Exercise and the Brain (1)

Exercise and
the Brain
Why Physical Exercise is
Essential to Peak Cognitive
Health
Robert W. Baloh
123
Exercise and the Brain
Robert W. Baloh
Exercise and the Brain

Why Physical Exercise is Essential
to Peak Cognitive Health
Robert W. Baloh
Neurology
University of California, Los Angeles
Los Angeles, CA, USA
ISBN 978-3-031-13923-9 ISBN 978-3-031-13924-6 (eBook)

https://doi.org/10.1007/978-3-031-13924-6
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Foreword 1
Exercise and the Brain is interesting and important from many perspectives.
Professor Baloh provides a concise overview of the role of physical activity in pre-
venting and treating common neurological symptoms and diseases. The book is also
a comprehensive guide to the safety and efficacy of different types of physical activ-
ity needed to sustain a healthy brain throughout one’s life span. Given the impor-
tance of the brain in all human activities, it is surprising that a book from this
perspective has not previously been written. Exercise and the Brain provides an
important step towards elevating the level of awareness of the consequences of dif-
ferent types of activity-related behaviors under a wide range of conditions on the
brain and one’s health. The level of detail regarding how physical activity can
enhance one’s functionality in a diseased or healthy state is very impressive. A good
example of how things have changed with regard to medical recommendations for
exercise is that only a few decades ago patients were told to remain inactive follow-
ing most surgeries. But today, the recommendation is to begin some type of exercise
on the day of surgery, even after major procedures such as hip replacement or heart
surgery. This change has evolved as a result of an increased understanding of the
biology of exercise.
Another interesting and important feature of the Exercise and the Brain is that it
is written so that it can be easily appreciated by a very wide audience with respect
to their levels of expertise. For example, a rather thorough history of exercise in
medicine is addressed. This history is important because it reflects the widely
changing views of civilizations and cultures as they have evolved. But generally,
there has been a persistent thought by scholars over the course of hundreds of years
that the functionality of an individual is dependent to a large extent on their patterns
of physical activity. These views are important because they shape important deci-
sions in our educational systems regarding how much and what kind of activity is
allotted on a regular basis at different ages. One can imagine a more scientifically
based discussion with parents with regard to exercise in the school’s curriculum. It
is remarkable how varied the opinions differ on the topic of physical activity in
sustaining one’s health even among the more advanced societies and countries.
In the past, the focus on the biology of exercise was mainly on the cardiovascular
and respiratory systems combined with considerations for how to enhance cardio-
vascular fitness and build muscles. Rarely, did the nervous system, or the endocrine
system become a point of interest in developing a greater understanding of one’s
v
vi Foreword 1
functionality. One of the first books that began to reach into the wider range of organ
systems when studying the science of physical activity, and particularly the nervous
system, was the Biology of Exercise, published in 1976. Exercise and the Brain is
obviously a major and total commitment to begin to understand how activity plays
an important role in the control of virtually all organ systems, especially the brain.
Advancements in technology is making it more and more possible to monitor organ
function during physical activity. There has been a proliferation of sensors that can
monitor for long periods multiple cardiovascular, pulmonary, metabolic, and brain
biomarkers in awake, fully functional states. These types of measurements can help
in monitoring what the patient does outside the clinic. This type of technology of
long duration monitoring periods of multiple physiological responses has been
focused initially on cardiovascular functions but is potentially applicable to all
organ systems including the brain.
V. Reggie Edgerton
Edgerton Neuromuscular Research Laboratory
Department of Integrative Biology and Physiology, UCLA
Los Angeles, CA, USA
Foreword 2
I first met Dr. Baloh when I was a medical student in 1997. As part of a summer
research program in Neurology, I worked on his study about balance disorders in
older people and also shadowed him in clinic. I had no idea how much that summer
would influence my medical career going forward. What set him apart in my mind,
both in the clinical and research settings, is his approach to solving problems. He
starts with a deep appreciation for the history of medicine and health in general. He
focuses on major issues, takes rigorous steps to evaluate those issues, and lets the
findings guide the process. This is why we all need to pay attention to Exercise and
the Brain. From his nearly 50 years of academic and clinical experience, he con-
cludes: “The brain is uniquely dependent on physical activity for optimal perfor-
mance and physical activity, whether planned (exercise) or part of one’s daily
routine, can prevent and treat many chronic neurological disorders.”
What is unique about Exercise and the Brain is that it is the first book to focus on
exercise for common neurological symptoms and disorders. In addition, it reviews
the history, basic science, and modern-day clinical trial results relevant to exercise
and the brain. Dr. Baloh’s background and experiences make him the ideal person
to tell this story. The book is also unique in the organization of the chapters on key
aspects of brain functioning including the developing brain, learning, the aging
brain, mental health, chronic pain, cerebrovascular disease, and cognitive function-
ing. It provides the key historical background—including fascinating stories about
exercise and a variety of cultures, including the Hadza, the Ache, Old Order Amish,
the Canadian Inuits, the Greek Spartans, and the Romans. It describes the pivotal
early scientific studies from Thomas Cureton about the benefits of exercise, Kenneth
Cooper (who also identified potential health consequences of extreme exercise), and
the Canadian Study of Health and Aging which provided links of exercise with
lower risks of Alzheimer’s disease. The data from modern-day randomized con-
trolled trials and meta-analyses of these trials is also described in detail.
vii
viii Foreword 2
The emphasis is on scientific data, but the material is presented in a straightfor-

ward way that should be understandable to anyone who is interested in improving
their brain health.
Kevin Kerber
Neurology, Wexner Medical Center
The Ohio State University
Columbus, OH, USA
Preface
The reason I exercise is for the quality of life I enjoy. (Kenneth Cooper)
Everyone has heard of the health benefits of physical exercise yet so few of us
exercise on a regular basis. Are human beings just lazy by nature? Our distant ances-
tors certainly weren’t lazy. They were either physically active or they died. Regular
physical activity was required for hunting, gathering, and preparing food and for
maintaining shelter. Evolution selected out those who were most physically fit.
In many ancient civilizations, physical fitness was the main attribute for advance-
ment in society. Leaders were selected on the basis of their physical, not their men-
tal, prowess. By contrast, in modern times, physical fitness is less important for
survival. People can earn a living without getting out of a chair or leaving the house.
In California, people drive to a convenience store a block away from home to pur-
chase food. But our brains were designed (evolved) needing physical activity for
best function.
People who exercise regularly have fewer chronic illnesses and live several years
longer than people who do not exercise. Furthermore, people who exercise regularly
have less anxiety and depression, enjoy life more and have better social interactions
than people who do not exercise. Why aren’t people getting the message?
Despite all of the advances in neuroscience that have occurred in the last century,
physical exercise is still the most effective way to prevent stroke and dementia, two
of the main causes of chronic morbidity and mortality in older people. Regular
exercise can cut the risk of developing stroke and dementia by as much as 50% and
exercise can accelerate recovery from stroke and delay progression of dementia.
Exercise is also effective treatment for numerous other common neurological
conditions including movement disorders, chronic low back and neck pain, migraine,
fibromyalgia, and balance disorders. It shouldn’t be so hard to convince people,
particularly older people, to exercise regularly. It is literally a matter of life and death.
What are my credentials to write a book about exercise and the brain? Although
my research has not focused on exercise physiology, I have maintained a longstand-
ing interest in the history of medicine, particularly the history of exercise in medi-
cine. As a professor of neurology at UCLA for almost 50 years, I have written and
reviewed literally hundreds of research grant proposals submitted to the National
Institute of Health (NIH) and private research institutes on a wide range of neuro-
logical topics. I have personally supervised several large NIH-funded research
ix
x Preface
projects that included basic science and clinical components. I recognize the
strengths and weaknesses of research studies and understand the limitations of
research data. Finally, I have served on countless hospital and departmental com-
mittees focused on improving public health and brain health.
In 1990, I submitted a research proposal to the National Institute of Aging enti-
tled Dizziness in Older People. The goal was to follow 200 people over the age of
75 with yearly examinations focusing on balance and cognitive function (see Chap.
6). Half of the people complained of balance problems and the other half considered
their balance normal. A unique feature of the study was that participants agreed to
postmortem examinations of the brain. The proposal was funded and enrolled sub-
jects were followed for a total of 15 years or until death.
At the end of the study, my colleagues and I were struck by the observation that
the only participants still alive and well were people who exercised regularly. Since
we did not formally measure physical activity levels in the participants and since
there may have been other reasons for the correlation between exercise and longev-
ity, we were cautious about conclusions but this chance observation was a key moti-
vating factor for my research into the effect of exercise on the brain and ultimately
in writing this book.
I have been an exerciser all of my life, but I must admit that it has become more
difficult to exercise as I have gotten older. I was an avid tennis player since child-
hood and I still recall the satisfaction I experienced after a good singles match. With
little effort I pushed myself to exhaustion while enjoying the rhythm of the move-
ment side-to-side, front to back, tracking, and hitting the tennis ball. I looked on my
tennis matches as the highlight of my day, anticipating that exhilarating feeling both
during and after the match.
But like so many people who participate in sports when young, as I got older it
became harder and harder to play a regular tennis schedule without injuries. Then I
developed lumbar spinal stenosis and singles tennis was no longer an option. Every
time I tried to play a match regardless of how much stretching and warming up
beforehand I was left with pain and stiffness for days to weeks after playing.
Playing doubles tennis never appealed to me since there was too much standing
around and too little exercise. I tried golf and although I enjoyed the challenge and
the camaraderie it provided relatively little exercise for the time spent. Often I felt
more stress and frustration after playing golf than before I started.
I needed an exercise routine that I could enjoy and anticipate on a daily basis that
would give me all of the health benefits and sense of well-being associated with
physical exercise without aggravating my back problem. I settled on a daily routine
of 10 min of resistance and stretching exercises followed by brisk walking along the
beach for 45 min (intermixed with three brief sprints).
When patients tell me their doctor blamed their symptoms on aging, I cringe and
suggest that aging does not cause symptoms, it’s the diseases that occur with aging
that cause symptoms. Inactivity is the single most important risk factor for develop-
ing the common conditions that occur with aging: type 2 diabetes, coronary heart
disease, arthritis, chronic pain, stroke, dementia, and balance disorders. Manage
these conditions and aging isn’t so bad.
Preface xi
This book focuses on the benefits of exercise for prevention and treatment of
chronic neurological disorders. It is a guide for finding the right exercise routine for
each individual. There is no-one-fits-all approach to exercise.
Many present-day people have little or no early life experience with exercise.
When we baby boomers attended school, physical education mostly consisted of
playing team sports. Teachers of physical education were invariably coaches, mostly
football and basketball coaches, who had little time for the majority of kids who did
not excel in team sports. The students who could most benefit from exercise were
largely ignored. In college, the emphasis was even more on team sports, you either
played team sports or you sat on the sidelines and cheered.
The goal of this book is to show the reader why nearly everyone needs to exer-
cise. There is a strong emphasis on the history of exercise in medicine. As we get
older, the need for exercise is even more important since our overall level of routine
daily physical activity is less. The brain needs physical activity both for normal
health and for preventing and treating diseases common with aging.
How much exercise is needed? As we will see throughout the book there is no-
one-fits-all rule with regard to the amount of exercise required. But there are some
generalizations that most agree upon. Some is better than none and more is better
than less. Start slowly and gradually build up the amount and intensity of exercise
over time. The ultimate goal is to improve your physical fitness and this requires an
incremental increase in effort.
The key is to make exercise a part of one’s daily routine. The beneficial effect of
exercise is transient, lasting days to weeks, so it must be a lifelong pursuit. Can we
exercise too much? Anything done in excess can potentially be dangerous but with
the common sense approach outlined in this book anyone, regardless of underlying
health condition, can find some type of exercise that is safe and effective.
The book is divided into three sections. Section 1 (Chaps. 1–3) provides an over-
view and historical background for understanding why physical activity is so impor-
tant for normal brain health. Section 2 (Chaps. 3–6) focuses on the importance of
physical activity in brain development, learning throughout life and successful
aging. Section 3 (Chaps. 7–10) covers the benefits of physical activity for preven-
tion and treatment of common neurological disorders including depression, chronic
pain, strokes, and dementia. Finally, I conclude with an overview chapter that sum-
marizes the current World Health Organization (WHO) recommendations for physi-
cal activity in children, adolescents, adults, older adults, pregnant women, and
patients with disabilities.
Neurology, UCLA, Los Angeles, CA, USA Robert W. Baloh

Acknowledgments
I want to thank my lovely wife Grace for her overall support and for suggesting
ways to make the book more readable. We both exercise regularly. Drs. Edgerton
and Kerber provided helpful comments and suggestions in addition to writing the
Forewords.
xiii
Contents
1
Exercise Is Good Medicine�� 1
Physicians and the “Exercise Pill” �� 1
Exercise, Physical Activity and Physical Fitness�� 2
Exercise for Health in Early America�� 3
Exercise and Early Neurology �� 4
Early Ideas on Physical Education�� 5
Thomas Cureton and the Science of Physical Education�� 6
Physical Fitness and Sports�� 6
Kenneth Cooper and Aerobics �� 7
Physical Inactivity and Poor Health�� 9
Physical Fitness and Longevity�� 10
Public Health Implications of Physical Inactivity�� 11
Body Weight and Energy Metabolism �� 12
Physical Fitness, Obesity and Cardiovascular Disease�� 13
Aerobic Versus Anaerobic Physical Activity �� 13
Oxygen Utilization and Fitness�� 14
Exercise Training for Improving Fitness �� 16
Beginning Exercise Training�� 18
References�� 19
2
Physical Activity and Brain Evolution �� 21
Hunter-Gatherer Societies�� 21
Energy Consumption in Primitive Societies�� 22
The Hazda�� 23
The Aché�� 24
Physical Activity in Hunter-Gatherers �� 25
The Thrifty Gene Hypothesis�� 26
Napoleon Chignon Popularizes Anthropology�� 26
Physical Activity and the Thrifty Gene Hypothesis�� 27
The APOE Gene and Late Onset Chronic Diseases�� 28
The Agricultural Revolution�� 29
Hunter-Gatherer Versus Agricultural Lifestyle�� 29
The Old Order Amish�� 31
The Canadian Inuits �� 31
xv
xvi Contents
Hunter-Gatherers didn’t Have it So Bad�� 32

The Industrial Revolution�� 34
Physical Inactivity and Chronic Diseases�� 35
References�� 39
3 Healthy Body for a Sound Mind �� 41
A
Chinese Martial Arts�� 41
Yoga and the Melding of the Mind and Body�� 44
Sparta and Physical Fitness�� 45
Herodicus of Cnidos�� 46
Hippocrates of Cos�� 47
Athens and the Greek Gymnasium�� 48
The Olympic Games�� 49
The Romans �� 50
Galen�� 52
The Middle Ages and the Soul Rules the body�� 54
The Age of Chivalry�� 55
The Renaissance�� 56
John Locke �� 58
Jean-Jacques Rousseau�� 60
Thomas Jefferson �� 63
Early Exercise Equipment�� 64
References�� 65
4 The Developing Brain�� 67
Link Between Upright Posture and Increasing Brain Size�� 68
Brain Growth After Birth �� 70
Cerebellar Expansion �� 70
Human Brain Development �� 71
Neuroplasticity and Brain Development�� 72
Physical Activity and Brain Development �� 73
Physical Activity Versus Rest During Pregnancy�� 74
Exercise During Pregnancy Is Beneficial to Mother and Child �� 75
Effect of Maternal Exercise on Fetal Brain Development �� 75
Physical Activity in Infants�� 77
Physical Activity in Preadolescent Children�� 79
Physical Fitness and Academic Performance�� 80
Physical Activity in Adolescent Children�� 81
Physical Fitness and Academic Performance in Adolescents�� 81
Physical Education and Academic Performance�� 82
How Does Exercise Influence Brain Development?�� 83
Exercise for Treating Abnormal Brain Development�� 84
References�� 85
5
Exercise, the Elixir for Learning�� 89
Physical Education and Learning�� 89
Basic Mechanisms of Learning�� 93
Contents xvii
How Exercise Improves Learning�� 94

Exercise and the Body-Brain Connection�� 95
Research Studies of Exercise on Learning and Memory �� 97
Sleep, Exercise and Learning�� 98
Exercise “High” �� 99
Green Exercise �� 103
Serotonin, Emotions and Learning�� 104
Serotonin Drugs and Learning �� 105
References�� 106
6 The Aging Brain �� 109
Energy Consumption and the Aging Brain�� 110
Early Life Experiences and the Aging Brain �� 111
Genes and Cognitive Aging �� 113
Telomere Length, Physical Activity and Aging �� 113
White Matter Abnormalities with Aging�� 115
Shrinkage of the Brain with Aging�� 118
Muscular Strength and Aging�� 120
Exercise for Prevention of Falls in Older People�� 121
Exercise for Improving Cognition in Older People �� 122
Combining Interventions to Prevent Cognitive Decline�� 126
7 Stress, Anxiety and Depression �� 129
What Exactly Is Stress �� 130
Neurobiology of Stress�� 132
Exercise and Stress Management�� 134
Posttraumatic Stress Disorder (PTSD)�� 135
Exercise for Treating PTSD �� 136
Anxiety�� 137
Exercise for Treating Anxiety�� 138
Depression�� 139
Animal Models of Depression �� 140
Exercise for Preventing Depression �� 142
Exercise for Treating Depression�� 143
8 Chronic Pain�� 147
Perception of Pain�� 148
Opioids and Chronic Pain�� 148
Central Sensitization and Chronic Pain �� 149
Inflammation and Chronic Pain �� 151
Chronic Pain and Fear Avoidance�� 151
Overview of Exercise for Chronic Pain �� 151
Chronic Low Back Pain �� 152
Current Approach to Treating Chronic Low Back Pain�� 153
xviii Contents
Exercise for Treating Chronic Low Back Pain�� 154

Chronic Neck Pain �� 155
Current Approach to Treating Chronic Neck Pain�� 155
Exercise for Treating Chronic Neck Pain�� 156
Headaches�� 157
Exercise for Tension-Type Headaches �� 158
Exercise for Treating Migraine Headaches�� 159
Fibromyalgia�� 160
Tender Points �� 160
Exercise for Treating Fibromyalgia �� 162
9 Cerebrovascular Disease �� 167
Cerebral Blood Flow and Exercise�� 168
Types of Strokes�� 170
Exercise and Stroke Prevention �� 170
Exercise and Rehabilitation After Stroke�� 172
Illustrative Case�� 174
How Does the Brain Recover from a Stroke�� 177
Delayed Recovery�� 178
Factors that Influence Recovery After Stroke�� 180
Goals for Stroke Rehabilitation �� 181
10 Dementia �� 185
Alzheimer Disease �� 186
Exercise and Alzheimer Disease Pathology�� 188
Exercise for Prevention of Alzheimer Disease�� 189
Exercise for Treating Alzheimer Disease�� 192
Vascular Dementia �� 193
Exercise and Vascular Disease Pathology�� 193
Exercise for Preventing Vascular Dementia�� 194
Exercise for Treating Vascular Dementia�� 194
Lewey Body/Parkinson Disease Dementia�� 194
Exercise and Lewey Bodies �� 195
Exercise for Prevention of Parkinson Disease �� 196
Exercise for Treating Parkinson Disease �� 196
Dementia due to Tau Protein Aggregation �� 197
Exercise for Preventing and Treating Tauopathies�� 198
11 Overview �� 201
World Health Organization (WHO) Guidelines�� 202
Infants <5 Years of Age�� 203
Children and Adolescents Ages 5–17 years �� 204
Adults Ages 18–64 Years �� 206
Contents xix
Older Adults Ages 65 Years and Older�� 206

Pregnant and Postpartum Women�� 206
People Living with Chronic Disabilities�� 207
Future Directions �� 207
Index �� 209
Exercise Is Good Medicine
1
Those who think they have no time for bodily exercise will sooner or later have to find time
for illness.—Edward Stanley [1]
Although there has been a gradual increase in human longevity over the past few
centuries, the improvement in life expectancy has come at the cost of an increased
burden of chronic diseases. Some even question whether living longer is worth it if
it means suffering through the later years.
Because of the profound effect on all aspects of human behavior and interaction,
chronic neurological diseases are the most feared of all chronic diseases. They typi-
cally don’t kill you, at least not directly, but they can make life unbearable. Although
there are currently no simple cures for any of these chronic neurological conditions
there is a proven way to delay the onset and decrease symptoms—increase physical
activity.
Dementia, the most feared of all chronic neurological diseases because of its
dehumanizing qualities, is rapidly increasing in frequency as the population ages.
Just delaying the onset a few years can markedly decrease the number of people
with dementia. Studies show that taking a brisk walk 3 or 4 times a week can delay
onset of dementia by as much as 5–10 years.
Physicians and the “Exercise Pill”
Despite the overwhelming scientific evidence that exercise delays the onset of most
chronic diseases and improves the quality of life, exercise is clearly underutilized by
health professionals. In an editorial entitled Exercise is medicine and physicians
need to prescribe it published in 2009, Robert Sallis, a family physician at Kaiser
Permanente in Southern California and at the time, president of the American
College of Sports Medicine, asked two simple questions: “If we had a pill that
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 1

R. W. Baloh, Exercise and the Brain,
https://doi.org/10.1007/978-3-031-13924-6_1
2 1 Exercise Is Good Medicine
conferred all the confirmed health benefits of exercise, would we not do everything
humanly possible to see to it that everyone had access to this wonder drug? Would
it not be the most prescribed pill in the history of mankind?” [2].
Why aren’t physicians prescribing the “exercise pill” for their patients? Two
obvious reasons are: (1) exercise is not a pill, it requires effort and commitment by
both physicians and patients and (2) our healthcare system in the United States that
incentivizes tests, procedures and drugs does not reward time spent making sure that
patients get adequate exercise. The paradox is that it costs at least $1500 per year
more to care for a patient who is physically inactive compared to a patient who is
physically active.
Cardiologists have done a reasonably good job of including exercise in the man-
agement of their patients with heart disease. A discussion of the role of exercise in
maintaining heart health is often included in a routine examination. Exercise is now
a part of cardiac rehab after heart attacks, stent placement and by-pass surgery.
Patients intuitively understand that exercise is important for heart muscle function.
But the role of exercise in brain function is less intuitively obvious. Discussions
of the role of exercise in brain health is not a part of most routine neurological
assessments even though there is compelling evidence that exercise decreases the
risk of stroke, helps maintain balance and prevent falls with aging, and improves
cognition and delays the onset of dementia with aging. Equally important, exercise
is critical for brain development in children and for learning throughout life.
Exercise, Physical Activity and Physical Fitness
The terms physical activity and exercise are often used interchangeably but it is
important to note at the onset that these terms are not exactly the same thing.
Physical activity refers to any movement requiring energy expenditure beyond the
resting level including manual labor, housework or walking to and from the grocery
store whereas exercise is a planned physical activity with the goal of maintaining or
improving physical fitness and health [3].
As a rule, physical activity regardless of whether planned or the result of daily
routine provides the same benefits for both physical fitness and health. The obvious
implication is that people who regularly perform manual labor do not need to exer-
cise as much as people who have a desk job. Indeed, before the industrial revolution
most people had a high level of daily physical activity and did not need to exercise.
Physical fitness, on the other hand, represents a combination of personal attri-
butes including cardiovascular fitness, muscle strength and endurance, body com-
position, balance and agility. Exercise, physical activity and physical fitness are
interrelated but there are multiple factors that influence physical fitness in addition
to exercise and physical activity such as genetic variants, health status and age. One
way to think of physical fitness is the ability to carry out daily tasks with vigor and
alertness without undo fatigue. It can be a rough estimate of one’s physical activity
over the past several months. Of the various attributes that make up physical fitness,
cardiovascular fitness has the largest impact on overall health particularly on chronic
age-related diseases.
Exercise for Health in Early America 3
Exercise for Health in Early America
In eighteenth century America, the routine practice of medicine was primitive still
based on ancient concepts of humors and vital spirits. Lifestyles were largely agri-
cultural and most people had a heavy dose of physical activity, plowing fields, hunt-
ing wild animals and herding domestic animals. Transportation was mainly through
walking and horseback riding. Although some physicians were aware of the benefits
of exercise in maintaining health, this information was not routinely conveyed to
patients who wanted medicines to treat their ills.
At the turn of the nineteenth century, several American physicians warned that
aggressive treatments such as blood letting, drugging and purging were ineffective
and potentially dangerous and that medical practitioners should reconsider the heal-
ing powers of nature espoused by Hippocrates and Galen. The Greek term “physis”
means natural or nature and was the root for “physick”, the word used for medicine
in the eighteenth Century, and for the term “physician”.
The value of physical activity for prevention and treatment of disease was invig-
orated when a New York physician, Shadrach Ricketson, published a book in 1806
entitled Means of Preserving Health and Preventing Disease. Ricketson espoused
that a sedentary lifestyle whether by choice or employment enfeebled the body
making it susceptible to disease. He argued that: “idleness and luxury create more
diseases than labour and industry” [4].
One of the most prominent American surgeons in the nineteenth century, John
Collins Warren, best known for the introduction of ether anesthesia into the surgical
theater, played a critical role in the birth of the nation’s fledgling physical education
movement. Warren studied abroad, obtaining his medical degree at the University of
Edinburgh in 1801 and returned to Boston where he joined his father, also a well
known surgeon, in practice. After his father’s death in 1815, Warren assumed the
Hersey Professorship in Anatomy and Surgery at Harvard University where he
served as the first dean of the Harvard Medical School and was a founding member
of the Massachusetts General Hospital.
Throughout his career, Warren had a keen interest in exercise and in 1845 he
published Physical Education and Preservation of Health in which he argued that
there must be a balance between intellectual and physical education. Warren empha-
sized that exercise must begin in early childhood and continue throughout life if one
hopes to maintain good health into old age. He noted that children were not meant
to be still for long periods of time and that parents should not force them to spend
long hours studying without breaks for physical activity. They should be allowed to
spend several hours playing without structure and they should not spend more than
6–7 h a day in a classroom.
The risk of emphasizing classroom studies over exercise was the development of
a “delicate constitution” that led to increased susceptibility to illness [5]. Like most
male physicians of his time, Warren considered girls to be the “weaker sex” with a
hyperactive nervous system that was particularly vulnerable to extended periods of
intellectual activity without breaks. He warned that literary pursuits could be destruc-
tive to the health of young women. He was particularly concerned about the effect on
the young lady’s posture of long hours “slumping” over a desk reading or writing.
For girls, Warren recommended walking outside in the open air, erect not looking
at the ground, and dancing in small groups stimulating muscles of the body and
lower limbs giving them grace and power. To exercise the upper extremities he sug-
gested the girls swing on a bar suspended from the ceiling with ropes, the “triangle”.
For boys, he recommended going to a gymnasium for a minimum of 2 h of physical
activity a day.
Exercise and Early Neurology
One of the founding fathers of American Neurology, S. Weir Mitchell, had a life-
long interest in exercise and repeatedly emphasized the importance of regular physi-
cal activity for maintaining good mental health. Mitchell grew up, was educated and
practiced medicine in Philadelphia where he specialized in treating women with
neurasthenia, a common neuropsychiatric diagnosis at the time. Mitchell developed
his interest in Neurology while working with soldiers with nerve and brain injuries
during the American civil war.
In the 1880s, Mitchell published two best selling books for the lay public: Wear
and Tear, or Hints for the overworked and Fat and Blood: An Essay on the Treatment
of Current Forms of Neurasthenia and Hysteria. In Wear and Tear, Mitchell sum-
marized his misogynistic views on women’s mental health shared by most neurolo-
gists of the time [6]. Although both men and women were susceptible to neurasthenia,
women were particularly susceptible because of their weak constitution. Mitchell
felt that young girls between the age of fourteen and eighteen were at particular risk
and that it was probably best not to try to educate girls in that age range. Their lim-
ited energy was best directed towards developing skills required for their future
roles as wives and mothers rather than being wasted on mental pursuits. Physical
activity was limited to that received during their household chores.
In Fat and Blood, Mitchell described his famous “rest cure” for women with
neurasthenia [7]. The women were sequestered from their family to prevent interfer-
ence and were confined to bed for 6–8 weeks. Twice a day in the morning and eve-
ning they were lifted onto a bedside lounge where they stayed while their bed was
remade. Throughout the day they were constantly fed great amounts of high fat
foods including two gallons of milk. This was done to restore the “fat and blood”
that was presumably depleted by stress and overwork.
The cruelest part of the treatment was that they were prohibited from reading,
writing or performing any type of intellectual activity. Not even manual tasks such
as sewing or crocheting were permitted. In place of physical activity they received
massages and electrical stimulation of their muscles, considered “passive exercise”.
Paradoxically, Mitchell repeatedly emphasized the importance of regular physi-
cal activity for good mental health particularly for his women patients with neuras-
thenia [8]. He suggested that one potential benefit of the rest cure was that it made
women eager to return to normal physical activities including exercise. Mitchell
even resorted to extreme methods to force his women patients out of bed to exercise.
For example, on one occasion he drove a patient half way home where he left her to
walk the rest of the way on her own.
Early Ideas on Physical Education 5
Mitchell noted that men with neurasthenia didn’t do so well with his rest cure so
for them, which included Teddy Roosevelt and Walt Whitman, he recommended the
“West cure”, sending them to visit the western part of the United States to engage in
vigorous physical activity and to write about their experiences.
Early Ideas on Physical Education
In 1887, J William White, another Philadelphia physician, published an article for

the Lippincott’s magazine lauding the benefits of exercise for acquiring and main-
taining good health that had a major impact on American physicians at the turn of
the century. White was a well respected surgeon and an avid sportsman who joined
the faculty of the University of Pennsylvania Medical School in 1874. He loved to
sail and in 1880 he swam the cold, rough ocean from Newport to Narragansett
Rhode Island making the 10 mile swim in 5 h and 40 min. White wrote that exercise
was “by far the most important therapeutic and hygenic agency at the command of
the physician” and that it was as good “as any of the drugs of the pharmacopeia.” [9].
By the end of the nineteenth century, all states mandated instruction in the “Laws
of Health” (physical education) in public schools. Two books published in the first
decade of the twentieth century nicely summarized the new emphasis of physical
fitness in maintaining good health.
In 1904, Harvard physician Dudley Sargent published Health, Strength and
Power based on his experience with physical education programs at several col-
leges [10]. After graduating from Bowdoin College in 1875, Sargent became an
instructor in gymnastics at Yale College and in the same year opened his own
private gymnasium in New York. A year later he was appointed assistant professor
of physical training and head of the Hemenway Gymnasium at Harvard University.
Sargent recognized the need for trained teachers in the field of physical education
and he developed a gymnasium in Cambridge that ultimately became the Sargent
School of Physical Education. He also organized courses in physical education
training at Harvard University summer school which he personally taught
until 1919.
In 1909, University of Pennsylvania physician and medical educator, R. Tait
McKenzie published Exercise in Education and Medicine in which he emphasized
the importance of teaching physical education to medical students and medical
practitioners. He pointed out that “Exercise and massage have been used as reme-
dial agencies since the days of Aesculapius, but definite instruction in their use has
seldom been given to medical students.” [11].
As with most of his fellow physicians, McKenzie divided exercise into two cat-
egories: active that required exertion of will-power and passive that did not require
exertion of will-power, both important for treating disease. Physicians used a vari-
ety of passive exercises at the time (massage, muscle stretching by hand or machine,
electrical stimulation of nerves and muscles) and McKenzie noted that passive exer-
cise had the advantage of being restful, not exhausting an over-wrought brain. He
warned that physicians often preferred “the administration of pill or draught to
purge the system” rather than the use of normal muscular activity.
With the onset of World War I and the subsequent great depression there was
little time for concern about physical fitness in the American population. When the
country was finally dragged into World War II, people were shocked to find out that
a third of all potential draftees could not pass a simple test of physical fitness. A
decade later, American school-age children were administered a standardized test of
physical fitness that included leg lifts, sit-ups, trunk lifts and toe touches and almost
60% failed at least one component of the test compared to less than 10% of European
children who took the test.
Thomas Cureton and the Science of Physical Education
In the first half of the twentieth century, there were no accepted standards for achiev-
ing physical fitness in children or adults. Into this vacuum stepped Thomas
K. Cureton Jr. who was recruited to the University of Illinois in Urbana in 1941 and
established the Physical Fitness Research Laboratory in the Department of Physical
Education for Men in 1944 [12]. Cureton would go on to produce scientific research
to corroborate his belief that physical fitness was a key to health and longevity.
Cureton developed tests for muscular strength and flexibility and cardiorespira-
tory endurance and identified exercise intensity guidelines necessary for improving
fitness levels. He is often considered to be the father of the twentieth century physi-
cal fitness revolution in America.
Cureton was a strong proponent of exercise for heart health and even though he
initially encountered skepticism from colleagues particularly in the cardiology
community, he doggedly persisted with research studies confirming his beliefs. For
example, most cardiologists at the time recommended against exercise after a heart
attack for fear of a repeat heart attack but Cureton showed that a gradual exercise
program actually decreased the risk of a recurrent heart attack.
In 1954, Cureton was featured in a CBS television series entitled: The Search for
Health and Fitness in which he emphasized the importance of exercise for maintain-
ing health and warned of the dangers of lack of physical activity. In a Time-Life
Book, The Healthy Life: How Diet and Exercise Affect Your Heart and Vigor pub-
lished in 1966 and read by millions of Americans, Cureton was pictured taking his
daily run through a cemetery near the University campus. The caption read: “As part
of his own fitness program, Dr. Thomas K. Cureton, Jr. jogs near the University of
Illinois. His workout takes him through a cemetery where some of his colleagues
who once called him a ‘health nut’ now rest.” [13].
Physical Fitness and Sports
By the mid twentieth century, it became clear that Americans were lagging
behind other countries in the level of physical fitness and that there were major
problems with the model of physical education as it was being taught in the
United States. Physical education had become synonymous with sports
Kenneth Cooper and Aerobics 7
education. In high schools, the football or basketball coach taught physical edu-
cation classes with an emphasis on the best athletes who excelled in the major
sports. The average student who had the most to gain from an exercise program
was largely ignored. At the college level, physical education courses were con-
sidered trivial, for major sport athletes on scholarship, allowing them to maintain
their grade point average.
Some of the nation’s leading educators considered post-graduate programs in
physical education a joke and recommended that universities cancel such programs.
Others called for a major reorganization of the programs placing an emphasis on
scientific research to create a true academic discipline. A few suggested changing
the name to exercise science or kinesiology to remove the stigma of the term physi-
cal education.
Into this quagmire, stepped the American College of Sports Medicine (ACSM)
in 1954 with the goal of introducing scientific methodology into the field of physical
education. A large number of the founders of the ACSM were physicians with an
interest in heart health. They wanted to bring exercise back into the realm of medi-
cine particularly in the field of cardiology. More recently the ACSM has spear-
headed the campaign to convince physicians and health workers that exercise is
medicine [14].
Based on the alarming statistics showing American children lagged behind chil-
dren in other parts of the world in physical fitness, President Eisenhower, in 1956,
established the President’s Council on Youth Fitness and the President’s Citizens
Advisory Committee on the Fitness of American Youth. In the early 1960s, President
Kennedy, who strongly believed in the benefits of exercise for improving the nation’s
health, wrote an article published in Sports Illustrated entitled The Soft American in
which he lamented that Americans were “under-exercised as a nation.”
Kennedy was well aware of the ancient Greek concept of a sound body for a
sound mind. He wrote: “The relationship between the soundness of the body and the
activities of the mind is subtle and complex. Much is not yet understood. But we do
know what the Greeks knew: that intelligence and skill can only function at the peak
of their capacity when the body is healthy and strong; that hardy spirits and tough
minds usually inhabit sound bodies.” [15].
The well-known author, James Michener, may have best summarized the
American situation in the mid twentieth century in his book Sports in America when
he wrote: “Our educational system was stressing so heavily the public games played
by a few semi-professional athletes posing as scholars that the general health of the
student body was going unattended, and the tests proved this.” [16].
Kenneth Cooper and Aerobics
Exercise for fitness and preventative health in the United States received a major
boost with the publication of Aerobics in 1968 by Kenneth Cooper [17]. By add-
ing an “s” to aerobic, the type of exercise that burns oxygen, Cooper introduced a
new exercise concept that rapidly caught the American public’s interest. Almost
over night, millions of people across the country began exercising routinely, meet-
ing their weekly and monthly point quotas of 30 points per week or 120 points
per month.
Cooper identified aerobic activities such as running, brisk walking, biking and
swimming and in the book he provided charts that assigned points for each activity
based on the duration and completed distance. For example, if you walked 2 miles
in 30–40 min you received 2 points but if you walked the same distance in 24–30 min
you received 4 points. If you ran 2 miles in 16–20 min you received 8 points whereas
if you ran the same distance in less than 13 min you received 12 points. He also
assigned points to different sporting activities with the highest number for hand ball
and racket ball and the lowest number for golf and horseshoes.
However points were acquired, it was important to spread the points out over the
week with exercise at least 4 times a week or every other day. Cooper was a “statis-
tics nut” and could rattle off a stream of statistics regarding the benefit of exercise
based on one’s age and fitness. For example, based on research performed at his
Institute he famously stated: “If you’re 80, you should be able to make a mile in
17 min. If you can, you have an 84 percent chance if you’re a man and an 86 percent
chance if you’re a woman to live to age 90.” [18] True to his statistics, he recently
turned 90 and is still exercising regularly although he has given up running and is
now taking brisk walks.
After completing medical school and graduate training in exercise physiology,
Cooper entered the United States Air Force where his task was to determine the
effects of exercise on the human body particularly in pilots and astronauts. He had
access to the most advanced testing equipment in the field of exercise physiology
and a seemingly unlimited supply of young healthy men to test the equipment on.
Most important, as is immediately obvious to the reader of Aerobics, Cooper was
personally fanatical about exercise and its health benefits.
Cooper described how young men who were anxious were able to relax, intro-
verts became extraverts, depression was cured and diabetics were able to reduce or
eliminate medications. The only thing that stood between the reader and better
health was proper motivation to stick to an exercise program. Of all the different
types of exercise assessed in Aerobics, Cooper preferred running since it provided
the most bang for the buck.
To Cooper, the bottom line was oxygen consumption and the goal of exercise
endurance training was to improve the amount of oxygen that the body can take in
and deliver to the organs. The difference between minimum oxygen requirement
and maximum oxygen capacity is a measure of cardiovascular fitness. The wider the
difference, the better the fitness. Interestingly, Cooper did not endorse several popu-
lar exercises at the time including calisthenics, weight lifting and isometrics because
they did not make much of a demand on oxygen consumption and therefore did little
to improve cardiovascular fitness. They might improve muscle size and strength but
he felt that exercise endurance was most important for overall health.
Two years after publishing Aerobics, which was translated into 16 languages and
sold several million copies, Cooper left the Air Force and set up a clinic and research
institute in Dallas, Texas that focused on the health benefits of exercise. Years later
Physical Inactivity and Poor Health 9
in 1984, Cooper and his many devoted followers faced a troubling dilemma when
Jim Fixx, Cooper’s friend and the author of the popular book, The Complete Book
of Running, died of a heart attack at age 52 while he was on his daily run. Fixx was
known to regularly run 60 miles a week. Could too much exercise be dangerous?
After grappling with this question, Cooper wrote a book called Running Without
Fear in which he concluded that Fixx’s death was due to hereditary causes and not
from too much exercise. However, over the subsequent years, Cooper began to
accumulate anecdotal evidence of excessive deaths from cancer, particularly pros-
tate cancer, in athletes who participated in extreme exercise events such as mara-
thons and Ironman competitions causing him to gradually change his mind on the
subject [19]. He admitted that extreme exercise may interfere with the body’s
immune system making these super athletes more susceptible to developing cancer.
It is important to note that these people were exercising at a level far beyond what
most people do accumulating hundreds of Cooper points per week and it can be
extremely misleading to base conclusions on anecdotal information without proper
sampling of a broad population. Curiously, the rate of heart attacks in the United
States peaked around the time of Cooper published Aerobics and subsequently has
been gradually decreasing although this trend is likely due to a variety of factors
including medical advancements and improved diets in addition to overall increased
exercise.
Physical Inactivity and Poor Health
As the evidence that increasing physical activity increased longevity and decreased
the risk of developing a variety of chronic diseases accumulated throughout the
twentieth century, it also became apparent that physical inactivity had the opposite
effect, decreasing longevity and increasing the risk of developing chronic diseases.
Compared to the difficulties of accurately measuring the level of physical activity, it
is relatively easy to measure physical inactivity and the number of people who are
physically inactive is rapidly increasing.
The Harvard alumni health study organized by Ralph Paffenbarger followed
almost 17,000 male alumni who graduated between 1916 and 1950 with regular
questionnaires documenting the level of physical activity (estimated Calories
expended per week), lifestyle characteristics and health outcomes [20]. Death rates
were highest in those who were physically inactive, i.e. expended less than 500
Calories per week, and the rates declined steadily as the expended Calories increased
from 500 to 3500 Calories per week. Beyond this point death rates slightly increased.
Of all the potential risk factors that were investigated, the relative risk of death was
highest for physical inactivity and smoking.
Paffenbarger received an MD degree from Northwestern University and a PhD in
epidemiology from Johns Hopkins University, and moved to the West Coast where
he was professor of epidemiology at UC Berkely and Stanford [21]. He maintained
a lifelong interest in the effects of exercise on health. He and his colleagues contin-
ued to follow the Harvard alumni and overall the relationship between physical
activity and longevity remained consistent [22]. Furthermore, it didn’t seem to mat-
ter if the exercise was carried out in a single session or broken up into multiple ses-
sions or if the exercise began later in life.
Paffenbarger, himself became an exercise fanatic in his mid 40s when he took up
competitive running. He competed in the Boston marathon 22 times and overall
finished more than 150 marathons. He suffered from heart disease for the last sev-
eral years of his life and died at age 84 of heart failure. The Harvard alumni study
had the tantalizing finding that extreme exercise, more than 3500 Calories expended
per week slightly increased the risk of cardiovascular death although the risk was
still much lower than someone who was physically inactive. Finally, it must be
noted that the Harvard alumni study focused mainly on affluent middle-aged white
men and thus was not necessarily representative of the overall population.
Physical Fitness and Longevity
After Kenneth Cooper established his clinic in Dallas, Texas, he organized a non-
profit research institute in 1970 with the goal of studying the long-term relationship
between exercise and health and wellness. In 1989, researchers at the institute
reported the results of follow up of 10,224 men and 3,120 women evaluated at the
Cooper Clinic from 1970 to 1981 [23]. Nearly all were middle to upper class whites
employed in white-collar jobs. A unique feature of the study was that in addition to
questionnaires about physical activity, on entry, subjects underwent a standardized
treadmill exercise test to quantify physical fitness. With this test subjects were mon-
itored on a treadmill that gradually increased grade and speed until the subject
reached maximum effort. The total treadmill time in seconds until the subject termi-
nated the test was shown to be a good estimate of maximum oxygen consumption,
the gold standard for cardiovascular fitness (discussed later in the chapter).
There were 240 deaths from all causes in men and 43 in women during follow up
and the mortality rate declined across physical fitness quintiles from 64.0 per 10,000
person years in the least fit men to 18.6 per 10,000 person years in the most fit and
39.5 per 10,000 person years in the least fit women to 8.5 per 10,000 person years
in the most fit. Both men and women in the unfit group were 8 times more likely to
die of cardiovascular disease, the most common cause of death, than men and
women in the highest quintile.
Interestingly, the largest drop in mortality occurred when moving from the first
quintile of physical fitness (those who were largely physically inactive) to the sec-
ond quintile (those with a relatively low level of physical activity) with a slow rate
of decline thereafter. Just a small improvement in physical fitness has a large health
benefit in someone who is physically inactive. Consistent with this notion, in a fol-
low up study published in 1995, they found that initially unfit men in the first quin-
tile who became at least moderately fit on a subsequent exam reduced their all-cause
death rate by 65% compared to their peers who remained unfit [24].
As we will see shortly, physical fitness and physical activity are interrelated but
they are not the same thing. There is a definite genetic component to physical fitness
Public Health Implications of Physical Inactivity 11
probably accounting for about 30% of the overall level of physical fitness. In other
words, it is easier for some people to become physically fit than others based on their
genetic profile. However, it is well established that increasing physical activity can
improve physical fitness regardless of genetic profile although it is still debated as to
how much and what kind of physical activity is best for improving physical fitness.
To address this question during follow up examinations of patients seen at the
Cooper Clinic between 1987 and 1993, researchers at the Cooper Institute used a
more elaborate physical activity questionnaire and identified the physical activity
patterns associated with low (first quintile), moderate (second and third quintile)
and high (fourth and fifth quintile) levels of physical fitness measured with their
standard treadmill test. In an article published in 1998, they reported that the aver-
age energy expenditure of men in the moderate to high fitness levels was 525–1650
Calories per week and for women, 420–1260 Calories per week [25].
These levels of energy expenditure could be achieved by walking most days of
the week. Indeed, men and women in the moderate and high fitness categories
reported walking between 130 and 167 min/week, physical activity levels that can
easily be achieved and tolerated by most middle aged and even older people. A rela-
tively small increase in energy expenditure, getting above about 500 Calories per
week was enough to have a significant impact on improving mortality rate and even
better improvement in mortality rate was achieved with energy expenditure around
1500 Calories per week, a level easily accomplished with regular brisk walks.
Public Health Implications of Physical Inactivity
In an article entitled Physical inactivity: the biggest public health problem of the
twenty-first century published in 2009, Steven Blair, one of the senior investigators
at the Cooper Institute, argued that “the crucial importance of physical activity is
undervalued and underappreciated by many individuals in public health and clinical
medicine.” [26].
To support his premise, Blair included a graph based on long-term follow up of
the large population of men and women from the Cooper Clinic showing the “attrib-
utable fraction” of deaths in the population that could have been avoided if a specific
risk factor had been absent. For example, if all smokers stopped smoking or all inac-
tive people began taking daily walks how many less deaths would have occurred.
The single largest attributable fraction of deaths was low physical fitness accounting
for about 16% of all deaths in men and women. By comparison, smoking accounted
for about 8% and obesity and type 2 diabetes accounted for about 3% each. Only
hypertension in men, accounting for about 15% of deaths, approached the number
attributable to physical inactivity.
Despite the high risk associated with physical inactivity, Blair speculated that the
typical physician was much more likely to order blood tests and check weight and
blood pressure than measure physical fitness during a routine exam. He argued that
physicians should at least ask about physical activity and talk about the importance of
exercise in the maintenance of good health. Unlike some earlier studies that touted the
health benefits of high-intensity exercise, the Cooper Institute study found that mod-
erate-intensity exercise such as brisk walking most days of the week for 30–40 min
was enough to achieve a high percentage of the potential health benefits of exercise.
Large healthcare systems like Kaiser Permanente have the flexibility to try inno-
vative approaches to public health, and Kaiser has made a major commitment to get
their patients to exercise more when they launched a massive campaign called
“Thrive” in 2004. Since 2009, Kaiser Permanente of Southern California has added
exercise to the vital signs to assess each patient’s exercise habit. In addition to
assessing height, weight and blood pressure, patients are asked: (1) “on average,
how many days per week do you engage in at least moderate (brisk walk or greater)
exercise” and (2) and “on average how many minutes per session.” [27].
The goal is to get all patients to do at least 150 min of exercise per week. From
their digital records they can identify high-risk patients and focus resources on these
patients. For example, statistics show that Kaiser spends about $1 out of every $10
caring for patients with type 2 diabetes. Fitness counselors can identify the highest
risk patients and work with them to increase their exercise level. Patients are sent a
pedometer with instructions on how to use it and goals for daily step counts. The
counselors then follow up the patients to provide encouragement and monitor com-
pliance. Time will tell how effective this program will be.
Body Weight and Energy Metabolism
Body weight is determined by a simple formula: energy intake (EI) minus energy
expenditure (EE) equals weight (W).
EI – EE = W
If you take in more energy (food) than you expend you will gain weight. On the
other hand, if you expend more energy than you take in you will lose weight. The
body uses energy in three ways: (1) at rest to maintain life-sustaining functions (the
so-called resting metabolic rate, RMR), (2) after food intake to digest and store
nutrients, and (3) during physical activity to increase respiration, circulation and
muscle contractions.
The calorie is a common unit used to measure the amount of energy intake and
expenditure. It is defined as the amount of energy needed to increase the tempera-
ture of 1 gram of water one degree Celsius. Since this is a tiny amount of energy, the
kilocalorie, 1000 calories (kcal or Calorie with a capital C) is the unit most com-
monly used to measure energy intake and expenditure.
The average American consumes about 3600 Calories in food per day (up 25%
from 1961). This is a lot of Calories to burn so it is not surprising that many
Americans are becoming obese. If the current trend continues, about 50% of the
population will be obese by 2050. The average resting metabolic rate and food
related energy expenditure rate use about 1800–2000 Calories per day and this num-
ber is relatively stable across human populations so the main way to increase energy
expenditure is to increase physical activity.
Aerobic Versus Anaerobic Physical Activity 13
Although it is possible to lose weight even with a high Calorie diet, research
studies have consistently shown that increasing physical activity alone without con-
trolling diet is not very effective for achieving long-term weight loss [28]. The com-
bination of decreasing food intake while increasing physical activity is the best
strategy to maintain weight loss.
Physical Fitness, Obesity and Cardiovascular Disease
Measurements of height and weight are routinely obtained during most doctor vis-
its. From these numbers the doctor can calculate your body mass index (BMI)
defined as weight in kilograms divided by height in meters squared (kg/m2). There
are several web sites that calculate BMI based on pounds and inches. A BMI <17.5
is underweight, 17.5–25 normal weight, >25 overweight, >30 mildly obese, >35
moderately obese and >40 severely obese.
In most cases, patients who are overweight or obese are told to diet and exercise
to help lose weight which will decrease the risk of developing a variety of chronic
medical conditions. But exercise has health benefits independent of its effect on
obesity. Numerous studies have found that exercise and improving physical fitness
attenuates and may even eliminate the risk of chronic diseases associated with obe-
sity. In other words, obese people benefit from exercise even if they do not
lose weight.
The Cooper Institute study mentioned earlier found that obese people who were
physically fit were less likely to die during follow up than people with normal
weight who were not physically fit [29]. A moderate to high cardiovascular fitness
level eliminated the elevated risk of all cause, cardiovascular and cancer mortality
associated with obesity. Other studies found that being physically fit did not com-
pletely reverse the elevated mortality risk associated with obesity but the benefit of
improved fitness was greater than the benefit of just losing weight. The message of
these studies is that physicians should be touting the benefits of exercise in over-
weight and obese patients even if they do not lose weight [30].
Aerobic Versus Anaerobic Physical Activity
Physical activity can be divided into two broad categories based on whether or not
oxygen is required: aerobic physical activity requires oxygen, anaerobic physical
activity does not require oxygen. By its very nature anaerobic physical activity
can only be maintained for brief bursts since it depends on stored energy in mus-
cle that is rapidly depleted. Aerobic physical activity uses fuel much more effi-
ciently than anaerobic physical activity and can be maintained for a much longer
time period.
Aerobic exercise is often called cardiovascular exercise or just “cardio” since
breathing and heart rate are increased for a sustained period of time. To maxi-
mize oxygen content in the blood you breathe faster and deeper and the heart rate
goes up to increase blood flow to muscles and back to the lungs. Examples of
aerobic exercise include swimming laps, brisk walking, running or cycling long
distances.
Since anaerobic exercise requires immediate energy, muscles rely on stored
energy sources mainly the break down of glucose to lactate. Anaerobic exercise
results in a build up of lactate in the muscles and measurements of blood lactate
levels can be used as a marker of anaerobic exercise. Examples of anaerobic exer-
cise include: brief sprints, jumping and weight lifting. Both types of exercise can
improve brain health and as we will see can have different mechanisms for improv-
ing brain function.
So which type of exercise is best for you? The simple answer is probably a com-
bination of both although it depends on your health and fitness goals. For those who
are just beginning to exercise it is probably best to focus on aerobic exercise to
increase fitness and endurance gradually increasing the duration, frequency and
intensity over time. In addition to its effect on the brain, aerobic exercise has obvi-
ous benefits to the cardiovascular system and has been shown to decrease the risk of
high blood pressure, type 2 diabetes, heart attacks, stroke and dementia.
Anaerobic exercise can be particularly beneficial for those who want to build
muscle bulk and to burn fat to lose weight. It can be added to aerobic exercise over
time providing additional benefits and new goals for an exercise routine. Anaerobic
exercise can also strengthen bones and increase overall stamina although it does
place a greater strain on muscles and joints so it may not be for everyone. As we will
see later, it also releases hormones (myokines) that can improve brain function.
Most research studies that have assessed the relationship between exercise and
cognitive function have focused on aerobic exercise since it is easiest to measure
and everyone can participate. There is an anaerobic component to all exercise, how-
ever, depending on the intensity, frequency and duration of the exercise.
Another way of looking at these two basic types of exercise is the strength—
endurance continuum. At one end of the continuum is anaerobic exercise character-
ized by brief heavy resistance strength exercises such as lifting near maximum
weight barbells while at the other end of the continuum is aerobic exercise charac-
terized by running or cycling for at least 30 min. The goal of the weight lifting is to
improve muscle strength while the goal of the running and cycling is to improve
cardiovascular fitness. In between these extremes are a wide variety of intermediate
types of exercise such as repetitive lifting of low weight barbells or brief bursts of
near maximum intensity sprinting or cycling. As a general rule, exercises on the
strength end of the continuum focus on the muscles involved in the exercise whereas
exercises on the endurance end of the continuum focus on cardiovascular fitness.
Oxygen Utilization and Fitness
Since muscles have a limited amount of stored energy that is rapidly depleted with
exercise, for any sustained physical activity, energy substrates (glucose and fat)
along with oxygen must be transported to the working muscles and by-products of
Oxygen Utilization and Fitness 15
the substrate breakdown (lactate and carbon dioxide) must be removed from the
muscles. This means that blood flow to and from the working muscles must increase
as much as 100-fold with very high intensity exercise [31].
The increase in blood flow is achieved by two main mechanisms: (1) redirecting
blood flow from other organs to the working muscles, and (2) increasing cardiac
outflow. Redistribution of blood flow is accomplished by dilatation of arteries to the
working muscles and constriction of arteries to other organs. The autonomic ner-
vous system manages the blood redistribution by relaxing the smooth muscles in the
walls of the small arteries supplying working muscles while constricting the mus-
cles in the walls of the small arteries supplying other tissues.
Cardiac outflow increases by increasing the heart rate and the stroke volume
associated with each heart beat. For example, with vigorous exercise the heart
rate can triple and the stroke volume nearly double so that cardiac outflow can
increase by about fivefold in someone who is physically fit. At the same time that
blood flow to working muscles is increasing, blood flow to the lungs and the
respiration rate are also increasing to improve the gas exchange rate, namely
oxygen extraction during inspiration and carbon dioxide removal during expira-
tion. The ventilation rate during vigorous exercise can increase from 15 to 20
times the resting rate.
The maximum oxygen uptake capacity is a good indicator of overall cardiovascu-
lar fitness reflecting the function of the entire oxygen delivery system [32].
Measuring the maximum oxygen uptake requires a sufficient physical effort to fully
tax the aerobic energy system. It is typically measured with a graded exercise test
on a treadmill or cycle ergometer in which the intensity is gradually increased while
measuring oxygen and carbon dioxide concentration in the inhaled and exhaled air
using a special breathing apparatus (Fig. 1.1). This was the method initially used by
Kenneth Cooper, mentioned earlier in his book Aerobics [16].
The maximum oxygen uptake occurs when oxygen consumption remains at a
steady state despite increased workload. An obvious limitation of maximum oxygen
uptake measurements is the need for specialized equipment that is not readily avail-
able to most people. Since it has been shown that there is a good correlation between
maximum oxygen uptake and timed trials of maximum performance such as the
time to run a specified distance or the distance one can cover in a specified time,
timed trials can be used as a rough estimate of maximum oxygen uptake.
Another way to estimate of maximum oxygen uptake is to use the maximum
heart rate that can be achieved under maximum exertion [28]. Since the maximum
heart rate is age dependent, a general formula of 220—age is often used to estimate
the expected maximum heart rate for a person of a given age. For example, if you
are 60 years-old, your maximum heart rate should be 220–60 or 160 beats per min-
ute. However, just as with maximum oxygen uptake, maximum heart rate varies
greatly with cardiovascular fitness and age so the best way to determine the maxi-
mum heart rate in someone regardless of fitness and age is to measure it directly on
an endurance test just like the one used to measure maximum oxygen uptake.
Instead of measuring the maximum oxygen consumption, one measures the maxi-
mum heart rate achieved during maximum performance.
Fig. 1.1 Apparatus for measuring maximum oxygen uptake capacity (VO2max) during a graded
exercise test on a treadmill
Exercise Training for Improving Fitness
The two main goals of exercise training are to improve fitness and to promote good
health [33]. These two goals are interrelated but each has unique features. For the
remainder of this chapter we will focus on cardiovascular fitness and later in the
book will focus on health related issues particularly brain health.
The best estimate of the energy expended during aerobic exercise is to measure
the volume of oxygen utilized during the exercise activity. One metabolic equivalent
(MET) is approximately the amount of oxygen consumed by an individual at rest
(the resting metabolic rate, RMR). By comparison, an average person uses approxi-
mately 4 METs during brisk walking and about 8 METs while jogging. Tables are
readily available on-line listing the METs associated with a wide variety of exer-
cises, physical activities and sports. But it is important to keep in mind that there is
a strong relationship between METs and maximum oxygen uptake capacity. The
number of METs associated with a specific exercise activity depends on an indi-
vidual’s fitness level.
With any physical activity there are three variables, intensity, duration and fre-
quency that determine the energy expended and the improvement in fitness achieved.
Exercise Training for Improving Fitness 17
It is important to have a balance between the intensity, duration and frequency when
planning any exercise routine. With a few important exceptions, one can think of
these three variables as being roughly equivalent to achieving the goal of improved
cardiovascular fitness. For example if you double the intensity you can roughly
halve the duration or if you double the frequency you can halve the duration.
There is a minimal intensity that must be achieved in order to improve fitness.
The relationship between intensity and improvement in fitness is not linear but
rather parabolic so that increasing intensity up to a certain level provides more ben-
efit than increasing duration, but at some point further increases in intensity are less
beneficial than increasing duration. Furthermore, it is important to spread the physi-
cal activity out over time with at least 3 sessions a week in order to maintain the
improvement in fitness.
One way to describe the intensity of any physical activity is to indicate the per-
centage of maximum oxygen uptake or maximum heart rate achieved during the
activity. Although the numbers vary slightly among sources, moderate intensity
activity is in the range of 50–69% and high intensity is >70% of maximum oxygen
uptake or maximum heart rate.
A simple but reliable technique to document the level of physical activity is to
monitor an individual’s heart rate throughout the day. For example, a 65 years old
woman with a maximum heart rate (beats per minute) of approximately 155 is doing
moderate physical activity when her heart rate is between 78–107 (55-69% of 155)
and vigorous physical activity when her heart rate is >107 (>70% of 155). The
World Health Organization (WHO) recommends that people should do a minimum
of 150 min/week of moderate intensity physical activity or 75 min/week of high
intensity physical activity (see Chap. 11).
Examples of moderate-intensity physical activities include:
• Walking at least 2.5 miles per hour

