Heckman2012 Motor Unit

P1: OTA/XYZ P2: ABC
JWBT335-c100087 JWBT335/Comprehensive Physiology July 31, 2012 8:55 Printer Name: Yet to Come
Motor Unit
C.J. Heckman*1 and Roger M. Enoka2
ABSTRACT
Movement is accomplished by the controlled activation of motor unit populations. Our under-
standing of motor unit physiology has been derived from experimental work on the properties of
single motor units and from computational studies that have integrated the experimental obser-
vations into the function of motor unit populations. The article provides brief descriptions of motor
unit anatomy and muscle unit properties, with more substantial reviews of motoneuron properties,
motor unit recruitment and rate modulation when humans perform voluntary contractions, and
the function of an entire motor unit pool. The article emphasizes the advances in knowledge on
the cellular and molecular mechanisms underlying the neuromodulation of motoneuron activity
and attempts to explain the discharge characteristics of human motor units in terms of these
principles. A major finding from this work has been the critical role of descending pathways from
the brainstem in modulating the properties and activity of spinal motoneurons. Progress has been
substantial, but significant gaps in knowledge remain. C 2012 American Physiological Society.
Compr Physiol 2:2629-2682, 2012.
Introduction channels. It is now known, for example, that all types of recep-
tors and ion channels have multiple subclasses, each encoded
The motor unit provides the primary output for the CNS, con- by a different gene, and thus the behavior of any neuron de-
verting sensory and descending neural inputs into forces to pends on its mixture of these subclasses. As discussed in this
generate movement. It is thus a neuromechanical transducer. article, the neurotransmitter serotonin (5-HT) provides an es-
The motor unit has two components: (i) the motoneuron and pecially clear example of this principle with its 14 subclasses
(ii) the muscle fibers that its axon innervates, with the latter of receptors (512). Three of these receptors (5-HT2a, b, and
referred to as the muscle unit. As the neuromuscular junctions c) are important for motoneurons as they can greatly increase
between axon terminals and muscle fibers are large, secure motoneuron excitability. In contrast, 5-HT1b,d receptors have
synapses, a motor neuron and its muscle unit normally func- net inhibitory effects on some spinal interneurons. Thus, the
tion as a single entity that represents the quantal elemental in release of 5-HT can be excitatory or inhibitory on a given
the control of movement. neuron, depending on the neuron’s receptor subtypes.
The goals of this article are to describe how the function Figure 1 illustrates the complexity of the motor output
of motor units emerges from the properties of motor neurons system. The image shows all the motoneurons within the S1
and muscle units, and how motor unit activity controls muscle segment in a 9-day-old mouse, revealing the close packing of
force. We emphasize the work completed since the chapter cell bodies and dendrites and suggesting that the motor output
on this topic was published in the Handbook of Physiology is generated in parallel by many motoneurons. Functionally,
series (60), much of which has been summarized in a number motoneurons exhibit a remarkable range of properties, includ-
of excellent reviews (10, 57, 58, 299-303, 325, 340, 343, 360, ing a tenfold range for spike threshold and a fivefold range for
532, 553, 562, 574) and an authoritative monograph (383). the spike afterhyperpolarization (AHP). Similarly for muscle
The tight coupling between action potentials generated by units, there is a fivefold range in contraction speed and a
a motoneuron and its muscle unit confers a unique advantage 100-fold range for maximum force and fatigue resistance. As
for studying the control of motor function by the nervous the electrical properties of the motoneuron strongly covary
system. Namely, muscle fiber action potentials are relatively with the mechanical properties of their muscle units, Burke
easy to measure and thus motoneurons are the only CNS et al. (91) identified three types of motor units: slow (type S),
cells for which the discharge times of action potentials can be fast fatigue resistant (type FR), and fast fatiguable (type FF).
readily quantified in humans. A full understanding of how the
modulation of motor unit discharge emerges from the inputs
and properties of motoneurons and muscle units, therefore, * Correspondence to [email protected]
can reveal the structure of motor commands in both normal 1 Northwestern University, Evanston, Illinois
and pathological states. 2 University of Colorado, Boulder, Colorado
Advances in this field of study have largely been driven by Published online, October 2012 (comprehensivephysiology.com)
the application of molecular and genetic methods to studies on DOI: 10.1002/cphy.c100087
the interactions between neurotransmitters, receptors, and ion Copyright
C American Physiological Society
Volume 2, October 2012 2629

P1: OTA/XYZ P2: ABC
Motor Unit Comprehensive Physiology
50 microns
Medial
Rostral
Figure 1 The motor output system of the S1 segment of a 9-day-old mouse. This is a two photon image of intracellular calcium in live
motoneurons. The motoneurons were loaded retrogradely with a calcium dye via the S1 ventral root. The view is from above, with the lateral
margin of the cord along the bottom of the figure (see orientiation arrows). A significant portion of the ventral root is apparent in the lower left
part of the image; the motoneurons lie along the lateral edge of the ventral cord. Note the range in size of cell bodies and the numerous dendritic
branches. Unpublished results from Mingchen Jiang, Shuaib Ahmed, and CJ Heckman. Figure prepared, with permission, by Rochelle Bright.
As discussed in Section “Basic Anatomy of the Motor Unit,” considerable overlap in the spatial distribution of targets for
however, the properties of human motor units cannot be cate- synaptic contacts (Fig. 1) (137, 172, 385, 585, 689).
gorized with this scheme. In this article, we often use Burke’s The number of motor units that innervate a muscle ranges
terminology when discussing work performed on experimen- from a few tens to several hundred, but these numbers are
tal animals, but adopt the terms low- and high-threshold motor difficult to determine with confidence as each of the available
units when referring to data obtained from humans. methods has limitations. One method involves counting mo-
toneurons that have been labeled by retrograde transport of
horseradish peroxidase (HRP) either by injection into a target
muscle or by exposing the cut nerve to the tracer (81,94). One
Basic Anatomy of the Motor Unit of the difficulties with this technique is delivering sufficient
HRP to the target muscle without involving other muscles.
Despite identification of the motor unit as the final common
With this approach, Jenny and Inukai (355) found that the mo-
pathway in 1925 (438, 632), our understanding of motor unit
tor nucleus for selected forelimb muscles of monkey ranged
physiology remains relatively rudimentary due to the limited
from 14 to 1271 (Table 1). Another method involves dissect-
knowledge on how the activity of many motor units is con-
ing human cadavers and counting the number of motor axons
trolled by the nervous system to produce intended actions
in peripheral nerves, but this requires an assumption about
(176, 496). This section describes the anatomical characteris-
the proportion of large-diameter axons that are efferent fibers.
tics of the motor units that produce muscle contractions and
Nonetheless, the estimates are similar to those obtained by
thereby the forces that are needed for movement.
counting labeled motoneurons: for example, first dorsal in-
terosseus = 119, first lumbrical = 96 (220). A third method
is based on measuring the amplitude of muscle potentials
Motor nucleus evoked by stimulating peripheral nerves (470, 471), which is
Individual muscles comprise a population of motor units that limited by the capacity to obtain an adequate sample of single
controls the force exerted by the muscle during a contrac- motor unit responses (454, 645, 646). The estimates obtained
tion. The motoneurons of the population are located in rela- with this electrophysiological method are typically lower than
tively close proximity in either the ventral horn of the spinal those based on anatomical observations, and are considerably
cord (e.g. Fig. 1) or the brain stem. Collectively, the mo- more variable. For example, the number of motor units in hu-
toneurons that innervate a muscle are arranged in a longitu- man tibialis anterior was estimated as 118 ± 50 (68), which
dinal cluster known as a motor nucleus or motoneuron pool is considerably fewer than the estimates of 445 from cadaver
(94, 592, 631, 679, 698). In a transverse section, the motor nu- dissection (220) and 300 from the twitch torques of single
clei of proximal muscles tend to be located more ventral and motor units (694). Although the electrophysiological method
lateral than motor nuclei for distal muscles, and the motor does seem capable of tracking changes in motor unit numbers
nuclei of anterior muscles are usually more lateral than those with a neuromuscular disorder (67, 547), particularly when
of posterior muscles (142, 355, 565, 597, 598). The extensive incorporating Bayesian statistical methodology (307, 577), it
dendritic projections of each motoneuron, however, ensure is likely not capable of providing quantitative measures of less
2630 Volume 2, October 2012

P1: OTA/XYZ P2: ABC
Comprehensive Physiology Motor Unit
Table 1 Motor Neuron Locations and Numbers for Selected Fore- vation numbers within a motor unit is typically represented
limb Muscles with an exponential function (190, 197, 238, 382, 398, 452,
489, 675, 678, 693, 694). The remodeling of motor unit ter-
Muscle Spinal location Number ritories that occurs with advancing age increases average
motor unit force, but does not appear to change the dis-
Biceps brachii C5-C7 1,051 tribution of motor unit forces within the motor unit pool
Triceps brachii C6-T1 1,271
Flexor carpi radialis C7-C8 235 (227, 465).
Extensor carpi radialis C5-C7 890 The fibers in each muscle unit are distributed throughout
Flexor carpi ulnaris C7-T1 314 some fraction of the muscle and intermingle with the fibers
Extensor carpi ulnaris C7-T1 216
Extensor pollicis longus C8-T1 14 of other muscle units (65, 708, 709). Counts of glycogen-
Abductor pollicis longus C8-T1 126 depleted fibers indicate that muscle unit territories extend
Flexor digitorum superficialis C8-T1 306 over 0.5% to 5.5% of the muscle cross-sectional area in rabbit
Extensor digitorum communis C8-T1 273
Flexor digitorum profundus C8-T1 475 masseter (709), 12% to 26% in the rat tibialis anterior (186),
Extensor digiti secundi proprius C8-T1 87 20% to 40% in a cat neck muscle (18), 25% to 75% in rat
Abductor pollicis brevis and flexor C8-T1 115 soleus (403), and 60% in cat medial gastrocnemius (568). In
pollicis brevis
Adductor pollicis C8-T1 370 addition to differences in breadth of the muscle unit territories,
First dorsal interosseus C8-T1 172 the densities of the fibers belonging to the same muscle unit
Lateral lumbricalis C8-T1 57 (fibers within a unit per 100 total muscle fibers) can differ
Data are from Jenny and Inukai (355) and are listed as pairs of an-
across muscles: 1 or less in cat soleus (91), 3 to 5 for cat
tagonistic muscles. gastrocnemius (95), 5 to 9 for a cat neck muscle (18), 4 to
12 for rat medial gastrocnemius (371), and 6 to 17 for rabbit
masseter (709).
profound reductions in motor unit numbers, such as during Similarly, the muscle fibers of a single motor unit often do
aging. not extend from one end of a muscle to the other end but in-
stead occupy a subvolume of the muscle (316, 420, 519, 729).
In an extreme example of such structure, Harris et al. (287)
Muscle unit used electrophysiological techniques to identify muscle unit
Some of the cadaveric dissections to estimate the size of the territories in the longest muscle in the human body, the sarto-
motoneuron pool, which is known as the motor unit pool when rius (Fig. 2). Of the 64 motor unit action potentials recorded
discussing both the central and peripheral components, have in five subjects, only 21 were detected at the most proximal
provided information on average number of muscle fibers and distal recording electrodes, which indicated that the mus-
in a muscle unit. For example, average innervation number cle unit fibers of these motor units extended the length of
(number of muscle fibers innervated by a single motoneuron) the muscle. The muscle fibers of the other 43 motor units
ranges from 5 to 10 for such muscles as rectus lateralis, either began or ended within a fascicle. Similarly, Farina and
stapedius, and tensor tympani (63, 108, 680) up to approx- colleagues used intramuscular and surface electromyogram
imately 1750 for large limb muscles such as medial gastroc- (EMG) recordings to demonstrate that the territories of single
nemius (220). Although these data are useful for between- motor units in the human medial gastrocnemius muscle are
muscle comparisons, it is the range within individual motor 2.5 cm or less, which is approximately 10% of the length of
unit pools that is more critical for understanding how the the muscle (701). One of the issues with muscle fibers termi-
nervous system controls muscle force. Glycogen-depletion nating within a fascicle is how transmission of the force from
studies indicate that innervation number varies within a the contractile proteins to the skeleton is modified by the inter-
motor unit pool, with low-threshold motor units containing posed connective tissue structures (446, 495, 496, 652, 683).
lower values (66, 95, 372). In the cat medial gastrocnemius As a consequence, the sum of the forces exerted by single
muscle, for example, innervation number ranges from 18 to motor units can be less than that achieved when all the motor
830 (569). units are activated concurrently, although this nonlinearity is
The range of innervation numbers can also be estimated modest (193, 530, 603) as discussed subsequently in Section
from measures of motor unit force due to the high corre- “Muscle Unit Physiology.”
lation between innervation number and maximal motor unit In some muscles, muscle unit territories can be limited to
force (66, 372, 681). With this approach, which involves de- discrete compartments within a muscle with each neuromus-
termining the range of motor unit tetanic forces and estimat- cular compartment being innervated by a different primary
ing the number of muscle fibers required to achieve these branch of the muscle nerve (538, 722). As a result of this
forces, Enoka and Fuglevand (197) estimated the innervation arrangement, a single muscle can comprise several distinct
numbers for the 120 motor units in the human first dorsal in- regions that each serves a different physiological function
terosseus muscle to range from 21 to 1770. As muscles com- (97, 194, 195, 201, 225, 375, 388, 578, 599, 669) For example,
prise many motor units that generate small forces and few the human biceps brachii muscle is innervated by three to
that exert large forces, the frequency distribution of inner- five primary branches of the musculocutaneous nerve, and

P1: OTA/XYZ P2: ABC
(A)
R1
R2
R3
R4
100 mm R5
Right
sartorius
(B)
Subject 1
R1
R2
R3
R4
R5
Subject 2 Subject 3
R1 R1
R2 R2
R3 R3
R4 R4
R5 R5
Subject 4 Subject 5
R1 R1
R2 R2
R3 R3
R4 R4
R5 R5
Figure 2 Muscle unit territories in the human sartorius muscle. (A) Arrangement of recording elec-
trodes (R1-R5) along the length of the sartorius muscle. (B) End-plate location (filled circles) and the
extent of muscle length along which the potentials for single muscle units were recorded. Each vertical
bar represents a single muscle unit. Adapted, with permission, from Harris et al. (287).

P1: OTA/XYZ P2: ABC
the motor units in the long head of the muscle appear to func- with intraneural stimulation, it is not possible to identify dis-
tion in two distinct populations. The motor units in the lateral tinct types based on the criteria proposed by Burke and col-
aspect of the long head were active when a flexion torque leagues (54, 237, 392, 673). Furthermore, the properties of
was exerted about the elbow joint, those in the medial aspect human motor units are distributed continuously within a mo-
were active when the muscle produced a supination torque, tor unit population and do not cluster into discrete groups
and those in the middle were active when the torque about the (Fig. 11) (237, 263, 392, 452, 477, 489, 671, 693). When dis-
elbow joint included both flexion and supination components cussing human motor units in this article, therefore, motor
(30, 668, 697) units are distinguished on the basis of recruitment threshold
The variation in muscle unit anatomy within a muscle force.
must be accommodated in the activation signals received by
the motoneuron pool when the goal is to produce a prescribed
action (31). Furthermore, the attachment sites to the skele- Surface electromyography
ton often enable a muscle to exert torques in more than Due to the high safety factor for synaptic transmission at
one direction about a joint and unwanted actions must be the neuromuscular junction during voluntary contractions, the
controlled by the appropriate activation of motor unit pools generation of an action potential by a motoneuron invariably
(241, 266, 579, 591, 691). Motor unit anatomy, therefore, con- results in the propagation of action potentials along all the
strains the activation strategies available to the CNS. muscle fibers of a muscle unit at approximately the same
time (200, 457, 596, 724). The sarcolemmal action potentials
contribute to extracellular currents that sum to generate a field
Motor unit types potential that can easily be recorded with electrodes placed
To quantify the association between the histological features on the skin over the muscle (239). As the amplitude of the
of a muscle and its contractile properties, muscle physiologists signal increases with the number of motor units involved in
have developed schemes that identify distinct types of mus- an action, the resulting EMG provides a global measure of
cle fibers. One popular scheme, for example, identifies three muscle activation (213).
isoforms (I, IIA, and IIX) of the myosin heavy chain (MyHC) In contrast to the ease of recording a surface EMG signal,
that influence maximal contraction velocity, with MyHC I its interpretation is more challenging (6, 155, 203, 212, 213).
being the slowest and MyHC IIX the fastest (74, 286, 609). The difficulty arises from the shapes of the surface-detected
In a similar vein, Burke and colleagues developed a scheme motor unit action potentials and their summation as an inter-
to identify different types of motor units (91, 92). The clas- ference signal (170, 240, 643). As the shape of each motor
sification criteria involved first determining the profile of an unit action potential depends on the number and anatomical
unfused tetanus and then measuring the rate of decline in characteristics of the muscle unit fibers, and on the properties
tetanic force to a prescribed protocol of electrical stimulation. of the recording electrodes (209), the shape differs between
The interstimulus interval for the unfused tetanus was set at motor units and across conditions (171,203) and is only mod-
1.25× contraction time of the motor unit twitch, and produced erately associated with motor unit size (377). Furthermore,
a profile that either did or did not increase monotonically dur- the motor unit potentials overlap in time to produce a signal
ing the tetanus; a profile that did not increase monotonically that comprises the sum of overlapping positive and negative
was described as exhibiting sag. Those units displaying sag phases of motor unit action potentials (145, 376, 727). The
were classified as fast-twitch (type F) motor units, whereas absolute amplitude of the interference EMG, therefore, is less
those with no sag were considered to be slow twitch (type S). than the magnitude of the motor output from the spinal cord,
The type F units were then subjected to 6 min of intermittent and the dissociation, which is termed amplitude cancella-
electrical stimulation (40 Hz for 330 ms, once per second) tion, increases with the magnitude of the interference signal
and the rate of decline in peak tetanic force was used to dis- (145, 207, 376).
tinguish motor units that were either fast-to-fatigue (type FF) Due to the distribution of the shapes of the motor unit
or fatigue-resistant (type FR). action potentials and the influence of these shapes on am-
Subsequent work, however, has demonstrated that the plitude cancellation, the association between the output from
properties of muscle fibers and motor units are not so dis- the spinal cord and the global amplitude of an EMG signal
crete (383): (1) muscle fibers can coexpress combinations is moderate but not strong (212). Furthermore, the character-
of the MyHC isoforms, such as types I and IIA or IIA and istics of the EMG, such as its power spectral content after
IIX (17, 72, 285); (2) the expression of sag in motor units rectification, cannot be used to determine such parameters as
is highly variable and difficult to detect reliably (110); and average discharge rate (213), changes in the discharge rate
(3) the protocol used to assess the sensitivity of motor units of low-threshold motor units (378, 501), upper limit of motor
to fatigue was intended to distinguish the capacity to sus- unit recruitment (204, 210, 702) unless the signal is cross-
tain force during intermittent contractions based on oxida- correlated with force (409), amount of motor unit synchro-
tive enzyme capacity, which ignores the many other impair- nization (168, 209), fluctuations in muscle force (212, 510),
ments that can cause fatigue during voluntary contractions or the decrease in muscle force during fatiguing contractions
(196, 211, 246). Even when human motor units are activated (167, 169).

P1: OTA/XYZ P2: ABC
(A) (C)
1 2 3
4 8 MU 1
MU 3
MU 5
49 53
54 55 56 1 mV
25 ms
MU 6
(B)
0.75
0.5
MU 9
Amplitude (mV)
0.25
0.75
0
0.5
–0.25 MU 11
0.25
(mV)
–0.5 0.0
49 4
0 1 –0.25
54
2 MU 13
5 55
3
56 –0.5
x (mm) 10 8
53
15
0 5 10 15 20 25 30 35 40
y (mm) MU 15
Figure 3 High-density surface electromyogram (EMG) recordings of motor unit activity in a human hand muscle. (A), surface
electromyogram (EMG) signals recorded with an electrode array (5 columns × 13 rows) placed over the abductor pollicis brevis
muscle of a healthy man as he sustained an isometric contraction at 10% of the maximal voluntary contraction force. The 61
electrodes were 5 mm apart and the signals were detected as bipolar recordings between adjacent electrodes. The columns were
aligned with the direction of the muscle fibers. (B) Distribution of multichannel EMG amplitude at the instant indicated by the red
dots and vertical lines in A. Some of the recording locations are indicated by numbers corresponding to those in A. Decomposition
of the multichannel surface EMG signal identified 18 motor units, 8 of which discharged action potentials at this instant and
contributed to the amplitude of the interference signal. (C) The amplitude of the action potentials for the eight motor units (MU) as
detected by the array at the instant shown in B. The amplitude distribution for the interference signal (B) corresponded closely with
the sum of the amplitude distributions for the eight motor units (C). The amplitude calibration (mV) refers to all amplitude maps.
Adapted, with permission, from Farina et al. (212).
More information about motor unit activity, however, can cations over muscle with an array of electrodes. Figure 3
be obtained with the use of techniques that can compensate provides an example of 56 bipolar recordings of motor unit
for the variability in the shapes of the motor unit action poten- activity in a human hand muscle during a low-force isometric
tials. This can be accomplished, for example, by decomposing contraction. The recordings show motor unit action potentials
an interference signal (surface or intramuscular) into the dis- during a 35 ms epoch (A) and amplitude distributions for
charge times of the motor units that contribute to the signal. the interference signal (B) and eight motor units (C) at one
As surface-recorded motor unit action potentials tend to have instant in time (vertical lines in A) during the contraction.
similar shapes, it is necessary to use a recording system that Such recordings can identify the discharge times of several
can identify the action potentials of the different motor units, motor units during low-force contractions (321-323), the re-
such as high-density surface EMG arrays (64, 215, 480). The modeling of motor unit territories with neurological disorders
method involves recording the surface EMG from several lo- (174, 365), the location of neuromuscular junctions for motor

P1: OTA/XYZ P2: ABC
units (413), and the estimation of muscle fiber conduction ve- though muscle unit properties are rarely if ever evaluated in
locity (211, 214, 481). However, current technology limits the the cited studies. This approach is reasonable because of the
application of high-density surface EMG to detecting the ac- strong correlations between electrical properties of the mo-
tivity of superficial motor units during isometric contractions toneuron and mechanical properties of the muscle unit (e.g.
at low forces (212). 734). It should also be kept in mind that all electrical properties
form a continuum (553) and that the “S, FR, FF” terminol-
ogy is used to specify typical properties for portions of this
Motoneuron Physiology continuum.
Experimental preparations for study

of motoneurons Leak and voltage sensitive channels
Before turning to specific ion currents, we provide a summary in motoneurons
of the different preparations available for study of motoneu- Leak channels set the resting membrane potential
rons. The key technique is intracellular recording, as this is
the only way changes in membrane potential of cell can be The leak channels in motoneurons, as in most cells, primar-
measured directly. Motoneurons were the first cells in the ily pass K+ and thus the resting potential is at about −70
vertebrate CNS to be successfully recorded using intracellu- mV (60, 553). This is the value typically seen with in vitro
lar electrodes (77, 653, 654, 725). This was achieved in the preparations where synaptic input is restricted. However, tonic
spinal cord of the anesthetized cat using sharp electrodes that synaptic input can alter the resting potential and substantially
impaled the soma. This in situ approach provided the basis depolarize resting potential. Thus, the resting potential should
for remarkable series of studies by Eccles, Kernell, and many not be thought of as a steady parameter. One of the greatest
labs (79), but this method has limitations. Recording stabil- difficulties in understanding motor unit function in intact be-
ity is difficult due to mechanical movements caused by the having animals is uncertainty about the value of the resting
cardiovascular and respiratory systems. Identification of ion potentials in human motoneurons.
channels via drug administration is difficult to achieve in a There is probably a diverse set of K channels that set
controlled fashion. In vitro preparations are superior in this the resting potential and at least one of these, the barium-
respect, although motoneurons are large and vulnerable to insensitive K channel, is controlled by neuromodulatory input
jury. The initial in vitro preparations for motoneurons were (see Section “Other neuromodulatory actions”). Depolariza-
done using turtle spinal cords by Hounsgaard and colleagues tion of resting potential and an increase in input resistance
(this species being highly resistant to anoxia) (331, 333) or were among the first effects noted in the initial studies of neu-
by using young rodents (where spinal cords are small and romodulators such as serotonin (5-HT) and norepinephrine
diffusion distances short) (284). Recently, in vitro recordings (NE) (659, 719, 720). In the turtle, this 5-HT sensitive leak
in adult rodent motoneurons have become routine due to the channel has been shown to belong to the two-pore K chan-
development of the adult sacral cord preparation, initially in nel family (possibly K2p3.1, i.e., TASK-1) (533). All leak
the rat (49) and then in the mouse (358). Moreover, record- channels show little variation in conductance with voltage
ing in adult rat motoneurons has been achieved with the slice and thus set the basic conductance of the cell across its full
preparation (111). range of behaviors. The effects of all other channels cannot
The in situ preparations remain important, especially now be assessed until the leak currents are removed—usually by
that voltage-clamp methods can be applied (426). These rela- simple subtraction.
tively intact preparations allow investigation of the full speci-
ficity of input from defined sensory and descending systems.
Subthreshold voltage-sensitive channels
Intracellular recordings in motoneurons in situ in the adult rat
and mouse are now routine (459, 479, 536, 540, 622). The de- Table 2 provides a summary of the main currents generated
cerebrate in situ preparation (329) remains especially impor- by voltage-sensitive ion channels in adult motoneurons. In
tant because it provides tonic activity in the brainstem nuclei addition to contributing to action potential generation, these
that are a primary source of neuromodulators in the spinal channels also modulate subthreshold behavior. Both Na and
cord (see Section “Neuromodulatory inputs control intrinsic Ca channels are active just subthreshold to spike initiation
excitability”). For many years, the decerebrate preparation (see Sections “Na channels generate action potentials and
was only successful in the cat but the rat may also be a vi- persistent inward currents” and “Calcium currents generate
able option (98). Studies in vitro often use patch electrodes, especially long lasting PICs).” A mixed-cation current, often
but the adult in situ and in vitro preparations rely on sharp referred to as H current, is strongly present in the subthresh-
electrodes. Both methods can provide long-lasting and stable old region in many motoneurons (553). The “H” refers to
recordings. its unusual behavior of being activated by hyperpolarization
One caveat should be noted. The sections reviewing the instead of depolarization (molecular name: HCN, for hyper-
electrical properties of motoneurons often use the type cat- polarized cyclic nucleotide activated—it is modified by neu-
egories of Burke and colleagues (S, FR, and FF) (88), even romodulatory inputs that alter cyclic AMP) (317). But note

Table 2 Summary of Voltage Sensitive Channels in Adult Motoneurons
P1: OTA/XYZ
JWBT335-c100087
Channel Presence shown in adult Pharmacological

Current Function composition Description (species/region) blocker Notes
Ih Resting membrane potential HCN1-4 (487, 518) Mixed-cationic current, Cat [cervical (586), lumbar ZD-7288 (71, 288) Conductance varies across
(475) activated by (275, 352, 734), sacral physiological types:
P2: ABC
Sag (41, 352, 658) hyperpolarization (608)] FF>FR>S (275, 734)

Subthreshold resonance Rat [facial
(461, 511, 734) (416, 497, 511, 518, 524),
Postinhibitory rebound (53) lumbar (41)]
Mouse [hypoglossal (573),
lumbar (459, 479), sacral
(458)]
IM Control of cell excitability Kv7.2/Kv7.3 Potassium current Rat spinal cord (166) XE991 (705)
(581) (KCNQ2/KCNQ3) activated by Mouse spinal cord
(705) muscarinic agonists (166, 522)
JWBT335/Comprehensive Physiology
INaP Spike initiation Prob Nav1.6 (637) Persistent sodium Cat lumbar (425) Riluzole (317)
(291, 406, 425, 482, 740) current Rat [hypoglossal (554, 733),
Repetitive firing sacral (434)]
(291, 406, 425, 482, 740) Guinea pig facial (514)
Amplification of synaptic
inputs (363, 461)
INaT Depolarization phase of the Nav1.1 (242, 714) Transient sodium Presumably all motoneurons TTX (317)
July 31, 2012
spike Nav1.3 (242, 439) current

Nav1.6 (242)
IN Entry of calcium during Cav2.2 (317) High-voltage activated Rat [hypoglossal (554), ω-conotoxin-GVIA HVA current density can
8:55
IP/Q spike activates Cav2.1 (317) (HVA) calcium sacral (434)] (43, 690) vary across motor pools
calcium-dependent current Mouse spinal (106) ω-Agatoxin-IVA (484)
potassium currents (690) (43, 690)
Idr Repolarization phase of the Kv?.? Delayed rectifier Cat lumbar (618, 737) TEA (317)
spike Kv?.? (414, 699) Rat [trigeminal (395), vagal 4-AP (414, 699)
Slo (BK) (474, 699) A-type currents (601)] TEA (317)
(414, 699) Guinea pig facial (117, 514) Iberiotoxin (317)
Large conductance
calcium-activated
potassium current
IAHP “Medium” SK1,SK2,SK3 Small conductance Cat lumbar (736) Apamin (317) AHP duration varies across
Printer Name: Yet to Come
afterhypolarization (493, 650) calcium activated Rat [facial (7, 395), sacral physiological types:
following each spike potassium current (432)] FF<FR<S (23, 734)
Guinea pig trigeminal (117) AHP duration varies across
species: cat (734)>rat
(23, 249, 687)>mouse
(459, 479)
IPIC Sustained firing Cav1.3 L-type calcium current Cat [lumbar Dihydropyridines Small motoneurons have
(49, 107, 329, 335, 422) (107, 434, 738) Voltage-sensitive (47, 128, 134, 422, 423), (317) longer lasting PICs than
Plateau potentials Cav2.2 (554) calcium current sacral (738)] ω-conotoxin-GVIA larger motoneurons
(49, 107, 329, 335, 423) Rat [hypoglossal (554), (43, 690) (422, 423)
Amplification of synaptic lumbar (98, 281, 687), In rat hypoglossal
inputs sacral (434)] motoneurons, calcium
(47, 329, 344, 421, 461) Mouse lumbar (107, 479) PIC is composed of
Guinea pig trigeminal (335) Cav2.2 (distal) and
Rat hypoglossal (554) Cav1.3 (proximal)
(499, 554)
P1: OTA/XYZ P2: ABC
(A) (B)
1.1
Impedance (MΩ)
–77 mV -
2 mV
1.0
0.9
4 nA
0.8
5s 1 10
Frequency (Hz)
(C)
0 50 pA
–20
V (mV)
0.5 s
–40
–60
–80
Figure 4 Voltage sensitive channels in motoneurons can generate complex effects. [(A), (B)]
The dynamics of the H-current induce a resonance in motoneuron subthreshold behavior. A
shows the voltage response of the neuron (upper trace) to an injected current of steadily increas-
ing frequency (lower trace). The voltage response grows and then declines. In B, the resulting
impedance versus input frequency shows a peak at about 10 Hz. Adapted, with permission, from
Manuel et al. (461). (C) L-type Ca currents have an intrinsic tendency to generate prolonged
tail currents. Increasing the duration of the voltage step increases the duration of the tail current
(compare red and blue traces to black). Recordings obtained in nucleated patches of membrane
from hypoglossal motoneurons. Modified, with permission, from Moritz et al. (499).
that activation of H current is slow, with a time constant of 10 generation (132,259). The persistent component is likely gen-
to 50 ms (553). Thus, it influences the dynamic performance erated by the same channels that generate the action potential
of the motoneuron and has recently been shown to induce a (553). Such a small fraction might seem unimportant, but the
subthreshold resonance; that is, an especially strong depolar- density of Na channels involved in the action potential is likely
ization produced by inputs with frequencies in the range of 10 high. Consequently, the small percentage remaining open for
to 12 Hz (461), as illustrated in Figure 4 A,B. As described longer periods can produce long-lasting depolarizations of 10
subsequently, neuromodulators depolarize the activation volt- to 20 mV (336, 427, 433, 435). The NaPIC is fundamental for
age for H current (60, 553) (see Section “Other neuromodu- spike initiation (see Section “The base state of motoneurons”),
latory actions”), potentially bringing this resonance into the although the spikes are generated by rapidly inactivating Na
range of spike generation, but this issue has not yet been fully channels (317). The NaPIC is also subject to strong neuro-
studied. modulatory control, especially by 5-HT and NE (see Section
“Neuromodulation of persistent inward currents”).
Na channels generate action potentials and
persistent inward currents Voltage-sensitive K channels
Na currents are the key elements in the generation of action The diversity of voltage-sensitive K channels is impressive,
potentials. There are nine classes of Na channels based on with 12 families identified on the basis of molecular structure
alpha subunits (115), but the subtype composition for mo- (Kv1-12), each with multiple subtypes (276). One major role
toneurons is not fully known. Moreover, this composition can for K currents is to help repolarize the spike. Blockage of
vary across the different regions of the motoneuron. In rat these “delayed rectifiers” substantially broadens spike width
embryonic motoneurons, axons contain both NaV 1.1 and 1.6 (317). At a minimum, Kv1,2, and 3 are involved in neuronal
subtypes (180). Both of these subtypes generate a substantial delayed rectification currents (276, 317). The exact mixture
persistent component; that is, a Na persistent inward cur- of K channels for motoneurons is unknown. Delayed-rectifier
rent (PIC) (259). The NaPIC is generated by a small fraction K currents show little inactivation (317). Part of the Kv3
(∼1-5%) of the total Na channels involved in action potential family generates the A-type K current (276), which rapidly

P1: OTA/XYZ P2: ABC
inactivates (317). Although A-type currents are present in by prolonging the duration of the voltage step. Similarly, re-
cultured and neonatal motoneurons (553), this current has peated constant-amplitude steps evoke progressively larger L-
not yet been detected in adult motoneurons. The Kv7 fam- type currents. This type of warm up has been demonstrated in
ily forms the m-type current, a voltage-sensitive K current motor unit firing patterns in animal preparations (46,153,657)
that is also ligand gated by the cholinergic agonist muscarine and in humans (261,326). The long-lasting L-type tail currents
(317). M currents occur in adult turtle motoneurons (9) and are the primary source of plateau potentials that induce self-
in young mammalian motoneurons (581). Future studies will sustained firing (see Section “Neuromodulation of persistent
likely show that this diverse ensemble of K channels is sub- inward currents”).
ject to regulation via neuromodulators. The main example at
present is the Kv2.1 channel and its control by cholinergic
input (see Section “Other neuromodulatory actions”). Ca-mediated K currents generate spike
afterhyperpolarizations
Calcium currents generate especially The entry of Ca during the action potential hyperpolarizes the
long-lasting PICs motoneuron via Ca-activated K channels (116), especially SK
There are multiple families of voltage-gated Ca channels with (KCa 2.1 and 2.2) (432, 553). The relatively slow time course
distinct behaviors: P/Q (Cav 2.1), N (Cav 2.2), L (Cav 1.1- of the hyperpolarization is due to the slow reduction in the
1.4), R (Cav 2.3), and T (Cav 3.1-3.3) (116). N, P, and L chan- free internal Ca by buffers and pumps. The result is a medium-
nels have clearly been established in motoneurons, whereas T duration AHP that lasts approximately 30 to 100 ms (553). In
and R channels appear to generate only small currents (553). neonatal motoneurons, a faster Ca-sensitive K current (BK)
N and P/Q are activated at high voltages and thus are nor- plays a significant role in spike repolarization (700), but it is
mally opened primarily during the action potential. The Ca not known if this occurs in the adult. Neonatal motoneurons
that enters the cell via N and P/Q during each action potential also exhibit a Na-sensitive K current, which probably plays a
is the primary drive for the Ca-sensitive K currents that gen- role in reducing excitability when Na levels increase during
erate the fast and medium AHPs after each spike (383, 553) prolonged firing (600). Again, it is not known if this Na-K cur-
(see Section “Ca-mediated K currents generate spike after- rent exists in adult motoneurons. Neuromodulatory control of
hyperpolarizations”). Motoneurons, as with many neurons, SK is well established (see Section “Other neuromodulatory
have two subtypes of L-type channels: CaV 1.2, which is actions”), but appears to be via control of Ca entry via N and
high-voltage activated, and CaV 1.3, which is low-voltage P/Q channels (553), although perhaps there are direct effects
activated (553). In fact, CaV 1.3 channels can have such a hy- from cholinergic inputs (483). If L-type Ca channels are open
perpolarized activation threshold that they can be active at or for prolonged periods (i.e., more than ∼ 1 s), the calcium
below the voltage threshold for spike initiation (553). L-type from this source can also induce a prolonged activation of SK
currents inactivate slowly (553), and it is clear that the CaPIC channels (432) that likely helps to deactivate the Ca PIC.
mediated by the CaV 1.3 channels plays a major role in pro-
longed motor output in both normal and pathological states
(see Section “Neuromodulatory control of persistent inward Other voltage-sensitive ion channels
currents” also Section “Spinal cord injury”). In general, it ap- Computer simulations using just a basic set of channels do
pears that the total PIC in motoneurons is about 50% NaPIC a good job in recreating the firing patterns of motoneurons
and 50% CaPIC (434, 435), although there may be differ- (see Section “Computer simulations of the motoneuron”).
ences in low- versus high-threshold motoneurons (427). Both Typically, these models have one Na current (or two if the
the CaPIC and the NaPIC are subject to strong neuromodula- transient and persistent components are simulated by sepa-
tion. In hypoglossal motoneurons, CaV 2.1/2.2 currents also rate models), one delayed-rectifier K current, SK linked to a
generate CaPICs (554), but probably at too depolarized a level lumped model of N and P/Q, and an L-type current that may
to provide sustained drive during repetitive firing. be weakly linked to SK as well (187,188,630). Consequently,
The CaPIC is highly unusual in its behavior. Unlike the the role of the many channel subfamilies is not clear, but per-
NaPIC, which is deactivated after the step that activates it is haps relates to providing a diverse substrate for homeostatic
turned off, the CaPIC tends to continue on even when the ac- and neuromodulatory regulation.
tivating input ceases and produces a prolonged “tail” current.
Figure 4 C shows that the L-type channels underlying the
CaPIC generate prolonged tail-currents in a patch of mem-
Channel aggregation
brane withdrawn from a brainstem motoneuron (499). The
long-lasting behavior of these L-type currents appears to be Both SK and Kv 2.1 channels exist in clusters opposed by
linked to a strong tendency for short-term plasticity, often large C synaptic boutons (483, 504). This cluster likely sub-
referred to as “warm up.” Figure 4 C also illustrates the mag- serves neuromodulation via cholinergic inputs from interneu-
nitude of this warm up. A voltage step that does not produce a rons (730). It is not yet known if this type of channel aggre-
long-lasting tail current can be induced to generate one simply gation occurs with other types of channels.

