramidal cells, and the
thus extends through several layers superficial to the term granule cell should therefore not be used of cortical neurons.
Golgi impregnation Thionine staining Myelin staining
1. Molecular layer
2. External granular layer
3. External pyramidal layer
4. Internal granular layer gure 33.1 The basic six-layered

structure of the neocortex. The three
columns show sections perpendicu-
lar to the cortical surface subjected
5. Internal pyramidal layer
to different staining methods. Left:
Appearance in Golgi-impregnated
sections, in which the cell bodies and
some of the dendrites can be seen.
Middle: A thionine-stained section,
in which only the cell bodies are vis-
6. Multiform layer ible. Right: Appearance after myelin
stainingthat is, the main pattern
of the myelinated axons is evident,
with perpendicular bundles of bers
entering the cortex, and horizontal
bundles of bers interconnecting
nearby parts of the cortex. Compare
Figs. 33.6 and 33.7.
33: THE CEREBRAL CORTEX: INTRINSIC ORGANIZATION AND CONNECTIONS 487
Area 4 Area 3b
1
1 Pia
2
2 3
5
3
6
White matter
White matter
gure 33.2 Cytoarchitectonics of the cerebral cortex. Photomicro- somatosensory cortex. This is not because there are more neurons
graph of a thionine-stained section through the central region of but because of more extensive dendritic trees, more axonal branches
the human brain. The section is perpendicular to the direction of the and boutons, and perhaps more glial cells. There is a tendency for
central sulcus. The six-layered structure is evident in area 4 (MI) and the cells to be arranged in vertically oriented rows or columns. See
in area 3b (SI), but development and appearance of the various layers also Fig. 12.3 with a corresponding section from the monkey.
are different in the two areas, especially with regard to layers 4 and 5. Magnication, 170.
The motor cortex in the precentral gyrus is much thicker than the
is similarly built. In primary sensory cortical areas,

Cortical Microstructure: Columns
layer 4 is especially well developed. In the striate area,
lamina four exhibits a further laminar subdivision We mentioned that the cortical neurons appear to be
(layer 4A, B, and C; see Fig. 33.5). Layer 3, the external organized into small units formed by cylinders or col-
pyramidal layer, can be recognized by its content of umns of tissue extending perpendicular to the surface
medium-sized pyramidal cells, whereas layer 5, the of the cortex. A tendency for cortical neurons to be
internal pyramidal layer, also contains many large pyra- arranged in perpendicular rows is evident from thionine-
midal cells. Layer 6, the multiform layer, contains many stained sections (Fig. 33.2). Figure 33.3A gives a simpli-
cells with spindle-shaped cell bodies. fied three-dimensional view of a column. Vernon B.
Considering only certain salient features, we can Mountcastle first observed the fact that neurons within
say that layers 2 and 4 are mainly receivingbeing such a column share functional properties that differ
most developed in the primary sensory areaswhereas from those in adjacent columns (in the monkey SI).
layers 3 and 5 are mainly efferent and send their axons He found that when a microelectrode was inserted per-
out of the part of the cortex in which they are located. pendicular to the cortical surface, the cells encountered
The pyramidal cells of layer 5 send their axons primar- as the electrode traversed the thickness of the cortex
ily to subcortical nuclei, and this layer is particularly had similar receptive fields. They were furthermore
well developed in the motor cortex (MI) (Fig. 33.2; see similar with regard to their stimulus specificity. In con-
Fig. 22.4). The layer 3 pyramidal cells send their axons trast, when the microelectrode was inserted obliquely,
primarily to other areas of the cortex (association and the receptive fields of the neurons moved with the
commissural fibers). Layer 6 is also largely efferent and advancement of the electrode. Based on such experiments,
sends many axons to the thalamus. it was proposed that neurons in the somatosensory
cortex (SI) with similar receptive fields and modalities target tend to be lumped together. There is, further-
are grouped together in columns with a diameter of more, a striking correspondence between the diameters
some hundred micrometers. A similar columnar arrange- of cortical dendritic trees and of the terminal patches
ment of neurons has been observed in the motor cortex formed by afferent fibers.
(MI), but with respect to muscles rather than to recep- It may not be feasible to find a definition that fits
tors (neurons within one column act on one or a few modules in all parts of the cortex, however. Indeed, dif-
synergistic muscles). Interestingly, a pyramidal cell with ferent criteria are used to define modules in the cortex,
all its dendrites and recurrent collaterals is contained and, depending on the criteria used, their shape and size
within a cortical tissue cylinder with a diameter of vary greatly. Further, the distribution neurons with dif-
about 350 m (Fig. 33.3A). Thousands of other neu- ferent properties is less schematic than the modular
rons are present within the same cylinder. concept might imply. In the visual cortex, in which the
segregation of functionally different neurons has been
most thoroughly investigated, cells sharing functional
Modular Organization of the Cerebral Cortex
properties are arranged in bands rather than in cylin-
Module is a more general term for columns and other ders (see Fig. 16.23). Another problem with the colum-
assemblies of neurons that share salient properties (in nar concept is that neurons in different layersfor
the cortex and elsewhere; see Chapter 16, under example, of the striate areaare not functionally iden-
Modular Organization of the Visual Cortex). It is tical (e.g., cells that are color-specific and cells that are
striking how connections and cytochemical markers movement-specific are located in different layers). Thus,
show a patchy distribution all over the cortex, strongly the modules may not always extend through the depth
suggesting some kind of modular pattern as a basic of the cortex but may be limited to one or a few layers
principle in the organization of the cerebral cortex. For (cf. color-specific blobs in the striate area; see
example, afferent projectionsfrom the thalamus or Fig. 16.24). To apply the columnar concept to such
from other parts of the cortexend in many, regularly cases confuses rather than clarifies.
spaced patches in the cortex rather than continuously The biologic significance of modular organization in
(Fig. 33.3B). This means that inputs from different the cortex and elsewhere (e.g., in the striatum and the
sources may converge systematically on cortical neu- cerebellum) is not fully understood. The modular
rons. Similarly, projection neurons with a common pattern gives each cortical neuron a varied afferent
A B
350 m Terminal cluster in a Pyramidal neuron

distant cortical area in lamina 3 Afferent fibers
from 1000 (?)
other neurons
gure 33.3 Columnar arrangement of

cortical neurons and clustering of cortico-
cortical terminal areas. A: A cylindrical
volume of cortical tissue forms a func-
tional unit (column), for example, in the
somatosensory cortex. Golgi-impregnated
neurons (from Conel 1939) show position
of cell bodies and the main orientation of
the dendrites. Note, however, that only a
fraction of the total neuronal population
within a column is shown in the gure.
B: Schematic. A pyramidal neuron in
Recurrent collateral cortical layer 3 (inset in A) and its main
(local feedback) connections: recurrent collaterals and cor-
ticocortical bers. A patch of termination
in a distant cortical area is also shown.
Each neuron forms many such patches
in several areas. The number of neurons
Columnar arrangement Corticocortical forming synapses on each layer 3 pyrami-
of cortical neurons White matter (association) fibers dal neuron is indicated.
input, with each neuron receiving samples of informa- proved in many instances to differ functionally, even
tion from several sources (several patches contact each though they were initially defined solely on the basis of
neuron). In the motor cortex, for example, a neuron the size, shape, and arrangement of the neuronal cell
might need to integrate information from the thalamus bodies. In many cases, a cytoarchitectonically defined
(perhaps from different subgroups in the VL nucleus), area is unique with regard to its afferent and efferent
from SI, and from the premotor cortex. Another advan- connections and the physiological properties of its cells.
tage of modular organization may be that it permits Although the borders between different cytoarchitec-
shorter intracortical connections and thus saves ner- tonic areas are sometimes easy to identify, as exemplified
vous tissue. Further, modules may be advantageous in the section of the visual cortex shown in Fig. 33.5,
during development by making it easier for growing more often the differences are rather subtle. Thus, it
axons to find their target. Some claim, however, that should not come as a surprise that authors often dis-
modular organization is merely a byproduct of how the agree with regard to the parcellation of the cortex into
nervous system develops and that it lacks an intrinsic areas. Today we try to define a cortical area not only
functional meaning. based on cytoarchitectonics but also by additional
criteria, such as fiber connections, cellular markers,
recordings of single-cell activity, and the behavioral
Afferents from Different Sources End in Different
effects of stimulation or ablation of the area in question.
Cortical Layers
The cortical layers differ with regard to the origin of
their extrinsic afferents. Thus, there is some degree of
specialization among the laminae with regard to what
kind of information they process. As we discuss later,
however, connections between the laminae ensure inte-
gration of their outputs. Schematically, pathways that
convey precise sensory information end primarily in
layer 4. This includes thalamocortical fibers from the
somatosensory relay nucleus, VPL, and from the relay
nuclei of the visual and auditory pathways, the lateral
and medial geniculate bodies. Association fibers (i.e.,
from other cortical areas) end preferentially in layers 2
to 4. Subcortical afferents with modulatory effects end
in several layers but especially in layer 1. Such fibers
arise in the intralaminar thalamic nuclei, in several
brain stem nuclei (the raphe nuclei, nucleus locus coer-
uleus, and dopaminergic cell groups in the mesencepha-
lon), and in the basal nucleus (acetylcholine).
The Cerebral Cortex Can Be Divided into

Cytoarchitectonic Areas
Even though all parts of the neocortex consist of six cell
layers, the thickness and structure of the various layers
vary from one area to another. This is observed most
easily in sections stained to visualize the cell bodies only
(Figs. 33.1, 33.2; see Fig. 22.4). Such cytoarchitectonic
differences form the basis of the subdivision of the
entire cortex into cytoarchitectonic areas, as done
around the turn of the century by Brodmann (1909)
and others (Fig. 33.4). This is briefly described in
Chapter 6, and several of the cytoarchitectonic areas
are mentioned in previous chapters. The development
of cytoarchitectonic areas is briefly discussed in
Chapter 9 (Specification of Cortical Cytoarchitectonic
Areas). gure 33.4 Brodmanns cytoarchitectonic map of the human brain.
The main importance of the division of the cortex The various areas are labeled with different symbols and numbers.
into cytoarchitectonic areas is that these areas have (From Brodmann 1909).
A B
Area 17
Area 18
Area 17
1 Area 18
1
2 Line of Gennari
2
3
4A
3
4B
4 4B
5 4C
6 5
gure 33.5 The transition between area 17 (the striate area) and nerve bers. Note the myelinated bers running parallel with the
area 18. A: Thionine-stained section from the human visual cortex. cortical surface in lamina 4B (the line of Gennari). See Fig. 16.17,
The various layers change in cell size, cell density, and thickness at the which shows the macroscopic appearance of the line of Gennari.
transition between the two cytoarchitectonic areas. Lamina 4 is par- Most areal borders are less clear cut than the border between areas
ticularly well developed in area 17, and is subdivided into sublayers 17 and 18.
(4A4C). B: Section from the same region stained to show myelinated
We return to connections and functions of different All cells belonging to the other main type of cortical
cortical areas later in this chapter. neurons, the nonpyramidal cells, have locally branch-
With regard to the size of cortical areas, there are ing axons that do not reach the white matterthat is,
surprisingly large individual variations. For example, they are the cortical interneurons (Fig. 33.7). Such
the volume of the striate area (the most easily identified interneurons may be classified into three main types on
one) varies by a factor of three among adult humans, the basis of the course and branching pattern of their
and similar differences have been documented for the axons. The first type has an axon that forms numerous
somatosensory cortex, the auditory cortex, and pre- terminal branches close to the cell body; it mediates
frontal cortical areas. Because the volume of the hemi- influence mainly to neighboring neurons within the
spheres does not show similar variations, this implies lamina in which the cell body is located. The second
that in a brain with a large striate area, other areas are type has an axon coursing perpendicularly or vertically
relatively smaller. Whether such anatomic differences toward either the cortical surface or the white matter,
also have functional significance is unknown, but con- giving off collaterals on its way; this enables the
ceivably, they may contribute to the large differences interneuron to influence neurons in several layers. The
between humans in mental and other capacities. third type sends its axon in a horizontal direction
(parallel to the cortical surface).
Even though this division into three kinds of cortical
Intracortical Connectivity: Interneurons and Pyramidal
interneurons is an oversimplification, it shows the main
Cell Collaterals
features of the intracortical connections, which permits
The pyramidal cells send their axon toward the white interactions among neighboring neurons, among neu-
matter to reach other parts of the cortex or subcortical rons within different layers, and among neurons located
cell groups. Thus, they are the projection neurons of at some distance within the same layer. Vertically ori-
the cortex (Fig. 33.3B and 33.6), which most likely ented axons (from either interneurons or pyramidal cell
constitute more than two-thirds of all cortical neurons. recurrent collaterals) ensure the communication among
The projection neurons send recurrent collaterals before neurons within a narrow cortical cylinder or column
the axon leaves the cortex and can thus influence the (Fig. 33.3A). The horizontal axonal branches mediate
level of activity among the cortical neurons in their communication among neurons in different columns.
vicinity. The recurrent collaterals may, for example, Such horizontal influences can be inhibitory or excit-
excite inhibitory interneurons and thereby limit the atory. In sensory cortical areas, the horizontal intracor-
activity of the parent cell and other pyramidal cells. tical connections mediate lateral inhibition, which
Lamina areas than in primary sensory areasmeasuring up to
1 Apical 9 mm in monkey posterior parietal cortex, although the
dendrite
2
majority of them are probably less than 1 to 2 mm.
Thus, cortical columns farther apart than this must
communicate by means of projection neurons with an
3 axon coursing in the white matterthat is, association
fibers (Fig. 33.3B). Such connections are discussed later
in this chapter.
4
5 Fast Excitation and Inhibition in the Cortex: Glutamate

and GABA
Axon
Most cortical neurons receive inputs from the thalamus
6
and other parts of the cortex with fast, excitatory synap-
Recurrent
collateral tic actions (glutamate acting on amino-methylisoxazole
White propionic acid [AMPA] receptors) and fast inhibition
matter
from interneurons (GABA acting on GABAA receptors).
Such synapses are responsible for precise and specific
gure 33.6 Cortical projection neurons. Schematic. The axons (red) information transfer in topographically organized con-
give off several recurrent collaterals on their way to the white matter. nections. In addition, cortical neurons are influenced by
The dendrites have numerous spines. The largest neurons, with the
slow, modulatory synaptic actions (we return to that later).
largest cell bodies and the thickest axons, are located in layer 5.
Drawing based on studies by Jones (1988) of the central region of the Most or perhaps all projection neuronsthose sending
monkey with the Golgi method. their axons to subcortical nuclei and those forming
association or commissural connectionsuse glutamate
as a neurotransmitter. Accordingly, physiological studies
increases the spatial resolution of the sensory informa- show that they have fast, excitatory synaptic actions (how-
tion (lateral inhibition is present at several levels of ever, there are also metabotropic glutamate receptors in
the sensory pathways; see Fig. 13.4). They may also the cortex). Glutamate released from pyramidal-cell collat-
contribute to cortical plasticity by modulating the size erals can also bind to N-methyl-D-aspartate (NMDA)
of the receptive fields of cortical neurons. receptors, which are thought to be involved in plastic
The majority of horizontal intracortical axons appear changes related to learning and restitution after brain
to be collaterals of pyramidal cells rather than of damage.
interneurons. They are generally longer in association A subgroup of cortical interneuronsspiny stellate
cellsis most likely also excitatory, as judged from,
among other things, the kind of synapse they form
Lamina (asymmetrical synaptic thickening, in contrast to the
1 symmetrical thickening found at most inhibitory corti-
cal synapses). As the name implies, this kind of interneu-
2
ron has numerous dendritic spines, and in this respect it
resembles the (excitatory) pyramidal cells. The rest of
3 the interneurons are termed aspiny because they have
few spines. These are inhibitory, with GABA as the pre-
dominant neurotransmitter. GABA-containing neurons
constitute 20% to 25% of all cortical neurons. Most of
4 the GABAergic interneurons also contain one or several
neuropeptides (such as substance P, somatostatin, vaso-
active intestinal peptide [VIP], cholecystokinin, and
5 neuropeptide Y).
There is some experimental evidence that, in some
cases, epilepsy may be related to selective loss of
6
GABAergic cortical interneurons.
gure 33.7 Main kinds of cortical interneurons. There are three Modulatory Synaptic Effects in the Cerebral Cortex
patterns of axonal distribution (in blue): in the immediate vicinity of
the cell body, horizontally in the layer of the cell body, and vertically Modulatory influences on cortical neurons are partly
spanning several layers. (Based on Jones 1987.) due to activation of metabotropic glutamate receptors
and GABA acting on GABAB receptors. In addition, nearby cortical cells and has been estimated to receive
neuropeptides colocalized with GABA exert modula- about 60,000 synapses (monkey).
tory effects, although we do not know their functional The enormous number of neurons and their complex
roles. Most studied, however, are modulatory actions interconnections within even a small volume of cortical
mediated by diffusely organized fiber systems from tissue explain why we still do not understand the basic
several brain stem and basal forebrain cell groups. rules underlying intracortical information processing.
We mentioned such connections in Chapter 5 (under Promising advances have been made, however, espe-
Modulatory Transmitter Systems) and in Chapter cially in the visual cortex (see under Intracortical
26 (under Pathways and Transmitters Responsible for Signal Traffic in the Visual Cortex).
Cortical Activation). The following neurotransmitters
are involved: acetylcholine, norepinephrine, serotonin,
Intracortical Signal Trafc in the Visual Cortex
dopamine, and histamine. In general, they act to
improve the precision of cortical signal transferfor Regarding intracortical signal traffic, detailed studies
example, by improving the signal-to-noise ratio. Such have been performed in the visual cortex with the use of
effects are probably important in relation to arousal, methods enabling the recording of single-cell activity in
focused attention, and motivation. Acetylcholine, relation to specific stimuli and subsequent intracellular
for example, brings layer 5 pyramids in the motor cor- injection of horseradish peroxidase. Thus, the dendritic
tex from a state with low-frequency burst firing to sin- and axonal patterns of individual, functionally charac-
gle-spike firing. In the latter state, the frequency of terized neurons can be determined. Successful attempts
single spikes depends on the degree of depolarization: have also been made to abolish the activity of neurons
that is, the intensity of synaptic excitatory inputs to the in specific layers and then study how the properties of
neuron from, for example, the premotor cortex and the neurons in other layers are changed. As expected from
thalamus. the known terminal pattern of axons from the lateral
geniculate body, neurons are first activated in layer 4
after visual stimuli (in addition, neurons in other layers
Intracortical Signal Trafc and Information Processing
with dendrites extending into layer 4 can be influenced).
Afferent fibers that end in a small volume of the cortex From layer 4, the excitation is propagated to layers 2
make excitatory synapses with a large number of pro- and 3, and from there to layers 5 and 6. Some cells in
jection neurons and interneurons. Thus, one afferent layer 6 send axons upward to layer 4. Presumably, at
fiber from the thalamus has been estimated to contact every step in such a pathway through the cortex some
about 5000 cortical neurons. The synaptic contacts are processing of the sensory information takes place, such
established in certain layers only, but the excitation is as integration by one neuron of the signals from other
propagated to other layers by the pyramidal cell recur- functionally different neurons. In accordance with this
rent collaterals and excitatory interneurons (spiny stel- assumption, the functional properties of neurons in dif-
late cells). At the same time, activation of numerous ferent layers vary, as shown with microelectrode record-
inhibitory interneurons serves to focus the excitatory ings after natural stimulation of receptors. A projection
signals and to limit the activity of the projection neu- neuron in layer 5 has quite different properties than a
rons. In addition, the inhibitory interneurons inhibit cell in layer 4; for example, the receptive fields of the
other inhibitory interneurons, with resulting disinhibi- layer 5 cells are larger (as a sign of convergence of sig-
tion. Horizontal axonal collaterals propagate both nals from several neurons in layer 4). Other properties
inhibition and excitation laterally from the focus of of layer 5 neuron also suggest that signals from func-
cortical excitation. This does not occur at random but tionally different layer 4 neurons converge on layer 5
so that functionally related neurons are interconnected. cells (via processing in layers 2 and 3).
Finally, the integrated signals are issuedespecially
from layer 3 and 5 pyramidsto other parts of the
Cortical Neurons Are Coincidence Detectors
cortex and subcortical cell groups (among them, the
motoneurons). Many cortical neurons react primarily when informa-
As we see, the activity of each cortical neuron (i.e., its tion about two events reaches them simultaneously,
firing frequency and firing pattern) depends on the like cells in the visual cortex that respond poorly to sig-
activity of the numerous other neurons with which it is nals from one eye only but vigorously to simultaneous
synaptically connected. Such connections reach a corti- signals from both eyes (binocular cells). Like a good
cal neuron from subcortical nuclei and other parts of detective who has a special eye for coincidences (events
the cortex and from cells in its immediate vicinity occurring simultaneously) and disregards numerous
(within a radius of a few millimeters in the horizontal trivial bits of information, the cortical neurons respond
direction). One cortical neuron, such as a pyramidal preferentially to certain coincidences of stimuli that
cell of the MI, integrates information from perhaps 600 have a survival value. This is the basis for association
learning; that is, learning the relationship between cause between the cortical representations of various body
and effect. We know that a novel or unexpected stimu- parts.
lus, or one occurring in an unusual context, causes Training of a sensory task can alter the cortical rep-
arousal and improved retention of new material. Often, resentation of the trained part (e.g., training roughness
synaptic changes occur when a neuron receive simulta- discrimination with the index finger). It seems likely
neous a specific input about a stimulus or the context that such examples of cortical plasticity are due, at least
and a modulatory input (e.g., acetylcholine from the partly, to changes in the synaptic efficacy of horizontal
basal nucleus) signaling the salience of the specific input connections. The same mechanism probably operates
(see Fig. 4.10). This characteristic property of cortical during recovery after brain damage that affected the
cells is probably built into the inborn wiring pattern cerebral cortex or its connections.
(hardware) of the brain, but it also needs proper use
to be further developed and maintained (see later, The
Parietal Lobe and the Development of the Ability to CONNECTIONS OF THE CEREBRAL CORTEX
Integrate Somatosensory and Visual Information).
Glutamatergic thalamocortical fibers appear to act The connections of the cerebral cortex with subcortical
through AMPA receptors on cortical neurons but not structures are described in several of the previous chap-
through NMDA receptors (the latter being related ters, where we deal with the terminal regions of the
to induction of long-term potentiation [LTP]). The major sensory pathways and the areas that give origin
recurrent pyramidal cell collaterals, however, act also to the descending pathways involved in motor control.
on NMDA receptors. Some experimental evidence Here we describe general aspects of connections between
shows that simultaneous activation of a cortical neuron the thalamus and the cerebral cortex and of the cortico-
from the thalamus (AMPA) and from other cortical cortical connections (association and commissural con-
neurons (NMDA) can induce LTP. In the monkey nections). Such knowledge is a necessary basis for the
motor cortex, LTP has been established during the following treatment of the cortical association areas
learning of new motor skills. Thus, not only are the and their functional roles.
cortical neurons especially sensitive to coincident
inputs, they may also be the cellular basis of associative
A Brief Survey of Cortical Connections
learning in the cortex.
We can classify the afferent connections of the cerebral
cortex as follows:
Horizontal Integration and Cortical Plasticity
1. Precise, topographically organized connections
The extensive horizontal intracortical connections
from the specific thalamic nuclei; each thalamic
appear to be crucial for the working of the cortex. They
nucleus supplies one particular part of the cortex
help explain why the response of so many cortical
2. Diffusely organized connections from the intrala-
neurons depends on the context of a stimulus (cf.
minar thalamic nuclei and several other subcortical
Chapter 16, under Color Constancy). As mentioned,
nuclei (the raphe nuclei, the nucleus coeruleus, dop-
horizontal connections ensure that the receptive fields
aminergic cell groups in the mesencephalon, and cho-
of cortical neurons are not static but subject to modifi-
linergic cell groups in the basal forebrain); such
cation by inputs from their neighbors. For example,
connections do not respect the cytoarchitectonic bor-
single cells in the visual cortex have smaller receptive
ders in contrast to the connections from the specific
fields and react more strongly when the attention of the
thalamic nuclei
animal is directed to the visual stimulus. Horizontal
3. Association fibersthat is, precisely organized
connections most likely also contribute to well-known
connections linking cortical areas within the same
psychophysical phenomena, such as the filling in of
hemisphere
missing lines in otherwise meaningful visual images.
4. Commissural fibersthat is, precisely organized
When blocking GABA receptors (and thus inhibitory
connections between areas in the two hemispheres
horizontal connections) the receptive fields of cortical
neurons enlarge immediately. After blocking GABA The efferent connections of the cerebral cortex can also
transmission, stimulation of a small peripheral spot be divided into subcortical and corticocortical ones
activates an area in the SI that is much larger than (association and commissural connections). The sub-
before. After amputation of a finger in monkeys, the cortical fibers are destined for the thalamus, the stria-
area in SI activated from the neighboring fingers tum, various brain stem nuclei (among them the pontine
enlarges immediately. These examples show that there nuclei projecting to the cerebellum), and the spinal
must exist excitatory connections in the cortex that are cord. The corticocortical connections are for the most
suppressed under ordinary conditions. Further, due to part reciprocalthat is, an area receives fibers from the
such modifiable connections there is a dynamic balance same areas to which it sends fibers.
connections from the (VPL) and the lateral geniculate

Specic Thalamocortical Connections
body are somatotopically and retinotopically orga-
The thalamus has been mentioned in several contexts nized, respectively, with a precision that enables the
(see Chapters 6 and 14 for descriptions of its gross cortex to extract information about minute spatial
anatomy and main subdivisions). The thalamus sup- details. Further, each thalamic nucleus sends fibers to
plies all parts of the neocortex with afferents. Each part more than one cortical area. We can take the mediodor-
of the cortex receives fibers primarily from one of the sal nucleus (MD) as an example. In the scheme, it is
specific thalamic nuclei. The main features of this topo- depicted as sending fibers to the prefrontal cortex (with-
graphic arrangement of the thalamocortical projection out any topographic arrangement). In reality, the MD
are shown in Fig. 33.8 (as we believe it is organized sends fibers to other parts of the cortex, too, such as
in humans). Figures 14.6 and 24.16 show the projec- parts of the cingulate gyrus. The MD furthermore con-
tions from the ventral thalamic nucleus in more detail, sists of several subdivisions, each supplying a different
based on experimental studies in monkeys with various part of the prefrontal cortex. The main point emerging
axonal tracing methods. Figure 16.20 shows the projec- from such knowledge is that the MD is not a functional
tion from the lateral geniculate nucleus to the visual unit. A small lesion, for example, must be expected to
cortex. produce quite different effects, depending on its exact
Conditions are more complex than shown in the dia- location within the MD.
grams, however. In the first place, the topographic Some of the specific thalamic nuclei are relay stations
arrangement is much more fine-grained. Thus, the pro- in the pathways for signals from sensory receptors to
jection from one thalamic nucleus is precisely arranged, specific cortical areas (vision, hearing, cutaneous sensa-
with subdivisions of the nucleus supplying minor tion, etc.). The ventral posterolateral nucleus (VPL)
parts only of the large fields shown in Fig. 33.8. receives afferents from the somatosensory pathways
As described in Chapters 14 and 16, the thalamocortical and projects to SI (areas 3, 1, and 2; see Figs. 14.2,
PMA SMA MI
SI MI SMA Cingulate gyrus SI
Posterior parietal Prefrontal cortex Posterior parietal
cortex (5, 7) cortex (5, 7)
Striate area (17) Temporal assosiation