• Dancing (ballroom or social)
• Water exercises
• Light gardening
• Doubles tennis
• Leisure biking at less than 10 miles per hour
Examples of high-intensity physical activities include:
• Running
• Aerobic dancing
• Swimming laps
• Hiking uphill
• Heavy gardening
• Singles tennis
• Fast cycling greater than 10 miles per hour
• Jumping rope
To improve cardiovascular fitness you need to gradually increase the amount

and intensity of physical activity over time. If you are just starting out from a base-
line of total inactivity it is important to slowly begin with short walks at a leisurely
speed several times a day. Walking outside in the fresh air provides additional
health benefits compared to walking inside. But just standing up and moving about
indoors increases METs expended from one to two or three per minute. Although
this small amount in physical activity will not increase fitness very much it can
improve health status and is a start toward activities that will significantly increase
fitness.
Beginning Exercise Training
If you are physically inactive or have a low level of physical activity, regardless of
age, there is little risk to increasing physical activity with walking. As suggested
above, begin with short distances and gradually build up. Even a small increase in
physical activity can have significant health benefits.
To improve cardiovascular fitness you need a baseline assessment of fitness that
requires increasing to maximum effort. Is it safe to push to a maximum level of
physical activity? The key variables are your age and overall health status with par-
ticular emphasis on heart status. Young, less than age 50, people without a personal
or family history of early onset heart disease don’t require any specific testing unless
they have symptoms such as chest pain when exercising. People between ages 50
and 65 should probably have a routine evaluation by their primary physician to be
sure there are no cardiac diseases or cardiovascular risk factors such as hypertension
or type 2 diabetes that would require monitoring and possibly medical treatment as
exercise is increased.
Anyone over the age of 65 should undergo a cardiac assessment including a car-
diac stress test to be sure it is safe to push toward maximum effort that is required
to estimate cardiovascular fitness. It is well known that decreased blood flow to the
heart muscle due to coronary artery disease in older people can result in nonspecific
symptoms such as chest tightness and indigestion without typical chest pain so you
can’t rely on the absence of symptoms to rule out coronary artery disease. Since the
cardiac stress test accurately monitors heart rate as one pushes toward maximum
endurance, it is a good way to estimate the baseline fitness for the start of fitness
training. Your cardiologist can provide you with a rough estimate of your maximum
oxygen uptake.
Obviously, the approach to designing a training exercise program depends on the
baseline level of fitness and is much different for a dedicated athlete, a weekend
recreational athlete or a person who is totally inactive [34]. Age and overall health
status are also critically important. As already noted, the greatest increase in fitness
and health status, “the biggest bang for the buck”, occurs with an increase in physi-
cal activity in a person who has previously been inactive. Getting that person to be
able to take brisk walks for a total of 150 min/week will achieve at least 60% of the
potential health benefits of exercise. A basic premise is to start with a low intensity
References 19
and short duration and gradually increase intensity and duration as training evolves.
The body needs weeks and in older people months to slowly adapt from low level
activity to increased physical activity.
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Physical Activity and Brain Evolution
2
Nothing in biology makes sense except in the light of evolution.—Theodosius Dobzhansky [1]
For most of our existence, humans have lived a hunter-gatherer lifestyle with high
levels of physical activity [2]. Two major changes in physical activity occurred in
the last 0.5% of our existence, first with the agricultural revolution that gradually
took place between approximately 12,000–5000 BC and second with the industrial
revolution that rapidly occurred between the late 18th to the early 20th centuries.
The invention of agriculture changed the nature of physical activity whereas indus-
trialization dramatically reduced the overall level of physical activity. Our brains
that evolved during times of high physical activity were subject to a variety of
chronic diseases when activity levels decreased.
Hunter-Gatherer Societies
Early human species, marked by increased brain size and use of stone tools devel-
oped about two million years ago and spread across Africa and Eurasia (Fig. 2.1).
Our species, Homo Sapiens, emerged about 300,000 years ago in Africa. It is just
one of several hunter-gatherer human species that relied on a mixture of wild ani-
mals and plant foods for survival.
Based on fossil evidence, early Homo Sapiens had a high death rate for new born
infants and children so that the average survival rate was less than 30 years. It would
be a mistake, however, to conclude that adults in these hunter-gatherer societies had
markedly shortened life spans compared to modern humans. Fossil records indicate
survival rates in people who live to age 40 have remained relatively stable for at
least 50,000 years.
From an evolutionary perspective what would be the advantage for Homo Sapiens
surviving so long after their reproductive life span? Anthropologists have specu-
lated that survival into the 70s and beyond can be explained based on the benefits of

https://doi.org/10.1007/978-3-031-13924-6_2
22 2 Physical Activity and Brain Evolution
Hunter Homo
Orangutans Gorillas Bonobos Chimpanzees gatherers Sapiens
Common ~ 16 million ~ 6 million ~ 2 million ~ 300,000

ancestor years ago years ago years ago years ago
Fig. 2.1 Evolution of the human species
having grandparents who possess knowledge of cultural traditions and hunting tech-
niques. Grandmothers were particularly important since they played a critical role
in childcare and household chores as younger women participated in food gathering
and preparation activities. Having older people in the societies improved the sur-
vival of younger people in their reproductive years.
Although there are several current day hunter-gatherer societies around the world
that have been studied in great detail, it is important to keep in mind that there are
limitations to the results of these studies as a model of ancient hunter-gatherer soci-
eties. In addition to the obvious differences in the overall environment of the planet
in which they live, these societies can’t help but be influenced by modern medicine
and technology that can affect their daily activity and health. Even with these poten-
tially confounding influences, anthropologists have consistently found that modern
day hunter-gatherer societies are much more physically active on a daily basis com-
pared to current Western societies.
Energy Consumption in Primitive Societies
Over time there was a gradual improvement in the energy content of food ingested
by our ancient hunter-gatherer relatives. Several million years ago, when humans
first evolved, their diet was largely fruits, insects and small vertebrates similar to the
diet of current day chimpanzees. Environmental changes at the time diminished
tropical forests leading to more open woodlands and less abundant food supplies.
Some early humans responded by developing large teeth and jaws to chew large
amounts of low energy vegetation while others changed to higher energy foods
particularly animal products. The former gradually became extinct while the latter
gradually increased brain size and brain function and were the first to make stone
tools, further improving their hunting and scavenging capabilities.
Early humans who developed large brains required more energy to feed the
brain. Humans expend about 25% of their resting metabolic rate to provide energy
for the brain compared to about 10% for nonhuman primates and 3–4% for other
The Hazda 23
mammals. Since the overall resting metabolic rate remained about the same in
evolving humans those with larger brains decreased the metabolic activity of other
organs particularly the gut which required less energy expenditure due to the
improved energy content of their diet (the conversion from low energy vegetation to
high energy animal products).
The average protein content of the hunter-gatherer diet was about 3 times higher
than that of contemporary diets whereas the fat content was about half that of con-
temporary diets. The extremely low fat content of the meat from wild game animals
ingested by hunter-gatherers helps explain this apparent paradox. The carbohydrate
content of the hunter-gatherer diet was about the same as that of contemporary diets
but the hunter-gatherer diet had a markedly higher fiber content.
When early humans evolved and gradually migrated out of Africa into the
warmer planes of south Asia, they were about as tall as modern humans but much
more muscular with a metabolic system supporting long distance travel as they
hunted and scavenged in hot climates. Fossil records indicate that about 500,000 years
ago intermediate forms developed and in Europe these intermediate species evolved
into Neanderthals and in Africa they evolved into anatomically modern Homo sapi-
ens about 300,000 years ago.
About 50,000 years ago there was a clear increase in technology and creativity
with markedly improved stone tools, better hunting techniques and food preserva-
tion. However, over the past million years of evolution resting metabolic rate (RMR)
and total energy expenditure (TEE) of hunter-gatherer societies remained about the
same with an average TEE/RMR ratio of about 2 [3]. By comparison, the TEE/
RMR ratio of a typical modern day office worker is about 1.4.
Based on the study of remaining hunter-gatherer societies, the typical daily rou-
tine involves days of vigorous physical activity alternating with days of rest and
light activity. Men hunt for several consecutive days followed by several days of rest
and women forage for a few days and rest for a few days. But even days of rest
include a good deal of physical activity. For women “resting” includes caring for
children often carrying a child for much of the first 2 years after birth, preparing and
cooking food, searching for firewood and water, and setting up campsites. Part of
the men’s rest periods consist of playing physical games and dancing often late into
the nights. Ritualistic dancing particularly related to spiritualism and healing among
men is common in these primitive societies.
The Hazda
The Hadza are a hunter-gatherer society living in the rough terrain of northern
Tanzania [4]. They hunt a wide variety of wild game and gather tubers, fruits, ber-
ries and honey. In addition to hunting and foraging for food they spend a good deal
of time collecting water and fuel for fires and walking to visit friends in the camp
and in neighboring camps. The Hadza have been friendly with visitors for decades
and several anthropologists have lived and worked among them. Of course, this
alone could influence their daily activity and health.
From the start researchers were impressed with the lack of chronic medical ill-
nesses including stroke and dementia in elderly members of the society. Obesity and
type 2 diabetes were almost unheard of in the Hazda. Although infant and child
mortality is high as with other current day hunter gatherer societies, it is not uncom-
mon to see people survive into their 70s and even 80s. The Hazda, both men and
women, young and old, walk 3–8 miles per day which translates to approximately
6000 to 16,000 steps per day. By comparison, most people in the United States walk
less than 5000 steps per day and at least a third are physically inactive taking less
than a 1000 steps per day.
The Aché
Of the current day hunter-gatherer societies that have been studied in great detail,
the Aché indigenous people of Paraguay have the highest average TEE/RMR ratio
(2.2 in men and 1.9 in women) indicating an extremely high level of daily physical
activity. A nomadic people who live in small bands supported entirely by wild forest
resources, the Aché were first discovered by Jesuits in the seventeenth century but
remained relatively isolated from the modern world until the twentieth century [5].
By late in the twentieth century their culture has been largely obliterated by ranch-
ers and large corporate landowners and they are confined to reservations by the
government.
Early contacts with the Aché in the late nineteenth century described hunter-
gatherers who lived mainly on palm pith and wild animals. They attached small
stones to their lips providing a ferocious appearance but overall were a peaceful
group. The men armed with bow and arrows left camp early in the morning walking
in a single file to begin their hunt. Once on the hunt they would spread out but
remain in earshot of each other so they could call for others to join once a prey was
discovered.
The most common prey were armadillos which they encountered about once
every 2 miles of walking followed by monkeys and deer which they encountered
about once every 6 miles of walking. The Aché hunting practices were extensively
studied and they were known for cooperation between hunters and humility in not
taking credit for the catch [6]. The emphasis was on distribution so that all wild
game was cooked and divided equally so that families received portions based on
their size unrelated to who captured or killed the prey. Overall the Aché hunters
were highly efficient focusing on the highest energy source prey achieving an esti-
mated 750 food Calories per hour of hunting.
Aché foraged mainly for palm hearts a rich source of starch but also for insect
larva, honey and some seasonal fruits. After cutting down a palm tree an opening
was made in the trunk to test for juicy pulp containing a high concentration of edible
starch. Observers noted that it took about 15 min to identify a promising palm tree
to cut down and only about one in eight palm trees cut down had useful starch.
Once a palm with good pulp was identified the women opened the entire trunk
and used axes to pound the palm pith to loosen it so that it could be removed and
Physical Activity in Hunter-Gatherers 25
taken back to the campsite for processing. The palm pith was soaked in a large pot
of water and then rung out handfull by handfull to extract the starch. The pot full of
water containing the starch was than used to cook wild meat producing a hot stew
or if cooled, a jell-like pudding. Although the whole process of extracting the palm
starch was tedious it was estimated to be even more efficient than hunting wild ani-
mals for generating food energy, producing about 1000 food Calories per hour
of work.
The high daily physical activity observed in the Aché is probably a good estimate
of the daily physical activity of ancient hunter-gatherer societies. The average
American walks about 4000 steps a day or roughly 2 miles. For average Americans
to approximate the TTE/RMR ratio of the Aché they would have to walk an addi-
tional 12 miles a day.
Physical Activity in Hunter-Gatherers
As noted in Chap. 1, a simple but reliable technique to document the level of physi-
cal activity is to monitor an individual’s heart rate throughout the day. The Hazda,
regardless of gender or age, spend on average about 75 min/day doing moderate to
vigorous physical activity whereas the average US citizen spends about 10 min a
day doing moderate to vigorous physical activity [7].
On the other hand, the Hazda spend between 8–10 h a day resting and about 7 h
sleeping which is comparable to time spent resting and sleeping by people in
Western societies.
But what does resting mean? As noted earlier, hunter-gatherer women continued
their many daily routines regardless of whether they were foraging or not. Men
continued to walk about visiting friends, dancing and playing games including run-
ning and jumping.
The Hadza don’t have reclining chairs or any chairs for that matter. Studies show
that they spend much of their resting time squatting, kneeling or sitting on the
ground, on a small rock if one is available.
Muscle electrical activity in the legs measured during the different resting posi-
tions reveals continuous activity particularly during squatting and kneeling not seen
in people sitting in a chair. Furthermore, getting up and down from the squatting,
kneeling and ground sitting positions requires a higher burst of muscle activity than
occurs with getting up and down from a chair. Although the muscle activity associ-
ated with squatting and kneeling is less than that associated with moderate to vigor-
ous physical activity, it does have major effects on the body’s metabolism and
ultimately on health risks.
Studies show that muscle inactivity with sitting is associated with the build up of
“bad” lipids in the blood that increase the risk of cardiovascular disease. These and
other similar studies suggest that light but continuous muscle activity is as impor-
tant as bouts of moderate to vigorous exercise for decreasing the risk of developing
chronic diseases. Even more important, it appears that the two types of physical
activity act through different but overlapping physiological mechanisms.
The obvious implication of these studies is that 30 minutes to an hour of moder-

ate to vigorous physical activity in a day with 8–10 h of sitting may not be good
enough. Breaking up prolonged periods of sitting without activity (for example with
periods of standing and moving about) may be equally important. In the process of
evolution, human metabolism developed in a background of more or less continu-
ous muscle activity. It was not built to deal with prolonged periods of sitting with
near absent muscle activity.
The Thrifty Gene Hypothesis
Why does physical inactivity have such a negative impact on our health? In 1962,
James Neel a professor of genetics at the University of Michigan, proposed the
“thrifty gene hypothesis” which, in brief, suggests that genes that were beneficial
for the high physical activity and the feast/famine food intake in hunter-gatherer
societies were positively selected for over millions of years but these same genes are
detrimental to modern day people who are relatively inactive and have plenty of
energy rich food [8].
Neel came to this hypothesis after spending time among the Yanomami Indians
in the Amazon rain forest where he was struck by the fact that there was no obesity
and rare cases of type 2 diabetes. By contrast, the epidemic of obesity and type 2
diabetes was well underway in modern Western societies. Both obesity and type 2
diabetes are major risk factors for developing cardiovascular disease including heart
attacks and stroke.
The Yanomami represent a group of approximately 20,000 primitive people liv-
ing in 200 to 250 villages along the border of Brazil and Venezuela. They are mainly
hunter-gatherers although the women maintain small gardens in addition to forag-
ing for a wide variety of foods including honey. The men are exclusively hunters for
wild game and even though wild animals represent only a small part of the Yanomami
diet, the hunting and sharing of wild game is a key part of their culture. Like other
hunter-gatherer people, Yanomami women and men have a high level of daily physi-
cal activity.
Napoleon Chignon Popularizes Anthropology
Neel was first introduced to the Yanomami by anthropologist, Napoleon Chignon,

whose book entitled Yanomamö: The Fierce People published in 1968 sold more
than three million copies (Chignon used a different spelling of the Indians’ name)
[9]. The book was controversial from the start since Chignon portrayed the
Yanomami as a violent society in which murders including of children were com-
mon both within villages and across villages. Other anthropologists, including the
French anthropologist, Jacques Lizot observed that although the Yanomami men
considered themselves warriors, violence was only sporadic and most of the time
the Yanomami were peace loving [10].
Physical Activity and the Thrifty Gene Hypothesis 27
Chagon made several popular films illustrating the Yanomami violent behavior
that were later found to be staged by Chignon. Regardless of the controversy,
Chignon’s book was a major stimulus to the field of anthropology and was must
reading for college students being introduced to the field. At Chignon’s invitation,
Neel first visited the Yanomami in the early 1960s just as a measles epidemic was
spreading through Yanomami villages. Neel arranged for a measles vaccine made
from an attenuated virus to be provided to the Yanomami but it proved to be too
little, too late and a large part of the population died from the virus.
Years later shortly after Neel’s death, an investigative journalist, Patrick Tierney
published a book entitled Darkness in El Dorado in which he concluded that
Chignon and Neel were experimenting on and endangering the Yanomami without
their consent and that they selfishly pursued their own scientific interests caring
little for the Yanomami people [11]. He even hinted that the vaccine may have con-
tributed to the measles epidemic and that Chignon and Neel could have done much
more to help the Yanomami people during the epidemic.
This whole controversy illustrates the many problems associated with modern
day scientists living among and studying these primitive societies. Obviously, there
can be unwanted damaging effects even if the motives are admirable. Although geo-
graphically isolated deep within the Amazon, the Yanomami were already influ-
enced by western culture for centuries using iron tools long before any anthropologists
visited the region. Earlier in the twentieth century local governments gave permis-
sion for missionaries to enter the region to “educate” the Indians.
When mineral reserves were identified in the latter part of the twentieth century
the Venezuela government built a road directly into the region allowing large num-
bers of people to enter and remove trees and gold at the expense of the Yanomami
tribes and their culture. With regard to Neel’s research, blood samples for genetic
testing were obtained and sent to several institutions in the United States but after
court battles it was determined that the samples were obtained without consent and
the samples were returned to the Yanomami who promptly dumped them into a local
river to join their ancestors.
Physical Activity and the Thrifty Gene Hypothesis
Neel’s thrifty gene hypothesis initially was well received and proponents suggested
that recurring famines were a driving force for the evolutionary selection of thrifty
genes. The thrifty genes allowed the body, particularly muscle, to become insulin-
resistant during periods of starvation in order to maintain high blood glucose levels
required by the brain. The hunter-gatherers did not develop type 2 diabetes and
obesity with the insulin-resistance because of their high level of physical activity.
Others argued that there was little evidence of prolonged starvation in the early
hunter-gatherer societies and that more likely thrifty genes developed to metabolize
energy-dense foods such as fruit and honey with a high fructose content as fast as
possible whenever such foods were available. Fructose, often called the “bad sugar”
is a major component of current day fast foods particularly soft drinks. Fructose is
rapidly converted into body fat.
Somewhat at odds with the thrifty gene hypothesis for type 2 diabetes is that
genetic studies in people with type 2 diabetes and insulin resistance have failed to
identify a clear thrifty gene [12]. Although there are definite genetic risk factors for
developing type 2 diabetes, a large number of genes each providing a small increase
in risk have been found and all together they explain only a fraction of the risk for
developing the disorder.
Another way to look at the thrifty gene hypothesis is that a genetic effect evolved
over millions of years during which total energy expenditure levels were consis-
tently high due to high physical activity. Even though food intake in Calories was
slightly higher in hunter-gatherers than in some current day people the energy
expenditure levels were much higher in the hunter-gatherers.
During millions of years of evolution, genes and gene variants were selected for
to efficiently generate energy required for a high level of physical activity since
survival depended on physical activity to find food.
On the other hand, genes and gene variants that might support a sedentary life-
style were eliminated from the gene pool since they interfered with the ability to
obtain food. As a result the genetic variants that were an advantage to survival in
stone-age people are a disadvantage in modern people with a sedentary lifestyle and
diets rich in fats and low in fiber [13]. Furthermore, with improved overall health
care, people are living longer so many more are exposed to the increased genetic
risk of developing chronic diseases.
The APOE Gene and Late Onset Chronic Diseases
The intriguing story of the APOE gene provides further support for the thrifty gene
hypothesis. APOE codes for the protein, Apolipoprotein E, that plays a key role in
lipid (fat) metabolism. Apolipoprotein E packages cholesterol and lipids carrying
them in the blood stream to cells throughout the body. In the brain, APOE not only
serves as the principal lipid transport vehicle but also in the production and deposi-
tion of amyloid, important in the pathology of Alzheimer type dementia. The APOE
gene has three common variants (alleles), 2, 3 and 4. The APOE 4 allele is strongly
associated with an increased risk for developing vascular disease and Alzheimer
disease [14, 15].
In evolutionary terms, the APOE 4 allele is the ancestral allele in human species
[16]. The 2 and 3 alleles evolved in the human lineage between 300,000 and 200,000
thousand years ago. Why did the APOE 4 allele persist despite its negative potential
effect on health and longevity? There are multiple possible evolutionary pressures
that may have selected for the APOE 4 allele [17].
With the feast/famine life style of the hunter-gatherers, the 4 allele insured better
fat accumulation for periods of famine. The APOE 4 allele enhanced the inflamma-
tory response to fight infectious diseases and the 4 allele improved gastrointestinal
absorption and renal reuptake of vitamin D protecting against vitamin D deficiency.
Finally, due to the short average lifespan of our early ancestors most people were
not subject the potential deleterious effects of the APOE 4 allele.
Hunter-Gatherer Versus Agricultural Lifestyle 29
Could the high level of physical activity of the early hunter-gatherer societies
have protected them from potential deleterious effects of the APOE 4 allele?
There is good evidence in modern day people that physical activity can mitigate
the adverse health effects of the APOE 4 allele and that inactivity enhances the
adverse effects (see Chap. 10) [17].
The Agricultural Revolution
Around 12,000 BC, agriculture was introduced in human populations at several

locations and it slowly spread replacing hunting and foraging to become the pre-
dominant subsistence system by 5000 BC [18, 19]. Some of the earliest locations
were in the Fertile Crescent of the Middle East, sub-Saharan Africa and the Yangzi
and Yellow River Basins of China. Although very recent in the evolutionary timeline
of Homo sapiens, many consider the transition from hunter-gather societies to agri-
cultural societies as being the most important cultural change in human evolution.
By providing a more reliable source of energy rich food, agriculture and the
associated domestication of animals led to a dramatic increase in birth rate and
population density. A planet that supported about eight million hunter-gatherers
easily supported more than 100 million people by 5000 BC. For the first time, some
members of society had leisure time to focus on intellectual pursuits independent of
their daily survival including development of written language, mathematics, poli-
tics and science.
Of course, the vast majority of people in these early agricultural societies worked
harder than their hunter-gatherer ancestors particularly women who were usually at
the bottom of the social structure. Not only did women have to work harder, they
were under constant pressure to reproduce and supply new workers to manage the
crops and tend to domesticated animals.
Hunter-Gatherer Versus Agricultural Lifestyle
Fossil remains from hunter-gatherer and early agricultural societies show surprising
differences. On average men and women in agricultural societies were several
inches shorter than those in hunter-gatherer societies. Compared to hunter-gatherers,
the farmers and their families had markedly increased enamel defects in their teeth
indicative of malnutrition, bone defects consistent with iron deficiency and degen-
erative spine disease consistent with intense physical labor. Furthermore, the aver-
age life expectancy at birth in hunter-gatherer societies was about 30 while in
agricultural societies it was about 20.
Since the main killer of the young in both societies was infectious disease, the
increased crowding of people in agricultural societies made them more susceptible
to developing infectious diseases. There was a marked increase in the prevalence of
viral infections, tuberculosis, syphilis and the plague in agricultural societies which
can be traced to the increased population density, rodents attracted to stored food,
fecal contamination and spread from domesticated animals [20].
How did physical activity and diet change with the advent of agriculture?
Certainly the nature of the physical activity changed dramatically although the
amount of physical activity remained high in agricultural societies (average TEE/
RMR ratios around 2) [3]. The many chores associated with growing food and rais-
ing cattle were highly repetitive and required a limited range of movement. Long
distance walking and running were infrequent in these early farmers compared to
hunter-gatherers but the intensity and duration of physical labor markedly increased.
As a rule, recreation and rest time were much less in the agricultural communi-
ties compared to the hunter-gatherer communities. On the other hand, the division
of labor was not equal on the farms and a small percentage of people, particularly
landowners and tribal leaders, did little physical labor. For example, in Britain this
led to the landed gentry who lived off the rental income from their country estates
and distained any type of physical labor.
Another important difference between hunter-gatherer and agricultural societies
was the role of women. As noted above, women in agricultural societies worked
harder and reproduced at a much higher rate. Studies comparing daily energy expen-
diture in current day hunter-gatherer and agricultural societies found that energy
expenditure in men was about the same but agricultural women expended signifi-
cantly more energy than hunter-gatherer women. Studies of current day farmers,
men and women, show that on average they consistently have a much higher level
of physical activity than city people.
Although there was relatively little change in the overall level of physical activity
with the shift from hunter-gatherer to agricultural life style there was a dramatic
change in the diets in these different societies. Rather than the diverse diet consist-
ing of hundreds of wild plants with a wide variety of nutrients consumed by most
hunter-gatherer people, farmers produced just a handful of crops and many farm
communities relied on a single crop for their main nourishment.
In the Americas, maize was a dominant crop whereas in China rice was the main
crop. This reliance on a few crops made these communities vulnerable to vitamin
and mineral deficiency, malnutrition and starvation. Nutritional deficiencies such as
wide spread protein, calcium and iron deficiency in the Americas and Vitamin A and
C deficiency in China were common.
Famines became a recurring problem. Probably even more important than the
changes in the nutritional content of farm crops was the sociological changes in the
concept of ownership. For the first time in human history private ownership of land
and food evolved so that people no longer shared food and possessions. This led to
social and economic inequalities and the development of hierarchical societies in
which a small segment of the population controlled most of the wealth.
Along with the change in diet, the use and abuse of alcohol and tobacco became
a problem for the first time with the agricultural revolution. Since honey and wild
fruits ferment and are a source of alcohol certainly some hunter-gatherer societies
drank alcoholic beverages but evidence suggests that the use of alcohol was ritual-
ized and periodic only available for special occasions. Furthermore, natural fermen-
tation was seasonal and produced much lower alcohol concentrations compared to
controlled fermentation in more modern societies. Although alcoholic beverages
The Canadian Inuits 31
were widely available in agricultural communities consumption was still limited by

cost and cultural restraints. It wasn’t until industrialization that one sees the solitary,
addictive use of alcohol so common in modern societies.
A few hunter gatherer groups such as the Australian Aborigines chewed season-
ally available wild tobacco but it wasn’t until about 5000 years ago that native
Americans began to grow and widely use tobacco. When Europeans arrived in
America they rapidly developed the habit and tobacco use spread around the world.
Early smoking of tobacco was with pipes and cigars only and it wasn’t until the
mid-nineteenth century that cigarettes were invented. Cigarette smoking became
socially acceptable in both men and women in the early twentieth century and major
health effects rapidly followed.
The Old Order Amish
Obviously, current day farmers with their advanced equipment and modern diets are
not a very good representation of farmers living thousands of years ago. One group
of farmers that have tried to avoid the influence of all modern devices are the Amish
people who continue to use labor intensive farming techniques. The Amish, a
Protestant sect that originated in Switzerland and migrated to America, now reside
in several states and in Canada.
The Old Order Amish in Eastern Pennsylvania maintain farms and resist all
forms of technology including electricity relying on horses for tilling the soil and
transportation. The women carry out all domestic work and childcare and help in the
fields and gardens. There have been numerous studies of the Old Order Amish
showing that there is a high level of daily physical activity and low incidence of
chronic diseases with aging.
In one study, 42% of the 455 community members were fitted with pedometers
to measure the number of steps taken daily for a week [21]. During the week, men
took on average more than 18,000 steps per day and women more than 14,000 steps
per day. By comparison the average person in the United States takes about 5000
steps per day. Not surprisingly obesity was rare in the Amish with only few women
of the 98 subjects in the study meeting the criteria for obesity compared to about
30% of the United States population. This low rate of obesity is even more impres-
sive when one considers that the Amish diet is rich in meat, eggs and dairy products.
Other studies have found a low rate of type 2 diabetes, cardiovascular disease and
Alzheimer disease in the Old Order Amish even with their hardy diet [22, 23].
Although genetic variants may play a role in decreasing susceptibility to these
chronic diseases, the data suggests that the high level of physical activity is the key
to their healthy aging.
The Canadian Inuits
What happens when hunter-gatherer societies rapidly evolve into agricultural soci-
eties? As a rule, there are major outbreaks of infectious disease, increased obesity
and increased incidence of chronic diseases such as type 2 diabetes and
cardiovascular disease. A good example of the process is the forced transition from
hunter-gatherer lifestyle to agricultural lifestyle that occurred with many native
populations in the Americas over the past few centuries. Some of these primitive
societies evolved from a hunter-gatherer lifestyle to a modern day lifestyle within a
few generations.
The Canadian Inuits living in the Arctic nicely illustrate effects of this rapid
change. These native people who traditionally had a very physical lifestyle in a
harsh environment (a TTE/RMR ratio of about 1.8 in both men and women) rapidly
transitioned into modern day communities with fast foods and motorized transpor-
tation. White-collar jobs replaced hunting and fishing as their only means of subsis-
tence. The result was a disaster not only for the culture but also for health and
longevity. Most developed a sedentary lifestyle, obesity became the norm and there
was a gradual increase in the chronic diseases associated with aging.
A recent seven-day pedometer study within the Inuit communities found that
participants had a relatively low level of physical activity with about 5000 steps per
day in summer and about 4000 per day in winter (TTE/RMR ratio less than 1.4)
[24]. Men were more active than women and obesity was more prominent in women
than men.
When participants were asked about factors that influenced the level of daily
activity two stood out, individual motivation and community walkability.
Interventions in the Inuit communities to increase daily physical activity were edu-
cating people on the importance of exercise for health and providing community
facilities such as parks and trails to encourage people to get out and exercise. Of
course these interventions are appropriate for all modern societies.
Hunter-Gatherers didn’t Have it So Bad
Was the invention of agriculture all that it was cracked up to be? In 1987, Jared
Diamond professor of Geography at UCLA and well known scientific writer pub-
lished a provocative article about the switch from hunter-gatherer lifestyle to agri-
cultural life style entitled The worst mistake in the history of the human race [25].
Diamond argued that while agriculture brought us abundant food that allowed an
exponential increase in reproduction there were important trade offs including less
variety of nutrients, increased risk of famine, social and sexual inequality, and “the
curse of our existence” despotism.
Diamond didn’t think that our distant hunter-gatherer ancestors had it so bad. He
pointed out that modern day hunter-gatherer societies such as the Kalahari Bushmen
and the Hazda of Tanzania spend on average about 15 hours a week obtaining food,
which is shared equally within their group. When one of the Bushmen was asked
why he didn’t change to farming like many of his neighbors he replied, “Why should
we, when there are so many mongongo nuts in the world?” Although the conversion
to agriculture may have had important benefits such as the emergence of science and
technology, Diamond concluded that overall the switch from foraging to farming
“was in many ways a catastrophe from which we have never recovered”.
Hunter-Gatherers didn’t Have it So Bad 33
Based on detailed descriptions of the modern day remnants of these primitive

hunter-gatherer societies by anthropologists and lay people alike, they were surpris-
ingly happy, child-like, playful, enjoying the moment. They loved to run, jump and
play games and socialize with their friends. But they also enjoyed resting and doing
nothing for hours at a time. They had no concept of time, living for the moment with
little planning for the future.
Hunter-gatherers were confident in their ability to find food when needed so they
did not store food for the future. Even though by today’s monetary standards they
would be considered impoverished they had few expectations and therefore were
rarely disappointed. Their happy-go-lucky attitude was not well received by early
Western missionaries who were among the first to interact with them. They were
called lazy, lacking in ambition, unreliable and even stupid of course reflecting the
regimented, time-oriented Western culture.
A good deal has been written about the initial encounters of European settlers
with the indigenous American people. Most of these natives lived a hunter-gatherer
lifestyle supplemented by cultivating a few crops (particularly maize) and keeping
a small number of domesticated animals. The puritanical beliefs of the early settlers
clashed with the perceived drollery of these “uncivilized people”.
In 1772, the Baptist minister, David Jones, was taken in by the Shawnee
Indians when he was ill and near starving [26]. He admitted the generosity of the
Shawnee and the quality of their food but was appalled at the frivolity of the
Indians, always singing, dancing and playing games as if they had not a care in
the world. These “savages” had no laws, no jails and apparently no organized
governing structure.
The Indians enjoyed telling stories and jokes and loved to gamble on games simi-
lar to cards and craps. They would gamble anything they had including their clothes,
often leaving the game completely naked. Not surprisingly, the Indians had a simi-
larly low opinion of the European invaders finding them regimented, grim and joy-
less and overly concerned about work and wealth accumulation. The Indians saw
the vast wilderness of the Americas as a storehouse of food, clothing and shelter
whereas the Europeans saw it as a resource to develop and create wealth.
One thing that all agreed upon was that many of the indigenous Americans were
remarkable athletes and fleet runners. Foot races were prestigious events that
focused on both speed and endurance. Participants would train for weeks with a
combination of physical and psychological conditioning consisting of diet, prayer
and abstainance from sex. Trainers for the athletes would oil and bathe them and
provide spiritual advice sometimes sabotaging opposing athletes if they got the
chance. The athletes believed that eating meat from certain animals such as deer or
rabbit could improve their speed whereas eating turtle was frowned upon.
Carl Lumholtz was a nineteenth century Norwegian explorer and ethnographer
who spent a year living with the Tarahumara Indians in the southwest United States
(at that time in Northwest Mexico), an indigenous nation famous for its runners who
could run down a deer [27]. Lumholtz timed the winner of a race over a 21 mile
course at 2 h and 21 min not a bad time considering that the participants had to kick
a ball and maintain it in front of them as they ran.
Everyone assumes that the English physician, Roger Banister, was the first
human to break a 4 min mile. But was he the first? In 1877, the commander of
Pawnee scouts employed in the Sioux and Cheyenne war, Luther North, timed his
best runner, Big Hawk Chief, on a 1 mile run [28]. He measured a time of 3 min
58 s. This was not considered an “official time” since it did not meet modern con-
trolled standards but it is not only possible but probable that some of these great
athletes broke a 4 min mile long before Roger Bannister.
The notion that our primitive ancestors, the hunter-gatherers, didn’t have it so
bad has been echoed by many others since Diamond’s article and was nicely illus-
trated in a book by anthropologist James Suzman entitled Affluence without
Abundance with the subtitle, the world’s most successful civilization [29]. Suzman
lived and worked for 25 years with one of the last groups of hunter-gatherers left on
Earth, the Bushmen in the Kalahari Desert of Namibia and Botswana.
The Bushmen survived as hunter-gatherers well into the twentieth century before
ultimately giving way to the invasion of modern technology. Suzman witnessed the
end of their hunter-gatherer existence and documented the change in their lifestyle.
The harsh landscape of the Kalahari desert isn’t exactly where one would look for
the world’s most successful civilization. It wouldn’t be the place to choose if one
were starting a farm or ranch. Yet, the Bushmen maintained a hunter-gatherer life-
style in this hostile environment for tens of thousands of years.
Not only did they survive but they thrived and according to Suzman were happy
and contented. Suzman noted that the bushmen really didn’t have a word for happi-
ness as we use the word to mean a form of aspiration for the future. They lived in
the moment and had words for current feelings such as joy and sadness but not for
future aspirations. Typically the Bushmen spent about 15 hours a week obtaining
food and another 15–20 h on domestic chores leaving a lot of time for socializing
and relaxation.
The Bushmen were skilled hunters and gatherers with a great deal of knowledge
about the animals and plants in the environment in which they lived. Suzman con-
cluded that their affluence could be traced to the fact that they had relatively few
needs that were easily met. By contrast, despite the technological advances of mod-
ern Western societies there is the perception of infinite wants yet limited means. The
result is that we work longer hours but are less content.
The Industrial Revolution
Unlike the transition from hunter-gatherer to agricultural societies in which there