P1: OTA/XYZ P2: ABC
Regional specialization of ion channels motoneuron in situ remains a fundamental limit to our under-
standing of dendritic processing of input.
The different roles of dendrites, soma, and axon in neuron
function have long been appreciated. Simplistically, the den-
Differences in ion channel properties in slow versus
drites receive synaptic inputs and transmit them to the soma,
fast motor units
where they are converted into spikes for transmission along
the axon. Initially, dendrites were considered to be purely The starting point for understanding the correlation of mo-
passive structures with only leak channels, but subsequently toneuron and muscle unit properties is the leak conductance
the studies by Redman and colleagues in the 1970s and 1980s (or its reciprocal, resistance). Type S motoneurons have a
suggested that the dendrites are active structures (126, 349). substantially higher resistance per unit membrane (specific
It has also long been appreciated that conversion of input to membrane resistance) than do FRs, which are greater than FFs
spikes is an interaction between the initial segment of the (273, 274, 553). This range of specific membrane resistances
axon, which has by far the greatest density of Na channels is at least threefold and, combined with the approximately
(180, 553), and the soma/proximal dendrites, which is where threefold range in surface area (89, 383, 384), induces about
SK exists (Fyffe, personal communication) and probably also a tenfold range in total input resistance. This wide range of
a substantial fraction of the delayed-rectifier K channels (504). input resistances plays a fundamental role in setting current
It is now also clear that SK and at least Kv 2.1 extend into the thresholds for spike initiation and is thus the key mechanism
proximal dendrites (504). of the size principle of motor unit recruitment (60, 311).
A major focus of research in the past 10 years has been There is also a clear difference in H current, which is
to identify the voltage-sensitive channels located in dendritic nearly absent in S motoneurons but very clear in FR and FFs
regions of motoneurons. Electrophysiological studies clearly (553, 734). This difference contributes to higher electrical
show that most of the total PIC is generated in dendritic conductance in FF motoneurons.
regions. Hounsgaard and Kiehn (332) activated the plateau In most pools of motor units, there is a strong correlation
potentials generated by PICs using extracellular fields to de- between the duration of the AHP and the twitch of the muscle
polarize dendrites and hyperpolarize somas, clearly demon- unit (383). The conductance change generated by the AHP is
strating a dendritic origin. Synaptic inputs are mostly located about the same in all motoneurons, so the differences in am-
on the dendrites (383, 553) and thus are close to dendritic plitude of the AHP in S, FR, and FF motoneurons is primarily
PIC-generating channels. In contrast, injected currents are re- due to the tenfold range in input resistances (460).
stricted to somatic regions, which are by far the most likely site The total PIC has a more hyperpolarized activation in S
of electrode penetrations. Studies in both voltage (421, 426) than FR or FF motoneurons (see Fig. 8: compare A-C) (422).
and current clamp (47, 428) have shown that PICs are acti- Moreover, the PIC in S motoneurons is much more sustained
vated at lower levels by synaptic input compared to injected than in FR or FFs, in which it decays within just 1 to 2 s
current, which is consistent with a dendritic PIC location. The (in Fig. 8 C, there is much less PIC on the descending phase
voltage-clamp studies revealed that at least 70% of the PIC of the triangular voltage command). Administration of intra-
is in dendritic regions (421). Overall, a primarily dendritic cellular QX314 to block Na currents reduces the amplitude
location for PIC channels is now well established, although it of the FF PIC, but prolongs its duration (427), suggesting
should be kept in mind that the somatic Na and Ca channels that the decay of the total PIC in these cells is primarily due
likely provide an important contribution to PICs as well. to the decay of the NaPIC. Note that the data in Figure 8 are
The precise location of the dendritic PIC channels, how- from a preparation with high neuromodulatory levels. PICs
ever, remains uncertain. Computer simulations by Rose are much smaller when neuromodulation is weak (see Section
and colleagues (87, 264) and by Elbasiouny and colleagues “Neuromodulatory control of persistent inward currents”).
(188, 189) suggest the main location of Cav 1.3 channels is Voltage thresholds for spike initiation appear to be ap-
midway out on the dendrites—although the optimal location proximately similar in S, FR, and FF motoneurons and spike
from simulations appears to be much closer to the soma in heights also appear to be similar (553). Given the higher in-
smaller type S cells (264). Immunohistochemical studies for put resistance of S motoneurons, this similarity may imply a
Cav 1.3 channels clearly show channels on both soma and den- scaling in density of Na channels, but this issue has not been
drites (28, 635, 655, 738, 739); as yet there is no indication in studied.
the immunohistochemical data for a middendritic concentra-
tion. The reason for this discrepancy is not clear. The situation Differences in ion channel properties in brainstem
is even less clear for the NaPIC. Experiments by Jones and versus spinal motoneurons
Lee (363), using the voltage-clamp methods discussed in the
There are differences between spinal and brainstem motoneu-
previous paragraph, strongly support the existence of a fast-
rons, but the degree of these is uncertain. Both CaPICs and
acting PIC in dendritic regions, with the most likely candidate
NaPICs have been demonstrated in brainstem motoneurons
being the NaPIC. Studies in cultured motoneurons demon-
(338,514,553,574,733). In hypoglossal motoneurons, CaPICs
strated that Na channels are in dendritic regions (419, 444).
are largely obscured by K currents, which were blocked to
Uncertainty about the location of dendritic Na channels in
allow their study (554,733). Serotonin and NE do not seem to

P1: OTA/XYZ P2: ABC
have a strong effect on these motoneurons (Marc Binder, per- Distribution of ionotropic inputs among the
sonal communication). In contrast, trigeminal motoneurons motoneuron pool
behave like spinal motoneurons with respect to the response An important aspect of the organization of ionotropic synaptic
to serotonin, which generates bistable behavior via NaPICs input is that most excitatory input systems have nonuniform
and CaPICs (336, 338). These cells are also responsive to distributions across the pool of motoneurons innervating a
metabotropic glutamate agonists (150). Trigeminal motoneu- single muscle. Such differences were already clear from the
rons, however, do exhibit a bursting mode that does not appear classic studies by Lundberg and colleagues, who found that
to be common in spinal motoneurons (150,151,339). System- the predominantly slow soleus muscle received large EPSPs
atic comparisons between brainstem and spinal motoneurons from muscle spindle Ia afferents (184). Burke and colleagues
are needed, but there can be no question that all motoneu- identified systematic differences between PSPs in S, FR, and
rons share the basic properties of Na, K, Ca, and Ca-mediated FF motoneurons (88). The amplitude of the PSP, however, is
K currents—any differences are likely to reflect densities or proportional to the input resistance of the cell, which varies
spatial distributions. over a tenfold range (see Section “The base state of motoneu-
rons”). To examine input distributions without the confound
Two main types of inputs to motoneurons, of the tenfold differences in input resistance, Heckman and
ionotropic and neuromodulatory Binder (294,295) used steady inputs and were able to measure
the synaptic current underlying the steady PSPs (single elec-
The classic studies of motoneuron inputs assessed the exci- trode voltage clamp methods for in situ preparations were not
tatory postsynaptic potentials (EPSPs) and inhibitory postsy- feasible at this time, due to lack of a generally available am-
naptic potentials (IPSPs) generated by sensory and descend- plifier). They referred to this quantity as the “effective synap-
ing inputs and this work was extended to measurement of tic current”, but it seems reasonable to simply use “synaptic
synaptic currents by Binder, Powers, and colleagues (60,553). current.”
Nonetheless, by the time the studies of synaptic currents be- Systematic studies by the Binder/Powers lab over a period
gan, work in invertebrates and then increasingly in vertebrates of 10 years identified the distribution of synaptic currents from
revealed a whole new class of synaptic inputs, referred to in Ia excitation, Ia reciprocal inhibition, recurrent inhibition,
this article as “neuromodulatory” to distinguish them from the rubrospinal input, vesitbulospinal input, and corticospinal in-
“ionotropic” inputs generating postsynaptic potentials (PSPs). put (61, 294, 295, 440, 560, 713). Figure 5 A summarizes this
Ionotropic receptors are pores that open when they bind a work. In general, excitatory inputs tend to be greatest in FF
neurotransmitter—for example, glutamate for most EPSPs motoneurons and least in S motoneurons, that is, to be greatest
and either GABA or glycine for most IPSPs (317). Neuromod- in large motoneurons. The excitatory input from Ia afferents
ulatory receptors also bind neurotransmitters, but instead of is the exception, with the opposite pattern. In contrast, the
opening ion channels this binding activates G-proteins that are inhibitory inputs studied thus far (Ia reciprocal inhibition and
coupled to intracellular signaling pathways (317). Although recurrent inhibition) generate approximately equal currents
a simplification, it is reasonable to characterize the functional in all motoneurons. Two key descending systems, the corti-
difference of these two systems as follows: ionotropic inputs cospinal and rubrospinal (both with little or no monosynaptic
depolarize and hyperpolarize the motoneurons and thus sub- component in the cat) appear to combine an excitatory input
serve specific motor commands and reflexes, whereas neu- that is larger in FFs with an approximately uniform inhibitory
romodulatory inputs control the state of excitability of the input (297, 298).
motoneuron by modulating its response to ionotropic input. Synaptic currents from several systems have not yet been
Thus, the response of a motoneuron to a given ionotropic measured, including cutaneous afferents, Ib tendon organ af-
input depends on the level and type of neuromodulatory in- ferents, and the monosynaptic component of the corticospinal
puts. The importance of neuromodulatory input cannot be system. In at least one motoneuron pool (cat medial gastroc-
overstated. For example, activity in axons that descend from nemius), the mixed excitatory and inhibitory PSPs from cu-
the brainstem and release either 5-HT or NE can increase the taneous and Ib input are similar (550, 551). Perhaps these
excitability of motoneurons as much as fivefold (see Section systems are distributed similarly to rubrospinal input. The
“Neuromodulatory inputs control intrinsic excitability”). similarity of the corticospinal EPSPs seen in primates to Ia
A third type of input is presynaptic inhibition, which acts EPSPs (109) suggests that the monosynaptic corticospinal
via synapses on synaptic terminals (594). The role of this sys- currents may be similar to Ia currents and be larger in type S
tem is probably to focus or gate ionotropic inputs and there is motoneurons.
little doubt that presynaptic inhibition of an ionotropic input
system can greatly reduce its impact (594). Relations be-
tween neuromodulatory input and presynaptic inhibition are
not clear. Although the emphasis in this article is on post- The base state of motoneurons
synaptic effects of neuromodulatory inputs on motoneurons, Before turning to the effects of neuromodulatory systems, it is
neuromodulatory systems can have presynaptic effects as well necessary to establish the “classic” (553) or “base state” of the
(282). motoneuron for recruitment and rate modulation. Although

P1: OTA/XYZ P2: ABC
(A) (B) (C)

Pyr
10 RN
20
DN 200
Voltage (mV)
Effective synaptic current (nA)
Ia excit.
Ia inhib.
0
Firing frequency (spikes/s)

Renshaw
5 –20 150
–40 Control
S
0 –60 100
FR
riluzole 2ndery
Current (nA)
50 50 FF
–5
0 Primary
–50
0
–10 0 1 2 3 4 5 0 20 40 60 80
0.5 1.0 1.5 2.0 >2.0 Time (s) Injected current (nA)
Steady state input resistance (MΩ)
Figure 5 Input organization and electrical behavior of motoneurons in the base state, without significant levels of neuromodulation. (A)
Summary of distribution of ionotropic synaptic currents within a motor pool. Data from a series of studies in motoneurons that innervate cat
ankle extensor muscles by Powers, Binder and colleagues (reviewed in reference 553). Inputs generated by electrical stimulation of descending
tracts [pyramidal (Pyr), rubrospinal (RN), vesitbulospinal (from Dieter’s nucleus (RN)], ventral roots (recurrent inhibition via Renshaw cells), and
tendon vibration [Ia monosynaptic excitation (Ia excit) and Ia disynaptic inhibition (Ia inhib)]. All measurements were made under steady-state
conditions. Figure modified, with permission, from reference 553). (B) Repetitive firing in response to a linearly rising injected current (control,
thin trace). The thick trace indicates the response after administration of riluzole to block the NaPIC; the transient Na current remains but spiking
cannot occur due to the lack of the acceleration in membrane potential due to the NaPIC (arrow on control trace). Redrawn, with permission,
from the authors from data from Kuo et al. (406). (C) Summary of frequency-current relations in S, FR, and FF motoneurons generated by linearly
increasing injected currents. Based on simulations, with permission, by Heckman and Binder (296).
this base state only applies to deeply anesthetized prepara- a small but crucial acceleration in depolarization (illustrated
tions [and probably to the sleeping state in normal animals in Fig. 5 B—see the arrow) that allows membrane potential
(353)], it is the foundation for all other motoneuron states. to achieve a sufficient rate of rise to allow NaT activation to
This topic was reviewed in detail in the Handbook chapter on escape its inactivation and produce a spike. As a result, the
this topic (60) and updated by Powers and Binder (553) and motoneuron exhibits only modest accommodation, which is
Kernell (383). the tendency for spike voltage threshold to depolarize as in-
The tenfold range of input resistances across a motor pool put slows (553,611). Rate adaptation has three phases: initial,
strongly predisposes the system to recruitment according to early, and late (383, 553). The initial adaptation consists of a
Henneman’s size principle (553). The tendency of excitatory rapid drop in firing rate over the first few spikes that depends
inputs to generate larger synaptic currents in FF than S mo- on initial rate. During the subsequent early adaptation, the
toneurons does not overcome this tenfold range (298). This re- decline is more gradual (time constant about 250 ms). Late
sult, based on computer simulations, is consistent with studies adaptation is a gradual slowing of firing with a time constant
in both human subjects and animal preparations (see Section of 10 to 20 s (383,553). The initial adaptation is probably due
“Computer simulations”). Recruitment order can be nearly to build up of the AHP and to Na channel inactivation, but the
randomized by combining an excitatory input that favors FF later phases likely involve multiple mechanisms. Although
recruitment with a background of inhibition, but mixing in slow inactivation of the Na currents seems a likely mecha-
any excitatory input that either favors S recruitment or is uni- nism for early (482) and late adaptation (733), blockage of
form restores the normal sequence (298). Thus, recruitment this current sometimes has little effect (733). Thus, multiple
tends to remain orderly despite a wide range of distributions mechanisms likely contribute (553).
of ionotropic synaptic input. The classic studies of Kernell and colleagues identified
The repetitive firing that emerges as threshold is exceeded the input-output function of the motoneuron in the base state
is the primary basis of rate modulation in motoneurons. The using injected currents to measure the frequency-current (F-I)
AHP generated by SK is the dominant factor determining fir- function (383). The F-I function exhibits a sharp threshold for
ing rates (383, 553), but the overall behavior of the motoneu- repetitive discharge and then two linear regions as discharge
ron during repetitive firing is complex. Initiation of each spike rates increase: the primary and secondary ranges (illustrated in
after an AHP requires the presence of at least a small NaPIC Fig. 5 C). The tenfold range of input resistances in S, FR, and
(291, 406, 425). This is because the rate of rise of voltage FF motoneurons provide a wide range of threshold currents for
as the AHP decays is relatively slow, allowing inactivation F-I functions (the different starting points along the x-axis for
of the transient Na current (NaT) to keep up with its acti- the F-I functions in Fig. 5 C). There are also differences in the
vation and preventing spike initiation. The NaPIC produces frequencies at threshold and at the transition to the secondary

P1: OTA/XYZ P2: ABC
range (arrows). However, these F-I functions predict that S then discovered that PIC-induced bistable behavior followed
firing rates reach high levels before full recruitment of FFs naturally from endogenous release of 5-HT and NE from the
is attained (the S in Fig. 5 C is firing at well over 100 Hz brainstem (128, 133, 328, 329, 329-332). By showing the pro-
when the final FF unit is recruited), which appears to be found influence of neuromodulatory systems in transforming
unrealistic compared with firing rates seen in human motor ionotropic input, this pioneering work initiated a revolution
units (see Fig. 14 below). This issue is considered below in in our understanding of motoneuron behavior.
Section “Input-Output Relations for an Entire Motor Pool and The two components of the PIC (the CaPIC and the
Muscle.” NaPIC) are both strongly facilitated by 5-HT acting via 5-HT2
A notable tendency of motoneuron repetitive firing in re- receptors and by NE via alpha 1 receptors (289,424,433,534).
sponse to triangular inputs is that the firing frequency at off- Both 5-HT2 and NE alpha1 receptors have subtypes. In the
set (derecruitment) is often lower than at onset (recruitment) sacral cord of the mouse, 5-HT2B,C receptors probably play
(721). This effect is sometimes seen in human motor unit the dominant role in PIC facilitation (289, 433). The subtypes
firing patterns (see Section “Slowly varying isometric con- for NE alpha 1 are not yet clear, but the alpha 1a receptors
tractions”; this rate hysteresis is distinct from the hysteresis may be important (703). The activation voltage for the PIC is
in input current generated by PIC activation and deactivation). hyperpolarized as monoaminergic level is increased, at least
This lower rate likely reflects the buildup of the AHP as repet- for sacral motoneurons in the rat (289,433); NE does not seem
itive firing continues (721), but the NaPIC and its effect on to have an overt hyperpolarizing effect on voltage threshold
spike initiation may also have a role (289, 291, 406). in the cat (421, 424). PICs are greatly reduced in amplitude
in preparations with deep anesthesia or acute spinal transec-
tion to reduce or block activity in descending monoaminergic
Neuromodulatory inputs control tracts—this was a major component in the evidence for the
intrinsic excitability fundamental role of these neurotransmitters (329, 486). As
A diversity of neurotransmitters is now known to have emphasized above, at least some NaPIC is required for spike
neuromodulatory effects on motoneurons and these are initiation during repetitive firing (406). In addition, a small
summarized in Table 3. It is highly probable that additional CaPIC may contribute to the onset of the secondary range at
ones will be discovered in future work. So far, however, 5-HT high levels of injected current in anesthetized or spinalized
and NE have the most potent effects on motoneurons and have preparations (299).
been the most thoroughly studied. The effects of these two Figure 7 uses a realistic motoneuron model to illustrate
systems on motoneurons are similar, but they are linked to the main components of the PIC-induced transformation in
different behaviors. Activity in the descending 5-HT system motoneuron behavior as background levels 5-HT and NE in-
likely increases in proportion to motor output (353), whereas put are increased. Two simple input forms were simulated:
the NE system varies with arousal (21). Both of these systems a step and a triangle, both applied as a pure excitatory input
originate in the brainstem, the caudal raphe for 5-HT and the with synaptic conductances distributed throughout the den-
locus coeruleus/subcoerulear nucleus for NE. The anatomy dritic tree [the model is based on a full reconstruction of a
of these systems is well described: both project monosynap- type FR motoneuron (188, 189)]. In the base state (as oc-
tically to motoneurons throughout the spinal cord (75, 324). curs in acutely spinalized preparations), the response of the
Moreover, the number of synapses per motoneuron is large, motoneuron is simple: once above threshold, discharge rate
with about 1500 for 5-HT (15) and perhaps 30% less for NE tracked the input. With moderate neuromodulation, the input
in cervical motoneurons in the adult cat (personal communi- was amplified to produce a much higher firing rate. More-
cation, Ken Rose). This is a greater number of synapses than over, firing continued after the input ceased. At high levels of
for the ionotropic input from Ia afferents (15). Moreover, neuromodulation, amplification was even greater and firing
the 5-HT (15) and NE (Ken Rose, personal communication) was prolonged to reach a stable steady state of self-sustained
synapses cover the entire cell, out to the distal dendrites, as firing—this is bistable behavior. With the triangular input, two
shown in Figure 6 (lumbar motoneuron in the adult cat). This further important PIC effects are revealed. The first was that
synaptic distribution is consistent with the dendritic locations once the amplification was complete, the cell became much
of PICs. less sensitive to additional excitatory input—for example, the
motoneuron response saturated so that increases in firing rate
are limited. The other is due to prolongation: offset of firing
Neuromodulation of persistent inward currents
occurs at a lower input level than onset, giving onset-offset
Schwindt and Crill were the first to study PICs in motoneurons hysteresis.
(see 325 for a short history of PICs in neurons) (615, 619). Thus, the PIC induces three basic phenomena in firing
This classic work established that PICs could generate bistable rate patterns: amplification, saturation/rate limiting, and pro-
behavior, in which the motoneuron continues to discharge ac- longation/hysteresis. These effects, except saturation, were
tion potentials after the input to the cell ceases. These studies clearly observed in the classic studies of the Copenhagen
relied on artificial agents to block K currents. The Copen- group (128, 329). Amplification and hysteresis in firing rate
hagen group (Hultborn, Hounsgaard, Kiehn and colleagues) can be easily evoked by triangular injected currents and have

P1: OTA/XYZ
JWBT335-c100087
Table 3 Summary of Neuromodulatory Effects on Motoneurons

P2: ABC
ATP/
5-HT NE ACh DA GABAb mGluR Adenosine TRH NK PKC
AP thrsh Reduced (338) Reduced (523) No change Reduced likely Reduced in Varied†
(415) D1 † (283) spinalized only (140)
(437)
AP hght Enhanced by Enhanced by No change No change† (462) No change (42) Reduced†
endogenous endogenous (415) (140)
5-HT2A&C α1 (290)
JWBT335/Comprehensive Physiology
(290)
CaPIC Enhanced (330, Enhanced Enhanced (128) Reduced by high No change† (462)
337, 433) by (128, 424, dose (437)
5-HT2 (411) 570)
NaPIC Enhanced Enhanced Enhanced (128) Enhanced by Enhanced (42)? No change via Reduced†
(337, 338) by (128, 424, high dose NK1 (3) (140)
July 31, 2012
5-HT2A&C 523) by α1 R (437)

(289, 290) (290)
AHP mAHP Reduced Depolarized mAHP reduced mAHP Reduced Increased via No change (42) mAHP no sig
(40, 52, 338, fAHP, via M2 R likely D1 † A1&2 (463) changes (3)
8:55
350, 719, reduced (415, 483) (283) sAHP reduced†

726) amp of (429)
mAHP (523)
Ih Enhanced (338, Reduced via Increased No change via
(Na/K) 416, 659) α2 R (524) NK1 (3)
depends on
cAMP† (417)
IA Enhanced Reduced likely
(523) D1 † (283)
Cav2 Reduced† Reduced† (150) Reduced via
(HVA) (40, 411) A1† (507)
Printer Name: Yet to Come
RN Increased Increased via Increased† (283) No change (437) Increased† No change Increased Increased via
(192, 338, α2 R (192, (19, 150, 173) (463, 485) (42,223,572) NK1 (3, 223,
350, 416, 416, 524) No change via Decrease† 429, 728)
433, 441) but and α1 R group-I† (462) (243)
not through (523)
5-HT2 (289)
or 5-HT1A&B †
(726)
† Results obtained from neonatal preparations only.

P1: OTA/XYZ P2: ABC
net synaptic current undergoes a dramatic increase as the

cell is depolarized by the voltage clamp, reaches a peak (full
PIC activation), and then sharply declines (saturation). The
amplification and saturation both increase with the level of
neuromodulation (as indicated by the different traces in B).
These current- and voltage-clamp studies demonstrate that
ionotropic input can be amplified as much as fivefold, which
surely has an enormous impact on input-output gain of the
motoneuron (58, 299, 302, 340).
Other neuromodulatory actions

Facilitation of the PIC is only one influence of 5-HT and NE
on motoneuron excitability. The resting membrane potential
is depolarized via actions on a K leak channel and on the
H current (553). In addition, spike threshold is hyperpolar-
ized (139, 218, 257, 399), perhaps by hyperpolarization of the
NaPIC (289) or by other mechanisms (548), and, at least in
young motoneurons, the AHP amplitude is reduced (553).
Many of these effects are also mediated by other neuro-
modulators (553) (see Table 3 for specific references). Unlike
the influence of 5-HT and NE on the PIC, most studies of other
neuromodulators have been done in neonatal preparations, so
the results may differ for adults. The most consistent influence
of neuromodulators is to depolarize motoneurons via the same
Figure 6 Distribution of neurotransmitter serotonin (5-HT) contacts K leak channel and H channel as noted above for 5-HT and
on a cat motoneuron. Each dot indicates the presence of a synaptic
bouton containing 5-HT. Reconstruction of the cell, with permission, by NE. Neuromodulators that cause this depolarization include
Dianne Dewey. Figure created from data from Alvarez et al. (15), with TRH and substance P (which are sometimes colocalized
permission from the authors. within 5-HT boutons on motoneurons) (469), and glutamate
via metabotropic glutamate receptors (Table 3). In most
cases, the neurons of origin for these neuromodulators are
subsequently been demonstrated in cat (see Fig. 8 B,D) unknown and the question of interactions between descend-
(47,423), rat (Fig. 8 E,F) (98,433,435,687), and mouse (479). ing systems and local systems within the spinal cord remains
That these firing behaviors are due to the PIC has been clearly unclear.
demonstrated in studies with voltage clamp, from the earliest In adult turtle motoneurons, the PIC is facilitated by 5-HT,
studies in vivo in the cat by Schwindt and Crill (615, 616) to metabotropic glutamate receptors, and cholinergic muscarinic
more recent work in cat in situ (Fig. 8 A vs. B and C vs. D) receptors (657). It is not yet clear if the same is true for mam-
(422, 423), rat in situ (E vs. F) (281, 687), rat in vitro (433), malian motoneurons, but the GABAb agonist baclofen can
and mouse in vitro (107). Moreover, the time course of ac- suppress CaPICs in both turtle and rat, although at a much
tivation of the PIC in voltage clamp accurately predicts the higher concentration than its presynaptic inhibitory effects
time course of firing rate acceleration (428), as illustrated in (437). Baclofen is the only inhibitory neuromodulator of mo-
Figure 21. toneurons that has been identified, but given the diversity of
Injected currents, however, are a highly artificial method neuromodulatory actions on other types of spinal neurons
of activating cells. Nonetheless, studies using natural synap- (158), more are likely to emerge.
tic input show the same PIC phenomena as injected current Motoneurons also receive a dopaminergic projection from
and have underscored the functional importance of amplifi- the brainstem (125). As with many other neuromodula-
cation and saturation. The PIC is activated at much lower tors, dopamine agonists increase input resistance in neonatal
levels of input with synaptic excitation than with injected motoneurons (283, 741), but have not yet been systemati-
current (47, 344, 421), a major component of the evidence cally studied in adult motoneurons. Density of dopaminergic
for the dendritic location of the PIC (see Section “Regional synapses on motoneurons is probably much less than for 5-HT
specialization of ion channels”). Thus, the PIC acts to am- and NE (cervical motoneurons, adult cat; personal communi-
plify excitatory input, as illustrated Figure 9 A (341) where cation, Ken Rose).
the firing response to sinusoidal stretch undergoes a dramatic One area in which a local neuromodulator system may
increase when PIC activation threshold is reached. Studies dominate the descending 5-HT and NE systems is in con-
in voltage clamp have revealed that the saturation is invari- trol of the AHP. In the adult, 5-HT and NE appear to have
ably linked to PIC amplification (344, 421) (Fig. 9 B). The only weak effects on the AHP (289, 424, 433). In contrast,

P1: OTA/XYZ P2: ABC
50 60
Enhanced Self-sustained firing
Enhanced
40 Standard
Firing rate (imp/s)

Firing rate (imp/s)
40
30 Standard
20 Standard
20
10 Minimal
Enhanced Minimal
0 0
0 1000 2000 3000 4000 5000 0 2000 4000 6000 8000 10000
10 Time (ms) Time (ms)
5
Somatic potential (mV)
5000

–10
–20
Enhanced
–30 state
–50 –45
–70
–70
10
5
0 3000
–10
–20
Standard state
–30
–50 –45
–70
–70
10
5
0 3000
–10
–20
–30 Minimal state
–50 –45
–70
–70
Synaptic Synaptic
activation activation
0 1000 2000 3000 4000 5000 0 2000 4000 6000 8000 10000
Time (ms) Time (ms)
Figure 7 Effects of increasing Ca persistent inward current (CaPIC) amplitude on the firing produced by an excitatory synaptic input. A highly
realistic motoneuron model was used to generate these results, based on a full reconstruction of a fast fatigue resistant (type FR) motoneuron
with more than 700 dendritic compartments (based on references 189 and 188). The CaPIC was generated at a primarily middendritic location
(87,188,264). On the left, a step increase in conductance is applied to excitatory synapses distributed throughout the dendritic tree. On the right,
the same simulated synapses were activated in a triangular fashion. From the bottom up, the amplitude of the CaPIC is increased progressively,
mimicking one of the main effects of increasing neuromodulatory input. Note the need for inhibitory input after the triangle of excitation to bring
firing to a stop at the highest level. Simulations, with permission, by Dr. Sherif ElBasiouny.

P1: OTA/XYZ P2: ABC
(A) 15 (B)
60
Low-threshold, likely S
10
50
Firing frequency (Hz)

5
Current (nA)
40
0
30
–5 20
–10 10
–15 0
–70 –60 –50 –40 –30 –10 –5 0 5 10
Voltage (mV) Injected current (nA)
(C) (D)
15 High-threshold, likely FF 100
10 80
Firing frequency (Hz)
Current (nA)
5 60
0 40
–5 20
–10 0
–70 –60 –50 –40 –30 0 10 20 30 40
Voltage (mV) Injected current (nA)
(E) (F)
4
55
Instantaneous frequency (Hz)
2 45
Current (nA)
0 35
25
–2
15
–4
–70 –60 –50 –40 –30 0 1 2 3 4 5
Voltage (mV) Current (nA)
Figure 8 Current-voltage (I-V) and frequency current (F-I) relations generated by triangular input waveforms in motoneurons with a
steady background of neuromodulatory input. Black arrows indicate ascending and descending phases. (A) I-V relation in a putative type
S motoneuron. The persistent inward current (PIC) onset is indicated by the red arrow. (B) F-I relation in the same type S motoneuron.
The red arrow indicates the onset of the acceleration in firing due to PIC activation, which occurs right at threshold for onset of repetitive
firing. Note that the hysteresis in PIC onset and offset (blue arrow) in A generates the hysteresis in firing onset and offset in B. (C) I-V
relation in a putative FF motoneuron. (D) F-I relation in the same FF motoneuron. The lesser degree of I-V hysteresis corresponds to
lesser F-I hysteresis. (E) I-V relation in a rat motoneuron. (F) F-I relation in the same rat motoneuron. As for the cat, the I-V hysteresis
produces F-I hysteresis. [(A)-(D)] Modified, with permission, from Lee and Heckman (422, 423). [(E), (F)] Modified, with permission, from
Hamm et al. (281).

P1: OTA/XYZ P2: ABC
20
(A) 100 (B) Firing
threshold Enhanced
[lmp./s]
Firing 16
Synaptic current (nA)

frequency 60 Standard
12
20 Minimal
8
4
Injected 20
current nA
0
Muscle 10
length mm –4
–70 –65 –60 –55 –50 –45 –40 –35 –30
5s Membrane potential (mV)
(C) (D)
–10
Membrane potential (mV)
10
–20
Excitatory
PIC deactivation synaptic current
–30 5
–40 Current (nA)

0
–50
–5 Inhibitory synaptic current

–60
0 200 400 600 800 1000 1200
Distance from cell body (μm) –10

–65 –60 –55 –50 –45 –40 –35
Voltage (mV)
Figure 9 The persistent inward current (PIC) amplifies both excitatory and inhibitory synaptic inputs. (A) Amplification during repetitive firing.
Lowest trace: sinusoidal muscle stretch to provide synaptic input. Next: linearly rising current injected into motoneuron to generate background
firing. Upper trace: firing pattern evoked by the combined stretch and current. The strong increase in firing range in the last few cycles is
due to amplification by the PIC (onset marked by green arrow). Modified, with permission, from Hultborn et al. (344). (B) Amplification of
excitatory synaptic current as a function of voltage clamp holding potential. As the membrane potential is depolarized (x-axis), synaptic current
(y-axis) increases and then decreases, demonstrating amplification and saturation. The vertical arrow indicates the approximate membrane
potential at which the cell would begin spiking in unclamped conditions. The three traces show increasing levels of neuromodulatory input, low
to high. Modified, with permission, from Lee and Heckman (421). (C) Computer simulation in which dendrites were depolarized by excitation
alone (upper traces) and then by combined excitation and inhibition. Excitation alone activated the PIC, but inhibition sharply reduced PIC
activation (red arrow). Modified, with permission, from Bui et al. (85). (D) Comparison of excitatory and inhibitory currents within one cell during
voltage clamp at various membrane potentials. The excitatory current shows the same amplification pattern seen in B but inhibition deactivates
the PIC and thus had its greatest influence in the voltage range where the PIC reaches its peak. Modified, with permission, from Hyngstrom
et al. (347).
recent studies have demonstrated that cholinergic input from in acutely spinalized preparations during the scratch reflex,
interneurons has a major impact on the AHP (483). Interneu- which is a remarkable finding whose mechanism is as yet
rons near the central canal (the V0c subclass) innervate the unknown (548).
large C boutons on the soma and proximal dendrites of mo-
toneurons (730). The postsynaptic structure facing the C ter-
minals has a remarkable structure in which muscarinic type Synaptic inhibition opposes neuromodulatory
cholinergic receptors are colocalized with Kv 2.1 and SK ion actions on PICs
channels. It seems reasonable to suppose that the reduction An obvious functional issue emerges from use of brainstem
of the AHP during locomotion and the scratch reflex is due neuromodulatory systems to control motoneuron excitabil-
to activation of this muscarinic system; that is, to a local neu- ity via PICs: at medium to high levels of neuromodulation,
romodulatory system. Hyperpolarization of spike threshold PICs strongly tend to prolong input and thus motoneurons
also is under local neuromodulatory control as it is evident would tend to keep going whenever they are activated. This

P1: OTA/XYZ P2: ABC
is clearly not the case and it has been emphasized since of continuous noise. This method, applied to motoneurons by
the discovery of bistable behavior that inhibition can return Binder, Powers, and colleagues (545,546, 5104, 558), allowed
the cell to the preinput baseline (329). Recent studies show the effects of spike timing to be taken into account, producing
that the PIC is in fact highly sensitive to synaptic inhibition a relatively simple transform with only one nonlinear term.
(86, 344, 347, 348, 405), as illustrated in Figure 9 C where As yet, all of this work is based on motoneurons with minimal
the addition of inhibition to excitation greatly reduces the neuromodulatory input, so the effect of dendritic PICs on this
activation of the PIC in the dendritic regions of a simulated transformation is unknown. Also, this approach is limited to
motoneuron. In Figure 9 D, the interaction of excitatory and small fluctuations in membrane potential; understanding the
inhibitory synaptic currents with the PIC is compared. Note variations in amplitude required in normal motor commands
as the excitatory current reaches a peak and then declines will probably require full-scale motoneuron models (see Sec-
due to PIC amplification/saturation, there is a sharp increase tion “Computer simulations”).
in an inhibitory current as it deactivates the PIC. This com- Methods to estimate PSPs from motoneuron firing pat-
plementary nature of excitatory and inhibitory effects on the terns usually rely on two methods: the poststimulus time
PIC shows that the inhibition deactivates the PIC generated histogram (PSTH) (e.g. 191) and the peristimulus frequency
by the excitation. Note also that inhibition is amplified by gram (PSF) (686). The PSTH is based on the timing of spike
the PIC—inhibitory current dramatically increases with de- occurrences following a stimulus, whereas the PSF is derived
polarization in Figure 9 D. This increase in inhibition has two from the firing frequency patterns following each stimulus. In-
components, as emphasized by Bui and colleagues (85, 86). tracellular studies by Türker and Powers show that the PSTH
Unlike excitation, driving force for inhibition increases with is especially sensitive to the rising phase of an EPSP, whereas
depolarization and then further amplification occurs due to the PSF can track the time course of the PSP (684, 686). An
deactivation of the PIC that has depolarized the dendrites. example of the utility of the PSF is provided by a recent study
Thus, inhibitory inputs have a strong impact once the PIC has by Gorassini and colleagues with a comparison of PSFs from
saturated the response to excitatory inputs. human subjects to those generated in intracellular studies,
Both recurrent inhibition and reciprocal inhibition are ef- which showed how a multiphasic PSF could be produced by a
fective PIC deactivators (85, 86, 347, 348), which was unex- simple combination of EPSP and IPSP (517). Thus far, how-
pected given that the synapses for recurrent inhibition are ever, the intracellular studies of the PSF and PSTH have not
probably located more distally than those for reciprocal inhi- considered potential effects of neuromodulation, which is a
bition (244, 455). Presumably this distal location would pro- significant limitation given that the NaPIC is likely to amplify
vide an advantage for recurrent inhibition (86), as the PIC these brief inputs.
location is primarily dendritic. Yet it is clear that the small The basic dynamics of the PIC are fairly clear, with ac-
amount of reciprocal inhibition generated by modest changes curate replication of amplification of slowly rising synaptic
in ankle angle can deactivate the PIC in ankle extensors by inputs being simulated by a dendritic CaPIC with a time con-
50% (347, 348). Perhaps there is an as yet undetected instant of about 50 ms (188, 189). Fast amplification has a time
hibitory neuromodulatory component via GABAb receptors constant of about 5 ms and is perhaps due to a dendritic NaPIC
for reciprocal inhibition. (630). A significant problem, however, is the strange behav-
An important point is that PIC control is restricted to in- ior of the CaPIC, as illustrated in Figure 4 C. The CaPIC
hibitory inputs. Excitatory input, such as the monosynaptic activates very slowly to inputs that just exceed its threshold,
input from muscle spindle Ia afferents, actives the PIC and exhibits a tendency to “warm up” with closely repeated inputs
its full transformation of amplification, saturation, and pro- and tends to be inconsistent in its response to repeats of the
longation. Turning off this excitatory input leaves the PIC same stimulus (428, 499) (see for example Fig. 4 C). A full
on (Fig. 7)—this is the essence of the prolongation of input understanding of the relation between CaPIC variability and
mediated by the PIC. Thus, it is the inhibitory inputs that motor output remains elusive.
oppose facilitatory PIC effects from descending brainstem
neuromodulatory systems (347, 348). In this specific sense,
inhibitory inputs such as recurrent and reciprocal inhibition Summation of inputs in the presence
directly control the intrinsic excitability of motoneurons. of dendritic PICs
The PIC has been shown to interact with excitatory ionotropic
input in a graded fashion during voltage clamp (347, 421)
Processing of transient synaptic inputs and linear summation of excitatory inputs has been demon-
The subthreshold behavior of medium to large PSPs has been strated during repetitive firing induced by current injection
thoroughly studied (553), but it is the suprathreshold effects (556, 564). These studies involved steady input and so were
during repetitive firing that are fundamental to motoneuron not influenced by the acceleration in firing rate as the PIC
behavior. A variety of approaches have been tried to create activates. Summation of larger inputs should encounter the
accurate models of the effects of single PSPs on motoneu- problem of PIC saturation (see Fig. 9 B,D). That is, if one
ron discharge rates (553), but the most accurate thus far is excitatory input fully activates the PIC, the addition of a sec-
based on a Wiener kernel approach derived from application ond input should have a much smaller influence. Summation