Temporal assosiation cortex
cortex Medial dorsal Auditory
nucleus (MD) Intralaminar cortex
thalamic nuclei
Anterior
nucleus
Pulvinar
Medial
Lateral nucleus
geniculate body
(LP, LD)
Ventral nucleus Lateral
(VPL, VL, VA) geniculate
body
gure 33.8 The thalamocortical projection. Highly simplied Overlap exists between the cortical terminal regions of different
scheme showing the main features of its topographic organization. thalamic nuclei but is not shown in the gure.
14.4, and 14.6); the lateral geniculate body or nucleus under Thalamostriatal Connections). Such connec-
receives afferents from the retina and projects to the tions are precisely organized (another fact speaking against
striate area (see Figs. 16.14 and 16.20); the medial the use of the term unspecific thalamic nuclei).
geniculate body is the last subcortical station in the
auditory pathways and it sends efferents to AI (see
Extrathalamic, Modulatory Connections to
Figs. 17.9 and 17.11). Other specific thalamic nuclei,
the Cerebral Cortex
the ventrolateral nucleus (VL) and the ventral anterior
nucleus (VA), are relay stations in the pathways from Apart from the major thalamocortical connections,
the cerebellum and the basal ganglia to the motor and several subcortical nuclei provide sparser cortical inputs
premotor cortical areas (see Fig. 24.16). Other thalamic without synaptic interruption in the thalamus (the
nuclei relay signals from limbic structures: the anterior raphe nuclei, the locus coeruleus, the mesencephalic
thalamic nucleus (A) receives afferents from the mam- ventral tegmental area [VTA], the basal nucleus, and
millary nucleus (which receives its main input from the the tuberomammillary nucleus in the hypothalamus).
hippocampal formation) and projects to the cingulate These nuclei supply most of the central nervous system
gyrus; and the mediodorsal nucleus (MD; Fig. 33.8) can with modulatory inputs and are in involved in a num-
relay signals from the amygdala to the frontal lobes. ber of functions, as discussed in previous chapters.
The posterior parietal cortex (areas 5 and 7) receives Briefly stated, the fibers from the aforementioned nuclei
fibers from the posterior part of the thalamus, the lat- exert a modulatory control over the excitability level of
eral posterior nucleus (LP), and parts of the pulvinar cortical neurons, with relation to wakefulness and
(Fig. 33.8; see Figs. 6.21 and 6.22). Other parts of the phases of sleep. In addition, they probably control more
pulvinar projects to the temporal lobe. The LP and the specifically selected cortical neuronal groups when our
pulvinar receive afferents from nuclei related to vision attention is focused on relevant, novel stimuli.
and eye movements, such as the superior colliculus and All of these transmitter-specific nuclei project to large
the pretectal nuclei, and may relay such information to parts of the cortex with no distinct topographic pat-
the posterior parietal cortex (see also Chapter 25, under tern. Nevertheless, recent studies in monkeys show that
Cortical Control of Eye Movements). However, the each nucleus (and thus fibers with a particular trans-
pulvinar is not primarily a relay nucleus but a link in a mitter) projects with a higher density to some than to
corticothalamiccortical circuit, as we will return other parts of the cortex. For example, dopaminergic
when discussing corticothalamic connections. fibers from the VTA end with highest density in the
prefrontal and temporal neocortex, whereas noradren-
ergic fibers from the locus coeruleus innervate especially
The Intralaminar Thalamic Nuclei
the central region (MI, SI). Further, fibers from the vari-
Modern tracer studies have shown that the cortical ous nuclei end in somewhat different cortical layers.
projections from each of the intralaminar nuclei end in A striking feature of the fibers is that, after having
certain parts of the cortex only; for example, the con- entered the cortex, they run horizontally for a consider-
tralateral nucleus (CL) sends fibers predominantly to able distance (in contrast to the vertical organization of
the parietal cortex. Nevertheless, the projections are the afferents from the specific thalamic nuclei). Further,
considerably more widespread and diffuse than those their actions are partly mediated by volume transmis-
from the specific thalamic nuclei and do not respect sion. (See Chapter 2, under Modulatory Transmitter
areal borders (the intralaminar nuclei were formerly Systems and Chapter 16, under Signal Pathways and
termed the unspecific thalamic nuclei). Physiologic Transmitters for the Activation of the Cerebral
studies indicate that the intralaminar nuclei exert gen- Cortex).
eral effects on the excitability of cortical neurons. Thus,
electrical stimulation produces a so-called recruiting
The Corticothalamic Connections
response in extensive parts of the cortex, which resem-
bles the EEG changes associated with arousal (desyn- All of the thalamic nuclei receive massive back-
chronization; see Chapter 26). The coactivation of projections from the cerebral cortex. In fact, the num-
cortical neurons by signals from the specific thalamic ber of corticothalamic fibers is much higher than the
nuclei and the intralaminar nuclei may be important for number of thalamocortical ones; for example, the rela-
the binding of specific stimuli with their saliencethat tionship for VPL has been estimated to 7:1. Yet, the
is, a form of coincidence detection that perhaps may be corticothalamic connections have until recently received
necessary for awareness of the stimulus. relatively little attention. The largest thalamic nuclei,
The tasks of the intralaminar nuclei are related not with weak or no inputs from peripheral sense organs
only to the cerebral cortex, because they have even such, have reciprocal connections with association
stronger connections with the striatum (see Chapter 23, areas in the parietal, temporal, and frontal lobes
3
(e.g., the pulvinar and the MD. These nuclei should synaptic input from the SI is removed. The same holds
presumably be viewed as dialogue partners for the cere- true for neurons in the lateral geniculate body and their
bral cortex rather than relay stations in pathways from input from the striate area. Thus, the cerebral cortex
subcortical nuclei. exerts strong top-down control of the signals it is going
In general, the nuclei receive afferents from the corti- to receive. Equally important, the corticothalamic con-
cal areas to which they send their efferentsthat is, the nections also influence the firing pattern of the thal-
thalamocortical and the corticothalamic connections amocortical neurons (burst or single-spike firing; see
are reciprocal. The corticothalamic projections are also Chapter 26, under Thalamic Neurons Have Two
precisely, topographically organized. As mentioned, States of Activity). For example, the feedback from
corticothalamic neurons have their cell bodies mainly in the cortex governs the synchronization of spindle oscil-
layer 6, whereas projections to other subcortical nuclei lations (burst firing) in various parts of the thalamus
arise mainly in layer 5. This indicates that the informa- during early stages of sleep.
tion received by the thalamus is not simply a copy of
information sent from the cortex to other regions.
Inhibition in the Thalamus: Interneurons and the
In view of the massive corticothalamic connections,
Reticular Thalamic Nuclei
the function of the thalamus cannot be limited to medi-
ating information from subcortical cell groups to the Inhibitory interneuronsthe majority GABAergic
cortex. Even for relay nuclei such as VPL, merely probably constitute one-fourth or more of all neurons
quantitative considerations show that crosstalk with in some of the thalamic nuclei. In the thalamic sensory
the cerebral cortex must be of major importance. All relay nuclei, the inhibitory interneurons may contribute
thalamic nuclei receive and presumably process vast to the enhancement of stimulus contrasts (by lateral
amounts of information from the cortex and is there- inhibition) and to selection of certain kinds of stimuli
fore intimately involved in processes taking place in the by suppressing other kinds (e.g., in relation to transmis-
cortex itself. That the corticothalamic fibers really influ- sion of signals from nociceptors). Opioid peptides and
ence the information processing in the thalamus is wit- other neuropeptides (such as substance P) are present in
nessed by several observations. For example, the receptive several of the thalamic nuclei, including those relaying
fields of neurons in the VPL increase dramatically if their nociceptive signals.
The reticular thalamic nucleus is unique among the
thalamic nuclei because virtually all neurons are
3 Some authors use the term rst-order thalamic nuclei of those primarily GABAergic. The nucleus, which forms a thin shell at
driven from peripheral sense organs (e.g., VPL and the lateral geniculate body), the lateral aspect of the thalamus (Fig. 33.9), sends its
which serve as relay stations in the large sensory pathways. Nuclei not receiving
such direct sensory inputs (such as the pulvinar and the MD) are termed higher
efferent fibers in the medial direction to end in the other
order thalamic nuclei (Sherman 2005). thalamic nuclei (and not to the cortex, differing also in
Anterior nucleus
Lateral dorsal
nucleus(LD)
Mediodorsal
nucleus (MD)
x
Reticular thalamic
nucleus
Ventral lateral
nucleus (VL)
Zona incerta Internal capsule Thalamus

Putamen
Mammillothalamic Mammillary body
tract Globus pallidus
Crus cerebri
Mammillary body
Optic tract
gure 33.9 The thalamus. Frontal section through the middle part of
the human thalamus. Schematic; myelin stained. (See also Figs. 3.24
and 3.27.)
Corticothalamic
neighboring areas (Fig. 33.3). For example, there are
neuron ample connections between the SI and area 5 posteri-
Cerebral cortex orly and the MI anteriorly. MI furthermore receives
Lamina 4
association fibers from the premotor area (PMA) and
Lamina 6 supplementary motor area (SMA). The longest associa-
+ tion fibers interconnect functionally related areas in
different lobes: for example, connections from the
Thalamus
extrastriate visual areas and the posterior parietal
cortex lead to the premotor and prefrontal areas.
+
When we follow the association connections out-
_ ward from the primary sensory areas (SI, VI, and AI),
+ signals first reach unimodal association areasthat is,
_
areas that process only on sensory modality (Figs. 33.11
Reticular thalamic +
nucleus and 33.12). From there, association fibers pass to poly-
modal areasthat is, areas that integrate sensory infor-
mation of different modalities. One area integrates
somatosensory and visual information, another visual
Thalamocortical
neuron and auditory, and so forth. The areas outside the pri-
mary sensory areas (such as the areas of the posterior
parietal cortex and the extrastriate areas) send their
efferent projections not only to their immediate neigh-
bors but also to distant areas in the frontal lobe
gure 33.10 Reciprocal thalamic connections with the cerebral
cortex and the reticular thalamic nucleus. Thalamocortical and corti-
(premotor and prefrontal areas) and to limbic corti-
cothalamic bers give off collaterals to the reticular thalamic nucleus. cal areas (the cingulate gyrus and the hippocampal
The neurons in this nucleus are GABAergic, and inuence signi- gyrus) (Figs. 33.11 and 33.12).
cantly the functional state of the thalamocortical neurons. As a rule, each cortical area establishes association
connections with many other areas; that is, there is a
this respect from the other thalamic nuclei). Both the

corticothalamic and thalamocortical fibers pass through Parahippocampal Cingulate gyrus
the reticular nucleus on their way to and from the gyrus (area 24)
thalamus and give off numerous collaterals that end in
the nucleus (Fig. 33.10). Further, the reticular nucleus
receives afferents from the mesencephalic reticular
formation and has reciprocal connections with the PAG
(which, among other things, is related to the control of
transmission of signals from nociceptors).
The function of the reticular thalamic nucleus is not Posterior
fully understood, but its connections indicate that it can parietal cortex
Prefrontal cortex
influence the activity of thalamocortical neurons and (area 46) 5
thus, indirectly, the activity of the cerebral cortex. SI 7
Indeed, electrophysiological studies show that the retic-
ular nucleus can synchronize the activity of neurons
throughout the thalamus. Further, its activity correlates
closely with changes of the EEG during sleep and wake-
fulness. Its relation to attention and control of sensory
information transfer to the cortex may explain why
lesions of the reticular nucleus reduce learning and
memory (of spatial tasks).
Polymodal
area
Association Connections of the Cerebral Cortex gure 33.11 Association connections of the somatosensory cortex
Vast numbers of association fibers ensure the coopera- (monkey). Only some ber connections are shown, to illustrate the
ow of information progressing from SI to the posterior parietal
tion among the cortical areas. The shortest association cortical areas, and from there to polysensory areas in the temporal
fibers connect minor parts within one area (so-called lobe, to the prefrontal cortex, and to limbic cortical regions. (Based
U fibers), whereas somewhat longer fibers link together on Jones and Powell 1970.)
Medial prefrontal connections going in opposite directions between two

cortex areas, notably with regard to laminar origin and desti-
nation. This has been most studied in visual cortical
areas. Fibers going outwardalso called feedforward
connectionsfrom the striate area to the extrastriate
areas arise mainly in layer 3 and end primarily in
layer 4. Fibers going backwardfeedback connec-
tionsarise in deep layers (layer 6) and end mainly in
Temporal association
cortex the most superficial layers. The outward connections
are precisely, topographically organized, whereas in
Posterior
Dorsolateral
parietal cortex
general, the backward connections show a less fine-
prefrontal grained topography. Based on their anatomic charac-
(area 7)
cortex
teristics, the outward connections from the sensory
areas appear to be concerned with segregation and spe-
cific convergence of sensory information. For example,
the striate area distributes different features of a visual
image to extrastriate areas that are specialized for anal-
ysis of color, motion, form, and so forth. The backward
connections are probably responsible for context-
Polymodal
area Visual cortex dependent modifications of sensory processing at the
(area 17, 18, 19) earlier stagesfor example, the well-known effect of
Inferotemporal context on receptive fields of neurons in primary sen-
cortex (visual sory areas. The backward connections may also pro-
association areas)
vide a prediction of the sensory input expected to arise
gure 33.12 Association connections of the visual cortex. Compare from a motor command, enabling the brain to compare
with Figure 33.9 and note similarities with regard to the progression the expected and actual results.
of information outward from the striate area. Only some connections
are shown. (Based on Jones and Powell 1970.)
Commissural Connections of the Cerebral Cortex
Most commissural fibers pass in the corpus callosum
(see Figs. 6.26 and 6.27). A small fraction courses in the
considerable divergence of information. At the same anterior commissure (in humans, 1%2%). The latter
time, there is also considerable convergence, as each area fibers are believed to belong primarily to the olfactory
receives afferents from several other areas (Figures 33.11 pathways. (In the monkey, the anterior commissure
and 33.12 give very simplified accounts). Together, the contains about 5% of all commissural fibers, mainly
many areas of the cortex are extensively interconnected, linking corresponding parts of the temporal lobes.)
forming complex networks specialized for specific
tasks. Complex functionssuch as control of attention
and speechare carried out by many areas in conjunc-
tion with each other by way of their association con- MI hand area
SI hand area
(hidden in the
nections. At the cellular level, the extensive association central sulcus)
connections enable neurons to integrate many, different
pieces of information and to act as coincidence detec-
Striate
tors, as discussed in the preceding text. area
Outward and Backward Corticocortical Connections

The discussion so far may give the impression that the
flow of information between various cortical areas goes
only in one direction, but this is not the case. Generally,
the association connections are reciprocal, enabling
areas to exert mutual influences. For example, there is
not a one-way traffic outward from the striate area
gure 33.13 Total distribution of commissural connections (monkey).
through successive stages of extrastriate areas, as at all Almost all parts of the cerebral cortex send and receive commissural
levels areas send fibers back to each other and to the connections, except the representation of the central visual eld in the
striate area. Differences exist, however, between the striate area and the SI and MI hand regions (shown in red).
Generally, commissural fibers interconnect corre- motor pathways; connections related to distal body
sponding areas in the two hemispheres. The density of parts are entirely crossed, whereas connections related
such fibers varies considerably among regions, however. to proximal parts are bilateral. It seems possible that
Some regions are almost or totally devoid of commis- commissural connections between, for example, the
sural fibers (Fig. 33.13), especially the striate area and hand areas, would disturb the independent control of
parts of the MI and SI that represent distal parts of the the hands (nevertheless, information about motor com-
extremities (the regions representing the hands and feet). mands and sensory signals pertaining to the distal body
Thus, regions of the cortex dealing with parts of the parts of one side can reach the other hemisphere by
body that usually work in a symmetrical fashion (such other cortical areas and their commissural connections.
as the two halves of the back) are amply interconnected, We return to the corpus callosum and the commis-
whereas parts that usually work independently (such as sural connections in Chapter 34 when dealing with
the hands) have few commissural fibers. A corresponding lateralization of functionsthat is, tasks that are the
organization is present in the somatosensory and the division of tasks between the two hemispheres.
34 Functions of the Neocortex
OVERVIEW lobethe inferotemporal cortexis dominated by

processed visual information important for object
This chapter deals primarily with functional aspects of recognition. The medial parts of the temporal lobe are
the cortical association areas, that is, parts of the cortex of special importance for learning and declarative mem-
that neither receive direct sensory information through ory, as discussed in Chapter 32.
the major sensory pathways nor send direct fibers to The insula, hidden in the lateral sulcus, receive all
subcortical motor nuclei. All of the cerebral lobes kinds of sensory information and is involved in pain
contain association areas, according to this definition. perception, homeostasis, and bodily awareness.
In Chapter 33, we discuss the connections of the asso- Language and speech depends on a distributed
ciation areas in general. Here we look at the main network with two special hubs, one in the frontal lobe
groups of association areas and their possible functions. (Brocas area) and one at the temporoparietal junction
It should be realized, however, that the functional roles (Wernickes area). The anterior (frontal) area is partic-
of a group of association areas, for example, those of ularly important for the expressive aspects of speech,
the frontal lobe, can be understood only if considered while the posterior area is more concerned with the
as part of distributed, task-specific networks involving sensory aspects.
other association areas and subcortical nuclei. The left hemisphere is dominant for speech in 95%
Typically, the association areas receive and integrate of the population. We also discuss further examples of
various kinds of information. Some are specialized for hemispheric specialization (lateralization). The corpus
integration of two or more sensory modalities; others callosum ensures that the two halves of the brain keep
integrate highly processed sensory information with each other updated and cooperate to obtain common
information about intentions and goals. The integrative goals.
capacity depends on proper use of sensory information, Finally, we discuss possible biologic bases of cognitive
and must be learned in early childhood. sex differences.
The posterior parietal cortex integrates visual and
somatosensory information, and is responsible for,
among other functions, the control of visually guided ASSOCIATION AREAS
behavior and spatial orientation. From the parietal
areas, signals pass to premotor and motor areas. The For some of the cortical areas, functional aspects are
posterior parietal cortical areas also have reciprocal discussed in previous chapters. Here we address pri-
connections with the cingulate gyrus and the prefrontal marily functions that can be ascribed to the so-called
cortex, mediating the influence of emotions, attention, association areas of the cerebral cortex. This term is not
and motivation on behavior produced by somatosen- precisely defined but is traditionally used for parts of
sory and visual stimuli. the cortex that neither receive direct sensory informa-
The prefrontal cortex, situated in front of the frontal tion through the major sensory pathways nor send
lobe motor areas, receives information about all sensory direct fibers to subcortical motor nuclei. All of the cere-
modalities and also about the motivational and emo- bral lobes contain association areas, according to this
tional state of the individual. It is of special importance definition.
for planning and initiation of goal-directed behavior. The connections of the association areas indicate that
More specifically, the prefrontal cortex is important for they are able to integrate information from sensory and
attention, for selection of a specific behavior among limbic parts of the cortex (i.e., the cingulate gyrus,
several possible ones, and for suppression of unwanted parts of the prefrontal cortex, and the hippocampal
behavior. These functions are of particular importance region) and thereafter issue commands to motor cortical
for social behavior. areas and (indirectly) to the hypothalamus.
The temporal association areas are particularly Comparison of the cerebral hemispheres of humans
concerned with high-level processing of auditory and and monkeys shows that the association areas occupy a
visual information. The cortex of the superior temporal much larger fraction of the total in humans than in
gyrus is characterized by its connections with the audi- monkeys. Comparison of monkeys with other mam-
tory cortex, whereas the inferior part of the temporal mals, such as cats and dogs, shows again that the main
500
34: FUNCTIONS OF THE NEOCORTEX 501
difference between them with regard to the cerebral Integration of Different Sensory Modalities
cortex is the relative size of the association areas. These Depends on Learning
parts of the cortex are of importance for what we may
loosely call higher mental functions, as we discuss here. The ability to integrate somatosensory and visual infor-
The association areas are not centers for specific mation and to use visual information to guide volun-
mental faculties, however. First, several areasoften tary movements is not inborn but learned in infancy
widely separatedparticipate in one task or function, and early childhood. Persons who were born blind but
and, further, one area participates in more than one gained their vision back as young adults do not manage
function. This is witnessed by the high degree of diver- to coordinate the visual information with the other
gence and convergence of the connections of the asso- senses and therefore cannot use the new sense. They
ciation areas, as discussed in the preceding text. Second, usually continue to use tactile sensation to see objects,
the operations of the association areas cannot be under- and, in fact, the visual information can be more confus-
stood if considered in isolation; the intimate connec- ing than helpful (this is described by Oliver Sacks in An
tions between the association areas and subcortical cell Anthropologist on Mars 1995).
groups, such as the thalamus, the basal ganglia, the Studies by Hyvrinen (1982) and coworkers exem-
amygdala, and the hippocampus, are essential for their plify how meaningful use of the systems is necessary for
normal functioning. sensory integration to take place during early develop-
Measurements of regional cerebral blood flow and ment. He studied how the properties of single cells in
metabolism during the performance of various cogni- the parietal cortex change during the phase in which an
tive tasks indicate that large parts of the cortex partici- infant monkey learns to combine visual and somatosen-
pate in all higher mental functions. When a person is sory information. Monkeys were prevented from seeing
asked to imagine that she is walking from one place to from birth (by suturing the eyelids) until they were
another in a city she knows, the activity increases in the between 6 months and 1 year old. At that time, few
extrastriate visual areas, in the posterior parietal cor- cells in area 7 responded to visual stimuli, in contrast to
tex, in parts of the temporal lobe, and in several pre- the normal situation at that age. An abnormally large
frontal areas. Solving a mathematical problem activates fraction of the cells were activated by passive soma-
many of the same cortical areas but with certain differ- tosensory stimuli and by active movements. Most strik-
ences, and a verbal task activates multiple areas that ing was the almost total absence of cells that could be
partly coincide with and partly differ from those acti- activated by both somatosensory and visual stimuli.
vated in the spatial and the mathematical tasks. Even 2 years after reestablishment of normal vision, the
In Chapter 16, we discussed the cortical substrate of single-cell properties of area 7 remained virtually unal-
visual imagery (under Consciousness and Visual tered, with very few cells responding to visual stimuli.
Experience). Properties of cells of the extrastriate cortex (area 19)
were also altered in the visually deprived monkeys; for
example, some cells were activated by somatosensory
Cognition and Cognitive Functions
stimuli (which never occurred in normal monkeys), and
The word cognition stems from the Latin word cognitio, there were fewer than normal visually driven cells.
meaning acknowledge, come to know. According Behaviorally, the monkeys were blind after opening of
to the Encyclopedia Britannica, cognition includes the eyes, and no improvement occurred during the next
every mental process that can be described as an expe- month. They bumped into obstacles, fell off tables, and
rience of knowing as distinguished from an experience were unable to retrieve food by sight alone. Threatening
of feeling or of willing. It includes, in short, all pro- faces did not frighten them, in contrast to normal mon-
cesses of consciousness by which knowledge is built keys at the same age. One monkey that was observed
up, including perceiving, recognizing, conceiving, and for 3 years improved to some extent, but it never
reasoning. Among neuroscientists today, the word regained the full use of vision. Brain-imaging studies of
is often used more broadly to include the affective humans born blind or deaf also indicate that consider-
aspects of higher mental functions. For example, the able reorganization takes place, as compared with nor-
scholarly book The New Cognitive Neurosciences mal persons. For example, in persons who have been
(2000) edited by Michael Gazzaniga deals not only blind since birth, the visual cortex is activated by soma-
with consciousness, language, memory, attention, and tosensory stimuli during Braille reading.
similar phenomena but also with emotions. This pre- In conclusion, the data indicate that the functional
sumably reflects the realization that there is no sharp properties of neurons in the association areas, and thus
distinction between brain structures that govern ratio- the capacity of the areas to contribute to certain tasks,
nal thought and actions on the one hand and those are determined to a large extent in early childhood.
that underlie emotions and subconscious drives on Further, there is only a limited possibility of regaining
the other. the proper function of these regions at a later stage
(see Chapter 9, under Sensitive (Critical) Periods). image and self-awareness are typical of lesions in the
The experiments also show that when one kind of sen- posterior parietal cortex (see later).
sory information is lacking during an early stage of There are numerous forms of apraxia (about 30 are
development, other sensory modalities take over parts listed by Petreska and coworkers in a comprehensive
of the cortex not normally used for processing that kind review). For example, ideational apraxia is used when
of sensory information. This has been shown also after it is not the execution of movements that is impaired
early lesions of the auditory system. (e.g., the use of a toothbrush) but the objects are used
inappropriately (e.g., to eat with the toothbrush).
Ideomotor apraxia is characterized by impaired execu-
Lesions of the Association Areas:
tion of a movement rather than the conceptualization
Agnosia and Apraxia
of its purpose. Basically, apraxia seems to . . . result
Lesions of association areas typically disturb higher- from a specific alteration in the ability to mentally
level aspects of sensory and motor functions. Agnosia is evoke actions, or to use stored motor representations
usually defined as the lack of ability to recognize objects for forming mental images of actions (Petreska et al.
(when not due to reduced sensation or dementia). 2007, p. 64). Although apraxia is most frequently
Apraxia is used similarly about the loss of the ability to observed after parietal or frontal lesions, lesions in
do certain, formerly well-known skilled actions (such other parts of the cortex and even subcortical ones may
as dressing, using household tools, copy a drawing, produce apraxia too.
etc.). There is no clear-cut distinction between these If in the term agnosia we include the inability to
two categories of symptoms, however. Loss of the abil- recognize complex sounds (like music, spoken words,
ity to copy a drawingcalled constructional apraxia and laughter), the distinction with speech disturbances
for example, may be due to the patient not being able to after brain damage (aphasia) becomes blurred. Further,
perceive more than a small piece of the drawing at a there are elements of apraxia in aphasia when it includes
time. Thus, she is not able mentally to put several pieces (as often happens) the inability to write (agraphia).
together. Patients with lesions of the association areas often have
Agnosia or apraxia seldom occurs as the only symp- symptoms belonging to several categories mentioned
tom, however, and even less frequent are cases with abovethat is, elements of aphasia, agnosia, and
isolated subcategories. Such cases are nevertheless of apraxia. This can only partly be explained by the fact
great theoretical interest because they shed light on how that many lesions are large and affect several special-
the brain works to solve specific tasks. Depending on ized regions. It also reflects that, although they are ana-
their site and size, cortical lesions can produce a wide tomically separated, association areas are extensively
specter of difficulties with perception. This concerns interconnected and their normal functioning requires
not only objects (strictly defined), but also all aspects of that they cooperate.
higher processing of sensory information. The word
agnosia is therefore used more widely than the defi-
Parietal Association Areas
nition may suggest. For example, we use the term visual
agnosia for loss of the ability to recognize objects and Usually areas 5 and 7located in the upper and lower
persons by sight, whereas tactile agnosia means loss of parietal lobules, respectivelyare considered to consti-
the ability to recognize objects by touch. tute the parietal association cortex (Fig. 34.1; see
Visual agnosia is the most common kind and has Fig. 33.4). The term posterior parietal cortex is also
been studied the most. It may appear in several varieties, used of this region. Both areas 5 and 7 can be further
each with a specific name. For example, prosopagnosia subdivided into parts differing in connections and func-
1
means inability to recognize familiar faces; autotopag- tional properties. These areas are intercalated between
nosia is inability to recognize ones own body parts; the visual cortical areas in the occipital lobe and the
simultanagnosia is the inability to perceive more than somatosensory cortex in the anterior parietal cortex.
one object at a time, and so forth. Inability to recognize Functionally, as one might expect from this location,
letters, alexia, is regarded by some as a special kind of areas 5 and 7 process and integrate somatosensory and
agnosia. To some extent, the different kinds of agnosia visual information. From these areas, signals are con-
can be attributed to lesions of specific parts of the cor- veyed to premotor and motor areas (Fig. 34.1), explain-
tex. For example, several kinds of visual agnosia are ing why a parietofrontal network is activated during
associated with lesions of specific parts of extrastriate
areas (see Chapter 16, under Further Processing of 1 There is some disagreement in the literature with regard to the parcellation
Sensory Information outside the Striate Area). Tactile of the posterior parietal cortex in humans. Brodmann (Fig. 33.3) placed areas
agnosia has been described after lesions at the parieto- 5 and 7 in the superior parietal lobule, whereas the inferior lobule contained
areas 39 and 40. Others, however, describe area 5 as located in the superior
temporal junction (see Chapter 14, under Lesions of parietal lobule and area 7 in the inferiorthat is, corresponding to the situation
the Somatosensory Areas). Disturbances of the body in monkeys.
Supplementary Posterior Grasping Reaching
motor area (SMA) SI Saccadic eye
parietal cortex Intraparietal
Prefrontal movements
sulcus
cortex 5 Central
Extrastriatal Pursuit eye
sulcus
7 cortex movements
Premotor
area (PMA)
Polymodal
Auditory association area
cortex gure 34.2 Subregions within the posterior parietal cortex with
relation to planning of specic kinds of movement. (Based on
gure 34.1 Association connections of the posterior parietal cortex Andersen and Buneo 2002.)
(monkey). Connections with the limbic cortical areas are not shown
(see Fig. 33.11). Visual and somatosensory information converge in
area 7. Connections are reciprocal.
most voluntary movements. The posterior parietal cor- parts are most affected. Some of the symptoms can be
tical areas also have ample connections (both ways) summarized as difficulties with the transformation of
with the cingulate gyrus and the prefrontal cortex. sensory stimuli into adequate motor actions. This can
These connections are assumed to mediate the influence probably be explained by lack of parietal influence on
of emotions, attention, and motivation on behavior the premotor areas. The understanding of the meaning
produced by somatosensory and visual stimuli. of sensory stimuli is seriously impaired (but usually not
Experiments with recording of single-cell activity in the mere recognition of a stimulus). This agnosia con-
area 5 of the monkey indicate that this area is essential for cerns especially the recognition of the form and spatial
the proper use of somatosensory information, for goal- position of objects. A typical symptom after right-sided
directed voluntary movements, and for the manipulation lesions is a tendency to neglect the opposite side of the
of objects. This fits well with the symptoms that arise in body and the visual stimuli from the opposite side.
humans after damage to the posterior parietal cortex, as Patients may suffer from apraxiathat is, they are
discussed next. Single-cell recordings indicate that area 7 unable to use well-known tools and objects. They may
has an important role in the integration of visual and further have problems with visually guided movements
somatosensory stimuli, which is essential for the coordi- (such as stretching out the arm to obtain an object).
nation of the eye and the handthat is, for visual guid- Even though the symptoms mentioned here are most
ance of movements. Area 7 is also involved in the control often seen after damage of the posterior parietal cortex,
of eye movements. Studies in monkeys suggest that cer- most of them have been described after lesions in other
tain subregions of the posterior parietal cortex are spe- parts of the brain, too, especially of the prefrontal cor-
cialized for reaching movements, grasp, saccades, and tex, the thalamus, and the basal ganglia, all of which
smooth-pursuit eye movements (Fig. 34.2). It further have connections with the parietal cortex. These struc-
appears that activity in these subregions is closely linked tures take part in a distributed network responsible for,
2
with the intention to move that is, the posterior pari- among other functions, the control of visually guided
etal cortex contains a map of intentions. behavior and spatial orientation.
Lesions of the posterior parietal cortex in humans
can cause different symptoms, depending on which
Properties of Single Neurons in the Posterior
Parietal Cortex
2 Stimulation of parietal and premotor cortical areas in awake patients under- Studies of monkeys with permanently implanted elec-
going surgery corroborates the importance of the parietal cortex for movement trodes have demonstrated a wide repertoire of proper-
intention and awareness of own movements. Stimulation of the Brodmanns
areas 7, 39, and 40 (Fig. 34.4) provoked an intention to move, and with increas- ties among neurons in areas 5 and 7. In general,
ing stimulus strength, the patients reported that they had actually performed the a task-related increase in firing frequency occurs only
movements (although no movement occurred). Stimulation of the premotor cor- when a stimulus is relevant and the attention of the
tex, on the other hand, produced overt movements but the patients were not
aware of them. Thus, Conscious intention and motor awareness arise from animal is directed toward the stimulus. Thus, many
increased parietal activity before movement execution. (Desmurget et al. 2009). neurons are virtually impossible to activate when the
animal is drowsy and inattentive. Some cells respond to This symptom occurs most often after damage to the
stimulation of proprioceptors, but their response is right parietal cortex, in cases of unilateral lesions. The
much more vigorous when a movement (stimulating use of tools is also difficult or impossible: for example,
the proprioceptors) is self-initiated by the monkey than the patient no longer knows how to use a hammer
when the joint is passively manipulated by the exam- (apraxia).
iner. In area 5, many neurons change their firing fre- Unilateral lesions of the right parietal lobe typically
quency in relation to manipulatory hand movements. produce negligenceneglectof the opposite body
Other neurons increase their firing in relation to reach- half and visual space. Such a patient behaves as if the
ing movements, but only when the hand is moved left part of his body does not exist. He dresses only the
toward an object the monkey wants to obtain (such as right side, shaves only the right half of the face, and so
an orange). The increase of firing in such neurons starts forth. He may deny that the left leg belongs to him and
at the time the animal discovers the objectthat is, claim that it belongs to the person in the adjacent bed,
before the arm movement startsand is therefore not a for example. A similar symptom is denial of the disease
result of proprioceptive stimulation. The American and the functional loss, called anosognosia. The patient
neurophysiologist Vernon B. Mountcastle, who first may deny that the limb is paralytic or that he is blind.
described such neurons, suggested that they might func- Thus, certain aspects of body knowledge no longer exist
tion as command neurons for the target-directed explo- in the mind of the patient, but the loss is not consciously
ration of our immediate surrounding extrapersonal perceived. When drawing a face, for example, the right
space. Such neurons appear to respond to the coinci- side is drawn normally, whereas the left side is vague or
dence of two events: a sensory stimulus (e.g., the sight not included in the drawing.
of an orange) and a signal that depends on motivation A peculiar constellation of symptoms, the Gerstmann
(whether the monkey is hungry and wants the orange; syndrome, can occur after lesions of the parietal lobe at
see Fig. 4.10). the transition to the temporal lobe (usually of the left
hemisphere). The symptoms are as follows: finger agno-
sia (the patient cannot recognize and distinguish the
More about Symptoms after Lesions of the Posterior
various fingers on her own or other peoples hands),
Parietal Cortex
agraphia (inability to write), sometimes alexia (inability
The most marked symptom produced by bilateral pari- to read), rightleft confusion, and, finally, dyscalculia
etal lesions is the inability to grasp and to manipulate (reduced ability to perform simple calculations, espe-
objects. Thus, the patient may be unable to move the cially to distinguish categories of numbers such as tens,
hand toward an object that is clearly seen, even though hundreds, and so forth). The most distinctive feature of
there are no pareses and no visual defects. Movements the syndrome is the finger agnosia, which can occur in
that do not require visual guidancesuch as buttoning, isolation. That finger agnosia can be the only symptom
bringing an object to the mouth, and so forthare of a parietal lobe lesion indicates that a disproportion-
performed normally. When the patient is asked to pour ally large part of the human parietal cortex is devoted
water from a bottle into a glass, he pours the water to the hand. Thus, the hand has a unique role as an
outside the glass over and over again, even though he exploratory sense organ and as a tool, and, further, it
can see clearly both the bottle and the glass. Such has a special place in our inner, mental, body image.
patients also have severe difficulties with the appraisal The British neurologist M. Critchley (1953, p. 210)
of distances and the size of objects. Further, to fix the expressed it as follows: The hand is largely the organ
gaze becomes difficult, especially to direct the gaze of the parietal lobe.
toward a point in the periphery of the visual field. The
identification of objects is difficult, because of the
Frontal Association Areas
inability to attend to more than one detail at a time
(such as seeing a cigarette but not the person who In this context we use the term association cortex
smokes it). This may be a fundamental defect after pari- only about the prefrontal cortexthat is, the parts of
etal lobe lesions, perhaps also explaining the difficulties the frontal lobe in front of areas 6 (premotor area
mentioned earlier with pouring water into a glass (the [PMA], supplementary motor area [SMA]) and 8 (the
patient is unable to locate in space the bottle and the frontal eye field) (Fig. 34.3; see Fig. 33.4). The prefron-
glass at the same time). tal cortex consists of several cytoarchitectonic areas,
Patients with parietal lobe lesions typically have each with a specific set of connections. Together, the
difficulties with drawing an object or a scene; again the prefrontal areas receive strong afferent connections
inability to perceive more than one feature at a time is from areas in the occipital, parietal, and temporal lobes
the probable basic defect. The parts of an object are and, in addition, from the cingulate gyrus (Fig. 34.3).
drawn separately, without the proper spatial relations, or Thalamic afferents come from the mediodorsal nucleus,
the drawing gives an extremely simplified representation. MD (see Fig. 33.8), which, in turn, receives afferents
Supplementary Posterior parietal
motor area (SMA) Central
cortex (area 7) s
sulcus
Prefrontal
cortex Extrastriatal Dorsolateral (DLPFC):
cortex Selecting, manipulating, and
monitoring the contents of
working memory
Anterior (APFC):
Selecting processes,
goals, and subgoals
Ventrolateral (VLPFC):
Premotor Updating and main-
area (PMA)
Inferotemporal taining the contents
cortex (visual of working memory
Auditory association areas) Orbitofrontal (OPFC):
association cortex Recognition of emotion
gure 34.3 Association connections of the prefrontal cortex (monkey).