was a major change in diet but relatively little change in overall daily physical activ-
ity, with the onset of the Industrial Revolution in the late eighteenth century there
was a gradual change in the level of daily physical activity as well as change in diet.
The industrial revolution that developed in Great Britain rapidly spread throughout
Western Europe, North America, Asia and the Mediterranean/North Africa over the
next century. As people migrated from rural areas to cities to seek work in industrial
factories, sedentary behavior with increasing levels of inactivity became the norm.
Physical Inactivity and Chronic Diseases 35
By the mid to late twentieth century, transportation was highly mechanized and
we entered a computer-driven world where most people’s physical activity was pro-
vided by infrequent recreational and leisure activities. For the first time in human
existence exercise, a planned physical activity carried out with the goal of improv-
ing physical fitness and health, became the predominant physical activity for
most people.
As the link between physical inactivity and chronic diseases became clear public
health officials warned people of the danger of inactivity and the importance of
exercise in preventing chronic diseases but the public response has been tepid at
best [30]. In the United States the rate of obesity and chronic diseases associated
with obesity are on the rise. It has been estimated that more than half the population
will be obese by the middle of the twenty-first century.
The switch from agriculture to industrialization was associated with improve-
ment in human health and longevity at least initially [31]. Modern industrialized
societies have the highest life expectancy at birth of any societies in the history of
the world. There are two main reasons for this improvement in health and longevity:
economic and public health.
As most individuals earned more, their food and housing improved so that many
could afford more nutritious food and better homes. On the other hand, the rapid
increase in population tended to drive down wages and increase infectious diseases
in a subset of the population. The increase in economic productivity for the first
time allowed communities to invest in public health improving sanitation, hygiene
and medical care.
Scientific medicine, which began in the mid nineteenth century reached its peak
in the mid twentieth century with the discovery of antibiotics and treatments for
common diseases such as hypertension, diabetes and coronary artery disease. But
with the increase in longevity came a new problem that so far has baffled medical
science, chronic neurological diseases associated with aging: Alzheimer disease,
vascular dementia, Parkinson disease etc. Inactivity, obesity, type 2 diabetes, hyper-
tension and associated vascular disease are risk factors for these chronic neurologi-
cal conditions.
Physical Inactivity and Chronic Diseases
The notion that inactivity could decrease longevity became known in the mid twen-
tieth century. At the time coronary artery disease was the leading cause of death
among middle age men. Medical researchers in London, England compared the
prevalence of coronary artery disease and the mortality rate in workers with seden-
tary jobs versus those with physically active jobs and found that men who were
inactive had a much higher rate of coronary artery disease and mortality than those
who were physically active [32, 33].
The researchers compared bus drivers on double-deck buses with the conductors
who constantly moved throughout the bus collecting tickets and they compared
physically active postmen with relatively inactive clerks and executives at the post
office. Not only did the physically inactive workers have more coronary artery epi-
sodes their symptoms were more severe than the physically active workers.
Study after study in the latter half of the twentieth century showed that the mor-
tality rate associated with the most common noninfectious causes of death (coro-
nary heart disease, type 2 diabetes, and breast and colon cancers) was higher in
inactive people compared to physically active people [34]. A comprehensive look at
all studies in 2008 concluded that at least 10% of all deaths from these common
noninfectious causes could be attributed to inactivity.
Despite these warnings, current levels of physical activity remain low in most
industrialized populations. In the United States, National Transportation surveys
showed a 1000% increase in the number of trips made from home by automobile
from 1969 to 2001 [35]. Not surprisingly, the number of trips made from home by
walking markedly decreased over the same time frame. As noted earlier, the average
number of steps per day for people in the United States is under 5000 steps which is
less than a third of the average number of steps per day in the Old Order Amish who
refuse to use modern transportation.
Less than half of people in the United States meet the minimal recommended
physical activity recommendations of the American Heart Association and about a
quarter of the population are considered physically inactive meaning they have little
or no physical activity throughout the day. Even more disturbing is the trend toward
lower level of physical activity in young people in the United States. There has been
a gradual decrease in the number of high school students enrolled in physical educa-
tion particularly in girls with the steepest decline in African Americans and Latinos.
Daily physical activities such as walking to school, home chores and recreational
activities are all decreased or absent. Many young people spend much of their time
indoors on the cell phones and computers and spend relatively little time outdoors
playing. Although the overall number of physically inactive adults has been slightly
decreasing in recent years this trend is not seen in African American and Latino
populations. Factors found to influence the level of physical activity include socio-
economic/cultural access and quality of health care, education and self-efficacy.
Although physical inactivity is the most important cause for the modern day
epidemic of obesity, as suggested in Chap. 1, weight is determined by the combina-
tion of energy intake (food) and energy output (resting metabolic rate + diet induced
energy expenditure + physical activity). Complicating matters, genetic variants are
important for both energy consumption and energy expenditure. These genetic vari-
ations occurred millions of years ago when early humans lived in a completely dif-
ferent environment than humans live in today.
There is little doubt that obesity was rare in hunter-gatherer societies while it is
very common in industrialized societies [36]. A simple but reliable measure of
body fat is the thickness in mm of the triceps skinfold made by pinching the skin
under the upper arm. The average triceps skinfold thickness in surviving hunter-
gatherers is about 5 mm whereas the average thickness of modern day people is
about 10 mm.
Although our primitive ancestors the hunter-gatherers probably ate as much food
and possibly even more than modern day people, the energy content of their food
Physical Inactivity and Chronic Diseases 37
was less. Our food is more energy rich in Calories than the wild fruit, vegetables and
game eaten by hunter-gatherers. The so-called energy-satiety ratio, the energy in the
amount of food necessary to create a feeling of fullness, is much higher for our food
than for the food consumed by these primitive societies. Also, hunter-gatherers
mostly drank water to quench their thirst whereas modern people consume large
amounts of high calorie beverages such as soft drinks and beer.
Hand in hand with the current epidemic of obesity is the epidemic of type 2 dia-
betes mellitus. Type 2 diabetes was rare in hunter-gatherer people while it affects up
to 10% of current day populations and there are predictions that it will affect a third
of the population by 2050 [37, 38]. Mortality statistics from New York City from
1866 to 1923 showed a ten fold increase in deaths from type 2 diabetes.
Like obesity, type 2 diabetes is caused by a combination of genetic and environ-
mental factors but the rapid recent epidemic is primarily due to environmental fac-
tors, energy rich diets and low physical activity. Obese people have fewer insulin
receptors and their cells are relatively resistant to insulin so their serum insulin
levels are higher than in lean people. This explains the paradoxical elevation of both
blood glucose and insulin levels with type 2 diabetes.
Serum insulin and glucose levels can be decreased by diets rich in fiber and com-
plex carbohydrates and by physical activity. The diet and physical activity levels of
hunter-gatherer people were ideal for preventing obesity and type 2 diabetes while
the diet and physical inactivity of industrialized people cause both conditions.
Interestingly, although obesity and type 2 diabetes are interrelated increasing physi-
cal activity and improving physical fitness can improve insulin sensitivity to some
degree independent of its effect on body weight.
One of the most dangerous health effects of obesity and type 2 diabetes is athero-
sclerosis, a disorder where arteries are clogged with fats, cholesterol and calcium
deposits on the inner walls in so-called plaques, restricting or blocking blood flow
[39]. Plaques occurring in the coronary arteries cause heart attacks while plaques
occurring in the arteries to the brain cause strokes. Clinical and autopsy studies
show a remarkably low incidence of atherosclerosis in a wide variety of surviving
hunter-gatherer societies. These findings correlate with a low incidence of heart
attacks and strokes in these populations.
Average total serum cholesterol levels in living primitive societies are about half
the levels in modern day societies, whereas, average serum levels of polyunsatu-
rated fats are much higher in the hunter-gatherers than in modern people. As with
obesity and type 2 diabetes, genetic variations that occurred over millions of years
in people with high levels of physical activity and diets rich in fiber and polyunsatu-
rated fats predisposed modern people with low levels of physical activity and energy
rich diets to develop atherosclerosis.
Interestingly, after peaking in the 1960s deaths due to coronary artery disease
and stroke has been decreasing due to a combination of better medical and surgical
treatments and a gradual change in lifestyle including decreased smoking and phys-
ical activity and diet more in keeping with our distant relatives the hunter-gatherers.
Unfortunately, this improvement in mortality from atherosclerosis is mostly seen in
higher socioeconomic populations and not in the poor.
Chronic, late life onset neurological diseases such as Alzheimer and Parkinson
disease are some of the most common causes of morbidity and mortality in modern
industrialized societies yet it is unclear whether these diseases even existed in prim-
itive societies. Fossil records are of little use for identifying these conditions and
there has been a remarkable lack of detailed neurological assessment of surviving
hunter-gatherer societies prior to their exposure to modern lifestyles. Certainly if
the diseases did exist they were relatively rare compared to modern times.
One argument commonly used to explain the lack of these late onset neurodegen-
erative diseases in primitive societies is that people did not live long enough to
develop the diseases. As suggested earlier in the chapter, however, even though the
average age of death of hunter-gatherer people was less than 30 years those who
survived past 30 lived nearly as long as current-day people. On the other hand, with
the cultural differences, would dementia in an elderly hunter-gatherer even be con-
sidered an illness?
Clinical cases of Alzheimer and Parkinson disease have not been identified in
other primates although typical pathology of these diseases is present in some older
primates and it can be increased with a variety of genetic and environmental manip-
ulations. Some have speculated that the evolutionary changes that allowed the
human species to develop its unique cognitive abilities also makes the species
uniquely susceptible to developing neurodegenerative diseases [40]. For example,
much of the pathology of Alzheimer disease is seen in the most recently evolved
areas of the cerebral cortex.
The human genome developed over millions of years of evolution most of it
before human species existed. In modern industrialized societies, a person’s health
status depends on a complicated interaction between the body’s metabolism deter-
mined by this ancient genetically controlled biology and modern lifestyle including
energy rich food and physical inactivity, much different from that of our primitive
ancestors [41]. As we will see in later chapters, there is overwhelming evidence that
exercise is effective for both prevention and treatment of these late onset neurode-
generative diseases.
Since diseases like type 2 diabetes, atherosclerosis, Alzheimer disease and
Parkinson disease are relatively rare in primitive populations and extremely com-
mon in industrialized societies, they are sometimes called diseases of modern civi-
lization, attributed to modern lifestyles [42]. The most common brain disease of all
in industrialized people, depression, is in many ways the prototypical “modern
disease” [43]. If it existed in hunter-gatherer and early agricultural societies it was
rare and modern epidemiological studies show an alarmingly rapid increase in the
frequency of depression in the past few centuries particularly in the past few
decades.
A study of the Kaluli aborigines in Papua New Guinea identified only a single
possible case of depression and studies of the Old Amish found only rare cases. By
comparison, a Swedish study found a ten fold increase in cases of depression in
young adults from the 1947 to 1972 and an American study found a more than two
fold increase of depression in adults from 1992 to 2002. Suicide rates have increased
at an alarming rate since the turn of the twenty-first century.
References 39
Depression is a neurological disease with characteristic neurological symptoms

and brain pathology, both gross structural and microscopic (See Chap. 7). Although
behavior symptoms are predominant there are many other symptoms including
altered immune function, impaired memory, increased sensitivity to pain and
extreme fatigue. There is a complete loss of the ability to find pleasure in living.
Finally, obesity, type 2 diabetes and atherosclerosis are more common in people
with depression than in people without depression. The common link between these
diseases appears to be the stress of living in modern industrialized societies and
overall lack of physical activity.
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A Healthy Body for a Sound Mind
3
I say the best of all exercises are not only those which are able to exercise the body vigor-
ously, but those which are also able to delight the soul. (Claudius Galenus (Galen)
[1] 129 AD)
The notion that exercise and physical fitness are important for a sound mind dates
back to ancient times long before people understood the relationship between the
mind and the brain. These people recognized the importance of exercise in main-
taining health and some even recommended exercise for brain health thousands of
years ago. The main difference between then and now is that physical inactivity was
relatively rare in early societies while it is common in modern societies. However,
there were elite classes in all of these societies who did not rely on physical activity
to survive. Some of the earliest and most persisting forms of exercise for the body
and mind were developed for these people.
Chinese Martial Arts
In prehistoric China more than 2000 years BC, the mythical Emperor of the first
Chinese dynasty, Ta Yü mandated regular bodily exercises to maintain health and
prevent disease [2, 3]. At a time when diseases overflowed his kingdom, he ordered
his subjects to perform daily military exercises called Ta Wu, the Great Dances to
produce a union between heaven and earth. Yü and his faithful followers thought
that if one’s body was not kept in motion the humors stopped flowing and disease
developed. Physical inactivity produced internal stoppages and organ malfunction.
Around 500 BC, Confucius recommended regular physical activity as an impor-
tant part of his moral and social teachings that shaped the Chinese culture. He taught
that daily rhythmic movements not only improved physical strength but also were
key to maintaining a healthy outlook on life. Stretching and breathing exercises were
recommended to relax the mind and obtain harmony with the universe (Fig. 3.1).

https://doi.org/10.1007/978-3-031-13924-6_3
42 3 A Healthy Body for a Sound Mind
Fig. 3.1 Stretching and breathing exercises as performed in ancient China
The ancient military dances evolved into Kung Fu, initially a fighting method
emphasizing self defense but later an exercise routine called Kung Fu Gymnastics
[4]. Kung Fu, which means trickery and quickness in Chinese, assumes different
positions of the feet and body with quick movements from one stance to another.
Often equated with karate in the Western world, Kung Fu spawned a Hollywood
movie genre called Kung Fu movies made popular in the West by such stars as
Bruce Lee and Jackie Chan. Kung Fu has a chaotic history in Chinese culture with
periods of being banned followed by periods of popularity but it is now popular not
only in China but throughout the world.
Another ancient form of Chinese martial arts is shadow boxing or Tai Chi. The
term Tai Chi, first used more than 3000 years ago, means the ultimate of the ultimate
referring to the vastness of the universe. As with Cong Fu it was originally intro-
duced as a fighting technique but gradually evolved into a form of spiritual exercise
not only good for the body but also for the mind.
Based on the ancient Chinese philosophy of Taoism, Tai Chi attempts to balance
the two opposite but complimentary elements yin and yang. Balancing yin and yang
leads to good health and longevity. To accomplish this goal, Tai Chi combines slow
movements and fixed stances with rapid movements and brief explosions of power.
Later versions focused more on slow rhythmic motions and stances that are toler-
ated better by older people with less pliable joints. The stories of how these styles
developed are part of Chinese lore and provide important insights into understand-
ing the role of Tai Chi in Chinese culture.
The classical style, the Chen style, was developed by Chen Wangting a sixteenth
century army officer who became interested in Taoism and retired to a life of farm-
ing and teaching martial arts [5, 6]. The Chen style which was practiced and gradu-
ally evolved over 17 generations of Chens, combined martial arts with an
understanding of traditional Chinese medicine focusing on mental concentration,
deep breathing and controlled motion. The Chens were secretive about their discov-
eries teaching just to people in their village mostly relatives.
Chinese Martial Arts 43
Lore has it that they only taught daughters-in-law and not daughters since the
latter could marry outside of the village. Divorce was not possible. It wasn’t until
the early twentieth century that Chen Fake, a 17th generation Chen began teaching
the Chen style of Tai Chi outside of the family village and the first book on the Chen
style was published by Chen Xin in 1932. Chen Fake, often considered the greatest
teacher of Tai Chi, lived and taught in Beijing up until his death in 1957.
Chen Fake was known for his remarkable abilities in Tai Chi and was universally
admired for his overall peaceful disposition. But it is said that as a child he was
spoiled, lazy and without ambition. His father was a renowned teacher of Tia Chi
but Chen Fake was not interested and his slovenly behavior was the laughing stock
of the village. This all changed when at age 14 he felt guilty and decided to follow
in the family tradition and master Tai Chi.
But due to his late start Chen Fake became despondent that he would never be
good at it. He studied with a cousin who already was an expert and no matter how
hard he tried he couldn’t seem to catch up with his cousin who kept getting better.
This all changed when he had an inspiration while out walking with his cousin. He
had left something behind and his cousin suggested that he go back and get it and
that he would walk slowly so Chen Fake could catch up with him. As Chen Fake ran
to catch up with his cousin it suddenly occurred to him that if he worked harder at
Tai Chi than his cousin he would eventually catch up and then exceed his cousin’s
ability.
From then on Chen Fake practiced with such intensity that he soon exceeded his
cousin and became a master of Tai Chi. The Chen style of Tai Chi is rich in tradi-
tional martial arts techniques with low stances and sudden bursts of power useful in
combat but difficult for older people.
Subsequent styles of Tai Chi have focused on more upright stances and slower
more gentle movements markedly expanding the potential pool of practitioners
including older people. Yang Lu-chan created a new style in the early nineteenth
century characterized by graceful, slow curving movements that were easy to learn.
Yang who would later be known as “Yang the invincible” loved martial arts as a
child but after being soundly defeated by a descendent of the Chen village he
became determined to learn the Chen style.
Since outsiders were not welcome, to gain access to the Chen village he posed as
a beggar and fainted at the door of the Chen village elder. He was taken in and
became a servant in the household where he was able to observe people practicing
the Chen style of Tai Chi through a hole in the wall. Later on when he was found to
be an imposter he faced the possibility of legal execution but the village elder was
so impressed with his skills and determination that he took him on as a pupil.
Subsequent styles including the Wu and Sun styles also focused on the graceful
slow curving movements of the Yang style and on the health benefits of Tai Chi sepa-
rate from the military self-defense benefits. The Wu style is characterized by a for-
ward leaning posture and rich hand movements while the Sung style by footwork
whereby if 1 ft moves forward or backward the other follows with brief bursts of
power with each change in direction. Because of these varied styles and techniques,
modern Tai Chi exercises can be tailored to an individual’s strengths and limitations.
Yoga and the Melding of the Mind and Body
Even more ancient than Chinese martial arts, yoga began as a spiritual meditation
and only relatively recently evolved into an exercise routine. Nearly everyone can
picture a monk sitting with legs crossed and each foot upturned resting on the thigh
of the other leg deep in meditation, the classic lotus posture of yoga. The origins of
yoga can be traced back more than 5000 years to the greatest civilization in the early
ancient world, the Indus-Sarasvati civilization, named after the two large rivers that
ran through northern India at the time [7, 8].
This was a highly advanced society with multistory buildings, a sewage system,
brick roads and large public baths. Their language, Sanskrit is the root language of
Greek and Latin and ultimately French, German and English. The earliest written
description of yoga which means “union” in Sanskrit was in a book called the Rig-
Veda that consisted of a collection of hymns that had been transmitted by word of
mouth for several generations of Indus-Sarasvati people. In Sanskrit the word rig
means praise and Veda means knowledge and this book along with three other Vedic
Hymnodies provided a foundation for the Hindu religion currently practiced by
more than a billion people world-wide.
These books of hymns have been compared to the Old Testament of the bible for
the Christian faith. Vedic yoga, which was part of the ritualistic beliefs of these
ancient people, was based on the notion that sacrifice was a way of reaching a union
between the material life and the world of spirits. In order to achieve such a union
one had to focus their mind for long periods of time transcending the limitations of
the mind to achieve transcendental reality. The hymns praised the masters of Vedic
yoga, called “seers” who were able to “see” the very fabric of existence.
Yoga was initially practiced primarily by Hindu priests part of their highly disci-
plined lifestyle of ritual and meditation. These early practitioners of yoga paid little
interest to the body but rather their goal was to leave the body and the physical
world behind and enter the spiritual world. But slowly over time a new breed of
yoga masters evolved who recognized the importance of the body as a temple of the
immortal spirit. They developed new yoga techniques to energize the body even to
change the chemistry of the body to improve the mind.
By mimicking the postures and movements of animals they sought to achieve a
balance with nature that animals seemed to possess. The series of movements in
different physical postures and breathing patterns are associated with modern yoga,
known as Hatha Yoga. Yoga as an exercise, a blending of Western gymnastics with
the postures of Hatha yoga, was not created until the early twentieth century.
The beginnings of modern yoga in America can be traced to the Parliament of
Religions held in Chicago in 1893 when the Swami Vivekananda introduced the
American public to yoga. A pupil of the great Ramakrishna, the young Vivekananda
had an impressive spiritual aura and became the star of the conference even though
he was previously unknown to the members. He subsequently traveled throughout
the United States teaching yoga and writing popular books on yoga.
Modern yoga as an exercise for the body and mind consists of a series of poses,
called asanas, connected by movements between poses, called viyasas, along with
Sparta and Physical Fitness 45
regulated breathing and periods of relaxation and meditation. Asanas played a rela-
tively minor role in traditional Hindu yoga but are the core of modern yoga with the
number of asanas approaching a thousand. Similarly the focus on spiritual libera-
tion of original Hindu yoga has been replaced by an emphasis on physical fitness
and meditation. Yoga is now a multi-billion dollar business world-wide with yoga
fitness centers, teachers and teacher certification, videos and books, along with
equipment and clothing.
Sparta and Physical Fitness
The importance of physical fitness was engrained in ancient Greek culture [9]. Their
appreciation of the beauty in the physically fit human body can be seen in the many
great works of art displayed in museums around the world. More than 700 years BC,
when Homer wrote the Illiad and other poems, he praised Greek warriors’ athletic
performances in chariot racing, wrestling, spear throwing and archery.
An example of the extreme of this reverence for physical fitness was the city-
state of Sparta in Southern Greece. This ancient warrior society dominated Greek
society for more than four centuries beginning around 800 BC [10, 11]. The oligar-
chic government of Sparta demanded total obedience of its subjects requiring men
to become warriors and women to give birth to warrior sons. Little else mattered.
Boys were taken from their families at age 6 or 7 and entered government spon-
sored special fitness programs designed to make them physically fit to become sol-
diers. There was little interest in traditional education. They learned fighting skills
at a young age and those who were determined to be unhealthy or unfit were eutha-
nized. An infant boy was brought before a council of old men who decided whether
or not he should be raised based on his physical condition and promise. The deci-
sion was final; there was no appeal.
Young girls also had to remain physically fit if they were to give birth to strong
children. Because of this important role, women were treated better and had more
rights than women in other parts of the ancient world. Men who died in combat and
women who gave birth to sons who died in combat were honored with elaborate
graves whereas those who died of other causes were buried in unmarked graves.
Once the young boys were removed from their families they entered a long
period of mental and physical abuse. They lived in squalled conditions sleeping in
rooms open to the sky on a pallet of hay or straw without bedclothes. Their hair
was closely cropped and they were given a single scant garment without shoes
regardless of the weather. Food was plain and scarce barely meeting a subsistence
level so most became adroit at stealing food to meet their constant hunger. As a rule
this was tolerated as long as they were not caught in which case punishment
was severe.
Whipping with rods or lashes was a common occurrence, considered good train-
ing for enduring pain in their future role as soldiers. At the many annual religious
festivals flogging of young boys to the drawing of blood was part of the entertain-
ment. The boys were organized into squads according to age for their gymnastic
training which included swimming, wrestling, running, jumping and throwing the
javelin and discus. The squads were combined into companies for military exer-
cises, marching in unison in time with music.
For special occasions the boys performed war dances combining movements
representing attacking and defending. The so-called Pyrrhic dance was a spectacu-
lar sight with whole companies joined together in rhythm to music imitating the
movements of war. As the boys moved into their late teens, they moved directly into
military service well prepared for their future role. They were taught to endure pain
and suffering and to show little sympathy or empathy for their enemy or in fact for
their fallen comrades. Sparta’s preoccupation with physical fitness had a great influ-
ence on the Greek physicians Herodicus and Hypocrates and Greek philosophers
Socrates and Plato and according to Bertrand Russell provided a framework for
later development of National Socialism.
Exercise was considered an integral part of Greek culture even before the time of
Homer with gymnasiums and palaestrae (wrestling schools) scattered throughout
Greece helping citizens meet their duty to maintain fitness [9]. The name gymna-
sium comes from the Greek term gymnós meaning “naked”. Men congregated at the
gymnasiums to socialize and train to compete in public games. The men practiced
and competed in the nude in appreciation of the beauty of the human body and as a
tribute to the gods.
According to Greek mythology, Asclepius was the first physician with God-
given powers to heal the sick. Asclepeions were temples scattered throughout
Greece typically combined with baths and gymnasia where sick people went to be
healed and healthy people went to maintain health. Medical treatments focused on
the individual’s lifestyle with emphasis on diet, exercise and spiritual needs. There
was an initial period of purification during which the individual was given purga-
tives, a cleansing diet and purifying baths followed by a referral to the gymnasium.
These asclepeions typically had wealthy patrons who used the facilities as one
might use modern day country clubs.
Herodicus of Cnidos
Two prominent Greek physicians practicing in the fifth century BC at neighboring

medical schools, Herodicus and Hippocrates, were heavily influenced by the exer-
cise culture of their time and emphasized the importance of exercise to maintain
good health and to cure disease. Although Hippocrates is often considered the
founder of modern medicine, Herodicus clearly had an important influence on
Hippocrates and was one of his earliest teachers.
The first medical school in Greece to separate medicine from myth and reli-
gion was located in Cnidos, a colony of Sparta in southern Greece. Cnidos was
an important port city for the passage of goods from the Middle East to ancient
Greece. Euryphon, a physician credited with starting the medical school in
Cnidos, taught that diet played the critical role in both health and disease. He felt
Hippocrates of Cos 47
that waste matter that developed in the abdomen with bad digestion could spread
throughout the body and eventually reach the brain where it caused symptoms of
disease. On the other hand, with good digestion the body and brain remained
healthy.
Herodicus, who studied under Euryphon, expanded on his teacher’s idea con-
cluding that the main cause for bad digestion was lack of body movement [12]. In
other words, for proper digestion regular physical activity was necessary. Bad diges-
tion could result in two types of body liquids, a sharp type and a bitter type.
Symptoms depended on the offending liquid type and on which organ it settled in,
the liver, the spleen or the brain. This was the first theory to explain how exercise
might affect the brain. Herodicus concluded that diet and physical activity were
both critical to maintaining good health. He recommended an unappealing diet rich
in grains and a high level of daily physical activity.
Herodicus himself participated in a variety of sports and was regularly seen out-
side the walls of the city walking back and forth for long periods of time. Not only
did Herodicus recommend exercise to maintain good health but for treating just
about any type of illness. Even patients with high fevers were told to run, wrestle
and then take hot baths.
Critics at the time warned that Herodicus killed more patients with this method
than he cured. Others suggested that his extreme diet made lives miserable even if
health improved. Given the rigid warrior mentality of the Spartan community in
which he lived, his fanatical approach to maintaining health and fitness was overall
well received.
Hippocrates of Cos
Directly across the sea from Cnidos was the city island of Cos where the second
major medical school was located. Hippocrates studied in Cnidos for a few years
(presumably with Herodicus) before moving to Cos where he would go on to revo-
lutionize Greek medicine, making it a profession independent of religion and
philosophy.
According to Greek mythology, after the fall of Troy, one of Asclepius’ sons,
Podaleirios migrated to the peninsula of Caria near Cnidos and married a local prin-
cess. His descendants later moved to either Cnidos or Cos where they passed down
their medical knowledge from father to son eventually leading to the two medical
schools. Like Herodicus, Hippocrates believed that diet and exercise were the key to
good health although he warned of the potential dangers of extreme exercise, too
much of a good thing.
Hippocrates recommended moderate exercise to aid digestion but warned that
extreme exercise could interfere with digestion and even cause stomach problems
[13]. He had a low regard for professional athletes who he felt carried exercise to the
extreme and after reaching their peak had no where to go but down. Hippocrates
championed the four humors (phlegm, yellow bile, black bile and blood) theory of
disease which in a nutshell proposed that all diseases including brain diseases were
caused by an imbalance between the four humors [14]. He was a strong proponent
for blood letting to treat a wide variety of diseases.
The origin of the humors theory is controversial although the sharp and bitter
bodily liquids of Herodicus likely correspond to phlegm and bile in the expanded
four humors theory. Hippocrates taught that good health including mental health
depended on eating right and exercising. He felt that moderate exercise produced a
balance in the four humors whereas inactivity, extreme exercise and excessive food
consumption could cause an imbalance and produce disease.
Like Herodicus, Hippocrates prescribed exercise for treating a variety of diseases
but he did not recommend exercise for people with a fever. For patients with con-
sumption he prescribed moderate daily walks. Diocles, a disciple of Hippocrates
recommended that young people should go to a gymnasium twice a day to exercise
while older people should take moderate walks to help with digestion but avoid long
walks which may cause indigestion.
Athens and the Greek Gymnasium
In Athens, there were multiple gymnasia with a strong emphasis on physical fitness
primarily for military purposes as in Sparta. Socrates and his pupil Plato regularly
visited gymnasia and participated in athletic games, in the nude like the other par-
ticipants. Athletic nudity was considered a statement of freedom and goodness, a
measure of one’s Greekness. The beautiful body was part of Greek lore dating back
to Homer.
Plato emphasized the importance of sport in developing a person’s character and
virtue in addition to physical fitness. He developed an academy at his gymnasium
where he combined mental training along with physical fitness training [15, 16].
Plato felt that a balance of mental and physical activity was important for the psychē
(the soul or what is now the mind) which was ultimately the source of health and
disease.
Exercise benefited the psychē more than the body. A beautiful psychē was more
important than a beautiful body. Like Hippocrates, Plato was critical of professional
athletes since he felt that they spent too much time training the body while neglect-
ing the mental part of the psychē. Plato divided the psychē into three parts, a rational
or wisdom-loving part, a spirited or honor loving part and an appetitive or pleasure-
loving part. The rational part was located in the brain, the spirited part in the heart
and the appetitive part in the liver.
Exercise was most beneficial to the rational and spirited parts. For good health
there had to be a balance between the three parts. As an example, Plato likened the
psychē to a two-horse chariot where the driver represented the rational part, a noble
horse representing the spirited part and an unruly horse representing the appetitive
part. The driver’s struggle to control the chariot as the unruly horse refuses to com-
ply with his demands is analogous to the rational part of the psychē’s struggle to
achieve excellence when the unruly part is not properly trained.
The Olympic Games 49
Unlike many in Athens at the time, Plato felt that women should participate in
gymnastic education and athletic games just like men. Although Spartan women
were encouraged to exercise and maintain physical fitness, this was primarily
from a military point of view whereas Plato felt that women should attend gym-
nasia to better prepare them for civic involvement that might include military and
government service. Women should be on the same footing as men for education
and physical fitness. Even though he acknowledged that women were on average
physically weaker than men, the psychē was more important than the body for all
activities including military service and one’s sex was a feature of the body not
the psychē.
The Olympic Games
It would be impossible to understand the role of exercise in ancient Greece without

considering the Olympic games [17]. Every 4 years athletes from all over Greece
congregated in a rural area called Olympia to participate in a series of athletic
events. The Games were only for “free” men and only for the best athletes in
each event.
The first written description of the Olympic games occurred in 776 BC but they
probably date back more than a century before that. Since at the time Greece was
divided into several city-states that were constantly at war, the Olympic games pro-
vided a transient unification of Greek society. Before the Games messengers trav-
eled from city to city to announce the date of the competition and to declare a sacred
truce to allow the athletes and spectators to travel to and from the Games.
Olympia was not a city but rather a rural sanctuary where only a small number of
priests and staff lived year around caring for the buildings and grounds. Olympia
was divided into two parts, a walled in sacred area of temples with the main one to
Zues, considered the father of the Games and a non-religious area outside the wall
consisting of training facilities and competition sites. For many centuries the com-
pletion sites were simply large rectangular fields with spectators sitting on grassy
hills surrounding the sites.
At the time of the Games, in addition to competitors, a wide variety of people
flocked to the site including as many as 50,000 spectators along with a wide variety
of merchants, artisans and musicians interested in gaining recognition. The athletes
trained on their own for several months before the games and a month before they
traveled to the city of Elis near Olympia where competitions were held to select the
best athletes to participate in the Olympic games. Since the athletes performed in
the nude, they covered their body with olive oil and fine sand to help protect the
skin and maintain body temperature in the hot sun. After the events they remove
the sweat, oil and sand with a curved instrument call a strigil followed by a
sponge bath.
The Olympic games consisted of 5 days of activities. The first day was ceremo-
nial as the chosen athletes were announced with a trumpet fanfare followed by
administration of an oath to respect the rules for the athletes and judges. The second
day was the most exciting with equestrian events topped by the chariot races and the
pentathion consisting of discuss and javelin throwing, wrestling, long jumping and
running.
The third day was a day of rest and religious ceremony. The highlight was the
sacrifice of 100 cows in honor of Zeus and a sharing of the meat with the athletes
and invited guests. The forth day consisted of foot racing, boxing and wrestling.
Athletes ran from 1 to as many as 24 laps around the stadium track. In the diaulos,
athletes ran the race armed with helmets, greaves and shields.
Opponents were chosen by drawing lots for boxing and wrestling matches. There
were no weight classes. The fight was over when one of the contestants raised a
finger to indicate capitulation. With one type of wrestling called pankration any-
thing was allowed except biting or putting fingers in the opponents nose or eyes.
If athletes did not obey the rules the judges could punish them during the event
with a whip or stick or they could be assessed a monetary fine. The money from the
fines was used for statues of Zues and the names of the cheating athletes were
inscribed in the base. On the fifth day, the winning athletes were honored and
crowned with traditional wreaths made of wild olive leafs. There were no second
and third place winners. Finally, on this last day there was a great banquet for the
athletes, judges and politicians. The Olympic games were held for more than a
thousand years by the Greeks and later the Romans until they were stopped in
393 AD by the Christian emperor Theodosius, who forbade all pagan
celebrations.
The Romans
The early Romans were similar to the Greek Spartans with a strong emphasis on
physical fitness for military service along with conquest and expansion [18]. Unlike
the Spartans, Roman children remained in their homes where they received a mea-
ger education from parents including the basics of reading, writing and counting
along with moral and religious instruction.
From the start young boys were prepared for their future military obligations.
Anyone between the age of 17 and 60 was eligible for conscription and all citizens
were expected to maintain physical fitness. New army recruits were required to
march at a military pace for more than 5 miles often with full military gear to weed
out the less fit. The soldiers were typically conscripted in the spring and often
released at the end of summer campaigns.
The military had a strong class structure with classes determined largely by
wealth and social status at least in the early years of the Republic. One had to own
real property to be eligible to serve in the military. The generals were selected
from the wealthiest aristocratic families often with generations of military leaders
made rich from bounty seized in prior wars. The first class soldiers were the
wealthiest citizens who fought without pay, providing their own equipment typi-
cally including sword, lance, helmet, greaves and shield. Second and third class
soldiers were ordinary citizens who were provided with weapons but were less
The Romans 51
heavily armed than the first class soldiers. Finally, the poorest citizens formed the
fourth and fifth classes who fought without armor and were given only light weap-
ons such a lance.
A legion consisted of 2000 first class soldiers, 1000 second and third class, and
1200 fourth and fifth class soldiers, along with 300 horsemen who rode bareback
and were mostly used for reconnaissance and communication. In addition to food
rations that typically consisted of about a bushel of wheat (a months supply), the
soldiers carried their armor and weapons, cooking utensils, along with tools and
implements for preparing and fortifying the nightly campsite (weighing as much as
85 lb). Their food consisted of cakes or porridge made from the wheat ground in
hand mills supplemented with wild game when available.
Military drilling was frequent and vigorous. They were taught to throw javelins
and fight with swords against simulated enemies and to rapidly entrench and defend
against an attacking enemy force. An average day’s march was 15 miles in the
morning but for training they were required to march 20 miles with full equipment
at a rate of 4 miles per hour with intermittent bursts of forced marching at 5 miles
per hour. As a result they conquered and ruled a large part of Western civilization for
centuries.
Around the third century BC, the Romans became more and more influenced by
Greek culture and at the time Greece became a Roman protectorate in 146 BC, the
Romans had adopted many features of the Greek education system. Young boys
educated at home in the basics, were sent to secondary schools where they studied
Greek and Latin along with a variety of subjects including poetry, music and
mathematics.
The Romans admired the Greek’s ability to speak in public and young men inter-
ested in a political career attended schools of rhetoric where they developed their
grammatical and oratorical skills [19]. Probably the most famous Roman orator,
Marcus Tullius Cicero, had a speech impediment as a child but after studying at the
school of the famous Greek orator, Apollonius Molon on the island of Rhodes, he
became a prominent Roman Senator and eventually was elected Consul.
Molon taught that public speaking was like running a race; it required a great
deal of strength and stamina. He had Cicero begin each morning with a vigorous
exercise routine that the future senator maintained throughout his life. The exercise
routine included 20 repetitions of touching the floor with knees straight, sit-ups with
hands behind the head and push-ups without bending the knees. Cicero was taught
to use his speech impediment to his advantage creating tension in the audience dur-
ing his speeches.
The popularity of the Greek outdoor gymnasium never took hold in Roman soci-
ety. Performing in the nude disgusted the average Roman and they lacked the love
of competition characteristic of the Greek athletes. Probably the closest Romans
came to the Greek gymnasium was the public bath present in every town of any size.
The public bath did provide space for exercise but the rooms and courts for exercise
were much smaller than the space for exercise in the Greek gymnasium. The baths
were primarily a meeting place with seats and walkways where people could con-
verse and read poetry.
Exercise and sports were primarily used to enhance the pleasure of the bath and
the meal that often followed. The most popular type of exercise were games played
with a ball filled with air, feathers or hair on a court with at least one large wall,
called a sphaeristerium.
With the end of the Roman Republic and the beginning of Imperial Rome in the
first century BC, the Roman military relied more and more on mercenary troops and
the average citizen no longer felt the need to prepare for military service. By this
time, the Greek national festivals including the Olympics were in decline and
despite efforts from several Roman emperors to revive interest in the games in Italy
there was little enthusiasm among the Roman people.
Amateur sportsmen were replaced by professional athletes who were uneducated
and treated as virtual slaves. Boxing and wrestling matches were violent and the
athletes were often crippled for life. By the first century AD, there was a dramatic
contrast between the sportsmanship of the ancient Greek sporting festivals and the
professionalism of the “sporting events” held in the Roman Coliseum. The main
events in the Coliseum were violent chariot races and gladiatorial combats between
men, men against animals and between animals all for the entertainment of the
cheering spectators [20].
The participants were mainly prisoners of war, slaves or condemned criminals
who were the property of their trainers who cared little about their safety. This
degeneracy marked the beginning of the end the Roman civilization that at its peak
controlled a large part of the civilized world. With the acquisition of power and
wealth there was less and less interest in physical fitness in the general population
and eventually the Roman empire fell to the more physically fit Northern and
Western European “Barbarians”.
Galen
The most important physician of the Roman era, Claudius Galenus, better known as
Galen, heavily influenced the Western world for more than 1500 years with his
medical teachings. He wrote extensively and much of what he wrote has been main-
tained [3, 21].
Galen was born in the ancient city of Pergamon the son of a wealthy Greek archi-
tect in about 130 AD. At the time, Pergamon was a major cultural center with a
library second only to the famous library in Alexandria. Galen trained in medicine
and philosophy and he preached that the profit motive of many of his compatriots
was incompatible with being a good doctor. He famously said that doctors must
learn to despise money.
After his training in Pergamon, Galen traveled extensively learning the latest
medical discoveries in Corinth, Smyrna and Alexandria before finally settling in
Rome. Paradoxically, he became a wealthy member of Roman society serving as the
personal physician to several emperors. Galen was a follower of Hippocrates and
believed in the four humor theory of disease. He introduced the practice of blood
letting into Roman society.
Galen 53
Galen was known for his detailed descriptions of anatomy even though he had
never dissected a human body. Dissection of humans was forbidden at the time.
Most of his anatomical work was done on pigs. His many errors in anatomical
details weren’t uncovered until the mid sixteenth century when Vasalius published
his famous book on human anatomy.
Like Hippocrates, Galen recommended moderate exercise both for maintaining
good health and for treating a variety of diseases [22]. He did not distinguish exer-
cise from work but rather he distinguished between motion and exercise. Digging a
ditch was exercise; leisurely walking was not. For motion to be exercise it had to
increase the heart rate and breathing rate.
Galen described three different qualities of exercise: speed, vigor and violence.
For example, running was swift, running up a hill was vigorous and throwing a
discus was violent. Walking was not exercise if it did not noticeably increase breath-
ing rate. Galen felt that it was important for physicians to understand the effects of
different forms of exercise on the human body so that they could select the right
exercise to prescribe for different illnesses just as they had to pick the right medica-
tion to prescribe.
Exactly what Galen meant by moderation in exercise is not that clear since the
definition of moderation varies from time to time in his writings but it is clear
that he had a negative opinion about extreme athletic events even some in the
Olympic games. Like Hippocrates and Plato before him, he felt that professional
athletes did not practice moderation and spent their lives over-eating, over-exer-
cising and over-sleeping. They exceeded the limits for good health and were
constantly in pain and when they finally stopped competing their bodies were
deformed.
Likely Galen came to these conclusions after seeing injured gladiators, wrestlers,
boxers and pentathletes as part of his official medical duties. While in Pergamon he
served as the primary physician for the gladiators. Gladiator contests rapidly became
the most popular spectator sport in all the Roman empire. When gladiatorial con-
tests were first introduced in Rome in 264 BC, there were 6 professional gladiators.
During the time of Julius Ceasar the number increased to 640 and in the reign of
Augustus around the time of the birth of Jesus there were 10,000 professional gladi-
ators. Compared to this violent contact sport, American football seems like
child’s play.
Galen did provide a description of what he considered the ideal exercise in a
short treatise entitled: On exercise with a small ball [1]. He began the article by not-
ing that the best form of exercise is one that uses all parts of the body and combines
physical activity with pleasure and delight. As an example, he noted that hunting
with hounds involves a variety of physical activities along with an enjoyable experi-
ence. The problem is that the sport was expensive, required a lot of free time and
was not available to the average citizen.
Galen felt that exercise with a small ball activated the entire body, required rela-
tively little time and was available even to the poorest man. Although Galen did not
provide detailed rules on how the game was played he provided a general outline.
It was a game of take away combined with wrestling. Two men on each side tried
to keep a man in the center from intercepting the ball. But the man in the middle
didn’t just intercept the ball in the air but could wrestle with either end man to take
it away.
For older people he recommended a gentler version of the game with slower and
less vigorous movements. The key was a combination of physical activity plus plea-
sure so that people would enjoy exercising. Galen was opposed to what he consid-
ered vigorous exercises such as running, jumping and discus throwing which
thinned the body too much and only strengthened parts of the body while other parts
remained idle. He also noted that these vigorous exercises killed many people due
to a ruptured blood vessel. No doubt, the rare occurrence of sudden death due to a
heart attack or stroke during vigorous exercise was a reason why many of these
ancient physicians emphasized moderation in exercise.
The Middle Ages and the Soul Rules the body
With the fall of the Roman Empire, there was a regression toward more primitive
societies, some with lifestyles that combined features of earlier hunter-gatherer and
agricultural societies [23]. The sturdy invading barbarian population intermixed
with the native population and large cities shrunk in size. As with earlier primitive
societies, physical activity levels were very high necessary for survival. Only a tiny
fraction of people had leisure time for games or exercise.
The teachings of Galen dominated medical thinking but trained physicians were
few and far between. Although the invading barbarians, particularly the German
tribes and Vikings from the North, influenced the local culture, it was the develop-
ment of the great Western religions, first Christian and later Islam, that had the most
impact on Roman and European culture for the next millennium. There was a dra-
matic swing of the pendulum from the worship of the body and physical fitness
characteristic of the early Greeks to contempt for the body and worship of the soul
characteristic of the early Christians and Mohammedans.
Overall, it was a grand experiment on the negative health effects of physical
inactivity. Like religions in the East these new religions were based on the doctrine
of asceticism, the idea that the body and the soul were in constant warfare with the
body being evil and the soul, pure and divine. The desires of the body must be
resisted lest they contaminate the soul. One should strive for a life of solitude and
contemplation avoiding physical indulgence at any cost.
Not surprisingly, these religious beliefs conflicted with the luxury and sensual
self-indulgence of the late Roman Empire forcing people with deep religious feel-
ings to want to escape from the excesses and live simple lives free of worldliness.
Many fled to the deserts where they lived a life of deprivation often leading to early
death. They were in a constant struggle to suppress normal human appetites and
impulses and often resorted to self-inflicted torture to subdue the desires of the flesh.
Early on, persecution of the Christians by the Romans glorified martyrdom and
the associated pain and suffering. This provided a direct way to release the soul and
enter the kingdom of heaven. By the fifth century AD, there were about 100,000
The Age of Chivalry 55
Christian hermits in the deserts of Egypt and an equal number scattered throughout
Asia Minor and Western Europe. The deprivations of these so-called “saints of the
desert” were legendary with some living in deserted dens, tombs and dried-up wells,
sleeping naked in swamps or not laying down at all for months, and living on small
quantities of food with long periods of fasting. There was no concern for body
cleanliness or fitness which had a disastrous effect on the health of the body and the
brain. Many reported visual and auditory hallucinations considered religious expe-
riences but likely due to physical and emotional deprivation.
From about the fifth to the twelfth century, the education of the young was almost
exclusively in the hands of the religious leaders. In the eighth century Charlemagne
(Charles the Great) dictated that all monasteries throughout his kingdom must have
a school for boys [24]. The Benedictine monks controlled the education of most
young Christian boys. The schools were associated with the local monasteries and
cathedrals and the students were primarily prepared for priesthood or the monastery.
Of course, teachers emphasized the Holy Scriptures and the writings of the leaders
of the church.
Students were taught the so-called seven liberal arts with the main focus on
grammar, rhetoric and logic and lesser emphasis on arithmetic, geometry, astron-
omy and music. Sports or play of any kind was frowned upon as wasteful and poten-
tially harmful to the soul. Physical neglect was the mark of a true scholar. Monastic
discipline pervaded all school activities and physical punishment typically with the
rod was routine. Fairness wasn’t an issue since the students were punished for sins
they committed in the past or were likely to commit in the future. Girls were not
admitted to the monastery schools and received practical training in the home.
The Age of Chivalry
The end of the twelfth century marked a dramatic shift in the Christian Church from
its ascetic beginnings to a warrior mentality necessitated by the Crusades that began
in 1096 and persisted into the late thirteenth century. Mohammedan warriors
invaded the Christian Holy Lands of the Middle East and the Christian hierarchy
was determined to drive out the invaders. In order to achieve this goal they needed
physically fit fighters to repel the “infidels” and they embraced new orders of soldier
monks, the Hospitallers, the Templars and the Teutonic Knights [25].
The romantic figures of Charlemagne and King Author and the concept of chiv-
alry became the model for the churches new military system. To develop a pipeline
of physically fit young men, boys around the age of 7 were sent to the court of a
local nobleman where he joined a group of young attendants to acquire the breeding
and develop the physical skills necessary to become a knight. Starting as a page, he
would perform domestic duties while being taught in the basics of reading, writing
and speaking in Latin and French by the ladies of the court along with the basics of
gallantry and courteous behavior.
Most important of all the boys spent long hours outdoors playing games and
learning physical skills by imitating the squires and knights that they hoped to
become. The young pages gradually progressed to squires after age 14. With this
promotion they acquired new responsibilities to the nobleman and prestige within
the household. At this stage their education was primarily focused on developing
physical skills needed to become a knight: training a falcon to hunt, hurling stones
and spears, shooting a bow and arrow, wielding a battle-axe and fencing. They
began with a dull wooden sword to master the basics and moved on to a sharpened
blade as their skills developed.
The young squire was trained to run, jump, swim, wrestle and climb ropes, poles
and ladders but foremost horsemanship. He practiced rapid mounting and dismount-
ing without stirrups, how to reach down and pick up objects from the ground and
how to give and take blows all while galloping in full armor. The young squires
followed their nobleman into battle serving as a groom adjusting and fastening
armor, caring for horses, supplying lances as needed and attending to wounds. Once
the squire reached the age of 21 he was eligible for knighthood assuming he had
proved his merit and fitness in training and battle and had the financial support for
such a costly profession.
Young knights often honed and tested their skills as warriors at the jousting tourna-
ments that were popular throughout Christian Europe in the thirteenth and fourteenth
century. As a public spectacle, these tournaments rivaled the Olympic games and
Coliseum gladiator events of the Greco-Roman era. They began as local competitions
between young knights with the goal of obtaining attention and potential financial
support from influential noblemen. With time they became a chief pastime of nobles
and their entourages and a training school for young knights during peacetime.
Nearly everyone is familiar with the jousting tournaments as depicted in movies
of the era of chivalry particularly those of King Author and his knights of the round-
table. Two horsemen in full armor holding a long lance galloped toward each other
and when they met at the center they attempted to knock the other off his horse with
the extended lance. They tried to hit their opponent’s breastplate but blows to the
head or neck were not uncommon. In some of the tournaments, the combat would
continue with swords after one of the contestants was knocked from his horse.
Usually the lances were tipped with a small flat metal plate and the swords were
blunted but, not surprisingly, injuries were common and occasionally deaths resulted
either from the blow of the lance or from injuries suffered during the fall.
For greater spectacle in large tournaments, a cavalry battle was reenacted as two
groups of knights in full armor fought each other with lance and sword. The last
crusade occurred in 1270 but the age of knighthood and combat tournaments per-
sisted well into the fourteenth century. In the fifteenth century with the invention of
gunpowder, the arms and armor of the knight was no longer relevant in battle and
the age of chivalry rapidly declined.
The Renaissance
With the Renaissance beginning in the fifteenth century there was a revival of inter-
est in the ancient Greek and Roman societies along with a renewed focus on the
human body and the importance of physical fitness [26, 27]. A key early figure in
The Renaissance 57
this revival was the Italian humanist and teacher Vittorino da Feltre (Vittorino
Rombaldoni) who was born in 1378 in the town of Feltre in the Republic of Venice.
In the fifth book of The Story of Civilization series, The Renaissance, historian Will
Durant described Vittorino as the epitome of the Renaissance man (l’uomo univer-
sale), a man with “health of body, strength of character and wealth of mind.”
After completing his education at the University of Padua, Vittorina was invited
to come to Mantua to tutor the children of the marquis of Mantua, Gianfrancesco
Gonzaga. In the process, Vittorino set up a school that rapidly became famous
throughout Italy and ultimately developed into a model of future secular boarding
schools. Young nobles from all over Italy flocked to Vittorino’s school giving it the
name, School of Princes. But Vittorino also admitted many local poor children at no
cost and treated them as equals with the noble children.
Studies focused on the Greek and Latin languages with courses in mathematics,
history, poetry, music, art and philosophy. In the process Vittorino introduced the
young men to the life of the ancient Greeks and Romans. Although the age of
knighthood and chivalry was in decline Vittorino also introduced his pupils to some
of the features of a knightly education. Vittorino felt strongly that a healthy body
makes a sound mind. He hired assistants to teach dancing, horsemanship, and fenc-
ing. Daily exercising included swimming, running and jumping, wrestling and a
range of ball games. Students were also instructed in archery, hunting and fishing
and military exercises with mock battles where one side attempted to storm a castle
or ambush the camp of the other side.
Vittorino lived with the students and often joined them in their exercising and
games and with excursions into the Alps where the students were taught to brave the
elements. He felt that it was important for students to spend long periods of time in
the open air and weather should not interfere with their daily exercise. Vittorino
made education so enjoyable that his school became known as The House of Joy
(La Casa Gioiosa) and it served as a model for future schools throughout Europe
particularly in England.
An Italian physician, Girolamo Mercuriali, published a book revisiting ancient
gymnastics, De Arte Gymnastical, in Venice in 1569, one of the first medical books
on physical education. The book was immensely popular at the time and is currently
one of the most sought after books by Renaissance book collectors. The son of a
physician, Mercuriali was born in the Northern Italian town of Forli in 1530. He
obtained his medical degree at the university of Padua and shortly after he was sent
on a political mission to the Vatican in Rome.
Living in the household of Cardinal Alexander Farnese, he had free access to the
vast Vatican libraries where he studied the medical writings of the ancient Greeks
and Romans. In the first half of his book he provides a detailed history of the ancient
gymnastic exercises referencing a total of 96 Greek and Roman authors. In the sec-
ond half of the book he focuses on the medical benefits of exercise both for prevent-
ing and treating disease which was largely a rehashing of the teachings of Hippocrates
and Galen.
The book, which was aimed at a broad audience and was later published in Paris
and Amsterdam, captured the imagination of the people in Europe who knew little
about the nature of athletics in the Classical world. It was the first of a series of
medical books published by Mercuriali leading to a professorship in medicine at the