P1: OTA/XYZ P2: ABC
of inhibition with excitation has only been examined during tial (183). Inhibitory inputs can oppose these actions. The
voltage clamp. Overall, this summation is less than linear, possibility that this toolbox is used to reconfigure motoneu-
due to the shunting effect of the inhibition. Once the PIC ron electrical properties to match the demands of different
becomes fully active, summation switches to greater than lin- motor tasks is considered in the final section of this article
ear (i.e., the actual sum is greater than the algebraic sum of (see Section “Input-Output Relations for an Entire Pool and
the individual inputs), because the inhibition deactivates the Muscle”).
PIC (347). These nonlinearities seen during voltage clamp are
generally modest however, around 10%. Studies of excitation
and inhibition summation during repetitive firing have not Computer simulations of the motoneuron
yet been done, but the influence of inhibition on PIC-induced Substantial advances have been made in achieving realistic
saturation of excitation may be especially important. computer simulations of motor neurons. The simplest models
deal with steady-state conditions and ionotropic inputs; these
have been used to estimate the net input-output function of
A unique ionotropic input: The NMDA system a pool of motor units and are reviewed in the final section.
The N-methyl-D-aspartate (NMDA) receptor is ionotropic, Initial dynamic models were of the threshold-crossing class,
but is unique in that its synaptic current increases as a func- in which each spike produces an AHP that interacts with a
tion of depolarization, instead of decreasing as for other glu- constant spike voltage threshold (553). Motoneurons, how-
tamatergic receptors. This increase occurs because Mg ions ever, exhibit a variable spike voltage threshold, depolarizing
block the NMDA pore when the cell is near the resting poten- as the AHP decays (553). Models incorporating this variation
tial and are displaced as the cell is depolarized, thus confer- were better able to capture motoneuron behaviors, especially
ring voltage-sensitive behavior (317). The NMDA receptor when coupled to conductances representing PICs (549). These
has long been known to play an essential role in locomotor models generally consisted of only a single compartment. Pro-
behavior in neonatal preparations (612) and administration of ducing true self-sustained firing that is stable for long periods
NMDA to neonatal motoneurons induces oscillations that are is improved by adding at least one dendritic compartment
resistant to tetrodotoxin (TTX) (319). The levels of NMDA re- (69).
ceptors on motoneurons may decline with age (553), but clear Motoneuron surface area is greatest in the extensive den-
evidence for existence of NMDA receptors on adult brain- dritic trees (see Figs. 6 and 24). As yet it is not technically
stem neurons was demonstrated by Durand and colleagues feasible to record directly from motoneuron dendrites—the
over 20 years ago; they showed that NMDA-induced oscilla- multiple branches taper rapidly and follow highly curved
tions in membrane potential similar to those seen in neonatal pathways. Direct dendritic recordings have been achieved in
motoneurons (182, 183). It seems reasonable to suppose that cell culture (418, 419, 444), but cultured motoneurons appear
adult spinal motoneurons also have NMDA receptors. The to lack significant CaPIC (406). Thus, computer simulations
source of this NMDA input remains uncertain. In lamprey remain the best approach to understanding how synaptic in-
motoneurons (12), NMDA receptors on motoneurons play an tegration has been transformed by the amplification due to
important role in locomotion, suggesting that the locomotor dendritic PICs (e.g., Figs. 7 and 9C). Only recently have mod-
CPG may be the primary source of activation of NMDA recep- els with fully reconstructed dendritic trees begun to include
tors on adult spinal motoneurons in mammals as well. Input voltage-sensitive conductances. As discussed above (see Sec-
from high-threshold sensory afferents mediating the flexion tion “Regional specialization of ion channels”), these com-
reflex may also have an NMDA component in the adult, as partmental models support a middendritic location for the
this input does show increased amplitude with depolariza- PIC (87, 188, 189), albeit shifting to more proximal loca-
tion (80). Many questions remain about how NMDA receptor tions in smaller motoneurons (264). Inhibitory interactions
activation interacts with the PICs facilitated by 5-HT and NE. with the PIC can also be effectively simulated via this ap-
proach (85, 86) (Fig. 9 C). Addition of somatic Na, K, and Ca
channels has allowed a remarkably good recreation of both
A “toolbox” for control of intrinsic electrical repetitive firing and voltage-clamp behavior of motoneurons
excitability of motoneurons with strong PICs, such as amplification of steady synaptic
The availability of neuromodulatory, NMDA, and inhibitory input (188, 189) (see Fig. 7). Simulations by Shapiro and Lee
inputs potentially provides a “toolbox” that can be used by show that adding Na channels to dendrites sharply reduces
motor commands to adjust the intrinsic excitability of mo- the electrical length of motoneurons and allows distal input
toneurons over a remarkably wide range. Descending neuro- to behave as if it is close to the soma (630). In addition, den-
modulation, with its influence on gain and threshold, has the dritic Na could potentially produce spike back-propagation or
capacity to increase input-output gain of a motor unit popula- even dendritic spikes (419, 444, 630). The Na PIC activates
tion over fivefold (344, 421). Inputs likely to be mediated by rapidly, causing the simulated total PIC to turn on in a nearly
NMDA receptors undergo voltage dependent amplification all-or-none fashion. The more graded activation of the PIC
and thus also induce a high motoneuron gain (80). NMDA usually seen in experimental studies (428, 564) may be due
inputs can also induce slow oscillations in membrane poten- to the existence of multiple dendritic branches, allowing the

P1: OTA/XYZ P2: ABC
PIC in each to activate with slightly different voltage thresh- toneurons. Muscle unit force, however, extends over a nearly
olds (105, 188, 189, 630). Much further modeling is needed 100-fold range, with the average for S motor units being
for processing of transient inputs in the active dendrites of about 10% of the average for FF motor units (226). As the
motoneurons. Initial work by Taylor and Enoka (665, 666) specific tension (force per cross-sectional area) of type I and
indicate that the presence of the PIC gives prominence to the type II mammalian muscle fibers is not significantly differ-
effect of fluctuations in inhibitory input, as the large den- ent (73, 443), the dramatic increase in force from S to FR
dritic depolarization due to the PIC causes excitatory inputs to FF motor units is primarily due to increases in innervation
to saturate (an example of the differential effect of the PIC on number (681), although differences in fiber diameter also con-
excitation vs. inhibition is shown in Fig. 7 D, where inhibitory tribute (73, 88, 383). Differences in contraction speed reflect
current increases as excitatory current saturates). Many uncer- basic differences in contractile protein, coupled with differ-
tainties remain about dendritic locations of voltage sensitive ences in the calcium-release system (88,383). The range from
channels and several motoneuron behaviors have not yet been S to FF motor units is approximately fivefold from the slowest
successfully simulated, including L-type Ca channel warm to the fastest motor unit (on average, S motor units are about
up. The full range of behavior possible with neuromodula- two to three times slower than FF motor units [88,226)]. How-
tion, inhibition, and NMDA input has not yet been addressed ever, there is considerable overlap in contraction speeds of
to any significant degree with modeling studies. FR and FF motor units. Differences in resistance to the Burke
fatigue protocol are perhaps the most striking: S units can
generate repeated submaximal contractions for many minutes
Muscle Unit Physiology with little fatigue, whereas FF units exhibit fatigue within a
few seconds—the range is at least 100-fold (88, 226).
Unlike the motoneuron, there have been few studies of indi-
vidual muscle units in the 15 years since the since the chapter
on this topic was published in the Handbook of Physiology se- Basic mechanical properties of muscle units
ries. Concurrent measurements of both motoneuron and mus- The fundamental properties of muscle are defined by three
cle unit—the motor unit in its normal functional state—has relations; the force-frequency (F-f), force-length (F-L) (i.e.,
not been done for almost 20 years. Initiated by the seminal length-tension), and force-velocity (F-V) functions (525). The
work of Burke and colleagues (88), the last such work in the F-f function specifies the conversion of motor neuron firing
cat was the classic studies by Munson and colleagues in the rate into isometric force and thus provides the fundamental
1980s (505 and 734) and in rats by Bakels and colleagues in link between the neural and mechanical components of the
the early 1990s (23). Nonetheless, the approach is reemerg- motor unit. The resulting force strongly depends on muscle
ing in the study of degenerative diseases of motoneurons (see length and muscle velocity due to the F-L and F-V functions.
Section “ALS”). Study of the mechanical properties of muscle Consequently, muscle force can be modeled by specifying a
and the molecular mechanisms of contraction have continued firing rate as the input for the appropriate F-f function and
at a remarkable pace, but these studies take place in the con- then adjusting the muscle force with the F-L and F-V func-
text of whole muscles and in vitro muscle preparations. Forces tions. This simple model is a variant of a standard class of
of single motor units are difficult to measure, because each muscle models referred to as Hill-type, being based on AV
unit has to be studied in situ in a whole muscle but only exerts Hill’s classic studies (731). Thus, the same pattern of action
a tiny proportion of the whole muscle force. Even the passive potentials generated by a motoneuron at one length and ve-
force of a whole muscle is usually much larger than that of locity will generate a different force when the muscle moves
an active motor unit (165, 304, 540). Thus, measurement of to a different length with a different velocity.
motor unit forces is usually confined to isometric conditions, These functions have all been measured for single motor
with only a handful of studies measuring forces during move- units. The F-f has the same normalized form for S, FR, and FF
ment and these restricted to constant velocity (165, 304, 539) muscle units, but with S units reaching tetanic forces at much
or brief stretches (540). lower frequencies than FR or FF muscle units due to slower
contraction times (383). The F-L relations of all muscle units,
however, appears to be similar, with any differences likely
Heterogeneity of muscle unit properties due to connective tissue and tendon compliance (222, 304,
The basic properties of muscle units from animal stud- 647)—there is no reason to expect length-dependent aspects
ies were thoroughly reviewed in previous Handbook of of sarcomere structure to differ in S versus FR versus FF units.
Physiology chapters (60, 88) and more recently by Kernell Most conclusions about differences in dynamic performance
(383), and so are only briefly summarized in this article. of S, FR, and FF motor units rely on measurements in whole
The range of motoneuron electrical properties is impressive, muscles that are predominantly type S (especially cat soleus)
but the heterogeneity of muscle unit mechanical properties is or FR/ FF (e.g., cat medial gastrocnemius) (135, 704). There
even greater (383). For example, motoneurons exhibit about are two exceptions. The F-V relation of individual motor
a tenfold range of input resistances, with the average for S units had been shown to vary as expected from differences
motoneurons being about three times the average for FF mo- in contraction speed, and so is steeper in S than FR and

P1: OTA/XYZ P2: ABC
FF units (165, 304, 539). Petit and colleagues (540) found a ied in experimental animals (type S, FR, and FF) and those
greater short-range stiffness (see Section “Nonlinear muscle in humans (low and high threshold) (see Section “Matching
properties”) for S motor units in response to quick stretches of of muscle unit and motoneuron properties”). Thus, current
individual muscle units. However, this effect was not observed understanding of the dynamic behavior of motor unit forces
in a recent comparison of slow and fast whole muscles (135, underlying normal movement is rather limited.
136). An important newer result by Petit and colleagues is that
S units develop their maximal power at lower velocities than
FRs or FFs, again consistent with slower contraction speeds Matching of muscle unit and
(541). It was suggested that rate modulation should vary with motoneuron properties
velocity, whereas power is controlled by recruitment.
Studies on anesthetized preparations established a remark-
Forces of motor units sum reasonably linearly. Single mo-
ably elegant matching between the electrical properties of
tor units in a large muscle may encounter some “stiction” due
motoneurons and the mechanical properties of their muscle
to microconnective tissue links with fibers of other motor
units. Henneman’s size principle of recruitment is grounded
units, but this disappears as soon as a few units become active
in the strong correlations between motoneuron input resis-
or the muscle moves (304, 557, 604); this low-level stiction
tance (which determines thresholds) and muscle unit forces
probably explains supralinear summation of motor unit pairs
(which define size on the output side) (see Section “The base
(123,557,682). As the number of active motor units increases,
state of motoneurons”). Due to the strong correlation between
summation becomes less than linear but this effect is mod-
the time courses of the motoneuron AHP time and the muscle
est, usually less than 10% of total force (530). This modest
unit twitch, Kernell and colleagues found that the frequency
nonlinearity is consistent with the Sandercock model of the
at which each motoneuron begins to fire action potentials
connective tissue matrix acting as a “common tendon” for all
(Fig. 5 C) produces approximately 10% of its muscle unit
motor units (604, 606). A greater degree of nonlinear sum-
force (383).
mation can be observed during rapid changes in stimulation
Because neuromodulation has a profound impact on mo-
rate or recruitment level (530), an effect also likely due to
toneuron properties (see Section “Neuromodulatory inputs
the interaction of active motor units with the common tendon
control intrinsic excitability”), its impact on motoneuron-
(604, 606). The above studies were done in isometric condi-
muscle unit matching needs to be considered. Neuromodula-
tions and further work is needed in the dynamic state.
tion is highly like to preserve the orderly recruitment pattern.
For example, PICs have more hyperpolarized voltage thresh-
Nonlinear muscle properties old in type S than FR and FF units (422). Moreover, the classic
studies of recruitment by Henneman and colleagues and the
Hill-type models of muscle are often used for computer sim-
systematic work by Cope and colleagues (124,131) were done
ulations of motor control, but fail to capture a number of
in the decerebrate preparation where brainstem neuromodu-
fundamentally important muscle properties. There are several
lation is strong. Neuromodulation may, however, disrupt the
prominent nonlinear behaviors of muscle that are likely to
frequency matching generated by the AHP-twitch time course
influence normal force generation (507, 602). First, there are
correlations. Activation of PICs and its inherent acceleration
strong interactions between muscle length, Ca sensitivity, and
and saturation appear to prevent steady firing at the initial
number of attached cross-bridges, resulting in an interaction
rate of the base state (e.g., Fig. 7). Moreover, a clear pattern
between the F-L and F-f functions (567). The optimal length
of initial firing rates in recordings of human motor units has
of muscle becomes longer as stimulation frequency decreases,
not emerged (see Section “Motor Unit Recruitment and Rate
an effect that has been demonstrated in S, FR, and FF mo-
Modulation in Humans”). Finally, recent studies suggest that
tor units (304). Second, velocity influences the rate of force
frequency matching may be species specific; mouse motoneu-
decay, with shortening speeding the rate of decay and length-
rons tend to begin steady firing at remarkably high rates that
ening slowing it (605); an effect that may be strongest in type
produce forces close to maximal tetanic values (Manuel and
S motor units. Third, force potentiates with moderate-to-high
Heckman unpublished data and 481)
activation frequency, an effect that may be strongest in FF and
FR units (78). Fourth, FR units can exhibit substantial fatigue
even at low stimulation rates (552) and “sag” in force profiles
of FR and FF units is often evident (88, 110). Fifth, although Motor Unit Recruitment and Rate
type S muscle units initially respond linearly to stretch, this
Modulation in Humans
“short-range stiffness” quickly declines (yields) and the rate
of force increase sharply declines (364); a major function of As the final common pathway, it is the activity of the motor
the stretch reflex is to compensate for this yield (327). As units that determines the magnitude and direction of the force
yet, there is no model of muscle, and certainly not of in- exerted by a muscle. The nervous system produces an intended
dividual motor units, which effectively captures all of these action by varying the force that is contributed by each motor
effects. Furthermore, there appear to be significant differences unit and the number of motor units that are activated for the
between the well-characterized properties of motor units stud- task.

P1: OTA/XYZ P2: ABC
(A) units exhibited low twitch torques (Fig. 11 A) and there was
1 a significant relation between twitch torque and recruitment
0.5 mV
threshold (Fig. 11 B). Time to peak twitch torque ranged from
2 20 to 86 ms, with a mean value of 45.6 ± 13.6 ms (Fig. 11 C).
1 There was no statistically significant relation between time to
2.5 N
2
peak torque and recruitment threshold for individual subjects
(Fig. 11 D), but time to peak declined slightly with an increase
2.5 s in recruitment threshold across the entire sample.
Motor unit twitch characteristics can change, however,
(B)
both acutely and in response to chronic interventions. For
Unit 1
example, twitch amplitude can be increased by preceding
2.5 mN activity (34, 93, 366, 674), muscle temperature (205), muscle
pain (206), and may be modifiable by the sympathetic nervous
system (582,583). Furthermore, twitch torque for motor units
Time to peak in tibialis anterior, but not the time-to-peak twitch torque,
increased after 12 weeks of training with rapid contractions
Unit 2 to lift a moderate load (693). Also, twitch torques are greater
for motor units in older humans (245, 628).
10 mN A more thorough characterization of motor unit contrac-
tile properties, however, requires the use of intraneural stim-
ulation to evoke responses at a range of stimulus frequencies
(237, 279, 452, 477, 670, 674, 718). By inserting a tungsten
50 ms microelectrode percutaneously into the peroneal nerve of hu-
man volunteers, Macefield et al. (452) were able to determine
Figure 10 Contractile properties of two motor units in first dorsal in- the contractile properties for 13 motor units from three mus-
terosseus as estimated with spike-triggered averaging. (A) The subject cles that extend the toes (extensor digitorum brevis, extensor
slowly increased the abduction force exerted by the index finger during
an isometric contraction and the action potentials discharged by two digitorum longus, and extensor hallucis longus). Twitch con-
motor units in first dorsal interosseus were detected with an intramus- traction and half-relaxation times (mean ± SE) were 74.8 ±
cular electrode. (B) The twitch forces of the two motor units (1 and 2) 3.9 ms and 78.6 ± 6.0 ms, respectively. Twitch forces ranged
were estimated with spike-triggered averaging of 512 discharge times.
The time to peak force (contraction time) was 65 ms for Unit 1 and from 6.3 to 78.1 mN (20.0 ± 4.0 mN). Maximal tetanic forces
39 ms for Unit 2. The peak forces were 2.9 and 14.7 mN, respectively. ranged from 29.9 to 199 mN (89.0 ± 16.5 mN), and were
Modified, with permission, from Desmedt and Godaux (160). elicited with stimulus frequencies from 15 to 100 Hz (me-
dian 50 Hz). The twitch-tetanus ratio ranged from 0.15 to
0.41 (0.22 ± 0.02). The steep portion of the force-frequency
relation extended from 5.5 ± 0.7 Hz to 16.3 ± 1.1 Hz, and
Contractile properties the frequency required to elicit half of the maximal force was
Due to variation in muscle fiber number, properties, and ar- 9.6 ± 0.6 Hz (Fig. 12).
rangement, the motor units that comprise a single muscle One caveat worth noting is that the motor unit twitches
exhibit a range of contractile properties. Although the tech- elicited by intraneural stimulation can differ from those ob-
nique has some limitations (101, 516, 667, 671), the twitch tained by spike-triggered averaging due to differences in the
characteristics can be estimated with spike-triggered aver- amount of slack in the muscle during the two procedures. For
aging (83, 398, 644). Figure 10 shows the recruitment and example, the values for twitch force, maximal rate of increase
discharge times for two motor units that were detected in in force, contraction time, and half-relaxation time for motor
first dorsal interosseus with an intramuscular electrode dur- units in human hand muscles are less with intramuscular and
ing a gradual increase in muscle force, and the corresponding intraneural stimulation compared with spike-triggered aver-
spike-triggered average forces for the two motor units (160). aging (398, 671).
In a comprehensive survey of motor unit properties in tib- In comparison with the contractile properties of motor
ialis anterior, Duchateau and colleagues used spike-triggered units in human thenar muscles (670, 673, 675, 718), those in
averaging to estimate the contractile properties of 528 motor the toe extensors had greater twitch forces, longer contrac-
units from ten subjects as they performed voluntary contraction times, greater twitch-tetanus ratios, the force-frequency
tions (694). The recruitment thresholds of the motor units relation was shifted to the left, and the force-frequency re-
ranged from 1% to 90% of maximal voluntary contraction lation was less steep (452). In both sets of data, there was
(MVC) torque for the dorsiflexor muscles, with 50% of the no statistically significant relation between twitch or tetanic
motor units having recruitment thresholds less than 20% MVC force and contraction time; thus, the force exerted by a slow
torque. The peak torque ranged from 0.7 to 171 mN·m with av- contracting motor unit did not differ from that for a faster con-
erage values (mean ± SD) of 25.5 ± 21.5 mN·m. Most motor tracting motor unit (54). Nonetheless, faster contracting motor

P1: OTA/XYZ P2: ABC
(A) (C)
0.3 0.2
Proportion of motor units
Proportion of motor units

0.15
0.2
0.1
0.1
0.05
0 0
0 20 40 60 80 100 120 140 160 180 20 30 40 50 60 70 80 100
Twitch torque (mN/m) Time to peak (ms)
(B) (D)
100 100
Time to peak (ms)

Twitch torque (mN/m)
75 75
50 50
25 25
0 0
0 20 40 60 80 100 0 20 40 60 80 100
Recruitment threshold (% MVC) Recruitment threshold (% MVC)
Figure 11 Contractile properties of 528 motor units in tibialis anterior as estimated with spike-triggered averaging. (A) Histogram of twitch
torques. (B) Relation between twitch torque and recruitment threshold for 40 motor units from a single individual. The linear relation (y = 0.72×
+ 13.0, r = 0.69) was statistically significant (P < 0.001). The relation for 514 motor units was slightly weaker (r = 0.61), but still statistically
significant (P < 0.001). (C) Histogram of time to peak torque. (D) The relation between time to peak torque and recruitment threshold for the
40 motor units from the same subject was not statistically significant (y = –0.09 + 47.4, r = –0.23). However, there was a slight, but statistically
significant, negative relation (y = –0.11× + 44.5, r = –0.21, P < 0.001) between time to peak torque and recruitment threshold for the sample
of 514 motor units. Modified, with permission, from Van Cutsem et al. (694).
units require greater discharge rates to reach half the maximal estimates of motor unit twitch force (Fig. 13). Furthermore,
force (237). Milner-Brown et al. (489) found that motor units with higher
recruitment thresholds had faster contraction times (range:
30-100 ms) than those with lower recruitment thresholds.
Recruitment during voluntary contractions When expressed relative to MVC force, therefore, the re-
Since the pioneering work of Adrian and Bronk (5), it has been cruitment threshold of a motor unit indicates the relative size
known that the force exerted by a muscle depends on the num- of a motor unit in the population that contributes to the mus-
ber of motor units recruited into action and the rates at which cle force. Accordingly, fatigue-induced changes in the force
these motor units discharge action potentials (176). Motor capacity of low-threshold motor units will reduce the recruit-
units are recruited in an orderly sequence (156, 629) that de- ment threshold of all larger motor units, despite minimal in-
pends on differences in motor neuron size (308,309,314,315). volvement in the task (35, 211). Furthermore, the magnitude
Consistent with the original and subsequent observations on and direction of the change in recruitment threshold during
cat hind-limb muscles (59, 124, 131, 278, 641, 732), human fatiguing contractions is related to the proportion of the task
motor units are recruited in order of increasing peak twitch that the motor unit is active, even when the contraction in-
force (100, 112, 160, 178, 494, 578, 676, 678, 697). Stein and volves only low-threshold motor units (211). One of the lim-
colleagues (490) provided the seminal demonstration of this itations of this measurement in humans, however, is that the
association with a comparison of the recruitment thresholds of measured force or torque rarely represents the output of a
motor units in the first dorsal interosseus muscle during a ramp single muscle, although the first dorsal interosseus is an ex-
increase in index finger abduction force with spike-triggered ception (Fig. 13). Nonetheless, recruitment order is relatively

P1: OTA/XYZ P2: ABC
(A) (A)
Frequency
50 pps
Trigger
2 5 6 10 15 20 30 50 80 100
Dorsiflexion force
100 mN
2s
Averager
(B)
100
Peak Force (% maximum)
80
60
40
20
0 (B)
0 20 40 60 80 100 100
Frequency (pps)
Figure 12 Relation between stimulus frequency and the force ex-

erted by single motor units located in muscles that extend the toes. (A)
Motor units activated by intraneural stimulation (upper trace) evoked a Twitch (mN)
dorsiflexion force (lower trace). (B) Relation between stimulus frequency
and normalized force (mean ± SE) for the 13 motor units. Modified, 10
with permission, from Macefield et al. (452).
resistant to change and is not influenced by such interven-

tions as aging (227, 391), limb immobilization (178), muscle
fatigue (4), or physical training (693).
The upper limit of motor unit recruitment is certainly 0.2 1 10 20
less than MVC force, and can differ between muscles. Most Recruitment threshold (N)
motor units in adductor pollicis, for example, are recruited at
Figure 13 Spike-triggered averaging of motor unit activity. (A) The
forces less than 30% MVC and none are recruited at forces experimental arrangement developed by Stein et al. (644) to estimate
greater than 50% MVC (177, 391, 404, 743), whereas motor the contractile properties of motor units in first dorsal interosseus during
units in biceps brachii and tibialis anterior are recruited up to a voluntary contraction. The isolated action potential of a motor unit
was used to trigger an averaging device that accumulated a running
approximately 90% MVC force (277, 404, 694). Not all hand average from the net force for a few hundred milliseconds each time
muscles have such low values for the upper limit of motor an event was detected. [Modified, with permission, from McComas
unit recruitment, however, as values of up to 78% have been (470) by Joel A. Enoka.] (B) Relation (r2 = 0.582) between the spike-
triggered average force and recruitment threshold force for motor units
reported for first dorsal interosseus (500, 677, 678). in first dorsal interosseus during a ramp contraction. Modified, with
permission, from Milner-Brown et al. (490).
Variability in recruitment order
Despite the general consensus that the recruitment of motor
units during voluntary contractions occurs in an order consis- It was also suggested that rapid contractions might involve
tent with the size principle (219, 362, 620), there have been the preferential recruitment of fast-contracting motor units
some suggestions that certain conditions require some flexi- (271, 345, 660). However, Desmedt and Godaux (160, 160)
bility in this scheme. Perhaps the first was the notion that it demonstrated that although recruitment threshold force de-
was possible to recruit a motor unit selectively while inhibit- clined with contraction speed (84, 692), the recruitment order
ing the recruitment of other motor units with lower thresholds for pairs of motor units in tibialis anterior and first dorsal in-
(20, 32, 33, 269, 270). Such a possibility, however, would re- terosseus was the same during slow ramp contractions and fast
quire an amount of control over the inputs received by each ballistic contractions. Although there were some reversals in
motor neuron as to exceed the capacity of the brain to accom- recruitment order (∼10% of trials), these involved motor units
modate all the possible combinations (310,668). Furthermore, with similar recruitment thresholds during ramp contractions
Henneman et al. (313) concluded that the records published (160). Even for apparent reversals involving motor units with
by the proponents of this level of flexibility did not support dissimilar recruitment thresholds, differences in axonal con-
this assertion. duction velocity can result in 5 to 10 ms differences in the

P1: OTA/XYZ P2: ABC
discharge times recorded in the muscle despite the concurrent discharging action potentials before higher threshold motor
generation of action potentials in the spinal cord (162). units during ramp contractions (649), and low-threshold units
A third condition that has been proposed to require (<10% EMGmax) appear to be about the same size (711).
changes in recruitment order is actions that involve a change Such observations, however, must be tempered by the pos-
in muscle length (466,629). As the synaptic input received by sibility of distinct intramuscular compartments and the dif-
a motor nucleus differs for isometric and anisometric contrac- ficulty associated with measuring muscle force to determine
tions (661-663, 692), there is the possibility that recruitment recruitment threshold and motor unit size (201).
order may change during shortening and lengthening contrac- Another condition that can influence recruitment order is
tions. Desmedt and Godaux (162) found that the recruitment manipulation of the feedback received by the motor neuron
order of motor units in first dorsal interosseus was similar pool. Garnett and Stephens (254) found that digital nerve stim-
for slow isometric contractions, ballistic isometric contrac- ulation of the index finger increased the recruitment threshold
tions, and slow and ballistic shortening contractions. Similar force of low-threshold motor units in first dorsal interosseus
results were obtained for motor units in biceps brachii dur- and decreased it for high-threshold motor units. Subsequently,
ing isometric contractions and slow shortening contractions Kanda and Desmedt (370) reported that rubbing the tips of
(661). There is less agreement, however, on recruitment order the index finger and thumb against each other could change
during lengthening contractions, which require different acti- both the recruitment threshold and recruitment order of high-
vation strategies (175). The uncertainty was underscored by threshold of motor units in first dorsal interosseus during a
Schieppati and colleagues when they reported that the motor precision pinch task. These observations were interpreted as
units involved in lowering an inertial load with lengthening indicating a preferential distribution of excitatory cutaneous
contractions of the calf muscles differed from those recruited input to high-threshold motor units, at least for this hand
to lift the load with shortening contractions (508, 509). Sub- muscle. Some estimates of the distribution of synaptic inputs
sequent investigators, but not all (334), have failed to demon- suggest that low-threshold cutaneous afferents are consistent
strate systematic differences in recruitment order between with this scheme (90, 181, 410, 551), although not all studies
shortening and lengthening contractions either when lifting have found the same result (298, 563). Perhaps the differen-
an inertial load (250, 412, 640, 651), pushing against a torque tial influence of cutaneous input on recruitment order only
motor (528, 651), or acting against an elastic load (122, 397). exists in motor nuclei involved in such tasks as manipulation
These results suggest that although recruitment order may dif- (370), and is not a scheme that is required for other actions
fer during some tasks that involve lengthening contractions, performed by limb muscles.
the order in which motor units are recruited remains relatively
consistent across contraction types.
In contrast to the preceding three conditions, there is more Modulation of discharge rate during
evidence that the order in which the motor units in a muscle voluntary contractions
are recruited can differ when the muscle contributes to differ- The relative contribution of a recruited motor unit to a given
ent actions (97, 599). For example, the first dorsal interosseus action depends on the rate at which it discharges action poten-
muscle produces most of the abduction force exerted by the tials. Although each motor unit can discharge action potentials
index finger but is one of several muscles that flex the inat rates that span its force-frequency relation (Fig. 12), the ob-
dex finger about the metacarpophalangeal joint. Desmedt and served rates for the same motor unit depend on the task being
Godaux (163) found that 8% of the 142 motor unit pairs in performed.
first dorsal interosseus consistently changed recruitment or-
der between the two tasks, which was subsequently confirmed
Slowly varying isometric contractions
during static (678) and dynamic contractions (676). Due to
a stronger correlation coefficient between the spike-triggered The recruitment threshold force of a human motor unit is typ-
average forces and recruitment thresholds during the abduc- ically measured as the force at which it begins to discharge
tion task compared with the flexion task, Desmedt and Go- action potentials repetitively during a slow, ramp increase in
daux (163) concluded that the distribution of central inputs muscle force (Fig. 10). Such recordings also indicate the
to the motor nucleus differed during the two actions. Such amount of discharge rate modulation that is exhibited by the
variability in recruitment order is not obligatory, however, as detected motor units to produce the prescribed rate of change
there were no changes when extensor digitorum communis in force. As described by Person and Kudina (535) for the
contributed to flexion and radial deviation of the wrist (578). rectus femoris muscle, the ramp increase and then decrease
Related to the potential influence of the prescribed action in force to a submaximal target during an isometric contrac-
on the recruitment order of the motor units in a muscle, some tion involved the concurrent recruitment and rate modulation
evidence suggests that size-related recruitment order may not of motor units (Fig. 14 A). Furthermore, earlier recruited
be so robust in trunk muscles (717). In trapezius, for example, motor units achieved greater peak discharge rates than later
motor units can exhibit abrupt changes in recruitment thresh- recruited motor units during these submaximal contractions
old and frequent substitution during sustained submaximal (146, 148, 149, 629, 660, 717), but not when the peak force
contractions (712, 717, 735), lower threshold units can stop reached values close to MVC force for leg muscles (199,520)

P1: OTA/XYZ P2: ABC
(A) crease in force differed from that for the decrease in force.
15 50
For example, the derecruitment threshold force and discharge
rate just prior to derecruitment for motor units 1 and 2 differed
12 40
from the values observed for the same two motor units dur-
ing the increase in force. Such differences are not consistent,
Discharge rate (pps)
however, as a lower derecruitment threshold force has been
Force (% maximum)
9 30 reported in some studies (35, 154, 251, 584, 656, 743), but
1 not in other studies (148, 211, 233, 235, 356, 488, 520, 529).
2
Some of this discrepancy is attributable to the difference in
6 3 4 20 the definition of the two events; whereas recruitment thresh-
old corresponds to the activation of a motor unit before it
contributes to the net force, derecruitment threshold denotes
3 10
the timing of the final action potential when the motor unit
is still contributing to the muscle force (175, 235). Whether
0
or not the derecruitment threshold is less than the recruitment
0
threshold, however, the discharge rate at derecruitment is of-
0 3 6 9 12
ten less (148, 154, 260, 502, 520, 649), and this is attributed
Time (s)
to activation of a PIC in the motoneuron (see Section “Neu-
(B)
25 romodulation of persistent inward currents”) (559, 688, 721)
coupled to a tendency for the AHP to become prolonged after
repeated action potentials (721).
20 Rate modulation has also been measured as subjects track
a continuously varying force target with an isometric contrac-
tion. When tracking a sinusoidal target, for example, motor
units in brachialis and biceps brachii discharged one burst of
15
action potentials with each cycle and this phase lead increased
with the frequency of the target (692). The magnitude of the
rate modulation, however, differed across motor units and
10
for isometric contractions compared with movements. Fur-
thermore, Knight and Kamen (393) found that the reduced
accuracy of older women to track a force target comprising
5 the sum of 0.15 and 0.45 Hz sine waves was associated with
less rate modulation compared with young women.
0
0 20 40 60 80 100 80 60 40 20 0 Isometric contractions at different target forces
Torque (% MVC) An alternative approach to characterize discharge rate modu-
lation is to record the activity of single motor units during brief
Figure 14 Rate modulation during ramp increases and decreases isometric contractions at a range of target forces. Moritz et al.
in muscle force. (A) The recruitment and derecruitment thresholds of
four motor units in rectus femoris, and the extent to which discharge (500) found that increases in the abduction force exerted by the
rate was modulated (pulses per second; pps) during ramp contractions index finger were accompanied by significant rate modulation
by the knee extensor muscles. The peak force during the isometric of single motor units in first dorsal interosseus (Fig. 15 A).
contraction was 33% maximal voluntary contraction (MVC). [Modified,
with permission, from Person and Kudina (535).] (B) The instantaneous The approximately 10 target forces for each motor unit were
discharge rate of 42 motor units in soleus during ramp-and-hold iso- selected to span the range of forces over which its action po-
metric contractions up to MVC force. Recruitment thresholds ranged tentials could be discriminated. All 38 motor units increased
from 0.2% to 96.4% MVC force. Adapted, with permission, from Oya
et al. (520). discharge rate from initial values, but 12 of the motor units
exhibited plateaus in discharge rate, which meant that they
did not contribute to further increases in finger force. Further-
(Fig. 14 B). Rate modulation among trapezius motor units, more, the change in discharge rate relative to the change in
however, appears to be less systematic (649,710,717). As with finger force was not related to recruitment threshold. Similar
contractile properties, discharge rates are adaptable. For ex- relations were observed for motor units in the genioglossus
ample, peak discharge rates, but not those at recruitment, dur- muscle during tongue protrusion (22), but not when individ-
ing slowly varying isometric contractions are reduced (∼40%) uals were exposed to mild hypercapnia (575).
after several weeks of limb immobilization (178). In contrast to the observations during the ramp contrac-
Figure 14 also indicates that the combination of recruit- tions (Fig. 14) but consistent with earlier work (56, 277,
ment and discharge rate modulation responsible for the in- 373, 396), minimal and peak discharge rates observed across

P1: OTA/XYZ P2: ABC
(A) ment threshold, and increased discharge rate during submaxi-

40
mal isometric contractions. The increase in discharge rate was
most prevalent at low targets (<10% MVC torque), whereas
30 recruitment was more significant at moderate targets (10-35%

MVC torque). These observations suggest that afferent feed-
back about muscle length can influence the modulation of
20 discharge rate at submaximal target forces.
When the data displayed in Figure 15A were incorporated
into a computational model of motor unit recruitment and rate
10
coding (238), it was possible to estimate the relative amount
of motor unit activity required to achieve muscle forces during
0 isometric contractions that ranged from 2% to 95% of maxi-
0 20 40 60 80 100 mum (Fig. 15 B). The figure indicates the relative changes in
Finger force (% MVC) recruitment and rate coding for this population of 180 motor
(B) units with progressive increases in the target force. Forces
30
95% less than 60%, for example, involve concurrent increases in
85% recruitment and rate coding, whereas forces greater than 70%
20 70% are achieved by increasing the rate coding of high-threshold
50% motor units.
30%
10 15%
5%
2% Rapid isometric contractions
0 An increase in the rate of force development requires motor
0 20 40 60 80 100 120 140 160 180 units to be activated sooner due to a constant delay between the
Motor unit # timing of the action potential and the onset of motor unit force,
and this adjustment appears as a reduction in recruitment
Figure 15 Motor unit activity in first dorsal interosseus during brief threshold (Fig. 16 A) (84, 160-162, 629, 660). The magnitude
isometric contractions at different target forces. (A) The discharge rate
of 38 motor units (each line is a different motor unit) as young adults of the reduction in recruitment threshold is greater in slow-
performed the isometric contractions (∼6 s) at approximately ten tar- contracting muscles compared with those that are faster, such
get forces with each motor unit. The target forces corresponded to an as soleus compared with masseter (161). Due to this reduction
abduction force exerted by the index finger. The lower limit of each line
indicates the minimal target forces at which the motor unit discharged in recruitment threshold, Desmedt and Godaux (160, 160)
action potentials repetitively. Twelve of the 38 motor units exhibited a estimated that most motor units in a muscle are likely to be
clear plateau in discharge rate. (B) The experimental data were used recruited when performing a rapid contraction with a load that
to modify the Fuglevand model of motor unit recruitment and rate
modulation (238) and the simulated data were compared with experi- is approximately one-third of maximum. Rapid contractions
mental measurements of the coefficient of variation for force across the are also characterized by faster rates of increase in discharge
operating range of the muscle [2-95% maximal voluntary contraction rate (Fig. 16 B).
(MVC) force]. The output of the model was indistinguishable from the
experimental measurements and the graph shows the corresponding Ballistic contractions correspond to strong, rapid contrac-
motor unit activity at each target force. Modified, with permission, from tions that are followed immediately by relaxation (576). Such
Moritz et al. (500). tasks are accomplished by motor units discharging three to
five action potentials at 60 to 120 pulses per second at the
onset of the contraction (162). The discharge rates underlying
the different target forces were greater for higher thresh- ballistic contractions can change in response to various
old motor units in both young (Fig. 15 A) and old humans interventions. For example, 12 weeks of training with rapid
(29). Although the greater discharge rates for high-threshold contractions that involved lifting a moderate load with the
motor units during this task can be predicted theoretically dorsiflexor muscles substantially increased the instantaneous
(292, 296, 666), there are experimental exceptions to this discharge rate of motor units in tibialis anterior and was asso-
observation (178, 660). These measures are also adaptable ciated with an 82% increase in the rate of torque development
as maximal discharge rates appear to decline with age and during ballistic isometric contractions (Fig. 17) (693). The
contribute to age-associated decreases in muscle strength change in discharge rate was not related to either the motor
(29, 394), but will increase in response to strength training unit time to peak torque or recruitment threshold. Similarly,
in both young and old humans (367). the lower maximal rates of torque development (48%) by
The combination of recruitment and rate coding used to the dorsiflexor muscles of older adults were associated with
achieve a specific target varies across the range of motion reduced (∼30%) peak discharge rates for motor units in
(13, 380, 476). For example, Pasquet et al. (527) found short- tibialis anterior (391). Significantly, the discharge rates that
ening the muscle fascicles in tibialis anterior by 13% to 19% can be achieved during ballistic contractions are greater than
by ankle dorsiflexion reduced MVC torque, lowered recruit- those observed during ramp and constant-force isometric