Note the convergence of all kinds of processed sensory information gure 34.4 Some functional specializations within the prefrontal
and the connections with PMA and SMA. Connections with limbic cortex. Regions that appear to be related to different aspects of mem-
cortical areas are not shown. ory, as judged from functional neuroimaging studies (PET and fMRI).
The orbitofrontal cortex is activated in association with explicit iden-
tication of emotional facial expressions. (Based on Fletcher and
Henson 2001, and Adolphs 2002.)
from the amygdala and the ventral pallidum (among prefrontal cortex. Probably, the prefrontal cortex tells
other places). In sum, the prefrontal cortex appears to the hippocampal region about the emotional coloring
receive information about all sensory modalities and and the context of information that is transmitted to
also about the motivational and emotional state of the the hippocampus from sensory areas.
individual. Learning of rules by association appears to be a
The prefrontal cortex sends efferents back to most of central task of the prefrontal cortex. This may be per-
the areas from which it receives afferents, among them formed by neurons that associate behaviorally relevant
the SMA and the PMA. In addition, many prefrontal but otherwise dissimilar bits of informationsuch as
efferents reach the caudate nucleus of the striatum (see that a red traffic light means stop. Appropriate behav-
Fig. 13.6). Finally, some efferents reach the amygdala ior requires that we are able to learn such rules, but
and the hypothalamus. equally important is that we can replace them quickly
Animal experiments, observations in brain-damaged with new ones. Both faculties suffer after damage to the
humans, and brain imaging in normal persons all give a prefrontal cortex.
fairly consistent picture of the major tasks of the pre- In conclusion, the prefrontal cortex is of crucial
frontal cortex. Figure 34.4 shows some tasks associated importance for our ability to organize our own lives
with particular prefrontal subdivisions. The prefrontal and to function socially. Indeed, the tasks mentioned
cortex is obviously of crucial importance for planning previously, such as planning and choice of behavior,
and initiation of goal-directed behavior. More specifi- choosing between signals with different emotional col-
cally, the prefrontal cortex is important for attention, oring, suppression of unwanted behavior, and so forth,
for selection of a specific behavior among several possi- are indispensable for social adaptation. Another impor-
ble, and for suppression of unwanted behavior. With tant factor in social functioning is empathy,3 which also
regard to selection, the prefrontal cortex cooperates seems to depend on the integrity of the prefrontal cor-
with the basal ganglia, as discussed in Chapter 23, under tex. However, the prefrontal cortex is not the only part
Functions of the Basal Ganglia. Further, the prefrontal of the cortex showing empathy-related activity. It
cortex is important for certain aspects of memory appears that empathy activates the same network that
both for working memory and for the long-term establish- is activated by the person experiencing the painful or
ment of memory traces. Working memory enables us to
retain a stimulus long enough for its evaluation and link-
ing with ongoing processes and memory. We discussed 3 Empathy is used with somewhat different meanings. Hein and Singer (2008)
refer to empathy as an affective state, caused by sharing the emotions and
in Chapter 32 that medial parts of the temporal lobe, sensory states of another person. They distinguish empathy from sympathy,
including the hippocampus, are necessary for declarative which they describe as emphatic concern or compassion. By emphasizing that
memory. Functional magnetic resonance imaging (fMRI) empathy is an affective state, they also distinguish it from the understanding of
other persons beliefs, intentions, and desires, which derives from reasoning
studies indicate, however, that we remember words (i.e., cognitively). Indeed, understanding another persons intentions is not the
or pictures only if their presentation also activates the same as sharing them.
distressing situation. The exact distribution of activity response given by the examiner to the first attempts at
would therefore vary with the specifics of the emotion sorting the cards. The rules can be changed without
experienced by the suffering person. warning. Normal persons understand fairly quickly
that the rule has been changed and alter their responses
accordingly, whereas patients with prefrontal lesions
Symptoms after Prefrontal Lesions
continue sorting in accordance with the first rule,
The prefrontal cortex consists of several subregions, in spite of repeated warnings that they are making
which differ with regard to their connections and func- mistakes.
tional properties. The symptoms of lesions that occur Emotional and personality changes after frontal lobe
in this area in humans are correspondingly varied, lesions are most common when the lesion includes the
and, further, the individual differences are fairly large orbitofrontal parts. Such symptoms are difficult to
even after seemingly identically placed lesions. In gen- evaluate, and the premorbid personality of the patients
eral, the symptoms are compatible with the functions appears to play a decisive role. Nevertheless, a general
discussed earlier. tendency is to become less emotional and to show
Prefrontal lesions typically produce changes of mood reduced emotional reactions to events. They also have
and personality, distinguishing them from lesions of difficulties in extracting the salient features from a com-
other parts of the cortex. Commonly, large lesions pro- plex situation, making their responses unpredictable
duce apathy, indifference, and emotional leveling-off. and often inappropriate. A test designed for such symp-
The patient appears to be uncritical compared with toms uses drawings of complex situations, in part with
before the damage. For example, he may behave in a a dramatic content, such as a man who has fallen
complacent and boastful manner, which he would never through the ice on a lake and is in danger of drowning.
have done before. The ability to alter the behavior on Patients with frontal lesions usually attend only to
the basis of experience from previous actions appears details, saying, for example, Since there is a sign say-
to be reduced. Clear-cut symptoms occur usually only ing Careful! on the beach, there may be a high-voltage
after bilateral damage to the prefrontal cortex. cable nearby. This kind of reduction results in inabil-
Occasionally, however, the first signs of a frontal-lobe ity to foresee the consequences of ones own actions
tumor are changes of behavior and personality. and poor insight into other peoples circumstances.
This leads to poor social adaptation, with isolation as
the final result.
More about Symptoms after Lesions of the
The reduced capacity to retain inner conceptions is
Prefrontal Cortex
most likely the reason such patients have increased
A striking defect after bilateral lesions of the dorsolateral distractibility, with reduced ability to perform tasks
prefrontal cortex (DLPFC) is the lack of the so-called that require continuous activity and attention. Motor
delayed response. A monkey sees that food is put into hyperactivity, which can be a symptom, may perhaps
one of two bowls. Then the sight of the bowls is blocked result from the increased distractibility. Thus, in mon-
for up to 10 min before the monkey is allowed to choose keys with prefrontal lesions, the hyperactivity disap-
one of the two. In contrast to normal monkeys, the pears when they are placed in an environment with
lesioned ones do not remember which bowl contained few stimuli.
the food (even though they do not show reduced per- In humans with frontal lobe tumors (e.g., a glioma or
formance in other more complicated memory tests). a metastasis from a malignant tumor elsewhere), a
The dorsolateral parts of the prefrontal cortex thus depressive disorder has been observed, but this may
appear to be necessary for the ability to form and retain rather be a condition of de-emotionalization and social
an inner conception of the existence of an object in time isolation.
and space when the object is no longer seen. Interestingly,
humans manage a similar test first at the age of about 1
The Temporal Association Cortex
year. Before that age, everything that is not seen or felt
is presumably nonexistent for the infant. A unitary functional role is even less evident for the
A characteristic symptom in humans with prefrontal temporal association areas than for those in the parietal
lesions is the inability to alter the response when the and frontal lobes. Apart from the auditory cortex (areas
stimulus changes; they continue to make the same 41 and 42) (see Fig. 17.11) and the phylogenetically
response even though it is no longer adequate. This old parts at the medial aspect (Fig. 31.1), the temporal
phenomenon is called perseveration. The Wisconsin lobe consists largely of Brodmanns areas 20, 21, and
card sort test is often used to reveal such a defect. The 22, which here are considered the association areas
person is asked to sort cards in accordance with certain (Fig. 34.4).
general rules, such as color, number, shape, and so The cortex of the superior temporal gyrus is charac-
forth. The correct rule to be applied is indicated by the terized by its connections with the auditory cortex,
whereas the inferior part of the temporal lobethe
Symptoms after Lesions of the Temporal Cortex
inferotemporal cortexis dominated by processed
visual information from the extrastriate visual areas. In Bilateral damage of the temporal lobes produces a syn-
addition, there are strong connections with the hip- drome dominated by pronounced amnesia.4 The amne-
pocampal formation (through the entorhinal area) and sia can be ascribed largely to the destruction of the
the amygdala. Electrical stimulation of the temporal hippocampal formation and neighboring areas in the
association cortex in humans evokes recall of memories parahippocampal gyrus. In addition, certain emotional
of past events or the experience of dreamlike sequences changes are presumably caused by the concomitant
of imagined events (such observations were first made destruction of the amygdala located in the tip of the
by the Canadian neurosurgeon Wilder Penfield, who temporal lobe. These aspects are discussed in Chapter 31.
stimulated the temporal lobe and other parts of the cor- In addition, the patients become very distractible: they
tex in patients in whom the cortex was exposed under have difficulty maintaining their attention on a certain
local anesthesia for therapeutic reasons). Finally, long stimulus or task. Finally, psychic blindness or visual
association fibers interconnect the temporal association agnosia is a typical symptom of temporal lobe lesions
areas with the prefrontal cortex (Fig. 34.3). that affect the inferotemporal parts. The patient is
The inferotemporal cortex is important especially for unable to recognize objects and persons she sees, even
the interpretation of complex visual stimuli, as judged though her vision is normal. As for other association
from experiments in monkeys. Thus bilateral removal areas, it is the interpretation of sensory information
of these regions makes the monkeys unable to recognize that is deficient, not the sensory experience as such.
and distinguish complex visual patterns. Information about size and shape of objects may never-
These and other observations led to the conclusion theless be available to the posterior parietal cortex to be
that the inferotemporal cortex is of special importance used in movement control, as discussed in Chapter 16,
for the categorization of visual stimuli. In monkeys, under Consciousness and Visual Experience.
some neurons of the inferotemporal cortex respond
only when the monkey sees, for example, a face or a
The Insula
hand. Some neurons respond preferentially to one
particular face, whereas other neurons respond to any The insula, sometimes called the fifth cerebral lobe, is
face. A neuron that responds briskly when the monkey mentioned in several chapters. This is because the
is shown a drawing of a face may stop firing when insula, as evident from positron emission tomography
important features are removed, such as the mouth (PET) and fMRI studies, participates in a wide range of
or the eyes. Whether monkeys and humanshighly cortical networks. Thus, activity changes in the insula
dependent on the ability to recognize faces and inter- occur in relation to somatic and visceral sensory pro-
pret facial expressionshave developed a separate sys- cesses, emotional regulation, and aspects of bodily
tem for face recognition is not settled. Selective loss of awareness. This part of the neocortex is hidden at the
face recognitionprosopagnosiasometimes occurs bottom of the lateral fissure (see Figs. 6.29, 6.30, 14.9,
after lesions of the temporal lobe and would seem to and 31.9), and consists of several cytoarchitectonic
suggest the existence of a separate face system. subdivisions. Anatomically, the insula is characterized
Further, fMRI studies show that activation in the fusi- by receiving all kinds of sensory information and by its
form gyrus in the inferotemporal cortex is associated extensive corticocortical connections with major parts
with face recognition in humans (see Fig. 16.26). Other of the cortex. Further, there are ample connections
data, however, are more compatible with a general among the subdivisions of the insula. It resides at the
network for object identification that is used also for junction of the frontal, parietal and temporal lobes and
face recognition. Thus, objects other than faces can has reciprocal connections with all three. This concerns,
activate the fusiform gyrus, and, conversely, face recog- for example, the orbitofrontal cortex, the cingulate
nition is associated with activation of several sites out- gyrus, the parahippocampal gyrus, the temporal pole,
side the fusiform gyrus. Because facial recognition is so the superior temporal sulcus, premotor areas, SII, and
important for social interactions and is used intensively the posterior parietal cortexthat is, regions involved
from birth, presumably a larger proportion of neurons in a wide specter of behaviors and mental processes.
in temporal association areas become specialized for
faces than for identification of other objects.
The medial temporal lobe and its importance for 4 The constellation of symptoms that occur after bilateral destruction of the
temporal lobes is named after the two American neurosurgeons Klver and
learning and declarative memory are discussed in Bucy (1937) who rst described it in monkeys. Besides amnesia, the animals
Chapter 32. In addition, lateral parts of the temporal lack emotional responses and aggressive behavior (increased tameness), and
lobe is necessary for semantic memorythat is, knowl- they withdraw from social contact. Furthermore, the syndrome includes
visual agnosia, a tendency to examine all objects by mouth, a tendency to pay
edge about facts, meaning of words, objects, and so attention to all visual stimuli, an irresistible urge to touch everything, and
forth, which was acquired some time ago. hypersexuality.
The insula receives afferents from several thalamic nuclei picture must furthermore be put into a meaningful
5
(Ventral anterior, Ventral posteromedial, Centromedian, context to form the basis for appropriate actions.
VPM, CM, and some other nuclei). The insula also has Imagine, for example, the continuous stream of chang-
reciprocal connections with the amygdala. ing information that must be evaluated and acted upon
We discuss the insula in Chapter 14 because it is when driving a car in heavy traffic. No area appears to
among the cortical regions activated by noxious stimuli receive all necessary information. Rather, it seems likely
and is an essential part of the network responsible for that neuronal groups in many parts of the cerebral cor-
the experience of pain. Further, the anterior insula is tex are interconnected in task-specific networks. The
activated in conjunction with strong emotions (espe- vast number of association fibers must obviously be
cially disgust) and is presumably a part of a network for essential in this respect. There is now much evidence
regulation of affect. that synchronization of activity in large-scale networks
The insula receives not only sensory signals from may be the substrate for the binding together of related
somatic structures, but is consistently activated both by pieces of informationand thus for our conscious
nonpainful and painful enteroceptive stimuli. For experience of our environment and ourselves. It should
example, nonpainful distension of hollow organs such be emphasized that while the anatomic connectivity
as the stomach and the esophagus activated the insula forms the hardwiring of the networks, their func-
associated with the subjective feeling of fullness. tioning depends on dynamic, moment-to-moment
Further, the awareness of ones own heartbeats is asso- fluctuations in synchronized activity. Presumably,
ciated with activation of the insula. Indeed, the insula engagement of specific networks shifts in the time scale
may thus play a particular role in our awareness of the of milliseconds. For example, we know from everyday
state of our internal organs. However, its role does not experience how our attention shifts instantaneously.
seem to be limited to monitoring the internal organs Another example concerns viewing of ambiguous pic-
and evoking subjective feelings referred to them. Thus, tures; the experience (e.g., duck or rabbit) changes with
the awareness of voluntary movements, and especially no time delay in spite of unchanged sensory input.
the feeling of body ownership, involves a network that
probably includes the insula (see Chapter 18). The con-
The Default-Mode Network
tribution of the insula in this respect presumably
depends on its integration of proprioceptive, vestibular, Among the cortical networks so far identified, the
and motor signals. so-called default-mode network seems to have a special
Finally, the anterior part of the insula receives olfac- position. It is characterized by consistently decreased
tory and gustatory signals and presumably contributes activity during goal-directed tasks, while it is active
to the integration of these modalities, and their further when the persons attention is not directed to any spe-
integration with other enteroceptive signals. cific task. The network comprises lateral parts of the
parietal cortex and regions on the medial aspect of the
hemisphere (posterior cingulate gyrus and adjoining
Task-Specic Networks Integrate and
posterior regions, and parts of the medial prefrontal
Analyze Information
cortex). The activity of the default-mode network is
The brain receives innumerable pieces of information, thought to be related to introspection. In support
which, to a large extent are treated in separate systems. of this assumption, an fMRI study showed increased
For example, separate neuronal populations encode activity in the default-mode network when the subject
different features of objects, such as color, form, move- contemplated a moral dilemma (requiring minimal cog-
ment, surface texture, heaviness, and so forth. With nitive engagement) whereas a color-word interference
regard to representation of space, the brain appears to task produced deactivation (Harrison et al. 2008).
possess several maps. Yet, we experience ourselves Nevertheless, the moral dilemma situation produced a
and our surroundings as entities, not as isolated pattern of activity within the network that differed
fragments. How can this paradox be explained? This from the activity in an eyes-closed resting state.
binding problemthat is, how various bits of informa- Disturbances of the default-mode network-activity
tion represented in different parts of the cortex are have been found in fMRI studies of several groups
integrated in the brainis closely linked with the of patients (e.g., chronic pain, attention-deficit/
problem of consciousness (see also Chapter 16, under hyperactivity disorder [ADHD], and mental diseases).
Consciousness and Visual Experience, and Chapter 26,
under Neurobiological Basis of Consciousness). The
brain must possess the ability to integrate, almost instan-
taneously, the activity in numerous specialized neuronal 5 It takes several hundred milliseconds from the arrival of sensory signals at
the cortical level to perception, as rst shown by Libet (1991) with stimulation
groups, each representing different features of, for experiments in humans. This might perhaps reect that in this situation it takes
example, a visual scene. To be useful, the integrated some time to bring the necessary networks in a state of synchronized activity.
For example, chronic pain patients show less than cortex during cognitive tasks. One may ask, however,
normal deactivation related to task performance. whether the symptoms are caused by the abnormal pre-
frontal activity, or whether the low activity is due to
other parts of the brain disturbing the execution of cog-
The Cerebral Cortex and Mental Disease
nitive tasks in the prefrontal cortex? In contrast to some
It is to be expected that diseases affecting complex func- other studies, no signs of abnormal brain asymmetry or
tions such as emotions, personality, sense of reality, cortical structure were found in this twin study. The
and thought would involve alterations in many parts of role of the ventral striatumespecially the nucleus
the brain, as well as in many neurotransmitters. Indeed, accumbensas a target for antipsychotic drugs was
attempts to explain mental illnesses by malfunction in discussed in Chapter 23, under The Ventral Striatum,
a single brain center or of one transmitter have not Psychosis, and Drug Addiction. The fact that the drugs
been successful. commonly used for the treatment of psychotic disor-
Evidence of changed structure, metabolism, or neu- ders are antidopaminergic (primarily D2 antagonists)
rotransmitters has been found most consistently in the gave rise to the hypothesis that schizophrenia is caused
prefrontal cortex and several limbic structures in by disturbances of dopamine actions pre- or postsynap-
patients with mental disorders. However, altered neu- tically. Recent studies have strengthened this theory
ronal activity in the prefrontal cortex (or any other for example, by showing an increased level of dopamine
structure) does not tell us that the primary pathology is receptors in the brains of schizophrenic patients. Other
there. Thus, the alterations in one area may be second- monoamines may be involved in schizophrenia as well,
ary to changed activity in other areas with which it is and PET studies suggest that untreated patients have
connected. Considering the many connections between reduced glutamate concentrations in the prefrontal cor-
the prefrontal cortex and the amygdala, ventral stria- tex. Especially altered N-methyl-D-aspartate (NMDA)-
tum, and hippocampal formation (among others), it receptormediated transmission has been reported in
seems likely that even if the primary pathology should several studies. Needless to say, the interpretation of
arise in only one of these structures, the symptoms such findings is not straightforward.
would be due to malfunctioning of the whole network. Many questions remain about the etiology and
Interestingly, computational models of schizophrenia pathophysiology of schizophrenia. Do defects of neu-
suggest that a basic problem may be that networks rotransmitters and receptors produce structural abnor-
(especially prefrontal ones) are unstable due to a low malities, or are abnormal brain networks the primary
signal-to-noise ratio. The latter may be due to faulty cause? There is evidence to suggest that the primary
dopamine actions, as dopamine normally would stabi- defect in schizophrenia is neurodevelopmental, but a
lize networks by increasing signal-to-noise ratio (by hypothesis of neurodegeneration (based on evidence of
acting on D1 receptors). Presumably, the final symp- slight but progressive loss of brain tissue) also has its
tomatology in a disease such as schizophrenia would proponents. We know that environmental factors must
reflect both the dysfunction caused by neuronal pathol- contribute, although we know little about their nature
ogy and the attempts by the rest of the brain to cope and how they interact with genetic predispositions.
with the disturbed functions. This would be so, regard-
less of whether schizophrenia turns out to be due to
defective receptor genes, a prenatal disturbance of neu- LANGUAGE FUNCTIONS AND SPEECH AREAS OF
ronal migration, or (most likely) a combination of many THE CEREBRAL CORTEX
factors.
Ever since the first accurate description of schizo- Clinical observations in the nineteenth century led to
phrenia, it has been postulated that the disease is caused the identification of two so-called speech areas in the
by alteration of the frontal lobes. This assumption was left hemisphere (Fig. 34.5). The anterior area is named
partly based on similarities between the symptoms in after the French physician Paul Broca, who in 1861
schizophrenia and in cases of frontal lobe damage. described loss of speechaphasiacaused by a lesion
Measurements of regional blood flow lend support to in the left frontal lobe just in front of the motor face
the theory that the prefrontal cortex may be involved in area. The posterior speech area is named after the
some manner. Thus, many schizophrenics have abnor- German neurologist Carl Wernicke, who discovered in
mally low blood flow in the prefrontal cortex at rest, 1874 that one of the clinically observed kinds of apha-
and various tasks that give increased flow in normal sia was associated with a lesion in the posterior part of
people failed to do so in these patients. In homozygous the superior temporal gyrus. Aphasia is defined as loss
twins discordant for schizophrenia, the affected twin (or disturbance) of speech due to a brain lesion. That
was found to have slightly smaller volume of the cere- speech depends almost entirely on only one hemi-
brum and of the hippocampus than the other, and sig- spherein most people, the leftis the most marked
nificantly less activation of the dorsolateral prefrontal and best-known example of lateralization (of function)
Precentral of the cortex participate. This may not be surprising

gyrus Central
Motor face area sulcus since language depends on several different processes,
such as storage of words in short-term memory, phono-
logic (sound) and semantic (meaning) processing in
relation to the lexicon in long-term memory, arrang-
ing words into sentences, and the issuing of commands
to motor areas about sound production. Silent reading
or repetition of words activates primarily the anterior
region (Fig. 34.6). Specific tests for semantic analysis
activate extensive areas in the temporal, prefrontal,
and inferior parietal cortices, including Brocas and
Wernickes areas (primarily in the left hemisphere).
Anterior speech Posterior Tests of phonologic analysis (like choosing matching
area (Broca) speech area
Auditory cortex words by sound similarity) activate partly the same and
(Wernicke)
partly different areas than semantic tests. As for other
gure 34.5 Speech areas of the human brain. Lesions of the anterior complex mental functions, the main tendency is that
speech area (of Broca) produce predominantly motor aphasia, extensive regions of the hemisphere participate in an
whereas lesions of the posterior speech area produce mainly sensory extensive network for language and speech, and that
aphasia. The posterior speech area as shown here comprises parts of
the inferior parietal lobule that were not included in the area described
different tasks activate overlapping regions.
by Wernicke. Long association bers interconnect the two areas, and Different parts of the network for language process-
these connections explain why a lesion between the two speech areas ing were suggested by Shalom and Poeppel (2008,
can produce aphasia (so-called conductance aphasia). Additional p. 125) to specialize as follows: . . . memorizing (learn-
areas of the cerebral cortex are also involved in language processing, ing new and retrieving stored primitives) in the tempo-
as shown with PET and fMRI.
ral lobe, analyzing (accessing subparts of stored items)
in the parietal lobe, and synthesizing (creating combi-
nations of stored representations) in the frontal lobe.
or hemispheric dominance. We return to the topic of Further, there is evidence of a specialization within each
lateralization later. region. For example, in Brocas area (or region), the
What are termed speech areas should, more cor- superior part (closest to the ventral premotor area)
rectly, be termed areas of aphasia, since we know appears to specialize in phonological processing, the
that their destruction produces various disturbances of midregion in syntactic processing, and the inferior part
language functions (aphasia), but we know less of how in semantic processing. A functional subdivision of
these areas contribute to the normal production of lan- Brocas area would agree with anatomic data, since it
guage and speech. Further, what rather broadly is consists of several cytoarchitectonic areas with differ-
referred to as the anterior and posterior speech ent connections.
areas (Fig. 34.5) consist in reality of functionally differ-
ent subregions.
Are There Brain Systems that Are Specic for Language?
fMRI and PET show that various tests of language
functions activate regions corresponding roughly to the A central question is whether language is produced by
areas of Broca and Wernicke, but also that other parts networks specialized for only this function, or by a
H V Visual cortex
Broca
gure 34.6 Activation of Brocas area as