University of Padua in 1575. In a story with a modern twist, Mercuriali’s fortunes
spiraled downward with his gross mishandling in the plague epidemic that devas-
tated Venice in 1576–1577.
The Venetian government asked Mercuriale to lead a team of physicians to advise
the local Board of Health on managing the outbreak. At the time Mercuriale was
summoned, the outbreak appeared to be under control with relatively few deaths.
This apparently caused Mercuriale to conclude that the disease could not possibly
be plague. He said that he would personally treat the people of Venice but only if the
quarantine and the special hospitals set up for infected people previously imple-
mented by the Board of Health were cancelled.
Even though the board of Health and other local officials strongly disagreed,
Mercuriale and his many assistants from the University freely moved between
affected and unaffected people in Venice and Padua providing a variety of treat-
ments. People with symptoms were allowed to move freely throughout the city.
Plague can be spread by respiratory droplets with coughing or sneezing which typi-
cally requires close contact (within 6 ft) of an infected person. Within a month of
Mercuriale’s leadership there was an exponential increase in the number of deaths
and the government ordered the return to quarantine and that Mercuriale and his
assistants be placed under quarantine themselves. By the conclusion of the epidemic
50,000 Venetians died of the plague. In an attempt to salvage his reputation,
Mercuriale published a book on the plague (De Pestilentia) in 1577 and he delivered
a series of lectures on the topic at the University of Padua.
John Locke
Of the many individuals who emphasized the importance of physical fitness in the
education of young people during the Renaissance, the English physician and phi-
losopher John Locke was one of the most influential and some consider him the
father of modern physical education [28]. Locke was born near Bristol England in
1632 and after early education at Westminster School he went on to study philoso-
phy and medicine at Crist Church, Oxford. After completing his medical studies,
Locke became the private physician of a friend Lord Ashley and later when Ashley
became the first Earl of Shaftesbury and Lord Chancellor, Locke served as his
Secretary of Presentations.
Locke’s ideas on the mind and physical education developed over the next
25 years during an eclectic career as tutor, politician, physician and philosopher.
After Shaftesbury left office, Locke spent 4 years in Paris tutoring the son of an
English nobleman and serving as physician to the wife of the English Ambassador.
He rejoined Shaftesbury in England on Shaftesbury’s return to power where he
served as a political advisor and tutor to Shaftesbury’s grandson.
Shaftesbury was a devout Protestant and his main political interest was in
preventing a Catholic King from gaining the throne. This ultimately led to his
downfall and he had to flee to Holland charged with treason by the English
John Locke 59
government. Locke later also fled to Holland with his only crime being his asso-
ciation with Shaftesbury and he was forced to go into hiding when the English
government asked the Dutch to turn him over as a traitor. It was during this time
that Locke, in his mid 50s, wrote two remarkable essays based on his lifetime of
study, “Essay Concerning Human Understanding” and “Some Thoughts
Concerning Education”.
Unlike contemporary philosophical thinking dominated by religious belief in a
supernatural soul, Locke considered the mind to be a blank slate at birth without
innate knowledge. A child learned through experience derived through sensory
experience, a revolutionary concept later reinvented by psychologists, BF Skinner
and Donald Hebb in the twentieth century. Locke also outlined the basic premise of
science: all information must be capable of being tested and retested and that one
must always be willing to discard an idea when it is proven to be wrong. Many of
the political, scientific and educational advances that occurred in England and
America in the nineteenth century can be traced directly back to Locke. Locke’s
liberal political beliefs are engrained in the Declaration of Independence and in the
Constitution of the United States of America.
In 1692 Locke wrote a letter to his friend Edward Clarke in which he attached his
essay “Some thoughts concerning education” outlining his suggestions for the edu-
cation of Clarke’s son [29]. This was not about educational systems but rather how
to educate a gentleman’s son. Locke was not interested in how to teach information
but rather how to make a cultivated gentleman who was wise, strong and coura-
geous. This was in stark contrast to education through rote memorization common
at the time.
Locke identified three main features of a gentleman’s education: physical educa-
tion, moral education and intellectual education. His famous phrase “a sound mind
in a sound body” summarizes his overall approach. One could not be truly happy in
life without both a strong mind and a strong body. Locke felt that exercise was key
to cultivating a child’s physical constitution because having a healthy body was
critical for morale and intellectual development.
As a way to get children interested in exercise Locke recommended that they
participate in a variety of sports appropriate for age. He was particularly fond of
swimming that had the added benefit of potentially saving the child’s life from
drowning but recommended any sport including horseback riding and fencing. By
learning and practicing sports, children could develop good exercise habits that
would serve then well throughout life. Locke emphasized the importance of exercis-
ing outside in the open air even in winter. He felt that being exposed to various
conditions from sun and wind to cold and rain would improve the endurance and
health both as a child and later as a grown up.
Locke believed that exposing children’s feet to the elements protected them from
catching cold. He recommended washing the feet every day in cold water and to
wear thin porous shoes so that when in the rain the feet would be wet. Clothing in
general should be light and loose particularly when exercising outdoors. Finally, the
child’s diet should be plain and simple with periods of fasting to train the child to
endure hunger.
Although the essay was about education of his friend’s son, Locke indicated that
most of his suggestions applied to girls as well. They also needed to develop good
habits in exercise as part of their education. Just like boys, girls needed to be out-
doors and exposed to sun, wind and rain to develop strong and healthy bodies. They
should not let concerns about adverse affects on their beauty limit their exposure to
the elements since the advantages they received from being outdoors far outweighed
any minor disadvantages.
Of Locke’s three aspects of a gentleman’s education he ranked physical educa-
tion first, morale development second and intellectual pursuits third. He felt that
morale values, virtue, wisdom and courage were the foundation of a gentleman.
Without morality one could not be a gentleman or live a happy life. In addition to
developing a strong body, sports cultivated a courageous and firm mind and helped
develop morale habits in children.
With regard to the obtaining intellectual knowledge, Locke emphasized under-
standing and thinking ability more than information learning since these attributes
provided a good foundation for learning throughout life. Children needed to be
taught how to get information rather than just information itself. Of course, he
emphasized the importance of learning basic skills, reading, writing, arithmetic and
logic but also emphasized the importance of dancing, gardening and the arts.
Locke’s ideas on education particularly physical education had a profound influence
on development of education throughout the Western world for the next several
centuries. In America, all of the founding fathers respected Locke’s opinions but
none more than Thomas Jefferson who became fanatical about exercise for a
healthy mind.
Jean-Jacques Rousseau
A great admirer of Locke, the Swiss French philosopher and writer, Jean-Jacques
Rousseau, was also a strong proponent of physical exercise in the education of chil-
dren. Like Locke, Rousseau’ s liberal political philosophy strongly influenced the
French Revolution and since his enlightened views on individual freedom conflicted
with the views of governments and religious institutions he had to flee prosecution
on several occasions.
In his book, Émile, ou De l’éducation (in English, Emile or on Education)
Rousseau follows the protagonist Emile, a boy orphaned at birth, as he develops
psychologically and morally from youth to adulthood [30]. Considered the most
important work on the philosophy of education in Western culture, the treatise
divided into five Sections, tackles difficult questions about the nature of educa-
tion and its importance in defining the relationship between a person and society.
He disagreed with Locke that one could reason with a child. A child’s mind was
not developed enough for reasoning and attempts to reason with a child only
confused the child. He famously wrote in Section 2 of Emile, “exercise his body,
his limbs, his senses, his strength, but keep his mind idle as long as you can.”
Jean-Jacques Rousseau 61
Rousseau served as a tutor on several occasions and he spent a great deal of time
thinking about how to best raise a child even though he never raised a child of
his own.
Rousseau was born in 1712 in Geneva which at the time was a city-state of the
Swiss Confederacy and the center of Protestant Calvinism [31]. His mother died 9
days after his birth from postpartum infection. Rousseau was raised by his father
and his father’s sister who taught him to read and write and to love books but at age
10 his father remarried and he was left with a maternal uncle who quickly sent him
to board with a Calvinist minister where he received some basic education and a
transient desire to become a Protestant minister.
At age 13 Rousseau was apprenticed to an engraver who regularly beat him and
by age 15 he ran away from Geneva and was briefly sheltered by a Catholic priest
in the Savoy region of the western Alps. The priest introduced Rousseau to a
29 years old noblewoman who was separated from her husband. She took Rousseau
under her wing initially serving as a mother figure but years later becoming his
lover. Like Rousseau, she had a Protestant background but had converted to
Catholicism and was being paid by local authorities to help bring Protestants into
the Catholic faith.
Rousseau rapidly converted to Catholicism which meant giving up his Geneva
citizenship and being disowned by his family. Through his remaining teenage years
Rousseau supported himself as a secretary and tutor and even briefly joined a semi-
nary with the thought of becoming a priest. Rousseau had been an indifferent stu-
dent and it wasn’t until his 20s with the support of his older lover that he seriously
took up the study of philosophy and mathematics and was exposed to the world of
ideas. This may explain his strong belief that children should enjoy their childhood
with play and exploration and should not be exposed to complex ideas such as those
in philosophy and religion until they reached adulthood.
In his 20s, Rousseau suffered from long bouts of hypochondria that engendered
a lifelong distrust of the medical profession. In Emile or on Education, he wrote:
“Live according to nature, be patient, get rid of doctors; you will not escape death,
but you will only die once; while doctors make you die daily through your disease
imagination.”
Rousseau had as many as four children of his own out of wedlock with a seam-
stress in Paris and all were given to a Foundling Hospital as newborns. The seam-
stress was the sole supporter of an extended family and Rousseau who himself was
barely making enough to survive took her and her mother into his house as servants.
Rousseau with the help of the mother convinced the woman to give her children up
because they were too poor to support them.
In his autobiographical treatise, Confessions, published after his death, Rousseau
defended his decision to give up the children, “I trembled at the thought of entrust-
ing them to a family ill brought up, to be still worse educated. The risk of the educa-
tion of the founding hospital was much less.” Not surprisingly, years later when
Rousseau became internationally known for his ideas on education of children his
abandonment of his own children served as fodder for his many critics.
Rousseau began his treatise on Emile’s education by emphasizing the impor-

tance of the mother–child bond that must develop in the first few days after delivery.
He was a strong proponent of breastfeeding and warned of the dangers of turning
over this duty to a wet nurse. There was no substitute for a mother’s love. The first
year was particularly important for brain development and the mother was crucial in
this development.
Rousseau ranted about the dangers of swaddling children which he felt was a
practice advantageous only to the caretaker. “The child is hung up on a nail like a
bundle of clothes and is left crucified while the nurse goes leisurely about her busi-
ness.” The newborn child needed to be free to move his extremities and flail about
in order for the brain to develop properly. Besides, the child was too weak to get into
any trouble and even as the child began to turn over and crawl, exploration of the
environment should be encouraged not inhibited.
These are generally accepted concepts for raising children in modern days but
were revolutionary in the 1700s. Like Locke, Rousseau encouraged the mother to let
the child play outdoors exposed to the elements. He recommended cold bathing
particularly of the feet and loose fitting clothing so there is no restriction of move-
ment. Rousseau strongly believed that exercise improved the child’s learning ability.
“Give his body continual exercise; make him robust and sound in order to make him
wise and reasonable; let him work, and move about, and run, and shout, and con-
tinually in motion; let him be a man of vigor, and soon he will be such by force of
reason…”.
Rousseau recommended that children begin playing games of skill such as shut-
tlecock, tennis, and soccer even before they had the strength to adequately compete
with older players. For example, with tennis he suggested that the child begin using
a soft ball and a small wooden racket to bounce the ball off the walls of a hallway
learning to judge the trajectory of the ball and the force required to send it back
against the wall. With time he would proceed to a harder ball and first a racket made
of parchment and then catgut.
As Emile reached his teenage years, Rousseau insisted that that he should
apprentice for a trade, not for future employment but so that he would overcome
common prejudices against the trades. His early education should already have
introduced him to gardening and the use of simple tools such as the hammer, file and
plane and because of his regular exercise he already had an agile body that could
perform all kinds of movements without effort.
Although Rousseau felt that the choice of trade should be left to the interests of
the pupil, he personally favored cabinetmaker since “it keeps the body sufficiently
exercised; it requires of the workman skill and ingenuity, and in the form of the
products which utility determines, elegance and taste are not excluded.” As Emile
approached maturity, Rousseau felt that he needed to acquire a new pastime one that
would give him pleasure and keep him in good humor while at the same time pro-
viding regular exercise and occupy his mind. Rousseau favored hunting since it
combined exercise with strategy but the key was that whatever Emile chose he had
to be wholly absorbed and passionate about it.
Thomas Jefferson 63
In the fifth and final section of his book, Rousseau addressed the education of
Emile’s future wife, Sophie. Rousseau exhibited the common prejudices of his time
about women, but like Plato and Locke, he felt that exercise was just as important
for the development of girls as for boys. Young girls should be allowed to run, jump
and shout and play games just like boys. Strength and vigor were critical for their
future role as mother and head of the household. He warned against the practice of
delicately rearing a young girl at home under the watchful eyes of her mother,
always scolded or flattered, not allowing her to freely move about and enjoy the
invigorating feeling of being outdoors in all kinds of weather.
Like many philosophers, Rousseau was interested in what makes people happy
and in the case of the treatise on Emile, what kind of education produces an adult
who is happy. His views on happiness can be summarized by a few simple premises:
Happiness is not wanting more than you have; Live for the moment, not the past or
the future; Constantly striving for happiness can make you wretched.
As noted in Chap. 1, living in the moment and not wanting more than you can
have were reasons why people in hunter-gatherer societies were generally happy.
Rousseau summarized his feelings on childhood education as follows: “There is
only one man who gets his own way—he who can get it single-handed, therefore
freedom, not power, is the greatest good. That man is truly free who desires what he
is able to perform, and does what he desires. This is my fundamental maxim. Apply
it to childhood, and all the rules of education spring from it.”
Thomas Jefferson
In the post revolutionary war period, America was still an agrarian society and most
people worked long hours and had little time for leisure [32]. But as in Great Britain
there was a small group of landed gentry who had leisure time to exercise. Thomas
Jefferson, one of the founding fathers, was one of these landed gentry.
Jefferson recommended a minimum of 2 h of exercise per day. In a letter to his
nephew Peter Carr in 1785, Jefferson advised Carr: “Give about two of them [hours]
every day to exercise; for health must not be sacrificed to learning. A strong body
makes the mind strong… Walking is the best possible exercise. Habituate yourself
to walk very far” [33]. Jefferson recommended walking in the afternoon not because
it was the best time to exercise but because it freed up the most productive time in
the morning to read, write and study. However, he did suggest a brief walk of about
a half hour in the morning after first arising to shake off sleep and get the animal
juices flowing. Jefferson calculated that he walked about 4 miles in an hour and thus
8 miles in his daily walks although he often walked much farther.
Jefferson noted that people who were not used to walking became fatigued after
walking just a few miles but after a month of walking could walk 15–20 miles with-
out fatigue. Jefferson boasted that he had never known or heard of a regular walker
who was not healthy and long-lived. He recommended exercising regardless of the
weather, wet or dry, warm or cold. Animals were exposed to all types of weather
without ill effects and he felt that men who are exposed to the elements were the
healthiest.
Contrary to his fellow landed gentry, Jefferson did not consider horseback riding
an exercise. In the same letter to his nephew he railed against the horse: “The
Europeans value themselves on having subdued the horse to the uses of man. But I
doubt whether we have not lost more than we have gained by the use of this animal.
No one has occasioned so much the degeneracy of the human body. An Indian goes
on foot nearly as far in a day, for a long journey, as an enfeebled white does on his
horse, and he will tire the best horses” [33].
Jefferson felt that exercise was critical for both men and women. In a letter to his
daughter, Martha, he advised: “Exercise and application produce order in our affairs,
health of body, cheerfulness of mind, and these make us precious to our friends...
You are not however to consider yourself as unemployed while taking exercise. That
is necessary for your health, and health is the first of all objects. For this reason if
you leave your dancing master for the summer, you must increase your other exer-
cise” [34].
Early Exercise Equipment
Although weights with handles, halteres, were first used by the ancient Greeks as
part of their exercise routine it wasn’t until the eighteenth century that dumbbells
became popular for the average person [35]. The word dumbbell originated in the
late sixteenth century when athletes in England first used bells with the clappers
removed for strengthening exercises, hence the term dumbbell. One can speculate
that this was simply a matter of convenience since heavy iron bells were widely
available and removing the clapper was easily done.
The use of dumbbells became popular in England in the early eighteenth century
when the poet, Joseph Addison, described using dumbbells in his exercise routine in
an essay published in The Spectator. In America, Benjamin Franklin popularized the
use of dumbbells later in the century. Franklin was a gadget man and was constantly
looking for new ways of doing things. He used the dumbbell similar to how a bell
was normally rung by attaching a rope to the clapperless bell, running the rope
through a pulley and then pulling on the rope.
In a letter to his son, William, from London in 1772, Franklin encouraged
William to exercise on a regular basis to keep healthy and prevent disease “since the
cure of them by physic is so very precarious” [36]. He went on to tell his son that
the dumbbell was an ideal form of exercise and that with 40 swings of the bell his
heart rate increased from 60 to 100 beats per minute and he felt warm all over.
Franklin had been an avid swimmer when he was younger but as he got older he
took to brisk walking and weight lifting.
Gradually clapperless bells were replaced with iron weights that could be
changed as one progressed. The early versions were canisters that were filled with
sand or shot to adjust the weight. Eventually these became too cumbersome and
were replaced by variable weights attached to the ends of a bar, hence barbells.
References 65
For those who favored horseback riding for exercise, the chamber horse was
ideal when the weather was bad. This was a modified chair with a bellows mecha-
nism so that the “rider” would bounce up and down as the bellows inflated and
deflated.
With the onset of the industrial revolution, the new concept of exercise as a
planned physical activity carried out with the specific goal of improving and main-
taining health developed. For the first time, a large segment of society was not get-
ting adequate physical activity in their daily work routine. As the negative health
implications of the lack of physical activity became widely known and accepted a
whole new industry developed around exercise equipment.
References
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Oxford University Press. p. 302.
2. Huard P, Wong M. The evolution of Chinese medicine. In: Chinese medicine. New York:
McGraw Hill; 1968. p. 8–71.
3. Tipton CM. Historical perspective: the antiquity of exercise, exercise physiology and the exer-
cise prescription for health. In: Simopoulos S, editor. Nutrition and fitness: cultural, genetic
and metabolic aspects. World review of nutrition and dietetics, vol. 98. Basel: Karger; 2008.
p. 198–245.
4. Henning SE. Academia encounters the Chinese martial arts. China Rev Int. 1999;6:319–32.
5. Xing Yi Quan Xue: the study of form-mind boxing by Sun Lu Tang. Translated by Albert Liu.
Pacific Grove, CA: High View Publication; 1993.
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tute.org.
7. Samuel G. The origins of yoga and tantra. Cambridge: Cambridge University Press; 2008.
8. Worthington V. A history of yoga. Boston: Routledge & Kegan Paul; 1982.
9. Robinson RS. Sources for the history of Greek athletics. Chicago: Ares Publishers; 1981.
10. Hooker JT. Ancient spartans. London: Dent; 1980.
11. Mitchell H. Sparta. Westport, CT: Greenwood Press; 1985.
12. Georgoulis AD, Kiapidou I-S, Velogianni L, et al. Herodicus, father of sports medicine. Knee
Surg Sports Traumatol Arthrosc. 2007;15:315–8.
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2014;38:109–2013.
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15. Reid HL. Plato’s gymnasium. Sport Ethics Philos. 2010;4:170–82.
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17. Kieran J, Daley A. The story of the Olympic Games. Philadelphia: Lippincott; 1961.
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19. Rawson E. Intellectual life in the late Roman Republic. London: Duckworth; 1985.
20. Kohne E, Ewigleben E, editors. Gladiators and Caesars. Berkeley: University of California
Press; 2000. p. 31–74.
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The Developing Brain
4
It is notorious that man is constructed on the same general type or model with other mam-
mals. All the bones in his skeleton can be compared with corresponding bones in a monkey,
bat, or seal… The brain, the most important of all the organs, follows the same law…
(Charles Darwin [1])
Over millions of years of evolution, cognitive activity and physical activity became
linked in the brain. As our ancient ancestors began to shift from the sedentary life-
style of the great apes to the more physically demanding life-style of the hunter-
gatherers the link developed. The transition from low to high levels of physical
activity began about 2 million years ago associated with a change in world climate.
Our distant ancestors were forced to move from lush forests with plentiful food
to more open plains requiring hunting and foraging. These new activities combined
elements of memory, spatial navigation and planning with high levels of physical
activity. The genes controlling brain molecular mechanisms that link cognition and
physical activity developed during this period of evolution associated with a rapid
expansion in brain size and functional capability.
Scientists have long felt that studying the development of embryos can teach us
a great deal about the evolutionary history of a species. In the late 1800s when the
study of evolution was in its infancy, many speculated that embryological develop-
ment represented a step-by-step reproduction of the evolutionary process. Although
this theory that embryological development recapitulates evolution is clearly an
oversimplification there can be no doubt that embryological development provides
a window into the evolutionary process.
The early embryos of a chick and human have similar heads, appendages and
tails. Both have slits and arches in the necks almost identical to the gill slits and gill
arches of fish suggesting that they all share a common ancestor. Similarly the devel-
oping brains in fish, chicks and humans have remarkable similarities in the earliest
stages of development. In the later stages of development the similarities are closest
to our living primates, particularly chimpanzees.

https://doi.org/10.1007/978-3-031-13924-6_4
68 4 The Developing Brain
Link Between Upright Posture and Increasing Brain Size
The development of upright posture in the human species nicely illustrates the grad-
ual relentless process of evolution [2, 3]. As far back as 8–10 million years ago our
distant ancestors, quadrupeds living mostly in trees, occasionally found it useful to
stand on their hind feet to reach up and pick fruit or to better see approaching
predators.
Certain anatomical variations such as the angle of the hip insertions and the
width of the bone just below the knees allowed some to stand longer than others and
the gene variants associated with these features were selected since they provided a
slight advantage for survival over those without the features. These early primates
still spent most of their time in trees but were able to walk upright short distances
when in more open spaces. Over time other advantages to an upright posture, free-
ing the forepaws to carry food and offspring and the ability to move efficiently and
rapidly on two feet across open landscape resulted in further skeletal changes lead-
ing to early humans that mostly walked on two feet.
Many of the fossil features of bipeds were present by about 2.5 million years ago
but it wasn’t until around 2 million years ago that fossil remains of the early human
species, Homo erectus, show the characteristic curvature of the low back, lengthen-
ing of the thigh bones and the straight insertion of the spine into the base of the skull
that are uniquely human (see Fig. 2.1). The fossil remains of these early humans
indicate that they were able to walk long distances, a big advantage at the time since
the climate in east Africa was becoming dryer and large areas of grassland were
replacing forests.
In his book Descent of Man, Charles Darwin speculated that early humans began
to walk upright in order to free the arms and hands to make tools and weapons and
be able to throw stones and spears to improve their hunting skills. But what came
first the upright posture or early stone tools? The archeological records suggest that
the first stone tools were made about 2.5 million years ago around the same time
that early humans became exclusively upright. The upright posture allowed activi-
ties such as making stone tools possible but other changes, notably changes in the
brain, were needed for early humans to develop the skills to design and use them.
Our closest living primate relatives, chimpanzees, provide insight into the early
evolution of the upright posture. On the evolutionary scale, chimps separated from
humans about 8 million years ago around the time that primates first began to try the
upright posture. Chimps live in trees and are mostly quadrupeds although they can
walk on two feet particularly when carrying valuable foods.
Researchers found that chimps walking on two feet use about 75% more energy
than modern humans walking similar distances [4]. This lack of efficiency of upright
walking in chimps compared to humans can be traced to skeletal differences such as
a shortened thigh bone connecting the upper thigh to the hip so that hip muscles
don’t effectively support the upright posture and weak knees that don’t allow stand-
ing on one foot. In the chimp, the spine enters the skull at the back assuring a bent-
forward posture whereas in humans it enters the skull in the center of the base
consistent with an upright posture. Studies have shown that the most energy
Link Between Upright Posture and Increasing Brain Size 69
Human: 1,500 g, 86 billion neurons
Chimpanzee: 380g
28 billion neuron
Cortex
Parietal
Occipital
Frontal
Temporal
~x3
Cerebellum
~x15 ~x200
1 cm
Macaque: 87g Marmoset: 8g

6 billion neurons 630 million neurons
Fig. 4.1 Evolution of the brain in primates from the marmoset monkey to humans
efficient way to walk on the ground is on two feet although there are consequences
to the strain on the spine. Chronic back pain is a common human malady.
Around 2 million years ago, as humans developed an exclusive upright posture
and the ability to walk long distances, there was an approximate threefold increase
in the size of the brain relative to the size of the body. The human brain is by far the
largest brain of all primates (Fig. 4.1) [5, 6]. But size alone does not explain the
remarkable capabilities of the human brain since some large mammals have larger
brains with more neurons than human brains but do not possess the unique cognitive
abilities.
At the time of the rapid human brain expansion there was an enlargement and
reorganization of the cerebral cortex, the convoluted surface of the brain that makes
up about 85% of the brain volume. Most of the expansion of the cerebral cortex
occurred in areas responsible for complex functions such as thinking and planning,
often called executive functions. Several possible explanations for the burst in
human brain size around 2 million years ago have been proposed (for example
Darwin’s tool making theory) but these theories lack information regarding cause
and effect so they are difficult to prove.
The increase in brain size came with a high price tag, a marked increase in energy
consumption. Despite its relatively small overall size compared to the rest of the
body, the human brain uses about a quarter of the body’s total energy consumption.
With the development of an upright posture and the associated increased mobility
there was an increase in the energy content of the diet and improved aerobic capac-
ity both of which contribute to brain growth. Fossil records from these early human
species show a tight correlation between skeletal features of the upright posture and
increased mobility with increasing brain size. There is convincing evidence that the
genetic and metabolic changes that accompanied the increased physical activity
directly contributed to the increase in brain size.
Brain Growth After Birth
With the skeletal changes in the spine and pelvis that occurred as our ancestors
began to walk upright there was a reconfiguration and narrowing of the birth canal
producing the so-called “obstetric dilemma.” How was the enlarging brain to make
it through the narrowed birth canal?
Evolution’s solution to the problem was to develop fissures in the skull bone
called fontanelles that remain open for the first year and a half of life allowing for
the head to be compressed as it passes through the birth canal and for the brain to
grow after birth [7, 8]. Brain growth after birth is a key feature of the human brain
and partly explains why experiences in the first few years of life are so critical in
brain development. In Chimpanzees and other non-human primates, the fontanelles
close shortly after birth.
Evolution can be an opportunistic process whereby solutions to one problem turn
out to be advantageous in other unexpected ways. The development of fontanelles
to solve the birth canal dilemma allowed the continued growth of the human brain
after birth which allowed for the development of many critical human brain func-
tions including language, thinking, planning and introspection. Many of the so-
called executive functions are carried out by the frontal lobes, the part of the human
brain that shows the greatest expansion compared to other primates. The main fon-
tanelles in the human skull are between the frontal and parietal bones and the frontal
fontanelle is the last to close.
Cerebellar Expansion
Although the main expansion in human brain size, the threefold enlargement of the
cerebral cortex, occurred about 2 million years ago, a second and possibly equally
important expansion occurred in the cerebellum about 1 million years ago [9]. The
cerebellum is located in the back at the base of the brain (see Fig. 4.1) and has been
traditionally thought to be critical for motor coordination allowing the smooth per-
formance of complicated motor activities such as running, playing the piano or hit-
ting a golf ball. Patients with damage to the cerebellum traditionally exhibit
imbalance and difficulty in timing and coordinating fine motor activities.
More recently it has become clear that patients with cerebellar damage have
impairment in cognitive functions including language and executive functions such
as thinking and planning. Unlike the cerebral cortex which has a markedly different
Human Brain Development 71
architecture varying with location and function, the cerebellar cortex has a simple
highly repetitive architecture. All incoming signals enter through a single pathway
and all outgoing signals exit through a single pathway.
Despite its relatively small size compared to the cerebral cortex the cerebellum
contains about 75% of the nerve cells (neurons) in the brain, most of which are
located in a layer of the cerebellar cortex called the granular cell layer. Based on the
architecture of the cerebellum it appears to be ideal for storing complex patterns of
neural activity that can be rapidly called upon without the need for conscious aware-
ness. These patterns of activity become more accurate with repetition and are stored
in the cerebellar cortex waiting to be called on by the cerebral cortex. An analogy
would be apps in a digital computer that are constantly being improved with use and
always ready to be called on to perform a specific function.
There are large reciprocal connections (tracts) between all areas of the cerebral
and cerebellar cortex but the main expansion in size of the cerebellum that occurred
about a million years ago was in the parts of the cerebellar cortex connected with
areas of the cerebral cortex involved with executive functions and language. In fact,
this evolutionary cerebellar expansion was probably key to development of lan-
guage which requires rapid automatic processing of complex information. Ideas
that pop into ones mind while thinking may be these subconscious neural patterns
developed and stored in the cerebellum called up by areas of the cerebral cortex
involved in executive functions, just as areas of the cerebral cortex involved in
motor functions call up stored neural patterns for complex motor activities such as
running or playing the piano.
Human Brain Development
The human brain is a remarkable organ. It begins as a cluster of a few cells at the
back of the developing embryo that is first noticeable as the neural tube around 4–5
weeks after conception. When fully developed the human brain has roughly 80–100
billion neurons and each neuron can have as many as 15,000 connections (synapses)
with other neurons [10]. The cells in the neural tube replicate as immature nerve
cells (neurons) and supporting cells (glia) and these cells migrate to their ultimate
location where they differentiate into mature neurons and glia cells.
The first neurons and synapses (connections) begin to develop in the spinal cord
as early as 7 weeks. As the neurons reach their final destination, an axon emerges as
an extension of the cell body. Extracellular growth molecules guide axons to their
target neurons and initiate the process of synapse formation on the target neurons.
The human spinal cord is itself a complex nervous system comparable to the com-
plete nervous systems of many animals.
Axons can be as short as 0.03 in. and as long as 4 ft. In addition to axons, neurons
develop branches (dendrites) to provide a large surface area for synaptic contacts.
At birth, the human brain is only about a quarter of its adult size and it isn’t until late
adolescence that it is fully developed. Therefore there is a long time for both posi-
tive and negative environmental factors to influence human brain development.
The most rapid expansion in brain growth occurs in the first 2 years of life as
neurons mature and synapses form (at different rates in different parts of the cere-
bral cortex). By the end of the second year of life the brain is approximately 80% of
the adult size. The early period of rapid synaptic formation then reaches a plateau
phase during which neurons form complex dendritic trees and the cerebral cortex
visibly thickens.
At about age 5, the cerebral cortex begins to show recognizable features of a
mature brain and the refinement process continues with gradual increase in thick-
ness to reach peak thickness around 10–12 years of age. It is during this period that
much of the pruning of inefficient synapses in the cerebral cortex occurs. The pro-
cess of synaptic pruning has a burst around puberty and by late adolescence the
synaptic density levels off at about 60% of the peak synaptic density present in
childhood [11].
Neuroplasticity and Brain Development
The Russian physician and physiologist, Ivan Petrovich Pavlov, conducted one of
the most important yet simple experiments in the history of neuroscience in the late
nineteenth century [12]. Based on his observation that dogs in the laboratory would
drool when they saw a lab coat, Pavlov surmised that the dogs associated the lab
coat with food because they always received food from someone wearing a lab coat.
To prove his theory he developed a method to precisely measure saliva produc-
tion and changed the “conditioning stimulus” from a lab coat to a loud noise, ring-
ing a bell. If he rang a bell each time that food was presented after multiple trials the
animals would automatically salivate when the bell rang even without food. This
learning to associate the bell with salivation dissipated with time after the training
stopped but could be reinstated with a brief period of retraining.
Pavlov concluded that there must be physical changes in brain connections asso-
ciated with this learning, a process that would later be called neuroplasticity. The
Spanish anatomist Ramon y Cajal had just formulated the “neuronal theory” based
on the idea that nerve fibers (axons) terminated next to the cell bodies of other neu-
rons and not in a latticed network as was generally accepted at the time [13]. Cajal
speculated that the junctions (synapses) between the axon terminals and the nerve
cell bodies and their branches called dendrites were important for learning within
the brain. He suggested that the connections between neurons could be reinforced
by multiplication of the axonal terminal branches. Of all animal brains, the human
brain is most plastic.
The evolution of neuroplasticity in the human brain dates back several million
years. Initial genes and gene variants that enhanced neuroplasticity evolved as far
back as 6–8 million years ago near the time that the human species separated from
our closest living relatives the chimpanzees.
When researchers compared the brain anatomy and neural circuitry in closely
related humans and chimpanzees (including identical twins) they found that overall
brain size and shape were genetically heritable in both species but cortical
Physical Activity and Brain Development 73
organization and underlying neural circuitry was much less genetically constrained
in humans than in chimpanzees [14]. The human brain is most plastic at birth and
during the first several years of growth and neuroplasticity continues throughout life.
The relative lack of genetic control over the microstructure of much of the human
brain allows for an increased environmental influence. The brain connections that
are most plastic are those between so-called cortical association areas, the parts of
the cerebral cortex that control higher level functions such as planning, memory and
language. The increase in brain plasticity explains why humans are shaped by social
and cultural context more than other animals and why even identical human twins
can have markedly different connections within their brains and behave differently.
There is extensive experimental data that associates brain development and plas-
ticity with environmental enrichment and physical activity. In the mid twentieth
century the Canadian psychologist, Donald Hebb performed pioneering experi-
ments showing how environmental enrichment during brain development could
change connectivity in the brain.
Hebb studied a range of animals from rodents to primates and concluded that
early sensory experience influences intelligence, a radical idea at the time since
most considered intelligence to be innate. Hebb initially came upon the idea when
he took a few rat pups home to play with his children. To his surprise, when he
returned the mature rats to the laboratory they were much more curious about their
environment than cage mates who never left the laboratory. Hebb went on to develop
a variety of “intelligence tests” for animals and humans.
Although the environment early in life influences the brain in all animals, humans
show the most dramatic influence of early life experience on intellectual develop-
ment. Hebb spent 5 years working with chimpanzees at the Yerkes Laboratory of
Primate Biology in Florida and later reminisced that he learned more about human
behavior studying chimpanzees than he did in any other period of his life with, of
course, the exception the first 5 years.
Hebb is best known for his theory on how the brain stores and modifies informa-
tion including ideas and behavior [15]. He proposed feedback loops of neurons,
called cell assemblies that constantly changed their connectivity based on sensory
input. A basic feature of Hebb’s cell assemblies later became known as a “Hebb
synapse”. Hebb proposed that when nerve cells within the assembly repeatedly fired
together their synaptic connectivity increases over time. Hebb suggested that new
growth and chemical changes occurred at the level of the synapse providing the
basic building blocks for learning (plasticity) within the brain. This concept has
subsequently been confirmed with the most advanced molecular biology techniques
and represents a fundamental concept in neuroscience.
Physical Activity and Brain Development
The notion that physical activity plays as important a role in brain development as
cognitive activity is relatively new but supporting research data is compelling par-
ticularly in animal studies [16]. Numerous studies in rodents show that wheel
running enhances neural growth and development along with associated behavioral
and cognitive functions. Physical activity increases the levels of synaptic proteins
and new synapse formation and enhances neuronal proliferation and survival.
Several growth factors known to enhance neuroplasticity are increased with
exercise including brain-derived neurotrophic factor (BDNF) and insulin-like
growth factor-1 (IGF-1). Furthermore, wheel running at an early postnatal age can
improve the outcome in several animal models of neurodevelopmental disorders.
For example, rat pups born to alcohol-intoxicated mothers have a variety of devel-
opmental neurobehavioral deficits that can be ameliorated with postnatal treadmill
exercise [17].
Repetitive fine motor activity, such as playing a musical instrument, changes the
connectivity of the human brain documented with high-resolution brain imaging
techniques. Sports that require extensive training involving eye hand coordination
such as golf and tennis produce similar brain changes. The structural changes occur
in a variety of brain areas including those involved in motor, sensory, spatial and
attention control.
Regular aerobic exercise produces long term increases in both white and grey
matter volume and increased metabolic activity in key brain cognitive centers.
Studies in endurance athletes indicate that exercise can have a beneficial effect on
brain structure and connectivity that improves cognitive ability over a lifetime [18].
Why would physical activity be so intertwined with brain development? As sug-
gested earlier, during evolution early humans engaged in a variety of cognitive func-
tions including planning, attention switching, and multi-tasking as they walked and
ran through complex environments. The evolution of genes and metabolic pathways
important for neuroplasticity and physical activity were intertwined.
Physical Activity Versus Rest During Pregnancy
In much of recent history, the lay and medical communities have frowned upon
mothers being physically active during pregnancy. This was based largely on theo-
retical concerns about the effects of physical activity on placental growth and poten-
tial rupture, fetal stress and development, premature deliveries, and even possibly
congenital defects.
But this was not the case with our distant ancestors. Women in hunter-gatherer
societies were very active throughout pregnancy carrying on their normal high level
of physical activity right up to giving birth. Similarly, working women in agricul-
tural societies performed their rigorous lifestyle throughout pregnancy. In many
cases the women weren’t even aware that they were pregnant until around 5 months
when they first felt the baby move, a process called “quickening”.
On the other hand, women in higher social classes, particularly noblewomen,
would cut themselves off from society for much of their pregnancy referred to as
“confinement” or “lying in”. The pregnant woman took to her rooms where only
other women were allowed to enter. Windows in the rooms were covered to block
out much of the light and the walls were covered with calming tapestries and images
to soothe the mother’s mind and thereby protect the unborn child. Religious artifacts
provided spiritual support both prior to and at the time of birth.
Effect of Maternal Exercise on Fetal Brain Development 75
The goal was to produce an environment like the womb, quiet and dark. With the
industrial revolution, more and more women were able to withdraw from their regu-
lar physical activities and confinement became more widely practiced among the
middle classes. The process was supported by early studies suggesting that women
who continued with high physical activity during pregnancy gave birth to smaller
babies than women who rested during pregnancy.
Exercise During Pregnancy Is Beneficial to Mother and Child
The idea that maternal exercise during pregnancy might actually be beneficial both
for the mother and the child didn’t begin to take hold until the latter half of the
twentieth century. A key researcher in the field was Dr. James Clapp III, professor
of Obstetrics and Gynecology at Case Western Reserve University in Cleveland
Ohio who published a series of research studies in the 1990s that changed the mind
of many of his colleagues regarding exercise by pregnant women.
In the Introduction to his book Exercise Through Your Pregnancy. A Compelling
Case for Exercise During and after Pregnancy coauthored with Catherine Cram,
Clapp noted that he became interested in the subject when several women in his
practice who were physical fitness buffs decided to go against conventional wisdom
and continue to exercise vigorously throughout their pregnancies [19]. Clapp was
impressed that these women thrived during their pregnancies and their offspring
were healthy and surprisingly fit.
Clapp decided to study them in detail and compare them to women who did not
exercise during pregnancy. In his initial publications he showed that women who
continued running and performing aerobic exercise routines that exceeded the rec-
ommended guidelines did not experience adverse effects. There was no increase in
the incidence of abortions, placental problems, congenital anomalies, premature
rupture of membranes or preterm labor when compared with women who just con-
ducted routine physical activities.
Furthermore, vigorous exercise during pregnancy was not dangerous to the fetus.
Clapp found that the offspring of women who had exercised vigorously weighed
less than the offspring of control women but most of this weight difference could be
traced to a difference in body fat. Offspring of women who exercised during preg-
nancy had on average 5% less body fat than those of women who did not exercise.
The offspring of exercising mothers continued to have lower overall weight and
body fat throughout childhood. Exercise during pregnancy may actually prevent
obesity in childhood.
Effect of Maternal Exercise on Fetal Brain Development
In his most frequently quoted study published in the Journal of Pediatrics in 1996,
Clapp compared the offspring of 20 women who exercised during pregnancy with
those of 20 women who just continued with normal activities [20]. All women were
enrolled in the study before pregnancy and were followed through pregnancy, labor
and delivery. Importantly, women in the two groups were individually matched for
potential confounding issues including, smoking, socioeconomic, education, mari-

tal stability, maternal and paternal weight and height, and pre-pregnancy exercise
type frequency and duration.
During pregnancy the women in the “exercise group” either ran, performed aero-
bics or skied cross country three or more times a week for at least 30 min at an
intensity of at least 55% of maximum capacity. The women in the “control group”
voluntarily stopped exercising during the pregnancy. All the pregnancies proceeded
uneventful and ended in full term uncomplicated deliveries and without any signs of
fetal distress at delivery. The offspring were evaluated in detail at birth and at 5
years of age, including assessment by a developmental psychologist who was
unaware of the mother’s exercise status.
At birth, measurements of head circumference and height were no different in
the two groups but offspring of women in the exercise group had significantly less
body fat (weight and skin fold thickness) than those in the no exercise group. But
the most interesting finding was that the offspring of exercising women performed
significantly better on tests of language skills and intelligence at age 5 than the off
spring of women who did not exercise during pregnancy.
Using a completely different approach, in 2015 researchers in Madrid Spain
assessed the relationship between physical activity in mothers before and during
pregnancy and the academic performance of 1,868 of the off spring between ages 6
and 18 [21]. Mothers were asked to respond yes or no to the questions: Did you
practice physical activity before pregnancy? Did you practice physical activity dur-
ing pregnancy? Not surprisingly, most women who indicated they were physically
active during pregnancy were also the ones who reported being physically active
before pregnancy while those who were physically inactive during pregnancy were
physically inactive before pregnancy.
So the study was mainly assessing the off spring of mothers who were physically
active versus those who were not physically active before and during pregnancy.
The results found that boys whose mothers reported being physically active had
significantly higher scores on math, language and total grade point average than
boys whose mothers were inactive. The difference in academic performance in the
girls in the two groups of mothers was not significantly different.
This approach has limitations since the mothers were retrospectively asked to
recall their level of activity and the relationship between before and during preg-
nancy physical activity levels were highly correlated. It does raise the interesting
possibility of a beneficial effect of exercise prior to pregnancy on the cognitive func-
tion of the off spring? Several other studies have found that regular exercise prior to
pregnancy does tend to lead to healthier pregnancies for the mothers with less
chances of developing hypertension and excessive weight gain. This alone could
have implications for the developing brain. Since women are usually unaware that
they are pregnant for the first few weeks, those who regularly exercise would natu-
rally be exercising during an early critical period of brain development even if they
later decide to decrease exercise once they know they are pregnant.
A problem with all of the studies comparing the off spring of women who do or
do not exercise during pregnancy is that it is next to impossible to control for all of
Physical Activity in Infants 77
the potential confounding variables in addition to exercise. For example, could