P1: OTA/XYZ P2: ABC
(A) ceed the load torque during shortening contractions and be

12 less than the load torque during lengthening contractions,
motor units are derecruited and discharge rate decreases
10
when lowering an inertial load with a lengthening contrac-
Recruitment threshold (kg)
tion (152,412,508,528,640,651). Similarly, differences were

8
found in discharge patterns when individuals resisted a torque
motor to perform slow shortening and lengthening contrac-
6
tions with a similar change in fascicle length in tibialis ante-
rior (528). The shortening contraction was characterized by
4
greater modulation of discharge rate and by the recruitment of
2
additional motor units that were then derecruited during the
lengthening contraction. Furthermore, anisometric contrac-
0 tions performed against an elastic load involve a substantially
greater amount of rate modulation during the shortening con-
0 2 4 6 8 10 12 traction than the lengthening contraction (122, 397). Thus, to
Time (s) match the force exerted by a muscle during a shortening con-
(B) traction, a lengthening contraction requires less motor unit
30 activity that usually includes a significant decrease in dis-
charge rate.
25
20 Sustained isometric contractions

The modulation of discharge rate when a person sustains an
15 isometric contraction at a force that exceeds the upper limit
of motor unit recruitment differs across muscles. For exam-
10 ple, the discharge rates of motor units in tibialis anterior
declined progressively during sustained high-force contrac-
5
tions in both young and old humans (593) and in forearm
extensor muscles of young adults (537), but did not change
0
0 2 4 6 8 10 from approximately 17 pps in a slow-contracting toe extensor
Time (s) muscle (extensor hallucis longus) despite significant fatigue
(453). The decline in discharge rate during sustained high-
Figure 16 Influence of contraction speed on the activity of motor force contractions does contribute to the decrease in MVC
units in tibialis anterior. (A) The recruitment thresholds of three motor force, and contrary to some interpretations (55,252,464), it is
units (indicated by different colors) when the force increased linearly
to 120 N in 0.4, 1.2, 2.3, 5.0, and 10.0 s. The target force was not a feedback-mediated strategy to match discharge rate to
approximately 50% maximal voluntary contraction. The recruitment the changing contractile properties of the muscle units (236).
thresholds were close to zero when the time to the target was less At lower target forces, those motor units recruited from
than 0.15 s. The decrease in recruitment threshold was greatest for the
motor unit with the highest threshold. (B) The increase in discharge for the onset of the contraction exhibit a decrease in discharge
one motor unit when the task was to reach the target in 1 s (yellow), rate, whereas newly recruited motor units experience first
5 s (purple), and 10 s (green). Based on data, with permission, from an increase in discharge rate and then a subsequent decline
Desmedt and Godaux (161).
(102, 112, 120, 129, 202, 208, 251, 501, 672). The concurrent
recruitment of new motor units and decline in discharge rate
contractions (162, 693), perhaps due to the accumulation of the previously activated motor units has been interpreted
of history-dependent effects during the longer lasting to indicate that the progressive increase in central drive to
contractions (695). the motor unit pool is superimposed on adjustments in intrin-
sic motor neuron properties, such as adaptation, and changes
in afferent feedback (112, 251, 359). Accordingly, the appli-
Anisometric contractions
cation of vibration was able to reverse the gradual decline
Although even isometric contractions involve a shortening in discharge rate of motor units in triceps brachii during a
of the muscle fibers (268, 351), a muscle is deemed to per- sustained submaximal (20% MVC) contraction (267). Fur-
form positive work when a load is lifted with a shortening thermore, the impact of the sustained activity appears to be
contraction and to do negative work when it lowers the load greatest on the most active motor units (112, 211).
with a lengthening contraction. As the performance capac- Despite the progressive increase in central drive during
ity of muscle differs for shortening and lengthening contrac- sustained submaximal contractions, some motor units stop
tions (13, 185, 374, 498), rate modulation can differ during discharging action potentials (112, 119, 198, 369, 537). In
the two actions. Because the net muscle torque must ex- some instances, the derecruitment of a motor unit during a

P1: OTA/XYZ P2: ABC
(A) (B)
Before After training
After training
20 Nm a a
Before
a
b b
100 ms
Before
b
0.5 mV c
After
Figure 17 Comparison of ballistic contractions performed with the dorsiflexor muscles before and after
12 weeks of training. (A) The torque (a) and rectified electromyogram (EMG) for tibialis anterior (B) produced
by one individual during the submaximal isometric contractions. The peak torque for both traces was
approximately 40% maximal voluntary contraction, but the rate of torque development was greater after
training. The recruitment thresholds were close to zero when the time to the target was less than 0.15 s. The
decrease in recruitment threshold was greatest for the motor unit with the highest threshold. (B) Schematic
representation of the changes in dorsiflexion torque and the discharge rate of motor units in tibialis anterior
(B and C). Training increased the instantaneous discharge rate (B) and the incidence of double discharges
(C). Modified, with permission, from Van Cutsem et al. (693).
constant-force contraction is accompanied by the recruitment noise experienced by the motorneurons presumably differed
of another motor unit, which is a phenomenon referred to as for the two conditions (104, 468, 645). In contrast, biceps
motor unit substitution. If the two units subsequently switch brachii motor units in older humans discharged repetitively
activity states again, the adjustment is described as motor unit for the same two conditions (526).
rotation (232). Studies on a number of hand, forearm, lower The modulation of discharge rate during a sustained iso-
leg, and trunk muscles have observed substitution and rota- metric contraction also depends on the compliance of the load
tion among motor units with similar recruitment thresholds supported by the muscle (389). When young humans sus-
during sustained submaximal contractions (38,39,716). Such tained an isometric contraction for approximately 160 s with
adjustments are attributed to changes in the balance between the elbow flexor muscles, the decline in discharge rate for the
the strength of the central motor command, PICs, and inac- same biceps brachii motor unit was greater when the arm sup-
tivation of voltage-gated channels, and are not considered to ported a mass compared with pushing against a rigid restraint,
be the result of a deliberate recruitment strategy controlled by despite a similar net muscle torque during the two conditions
the CNS (38, 456, 712). (501, 595). Furthermore, the coefficient of variation for in-
The influence of changes in the balance of synaptic input terspike interval increased only when the task involved the
and intrinsic motor neuron properties on rate modulation is more compliant load. Due to the difference in discharge rate
underscored by observations on the discharge characteristics modulation during these two conditions, the constant-force
of motor units recruited during a sustained isometric contrac- contractions were sustained by greater reductions in recruit-
tion. In this protocol, the recruitment threshold of a single ment threshold when the load was more compliant (35).
motor unit is first determined and then the individual sus-
tains an isometric contraction at a target force that is less the
recruitment threshold of the motor unit until the motor unit
Mechanisms underlying rate modulation
is eventually recruited. When young humans performed this In addition to the magnitude of discharge rate modulation,
task with the elbow flexor muscles, the discharge character- the recordings of motor unit discharge times have been used
istics of biceps brachii motor units at recruitment depended to infer details about the synaptic input and the state of the
on the difference between the target force and the recruitment motorneurons during voluntary contractions. Examples of this
threshold force of the unit (580). The same motor units dis- approach include the quantification of correlated discharges,
charged repetitively when the target force was approximately variability in discharge times, double discharges, and indices
5% MVC less than recruitment threshold, but intermittently of PICs.
for a larger difference (∼10% MVC) between the two forces The two primary measures for correlated discharges are
(Fig. 18). As the discharge times were much more variable short-term motor unit synchronization and common drive
when the motor units discharged intermittently, the synaptic (510, 627). A greater-than-chance number of coincidental

P1: OTA/XYZ P2: ABC
Young Old
0.5 s 0.5 s
{
{ {
5s
{ 5s
0.5 s
0.5 s
Figure 18 Discharge characteristics of human biceps brachii motor units when recruited during a sustained isometric contraction. Left, rep-
resentative trains of action potentials for a motor unit in an young human when the target force was set at a small [∼5% maximal voluntary
contraction (MVC); blue] and large (∼10% MVC; red) difference below the recruitment threshold force of the motor unit. Right, similar recordings
for a biceps brachii motor unit in an old human. Modified, with permission, from Pascoe et al. (500).
discharge times produces a central peak in the cross- The other measure of correlated discharge times, common
correlation histogram and denotes the presence of motor drive, is used as an index of the concurrent modulation of
unit synchronization, which is presumed to be caused ei- motor unit discharge rates due to common synaptic inputs
ther by branched common input to the spinal motorneurons (149). Common drive can be quantified for pairs of motor
(143, 390, 515, 621) or by presynaptic synchronization due units as the peak in the cross-correlation function at zero lag
to common input to efferent fibers from the motor cortex (146, 492, 510) or the amount of coherence (0-4 Hz) derived
(24, 217, 610, 638). The amount of motor unit synchroniza- from the frequency spectra for the discharge times of pairs
tion between pairs of motor units is variable and is influenced of motor units (121, 442, 491, 503). Common drive appears
by such factors as the task that is examined, the motor units to provide an index of descending input to a motor nucleus
and muscles involved in the action, the habitual physical ac- as it decreases with vibration of the muscle, increases with
tivity that is performed by the individual, and the integrity of voluntary sway during upright standing, and contributes to
descending pathways (30, 141, 389, 473, 510, 613, 614, 624- the spontaneous discharge of motor units in spastic-paretic
626, 636, 723). As the strength of motor unit synchronization muscles (147, 492, 503). However, the 1 to 3 Hz coherence in
is relatively weak (∼0.2-0.8 extra synchronous discharges per the discharge times for pairs of motor units is present after
second), it does not influence muscle force during a constant- cortical or capsular stroke (216), which suggests that common
force contraction (386, 727). It seems likely that modula- drive originates somewhere other than the motor cortex (542,
tion of motor unit synchronization reflects changes in shared 715). Also, the common drive is limited to agonist muscles,
synaptic drive of common presynaptic inputs rather than a and perhaps their synergists, but likely not the antagonist
strategy to elicit an intended functional outcome (76, 113, muscle when it is coactivated with an agonist muscle (430,
607, 623). 431). Nonetheless, the common modulation of motor unit

P1: OTA/XYZ P2: ABC
discharge rates has a significant influence on the fluctuations (A)

in force during steady contractions (510).
25
The variability in discharge times, which is typically ex-
Elbow force (N)

pressed as the coefficient of variation for interspike interval, 20
varies as a function of the difference between the recruitment 15
threshold force of the motor unit and the force exerted by 10
the muscle (208, 535). It is greatest (∼35%) when the mus- 5
cle force during a brief constant-force contraction is only 0
slightly above recruitment threshold, and declines to steady-
state value of approximately 10% when the force is 5% or (B)
more above recruitment threshold (29, 500). Conversely, the 20
coefficient of variation for interspike interval can increase pro- Test unit
Firing rate (pps)

gressively during longer duration contractions (467,500,595). 15
Motor units recruited during a sustained contraction, however, 10
can exhibit high or low variability in discharge times due to
5
the influence of such factors as the difference between the
target force and recruitment threshold force, the compliance 0
of the load, and the age of the individual (Fig. 18).
The variability in discharge times at low mean discharge 20
rates has been exploited to estimate the time course of the Reporter unit
Firing rate (pps)

AHP phase (400, 561, 562). One technique, known as the in- 15 15.3 pps
terval death rate analysis (468), transforms distributions of 10 11 pps
interspike intervals into a reasonable estimate of the trajec-
5
tory of the AHP phase relative to the voltage threshold of a
motorneuron (450, 555, 561). This approach has shown that 0
the time constant of the AHP trajectory is significantly related
to the twitch time course and minimal discharge rate of hu- 5s
man motor units (263, 449), and that the time constant can be
modulated by vibration of the agonist and antagonist muscles Figure 19 The paired motor unit technique to estimate the contri-
bution of persistent inward currents (PICs) to motor unit discharge. (A)
(451) and 2 weeks of strength training by both young and old Slow ramp increase and decrease in force exerted by the elbow flexor
humans (120). The variability in discharge times, however, muscles. (B) The modulation of discharge rate for two motor units that
appears also to be influenced by recurrent inhibition (467). were recruited during the task. The motor unit with the lower recruit-
ment threshold, indicated as the reporter unit, provides an estimate of
Rate modulation can also include brief interspike intervals the synaptic drive received by the two motor units. Dashed vertical lines
(≤10 ms) that are referred to as double discharges or doublets denote the recruitment and derecruitment thresholds of the test motor
(157, 258). Most double discharges occur during tasks when unit so that the difference in the discharge rate of the reporter unit
(delta discharge frequency; F) at these two instances can be deter-
muscle force changes rapidly, rather than during sustained mined to provide an index of the amplitude of the PIC during the ramp
contractions (36, 118, 160, 648) and are less frequent in old contractions. Modified, with permission, from Mottram et al. (502).
humans compared with young humans (118, 391). Double
discharges may involve the generation of a second action
potential when a motor neuron is in a state of increased de- motor units have been used to infer the activation of PICs
polarization, or delayed depolarization, that occurs during (303). The paired motor unit technique provides one approach
the decline in the action potential. Delayed depolarization to estimate the contribution of the PIC to the activation of a
is attributed to the antidromic invasion of the dendrites by motor unit (260, 387). The technique involves recording the
the outgoing action potential (25, 103, 381), and the duration discharge of two motor units during slow ramp contractions
of the AHP is prolonged after the second action potential and using the difference in rate modulation to estimate the
(103, 402). It has also been proposed that single and multiple relative contribution of the motorneuron PIC to the discharge
double discharges may involve a plateau potential that is su- of the motor unit (Fig. 19). One of the assumptions with this
perimposed on the delayed depolarization (402), even though technique is that the rate modulation exhibited by the reporter
double discharges can be evoked by the application of tran- unit provides a reasonable estimate of the synaptic input to
scranial magnetic stimulation over the motor cortex (37,144). the motorneuron pool (48, 262, 559). Such estimates indicate
Consistent with an influence by descending inputs (401), the that approximately 40% of the rate modulation of motor units
incidence of double discharges can be increased with training during slow ramp contractions is provided by the PIC (260),
(36, 693). Nonetheless, the functional significance of double but this likely underestimates the absolute contribution (303).
discharges remains uncertain (253). Although motor units in spastic-paretic muscle also ex-
Given the significant influence of PICs on motorneuron hibit PIC activity, as indicated with the paired motor unit
excitability, some observations on rate modulation of human technique, its amplitude did not differ from healthy control

P1: OTA/XYZ P2: ABC
subjects (502). Furthermore, changes in the intrinsic proper- The model of Heckman and Binder focused on under-
ties of motorneurons, such as PICs, are not responsible for the standing how the organization of synaptic input influences
spontaneous discharge of motor units in the spastic-paretic bi- steady behavior of the motoneuron pool and its muscle; this
ceps brachii of stroke survivors (503), whereas they do appear work was extensively reviewed in the chapter on this topic
to contribute to the low discharge variability, spontaneous dis- published in the Handbook of Physiology series (60). The
charge, and spinal cord hyperexcitability after spinal cord in- main conclusions were that the steady-state transformation
jury (262, 326, 742). Also, the sustained motor unit discharge of synaptic input to isometric force is sigmoidal (as also
after a muscle has either been vibrated (368, 387) or exposed seen with the Fuglevand model) and remains so despite large
to wide-pulse, high-frequency electrical stimulation (127) is changes in organization of synaptic input (see Fig. 20 A, red
attributed to the PIC activity. Nonetheless, the technical chal- curve). This stability is largely attributable to Henneman’s
lenges associated with determining the contribution of PICs size principle of recruitment (293, 296, 297). The recruitment
to rate modulation during voluntary contractions performed of progressively larger motor units confers an upward curva-
by humans are formidable (303, 649). ture to this function at low input levels; the opposite curvature
at high levels is due to progressive achievement of tetanic
force in largest motor units.
The need to develop new models of the motor pool is evi-
Input-Output Relation for an Entire dent from two perspectives: first, the potent influence of neu-
Motor Pool and Muscle romodulators on motoneuron properties (see Section “Neuro-
modulatory inputs control intrinsic excitability”), and second,
Computer simulations of the motor unit pool the differences in steady versus dynamic input-output be-
As yet there is no way to measure the transformation of havior of motoneurons (see Section “Processing of transient
synaptic currents into muscle forces for the full range synaptic inputs”) and their muscle units (see Section “Muscle
of input-output behavior of a motor pool and its muscle. Unit Physiology”). Figure 20 A illustrates how dramatically
Synaptic input cannot be measured directly in humans and brainstem neuromodulatory input can alter the steady-state
controlled input across the full range is not feasible in animal behavior of the pool input-output function. The simulations
preparations. Thus, Fuglevand and colleagues (238) and in this figure were based on the Heckman and Binder model
Heckman and Binder (293, 296, 297) turned to computer (296) and provide a preliminary estimate of the tremendous
simulations to investigate the input-output function of this increase in net input-output gain due to subthreshold depo-
highly parallel motor output system—the motor unit pool larization, spike threshold hyperpolarization, AHP reduction
(i.e., a pool of motoneurons in the spinal cord and the muscle and PIC amplification (compare red to green to blue func-
that they innervate). The models were based on the extensive tions). Note also that this figure suggests a solution to an issue
experimental data on the steady-state properties of motoneu- first identified by Binder (57) from consideration of this lab’s
rons and muscle units, and the motoneuron data came from study of the distribution of synaptic currents to motoneurons;
deeply anesthetized animals lacking significant brainstem namely, that the measured current amplitudes from various
neuromodulation. input sources (Fig. 5 A), even when summed together, are in-
The model of Fuglevand et al. (238) focused on under- sufficient to drive the motor pool to its full output (see arrow
standing EMG-force relation and has been used extensively in Fig. 20 A). Cushing and Rose (138) identified the same
for analysis of data from humans (167,361,378,379,500,633). problem in a simulation of a single large motoneuron with
An important advantage of this model is that the individual accurate representation of its dendritic tree. Even when all
muscle action potentials and isometric forces for each motor excitatory synapses were activated, the motoneuron did not
unit action potential are specified, allowing investigation of generate sufficient current at the soma to push membrane po-
the fine structure of motor outflow, including noise. A notable tential much above recruitment threshold. If neuromodulatory
feature of noise in motor output is that it exhibits signal depen- effects are as large as Figure 20 A suggests, then the decreased
dence; that is, the amplitude of the noise fluctuations increases threshold and increased slope of the function puts maximum
with voluntary force (280,361,645). As Henneman originally output well within the scope of the available ionotropic input.
suggested in 1965 (312), this phenomenon arises from the The above simulations were during steady conditions,
recruitment of progressively larger motor units (280, 361). whereas most normal motor behavior is dynamic. Accurate
Yet it remains difficult to simultaneously achieve accurate simulations of dynamic motoneuron and muscle unit behav-
EMG-force relations and appropriate signal-dependent noise iors are needed, but it seems reasonable to expect that the
in these models, and the chief limitation is uncertainty about overall sigmoidal form of the transformation will be main-
the neural drive from the motor pool to muscle (379), as spec- tained in dynamic states. Studies in human subjects applying
ified by the processing of synaptic input by motoneuron prop- dynamic inputs onto a range of steady background levels are
erties. Factors such as the PICs in dendrites of motoneurons consistent with this expectation. These studies generally find a
have a strong impact on noise (664) and, in general, neu- linear relation between reflex response and background force
romodulators seem likely to have a large influence on both at low levels, followed by an extended constant-amplitude re-
EMG-force relations and output noise. gion (96 and 114). A plot of reflex-induced change in output

P1: OTA/XYZ P2: ABC
(A) (B)
0 High Medium
Total muscle force (normalized)
Low
0.8
0.6
Scratching
1s
0.4
15 mV
0.2
0.0
0 10 20 30 40 50 60 70 80 Weight support
Synaptic input (nA of current)
Figure 20 The range of motoneuron electrical behaviors is very wide. (A) Influence of the level of neuromodulation (low, medium, and
high) on net input-output gain of a pool of motor units. Computer simulations based on Heckman and Binder (296, 298). The arrow
indicates the approximate sum of synaptic currents from the excitatory synaptic input systems illustrated in Figure 5A. The simulations
included increased persistent inward currents (PICs), depolarized rest potentials and decreased spike thresholds. (B) One motoneuron
exhibiting two very different electrical behaviors, depending on motor task. The cell was initially depolarized during scratching, possibly
activating a PIC, but then onset of strong inhibition (red arrow) eliminated the influence of the PIC. Once a new baseline was established,
the oscillation of the scratch began. In the same cell, an irritating stimulus to the opposite side of the body evoked a weight support
response with a sustained plateau (presumably PIC driven) with only minor oscillations. Input conductance during scratch was much
greater than during weight support. Modified, with permission, from Perreault (531).
versus background force approximates the derivative of the predict very high firing rates for S motoneurons by the time
input-output function. The derivative of a sigmoidal function the input levels have risen sufficiently to recruit FR and FF
is initially linear and then becomes constant, just as revealed motoneurons. These high rates are clearly evident in Fig. 5 C.
by these reflex studies. Some form of rate limiting of S and perhaps FR motoneurons
is needed to overcome this problem. Computer simulations
of this issue (293, 296) focused on 3 factors related to the
Emergence of patterns of motor output from the organization of ionotropic input: differences in distribution of
inputs and properties of motor neurons synaptic current in S versus FF motoneurons (Fig. 5 A), effects
The review of firing patterns of human motor units in the of inhibitory inputs, and nonlinear input summation. A new
previous section (see Section “Motor Unit Recruitment and mechanism emerged from the studies of neuromodulation on
Rate Modulation in Humans”) shows considerable diversity, the PIC. The saturation that accompanies PIC activation lim-
despite the restriction of most studies to isometric condi- its the firing rates of low-threshold motoneurons, in a manner
tions (e.g. Fig. 14 B). As the full range of motor behaviors that resembles the rate limiting often seen in human motor
is examined—from posture to locomotion and from precise unit recordings. This similarity is illustrated in Fig. 21 with
finger movements to maximal voluntary contractions—it is a comparison of the firing pattern due to PIC activation in a
likely that an even greater diversity will emerge. Thus, a pool cat motoneuron to the firing pattern in a human. Thus, the
of motor units must be able to produce a wide range of firing presence of a PIC is sufficient to limit firing rate (see also
patterns. In general, this diversity could be achieved via two Fig. 7) (422, 423, 428) and it has been argued that the rela-
mechanisms: diversity in the organization of synaptic input tively modest changes of firing rate occurring once this limit
or in the intrinsic properties of motoneurons. The discovery has been reached should be considered a “preferred” firing
of the importance of neuromodulatory input has altered our range for motoneurons (325). Recent studies, however, sug-
understanding of this issue, as these inputs modify intrinsic gest that having inhibition mixed in with excitation might be
properties of motoneurons (see Section “Neuromodulatory just as important as the PIC in limiting firing rate (Randall
inputs control intrinsic excitability”). Powers, personal communication; Andrew Fuglevand, per-
sonal communication), consistent with the role suggested for
inhibition in the computer simulations noted just above (297).
Saturation in rate modulation in steady and slowly A crucial point to keep in mind is that PIC-induced satura-
varying conditions tion only applies to excitatory input, because inhibitory inputs
Simulations of the motor unit pool for steady and slowly ris- readily deactivate an already established PIC (see Fig. 9 C,D).
ing inputs encounter a major difficulty in replicating firing Therefore, the rate limiting influence of the PIC component
patterns in both humans and animals: the responses of mo- will make the motor unit insensitive to additional excitation
toneurons to injected currents in anesthetized preparations but highly responsive to additional inhibition.

P1: OTA/XYZ P2: ABC
(A) (B) 20 (C) Human motor unit

Cat motoneuron Cat motoneuron
firing pattern
Firing rate (spikes/s)

firing pattern
Firing rate (spikes/s)

synaptic current 40
Synaptic current
5 nA 10
20
PIC saturation PIC rate limiting

0 0
PIC acceleration
PIC amplification
5
5N
5 mm
5 mm
10
2s 2s 2s
Figure 21 The PIC can generate saturation in firing rate. (A) In a cat extensor motoneuron, linear stretch of an extensor
muscle (lower panel) produces a linear increase in synaptic current when the cell is held hyperpolarized to prevent persistent
inward current (PIC) activation (thin trace, upper left panel). When the voltage clamp holding potential was depolarized
to the approximate voltage at which spikes would be initiated in unclamped conditions (thick trace, upper left), the PIC
amplifies (green arrow) and then saturates (red arrow) the input. (B) The firing response in the same cell to the same
linear stretch, resulting in firing rate acceleration (green arrow) and rate limiting (red arrow). Data in A and B taken, with
permission, from Lee et al. (428). (C) Firing pattern of a human biceps motor unit (upper panel) in response to a voluntary
effort to linearly increase elbow flexion torque (bottom panel). Note the similarity to the firing pattern in the cat motoneuron
in B. Data provided by Carol Mottram, with permission, from the database of reference (502).
One perplexing feature is the diversity of motor unit firing tonically active in the decerebrate cat preparation (256). This
patterns in slow or steady contractions. A rapid rate of rise raises the obvious question of what happens when changes
followed by significant rate limiting of low threshold units from baseline are needed; that is, when motoneurons need to
is often seen, but not always. Figure 14 B shows substan- increase or decrease muscle force? This question is addressed
tial variability in motor unit patterns across motor units and in the following two subsections.
subjects. The explanation for this diversity is not clear, but
the PIC does sometimes exhibit a surprising degree of vari-
ability in its activation (428). Variation in the organization of Diffuse descending neuromodulation, specific
inhibitory input and neuromodulatory input could also play local inhibition
an important role in motor unit firing pattern variation, but
The descending brainstem neuromodulatory systems project
this issue is unresolved.
diffusely within the spinal cord (75, 324). It is thus highly
unlikely that the excitability of different motor unit pools can
be independently controlled by this diffuse system, although
Role of inhibition
further studies are needed to determine the full extent of this
It may seem paradoxical for inhibition to be mixed with ex- property. Inhibition potentially provides a solution to this spa-
citation in generating motor output, yet inhibitory input may tial problem. The PIC is highly sensitive to small changes in
be required to control the potent effects of the PIC to am- reciprocal inhibition—the reciprocal inhibition generated by
plify, saturate, and prolong excitatory inputs. Recent studies a mere 20◦ change in angle of the ankle can reduce the PIC by
suggest that motoneurons may often operate from a baseline 50% (348). The full functional significance of this strong cou-
consisting of a mixture of steady excitation and inhibition [as pling between motoneuron excitability and joint angle is not
appears to be the case in several regions of the cortex (164)]. clear, but reciprocal inhibition is sharply focused—as sharply
This baseline of excitation and inhibition has recently been as Ia monosynaptic excitation (513). Moreover, Ia excitation
demonstrated to exist in both the spinalized turtle prepara- and inhibition dominate sensory input during passive joint
tion (51) and the intact cord of a decerebrate cat preparation rotations (346). For example, ankle extensor motoneurons
(347,348). Moreover, studies in the cervical cord of the awake are strongly affected by ankle rotations in the sagittal plane,
behaving primate show that about 80% of the interneurons but much less by out-of-plane ankle motions or by any rota-
have tonic firing (221), which is similar to the proportion tions at the knee or hip, despite the many cutaneous, muscle,
observed in the intact cord of the decerebrate cat (unpub- and joint afferent systems activated by these rotations. Be-
lished data, Michael Johnson and C.J. Heckman). These ac- cause the Ia inhibitory interneurons that mediate reciprocal
tive interneurons presumably include inhibitory ones, as the inhibition receive strong projections from a wide range of
interneurons mediating Ia reciprocal inhibition are usually descending input systems (26), this inhibitory system can be

P1: OTA/XYZ P2: ABC
used to “sculpt” specific patterns of motor pool excitability eronymous negative force feedback (472,588) and descending
from the diffuse background of brainstem neuromodulation. monoaminergic systems may select appropriate interneuronal
Thus, Sherrington’s “myotatic unit” defined by antagonist circuits for movements (318,354). As yet, the interactions be-
motor pools may provide the fundamental spatial focusing tween changing synaptic connections and changing intrinsic
for control of motoneuron excitability. neuron properties in these interneuronal circuits is far from
clear, but the example of the motoneuron clearly illustrates
the range of possibilities for altering intrinsic excitability.
Coupling of inhibition to excitation
in motor commands
In the turtle scratch reflex, depolarization of motoneurons can Estimation of motoneuron properties and inputs
occur via concurrent increases in excitation and inhibition – from firing patterns in humans
with the increase in excitation being greater than that of inhi- The tight coupling between motoneuron and muscle unit ac-
bition. Berg et al. (51) speculate that the function of this “bal- tion potentials provides the possibility that motor unit firing
anced” mode is to minimize the role of PICs and other neuro- patterns can be “reverse engineered” to identify the underly-
modulatory effects on motoneurons and allow the ionotropic ing organization of synaptic input and sets of intrinsic prop-
component of motor command full control of motoneuron erties for the activated pool of motoneurons. Techniques to
behavior. Perhaps the inhibition involved in limiting firing achieve important aspects of this goal were discussed above
rate arises in part from a mild version of “balanced” organi- (see Section “Mechanisms underlying rate modulation”). In
zation (see Section “Saturation in rate modulation in steady several cases, it has been possible to perform experiments in
and slowly varying conditions”). In contrast, recent studies animals to evaluate the advantages and limitations of these
by Johnson and Heckman (unpublished data and 371) show approaches.
that sensory input during ankle rotation in the decerebrate cat Estimation of the time course of PSPs in human motor
is organized in a “push-pull” fashion (see also 264), in which units via the PSF and PSTH methods (see Section “Process-
the tonic inhibition and excitation are modulated in opposite ing of transient synaptic inputs”) have been analyzed using
directions so that depolarization is produced both by excita- intracellular recordings in motoneurons in vitro by Türker and
tion and disinhibition and hyperpolarization by inhibition and Powers (562, 685). This analysis supported the ability of the
disfacilitation. A similar organization appears to occur during PSF to capture the decay of the PSP and moreover revealed
fictive scratch and fictive locomotion in the cat (256). It has effects of differences in background firing rate. A close cor-
been argued that this push-pull organization allows the potent respondence between animal and human studies was used to
amplification of the dendritic PIC to be used while preventing develop the delta F method of estimating the amplitude of
the tendency of the PIC to prolong input (360). Balanced and PICs in human subjects (260, 506), with the hysteresis first
push-pull organizations may underlie much of the diversity identified in motoneuron F-I functions (as in Fig. 8) forming
of normal motor output, but considerable further research is the primary basis for this method. The methods to estimate
needed. the duration of the AHP have also been examined in animal
studies (555). Although the animal studies revealed that the
amplitude of the AHP could not be reliably estimated with this
Reconfiguration of motoneuron electrical method, the time course estimation was reasonably accurate.
properties for different motor behaviors? The development of realistic models of both motoneurons
The potent effects of neuromodulatory, inhibitory, and NMDA and muscle units will likely be essential for understanding the
inputs on motoneuron excitability constitute a revolution in genesis of human motor unit firing patterns.
our thinking about their input-output relations. Instead of mo- Overall we are a long way from the goal of “reverse engi-
toneurons having a consistent threshold and primary range of neering” motor unit firing patterns. Nonetheless, initial suc-
firing, it now becomes possible to consider that their electri- cesses such as the validation of human estimation methods in
cal properties may be reconfigured for different motor tasks animal preparations noted in the previous paragraph and the
(301, 303). The clearest example yet demonstrated for this correspondence of features of human motor unit firing pat-
reconfiguration is illustrated in Figure 20 B (531). Here a terns to those generated by PICs in animal preparations (see
motoneuron operates in “PIC” mode during a postural task Section “Saturation in rate modulation in steady and slowly
but in a non-PIC, oscillatory mode during the scratch reflex. varying conditions” and Fig. 21) strongly suggest that further
In addition, this study showed that the input resistance of effort in this research direction is highly worthwhile.
motoneurons was much lower during the scratch reflex than
during weight support. Many further studies along these lines
are needed, but the concept that motoneuron electrical prop- Changes in motoneuron electrical properties
erties can be reconfigured for different motor behaviors fits in exercise and disease
well with concepts of reconfiguration of spinal interneuronal Muscle unit plasticity in response to exercise and disuse
circuits (234, 342). For example, the CPG output can reveal a is enormous and the subject of many reviews (1, 62, 179,
homonymous positive force feedback against a context of het- 224, 639). Changes in motoneuron properties are much less

P1: OTA/XYZ P2: ABC
dramatic, but definitely occur. Injury and disease induce sur- (A) (B)
S2 injury
prisingly large changes in motoneuron properties and the en- LLR
suing motoneuron recovery reveals both remarkable adapt- EMG
ability and clear constraints.
Tail spasm
Exercise adaptations in motoneurons
Most is known about adaptations in response to endurance
Stimulation
exercise, especially from work performed by Gardiner and
Stimulation
colleagues (247, 248). Endurance exercise tends to lower mo-
toneuron excitability (44, 45): resting potential is hyperpo- + SB242084
5-HT in normal rat
larized; AHP duration increases; the capacitance of high-
threshold motoneurons increases, suggesting an increase in
size; and there is a small increase in dendritic arbor in many mn
motoneurons (255). Furthermore, there are increases in en-
zymes associated with aerobic metabolism and axon trans-
port, the rate of rise of the action potential, and the speed
of transmission at the neuromuscular junction (44, 45). These
electrical changes are relatively modest compared with the
modulation that can be achieved with such neuromodulators 5-HT in chronic spinal rat
as 5-HT, but likely represent important adaptations for con- + SB206553
trolling motor output.
Spinal cord injury
0.2 mV
The elimination of brainstem monoaminergic inputs imme-
diately after spinal transection induces a dramatic loss of
1s
excitability of motoneurons—this basic result was essential
in establishing the importance of 5-HT and NE for bistable Figure 22 Plasticity in motor output to chronic spinal injury. Column
behavior by the Copenhagen group [(333), see Section “Neu- (A) Upper panel: testing of tail spasticity in a rat with chronic injury
romodulatoin of persistent inward currents”]. Thus, PICs be- at the S1 level. Note the electromyogram (EMG) recording in the tail
muscle (records illustrated in column B). The two images below indicate
come small in acute spinal injury, but a remarkable series the level of neurotransmitter serotonin (5-HT) in the rat spinal cord
of studies by Bennett and colleagues have shown that PICs before and after chronic spinal injury. The “mn” in the upper image
undergo a dramatic recovery in amplitude in chronic spinal indicates the cell body of a motoneuron. The arrow in the bottom image
indicates a 5-HT containing fiber, which is rare postinjury. Column (B)
injury (8, 48-50, 290, 433-436, 506, 570). Using the in vitro tail muscle electromyograms (EMGs) recorded in response to electrical
rat sacral cord preparation, they demonstrated that PICs un- stimulation to the tip of the tail (see A, top). This brief stimulus evokes
dergo upregulation within about 12 weeks posttransection, to a long-lasting reflex (LLR), which is generated mainly by motoneuron
persistent inward currents. Addition of an antagonist (SB242084) to
re-attain large amplitudes. Whether these upregulated ampli- block binding of 5-HT has no significant effect (middle EMG, blue).
tudes are similar to that of PICs in the normal state is not In contrast, an inverse agonist (SB206553), which blocks constitutive
yet clear, but both the CaPIC and NaPIC adapt. Long-lasting 5-HT receptor activity, greatly reduces the LLR (red). Modified, with
permission, from Murray et al. (506).
spasms recover with the same time course and the recovered
PIC is a primary cause of these spasms (436, 506). The in-
crease in NaPIC can also lead to slow and highly regular tonic
firing (434, 435). 5-HT antagonists do block constitutive activity and are thus
Recent work from the Bennett and Fouad labs, done in considered inverse agonists, whereas pure neutral antagonists
collaboration with several other groups, has identified a ma- operate in the classic mode of preventing binding of 5-HT
jor mechanism of this PIC-induced recovery (506). 5-HT2 (512).
receptors undergo a transformation to become constitutively An odd aspect of chronic spinal cord injury is that changes
active—that is, they activate G-protein coupled intracellular in most motoneuron electrical properties are small compared
pathways that facilitate the PIC without significant binding with the remarkable recovery of the PIC. Resting potential,
of endogenous 5-HT, which remains low. This result is illus- input resistance, and AHP properties are changed little in
trated in Figure 22. It is likely that plasticity also occurs in the chronic spinal injury animals (99, 320). Perhaps this lack
NE system, but these studies are ongoing (570). The implica- of change means that only 5-HT2 receptors [and probably,
tion of constitutive activity in 5-HT2 receptors for therapeutic the NE alpha 1 receptors that also facilitate the PIC—see
control of spasms is clear: drugs to control spasms should (570, 571)] can exhibit substantial plasticity, as it appears
target constitutive activity. Fortunately, it appears that many likely that resting potential and input resistance are controlled