demonstrated with fMRI. An anatomic
(T1-weighted) MRI is produced rst, there-
after color-coded activity data are superim-
posed on the brain image. Activity in the
visual cortex occurs because the test of lan-
guage functions starts with reading of word.
(Courtesy of Dr. S.J. Bakke, Rikshospitalet
Visual cortex University Hospital, Oslo, Norway.)
more general system taking part also in other cognitive together to form meaningful words and sentences.
functions. Although rare, over the years many patients Words that are heard cannot be repeated. In contrast to
have been described with selective loss of language motor aphasia, spontaneous speech is fluent, but sounds
functions without other cognitive defects, and vice are often put together into meaningless words, and
versa. Such observations have been taken to support proper words lack relation to each other (word-
the specificity hypothesis. Still, PET and fMRI data salad). Usually, sensory aphasia is combined with
show considerable overlap among cerebral regions acti- alexiathe inability to read.
vated by language tasks and by other cognitive tasks. In reality, the pure forms of aphasia are very seldom
Further, connectionist-modeling (computer-based mod- encountered; in most patients there is a mixture of
els of neural networks) shows that the multipurpose motor and sensory symptoms, with one or the other
hypothesis is not incompatible with the evidence of dominating. Often there are other symptoms as well,
selective defects from brain-damaged patients. Models since lesions of the hemispheres are rarely confined to
can simulate language learning, such as learning to read the speech areas. Further, similarities between word
words. Although such networks do not have segregated blindness (alexia, dyslexia) and visual agnosia may be
pathways for different functions, partial damage may caused by lesions of the parietal lobe and the inferotem-
produce selective visual or semantic defects (somewhat poral cortex. Alternatively, elementary symptoms of
similar to a child with dyslexia). Such modeling experi- aphasiasuch as agraphia or alexiamay sometimes
ments challenge the commonly held assumption that occur in isolation or in combination with other kinds
the fractionation of behaviour reflects an underlying of symptoms (see Gerstmanns syndrome, described
fractionation of the brain systems that control such previously).
behaviour (Nobre and Plunkett 1997). Thus, a spe- The relationship between specific aphasic symptoms
cific impairment after a brain damage does not mean and the anatomic location of a brain lesion is not
that the brain possess a specific module responsible for absolute. Virtually all forms of aphasia have been
the lost function. described after lesions in unexpected parts of the brain.
Thus, we can only say that the probability of speech
disturbances is highest when the lesion affects one or
Aphasia
both of the areas depicted in Fig. 33.5 (or the asso-
There is an enormous literature dealing with the distur- ciation fibers interconnecting the anterior and posterior
bances of speech and language, and there are numerous speech areas).
classifications of aphasias. Also, there is no lack of
hypotheses for the cause, whereas understanding of the
basic mechanisms underlying language and speech is THE DIVISION OF TASKS BETWEEN THE HEMISPHERES
still limited. This should come as no surprise, however,
considering the complexity of the function in question. The fact that the two hemispheres are connected by
Very schematically, there are two main types of afferent and efferent fiber tracts with the opposite body
aphasia. The simplest type is the so-called motor apha- half is proof that there is a division of tasks between the
sia. This occurs most often after destruction of Brocas hemispheres. We have mentioned speech as a function
area (the anterior speech area). The patient more or less that is largely taken care of by one hemisphere (the left),
completely loses the ability to speak and typically pro- and here we discuss other examples of lateralization of
duces only single words in a sort of telegraphic style. functions. This does not mean, of course, that the two
The few words used may also be applied wrongly. hemispheres are independent units: the commissural
Other names used for this type are nonfluent aphasia connections ensure that information reaching one hemi-
(because the speech becomes stuttering) and expressive sphere also reaches the other and that commands issued
aphasia. The understanding of language is usually pre- to lower parts of the brain also are known to both
served, whereas the production of speech is deficient. hemispheres. Complex functions are usually carried out
Nevertheless, there are no signs of pareses of the mus- by cooperation of the two hemispheres, and, as dis-
cles involved in speech production. Often, motor apha- cussed, lesions of the association areas often have to be
sia is combined with agraphiathe inability to express bilateral to produce clear-cut functional deficits.
language in writing.
In patients with sensory or receptive aphasia, the
Are the Two Hemispheres Anatomically Different?
lesion usually affects more posterior parts of the hemi-
sphere at the junction between the parietal, temporal, Many differences have been reported but most of them
and occipital lobesthat is, in or close to the Wernickes are small and, further, based on small samples. This,
or the posterior speech area (Fig. 33.5). Typically, the together with the large individual variations in brain
comprehension of language is most severely affected. anatomy (e.g. with regard to size of cortical areas
The various elementary sounds are not properly put and total brain size) might explain why many reported
differences have not been confirmed by later studies. solves the task as well as when using the right eye.
In general, there are no anatomic datawith regard to Thus, the left hemisphere also has learned the task. This
neuronal numbers, synaptic densities, size of areas, must be dependent on an effective transmission of visual
and so forththat explain why one hemisphere per- information from one hemisphere to the other, as can
forms certain tasks better than the other (hemispheric be demonstrated by cutting the corpus callosum (and
specializations). the anterior commissure) before the discrimination
The most robust anatomic difference between the left training starts. Then the animal learns the task only
and the right hemisphere in humans concerns the upper with the right hemisphere when the left eye is occluded.
face of the temporal lobe. The temporal plane (planum The transmission of visual information from one hemi-
temporale) in the vicinity of the auditory cortex is sphere to the other in this experiment must depend on
reported to be more extensive on the left than on the commissural connections between the extrastriate and
right side in about 70% of the population (see probably the inferotemporal areas, since the striate area
Chapter 17, under Asymmetrical Organization of the lacks commissural fibers (Fig. 33.13).
6
Auditory Cortex in the Temporal Plane). The differ- Corresponding experiments have shown that tactile
ence appears to be present before birth, and recent and kinesthetic signals are also transferred through the
studies indicate that the lateralization of language func- corpus callosum. A monkey with transsection of the
tions is determined prenatally. It is well known that corpus callosum (and the anterior commissure) is
early brain damage (in infancy, before language has trained to open a box with the right hand only (without
been acquired) has less severe effects on language func- being allowed to see the box). After some training, the
tions than lesions that occur later. Because, obviously, opening is performed swiftly. If the monkey is then pre-
in such early cases of brain damage the right hemisphere vented from using the right hand, the task has to be
takes over the language functions, it was concluded learned over again with the left handno learning had
that language function is not initially lateralized. taken place in the right hemisphere (which controls the
However, a more likely interpretation is that even left hand). A monkey with an intact corpus callosum
though there is an inborn tendency for lateralization of uses both hands with identical dexterity to solve this
speech, at an early stage the right hemisphere has not task, even though only one hand was used during the
been fully occupied by other tasks and therefore can training period.
substitute for the left hemisphere. At later stages, both There is a certain topographic arrangement of the
hemispheres are fully used and specialized for specific commissural fibers within the corpus callosum. As one
tasks and therefore are unable to take over new com- might expect, the posterior parts are necessary for the
plex functions. Incidentally, the capacity of the right transfer of visual information, whereas the anterior and
hemisphere to develop normal language in young chil- middle parts are necessary for transfer of somatosen-
dren favors the view that language is not dependent on sory signals. (See Chapter 26, under Neurobiological
a language-specific, genetically determined network. Basis of Consciousness with a description of a patient
with damage of the middle part of the corpus callosum
and abolished transfer of tactile information.)
Function of the Commissural Connections:
The ample commissural connections make it possible
The Corpus Callosum
for the two hemispheres to specialize and to share tasks
Here we mention a few examples of the significance of between them. Both are not required to be equally good
the commissural connections. When the optic nerve at all tasks. Nevertheless, they keep each other con-
fibers that cross in the optic chiasm are cut (see stantly informed (just as one would expect of hospital
Fig. 16.16), signals from one eye reach only the hemi- specialists sharing the responsibility for one patient).
sphere of the same side. After such an operation, mon- The brain, even though in a sense consisting of two
keys are trained in a visual discrimination task (to anatomic parts, functions as a unit for the whole body
distinguish a triangle and a circle to obtain a fruit and our extrapersonal space. The degree of hemispheric
reward) with a patch that occludes vision in the left eye. specialization or lateralization of functions can be
The learning must depend on processes taking place in studied only after eliminating the callosal transfer of
the right hemisphere, which receives visual information information.
from the right eye. When the monkey has learned the
task with the right eye, the occlusion is reversed.
Cerebral Lateralization and Dominance
Nevertheless, even when using the left eye, the monkey
Data showing that the two hemispheres are different
have received much attention since the early 1970s, and
6 In more than 90% of persons, the language function depends on the left
hemisphere; thus, the relationship between speech lateralization and anatomic many simplistic statements about the functions of the
asymmetry is not absolute. right and the left hemispheres have been put forward.
Recent studies provide a much more complex picture, such questions addressing phenomena in the transition
however. A specialist in the field of cerebral lateraliza- zone between neuroscience, philosophy, and religion.
tion wrote a few years ago: The time has come to put To argue that humans consist of two personalities, one
the brain back together again. Another scientist in each of the hemispheres, is a gross oversimplifica-
launched the expression dichotomania about the urge tion, of course. The normal cooperation and interac-
to equate the many examples of duality in human nature tion between the hemispheres is so intimate that our
with the two halves of the brain (leftright): scientist mental life and behavior are caused by their collective
artist, conscioussubconscious, rationalismmysticism, activities.
masculinefeminine, and so forth. The truth is that both
hemispheres take part in most functions; the differences
Lateralization of Language
concern mainly how efficient they carry out individual
processes, like elements of language functions, emo- When one hemisphere is most important for a certain
tional processing, visual object recognition, and so forth. function, we say that it is dominant for that function,
For example, many studies show that the left hemi- whereas the other hemisphere is recessive. The most
sphere usually is superior with regard to analytical and clear-cut example of such cerebral dominanceor, in
logical thinking as expressed verbally and in numbers, other words, lateralization of functionis speech, as
while the right hemisphere is superior with regard to mentioned above. For most people, even for most left-
spatial abilities, the comprehension of complicated handers, the left hemisphere is responsible for most
patterns, and drawing. aspects of language functions. About 95% of right-
handers have left hemisphere language dominance, while
the corresponding number for left-handers is about 70%
Studies of Split-Brain Patients
(there is obviously not a strong correlation between the
A wealth of information on the topic of hemispheric lateralization of speech and hand preference).7 Several
specializations (lateralization) has been provided by the kinds of investigation have confirmed the lateralization
study of so-called split-brain patientspatients in of language. Studies of split-brain patients are especially
whom the corpus callosum has been transected (this is instructive in this respect. They confirm, among other
done in severe cases of epilepsy, to prevent spread of things, that the right hemisphere is mute in most people
the abnormal discharges from one hemisphere to the (even though it may express single words when strong
other). The American Roger Sperry was awarded the emotions are aroused). When a split-brain patient is
Nobel Prize in 1981 for his pioneering studies of split- asked to identify with the right hand an object that is
brain patients. Even though lateralization is probably not seen, he can easily tell the name of the object, what
most marked in humans, there is much evidence that it it is used for, and so forth. This is because the tactile
also occurs in animals (e.g., the ability to sing depends information comes to the left, speech-dominant hemi-
on cell groups in the left side of the brain in birds). sphere. When the left hand is used for the same test,
Split-brain patients manage well in everyday life, however, the patient is unable to name the object,
mainly because visual information reaches both hemi- because the information reaches only the mute right
spheres (because we move the gaze constantly) and hemisphere. The patient nevertheless shows signs of
there are some bilateral sensory and motor pathways. appropriate emotional reactions to the object. That the
These patients get into trouble, however, if, for exam- right hemisphere understands the nature of the object
ple, somatosensory information is not supplemented is further supported by other experiments in which the
with visual information. The preceding example of the right hemisphere is presented with a picture of, for
commissurotomized monkey and tactile learning is example, a key. Even though the patient cannot say
relevant for split-brain patients, too. In some situations, anything about the object, he nevertheless picks out
conflicts may arise between commands issued from the with the left hand a key among several objects (which
two hemispheres; for example, the left hemisphere may are not seen). Such data show that the right hemisphere
command the right hand to start dressing, whereas the
left hand is ordered to undress.
7 The numbers concerning language dominance come mainly from studies
Studies of split-brain patients raise interesting ques- in which one hemisphere was temporarily anesthetized by injection of
tions, such as whether the two hemispheres have inde- a barbiturate into the internal carotid artery. In general, recent brain-
pendent consciousness and what the relation is between imaging studies agree with these data. One fMRI study found that among
50 right-handed persons, 96% had largely left hemisphere activation when
consciousness and language and between intelligence performing a language task (word finding); 4% had bilateral activation,
and language (see also Chapter 16, under Visual but no one had larger right than left activation. In contrast, 76% of left-
Awareness and Synchronized Network Activity handers had left hemisphere activation with the same test, 14% had bilat-
eral activation, and 10% had right hemisphere activation. Thus, it appears
and Chapter 26, under Neurobiological Basis of that only about 10% of left-handers have right hemisphere dominance for
Consciousness). No simple answers are available to language.
can understand concrete language. It understands both This is supported by PET studies of musicians practic-
speech and writing of this kind but cannot express ing sight-reading (i.e., at the same time reading and
understanding through languageonly through action. playing an unfamiliar score).
As mentioned, the right hemisphere can utter a few
words especially when they are emotionally loaded,
Ear and Visual Field Dominance
while it cannot manage abstract or rare words or gram-
matical analysis. A certain degree of ear dominance exists in most
Not all aspects of language function are localized to people, corresponding to speech lateralizationthat is,
the dominant hemisphere. The modulation and melody the right ear is dominant for most people. This phe-
of the sounds of speech, prosody, appears to largely nomenon can be studied by use of so-called dichotic
depend on the right hemisphere, as witnessed by several listening. Two words are presented at the same time,
clinical reports. Thus, in some patients who suffered a one to each ear. Afterward, most people say that they
right hemisphere stroke, prosody was changed or reduced heard the word presented to the right ear. Visual field
without concomitant aphasia. Brain-imaging studies dominance has been described in studies in which dif-
show activation in the right hemisphere in tests for per- ferent visual stimuli are presented to the two hemi-
ception of prosody, notably in the region corresponding spheres simultaneously. With regard to written words
to the Brocas area and in the superior temporal gyrus and letters, there is a tendency to prefer those presented
(but also some activation of the left hemisphere). in the right visual field (that is, those transferred to the
Patients with loss of prosody may also be unable to left hemisphere). For face recognition, the reverse situa-
judge the emotional aspects of the speech of other tion appears to exist for most people, as can be demon-
persons; for example, they cannot decide whether the strated by the presentation of so-called chimeric
person is sad or happy. Such an intonational agnosia portraits composed of two left halves and two right
may have serious effects on the social life of the patient. halves, respectively. The person is asked which of the
The importance of the prosody illustrates that much of chimeric portraits most resembles the original (authen-
what we regard as verbal communication is, in fact, tic) portrait. Most persons claim that the chimeric por-
nonverbal. trait consisting of two right facial halves most resembles
the original. This is taken to suggest that the right hemi-
sphere dominates in the analysis of faces and other
Lateralization of Music
complex visual patterns. Another indication of this is
With regard to the ability to appreciate and express that when the shape of letters is made sufficiently
music, there is no simple division of labor between ornate, the right hemisphere appears to become neces-
the hemispheres, although it has been assumed that the sary for their interpretation.
right hemisphere is most important. Indeed, that the
perception of a melody depends mainly on the right
Lateralization of Hand Function
hemisphere was supported by a study using the Doppler
technique to measure changes of total blood flow to the With regard to lateralization of hand functions, the
hemispheres during various tasks. The right-sided dom- hemispheric differences are less clear-cut than for lan-
inance was true only for nonmusicians, however: pro- guage. It is not a question of the ability to use the hand,
fessional musicians showed left hemisphere dominance but a matter of preference of one hand for most or all
for the same task that was presented to the nonmusi- tasks. Even though hand preference is inheritable, there
cians. Listening to rhythm activated the left hemisphere are also strong social factors that contribute to the final
most strongly in both groups. Furthermore, left hemi- outcome of hand preferencefor example, in writing.
sphere activation was relatively larger when the person There is most likely a gradual transition with regard to
listened attentively, trying to discriminate musical ele- the strength of hand preference, from those with a
ments, rather than having the music as a background. strong tendency to use the right hand for all tasks if
Imagining a familiar tune was found with PET to acti- possible (writing, drawing, use of tools, eating, and so
vate association areas around the right auditory cortex forth) to those with an equally strong tendency to use
and frontal regions on both sides. The supplementary the left hand. The latter group probably constitutes 2%
motor areawhich is important for rhythmic and to 3% of the total population. Hand preference starts
sequential movementsis activated when imagining to become expressed from the second year of life and is
tunes, perhaps because there is a motor element in music usually finally established at the age of 5 to 6.
imagination.
Amusia most often occurs together with aphasia, but
Lateralization of Emotions
it has also been reported to occur in isolation. This sug-
gests that language and music use largely separate parts Early observations of split-brain patients suggest that
of the cortex, although they appear to lie close together. the right hemisphere is dominant for the expression
of emotions, but further studies show that the right SEX DIFFERENCES AND THE CEREBRAL CORTEX
hemisphere does not dominate all aspects of emotional
behavior. Thus, the two hemispheres appear to be Gender and Cortical Structure
specialized for specific aspects of emotions. We men-
Many studies show that, on the average, men perform
tioned prosody as an example of right hemisphere
better than women on certain spatial tasks (shown most
dominance. Overall, the right hemisphere appears to
convincingly for imaginary rotation of a figure).
be the best at perceiving emotional expressions, whereas
Women, in contrast, excel on tasks that require verbal
both hemispheres are involved in the experience and
fluency, perceptual speed, and some fine-motor skills
expression of emotions. The left hemisphere may be
(many other cognitive differences have been proposed
the best judge of certain kinds of emotional expressions,
but few have been convincingly documented). Many
however. Some data have been interpreted to show
speculative explanations have been offered. From an
that the right hemisphere is dominant as to the experi-
evolutionary point of view, it is now common to explain
ence of strongly negative feelings (and the left as
such sex differences by the living conditions during
to positive feelings). Patients with strokes affecting the
early human history, along with the different roles held
left hemisphere tend to have more depressive reactions
by men and women. Although cognitive sex differences
than patients with corresponding right-sided lesions
thus may have a genetic basis, environmental influences
(the right hemisphere understands the agony of the
interact with genetic predispositions to produce the
left?). Right hemisphere lesions, especially when they
final cognitive make-up of the individual. Nevertheless,
affect the frontal lobe, appear to have a stronger ten-
the average cognitive sex differences are small, and very
dency to produce a somewhat inadequate elevation
much smaller than the variability among individuals of
of mood.
the same sex. As said by the Canadian psychologist
Doreen Kimura (1996, 259): In the larger compara-
Further Examples of Hemispheric Specializations tive context, the similarities between human males and
females far outweigh the differences.
Studies with detailed analyses of specific aspects of
With regard to neuroanatomic sex differences, the
broader categories of cerebral functions reveal that the
most obvious is the difference in brain volume: the
division of labor between right and left is more compli-
brain is on average 10% heavier in men than in women.
cated than is apparent from the first split-brain obser-
Most, but not all, of this difference can be accounted
vations. Sophisticated studies of visual perception show
for by different body weights. The temporal plane
that the right hemisphere is superior to perceive and
(involved in language processing) has been reported to
remember specific characteristics of objects (for exam-
be larger in women than in men. Whether this is caus-
ple, the face of a person), whereas the left is better at
ally related to sex differences in verbal fluency is so far
categories (a face versus other kinds of objects). A dif-
unknown, however. Studies at a more detailed level
ferent picture emerged in a study comparing patients
offer many data but, unfortunately, conflicting results
with lesions in the superior temporal gyrus as to their
make it difficult to draw conclusions. Yet, it seems
ability to identify letters. Those with right-hemisphere
fairly well documented that women have a slightly
lesions had difficulties with identification of a letter
thicker cortex in parts of the parietal and temporal
when it was composed of many small ones, but they
lobes (as studied with MRI). On the other hand, one
easily perceive the small letters. Those with a left-
study reported higher synaptic density in men than in
hemisphere lesion had difficulties with identification of
women. A morphometric study found no difference in
the small letters, but they easily identified the big one.
cortical thickness but that men had on average some-
Thus, the right hemisphere is good at identifying the
what higher cortical neuronal density than women
overall shape, whereas the left is good at seeing the
(117,000 31,000 and 101,000 26,000 per mm ,
2
details. It may seem paradoxical that the left hemi-
respectively). Even if this finding should be confirmed,
sphere is specialized both for identification of broad
the large individual variation within each sex makes
categories and details (and that the right hemisphere is
any inferences about causal relationships doubtful.
specialized for identification of specific properties and
With PET and fMRI sex differences in brain activation
the overall shape). Most likely, however, this reflects
patterns have been looked for. For example, one study
that different principles govern lateralization of visual
found that men and women activated somewhat differ-
and semantic memory. Another lateralization of a spe-
ent parts of the brain when they were trying to find
cific function does not fit with the usual right-left
their way out of a (virtual) labyrinth. Apart from many
dichotomy of functions. Thus, the right hemisphere is
regions activated in both sexes, men activated the left
best at measuring distance (e.g., the distance between a
hippocampus, whereas women activated the right fron-
dot and a line), whereas the left hemisphere excels at
toparietal region. Other studies also point to gender
judging mutual positions (whether the dot is above or
differences in activation patterns but the interpretation
below the line).
of such findings is far from straightforward. It is not to the combination of biologic and environmental
advisable to make firm statements as to the biologic factors.
bases of gender differences on the basis of small statistical In which respects are the brains of men and women
associations. different? Sex differences in the corpus callosum are
very small at best, and can hardly explain the observed
cognitive differences. The neuroanatomic differences
Sex Differences and Lateralization
in the structure of the cerebral cortex lack so far explan-
Cognitive sex differences have been speculatively linked atory power. The most obvious microanatomic differ-
with more or less convincingly demonstrated sex differences between the brains of men and women are found
ences in lateralization and brain structure. Some obser- in the hypothalamus (see Chapter 30, under The
vations suggest, for example, that men have stronger Hypothalamus, Sexual Functions, and Sex Differences).
lateralization of, for example, visuospatial abilities, Although the structural sex differences in the hypothal-
whereas women to a higher degree use both hemi- amus presumably relate mainly to differences in sexual
spheres. (It is not obvious, however, that a strong later- functions, we cannot exclude sex differences also in
alization gives a higher visuospatial ability; the reverse hypothalamic influences on other cell groups, such as
might just as well be the case.) It was then studied the amygdala and the cerebral cortex. Further, we know
whether there might be sex differences in the cross- that receptors for sex hormones are found in many
sectional area of the corpus callosum, which would cor- parts of the brain outside the hypothalamus (e.g., the
relate with differences in lateralization; that is, a corpus amygdala and the prefrontal cortex, just to mention
callosum with relatively few fibers was expected to cor- two regions related to emotions and emotional reac-
relate with a high degree of lateralization. Indeed, some tions). Experiments in rats and monkeys clearly show
studies reported that the corpus callosum is relatively that exposure to male sex hormones during early criti-
larger in cross section in women than in men. These cal phases of development leads to certain behavioral
speculations have not been confirmed by further and characteristics in later life. Indirect evidence suggests
more comprehensive studies, however. First, the that this may be so also in humansfor example,
reported differences as for visuospatial abilities consti- regarding spatial abilities. Further, some cognitive func-
tute merely a few percentages of the individual variations have been shown to vary in the same individual
tions among members of the same sex. Furthermore, with variations in the level of sex hormones (in both
the notion that men have more marked lateralization men and women). Thus, sex differences in distribution
than women cannot be accepted as generally valid. and densities of hormone receptors, in conjunction with
Finally, several studies have not been able to confirm different hormonal makeup, may form the basis for
the sex differences in the size of the corpus callosum. psychological sex differences. The blood level of hor-
They are at best small, whereas the individual varia- mones would then modulate the excitability of specific
tions again are surprisingly large. In fact, an inverse neuronal populations. In addition, subtle differences in
relationship between brain weight and cross-sectional the cerebral wiring patterns and synaptic organizations
area of the corpus callosum has been reported: smaller might contribute to the sex differences, as they would
brains, regardless of sex, would be expected to have contribute to differences among persons of the same
relatively larger corpus callosum. In monkeys the num- sex. These differences might be genetically determined
ber of axons in the corpus callosum varies among indi- or use-dependent, or most likely both.
viduals by a factor of 2. To complicate matters, one
report claimed that the corpus callosum is about 10%
Nature or Nurture?
larger in left-handers (and persons using both hands
equally) than in right-handers. This does not support a The final performance of the brain is a product of
correlation between superior visuospatial abilities, genetic and environmental influences, as discussed in
strong lateralization, and a small corpus callosum. Chapter 9. Environmental challenges induce structural
In conclusion, the available data do not support that and neurochemical adaptations in the nervous system
sex differences in cognitive and other abilities can be expressed through altered behavior. There is now an
explained by differences in lateralization. intense search for genes that influence social behavior.
Such genes would be expected to participate in the
establishment and refinement of the many task-specific
Psychological Differences and Biology
networks discussed in this book. It is striking, however,
Arguably, men and women differ more in other aspects that the search for genes with decisive influence on
of their psychology than cognitionfor example, in human behavior has not been successful. Rather, it appears
aggression and emotional reactions. Some differences that personality as well as cognition and emotions
are expressed very early, including preferred activities. are under the influence of numerous genes, each pro-
Most researchers today would ascribe such differences viding a very small contribution to the final phenotype.
For example, while cognitive abilities (IQ) are among statistical associations to make grand claims about
the most genetically controlled traits (40%80% of the human nature.
variability can be explained by heritage) it has proved In conclusion, all developmentwhether genetically
very hard to find a connection between specific genes determined or notinvolves synaptic changes, and
and IQ. Considering that, presumably, each of the from the time of birth there is a dynamic interplay
many contributing genes is under epigenetic influence, between genes and the environment in the establish-
the number of variables that determine our final behav- ment, maintenance and functional regulation of billions
ior becomes astounding. Indeed, as said by Story Landis of synapses. A genetically determined dispositionfor
and Thomas Insel in an editorial in Science (2008, example, a certain temperamentevokes a certain kind
p. 821): Genes code for proteins, not for behaviors. of response from other people. The response induces
They go on pointing out . . . genomics is not destiny. synaptic and neurochemical changes in the brain as a
Indeed, if genomic sequence determines anything basis for behavior adaptations. To sort out the mutual
behaviorally, it determines diversity. It is important roles of nature and nurture in the formation of a per-
that we be wary about extrapolating from model sons psychology and behavior then becomes virtually
organisms to humans. We must also avoid using small impossible.
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Index
A. See Amyloid -protein Adhesion molecules, 106n1 Amino acid transmitters, 53,
Abdomen, 399, 42122 Adolescence, 133 5758, 59f
Abdominal reex, 323 Adrenal cortex, 454 -aminobutyric acid. See GABA
Abdominal viscera, 421 Adrenal medulla, 118 Amino-methylisoxazole-propionic acid.
Abducens nerve, 85, 406, 407 -adrenergic receptors, 65, 429 See AMPA receptors
Abducens nucleus, 401f Adrenergic receptors, 207 Amnesia, 473, 479
Abulia, 339 pain and, 207 case study, H.M., 47980
Accessory nerve (Eleventh cranial nerve), subgroups, 429 confabulation, 481
72, 397, 398f -adrenergic receptors, 65, 429 Korsakoffs syndrome, 48081
Accessory olfactory bulb, 270 Adrenocorticotropic hormone mammillary body and, 481
Accommodation, 21718, 366 (ACTH), 446, 448, 454, 455 perirhinal cortex, 479
Accommodation reex, 4089, 409f Aerobic capacity, aging brain, 143 temporal lobe damage, 507
Acetylcholine esterase (AchE), 53, 54, Afferent connections, 16f, 373 AMPA/kainate receptors, 59, 493
223, 282, 283, 284f, 329, 330, 431 amygdala, 46265, 464f AMPA receptors (Amino-
AD and, 145 cerebellum, 345 methylisoxazole-propionic acid),
botulinum toxins and, 43 Afferent bers, 18386 52, 53, 60
cerebral cortex, 492 cerebellum, 343 cortical neurons, 491
CNS and, 6263 monoaminergic, 126 Amphetamine, 7071, 338
efferent bers and, 246 Afferent link, 289 narcolepsy, 359
plasticity and, 475 1 afferents, 293n6 Amplitude, 24344
postganglionic neurons, 429 Afterimages, 237 Ampulla, 253
structure of, 63f Age-dependent memory loss, 14142 Ampullar crista, 256f
synthesis, 54, 55f Aging, nervous system and, 13946 Amputation, body image after, 213
visceral efferent neurons, 413 brain shrinkage, 141 Amusia, 514
Acetylcholine receptor blockers, 6364 EEG and, 384 Amygdala (Amygdaloid nucleus), 93,
Acetylcholine receptors (AchRs), 63 motor performance, 14243 94f, 204, 269, 273, 274, 380,
AchE. See Acetylcholine esterase neuron loss, 140 440, 461, 46268, 463f, 464f,
Achromatopsia, 238 Agnosia, 23738, 239, 252, 502, 507, 473, 476
AchRs. See Acetylcholine receptors 514. See also specic agnosia afferent connections, 46265, 464f
Acoustic agnosia, 252 Agraphia, 502 anxiety, 466
Acoustic neuroma, 247 Airways, 428 conditioned fear, 465, 465f
ACTH. See Adrenocorticotropic Akinesia, 332, 340 conditioned taste aversion, 274
hormone Akinetopsia, 238 CRH, 467
Actin laments Alarm system, 199200 damage to, 467n4
cytoskeleton, 17 Alar plates, 122 frequent urination and, 435
vesicle movement and, 41f, 42 Alcohol PAG and, 209
Action potential, 28, 45 GABAA receptors, 62 prefrontal efferents and, 505
axon, 35, 35f NMDA receptors and, 61 retinohypothalamic tract, 444
frequency of, 38, 38f Alexia, 502, 511 tasks of, 466
regeneration of, 36 Alien limb syndrome, 317n8 Amygdaloid nucleus. See Amygdala
stimulus and, 164 Allodynia, 168, 206 Amyloid -protein (A), 144
threshold for, 43f ALS. See Amyotrophic lateral sclerosis Amyloid-cascade hypothesis, 144
voltage-gated sodium Altered brain networks, 2067 Amyotrophic lateral
channels and, 3435, 34f Alzheimers disease (AD), 1718, 139, sclerosis (ALS), 297, 388
Activating system, 381 14346, 477n2 Analgesia, 210
Acupuncture, 210 acetylcholine, 6263 nociception and, 208
AD. See Alzheimers disease basal nucleus, 471 Analgesic drugs, 214
Adaptation, 163 cortical atrophy, 145f Anastomoses, 112
Adaptive response, 57, 15051 Amacrine cells, 219, 223 Anatomic terms, 73
Adenosine, 68 Ambiguus nucleus, 394, 400 Anencephaly, 12930
Adenosine triphosphate. See ATP Amines, 53 Anesthetics, 62
Adequate stimulus, 175 Amino acids, 53 Aneurysm, 99
Rufni-like receptors, 180, 180f blood-brain barrier, 107 Angina pectoris, 433n2
temperature and, 169 taurine, 22 Angular acceleration, 253, 255
569
570 INDEX
Animal experiments Apathy, 339 fear, 465