mothers who exercise also have a better diet and prenatal care or could they have
better child support after delivery? Furthermore, these studies do not provide insight
into the mechanism of the beneficial effect of exercise. Could it be that some phe-
nomena associated with exercise (e.g. sound, vibration, motion, rapid heartbeat)
was altering brain development in the off spring.
To answer these questions investigators have turned to studies in animals particu-
larly rats where confounding variables can be better controlled and brain tissue
samples can be examined [22]. How do you measure intelligence in a rat?
Fortunately, there are reliable ways. Research studies in pregnant rats have consis-
tently shown a beneficial effect of exercise on brain function in pups at widely vary-
ing time intervals after delivery. The most common forms of exercise are running on
a wheel or treadmill and swimming in regular sessions throughout the 3 weeks of a
rat’s pregnancy.
As a measure of brain function in the off spring, the pups have to remember the
location of a submerged escape platform in an open swimming arena, make their
way through a T maze to find a reward or learn to avoid the location where a previ-
ous adverse stimulus such as a foot shock was delivered. The time required to reach
the goal provides a quantitative measurement of performance. The beneficial effects
of exercise are seen whether the mother’s exercise is forced or voluntary and regard-
less of the type of exercise.
As a sample study, in 2003 researchers in Thailand compared the performance on
a T maze test of pups born to 20 pregnant rats who exercised on a treadmill (speed
20 m/min) for 30 min sessions 5 days a week with that of 20 control pregnant rats
who did not exercise [23]. This level of exercise is vigorous for a rat but rats love to
exercise even pregnant rats.
The pups of mothers who exercised during pregnancy had a significant improve-
ment in spatial learning demonstrated by a significant decrease in total time from
starting to reaching target and total number of errors compared to the matched con-
trols when tested between days 40 and 47 after delivery (early adolescence in a rat).
Even more important the investigators found that the improved spatial learning cor-
related with a significant increase in production of brain-derived neurotrophic factor
(BDNF) in the brains of the pups from the mothers who exercised during pregnancy.
BDNF is well known to regulate the development, proliferation and differentiation
of neurons particularly in the hippocampus, a key area of the brain for spatial learn-
ing (discussed in Chap. 5).
Physical Activity in Infants
As noted earlier, the human brain continues to grow after birth with the greatest
growth occurring in the first 2 years of life. The average human brain weighs about
14 oz at birth and it rapidly increases in weight to about 35 oz by the end of the first
year. For comparison, the average weight of an adult brain is about 50 oz. During
the first year, dendritic branching rapidly increases to allow increased synaptic
connections between neurons and the axons develop an insulating myelin sheath
generated by a special type of glial cell that markedly increases the speed of axonal
conduction.
Not surprisingly, the first year is critical in brain development. In order for axons
to grow and for synapses to form, sensory signals from the environment must be
constantly arriving in the brain. Harvard neuroscientists, David Hubel and Torsten
Wiesel provided proof of the importance of sensory input to the developing brain.
Their work on the developing visual cortex beginning in the 1960s led to a Nobel
Prize in Medicine in 1981 [24].
Based on reports that animals raised in the dark had permanent visual impair-
ment despite later returning to normal visual environment, Hubel and Wiesel per-
formed systematic studies of the effect of visual deprivation in the first few months
of life on the developing visual cortex in kittens and monkeys. They showed that
visual deprivation during this critical time in brain development interfered with syn-
apse formation in the visual cortex and led to permanent visual impairment. This
explains why children born with congenital cataracts have permanent visual impair-
ment unless the cataracts are removed within the first few months of life. The same
process occurs with touch and sound and explains the importance of touching and
talking to babies in this critical period of brain development.
Although there have been a large number of studies both in humans and other
animals showing the importance of an “enriched sensory environment” on newborn
brain development, there have been relatively few studies on the effect of physical
activity on brain development in babies. How would one even begin to get a baby to
exercise? On the other hand, it seems intuitive that restricting physical activity in a
baby is detrimental to normal brain development.
Remarkably, a man who gave his own children to a Foundling Home, Jean-
Jacques Rousseau, was one of the first to warn of the dangers of swaddling babies
and the importance of letting babies freely move about and explore their environ-
ment for proper brain development (see Chap. 3). There is now consensus that
babies should be encouraged to be physically active every day, throughout the day
in a variety of ways.
Before they are able to crawl babies should be encouraged to reach, grasp, push
and pull and they should be placed on their tummy on the floor for 30 min sessions
to improve neck and extremity strength. Once they begin to crawl they should be
encouraged to crawl and explore their environment as much as possible. Regular
playtime with the mother or caretaker is important for both sensory stimulation and
physical activity.
As the child begins to walk entering the second year of life regular physical
activity is even more important and a child should have at least 3 h of physical play
every day including playing outdoors. Play should vary from relatively light activi-
ties such as getting up and down and rolling about to more vigorous activities such
as hopping, skipping and jumping. Later in the second year the child should be
encouraged to climb, play in water, begin to ride a bike and catch and toss a ball.
Older pre-schoolers (aged 3–4) should also spend at least 3 h a day doing physical
activities but in addition at least 1 h a day of moderate to vigorous exercise. This can
include riding a bike, swimming and more vigorous play with running and chasing.
Physical Activity in Preadolescent Children 79
Physical Activity in Preadolescent Children
Although a large number of studies have found a positive effect of exercise on cog-
nitive function in preadolescent children, there are also studies with disparate find-
ings likely due to differences in the type, frequency, intensity and duration of
exercise and different measures of cognitive function [16, 25]. For example, studies
showed that a single bout of aerobic exercise of moderate intensity (heart rate of at
least 60% of maximum) for 20–30 min improved a variety of measures of cognitive
function including reading comprehension compared to control children who did
not exercise. On the other hand, a single brief bout (less than 10 min) of intense
exercise or prolonged low intensity exercise (several hours) leading to fatigue may
transiently decrease cognitive performance.
Another important variable is age. Some studies suggest that older children
obtain more cognitive benefits than younger children from exercise but this may
simply be due to problems in measuring exercise level in younger children. Rather
than measuring the amount and intensity of exercise most studies have measured a
child’s physical fitness and related the level of fitness to measures of cognitive func-
tion. As noted in Chap. 1, exercise and physical fitness are interrelated but they are
not the same thing.
One way of looking at the relationship between exercise and physical fitness is
that exercise is part of the journey toward the destination of physical fitness.
Certainly, children who exercise regularly are better physically fit than those who do
not exercise but fitness depends on more than exercise. Genes, diet, and socioeco-
nomic status can all influence fitness independent of exercise.
In order to interpret studies of physical fitness in children it is important to under-
stand how physical fitness is measured and how it relates to exercise. As discussed
in Chap. 1, the gold standard for measuring cardiovascular fitness is the maximum
rate of oxygen consumption possible during exercise of increasing intensity (see
Fig. 1.1). To accurately measure the maximum oxygen uptake one needs sophisti-
cated equipment that can measure oxygen consumption while exercising. Since the
measurements are cumbersome and mostly restricted to a laboratory setting other
surrogate markers to estimate maximum oxygen uptake are commonly used.
A commonly used marker of cardiovascular fitness is the heart rate achieved dur-
ing exercise reported as the percentage of the maximum heart rate for a person of a
given age. A limitation of using heart rate as a measure of fitness is that heart rate
can be influenced by a variety of factors including stress and anxiety that are often
present when children are being monitored for performance. Another way to mea-
sure cardiovascular fitness in children is to measure aerobic capacity with timed
runs or walks.
Beginning in the early 1980s the Progressive Aerobic Cardiovascular Endurance
Run (PACER) was developed to assess cardiovascular fitness in school aged chil-
dren and over the years, children have been tested with the PACER in all 50 states.
The PACER is a multiple stage run that progressively gets more difficult as it con-
tinues. Students run back and forth as many times as they can with each lap started
with a beep sound. The laps get faster and faster until the student reaches their maxi-
mum lap score.
As with heart rate, the maximum oxygen uptake can be estimated from the per-
formance on the PACER using a standardized formula. Typically the Pacer score is
combined with measures of muscle strength (push-ups and curl-ups to a specific
cadence), muscle flexibility (back-saver sit and reach test) and an estimate of obe-
sity (body mass index (BMI) and skin fold thickness) to produce a FITNESSGRAM,
a measure of overall physical fitness [26]. Children are graded as in the healthy fit-
ness zone or needs improvement for each subtest and for the overall FITNESSGRAM.
Physical Fitness and Academic Performance
In the late1990s, the state of California mandated that schools perform physical fit-
ness measurements annually on all students in fifth, seventh and ninth grades and
that students be provided with their individual scores. The FITNESSGRAM was
chosen as the measure of physical fitness [27]. The PACER was initially used to
measure aerobic capacity but subsequently it was largely replaced with a mile run.
In a California 2001 report of the Department of Education to the governor and
legislature, educators observed a strong correlation between physical fitness mea-
sured with the FITNESSGRAM and academic performance on standardized tests in
all three grades. In a follow up report published in 2012, there was an alarming drop
in the performance on the FITNESSGRAM from 2009 to 2011 at all three grade
levels with the largest drop in fifth graders. The changes in the FITNESSGRAM
could be traced to decreases in aerobic capacity and increases in obesity measure-
ments with little change in muscle strength and flexibility measurements. For exam-
ple, from 2009 to 2011 fifth graders on average had a 4.3% drop in aerobic capacity
and a 16.3% increase in obesity.
In 2007, researchers from the University of Illinois in Urbana reported on the
results of a study using the FITNESSGRAM to assess the relationship between
physical fitness and academic performance on standardized achievement tests in
259 preadolescent children (third and fifth graders) at 4 schools, 2 schools from
high socioeconomic areas and 2 schools from low socioeconomic areas [28]. They
accounted for the influence of age, sex, school effectiveness (based on overall aca-
demic achievement) and poverty index.
The main finding of the study was that children who exhibited higher levels of
physical fitness had significantly higher test scores in reading and mathematics
regardless of these potential confounding variables. Specifically, aerobic capacity
measured with PACER was positively related to academic achievement whereas
obesity measured by BMI was negatively related. The study not only confirmed the
earlier California study but showed that physical fitness was equally important for
improving academic performance in low performing schools in low socioeconomic
areas as in high performing schools in high socioeconomic areas [29].
Are there some cognitive functions that are more associated with brain develop-
ment than others? The so-called executive functions mentioned earlier are a subset
of cognitive functions involved with intentional interaction with the environment
that have been linked to development of the frontal lobes, a late developing part of
Physical Fitness and Academic Performance in Adolescents 81
the cerebral cortex. These functions include planning, working memory and inhibi-
tory control as well as other processes under conscious control that help avoid mak-
ing errors.
Studies in preadolescent children (4–8 years of age) show that they have rela-
tively poor executive functions demonstrated by the inability to hold two or more
pieces of information in working memory and to ignore irrelevant information. In
late adolescence, as the frontal lobe and its connections become fully developed,
performance on neuropsychological tests of executive function reach adult levels.
Researchers from the University of Illinois compared measures of physical fit-
ness (the FITNESSGRAM) with performance on a test of executive function in 74
children between the ages of 7 and 12 years [30]. Not surprisingly, older children
and children with higher IQs performed the best on the test, but greater aerobic fit-
ness was correlated with better performance on the test of executive function inde-
pendent of age and IQ. They concluded that all types of cognitive functions including
executive function are improved with improved physical fitness.
Physical Activity in Adolescent Children
As with younger children, numerous studies in adolescents have found a positive

relationship between physical fitness and cognitive performance. In 2003,
Researchers at Arizona State University reported a meta-analysis of 44 studies pub-
lished up to that time on the relationship between physical activity and cognition in
school age children and adolescents [25]. A meta-analysis combines the data from
multiple studies thereby increasing the number of subjects and the power of the
analysis. A limitation of meta-analysis is the lack of uniformity of measures of
physical activity and cognitive function in different studies.
Overall the researchers found a significant positive effect of physical activity on
cognitive function in children and adolescents across the age spectrum with an aver-
age effect size of .32, a moderate effect. The largest effect size of .48 was seen in
young teenagers around puberty with the next highest of .40 in the youngest ele-
mentary students. Interestingly, these time periods correlate with very active periods
of synaptic pruning in the developing brain.
Physical Fitness and Academic Performance in Adolescents
A few studies on the relationship between physical activity and cognitive perfor-
mance in adolescents are notable for the large number of participants. In 2009,
researchers in Sweden published a study of 1,221,727 late adolescents comparing
the level of physical fitness with academic performance at age 18 with academic and
socioeconomic achievements later in life [31].
The researchers reviewed the records of 18 years old Swedish male subjects in
the Swedish Military Service Conscription Register who were enlisted for military
service between 1968 and 1994. This represented 97% of the male Swedish
population born between 1950 and 1976. Another strength of the study was that it
included 268,496 full-sibling pairs, 3147 twin pairs and 1432 monozygotic twin
pairs allowing an assessment of genetic and home environment variables on the
outcomes.
Cardiovascular fitness was measured with a cycle ergonometry test, muscle
strength by knee extension, elbow extension and handgrip and cognitive function by
tests in four areas (logical performance, verbal synonyms and opposites, visual/
spatial/geometric perception and technical/mechanical skills). The four cognitive
test results were combined to produce a single global cognitive score. In addition,
the researchers obtained participant’s performance in physical education classes at
age 15 and their subsequent level of education (university degrees) and occupation
(professions ranked from low to high socioeconomic index).
The study found that fitness was strongly associated with cognitive performance
at age 18 and predicted future academic performance and socioeconomic status.
Changes in cardiovascular fitness between ages 15 and 18 also predicted academic
performance at age 18. Analysis of the sibling pairs and monozygotic twins showed
that the association between fitness and academic performance was largely indi-
vidual specific and not due to shared environmental or genetic influences. Heritability
explained less than 15% of the beneficial effect of cardiovascular fitness on cogni-
tive function.
In a 2010 study in women, researchers in Toronto and San Francisco came at the
problem from a completely different direction and came to similar conclusions [32].
They evaluated cognitive function in 9344 women over the age of 65 using the
Mini-Mental State Examination (MMSE) and compared the results with their self-
reported level of physical activity in their teens, 30s, 50s and late life. Neurologists
commonly use the MMSE test to identify early signs of dementia.
A standard questionnaire was used to assess physical activity and to simplify the
analysis women in each age category were dichotomized into physically inactive
and physically active. Overall, women who were physically active at any time dur-
ing their life were less likely to have cognitive impairment late in life. The effect
was greatest for physical activity during teenage years and the authors concluded
that physical activity early in life builds up “cognitive reserve” that has long-lasting
benefits.
Physical Education and Academic Performance
Many adolescents rely on physical education courses for exercise. Currently, the
number of participants in physical education progressively decreases with age so
that by the senior year in high school less than 25% of students are enrolled in
physical education classes. Probably even more important, only a small percentage
of students who enroll in physical education classes participate in meaningful
exercise.
From January to May of 2007, Spanish researchers performed a prospective
study of the effects of increasing the frequency and intensity of physical education
How Does Exercise Influence Brain Development? 83
classes on adolescents’ cognitive performance and academic achievement [33].

Adolescents in 3 high school classes in southeast Spain (43 boy and 23 girls, ages
12–14 years) were randomly allocated to a control group who received the usual 2
physical education sessions per week, an experimental group who received 2 addi-
tional physical education sessions per week and a second experimental group that
received four physical education sessions per week and in addition a focus on
increasing the intensity of exercise during the classes.
Cognitive performance on a standardized intelligence test and school grades
before and after the intervention were used to evaluate the benefit of increasing
exercise on cognitive function. Both intelligence test scores and school grades sig-
nificantly increased in the experimental group with increased frequency and inten-
sity of physical education sessions compared to the control group. The group that
only increased frequency of sessions did not show a significant difference compared
to the control group.
This and other studies suggest that the type of exercise during physical education
classes is important in achieving the goal of improved cognitive performance.
Another key finding of these studies is that despite the fact that attending physical
education classes decreases the number of hours available for academic courses in
no case did attending physical education classes decrease academic performance.
How Does Exercise Influence Brain Development?
New brain imaging techniques, particularly magnetic resonance imaging (MRI),

provide investigators a way to assess the role of aerobic exercise on human brain
structure and function for the first time. Although a few studies have been per-
formed in younger children most have been conducted in adolescents for reasons of
cooperation and consent.
Investigators at the University of Southern California performed a series of stud-
ies in the past decade demonstrating changes in brain structure in adolescents (ages
15–18) associated with aerobic exercise [34]. Since the studies were performed on
a small number of adolescents in a laboratory setting they were able to use the gold
standard for measuring aerobic fitness, the maximum oxygen uptake capacity.
They utilized MRI to compare cortical thickness and white matter integrity in
regular exercisers versus non-exercising, similar weight matched control adoles-
cents. Those with greater aerobic fitness had significantly larger hippocampal and
middle frontal cortex volume and better microstructure of nerve fibers running to
and from the frontal cortex than those with lesser aerobic fitness.
A special type of MRI (fMRI) that measures blood flow as a marker of neuronal
activity was used to measure brain function during cognitive tasks. The same
15–18 year old adolescents were examined with fMRI to determine if there was a
difference in neuronal activity in regular exercisers versus lean matched controls
during an associative learning task. The teens were given randomly paired words
and told they would later need to recall the word pairs. fMRI measurements during
the learning task showed that neuronal activity in the hippocampus of lower-fit
adolescents was significantly greater than activity in the hippocampus of higher-fit

adolescents suggesting that less-fit adolescents needed to use more brain resources
to learn new information than higher-fit adolescents.
Studies in developing rats have consistently shown that exercise results in
increased neuronal, axonal and synaptic density, increased expression of neuro-
trophic factors such as BDNF and improved cognitive performance. Most of these
studies have been performed in adolescent rats since they love exercise and are
easier to test than younger pups [16, 35].
Interestingly, the exercise-induced effect on neuronal development is similar in
the progeny of exercised mothers described earlier in the chapter and exercised
adolescent rats. Furthermore, early life exercise in rats produces more robust and
long-lasting effects than exercise in adulthood. The likely explanation is that early
life exercise improves brain development. Although neuroplasticity and learning
occurs throughout life it is greatest in the developing brain.
In humans, exercise has a positive impact on academic performance through a
variety of direct and indirect physiological, cognitive, emotional, and learning
mechanisms. Cognitive and motor skills develop in tandem through a dynamic
interaction. In addition to its affect on neurodevelopment, exercise can influence
cognitive function by increasing brain blood flow and oxygenation, hormonal
release and increasing level of arousal. Time spent outside the classroom exercising
can relieve boredom and lead to higher attention levels when returning to class.
Exercise for Treating Abnormal Brain Development
Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disor-

der affecting nearly 10% of children [36]. ADHD begins during preschool years and
persists throughout adolescence and adulthood causing significant functional dis-
ability over a lifetime. The main neuropsychological symptoms of ADHD are
hyperactivity, poor attention and impulsivity. Overall, Children with ADHD per-
form poorly on tests of executive functioning.
The cause of ADHD is poorly understood although there are clear genetic and
environmental risk factors and some even consider it a genetic disease. MRI studies
in children with ADHD do not show a specific pathology but rather widespread
volume loss in cortical and subcortical regions. Overall brain development appears
to be 2–3 years delayed compared to age matched control children. The most con-
sistent volume loss is seen in the prefrontal cortex, the basal ganglia and the
cerebellum.
Functional MRI studies also suggest developmental delay with findings of poor
executive function and susceptibility to interference similar to those seen in very
young children. Current treatment of ADHD consists of stimulant drugs and behav-
ioral therapy that decrease hyperactivity and improve attention. These treatments
provide short-term symptomatic improvement but don’t seem to alter the long-term
course of the disease.
References 85
Interestingly, many of the abnormal brain mechanisms that have been associated
with ADHD are the same mechanisms that are altered by exercise. Several studies
have shown that a single bout of exercise or a course of exercise can ameliorate
ADHD symptoms with or without other treatments but as in the case of other treat-
ments it is unclear whether exercise can alter the underlying disease process. If
ADHD is indeed a brain developmental disorder, interventions must occur early in
childhood when the brain is most rapidly developing.
Although stimulant medications are very popular for treating ADHD symptoms
and numerous studies have document effectiveness, many parents prefer not to give
them to their young children. Furthermore, side effects are common and the drugs
can aggravate underlying heart conditions. Studies show that less than half of chil-
dren take the medication for more than 2 months and less than 10% maintain long-
term treatment.
Behavioral interventions are more accepted by parents but are not widely avail-
able in part due to costs and may be less effective than medications. On the other
hand, exercise interventions are widely available, broadly accepted and likely as
effective as medications and behavioral therapy.
Some of the most convincing evidence for exercise treatment for ADHD comes
from studies in an animal model of ADHD, the so-called spontaneous hypertensive
rat [37]. The rat pups show many of the typical features of ADHD including hyper-
activity and impaired impulse control and as in humans the disorder persists
throughout life. These rodents have abnormal brain development with changes in
neurotransmitters and neurotrophins similar to those seen in humans with ADHD
and these alterations are reversed by exercise, either a single bout or prolonged
course. Exercise induced increases in catecholamine neurotransmitters (noradrena-
lin and dopamine) and BDNF correlate with improvement in cognitive function [38].
While the results of exercise in the animal model of ADHD are robust and con-
vincing one must keep in mind the limitations in comparing cognitive function mea-
surements in rats and humans. Studies on the effectiveness of exercise in children
with ADHD have more variable results depending on exercise characteristics such
as duration, intensity and age at onset. Although catecholamine and BDNF levels
have been measured in blood samples from children with ADHD it is unclear
whether these measurements reliably reflect brain levels of catecholamine and
BDNF. Preliminary studies with MRI and fMRI show changes in brain structure and
function after exercise that correlate with the neuroprotective effect of exercise but
so far such studies have not been performed in children with ADHD.
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Exercise, the Elixir for Learning
5
Physical fitness is not only one of the most important keys to a healthy body it is the basis
of dynamic and creative intellectual activity. (John F. Kennedy [1])
Learning is what brains do. From an evolutionary point of view, brains developed as
a survival mechanism for organisms to adapt to the constantly changing environ-
ment. When we learn something, physical changes occur in our brains. Old connec-
tions are altered and new connections are forged. The changes occur at both the
molecular and gross structural level.
Learning occurs throughout the lifetime of an organism although the process is
accelerated during early development. There is overwhelming evidence that exer-
cise improves learning and continues to be beneficial for learning long after brain
development is complete. Based on empirical observations that students who exer-
cise regularly learn faster there is a long tradition of combining physical and mental
training in secondary education systems around the world.
Physical Education and Learning
The Greek fascination with the beauty of the human body and the belief that physi-
cal fitness is the key to health and happiness remained dormant for more than a
thousand years as human populations were preoccupied with survival during long
periods of cultural upheaval, war and pestilence during the Dark Ages. There was a
revival in physical fitness with the Renaissance but it wasn’t until the eighteenth
century that the value of planned physical activity in schools was rediscovered. In
Europe the term gymnasium became synonymous with middle school.
In Germany, Johann Bernard Basedow, opened a school that included exercise and
games that served as a model for future education programs [2, 3]. Basedow, the son
of a Hamburg wigmaker, planned to follow in his father’s footsteps but after attending
school at the Johanneum in Hamburg, famous for its classical education, he entered

https://doi.org/10.1007/978-3-031-13924-6_5
90 5 Exercise, the Elixir for Learning
the University of Leipzig to study theology. From 1753 to 1761, Basedow served as
professor of moral philosophy in a school for young noblemen at Soroe in Denmark
where he developed his ideas on combining physical and mental training in schools.
The school at Soroe not only included traditional teaching but also teaching of
horseback riding, fencing and dancing and in various sports including gymnastics.
After leaving Soroe, Basedow returned to Germany near Hamburg where he taught
theology and philosophy and crystalized his ideas on education. He was strongly
influenced by Rousseau’s book on educating Emile (see Chap. 3), and decided to
give up teaching and focus on educational reform in Germany.
In 1774, Basedow published a four volume illustrated textbook for children,
Elementary Book, containing a complete system of primary education to help stu-
dents learn. He also published a companion Method Book for parents and teachers.
In the same year, Basedow opened his private academy, the Philanthropinum, a
name based on philanthropy, the desire to promote the welfare of others. The school
was to serve as a model for education in Germany and included many innovations
including daily physical education.
Basedow wanted his school to be open to all children, rich and poor treated
equally. In the initial prospectus, 5 h a day were allotted to studies, 3 h to recreation
including riding, fencing, dancing and music, and 2 h to manual labor. In the sum-
mer, the school was to be conducted in tents in the field allowing opportunity for
hunting, fishing, boating, swimming and climbing and the study of natural sciences.
Early on the boys were introduced to the so-called knightly exercises of dancing,
fencing, horseback riding and horse vaulting. In January 1776, Basedow turned over
the physical training at the school to one of the teachers, Johann Friedrich Simon
who had a particular interest in classical Greek gymnastics. For the broad jump,
Simon had ditches dug, widest in the middle at about 8 ft tapering to almost a point
at the ends. The students began at the width they could easily clear and then gradu-
ally moved to the wider sections as they improved in jumping skills.
For the high jump, two vertical posts two and a half feet apart had holes bored at
inch intervals and wooden pegs inserted at the desired height. A stick rested on the
pegs providing a barrier that was safe but easily displaced if it was hit with a foot.
Students were also taught to balance themselves on a tapering beam mounted 4 ft
above the ground or on narrow planks stretched across ditches.
Surprisingly, despite the innovative teaching methods introduced at the
Philanthropinum relatively few parents were willing to subject their children to
these “modern” teaching methods. A year and a half after the school’s initial fanfare
only 15 students including Basedow’s daughter were enrolled. Basedow became
more and more frustrated with school administration and by the spring of 1778 he
resigned as director of the school.
One of the teachers in Basedow’s Philanthropinum, Christian Gotthilf Salzmann
left the school a few years after Basedow and founded his own school in 1785, the
Schnepfenthal Institute in the district of Gotha, Germany which continues function-
ing today more than 235 years later. The son of a Protestant minister, Salzmann, also
a pastor, was interested in teaching children and joined Basedow’s experiment
where he wrote several papers on educational reform.
Physical Education and Learning 91
The motivation for starting the new school was to educate the children of his own
large family and to test new educational theories particularly those of Basedow. The
teaching of modern languages became a focus and remains so up to the present time.
As Salzmann prepared to open his new school he had selected a few teachers but the
only pupils were his own children so he began a search for other children to join the
school free of charge.
Salzmann read about the death of Dr. Friedrich Wilhelm Hitter a respected physi-
cian in the town of Quedlinburg about 70 miles to the north. Hitter had 6 children,
the youngest Karl, age 3, was said to be exceptional for his age. Salzmann decided
to send two of his friends to Quedlinburg to see if any of Hitter’s children would be
appropriate for his new school. Frau Hitter was having financial difficulty support-
ing the tutor for her children after the death of her husband and Salzman’s friends
convinced her to visit the Salzmann’s school.
On June 7, 1785 Frau Hitter, Karl, Johannes, and the tutor, Johan GutMuths left
for Schnepfenthal taking almost 2 days to make the 70 mile journey. After staying
several days, Frau Hitter was so impressed with Salzmann and his school that she
agreed to leave Karl and Johannes to stay at the school. GutsMuths also decided to
stay on as an assistant teacher. Karl Hitter would become a famous geographer,
often considered the father of the modern school of German geography and
GutsMuths would develop the basic principles of gymnastics and is generally con-
sidered the “grandfather” of physical education.
After arriving at Schnepfenthal with the two young Hitter boys, GutsMuths
began his career as teacher and author that would span more than 50 years during
which he became a legend to the students that attended the school. In addition to
teaching geography and a variety of other subjects, he conducted daily gymnastic
exercises with the children. Twelve years after arriving he married Salzman’s niece
and would have 11 children, 8 sons and 3 daughters swelling the ranks of the student
population at Schnepfenthal.
GutsMuths provided detailed descriptions of his exercise routines in a book
published in 1793, considered the first detailed manual on modern gymnastics.
The book, issued in two volumes, contained copperplate illustrations of the
different exercises and explanatory drawings of the apparatuses used for the
exercises. Some of the routines were those developed at Basedow’s
Philanthropinum but it also included new routines developed by GutsMuths
including: climbing up and down rope ladders, swinging on ropes, crawling on
the underside of a horizontal bar, jumping over ropes being swung close to the
ground, performing exercises while balancing on one foot and lifting weights
hung on bars.
GutsMuths recommended keeping detailed records of each child’s performance
in order to document progress and special needs. In 1796 he described 105 different
games arranged in groups based on the faculties (attention, memory, judgment) they
test or develop and in 1798 he systematically reviewed different swimming tech-
niques. GutsMuths celebrated 50 years of teaching at Schnepfenthal in June 1835
still conducting daily gymnastic exercises and a busy teaching schedule. He finally
retired 4 years later and died peacefully a year after.
In 1811, a German teacher, Friedrich Ludwig Jahn, opened the first open-air
gymnasium (Turnplatz) in Berlin where he taught young men the importance of
gymnastics and calisthenics in fresh air for maintaining physical and mental health.
He was an ardent German Nationalist growing up in a country ruled by Napoleon’s
invading army. A strong motivation for his interest in the physical fitness in his
young pupils was to prepare them to fight and repel the French army.
In his gymnasium, Jahn developed all of the modern day gymnastic equipment
including parallel bars, the high bar, gymnastic rings and the pommel horse along
with exercise routines for using each piece of equipment. In 1816, he published a
book summarizing his gymnastic system, which became the “bible” for gymnastics
and rapidly spread throughout Germany and the rest of Europe. In the book, he
emphasized that gymnastics were not limited to fixed routines on the devices, but
any type of physical activity in the fresh air. Jahn is universally accepted as the
father of modern gymnastics.
A Swedish contemporary of Jahn, Lars Peter Ling developed the Swedish school
of gymnastics that focused mostly on calisthenics with minimal use of apparatuses.
Ling who was born in 1776 the son of a minister, obtained his degree in Theology
at Uppsala University in 1799. He then traveled and studied throughout Europe for
5 years becoming fluent in German, French and Danish and writing poetry in all
three languages in addition to Swedish. While he was taking fencing lessons in
France, he noticed that the exercise used in preparation for fencing was helpful for
his rheumatism attributed to gout and he began a lifelong interest in the medical
benefits of exercise.
On returning to Sweden, Ling developed a daily routine of exercises followed
by fencing and he became a teacher of fencing at Lund University. To better under-
stand the scientific basis for the health benefits of exercise he attended classes in
anatomy and physiology at the medical school and eventually he outlined a system
of gymnastics that could be used by medical doctors for a wide range of medical
conditions.
Unlike the “heavy” German gymnastic system with regimented techniques on
different apparatuses, the Swedish system was “light” with gymnastic exercises
including breathing, stretching and massage designed to provide health benefits to
the participant. Ling believed that gymnastic exercises needed to be individually
adapted for people based on their habits, personality and health conditions. They
needed to be based on knowledge of the human body and there was no “ones fits all”
exercise.
In 1813, Ling founded the Royal Central Gymnastic Institute for training gym-
nastic instructors in Stockholm where he was known for developing free calisthen-
ics often accompanied by joyful singing. He abhorred boring repetition and mixed
in imitative movements such as sawing and chopping and used simple apparatuses
like a rope or beam.
Ling did not provide detailed documentation of his system of gymnastics as Jahn
did in Germany but Ling was an outstanding teacher and he had many loyal disci-
ples. Initially, the established Swedish medical community was suspicious of Ling’s
Basic Mechanisms of Learning 93
exercise therapy but with time he won them over and he was elected a member of
the Swedish General Medical Association in 1831. Even more impressive Lind’s
gymnastic system has developed a world-wide following and is often referred to as
one of Sweden’s best exports.
Basic Mechanisms of Learning
As discussed in Chap. 4, the human brain is plastic constantly changing connections

between neurons based on experience—learning. Understanding the basic mecha-
nisms of brain plasticity, however, would require improvements in technology and
molecular biology that only became available in the latter half of the twentieth cen-
tury. With these techniques Viennese born, Eric Kandel, performed a series of key
experiments on neural plasticity and learning in the giant marine snail, aplysia [4].
Kandel chose the snail because the brain was small and easily accessible. He
correctly surmised that what he learned from this relatively simple brain would be
applicable to the human brain. The brain of the sea snail consists of about 20,000
neurons located in 9 separate groupings or ganglia. With time Kandel was able to
map out all of the neurons and their connections in one of the ganglia, the abdomi-
nal ganglia consisting of about 2000 neurons.
Kandel focused on one reflex mediated by the abdominal ganglia, the gill-
withdraw reflex. Stimulating a point on the skin of the siphon caused the gill to
withdraw to protect it from damage. The reflex was mediated by six sensory neu-
rons that relayed the sensation to two interneurons and on to six motor neurons that
innervated muscles that caused the gill to retract. One cell in the ganglia (R2) was
so large that it was easily identified by the naked eye without the need for magnifica-
tion. He was able to penetrate the neurons with a glass pipet and maintain record-
ings for many hours. By electrically stimulating axons synapsing on R2 from other
neurons in the ganglia while recording from R2 he was able to show how synapses
physically change with experience, how they learn.
Kandel studied the molecular basis for learning at the synapse between the sen-
sory and motor neurons in the gill-withdraw reflex. The neurotransmitter released at
the sensory-motor synapse was glutamate, which others had already shown to be the
main excitatory neurotransmitter in mammalian brains. Shocking the tail of the ani-
mal enhanced glutamate release and synaptic transmission at the synapse for several
minutes after the shock.
The tail shock activated interneurons whose axon terminals released the neu-
rotransmitter serotonin at synapses on the axon terminals of the sensory neurons.
Serotonin receptors in the presynaptic membrane then activated a cascade of intra-
cellular “second messengers” that increased the amount of glutamate released at the
sensory-motor synapse.
If the animal received a long series of shocks to the tail it produced a much lon-
ger sensitization associated with sprouting of new synaptic terminals between the
sensory and motor cells. In this case, a second messenger entered the nucleus of the
sensory cell activating specific genes to produce proteins for forming new synapses.
This process called long-term potentiation (LTP) is the most studied model of neu-
ronal synaptic plasticity.
Early phase LTP does not require new protein synthesis and lasts for up to 3 h
and late phase LTP requires new protein synthesis and lasts for more than 3 h and
can last for as long as the animal lives. LTP in the brain is a key factor in learning
and memory. Learning can occur by increasing the amount of neurotransmitter
released at an individual synapse or by increasing the number of synapses.
Unlike other organs of the body that are constantly renewing themselves by
regenerating new cells from immature stem cells, the human brain is relatively sta-
ble with very little neuronal turnover after development. However, in parts of the
hippocampus new neurons are constantly being produced from progenitor stem
cells, a process that continues throughout life, although diminishing with aging [5].
Neuroplasticity and neurogenesis are important for learning and behavior and
both are affected by exercise [6]. During learning, information is stored in memory
in three phases: encoding, consolidation and retrieval. Although important for all
three phases, the hippocampus is particularly important for encoding new memories
(short-term memories) whereas during consolidation, memories are stored in large
neuronal networks throughout the brain with the prefrontal cortex orchestrating the
process (long-term memories).
Concepts (stored in neuronal assembles) are linked in memory so that when a
concept is activated during encoding or retrieval the activation spreads to other
related concepts. This explains why new memories are influenced by prior experi-
ences and beliefs and why some memories are inaccurate. As meditation guru Allan
Lokos wrote: Don’t believe everything you think [7]. The prefrontal cortex is impor-
tant during retrieval of memories by monitoring the process to verify accuracy. The
monitoring process allows a person to separate activated concepts based on infor-
mation from those based on misinformation.
How Exercise Improves Learning
Neurotransmitters, neurotrophins and hormones released during exercise enhance

neuroplasticity and neurogenesis. In animal models, inactivity shrinks the hippo-
campus producing an anxiety/depression like state. By contrast, exercise increases
hippocampal volume, improves neuroplasticity and neurogenesis and relieves anxi-
ety and depression symptoms. Such animal studies suggest a central role for neuro-
plasticity and neurogenesis in brain function and provide a mechanism to explain
why exercise improves learning [8, 9].
Brain-derived neurotrophic factor (BDNF) has a central role in neuroplasticity
and neurogenesis (Fig. 5.1). In both animal and human studies BDNF plays a role
in mediating the effect of exercise on learning. Studies in rodents show that long
term potentiation (LTP) associated with learning a new task, increases BDNF levels
in the brain. Injecting BDNF directly into the brain improves learning and inhibiting
BDNF in the brain impairs learning.
Exercise and the Body-Brain Connection 95
BDNF
Hippocampus
ned neuroplasticity
ned synaptic
connections
Myelin remodeling
Neurogenesis
Improved:
Spacial memory, navigation,
decision making, planning
Fig. 5.1 Role of exercise induced release of brain derived neurotrophic factor (BDNF) in the hip-
pocampus of the brain
There is a generalized exercise-dependent increase in brain BDNF and the

increase roughly correlates with exercise amount (intensity + duration + frequency)
of exercise. Physically fit individuals have a better BDNF exercise response than
sedentary individuals and sporting activities may induce better BDNF responses
than just running or walking probably due to the combined physical and cognitive
aspects of sports.
In his book Spark: The Revolutionary New Science of Exercise and the Brain,
psychiatrist John Ratey called BDNF, Miracle-Gro for the brain [10]. When you
exercise you are sprinkling Miracle-Gro on your brain. For obvious reasons it is not
possible to measure BDNF levels in the human brain while exercising but there have
been numerous studies showing beneficial affects of exercise on learning in humans
and a few have correlated improved learning with increased BDNF levels in
the blood.
Exercise and the Body-Brain Connection
Unlike other organs of the body where gaps between the lining endothelial cells of
capillaries allow substances in the blood to readily cross into the organ tissue, cells
lining capillaries of the brain have tight junctions forming a highly selective semi-
permeable membrane called the blood brain barrier. Proteins particularly large
proteins that have a positive or negative charge have difficulty crossing the blood
brain barrier unless there is a specific transporter for the protein built into the capil-
lary cells.
The blood brain barrier is obviously important in determining the relationship
between blood and brain BDNF levels at rest and during exercise. Why not just give
people injections of BDNF and avoid all the hassle of getting them to exercise?
Animal studies suggest that some BDNF does cross the blood brain barrier and
there is a correlation between blood and brain levels but there is no evidence for a
selective transporter of BDNF [11, 12]. Only a fraction of BDNF injected into the
blood gets into the brain.
The relationship between blood and brain BDNF levels is even more compli-
cated since blood platelets produce BDNF so there are too components to blood
BDNF, serum and platelet fractions. Even if some serum BDNF does cross the BBB
and enters brain tissue it is widely distributed and not localized to areas such as the
hippocampus where it can have the most beneficial effect. Increasing BDNF levels
throughout the brain could lead to suppression of BDNF receptors and undesirable
side effects. Exercise increases BDNF levels in the brain primarily through increased
synthesis in the brain and not through BDNF entering the brain from the blood [13].
Some growth factors produced in the body do enter the brain during exercise, and
like BDNF, enhance learning. So-called myokines are small proteins or peptides
produced and secreted by muscle during exercise to improve muscle function but
also influence brain function when they cross the blood brain barrier [14, 15].
The story of the myokine, insulin-like growth factor (IGF-1) shows one way that
physical activity and cognitive function became linked during evolution. IGF-1 is
produced by muscle to increase fuel needed for a sudden burst of contractions dur-
ing exercise. Along with insulin, it allows glucose to enter cells throughout the
body. Glucose is a major source of quick energy to muscle and the sole source of
energy in the brain. Glucose is critical for brief high intensity exercise, anaerobic
exercise.
When IGF-1 enters the brain through a selective transporter in the blood brain
barrier, it takes on a completely different role interacting with BDNF to augment
learning. IGF-1 increases BDNF production and signals neurons to produce the
neurotransmitters serotonin and glutamate important for LTP and learning. In our
distant ancestors, physical activity and learning became interlinked via this mes-
senger from muscle to the brain.
Another myokine that links muscle activity and cognitive function is vascular
endothelial growth factor (VEGF). With aerobic exercise, muscles up-regulate the
production of VEGF which is a signal to produce new capillaries both in muscle and
in brain. VEGF also protects the integrity of the BBB so that only select proteins can
cross the BBB. VEGF is increased after head trauma and stroke part of the repair
process after brain injury.
In addition to the signals sent to the brain during exercise, the brain sends signals
to the body initiating the cardiovascular responses needed for the increased meta-
bolic requirements of contracting muscles. The hypothalamus activates the sympa-
thetic division of the autonomic nervous system releasing noradrenalin and sending
Research Studies of Exercise on Learning and Memory 97
hormonal signals to the adrenal glands to release cortisol and adrenalin into the
blood stream (see Chap. 7). This prepares the body for physical activity by increas-
ing blood pressure, heart rate and respiration and stimulates release of glucose from
the liver for energy.
There is a redistribution of cardiac output with increase to exercising muscle
and brain and decrease to visceral organs particularly the gut. Cortisol supports
energy production during long periods of exercise by facilitating the breakdown
of fats and proteins to glucose. This process can in turn increase sensory alertness
and speed up mental processes in the brain leading to better memory storage and
retrieval.
Although cognitive performance initially improves with increasing levels of
physiological arousal, prolonged duration and intensity of exercise may cause it to
deteriorate due to dehydration and fatigue. Similarly prolonged elevation of corti-
sol with extreme exercise can damage muscle by breaking down muscle protein
for fuel.
Research Studies of Exercise on Learning and Memory
Studies in rodents show that aerobic exercise produces functional and structural
changes throughout the brain but the effects are most pronounced in the hippocam-
pus, the area of the brain essential for memory formation and spatial navigation [16,
17]. Running on a wheel increases the birth of new neurons, synaptic plasticity and
BDNF levels in the hippocampus which correlates with improved spatial memory
function on maze tests in the rodents.
Remarkably, the effect of exercise on the hippocampus is about the same regard-
less of whether the animal is housed in a bare cage with just a running wheel or in a
cage with enriched environment or other rodents for socializing. This suggests that
exercise is fundamental to the learning process in rodents.
Most studies on the effect of aerobic exercise on learning in humans have focused
on children because of the desire to improve education (discussed in the prior chap-
ter) and on older adults because of the desire to prevent cognitive decline with aging
(discussed in the next chapter). Although fewer studies have been conducted in
middle-aged adults, there is convincing evidence that exercise improves learning
and memory in people of all ages [18].
Studies can be divided into two broad categories: retrospective studies assessing
the effect of long-term exercise and physical fitness on learning and prospective
studies assessing the effect of a single bout or a short period of exercise on learning.
Both categories of studies have consistently shown a beneficial effect of exercise on
learning with a few exceptions. Exercise that leads to dehydration and/or extreme
fatigue can transiently impair learning and memory.
The problem with retrospective epidemiological studies of exercise on learn-
ing is that recall of exercise may be inaccurate and it is impossible to control for
the many possible confounding variables. For example, the apparent benefits of
exercise may be due to an overall healthier lifestyle of people who exercise
regularly. They typically don’t smoke, eat better and have a higher socioeco-
nomic status than people who do not exercise. It is even possible that a preexist-
ing illness or undiagnosed cognitive disorder is the reason a person decides not
to exercise.
The obvious advantage of a prospective study is that learning can be quantified
with and without and before and after exercise in the same subject. In a recent meta-
analysis of studies on the effect of a single bout of exercise on learning in young
adults (ages 18–35), Swedish investigators identified 13 studies published between
2009 and 2019 in which participants were randomly assigned to either exercise or
control sessions [19]. Exercise for as short as 2 min to as long as 1 h (walking, run-
ning or bicycling) at moderate to high intensity had a favorable effect on learning
and memory measured with neuropsychological testing.
Although some of the studies attempted to determine the effect of different dura-
tions and intensities of exercise on learning and memory the results were conflicting
probably due to the small number of subjects and differing exercise conditions. A
few studies compared the effect of exercise before and after a memory task and
found that exercise before improved memory better than exercise after the task sug-
gesting that exercise may be more helpful for the encoding phase of learning than
for the consolidation phase. Clearly, more controlled studies in larger numbers of
subjects are needed to accurately assess the importance of the timing, duration and
intensity of exercise on learning in children and adults.
Sleep, Exercise and Learning
The notion that the main purpose of sleep is to rest the body and the brain is a gross
oversimplification. Sleep plays an active role in learning and behavior and there is a
complex interrelationship between sleep and exercise. Exercise can treat insomnia
while sleep deprivation can cause mental and physical impairment similar to that
seen with physical inactivity. Sleep deprivation and physical inactivity are two of
the most important public health problems facing modern day societies.
Recent research has shown a central role for sleep in learning and memory.
Furthermore, sleep is critical for maintaining mental alertness and overall cognitive
function. In certain occupations such as medical interns and airline pilots, adequate
sleep can be the difference between life and death.
Sleep provides a critical time window during which the brain is free from out-
side environmental sensory activity so that it can consolidate newly acquired
memories. During sleep, activity in the hippocampus increases after a learning
task and sleep enhances connections among neuronal networks (cell assemblies)
for memory consolidation via connections between the hippocampus and prefron-
tal cortex.
Suppression of sleep (sleep deprivation) prior to learning tasks impairs acquisi-
tion and consolidation of memories and sleep deprivation after learning tasks
impairs consolidation of the memories. For example, in rats, 1–2 days of sleep
deprivation impairs learning and memory performance on a water maze test. These
same rats have decreased early phase and late phase LTP activity and BDNF levels
Exercise “High” 99
in the hippocampus compared to control rats. Exercising the sleep-deprived rats

improves learning and memory performance and reverses the changes in LTP and
BDNF [20].
Like exercise, adequate sleep is essential for good health. Sleep deprivation is a
risk factor for cardiovascular disease, metabolic disorders, psychiatric illness and a
shortened life span. About 30% of working adults report getting less than 6 h of
sleep per night. A third of all adults report some type of sleep impairment with the
most common being insomnia and obstructive sleep apnea.
Current treatments such as hypnotic medications (sleeping pills) for insomnia
and continuous positive airway pressure (CPAP) for sleep apnea are helpful tran-
siently but long-term benefits are less clear. Regular use of sleeping medications
invariably leads to problems with decreasing efficacy and dependency and CPAP
masks can be uncomfortable and interfere with sleep.
Considering its widespread availability and wide-range of health benefits, exer-
cise represents a potential primary and supplemental treatment for both insomnia
and sleep apnea. Most studies on the effect of exercise on sleep have focused on
older adults with sleep problems since this is the population with the most sleep
complaints. The results indicate a moderate improvement in sleep with exercise
training although the type and severity of sleep dysfunction was variable and not
well documented in most studies.
A few studies that looked at adults with documented chronic insomnia found
more consistent benefits from exercise. In one study of older adults with chronic
insomnia, aerobic exercise for 4 months not only significantly improved sleep qual-
ity but also decreased daytime sleepiness and symptoms of depression [21]. The
effect of a single bout of exercise on sleep quality is less clear although most studies
found a modest affect in adults without sleep complaints.
One study in middle-aged adults with insomnia found that a single bout of
moderate-intensity aerobic exercise but not high-intensity aerobic or anaerobic
exercise improved sleep compared to a control night without a prior bout of exercise
[22]. Exercise has an even more impressive effect on obstructive sleep apnea. Since
obesity is a major risk factor for sleep apnea one might assume that exercise
improves sleep apnea by decreasing obesity.
A meta-analysis of 5 published studies on the effect of exercise on obstructive
sleep apnea found a 32% reduction in sleep apnea severity despite no significant
change in body weight [23]. As noted in Chap. 1, exercise is not very effective for
weight reduction unless it is combined with dietary restrictions. Clearly exercise has
a beneficial effect on sleep apnea separate from its effect on weight. One would
expect that combining exercise with a weight reduction diet would be even more
beneficial for sleep apnea than exercise alone.
Exercise “High”
We may understand the nuts and bolts of how the brain learns and how the learning
process is enhanced by exercise but that does not explain why some people choose
to exercise while others choose not to exercise. The human brain is much more
complex than a simple learning machine. It is highly influenced by emotions (fear,