P1: OTA/XYZ P2: ABC
by a different 5-HT receptor subclass and the AHP is not mod- (A)
ulated by 5-HT in the adult (433). Although much more study
Motoneuron
of this issue is needed, these results on chronic spinal injury intracellular
constitute a major advance in our understanding of both the record
1 Electrical 2 Muscle
mechanism of spasms in spinal injury and in the range of stimulation stretch
plasticity that can be achieved by motoneurons.
Motor
Peripheral nerve injury
Motoneurons have an impressive capacity to recover from
axonal injury. Initially, motoneurons, especially the FRs and
FFs, undergo changes in electrical properties that make them
more like S motoneurons, with lowered input resistances and
longer AHPs (229, 272, 312, 544). Reinnervation of muscle (B)
units is reasonably successful and causes motoneuron prop-
erties to return to near-normal states, restoring the normal
Control
matching of electrical and mechanical properties within the
motor unit (230, 544). If the axotomy is maintained, distal
portions of motoneuron dendrites start to develop axon-like
properties, an extraordinary plastic transformation that is per-
MN 1
haps an attempt to form new connections (447, 448). More-
0.5 mV
over, these “axon-like” dendrites have recently been shown to 0.4 s
initiate action potentials and release synaptic vesicles (478).
This dendritic transformation is illustrated in Figure 24 A. On MN 2
the sensory side, reinnervation of peripheral receptors occurs
although with less success due to some afferents reconnect- Electrically evoked Stretch evoked
ing with the wrong receptor types (82). Axotomized primary synaptic potential synaptic potential
afferents also change synaptic connections in the spinal cord,
Figure 23 Plasticity following peripheral nerve reinnervation. (A) Il-
and regeneration does not necessarily restore normal synaptic lustration of the paradigm to study recovery from chronic peripheral
connections (82), for example, those made with motoneurons nerve injury. Intracellular recording in a motoneuron (in ventral spinal
by muscle spindle Ia afferents. These peripheral and central cord, left) is used to record the responses to either electrical stimulation
of the muscle nerve (1) or muscle stretch (2). (B) EPSPs generated by
problems combine to reduce synaptic excitation of motoneu- electrical stimulation (left column) and muscle stretch (right column).
rons in response to muscle stretch, as illustrated in Figure 23 Note that some motoneurons (e.g., MN2) respond to electrical stim-
(14) and to limit recovery of the muscle stretch reflex and ulation but not stretch, indicating the peripheral reinnervation of the
stretch receptor in muscle has failed. Also, the response to electrical
of interjoint coordination during walking (2, 130, 445). These stimulation is weaker than in control (e.g., MN1). As a result, the stretch
are clear illustrations of limits in recovery. reflex does not recover. Modified, with permission, from Alvarez et al.
(14).
ALS
Studies of alterations in motoneuron electrical properties in membrane resistance (187). The NaPIC is increased (696)
the standard transgenic mouse model of amyotrophic lat- and so too is the CaPIC (Quinlan and Heckman unpublished
eral sclerosis (ALS), the mutant SOD1 mouse (587, 634), results), but there are significant differences in variants of the
have been underway for several years. The first such studies SOD1 model (521) and it is not yet clear what happens as the
were in motoneurons cultured from mouse embryos, which animal progresses beyond the neonatal state.
demonstrated a marked increase in excitability manifest as These changes in electrical and anatomical properties
changes in threshold and slope of the frequency-current rela- occur remarkably early, within 5 to 10 days of birth
tion (407,408,543) that were driven in large part by increased (16, 70, 521, 696) in a disease model where symptom onset
NaPICs (408). Similar results were obtained in cultured corti- occurs in the adult state and end stage is at 130 days or more.
cal cells (543). Studies in motoneurons from neonatal animals The availability of new preparations for intracellular record-
have also identified a number of changes in motoneurons, but ing in adult mouse motoneurons, an in vitro sacral cord prepa-
here the picture is not as clear as in the cell culture work. ration (357, 358) and in vivo recording in the anesthetized
A striking finding by Durand and colleagues is that SOD1 animal (459, 479), will now allow the changes in motoneu-
motoneurons undergo a dramatic increase in branching of rons to be assessed throughout the life span of the animal.
proximal dendrites (16), illustrated in Figure 24 B. Input re- Moreover, the in vivo preparation has been achieved without
sistance of the SOD1 motoneurons is decreased, in part by paralysis (Manuel and Heckman, unpublished results), allow-
this anatomical alteration and in part by decreased specific ing the question of whether neuromuscular junction failure

P1: OTA/XYZ P2: ABC
(A) toneuron properties recover with reinnervation after periph-

eral nerve injury, but synaptic inputs remain compromised;
motoneuron properties are compromised in ALS. Advances
in knowledge on motoneuron, muscle unit, and motor unit
physiology will contribute significantly to our understanding
of adaptations and underlying mechanisms associated with
physical activity and disease.
250 microns
Conclusion
(B)
As the final common pathway from the nervous system to
muscle, the motor unit represents the fundamental element
by which the nervous system controls movement. The re-
cruitment and rate modulation of motor units, and hence the
force exerted by a muscle, depends on the interaction be-
tween the synaptic input received by the motoneuron pool
and the intrinsic properties of the motoneurons. Integrating
200 microns observations from studies on the interactions between neu-
rotransmitters, receptors, and ion channels with those on the
Figure 24 Dramatic changes in motoneuron morphology in re- discharge characteristics of human motor units during volun-
sponse to injury and disease. (A) Prolonged axotomy of adult cat mo-
toneurons induces conversion of dendrites to axons, especially in the tary contractions has driven advances in this field of study.
distal regions. The cell on the left is normal. The one on the right has When technology has limited the information that can be ob-
undergone prolonged axotomy. The distal extensions from the den- tained from experimental work, progress has been augmented
drites, such as those into the white matter at the left, have converted to
an axon-like phenotype and exhibit significant myelination. Provided by a number of innovative modeling studies. A unique feature
by Ken Rose from the databank of cells stained by Rose and McDermid of this field, as indicated in the article, is the interaction be-
(see also reference 447 and 448). (B) Increased dendritic branching in tween investigators who focus on the cellular and molecular
a mouse model of amyotrophic lateral sclerosis. A normal motoneu-
ron is illustrated on the left, while the cell on the right is from a mutant aspects of motor unit function and those who record motor
SOD1 animal. In both cases, the animals were less than 10 days old, unit activity when humans perform voluntary contractions.
so these profound anatomical changes occur long before symptom Since 1997, for example, these investigators have convened
onset. Different colors indicate the multiple branches originating from
primary trunks extending from different parts of the soma. Modified, biennial international meetings to foster such an exchange of
with permission, from Amendola and Durand (16). information (see http://motoneuron2010.parisdescartes.fr/).
There has been a revolution in this field since the chapter
on this topic was published in the Handbook of Physiology
(27, 305, 306) precedes motoneuron failure to be directly ad- series. It is now recognized that motor unit function depends
dressed. The issue of the range of motor unit properties is critically on the influence of neuromodulators. For example,
clearly also important, as loss of force proceeds in reverse neuromodulators can reconfigure the electrical properties of
order to the size principle, proceeding from FF to S motoneu- motoneurons to match the demands of an impending motor
rons (305, 306, 566). action and even depolarization of membrane potential to reach
There is also considerable evidence that synaptic inputs voltage threshold is not possible without input from neuro-
to motoneurons are involved, as the main hypothesis for ex- modulators. There has been a significant effort, therefore, on
citotoxicity leading to degeneration is excessive Ca entering identifying the cellular and molecular mechanisms underly-
via Ca-permeant AMPA receptors (589, 590). Even cultured ing neuromodulation, and substantial progress has been made
SOD1 motoneurons have altered AMPA receptors (11, 642). in this endeavor. Although there remain significant gaps in
Moreover, near end stage, NMDA-driven oscillations via cir- knowledge between the details of neuromodulation and the
cuits of interneurons appear to be a major source of sponta- observed discharge characteristics of human motor units, the
neous discharges (357). rate of progress in this field suggests that there will be signif-
icant advances in the next decade.
Homeostasis in motoneurons: summary
Motoneurons are capable of a wide range of adaptations. Acknowledgements
Changes evoked by exercise are modest compared with the
enormous plasticity of the muscle unit, but disease states in- We thank Drs. Marc D. Binder, Timothy C. Cope, Jacques
duce pronounced adaptations. Yet there are limitations to the Duchateau, Dario Farina, Alain Frigon, Andrew J. Fuglevand,
capacity of the motoneuron to recover from an insult: PICs re- Katrina S. Maluf, Randall K. Powers, and Thomas G. Sander-
turn after spinal injury, but the resting potential does not; mo- cock for reviewing this article. We also thank Prof. Robert S.

P1: OTA/XYZ P2: ABC
Hutton for introducing us to this field of study. Tables 2 and 3 22. Bailey EF, Rice AD, Fuglevand AJ. Firing patterns of human genioglos-
sus motor units during voluntary tongue movement. J Neurophysiol 97:
were prepared with the help of Drs. Marin Manuel and Kathy 933-936, 2007.
Quinlan. Our experimental work and modeling studies have 23. Bakels R, Kernell D. Matching between motoneurone and muscle
been supported by grants AG09000, NS43275, NS034382, unit properties in rat medial gastrocnemius. J Physiol 463: 307-324,
1993.
NS071951, and NS051462 from the National Institutes of 24. Baker SN, Spinks R, Jackson A, Lemon RN. Synchronization in
monkey motor cortex during a precision grip task. I. Task-dependent
Health. modulation in single-unit synchrony. J Neurophysiol 85: 869-885,
2001.
25. Baldissera F, Campadelli P, Piccinelli L. Neural encoding of input
transients investigated by intracellular injection of ram currents in cat
α-motoneurones. J Physiol 328: 73-86, 1982.
References 26. Baldissera F, Hultborn H, Illert M. Integration in spinal neuronal sys-
tems. In: Brooks VB, editor. Handbook of Physiology. The Nervous Sys-
1. Aagaard P, Suetta C, Caserotti P, Magnusson SP, Kjaer M. Role of the tem. Motor control. Bethesda: American Physiological Society, 1981,
nervous system in sarcopenia and muscle atrophy with aging: Strength pp. 509-595.
training as a countermeasure. Scand J Med Sci Sports 20: 49-64, 27. Balice-Gordon RJ, Smith DB, Goldman J, Cork LC, Shirley A, Cope
2010. TC, Pinter MJ. Functional motor unit failure precedes neuromuscular
2. Abelew TA, Miller MD, Cope TC, Nichols TR. Local loss of proprio- degeneration in canine motor neuron disease. Ann Neurol 47: 596-605,
ception results in disruption of interjoint coordination during locomo- 2000.
tion in the cat. J Neurophysiol 84: 2709-2714, 2000. 28. Ballou EW, Smith WB, Anelli R, Heckman CJ. Measuring dendritic
3. Adachi T, Huxtable AG, Fang X, Funk GD. Substance P modulation of distribution of membrane proteins. J Neurosci Methods 156: 257-266,
hypoglossal (XII) motoneuron excitability during development: Chang- 2006.
ing balance between conductances. J Neurophysiol 104, 854-872, 2010. 29. Barry BK, Pascoe MA, Jesunathadas M, Enoka RM. Rate coding is
4. Adam A, De Luca CJ. Recruitment order of motor units in human compressed but variability is unaltered for motor units in a hand muscle
vastus lateralis muscle is maintained during fatiguing contractions. J of old adults. J Neurophysiol 97: 3206-3218, 2007.
Neurophysiol 90: 2919-2927, 2003. 30. Barry BK, Pascoe MA, Riek S, Carson RG, Enoka RM. Common input
5. Adrian E, Bronk D. The discharge of impulses in motor nerve fibres. to different regions of biceps brachii long head. Exp Brain Res 193:
Part II. The frequency of discharges in reflex and voluntary contractions. 351-359, 2009.
J Physiol 67: 119-151, 1929. 31. Barry BK, Riley ZA, Pascoe MA, Enoka RM. A spinal pathway between
6. Adrian ED. Interpretation of the electromyogram. Lancet 1: 1229-1233, synergists can modulate activity in human elbow flexor muscles. Exp
1281-1285, 1925. Brain Res 190: 347-359, 2008.
7. Aghajanian GK, Rasmussen K. Intracellular studies in the facial nucleus 32. Basmajian JV. Control and training of individual motor units. Science
illustrating a simple new method for obtaining viable motoneurons in 141: 440-441, 1963.
adult rat brain slices. Synapse 3: 331-338, 1989. 33. Basmajian JV. Control of individual motor units. Am J Phys Med 46:
8. Agrawal N, Hamam BN, Magistretti J, Alonso A, Ragsdale DS. Persis- 480-486, 1967.
tent sodium channel activity mediates subthreshold membrane potential 34. Baudry S, Klass M, Duchateau J. Postactivation potentiation influences
oscillations and low-threshold spikes in rat entorhinal cortex layer V differently the nonlinear summation of contractions in young and el-
neurons. Neuroscience 102: 53-64, 2001. derly adults. J Appl Physiol 98: 1243-1250, 2005.
9. Alaburda A, Perrier JF, Hounsgaard J. An M-like outward current 35. Baudry S, Rudroff T, Pierpoint LA, Enoka RM. Load type influences
regulates the excitability of spinal motoneurones in the adult turtle. J motor unit recruitment in biceps brachii during a sustained contraction.
Physiol 540: 875-881, 2002a. J Neurophysiol 102: 1725-1735, 2009.
10. Alaburda A, Perrier JF, Hounsgaard J. Mechanisms causing plateau 36. Bawa P, Calancie B. Repetitive doublets in human flexor carpi radialis
potentials in spinal motoneurones. Adv Exp Med Biol 508: 219-226, muscle. J Physiol 339: 123-132, 1983.
2002b. 37. Bawa P, Lemon RN. Recruitment of motor units in response to tran-
11. Albo F, Pieri M, Zona C. Modulation of AMPA receptors in spinal scranial magnetic stimulation in man. J Physiol 471: 445-464, 1993.
motor neurons by the neuroprotective agent riluzole. J Neurosci Res 38. Bawa P, Murnaghan C. Motor unit rotation in a variety of human
78: 200-207, 2004. muscles. J Neurophysiol 102: 2265-2272, 2009.
12. Alford S, Grillner S. CNQX and DNQX block non-NMDA synaptic 39. Bawa P, Pang MY, Olesen KA, Calancie B. Rotation of motoneurons
transmission but not NMDA-evoked locomotion in lamprey spinal cord. during prolonged isometric contractions in humans. J Neurophysiol 96:
Brain Res 506: 297-302, 1990. 1135-1140, 2006.
13. Altenburg TM, de Ruiter CJ, Verdijk PW, van Mechelen W, de Haan A. 40. Bayliss DA, Umemiya M, Berger AJ. Inhibition of N- and P-type
Vastus lateralis surface and single motor unit electromyography during calcium currents and the after-hyperpolarization in rat motoneurones
shortening, lengthening and isometric contractions corrected for mode- by serotonin. J Physiol 485: 635-647, 1995.
dependent differences in force-generating capacity. Acta Physiol (Oxf) 41. Bayliss DA, Viana F, Bellingham MC, Berger AJ. Characteristics and
196: 315-328, 2009. postnatal development of a hyperpolarization-activated inward current
14. Alvarez FJ, Bullinger KL, Titus HE, Nardelli P, Cope TC. Permanent in rat hypoglossal motoneurons in vitro. J Neurophysiol 71: 119-128,
reorganization of Ia afferent synapses on motoneurons after peripheral 1994.
nerve injuries. Ann N Y Acad Sci U S A 1198: 231-241, 2010. 42. Bayliss DA, Viana F, Berger AJ. Mechanisms underlying excitatory ef-
15. Alvarez FJ, Pearson JC, Harrington D, Dewey D, Torbeck L, Fyffe fects of thyrotropin-releasing hormone on rat hypoglossal motoneurons
RE. Distribution of 5-hydroxytryptamine-immunoreactive boutons on in vitro. J Neurophysiol 68: 1733-1745, 1992.
alpha-motoneurons in the lumbar spinal cord of adult cats. J Comp 43. Bean B, Mintz I. Pharmacology of different types of calcium channels
Neurol 393: 69-83, 1998. in rat neurons. In: Handbook of Membrane Channels: Molecular and
16. Amendola J, Durand J. Morphological differences between wild-type Cellular Physiology. Peracchia C: Academic Press, 1994.
and transgenic superoxide dismutase 1 lumbar motoneurons in postnatal 44. Beaumont E, Gardiner P. Effects of daily spontaneous running on the
mice. J Comp Neurol 511: 329-341, 2008. electrophysiological properties of hindlimb motoneurones in rats. J
17. Andersen JL, Aagaard P. Effects of strength training on muscle fiber Physiol 540: 129-138, 2002.
types and size; consequences for athletes training for high-intensity 45. Beaumont E, Gardiner P. Endurance training alters the biophysical
sport. Scand J Med Sci Sports 20(Suppl 2): 32-38, 2010. properties of hindlimb motoneurons in rats. Muscle Nerve 27: 228-236,
18. Armstrong JB, Rose PK, Vanner S, Bakker GJ, Richmond FJ. Compart- 2003.
mentalization of motor units in the cat neck muscle, biventer cervicis. 46. Bennett DJ, Hultborn H, Fedirchuk B, Gorassini M. Short-term plas-
J Neurophysiol 60: 30-45, 1988. ticity in hindlimb motoneurons of decerebrate cats. J Neurophysiol 80:
19. Arvanian VL, Motin V, Mendell LM. Comparison of metabotropic 2038-2045, 1998a.
glutamate receptor responses at segmental and descending inputs to 47. Bennett DJ, Hultborn H, Fedirchuk B, Gorassini M. Synaptic activation
motoneurons in neonatal rat spinal cord. J Pharmacol Exp Ther 312: of plateaus in hindlimb motoneurons of decerebrate cats. J Neurophysiol
669-677, 2005. 80: 2023-2037, 1998b.
20. Ashworth B, Grimby L, Kugelberg E. Comparison of voluntary and 48. Bennett DJ, Li Y, Harvey PJ, Gorassini M. Evidence for plateau poten-
reflex activation of motor units. Functional organization of motor neu- tials in tail motoneurons of awake chronic spinal rats with spasticity. J
rones. J Neurol Neurosurg Psychiatry 30: 91-98, 1967. Neurophysiol 86: 1972-1982, 2001.
21. Aston-Jones G, Rajkowski J, Cohen J. Locus coeruleus and regulation 49. Bennett DJ, Li Y, Siu M. Plateau potentials in sacrocaudal motoneurons
of behavioral flexibility and attention. Prog Brain Res 126: 165-182, of chronic spinal rats, recorded in vitro. J Neurophysiol 86: 1955-1971,
2000. 2001.

P1: OTA/XYZ P2: ABC
50. Bennett DJ, Sanelli L, Cooke CL, Harvey PJ, Gorassini MA. Spastic to motoneuron pools - a mechanism for muscle synergy. In: Pierrot-
long-lasting reflexes in the awake rat after sacral spinal cord injury. J Deseilligny I, Jami L, Zytnicki D, editors. Muscle Afferents and Spinal
Neurophysiol 91: 2247-2258, 2004. Control of Movement Pergamon Press, 1992, pp. 187-194.
51. Berg RW, Alaburda A, Hounsgaard J. Balanced inhibition and excita- 77. Brock LG, Coombs JS, Eccles JC. The recording of potentials from
tion drive spike activity in spinal half-centers. Science 315: 390-393, motoneurones with an intracellular electrode. J Physiol 117: 431-460,
2007. 1952.
52. Berger AJ, Bayliss DA, Viana F. Modulation of neonatal rat hypoglos- 78. Brown IE, Loeb GE. Measured and modeled properties of mammalian
sal motoneuron excitability by serotonin. Neurosci Lett 143: 164-168, skeletal muscle. I. The effects of post-activation potentiation on the
1992. time course and velocity dependencies of force production. J Muscle
53. Bertrand S, Cazalets JR. Postinhibitory rebound during locomotor-like Res Cell Motil 20: 443-456, 1999.
activity in neonatal rat motoneurons in vitro. J Neurophysiol 79: 342- 79. Brownstone RM. Beginning at the end: Repetitive firing properties in
351, 1998. the final common pathway. Prog Neurobiol 78: 156-172, 2006.
54. Bigland-Ritchie B, Fuglevand AJ, Thomas CK. Contractile proper- 80. Brownstone RM, Gossard JP, Hultborn H. Voltage-dependent excita-
ties of human motor units: Is man a cat? Neuroscientist 4: 240-249, tion of motoneurones from spinal locomotor centres in the cat. Exp
1998. Brain Res 102: 34-44, 1994.
55. Bigland-Ritchie BR, Dawson NJ, Johansson RS, Lippold OC. Reflex 81. Brushart TM. Preferential motor reinnervation: A sequential double-
origin for the slowing of motoneurone firing rates in fatigue of human labeling study. Restor Neurol Neurosci 1: 281-287, 1990.
voluntary contractions. J Physiol 379: 451-459, 1986. 82. Brushart TM. Nerve Repair. New York: Oxford University Press, 2011.
56. Bigland B, Lippold OC. Motor unit activity In the voluntary contraction 83. Buchthal F, Schmalbruch H. Contraction times and fibre types in intact
of human muscle. J Physiol 125: 322-335, 1954. human muscle. Acta Physiol Scand 79: 435-452, 1970.
57. Binder MD. Integration of synaptic and intrinsic dendritic currents in 84. Büdingen HJ, Freund HJ. The relationship between the rate of rise
cat spinal motoneurons. Brain Res Brain Res Rev 40: 1-8, 2002. of isometric tension and motor unit recruitment in a human forearm
58. Binder MD. Intrinsic dendritic currents make a major contribution to muscle. Pflügers Arch 362: 61-67, 1976.
the control of motoneurone discharge. J Physiol 552: 665, 2003. 85. Bui TV, Grande G, Rose PK. Multiple modes of amplification of synap-
59. Binder MD, Bawa P, Ruenzel P, Henneman E. Does orderly recruitment tic inhibition to motoneurons by persistent inward currents. J Neuro-
of motoneurons depend on the existence of different types of motor physiol 99: 571-582, 2008a.
units. Neurosci Lett 36: 55-58, 1983. 86. Bui TV, Grande G, Rose PK. Relative location of inhibitory synapses
60. Binder MD, Heckman CJ, Powers RK. The physiolgocial control of and persistent inward currents determines the magnitude and mode of
motoneuron activity. In: Rowell LB, Shepherd JT, editors. Handbook of synaptic amplification in motoneurons. J Neurophysiol 99: 583-594,
Physiology: Exercise, Regulation and Integration of Multiple Systems. 2008b.
New York: Oxford Univ Press, 1996, pp. 1-53. 87. Bui TV, Ter-Mikaelian M, Bedrossian D, Rose PK. Computational
61. Binder MD, Robinson FR, Powers RK. Distribution of effective synap- estimation of the distribution of L-type Ca(2+ ) channels in motoneurons
tic currents in cat triceps surae motoneurons. VI. Contralateral pyrami- based on variable threshold of activation of persistent inward currents.
dal tract. J Neurophysiol 80: 241-248, 1998. J Neurophysiol 95: 225-241, 2006.
62. Blazevich AJ. Effects of physical training and detraining, immobilisa- 88. Burke RE. Motor units: Anatomy, physiology, and functional organi-
tion, growth and aging on human fascicle geometry. Sports Med 36: zation. In: Brooks VB, editor. Handbook of Physiology, The Nervous
1003-1017, 2006. System, Motor Control. Bethesda, MD: American Physiological Soci-
63. Blevins CE. Innervation patterns of the human stapedius muscle. Arch ety, 1981, pp. 345-422.
Otolaryngol 86: 136-142, 1967. 89. Burke RE, Dum RP, Fleshman JW, Glenn LL, Lev-Tov A, O’Donovan
64. Blok JH, van Dijk JP, Drost G, Zwarts MJ, Stegeman DF. A high- MJ, Pinter MJ. A HRP study of the relation between cell size and motor
density multichannel surface electromyography system for the charac- unit type in cat ankle extensor motoneurons. J Comp Neurol 209: 17-28,
terization of single motor units. Rev Sci Instrum 73: 1887-1897, 2002. 1982.
65. Bodine SC, Garfinkel A, Roy RR, Edgerton VR. Spatial distribution of 90. Burke RE, Jankowska E, ten Bruggencate G. A comparison of periph-
motor unit fibers in the cat soleus and tibialis anterior muscles: Local eral and rubrospinal synaptic input to slow and fast twitch motor units
interactions. J Neurosci 8: 2142-2152, 1988. of triceps surae. J Physiol 207: 709-732, 1970.
66. Bodine SC, Roy RR, Eldred E, Edgerton VR. Maximal force as a 91. Burke RE, Levine DN, Salcman M, Tsairis P. Motor units in cat soleus
function of anatomical features of motor units in the cat tibialis anterior. muscle: Physiological, histochemical and morphological characteris-
J Neurophysiol 57: 1730-1745, 1987. tics. J Physiol 238: 503-514, 1974.
67. Boe SG, Antonowicz NM, Leung VW, Shea SM, Zimmerman 92. Burke RE, Levine DN, Tsairis P, Zajac FEd. Physiological types and
TC, Doherty TJ. High inter-rater reliability in analyzing results of histochemical profiles in motor units of the cat gastrocnemius. J Physiol
decomposition-based quantitative electromyography in subjects with 234: 723-748, 1973.
or without neuromuscular disorder. J Neurosci Methods 192: 138-145, 93. Burke RE, Rudomin P, Zajac FE III. The effect of activation history
2010. on tension production by individual muscle units. Brain Research 109:
68. Boe SG, Dalton BH, Harwood B, Doherty TJ, Rice CL. Inter-rater 515-529, 1976.
reliability of motor unit number estimates and quantitative motor unit 94. Burke RE, Strick PL, Kanda K, Kim CC, Walmsley B. Anatomy of
analysis in the tibialis anterior muscle. Clin Neurophysiol 120: 947-952, medial gastrocnemius and soleus motor nuclei in cat spinal cord. J
2009. Neurophysiol 40: 667-680, 1977.
69. Booth V, Rinzel J, Kiehn O. Compartmental model of vertebrate mo- 95. Burke RE, Tsairis P. Anatomy and innervation ratios in motor units of
toneurons for Ca2+-dependent spiking and plateau potentials under cat gastrocnemius. J Physiol 234: 749-765, 1973.
pharmacological treatment. J Neurophysiol 78: 3371-3385, 1997. 96. Burne JA, Carleton VL, O’Dwyer NJ. The spasticity paradox: Move-
70. Bories C, Amendola J, Lamotte d’Incamps B, Durand J. Early elec- ment disorder or disorder of resting limbs? J Neurol Neurosurg Psychi-
trophysiological abnormalities in lumbar motoneurons in a transgenic atry 76: 47-54, 2005.
mouse model of amyotrophic lateral sclerosis. Eur J Neurosci 25: 451- 97. Butler TJ, Kilbreath SL, Gorman RB, Gandevia SC. Selective recruit-
459, 2007. ment of single motor units in human flexor digitorum superficialis
71. BoSmith RE, Briggs I, Sturgess NC. Inhibitory actions of ZENECA muscle during flexion of individual fingers. J Physiol 567: 301-309,
ZD7288 on whole-cell hyperpolarization activated inward current (If) 2005.
in guinea-pig dissociated sinoatrial node cells. Br J Pharmacol 110: 98. Button DC, Gardiner K, Marqueste T, Gardiner PF. Frequency-current
343-349, 1993. relationships of rat hindlimb alpha-motoneurones. J Physiol 573: 663-
72. Bottinelli R. Functional heterogeneity of mammalian single muscle 677, 2006.
fibres: Do myosin isoforms tell the whole story? Pflugers Arch 443: 99. Button DC, Kalmar JM, Gardiner K, Marqueste T, Zhong H, Roy RR,
6-17, 2001. Edgerton VR, Gardiner PF. Does elimination of afferent input modify
73. Bottinelli R, Canepari M, Pellegrino MA, Reggiani C. Force-velocity the changes in rat motoneurone properties that occur following chronic
properties of human skeletal muscle fibres: Myosin heavy chain isoform spinal cord transection? J Physiol 586: 529-544, 2008.
and temperature dependence. J Physiol 495(Pt 2): 573-586, 1996. 100. Calancie B, Bawa P. Voluntary and reflexive recruitment of flexor
74. Bottinelli R, Reggiani C. Human skeletal muscle fibres: Molecular and carpi radialis motor units in humans. J Neurophysiol 53: 1194-1200,
functional diversity. Prog Biophys Mol Biol 73: 195-262, 2000. 1985.
75. Bowker RM, Westlund KN, Sullivan MC, Coulter JD. Organization 101. Calancie B, Bawa P. Limitations of the spike triggered averaging tech-
of descending serotonergic projections to the spinal cord. In: Kuypers nique. Muscle Nerve 9: 78-93, 1986.
HGJM, Martin GF, editors. Descending Pathways to the Spinal Cord. 102. Calder KM, Stashuk DW, McLean L. Physiological characteristics of
Progress in Brain Research. Amsterdam: Elsevier, 1982, pp. 239- motor units in the brachioradialis muscle across fatiguing low-level
265. isometric contractions. J Electromyogr Kinesiol 18: 2-15, 2008.
76. Bremner FD, Baker JR, Harrison LM, Carr L, Farmer SF, Stephens JA. 103. Calvin WH, Schwindt PC. Steps in production of motoneuron spikes
Activity in branches of last order common stem presynaptic input fibers during rhythmic firing. J Neurophysiol 35: 297-310, 1972.

P1: OTA/XYZ P2: ABC
104. Calvin WH, Stevens CF. Synaptic noise and other sources of random- 132. Crill WE. Persistent sodium current in mammalian central neurons.
ness in motoneuron interspike intervals. J Neurophysiol 31: 574-587, Annu Rev Physiol 58: 349-362, 1996.
1968. 133. Crone C, Hultborn H, Kiehn O, Mazieres L, Wigström H. Maintained
105. Carlin KP, Bui TV, Dai Y, Brownstone RM. Staircase currents in changes in motoneuronal excitability by short-lasting synaptic inputs
motoneurons: Insight into the spatial arrangement of calcium channels in the decerebrate cat. J Physiol 405: 321-343, 1988.
in the dendritic tree. J Neurosci 29: 5343-5353, 2009. 134. Crone C, Hultborn H, Kiehn O, Mazieres L, Wigstrom H. Maintained
106. Carlin KP, Jiang Z, Brownstone RM. Characterization of calcium cur- changes in motoneuronal excitability by short-lasting synaptic inputs
rents in functionally mature mouse spinal motoneurons. Eur J Neurosci in the decerebrate cat. J Physiol 405: 321-343, 1988.
12: 1624-1634, 2000. 135. Cui L, Maas H, Perreault EJ, Sandercock TG. In situ estimation of
107. Carlin KP, Jones KE, Jiang Z, Jordan LM, Brownstone RM. Dendritic tendon material properties: Differences between muscles of the feline
L-type calcium currents in mouse spinal motoneurons: Implications for hindlimb. J Biomech 42: 679-685, 2009.
bistability. Eur J Neurosci 12: 1635-1646, 2000. 136. Cui L, Perreault EJ, Maas H, Sandercock TG. Modeling short-range
108. Carlsöö S. Motor units and action potentials in masticatory muscles. stiffness of feline lower hindlimb muscles. J Biomech 41: 1945-1952,
An electromyographic study of the form and duration of the action 2008.
potentials and an anatomic study of the size of the motor units. Acta 137. Cullheim S, Fleshman JW, Glenn LL, Burke RE. Membrane area and
Morphol Neerl Scand 2: 13-19, 1958. dendritic structure in type-identified triceps surae alpha motoneurons.
109. Carp JS. Monosynaptic EPSPs in primate lumbar motoneurons. J Neu- J Comp Neurol 255: 68-81, 1987.
rophysiol 70: 1585-1592, 1993. 138. Cushing S, Bui T, Rose PK. Effect of nonlinear summation of synap-
110. Carp JS, Herchenroder PA, Chen XY, Wolpaw JR. Sag during unfused tic currents on the input-output properties of spinal motoneurons. J
tetanic contractions in rat triceps surae motor units. J Neurophysiol 81: Neurophysiol 94: 3465-3478, 2005.
2647-2661, 1999. 139. Dai Y, Jones KE, Fedirchuk B, McCrea DA, Jordan LM. A modelling
111. Carp JS, Tennissen AM, Mongeluzi DL, Dudek CJ, Chen XY, Wolpaw study of locomotion-induced hyperpolarization of voltage threshold in
JR. An in vitro protocol for recording from spinal motoneurons of adult cat lumbar motoneurones. J Physiol 544: 521-536, 2002.
rats. J Neurophysiol 100: 474-481, 2008. 140. Dai Y, Jordan LM, Fedirchuk B. Modulation of transient and persistent
112. Carpentier A, Duchateau J, Hainaut K. Motor unit behaviour and con- inward currents by activation of protein kinase C in spinal ventral
tractile changes during fatigue in the human first dorsal interosseus. J neurons of the neonatal rat. J Neurophysiol 101: 112-128, 2009.
Physiol 534: 903-912, 2001. 141. Dartnall TJ, Nordstrom MA, Semmler JG. Motor unit synchronization
113. Carr LJ, Harrison LM, Stephens JA. Evidence for bilateral innervation is increased in biceps brachii after exercise-induced damage to elbow
of certain homologous motoneurone pools in man. J Physiol 475: 217- flexor muscles. J Neurophysiol 99: 1008-1019, 2008.
227, 1994. 142. Dasen JS, Liu JP, Jessell TM. Motor neuron columnar fate imposed by
114. Cathers I, O’Dwyer N, Neilson P. Variation of magnitude and timing of sequential phases of Hox-c activity. Nature 425: 926-933, 2003.
wrist flexor stretch reflex across the full range of voluntary activation. 143. Datta AK, Farmer SF, Stephens JA. Central nervous pathways underly-
Exp Brain Res 157: 324-335, 2004. ing synchronization of human motor unit firing studied during voluntary
115. Catterall WA, Goldin AL, S.G. W. Voltage-gated sodium chan- contractions. J Physiol 432: 401-425, 1991.
nels. IUPHAR database (IUPHAR-DB): http://www.iuphar-db.org/ 144. Day BL, Dressler D, Maertens de Noordhout A, Marsden CD,
DATABASE/FamilyMenuForward?familyId=82, 2010. Nakashima K, Rothwell JC, Thompson PD. Electric and magnetic
116. Catterall WA, Perez-Reyes E, Snutch TP, JS. Voltage-gated calcium stimulation of human motor cortex: Surface EMG and single motor
channels. IUPHAR database (IUPHAR-DB) http://www.iuphar-db.org/ unit responses. J Physiol 412: 449-473, 1989.
DATABASE/FamilyMenuForward?familyId=80, 2010. 145. Day SJ, Hulliger M. Experimental simulation of cat electromyogram:
117. Chandler SH, Hsaio CF, Inoue T, Goldberg LJ. Electrophysiological Evidence for algebraic summation of motor-unit action-potential trains.
properties of guinea pig trigeminal motoneurons recorded in vitro. J J Neurophysiol 86: 2144-2158, 2001.
Neurophysiol 71: 129-145, 1994. 146. De Luca CJ, Erim Z. Common drive of motor units in regulation of
118. Christie A, Kamen G. Doublet discharges in motoneurons of young and muscle force. Trends Neurosci 17: 299-305, 1994.
older adults. J Neurophysiol 95: 2787-2795, 2006. 147. De Luca CJ, Gonzalez-Cueto JA, Bonato P, Adam A. Motor unit re-
119. Christie A, Kamen G. Motor unit firing behavior during prolonged cruitment and proprioceptive feedback decrease the common drive. J
50% MVC dorsiflexion contractions in young and older adults. J Elec- Neurophysiol 101: 1620-1628, 2009.
tromyogr Kinesiol 19: 543-552, 2009. 148. De Luca CJ, LeFever RS, McCue MP, Xenakis AP. Behaviour of human
120. Christie A, Kamen G. Short-term training adaptations in maximal motor motor units in different muscles during linearly varying contractions. J
unit firing rates and afterhyperpolarization duration. Muscle Nerve 41: Physiol 329: 113-128, 1982a.
651-660, 2010. 149. De Luca CJ, LeFever RS, McCue MP, Xenakis AP. Control scheme
121. Christou EA, Rudroff T, Enoka JA, Meyer F, Enoka RM. Discharge governing concurrently active human motor units during voluntary con-
rate during low-force isometric contractions influences motor unit co- tractions. J Physiol 329: 129-142, 1982b.
herence below 15 Hz but not motor unit synchronization. Exp Brain 150. Del Negro CA, Chandler SH. Regulation of intrinsic and synaptic prop-
Res 178: 285-295, 2007. erties of neonatal rat trigeminal motoneurons by metabotropic gluta-
122. Christova P, Kossev A. Human motor unit activity during concentric mate receptors. J Neurosci 18: 9216-9226, 1998.
and eccentric movements. Electromyogr Clin Neurophysiol 40: 331- 151. Del Negro CA, Hsiao CF, Chandler SH, Garfinkel A. Evidence for a
338, 2000. novel bursting mechanism in rodent trigeminal neurons. Biophys J 75:
123. Clamann HP, Schelhorn TB. Nonlinear force addition of newly re- 174-182, 1998.
cruited motor units in the cat hindlimb. Muscle Nerve 11: 1079-1089, 152. Del Valle A, Thomas CK. Firing rates of motor units during strong
1988. dynamic contractions. Muscle Nerve 32: 316-325, 2005.
124. Clark BD, Dacko SM, Cope TC. Cutaneous stimulation fails to alter 153. Delgado-Lezama R, Perrier JF, Nedergaard S, Svirskis G, Hounsgaard
motor unit recruitment in the decerebrate cat. J Neurophysiol 70: 1433- J. Metabotropic synaptic regulation of intrinsic response properties of
1439, 1993. turtle spinal motoneurones. J Physiol 504: 97-102, 1997.
125. Clemens S, Hochman S. Conversion of the modulatory actions of 154. Denier van der Gon JJ, ter Haar Romeny BM, van Zuylen EJ. Behaviour
dopamine on spinal reflexes from depression to facilitation in D3 re- of motor units of human arm muscles - differences between slow iso-
ceptor knock-out mice. J Neurosci 24: 11337-11345, 2004. metric contraction and relaxation. J Physiol 359: 107-118, 1985.
126. Clements JD, Nelson PG, Redman SJ. Intracellular tetraethylammo- 155. Denny-Brown D. Interpretation of the electromyogram. Arch Neurol
nium ions enhance group Ia excitatory post-synaptic potentials evoked Psychiatry 61: 99-128, 1949.
in cat motoneurones. J Physiol Lond 377: 267-282, 1986. 156. Denny-Brown D, Pennybacker JB. Fibrillation and fasciculation in vol-
127. Collins DF, Burke D, Gandevia SC. Sustained contractions produced untary muscle. Brain 61: 311-334, 1938.
by plateau-like behaviour in human motoneurones. J Physiol 538: 289- 157. Denslow JS. Double discharges in human motor units. J Neurophysiol
301, 2002. 11: 209-215, 1948.
128. Conway BA, Hultborn H, Kiehn O, Mintz I. Plateau potentials in α- 158. Derjean D, Bertrand S, Le Masson G, Landry M, Morisset V, Nagy F.
motoneurones induced by intravenous injection of L-DOPA and cloni- Dynamic balance of metabotropic inputs causes dorsal horn neurons to
dine in the spinal cat. J Physiol 405: 369-384, 1988. switch functional states. Nat Neurosci 6: 274-281, 2003.
129. Conwit RA, Stashuk D, Suzuki H, Lynch N, Schrager M, Metter EJ. 159. Desmedt JE, Godaux E. Ballistic contractions in man: Characteristic
Fatigue effects on motor unit activity during submaximal contractions. recruitment pattern of single motor units of the tibialis anterior muscle.
Arch Phys Med Rehabil 81: 1211-1216, 2000. J Physiol 264: 673-693, 1977a.
130. Cope TC, Bonasera SJ, Nichols TR. Reinnervated muscles fail to pro- 160. Desmedt JE, Godaux E. Fast motor units are not preferentially activated
duce stretch reflexes. J Neurophysiol 71: 817-820, 1994. in rapid voluntary contractions in man. Nature 267: 717-719, 1977b.
131. Cope TC, Clark BD. Motor-unit recruitment in the decerebrate cat: Sev- 161. Desmedt JE, Godaux E. Ballistic contractions in fast or slow human
eral unit properties are equally good predictors of order. J Neurophysiol muscles: Discharge patterns of single motor units. J Physiol 285: 185-
66: 1127-1138, 1991. 196, 1978.