5-HT receptor, 66 Aphasia, 509, 511 human, 249f
amygdala, 464 ApoE4 gene, 145, 146 unilateral damage to, 250
AQP4 and, 23 Apomorphine, 400 Auditory pathways, 240, 24751
avulsion of nerve root, 300 Apoptosis, 128 components, 249
brain, 136 Appendicitis, 436 descending control of, 25051
cats, 194n3 Apraxia, 203, 319, 502, 503, 504 GABA and, 250
decerebrate animals, 261 Aquaporins, 2223, 100 Auditory reexes, 25051
dermatomes, 185n9 Arachidonic acid, 106 Auditory signals, 380
embryonic neuroblasts, Arachnoid, 97, 118, 118f Auditory system, 24052
transplantation and, 150 Arachnoid granulations, 103, 103n4 Autoantibodies, 284
bers, 177 Arachnoid villi, 97 Autobiographic memory, 47778
homeostasis, 2627 CSF and, 103 Automatic movements, 27879,
information, 13536 Arbor vitae, 96 301, 31113
lesion experiments in, 191 Arealization, 126 Automatic nervous system, 136, 411
monkeys Area postrema of medulla, 400 Autonomic circulatory control, 1045
A1 core region, 251n6 Arginine, 68 Autonomic functions, 46872
fractionated movements, 308 Arm muscles, 296 Autonomic ganglia, 41415
kinesthesia, 195 Arousal drugs and, 431
primary afferent bers, 195n4 histamine and, 66 visceral efferent bers, 413
monocytes, 26 locus coeruleus, 378 Autonomic ganglion, 415f
muscle nociceptors, 173n4 nigrostriatal neurons, 336 Autonomic innervation, 417t
neuroblasts, 150 Arterial system, 10811 Autonomic motor neurons, 77
noxious stimuli, 203 Arteries Autonomic nervous
OECs, 149 painful stimuli, 437 system, 411, 42529
olfactory imprinting, 270 spinal cord and, 110 actions of, 416t
plasticity, 13638, 137f Arthritis, 181 anatomic features, 415f
prisms, 366 Articial joints, 182 circulatory organs and, 42526
sensory receptors, 164 Aspartame, 272 defense and maintenance, 425
sleep phases, 388 Aspartate, 59 drugs, 43031
stimulation studies, 191 Association areas, 500501 neurotransmitters, 42931
stress-induced analgesia, 211 Association cortex, 5046 peripheral part, 414f
substitution, 147, 15354 Association bers, 90, 493 respiratory organs and, 426
Anion distribution, 31 Associative learning, 477 skin, 427
Anosognosia, 504 Astrocytes (Astroglia), 19, 20f, 22, 106 Autonomic plexuses, 41415
Ansa cervicalis, 397 blood ow and, 20 Autonomic processes,
-antagonists, 435 homeostatic functions of, 19, hypothalamus, 444
Anterior cerebral artery, 108, 109f 2122, 21f Autoreceptors, 53, 57
Anterior choroid artery, 108, 109f after injury, 27 Autoregulation, 104
Anterior cingulate cortex, 469, 470 Asynergia, 358 Autotopagnosia, 502
Anterior cingulate gyrus, 203 Ataxia Awareness, 253
experimental studies, 203 dorsal columns, 195 Axial muscles, 292, 304, 309
social experience, 136 neocerebellar syndrome, 358 Axoaxonic synapses
Anterior commissure, 90, 90f, 270, Athetoid dyskinesias, 341 presynaptic inhibition, 47f
49899 ATP (Adenosine triphosphate), 53 transmitter release and, 47
Anterior communicating artery, 110 adenosine and, 6768 Axodendritic synapses, 7f, 8, 10f
Anterior inferior cerebellar artery, 109 mitochondria and, 56 Axonal growth cone, 132, 132f
Anterior inferior cerebellar artery nociceptors, 166, 166n1, 168f Axonal membrane, 36
occlusion, 406 sodium-potassium pump, 3132 Axonal pathnding, 132
Anterior median ssure, 74, 75f ATPases Axonal reex, 43839, 438f
Anterior pituitary hormones, 446 MAPs as, 18 Axonal regeneration, 149
Anterograde amnesia, 479, 480 type1 & type 2 bers, 280 Axonal transport, 17, 18f
Anterograde axonal transport, 17, 18f Atropine cytoskeleton and, 1618
Anterolateral funiculus, 199 acetylcholine receptors and, 64 machinery of, 18
Antibodies, 54 autonomic nervous system and, 430 Axonal varicosities, 54
Anticipatory control, 311, 312 muscarinic receptors and, 63 Axonic synapses, 8, 10f
Antidromic impulse conduction, 37 Attention, 202 Axons (Nerve bers), 5, 6f.
Antidromic signals, 43839 acetylcholine, 6263 See also Myelinated axons;
Antihistamines, 66 biogenic amines and, 65 Unmyelinated axons
Antipsychotic drugs cerebral cortex, 492 Axons, 178, 299
(Neuroleptics), 70, 337 locus coeruleus, 378 Axons, 178
Anxiety prefrontal cortex, 505 Axons, 175, 178
amygdala and, 466 Auditory areas, 252, 252n7 collaterals, 5, 6f, 117, 13233
neurotransmitters and, 46768 Auditory belt, 252 electrical properties of, impulse
nocebo hyperalgesia v., 213 Auditory cortex, 92, 25152 propagation and, 36
serotonin transporter, 66 asymmetrical organization of, 25152 impulses in, 15
taste sensation and, 272 enriched environments, 135 initial segment of, 35, 35f
INDEX 571
insulation and protection, 11, 2326 Bipolar cells, 222, 222f blood supply to, main arterial
muscle cells and, 5 Bipolar neurons, 7 branches, 111f
myelinated v. unmyelinated, 10 Bitemporal hemianopsia, 232 changes, during adolescence, 133
outgrowths, 130 Bitter substances, 272 coverings, 97103
nervous system development, 117 Bladder development, early stages, 119f, 120f
time of birth, 13334 emptying, 424, 429, 435 diseases, mGluRs, 60
protection of, 26 reexes, 434 embryonic development and, 99n1
regeneration of, 23 innervation, 424f endothelial cells, blood-brain
Axosomatic synapses, 8 parasympathetic innervation, 428 barrier, 1067
Axospinous synapses, 8, 9f, 10f parasympathetic system and, 424 environment and, genetic
Bladder control inuences v., 51617
Backward-feedback connections, 498 cortical activity and, 436 hard-wiring, 130
Baclofen, 322 sympathetic system and, 435 human, weight of, 13435
Balance, 18283 Blindsight, 238 imaging, 7374
Ballistics movements, 278 Blind spot, 22425, 225n3, 233 main arteries of, 109f
Barbiturates, 107 Blink reex, 403 neuronal activity and connectivity,
Baroreceptors, 399400, 401 -blockers, 431 studying, 15152
Basal forebrain (Basal prosencephalon), Bloodbrain barrier, 65, 104, placebo analgesia, 212f
461, 47072 105f, 106 postnatal growth, 134
cholinergic neurons, 471 barbiturates, 107 processes, recovery of function
components, 471f cerebral microcirculation, 1048 and, 15055
Basal ganglia, 73, 93, 94f, 32442 endocytotic vesicles, 106 sensory signals and, 200
direct v. indirect glucose, 107 social experience, 136
pathways, 33536, 335f median eminence, 108 topographic maps, 13334
diseases, 33940 Blood ow true information and, 164
efferent connections, 32829, 330 astrocytes and, 20, 20f ventricular system, 81
efferents, 332 distribution, 426 volume, 515
evaluation, 338 sympathetic bers and, 42526 wiring pattern of, 13, 18, 18f
facial expressions, 403 Blood-nerve barrier, 26 Brain arteries, communications
focal lesions of, 339 Blood pressure, 399400 between, 110
frontal plane, 326f control of, 426 Brain capillaries, blood-brain
functions of, 33839 sympathetic bers and, 42526 barrier, 106
interval timing, 339 Blood supply, CNS and, 10413 Brain damage, 14756
locomotor movements, 313 Blood vessels observations of, 191
MI and, 315 histamine and, 66 prenatal, 156
prenatal development and, 124 NO and, 69 Brain-derived neurotrophic factor
shape and position, 325f Blushing, 429 (BDNF), 50n5, 128
striatum and, 32627 Bodily homeostasis, 411 aging brain, 143
structure and connections, 32436 Bodily posture, labyrinthine Brain edema, 27, 32, 103
voluntary movement and, 313 reexes, 25963 Brain-imaging techniques, 201f
Basal lamina, 283 Body balance, 294 Brain injuries
Basal nucleus (of Meynert) Body image, 26465 hippocampus, 148
AD and, 14445, 145f after amputation, 213 neurotrophins after, 129
degeneration, 139 disturbances of, 502 parallel pathways and, 14
Basal plates, 122 Body scheme, 26465 reparative processes, 14750
Basal prosencephalon. Body temperature, hypothalamus vasogenic brain edema, 22
See Basal forebrain and, 44950 Brain primordium, 120f
Basilar artery, 109, 109f Bony spiral lamina, 241 Brain stem, 72, 80, 392f, 413
Basilar membrane, 24041, 246 Born-blind humans, 501 activating system of, 373
Basket cell, 351 Born-deaf children, cochlear efferents to, 332
BDNF. See Brain-derived implant, 24647 eye movements and, 36569
neurotrophic factor Born-deaf humans, 501 postural control and, 312
Behavior, 44041 Botulinum toxin, 284 prenatal development
Behavioral exibility, 469 joint mobility, 322 and, 12224
Behavior shift, basal ganglia and, 338 transmitter release and, 43 pyramidal tract and, 302, 302f
Bells palsy, 402 Boutons. See Nerve terminals sleep, 388
Benzodiazepines, 467 Bowel, excitatory neurons and, 425 spinal networks and, 311
Bergman cells, 19 Bradykinesia, 339 subdivisions of, 81
Betz cells. See Giant cells of Betz Parkinsons disease, 340 taste buds and, 274
Biceps reex, 292 Bradykinin Brain stem centers
Bilateral connections, 15, 15f blood-brain barrier, 107 coordination of behavior, 44041
Binding sites, 54 nociceptors, 166 eye movement control, 367
Binocular cells, 234 Brain Brain stem lesions, 396
Binocular disparity, 234 adolescence, 133 Brain stem reexes, 289, 391, 394
Binocular zone, 217 age-related changes, 13946 Brain structures, 139
Biofeedback, 288n4, 316 anchoring of, 98 Brain system, language functions
Biogenic amines, 53, 6465 basal aspect, 81f and, 51011
572 INDEX
Brain weight, 13435 Central motor pathways. See Upper Cerebral cortex, 63, 73, 90, 362
aging and, 139 motor neurons afferent connections, 327, 327f, 348
cognitive sex differences, 516 Central nervous system (CNS), 5, 74f, classication of, 4934
Branchial muscles, 394 262, 277 automatic movements and, 279
Bridging veins, 112 AchE, 6263 back-projections from, 49596
Brocas area, 510, 510f axonal regeneration, 149 brain stem and, 311
language and speech, 500 blood supply, 10413 cholinergic neurons and, 470
Brodmanns cytoarchitectonic map, 489f fundamental feature of, 1314 commissural connections of, 49899
Bronchial muscles, epinephrine and, 426 injury and, 2627 connections of, 49399
Bulbospongiosus muscle, ejaculation meninges and, 97 cytoarchitectonics, 487f, 489, 489f
reexes, 436 prenatal development and, 11718 differentiation to, 126f
Bundle of axons, 12 Central pareses, 296, 299, 299f, divisions, 93
-bungarotoxin, 64 319, 406 extrathalamic modulatory
Burst neurons, 38, 38f, 388 facial expressions, 403 connections, 495
negative v. positive eye movement, 362
Cadherins, 7 symptoms, 31920 gender, 51516
Cajal-Retzius cells, 127 Central region (of brain), 303f histamine and, 66
Calcitonin gene-related peptide Central sensory tract, cranial nerve hypothalamus, 444
(CGRP), 282 nuclei and, 39496 intermediate zone, 350
Calcium Cerebellar cortex, 95, 203, 343, 343f interneurons, 9
membrane excitability, 36 afferents to, 352 intracortical signal trafc, information
neuronal excitability and, 3536 fractured somatotopy, 35354 processing and, 492
Calcium channels, 429 inhibitory interneurons, 351f352 language, speech areas, 50910
acetylcholine and, 63 layers of, 35051 layers of, 93
glial cells and, 1920 myelination of, 129 levels of organization, 48384
modulatory transmitter actions, 45 postnatal development, 134f long-latency stretch reex, 294
neurotransmitter release, 39 somatotopic localization, 347f mental disease, 509
Calcium concentration structure, 351f mental disease and, 509
intracellular, 60 vestibular nuclei and, 258 modulatory synaptic effects, 49192
synaptic plasticity, 50 zonal organization, 356f molecular organization, 48889
Calcium-dependent transmitter Cerebellar face area, 360 pain perception, 202f
release, 41f Cerebellar occulus destruction, 360 pain perception and, 202f
Calcium signal, 20 Cerebellar hemispheres, 95, 345 prenatal development and, 125
Caloric test, 261 Cerebellar hypotonia, 359 rats, 135
Cancer cells, metastatic, 107 Cerebellar lesions, 35758, regions of, 16f
Capillaries, 19 357f, 357n6 sex differences and, 51516
Capsaicin, 166n1 Cerebellar nuclear neurons, sleep, 15
Capsular hemiplegia, 152, 304, 321, 323 spontaneously active, 355 subdivisions, 9192
Cardiac output, 42526 Cerebellar nuclei, 95, 354f Cerebral hemispheres, 89, 91, 91f, 94f
Cardiac plexus corticonuclear connections and, 354 association areas, 500501
bers of, 416 efferent connections, 35556 division of tasks, 51115
parasympathetic bers, 424 Cerebellar peduncles, 343f internal structure of, 95f
Cataracts, 138 Cerebellar plasticity, 353n5 lateral ventricles and, 100f
Catecholamines, 6465, 67, 207 Cerebellar tonsils, 103 medial wall of, 317
Cations, 29 Cerebellum (little brain), 72, 73, prenatal development and, 124
Caudate nucleus, 93 9596, 96f, 310, 34361, 343f undamaged, 153
afferents, 327, 327f, 332 cognitive functions, 36061 Cerebral ischemia, 22
Cavernous sinus, 113, 113f efferent connections, 35457 Cerebral lateralization, 51213
CCK. See Cholecystokinin locomotor movements, 313 Cerebral palsy, 15556
Cell-adhesion molecules, embryonic MI and, 315 Cerebral peduncle, 85
development and, 131 motion sickness and, 265 Cerebral ventricles, 99103
Cell bodies (neuronal somata), 6f, 57 motor learning and, 35960 Cerebrocerebellar pathway, 249
Cell damage, 60 myelination of, 129 Cerebrocerebellum connections, 348n1
Cell death parts of, 343, 345 Cerebrospinal uid (CSF)
calcium concentration, 6061 prenatal development and, 123 astrocytes and, 19
GluRs, 6061 restitution, 15354, 154f cerebral ventricles, 99103
ischemia and, 147 sagittal zones, 356 choroid plexus and, 99n2
Cell differentiation, 11718 subdivisions, 345f circulation and drainage of, 1023
Cell membrane subdivisions/afferent composition and functions, 1012
depolarization, 36 connections, 34350 as signal pathway, 102
permeability, 2829 timing (of events) theory, 359 and ventricles, 103
Cellular mechanisms, 137 vestibular nuclei and, 258, 35455 Cerebrum, 72, 8990
Central auditory system damage, 252 voluntary movement and, 313 Cervical exure, 118
Central canal of spinal cord, 81 Cerebral aqueduct, 97 Cervical nerves, 76
Central deafness, 247 Cerebral arteries, 11011 c-fos, 34
Central facial pareses, 4023 Cerebral blood ow, 1920 CGRP. See Calcitonin gene-related
Central motor lesions, 397 Cerebral circulation, 1045 peptide
INDEX 573
Channelopathies, 33 Clozapine, 70 Conductive deafness, 247
Charcot-Marie-Tooth disease, 27 CNS. See Central nervous system Cone opsin molecules, 219
ChAT. See Choline acetyltransferase - coactivation, 178, 295 Cones
Chemical synapses, 40 Cocaine, 70, 338 degree of activation, 221
Chemoreceptors, 162, 165, 271 Cochlea, 24047, 242f, 243f photopigment of, 219
Chemotropic localization, 274 Cochlear duct, 24041 Conuence region, 112
Children Cochlear implant Connective tissue
cochlear implant, 24647 deafness, 247 extracellular uid and, 297
hydrocephalus, 103 hearing and, 24647 muscle and, 286
mirror movements, 156 sensitive periods, 138 Conscious feelings, 399
seizures, 155 Cochlear nerve Consciousness
spinal cord in, 74 cochlear nuclei and, 24748 EEG, 384, 384n3
Chimeric portraits, 514 skull fractures and, 247 EMG, 384
Chloride, 31 Cochlear nerve bers, 248, 249 neurobiologicals, 38384
Chloride ions, 31 Cochlear nuclei, 240 nociceptors and, 199
Cholecystokinin (CCK), 213 ascending pathways from, 248 Conscious sensations, 18485
Choline acetyltransferase cochlear nerve and, 24748 Constraint-induced movement therapy
(ChAT), 63, 282 efferent bers from, 249 (CI therapy), 155
Cholinergic interneurons, 32930 Cognition, 501 Contagious yawning, 388
Cholinergic neurons Cognitive functions, 73, 323 Context, 48182
basal forebrain, 471 cerebellum, 36061 Contours, retinal ganglion
cerebral cortex and, 470 Cognitive map, 481 cells, 22324
ChAT and, 63 Cognitive sex differences, 500, 516 Contraction
sleep, 388, 389 Coincidence detectors tendon organs and, 179
Chorda tympani, 404 cortical neurons, 49293 visceral receptors, 432
Choroid, 99, 101f, 216 neurons, 49 Contraction velocity, 285, 287
CSF production, 99n2 Colchicine, 57 Contracture, 322
embryonic development of, 101f Cold receptors, 169 Contrast, 224f
prenatal development and, 121, Cold sensory units, 171 Convergence, 221
124, 125 Collagen bers, 26 receptive elds and, 160
structure of, 101f Collaterals, 374 of visual axes, 366
Chromafn cells, epinephrine, 421, 429 Collateral sprouting, 14950, 300 Coping strategies, 390
Chromosome 4, genetic defect, Colocalization, 5556, 70 Cordotomy, 197, 199, 322n12
Huntingtons disease, 342 Color, 237 Core projection, 249
Chronic pain, anterior cingulate Color blindness, 221 Cornea, 21516
gyrus, 203 Color constancy, 23637 Corneal reex, 394, 403, 406
Chronic pain syndromes, 199 Color opponens, 23637 Corollary discharge, 179, 250
Cilia of sensory cells, 240 Color-specic blobs, in striate Corpus callosum, 90, 513
Ciliary muscles, 215 area, 234f cognitive sex differences, 516
Cingulate gyrus, 468, 468n5 Color-specic cells, 235 commissural connections of, 49899
connections of, 469f Color vision, 221, 23637 tactile/kinesthetic signals, 512
pain system and, 205 Coma, 387 Corpus striatum, prenatal development
Circadian rhythms, 451, 452n6 Command neurons, 504 and, 124
Circle of Willis, 110 Commissural connections, 15, 15f, Cortex-basal ganglia-thalamus-cortex
Circuit of Papez, 462 493, 511 parallel circuits, 327f, 330f
Circulation, 82, 382 function of, 512 Cortical activation
nerve groups and, 72 monkey, 498f age and, 142, 142f
Circulatory organs, 42526 Commissural bers, 90, 315 pathways/transmitters, 386
Circumventive goal-directed Communicating arteries, 104 Cortical afferent connections, 493
movements, 318 Compensation, 15051 Cortical association areas, 500517
Circumventricular organs, 104, vestibular apparatus and, 151 Cortical cytoarchitectonic areas, 126
108, 108f Compensatory movement (of eyes), head Cortical interneurons, 49091, 491f
Cisterns, 97 movement, 260 Cortical layers, afferents and, 489
CI therapy. See Constraint-induced Complex cells, 23334 Cortical microstructure
movement therapy Complex regional pain syndrome columns, 48788, 488f
Clasp-knife reex, 323 (CRPS), 207, 437 Cortical neurons
Classical neurotransmitter, 53, 5556, Compressed nerve, 300 AMPA receptors, 491
57, 58t, 69f Concentration gradient, 29 as coincidence detectors, 49293
Clathrin, 42 Concentric contractions, 278 gender studies, 51516
Claudins, 106n1 Conditioned responses, 211, 289, 360 Cortical pain network, 213
Claustrum, 94 Conditioned taste aversion, 274 modes of activation, 213f
Climbing bers Conductance, 29n2 Cortical plasticity
error signal, 353 Conduction deafness, 24445 horizontal integration, 493
graded information from, 353 Conduction velocities sensory cortical areas, 49091
inferior olive and, 352 dorsal root bers and, 166 Cortical plate, prenatal development
Clitoris, 424 pyramidal tract, 306 and, 125
Clonus, 293 unmyelinated axons v. myelinated, 37 Cortical processing, 274
574 INDEX
Cortical projection neurons, 356, precision grip and, 295 Dichotic listening, 514
490, 491f Cutaneous sensation, exteroceptor Diencephalon, 72, 8687, 87f, 89, 89f,
Cortical somatotropic pathway, epileptic and, 166 99, 21819
seizures, 194 Cutaneous sensory units, 171 prenatal development, 124
Corticonuclear connections, 355f Cytoarchitectonic areas Differentiation, 117
cerebellar nuclei and, 354 cerebral cortex, 487f, 489, 489f Diffusion, 43
Corticonuclear projections, 356 SI subdivision, 201 Diffusion-weighted imaging. See
Corticopontine pathway, 249f Cytoskeleton, 1618 Magnetic encephalography
Corticoreticular bers, 380 Cytotoxic brain edema, 22 Digestion, 452
Corticoreticulospinal pathways, 301, Dihydroxyphenylalanine. See DOPA
3089, 310, 380 Dark adaptation, 21920 Dinate gyrus, 473
Corticospinal bers, 3067 Deafferentation pain, 204, 207 Diplopia (Double vision), 363, 407
Corticospinal neuron, 3067, 316 Deafness, 247 Direct corticobulbar pathways, 303f
Corticospinal tract. See Pyramidal tract Decerebrate animals, 441 Direct corticospinal pathways, 303f
Corticosteroids, 456 Decerebrate rigidity, 263 Direction-selective cells, 234
Corticothalamic connections, 22829, Decibels, 244 Direct spinocerebellar tracts, 34647
384, 49596 Declarative memory, 477 Discriminative sensation, 17172,
Corticothalamic bers, 229 temporal lobe and, 478 195, 202
Corticothalamic projections, 22829 Deep-brain stimulation, 342 Diseases
Corticotropin-releasing hormone (CRH), Deep cerebral veins, 112 aquaporins in, 2223
448, 467 Default-mode network, 508 of basal ganglia, 33940
Cough reex Degeneration of pyramidal tract, 321f cerebellar functions and
nucleus ambiguus and, 400401 Degenerative brain diseases, 452 symptoms, 357
receptors producing, 434 Dja vu, 269 expectation and, 45556
Cramps, 297 Delayed response, 506 expectation v., hypothalamus, 45556
Cranial nerve examination, 39596 Dementia, 139 muscle tone and, 298
Cranial nerve ganglia, 82 Huntingtons disease, 342 neuromuscular transmission, 284
Cranial nerve nuclei, 72, 391, infections and, 143 pathologic yawning, 388
39496 neurogenerative diseases and, 14346 of peripheral nerves, 27
columns of, 392f, 393f Dendrites, 5, 373 visual cortex, 231
embryonic life, 392, 394 excitatory synapses, 47 Disequilibrium, 265
organization of, 393f reticular formation and, 375f Disinhibition, 49, 49f, 222, 293, 333
position of, 395f retinal ganglion cells and, 22627 Disparity of images, 234
Cranial nerves, 72, 8182, 244, Dendritic arborizations, 225 Distal muscles (of hand and foot), 283
391409, 392f. See also specic of spinal neurons, 80f Distributed neural networks. See Neural
cranial nerves Dendritic spines, 6 networks
brain stem lesions, 396 excitatory synapses, 47 Divergence of connections, 1314, 13f
corticobulbar tract, 395, 396f memory, 47 Dizziness, 265, 407
extraocular muscles and, 406 Dendrodendritic synapses, 41, 269 DOPA (Dihydroxyphenylalanine), 65.
eyes and, 362 Dentate gyrus, 474 See also Levodopa
ber types, 391 Dentate nucleus bers, 355 Dopamine, 43, 53, 65, 210n4, 223, 449
medial lemniscus system, 395 Denticulate ligaments, 98, 98f cerebral cortex, 492
myelination of, 129 Depolarization, 28 in striatum, 33435
organization of, 39196 membrane potential, 33 synthesis, 54, 55f, 64f
preganglionic parasympathetic strong v. weak, 38f Dopamine -hydroxylase, 64f, 65
bers, 42224 Depression Dopamine hypothesis of
prenatal development and, 124 amygdala and, 468 schizophrenia, 70
from rhombencephalon, 121f habenula and, 89 Dopamine receptors
CRH. See Corticotropin-releasing MAO inhibitors, 70 age-related decline, 141
hormone pain perception and, 213 schizophrenia, 509
Cribriform plate, 103 serotonin transporter, 66 types of, 335
Critical period. See Sensitive period taste sensation and, 272 Dopaminergic drugs, 388
Cristae, 258 TCAs and, 70 Dopaminergic bers. See Mesencephalic
CRPS. See Complex regional pain Depth cues, 236 ventral tegmental area
syndrome Dermatomal maps, 185f, 186 Dopaminergic neurons, 64
Crushed nerve, 300 Dermatomes, 166 Dopaminergic neuron transplantation, 341
CSF. See Cerebrospinal uid animal experiments, 185n9 Dopaminergic nigrostriatal pathway,
Cuneocerebellar tract, 34748 determining, 186 33435
Curare, 6364, 284 local anesthesia, 186 Dopaminergic striatal afferents, 327
Cutaneous low-threshold overlapping of, 18586 Dorsal column, 190
mechanoreceptors, 165 Descending axons, 193 medial lemniscus and, 19192
dorsal horn and, 186 Desynchronization, 384 visceral nociceptors and, 43334
foot, 263 Deviation of jaw, trigeminal Dorsal column-medial lemniscus system,
SI and, 307 pareses, 406f 190, 191f
sole of foot and, 263 Dexterity, 301 clinical examination of, 19596
Cutaneous receptors, 167f Diabetes insipidus, vasopressin, 44647 functions of, 19495
postural control and, 31112 Diathesis, genetically determined, 25 single-unit properties in, 194
INDEX 575
Dorsal column nuclei, 190 Efference copy, 17980, 315, 365 Encephalitis, 103
Dorsal horn Efferent cholinergic bers, 257n1 Endocochlear potential, 240
consciousness and, 311 Efferent connections, 345, 373 Endocrine system, 411
bers from, 18687 Efferent link, 280, 289 hypothalamus and, 440, 44549
neurons, 186 Efferent nerve bers immune system and, 454
presynaptic inhibition, 48, 48f acetylcholine and, 246 Endocytosis, 42
Dorsal nucleus cells, 249 of cochlear nerve, 248 Endolymph, 240, 253
Dorsal rami, 7980 hair cells and, 244 Endoneurium, 26
Dorsal rhizotomy, 184 Efferent reticular cell groups, 379f -endorphin, 210
Dorsal root(s), 72, 75, 79 Ejaculation reexes, 436 Endorphin hypothesis, 212
irritation and, 186 Ekman, P., facial expressions, 458 Endorphins, 204, 210
sensory neurons, 78 Elderly, 13940, 14142, 142f. Endurance, 287
Dorsal root bers, 190 See also Aging Engrailed 2 gene, 122
classication of, 18384 Electrical stimulation Enkephalin, 70, 210
conduction velocity and, 166 amygdala and, 466 En passage boutons, 7, 10f
differential terminal patterns, 186n10 dermatomes, 186 Enriched environments, 135, 135n9
spinothalamic neurons, 19697 of reticular formation, 309 Enteric nervous system (mini-brain
terminal pattern of, 183f tracts/cells groups, 191 of gut), 411, 413, 42425
Dorsal root ganglia, 183, 184 Electrical synapses, 222 Enteric neurons. See Vasoactive
Dorsal spinocerebellar tracts, 34748 Electric capacity, axonal membrane intestinal peptide
Dorsolateral prefrontal cortex (DLPFC), and, 36 Enteric plexuses, 425
lesions of, 506 Electric coupling (Gap junctions), 19, 40 Enteroceptive signals, 163
Double vision. See Diplopia glial cells, 40 Enteroceptors, 159, 163
Dreaming, 35960, 387, 390 smooth muscle cells, 414 Entorhinal cortex, 144
Dreamy state, 269, 466 Electroencephalography (EEG), 152, Enuresis, 434n3
Drug addiction, ventral striatum 385, 385f Environment
and, 33738 consciousness, 384, 384n3 auditory cortex, 135
Drugs epilepsy, 384 nervous system, malformations of,
autonomic ganglia, 431 Electromyography (EMG), 298, 299 12930
autonomic nervous system, 43031 consciousness, 384 nervous system development, 13538
bloodbrain barrier, 107 muscle tone, 297 neuronal phenotype and, 127
chronic pain, 214 Electrotonic synapsis, synchronized Ependyma, 19
GABAA receptors, 62 activity and, 40 Ependymal cells, 121
multifarious effects, 71 Eleventh cranial nerve. See Accessory Ephaptic transmission, 401
nervous system, 7071, 12930 nerve Epidural plexus, 113
restitution, 150 Embryo Epilepsy, 127, 269, 513
transmitter actions and, 57 nervous system, 11738 EEG and, 384
Ductus deferens neuronal connections in, GABAergic cortical interneurons, 491
innervation, 418 distances of, 130, 131f neurons, 33
muscles of, 414 Embryology, vagus nerve, 398 Epileptic seizures, 231
sympathetic bers and, 427 Embryonic development cortical somatotropic pathway, 194
Dura, 97, 112f acetylcholine receptors, 283 inhibitory interneuron and, 48
Dural sac, 9798 vagus nerve, 398, 399 MI, 316
Dura mater, 9798 Embryonic life Epinephrine. See Norepinephrine
Dynamic processes, 71 retina, 21819 Episodic memory, 47778
Dynamic sensitivity, 176, 177, 178 sympathetic ganglion, 41819 Epithalamus, 89
duct receptors and, 255 EMG. See Electromyography EPSP. See Excitatory postsynaptic
receptors and, 163 Emmetropic eye, 218 potential
of utricle and saccule, 255 Emotionally driven behavior, 336 Equilibrium, 25365
Dynamin, 42 Emotions, 269, 323, 461 Equilibrium potential, 31
Dynorphin, 210 amygdala and, 46667 Erection reexes, 436
Dyscalculia, 504 autonomic system and, 429 Ergoreceptors, 17374, 181
Dyskinesia, 339 basal ganglia and, 338 Error signal, climbing bers, 353
Dysmetria, 358 cortical control of, 46872 Esophagus, 398
Dyssynergia, 435 emotional reactions and, 458 Eustachian tube, 214
Dystonias, 339 facial muscles of, 403 Excitability
frontal lobe lesion, 506 basis of, 2834
Ear, 241f habenula and, 89 of motoneurons, 320
Ear dominance, 514 hypothalamus, 45758 Excitatory actions, 42
EBA. See Extrastriatal body area lateralization of, 51415 Excitatory afferents, 331
Eccentric contractions, 278 monoamines for, 376 Excitatory neurons, 368
Edema negative, 466 bowel and, 425
brain and, 27 neocortex and, 469 Excitatory postsynaptic potential (EPSP),
vasogenic, 22 Empathy, 505, 505n3 40, 44, 44f, 45f
Edinger-Westphal nucleus, 407, 408, 409 Emptying reexes, of rectum, 434 miniature, 42
EEG. See Electroencephalography Encapsulated endings, 180 monoaminergic receptors and, 65
Effector, 289 Encapsulated receptors, 165, 169 slow, 46, 60
576 INDEX
Excitatory synapses, 40, 47 Face fMRI. See Functional MRI