pleasure, anxiety) controlled by a variety of neuronal networks throughout
the brain.
The process of evolution is not neat and ordered but rather haphazard with com-
plex interactions between primitive neuronal networks deep in the brain and more
recently evolved networks in the cerebral cortex. Many of our emotions and behav-
iors are ingrained in the primitive deep brain networks encoded in our genes. As
described in Chap. 2, in the early stages of evolution physical activity was closely
linked with the search for food. The reward for the physical activity was readily
apparent—finding food.
For contemporary people, physical activity is rarely needed to find food but
physical activity including planned exercise can be pleasurable even exhilarating.
Trained athletes describe a range of pleasurable sensations with exercise from relax-
ation to euphoria, a “runners high”. Exercise-induced mood change is not exclusive
to running but can be produced by any type of sustained physical activity.
People who exercise tend to be happier and more satisfied with life. Overall they
tend to be more connected with other people and are less likely to be lonely or
depressed.
How is physical activity linked to such a wide variety of psychological benefits?
Both wild and laboratory bred strains of rodents are highly motivated to run on
wheels and will voluntarily run for long distances. If given a choice they will choose
an environment that contains a running wheel over one that does not and they can
be taught to perform a variety of learning tasks using access to a running wheel as
a reward.
Researchers at McGill University in Canada made the remarkable observation in
the mid twentieth century that after they implanted an electrode in the forebrain of
a rat, the rat would continuously press a bar in their cage that electrically stimulated
the forebrain at the exclusion of all other activities even eating [24]. As it turned out,
stimulating the electrode was triggering the release of the neurotransmitter dopa-
mine within a neuronal network that became known as the motivation/reward net-
work. The network, which included neurons in the prefrontal cortex, hippocampus
and several subcortical nuclei, controlled a range of emotions including feelings of
pleasure and well being.
In rats and humans, physical activity increases dopamine release in the motiva-
tion/reward network and can produce pleasurable feelings [25]. Rats given drugs
that block dopamine transmission and humans with Parkinson disease who have
loss of dopamine producing neurons, exhibit decreased voluntary physical activity
and blunted feelings of pleasure.
There appears to be a complex interrelationship between physical activity and
the motivation/reward network whereby physical activity increases dopamine trans-
mission producing pleasurable sensations and decreased dopamine transmission in
the network decreases the motivation to be physically active. Over time, a regular
exercise program can modify the motivational/reward network increasing dopamine
release and the number of dopamine receptors, a type of learning that expands the
capacity for experiencing joy and pleasure in one’s life.
Exercise “High” 101
Some athletes have noted a similarity of the “high” experienced after endurance
running to the “high” sensation they experienced after being given opioid drugs for
pain relief. Endorphins are the main neurotransmitter in a powerful neuronal pain
network that modulates pain transmission in the spinal cord and brain (see Chap. 8).
Endorphin receptors in the central pain network are activated by opium and its many
synthetic derivatives (opioids) explaining why these drugs are effective in pain
control.
There is a close interaction between the central pain network and the motivation/
reward network with endorphin receptors in the prefrontal cortex and hippocampus
that can explain the initial high after opioid use and aspects of drug addiction [26].
Chronic use of opioids decreases the number of dopamine receptors in the motiva-
tion/reward network so that addicts are unmotivated and less able to enjoy pleasure.
Thus the need for more and more drug to obtain a “high”. Increasing dopamine
transmission within the motivation/reward network with exercise can be an impor-
tant part of treatment for drug addiction.
Other athletes compare the “high” they experience with exercise to the sensation
they experience after smoking cannabis, a “don’t worry be happy” feeling.
Endocannabinoids are brain neurotransmitters that activate a variety of neuronal
networks including the motivational/reward network. The prefrontal cortex, hippo-
campus and the amygdala are rich in endocannabinoid receptors and cannabinoid
drugs such as cannabis bind to these receptors reducing stress and anxiety and pro-
moting feelings of optimism [27].
The amygdala is an almond shaped nucleus deep in the temporal lobe, long
known to be important in generating fear and anxiety. Impaired prefrontal inhibitory
control of the amygdala can lead to chronic hypersensitivity and a persistent state of
fear and anxiety. Exercise releases endocannabinoids that bind to receptors in the
amygdala and helps control symptoms of stress and anxiety. Like endorphins, endo-
cannabinoids increase dopamine production in the motivation/reward network
which in turn improves feelings of pleasure and contentment.
With exercise both endorphins and endocannabinoids are released. The endor-
phins and endocannabinoids don’t just make us feel better; they help people bond
together and improve exercise performance. Scientists have long speculated that
exercise has a positive effect on social cohesion.
In 1912, the pioneering French sociologist, Émile Durkheim, called the euphoric
feeling that people experience when rhythmically moving together collective effer-
vescence [28]. Dating back to our most primitive ancestors, group dancing has been
part of all human cultures. The cooperative nature of dancing may have served an
evolutionary function by enhancing social bonding among group members.
But could there be too much of a good thing? In the mid fourteenth century,
hundreds of people along the Rhine river valley in Europe developed a strange com-
pulsion to dance. They would dance day and night without pausing to eat or sleep.
The behavior migrated to towns throughout Europe and then gradually subsided
over a few months.
The so-called dancing mania resurfaced more than a century later in Strasbourg
and in this case it was well documented by physicians and monks in the area. About
400 men, women and children participated and several died (presumably from
dehydration and extreme fatigue). The dancing mania was thought to be a form of
mass hysteria although the cause remained obscure [29]. It involved a wide segment
of the population; everyone seemed to be susceptible.
The compulsive nature of the dancing brings to mind the rats that continued to
press a lever to stimulate the motivation/reward network in their forebrain ignoring
food and water. Could the release of endorphins during dancing cause a euphoria
that became a type of addiction?
The collective joy associated with synchronous movements in groups of people
has been attributed to the release of endorphins in the brain. Several studies found
an increase in pain tolerance after synchronized rowing where pain tolerance was
used as a surrogate marker of endorphin release [30]. But was it the physical activity
or the synchronized behavior that caused the release of endorphins and the increase
in pain tolerance.
To answer that question, researchers from Oxford University in the UK mea-
sured pain tolerance in 164 teenaged students (boys and girls) after synchronized or
unsynchronized dance movements on their feet (high exertion) or while sitting and
just performing hand movements (low exertion) [31]. Groups of three students were
randomly assigned to one of four conditions: high exertion/synchronized, high exer-
tion/unsynchronized, low exertion/synchronized and low exertion/unsynchronized.
As with the studies on rowing, pain tolerance was measure by gradual inflation of a
blood pressure cuff and the participant indicated the pressure at which they became
uncomfortable. Both exertion and synchrony had independent positive effects on
elevating pain threshold. These studies suggest that exercising with synchronous
movements in groups may be more beneficial to learning and brain health than exer-
cising alone.
Exercising in groups doesn’t just make us feel better but can help us develop trust
and closer feelings for others. The collective endorphin and endocannabinoid rush
seems to help people bond and form friendships even with people we don’t know.
Exercise can be a way to better connect with friends and family. Married couples
that exercise together report feeling closer and more loved after the exercise than
before. Exercise can be a way to defuse anger and hostile feelings that develop in a
relationship.
Rhythmic group exercise not only enhances bonding, but rhythmicity and social
bonding enhance exercise performance. In one study of elite players from a rugby
team in England, players who participated in a synchronized warm up session per-
formed significantly better on in a high intensity running test than players who
participated in a non-synchronized warm up session [30].
Participants on team sports often report performing at a higher level with their
teammates than when exercising alone. In sports such as tennis where players
develop a feeling of rhythmicity with their opponent as the ball goes back and forth,
the players report increased endurance for high intensity exercise that would not be
possible when exercising alone.
Group exercises can be improved by rhythmicity such as adding music to group
aerobics and breathing in unison to group yoga. A single bout of exercise provides
Green Exercise 103
a jolt of endorphins and endocannabinoids but a long term exercise program changes
the level of receptors and connectivity between neuronal networks expanding ones
ability to bond with other people.
Green Exercise
One of the main challenges when anyone begins an exercise program is to maintain
motivation to complete the program. As suggested in the prior section, exercising in
groups with social bonding can be a strong motivating factor to persist with exer-
cise. Another motivating factor that recently has received special attention is exer-
cise in the outdoors, so-call green exercise.
Since our hunter-gatherer ancestors evolved in an open natural environment, we
may have inherited an innate bond with nature, E.O. Wilson’s biophilia hypothesis
[32]. Nature does not require our constant attention and may have restorative pow-
ers allowing us to recover from mental fatigue.
Several recent studies have found that compared to exercising indoors, outdoor
exercise improves participation, increases intensity and persistence and leads to bet-
ter physical and mental health benefits [33, 34]. Furthermore, since green exercise
is typically conducted in public outdoor spaces there is no need for costly equip-
ment and indoor space. Simply walking outdoors is probably the easiest of all exer-
cises to maintain adherence.
In addition to motivating people to exercise, there is evidence that people per-
ceive exercise as easier outdoors in a natural environment. When people walk out-
doors without specific instructions they tend to walk faster with less perceived effort
than when walking indoors. People tend to reach a higher peak heart rate when
running outdoors compared to running on a treadmill indoors suggesting that exer-
cise in open spaces is perceived as less demanding than exercise indoors.
One’s perception of effort is a complex brain process that depends on integration
of multiple sensory signals and memories of past experiences. Being outside tends
to improve mood and lessen anxiety and exercising in a green environment enhances
feelings of revitalization and enthusiasm. Physiological measures of stress includ-
ing blood pressure, heart rate variability and stress hormones tend to be less when
people exercise with a rural visual background versus an urban visual background.
With the industrial revolution and rapid urbanization of the world’s population
there is less and less green space available for outside activities such as sports and
planned exercise. The founders of many of the world’s great cities had the foresight
to plan and develop urban parks because they considered green spaces important for
public wellbeing. Studies suggest that just living near green open spaces improves
physical and mental health.
But as the availability of outdoor spaces have become more limited, people have
moved indoors to exercise in gymnasia, sports clubs and at home. One European
study found that people living near green open spaces were much more likely to be
physically active and much less likely to be obese than people not living near green
areas [35]. One simple and proven way to decrease the world’s epidemic of physical
inactivity is to develop and maintain urban parks and open spaces where all people
can play games and exercise.
Socioeconomic status is currently the single most important determining factor
as to whether or not a person has access to green open spaces. Not only are people
of low socioeconomic status less likely to live near green areas, they cannot afford
transportation to reach green areas and even if there are nearby parks they are less
well maintained than parks in affluent areas. Just going outside can be dangerous in
many urban centers.
Serotonin, Emotions and Learning
The neurotransmitter serotonin has long been linked to the emotional aspects of
human behavior including depression, anxiety disorder and impulsivity and drugs
that increase brain serotonin levels are popular treatments for these conditions (as
discussed in Chap. 7). Most serotonin containing neurons are located in the raphe
nuclei located at the back of the brainstem near the midline. Neurons in the raphe
nuclei send their axons throughout the brain with major projections to the central
pain and motivation/rewards networks and to emotional centers such as the amyg-
dala and prefrontal cortex.
There is compelling evidence that serotonin plays an important role in learning
and memory particularly the emotional aspects of learning and memory. As noted
earlier in the chapter, serotonin was found to be a key component of learning within
the simple gill-withdraw reflex of the sea snail, Aplysia by Erik Kandell. Studies in
rodents have found that exercise increases serotonin levels in key memory centers
including the hippocampus and prefrontal cortex and that the level of brain sero-
tonin increases with increasing duration and intensity of exercise [16, 36]. Improved
performance on maze tasks correlates with increases in serotonin and post exercise
serotonin and BDNF levels are positively correlated.
Exercise-induced increases in brain serotonin are also thought to contribute to
fatigue with prolonged exercise. Exercise-induced fatigue can be broken down into
two components, peripheral fatigue due to decreasing fuel for muscle contractions
and central fatigue due to changes in neurotransmitters particularly serotonin and
dopamine.
With prolonged wheel running in rats to the point of exhaustion (about 3 h),
serotonin levels continue to increase while dopamine levels return to baseline after
an initial peak at 1 h. A high serotonin to dopamine ratio seems to support a low
physical activity exhausted state while a low serotonin to dopamine ratio supports a
high physical activity enthusiastic state. Consistent with this theory, lowering brain
serotonin levels with drugs can prolong the time that rodents can run before they
reach exhaustion.
For obvious reasons it is not possible to measure serotonin levels in the brain of
human subjects during exercise or while learning new information. Serotonin levels
in the blood can be traced to two fractions, the largest fraction stored in platelets and
a smaller fraction free in serum. The bound platelet fraction does not cross the blood
Serotonin Drugs and Learning 105
brain barrier but some of the serum fraction does cross the barrier via a transporter.
Studies show that measuring serum serotonin levels provides a rough estimate of
brain serotonin levels.
In human subjects serum serotonin levels increase with exercise and continue to
increase with increasing intensity and duration of exercise. The most consistent
elevation in serum serotonin is seen after prolonged high intensity exercise. In one
study, German investigators measured the effect of different intensities of exercise
on serum serotonin levels and on cognitive performance assessed with the Stroop
test, a measure of attention and impulse inhibition thought to be under prefrontal
cortex control [37].
They studied 121 physically fit young adults who were randomly assigned to
either a sedentary control group, a low intensity exercise group (45–50% maximum
heart rate), a moderate intensity exercise group (65–70% maximum heart rate) or a
high intensity exercise group (85–90% maximum heart rate). Subjects in each exer-
cise group began with a 5-min warm up and then cycled for 30 min at their desig-
nated heart rate that was constantly monitored to keep it in the prescribed range.
Subjects in the control group underwent relaxation training. Before and after the
sessions subjects had their blood drawn for serum serotonin levels and performed
the Stroops test.
Exercise significantly increased serum serotonin levels with a positive linear cor-
relation between serotonin concentration and exercise intensity. Individuals with the
largest enhancements in response inhibition on the Stroops test showed the greatest
increase in serum serotonin. Although statistically significant, the size of the
exercised-induced serotonin effect on cognitive performance was small indicating
that serotonin was only one of many factors that determined performance on the
Stroops test.
Serotonin Drugs and Learning
Drugs that alter brain serotonin levels such as the selective serotonin reuptake inhib-
itors (SSRIs) are among the most commonly prescribed drugs used by physicians.
They are mostly prescribed for depression but are also used for a wide range of
conditions including eating disorders, anxiety and obsessive-compulsive disorder.
These drugs have complicated effects on brain serotonin transmission initially
impairing transmission but with chronic use improving serotonin transmission.
Most studies on the effect of SSRIs on learning have been conducted in people
with depression who already have learning deficits particularly in cognitive and
emotional executive functions. The beneficial effects of SSRIs in patients with
depression are delayed requiring weeks and sometimes even months for improve-
ment in symptoms including improvement in cognitive and behavioral functions.
Only a few studies have looked at the effect of SSRIs in normal healthy subjects.
In one blinded placebo controlled study, a single 20 mg dose of the SSRI, escitalo-
pram, given to healthy volunteers impaired learning and cognitive flexibility while
improving impulse control compared to those given placebo [38]. The authors
speculated that the results reflected a differential modulation of serotonin in differ-

ent brain circuits. For obvious reasons studies on long-term use of SSRIs in normal
human subjects have not been conducted although long-term use in monkeys pro-
duced shrinkage of the hippocampus on magnet resonance images of the brains.
These types of studies illustrate the difficulties in trying to assess the role of a
single variable such as the overall brain serotonin level on such a complicated pro-
cess as learning in the brain that involves multiple neuronal networks and a wide
variety on neurotransmitters and receptors all influenced by one’s genes and envi-
ronment. Unlike a drug that modifies a single variable in the complex process of
learning, exercise modifies a wide range of variables that evolved over millions of
years all with the goal of improving brain function. Furthermore, as we will see in
Chap. 7, exercise is at least as good if not better than SSRIs for treating the symp-
toms and signs of depression.
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The Aging Brain
6
From an evolutionary perspective, exercise tricks the brain into trying to maintain itself for
survival despite the hormonal cues that it is aging.—John Ratey [1]
Everyone is familiar with the visible effects of aging: muscles, tendons and joints
lose strength and flexibility producing slower movements and a bent forward pos-
ture, skin becomes dry and brittle causing wrinkles, and eye sight and hearing dete-
riorate requiring glasses and hearing aids. Our reflexes slow down, it is more difficult
to maintain attention, we are more easily distracted, and our coordination and bal-
ance deteriorate. Yet the most devastating effect of aging is cognitive decline.
Anyone over the age of 65 has experienced a temporary memory lapse that can
be embarrassing and even frightening. In my many years practicing neurology, I
can’t count the number of times I had to reassure someone that they were not devel-
oping Alzheimer’s disease but just having a “senior moment”. But how do we dif-
ferentiate a senior moment from medical conditions such as minimal cognitive
impairment or dementia.
As we will see, this can be difficult and there is a spectrum of cognitive impair-
ment with aging with blurred boundaries between the different degrees of impair-
ment. Some cognitive functions such as language skills, mathematical abilities and
general knowledge are relatively resistant to age-related decline whereas other
aspects such as memory, executive functions and processing speed are more suscep-
tible to age-related decline. Slowing in the speed of information processing has a
substantial impact on age-associated decline in all cognitive activities.
There are currently about as many people over the age of 60 as there are under
the age of 15 in the global population. With aging of the world’s population the
problem of age related cognitive decline is becoming a major socioeconomic con-
cern. All older people have some cognitive decline that as it progresses can impair
their ability to carry out everyday activities, make important decisions and live
independently.
https://doi.org/10.1007/978-3-031-13924-6_6
110 6 The Aging Brain
But some people have more rapid cognitive decline than others. The popular
media is rife with articles promoting a wide variety of products and lifestyle changes
to improve brain health and prevent cognitive decline with aging. Most researchers
agree that currently the main risk factors for developing cognitive decline with
aging are physical inactivity, smoking, obesity, type 2 diabetes and the APOE 4
genotype while the only proven protective factors are exercise, a healthy diet, and
regular cognitive activity.
Energy Consumption and the Aging Brain
There is a marked fluctuation in the energy consumption of the human brain over a
lifetime. The energy needs of a child’s brain rapidly increase after birth reaching
adult levels by about age two. From age 4 to 10 the energy consumption of a child’s
brain far exceeds that of an adult’s brain [2]. After age 10 the brain metabolic rate
gradually declines into the late teens where it again reaches adult values. From this
point, there is a very gradual decline in brain metabolic rate throughout the reminder
of life.
During the high energy consumption period of childhood the brain develops
numerous excessive connections (synapses) between neurons more than are needed
that will eventually be pruned based on use. Only those that are utilized are main-
tained. This explains why the childhood window of increased metabolic rate from
age 4 to 10 is critical for developing social behavior and learning new skills such as
a second language. During adolescence the window gradually closes as the number
of brain synapses approach adult numbers.
From an evolutionary point of view, it has been argued that the high energy levels
required in childhood are necessary for the rapid learning required for the child to
become a functioning member of the society [3]. The cost of the high energy is
acceptable in childhood considering the benefits. By the time individuals reach
adulthood, however, they have learned and stored enough information to survive so
they can afford to cut back on the energy needs of the brain.
At the cellular level this means that neurons and synapses that are not being regu-
larly used are pruned saving valuable energy as people age. It is interesting to com-
pare the changes in the brain that occur with normal aging to those in the brains of
people with dementia. Some of the cellular changes are similar although present to
a lesser degree in normal older people. This has led some to suggest that everyone
will eventually develop dementia if they live long enough.
The genes and gene variants responsible for these changes in the brain with
age are present in all of us and it is just a matter of each individual’s gene profile,
lifestyle and how long we live that determines whether or not we develop demen-
tia. Exercise and a healthy diet don’t cure dementia they just delay the age
of onset.
Diseases such as Alzheimer Disease that develop late in life are not subject to the
usual selection forces on reproduction seen with earlier onset diseases. In other
words, they are not directly linked to survival of the species [4]. Although some
Early Life Experiences and the Aging Brain 111
people with a genetic profile making them extremely susceptible to develop

Alzheimer disease can show subtle cognitive defects early in life, it is rare for cogni-
tive impairment obvious to everyone to occur before the age of 55.
In primitive hunter gatherer societies, the hunting and foraging abilities peaked
at around age 25 and then remained relatively stable until about age 45 after which
there was a progressive decline so that eventually people lost the ability to obtain
enough food to meet their personal needs. Unlike our closest primate relatives and
most other mammals where death due to starvation follows inability to find food,
older people in hunter-gatherer societies could rely on younger members to supple-
ment their diet.
During periods of food scarcity the oldest members of the society were most
threatened by starvation. Since these older hunter-gatherer people down regulated
the resting metabolic rate of the brain, they were better prepared to weather periods
of food scarcity. In modern Western societies where more people live to old age and
food is relatively abundant, the genetically programed down regulation of brain
metabolism with aging is maladaptive. Using as many neurons and synapses as pos-
sible slows this programmed neuronal pruning process with aging and delays the
onset of dementia.
Increasing physical activity improves cognitive function and can protect the
brain against cognitive decline with aging. On the other hand, chronic inactivity
associated with modern industrialized societies reduces the brain’s plastic capabil-
ity and leads to brain atrophy with aging and chronic neurodegenerative diseases
[5]. Any period of inactivity causes the brain to decrease neuroplasticity and increase
the risk of developing age-related cognitive decline and neurodegenerative diseases.
Increasing physical activity after periods of inactivity resets and slows the aging
process but probably will not completely reverse the changes in the brain that
occurred during the period of inactivity. A wide range of factors influence the start-
ing point of the overall risk for developing age related cognitive decline and late
onset neurodegenerative diseases including education, access to health care, physi-
cal activity, nutrition and of course genetic risk factors such as the APOE gene allele.
Early Life Experiences and the Aging Brain
The structure of the brain is constantly changing throughout life beginning in utero
and extending into old age and some of the patterns of change with aging are similar
to those that occur during development. For example, production of new synapses
and pruning of old synapses is a lifelong process. So, in some ways, aging in the
brain starts when we are still in the womb.
It is well known that exposure to toxins in utero such as alcohol or opioids can
cause lifelong changes in brain structure and impair cognitive function that acceler-
ates later in life. The Helsinki Birth Cohort Study is one of the most detailed studies
on the relationship between early development and later life outcomes [6]. The
cohort consisted of people born in Helsinki, Finland between 1934–1944 with
developmental details abstracted from birth, child welfare and school health records
and later followed from 1971 onwards documenting adult health outcomes includ-
ing cognitive decline.
Some of the more interesting findings from different sub-studies within the
cohort include: premature birth increased the risk of developing cognitive decline in
later life, early life stress from parental separation of children during the war
increased the risk of developing frailty in old age, and earlier infant motor develop-
ment predicted better performance on measures of muscle strength, muscle endur-
ance, and aerobic fitness in adults.
Of all the possible factors that predict cognitive ability in old age, cognitive abil-
ity measured in childhood is by far the single best predictor. Childhood intelligence
accounts for around 50% of the variance in cognitive ability in people in the eighth
decade without dementia.
On June 4, 1947 almost all the people born in 1936 and attending school in
Scotland took the same validated cognitive ability test. The Lothian Birth Cohort
study on aging consisted of a detailed follow up of the survivors in their 70s who
lived in the Lothian area of Scotland, most of whom lived in Edinburgh [7, 8]. The
first follow up cognitive testing was performed on 1091 individuals at age 70 and
the most recent on 550 individuals at age 79. The goal of the study was to identify
factors that accounted for changes in cognitive function from age 11 to age 70 and
to identify which factors predicted cognitive decline between ages 70 and 79.
Not surprisingly, cognitive test performance at age 11 was a good predictor of
cognitive test performance at age 70. Smarter kids tended to be smarter older peo-
ple. The only other factors that independently predicted cognitive test performance
at age 70 were social status and level of physical activity.
The study design allowed researchers to test for reverse causation on the relation-
ship between cognitive performance and other variables such as socioeconomic sta-
tus, tobacco and alcohol consumption, and body mass index, a measure of obesity.
Remarkably, the data showed that the effect of these variables was attenuated or
eliminated after childhood cognitive performance was controlled for suggesting that
the association between cognitive function and these variables was explained in part
by the effects of earlier intelligence. In other words, smarter children were more
likely to overcome socioeconomic disadvantage and less likely to use tobacco,
excessive alcohol or be obese.
A major strength of the Lothian Birth Cohort study was the systematic follow up
of a subset of the participants in their 70s. A subset of 731 participants underwent
physical fitness testing and detailed MRI studies of the brain in addition to cognitive
testing at age 73 and 488 of these underwent repeat MRI studies and cognitive test-
ing at age 76 [8]. The physical fitness score combined measures of grip strength,
forced expiratory volume and a 6 meter walk time.
The MRI studies of the brain showed grey and white matter volume loss consis-
tent with decline in cognitive function between ages 73 and 76. Probably the most
important finding with regard to cognitive and structural brain decline with aging
was that the process was multifaceted and factors that predicted baseline cognition
and grey and white matter volume did not necessarily predict longitudinal changes.
For example, although measures of cognitive function at age 11 and subsequent
Telomere Length, Physical Activity and Aging 113
level of education predicted measures of cognitive function and brain structure at

age 73, childhood cognitive performance and education did not predict decline in
these measures with the follow up examination at age 76.
Of the wide variety of social, demographic, health and genetic variables assessed
in statistical models, only physical fitness and the APOE 4 genetic allele had a con-
sistent statistically significant effect on cognitive and brain volume decline from age
73 to age 76. Those who were physically fit had a significantly slower decline than
those who were not fit while those with an APOE 4 allele had a significantly faster
decline than those with APOE 2 and 3 alleles. Recall that exercise not only improves
physical fitness but also diminishes the adverse effects of the APOE 4 allele.
Genes and Cognitive Aging
Although there can be little doubt that genes play a major role in determining cogni-
tive ability both in young and older people, attempts to identify specific genes and
gene variants that predict cognitive aging have been largely unsuccessful [9]. Based
on studies of identical and non-identical twins (raised together or apart) and families
with adopted children, heredity appears to explain about 50% of overall cognitive
ability.
The genetic contribution to intelligence variation is about 40% in childhood and
about 60% in older people. Even the APOE4 allele, by far the best genetic predictor
of cognitive decline with aging, explains only 1–2% of the variance of cognitive
aging. Several other gene variants including a variant of the BDNF gene have been
shown to have a slight effect on cognitive aging but studies have been performed on
selected populations and different genes may be important in different populations.
It is possible that different genes influence cognition at different ages even in what
is considered old age. At the present time it appears that there are many (hundreds)
of gene variants that influence cognition, each with a slight (<1%) influence some
increasing and some decreasing the risk of developing age related cognitive decline.
Telomere Length, Physical Activity and Aging
Telomeres are caps at the end of each chromosome made of nucleoproteins that
protect the genetic information stored in the chromosome so that it does not degrade
over time. If a cell’s telomeres deteriorate the cell undergoes a type of programmed
death called apoptosis. It has long been known that telomere length decreases with
aging and there is a good correlation between chronological age and telomere length.
Epidemiological studies show that short telomere length is associated with all-
cause mortality and several age-related chronic diseases including cardiovascular
disease, type 2 diabetes and dementia [10]. In a study of almost 20,000 people over
a wide age range, researchers found that those with the shortest telomeres had a
25% greater chance of dying of any cause compared to those with the longest
telomeres.
Studies on the effect of telomere length on cognitive function in older people

without dementia have been less consistent although some studies that included
detailed neuropsychological testing found that shorter telomere length is associated
with poorer learning and memory in older people. Since telomere length is closely
associated with socioeconomic status and overall health status it can be difficult to
be sure which of these variables is most important for the observed cognitive
decline.
Studies on the relationship between physical activity and telomere length have
been about equally split between those that found a significant positive relationship
between physical activity and telomere length and those that did not find such a
relationship. But many of these studies did not use validated methods to measure
physical activity or control confounding variables.
One study on the relationship between physical activity and telomere length is of
note for the large population size and its method of quantifying physical activity.
The National Health and Nutritional Survey (NHANES) is an ongoing survey con-
ducted by the Centers for Disease Control (CDC) that assesses lifestyle, health and
nutrition status of US citizens. During the 1999–2002 NHANES cycles all partici-
pants ages 20 years and older were invited to give DNA samples for measurement
of telomere length and the overall data became accessible to the public on-line in
2014. Larry Tucker, a researcher at Brigham Young University in Provo Utah mined
the data to explore the relationship between telomere length and physical activity
and published the results in 2017 [11].
Tucker identified 5823 participants (2766 men and 3057 women) with complete
data for his analysis. The exposure variable was physical activity measured in MET
minutes in the past 30 days and the outcome variable was telomere length.
Demographic covariates included age, gender, race and education and lifestyle
covariates included body mass index (BMI), smoking and alcohol use.
As noted in Chap. 1, METs are defined by the ratio of the physically active meta-
bolic rate relative to the resting or basal metabolic rate. For example, a MET value
of 4 means you are exerting four times the energy that you exert when you are sit-
ting still. Washing dishes or taking a slow stroll has a MET value of about 2, brisk
walking or working in the yard a value of about 5, and running or digging a ditch a
value around10. MET values have been established for all common physical activi-
ties (NHANES website) and self reported MET minutes (time spent doing the activ-
ity) are a valid estimate of overall physical activity.
The CDC recommends that American adults should engage in at least 500 to
1000 MET-minutes per week. Interestingly, in the NHANES study more than half
of the participants did not reach the minimal recommended physical activity level
and more than a third reported no regular physical activity at all. As expected telo-
mere length was strongly associated with chronological age with telomeres becom-
ing 15.6 base pairs shorter with each year of aging. After adjusting for all of the
potentially confounding covariates, physical activity in MET-minutes was highly
correlated with telomere length. Participants who reported more than 1000 MET-
minutes per week had telomeres that were on average 140 base pairs longer than
those who reported little or no physical activity per week or a biological aging
White Matter Abnormalities with Aging 115
advantage of about 9 years. In other words, a 79 years old person who is highly
physically active had a telomere length comparable to a 70 years old person who
was not physically active.
White Matter Abnormalities with Aging
X-ray machines have been available since the turn of the twentieth century but
x-rays of the head show only the skull bones and nothing about brain structure. The
introduction of x-ray computerized tomography (CT) in the mid 1970s provided the
first real images of brain structure. CT uses computers to reconstruct the internal
structure of the brain from x-ray transmission measurements. CT could identify
gross brain abnormalities such as most tumors, tissue damage from stroke and gross
shrinkage but not more subtle abnormalities.
The major breakthrough in brain imaging was the introduction of magnetic reso-
nance imaging (MRI) in the late 1970s. Magnetic resonance spectroscopy was used
in the field of chemistry as far back as the 1940s to determine the structure and
composition of molecules. An American chemist, Paul Christian Lauterbur built the
first MRI machine when he was professor at the State University of New York at
Stony Brook. One of the first images taken by Lauterbur’s MRI machine was the
inside of a small clam his daughter had found.
Remarkably, the MRI can distinguish between a container of ordinary water
(H2O) and a container of heavy water (D2O), important because water is the most
common molecule in the brain and brain damage often changes the water content.
MRI can identify slight differences in brain water content.
As MRI was more widely used in the early 1980s it became apparent that most
older people exhibited hyperintensities in the white matter deep in the brain even
though many of these people appeared perfectly normal (Fig. 6.1). Recall that the
brain tissue is divided into grey matter where most of the neurons are located and
white matter where most of the fiber tracts are located. Radiologists, unsure of what
to make of these white matter findings on brain MRIs facetiously called them
“unidentified bright objects - UBOs”. Gross post mortem examination of the brains
in patients with white matter hyperintensities on MRI were mostly unremarkable
and microscopic examination identified a range of findings from occasional signs of
mini-strokes to completely normal appearing tissue.
In the early 1980s, I became interested in why so many older people had gait and
balance problems and increased risk of falling. It was well known that falls were a
leading cause of morbidity and mortality in older people particularly older people
with cognitive impairment. Was the same brain process that caused cognitive
impairment also causing balance problems and if so what was the process and what
could be done about it.
I organized a team of collaborators at UCLA and submitted a grant proposal to
the National Institute of Aging to study balance problems with aging using a longi-
tudinal study design whereby we would follow 200 people over the age of 75 (100
who complained of balance problems and 100 who had no balance complaints) with
Fig. 6.1 White matter

hyperintensities on a
magnetic resonance Gray matter
imaging (MRI) of the
brain. (a) Older person White matter
with minimal
hyperintensities and (b)
Older person with
prominent hyperintensities Ventricles
White matter
hyperintensities
yearly examinations consisting of tests of balance (a wide range of tests including

tests of inner ear balance function) and cognitive function (mini-mental status
examination) along with routine medical examinations.
An important feature of the proposed study was inclusion of the relatively new
brain imaging technique MRI, every 3 years, to see if there were structural changes
in the brain that correlated with deterioration in balance and cognition. We were
particularly interested in whether the amount of white matter hyperintensities on
MRI correlated with the degree of gait and cognitive impairment with aging. The
final key component of the study was that participants agreed to post mortem exami-
nation of the brain after death to allow a correlation of the clinical and imaging
findings with actual pathological changes in the brain.
The inner ear has two major sensory organs, the cochlea for hearing and the ves-
tibular apparatus for balance. Since age related changes in the cochlea are a well
White Matter Abnormalities with Aging 117
known contributor to age related hearing loss it was not unreasonable to question
whether age related changes in the vestibular apparatus might be a factor in age
related balance problems. However, although we were able to document a modest
deterioration of inner ear balance function with aging the effect was minor and did
not correlate with gait problems or susceptibility to falls. In a nutshell, age related
loss in the inner ear balance function is not an important cause of age related gait
and balance problems.
By contrast, the amount of white matter hyperintensities on MRI was strongly
correlated with both age related deterioration in balance and cognitive function [12,
13]. We graded the white matter hyerintensities as mild, moderate and severe and
those with severe hyperintensities consistently had the most severe balance and cog-
nitive dysfunction.
Our study did not include quantitative measures of exercise or physical fit-
ness, but it became obvious to us after getting to know the participants with
yearly examinations over all of those years that exercise was a key to maintaining
balance and cognition with aging. The effect was so dramatic that near the end of
the study, the only people still alive were those who were physically active. The
observation changed both my personal and professional outlook on exercise. I
became convinced of the importance of regular exercise for my patients and
for myself.
So what do white matter hyperintensities on MRI really represent? To answer
this question one must understand the importance of the neurovascular unit in the
aging brain. The brain is not just made up of neurons but rather of neurovascular
units composed of neurons, supporting glial cells and small blood vessels. Each
neuron, its axon and synapses, is surrounded by supporting glial cells that make
direct contact with nearby small blood vessels supplying the neuron with nutrients
and clearing the extracellular space of neurotransmitters.
As noted in Chap. 5, the blood vessels are tightly sealed (the blood brain barrier)
so that only selective molecules can enter the brain tissue thus protecting the neu-
rons and glial cells from potential toxins. Dysfunction of any of the three elements
of the neurovascular unit can impair synaptic transmission and lead to cognitive
decline. In our study of aging brains, post mortem examination of areas that had
prominent white matter hyperintensities on MRI prior to death showed remarkably
little on gross examination or on routine microscopic examination.
With special stains specific for glial cells we found enlarged swollen glial cells
[13]. We speculated that the glia cells took up proteins due to local break down in
the blood brain barrier leading to increased water content and an increased signal on
the MRI. In other words, the white matter hyperintensities on MRI were due to
small blood vessel damage leading to glia and neuronal dysfunction.
Consistent with this notion, two of the main risk factors in addition to aging for
developing white matter hyperintenisies on MRI are hypertension and type 2 diabe-
tes both well known causes of small vessel damage. Furthermore, other markers of
small vessel disease on MRI such as tiny infarcts, often called lacunes, were much
more common in people with prominent white matter hyperintensities than in those
with minimal white matter hyperintensities.
Over the subsequent years there have been numerous studies documenting a
strong relationship between the volume of white matter hyperintensities on MRI of
the brain and cognitive and balance decline with aging. About two thirds of people
between the ages of 60 and 70 have white matter hyperintensities and over 90% of
people between the ages of 70 and 80 have white matter hyperintensities.
Longitudinal studies in older people show a progression rate of white matter hyper-
intensities of about 0.5% per year in the seventh decade and about 5% per year in
the eighth decade [14, 15].
In our study, we were impressed with how patches of white matter hyperintensi-
ties gradually grew over the years so that some participants who lived into the 90s,
had hyperintensity throughout much of the white matter. Also, numerous studies
have shown that measures of cardiovascular fitness, physical activity and exercise
are all inversely related to the volume of white matter hyperintensities [16]. People
who exercise regularly and are physically fit have less white matter hyperintensities
than those who do not exercise and are not fit.
The benefits of physical fitness and physical activity seem to be most pronounced
in the critical eighth decade when the impact of white matter hyperintensities is
most prominent. For example, in the Lothian Birth Cohort study mentioned earlier,
the level of cardiovascular fitness at age 73 was the best predictor of the volume of
white matter hyperintensities on MRI at age 76 of all the variables assessed includ-
ing socioeconomic status, smoking, education level, APOE 4 allele and the presence
of other health conditions.
How does exercise and physical fitness protect against developing white matter
hyperintensities on MRI? As suggested earlier, there is compelling evidence that
white matter hyperintensities are due to small vessel disease in the brain. Exercise
is known to decrease the risk of developing hypertension and type 2 diabetes, two
well know risk factors for developing small vessel disease. But the benefit of exer-
cise in preventing white matter hyperintensities is still present even if people with
hypertension and type 2 diabetes are removed from study populations.
Aerobic exercise improves cardiorespiratory fitness increasing cerebral blood
flow and improving endothelial cell function in the small blood vessels of the blood
brain barrier. Overall, the volume of white matter hyperintensities is a rough esti-
mate of cerebral blood flow – low volume hyperintensities indicates good cerebral
blood flow and high volume hyperintenisies indicates poor cerebral blood flow. As
noted in Chap. 5, exercise leads to the release of vascular endothelial growth factor
(VEGF) that helps maintain the endothelial lining of the small vessels and leads to
the production of new small vessels. VEGF improves blood flow to both brain and
muscles in older people.
Shrinkage of the Brain with Aging
With MRI, for the first time, researchers were able to measure the volume of spe-
cific brain regions in living human subjects and demonstrate changes that occur
with aging. Studies show a gradual shrinkage of the brain, both grey and white
Shrinkage of the Brain with Aging 119
matter, in normal older people without dementia [17, 18]. The greatest shrinkage
(1–2% yearly) occurs in the frontal and temporal lobes, regions known to be critical
for memory storage and executive cognitive functions. Higher rates of shrinkage
particularly in these brain regions are associated with an increased risk of develop-
ing dementia but shrinkage is only one of multiple risk factors for developing
dementia.
Numerous cross sectional studies have shown that regular exercise and improved
physical fitness are associated with higher brain volume measurements on MRI
(grey and white matter) and better performance on memory and cognitive tests com-
pared to people who are physically inactive [19, 20]. Based on animal studies the
exercise effect on brain volume is due to a range of factors including dendritic
growth with increased synaptic connections, maintenance of axonal integrity and
growth of new small blood vessels.
Do the structural changes in the brain that occur with exercise reverse the effects
of aging or just delay the effects? To answer this question one needs to make serial
brain volume measurements in the same older person over time and compare the
changes in brain volume in people who are physically active with those who are
physically inactive. A few such studies suggest that age related brain shrinkage is at
least partially reversible with regular exercise.
Researchers at the University of Illinois followed 69 sedentary community-
dwelling normal volunteers between ages 60–79 years, half randomly assigned
to an aerobic training program and the other half to a toning and stretching
control group [21]. MRIs of the brain for estimates of grey and white matter
volume were obtained before and after a 6 month exercise intervention. Aerobic
and control groups attended three 1 h sessions per week. Estimates of cardiovas-
cular fitness were derived from peak heart rate responses to graded exercise
testing.
The aerobic exercise group began with 40–50% peak heart rate increasing to
60–70% peak hear rate over the course of the study. Significant increases in both
grey and white matter volume were seen as a function of fitness training for the
older people who underwent aerobic exercises but not for the older people who
participated in the stretching and toning group. The main limitation of this study
was the short period of follow up and the small number of subjects.
In another larger study, researchers at multiple sites in the United States
recruited 120 physically inactive community-dwelling older people [22]. After
baseline fitness testing, 60 were assigned to an aerobic exercise group and 60 to a
stretching control group followed for a year with an MRI of the brain performed
at the onset, at 6 months and at the end of the study. The investigators focused on
the volume of the hippocampus, the part of the temporal lobe critical for memory
formation.
For the aerobic exercise group, participants started by walking for 10 mins and
increasing walking duration weekly in 5 min increments until they achieved a dura-
tion of 40 mins by week seven. For the remainder of the study they walked 40 mins
per session. The targeted heart rate zone was 50–60% of maximum heart rate for
weeks one to seven and 60–75% maximum for the remainder of the program. Every
4 weeks participants were given feedback regarding their performance and if heart
rate was not in the correct zone they were encouraged to improve performance in
the next month.
Aerobic exercise training over the year increased the volume of the hippocampus
(left and right) by 2% whereas the volume of the hippocampus in the control stretch-
ing group decreased by 1.4%. Furthermore, the reversal of hippocampal volume
loss with exercise was associated with improved performance on a computerized
spatial memory test. Although more such studies are needed, these studies suggest
that a modest course of exercise training can reverse the normal age related volume
loss in the brain particularly in critical memory and cognitive areas such as the
hippocampus.
Muscular Strength and Aging
Skeletal muscle weakness and shrinkage (atrophy) that regularly occurs with aging
has many serious health consequences, altering routine daily activities, increasing
the risk of falling, increasing susceptibility to a variety of chronic diseases and
increasing the rate of all-cause mortality [23]. A classic viscous cycle often devel-
ops, whereby, loss of muscle bulk leads to decreased physical activity which in turn
accelerates the muscle loss. Furthermore, decreased muscle bulk and strength has a
variety of psychosocial effects: reduced independence and quality of life, social
isolation and increased depression. Muscle weakness is a common reason given for
not exercising by older people who do not indulge in the minimal exercise required
to stay healthy.
Skeletal muscles are attached to bones by tendons so decreased muscle activity
can have secondary negative effects on joint mobility and bone density. The com-
bined medical costs of dealing with the consequences of muscle weakness and asso-
ciated joint and bone disorders in older people is a huge burden on society that could
be mitigated simply by convincing older people to exercise. Of all the consequences
of aging, loss of muscle bulk and strength is most amenable to reversal with regular
exercise.
During exercise muscles secrete myokines that play a key role in preventing and
attenuating age-relate muscle weakness and atrophy [24]. As suggested earlier,
myokines can also affect other organs including the brain decreasing the risk of
developing cardiovascular disease, stroke and dementia.
A recent review identified 13 myokines whose secretion is influenced by aging and
controlled by the level of physical activity. Many are regulated by aerobic exercise,
others by anaerobic exercise while some, such as VEGF, are increased by both types of
exercise. Therefore, the ideal exercise program for older people should include some
combination of aerobic and anaerobic exercise. Examples of common aerobic exer-
cises for seniors would include walking, swimming and cycling whereas anaerobic
exercises would be wall push backs, leg lifts, ankle and toe tapping and weight lifting.
An example of a myokine secreted by muscle during aerobic exercise is apelin.
This peptide that is released during exercise has several subtypes and has been
Exercise for Prevention of Falls in Older People 121
shown to improve muscle bulk and strength in both human and rodent studies.
Apelin blood levels decrease with aging and may be a reliable marker of age related
muscle wasting. Aerobic exercise increases plasma apelin levels and apelin recep-
tors are potential targets for development of new drugs for treating age related mus-
cle wasting.
IGF-1 is an example of a myokine that is secreted by muscles during anaerobic
exercise. This multifunctional peptide is a growth hormone necessary for normal
muscle and bone growth and development. IGF-1 blood levels are low in community-
dwelling older people and are another potential marker for muscle wasting in the
elderly. Weight lifting was shown to increase IGF-1 levels and muscle bulk and
strength in women between the age of 72 and 98 years [25].
Exercise for Prevention of Falls in Older People
Age-related brain and muscle changes are among the most common causes for
imbalance and falls in older adults. About a third of people over the age of 65 living
at home fall every year and the percentage is higher in older people living in assisted
care facilities [26, 27]. Falls are a leading cause of morbidity in older people often
leading to injury, loss of independence and decreasing quality of life. About 10% of
falls are associated with bone fractures that markedly increase morbidity and chance
of death from complications.
Older people are often deconditioned with limited endurance [28]. About a third
of people over the age of 65 have difficulty walking 3 city blocks or climbing a
flight of stairs. About 20% require a walker to move about. The so-called “senile
gait” characterized by slow, broad based, shuffling steps is an extreme gait disorder
often caused by the age-related brain atrophy and white matter hyperintensities
described earlier.
Of all the interventions to decrease the risk and number of falls in older people
that have been evaluated in controlled treatment trials, exercise clearly stands out as
being most effective for the most people. Researchers in New Zealand, Australia,
United Kingdom and Canada conducted a mega-review of interventions to decrease
the risk and number of falls in older people in 2009 [29]. They identified a total of
111 randomized controlled trials with a total of 55,303 participants. Of these, 43
studies focused on exercise.
Exercise programs for fall prevention targeted some combination of strength,
balance, flexibility and endurance. Programs that contained two or more of
these components consistently reduced the risk of falls and the number of peo-
ple falling. The 3 most common categories of exercise in the studies, super-
vised groups, Tai Chi groups and individualized exercise programs at home, all
produced similar results—about a third reduction in the risk and number
of falls.
Other interventions that were effective in subsets of people included: improving
home safety in high-risk people, gradual withdrawal of sedating drugs in over-
medicated people, cataract surgery in people with severe visual loss and pacemaker
surgery in people with syncope. Vitamin D and calcium or hormonal replacement in