P1: OTA/XYZ P2: ABC
162. Desmedt JE, Godaux E. Voluntary motor commands in human ballistic 190. Elek JM, Kossev A, Dengler R, Schubert M, Wohlfahrt K, Wolf W.
movements. Ann Neurol 5: 415-421, 1979. Parameters of human motor unit twitches obtained by intramuscular
163. Desmedt JE, Godaux E. Spinal motoneuron recruitment in man: rank microstimulation. Neuromuscul Disord 2: 261-267, 1992.
deordering with direction but not with speed of voluntary movement. 191. Ellaway PH. Cumulative sum technique and its application to the anal-
Science 214: 933-936, 1981. ysis of peristimulus time histograms. Electroencephalogr Clin Neuro-
164. Destexhe A, Rudolph M, Pare D. The high-conductance state of neo- physiol 45: 302-304, 1978.
cortical neurons in vivo. Nat Rev Neurosci 4: 739-751, 2003. 192. Elliott P, Wallis DI. Serotonin and L-norepinephrine as mediators of
165. Devasahayam SR, Sandercock TG. Velocity of shortening of single altered excitability in neonatal rat motoneurons studied in vitro. Neu-
motor units from rat soleus. J Neurophysiol 67: 1133-1145, 1992. roscience 47: 533-544, 1992.
166. Devaux JJ, Kleopa KA, Cooper EC, Scherer SS. KCNQ2 is a nodal K+ 193. Emonet-Denand F, Laporte Y, Proske U. Summation of tension in
channel. J Neurosci 24: 1236-1244, 2004. motor units of the soleus muscle of the cat. Neurosci Lett 116: 112-117,
167. Dideriksen JL, Enoka RM, Farina D. Neuromuscular adjustments that 1990.
constrain submaximal EMG amplitude at task failure of sustained iso- 194. English AW. An electromyographic analysis of compartments in cat
metric contractions. J Appl Physiol 111: 485-494, 2011. lateral gastrocnemius muscle during unrestrained locomotion. J Neu-
168. Dideriksen JL, Falla D, Baekgaard M, Mogensen ML, Steimle KL, rophysiol 52: 114-125, 1984.
Farina D. Comparison between the degree of motor unit short-term 195. English AW, Letbetter WD. Anatomy and innervation patterns of cat
synchronization and recurrence quantification analysis of the surface lateral gastrocnemius and plantaris muscles. Am J Anat 164: 67-77,
EMG in two human muscles. Clin Neurophysiol 120: 2086-2092, 1982.
2009. 196. Enoka RM, Baudry S, Rudroff T, Farina D, Klass M, Duchateau J.
169. Dideriksen JL, Farina D, Enoka RM. Influence of fatigue on the simu- Unraveling the neurophysiology of muscle fatigue. J Electromyogr
lated relation between the amplitude of the surface electromyogram and Kinesiol 21: 208-219, 2011.
muscle force. Philos Transact A Math Phys Eng Sci 368: 2765-2781, 197. Enoka RM, Fuglevand AJ. Motor unit physiology: Some unresolved
2010. issues. Muscle Nerve 24: 4-17, 2001.
170. Dimitrov GV, Arabadzhiev TI, Hogrel JY, Dimitrova NA. Simulation 198. Enoka RM, Robinson GA, Kossev AR. Task and fatigue effects on
analysis of interference EMG during fatiguing voluntary contractions. low-threshold motor units in human hand muscle. J Neurophysiol 62:
Part I: What do the intramuscular spike amplitude-frequency histograms 1344-1359, 1989.
reflect? J Electromyogr Kinesiol 18: 26-34, 2008. 199. Erim Z, De Luca CJ, Mineo K, Aoki T. Rank-ordered regulation of
171. Dimitrova NA, Dimitrov GV. Amplitude-related characteristics of mo- motor units. Muscle Nerve 19: 563-573, 1996.
tor unit and M-wave potentials during fatigue. A simulation study using 200. Ermilov LG, Mantilla CB, Rowley KL, Sieck GC. Safety factor for
literature data on intracellular potential changes found in vitro. J Elec- neuromuscular transmission at type-identified diaphragm fibers. Muscle
tromyogr Kinesiol 12: 339-349, 2002. Nerve 35: 800-803, 2007.
172. Dityatev AE, Chmykhova NM, Dityateva GV, Babalian AL, Kleinle 201. Falla D, Farina D. Motor units in cranial and caudal regions of the
J, Clamann HP. Structural and physiological properties of connections upper trapezius muscle have different discharge rates during brief static
between individual reticulospinal axons and lumbar motoneurons of contractions. Acta Physiol (Oxf) 192: 551-558, 2008a.
the frog. J Comp Neurol 430: 433-447, 2001. 202. Falla D, Farina D. Non-uniform adaptation of motor unit discharge
173. Dong XW, Feldman JL. Distinct subtypes of metabotropic glutamate rates during sustained static contraction of the upper trapezius muscle.
receptors mediate differential actions on excitability of spinal respira- Exp Brain Res 191: 363-370, 2008b.
tory motoneurons. J Neurosci 19: 5173-5184, 1999. 203. Farina D. Interpretation of the surface electromyogram in dynamic
174. Drost G, Stegeman DF, Schillings ML, Horemans HL, Janssen HM, contractions. Exerc Sport Sci Rev 34: 121-127, 2006.
Massa M, Nollet F, Zwarts MJ. Motor unit characteristics in healthy 204. Farina D. Counterpoint: Spectral properties of the surface EMG do
subjects and those with postpoliomyelitis syndrome: A high-density not provide information about motor unit recruitment and muscle fiber
surface EMG study. Muscle Nerve 30: 269-276, 2004. type. J Appl Physiol 105: 1673-1674, 2008.
175. Duchateau J, Enoka RM. Neural control of shortening and lengthening 205. Farina D, Arendt-Nielsen L, Graven-Nielsen T. Effect of tempera-
contractions: Influence of task constraints. J Physiol 586: 5853-5864, ture on spike-triggered average torque and electrophysiological prop-
2008. erties of low-threshold motor units. J Appl Physiol 99: 197-203,
176. Duchateau J, Enoka RM. Human motor unit recordings: Origins and 2005.
insight into the integrated motor system. Brain Res 1409: 42-61, 2011. 206. Farina D, Arendt-Nielsen L, Roatta S, Graven-Nielsen T. The pain-
177. Duchateau J, Hainaut K. Human-muscle adaptation to exercise. J Bio- induced decrease in low-threshold motor unit discharge rate is not as-
phys Med Nucl 5: 249-253, 1981. sociated with the amount of increase in spike-triggered average torque.
178. Duchateau J, Hainaut K. Effects of immobilization on contractile prop- Clin Neurophysiol 119: 43-51, 2008.
erties, recruitment and firing rates of human motor units. J Physiol 422: 207. Farina D, Cescon C, Negro F, Enoka RM. Amplitude cancellation
55-65, 1990. of motor-unit action potentials in the surface electromyogram can be
179. Duchateau J, Semmler JG, Enoka RM. Training adaptations in the estimated with spike-triggered averaging. J Neurophysiol 100: 431-440,
behavior of human motor units. J Appl Physiol 101: 1766-1775, 2008.
2006. 208. Farina D, Falla D. Discharge rate of sternohyoid motor units activated
180. Duflocq A, Le Bras B, Bullier E, Couraud F, Davenne M. Nav1.1 is with surface EMG feedback. J Neurophysiol 101: 624-632, 2009.
predominantly expressed in nodes of Ranvier and axon initial segments. 209. Farina D, Fattorini L, Felici F, Filligoi G. Nonlinear surface EMG
Mol Cell Neurosci 39: 180-192, 2008. analysis to detect changes of motor unit conduction velocity and syn-
181. Dum RP, Kennedy TT. Synaptic organization of defined motor unit chronization. J Appl Physiol 93: 1753-1763, 2002.
types in cat tibialis anterior. J Neurophysiol 43: 1631-1644, 1980. 210. Farina D, Fosci M, Merletti R. Motor unit recruitment strategies in-
182. Durand J. NMDA actions on rat abducens motoneurones. Eur J Neu- vestigated by surface EMG variables. J Appl Physiol 92: 235-247,
rosci 3: 621-633, 1991. 2002.
183. Durand J. Synaptic excitation triggers oscillations during NMDA re- 211. Farina D, Holobar A, Gazzoni M, Zazula D, Merletti R, Enoka RM. Ad-
ceptor activation in rat abducens motoneurons. Eur J Neurosci 5: 1389- justments differ among low-threshold motor units during intermittent,
1397, 1993. isometric contractions. J Neurophysiol 101: 350-359, 2009.
184. Eccles JC, Eccles RM, Lundberg A. The convergence of monosynaptic 212. Farina D, Holobar A, Merletti R, Enoka RM. Decoding the neural drive
excitatory afferents on to many different species of alpha motoneurones. to muscles from the surface electromyogram. Clin Neurophysiol 121:
J Physiol 137: 22-50, 1957. 1616-1623, 2010.
185. Edman KA. Double-hyperbolic force-velocity relation in frog muscle 213. Farina D, Merletti R, Enoka RM. The extraction of neural strategies
fibres. J Physiol 404: 301-321, 1988. from the surface EMG. J Appl Physiol 96: 1486-1495, 2004.
186. Edström L, Kugelberg E. Histochemical composition, distribution of 214. Farina D, Negro F. Estimation of muscle fiber conduction velocity with
fibres and fatiguability of single motor units. Anterior tibial muscle of a spectral multidip approach. IEEE Trans Biomed Eng 54: 1583-1589,
the rat. J Neurol Neurosurg Psychiatry 31: 424-433, 1968. 2007.
187. Elbasiouny SM, Amendola J, Durand J, Heckman CJ. Evidence from 215. Farina D, Negro F, Gazzoni M, Enoka RM. Detecting the unique repre-
computer simulations for alterations in the membrane biophysical prop- sentation of motor-unit action potentials in the surface electromyogram.
erties and dendritic processing of synaptic inputs in mutant superoxide J Neurophysiol 100: 1223-1233, 2008.
dismutase-1 motoneurons. J Neurosci 30: 5544-5558, 2010. 216. Farmer SF, Bremner FD, Halliday DM, Rosenberg JR, Stephens JA.
188. Elbasiouny SM, Bennett DJ, Mushahwar VK. Simulation of dendritic The frequency content of common synaptic inputs to motoneurones
CaV1.3 channels in cat lumbar motoneurons: Spatial distribution. J studied during voluntary isometric contraction in man. J Physiol 470:
Neurophysiol 94: 3961-3974, 2005. 127-155, 1993.
189. Elbasiouny SM, Bennett DJ, Mushahwar VK. Simulation of Ca2+ 217. Farmer SF, Swash M, Ingram DA, Stephens JA. Changes in motor unit
persistent inward currents in spinal motoneurones: Mode of activation synchronization following central nervous lesions in man. J Physiol
and integration of synaptic inputs. J Physiol 570: 355-374, 2006. 463: 83-105, 1993.

P1: OTA/XYZ P2: ABC
218. Fedirchuk B, Dai Y. Monoamines increase the excitability of spinal 246. Gandevia SC. Spinal and supraspinal factors in human muscle fatigue.
neurones in the neonatal rat by hyperpolarizing the threshold for action Physiol Rev 81: 1725-1789, 2001.
potential production. J Physiol 557: 355-361, 2004. 247. Gardiner P, Beaumont E, Cormery B. Motoneurones “learn” and “for-
219. Feiereisen P, Duchateau J, Hainaut K. Motor unit recruitment order get” physical activity. Can J Appl Physiol 30: 352-370, 2005.
during voluntary and electrically induced contractions in the tibialis 248. Gardiner P, Dai Y, Heckman CJ. Effects of exercise training on alpha-
anterior. Exp Brain Res 114: 117-123, 1997. motoneurons. J Appl Physiol 101: 1228-1236, 2006.
220. Feinstein B, Lindegård B, Nyman E, Wohlfart G. Morphologic stud- 249. Gardiner PF, Kernell D. The “fastness” of rat motoneurones: Time-
ies of motor units in normal human muscles. Acta Anat 23: 127-142, course of afterhyperpolarization in relation to axonal conduction ve-
1955. locity and muscle unit contractile speed. Pflugers Arch 415: 762-766,
221. Fetz EE, Perlmutter SI, Prut Y, Seki K, Votaw S. Roles of primate spinal 1990.
interneurons in preparation and execution of voluntary hand movement. 250. Garland SJ, Cooke JD, Miller KJ, Ohtsuki T, Ivanova T. Motor unit
Brain Res Brain Res Rev 40: 53-65, 2002. activity during human single joint movements. J Neurophysiol 76: 1982-
222. Filippi GM, Troiani D. Relations among motor unit types, generated 1990, 1996.
forces and muscle length in single motor units of anaesthetized cat 251. Garland SJ, Enoka RM, Serrano LP, Robinson GA. Behavior of motor
peroneus longus muscle. Exp Brain Res 101: 406-414, 1994. units in human biceps brachii during a submaximal fatiguing contrac-
223. Fisher ND, Nistri A. Substance P and TRH share a common effector tion. J Appl Physiol 76: 2411-2419, 1994.
pathway in rat spinal motoneurones: An in vitro electrophysiological 252. Garland SJ, Gossen ER. The muscular wisdom hypothesis in human
investigation. Neurosci Lett 153: 115-119, 1993. muscle fatigue. Exerc Sport Sci Rev 30: 45-49, 2002.
224. Fitts RH, Riley DR, Widrick JJ. Functional and structural adapta- 253. Garland SJ, Griffin L. Motor unit double discharges: Statistical anomaly
tions of skeletal muscle to microgravity. J Exp Biol 204: 3201-3208, or functional entity? Can J Appl Physiol 24: 113-130, 1999.
2001. 254. Garnett R, Stephens JA. Changes in the recruitment threshold of motor
225. Fleckenstein JL, Watumull D, Bertocci LA, Parkey RW, Peshock RM. units produced by cutaneous stimulation in man. J Physiol 311: 463-
Finger-specific flexor recruitment in humans: Depiction by exercise- 473, 1981.
enhanced MRI. J Appl Physiol 72: 1974-1977, 1992. 255. Gazula VR, Roberts M, Luzzio C, Jawad AF, Kalb RG. Effects of limb
226. Fleshman JW, Munson JB, Sypert GW, Friedman WA. Rheobase, input exercise after spinal cord injury on motor neuron dendrite structure. J
resistance, and motor-unit type in medial gastrocnemius motoneurons Comp Neurol 476: 130-145, 2004.
in the cat. J Neurophysiol 46: 1326-1338, 1981. 256. Geertsen SS, Stecina K, Meehan CF, Nielsen JB, Hultborn H. Recipro-
227. Fling BW, Knight CA, Kamen G. Relationships between motor unit cal Ia inhibition contributes to motoneuronal hyperpolarisation during
size and recruitment threshold in older adults: Implications for size the inactive phase of locomotion and scratching in the cat. J Physiol,
principle. Exp Brain Res 197: 125-133, 2009. 589: 119-134, 2011.
228. Foehring RC, Sypert GW, Munson JB. Properties of self-reinnervated 257. Gilmore J, Fedirchuk B. The excitability of lumbar motoneurones in
motor units of medial gastrocnemius of cat. I. Long-term reinnervation. the neonatal rat is increased by a hyperpolarization of their voltage
J Neurophysiol 55: 931-946, 1986a. threshold for activation by descending serotonergic fibres. J Physiol
229. Foehring RC, Sypert GW, Munson JB. Properties of self-reinnervated 558: 213-224, 2004.
motor units of medial gastrocnemius of cat. II. Axotomized mo- 258. Gilson AS, Mills WB. Activities of single motor units in man during
toneurons and time course of recovery. J Neurophysiol 55: 947-965, slight voluntary efforts. Am J Physiol 133: 658-669, 1941.
1986b. 259. Goldin AL. Resurgence of sodium channel research. Annu Rev Physiol
230. Foehring RC, Sypert GW, Munson JB. Motor-unit properties following 63: 871-894, 2001.
cross-reinnervation of cat lateral gastrocnemius and soleus muscles with 260. Gorassini M, Yang JF, Siu M, Bennett DJ. Intrinsic activation of hu-
medial gastrocnemius nerve. I. Influence of motoneurons on muscle. J man motoneurons: Possible contribution to motor unit excitation. J
Neurophysiol 57: 1210-1226, 1987a. Neurophysiol 87: 1850-1858, 2002a.
231. Foehring RC, Sypert GW, Munson JB. Motor-unit properties following 261. Gorassini M, Yang JF, Siu M, Bennett DJ. Intrinsic activation of hu-
cross-reinnervation of cat lateral gastrocnemius and soleus muscles with man motoneurons: Reduction of motor unit recruitment thresholds by
medial gastrocnemius nerve. II. Influence of muscle on motoneurons. repeated contractions. J Neurophysiol 87: 1859-1866, 2002b.
J Neurophysiol 57: 1227-1245, 1987b. 262. Gorassini MA, Knash ME, Harvey PJ, Bennett DJ, Yang JF. Role
232. Forbes A. The interpretation of spinal reflexes in terms of present of motoneurons in the generation of muscle spasms after spinal cord
knowledge of nerve conduction. Physiol Rev 2: 361-414, 1922. injury. Brain 127: 2247-2258, 2004.
233. Freund H-J, Budingen HJ, Dietz V. Activity of single motor units 263. Gossen ER, Ivanova TD, Garland SJ. The time course of the motoneu-
from human forearm muscles during voluntary isometric contractions. rone afterhyperpolarization is related to motor unit twitch speed in
J Neurophysiol 38: 933-946, 1975. human skeletal muscle. J Physiol 552: 657-664, 2003.
234. Frigon A. Reconfiguration of the spinal interneuronal network during 264. Grande G, Bui TV, Rose PK. Estimates of the location of L-type Ca2+
locomotion in vertebrates. J Neurophysiol 101: 2201-2203, 2009. channels in motoneurons of different sizes: A computational study. J
235. Fuglevand AJ, Dutoit AP, Johns RK, Keen DA. Evaluation of plateau- Neurophysiol 97: 4023-4035, 2007.
potential-mediated ‘warm up’ in human motor units. J Physiol 571: 265. Grande G, Bui TV, Rose PK. Distribution of vestibulospinal contacts on
683-693, 2006. the dendrites of ipsilateral splenius motoneurons: An anatomical sub-
236. Fuglevand AJ, Keen DA. Re-evaluation of muscle wisdom in the human strate for push-pull interactions during vestibulocollic reflexes. Brain
adductor pollicis using physiological rates of stimulation. J Physiol 549: Res 1333: 9-27, 2010.
865-875, 2003. 266. Gregor RJ, Smith DW, Prilutsky BI. Mechanics of slope walking in the
237. Fuglevand AJ, Macefield VG, Bigland-Ritchie B. Force-frequency and cat: Quantification of muscle load, length change, and ankle extensor
fatigue properties of motor units in muscles that control digits of the EMG patterns. J Neurophysiol 95: 1397-1409, 2006.
human hand. J Neurophysiol 81: 1718-1729, 1999. 267. Griffin L, Garland SJ, Ivanova T, Gossen ER. Muscle vibration sustains
238. Fuglevand AJ, Winter DA, Patla AE. Models of recruitment and rate motor unit firing rate during submaximal isometric fatigue in humans.
coding organization in motor-unit pools. J Neurophysiol 70: 2470-2488, J Physiol 535: 929-936, 2001.
1993. 268. Griffiths RI. Shortening of muscle fibres during stretch of the active
239. Fuglevand AJ, Winter DA, Patla AE, Stashuk D. Detection of motor cat medial gastrocnemius muscle: The role of tendon compliance. J
unit action potentials with surface electrodes: Influence of electrode Physiol 436: 219-236, 1991.
size and spacing. Biol Cybern 67: 143-153, 1992. 269. Grimby L, Hannerz J. Recruitment order of motor units on volun-
240. Fuglsang-Frederiksen A. The utility of interference pattern analysis. tary contraction: Changes induced by proprioceptive afferent activity.
Muscle Nerve 23: 18-36, 2000. J Neurol Neurosurg Psychiatry 31: 565-573, 1968.
241. Fukunaga T, Kawakami Y, Kuno S, Funato K, Fukashiro S. Muscle 270. Grimby L, Hannerz J. Differences in recruitment order of motor units
architecture and function in humans. J Biomech 30: 457-463, 1997. in phasic and tonic flexion reflex in “spinal man”. J Neurol Neurosurg
242. Fukuoka T, Kobayashi K, Noguchi K. Laminae-specific distribution of Psychiatry 33: 562-570, 1970.
alpha-subunits of voltage-gated sodium channels in the adult rat spinal 271. Grimby L, Hannerz J. Firing rate and recruitment order of toe extensor
cord. Neuroscience 169: 994-1006, 2010. motor units in different modes of voluntary conraction. J Physiol 264:
243. Funk GD, Kanjhan R, Walsh C, Lipski J, Comer AM, Parkis MA, 865-879, 1977.
Housley GD. P2 receptor excitation of rodent hypoglossal motoneuron 272. Gustafsson B, Pinter MJ. Effects of axotomy on the distribution of
activity in vitro and in vivo: A molecular physiological analysis. J passive electrical properties of cat motoneurones. J Physiol 356: 433-
Neurosci 17: 6325-6337, 1997. 442, 1984a.
244. Fyffe RE. Spatial distribution of recurrent inhibitory synapses on spinal 273. Gustafsson B, Pinter MJ. An investigation of threshold properties
motoneurons in the cat. J Neurophysiol 65: 1134-1149, 1991. among cat spinal alpha-motoneurones. J Physiol 357: 453-483, 1984b.
245. Galganski ME, Fuglevand AJ, Enoka RM. Reduced control of motor 274. Gustafsson B, Pinter MJ. Relations among passive electrical properties
output in a human hand muscle of elderly subjects during submaximal of lumbar alpha-motoneurones of the cat. J Physiol 356: 401-431,
contractions. J Neurophysiol 69: 2108-2115, 1993. 1984c.

P1: OTA/XYZ P2: ABC
275. Gustafsson B, Pinter MJ. Relations among passive electrical properties 303. Heckman CJ, Mottram C, Quinlan K, Theiss R, Schuster J. Motoneuron
of lumbar alpha-motoneurones of the cat. J Physiol 356: 401-431, excitability: The importance of neuromodulatory inputs. Clin Neuro-
1984d. physiol 120: 2040-2054, 2009.
276. Gutman GA, Chandy KG, Grissmer S, Lazdunski M, Mckinnon D, 304. Heckman CJ, Weytjens JLF, Loeb GE. Effect of velocity and mechani-
Pardo LA, Robertson GA, Rudy B, Sanguinetti MC, Stühmer W, X. cal history on the forces of motor units in the cat medial gastrocnemius
W. Voltage-gated potassium channels. IUPHAR database (IUPHAR- muscle. J Neurophysiol 68: 1503-1515, 1992.
DB): http://www.iuphar-db.org/DATABASE/FamilyMenuForward? 305. Hegedus J, Putman CT, Gordon T. Time course of preferential mo-
familyId=81, 2010. tor unit loss in the SOD1 G93A mouse model of amyotrophic lateral
277. Gydikov A, Kosarov D. Some features of different motor units in the sclerosis. Neurobiol Dis 28: 154-164, 2007.
biceps brachii muscle. Pflugers Arch 347: 75-88, 1974. 306. Hegedus J, Putman CT, Tyreman N, Gordon T. Preferential motor unit
278. Haftel VK, Prather JF, Heckman CJ, Cope TC. Recruitment of cat loss in the SOD1 G93A transgenic mouse model of amyotrophic lateral
motoneurons in the absence of homonymous afferent feedback. J Neu- sclerosis. J Physiol 586: 3337-3351, 2008.
rophysiol 86: 616-628, 2001. 307. Henderson RD, Ridall PG, Hutchinson NM, Pettitt AN, McCombe PA.
279. Häger-Ross CK, Klein CS, Thomas CK. Twitch and tetanic properties Bayesian statistical MUNE method. Muscle Nerve 36: 206-213, 2007.
of human thenar motor units paralyzed by chronic spinal cord injury. J 308. Henneman E. Relation between size of neurons and their susceptibility
Neurophysiol 96: 165-174, 2006. to discharge. Science 126: 1345-1347, 1957.
280. Hamilton AF, Jones KE, Wolpert DM. The scaling of motor noise with 309. Henneman E. Functional organization of motoneuron pools: The size
muscle strength and motor unit number in humans. Exp Brain Res 157: principle. Proc Int Union Physiol Sci 12: 50, 1977.
417-430, 2004. 310. Henneman E, Clamann HP, Gillies JD, Skinner RD. Rank order of
281. Hamm TM, Turkin VV, Bandekar NK, O’Neill D, Jung R. Persistent motoneurons within a pool: Law of combination. J Neurophysiol 37:
currents and discharge patterns in rat hindlimb motoneurons. J Neuro- 1338-1349, 1974.
physiol 104: 1566-1577, 2010. 311. Henneman E, Mendell LM. Functional organization of motoneuron
282. Hammar I, Jankowska E. Modulatory effects of alpha1-,alpha2-, and pool and its inputs. In: Brooks VB, editor. Handbook of Physiology,
beta -receptor agonists on feline spinal interneurons with monosynaptic The Nervous System, Motor Control. Bethesda, MD: American Physi-
input from group I muscle afferents. J Neurosci 23: 332-338, 2003. ological Society, 1981, pp. 423-507.
283. Han P, Nakanishi ST, Tran MA, Whelan PJ. Dopaminergic modulation 312. Henneman E, Olson CB. Relations between structure and function in
of spinal neuronal excitability. J Neurosci 27: 13192-13204, 2007. the design of skeletal muscle. J Neurophysiol 28: 581-598, 1965.
284. Harada Y, Takahashi T. The calcium component of the action potential 313. Henneman E, Shahani BT, Young RR. Voluntary control of human
in spinal motoneurones of the rat. J Physiol 335: 89-100, 1983. motor units. Neurology 25: 368-368, 1975.
285. Harridge SD. Plasticity of human skeletal muscle: Gene expression to 314. Henneman E, Somjen G, Carpenter DO. Excitability and inhibitabil-
in vivo function. Exp Physiol 92: 783-797, 2007. ity of motoneurons of different sizes. J Neurophysiol 28: 599-620,
286. Harridge SD, Bottinelli R, Canepari M, Pellegrino MA, Reggiani C, 1965a.
Esbjornsson M, Saltin B. Whole-muscle and single-fibre contractile 315. Henneman E, Somjen G, Carpenter DO. Functional significance of cell
properties and myosin heavy chain isoforms in humans. Pflugers Arch size in spinal motoneurons. J Neurophysiol 28: 560-580, 1965b.
432: 913-920, 1996. 316. Hijikata T, Ishikawa H. Functional morphology of serially linked skele-
287. Harris AJ, Duxson MJ, Butler JE, Hodges PW, Taylor JL, Gandevia tal muscle fibers. Acta Anat (Basel) 159: 99-107, 1997.
SC. Muscle fiber and motor unit behavior in the longest human skeletal 317. Hille B. Ion Channels of Excitable Membranes. Sunderland, Mass:
muscle. J Neurosci 25: 8528-8533, 2005. Sinauer, 2001.
288. Harris NC, Constanti A. Mechanism of block by ZD 7288 of the 318. Hochman S, Garraway SM, Machacek DW, Shay BL. 5-HT recpeptors
hyperpolarization-activated inward rectifying current in guinea pig sub- and the neuromodulatory control of spinal cord function. In: Cope TC,
stantia nigra neurons in vitro. J Neurophysiol 74: 2366-2378, 1995. editor. Motor Neurobiology of the Spinal Cord. London: CRC Press,
289. Harvey PJ, Li X, Li Y, Bennett DJ. 5-HT2 receptor activation facilitates 2001, pp. 47-87.
a persistent sodium current and repetitive firing in spinal motoneurons 319. Hochman S, Jordan LM, Schmidt BJ. TTX-resistant NMDA receptor-
of rats with and without chronic spinal cord injury. J Neurophysiol 96: mediated voltage oscillations in mammalian lumbar motoneurons. J
1158-1170, 2006a. Neurophysiol 72: 2559-2562, 1994.
290. Harvey PJ, Li X, Li Y, Bennett DJ. Endogenous monoamine receptor 320. Hochman S, McCrea DA. Effects of chronic spinalization on ankle
activation is essential for enabling persistent sodium currents and repet- extensor motoneurons. II. Motoneuron electrical properties. J Neuro-
itive firing in rat spinal motoneurons. J Neurophysiol 96: 1171-1186, physiol 71: 1468-1479, 1994.
2006b. 321. Holobar A, Farina D, Gazzoni M, Merletti R, Zazula D. Estimating mo-
291. Harvey PJ, Li Y, Li X, Bennett DJ. Persistent sodium currents and tor unit discharge patterns from high-density surface electromyogram.
repetitive firing in motoneurons of the sacrocaudal spinal cord of adult Clin Neurophysiol 120: 551-562, 2009.
rats. J Neurophysiol 96: 1141-1157, 2006c. 322. Holobar A, Minetto MA, Botter A, Negro F, Farina D. Experimental
292. Hatze H, Buys JD. Energy-optimal controls in the mammalian neuro- analysis of accuracy in the identification of motor unit spike trains from
muscular system. Biol Cybern 27: 9-20, 1977. high-density surface EMG. IEEE Trans Neural Syst Rehabil Eng 18:
293. Heckman CJ. Computer simulations of the effects of different synaptic 221-229, 2010.
input systems on the steady-state input-output structure of the motoneu- 323. Holobar A, Zazula D. Multichannel blind source separation using con-
ron pool J Neurophysiol 71: 1727-1739, 1994. volution kernel compensation. IEEE Trans Acoust, Speech, Signal Pro-
294. Heckman CJ, Binder MD. Analysis of Ia-inhibitory synaptic input to cess 55: 4487-4496, 2007.
cat spoinal motoneurons evoked by vibration of antagonist muscles. J 324. Holstege JC, Kuypers HG. Brainstem projections to spinal motoneu-
Neurophysiol 66: 1888-1893, 1991. rons: An update. Neuroscience 23: 809-821, 1987.
295. Heckman CJ, Binder MD. Analysis of effective synaptic currents gen- 325. Hornby TG, McDonagh JC, Reinking RM, Stuart DG. Motoneurons:
erated by homonymous Ia afferent fibers in motoneurons of the cat. J A preferred firing range across vertebrate species? Muscle Nerve 25:
Neurophysiol 60: 1946-1966, 1988. 632-648, 2002.
296. Heckman CJ, Binder MD. Computer simulation of the steady-state 326. Hornby TG, Rymer WZ, Benz EN, Schmit BD. Windup of flexion
input-output function of the cat medial gsatrocnemius motoneuron pool. reflexes in chronic human spinal cord injury: A marker for neuronal
J Neurophysiol 65: 952-967, 1991. plateau potentials? J Neurophysiol 89: 416-426, 2003.
297. Heckman CJ, Binder MD. Computer simulations of motoneuron firing 327. Houk JC, Rymer WZ. Neural control of muscle length and tension. In:
rate modulation. J Neurophysiol 69: 1005-1008, 1993a. Brooks V, editor. Handbook of Physiology. Washington DC: American
298. Heckman CJ, Binder MD. Computer simulations of the effects of differ- Physiological Society, 1981, pp. 257-323.
ent synaptic inputs systems on motor unit recruitment. J Neurophysiol 328. Hounsgaard J, Hultborn H, Jespersen B, Kiehn O. Intrinsic membrane
70: 1827-1840, 1993b. properties causing a bistable behaviour of alpha-motoneurones. Exp
299. Heckman CJ, Gorassini MA, Bennett DJ. Persistent inward currents Brain Res 55: 391-394, 1984.
in motoneuron dendrites: Implications for motor output. Muscle Nerve 329. Hounsgaard J, Hultborn H, Jespersen B, Kiehn O. Bistability of alpha-
31: 135-156, 2005. motoneurones in the decerebrate cat and in the acute spinal cat after
300. Heckman CJ, Hyngstrom AS, Johnson MD. Active properties of mo- intravenous 5-hydroxytryptophan. J Physiol 405: 345-367, 1988a.
toneurone dendrites: Diffuse descending neuromodulation, focused lo- 330. Hounsgaard J, Hultborn H, Jespersen B, Kiehn O. Bistability of alpha-
cal inhibition. J Physiol 586: 1225-1231, 2008. motoneurones in the decerebrate cat and in the acute spinal cat after
301. Heckman CJ, Johnson M, Mottram C, Schuster J. Persistent inward cur- intravenous 5-hydroxytryptophan. J Physiol 405: 345-367, 1988b.
rents in spinal motoneurons and their influence on human motoneuron 331. Hounsgaard J, Kiehn O. Ca++ dependent bistability induced by sero-
firing patterns. Neuroscientist 14: 264-275, 2008. tonin in spinal motoneurons. Exp Brain Res 57: 422-425, 1985.
302. Heckman CJ, Lee RH, Brownstone RM. Hyperexcitable dendrites in 332. Hounsgaard J, Kiehn O. Calcium spikes and calcium plateaux evoked
motoneurons and their neuromodulatory control during motor behavior. by differential polarization in dendrites of turtle motoneurones in vitro.
Trends Neurosci 26: 688-695, 2003. J Physiol 468: 245-259, 1993.