Excitatory transmitter, 40 alarm in, 466 Focal dystonia of hand, 298
Exocytosis, of vesicles, 4142 recognition, 238 Focal ischemia
Experience, 143n2 Facial colliculus, 85, 402 brain injuries, 147
Experimental animals Facial expressions, 403 cellular changes, 148f
cerebellum, 357 Facial muscles, 402 Focused attention, 386
CSF and, choroid plexus and, 99n2 Facial nerve (Seventh cranial nerve), 72, receptive eld and, 160
eye/head movements, 310 266, 402 Folia, 95
PAG and, 209 abducens nucleus and, 401f Follicle-stimulating hormone (FSH), 446
social attachments and, 457 peripheral lesion of, 402 Fornix, 444, 463f
vascular stria, 241n1 reexes and, 403 amnesia, 476
Explicit memory, 477 Facial nerve paresis, 251 Fovea centralis, 22425, 225f
Expressive aphasia, 511 Facial nucleus, 402 Fractionated movements, 308
Extended amygdala, 472 Facial skin, trigeminal branches in, 404f FRAs. See Flexor reex afferents
Extensors (triceps muscle), 307 Facilitation, 51 Free-ending receptors, 180
Exteroceptive signals, 163 Facilitatory region, of reticular Free nerve endings, 16162
Exteroceptors, 163, 165 formation, 38182, 381f Free receptors, 165, 166
Extracellular uid, 43 Fainting, 429 Frequency coding, 3839
Extracellular ions, 21 Falling, 26061 Frequency curve, 246
Extracellular molecules, 131 Familial hemiplegic migraine, gene Frontal association areas, 5046
Extracellular osmotic pressure, 22 coding and, 33 Frontal eye eld, 310
Extrafusal muscle bers, 174 Fascicles, 26, 26f Frontal lobe, 91
Extraocular muscles, 216, 363f Fastigial nucleus, 356 Frontal lobe lesion, personality change
actions of, 36263 Fast pain, 184 and, 506
control, precise, 364 Fast twitch, 285 Frontal lobe tumor, 506
cranial nerves and, 406 Fat, 272 Frontoparietal network, 384
lesions of, 407 Fatigability, 322 Frontotemporal dementia (FTD), 144, 146
nerves of, 405 Fear behavior, 429 FSH. See Follicle-stimulating hormone
Extrapyramidal system, 301 amygdala, 464, 465 FTD. See Frontotemporal dementia
Extrastriatal body area (EBA), 26465 auditory cortex, 465 Functional MRI (fMRI), blood ow
Extrastriate visual areas, 231, 233, conditioned, 467 measurement, 151
235, 238f Fear-provoking stimuli, amygdala Functional specializations, A1 and, 252
Extrasynaptic receptors, 56, 56f and, 463 Functional unit, 12
Extremities, 309 Feedback, 17 Fusiform gyrus, 238
commissural connections, 499 movements and, 290 Fusimotor bers, 175
innervation, 42021, 421f, 422 reciprocal connections and, 1415, 15f Fusimotor axons, 177
sympathetic innervation of, 41920 Feedback connections, 315 Fusion, 42
Eye, 216f. See also Visual axes (of eyes) Feed-forward connections, 15, 312, 498
cranial nerves, 362 Feeding behavior, 452 GABA (-aminobutyric acid), 43, 53, 55,
far point of, 218 Feeding control, 45253 61, 70
movement, 253, 332 Fever, 450 auditory pathways, 250
brain stem, 36569 FGFs. See Fibroblast growth factors colocalization of, 56
cerebellar lesions, 358 A bers, 184, 186 cortical neurons, 491, 492
cerebral cortex, 362 bers, 177 epilepsy, 33
conjugated, 36364 Fibroblast growth factors (FGFs), 128 medium spiny neurons and, 32829
control of, 36270 Fibromyalgia, 205, 456 photoreceptors, 223
cortical control, 369 Fictive locomotion, 312 presynaptic inhibition and, 48, 48f
horizontal, 362, 367, 367f Fifth cranial nerve. See Trigeminal nerve slow IPSP, 62
horizontal conjugate, control Filopodia, 131 synthesis, 54, 55f
of, 367f Final common pathway GABAA receptors (-aminobutyric
kinds, 36566 motor neuron and, 14 acidA receptors), 56, 6162
muscle system and, 382 skeletal muscles, 28081 GABAergic efferent connections, 324
nerve groups and, 72 Final integrative area, 238 GABAergic bers, 352, 353
reading, 366 Finger tapping, motor cortex and, 315 GABAergic interneurons, 229
rotatory, 362 Firing frequency, 284 GABAergic neurons, 334f
vertical, 362, 367f neuron and, 46 reticular thalamic nucleus and, 49697
vestibular reexes, 25963 Firing patterns, 3839 GABAergic projection neurons, 32930
vestibular signals and, 260 Flexibility, 279 Gain modulation, 295
muscles, testing, 364t Flexion (withdrawal) reex, 280, 290, Gait ataxia, cerebellar lesions, 358
muscles and nerves, 407f 290f, 296 Gallbladder, vagus nerve, 399
neutral position, 363 Flexor reex afferents (FRAs), 29091 gamma dynamic, 177
parasympathetic innervation, 428 Flexors (of ankle joint), 307 gamma static, 177
refracting media and, 21518 Flexors (of thumb), 307 Ganglion, 5, 12, 413
structural features, 21516 Flexures, 118, 119f afferent bers and, 39192
sympathetic bers and, 427 Flocculonodular lobe, 345 neurons and, 1112
vesicles, prenatal development in monkeys, 35758 Gap junctions. See Electric coupling
and, 124 Fluoxetine (Prozac), 70 Gastrin-releasing peptide (GRP), 425
INDEX 577
Gastrointestinal tract Glutamate receptors (GluRs), 59, 60n2 Health
innervation, 418 Glutamatergic corticospinal neurons, aquaporins in, 2223
sympathetic bers and, 427 306, 334f expectation v., 45556
Gating mechanism, 334 Glutamatergic neurons, 57, 59f Hearing, cochlear implant, 24647
Gaze Glutamatergic thalamocortical Heart
xation, 370 bers, 493 inferior cardiac nerves, 421
holding, 366 Glycine, 61 parasympathetic innervation, 428
paralysis, 369 auditory pathways, 250 vagus nerve, 398
trochlear nucleus, 407 cellular metabolism and, 54 visceral efferent vagus
Gender colocalization of, 56 bers, 398n3
cerebral cortex and, 51516 mutations and, 33 Hemiballismus, 334, 339
psychological differences, 516 Glycine receptors, 61 Hemiplegia, 152, 307, 322f
Gene expression, 50 Glycolipids, 2324 child, 155
General anesthesia, 383 Goal-directed behavior, prefrontal by perinatal stroke, 156
EEG and, 384 cortex, 505 Hemispheric dominance, 510
hyperthermia, 450 Goal-directed movements, 235 Heschls gyrus, 251
General somatic afferent cranial Golgi tendon organ, 178 Heteroreceptors, 53, 57
nerve nuclei, 394 Gonadotropic hormones, 446, 452 High-threshold
General somatic afferent GP. See Globus pallidus mechanoreceptor, 16162, 181
vestibulocochlear nerve, 394 G protein-coupled receptors, 161 High-threshold receptors, 165
Genes G proteins, 42, 43f, 56 High-threshold units, 197
AD and, 145 Gracile fascicle, 191 Hippocampal architecture, 476
cognitive abilities v., 517 Gracile nucleus, 191, 191f Hippocampal ssure, 99
nervous system, malformations Graded potential, 43 Hippocampal formation, 474f
of, 12930 Grasp reex, 289, 312, 317 afferent connections, 47475
prenatal development and, 117 Gray matter, 5, 11, 12f, 72 connections, 474
Genetic polymorphisms, sweet aging, 14041 efferent connections of, 476, 476n1
substances, 272 prenatal development and, 121 learning and memory, 47382
Genetic programming, 13334 Great cerebral vein of macroscopic appearance, 47374
Genital organs, 202n8 Galen, 112, 112f Hippocampal sulcus, 92
parasympathetic system and, 424 GRH. See Growth hormone-releasing Hippocampus, 92, 473, 474f, 475f
SI and, 2023 hormone amygdala and, 463f
sympathetic bers and, 427 Grid neurons, hippocampus, 48182 brain injuries, 148
Genu of facial nerve, 402 Group Ib ber, 178 destruction of, 480
Gerstmann syndrome, 504 slowly adapting, 179 enriched environments, 135
GH. See Growth hormone Group II muscle afferents, 294 grid neurons, 48182
Giant cells, 374 Growth cone, 17 prenatal development and, 125
Giant cells of Betz, 303 Growth factors, 128, 150 signal pathways through, 477f
Glial cells, 5, 1939, 68 Growth hormone (GH), 446 social experience, 136
categories, 19 Growth hormone-releasing hormone Histamine, 65, 67
chronic pain, 206 (GRH), 449 bloodbrain barrier, 107
electric coupling and, 40 GRP. See Gastrin-releasing peptide cerebral cortex, 492
histamine and, 66 Gustatory system, 27174 itching and, 170
homeostasis and, 19 substance P, 439
specialized forms, 19 Habenula, 89, 331, 336n10 Histamine receptors, 66
Global ischemia Habituation, 477 Histaminergic neurons, 386
anterograde amnesia, 480 Hair cells (sensory cells), 244 Homeostasis, 165, 432
brain injuries, 147 auditory system, 240 astroglia, 21f
Globus pallidus (GP), 33132 damage, 247 microglial cells and, 2627
Glossopharyngeal nerve (Ninth cranial depolarization of, 24445 PAG, 209
nerve), 84, 266, 273, 401 hyperpolarization of, 24445 silent nociceptors, 168
Glucose, 107, 274 of utricular macula, 256f Homeostatic control, pain system
GluRs. See Glutamate receptors Hair roots, 427 and, 205
GLUT1, 107, 107n3 Hairy skin (human), 427n3 Homonymous hemianopsia, 233
Glutamate, 43, 53, 55, 57, 59f, 106, Haloperidol, 342 Horizontal cells, 222
222, 333, 476 Hand function, 514 Horizontal conjugate eye
amygdala and, 467 Head movements, 367f
brain injuries, 147 movement, 258, 260, 332 Horizontal connections
cellular metabolism and, 54 muscles of, 305 cortical plasticity, 49091
corticostriatal bers, 333 position, 255, 25657 as psychophysical phenomena, 493
inner hair cells and, 245 rotation, 25455, 263 Horizontal integration, cortical
photoreceptors and, 215 sympathetic denervation of, 421 plasticity, 493
receptor blockers, 148 sympathetic innervation of, 41920 Hormone(s), 447
synthesis, 59 Headache, 99 anterior pituitary, 446
transporters, 61 meningeal irritation, 99 hypothalamic neurons, 445f
Glutamate-glutamine circuit, 59f Head injuries, 103, 386 hypothalamus, 66, 443
Glutamate hypothesis, 61, 148 Head trauma, 408 psychic functions and, 456
578 INDEX
Hormone(s) (continued) Immune reactions, CNS and, 27 Insula (fth cerebral lobe), 91, 91f, 202,
releasing, 44748 Immune system, 454f 274, 5078
secretion, 66 fever, 450 pain, 198, 205
Horners syndrome, 396, 406, 421, hypothalamus and, 45458 sensory information, 500
422f, 427 lymphoid organs, 454, 454f Insulin, 274
Hox genes, prenatal development nervous system and, 440 Integrated image, 235
and, 122 silent nociceptors, 168 Integration, 373, 374
Huntingtons disease, 339, 34142 visceral afferents and, 432 Intensional tremor, 359
Hydrocephalus, 103, 130 Immunocytochemistry, 54 Intensity, sound waves, 240
Hyperacusis, 403 Impulse conduction, negative Interareal synaptic organization, 485
facial nerve paresis, 251 feedback to, 12f Intermediary laments, 1718
Hyperalgesia, 168, 204, 206 Impulse propagation, 3638 Intermediate nerve, 402, 404
Hypercalcemia, 36 speed of, axon isolation and, 1011 tongue and, 273
Hypercapnia, 104 Inactivated Na+ channels, 34, 34n4 Intermediate zone, 345, 350, 350f
Hyperexcitability, 204 Inclusion bodies, neurodegenerative Intermediolateral cell column, 77,
Hyperhidrosis, 437 diseases, 144 418, 418f
Hypermetropia, 218 Incomplete severance of nerve, 300 Internal capsule, 304
Hyperpolarization, 33, 35 Indirect corticospinal damage of, 304
Hyperreexia, 150, 29899, 301, 320 pathways, 30811, 311 infarction in, 321f
Hyperthermia, 450 Indirect spinocerebellar tracts, 347 pyramidal tract and, 302, 302f
Hypertonia, 298 Inferior collicular brachium, 248, 248f Internal carotid artery, 104, 108, 109f
Hyperventilation, 384 Inferior colliculus, 248, 248f, 249, 250 Internal granular layer,
Hypocalcemia, 36 Inferior oblique muscle, 363 neocortex, 48687
Hypocretin (Orexin), 359, 451 Inferior olivary nucleus, 8384 Internal jugular vein, 112
Hypogastric plexus, 422f Inferior olive, 310 Internal limiting membrane, prenatal
Hypoglossal canal, 397 climbing bers, 352 development and, 120
Hypoglossal nerve (Twelfth cranial harmaline, 353 Interneuron(s), 5, 89, 11f, 15,
nerve), 72, 84 timing (of events) theory, 359 15f, 197
somatic efferent bers and, 39697 Inferotemporal cortex, 507 enteric plexuses, 425
Hypoglossal nucleus, 84 Inammation negative feedback to, 12f
Hypophyseal portal system, 44748 mediators of, 16667 retina, 215, 219
Hypothalamic afferent connections, 443, nervous tissue, reaction of, 27 tasks of, 910, 11f
443f, 444, 444f nociceptive sensory units, 173 Internuclear ophthalmoplegia, 367
Hypothalamic centers, 449 Inammatory pain, blood-brain Interposed nuclei, 355
Hypothalamic nuclei, 441, 443 barrier, 107 Interventricular foramen, 89
Hypothalamic sulcus, 88, 88f Information, sensory signals, 343 Intonational agnosia, 514
Hypothalamus, 88, 88f, 204, 269, 273, Infrahyoid muscles, 397 Intoxications, dementia and, 143
380, 411, 433 Infundibulum, 89 Intracellular calcium, 51
afferent connections of, 440 Inherited channelopathies, 33 Intracerebellar nucleus, 343, 343f
amygdala, 464 Inhibiting systems, 211 Intracortical connectivity, 49091
arcuate nucleus, 453 Inhibition, reex/voluntary Intracortical signal trafc,
central autonomic system, 44058 movements, 309 information processing and,
crying and, 404 Inhibitory amino acid transmitters, 61 cerebral cortex, 492
endocrine system and, 44549 Inhibitory burst neurons, 368 Intracortical synaptic
facial expressions, 403 Inhibitory hormones, 447 organization, 485
food intake, 66 Inhibitory interneuron, 312 Intracranial expansive process, 103
gender and, 516 discriminative sensation and, 172 Intracranial hemorrhage, 103
histamine and, 66 nervous system, 49, 49f Intrafusal muscle bers, 165, 174
immune system and, 45455 Inhibitory neurons, 307, 388 Intralaminar thalamic nuclei, 191n1,
lesions, 388 Inhibitory postsynaptic potential 386, 495
mental functions, 45558 (IPSP), 40, 44, 44f, 45, 45f, 65 Introspection, default-mode
metabolism, 452 Inhibitory region of reticular formation, network, 508
neurotransmitters, 44243 38182, 381f Intumescences, 74, 75f, 7677
optic nerve and, 228f Inhibitory synapses, 47, 48 Ion channels, 28, 29f
posterior pituitary v., 446 Inhibitory transmitter cell membrane permeability
prefrontal efferents and, 505 IPSP at, 40 and, 2829
prenatal development and, 124 short-circuits, 44 salty and sour substances, 272
structure and connections, 44145, Injury, 27 structure of, 3233
442f astrocytes, 27 Ion concentrations, 35
Hypoxia, 22, 104 microglia and, 2627 IPSP. See Inhibitory postsynaptic
Inner hair cells, 244, 245f potential
Ia-inhibitory interneurons, 293 mechanoelectric transduction, 24445 Iris, 216
Ib ber afferents, 179 innervation, 177n6 Irritation, cochlear nerve, 247
Ideomotor apraxia, 502 Inotropic receptors, 39, 53, 59 Ischemia, 173
Imagining, 514 transmitters an, 4243, 43f blood-brain barrier, 107
Immediate early-genes, 34 in situ hybridization techniques, 54 cell death and, 147
Immune mediators, 25 Insomnia, 383 Islands, 330
INDEX 579
Isometric contractions, 278 Lateral lemniscus, 248, 248f Lidocaine, 168
Isoprenaline, 431 Lateral pontine infarction, 406 Ligand-gated channels, 28, 3233
Itching, histamine and, 170 Lateral recesses, 99 Light
Lateral ventricles, 99 adaptation, 21920
Jackson epileptic seizures, 316 Learning, 52, 202, 27879 intensity, 22324
Jacksonian ts, 194 acetylcholine, 6263 P cells, 22627
Jaws, voluntary movement, 406 amygdala and, 467 retinohypothalamic tract, 444
Jendrassik maneuver, stretch basal ganglia and, 338 Light reex, 4089, 409f
reex and, 292f biogenic amines and, 65 Limbic structures, 313, 459, 462f
Jet lag, melatonin, 452 cellular basis for, 49n4 Limbic system, 46162
Joint dendritic spines, 47 Lingual nerve, 404
neocerebellar syndrome and, 358 dopamine and, 336 Lipid-soluble steroid hormones,
nociceptors, 181 enriched environments, 135 hypothalamic neurons and, 445f
receptors, 165, 180 hippocampal formation, 47382 Lissencephaly, 127
J receptors, 434 hippocampus, 93, 48182 Lithium, 71n11
Jugular foramen, accessory nerve by imitation, 318 Liver, 399
and, 397 kinds of, 477 Local anesthetics, 185n8
Junctional folds, 283 motor cortex and, 319 sensory bers and, 18485
of motor task, 292 Locked-in syndrome, 387
Kainate receptors, 59n1 NMDA receptor and, 60 Locomotion, 301, 31113
K+ cation, 241 olfactory bulb, 269 reex modulation and, 29596
cilia of sensory cells, 240 pain and, 205 spinal network and, 134
glutamate and, 61 processes, 15051, 15455 Locus coeruleus, 374, 37778, 377f
+
K channels of rules, 505 Longitudinal cerebral ssure, 89
acetylcholine and, 63 sensitive periods and, olfactory Longitudinal localization, 354
modulatory transmitter actions, 45 sensation in, 270 Long-latency stretch reex, 280, 29394,
serotonin receptors, 66 sensory feedback and, 277 307, 320n10
Ketamine, NMDA receptors and, 61 sensory modalities, integration of, 501 Long-term depression (LTD), 51
Key enzymes, 53 signal, pain as, 204 mossy ber signals, 353
Kinesin family, 18, 18f synaptic plasticity, 49, 50f Long-term plasticity, 51
Kinesthesia, 165, 18182, 2023 use-dependent, 40 Long-term potentiation (LTP), 51
dorsal columns and, 195 Length sensitivity, 177 hippocampal plasticity, 475
perception, 190 Lens, far v. near points, 217 memory v., 478
various receptors, 182 Lenticulostriate arteries, 108, 110f NMDA receptors and, 53, 60
Kinocilium, 254 Leptin, 452 psychomotor speed, 14142
K+ ions, 28 Lesion(s), 191 Lower motor neurons, 280, 301
concentration of, 30, 30f, 31f affecting uncus, 269 Low-frequency sounds,
forces acting on, 30f aphasia and, 511 superior olive, 250
unequal distribution, 31f of association areas, 502 Low-threshold C-bers, 169n2
Knowledge systems of brain, 482 of dorsal column, 195 Low-threshold cutaneous
Korsakoffs syndrome, 48081 of dorsolateral prefrontal cortex, 506 mechoreceptors, 171
extraocular muscles, 407 Low-threshold receptors, 162, 165, 180
Labyrinth, 240, 242f, 253 extrastriate area, 23738 around joints, 180
parts of, 24041, 242f, 243 hearing loss and, 247 exion reex and, 290
Labyrinthine artery, 109 of hypoglossal nerve, 397 sensory trigeminal nucleus, 405
Labyrinthine reexes, bodily of internal capsule, 323 signals, 184
posture, 25963 medial longitudinal fasciculus, 367f in skin, 169
Lamellae, myelin sheath, 23, 23f medial temporal lobe, 48081 Low-threshold units, 197
Laminae, 79, 79f, 186, 19697 in medulla, 396, 396f LTD. See Long-term depression
Lamina I neurons, 199n6, 200 medullary pyramid, 323 LTP. See Long-term potentiation
Laminal gland, intermediate nerve, 402 MI, 31314 Lumbar intumescence, 79f
Language, 155, 513 motor cortex, 318 Lumbar nerves, 76
brain and, 16 oculomotor nerve, 408, 408f Lumbar puncture, 98
processing, 510 of parietal lobe, 504 Lungs
and speech, 500 PMA, 318 stretch receptors, 434
speech areas, 50910 posterior parietal cortex, 203, 504 sympathetic bers and, 426
Large intestine, vagus nerve, 399 PPRF, 367 visceral reexes and, 434
Larynx pyramidal tract, 402 Luteinizing hormone (LH), 446
somatic efferent vagus bers, 400 somatosensory area, 2023 Lymphocytes, 454
vagus nerve, 399 sympathetic trunk, 421
Latency, 280 upper motor neurons, 308, 32223 Macromolecules, blood-brain
Lateral corticospinal tract, 304 humans v. monkeys, 308, barrier, 107
Lateral geniculate body, 228f, 229, 229f, 308n1, 308n2 Maculae, 253
230, 495 vagus nerve, 400 Macula lutea, 22425
signal processing in, 22829 visual eld decits after, 232f Magnetic encephalography
Lateral inhibition, 172, 172f, 219 Levodopa, 65, 70, 341 (MEG), 74, 153
Lateralization (of function), 50910 LH. See Luteinizing hormone Magnetic resonance imaging. See MRI
580 INDEX
Magnication factor, 201 Memory, 52, 269 Microtubule-associated proteins (MAPs),

Magnocellular neuroendocrine acetylcholine, 6263 17, 18
system, 446 dendritic spines, 47 Microtubules
Magnocellular red nucleus, 310 elderly v. young, 140 cytoskeleton, 17
Male sex hormones, 516 enriched environments, 135 vesicle movement and, 41f, 42
Malleus, 243 hippocampal-cortical dialogue, 480 Micturition, 435
Malnutrition, 107 hippocampal formation, 47382 Middle cerebral artery, 108, 109f, 110f
Mammillary body, 88 hippocampus, 93, 48182 Middle ear, 241f, 243f
amnesia and, 481 kinds of, 477 Middle superior temporal area (MST), 369
Mammillary nucleus LTP v., 478 Migraine, 105, 437
amygdala and, 463f mammillary nucleus, 445 Migration, 127
connections of, 445f prefrontal cortex, 505 Mimetic muscles, 402
hypothalamus, 445 synaptic plasticity, 49 Miniature EPSP, 42
Mammillothalamic tract, 89 use-dependent, 40 Miniature eye movement, 370
Mandibular nerve, 404 Memory tests, 14243 Mirror movements, 156, 294
MAO. See Monoamine oxidase Meningeal ramus, 80 Mirror neurons, 318
MAO-A. See Monoamine oxidase-A Meninges, 97, 98f Misfolding, 139
MAO-B. See Monoamine oxidase-B Meningitis, 99 Mitochondria, ATP and, 56
MAO inhibitors. See Monoamine Meningomyelocele, 130 Mitral cells, 268
oxidase inhibitors Mental capacity, 140 MLR. See Mesencephalic locomotor
MAPs. See Microtubule-associated Mental fatigue, 470 region
proteins Mental imagery, 178 Modular organization, 234, 343, 356, 388
Masseter reex, 394, 406 Mental state, 383 Modulatory neurotransmitters, 378
Masticatory muscles, 406 Merkel disks, 165, 171 Modulatory synaptic actions, cortical
Maxillary nerve, 404 Mesencephalic locomotor region neurons, 491
Maximal force, 288 (MLR), 313 Modulatory synaptic effects, 46, 374
MBP. See Myelin basic protein Mesencephalic reticular formation, 386, Modulatory transmitter actions, 45
M cells, 228f, 236 387, 497 Modulatory transmitter systems, 67
retinal ganglion cells and, 22627 Mesencephalic trigeminal Modules, 357
MD. See Mediodorsal nucleus nucleus, 368, 405 cerebellum, 343, 356
Mechanoreceptors, 162, 165 Mesencephalic ventral tegmental area cerebral cortex, 488
of skin, 169 (VTA), 337, 495 Molecular layer
Medial forebrain bundle, 472 Mesencephalon (midbrain), 72, 8586, cerebellar cortex, 35051
Medial geniculate body, 92, 495 86f, 87f, 227, 304 neocortex, 486
of thalamus, 248, 248f cranial nerve nuclei, 395f Molecular organization, 48889
Medial lemniscus, 84, 92, 193 dorsal side, 86 Monamines, 64
Medial longitudinal fasciculus, 8485, premotor networks of, 330 plastic changes and, 154
258, 362 red nucleus, 31011 restitution, 150
Medial temporal lobe retinal ganglion cells, 227 Monoamine oxidase (MAO), 66
aging and, 139 Mesial temporal sclerosis, 479f Monoamine oxidase-A (MAO-A), 66
semantic memory, 507 Mesolimbic dopaminergic Monoamine oxidase-B (MAO-B), 66
Medial vestibulospinal system, 337 Monoamine oxidase inhibitors (MAO
tract, 258, 310 Mesolimbic reward system, 337 inhibitors), 70
Mediodorsal nucleus (MD), 494 Metabolic activity, of nerve cells, 56 Monoamine receptors, 58t, 6566
Medium spiny neurons, 32829, 328f Metabotropic glutamate receptors Monoaminergic neurons, 67
Medulla, 72, 8385, 83f (mGluRs), glutamate and, 59 Monoaminergic transmitters, 64
cranial nerve nuclei, 395f Metabotropic receptors, 39, 53, 56, 60 Monocular zone, 217
dorsal side, 85, 86f biogenic amines and, 65 Monomine, drugs altering, 7071
lesions, 396, 396f G proteins and, 42, 43f Monosynaptic stretch reex, 28081,
vagus nerve and, 398 Metaplasticity, 50 289, 291, 292, 320
Medullary conus, 74 Metaraminol, autonomic nervous system Mood, 65
Medullary pyramid, 304 and, 43031 Morphine, 210, 338
Medullary reticulospinal tract, 309 Metencephalon, 119 Morphogens, 118n1, 126
MEG. See Magnetic encephalography mGluRs. See Metabotropic glutamate Mossy bers, 352, 360, 476
Meissner corpuscles, 165, 169n3, 171 receptors fractured somatotopy, 35354
skin and, 169 MI. See Primary motor cortex fractured somatotopy and, 35354
Melanocytes, 118 Microelectrodes, 31 movements, 353
Melatonin Microglia injury, 2627 Motion sickness, 265
degenerative brain diseases, 452 Microglial cells, 19 Motivation, 154, 269, 274, 323
hypothalamus and, 45152 brain, 26 basal ganglia and, 338
Membrane potential, 28, 29, 30f inammatory process and, 25 biogenic amines and, 65
alteration of, 33 Microglial cells scan, 26 cerebral cortex, 492
ion distribution, 30, 30f Microneurographic studies, 207, 297 monoamines for, 376
Membrane proteins, 6, 24 consciousness, 181 nigrostriatal neurons, 336
Membrane resistance, axon and, 36 Ia afferent bers, 178 retinohypothalamic tract, 444
Membranous labyrinth, 240, sensory units and, 173 voluntary movements
241f, 253 vasomotor reexes, 426 and, 31113
INDEX 581
Motoneurons, 77 MRI (Magnetic resonance Myelinated bers, 139, 184
columnar arrangement, 282, 282f imaging), 73, 74f Myelination, 129
excitability, 293 conventional planes of, 92f Myelin basic protein (MBP), 24
size, 286, 286n2 neuronal activity and connectivity, Myelin sheath, 10, 19, 2324, 23f
sleep, 389 15152 Myenteric plexus, 424
-motoneurons, 178, 280 striate area, 23031 Myoglobin, 285
ring of, 298 MS. See Multiple sclerosis Myopia, 218n1
reticulospinal bers, 309 MST. See Middle superior temporal area Myosin ATPase, 285
-motoneurons, 175, 178, 280, 297, Mller cells, 19 Myotome muscles, 394
307, 38182 Multiple sclerosis (MS), 2425, 103, 107
action of, 177f Multipolar neurons, 41415 Na+ ions, 28
animal experiments, 177 Multipurpose hypothesis, 511 equilibrium potential for, 3031
ring, 321 Multisensory integration, 256 glutamate and, 61
reticulospinal bers, 309 Multiunit arrangement, organs, 414 unequal distribution, 31f
selective activation, 178 Muscarinic receptors, 53, 63, 413 Naloxone, 209, 210, 212
Motor aphasia, 511 acetylcholine and, 63 NANC transmission. See Noncholinergic/
Motor areas, 31314 narcolepsy, 359 nonadrenergic transmission
Motor axons sleep, 388 Narcolepsy, 359
neuropathies and, 27 Muscle(s) Narcotic drugs, 337
regeneration of, 300 atrophy, 299 Natural killer cells, 454
Motor control, 378 contraction, 285 Nature, nurture v., 51617
Motor cortical areas ergoreceptors and, 17374 Nausea and vomiting, visceral pain and,
descending pathways, 30123 eye, 407f 437
voluntary movements and, 31319 fascia, 286 Nav1.7 channel, 168
Motor cranial nerve nuclei, 82, 123 nociceptors in, 173 N-CAMs. See Neuronal-cell adhesion
Motor end plates, 283f, 284f viscoelastic properties, 322 molecules
Motor imagery, 318 weak contractions and, 178 Near point of eye, 218
Motor intentions, 318 Muscle cells Neck
Motor learning axon and, 5 labyrinthine reexes, 26162
cerebellum, 343, 35960 skeletal muscles and, 28485 muscles, 397
climbing bers, 353 Muscle bers reexes, 261
Motor neglect, 317 classication, 173 sympathetic innervation of, 41920
Motor networks, voluntary movement skeletal muscles and, 28485 Negative feedback, 57
and, 31319 types, 285f, 286 interneurons and, 10, 49f
Motor neurons, 72, 425 Muscle force Neocerebellar syndrome, 358
Motor performance, age and, 14243 gradation of, 28788 Neocerebellum, 345
Motor systems perception of, 17980 Neocortex
enriched environments, 135 Muscle spasms, 320 emotions and, 469
movements and, 27779 Muscle spindle(s), 165, 175f, 201, 262, external pyramidal layer, 487
Motor thalamus, 315 307, 405 functions of, 500517
Motor tract, cranial nerve nuclei and, extraocular muscles, 36465 layers, 48687, 486f
39496 functional properties, 176, 176f molecular layer, 486
Motor trigeminal nucleus, 394, 406 innervation, 177 Neostigmine, 284
Motor units, 280, 286, 287f innervation of, 175f Neostriatum, 325
ber types and, 287 polysynapatic routes from, 294 Nerve(s), 12
number of, 17576 reticular formation, 309 eye, 407f
Motor unit size, motoneuron signals from, 178 impulses
size v., 286 structure/innervation of, 17475 pathways and, 13f, 14, 14f
Movement(s) Muscle-spindle signals, 36465 patterns of, 38f
classication of, 27879 Muscle tendon, microneurographic synapse and, 5
control, 73 studies, 173 nucleus and, 13f
ber type used, 287n3 Muscle tone, 296 Nerve cell body, 5, 6f
GP and, 338n11 determinate for, 297 Nerve cells, 56, 89, 3839
hands, 317 diseases and, 298 Nerve bers. See Axons
head and eyes, 251 lesions of upper motor neurons, 308 Nerve growth factor (NGF), 128
melodies, 314 reex contraction and, 297 Nerve root, 75
planning, 338 REM sleep, 387 Nerve terminals (terminal bouton), 6f, 7,
purposeful, 316 Musculoskeletal system, 173 9f, 40, 4142
sensation and, 277 Music, lateralization of, 514 presynaptic v. postsynaptic, 47
striate areas, 236 Myasthenia gravis, 284 Nervous system
suppression, 318 Myelencephalon, prenatal development development, 11738
velocity, 180 and, 119 drugs and, 7071
Movement-related Myelin, 23 immune system and, 45455
information, 264 Myelinated axons, 24. See also inhibitory interneuron, exibility of,
Moving stimuli Unmyelinated axons 49, 49f
P cells, 227 conduction velocities in, 37 malformations of, prenatal
striate area cells, 234 impulse conduction in, 36, 37, 37f development and, 12930
582 INDEX
Nervous system (continued) Neuronal time of birth, genetic N-methyl-D-aspartate receptors.