women did not decrease the risk or number of falls but may provide protection from
fractures.
The authors concluded that the benefit of exercise programs for reducing the risk
and rate of falling in older people should be considered as established. Further
research regarding the different components within each exercise category might be
justified but would require many more participants to have the power to discern
differences.
Exercise for Improving Cognition in Older People
A popular theory that neurologists have long used to explain why some older
people are relatively resistant to developing dementia is the Cognitive Reserve
Theory. In a nutshell, the theory proposes that cognitive activity over a lifetime
provides the brain with a cognitive reserve capacity so that the deleterious effects
of aging and chronic neurological diseases are delayed in onset [30]. On the other
hand, once symptoms begin in people with high cognitive reserve they progress
more rapidly since the underlying pathology has advanced further by the time
symptoms begin.
A related but different theory is the Brain Reserve Theory which states that larger
brains with more neurons and synapses are protected from developing age-related
neurological diseases. The two theories differ in that Brain Reserve is fixed, once
the disease threshold is reached cognitive decline begins, whereas, Cognitive
Reserve is changeable, the threshold can be altered by lifetime experiences. For
example, higher levels of education correlates with lower levels of cognitive decline
and lower risk of developing dementia.
Cognitive and Physical Activity Reserve The Cognitive Reserve Theory needs to
be expanded to include lifelong physical activity. Lifelong physical activity may not
only delay the onset of age related disease symptoms but may alter the underlying
pathological changes.
As our distant ancestors searched for food, they moved through complex envi-
ronments that required anticipation, increased attention and multi-tasking. The
faster they moved the more cognitive challenges the brain faced, linking physical
activity with cognition. This link between cognitive and physical demands produced
a selection pressure on genes and gene variants that favored joint metabolic pro-
cesses important for neuroplasticity (see Chap. 2).
Brain-derived neurotrophic factor (BDNF) is a key signaling molecule for trig-
gering neuroplasticity in the brain and is increased by both cognitive activity and
physical activity. Increased BDNF and the associated increase in brain neuroplasti-
city can protect against a variety of life long effects including environmental toxins
and stress that contribute to developing age related chronic neurological diseases.
Slight genetic variations in the gene that codes for BDNF can decrease the
Exercise for Improving Cognition in Older People 123
activity-dependent secretion of BDNF and increase the likelihood of developing age

related diseases.
Neuroplasticity is a complex process that consists of three major components:
changes in the number and strength of synaptic connections between nerve cells,
myelin remodeling (myelin is the fatty covering of nerve fibers that improves the
speed of signal transmission) and neurogenesis (see Fig. 5.1). Unlike other body
organs that are constantly generating new cells from stem cells throughout life, the
brain is relatively stable with only one area, the dentate nucleus in the hippocampus,
where new cell (neuronal) formation is important for cognitive function.
All three components of neuroplasticity are enhanced with BDNF release and all
three gradually decrease with normal aging. The vulnerability to brain atrophy that
commonly occurs with normal aging can be traced at least in part to the mismatch
between human evolutionary history and the low physical activity levels common in
current day older populations. In other words, age related brain atrophy is a response
to overall decreased cognitive and physical activity. If you don’t use it, you lose it.
An obvious implication of this linked cognitive-physical activity theory is that
combining exercise with cognitive activity should be more beneficial than either
activity alone. Traditional gym-based exercises such as running on a treadmill may
not be as effective as running through a stimulating new environment? Even running
through the same neighborhood day after day may not provide the novel cognitive
experience of running through a new environment.
What type and intensity of physical and cognitive activity provide the most ben-
efit for maintaining brain health? As our distant ancestors foraged for food, much of
their time was spent walking at a moderate speed using cognitive skills such as plan-
ning, spatial navigation and memory. Hunters had occasional bursts of high inten-
sity physical activity as they pursued their prey. Simulating these combined physical
and cognitive activities might be the best way to maintain brain health.
Fortunately, this is not a difficult proposition for most people to achieve. Walking
at a moderate speed (about 3 miles per hour or 6000 steps per hour) through a stimu-
lating outside environment is ideal for everyone, particularly for older people.
Occasional brief periods of jogging (seconds) can be intermixed with the walking.
Most people won’t walk several hours per day like our hunter-gatherer ancestors but
a least an hour a day is a reasonable target.
There is evidence from both animal and human studies that combining cognitive
and physical activity is more beneficial for brain health than either activity alone
[31, 32]. A key to all of these studies is identifying a marker that reliably indicates
improved brain function.
In animals it is possible to directly examine brain tissue for evidence of neuro-
plasticity whereas in humans, investigators must rely on performance measure-
ments and indirect measures of brain metabolism. Several studies in rodents found
increased BDNF levels and increased new neuron production in the hippocampus in
mice and rats after combining exercise with environmental enrichment compared to
exercise alone. Exercise increased both BDNF levels and new neuronal production
compared to no exercise but the effect was greater if exercise and environmental
enrichment were combined.
Of interest, one study found that mild to moderate exercise was better than
intense exercise for enhancing new neuron production in the hippocampus and
improving spatial memory in rats. The enhanced neuron production and spatial
memory was not associated with changes in the BDNF pathway but rather with
changes in other pathways involving protein synthesis and lipid metabolism indicat-
ing that the relationship between exercise and cognitive function is a complex pro-
cess involving multiple metabolic pathways. The beneficial effects of mild to
moderate exercise may be mediated through different pathways than the effects of
intense exercise. These are early studies and many more are needed to establish the
types of exercise and the forms of environmental enrichment to obtain the best
improvement in brain neuroplasticity.
Preliminary studies in human subjects also suggest that combined exercise and
cognitive activities is better for brain health than either activity alone [33, 34].
Assessing these early studies can be difficult, however, because of the large number
of variables that need to be controlled. For example, the duration, frequency and
type of exercise and cognitive sessions, baseline measures of physical fitness, cog-
nitive performance and health, and a wide range of possible outcome measurements
are all important variables.
An illustrative study that found support for the notion that exercise combined
with cognitive training in older people is better than exercise alone was conducted
by a group of investigators in New York and Illinois between 2008 and 2010. Older
subjects were recruited from eight independent living centers and randomized into
a 3 month exercise routine on a stationary bicycle with one group riding the bike on
a virtual reality tour while the other group just exercised without any cognitive
stimulation. Not only did cognitive performance measurements improve more in the
virtual bike tour group than the control group, the virtual tour group had a 23%
reduction in the risk of developing mild cognitive impairment (MCI), a condition
associated with a high risk of later developing dementia.
However, despite the randomization process the virtual tour group was signifi-
cantly younger (average 75.7 versus 81.6 years) and had significantly fewer years of
education (average 12.6 versus 14.8 years) than the control group, factors that could
bias the results. Other similar studies comparing a virtual dance game or exercise
while performing memory tasks or while learning a foreign language compared to
exercise alone also found better cognitive improvement with the combination of
exercise and cognitive stimulation than with exercise alone.
Diet and Cognitive Aging There has been a recent surge of interest in the role of
diet in healthy aging and a variety of nutrients and diets have been recommended to
delay the onset, or slow the progression of age-related cognitive decline [35].
Nutrients can be divided into two broad categories: micronutrients such as vitamins,
amino acids and minerals and macronutrients such as proteins, fats and carbohy-
drates. Diet focuses on the combination of micro- and macronutrients consumed.
Of the many micronutrients that might influence brain function researchers have
mainly focused on the B-vitamins, antioxidants and omega-3 fatty acids.
Exercise for Improving Cognition in Older People 125
Epidemiological studies looking at cross sections of older people have suggested a

protective role for B-vitamins (B-12, B-6 and B-9), antioxidants (vitamins C, E,
beta-carotene and flavonoids) and omega-3 fatty acids (particularly docosahexae-
noic acid, DHA) in maintaining cognitive function in older people although con-
trolled longitudinal treatment trials have been less impressive.
Recent meta-analyses of the controlled treatment trials to date on B-vitamins,
antioxidants and omega-3 fatty acids have concluded that the data does not support
routine use of any of these micronutrients to prevent cognitive decline in normal
older people although the number of good studies are limited and more need to be
conducted [36]. Furthermore, there may be subcategories of older people who ben-
efit from these micronutrients and others who don’t.
The VITACOG study recruited 270 community-dwelling subjects greater than
70 years old with mild cognitive impairment and randomly assigned subjects to
receive a daily placebo tablet or a tablet containing vitamins B12, B6 and B9 for
2 years and measured brain atrophy with MRI and performance on the mini-mental
status examination before and after treatment [37]. Those who received the
B-vitamins had significantly less progression of brain atrophy and a slower rate of
decline on the mini-mental status examination than those who received the placebo.
Most of the effect of the B-vitamins occurred in a subgroup of older people who had
elevated baseline blood homocysteine levels, which is a known risk factor for devel-
oping mild cognitive impairment. So older people with mild cognitive impairment
and elevated homocysteine levels may benefit from daily B-vitamins.
Recently, investigators have directed their attention to combinations of micronu-
trients in preventing cognitive decline in normal older people. The combination of
omega-3 fatty acids and B-vitamins may be more beneficial than either nutrient
alone. The combination of omega-3 fatty acids, vitamins A,E and D and carotenoids
has been recommended but controlled treatment trials need to be performed. Several
combinations of nutrients have been recommended for treating Alzheimer Disease.
Considering the complex interaction between micro- and macro-nutrients, many
researchers have focused on a whole diet approach rather than specific nutrients for
preventing cognitive decline with normal aging. Many of the nutrients considered
important for brain health are abundant in a variety of foods so a whole diet approach
is a good way of providing the right combination of nutrients.
The Mediterranean diet has been the most extensively studied diet plan regarding
brain aging and brain health [38]. Although several variants of the diet originated
around the Mediterranean Basin, all are characterized by an abundance of plant
foods including fruits, vegetables, breads, cereals, legumes, nuts and seeds. The
main source of fat is olive oil and dairy products are mostly limited to cheese and
yogurt. Protein is primarily derived from fish and poultry with low amounts of red
meat. Alcohol is consumed in modest amounts usually as red wine with meals.
Clinical trials suggest that adherence to the Mediterranean diet is associated with
slower rates of decline in cognitive function and with lower risk for cognitive
impairment with aging. The PREDIMED study was conducted at multiple centers
in Spain on older people who had high cardiovascular risk factors between ages
55–80 years from May 2005 to December 2010 [39]. Participants were randomly
assigned to either a Mediterranean style diet with extra-virgin olive oil, a

Mediterranean style diet with mixed nuts or a low fat intake diet. After six and a half
years of follow up, participants on either Mediterranean diet had higher global cog-
nitive performance scores than those on the control low fat diet. Similarly, the
NU-AGE study performed at multiple locations in Europe between 2011 and 2016
found that participants who closely adhered to a Mediterranean style diet had sig-
nificantly better overall memory and cognitive function than those who had low
adherence to the diet [40].
Combining Interventions to Prevent Cognitive Decline
Considering the large number of factors that have been shown to influence age-
related cognitive decline, combining interventions known to decrease the risk of
cognitive decline seems a logical approach to achieve maximum benefit. For exam-
ple, as noted in an earlier section, combining physical and cognitive activity seems
to get better results than either activity alone.
Although clinical trials combining multiple interventions for preventing age-
related cognitive decline are still in the early stages, a proof of concept study con-
ducted in Finland is of interest since the results were promising and it provided a
good example of the types of interventions that might be included in this approach.
The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and
Disability (FINGER) assessed a multidomain approach to prevent cognitive decline
in at-risk elderly people from the general population [41].
Between September, 2009 and November 2011, 1260 participants were ran-
domly assigned to the intervention group or control group. Potential subjects
underwent a standardized neuropsychological test battery and those selected had
cognitive performance at the mean level or slightly lower than expected for age
according to Finnish population norms. At the start, all participants (control and
intervention groups) met with the study nurse and received oral and written advice
on diet and physical, cognitive and social activities for a healthy lifestyle. Routine
blood tests were performed on all participants at the beginning, 6, 12 and 24 months
and test results were mailed to them along with written information about signifi-
cance of the measurements and advice to contact their health care provider if
deemed necessary.
The intervention group received additional sessions on diet, exercise, cognitive
training, social activities and managing metabolic and cardiovascular risk factors.
Subjects in the intervention group met regularly with nutritionists and developed a
diet plan based on age, health status and weight. Recommended diets favored fruit
and vegetables, whole grain cereal products, low-fat meat and dairy products, limit-
ing sucrose intake, vegetable margarine or rapeseed oil instead of butter and fish at
least twice a week. Exercise training was guided by physiotherapists in a gym with
individually tailored programs and group sessions consisting of muscle strength
training (1–3 sessions per week), aerobic exercise (2–5 sessions per week), and
posture and balance training. Cognitive training included group sessions led by
References 127
psychologists and individual in home computer-based training sessions that focused

on executive processes, working memory, episodic memory, and mental speed.
Social activities were encouraged in the numerous group meetings associated the
other intervention components. Finally, management of metabolic and cardiovascu-
lar risk factors was achieved with additional meetings with the study nurse and
physician and referral to the participants own physician or clinic if medications
were considered appropriate.
The primary outcome measurement of the study was the change in cognitive
performance on the neuropsychiatric test battery total score from the baseline mea-
surement to measurement 2 years later. Participants in the intervention group had
significantly higher total scores on neuropsychological testing at 2 years compared
to the control group. Of the different test categories, tests of executive function and
processing speed showed the greatest effect. The investigators concluded that multi-
domain intervention improves or maintains cognitive functions in at-risk elderly
people in the general population.
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Stress, Anxiety and Depression
7
It is not stress that kills, it is our reaction to it.—Hans Selye [1]
Everyone has experienced stress, a feeling of being overwhelmed, unable to cope.

How we react to that feeling can affect our overall health and our susceptibility to
illness. Short periods of emotional stress may be no problem and may even improve
performance in an athlete or a scholar. But longer periods of emotional stress are
nearly always harmful causing emotional and physical problems. Of all the factors
that influence stress, regular exercise provides the most consistent benefit.
Is it stress or the perception of stress that causes the problem? Human beings are
unique among animals in that they don’t necessarily have to be in a potentially dan-
gerous situation to experience stress. Just anticipating or even imagining a stressful
situation can elicit a stress response. Studies in people who complain of frequent
symptoms (often called somatic awareness or somatic focus) show that they feel a
high level of stress even when there is little actual stress [2].
The number of reported daily symptoms is much better correlated with the level
of perceived stress than with health status. Furthermore, stress permeates every-
one’s life, from the stress of driving to work or working in a demanding job to the
stress of dealing with a financial or family health crisis. If stress, whether real or
perceived, is not managed it can take a toll on the body and produce a variety of
chronic illnesses. Given that stress exacerbates nearly all known disease processes,
managing stress is the foundation for maintaining good health.
The relationship between stress and illness is complex. Everyone responds dif-
ferently to stress. A person’s genetic background, personality, coping skills and
social support system all influence the susceptibility to stress. Chronic stress
decreases a person’s ability to mount an effective immune response. Nearly all mea-
sures of immune function diminish with chronic stress [3].
People with immune deficits are particularly susceptible to stress. Many com-
mon diseases such as asthma, diabetes, hypertension and coronary artery disease are
greatly influenced by stress [4, 5]. An asthma attack can be reliably triggered in a
https://doi.org/10.1007/978-3-031-13924-6_7
130 7 Stress, Anxiety and Depression
susceptible person simply by placing them in situation where they are unable to
cope. Stress can change the amount of insulin required by a patient with type I dia-
betes or the amount of L-dopa required by a patient with Parkinson disease. Even
cancer is affected by stress. Studies in women show that a diagnosis of breast cancer
is more likely if there was a recent loss of a loved one or other traumatic event. In
men, lack of satisfying relationships with friends and family increases the risk of
prostate cancer.
What Exactly Is Stress
Even though we all experience stress, most of us would have a difficult time saying
exactly what stress represents. From a biological perspective, stress plays a central
role in the evolutionary process and in cellular homeostasis. Organisms evolve by
adapting to stress and biological systems must have a cellular stress response in
order to monitor and repair stress related cellular damage.
A stressor can be defined as any event or experience that threatens one’s ability
to adapt and cope. Examples of common environmental stressors include extreme
temperature changes, exposure to toxins, traumatic events and food shortage.
In the mid-nineteenth century the pioneering French physiologist Claude Bernard
introduced the concept that body metabolic systems overall function to maintain a
constant internal environment that he called the internal milieu. The body maintains
the internal environment by a range of compensatory reactions designed to restore a
state of equilibrium in response to environmental stressors. Bernard is probably best
known for his work showing how the liver breaks down glycogen to produce glu-
cose in the face of decreased blood glucose.
An American physiologist at Harvard Medical School, Walter B. Cannon, pro-
vided the first real insight into how stress could lead to physical symptoms in the
early twentieth century [6]. Initially working on digestive disorders Cannon noted
that emotions such as fear and anger interrupted gastric secretions and impaired
digestion whereas happiness and satisfaction improved digestion.
To study the phenomena, Cannon applied painful electrical stimuli to anesthe-
tized animals and noted increased secretion of adrenalin into the blood from the
adrenal glands which was associated with increased breathing rate, dilation of the
pupils, increased heart rate, and increased circulation to muscles and brain at the
expense of the gut. All of these effects could be reproduced in the same animal by
simply injecting adrenalin into the blood stream. Cannon explained these findings
in evolutionary terms suggesting that these primitive reflexes served the purpose
of “survival of the fittest”. In 1915, he coined the term “fight or flight response”
which were the only two options available for primitive prey in the face of a
predator.
Cannon showed that adrenalin release from the adrenal gland was under control
of the sympathetic nervous system reflexively activated by emotional stimuli
(Fig. 7.1). The sympathetic nervous system is composed of nerves and nerve gan-
glia (groupings of nerve cells) outside of the central nervous system that controls
What Exactly Is Stress 131
Stress
Hypothalamus
Pituitary gland
Sympathetic ACTH
Nervous Adrenocorticotropic
system Hormone
Adrenal glands
Adrenal medulla Adrenal cortex

releases adrenaline releases cortisol
Fig. 7.1 Stress triggers release of adrenalin and cortisol by the adrenal gland via the hypothalamic-
sympathetic-adrenal axis and the hypothalamic-pituitary-adrenal axis
the smooth muscle of gut, blood vessels and glands. The adrenal gland and sympa-
thetic nervous system worked closely together as a unit, the sympathetic-adrenal
axis, to control the internal environment in stressful situations.
The primary neurons for the sympathetic nervous system are located in the hypo-
thalamus, part of the brain’s emotion control system called the limbic system.
Cannon’s hypothalamic-sympathetic-adrenal axis provided neurologists and psy-
chiatrists an anatomical substrate to explain how stress and psychological emotions
could produce somatic symptoms. Stress activated neurons in the hypothalamus
activating the sympathetic nervous system and releasing systemic hormones includ-
ing adrenalin. This in turn could result in a range of symptoms including general-
ized shaking, agitation, palpitations, sweating, shortness of breath, nausea,
abdominal pain, near-faint dizziness, ringing in the ears and difficulty concentrating
all symptoms common with emotional stress.
In the mid twentieth century, the Hungarian born Canadian endocrinologist,

Hans Selye, described another key neuroendocrine component of the stress response,
the hypothalamic-pituitary-adrenal axis (Fig. 7.1) [7]. He pointed out that connec-
tions from the hypothalamus to the nearby pituitary gland had an equally prominent
role in generating stress related neuropsychological symptoms as Cannon’s
hypothalamic-sympathetic-adrenal axis. He emphasized the role of adrenocortico-
tropic hormone (ACTH) that controls the release of cortisol (a steroid) by the cortex
of the adrenal gland.
With stress, the hypothalamus triggers release of ACTH from the pituitary gland
which in turn triggers the release of cortisol by the adrenal gland. Selye emphasized
the importance of cortisol in such basic processes as sleep, muscle function and
immune responses. Animals injected with cortisol are much more susceptible to
infections and a variety of medical illnesses.
An interesting consequence of the stress induced increased secretion of ACTH, is
the so-called “stress shift” of pituitary activity. With the chronic increased secretion
of ACTH the pituitary gland cannot maintain optimal production of other important
hormones such as the gonadotrophic hormones (sex hormones). Female rats exposed
to physical and emotional stressors stopped menstruating, developed ovarian atrophy
and during lactation stopped milk secretion. Male rats developed involution of the
testes. Clinical studies in humans found that stress caused decreased libido and fertil-
ity in both sexes accompanied by amenorrhea in women and impotence in men.
The emotional brain, the limbic system, plays a major role in the body’s response
to stress. Limbic connections from the hippocampus to the hypothalamus activate
Cannon’s sympathetic-adrenal axis and Selye’s hypothalamic-pituitary-adrenal axis
producing the wide variety of somatic symptoms mentioned earlier. Recall that the
hippocampus is a critical learning and memory center in the brain and not only is one
of the most plastic regions of the brain but the only region that new neurons are con-
stantly being produced from progenitor stem cells. Both neuroplasticity and neuro-
genesis are important for learning and behavior and are highly susceptible to stress.
Cortisol released from the adrenal cortex during chronic stress activates steroid
receptors in the hippocampus producing a positive feedback loop via its connections
to the hypothalamus. As suggested earlier, exercise appears to be the perfect anti-
dote for stress. Yet, exercise itself induces neuroendocrine responses similar to that
of other environmental stressors. Exercise is a type of stress. This paradox has lead
to the “inoculation hypothesis”, the notion that regular low levels of stress with
exercise improves the body’s ability to respond to other environmental stressors,
like being vaccinated against stress. As long as the stress is not too severe and neu-
rons have time to adapt, in the long run, the connections between neurons are stron-
ger and we are better able to cope.
Neurobiology of Stress
As discussed in Chap. 5, growth factors are molecules critical for development, dif-
ferentiation and plasticity of neurons in the brain. Of the four groups of growth
factors expressed in the brain, brain-derived neurotrophic factor (BDNF) plays a
Neurobiology of Stress 133
critical role in mediating the effects of stress on brain function [8]. BDNF is highly
expressed in the hippocampus and the level of expression is very responsive to
stress. BDNF is a molecular intermediary for neuroplasticity and neurogenesis in
the hippocampus.
In rodent models that measure the animal’s ability to suppress fear with learning,
BDNF plays a key role in fear conditioning, consolidating fear memories and facili-
tating extinction learning. Slight genetic variants in the BDNF peptide or its recep-
tor, decrease BDNF signaling and increase the risk of developing stress induced
psychogenic illnesses including depression and post traumatic stress disorder
(PTSD) [9]. BDNF signaling is also influenced by female hormones which could in
part explain the increased incidence of stress-related illnesses in women.
In animal models, chronic stress decreases brain BDNF levels, impairs neuro-
plasticity and neurogenesis, and shrinks the hippocampus producing an anxiety/
depression like state [10]. By contrast, physical activity increases brain neurotroph-
ins, improves neuroplasticity and neurogenesis, reverses hippocampal shrinkage
and relieves anxiety and depression symptoms.
Chronic stress is associated with the increased levels of proinflammatory cyto-
kines released by activated immune cells, macrophages in the blood and microglia
in the brain. Cytokines such as interleukins are peptides that control the inflamma-
tory response. They not only alter the immune response but also contribute to the
brain effects of stress [11].
In animal models, stress related release of interleukins impairs neuroplasticity
and prevents new synapse formation in the hippocampus. Drugs that block cyto-
kines prevent these antineurogenic effects and the behavioral symptoms of
depression caused by stress [12, 13]. Cytokine release with stress in humans
induces symptoms of depression including feelings of hopelessness and sleep
disturbances.
Cytokine levels are elevated in the blood of depressed patients and genes that
code for cytokines are upregulated in the prefrontal cortex in patients with depres-
sion. The combination of decreased BDNF signaling and increased cytokine signal-
ing provides a potent biological trigger for anxiety and depression along with other
psychogenic illnesses associated with chronic stress.
When the brain perceives a stimulus or perception as stressful, physiological and
behavioral changes are initiated in an effort to adapt to the stress (the stress response).
The goal is to maintain metabolic equilibrium and survive. Two molecules that play
a key role in the stress response are adrenalin and cortisol the products of the
autonomic-adrenal-axis and the hypothalamic-pituitary –adrenal axis described ear-
lier. With chronic stress adrenalin and cortisol can accumulate and have adverse
effects on neural, endocrine and immune systems leading to a variety of chronic
diseases.
Behavioral responses to stress are highly dependent on the motivational/reward
network imbedded deep within the brain (see Chap. 5). Although for centuries, plea-
sure and pain have been considered opposite emotions, two ends of a spectrum of
emotion, both pleasure and pain are important for survival and potentially can merge
into one another [14]. The brains emotional system, the limbic system and the moti-
vational/reward system are functionally and biologically interconnected.
Major components of the motivational/reward network are located in the limbic

system. For example, recall of pleasurable and painful experiences are accessed
through hippocampal memory mechanisms. The central relay station of the motiva-
tional/reward network is a nucleus near the base of the brain called the ventral teg-
mental area (VTA). Dopamine neurons in the VTA project to multiple limbic
structures. The amygdala, a critical junction of the limbic and rewards systems is
rich in receptors for dopamine and the inhibitory neurotransmitter, GABA. Treatments
for stress including drugs that mimic the action of GABA such as diazepam (Valium)
and alternative medical treatments such as meditation and acupuncture are thought
to produce their calming effects by activating the inhibitory receptors in the amyg-
dala and other limbic structures.
These same limbic areas are linked to the endogenous opioid system. Dopamine
is formed in the synthesis of endogenous opioids and is a key neurotransmitter in the
amygdala. As an overview, the amygdala helps decide whether an experience is
pleasurable or painful and produces associations between the experience and other
similar emotions, the hippocampus generates memories of the experience, how,
when and where it and similar experiences occurred and the frontal cortex monitors
and coordinates the process and ultimately determines the resulting behavior.
Exercise and Stress Management
Exercise should be a part of any stress management program whether dealing with
acute, episodic, or chronic stress. An obvious advantage of incorporating exercise
into a stress management program is the well-documented physical and psychologi-
cal health benefits of exercise. However, it is important to keep in mind that exercise
is only one component of stress management and it does not deal with the sources
of chronic stress.
The physiological mechanisms that explain how exercise helps manage stress
have been systematically evaluated in recent years and there is overwhelming
research confirming a beneficial effect of exercise on chronic stress [15–17]. All of
the mechanisms of stress production discussed in the prior sections are influenced
by exercise. Human and animal research demonstrate how physically activity
improves the way the body handles stress by altering stress hormones such as adren-
alin and cortisol and neurotransmitters such as dopamine, opioids and serotonin that
affect mood and behaviors.
By releasing stress hormones in a regular controlled fashion, exercise allows the
body to gradually adapt to the hormones and the associated symptoms. People feel
calmer after a bout of aerobic exercise and this calming effect often lasts for several
hours after the exercise is finished. Exercise enhances the release of dopamine,
endogenous opioids, and the inhibitory neurotransmitter, GABA all of which pro-
duce a calming effect.
Chronic stress interferes with memory circuits in the hippocampus and prefron-
tal cortex which correlates with decreased expression of brain-derived neurotrophic
factor (BDNF) and the neurotransmitter serotonin. Exercise increases BDNF and
Posttraumatic Stress Disorder (PTSD) 135
serotonin levels in these brain regions and reverses the associated cognitive and
memory deficits associated with chronic stress. Finally, exercise blocks the cytokine
release associated with chronic stress and reverses the immune deficits associated
with stress.
Studies show that the physiological adaptations that improve the way the brain
handles and recovers from stress occur with currently recommended exercise levels,
i.e. 150 mins of moderate-intensity aerobic exercise per week or 75 mins of
vigorous-intensity aerobic exercise per week. For someone who experiences work-
related stress, exercise sessions can be broken up into 10–15 mins sessions through-
out the day to fit the workday schedule.
Exercise also provides a psychological break from daily stressors. In one study,
college-aged women who reported that studying was very stressful, completed a
standardized questionnaire on stress and anxiety symptoms before and after four
research conditions over 4 days: quiet rest, studying, exercise alone and exercise
while studying [18]. The 4 conditions were counterbalanced across students and
each condition lasted 40 mins. The “exercise alone” condition had the greatest
calming effect suggesting that a part of the benefit of exercise is due to simply
removing a person from daily stressors.
Posttraumatic Stress Disorder (PTSD)
The syndrome initially called the post-Vietnam syndrome and then posttraumatic
stress syndrome (PTSD) consisted of three basic features: (1) flashbacks and dreams
of a distressing traumatic event; (2) loss of emotion and avoidance of situations
reminiscent of a traumatic event; and (3) a constant state of increased arousal (anxi-
ety) [19]. The initial definition of PTSD conceived of the stress necessary to cause
the disorder as a catastrophic event, outside the realm of normal human experience.
This feature of placing great importance on the causative agent was unique to psy-
chiatric diagnoses. But what is catastrophic stress to one person may not be to
another person. Clearly during the Vietnam War most people exposed to traumatic
events did not develop PTSD.
How was PTSD different from other psychiatric disorders such as anxiety and
depression? PTSD is not just a fear-based anxiety or depressive disorder but rather
a trauma and stress related disorder requiring that the onset be preceded by an
adverse environmental event. The triad of symptoms mentioned above is character-
istic and the symptoms must last for at least a month before PTSD can be diagnosed.
Since its initial description in 1980, PTSD has become associated with a range of
life traumas from military combat to natural disasters, terrorist attacks and physical
or sexual assaults. It has become one of the most common psychiatric diagnoses
causing a major personal and societal burden. Up to 10% of people in the United
States suffer from PTSD.
Complicating matters, most people with PTSD meet the diagnostic criteria for at
least one other psychiatric diagnosis particularly depression and anxiety disorder.
They have increased rates of surgery, more co-morbid medical conditions and
undergo more medical procedures than the general population. They go from physi-
cian to physician and yet they often end up frustrated with the system.
As a rule, people with PTSD become physically inactive and lose interest in
recreational activities. Current treatments consisting of cognitive behavioral ther-
apy, exposure therapy and antidepressant drugs provide only marginal benefit. In
recent years, exercise has been gaining momentum as a promising primary and
adjuvant treatment for PTSD.
Exercise for Treating PTSD
Two of the prominent features of PTSD are hyperarousal and avoidance behavior
almost as though the person is in a constant state of “fight or flight”. Patients with
PTSD become super sensitive to physiological arousal cues such as rapid heartbeats
and increased breathing rate and exposure to exercise can increase tolerance and
lead to desensitization of these physiological sensations. Patients with PTSD who
exercise learn that these body sensations can be normal and not necessarily cata-
strophic related to some traumatic event. Numerous studies have verified that peo-
ple with PTSD who exercise regularly have fewer hyperarousal symptoms over time.
A variety of observational and interventional research studies have found a posi-
tive effect of aerobic exercise, either alone or in combination with other treatments
for PTSD [20]. Furthermore, the benefit was seen in both military and civilian popu-
lations, men and women and young and old. Several observational studies that
assessed the intensity of exercise performed suggest that high intensity exercise was
more beneficial than low or moderate intensity exercise for both preventing and
treating PTSD symptoms.
In a prospective study of 38,883 randomly selected U.S. veterans (mostly men),
4% met the diagnostic criteria for PTSD at onset [21]. Veterans who reported regu-
lar vigorous exercise for at least 20 mins twice a week were significantly less likely
to develop new PTSD symptoms or have persistent symptoms on a standard ques-
tionnaire at 3–5 years of follow up compared to those who did not perform vigorous
exercise.
In another study of 182 community-living adults with PTSD (72% women) those
who reported engaging in vigorous exercise (running or cycling) had significantly
fewer avoidance and hyperarousal symptoms than those who reported mild or mod-
erate exercise (non-exhaustive sports) at 3 months follow up. In these studies, vigor-
ous exercise was determined by self reports that are notoriously unreliable for
quantifying exercise intensity and amount. They are consistent with the notion that
vigorous exercise may allow for exposure and desensitization to arousal cues asso-
ciated with the hyperarousal state better than low level exercise.
There have been only a few longitudinal randomized studies of exercise for treat-
ing PTSD symptoms. One study examined the influence of aerobic training exer-
cises on PTSD symptoms in a community dwelling sample of 33 patients with
PTSD (75% women) [22]. The participants took part in six 20 min moderate-
intensity aerobic exercise sessions (60–80% maximum heart rate) over 2 weeks.
Anxiety 137
The duration of PTSD symptoms varied greatly within the exercise treated group
although most had symptoms for 1–4 years.
The exercise significantly reduced self reported symptoms with the greatest
effect on avoidance symptoms. Interestingly, participants with lower cardiovascular
fitness levels at baseline, measured with a bicycle ergometer, had a significantly
greater reduction in PTSD symptoms than those who were better physically fit at the
start. This finding suggests that PTSD patients who are not physically fit (by far the
majority) have the most to gain by an exercise program.
Another randomized treatment trial of exercise for PTSD symptoms in veterans
(91% men) found that moderate intensity aerobic and anaerobic exercise (3 h ses-
sions per week for 12 weeks) significantly reduced PTSD symptom severity com-
pared to wait list controls [23]. Hyperarousal symptoms benefited the most from the
exercise treatment. A few other studies that combined exercise with routine treat-
ments of PTSD symptoms found that exercise added additional benefit to “care as
usual”. These studies suggest that exercise can decrease PTSD symptoms but the
sample sizes were small and most lacked appropriate control groups. Clearly more
studies are needed to determine the best type and duration of exercise for treating
PTSD symptoms.
Anxiety
Anxiety is a feeling of nervousness and unease that everyone can experience typi-
cally associated with an imminent event or something perceived beyond control.
When the feeling becomes a persistent aversive state it is considered an anxiety
disorder.
There are numerous types of anxiety disorders including generalized anxiety
disorder, agoraphobia, social anxiety disorder, separation anxiety disorder and pho-
bias [24]. All are characterized by a state of excessive uneasiness and apprehension
often with compulsive behavior and panic attacks. Anxiety disorders are the most
prevalent mental health disorders, affecting almost a third of adolescents and up to
a quarter of the world’s population. Furthermore, anxiety disorders are comorbid
with variety of other mental health disorders particularly depression.
Long periods of emotional stress can lead to anxiety. With improved under-
standing of the brain’s emotional control system, the limbic system, a neurobio-
logical model for anxiety has evolved. A key part of the limbic system is an almond
shaped nucleus deep in the temporal lobe, the amygdala, long known to be impor-
tant for experiencing emotions such as fear and anger. Incoming sensory signals
can result in activation of a subgroup of neurons in the amygdala generating
anxiety.
These excitatory neurons in the amygdala are normally kept in check by inhibi-
tory feedback under the control of the prefrontal cortex, the key center for managing
complex cognitive behavior such as planning and problem solving (so-called execu-
tive functions). Impaired prefrontal inhibitory control of the amygdala can lead to
chronic hypersensitivity and a persistent state of anxiety.
Slight variants in the genes that code for key proteins in the fear network help
explain why certain people are more sensitive to developing anxiety attacks. People
with anxiety are hypersensitive to sensory stimuli including light, sound, motion,
pain, and smell. They often startle with just the slightest touch. The paradox is that
despite the heightened sensitivity overall brain function is inefficient.
When discussing this problem with patients I often use the analogy of a motor
running out of gear. Patients have difficulty concentrating and focusing their atten-
tion (brain fog) and often complain of memory impairment. They are easily dis-
tracted and are less productive in their work. They have difficulty getting asleep and
never feel rested. Anxiety occurs with many illnesses and it is part of many degen-
erative neurological conditions and may even be the initial manifestation of a vari-
ety of neurological diseases including dementia.
From an evolution point of view, the primitive emotion of fear was key to sur-
vival for our early mammalian ancestors [25]. An unexpected sound or smell would
trigger fear and a search for a safe haven. But if fear persists and there is no safe
haven anxiety develops.
Some psychiatrists consider generalized anxiety disorder to be the result of an
unsuccessful search for safety. It is built into our primitive brain (hard wired) ready to
be activated by the appropriate environmental circumstance. Early social animals
assigned the role of an anxious individual to a single member of the group, a sentry,
who would post in a high perch diligently watching for potential predators while the
rest of the group foraged without anxiety. Early primates developed a variety of warn-
ing calls that required different responses of the group depending on the type of threat,
a leopard, an eagle or a snake. A member of the group who did not trust the sentry or
was unaware of the sentry’s existence might be thought to have anxiety disorder.
In some ways, anxiety is a lack of trust, perhaps due to bad experiences with trust
in the past. Thus, the therapy of having group members fall backwards to be caught
by other group members, a way to develop an attitude of trust. Our ancestors, the
hunter-gatherers, lived in relatively small groups, usually about 15 but no more than
50 adults, so it was relatively easy to develop trust among the members and fears
were discussed and support provided.
In our modern world of more than 6 billion people, news travels at the speed of
light and individuals listen and watch the news on their own often with little chance
to discuss or comment upon it. The only world that existed for our hunter-gatherer
ancestors was the world they experienced on a daily basis whereas modern people
are constantly bombarded with bad news from all around the world on a minute-to-
minute basis. No wonder, so many people in modern day societies have some type
of anxiety disorder.
Exercise for Treating Anxiety
The notion that exercise can ameliorate anxiety dates back thousands of years
mostly based on personal observations. People who were anxious felt better after
exercise. The basic idea is that by increasing heart rate, breathing and sweating
Depression 139
during exercise, one simulates the feelings of arousal associated with anxiety and
learns that these physical symptoms do not necessarily lead to an anxiety attack.
One becomes comfortable with these feelings and over time the brain learns to
accept them as normal feelings.
People who are anxious are more likely to be physically inactive than people
who are not anxious. Presumably, in this case the increased heart rate, breathing and
sweating associated with exercise frighten the person and they learn to avoid the
symptoms by being inactive. Epidemiological studies suggest that the amount of
physical activity is inversely associated with symptoms of anxiety in the general
population [26]. A World Health Survey of 47 countries found that people who are
at least moderately physically active are a third less likely to have an anxiety disor-
der than people who are physically inactive.
Exercise dampens the stress response and improved physical fitness protects
against anxiety. As noted earlier, stress activates the hypothalamic sympathetic
adrenal axis and the hypothalamic pituitary adrenal axis to produce many of the
symptoms of anxiety. Regular exercise decreases this stress response by adaptation
over time. The result is a protection against a wide range of stressors related to anxi-
ety disorders.
Several random controlled studies found that aerobic exercise prior to a psycho-
social stressful event significantly decreased systolic and diastolic blood pressure
associated with the event [27]. Furthermore, higher levels of exercise had a larger
impact than lower levels of exercise. Highly trained athletes have a lower heart rate
and less cortisol release in response to stressors than untrained controls.
A twelve-week exercise program that increased physical fitness significantly
reduced the heart rate, heart rate variability and release of cortisol to environmental
stressors compared to a control group in a relaxation program. Exercise also has an
important psychological impact that works in tandem with the biological mecha-
nisms to reduce symptoms of anxiety. Exercise leads to increased release of endor-
phins, cannabinoids, and dopamine all of which have mood-enhancing anxiolytic
effects.
What kind of exercise is best for enhancing anxiolytic effects has not been sys-
tematically studied but aerobic exercise of at least moderate intensity on a regular
basis to improve cardiovascular fitness appears to be best option based on current
knowledge. In a study of 19,288 participants in the Netherlands Twin Registry, peo-
ple who reported at least 240 minutes a week of moderate aerobic exercise had
significantly less symptoms of anxiety and neuroticism than people who did not
exercise regularly [28].
Depression
Depression is a serious brain disease associated with molecular and structural brain
damage and a high rate of morbidity and mortality. According to a report by the World
Health Organization (WHO), major depressive disorders will be the leading cause of
disability in the world by 2030. Nearly 800,000 people die every year due to suicide.
A simple definition of depression is sadness gone awry. Everyone experiences

sadness associated with life’s trials and tribulations but when people feel sad and
hopeless all of the time they are suffering from depression. They loose the ability to
experience joy or pleasure.
The cause of depression is a complex combination of genetic and environmental
factors with chronic stress being the leading environmental trigger. At the present
time the diagnosis is based on identifying a combination of psychosocial and physi-
cal symptoms outlined in the Diagnostic and Statistical Manual of Mental Disorders
(DSM) of the American Psychiatric Society. There is an active search for biological
markers of the disease and both molecular and structural correlates have been iden-
tified in subsets of patients but they are currently not reliable enough for a definitive
diagnosis. As noted in the prior section, there is a high comorbidity of anxiety and
depression and there is also comorbidity of depression and numerous other chronic
conditions including sleep disorders, eating disorders, and dementia.
For a diagnosis of depression a person must be experiencing five or more of the
following symptoms during the same 2-week period and at least one of the symp-
toms is either depressed mood or loss of interest or pleasure [29].
1. Depressed mood most of the day, nearly every day.

2. Markedly diminished interest or pleasure in all, or almost all, activities most of
the day, nearly every day.
3. Significant weight loss when not dieting or weight gain, or decrease or increase
in appetite nearly every day.
4. A slowing down of thought and a reduction of physical movement (observable
by others, not merely subjective feelings of restlessness or being slowed down).
5. Fatigue or loss of energy nearly every day.
6. Feelings of worthlessness or excessive or inappropriate guilt nearly every day.
7. Diminished ability to think or concentrate, or indecisiveness, nearly every day.
8. Recurrent thoughts of death, recurrent suicidal ideation without a specific plan,
or a suicide attempt or a specific plan for committing suicide.
To meet the criteria for a diagnosis of depression, these symptoms must cause the
person clinically significant distress or impairment in social, occupational, or other
important areas of functioning. The symptoms must also not be a result of substance
abuse or another medical condition. The presence of anxiety in patients with depres-
sion may affect prognosis, treatment options, and the patient’s response to them.
Animal Models of Depression
Much of what we know about the molecular mechanisms of depression comes from
studies in animals particularly rodents [30]. The obvious question is: how do you
make a rat depressed? Actually it is not that difficult although like with humans
there are genetic and environmental susceptibility factors so some animals are more
easily depressed than others even among animals of the same strain.
Animal Models of Depression 141
Early-life stress such as maternal separation and limiting nesting can lead to life-
long behavioral and hormonal changes typical of depression. The most common
model of depression in rodents is a chronic stress model. A high percentage of rats
will become depressed when exposed to chronic stress.
A commonly used stress model combines a variety of minor stressors over a long
period of time. For example, every day for 4–8 weeks rats experience different
“micro-stressors” lasting about half the day. These include: lights on and off every
2 h, cage tilting, strobe flashing lights, pouring water into the cage to damp the bed-
ding, and pairing two rats with an unfamiliar partner at each session. Over time the
animals develop anhedonia, a decreased interest in activities that used to be pleasur-
able. This behavior is typically manifested by decreased consumption of dilute
sugar water and decreased sexual activity.
Examination of the brains of “depressed rats” reveals a wide variety of molecular
and structural changes that remarkably parallel changes seen in human brains of
depressed patients [30]. The hippocampus is visibly shrunken due to loss of den-
dritic spines and synapses, decreased neurogenesis, and alterations in glial cells.
Recall that the hippocampus is a key memory center in the temporal lobe that is part
of the limbic system and an important regulator of the hypothalamic-pituitary-
adrenal axis, so important in the stress response.
Hippocampal neurons express a high level of steroid receptors that when acti-
vated by stress hormones result in impaired neuronal function and plasticity. At the
molecular level, chronic stress reduces brain-derived neurotrophic factor (BDNF)
expression in the hippocampus, a potent regulator of dendritic complexity in the
hippocampus. These research finding have caused some to speculate that BDNF is
the key molecule accounting for the pathological changes and symptoms of depres-
sion, “the BDNF theory of depression.”
Another cortical area that shows prominent changes in the chronic stress model
of depression is the prefrontal cortex (PFC), particularly the medial (near the cen-
ter) part of the PFC. This region is critically important for regulation of executive
functions, emotions and memories through reciprocal connections to the hippo-
campus and another key limbic structure, the amygdala. Atrophy in the PFC is
associated with loss of neuronal dendrites and synapses and also loss of all types
of glial cells.
Stress seems to have a detrimental effect on glial cells throughout the brain in
both animal and human studies leading some researchers to speculate that altera-
tions in glial cells may play a key role in causing depression. At the molecular level,
inhibitory neurons in the PFC that release GABA, the main inhibitory neurotrans-
mitter, are selectively susceptible to chronic stress. These inhibitory neurons are
important for controlling activity in the hippocampus and amygdala and disruption
of the excitatory/inhibitory balance between the PFC and these critical limbic struc-
tures can cause disturbed emotional and cognitive brain function.
As noted in prior chapters, rats love to run and given access to a running wheel
will voluntarily run on a regular basis whether in the wild or in a laboratory.
Numerous studies in rats found that regular running increases BDNF expression in
the hippocampus and blunts the hypothalamic-pituitary-adrenal-axis response to
stress gradually over days to weeks. Initially, with the onset of running, there is an
increase in blood cortisol levels consistent with exercise being a stressor but gradu-
ally with time the cortisol levels decrease as adaptation occurs.
Allowing rats exposed to chronic stress, to run for a few hours a day either delays
the onset or completely prevents the development of depression. The picture is more
complicated when evaluating the effect of running on animals who already have
depression since they lose interest in all activities including running. Forced run-
ning can actually increase stress and potentially aggravate the problem.
Exercise for Preventing Depression
There is overwhelming evidence that people who have regular physical activity and
are physical fit are much less likely to develop depression than people who are
physically inactive and are not physically fit. The relationship between physical
activity and depression is complicated since people who are depressed are less moti-
vated to exercise and lose interest in all activities. So if you are inactive you are
more likely to become depressed and if you are depressed you are more likely to be
physically inactive.
In 1969, William Morgan published a landmark paper documenting that physi-
cally fit patients were less likely to be depressed compared to unfit patients [31].
Morgan reported an inverse relationship between measures of physical fitness and
depression and suggested that exercise protected against developing depression.
Subsequently, a wide variety of research studies have concluded that physical activ-
ity protects against developing depression, that even low doses of physical activity
are protective and that high intensity activity protects more than low intensity activ-
ity [32].
A recent meta-analysis published in the American Journal of Psychiatry identi-
fied 49 prospective cohort studies published before October 2017 evaluating the
effect of physical activity on the incidence of depression developing in people who
were free of depression at baseline [33]. Overall, physical activity consistently pro-
tected people from developing depression in the future. This result was found
regardless of age, sex and region of the world. All but a few of the studies found a
clear dose response with frequent, higher intensity physical activity providing more
protection than less frequent, lower intensity physical activity.
The World Health Organization’s minimal physical activity level of at least
150 minutes per week of moderate to vigorous physical activity was consistently
effective in lowering the risk of developing depression. A potential limitation of
these studies is the reliance on self-reported physical activity levels even though
most of the physical activity questionnaires used were validated in separate studies.
As noted on numerous occasions throughout this book, physical fitness is not the
same as physical activity but it is a reasonable estimate of one’s overall physical
activity. Numerous studies, beginning with Morgan’s study mentioned earlier, have
shown that measures of physical fitness particularly cardiovascular fitness are a
good predictor of the likelihood of developing depression in the future.
Exercise for Treating Depression 143
In one very large cohort of 18-year old Swedish men who enlisted for military
service between 1968 and 2005, 1,117,292 men, who had no symptoms of depression
at baseline, were followed for 3–40 years for developing severe depression requiring
hospitalization [34]. All men underwent a measure of cardiovascular fitness at base-
line based on the maximum heart rate achieved on a graded cycle ergonometric test.
Cardiovascular fitness at age 18 was highly predictive of the risk of developing serious
depression in adulthood (hazard ratio ≈ 2). In other words, if you were not physically
fit you were twice as likely to develop depression than if you were physically fit.
Exercise for Treating Depression
Exercise was used to treat depression in the United States as early as the turn of the
twentieth century. A major breakthrough in our acceptance of the value of exercise
for treating depression occurred in 1999 when James Blumenthal and colleagues at
Duke University published a paper comparing the benefit of exercise versus the
selective serotonin reuptake inhibitor (SSRI) sertraline (Zoloft) in a 16-week trial
for treating depression (called the Standard Medical Intervention and Long-term
Exercise—SMILE trial) [35].
The exercise consisted of walking or jogging at 70–85% of their maximum aero-
bic fitness for 30 minutes along with a 10 min warm-up and 5 min cool down.
Surprisingly, at the end of the 16 weeks depressed patients who exercised had the
same result as patients treated with the antidepressant medication Zoloft. Nearly
half had complete recovery while only about a third had no response to either treat-
ment. The recovery began earlier in the drug treated group but the exercise group
caught up to the drug treated group by the end of the trial.
The study focused on older patients and clearly showed that it was possible to get
depressed patients motivated to exercise and that they stuck with the exercise as
well as similar aged people who were not depressed. When the patients were fol-
lowed up 6 months after the study was completed, remarkably, exercise worked
better than the antidepressant medication, only 30% of the exercise group were
depressed whereas 52% of the drug treated group remained depressed.
The implications of this study were immediately apparent and not surprisingly
there was a great deal of skepticism both by patients and physicians. Antidepressant
drugs, particularly SSRIs, are among the most prescribed drugs in the world and
side effects from these drugs are common. If the same result can be obtained by
exercise, that has many additional benefits without any significant side effects, how
can physicians justify prescribing antidepressant drugs.
An unexpected finding of the study was the lack of additional benefit when com-
bining exercise and drug treatment. The study design included 156 patients divided
equally into three study groups, exercise alone, Zoloft alone, and exercise plus
Zoloft. Patients receiving exercise and Zoloft did not receive additional benefit. The
researchers speculated that this may have been due to the fact that some of the
patients signed up for the study because they were interested in the benefits of exer-
cise and may have been negative toward taking medications.
Another potential flaw in the study was the lack of a placebo control group or a
placebo pill along with exercise in the exercise group. The authors argued that the
potential value of including a placebo control group was judged to be minimal com-
pared to the potential negative impact on those in a control group assigned to an
intervention thought to be less effective. They pointed out that prior clinical trials
for treating depression found that 20–30% percent of patients receiving a placebo
recovered about half the rate of recovery of their patients in the three study groups.
This high placebo rate does emphasize the importance of a person’s expectations
when receiving any treatment for depression. If they believe the treatment will work
it has a much better chance of success (treatment effect + the placebo effect) than if
they believe it will not work (treatment effect alone). In a few studies that used pla-
cebo pills altered to produce noticeable side effects, the response to the placebo was
not significantly different from that of the response to an SSRI pill.
The placebo effect of exercise may be even stronger than the “hyped up” placebo
pills. Exercise and placebos are known to activate the motivational/reward network
and with exercise patients feel as though they are participating in their treatment and
recovery. Even if the exercise and SSRI pill effects were all placebo effects, exercise
would still be preferable to the pill since it has other health benefits and no signifi-
cant side effects.
There have probably been more studies on the effect of exercise for treating
depression than for treating any other brain disease [36]. More than 10 systematic
reviews and meta-analyses of these studies have been published since the turn of the
century and many were high-quality randomly controlled studies comparing exer-
cise versus control groups. Overall, the studies found that aerobic exercise is effec-
tive treatment for depression with significant reduction in symptoms compared to
control groups and the benefit of exercise is comparable to that of psychological
therapies and antidepressant drugs.
Furthermore, exercise is effective at improving cardiorespiratory fitness and
improvement in fitness correlates with improvement in depression. A few studies
that used exercise as co-adjuvant therapy with an antidepressant drug found a mod-
est additional benefit of exercise on top of the drug benefit. The great majority of the
studies on exercise for treating depression have focused on aerobic exercise with
only a few including resistance training. At this point it is impossible to say whether
resistance exercise is as beneficial as aerobic exercise. Another potentially impor-
tant question is whether a skilled instructor supervising the exercise increases the
benefit. If nothing else the instructor might improve compliance with the exercise
routine.
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Chronic Pain
8
Of pain you could wish only one thing: that it should stop. Nothing in the world was so bad
as physical pain. In the face of pain there are no heroes.―George Orwell [1]
Chronic pain is generally defined as pain that lasts longer than the time it takes
for a tissue to heal, in the range of 3 months. Severe or high-impact chronic pain is
defined as a persistent pain with substantial restriction of life activities that lasts
longer than 6 months [2]. For much of recorded history, patients with chronic pain
were told to rest and avoiding activities. Only in recent times have physicians
become aware of the benefit of exercise for treating chronic pain.
Pain is unique among body symptoms since it is often a warning signal of tissue
damage. It is inherently frightening. When it is chronic, pain can become an illness
in itself and have a major impact on a person’s wellbeing. Chronic pain is the most
common somatic symptom in American society. As many as 30–40% of the general
population suffers from some type of chronic pain and many of these people take
daily pain medications [3]. The most common sites at which people experience
chronic pain are the low-back, neck and head.
In 1980 more than 10 billion dollars were spent on disability payments to
American patients with chronic pain problems. At the turn of the twenty-first cen-
tury, an estimated 100 billion dollars per year was spent on treating chronic pain and
65 billion dollars per year was lost from missed workdays due to chronic pain. In
2011, the National Academy of Medicine estimated that chronic pain costs between
560 to 635 billion dollars per year for direct medical interventions, lost productivity
and disability [4].
Not only are patients with chronic pain a massive financial burden on the health
care system and society, they personally suffer greatly and are at high risk of being
harmed from unnecessary tests, hospitalizations and surgeries.
https://doi.org/10.1007/978-3-031-13924-6_8
148 8 Chronic Pain
Perception of Pain
The International Association for the Study of Pain defines pain as “an unpleasant
sensory and emotional experience that is associated with actual or potential tissue
damage or described in such terms” [5]. For centuries physicians have debated
whether pain is a sensation or an emotion. It is both.
The prominent eighteenth century English physician, Erasmus Darwin, grandfa-
ther of Charles Darwin, argued that pain was not a special sense since it could be
produced by extreme stimulation of any of the senses including the sensations of
vision, hearing, touch, hot and cold. The eighteenth century English philosopher,
David Hartley, felt that pain was pleasure carried beyond a due limit resulting from
violent vibrations in the nerves and brain. Even after distinct pain nerves and brain
pathways were identified in the latter part of the nineteenth century, physicians and
researchers emphasized that the sensation of pain was not like the other primary
sensations.
In the mid twentieth century, the English neurologist William Gooddy pointed
out that although impulse patterns in nerves and nerve centers in the brain provide
the neurophysiological basis for pain and can influence the quality of pain, they do
not determine whether or not an individual experiences pain [6]. All agree that there
is a major psychological component to pain that is highly individual and influenced
by past experience.
Opioids and Chronic Pain
Most patients with chronic pain are given a prescription for an opioid drug at some
time in the course of their pain syndrome. Although opioids may be helpful for
acute pain particularly after injury there is no evidence that opioids are helpful for
chronic pain. Just the opposite, they can make the pain worse.
About two million people in the United States are addicted to opioids and nearly
20% of the population is given a prescription for an opioid drug every year [7].
Deaths from opioid overdose continue to increase and have been declared a national
public health emergency. Many of these deaths due to overdose occur in people
initially given a prescription of opioids for chronic pain.
In a recent controlled treatment trial, 240 patients at Veterans’ hospitals with
chronic low back, hip or knee pain were randomly assigned to receive an opioid
drug or a non-opioid pain medication (acetaminophen—Tylenol or ibuprofen—
Advil) [8]. During 1 year of follow up, participants were assessed for pain intensity,
and adverse effects of the medications. At the end of the year, people who received
the non-opioid drugs reported less intense pain while people who received opioid
drugs had more adverse effects. There is a growing consensus that opioids are not
useful for treating chronic pain.
Central Sensitization and Chronic Pain 149
Central Sensitization and Chronic Pain
Chronic pain is a disease of the brain manifested by an abnormal perception of pain.