P1: OTA/XYZ P2: ABC
333. Hounsgaard J, Mintz I. Calcium conductance and firing properties of 361. Jones KE, Hamilton AF, Wolpert DM. Sources of signal-dependent
spinal motoneurones in the turtle. J Physiol 398: 591-603, 1988. noise during isometric force production. J Neurophysiol 88: 1533-1544,
334. Howell JN, Fuglevand AJ, Walsh ML, Bigland-Ritchie B. Motor unit 2002.
activity during isometric and concentric-eccentric contractions of the 362. Jones KE, Lyons M, Bawa P, Lemon RN. Recruitment order of mo-
human first dorsal interosseus muscle. J Neurophysiol 74: 901-904, toneurons during functional tasks. Exp Brain Res 100: 503-508, 1994.
1995. 363. Jones SM, Lee RH. Fast amplification of dynamic synaptic inputs in
335. Hsiao C-F, Wu N, Chandler SH. Voltage-dependent calcium currents spinal motoneurons in vivo. J Neurophysiol 96: 2200-2206, 2006.
in trigeminal motoneurons of early postnatal rats: Modulation by 5-HT 364. Joyce GC, Rack PMH, Westbury DR. The mechanical properties of
receptors. J Neurophysiol 94: 2063-2072, 2005. cat soleus muscle during controlled lengthening and shortening move-
336. Hsiao CF, Del Negro CA, Trueblood PR, Chandler SH. Ionic basis for ments. J Physiol 204: 461-474, 1969.
serotonin-induced bistable membrane properties in guinea pig trigem- 365. Kallenberg LA, Hermens HJ. Motor unit properties of biceps brachii
inal motoneurons. J Neurophysiol 79: 2847-2856, 1998. in chronic stroke patients assessed with high-density surface EMG.
337. Hsiao CF, Del Negro CA, Trueblood PR, Chandler SH. Ionic basis for Muscle Nerve 39: 177-185, 2009.
serotonin-induced bistable membrane properties in guinea pig trigem- 366. Kamavuako EN, Farina D. Time-dependent effects of pre-conditioning
inal motoneurons. J Neurophysiol 79: 2847-2856, 1998. activation on muscle fiber conduction velocity and twitch torque. Mus-
338. Hsiao CF, Trueblood PR, Levine MS, Chandler SH. Multiple effects of cle Nerve 42: 547-555, 2010.
serotonin on membrane properties of trigeminal motoneurons in vitro. 367. Kamen G, Knight CA. Training-related adaptations in motor unit dis-
J Neurophysiol 77: 2910-2924, 1997. charge rate in young and older adults. J Gerontol A Biol Sci Med Sci
339. Hsiao CF, Wu N, Chandler SH. Voltage-dependent calcium currents 59: 1334-1338, 2004.
in trigeminal motoneurons of early postnatal rats: modulation by 5-HT 368. Kamen G, Sullivan R, Rubinstein S, Christie A. Evidence of self-
receptors. J Neurophysiol 94: 2063-2072, 2005. sustained motoneuron firing in young and older adults. J Electromyogr
340. Hultborn H. Plateau potentials and their role in regulating motoneuronal Kinesiol 16: 25-31, 2006.
firing. Adv Exp Med Biol 508: 213-218, 2002. 369. Kamo M. Discharge behavior of motor units in knee extensors during
341. Hultborn H. Changes in neuronal properties and spinal reflexes during the initial stage of constant-force isometric contraction at low force
development of spasticity following spinal cord lesions and stroke: level. Eur J Appl Physiol 86: 375-381, 2002.
Studies in animal models and patients. J Rehabil Med, 41 (Suppl): 370. Kanda K, Desmedt JE. Cutaneous facilitation of large motor units and
46-55, 2003. motor control of human fingers in precision grip. Adv Neurol 39: 253-
342. Hultborn H. State-dependent modulation of sensory feedback. J Physiol 261, 1983.
533: 5-13, 2001. 371. Kanda K, Hashizume K. Changes in properties of the medial gastroc-
343. Hultborn H, Brownstone RB, Toth TI, Gossard JP. Key mechanisms for nemius motor units in aging rats. J Neurophysiol 61: 737-746, 1989.
setting the input-output gain across the motoneuron pool. Prog Brain 372. Kanda K, Hashizume K. Factors causing difference in force output
Res 143: 77-95, 2004. among motor units in the rat medial gastrocnemius muscle. J Physiol
344. Hultborn H, Denton ME, Wienecke J, Nielsen JB. Variable amplifica- 448: 677-695, 1992.
tion of synaptic input to cat spinal motoneurones by dendritic persistent 373. Kanosue K, Yoshida M, Akazawa K, Fuji K. The number of active
inward current. J Physiol 552: 945-952, 2003. motor units and their firing rates in voluntary contraction of human
345. Hutton RS, Enoka RM. Kinematic assessment of a functional role for brachialis muscle. Jpn J Physiol 29: 427-443, 1979.
recurrent inhibition and selective recruitment. Exp Neurol 93: 369-379, 374. Katz B. The relation between force and speed in muscular contraction.
1986. J Physiol 96: 45-64, 1939.
346. Hyngstrom A, Johnson M, Schuster J, Heckman CJ. Movement-related 375. Keen DA, Fuglevand AJ. Distribution of motor unit force in human ex-
receptive fields of spinal motoneurones with active dendrites. J Physiol tensor digitorum assessed by spike-triggered averaging and intraneural
586: 1581-1593, 2008. microstimulation. J Neurophysiol 91: 2515-2523, 2004.
347. Hyngstrom AS, Johnson MD, Heckman CJ. Summation of excitatory 376. Keenan KG, Farina D, Maluf KS, Merletti R, Enoka RM. Influence
and inhibitory synaptic inputs by motoneurons with highly active den- of amplitude cancellation on the simulated surface electromyogram. J
drites. J Neurophysiol 99: 1643-1652, 2008. Appl Physiol 98: 120-131, 2005.
348. Hyngstrom AS, Johnson MD, Miller JF, Heckman CJ. Intrinsic electri- 377. Keenan KG, Farina D, Merletti R, Enoka RM. Amplitude cancellation
cal properties of spinal motoneurons vary with joint angle. Nat Neurosci reduces the size of motor unit potentials averaged from the surface
10: 363-369, 2007. EMG. J Appl Physiol 100: 1928-1937, 2006a.
349. Iansek R, Redman SJ. The amplitude, time course and charge of uni- 378. Keenan KG, Farina D, Merletti R, Enoka RM. Influence of motor unit
tary excitatory post-synaptic potentials evoked in spinal motoneurone properties on the size of the simulated evoked surface EMG potential.
dendrites. J Physiol 234: 665-688, 1973. Exp Brain Res 169: 37-49, 2006b.
350. Inoue T, Itoh S, Kobayashi M, Kang Y, Matsuo R, Wakisaka S, Mori- 379. Keenan KG, Valero-Cuevas FJ. Experimentally valid predictions of
moto T. Serotonergic modulation of the hyperpolarizing spike afterpo- muscle force and EMG in models of motor-unit function are most
tential in rat jaw-closing motoneurons by PKA and PKC. J Neurophys- sensitive to neural properties. J Neurophysiol 98: 1581-1590, 2007.
iol 82: 626-637, 1999. 380. Kennedy PM, Cresswell AG. The effect of muscle length on motor-unit
351. Ito M, Kawakami Y, Ichinose Y, Fukashiro S, Fukunaga T. Noniso- recruitment during isometric plantar flexion in humans. Exp Brain Res
metric behavior of fascicles during isometric contractions of a human 137: 58-64, 2001.
muscle. J Appl Physiol 85: 1230-1235, 1998. 381. Kernell D. The delayed depolarization in cat and rat motoneurons.
352. Ito M, Oshima T. Electrical behaviour of the motoneurone membrane Progr Brain Res 12: 42-55, 1964.
during intracellularly applied current steps. J Physiol 180: 607-635, 382. Kernell D. Organized variability in the neuromuscular system: A survey
1965. of task-related adaptations. Arch Ital Biol 130: 19-66, 1992.
353. Jacobs BL, Martin-Cora FJ, Fornal CA. Activity of medullary seroton- 383. Kernell D. The Motoneurone and Its Muscle fibres. Oxford: Oxford
ergic neurons in freely moving animals. Brain Res Brain Res Rev 40: University Press, 2006.
45-52, 2002. 384. Kernell D, Zwaagstra B. Input conductance axonal conduction velocity
354. Jankowska E. Interneuronal relay in spinal pathways from propriocep- and cell size among hindlimb motoneurones of the cat. Brain Res 204:
tors. Prog Neurobiol 38: 335-378, 1992. 311-326, 1981.
355. Jenny AB, Inukai J. Principles of motor organization of the monkey 385. Kernell D, Zwaagstra B. Size and remoteness: Two relatively indepen-
cervical spinal cord. J Neurosci 3: 567-575, 1983. dent parameters of dendrites, as studied for spinal motoneurones of the
356. Jesunathadas M, Marmon AR, Gibb JM, Enoka RM. Recruitment and cat. J Physiol 413: 233-254, 1989.
derecruitment characteristics of motor units in a hand muscle of young 386. Kidgell DJ, Sale MV, Semmler JG. Motor unit synchronization mea-
and old adults. J Appl Physiol 108: 1659-1667, 2010. sured by cross-correlation is not influenced by short-term strength train-
357. Jiang M, Schuster JE, Fu R, Siddique T, Heckman CJ. Progressive ing of a hand muscle. Exp Brain Res 175: 745-753, 2006.
changes in synaptic inputs to motoneurons in adult sacral spinal cord of 387. Kiehn O, Eken T. Prolonged firing in motor units: Evidence of plateau
a mouse model of amyotrophic lateral sclerosis. J Neurosci 29: 15031- potentials in human motoneurons? J Neurophysiol 78: 3061-3068,
15038, 2009. 1997.
358. Jiang MC, Heckman CJ. In vitro sacral cord preparation and mo- 388. Kilbreath SL, Gorman RB, Raymond J, Gandevia SC. Distribution of
toneuron recording from adult mice. J Neurosci Methods 156: 31-36, the forces produced by motor unit activity in the human flexor digitorum
2006. profundus. J Physiol 543: 289-296, 2002.
359. Johnson KV, Edwards SC, Van Tongeren C, Bawa P. Properties of 389. Kilner JM, Alonso-Alonso M, Fisher R, Lemon RN. Modulation of
human motor units after prolonged activity at a constant firing rate. Exp synchrony between single motor units during precision grip tasks in
Brain Res 154: 479-487, 2004. humans. J Physiol 541: 937-948, 2002.
360. Johnson MD, Heckman CJ. Interactions between focused synaptic in- 390. Kirkwood PA, Sears TA. The synaptic connexions to intercostal mo-
puts and diffuse neuromodulation in the spinal cord. Ann N Y Acad Sci toneurones as revealed by the average common excitation potential. J
1198: 35-41, 2010. Physiol 275: 103-134, 1978.

P1: OTA/XYZ P2: ABC
391. Klass M, Baudry S, Duchateau J. Age-related decline in rate of torque 417. Larkman PM, Kelly JS. Modulation of IH by 5-HT in neonatal rat mo-
development is accompanied by lower maximal motor unit discharge toneurones in vitro: Mediation through a phosphorylation independent
frequency during fast contractions. J Appl Physiol 104: 739-746, action of cAMP. Neuropharmacology 36: 721-733, 1997.
2008. 418. Larkum ME, Launey T, Dityatev A, Luscher HR. Integration of exci-
392. Klein CS, Häger-Ross CK, Thomas CK. Fatigue properties of human tatory postsynaptic potentials in dendrites of motoneurons of rat spinal
thenar motor units paralysed by chronic spinal cord injury. J Physiol cord slice cultures. J Neurophysiol 80: 924-935, 1998.
573: 161-171, 2006. 419. Larkum ME, Rioult MG, Luscher HR. Propagation of action poten-
393. Knight CA, Kamen G. Modulation of motor unit firing rates during a tials in the dendrites of neurons from rat spinal cord slice cultures. J
complex sinusoidal force task in young and older adults. J Appl Physiol Neurophysiol 75: 154-170, 1996.
102: 122-129, 2007. 420. Lateva ZC, McGill KC. Estimating motor-unit architectural properties
394. Knight CA, Kamen G. Relationships between voluntary activation and by analyzing motor-unit action potential morphology. Clin Neurophys-
motor unit firing rate during maximal voluntary contractions in young iol 112: 127-135, 2001.
and older adults. Eur J Appl Physiol 103: 625-630, 2008. 421. Lee RH, Heckman CJ. Adjustable amplification of synaptic input in
395. Kobayashi M, Inoue T, Matsuo R, Masuda Y, Hidaka O, Kang Y, the dendrites of spinal motoneurons in vivo. J Neurosci 20: 6734-6740,
Morimoto T. Role of calcium conductances on spike afterpotentials in 2000.
rat trigeminal motoneurons. J Neurophysiol 77: 3273-3283, 1997. 422. Lee RH, Heckman CJ. Bistability in spinal motoneurons in vivo: Sys-
396. Kosarov D, Gydikov A. Dependence of the discharge frequency of tematic variations in persistent inward currents. J Neurophysiol 80:
motor units in different human muscles upon the level of the iso- 583-593, 1998a.
metric muscle tension. Electromyogr Clin Neurophysiol 16: 293-306, 423. Lee RH, Heckman CJ. Bistability in spinal motoneurons in vivo: Sys-
1976. tematic variations in rhythmic firing patterns. J Neurophysiol 80: 572-
397. Kossev A, Christova P. Discharge pattern of human motor units dur- 582, 1998b.
ing dynamic concentric and eccentric contractions. Electroencephalogr 424. Lee RH, Heckman CJ. Enhancement of bistability in spinal motoneu-
Clin Neurophysiol 109: 245-255, 1998. rons in vivo by the noradrenergic alpha(1) agonist methoxamine. J
398. Kossev A, Elek JM, Wohlfarth K, Schubert M, Dengler R, Wolf W. Neurophysiol 81: 2164-2174, 1999.
Assessment of human motor unit twitches–a comparison of spike- 425. Lee RH, Heckman CJ. Essential role of a fast persistent inward current
triggered averaging and intramuscular microstimulation. Electroen- in action potential initiation and control of rhythmic firing. J Neuro-
cephalogr Clin Neurophysiol 93: 100-105, 1994. physiol 85: 472-475, 2001.
399. Krawitz S, Fedirchuk B, Dai Y, Jordan LM, McCrea DA. State- 426. Lee RH, Heckman CJ. Influence of voltage-sensitive dendritic conduc-
dependent hyperpolarization of voltage threshold enhances motoneu- tances on bistable firing and effective synaptic current in cat spinal
rone excitability during fictive locomotion in the cat. J Physiol 532: motoneurons in vivo. J Neurophysiol 76: 2107-2110, 1996.
271-281, 2001. 427. Lee RH, Heckman CJ. Paradoxical effect of QX-314 on persistent
400. Kudina LP, Alexeeva NL. After-potentials and control of repetitive inward currents and bistable behavior in spinal motoneurons in vivo. J
firing in human motoneurones. Electroenceph clin Neurophysiol 85: Neurophysiol 82: 2518-2527, 1999.
345-353, 1992a. 428. Lee RH, Kuo JJ, Jiang MC, Heckman CJ. Influence of active dendritic
401. Kudina LP, Alexeeva NL. Repetitive doublets of human motoneurones: currents on input-output processing in spinal motoneurons in vivo. J
Analysis of interspike intervals and recruitment pattern. Electroen- Neurophysiol 89: 27-39, 2003.
cephalogr Clin Neurophysiol 85: 243-247, 1992b. 429. Lepre M, Olpe HR, Brugger F. The effects of neurokinin-1 receptor ag-
402. Kudina LP, Andreeva RE. Repetitive doublet firing of motor units: onists on spinal motoneurones of the neonatal rat. Neuropharmacology
Evidence for plateau potentials in human motoneurones? Exp Brain 35: 511-522, 1996.
Res 204: 79-90, 2010. 430. Levenez M, Garland SJ, Klass M, Duchateau J. Cortical and spinal
403. Kugelberg E. Histochemical composition, contraction speed and fa- modulation of antagonist coactivation during a submaximal fatiguing
tiguability of rat soleus motor units. J Neurol Sci 20: 177-198, 1973. contraction in humans. J Neurophysiol 99: 554-563, 2008.
404. Kukulka CG, Clamann HP. Comparison of the recruitment and dis- 431. Levenez M, Kotzamanidis C, Carpentier A, Duchateau J. Spinal reflexes
charge properties of motor units in human brachial biceps and adductor and coactivation of ankle muscles during a submaximal fatiguing con-
pollicis during isometric contractions. Brain Res 219: 45-55, 1981. traction. J Appl Physiol 99: 1182-1188, 2005.
405. Kuo JJ, Lee RH, Johnson MD, Heckman HM, Heckman CJ. Active den- 432. Li X, Bennett DJ. Apamin-sensitive calcium-activated potassium cur-
dritic integration of inhibitory synaptic inputs in vivo. J Neurophysiol rents (SK) are activated by persistent calcium currents in rat motoneu-
90: 3617-3624, 2003. rons. J Neurophysiol 97: 3314-3330, 2007.
406. Kuo JJ, Lee RH, Zhang L, Heckman CJ. Essential role of the persistent 433. Li X, Murray K, Harvey PJ, Ballou EW, Bennett DJ. Serotonin fa-
sodium current in spike initiation during slowly rising inputs in mouse cilitates a persistent calcium current in motoneurons of rats with and
spinal neurones. J Physiol 574: 819-834, 2006. without chronic spinal cord injury. J Neurophysiol 97: 1236-1246, 2007.
407. Kuo JJ, Schonewille M, Siddique T, Schults ANA, Fu RG, Bar PR, 434. Li Y, Bennett DJ. Persistent sodium and calcium currents cause plateau
Anelli R, Heckman CJ, Kroese ABA. Hyperexcitability of cultured potentials in motoneurons of chronic spinal rats. J Neurophysiol 90:
spinal motoneurons from presymptomatic ALS mice. J Neurophysiol 857-869, 2003.
91: 571-575, 2004. 435. Li Y, Gorassini MA, Bennett DJ. Role of persistent sodium and calcium
408. Kuo JJ, Siddique T, Fu R, Heckman CJ. Increased persistent Na+ currents in motoneuron firing and spasticity in chronic spinal rats. J
current and its effect on excitability in motoneurones cultured from Neurophysiol 91: 767-783, 2004.
mutant SOD1 mice. J Physiol 563: 843-854, 2005. 436. Li Y, Harvey PJ, Li X, Bennett DJ. Spastic long-lasting reflexes of the
409. Kutch JJ, Kuo AD, Rymer WZ. Extraction of individual muscle me- chronic spinal rat studied in vitro. J Neurophysiol 91: 2236-2246, 2004.
chanical action from endpoint force. J Neurophysiol 103: 3535-3546, 437. Li Y, Li X, Harvey PJ, Bennett DJ. Effects of baclofen on spinal reflexes
2010. and persistent inward currents in motoneurons of chronic spinal rats
410. LaBella LA, Kehler JP, McCrea DA. A differential synaptic input to with spasticity. J Neurophysiol 92: 2694-2703, 2004.
the motor nuclei in triceps surae from the caudal and lateral cutaneous 438. Liddell EGT, Sherrington CS. Recruitment and some other factors of
sural nerves. J Neurophysiol 61: 291-301, 1989. reflex inhibition. Proc R Soc Lond Biol 97: 488-518, 1925.
411. Ladewig T, Lalley PM, Keller BU. Serotonergic modulation of intra- 439. Lindia JA, Abbadie C. Distribution of the voltage gated sodium channel
cellular calcium dynamics in neonatal hypoglossal motoneurons from Na(v)1.3-like immunoreactivity in the adult rat central nervous system.
mouse. Brain Res 1001: 1-12, 2004. Brain Res 960: 132-141, 2003.
412. Laidlaw DH, Bilodeau M, Enoka RM. Steadiness is reduced and motor 440. Lindsay AD, Binder MD. Distribution of effective synaptic currents
unit discharge is more variable in old adults. Muscle Nerve 23: 600-612, underlying recurrent inhibition in cat triceps surae motoneurons. J Neu-
2000. rophysiol 65: 168-177, 1991.
413. Lapatki BG, Oostenveld R, Van Dijk JP, Jonas IE, Zwarts MJ, Stege- 441. Lindsay AD, Feldman JL. Modulation of respiratory activity of neonatal
man DF. Topographical characteristics of motor units of the lower rat phrenic motoneurones by serotonin. J Physiol 461: 213-233, 1993.
facial musculature revealed by means of high-density surface EMG. J 442. Lowery MM, Myers LJ, Erim Z. Coherence between motor unit dis-
Neurophysiol 95: 342-354, 2006. charges in response to shared neural inputs. J Neurosci Methods 163:
414. Lape R, Nistri A. Voltage-activated K+ currents of hypoglossal mo- 384-391, 2007.
toneurons in a brain stem slice preparation from the neonatal rat. J 443. Lucas SM, Ruff RL, Binder MD. Specific tension measurements in
Neurophysiol 81: 140-148, 1999. single soleus and medial gastrocnemius muscle fibers of the cat. Exp
415. Lape R, Nistri A. Current and voltage clamp studies of the spike medium Neurol 95: 142-154, 1987.
afterhyperpolarization of hypoglossal motoneurons in a rat brain stem 444. Luscher HR, Larkum ME. Modeling action potential initiation and
slice preparation. J Neurophysiol 83: 2987-2995, 2000. back-propagation in dendrites of cultured rat motoneurons. J Neuro-
416. Larkman PM, Kelly JS. Ionic mechanisms mediating 5- physiol 80: 715-729, 1998.
hydroxytryptamine- and noradrenaline-evoked depolarization of adult 445. Maas H, Prilutsky BI, Nichols TR, Gregor RJ. The effects of self-
rat facial motoneurones. J Physiol 456: 473-490, 1992. reinnervation of cat medial and lateral gastrocnemius muscles on

P1: OTA/XYZ P2: ABC
hindlimb kinematics in slope walking. Exp Brain Res 181: 377-393, 471. McComas AJ, Fawcett PR, Campbell MJ, Sica RE. Electrophysiologi-
2007. cal estimation of the number of motor units within a human muscle. J
446. Maas H, Sandercock TG. Are skeletal muscles independent actuators? Neurol Neurosurg Psychiatry 34: 121-131, 1971.
Force transmission from soleus muscle in the cat. J Appl Physiol 104: 472. McCrea DA, Rybak IA. Organization of mammalian locomotor rhythm
1557-1567, 2008. and pattern generation. Brain Res Rev 57: 134-146, 2008.
447. MacDermid V, Neuber-Hess M, Short C, Rose PK. Alterations to neu- 473. McIsaac TL, Fuglevand AJ. Common synaptic input across motor nu-
ronal polarity following permanent axotomy: A quantitative analysis clei supplying intrinsic muscles involved in the precision grip. Exp
of changes to MAP2a/b and GAP-43 distributions in axotomized mo- Brain Res 188: 159-164, 2008.
toneurons in the adult cat. J Comp Neurol 450: 318-333, 2002. 474. McLarnon JG. Inactivation of a high conductance calcium dependent
448. MacDermid VE, Neuber-Hess MS, Rose PK. The temporal sequence of potassium current in rat hippocampal neurons. Neurosci Lett 193: 5-8,
morphological and molecular changes in axotomized feline motoneu- 1995a.
rons leading to the formation of axons from the ends of dendrites. J 475. McLarnon JG. Potassium currents in motoneurones. Prog Neurobiol
Comp Neurol 468: 233-250, 2004. 47: 513-531, 1995b.
449. Macdonell CW, Ivanova TD, Garland SJ. Afterhyperpolarization time- 476. McNulty PA, Cresswell AG. Recruitment of single human low-
course and minimal discharge rate in low threshold motor units in threshold motor units with increasing loads at different muscle lengths.
humans. Exp Brain Res 189: 23-33, 2008. J Electromyogr Kinesiol 14: 369-377, 2004.
450. MacDonell CW, Ivanova TD, Garland SJ. Reliability of the interval 477. McNulty PA, Falland KJ, Macefield VG. Comparison of contractile
death rate analysis for estimating the time course of the motoneurone properties of single motor units in human intrinsic and extrinsic finger
afterhyperpolarization in humans. J Neurosci Methods 162: 314-319, muscles. J Physiol 526(Pt 2): 445-456, 2000.
2007. 478. Meehan CF, MacDermid VE, Montague SJ, Neuber-Hess M, Rose
451. MacDonell CW, Ivanova TD, Garland SJ. Changes in the estimated time PK. Dendrite-derived supernumerary axons on adult axotomized motor
course of the motoneuron afterhyperpolarization induced by tendon neurons possess proteins that are essential for the initiation and propa-
vibration. J Neurophysiol 104: 3240-3249, 2010. gation of action potentials and synaptic vesicle release. J Neurosci 31:
452. Macefield VG, Fuglevand AJ, Bigland-Ritchie B. Contractile properties 6732-6740, 2011.
of single motor units in human toe extensors assessed by intraneural 479. Meehan CF, Sukiasyan N, Zhang M, Nielsen JB, Hultborn H. Intrin-
motor axon stimulation. J Neurophysiol 75: 2509-2519, 1996. sic properties of mouse lumbar motoneurons revealed by intracellular
453. Macefield VG, Fuglevand AJ, Howell JN, Bigland-Ritchie B. Discharge recording in vivo. J Neurophysiol 103: 2599-2610, 2010.
behaviour of single motor units during maximal voluntary contractions 480. Merletti R, Holobar A, Farina D. Analysis of motor units with high-
of a human toe extensor. J Physiol 528(Pt 1): 227-234, 2000. density surface electromyography. J Electromyogr Kinesiol 18: 879-
454. Major LA, Jones KE. Simulations of motor unit number estimation 890, 2008.
techniques. J Neural Eng 2: 17-34, 2005. 481. Mesin L, Damiano L, Farina D. Estimation of average muscle fiber
455. Maltenfort MG, McCurdy ML, Phillips CA, Turkin VV, Hamm TM. conduction velocity from simulated surface EMG in pinnate muscles.
Location and magnitude of conductance changes produced by Renshaw J Neurosci Methods 160: 327-334, 2007.
recurrent inhibition in spinal motoneurons. J Neurophysiol 92: 1417- 482. Miles GB, Dai Y, Brownstone RM. Mechanisms underlying the early
1432, 2004. phase of spike frequency adaptation in mouse spinal motoneurones. J
456. Manning CD, Miller TA, Burnham ML, Murnaghan CD, Calancie B, Physiol 566: 519-532, 2005.
Bawa P. Recovery of human motoneurons during rotation. Exp Brain 483. Miles GB, Hartley R, Todd AJ, Brownstone RM. Spinal cholinergic in-
Res 204: 139-144, 2010. terneurons regulate the excitability of motoneurons during locomotion.
457. Mantilla CB, Rowley KL, Zhan WZ, Fahim MA, Sieck GC. Synaptic Proc Natl Acad Sci U S A 104: 2448-2453, 2007.
vesicle pools at diaphragm neuromuscular junctions vary with motoneu- 484. Miles GB, Lipski J, Lorier AR, Laslo P, Funk GD. Differential expres-
ron soma, not axon terminal, inactivity. Neuroscience 146: 178-189, sion of voltage-activated calcium channels in III and XII motoneurones
2007. during development in the rat. Eur J Neurosci 20: 903-913, 2004.
458. Manuel M. (Unpublished observations). 485. Miles GB, Parkis MA, Lipski J, Funk GD. Modulation of phrenic
459. Manuel M, Iglesias C, Donnet M, Leroy F, Heckman CJ, Zytnicki D. motoneuron excitability by ATP: Consequences for respiratory-related
Fast kinetics, high-frequency oscillations, subprimary firing range in output in vitro. J Appl Physiol 92: 1899-1910, 2002.
adult mouse spinal motoneurons. J Neurosci 29: 11246-11256, 2009. 486. Miller JF, Paul KD, Lee RH, Rymer WZ, Heckman CJ. Restoration of
460. Manuel M, Meunier C, Donnet M, Zytnicki D. How much afterhyperpo- extensor excitability in the acute spinal cat by the 5-HT2 agonist DOI.
larization conductance is recruited by an action potential? A dynamic- J Neurophysiol 75: 620-628, 1996.
clamp study in cat lumbar motoneurons. J Neurosci 25: 8917-8923, 487. Milligan CJ, Edwards IJ, Deuchars J. HCN1 ion channel immunore-
2005. activity in spinal cord and medulla oblongata. Brain Res 1081: 79-91,
461. Manuel M, Meunier C, Donnet M, Zytnicki D. Resonant or not, two am- 2006.
plification modes of proprioceptive inputs by persistent inward currents 488. Milner-Brown HS, Stein RB, Yemm R. Changes in firing rate of human
in spinal motoneurons. J Neurosci 27: 12977-12988, 2007. motor units during linearly changing voluntary contractions. J Physiol
462. Marchetti C, Taccola G, Nistri A. Distinct subtypes of group I 230: 371-390, 1973a.
metabotropic glutamate receptors on rat spinal neurons mediate com- 489. Milner-Brown HS, Stein RB, Yemm R. The contractile properties of
plex facilitatory and inhibitory effects. Eur J Neurosci 18: 1873-1883, human motor units during voluntary isometric contractions. J Physiol
2003. 228: 285-306, 1973b.
463. Marks JD, Donnelly DF, Haddad GG. Adenosine-induced inhibition of 490. Milner-Brown HS, Stein RB, Yemm R. The orderly recruitment of
vagal motoneuron excitability: Receptor subtype and mechanisms. Am human motor units during voluntary isometric contractions. J Physiol
J Physiol 264: L124-L132, 1993. 230: 359-370, 1973c.
464. Marsden CD, Meadows JC, Merton PA. “Muscular wisdom” that mini- 491. Minetto MA, Holobar A, Botter A, Farina D. Discharge properties of
mizes fatigue during prolonged effort in man: Peak rates of motoneuron motor units of the abductor hallucis muscle during cramp contractions.
discharge and slowing of discharge during fatigue. Adv Neurol 39: 169- J Neurophysiol 102: 1890-1901, 2009.
211, 1983. 492. Mochizuki G, Ivanova TD, Garland SJ. Factors affecting the common
465. Masakado Y, Noda Y, Nagata MA, Kimura A, Chino N, Akaboshi modulation of bilateral motor unit discharge in human soleus muscles.
K. Macro-EMG and motor unit recruitment threshold: Differences be- J Neurophysiol 97: 3917-3925, 2007.
tween the young and the aged. Neurosci Lett 179: 1-4, 1994. 493. Mongan LC, Hill MJ, Chen MX, Tate SN, Collins SD, Buckby L,
466. Maton B. Fast and slow motor units: Their recruitment for tonic and Grubb BD. The distribution of small and intermediate conductance
phasic contraction in normal man. Eur J Appl Physiol Occup Physiol calcium-activated potassium channels in the rat sensory nervous system.
43: 45-55, 1980. Neuroscience 131: 161-175, 2005.
467. Mattei B, Schmied A, Mazzocchio R, Decchi B, Rossi A, Vedel JP. 494. Monster AW, Chan H. Isometric force production by motor units of
Pharmacologically induced enhancement of recurrent inhibition in hu- extensor digitorum communis muscle in man. J Neurophysiol 40: 1432-
mans: Effects on motoneurone discharge patterns. J Physiol 548: 615- 1443, 1977.
629, 2003. 495. Monti RJ, Roy RR, Edgerton VR. Role of motor unit structure in
468. Matthews PB. Relationship of firing intervals of human motor units to defining function. Muscle Nerve 24: 848-866, 2001.
the trajectory of post-spike after-hyperpolarization and synaptic noise. 496. Monti RJ, Roy RR, Hodgson JA, Edgerton VR. Transmission of forces
J Physiol 492: 597-628, 1996. within mammalian skeletal muscles. J Biomech 32: 371-380, 1999.
469. Maxwell L, Maxwell DJ, Neilson M, Kerr R. A confocal microscopic 497. Moore J, Appenteng K. The membrane properties and firing charac-
survey of serotoninergic axons in the lumbar spinal cord of the rat: teristics of rat jaw-elevator motoneurones. J Physiol 423: 137-153,
Co-localization with glutamate decarboxylase and neuropeptides. Neu- 1990.
roscience 75: 471-480, 1996. 498. Morgan DL, Whitehead NP, Wise AK, Gregory JE, Proske U. Tension
470. McComas AJ. Motor unit estimation: Anxieties and achievements. changes in the cat soleus muscle following slow stretch or shortening
Muscle Nerve 18: 369-379, 1995. of the contracting muscle. J Physiol 522(Pt 3): 503-513, 2000.

P1: OTA/XYZ P2: ABC
499. Moritz AT, Newkirk G, Powers RK, Binder MD. Facilitation of somatic 526. Pascoe MA, Holmes MR, Enoka RM. Discharge characteristics of bi-
calcium channels can evoke prolonged tail currents in rat hypoglossal ceps brachii motor units at recruitment when older adults sustained an
motoneurons. J Neurophysiol 98: 1042-1047, 2007. isometric contraction. J Neurophysiol 105: 571-581, 2011.
500. Moritz CT, Barry BK, Pascoe MA, Enoka RM. Discharge rate vari- 527. Pasquet B, Carpentier A, Duchateau J. Change in muscle fascicle length
ability influences the variation in force fluctuations across the working influences the recruitment and discharge rate of motor units during
range of a hand muscle. J Neurophysiol 93: 2449-2459, 2005. isometric contractions. J Neurophysiol 94: 3126-3133, 2005.
501. Mottram CJ, Jakobi JM, Semmler JG, Enoka RM. Motor-unit activity 528. Pasquet B, Carpentier A, Duchateau J. Specific modulation of motor
differs with load type during a fatiguing contraction. J Neurophysiol unit discharge for a similar change in fascicle length during shortening
93: 1381-1392, 2005. and lengthening contractions in humans. J Physiol 577: 753-765, 2006.
502. Mottram CJ, Suresh NL, Heckman CJ, Gorassini MA, Rymer WZ. 529. Patten C, Kamen G. Adaptations in motor unit discharge activity with
Origins of abnormal excitability in biceps brachii motoneurons of force control training in young and older human adults. Eur J Appl
spastic-paretic stroke survivors. J Neurophysiol 102: 2026-2038, Physiol 83: 128-143, 2000.
2009. 530. Perreault EJ, Day SJ, Hulliger M, Heckman CJ, Sandercock TG. Sum-
503. Mottram CJ, Wallace CL, Chikando CN, Rymer WZ. Origins of spon- mation of forces from multiple motor units in the cat soleus muscle. J
taneous firing of motor units in the spastic-paretic biceps brachii muscle Neurophysiol 89: 738-744, 2003.
of stroke survivors. J Neurophysiol 104: 3168-3179, 2010. 531. Perreault MC. Motoneurons have different membrane resistance during
504. Muennich EA, Fyffe RE. Focal aggregation of voltage-gated, Kv2.1 fictive scratching and weight support. J Neurosci 22: 8259-8265, 2002.
subunit-containing, potassium channels at synaptic sites in rat spinal 532. Perrier JF, Alaburda A, Hounsgaard J. Spinal plasticity mediated by
motoneurones. J Physiol 554: 673-685, 2004. postsynaptic L-type Ca2 + channels. Brain Res Brain Res Rev 40: 223-
505. Munson JB, Foehring RC, Lofton SA, Zengel JE, Sypert GW. Plasticity 229, 2002.
of medial gastrocnemius motor units following cordotomy in the cat. J 533. Perrier JF, Alaburda A, Hounsgaard J. 5-HT1A receptors increase ex-
Neurophysiol 55: 619-634, 1986. citability of spinal motoneurons by inhibiting a TASK-1-like K+ current
506. Murray KC, Nakae A, Stephens MJ, Rank M, D’Amico J, Harvey PJ, in the adult turtle. J Physiol 548: 485-492, 2003.
Li X, Harris RL, Ballou EW, Anelli R, Heckman CJ, Mashimo T, 534. Perrier JF, Hounsgaard J. 5-HT(2) receptors promote plateau potentials
Vavrek R, Sanelli L, Gorassini MA, Bennett DJ, Fouad K. Recovery of in turtle spinal motoneurons by facilitating an L-type calcium current.
motoneuron and locomotor function after spinal cord injury depends J Neurophysiol 89: 954-959, 2003.
on constitutive activity in 5-HT2C receptors. Nat Med 16: 694-700, 535. Person RS, Kudina LP. Discharge frequency and discharge pattern of
2010. human motor units during voluntary contraction of muscle. Electroen-
507. Mynlieff M, Beam KG. Adenosine acting at an A1 receptor decreases cephalogr Clin Neurophysiol 32: 471-483, 1972.
N-type calcium current in mouse motoneurons. J Neurosci 14: 3628- 536. Peshori KR, Collins WF, Mendell LM. EPSP amplitude modulation
3634, 1994. at the rat Ia-alpha motoneuron synapse: Effects of GABAB receptor
508. Nardone A, Romano C, Schieppati M. Selective recruitment of high- agonists and antagonists. J Neurophysiol 79: 181-189, 1998.
threshold human motor units during voluntary isotonic lengthening of 537. Peters EJ, Fuglevand AJ. Cessation of human motor unit discharge
active muscle. J Physiol 409: 451-471, 1989. during sustained maximal voluntary contraction. Neurosci Lett 274:
509. Nardone A, Schieppati M. Shift of activity from slow to fast muscle 66-70, 1999.
during voluntary lengthening contractions of the triceps surae muscles 538. Peters SE. Structure and function in vertebrate skeletal-muscle. Am
in humans. J Physiol 395: 363-381, 1988. Zool 29: 221-234, 1989.
510. Negro F, Holobar A, Farina D. Fluctuations in isometric muscle force 539. Petit J, Chua M, Hunt CC. Maximum shortening speed of motor units
can be described by one linear projection of low-frequency components of various types in cat lumbrical muscles. J Neurophysiol 69: 442-448,
of motor unit discharge rates. J Physiol 587: 5925-5938, 2009. 1993.
511. Nguyen Q-T, Wessel R, Kleinfeld D. Developmental regulation of ac- 540. Petit J, Filippi GM, Emonet-Denand F, Hunt CC, Laporte Y. Changes in
tive and passive membrane properties in rat vibrissa motoneurones. J muscle stiffness produced by motor units of different types in peroneus
Physiol 556: 203-219, 2004. longus muscle of cat. J Neurophysiol 63: 190-197, 1990.
512. Nichols DE, Nichols CD. Serotonin receptors. Chem Rev 108: 1614- 541. Petit J, Giroux-Metges MA, Gioux M. Power developed by motor units
1641, 2008. of the peroneus tertius muscle of the cat. J Neurophysiol 90: 3095-3104,
513. Nichols TR, Cope TC, Abelew TA. Rapid spinal mechanisms of motor 2003.
coordination. Ex Sport Sci Rev 27: 255-284, 1999. 542. Pettersen V, Bjorkoy K, Torp H, Westgaard RH. Neck and shoulder
514. Nishimura Y, Schwindt PC, Crill WE. Electrical properties of facial muscle activity and thorax movement in singing and speaking tasks
motoneurons in brainstem slices from guinea pig. Brain Res 502: 127- with variation in vocal loudness and pitch. J Voice 19: 623-634, 2005.
142, 1989. 543. Pieri M, Carunchio I, Curcio L, Mercuri NB, Zona C. Increased per-
515. Nordstrom MA, Fuglevand AJ, Enoka RM. Estimating the strength of sistent sodium current determines cortical hyperexcitability in a ge-
common input to human motoneurons from the cross-correlogram. J netic model of amyotrophic lateral sclerosis. Exp Neurol 215: 368-379,
Physiol 453: 547-574, 1992. 2009.
516. Nordstrom MA, Miles TS, Veale JL. Effect of motor unit firing pattern 544. Pinter MJ, Vanden Noven S, Muccio D, Wallace N. Axotomy-like
on twitches obtained by spike-triggered averaging. Muscle Nerve 12: changes in cat motoneuron electrical properties elicited by botulinum
556-567, 1989. toxin depend on the complete elimination of neuromuscular transmis-
517. Norton JA, Bennett DJ, Knash ME, Murray KC, Gorassini MA. sion. J Neurosci 11: 657-666, 1991.
Changes in sensory-evoked synaptic activation of motoneurons after 545. Poliakov AV, Powers RK, Binder MD. Functional identification of the
spinal cord injury in man. Brain 131: 1478-1491, 2008. input-output transforms of motoneurones in the rat and cat. J Physiol
518. Notomi T, Shigemoto R. Immunohistochemical localization of Ih chan- 504(Pt 2): 401-424, 1997.
nel subunits, HCN1-4, in the rat brain. J Comp Neurol 471: 241-276, 546. Poliakov AV, Powers RK, Sawczuk A, Binder MD. Effects of back-
2004. ground noise on the response of rat and cat motoneurones to excitatory
519. Ounjian M, Roy RR, Eldred E, Garfinkel A, Payne JR, Armstrong A, current transients. J Physiol 495(Pt 1): 143-157, 1996.
Toga AW, Edgerton VR. Physiological and developmental implications 547. Porter CL, Alvarez A, Jones KE, Ming Chan K. Test–retest reliability of
of motor unit anatomy. J Neurobiol 22: 547-559, 1991. a modified multiple point stimulation technique for motor unit number
520. Oya T, Riek S, Cresswell AG. Recruitment and rate coding organisation estimation. Clin Neurophysiol 119: 2287-2290, 2008.
for soleus motor units across entire range of voluntary isometric plantar 548. Power KE, McCrea DA, Fedirchuk B. Intraspinally mediated state-
flexions. J Physiol 587: 4737-4748, 2009. dependent enhancement of motoneurone excitability during fictive
521. Pambo-Pambo A, Durand J, Gueritaud JP. Early excitability changes in scratch in the adult decerebrate cat. J Physiol 588: 2839-2857, 2010.
lumbar motoneurons of transgenic SOD1G85R and SOD1G(93A-Low) 549. Powers RK. A variable-threshold motoneuron model that incorporates
mice. J Neurophysiol 102: 3627-3642, 2009. time- and voltage-dependent potassium and calcium conductances. J
522. Pan Z, Kao T, Horvath Z, Lemos J, Sul J-Y, Cranstoun SD, Bennett Neurophysiol 70: 246-262, 1993.
V, Scherer SS, Cooper EC. A common ankyrin-G-based mechanism 550. Powers RK, Binder MD. Determination of afferent fibers mediating
retains KCNQ and NaV channels at electrically active domains of the oligosynaptic group I input to cat medial gastrocnemius motoneurons.
axon. J Neurosci 26: 2599-2613, 2006. J Neurophysiol 53: 518-529, 1985a.
523. Parkis MA, Bayliss DA, Berger AJ. Actions of norepinephrine on rat 551. Powers RK, Binder MD. Distribution of oligosynaptic group I input
hypoglossal motoneurons. J Neurophysiol 74: 1911-1919, 1995. to the cat medial gastrocnemius motoneuron pool. J Neurophysiol 53:
524. Parkis MA, Berger AJ. Clonidine reduces hyperpolarization-activated 497-517, 1985b.
inward current (Ih) in rat hypoglossal motoneurons. Brain Res 769: 552. Powers RK, Binder MD. Effects of low-frequency stimulation on the
108-118, 1997. tension-frequency relations of fast-twitch motor units in the cat. J Neu-
525. Partridge LD, Benton LA. Muscle, the motor. In: Brooks VB, edi- rophysiol 66: 905-918, 1991.
tor. Handbook of Physiology, The Nervous System, Motor Control. 553. Powers RK, Binder MD. Input-output functions of mammalian mo-
Bethesda, MD: American Physiological Society, 1981, pp. 43-106. toneurons. Rev Physiol Biochem Pharmacol 143: 137-263, 2001.