parts of, 7296 programming, 133 See NMDA receptors
postnatal & prenatal development, Neuron migration, 117 NO. See Nitric oxide
11738 Neuropathic pain, 207 Nocebo, 204
programmed cell death and, 128 Neuropathies, 27, 181, 182 Nocebo effect, 211, 21213
Nervous tissue cancer, 27 Nocebo hyperalgesia, anxiety v., 213
astroglial processes in, 22f cramps and, 297 Nociceptive signals, 193
optic properties, 34 gait, 263 peripheral routes, 433
organization of, 518 gait and, 263 Nociceptive signal transmission,
reaction of, 27 Neuropeptides, 5354, 57, 70, 166, 223 descending systems for, 208f
Neural connections colocalized, 69 Nociceptive stimuli, spinothalamic cells,
convergence of, 1314, 14f enteric plexuses, 425 19899
divergence of, 13f nerve terminal and, 69f Nociceptors, 16364, 165, 16668,
Neural crest cells, 118, 118f Neuropeptide Y (NPY) 166n1, 168f, 184
Neural networks, 26465 amygdala and, 468 activation, 168f
brain and, 16, 16f hypothalamus and, 452, 453 alarm system, 199200
Neural plate, neural groove Neurotransmitter(s), 5, 7, 54, 282 heat and, 166n1
and, 119f age, 139, 141 pain perception and, 205
Neural tube anxiety and, 46768 sensory trigeminal nucleus, 405
cranial end, development, 11819 autonomic nervous system, 42931 transmission from, central control of,
defective closure of, 129 colocalization of, 5556 20811
formation of, 118, 118f concentration, 21 visceral receptors, 432
Neuroblasts, 150 excitatory amino acid Node, 16
Neurodegenerative diseases, 14346. transmitters, 5758 Node of Ranvier, 23f, 24, 28, 37
See also specic disease general aspects, 5357 Nonadrenergic transmission, autonomic
aging and, 139 hypothalamus, 44243 nervous system, 430
dementia and, 14346 inactivation of, 4344 Noncholinergic/nonadrenergic (NANC)
molecular mechanisms in, 144 neuronal content of, 54 transmission, autonomic nervous
neurotrophins and, 129 in olfactory bulb, 269 system, 430
Neurodegenerative disorders and receptors, 5371 Nondeclarative memory, 477
blood-brain barrier, 107 release of, 4142 Nonuent aphasia, 511
excitatory amino acid transmitters sleep, 389 Noradrenergic neurons, 67
and, 61 synthesis of, 57 Norepinephrine (Epinephrine), 43, 53,
Neurobrillary tangles, 144 Neurotransmitter receptors, 53 65, 204, 208, 311, 374
Neurobrils, 1617 density, 57 AD and, 145
Neurogenesis, adult brain, 14849 extrasynaptic function, 54, 56f bronchial muscles and, 426
Neurogenic inammation, 208, 208f Neurotrophin family. See Nerve cerebral cortex, 492
Neuroimaging, 105 growth factor chromafn cells, 429
Neuroleptics. See Antipsychotic drugs Neurotrophins, 70, 128 sympathetic stimulation and, 421
Neuromeres, 119, 121 brain injuries and, 129 dopamine -hydroxylase and, 65
Neurometric borders, 122 restitution, 150 postganglionic neurons, 429
Neuromuscular junction, 283 synaptic plasticity and, 128 sensory information processing, 376
Neuron(s) Neurovascular unit, 104, 105f sleep, 389
aging, 140 Newborn synthesis, 54, 55f, 64f
astrocytes and, 19 plantar reex, 322 Novel movement, 317
classications of, 5 REM sleep, 35960 NPY. See Neuropeptide Y
coupling of, 1216 Nexus junction, 40 NRM. See Raphe magnus nucleus
cytoskeleton in, 17f NGF. See Nerve growth factor Nuclear bag ber, 174, 177n5
information integration, 46 Nicotine addiction, AchR subunits, 64 Nuclear chain ber, 174
multipolar, 6, 8f Nicotinic receptors, 53, 63 Nuclei
neural crest cells, 118, 118f Nigra, 331, 331f of auditory pathways, 248f
organelles and, 56 Nigrostriatal neurons, 336 brain hard wiring, 130
pacemaker properties, 312 Nigrothalamic bers, 333 CNS and, 5
prenatal development and, 120 Ninth cranial nerve. See neurons and, 1112
processes of, 512 Glossopharyngeal nerve tract and, 13f
reticular formation and, 376f Nitric oxide (NO), 6869, 106 Nucleus accumbens, 209
spinal gray matter, 77 Nitroglycerin, 69 ventral striatum, 337f
ultrastructure of, 7f NMDA (N-methyl-D-aspartate), receptor Nucleus ambiguus, 398n3
Neuronal activity markers, 3334 agonists, 478, 491 Nucleus ruber. See Red nucleus
Neuronal birth, time of, 130 NMDA receptors (N-methyl-D-aspartate Nurture, nature v., 51617
Neuronal-cell adhesion molecules receptors), 52, 53, 60, 61, 493 Nystagmus, 260, 357
(N-CAMs), 131 alcohol and, 62 vestibular stimulation, 26061
Neuronal excitability, 2839 glutamate and, 59
Neuronal network, 134 ischemic cell death, 148 Obese people, leptin and, 453
Neuronal plasticity, 70 LTP on, 60 Object identication, 235
Neuronal shape, 1617 pain and, 206 Objects/space association, hippocampus,
Neuronal somata. See Cell bodies N-methyl-D-aspartate. See NMDA 48182
INDEX 583
OBPs. See Odorant-binding proteins Organic acids, 107 Pain-related networks, gray & white
Occipital lobe, 91 Organ of Corti, 241, 242f, 243f, 244 matter, 206
Ocular dominance columns, 234, 234f Organs Pallidothalamic bers, 304, 332
Ocular premotor networks, 368 autonomic control and, 414 Pallium, prenatal development and, 124
Oculomotor complex, 408 visceral efferent neurons, 41314 Palpation, muscle tone and, 296
Oculomotor control, 333 Orientation Paradoxical cold (sensation), 169
Oculomotor nerve, 85, 406, 4078 head and body, 379 Parallel ascending auditory
paresis, 408f mammillary nucleus, 445 pathways, 248f
Oculomotor nucleus, 86 Orientation selectivity, 233 Parallel channels, core region, to belt
Odorant-binding proteins (OBPs), 267 Orienting movements, muscle system region, 251
Odorant receptor proteins (ORs), 267 and, 382 Parallel circuits, basal ganglia, 33233
OECs. See Olfactory ensheathing cells ORs. See Odorant receptor proteins Parallel pathways
Olfaction, 26674 Orthodromic impulse conduction, 37 hippocampal formation, 476
Olfactory bulb, 81f, 82, 92, 119, 266, Orthostatic hypotension, 428 reciprocal connections and, 1415, 15f
26869 Oscillatory movements, 293 Paralyzed muscles, 280, 299
olfactory epithelium, 267f Osmolarity, 22 Paramedian pontine reticular formation
Olfactory cortex, 92 Osmotic equilibrium, sodium-potassium (PPRF), 362
processing outside, 26970 pump, 3132 horizontal movements, 367
Olfactory ensheathing cells (OECs), 149 Otoacoustic emissions, 246 lesion in, 367
Olfactory epithelium, 267, 267f Otoliths, 253, 256f neurons, properties, 368
area of, 267n1 Otosclerosis, 247 Paranoid psychoses, 338
Olfactory imprinting, 270 Outer hair cells, sound waves, 24546 Parasympathetic cranial nerves, 432
Olfactory nerve, 72, 82, 268, 268f Ownership, 315 Parasympathetic bers
Olfactory receptor cells, 26768 vestibular apparatus and, 264 effects of, 42829
Olfactory receptors, 271 Oxidative metabolism, neurons pupil (of eyeball), 408
Olfactory signals and, 56 Parasympathetic innervation, 416, 418
behavior of, 270 Oxytocin, 446, 447 Parasympathetic system, 423f
control pathways for, 268, 268f peripheral parts of, 42225
sexual reexes, 270 P1 receptors, 68 Parasympathetic systems, sympathetic
Olfactory system, 26671 P2 receptors, 68 system v., 416
Olfactory tract, 266, 268 P2x receptors, 68 Paravertebral ganglia, sympathetic trunk
Oligodendrocytes, 19 P2y receptors, 68 with, 420f
Olivocerebellar projections, 356 Pacemaker properties Paravertebral plexuses, sympathetic
Omnipause neurons, 368 inferior olive and, 353 trunk with, 420f
Operant conditioning, 477 neurons and, 312 Paresis, 251. See also Central pareses
Ophthalmic artery, 108, 109f nuclear neurons and, 355 abducens nerve, 407f
Ophthalmic nerve, 404 Pacinian corpuscles, 165, 170 of genioglossus muscle, 397
eye movements and, 365 PAG (Periaqueductal gray), 204, 208 of lateral rectus muscle, 364
Ophthalmoplegia, 366 fear response, 465 lesions of MI, 31314
Opiate receptors, 210 stress responses, 209 oculomotor nerve, 408, 408f
Opiates, 210 Pain, 203, 20414, 378 of right abducens nerve, 407f
Opioid-dependent analgesia, 209 behavior, 205 stroke and, 152
Opioid peptides, 208, 209, 210n4, 496 cordotomy and, 197 Paretic muscles, contractile
Optic chiasm, 88, 132, 227, 232 default-mode network, 508 properties, 322
Optic nerve, 72, 86, 88, 215, 225f A bers and, 184 Parietal association areas, 5023
Optic nerve bers, 229 distinctive features, 2045 Parietal insular vestibular cortex
Optic papillae, 227 expectation, 211, 467 (PIVC), 263, 263n4
optic nerve and, 225f importance of, 2045 Parietal lobe, 91
Optic radiation, 215, 229f, 304 insula and, 508 Parieto-occipital sulcus, 91
visual defects and, 233 intensity, interneurons and, 10 Parietotemporal region, 362
Optic system, visual pathway damage, receptors, 68 Parkinsons disease, 65, 70, 29899, 318,
231, 231f sensation, 20811 332, 333, 334, 339, 34041, 403
Optic tract, 227 system, out-of-control, 2057 gait disturbances, 313
damage, 233 that radiates, 206 levodopa, 70
Optokinetic eye movements, elderly, 142f treatment, 21314 PPN and, 332
Optokinetic nystagmus, 260, 365, 370 Painful stimuli, 46 therapeutic approaches, 341
Optokinetic reexes, 368 Pain-induced analgesia, 210 Parotid gland, glossopharyngeal
Optokinetic reex movements, 365 Pain-modulating systems, 21011 nerve, 401
Orbitofrontal cortex, 269, 274 Pain network, 203, 213 Pars compacta, 330, 331
behavioral exibility and, 469 expectancy and, 211 Pars reticulata, 33031
conditioned taste aversion, 274 Pain perception Parvocellular neuroendocrine
hypothalamus, 444 ascending connections modulating, system, 447
pain system and, 205 20910 Parvocellular pathway, 236
Orexin. See Hypocretin cerebral cortex and, 202f Passive stretch
Organelles depression, 213 of muscles, 286
neurobrils, 17 emotional, 198 tendon organs and, 179
neurons and, 56 spinothalamic tract, 198 Patellar reex, 28081
584 INDEX
Pathologic pain, 204, 205, 207 Phenotypes, 33 Plastic processes, 320

Pathologic yawning, 388 Phentolamine, autonomic nervous Plateau potentials, 3839, 298
Patterns, striate areas, 236 system and, 431 postural tasks and, 311
P cells, 228f, 236 Pheromones, 27071 Plate potential, 284f
retinal ganglion cells and, 22627 Phonologic analysis tests, 510 Plexuses, 80, 166, 280
Pedunculopontine nucleus (PPN), 332 Photopic vision, 221 PMA. See Premotor area
Pelvic organs, postganglionic Photoreceptor-Na+ channels, 221 PMP-22. See Peripheral myelin
parasympathetic system and, 424 Photoreceptors, 162, 215 protein-22
Pelvic plexus, 422f density of, 225 PNS. See Peripheral nervous system
Pelvis, sympathetic innervation, 42122 depolarized state of, 221 POA. See Preoptic area
Penicillin, blood-brain barrier, 107 postural control and, 31112 Poison, 284
Penis, 424 process of, 218 Poliomyelitis, 282
Penumbra, 147 Physical activity Polymodal nociceptors, 167, 181
Perception of melody, 514 aging brain, 143 Polymorphism, 66
Perforator arteries, 110 benecial effects, 128 Polysynaptic information, 34748
Periaqueductal gray (PGA), 86, 381 Physostigmine, 284 Polysynaptic reex, 290
autonomic functions and, 441 Pia, 97 Polysynaptic stretch reex, 280
visceral pain and, 437 neural crest cells, 118, 118f Pons, 72, 84f, 85
Perihypoglossal nuclei, 368 Pia mater, 97 conditioned taste aversion, 274
Perimetry (of eye), 217 Pigmented epithelium, 218, 218f cranial nerve nuclei, 395f
Perineurium, 26, 26f Pillar cells, 244 dorsal side, 85, 86f
Peripheral axons, 299 Pilocarpine, autonomic nervous system prenatal development and, 123
Peripheral facial pareses, 402, 403f, 406 and, 43031 sleep, 388
Peripheral lesions (of auditory system), Piloerection, 427 Pontine nuclei, 85, 132
hearing loss and, 247 Pineal body, 89 Pontine reticular formation, 382
Peripheral motor neurons, 280 blood-brain barrier, 108 Pontine reticulospinal tract, axial
injury of, 299 prenatal development and, 124 muscles and, 309
and reexes, 280300 Pineal gland, melatonin, 45152 Pontine reticulotegmental nucleus
Peripheral myelin protein-22 Pitch, sound waves and, 240 (PRN), 369
(PMP-22), 23n2 Pituitary gland, 89 Pontocerebellar tract, 348
Peripheral nerves, 12, 25f, 75 hypothalamus and, 442f, 44546 Pontocerebellum, 345f
axons and, protection of, 26 PIVC. See Parietal insular Population coding, 274
connective tissue components, vestibular cortex Position, upright, 31112
layers of, 26 Placebo analgesia, brain regions Positron emission tomography. See PET
diseases of, 27 and, 212f Postcentral gyrus, 92
injury of, 299 Placebo effect, 204, 21112, 212 Posterior cerebral arteries, 110
pressure and, 185 Place cells, hippocampus, 48182 Posterior communicating artery, 110
skin and, 427 Plantar reex, 322 Posterior inferior cerebellar
Peripheral nervous system (PNS), 5 Parkinsons disease, 340 artery, 109, 109f
damaged axon and, 23 upper motor neuron lesions, 32223 Posterior median ssure, 74, 75f
NO and, 68 Plastic changes, 2067 Posterior parietal cortex, 190, 202, 303,
Peripheral pareses, 299, 299f altered brain networks and, 2067 314, 500
of hypoglossal nerve, 397, 397f Plasticity, 40, 42, 4952, 70, 117, association connections, 5023, 503f
negative v. positive symptoms, 31920 13638, 137f, 204, 268, 353n5, lesions of, 504
Peripheral receptors, 139, 141 475. See also Synaptic plasticity parcellation of, 502n1
Peristolic contractions, parasympathetic biogenic amines and, 65 single neurons in, 5034
bers, 428 brain injury and, 147 subregions within, 5023, 503f
Permeability, 2829 calcium concentration, 50 vestibular nuclei and, 258
Perseveration, 506 central pain system, 21314 voluntary movements and, 319
frontal lobe damage, 318 cerebral palsy, 15556 Posterior pituitary
Persistent vegetative state, 387 cortical, 49091, 493 bloodbrain barrier, 108
PET (Positron emission tomography) elderly, 142f hypothalamus v., 446
neuronal activity and connectivity, environmental challenges, 50 prenatal development and, 124
studying, 15152 horizontal connections, 49091 Posterior spinal arteries, 110
striate area, retinotopical organization horizontal integration, 493 Postganglionic bers, 419
of, 23031 hypothesis, 388 synapses and, 414
visual imagery and, striate learning, 49, 50f Postganglionic nerve terminals,
area and, 239 LTP, 475 presynaptic receptors and, 430
PGA. See Periaqueductal gray memory, 40, 49 Postganglionic neurons, 413, 429
Phantom pain, 207 neuronal, 70 Postherpetic neuralgia, 207
Pharynx neurotrophins, 128 Postmitotic neuroepithelia cells, 125
glossopharyngeal nerve, 401 NRM, 475 Postnatal development, nervous system,
somatic efferent vagus bers, 400 pain system and, 205 11738
Phasic reex responses, 259, 261 sensitive periods, 136 Postprandial hypotension, 428
Phasic stretching, 292 sensory cortical areas, 49091 Postrotational past pointing, 260
Phasic stretch reex, 292 short-term, 50 Postrotatory nystagmus, 260
Phencyclidine, NMDA receptors and, 61 sleep and, 388 Postsynaptic density, 6f, 7
INDEX 585
Postsynaptic dorsal column neurons, 193 Primary afferent bers, dorsal columns Pseudogenes, 267
Postsynaptic membrane, 7, 9f, 39 and, 193 Pseudounipolar neurons, 6, 8f
depolarization of, 42 Primary afferent units, taste cell Psychological reward mechanisms, pain
Posttetanic potentiation, 51 specicity and, 273 and, 213
Postural control, 379 Primary afferent vestibular bers, 258 Psychomotor speed
development, 312 Primary auditory area, 251 elderly and, 14142
neuropathies, 263 thalamocortical axons, 240 elderly v. young, 140
reticulospinal tracts, 309 Primary auditory cortex Psychophysical phenomena, horizontal
Postural reexes, 253, 31113 (A1 core region), 249 connections as, 493
CNS and, 262 monkey studies, 251n6 Psychosis, ventral striatum and, 33738
Parkinsons disease, 340 neurons, 251 Psychosomatic disorders, 456
Postural tasks, plateau potentials treatment, 252 Psychosomatic interrelations, 440
and, 311 Primary motor cortex (MI), 301, 334 hypothalamus, 455
PPN. See Pedunculopontine nucleus commissural connections, 499 Ptosis, 284
PPRF. See Paramedian pontine reticular connections of, 315 Pulvinar, 87, 231
formation nger tapping and, 315 Punishment and reward, pain and, 205
Pre-Btzinger complex, 382 functional organization, 316 Pupil (of eyeball), 215
Precerebellar nuclei, 348n1 lesions, pareses and, 31314 parasympathetic bers, 408
Precision grip locomotor movements, 313 Pupillary constriction, 220, 366
cerebellar lesions, 358 proprioceptors and, 200 accommodation reex, 409
cutaneous receptors and, 295 regions of, size of, 316f Pupillary sphincter muscle, 216
Precursor cells, differentiation of, 117 of rodents, descending axons Purinoceptors, 27172
Prefrontal cortex, 238, 348, 500, 5046 from, 133 Purkinje cell dendritic tree, cerebellar
aging, 140 single neurons of, 31617 cortex, 35051
association connections of, 505f SMA, 317 Purkinje cell layer, cerebellar cortex,
emotions and, 469 somatotopic organization, 303, 303f 35051
functional specializations within, 505f Primary olfactory cortex, 269 Purkinje cells, 344, 351, 35455, 359
Prefrontal lesions, symptoms, 506 Primary sensory ending (of muscle climbing bers, 353
Preganglion bers, sympathetic trunk spindle), 174, 176 mossy/climbing bers, 352
and, 41819 Primary sensory neurons, 70, 190 nuclear neurons and, 355
Preganglionic neurons, 77, 413, 429 Primary somatosensory area, 2012 Pursuit movements, 370
visceral efferent bers, 413 Primary taste afferents Putamen, afferent
Preganglionic parasympathetic bers, (sensory units), 273 connections, 327, 327f
cranial nerves and, 42224 Primary taste areas, 274 Pyramidal cell collaterals, intracortical
Preganglionic parasympathetic neurons, pathways, 27374 connectivity and, 49091
cell bodies of, 422 Primary vesicles, 118, 119f, 120f Pyramidal decussation, 82f, 83
Preganglionic sympathetic neurons, 413 Primary vestibular afferents, 346 Pyramidal tract (Corticospinal tract), 73,
Premenstrual syndrome, psychic Primary visual cortical area, 227 83, 3018, 348
functions and, 456 PRN. See Pontine reticulotegmental conduction velocity, termination
Premotor area (PMA), 301 nucleus and, 306
lesions of MI, 314 Proglumide. See Cholecystokinin course and crossing of, 302f, 3045
Premotor networks, 330, 362, 365, 373 Programmed cell death, 12728, 13233 cranial nerves and, 395, 396f
reticular formation, 378 Projection neurons, 5, 89, 11f, 132, early damage, 156
Prenatal development, 11735 328n2 emotion, 403
external limiting membrane, 120 collateral of, 11f facial muscles and, 402, 403
eye, 124 collaterals, 6f, 8, 11f bers
nervous system, 11738 Prolactin, 446, 449 conduction velocities of, 306
Preoptic area (POA), fever, 450 Prolactin-releasing hormone (PRH), 449 monosynaptic cortico-motoneural
Presbyopia, 218 Proprioceptive feedback, 182 connections, 306
Presenile dementia, 144 Proprioceptive low-threshold spinal reex arcs and, 307
preSMA. See Presupplementary mechanoreceptors, 165 function, 3078
motor area Proprioceptive signals, 163, 368 jaws, voluntary movement, 406
Pressure perception, 190 Proprioceptors, 159, 163, 165, myelination and, 129
Presupplementary motor area 18283, 201 origin of, 3034, 303f
(preSMA), 317 deep sensation, 172 position and crossing of, 3056
sequential movements, 319 Propriospinal bers, 78, 79, 193, 313 position and somatotopic pattern, 305f
Presynaptic facilitation, 48 Propriospinal neurons, 72, 79, 79n2 terminal regions of, 306f
Presynaptic inhibition, 47, 292, 295, 320 Prosencephalon, prenatal development Pyramidal tract syndrome, 323
axoaxonic synapses and, 47f and, 119 Pyridostigmine, blood-brain
mechanisms involved, 48 Prosopagnosia, 238, 502, 507 barrier, 107
Presynaptic membrane, 7, 9f, 57, 64f Protein, 31 Pyrogens, fever, 450
Presynaptic transmitter receptors, 57 Protein kinases, 42
Pretectal nuclei, 231 Protein synthesis Quanta, neurotransmitters and, 42
Prevertebral plexuses, 416, 422 altered, 50
Prevertebral sympathetic ganglia, 419 neurons and, 56 Radial glia, prenatal development
PRH. See Prolactin-releasing hormone rER, 6 and, 125
Priapism, 436 Prozac. See Fluoxetine Ramp movements, 278
586 INDEX
Raphe magnus nucleus (NRM), 67, 209, peripheral motor neurons Retinoic acid, prenatal development
373, 374, 37677, 376f and, 280300 and, 122
efferent connections, 377f postural control and, 312 Retinotopic localization, 230
hippocampal plasticity, 475 structural basis of, 289 Retrograde amnesia, 479
Raphe neurons, 359n8 suppressed voluntarily, 289 Reward-based movement control, 317
Raphespinal bers, serotonin and, 311 trigeminal nerve and, 4056 Rexeds lamina IX, spinal cord
rCBF. See Regional cerebral blood ow visual pathways, 215 and, 282
Readiness potential, 313 Reex arc, 280, 289f Rhinencephalon, 266
Reading, eye movements, 366 Reex sympathetic dystrophy (RSD), 207 Rhodopsin, 219, 221
Receptive elds, 172f Refractory period, 35 Rhombencephalon, 118, 119
convergence and, 160 Regeneration cranial nerves from, 121f
as dynamic, 160 axons of, 23 prenatal development and, 119
of sensory neuron, 159 factors inuencing, 299 Rhomboid fossa, 99
Receptor(s). See also specic receptors Regional cerebral blood ow (rCBF) Rhombomeres, prenatal development
classication of, 163 cognitive tasks and, 500501 and, 119, 121
bers from, 18687 neuronal activity and, 1056 Rhythm, nger movements in, 359
mechanical forces, 161, 162f stroke and, 152 Rhythm generators, 301, 31213
postural control and, 31112 REM sleep, 387, 388 Rhythmic ring, 69
properties and classication Renshaw cells, 293, 307, 312, 320 inferior olive and, 353
of, 16162 Repair processes, 19 Rhythmic locomotor
sensory experience, 16364 Repetition movement, basal ganglia movements, 313n4, 382
in skin, 166 and, 338 Rhythm perception, 361
stimulus energy and, 162 Repetitive behavior, Tourettes timing (of events) theory, 359
types, 26263 syndrome, 342 Right hemisphere (of brain)
2 receptor, 429 Repolarization, 28 emotion, 51415
2 receptor, 429 rER. See Rough endoplasmic language and, 51314
p75NTR, 128, 128n6 reticulum Right hemisphere lesions, 515
Receptor potentials, 159 Resonance theory of Helmholtz, 246 Right-left confusion, 504
hyperpolarization and, 245 Respiration, 301 Rigidity, 339
sensory cell and, 16061 reticular formation, 82, 382 Parkinsons disease, 340
Receptors Respiratory organs, autonomic nervous spasticity and, 29899
temperature, 161 system, 426 Rinne test, 247
withdrawal symptoms, 57 Resting muscle tone, 280, 297 Rods, 215, 22021
Receptor site, binding of Resting potential, 28 Root compressions, dermatomal
transmitter molecule, 32 Resting tremor, 339 maps, 185f, 186
Reciprocal connections, 16f Restitution, 150, 15556 Rostral ventrolateral medulla
cortical areas, 498 Retardation, movements and, 322 (RVLM), 382
feedback, 1415, 15f Reticular formation, 72, 259, 3089, Rotational VOR, 366
parallel pathways and, 1415, 15f 315, 332, 374f, 375f, 433 Rough endoplasmic reticulum (rER), 280
Reciprocal inhibitions, 293, 307, 320 afferent connections of, 380 light microscopy, 6, 7f
Reciprocal thalamic connections, 497f through brain stem, 8283 protein synthesis and, 6, 6f
Recruitment, 288 circulation, 82 Round window, 243, 24445
Rectum dendrites and, 375f RSD. See Reex sympathetic dystrophy
emptying reexes, 434 efferent connections of, 37879 Rubrospinal tract, 310
postganglionic parasympathetic functions of, 38183 Rufni corpuscles, 165, 171
system and, 424 integration, 374 slowly adapting, 170
sympathetic bers and, 427 mental processes, 38283 RVLM. See Rostral ventrolateral medulla
Recurrent collaterals, 293 pathways, 386
Recurrent inhibition, 293f, 320 position, 379f Saccades, 365, 369
Red muscles, 28485 structure and connections, 37381 Saccadic movement, 362, 365
Red nucleus (Nucleus ruber), 315 superior colliculus, 380 head direction and, 260
inferior olive, 352 vestibular nuclei and, 258 Saccular maculae, 255f
mesencephalon and, 31011 Reticular thalamic nucleus, 384 Sacculus, head position and, 255
Reelin, Cajal-Retzius cells, 127 GABAergic neurons and, 49697 Sacral nerves, 76
Referred pain, 173, 199, 432, 436, Reticulospinal bers, 3089 Sagittal zones, cerebellum, 356
438, 438f Reticulospinal tracts, 309 Saliva, secretion of, 4034
Reex, 28889 Retina, 21827, 218f, 220f Salivary glands, 273
centers, 289, 399400, 41415 central v. peripheral parts, 225, 226f Salt concentration (of blood),
central modulation of, 295 interneurons in, 22223 subfornical organ and, 108
contraction, 297, 300 signal transmission in, 22122 Scala tympani, 241
during development, 289 Retinal, 219 Scala vestibuli, 243
facial nerve and, 403 Retinal ganglion cell, 219, 222, 222f, Schaffer collaterals, 476
fundamental properties of, 288 22627 Schizophrenia, 509
head movements, 310 monkey, 226f Schwann cells, 23, 26, 149, 166, 299
masticatory muscles, 406 receptive elds of, 223 PNS and, 19
modulation, 295 Retinal slip, 365 Sciatica, 186, 282
arm muscles, 296 Retinohypothalamic tract, 444 Sciatic nerve, cross-section, 25f
INDEX 587
Scopolamine, acetylcholine receptors Sensory trigeminal nucleus, 84, 85, Size principle of recruitment, 288
and, 64 401, 405 Skeletal muscle(s)
Scotopic vision, P cells, 22627 subdivisions, 405 actions on, 38182
Secondary sensory ending (of muscle Sensory unit, 159 sensory innervation of, 174f
spindle), 174 density of, 171, 172f sympathetic bers and, 426
Secondary vestibular afferents, 346 and receptive elds, 15960, 159f Skeletal muscle cells, acetylcholine
Segmental innervation, 18586 Sensory visceral neurons, visceral reexes and, 63
Segregation, 23536 and, 43239 Skin
striate areas, 236 Septal nuclei, 471 mechanoreceptors of, 169
Seizures, children and, 155 Septum, endocrine cells of, neural crest peripheral nerves and, 427
Selective cell death, 117 cells, 118 sympathetic bers and, 427
Selective serotonin-uptake inhibitors. Septum pellucidum, 99 Skin receptors, microneurographic
See SSRIs Sequential movements, timing (of events) of, 171
Self-recognition, motor systems and, 278 theory, 359 Skull fractures, cochlear nerve and, 247
Semantic analysis, tests for, 510 Serotonergic neurons, 67, 374, 386 Sleep, 373, 38790
Semantic memory, 47778 Serotonin, 43, 65, 6667, 204, 208. cerebral cortex, 15
medial temporal lobe, 507 See also Raphe magnus nucleus cholinergic neurons, 388
Semicircular duct receptors, angular AD and, 145 dorsolateral pons, 388
acceleration, 255 hypothalamus and, 451 hippocampal-cortical dialogue, 480
Semicircular ducts, 25455 plateau potentials, spinal motor hypothalamus and, 45051
Senile plaques, 144 neurons and, 39 reticular formation, 82
Sensation raphe nuclei and, 378 Sleep hypothesis, 388
discriminatory aspects, 190 raphespinal bers, 311 Sleep-wake-cycle, hypothalamus
service of, movements in, 277 sensory information processing, 376 and, 451
Sense organs, 159 sleep, 389 Slowly adapting low-threshold
Sensitive periods (critical period), 136 synthesis, enzymes in, 64f mechanoreceptor, 170
cellular mechanisms and, 137 taste buds and, 272 Slow pain, 184
in humans, examples, 138 Serotonin receptors, groups of, 6566 Slow-pursuit movements, 362
start and end of, 13738, 137f synthesis, 58t, 65n9 Slow twitch, 285
Sensitivity, v. specicity, pain system Serotonin reuptake inhibitors, pathologic Slow-wave sleep, 387
and, 205 yawning, 388 SMA. See Supplementary motor area
Sensitization, 206, 430 Serotonin transporter, gene Small cells, 374
nociceptors, 168 coding for, 66 Small molecule transmitters,
Sensorineural (nerve) deafness, 247 Seventh cranial nerve. See Facial nerve colocalization of, 70
Sensory aphasia, 511 Sex differences, and lateralization, 516 Smell, receptor cells for, 26667
Sensory cranial nerve nuclei, 82 Sex hormones, hypothalamic neurons Smooth muscle cells
Sensory feedback, 277 and, 445f gap junctions, 414
Sensory bers Sexual dimorphism, 436 muscarinic receptors and, 63
categories, 18485 Sexual reexes, olfactory signals, 270 Smooth-pursuit movements, 365
dorsal roots and, 18386 Shift behavior, locus coeruleus, 378 Snake venom, 64, 284
ventral branches (of spinal nerves), 185 Shingles, dermatomes and, 186 Social adaptation
ventral nerve root and, 184 Short-term depression, 51 frontal lobe lesion, 506
to visceral organs, 433f Short-term plasticity, 50, 51 prefrontal cortex, 505
Sensory information Sickness behavior Social behavior, pheromones, 270
context and, 49 silent nociceptors, 169 Social disinhibition, amygdala, 466
inhibitory synapses, 48 visceral afferent vagus bers, 399 Social experience, brain, 136
insula, 500 Sigmoid sinus, 112 Social pain, 205
loss of, 213 Signal-to-noise ratio, 67 Sodium-potassium pump, osmotic
processing, outside SI, 202 age-related decline, 141 equilibrium and, 3132
Sensory innervation, from trigeminal cerebral cortex, 492 Soma, 5
nerve, 105 at synapse, 39 EPSP recorded in, 47
Sensory nerve bers, 78 Signal transmission, at synapse, 41f Somatic afferent bers, 391
Sensory neurons (Spinal ganglion cells), Sign of Babinski, 322, 323f cranial nerves, 391
68, 72, 183, 208f Signpost molecules, 131, 132 trigeminal nerve, 404
dorsal roots and, 78 Silent nociceptors, 165, 167, 168, Somatic afferent nuclei, 394
enteric plexuses, 425 181, 432 Somatic efferent bers, 400
GABAB receptors, 62 Silent synapses, 5152 cranial nerves, 391
hypothalamus, 443 NMDA activation, 51f hypoglossal nerve, 39697
in spinal cord, 78f Simple cells, 233 Somatic motor neurons, 77
pyramidal tract and, 307 Simple cuboid epithelium, 99100 Somatosensory cortex, 190
Sensory nuclei of vagus, 82f, 85 Simultanagnosia, 502 association connections, monkey, 497f
Sensory receptors, 15964 Sinemet, 65 commissural connections, 499
adequate stimulus of, 159 Single cell activity, recording, 31 cortical regions, 200203
classication of, 159 Single-spike neurons, 38, 38f thalamic afferent nucleus of, 198f
kinds of, 160f Single-unit arrangement, organs, 414 Somatosensory loss, 183, 501
Sensory signals, 343 Sinuses, venous blood and, 11112 Somatosensory pathways, 190, 193f
Sensory stimuli, 466 Sinus nerve, baroreceptors and, 401 central, 190200, 191f
588 INDEX
Somatosensory regions, 201f ventricular system, 81 Sternocleidomastoid, accessory nerve