P1: OTA/XYZ P2: ABC
554. Powers RK, Binder MD. Persistent sodium and calcium currents in rat 582. Roatta S, Arendt-Nielsen L, Farina D. Sympathetic-induced changes
hypoglossal motoneurons. J Neurophysiol 89: 615-624, 2003. in discharge rate and spike-triggered average twitch torque of low-
555. Powers RK, Binder MD. Relationship between the time course of the threshold motor units in humans. J Physiol 586: 5561-5574, 2008.
afterhyperpolarization and discharge variability in cat spinal motoneu- 583. Roatta S, Farina D. Sympathetic actions on the skeletal muscle. Exerc
rones. J Physiol 528(Pt 1): 131-150, 2000. Sport Sci Rev 38: 31-35, 2010.
556. Powers RK, Binder MD. Summation of effective synaptic currents and 584. Romaiguere P, Vedel JP, Pagni S. Comparison of fluctuations of motor
firing rate modulation in cat spinal motoneurons. J Neurophysiol 83: unit recruitment and de-recruitment thresholds in man. Exp Brain Res
483-500, 2000. 95: 517-522, 1993.
557. Powers RK, Binder MD. Summation of motor unit tensions in the 585. Rose PK, Cushing S, Grande G, Bui T. Functional diversity of mo-
tibialis posterior muscle of the cat under isometric and nonisometric toneuron dendrites: By accident or design? Arch Ital Biol 145: 175-191,
conditions. J Neurophysiol 66: 1838-1846, 1991. 2007.
558. Powers RK, Dai Y, Bell BM, Percival DB, Binder MD. Contributions of 586. Rose PK, Vanner SJ. Differences in somatic and dendritic specific
the input signal and prior activation history to the discharge behaviour membrane resistivity of spinal motoneurons: An electrophysiological
of rat motoneurones. J Physiol 562: 707-724, 2005. study of neck and shoulder motoneurons in the cat. J Neurophysiol 60:
559. Powers RK, Nardelli P, Cope TC. Estimation of the contribution of 149-166, 1988.
intrinsic currents to motoneuron firing based on paired motoneuron 587. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A,
discharge records in the decerebrate cat. J Neurophysiol 100: 292-303, Donaldson D, Goto J, O’Regan JP, Deng HX, et al. Mutations in Cu/Zn
2008. superoxide dismutase gene are associated with familial amyotrophic
560. Powers RK, Robinson FR, Konodi MA, Binder MD. Distribution of lateral sclerosis. Nature 362: 59-62, 1993.
rubrospinal synaptic input to cat triceps surae motoneurons. J Neuro- 588. Ross KT, Nichols TR. Heterogenic feedback between hindlimb exten-
physiol 70: 1460-1468, 1993. sors in the spontaneously locomoting premammillary cat. J Neurophys-
561. Powers RK, Türker KS. Deciphering the contribution of intrinsic and iol 101: 184-197, 2009.
synaptic currents to the effects of transient synaptic inputs on human 589. Rothstein JD. Current hypotheses for the underlying biology of amy-
motor unit discharge. Clin Neurophysiol 121: 1643-1654, 2010. otrophic lateral sclerosis. Ann Neurol 65(Suppl 1): S3-9, 2009.
562. Powers RK, Türker KS, Binder MD. What can be learned about mo- 590. Rothstein JD. Excitotoxicity hypothesis. Neurology 47: S19-S25; dis-
toneurone properties from studying firing patterns? Adv Exp Med Biol cussion S26, 1996.
508: 199-205, 2002. 591. Roukoz S, Naccache N, Sleilaty G. The role of the musculocutaneous
563. Prather JF, Clark BD, Cope TC. Firing rate modulation of motoneurons and radial nerves in elbow flexion and forearm supination: A biome-
activated by cutaneous and muscle receptor afferents in the decerebrate chanical study. J Hand Surg Eur 33: 201-204, 2008.
cat. J Neurophysiol 88: 1867-1879, 2002. 592. Routal RV, Pal GP. A study of motoneuron groups and motor columns
564. Prather JF, Powers RK, Cope TC. Amplification and linear summation of the human spinal cord. J Anat 195(Pt 2): 211-224, 1999.
of synaptic effects on motoneuron firing rate. J Neurophysiol 85: 43-53, 593. Rubinstein S, Kamen G. Decreases in motor unit firing rate during sus-
2001. tained maximal-effort contractions in young and older adults. J Elec-
565. Price SR, De Marco Garcia NV, Ranscht B, Jessell TM. Regulation tromyogr Kinesiol 15: 536-543, 2005.
of motor neuron pool sorting by differential expression of type II cad- 594. Rudomin P. Selectivity of the central control of sensory information in
herins. Cell 109: 205-216, 2002. the mammalian spinal cord. Adv Exp Med Biol 508: 157-170, 2002.
566. Pun S, Santos AF, Saxena S, Xu L, Caroni P. Selective vulnerability and 595. Rudroff T, Jordan K, Enoka JA, Matthews SD, Baudry S, Enoka RM.
pruning of phasic motoneuron axons in motoneuron disease alleviated Discharge of biceps brachii motor units is modulated by load compli-
by CNTF. Nat Neurosci 9: 408-419, 2006. ance and forearm posture. Exp Brain Res 202: 111-120, 2010.
567. Rack PMH, Westbury DR. The effects of length and stimulus rate on 596. Ruff RL. Neurophysiology of the neuromuscular junction: Overview.
tension in the isometric cat soleus muscle. J Physiol 204: 443-460, Ann N Y Acad Sci U S A 998: 1-10, 2003.
1969. 597. Ruigrok TJ, Crowe A. The organization of motoneurons in the turtle
568. Rafuse VF, Gordon T. Self-reinnervated cat medial gastrocnemius lumbar spinal cord. J Comp Neurol 228: 24-37, 1984.
muscles. II. Analysis of the mechanisms and significance of fiber 598. Ryan JM, Cushman J, Jordan B, Samuels A, Frazer H, Baier C. Topo-
type grouping in reinnervated muscles. J Neurophysiol 75: 282-297, graphic position of forelimb motoneuron pools is conserved in verte-
1996. brate evolution. Brain Behav Evol 51: 90-99, 1998.
569. Rafuse VF, Pattullo MC, Gordon T. Innervation ratio and motor unit 599. Saboisky JP, Butler JE, Fogel RB, Taylor JL, Trinder JA, White DP,
force in large muscles: A study of chronically stimulated cat medial Gandevia SC. Tonic and phasic respiratory drives to human genioglos-
gastrocnemius. J Physiol 499(Pt 3): 809-823, 1997. sus motoneurons during breathing. J Neurophysiol 95: 2213-2221,
570. Rank MM, Li X, Bennett DJ, Gorassini MA. Role of endogenous release 2006.
of norepinephrine in muscle spasms after chronic spinal cord injury. J 600. Safronov BV, Vogel W. Single voltage-activated Na+ and K+ channels
Neurophysiol 97: 3166-3180, 2007. in the somata of rat motoneurones. J Physiol 487: 91-106, 1995.
571. Rank MM, Murray KC, Stephens MJ, D’Amico J, Gorassini MA, Ben- 601. Sah P, McLachlan EM. Potassium currents contributing to action po-
nett DJ. Adrenergic receptors modulate motoneuron excitability, sen- tential repolarization and the afterhyperpolarization in rat vagal mo-
sory synaptic transmission and muscle spasms after chronic spinal cord toneurons. J Neurophysiol 68: 1834-1841, 1992.
injury. J Neurophysiol 105: 410-422, 2011. 602. Sandercock TG. Nonlinear summation of force in cat soleus muscle
572. Rekling JC. Excitatory effects of thyrotropin-releasing hormone (TRH) results primarily from stretch of the common-elastic elements. J Appl
in hypoglossal motoneurons. Brain Res 510: 175-179, 1990. Physiol 89: 2206-2214, 2000.
573. Rekling JC, Champagnat J, Denavit-Saubié M. Electroresponsive prop- 603. Sandercock TG. Nonlinear summation of force in cat tibialis anterior:
erties and membrane potential trajectories of three types of inspiratory A muscle with intrafascicularly terminating fibers. J Appl Physiol 94:
neurons in the newborn mouse brain stem in vitro. J Neurophysiol 75: 1955-1963, 2003.
795-810, 1996. 604. Sandercock TG. Summation of motor unit force in passive and active
574. Rekling JC, Funk GD, Bayliss DA, Dong XW, Feldman JL. Synap- muscle. Exerc Sport Sci Rev 33: 76-83, 2005.
tic control of motoneuronal excitability. Physiol Rev 80: 767-852, 605. Sandercock TG, Heckman CJ. Force from cat soleus muscle during
2000. imposed locomotor-like movements: Experimental data versus hill-type
575. Richardson PA, Bailey EF. Tonically discharging genioglossus motor model predictions. J Neurophysiol 77: 1538-1552, 1997.
units show no evidence of rate coding with hypercapnia. J Neurophysiol 606. Sandercock TG, Maas H. Force summation between muscles: Are
103: 1315-1321, 2010. muscles independent actuators? Med Sci Sports Exerc 41: 184-190,
576. Richer P. Note sur la contraction du muscle quadriceps dans l’acte de 2009.
donner un coup de pied. Société de Biologie 47: 204-205, 1895. 607. Santello M, Fuglevand AJ. Role of across-muscle motor unit synchrony
577. Ridall PG, Pettitt AN, Henderson RD, McCombe PA. Motor unit num- for the coordination of forces. Exp Brain Res 159: 501-508, 2004.
ber estimation–a Bayesian approach. Biometrics 62: 1235-1250, 2006. 608. Sasaki M. Membrane properties of external urethral and external anal
578. Riek S, Bawa P. Recruitment of motor units in human forearm exten- sphincter motoneurones in the cat. J Physiol 440: 345-366, 1991.
sors. J Neurophysiol 68: 100-108, 1992. 609. Schiaffino S, Reggiani C. Molecular diversity of myofibrillar proteins:
579. Riley ZA, Baudry S, Enoka RM. Reflex inhibition in human biceps Gene regulation and functional significance. Physiol Rev 76: 371-423,
brachii decreases with practice of a fatiguing contraction. J Neurophys- 1996.
iol 100: 2843-2851, 2008. 610. Schieber MH, Rivlis G. A spectrum from pure post-spike effects to
580. Riley ZA, Maerz AH, Litsey JC, Enoka RM. Motor unit recruitment in synchrony effects in spike-triggered averages of electromyographic ac-
human biceps brachii during sustained voluntary contractions. J Physiol tivity during skilled finger movements. J Neurophysiol 94: 3325-3341,
586: 2183-2193, 2008. 2005.
581. Rivera-Arconada I, Lopez-Garcia JA. Effects of M-current modulators 611. Schlue WR, Richter DW, Mauritz KH, Nacimiento AC. Accomoda-
on the excitability of immature rat spinal sensory and motor neurones. tion and Na-inactivation in cat spinal motor neurons. Pflugers Arch
Eur J Neurosci 22: 3091-3098, 2005. 332(Suppl 332): R383, 1972.

P1: OTA/XYZ P2: ABC
612. Schmidt BJ, Jordan LM. The role of serotonin in reflex modulation and 641. Sokoloff AJ, Siegel SG, Cope TC. Recruitment order among motoneu-
locomotor rhythm production in the mammalian spinal cord. Brain Res rons from different motor nuclei. J Neurophysiol 81: 2485-2492, 1999.
Bull 53: 689-710, 2000. 642. Spalloni A, Albo F, Ferrari F, Mercuri N, Bernardi G, Zona C,
613. Schmied A, Pagni S, Sturm H, Vedel JP. Selective enhancement of mo- Longone P. Cu/Zn-superoxide dismutase (GLY93-->ALA) mutation
toneurone short-term synchrony during an attention-demanding task. alters AMPA receptor subunit expression and function and potentiates
Exp Brain Res 133: 377-390, 2000. kainate-mediated toxicity in motor neurons in culture. Neurobiol Dis
614. Schmied A, Vedel JP, Pagni S. Human spinal lateralization assessed 15: 340-350, 2004.
from motoneurone synchronization: Dependence on handedness and 643. Stålberg E, Chu J, Bril V, Nandedkar S, Stalberg S, Ericsson M. Au-
motor unit type. J Physiol 480(Pt 2): 369-387, 1994. tomatic analysis of the EMG interference pattern. Electroencephalogr
615. Schwindt P, Crill WE. A persistent negative resistance in cat lumbar Clin Neurophysiol 56: 672-681, 1983.
motoneurons. Brain Res 120: 173-178, 1977. 644. Stein RB, French AS, Mannard A, Yemm R. New methods for analyzing
616. Schwindt PC, Crill WE. Properties of a persistent inward current in motor function in man and animals. Brain Res 40: 187-192, 1972.
normal and TEA-injected motoneurons. J Neurophysiol 43: 1700-1724, 645. Stein RB, Gossen ER, Jones KE. Neuronal variability: Noise or part of
1980a. the signal? Nat Rev Neurosci 6: 389-397, 2005.
617. Schwindt PC, Crill WE. Role of a persistent inward current in motoneu- 646. Stein RB, Yang JF. Methods for estimating the number of motor units
ron bursting during spinal seizures. J Neurophysiol 43: 1296-1318, in human muscles. Ann Neurol 28: 487-495, 1990.
1980b. 647. Stephens JA, Reinking RM, Stuart DG. The motor units of cat medial
618. Schwindt PC, Crill WE. Differential effects of TEA and cations on gastrocnemius: Electrical and mechanical properties as a function of
outward ionic currents of cat motoneurons. J Neurophysiol 46: 1-16, muscle length. J Morphol 146: 495-512, 1975.
1981a. 648. Stephenson JL, Maluf KS. Discharge behaviors of trapezius motor units
619. Schwindt PC, Crill WE. Negative slope conductance at large depolar- during exposure to low and high levels of acute psychosocial stress. J
izations in cat spinal motoneurons. Brain Res 207: 471-475, 1981b. Clin Neurophysiol 27: 52-61, 2010.
620. Scutter SD, Türker KS. Recruitment stability in masseter motor units 649. Stephenson JL, Maluf KS. Dependence of the paired motor unit analysis
during isometric voluntary contractions. Muscle Nerve 21: 1290-1298, on motor unit discharge characteristics in the human tibialis anterior
1998. muscle. J Neurosci Methods 198: 84-92, 2011.
621. Sears TA, Stagg D. Short-term synchronization of intercostal motoneu- 650. Stocker M, Pedarzani P. Differential distribution of three Ca(2+)-
rone activity. J Physiol 263: 357-381, 1976. activated K(+ ) channel subunits, SK1, SK2, and SK3, in the adult
622. Seburn KL, Cope TC. Short-term afferent axotomy increases both rat central nervous system. Mol Cell Neurosci 15: 476-493, 2000.
strength and depression at Ia-motoneuron synapses in rat. J Neurosci 651. Stotz PJ, Bawa P. Motor unit recruitment during lengthening contrac-
18: 1142-1147, 1998. tions of human wrist flexors. Muscle Nerve 24: 1535-1541, 2001.
623. Semmler JG. Motor unit synchronization and neuromuscular perfor- 652. Street SF. Lateral transmission of tension in frog myofibers: A my-
mance. Exerc Sport Sci Rev 30: 8-14, 2002. ofibrillar network and transverse cytoskeletal connections are possible
624. Semmler JG, Kornatz KW, Dinenno DV, Zhou S, Enoka RM. Motor transmitters. J Cell Physiol 114: 346-364, 1983.
unit synchronisation is enhanced during slow lengthening contractions 653. Stuart DG, Brownstone RM. The beginning of intracellular recording
of a hand muscle. J Physiol 545: 681-695, 2002. in spinal neurons: Facts, reflections, and speculations. Brain Res 1409:
625. Semmler JG, Kornatz KW, Meyer FG, Enoka RM. Diminished task- 62-92, 2011.
related adjustments of common inputs to hand muscle motor neurons 654. Stuart DG, Clarac F, Barbara JG, Brownstone RM, Duchateau J, Enoka
in older adults. Exp Brain Res 172: 507-518, 2006. RM. Paths of discovery in motoneuron neurobiology. Brain Res 1409:
626. Semmler JG, Nordstrom MA. Motor unit discharge and force tremor in 1-2, 2011.
skill- and strength-trained individuals. Exp Brain Res 119: 27-38, 1998. 655. Sukiasyan N, Hultborn H, Zhang M. Distribution of calcium chan-
627. Semmler JG, Nordstrom MA, Wallace CJ. Relationship between motor nel Ca(V)1.3 immunoreactivity in the rat spinal cord and brain stem.
unit short-term synchronization and common drive in human first dorsal Neuroscience 159: 217-235, 2009.
interosseous muscle. Brain Res 767: 314-320, 1997. 656. Suzuki S, Hayami A, Suzuki M, Watanabe S, Hutton RS. Reductions in
628. Semmler JG, Steege JW, Kornatz KW, Enoka RM. Motor-unit synchro- recruitment force thresholds in human single motor units by successive
nization is not responsible for larger motor-unit forces in old adults. J voluntary contractions. Exp Brain Res 82: 227-230, 1990.
Neurophysiol 84: 358-366, 2000. 657. Svirskis G, Hounsgaard J. Transmitter regulation of plateau properties
629. Seyffarth H. The behaviour of motor units in voluntary contractions. in turtle motoneurons. J Neurophysiol 79: 45-50, 1998.
Skrifter utgitt av Det Norske Videnskaps-Akademi I Oslo. I. Mat Naturv 658. Takahashi T. Inward rectification in neonatal rat spinal motoneurones.
Klasse 4: 1-63, 1940. J Physiol 423: 47-62, 1990.
630. Shapiro NP, Lee RH. Synaptic amplification versus bistability in mo- 659. Takahashi T, Berger AJ. Direct excitation of rat spinal motoneurones
toneuron dendritic processing: A top-down modeling approach. J Neu- by serotonin. J Physiol 423: 63-76, 1990.
rophysiol 97: 3948-3960, 2007. 660. Tanji J, Kato M. Firing rate of individual motor units in voluntary
631. Sharrard WJ. The distribution of the permanent paralysis in the lower contraction of abductor digiti minimi muscle in man. Exp Neurol 40:
limb in poliomyelitis; a clinical and pathological study. J Bone Joint 771-783, 1973.
Surg Br 37-B: 540-558, 1955. 661. Tax AA, Denier van der Gon JJ, Gielen CC, van den Tempel CM.
632. Sherrington CS. Remarks on some aspects of reflex inhibition. Proc R Differences in the activation of m. biceps brachii in the control of slow
Soc Lond B97: 519-545, 1925. isotonic movements and isometric contractions. Exp Brain Res 76: 55-
633. Shinohara M, Keenan KG, Enoka RM. Contralateral activity in a ho- 63, 1989.
mologous hand muscle during voluntary contractions is greater in old 662. Tax AAM, Vandergon JJD, Erkelens CJ. Differences in coordination of
adults. J Appl Physiol 94: 966-974, 2003. elbow flexor muscles in force tasks and in movement tasks. Exp Brain
634. Siddique T, Deng HX. Genetics of amyotrophic lateral sclerosis. Hum Res 81: 567-572, 1990.
Mol Genet 5: 1465-1470, 1996. 663. Tax AAM, Vandergon JJD, Gielen CCAM, Kleyne M. Differences in
635. Simon M, Perrier JF, Hounsgaard J. Subcellular distribution of L- central control of M-biceps-brachii in movement tasks and force tasks.
type Ca2+ channels responsible for plateau potentials in motoneurons Exp Brain Res 79: 138-142, 1990.
from the lumbar spinal cord of the turtle. Eur J Neurosci 18: 258-266, 664. Taylor AM, Christou EA, Enoka RM. Multiple features of motor-unit
2003. activity influence force fluctuations during isometric contractions. J
636. Smith HC, Davey NJ, Savic G, Maskill DW, Ellaway PH, Frankel Neurophysiol 90: 1350-1361, 2003.
HL. Motor unit discharge characteristics during voluntary contraction 665. Taylor AM, Enoka RM. Optimization of input patterns and neuronal
in patients with incomplete spinal cord injury. Exp Physiol 84: 1151- properties to evoke motor neuron synchronization. J Comput Neurosci
1160, 1999. 16: 139-157, 2004a.
637. Smith MR, Smith RD, Plummer NW, Meisler MH, Goldin AL. Func- 666. Taylor AM, Enoka RM. Quantification of the factors that influence
tional analysis of the mouse Scn8a sodium channel. J Neurosci 18: discharge correlation in model motor neurons. J Neurophysiol 91: 796-
6093-6102, 1998. 814, 2004b.
638. Smith WS, Fetz EE. Effects of synchrony between primate corticomo- 667. Taylor AM, Steege JW, Enoka RM. Motor-unit synchronization alters
toneuronal cells on post-spike facilitation of muscles and motor units. spike-triggered average force in simulated contractions. J Neurophysiol
Neurosci Lett 96: 76-81, 1989. 88: 265-276, 2002.
639. Snijders T, Verdijk LB, van Loon LJ. The impact of sarcopenia and 668. ter Haar Romeny BM, van der Gon JJ, Gielen CC. Relation between
exercise training on skeletal muscle satellite cells. Ageing Res Rev 8: location of a motor unit in the human biceps brachii and its critical
328-338, 2009. firing levels for different tasks. Exp Neurol 85: 631-650, 1984.
640. Søgaard K, Christensen H, Jensen BR, Finsen L, Sjogaard G. Motor 669. Theeuwen M, Gielen CC, Miller LE, Doorenbosch C. The relation
control and kinetics during low level concentric and eccentric con- between the direction dependence of electromyographic amplitude and
tractions in man. Electroencephalogr Clin Neurophysiol 101: 453-460, motor unit recruitment thresholds during isometric contractions. Exp
1996. Brain Res 98: 488-500, 1994.

P1: OTA/XYZ P2: ABC
670. Thomas CK, Bigland-Ritchie B, Johansson RS. Force-frequency rela- adult-onset neurodegenerative disease amyotrophic lateral sclerosis. J
tionships of human thenar motor units. J Neurophysiol 65: 1509-1516, Neurosci 28: 10864-10874, 2008.
1991. 697. van Zuylen EJ, Gielen CC, Denier van der Gon JJ. Coordination and
671. Thomas CK, Bigland-Ritchie B, Westling G, Johansson RS. A com- inhomogeneous activation of human arm muscles during isometric
parison of human thenar motor-unit properties studied by intraneural torques. J Neurophysiol 60: 1523-1548, 1988.
motor-axon stimulation and spike-triggered averaging. J Neurophysiol 698. Vanderhorst VG, Holstege G. Organization of lumbosacral motoneu-
64: 1347-1351, 1990. ronal cell groups innervating hindlimb, pelvic floor, and axial muscles
672. Thomas CK, del Valle A. The role of motor unit rate modulation versus in the cat. J Comp Neurol 382: 46-76, 1997.
recruitment in repeated submaximal voluntary contractions performed 699. Viana F, Bayliss DA, Berger AJ. Multiple potassium conductances
by control and spinal cord injured subjects. J Electromyogr Kinesiol and their role in action potential repolarization and repetitive firing
11: 217-229, 2001. behavior of neonatal rat hypoglossal motoneurons. J Neurophysiol 69:
673. Thomas CK, Johansson RS, Bigland-Ritchie B. Attempts to physiologi- 2150-2163, 1993a.
cally classify human thenar motor units. J Neurophysiol 65: 1501-1508, 700. Viana F, Bayliss DA, Berger AJ. Multiple potassium conductances
1991. and their role in action potential repolarization and repetitive firing
674. Thomas CK, Johansson RS, Bigland-Ritchie B. Pattern of pulses that behavior of neonatal rat hypoglossal motoneurons. J Neurophysiol 69:
maximize force output from single human thenar motor units. J Neu- 2150-2163, 1993b.
rophysiol 82: 3188-3195, 1999. 701. Vieira TM, Loram ID, Muceli S, Merletti R, Farina D. Postural activa-
675. Thomas CK, Johansson RS, Westling G, Bigland-Ritchie B. Twitch tion of the human medial gastrocnemius muscle: Are the muscle units
properties of human thenar motor units measured in response to intra- spatially localised? J Physiol 589: 431-443, 2011.
neural motor-axon stimulation. J Neurophysiol 64: 1339-1346, 1990. 702. von Tscharner V, Nigg BM. Point: Spectral properties of the surface
676. Thomas CK, Ross BH, Calancie B. Human motor-unit recruitment dur- Emg can characterize motor unit recruitment strategies and muscle fiber
ing isometric contractions and repeated dynamic movements. J Neuro- type. J Appl Physiol 105: 1671-1673, 2008.
physiol 57: 311-324, 1987. 703. Wada T, Hasegawa Y, Ono H. Characterization of alpha1-adrenoceptor
677. Thomas CK, Ross BH, Stein RB. Motor-unit recruitment in human subtypes in facilitation of rat spinal motoneuron activity. Eur J Phar-
1st dorsal interosseous muscle for static contractions in 3 different macol 340: 45-52, 1997.
directions. J Neurophysiol 55: 1017-1029, 1986. 704. Walmsley B, Proske U. Comparison of stiffness of soleus and medial
678. Thomas CK, Ross BH, Stein RB. Motor-unit recruitment in human gastrocnemius muscles in cats. J Neurophysiol 46: 250-259, 1981.
first dorsal interosseous muscle for static contractions in three different 705. Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen IS, Dixon
directions. J Neurophysiol 55: 1017-1029, 1986. JE, McKinnon D. KCNQ2 and KCNQ3 potassium channel sub-
679. Tomlinson BE, Irving D. The numbers of limb motor neurons in the units: Molecular correlates of the M-channel. Science 282: 1890-1893,
human lumbosacral cord throughout life. J Neurol Sci 34: 213-219, 1998.
1977. 706. Wang LC, Kernell D. Proximo-distal organization and fibre type region-
680. Torre M. Nombre et dimensions des unités motrices dans les muscles alization in rat hindlimb muscles. J Muscle Res Cell Motil 21: 587-598,
extrinsêques de l’œil et, en général, dans les muscles squélettiques reliés 2000.
à des organs de sens. Arch Suisses Neurol Psychiatry 72: 362-376, 1953. 707. Wang LC, Kernell D. Quantification of fibre type regionalisation: An
681. Tötösy de Zepetnek JE, Zung HV, Erdebil S, Gordon T. Innervation analysis of lower hindlimb muscles in the rat. J Anat 198: 295-308,
ratio is an important determinant of force in normal and reinnervated 2001.
rat tibialis anterior muscles. J Neurophysiol 67: 1385-1403, 1992. 708. Wang LC, Kernell D. Fibre type regionalisation in lower hindlimb
682. Troiani D, Filippi GM, Bassi FA. Nonlinear tension summation of muscles of rabbit, rat and mouse: A comparative study. J Anat 199:
different combinations of motor units in the anesthetized cat peroneus 631-643, 2001.
longus muscle. J Neurophysiol 81: 771-780, 1999. 709. Weijs WA, Jüch PJ, Kwa SH, Korfage JA. Motor unit territories and
683. Trotter JA. Interfiber tension transmission in series-fibered muscles of fiber types in rabbit masseter muscle. J Dent Res 72: 1491-1498, 1993.
the cat hindlimb. J Morphol 206: 351-361, 1990. 710. Westad C, Mork PJ, Westgaard RH. Firing patterns of low-threshold
684. Türker KS, Powers RK. Effects of common excitatory and inhibitory trapezius motor units in feedback-controlled contractions and voca-
inputs on motoneuron synchronization. J Neurophysiol 86: 2807-2822, tional motor activities. Exp Brain Res 158: 465-473, 2004.
2001. 711. Westad C, Westgaard RH. The influence of contraction amplitude and
685. Türker KS, Powers RK. Estimation of postsynaptic potentials in rat firing history on spike-triggered averaged trapezius motor unit poten-
hypoglossal motoneurones: Insights for human work. J Physiol 551: tials. J Physiol 562: 965-975, 2005.
419-431, 2003. 712. Westad C, Westgaard RH, De Luca CJ. Motor unit recruitment and
686. Türker KS, Schmied A, Cheng HB. Correlated changes in the firing derecruitment induced by brief increase in contraction amplitude of the
rate of human motor units during voluntary contraction. Exp Brain Res human trapezius muscle. J Physiol 552: 645-656, 2003.
111: 455-464, 1996. 713. Westcott SL, Powers RK, Robinson FR, Binder MD. Distribution of
687. Turkin VV, O’Neill D, Jung R, Iarkov A, Hamm TM. Characteristics vestibulospinal synaptic input to cat triceps surae motoneurons. Exp
and organization of discharge properties in rat hindlimb motoneurons. Brain Res 107: 1-8, 1995.
J Neurophysiol 104: 1549-1565, 2010. 714. Westenbroek RE, Merrick DK, Catterall WA. Differential subcellular
688. Udina E, D’Amico J, Bergquist AJ, Gorassini MA. Amphetamine in- localization of the RI and RII Na+ channel subtypes in central neurons.
creases persistent inward currents in human motoneurons estimated Neuron 3: 695-704, 1989.
from paired motor-unit activity. J Neurophysiol 103: 1295-1303, 2010. 715. Westgaard RH, Bonato P, Westad C. Respiratory and stress-induced
689. Ulfhake B, Kellerth JO. A quantitative light microscopic study of the activation of low-threshold motor units in the human trapezius muscle.
dendrites of cat spinal alpha-motoneurons after intracellular staining Exp Brain Res 175: 689-701, 2006.
with horseradish peroxidase. J Comp Neurol 202: 571-583, 1981. 716. Westgaard RH, De Luca CJ. Motor unit substitution in long-duration
690. Umemiya M, Berger AJ. Properties and function of low- and high- contractions of the human trapezius muscle. J Neurophysiol 82: 501-
voltage-activated Ca2+ channels in hypoglossal motoneurons. J Neu- 504, 1999.
rosci 14: 5652-5660, 1994. 717. Westgaard RH, De Luca CJ. Motor control of low-threshold motor units
691. van Antwerp KW, Burkholder TJ, Ting LH. Inter-joint coupling ef- in the human trapezius muscle. J Neurophysiol 85: 1777-1781, 2001.
fects on muscle contributions to endpoint force and acceleration in a 718. Westling G, Johansson RS, Thomas CK, Bigland-Ritchie B. Measure-
musculoskeletal model of the cat hindlimb. J Biomech 40: 3570-3579, ment of contractile and electrical properties of single human thenar
2007. motor units in response to intraneural motor-axon stimulation. J Neu-
692. van Bolhuis BM, Medendorp WP, Gielen CC. Motor unit firing behav- rophysiol 64: 1331-1338, 1990.
ior in human arm flexor muscles during sinusoidal isometric contrac- 719. White SR, Fung SJ. Serotonin depolarizes cat spinal motoneurons in
tions and movements. Exp Brain Res 117: 120-130, 1997. situ and decreases motoneuron afterhyperpolarizing potentials. Brain
693. Van Cutsem M, Duchateau J, Hainaut K. Changes in single motor unit Res 502: 205-213, 1989.
behaviour contribute to the increase in contraction speed after dynamic 720. White SR, Fung SJ, Barnes CD. Norepinephrine effects on spinal mo-
training in humans. J Physiol 513(Pt 1): 295-305, 1998. toneurons. Prog Brain Res 88: 343-350, 1991.
694. Van Cutsem M, Feiereisen P, Duchateau J, Hainaut K. Mechanical 721. Wienecke J, Zhang M, Hultborn H. A prolongation of the postspike af-
properties and behaviour of motor units in the tibialis anterior during terhyperpolarization following spike trains can partly explain the lower
voluntary contractions. Can J Appl Physiol 22: 585-597, 1997. firing rates at derecruitment than those at recruitment. J Neurophysiol
695. van Groeningen CJ, Nijhof EJ, Vermeule FM, Erkelens CJ. Relation 102: 3698-3710, 2009.
between torque history, firing frequency, decruitment levels and force 722. Windhorst U, Hamm TM, Stuart DG. On the function of muscle and
balance in two flexors of the elbow. Exp Brain Res 129: 592-604, 1999. reflex partitioning. Behav Brain Sci 12: 629-645, 1989.
696. van Zundert B, Peuscher MH, Hynynen M, Chen A, Neve RL, Brown 723. Winges SA, Kornatz KW, Santello M. Common input to motor units
RH, Jr., Constantine-Paton M, Bellingham MC. Neonatal neuronal of intrinsic and extrinsic hand muscles during two-digit object hold. J
circuitry shows hyperexcitable disturbance in a mouse model of the Neurophysiol 99: 1119-1126, 2008.

P1: OTA/XYZ P2: ABC
724. Wood SJ, Slater CR. Safety factor at the neuromuscular junction. Prog 735. Zennaro D, Laubli T, Krebs D, Klipstein A, Krueger H. Continuous,
Neurobiol 64: 393-429, 2001. intermitted and sporadic motor unit activity in the trapezius muscle
725. Woodbury JW, Patton HD. Electrical activity of single spinal cord during prolonged computer work. J Electromyogr Kinesiol 13: 113-
elements. Cold Spring Harb Symp Quant Biol 17: 185-188, 1952. 124, 2003.
726. Wu SY, Wang MY, Dun NJ. Serotonin via presynaptic 5-HT1 receptors 736. Zhang L, Krnjević K. Apamin depresses selectively the after-
attenuates synaptic transmission to immature rat motoneurons in vitro. hyperpolarization of cat spinal motoneurons. Neurosci Lett 74: 58-62,
Brain Res 554: 111-121, 1991. 1987.
727. Yao W, Fuglevand RJ, Enoka RM. Motor-unit synchronization in- 737. Zhang L, Krnjević K. Intracellular injection of Ca2+ chelator does not
creases EMG amplitude and decreases force steadiness of simulated affect spike repolarization of cat spinal motoneurons. Brain Res 462:
contractions. J Neurophysiol 83: 441-452, 2000. 174-180, 1988.
728. Yasuda K, Robinson DM, Selvaratnam SR, Walsh CW, McMorland AJ, 738. Zhang M, Moller M, Broman J, Sukiasyan N, Wienecke J, Hultborn
Funk GD. Modulation of hypoglossal motoneuron excitability by NK1 H. Expression of calcium channel CaV1.3 in cat spinal cord: Light and
receptor activation in neonatal mice in vitro. J Physiol 534: 447-464, electron microscopic immunohistochemical study. J Comp Neurol 507:
2001. 1109-1127, 2008.
729. Young M, Paul A, Rodda J, Duxson M, Sheard P. Examination of 739. Zhang M, Sukiasyan N, Moller M, Bezprozvanny I, Zhang H, Wienecke
intrafascicular muscle fiber terminations: Implications for tension de- J, Hultborn H. Localization of L-type calcium channel Ca(V)1.3 in cat
livery in series-fibered muscles. J Morphol 245: 130-145, 2000. lumbar spinal cord–with emphasis on motoneurons. Neurosci Lett 407:
730. Zagoraiou L, Akay T, Martin JF, Brownstone RM, Jessell TM, Miles 42-47, 2006.
GB. A cluster of cholinergic premotor interneurons modulates mouse 740. Zhong G, Masino MA, Harris-Warrick RM. Persistent sodium currents
locomotor activity. Neuron 64: 645-662, 2009. participate in fictive locomotion generation in neonatal mouse spinal
731. Zajac FE. Muscle and tendon: Properties, models, scaling, and appli- cord. J Neurosci 27: 4507-4518, 2007.
cation to biomechanics and motor control. Crit Rev Biomed Eng 17: 741. Zhu H, Clemens S, Sawchuk M, Hochman S. Expression and distri-
359-411, 1989. bution of all dopamine receptor subtypes (D(1)-D(5)) in the mouse
732. Zajac FE, Faden JS. Relationship among recruitment order, axonal lumbar spinal cord: A real-time polymerase chain reaction and non-
conduction velocity, and muscle-unit properties of type-identified motor autoradiographic in situ hybridization study. Neuroscience 149: 885-
units in cat plantaris muscle. J Neurophysiol 53: 1303-1322, 1985. 897, 2007.
733. Zeng J, Powers RK, Newkirk G, Yonkers M, Binder MD. Contribu- 742. Zijdewind I, Thomas CK. Spontaneous motor unit behavior in human
tion of persistent sodium currents to spike-frequency adaptation in rat thenar muscles after spinal cord injury. Muscle Nerve 24: 952-962,
hypoglossal motoneurons. J Neurophysiol 93: 1035-1041, 2005. 2001.
734. Zengel JE, Reid SA, Sypert GW, Munson JB. Membrane electrical 743. Zijdewind I, Thomas CK. Motor unit firing during and after voluntary
properties and prediction of motor-unit type of medial gastrocnemius contractions of human thenar muscles weakened by spinal cord injury.
motoneurons in the cat. J Neurophysiol 53: 1323-1344, 1985. J Neurophysiol 89: 2065-2071, 2003.

Heckman2012 Motor Unit

Uploaded by

Copyright:

Available Formats

Heckman2012 Motor Unit

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Heckman2012 Motor Unit

Uploaded by

Copyright:

Available Formats

P1: OTA/XYZ P2: ABC

Compr Physiol 2:2629-2682, 2012.

Volume 2, October 2012 2629

Motor Unit Comprehensive Physiology

2630 Volume 2, October 2012

Comprehensive Physiology Motor Unit

Volume 2, October 2012 2631

Motor Unit Comprehensive Physiology

2632 Volume 2, October 2012

Comprehensive Physiology Motor Unit

Volume 2, October 2012 2633

Motor Unit Comprehensive Physiology

2634 Volume 2, October 2012

Comprehensive Physiology Motor Unit

Experimental preparations for study

Volume 2, October 2012 2635

Channel Presence shown in adult Pharmacological

Sag (41, 352, 658) hyperpolarization (608)] FF>FR>S (275, 734)

spike Nav1.3 (242, 439) current

Comprehensive Physiology Motor Unit

Volume 2, October 2012 2637

Motor Unit Comprehensive Physiology

2638 Volume 2, October 2012

Comprehensive Physiology Motor Unit

Volume 2, October 2012 2639

Motor Unit Comprehensive Physiology

2640 Volume 2, October 2012

Comprehensive Physiology Motor Unit

(A) (B) (C)

Firing frequency (spikes/s)

Volume 2, October 2012 2641

Motor Unit Comprehensive Physiology

2642 Volume 2, October 2012

Table 3 Summary of Neuromodulatory Effects on Motoneurons

5-HT2A&C 523) by α1 R (437)

350, 719, reduced (415, 483) (283) sAHP reduced†

† Results obtained from neonatal preparations only.

Motor Unit Comprehensive Physiology

net synaptic current undergoes a dramatic increase as the

Other neuromodulatory actions

2644 Volume 2, October 2012

Comprehensive Physiology Motor Unit

Firing rate (imp/s)

Somatic potential (mV)

Somatic potential (mV)

Somatic potential (mV)

Volume 2, October 2012 2645

Motor Unit Comprehensive Physiology

Firing frequency (Hz)

15 High-threshold, likely FF 100

2646 Volume 2, October 2012

Comprehensive Physiology Motor Unit

Synaptic current (nA)

–40 Current (nA)

–5 Inhibitory synaptic current

Distance from cell body (μm) –10

Volume 2, October 2012 2647

Motor Unit Comprehensive Physiology

2648 Volume 2, October 2012