Somatosensory system vestibular nuclei and, 258 and, 397
central parts of, 190203 Spinal ganglion, 7576, 184f Stiffness of neck, meningitis and, 99
peripheral parts of, 16589 Spinal ganglion cells. See Sensory Stimulation experiments, 191
Somatostatin, 448 neurons Stimulus, 280, 290. See also Nociceptive
Somatotopical organization, of MI, 303 Spinal gray matter stimuli
Somatotopic localization, 354 neuron types, 77 action potential, 164
Sound localization, 24950 spinal cord, 77 threatening, PGA, 441
superior olive and, 250 zones of, 79 for visceral nociceptors, 437
Sound pressure Spinal interneurons, 68, 70, 72, 295, 347 Stimulus energy
logarithmic scale for, 244 cell groups and, cooperation origin of, 163
measurement of, 244 between, 7879 receptors and, 162
Sound waves, 240 signal pathways, switching of, 296f Stimulus recognition memory, perirhinal
cochlea and, transmission to, 24344 Spinal lamina, amygdala and, 463 cortex, 479
outer hair cells and, 24546 Spinal motor neurons, 132, 378 Stomach
Sour substances, 272 Ib ber afferents, 179 distension of, taste bud signals
Spasticity, 320 serotonin, plateau potentials, 39 and, 274
baclofen, 322 Spinal nerve roots, 103 vagus nerve, 399
development of, 32021 Spinal nerves, 7576 VIP and, 430
lesions of upper motor neurons, in branches (rami), 7980 Strabismus, 229, 230, 407
humans, 308 prenatal development and, 124 Straight sinus, 112
Spatial features, 235 spinal cord and, 7576 Strength of response, 292
Spatial memory, 332 Spinal network, locomotion and, 134 Stress, hypothalamus, 457
Spatial orientation, 500 Spinal reex arcs, pyramidal tract Stress-induced analgesia, 211
hippocampus, 481 bers, 307 Stress responses, PAG, 209
Spatial resolution, 221 Spinal reexes, 262, 289 Stretching, muscle tone and, 296
Spatial summation, 45 Spinal segment, 7677, 80 Stretch receptors, lungs and, 434
visceral receptors, 432 Spinal tract of trigeminal nerve, 405 Stretch reexes, 280, 290, 291
Spatial tasks, gender and, 515 Spinal trigeminal nucleus, 405 external resistance, 295
Special somatic afferent vestibulocochlear Spinal white matter, spinal cord, 77 precision movements and, 295
nerve, 394 Spines, of dendrites, 6, 6f, 9f, 10f function of, 29495
Species-specic sounds, 252 Spinocerebellar tracts, 347, 347f Jendrassik maneuver and, 292f
Specicity hypothesis, 511 Spinocerebellum, 236f, 343 Striatal interneurons, 32930
Specic thalamic nuclei, 191, 493, 494 Spinoreticular bers, 379 Striatal projection neurons, 32829
Speech, left hemisphere, 500 Spinoreticulothalamic pathway, 380 Striate area, 227, 229f, 230
Speech ataxia, 359 Spinothalamic cells, nociceptive color-specic blobs, 234f
Sperry, R., split-brain patients, 513 stimuli, 19899 commissural connections, 499
Spina bida, 130 Spinothalamic pathway, cranial dorsal pathways, 23536
Spinal cord, 72, 7480, 75f nerves, 395 dorsal & ventral pathways, 235f
1 afferents, 293n6 Spinothalamic tract, 190, 196, 196f, 380 neurons in, properties of, 23334
afferents from, 346 terminations of, 198 retinotopical organization of, 23031
anchoring of, 98 Spinothalamic tract units, transition, 490f
arterial supply, 111f properties of, 197 visual awareness, 23839
arteries and, 110 Spiny stellate cells, cortical neurons, 491 Striatum, 94f, 324, 325, 331, 331f
brain stem nuclei and, 309f Spiral ganglion, 24748 afferent connections, 326, 327f
brain stem to, monoaminergic Splanchnic nerves, 432 compartments in, 330
pathways, 311 preganglion bers as, 419 dopamine depletion in, 336
cervical level, 80f Split-brain patients dopamine in, 33435
cross-section, lumbar level, 75f corpus callosum, 513 matrix, 330
bers to, 258 studies of, 513 prefrontal efferents and, 505
intermediate zone, 350 Spontaneous nystagmus, 261 Striosome, 330
lumbar level, 79f SSRIs (Selective serotonin-uptake Stroke
motor pathways to, inhibitors), 70 of left hemisphere, 515
direct/indirect, 302f avors and, 273 recovery after, 15253
myelination and, 129 Stabilizing, and moving, 278 studies, 15253
neurons, 13f, 76f Staining methods, neurons and, 6, 7f, 8f restitution after, phases, 151
painful stimuli and, 46 Stapedius reex, 403 Strychnine, glycine receptors, 61
nociceptors in, signal transmission Stapes, 243 Subarachnoid hemorrhage, 97
from, 197f Startle response, 25051 meningeal irritation, 99
prenatal development and, 12224 Static sensitivity, 176 Subarachnoid space, 97, 101f
repair, axonal regeneration, 149 receptors and, 163 Subcortical afferents, 378, 493
segments, 72, 7677 Stem cell transplantation, 341 Subcortical pain network, 213
sensory neurons in, pyramidal tract Stereochemical theory, 267 Subdural hematoma, chronic, 112
and, 307 Stereocilia, 24445, 245n4, 254 Subdural space, 9798
subarachnoidal space of, meninges Stereoscopic vision, 234, 366 Sublingual salivary glands, intermediate
and, 98f Stereospecicity, 266 nerve, 402
subunits of, brain and, 80 Stereotyped voluntary movements, Submandibular gland, intermediate
venous drainage of, 113 of extremities, 309 nerve, 402
INDEX 589
Substance P, 166, 168, 181, 496 nerve impulse and, 5 Telencephalon, prenatal development
with glutamate, 70 neuronal activity and, 117 and, 124, 125f
pain and, 206, 438f neurotransmitter handling, 4144 Temperature, 169
vasodilation and, 439 postganglionic bers, 414 adequate stimulus, 169
Substantia gelatinosa, 186, 209f signal transmission at, 41f hypothalamus, 66
Substantia nigra, 67, 86, 327, 328f, silent, 5152 receptors and, 161
33031 types of, 4449 Temporal association areas, 500
Parkinsons disease, 340 Synapsin Temporal association cortex, 5067
Substitution, 15051 actin laments and, 41f, 42 Temporal intervals, timing (of events)
brain damage and, 147 phosphorylation of, 42 theory, 359
examples, animal studies, 15354 Synaptic actions, fast v. slow, 45, 45f Temporal lobe, 91, 269
Subthalamic nucleus, 333 Synaptic cleft, 7 declarative memory, 478
ongoing movements, 334 transporters and, 43, 44f Temporal plane, 251, 511
Subthreshold depolarization, 45 Synaptic connections, nervous system Temporal summation, 45
Sucking reex, 289 development, 117 Tendon organs, 165, 17879
trigeminal nerve and, 406 Synaptic density, restitution, 15354, adequate stimulus, 17879
Sudden infant death syndrome, 382 154f autogenic inhibition of, 307
Summation, 14f, 45, 45f Synaptic efcacy, change of, 50 contracting muscle, 180
Supercial veins, 111 Synaptic integration, examples, 46 functional properties, 179f
Superior cervical ganglion, head and, 420 Synaptic numbers, aging and, 139 nociceptors in, 173
Superior colliculus, 23031 Synaptic plasticity, 42, 4952, 57, 67 Tenth cranial nerve. See Vagus nerve
early development, 133n7 calcium concentration and, 50 Terminal bouton. See Nerve terminals
reticular formation, 380 drugs and, 70 Tertiary sensory neuron, 190
vestibular nuclei and, 258 kinds of, 50 Testosterone, psychic functions and, 456
Superior colliculus receptors, gradients mechanisms for, 50 Tetanic contraction, 284
of, 133 neurotrophins and, 128 Tetanic tension, 288
Superior oblique muscle, 363 use-dependent, 40, 117 Tetanus, 284
Superior olivary complex, 249 Synaptic potentials, 39, 4449, 44f, 45f Tetanus toxin, 43
Superior olive, sound localization Synaptic signal transfer, 43 glycine and, 61
and, 250 Synaptic vesicles Tetany, 36
Superior rectus muscle, 363 recycling of, 41f Thalamic lesions, 481
Superior sagittal sinus, 11112 transport of, 42 Thalamic nuclei, 191
Supplementary motor area (SMA) Synaptogenesis, synaptic plasticity, 50 SI, 198f
imagining, 514 Synchronization (-waves), Thalamic pain, 207
lesions of MI, 314 of EEG, 385 Thalamocortical connections, 356f
in MI, 317 Synchronized network activity, 508, retinotopic arrangement of, 230
Supporting cells, 267 508n5 Thalamocortical neurons
cilia and, 244 visual awareness and, 239 activity states, 384
Supramotor areas, 314 Synchronous ring, Purkinje disinhibition of, 334
Sweat glands, sympathetic bers cells, 355 Thalamocortical pathway, 194
and, 427 Syntaxin, botulinum toxins and, 43 Thalamocortical projection, 494, 494f
Sweets, cats, 272 Thalamostriatal bers
Sweet substances, 272 Tactile agnosia, 203 glutamate and, 333
cats, 272 Tactile recognition task, 361 sources of, 328
Switching, 324 Target organs, trophic factors Thalamotomy, 340
Sylvian ssure, 91, 91f and, 13031 Thalamus, 7273, 87, 87f, 88f, 90,
Sympathectomy, 437 Target size, 12728 190, 259, 273, 355, 433,
Sympathetic block, 437 Taste 487, 496f
Sympathetic ganglion, embryonic life, conscious experience of, 274 GABAergic efferent connections, 324
41819 qualities, 272 histamine and, 66
Sympathetic system receptor cells, 266 inhibition to, 49697
control, function-specic, 428 receptors, 27172 pain and, 206
CRPS and, 207 cortical regions and, 273f premotor networks of, basal ganglia
parasympathetic systems v., 416 signals, 271n1 and, 330
peripheral parts, 41822 pathways, 271f, 27374 prenatal development and, 124
Sympathetic trunk, 413, 419f Taste buds, 266, 27172, 271f REM sleep, 387
with paravertebral ganglia, 420f brain stem, 274 sensory information and, 192
preganglion bers and, 41819, 418f chemoreceptors, 271 voluntary movement and, 313
Synapse, 5, 9f, 47n3, 117 glossopharyngeal nerve, 401 Theophylline, 68
AD and, 144 intermediate nerve, 402 asthma and, 68
aging, 140 receptor cells on, 271n2 Thermoreceptors, 162, 165, 169, 271
elimination of, 13233 Taste cell hypothalamus, 443
formation/elimination of, newborn/ sensitivity, 27273 sensory trigeminal nucleus, 405
adult, 133 specicity, 273 Thermosensitive units, 197
function, 4052 Tau, 18 Theta rhythm, 390
functional signicance of, 47 TCA. See Tricyclic antidepressants Thick dorsal root bers, 190
kittens, visual cortex and, 135n8 Tears, secretion of, 4034 Thick myelinated bers, trigeminal
nerve cells, 78 Tectospinal tract, 30910 nerve, 405
590 INDEX
Thin dorsal root bers, 190 Transneuronal degeneration, 230 conduction velocities in, 37
Thoracic nerves, 76 Transplantation impulse conduction in, 36, 36f, 37
Threshold value, 34, 45, 45f of neural precursor cells, 150 Unmyelinated (sensory) bers, 184
receptors and, 16263 stem cell, 341 Upper motor neurons, 301
THS. See Thyroid-stimulating hormone Transporter molecules, blood-brain damage to, 301
Thyroid-stimulating hormone barrier, 106 interruption of, symptoms of, 31923
(THS), 446 Transporter proteins (Transporters), 66 lesions, plantar reex, 32223
Thyrotropin-releasing hormone extracellular uid and, 43 Upper motor syndrome, 319
(TRH), 377, 448 pharmacologic aspects, 44 features, 32122
Tickling, 170, 200 vesicle membrane and, 41f, 42 Urethra, VIP and, 434
Tight junctions, 100 Transporters. See Transporter proteins Urge incontinence, 435
blood-brain barrier, 106 Transverse lesions of cord, 29091 Use-dependent synaptic
taste bud cells and, 272 locomotor movements and, 313 plasticity, 117, 268
Timing (of events), 13132 Transverse sinuses, 112 Utricle, 253
cerebellum, 343 Trapezius, accessory nerve and, 397 Utricular maculae, 255f
Timing theory, 359 Traumatic brain injury. See Brain injuries sensory (hair) cells, 256f
Timing (of events) theory Tremor, Parkinsons disease, 340 Utriculus, head position and, 255
cerebellum, 359 TRH. See Thyrotropin-releasing
inferior olive, 359 hormone Vagus nerve (Tenth cranial
Tinnitus, 247 Tricyclic antidepressants (TCA) nerve), 84, 273, 398401
Tiny excitatory postsynaptic potential depression and, 70 bronchi of lung, 398
(EPSP), quantum and, 42 narcolepsy, 359 embryology, 398
Tissue stiffness, muscle tone and, 29697 Trigeminal bers, division of, 405n4 immune system and, 455
T lymphocytes, inammatory process Trigeminal nerve (Fifth cranial nerve), paralysis, 400f
and, 25 72, 84, 85, 4045 preganglionic parasympathetic
TMS. See Transcranial magnetic branches, facial skin bers, 423
stimulation distribution, 404f silent nociceptors, 169
TNS. See Transcutaneous nerve sensory innervation from, 105 Varicosities, 414
stimulation Trigeminal nucleus, 403f biogenic amines, 65
Tongue, reex movements of, 397 signals, central transmission of, 405 cholinergic neurons and, 63
Tonic reex effects, 261 Trigeminal pareses, deviation Vascular cognitive impairment
Tonotopic localization, 246 of jaw, 406f (VCI), 143n3
Topographic maps, brain and, 13334 Trk. See Tyrosine-kinase receptors dementia and, 143
Total synaptic input, 46 Trochlear nerve, 86, 406, 407 Vascular diseases, 297
Touch perception, 190 Trophic factors Vascular plexuses, in ventricles, 99100
Tourettes syndrome, 339, 342 neurons and, 12728 Vascular striavestibular membrane, 241
deep-brain stimulation, 342 target organs and, 13031, 131f Vasoactive intestinal peptide
Toxic substances, neuropathies, 27 TRP. See Transient receptor potential (VIP), 425, 430
Toxins, transmitter release and, 43 TRPVI channel, nociceptors, 166n1 urethra, 434
Trachea, vagus nerve, 398 Tryptophan hydroxylase, 71 Vasodilation
Tract Tuberoinfundibular tract, 447 substance P, 439
bundle of axons and, 12 Tubulin, 18 sweat secretion and, 427
nucleus and, 13f Tumors, 506 sympathetic bers and, 426
spinal white matter and, 78 dementia and, 143 Vasogenic brain edema, 22
Tract of Lissauer, 196, 196n5 of pituitary, 23132, 233f Vasomotor reexes, 434
Training, 154 Twelfth cranial nerve. See Hypoglossal microneurographic technique, 426
receptive elds, 160 nerve Vasopressin (ADH), 44647
Transcranial magnetic stimulation Twitch, 284 VCI. See Vascular cognitive impairment
(TMS), 304 Twitch contractions, eye muscles, 364 Velocity of stretching, 292, 320
age and, 143 Two-point discrimination, 172 Venous sinuses, 111, 112f, 113f
stroke patients, restituted, 153 Two-point threshold, 172, 172f dura and, 112f
Transcription, of genes, 70 Tympanic cavity, 243 Venous system, 11113
Transcription factors, prenatal Tympanic membrane, 243 Ventral branches (of spinal nerves),
development and, 122 Type 1 bers, 287 sensory bers and, 185
Transcutaneous nerve stimulation Type 1 joint receptor, 180, 180f Ventral corticospinal tract, 304
(TNS), 210 Type 2 bers, 287 Ventral nerve root, 72, 79
Transduction, 159, 16061 Type 2 joint receptor, 180 sensory bers in, 184
mechanisms, 266 Tyrosine-kinase receptors (Trk), 128, Ventral pathways, striate area and, 23536
Transient receptor potential 128n5 Ventral posterolateral nucleus (VPL), 494
(TRP), 161n1, 162f Ventral posteromedial nucleus
transduction and, 161 U bers, 497 (VPM), 193
Transmitter. See Neurotransmitter Ultrastructural analysis, Ventral ramus, 7980
Transmitter candidates, 54 neurotransmitters, Ventral reticulospinal tracts, 379
Transmitter-gated ion channels, 32 immunocytochemical methods Ventral roots, 75
Transmitter-gated K+ channel, 44 and, 54, 55f plexuses and, 280
Transmitter release, 41f Umami taste, 272 Ventral spinocerebellar tracts, 34748
axoaxonic synapses, 47 Uncinate ts, 269 Ventral striatopallidal, 33639
toxins and, 43 Unmyelinated axons, 2526, 28 basal forebrain, 47172
INDEX 591
Ventral striatum, 33639 Visceral afferent neurons, 411 Voltage-clamp technique, 31
with nucleus accumbens, 337f Visceral afferent signals, central Voltage-gated Ca2+ channels, membrane
Ventral tegmental area (VTA), 67 pathways for, 433 potentials and, 39
afferents to, 337 Visceral afferent vagus bers, 399 Voltage-gated channels, 28, 32, 33
Ventricles Visceral arches Voltage-gated potassium
cerebrospinal uid, 103 neural crest cells, 118, 118f channels, 33, 43
location and form of, 99 prenatal development and, 124 Voltage-gated sodium channels, 168
shape and size, 103 Visceral efferent bers, 391 action potential, 3435
total volume of, 102n3 cranial nerves, 391 action potential and, 3435, 34f
vascular plexuses in, 99100 nucleus of Edinger-Westphal, 407 Voltage gradient, 29
Ventricular system, 97103 organs and, 413 Voltage-sensitive uorescent dye,
Verbal uency, gender and, 515 Visceral efferent neurons neuronal activity and, 3334
Vergence movements, 366f, 367f parasympathetic division, 41331 Volume transmission, 53, 55, 63
Vermal oculomotor area, sympathetic division, 41331 biogenic amines, 65
cerebellum, 369 Visceral efferent vagus bers, 39899 Voluntary contractions, 300
Vertebral artery, 1089, 109f Visceral nociceptors, stimuli for, 437 Voluntary movements, 18283, 27879,
Vertigo, 265 Visceral organs, 373 295, 314f
Vesicle transport. See Synaptic vesicles sensory bers to, 433f cerebellum, 343, 360
Vestibular apparatus, 254f, 362 Visceral pain, 432, 43639 dorsal column-medial lemniscus
compensation and, 151 Visceral receptors, 432 system, 195
inner ear, 253 Visceral reexes, 434 jaws, pyramidal tract, 406
sensory cells of, 257f sensory visceral neurons and, 43239 posterior parietal cortex and, 319
signals from, cortical areas and, 264f vagus nerve, 399400 reciprocal inhibition and, 307
structure and function, 25356 Vision reticulospinal tracts, 310
unilateral destruction of, 265 body equilibrium and, 263 vestibular reexes and, 258
Vestibular complex, 257 normal, 239 Voluntary saccades, 366, 369
Vestibular connections, 259f Visual acuity, 22425 Vomeronasal organ, 270
Vestibular hair cells, 254 receptive elds and, size of, 22425 Vomiting reex, 108, 400, 434
Vestibular labyrinth function, Visual agnosia, 239, 502, 507 VORs. See Vestibulo-ocular reexes
caloric test, 261 Visual aura, 231 VPL. See Ventral posterolateral nucleus
Vestibular membrane, 24445 Visual awareness VPM. See Ventral posteromedial nucleus
Vestibular nerve, 84 striate area, 23839 VTA. See Mesencephalic ventral
Vestibular nuclei, 253, 257, 257f, 368 synchronized network activity, 239 tegmental area; Ventral tegmental
angular acceleration, 258 Visual axes (of eyes), 36263 area
cerebellum, 346 Visual cortex, 92, 13233,
connections of, 25659 23637, 498f Wakefulness
static position/linear acceleration, 258 intracortical signal trafc, 492 histamine and, 66
Vestibular nystagmus, 260 layers, 490f nerve groups and, 72
Vestibular receptors modular organization of, 23435 reticular formation, 82
ankle strategy and, 263 visual information and, processing, Walking, stretch reexes and, 295
postural control and, 31112 23339 Wallenbergs syndrome, 396
Vestibular reexes, 25963 Visual eld, 21617, 217f, 230, 514 Water intake, hypothalamus, 66
eye movement, 25963 central parts, 231 Waves (EEG), 384
voluntary movement and, 258 decits, lesions of visual waves, 384
Vestibular signals, 26365, 380 pathways, 232f waves, 384
Vestibular stimulation, 26061 movement, blindsight and, 238 WDR. See Wide dynamic range units
Vestibular system, multisensory visual signals from, 22930 Weber deception, 161n2
integration and, 256 Visual guided movements, apraxia Weber test, 247
Vestibulocerebellar bers, 259 and, 503 Wernicks area
Vestibulocerebellum, 236f, 343, 345 Visual images, fusion of, 229f, 230 language and speech, 500
Vestibulocochlear nerve, 85, 4012 Visual information, 262, 262n3 speech and, 510
Vestibulo-ocular reexes (VORs), 258, integration of, 238 White communicating ramus, 419
25960, 365, 366f, 368 processing, 235 White matter, 5, 11, 12f. See also Spinal
cerebellum, 360 subconscious use, 239 white matter
elderly and, 142 Visually guided behavior, 500 aging, 140, 141
external conditions, 366 Visually guided movements, 348 prenatal development and, 121
inferior olive, 352 Visual pathways, 215, 228f, 231 White muscles, 28485
Vestibulospinal tracts, 260, 261, 310 cells, 224f Wide dynamic range units (WDR), 197
Vibration, 170, 171 organization of, 22733 Wiring pattern (of brain), 13, 18, 18f
perception, 190 retinotopic localization, 231f Wisconsin card sort test, 506
posture and, 262 retinotopic organization of, 215, 230 Withdrawal reex, 290
Villi, 99 Visual pigments, 220f Withdrawal symptoms, receptors, 57
VIP. See Vasoactive intestinal peptide Visual reexes, 215 Wnt7, 107n3
Viruses, nervous system, 12930 Visual signals, 380 Writers cramp, 298
Viscera, sympathetic innervation, 42122 Visual system, 21540
Visceral afferent cranial nerve nuclei, 392 Vitreous body, 216 X-ray imaging, 73
Visceral afferent bers, 432 Vocalization and, auditory neurons
cranial nerves, 391 and, 250 Yawning, 388

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The Central Nervous System

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PER BRODAL, MD, PHD

Oxford New York

Copyright 1992, 1998, 2004, 2010 by Oxford University Press, Inc.

Published by Oxford University Press, Inc.

Oxford is a registered trademark of Oxford University Press

All rights reserved. No part of this publication may be reproduced,

Library of Congress Cataloging-in-Publication Data

Printed in the United States of America

Preface, v The Brain Stem, 80

PART III SENSORY SYSTEMS 19. Olfaction and Taste, 266

27. The Cranial Nerves, 391 PART VII LIMBIC STRUCTURES

G ENERAL information about the structure and

Cell body (soma) Dendrite

A The term terminal bouton is used when the bouton sits

Two Main Kinds of Nerve Cell: Projection Neurons

gure 1.7 Synapses. A, B: Electron micro- a

interneuron leads to a delay in the propagation of the

Many of the tasks performed by the nervous system

Neurons Are Collected in Nuclei and Ganglia

with another is called a tract (tractus; Figs. 1.15 and

gure 1.15 Nucleus and tract. Left: Schematic

Muscle Spinal cord neurons

Nucleus SPINAL CORD

Another equally ubiquitous feature, convergence of b

Couplings Contributing to Continuous

Parallel pathways Reciprocal (feedback) Commissural connections

Data-based models of neural networks have provided

Afferent connections with

ANTEROGRADE TRANSPORT RETROGRADE TRANSPORT

Injected tracer Injected tracer

gure 1.25 Axonal transport. The

gure 2.1 Astrocytes. Photomicrographs

Capillary Cerebral ventricle with

gure 2.3 The relationship between astroglia and neurons, blood

Glial cell nuclei

Capillaries Large nerve Astrocyte processes

gure 2.6 Myelin sheath, myelination, and

Oligodendrocytes and Schwann Cells

gure 2.7 Myelinated and unmyeli-

(Figs. 2.62.8). During early development, several MICROGLIA AND REACTIONS OF

Reaction of Nervous Tissue to Injury and Inammation Diseases of Peripheral Nerves

OVERVIEW of Na+ ions, the membrane potential is restored by the

Ion channel Open Closed

Subunit Ion Transmitter

gure 3.2 Ion channels. Five protein subunits are

+ from the interior of the cell, making the interior negative

+ | rons). The resting potential in most neurons, however,

is lower than the equilibrium potential for K because

1/50th of the permeability to K+). Therefore, some pos-

Na+ electrodes can be used to record the activity of single

with open K+ channels, largely explain the resting membrane potential.

and advanced computer technology) gives an impres- Membrane potential

Calcium and Neuronal Excitability

along its length. The amount of current being lost is