People perceive pain even in the absence of a painful stimulus. The switch from
acute to chronic pain is a shift from tissue pathology to brain pathology. With cen-
tral sensitization, the peripheral nervous system sends more pain signals to the cen-
tral nervous system and the brain and spinal cord provide less inhibition of incoming
pain signals (Fig. 8.1).
When pain signals in peripheral nerves arrive at the spinal cord, they trigger the
release of the excitatory neurotransmitter, glutamate, which crosses the synapse to
activate secondary transmission neurons that carry the pain signals up the spinal
cord to the brain. As noted in Chap. 5, repetitive release of glutamate can lead to the
process of long term potentiation (LTP), a type of neural plasticity whereby more
glutamate receptors are expressed in the secondary neurons and new synapses are
formed between the primary and secondary neurons.
The overall effect is that secondary pain neurons become more sensitive to
peripheral pain signals—central sensitization. The process of LTP occurs in the
spinal cord and at other pain relay stations in the brain. The result is that any persis-
tent source of pain even with minor surgeries can potentially trigger central hyper-
sensitivity to pain. This explains why some surgeons recommend using local
anesthetic injections near the site of surgery in addition to general anesthesia during
Fig. 8.1 Pain signals from

peripheral receptors can Increased peripheral
lead to central sensitization pain input
to pain by enhancing pain
transmission through
spinal cord and brain
pathways and by
diminishing inhibitory Increased spinal cord
feedback pathways pain activity
Increased brain pain

activity and decreased
inhibitory feedback
Central sensitization
to pain
150 8 Chronic Pain
an operation. The barrage of pain signals triggered during surgery can potentially
lead to pain hypersensitivity and chronic pain after surgery even though the patient
is unaware of pain while under the general anesthesia.
Pain transmission at the level of the spinal cord is normally kept in check by a
descending inhibitory pathway originating in the brainstem called the descending
pain modulatory system (DPMS) [9]. The DPMS receives direct input from the
spinal cord pain transmission neurons and provides negative feedback by activating
spinal cord inhibitory interneurons. The DPMS also projects to emotional centers in
the brain (the limbic system) and receives feedback from that system modulating
the emotional reaction to pain.
Endogenous opioids (endorphins) are the main neurotransmitter within the
DPMS and the DPMS has the largest number of opioid receptors in the brain. The
DPMS provides a mechanism for multiple factors to influence pain sensitivity. It is
suppressed by stress, depression and anxiety and activated by opioid drugs, relax-
ation techniques, exercise, acupuncture and placebo treatments.
If you believe a pain treatment will work, the DPMS is activated, endorphins
are released, and the pain is relieved. The DPMS also plays an important role in
stress-induced analgesia. In 1946 the American anesthesiologist Henry Knowles
Beecher described how the majority of soldiers that he treated during WW II
with major injuries such as compound fractures and penetrating wounds of the
chest reported slight or no pain and did not ask for pain medication [10]. He
speculated that the strong emotions associated with the injuries somehow sup-
pressed the pain.
Similarly athletes who suffer severe injuries in sport often do not experience pain
until the game is over. From an evolutionary perspective reduction in pain during
extreme but brief stress makes sense since it allows an animal to react as if there
were no pain improving chances of survival. The opposite effect where chronic
stress and anxiety suppress the DPMS and increase pain sensitivity is maladaptive
but commonly occurs with chronic pain disorders.
A variety of neurotransmitters modulate the degree of central sensitization
and provide a mechanism for stress and psychological factors to influence the
sensitization process. For example, endogenous opioids activate interneurons
that release the main inhibitory neurotransmitter, GABA, decreasing excitatory
transmission.
The monoamines, noradrenaline, serotonin and dopamine modify excitatory and
inhibitory transmission throughout the brain’s pain pathways and endocannibinoids
modulates the release of all three of these transmitters. Slight genetic variations in
these transmitter proteins and/or their receptors can increase susceptibility to
chronic pain.
Exercise has been shown to reverse many of the molecular and cellular changes
in the spinal cord and brain that occur with central sensitization and chronic pain.
For example, exercise enhances neuroplasticity and the release of serotonin, nor-
adrenaline and dopamine all of which can suppress chronic pain [11]. In healthy
people exercise initiates the release of endogenous opioids in the DPMS causing
exercise-induced analgesia [12]. Unfortunately, in some chronic pain syndromes
Overview of Exercise for Chronic Pain 151
exercise induced analgesia is diminished, at least initially when beginning exercise,

so exercise programs should be started slowly with gradually increasing levels over
weeks to months.
Inflammation and Chronic Pain
Both local and systemic inflammation can initiate central sensitization and chronic
pain [13]. Studies in patients with chronic pain show a shift in the balance of pro-
and anti-inflammatory cytokines causing tissue pain receptors to become hyperac-
tive with lowered threshold for activation. This amplified input from tissues can
initiate central sensitization as described in the prior section.
Lack of physical activity tips the balance in inflammatory cytokines to pro-
inflammatory cytokines whereas exercise does just the opposite. By increasing anti-
inflammatory cytokines, exercise can prevent and even reverse the process of central
sensitization. In order to achieve the anti-inflammatory effect exercise needs to be
persistent on a regular basis even if low intensity.
Chronic Pain and Fear Avoidance
It is natural for people to think of pain as a warning sign of some underlying health
condition. Pain signals arriving in the brain activate areas deep in the brain involved
in emotions such as fear and anxiety. Patients with chronic pain often develop a fear
of movement believing that any kind of movement will aggravate the pain. This
leads to inactivity that further compounds the problem.
A combination of exercise and cognitive behavioral therapy can help patients
overcome these inaccurate beliefs and improve chronic pain. The goal of the ther-
apy is to expose them to feared movements with a gradual exercise program and
convince them that their pain is cognitively mediated and not a danger signal. By
exposing them to movements in a controlled and supervised setting they become
desensitized to the previously feared movements. Exercise can help reverse the vis-
cous cycle of fear avoidance and pain catastrophizing commonly seen with
chronic pain.
Overview of Exercise for Chronic Pain
In recent years, there have been a large number of publications in the scientific lit-
erature documenting the benefit of exercise for chronic pain associated with a wide
variety of medical and neurological conditions. Since low back pain, neck pain and
headache are the most common chronic pain syndromes, they tend to be the focus
of the most studies. Overall, exercise has been shown to decrease the severity of
pain with each of these syndromes and inactivity has been shown to be a major risk
factor for developing the syndromes (discussed later in this chapter).
152 8 Chronic Pain
Despite the evidence for exercise as a promising treatment for chronic pain,
implementation of exercise programs has lagged behind pharmacological treat-
ments for chronic pain particularly in some of the highest risk populations such as
older women, people with multiple preexisting disorders and ethnic and minority
populations.
In 2017, researchers in Scotland published an overview of all the prior published
meta-analysis reports on the effect of exercise on chronic pain [14]. They identified
21 reviews that included 264 studies (19,642 participants) that compared the effect
of exercise versus a control group without exercise for management of chronic pain.
A wide range of chronic pain syndromes were studied including low back and neck
pain, arthritis and fibromyalgia. Interventions ranged from aerobic, strength and
flexibility exercises to yoga, Pilates and ta chi. They concluded that exercise consis-
tently had a significant mild to moderate benefit in reducing the severity of chronic
pain along with improving overall physical and mental health.
At the same time there was no evidence of any harmful effects of exercise on
patients with chronic pain. Some participants reported initial increased muscle sore-
ness and pain but that subsided after a few weeks of regular exercise. The main limi-
tations of the studies were small numbers of participants per study (most had fewer
than 50 participants) and the length of follow up (rarely beyond 6 months). Since
each chronic pain syndrome has unique clinical features with different underlying
mechanisms it is important to examine the benefit of exercise on specific syndromes.
Chronic Low Back Pain
With the industrialization of Western societies in the early twentieth century, chronic
back pain and disability at work were increasing at an alarming rate. Industries
attempted to hire workers who were physically fit and working practices were modi-
fied to minimize back strain. With recruiting for the First World War, the military
questioned whether development of back pain might be a fitness problem rather
than a medical problem and developed special units to improve fitness for the many
men who developed back pain during training exercises [15].
In the Second World War, chronic low back pain became the most common cause
for hospitalization and withdrawal from active duty in soldiers [16]. At that time the
concept of fibrositis, an inflammation of the fibrous tissue of the back, became pop-
ular to explain chronic low back pain. Fibrositis was also used to explain other
chronic work related injuries to the neck and extremities and later more generalized
body pain that evolved into the concept of fibromyalgia. After the Second World
War, a large medico-legal industry developed around the concept that chronic back
pain due to repetitive trauma was a major cause of disability and that rest was the
best treatment. This occurred even though evidence of back injury could not be
identified in most cases and rest didn’t seem to help.
In the mid twentieth century, the notion that low back pain was commonly caused
by degenerative changes in the spine became popular in both the lay and medical
communities. Each intervertebral disc contains a gelatinous center surrounded by a
Current Approach to Treating Chronic Low Back Pain 153
fibrous band, which in turn is surrounded by a strong ligament [17]. With trauma
and aging, degenerative arthritic changes occur in the gelatinous center and the sur-
rounding fibrous disc. The gelatinous center slowly degrades from a resilient gel to
a hardened substance.
Disc protrusions (where the gelatinous center bulges through the fibrous disc but
is held in check by the annular ligament) occur in more than 50% of normal people,
particularly in the low back region. Pain can result from activation of nerve endings
in the outer ligament, compression of a spinal nerve, or an inflammatory response
triggered by chemicals released from the bulging disc.
But what was the relevance of these degenerative changes in the vast majority of
people with chronic low back pain? As better imaging became possible first with
computed tomography (CT) and then magnetic resonance imaging (MRI) it became
apparent that everyone has degenerative changes in the spine and that the degree of
the degenerative changes did not correlate with the severity of back pain [18].
Making matters even worse, the number of back surgeries for chronic low back pain
was increasing exponentially while the number of patients with chronic low back
pain was also increasing at an alarming rate.
Current Approach to Treating Chronic Low Back Pain
Nearly everyone experiences low back pain at some time so not surprisingly, the
impact on overall health care costs and costs to individuals are considerable [19]. A
definitive diagnosis is possible in only about 15% of people with low back pain;
most are labeled as non-specific low back pain (NSLBP) [20]. This is a real problem
for the wide variety of medical disciplines that deal with these patients. How do you
treat a condition when the cause is unknown?
At the present time most physicians recommend a conservative approach—keep
active, continue with regular activities as much as possible, and use pain medica-
tions as little as possible [21]. There is general agreement that bed rest should be
avoided as much as possible. With an acute injury, management should focus on
getting the person mobile as quickly as possible.
Manual therapies such as traction and back manipulations are commonly used
but there are no definitive clinical trials proving that these treatments are more effec-
tive than conservative management for NSLBP. Several clinical trials have con-
cluded that traction is of no benefit even in patients with objective evidence of nerve
root impingement.
Another dilemma with NSLBP is whether or not to image the low back. Routine
x-rays are rarely useful. CT and MRI are more useful but the increased sensitivity
can be a problem since ubiquitous “disc disease” often has nothing to do with the
patient’s symptoms [22]. Surgery on the back, particularly when the indication for
surgery is not absolutely clear, is a major risk factor for developing chronic low
back pain.
Since chronic low back pain is often resistant to treatment, patients become frus-
trated with traditional medical care and seek alternative treatments. Most patients
154 8 Chronic Pain
can accept the uncertainty of diagnosis but it is critical that they perceive that they
are being taken seriously [23]. NSLBP has many risk factors. A kind of priming of
the pump occurs such that people that have had pain experiences in the past are
more susceptible to developing chronic pain.
Psychosocial factors play a critical role in determining whether or not one devel-
ops chronic low back pain. Social networks, level of routine activity and expecta-
tions all affect the risk for developing chronic back pain. Numerous studies have
found a high rate of comorbidity of depression, somatization, anxiety and stress in
patients with chronic low back pain [24]. Finally, variations in genes that code for
key proteins within the brain pain pathways have been shown to increase pain sen-
sitivity in humans and in several animal models [25].
There is convincing evidence that regular physical activity, whether a structured
exercise program or exercise associated with leisure activities decreases the risk for
developing chronic low back pain [26]. On the other hand, “Catastrophising”,
avoiding physical activity and always expecting the worst, increases the disability
associated with chronic back pain (the so-called nocebo effect, the opposite of the
placebo effect). If one anticipates a catastrophic consequence of an activity such as
exercise one will avoid the activity.
People need constant reassurance that activities such as exercise are not causing
their chronic low back pain. Just the opposite, inactivity is a major risk factor for
developing chronic low back pain [27].
Since pain normally signals impending danger or harm it is not surprising that
patients with pain might avoid activities such as exercise that can induce or exacer-
bate pain. While this may be an appropriate reaction to acute pain, fear-avoidance
behavior can lead to increased disability with chronic low back pain. Muscles
become weak, joints become stiff and bones become thinner. Regular exercise is
absolutely necessary for successful living with chronic low back pain. Although any
exercise is better than none, a combination strengthening and stretching of the back
muscles along with aerobic exercise three times per week is recommended.
Exercise for Treating Chronic Low Back Pain
Since chronic low back pain is so common and since in most cases no cause can be
found, there have been many controlled studies on the effect of exercise on NSLBP,
probably more than any other medical condition. The bottom line is that exercise is
clearly better than inactivity for managing NSLBP. A range of exercise techniques
have been assessed (yoga, tai chi, Pilates, aerobic, strengthening and flexibility) and
all show a significant benefit with minimal risks. Direct comparisons between dif-
ferent exercise routines are rare so it is difficult to be certain of the best regimen.
A comprehensive review published in 2016 focused on studies of aerobic,
strengthening and flexibility exercise for treating NSLBP and found that all three
types of exercise are beneficial [28]. Since NSLBP is a heterogeneous condition
with multiple causative factors, a general exercise program combining aerobic,
muscle strengthening and flexibility exercise is the best overall choice. Since any
Current Approach to Treating Chronic Neck Pain 155
type of exercise is better than no exercise, individuals with NSLBP should select the
exercise routine that they are most comfortable with and stick with it so that it
becomes part of their daily routine.
Brisk walking is a non-specific type of exercise that improves aerobic fitness,
stretches the back and pelvis and improves strength in the large muscles of the back
and lower extremities [29]. Research studies suggest that walking can be as effec-
tive as more formal exercise for reducing pain and improving function in patients
with NSLBP in some patients. For best results, back stretching exercises are per-
formed prior to walking. Overall walking programs show similar patient satisfac-
tion and compliance as other exercise regimens. Some studies suggest that patient
participation in walking programs is enhanced by using devices to monitor effort
and performance or in supervised sessions. There is the added benefit that no special
exercise equipment is required.
Chronic Neck Pain
Chronic neck pain is an extremely common musculoskeletal disorder that often

leads to long-term disability. More than 50% of adults experience neck pain every
year and the prevalence of chronic neck pain is steadily increasing [30, 31]. Women
are almost twice as likely to have chronic neck pain as men. The neck pain interferes
with work in about 3% of people and interferes with social activities in about 5%
of people.
People who work for long periods of time performing monotonous tasks or sit-
ting at a desk with the neck constantly flexed are particularly vulnerable to develop-
ing chronic neck pain. Acute neck pain after injury such as a whiplash injury can
evolve into chronic neck pain particularly if the neck is immobilized for long peri-
ods of time or the person is inactive. Patients with chronic non-specific neck pain
often have associated chronic non-specific low back pain and chronic headaches
suggesting that these chronic pain disorders tend to cluster in certain individuals.
Current Approach to Treating Chronic Neck Pain
As with chronic back pain, no evidence for musculoskeletal damage can be identi-
fied in the vast majority of people with chronic neck pain. Most undergo imaging of
the neck including standard x-rays, CT and MRI but these tests are rarely helpful for
a diagnosis. Despite the lack of effectiveness of these imaging techniques, patients
have high expectations of modern technology and often visit multiple physicians
requesting repeat imaging year after year.
Evidence for a beneficial effect of pain medications for chronic neck pain is
extremely limited even though most patients are usually given pain medications
including opioids at some time in the course of the disorder. As with low back pain,
these medications may be helpful for acute neck pain particularly after injury but
often worsen chronic neck pain. Tranquilizers and antidepressant medications
156 8 Chronic Pain
provide relief in a small subset of patients with chronic neck pain probably in those
with the common co-morbidities of anxiety and depression. Heat and massage, spi-
nal manipulations and ultrasound treatments are commonly used for treating chronic
neck pain but convincing statistical support for efficacy of any of these treatments is
lacking.
In recent years it has become apparent that immobilizing the neck for long peri-
ods of time is counter productive and can aggravate chronic neck pain. Treating
chronic neck pain with a soft collar is a formula for disaster. Patients with chronic
non-specific neck pain need to move the neck though a full range of motion on a
regular basis.
Exercise for Treating Chronic Neck Pain
Compared to exercise for chronic low back pain the number of studies of exercise
for treating chronic neck pain are relatively few. Most studies focused on exercises
for the neck and upper body although a few also included whole body aerobic exer-
cise. Examples of muscle strengthening exercises include: using elastic bands in the
sitting position to perform 80% maximum voluntary isometric contraction of the
neck for 15 repetitions and using heavy dumb bells to strengthen the shoulders, neck
and upper body performed with high intensity and low repetitions. Endurance train-
ing includes: repetitive lifting of the head from a bed in the lying position and lifting
low weight dumb bells 20 times per set for three sets.
Overall the studies found that strengthening and endurance exercises signifi-
cantly improved pain and functional mobility compared to control groups who were
told to stretch and exercise the neck but did not undergo a structured exercise pro-
gram [32]. One review compared the benefit of a short term exercise programs
(10–12 weeks) with long term programs (at least a year) and found that short term
programs improved symptoms and function immediately after the program was
completed but not at a 1 year follow up [33]. By comparison, long-term interven-
tions resulted in long term improvement for at least 3 year of follow up. For exam-
ple, in one study patients trained in a rehabilitation center for 12 days and then
independently performed the exercises at home for 12 months. The authors specu-
lated that the reason the benefits lasted for 3 years was that the patients either devel-
oped an exercise habit or they independently restarted exercises in response to
recurrent neck pain.
As with chronic low back pain, aerobic exercise and the associated improvement
in fitness can provide additional benefits to localized strengthening and stretching
exercises. A recent controlled trial of a combination of aerobic exercise and strength-
ening exercises for chronic neck pain found that aerobic exercise improved long-
term pain relief and functional recovery better than strengthening exercises alone
[34]. Patients were randomly assigned to two groups, one receiving supervised
neck-specific exercises at a physical therapy center and the other a combination
neck-specific exercises and aerobic exercise twice a week. The neck exercises were
performed with resistance elastic bands with gradual increasing resistance from
Headaches 157
light to heavy. Once a patient could perform 30 repetitions with a 3-s hold at the end
range they moved on to the next level of resistance. Aerobic exercise consisted of
cycling at 60% of the age-predicted maximum heart rate for 20 mins during the first
week, 30 minutes during the second week and 45 minutes during the third and
remaining 6 weeks.
At the end of the 6-week formal intervention, both groups were given instruc-
tions to perform similar neck-specific exercises 3 times a week at home. The aerobic
exercise group was told to walk or cycle for at least 30 mins at moderate intensity at
least 3 days a week in addition to the neck-specific exercises. Pain intensity was
assessed immediately after the supervised sessions and at 3 and 6 months follow
up visits.
Interestingly, there was no significant difference in pain intensity in the two
groups at the initial assessment but the group that performed aerobic exercise had
significantly less pain at the 3 and 6 months follow up visits compared to the group
that just performed neck-specific exercises. Since prior studies have shown that it
takes a few months for aerobic exercise to improve cardiovascular fitness, the
delayed effect of aerobic exercise was probably due to the delayed improvement in
fitness. This finding suggests that in order to be effective, aerobic exercise must be
frequent and intense enough to improve fitness.
Finally, a few practical considerations based on clinical experience. Since people
who spend long periods of time sitting with their neck flexed are more likely to
develop chronic neck pain, a few simple measures such as elevating a computer or
reading material to eye level and sleeping with a thin pillow or neck pillow can be
very helpful. People who work at repetitive tasks for long periods of time need to
take breaks by getting up and moving about if just for a minute or so. Those with a
combination of chronic low back and neck pain can mount reading material or com-
puter at eye level and work while standing.
Headaches
As with back pain, just about everyone has experienced a headache at some time in
their life and in many headaches are chronic and disabling. There are two common
primary headache disorders: tension-type headaches and migraine headaches. Both
of these headache disorders can become chronic and occur daily, particularly when
pain medications are used daily, producing so-called medication overuse headache.
Chronic neck pain and chronic tension-type headaches commonly occur together.
Primary headache disorder means that the headaches are a primary illness and
not due to some other neurological disorder. Although there are several differences
between the two types of headaches, the main difference is pain severity, migraine
headaches are typically more severe and restrict activities more than tension-type
headaches. But both types of headache can be disabling and lead to lost workdays.
Migraine headaches are often throbbing and one sided and are associated with
nausea and/or light and sound sensitivity, whereas, tension-type headaches are on
both sides, described as pressing or tightness and are not associated with nausea and
158 8 Chronic Pain
usually do not have light or sound sensitivity. Both types of headaches can last from
hours to days although tension-type headaches tend to be shorter in duration.
Finally, both types of headaches can occur in the same person and both are triggered
by a variety of biological and psychological factors.
Tension-type headaches are the most common type of headache with a lifetime
prevalence of about 70% in men and 90% in women so just about everyone has had
one at some time. By contrast, the lifetime prevalence of migraine headaches is
about 5% in men and 15% in women.
Medication overuse headache is caused by mistreatment of tension-type or
migraine headaches; it does not occur separately. About 75% of cases of medication
overuse headache occur in people with migraine while about 25% occur in people
with tension-type headaches.
Because of the high prevalence of tension-type headaches the overall cost and
disability in society is about the same for tension-type headaches and migraine
headaches even though migraine headaches are typically much more severe. In one
population study, patients with tension-type headaches reported an average of nine
lost work days and 5 days in which they experienced decreased efficiency every
year. In a European study on the global burden of disease, migraine was the number
one cause of disability in the age group 15–49, a timeframe many would consider
the most productive years in a person’s life [35].
The most conspicuous precipitating factor for both tension type and migraine
headaches is stress. Other common triggers are alcohol, caffeine withdrawal,
weather (barometric) changes and menstruation. Sleep disturbances are common
with both types of headaches. Improvement of the headache during pregnancy is
more frequent with migraine than with tension-type headaches.
Depression is tightly interrelated with both migraine and tension type headaches.
As with chronic low back pain, there is a bidirectional relationship between migraine
and depression; people with depression are at increased risk of developing migraine
headaches and people with migraine headaches are at increased risk of developing
depression. This observation suggests that there is a shared mechanism for these
common disorders. The relationship of depression and tension-type headaches is
more complex but clearly there is an increased incidence of depression in patients
with chronic tension-type headaches (15 or more days of headaches a month).
Tension-type headache sufferers have central sensitization to pain in cranial tissues
and depression further increases the central sensitization to pain [36].
Exercise for Tension-Type Headaches
There is a parallel in the studies of exercise for treating chronic neck pain and
tension-type headaches. Most of the studies included patients with both chronic
neck pain and tension-type headaches and most focused on strengthening the neck
and upper body with a few including aerobic exercise. Both neck strengthening
exercise and aerobic exercise has been shown to decrease the frequency and severity
of tension-type headaches in controlled treatment trials [37, 38].
Exercise for Treating Migraine Headaches 159
Since the main trigger for tension-type headaches is stress, exercise may work by
relaxing head and neck muscles. Anecdotal reports suggest that exercises that com-
bine physical activity with relaxation techniques such a yoga and tai chi are particu-
larly effective in reducing headache frequency and severity. One study treated
patients with chronic tension type headaches with exercise, acupuncture or relax-
ation techniques and found comparable reduction in headache frequency and inten-
sity in all three groups [39].
Another study looked at the effect of aerobic exercise on patients with migraine
who had co-existing tension-type headaches and chronic neck pain (also common)
[40]. The aerobic exercise consisted of 45 mins on a bike or cross trainer or with
brisk walking three times a week. Controls just continued with routine activity. The
exercise group had a significant improvement in physical fitness and significantly
reduced tension-type headaches and neck pain. There was a trend toward reduction
in Migraine headache frequency and pain but the difference was not significant
compared to controls.
Exercise for Treating Migraine Headaches
The relationship between exercise and migraine headaches is more complex than
the relationship between exercise and tension-type headaches since there are clear
examples of where exercise can trigger a migraine-like headache or make a migraine
headache worse. On the other hand, controlled treatment trials consistently show
that patients with migraine headaches who exercise regularly have less frequent and
less intense migraine headaches than patients with who do not exercise. This is not
that surprising since many of the same neuromodulators (neurotransmitters and
neurotrophic factors) involved in the cause of migraine headaches are influenced by
aerobic exercise. Likely, patients with migraine headaches respond differently to
exercise if it occurs during or just before a headache when they are “primed” to
develop a headache or if it occurs during the baseline state.
The International Headache Society includes a category of headaches, primary
exertional headaches (PED) in their headache classification characterized by a pul-
sating headache, lasting 5 mins to 48 h, brought on by and occurring only during or
after physical exertion [41]. The headaches also typically had other migraine symp-
toms including phonophobia, photophobia, nausea and vomiting. The exertional
headaches were particularly common in adolescents commonly induced during
track and field, ball sports and swimming. Complicating the classification, about
50% of adolescents with exertional headaches also had typical migraine headaches
at other times unassociated with physical exertion.
About one in five patients with migraine headaches list exercise as a trigger for
their headaches [42]. An obvious question is: are the headaches induced by physical
exertion or is it some other factor associated with exercise such as overheating and
dehydration? Warm up and cool down with exercise may be an important factor
[43]. For example, a 26 years old women experienced occasional migraine head-
aches after a strenuous swim without warm up but after being instructed to always
160 8 Chronic Pain
warm up before a swim she did not have a migraine headache for several months.
She then tried to swim without warming up and again suffered a migraine headache.
On the other hand, some people find that if they exercise when they feel a
migraine headache coming on they can abort the headache [44]. A 43 years old
exercise instructor noted that she could abort her typical migraine headache by run-
ning during the prodromal phase. Aerobic exercise is known to inhibit pain through
release of a variety of substances including endorphins, endocannabinoids, neuro-
trophic factors and anti-inflammatory factors [45].
A meta-analysis of published controlled treatment trials found an overall signifi-
cant benefit for aerobic exercise in reducing the severity, frequency and duration of
migraine headaches [46]. The possibility of triggering a migraine headache can be
ameliorated by gradually increasing the intensity and duration when beginning the
exercise program [47].
Fibromyalgia
Fibromyalgia is a chronic pain syndrome characterized by generalized sensitivity to

pain. For centuries pain involving muscles and joints was called rheumatism. In the
early nineteenth century, the Scottish physician, William Balfour, suggested that
inflammation of the fibrous connective tissue of muscle was the cause of general-
ized muscle pain [48]. He was the first to describe focal muscle tenderness, tender
points, where mild pressure caused pain and discomfort.
Others suggested that muscle pain resulted from hyperactive nerve endings or
exudates from abnormal muscle vasculature. In the late nineteenth century, the
American Neurologist, George Beard included generalized pain along with fatigue
and a variety of other somatic symptoms in his neurasthenia syndrome which he
attributed to the stress of modern living.
At the beginning of the twentieth century, the famous English neurologist, Sir
William Gower, described a new syndrome called fibrositis characterized by spon-
taneous generalized pain, sensitivity to muscle compression, chronic fatigue and
sleep disturbance, the basic features of modern day fibromyalgia. Gower noted that
the anti-inflammatory drug aspirin was of little use in treating the condition and he
recommended heat, massage, and local cocaine injections (for local anesthesia).
During World War I and II, fibrositis was a common diagnosis among the soldiers
and considering the absence of inflammation and its association with stress and
depression, some called it psychogenic rheumatism. The debate as to whether fibrosi-
tis (fibromyalgia) is an organic or psychogenic illness persists up to the present time.
Tender Points
The modern syndrome of fibromyalgia was shaped by a series of publications by the

Canadian rheumatologist Hugh Smythe in the 1970s [49]. Smythe described fibro-
myalgia as a generalized pain syndrome associated with fatigue, sleep impairment,
Tender Points 161
and emotional distress and he emphasized the importance of tender points for mak-
ing the diagnosis. Investigators as far back as Balfour noted the presence of tender
points but Smythe made them part of the diagnostic criteria.
Tender points are pain sensitive areas typically where muscle tendons insert near
a joint. Slight pressure in these areas causes pain so that the person flinches and
pulls back. These tender points seem to be just below the skin and are scattered
throughout the body in circumscribed areas in the neck, back, elbows, knees, chest
and buttocks. Smythe initially required the presence of 12 tender points in 14 pre-
determined sites whereas later criteria for fibromyalgia of the American College of
Rheumatology required only 11 tender points in 18 predetermined sites.
In essence, the presence of a high percentage of tender points was thought to be
key to recognition and acceptance of the syndrome [50]. What do tender points
represent and what are they telling us about the cause of fibromyalgia? Smythe sug-
gested that the tender points were part of a deep tissue hyperalgesia (hypersensitiv-
ity to pain) and that they might originate from bone rather than muscle or tendons.
But are tender points specific for and diagnostic of fibromyalgia? Here is where
things get confusing. A study comparing 50 patients with fibromyalgia and 50
healthy normal subjects published in 1981 is frequently quoted as proof that tender
points are specific for fibromyalgia [51]. The number of tender points in the patients
with fibromyalgia was significantly greater than the number in the control subjects.
But by definition patients with fibromyalgia must have tender points and in order for
control subjects to be considered healthy they likely won’t have tender points.
Patients with fibromyalgia are aware of the locations of the expected tender
points and the importance of the tender points in the diagnosis. Furthermore, several
other diagnoses were more common in the patients with fibromyalgia than the
healthy controls including chronic fatigue syndrome, irritable bowel syndrome, pri-
mary dysmenorrhea, tension-type headaches and migraine headaches [52]. Others
soon pointed out that there was an overlap between fibromyalgia and several other
psychogenic illnesses including panic disorder, depression, bulimia and obsessive
compulsive disorder and that tender points were common in patients with these ill-
nesses as well [53].
This set up a classic battle between the lumpers and the splitters. The splitters
feel that fibromyalgia is a unique symptom profile with the specific finding of tender
points while the lumpers consider fibromyalgia to be part of a disease spectrum with
overlapping symptoms and findings initially called “affective spectrum disorder”.
Most physicians agree that there are major psychosocial factors involved in the
cause of fibromyalgia. But like with all illnesses, biological factors are also impor-
tant including genetic susceptibility variants, earlier life experiences with illness
and pain and hormonal changes associated with stress.
Since the pain with fibromyalgia is as severe as any organic cause of pain, one
might reasonably ask: is there a difference between psychogenic and organic pain?
Based on current understanding of brain pain mechanisms, the answer is no, there
is no clear boundary between “organic” and “psychogenic” pain. With chronic pain,
regardless of the cause, chemical and structural changes occur in brain pain path-
ways producing “central sensitization” (discussed earlier in the chapter).
162 8 Chronic Pain
Complicating matters further, organic factors such as infection and injury can initi-
ate pain and psychosocial factors such as fear and stress can determine whether it
resolves or becomes chronic.
Exercise for Treating Fibromyalgia
Despite the large number of controlled treatment trials of exercise for fibromyalgia
recent meta-analysis reviews have concluded that the quality of the trials was low
and they did not provide definitive conclusions [54–56]. Problems with the studies
included: short duration of exercise treatment and follow up, lack of details about
exercise quantity and quality, and highly variable outcome measures. The maximum
length of training was 12 weeks and patients with fibromyalgia often reported dif-
ficulty staying on the exercise routines. None of the trials looked into strategies to
help patients stay on the exercise routines.
Overall the studies found that there was no evidence that exercise worsened the
condition or produced significant side effects. As a rule, patients who exercised
improved physical fitness and reported improved subjective measures of quality of
life compared to those who did not exercise but there were mixed results regarding
improvement in chronic pain. As to the best type of exercise, aerobic exercise
showed the most benefit in the largest number of studies but a few found that a
combination of aerobic exercise along with strengthening and stretching exercises
may provide additional benefit. Clearly, well designed studies with long term follow
up are needed for more definitive conclusions.
Since there is a lack of definitive research data, physicians and patients must take
a common sense approach to the use of exercise for treating fibromyalgia. As sug-
gested earlier, patients with fibromyalgia often have a natural reluctance to exercise
for fear that it will aggravate their pain. This fear can be overcome by beginning
exercise very slowly initially with short periods of light exercise such as leisurely
walking for a few minutes. The exercise should be very gradually increased in inten-
sity with an ultimate goal of reaching moderate intensity exercise such as a brisk
walk two or three times a week. There will be good days and bad days but persis-
tence is the key to long-term benefit.
Water exercises can be good to start with since they can improve strength and
balance while reducing weight-bearing stress on joints. Exercising in warm water
also relaxes muscles which can reduce pain. Exercises such as yoga and tai chi that
combine slow movements, deep breathing and relaxation techniques are usually
well tolerated by patients with fibromyalgia and have the added benefit of relieving
stress, an important trigger for fibromyalgia symptoms.
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Cerebrovascular Disease
9
It does not matter how slowly you go as long as you do not stop. Confucius [1]
Strokes and heart attacks are the leading cause of morbidity and mortality in the
world. There are obvious similarities between the two conditions (most strokes and
heart attacks are due to blockage of arterial blood supply) and both disorders share
common risk factors (obesity, type II diabetes, hypertension, stress, inactivity and
hyperlipidemia). The blockages are usually due to atherosclerosis, a deposit of lip-
ids that form plaques in larger arteries and arteriosclerosis, a stiffening and thicken-
ing, primarily seen in smaller arteries.
The most common cause of both heart attacks and strokes is atherosclerosis
whereas arteriosclerosis is a much more common cause of stroke than heart attacks.
A small artery blockage in the heart has a relatively minor impact on overall heart
muscle function whereas a small artery blockage in the brain can have a major func-
tional impact if the artery happens to supply a critical brain region such as a key
fiber tract or neuronal center.
Although there are many similarities between coronary artery disease and cere-
bral artery disease, prevention and treatment of strokes have lagged behind preven-
tion and treatments of heart attacks. One obvious reason for this relative lack of
progress in managing strokes is that the brain and it’s vasculature are much more
complex than the heart and it’s vasculature. The heart is a muscle with relatively
homogeneous architecture throughout and uniform function whereas the brain has
extremely variable architecture and a wide range of functions.
The heart is supplied by three main arteries with relatively little overlap whereas
the brain is supplied by four main arteries that interconnect at the base and form
multiple branches many of which overlap for collateral circulation. Strokes can
present with such variable symptoms and signs as paralysis (one or both sides),
language disturbance, incoordination, cognitive and memory impairment, behav-
ioral changes and altered levels of consciousness. By comparison heart attacks pres-
ent with relatively few symptoms and signs including chest pain, shortness of
breath, weakness and altered levels of consciousness.
https://doi.org/10.1007/978-3-031-13924-6_9
168 9 Cerebrovascular Disease
Most people are aware of the urgency of dealing with early symptoms of a heart
attack whereas many don’t recognize early symptoms of a stroke. Doctors have only
recently emphasized the importance of rapid response when dealing with a stroke.
Procedures such as stenting and bypass surgery that have been remarkably effec-
tive for treating heart attacks have had a limited impact on treating strokes.
Intravascular injection of thrombolytic agents (drugs that dissolve clots) is the first
major breakthrough for treating acute strokes. However, to be effective the injection
must be done within a few hours of onset of the stroke and there is a risk of bleeding
into the area of infarction.
Despite the large body of evidence showing that exercise is as effective for man-
aging patients with strokes as for managing patients with heart attacks, neurologists
have lagged far behind their cardiology colleagues in prescribing exercise for the
prevention and treatment of cerebrovascular disease.
Cerebral Blood Flow and Exercise
As noted in Chap. 1, the human brain uses about 20% of total oxygen consumption
at rest despite the fact that it represents only about 2–3% of the total body mass. The
brain consumes this large amount of energy despite the fact that it lacks any mean-
ingful energy storage. Therefore, the brain is entirely dependent on changes in blood
flow to meet its changing energy needs.
The main regulators of cerebral blood flow are; arterial blood gases (carbon diox-
ide and oxygen), brain metabolism, blood pressure, cardiac output, and innervation
of the cerebral vasculature (Fig. 9.1) [2, 3]. Cerebral blood flow is extremely sensi-
tive to changes in blood carbon dioxide levels increasing approximately 3–5% with
nCO2
nCardiac
output pO2
nNitric
nBlood
oxide
pressure CBF
nAutonomic pGlucose
nervous activity n Lactate
CBF Cerebral blood flow
Fig. 9.1 Exercise influences cerebral blood flow (CBR) through multiple mechanisms
Cerebral Blood Flow and Exercise 169
each millimeter of mercury increase in carbon dioxide. Drops in blood oxygen

(such as in high elevations) also lead to increased cerebral blood flow but the effect
is relatively small until oxygen levels become critically low.
The brain extracts glucose and oxygen from the blood and in the process of
metabolism converts these molecules to lactate and carbon dioxide which in turn
controls regional blood flow as neural activity increases and decreases in different
areas. There is a longstanding myth in neurological teaching that cerebral blood
flow is insensitive to changes in systemic blood pressure, so-called cerebrovascular
autoregulation. However, cerebral blood flow is related to systemic blood pressure
although there is a part of the curve where cerebral blood flow is relatively main-
tained regardless of blood pressure and the slope of increasing blood flow with
increasing blood pressure is less steep than the slope of decreasing blood flow with
decreasing blood pressure.
The relationship between cardiac output and cerebral blood flow is complex
because many of the same factors (e.g. carbon dioxide, metabolism and blood pres-
sure) control both processes. As a ballpark figure, a 30% drop in cardiac output
leads to about a 10% drop in cerebral blood flow.
The notion that cerebral arteries are under neural control dates back to Thomas
Willis in the seventeenth century. Willis was an alchemist and physician who per-
formed some of the first detailed dissections of the human brain. The “circle of
Willis” refers to the joining of arteries at the base of the brain that helps provide
collateral circulation to the brain when an arterial blockage occurs. Subsequent
studies have shown that small and large arteries throughout the brain receive a rich
autonomic nerve supply (sympathetic and parasympathetic) which controls cerebral
blood flow by constricting and relaxing smooth muscle in the walls of the arteries.
With exercise, the cardiovascular system is challenged with the difficult task of
providing markedly increased blood flow to active musculature while still maintain-
ing adequate blood supply to vital organs such as the heart, lungs and most impor-
tantly the brain [4]. The brain requires as much as 30% increased blood flow to
maintain neural and hormonal circuits that are activated during exercise. Skeletal
muscle requires up to twice the resting blood flow.
In order to provide the increased blood flow to muscle and brain with exercise,
whole-body oxygen consumption, arterial blood pressure, heart rate, cardiac output,
respiratory rate, and metabolism all increase (Fig. 9.1). The arterial carbon dioxide
levels increase based on pulmonary ventilation which is determined primarily by
exercise intensity. In addition, the balance between sympathetic and parasympa-
thetic autonomic neural control of the cerebral arteries is altered to redistribute
blood flow.
The change in cerebral blood flow during exercise is biphasic with a gradual
increase in blood flow with increasing exercise intensity until approximately 60%
maximum oxygen uptake and then a plateau and even a slight decrease at high
intensity levels. Of the various factors that regulate cerebral blood flow mentioned
above, the main factor determining cerebral blood flow during exercise is arterial
carbon dioxide level which is controlled by metabolism, ventilation rate and exer-
cise intensity.
Types of Strokes
Strokes can be divided into two broad categories: ischemic stroke due to blockage
of blood flow and hemorrhagic stroke due to bleeding either into the brain itself or
into the spinal fluid surrounding the brain causing subarachnoid hemorrhage.
Infarction refers to the area of brain damaged by an ischemic stroke. A transient
ischemic attack is an ischemic episode that clears within 24 h and leaves no evi-
dence of structural brain damage.
This chapter will focus on ischemic stroke since it is by far the most common
type of stroke and it is the type of stroke most affected by exercise. In some cases,
bleeding can occur into an area of infarction so that an ischemic stroke can be the
cause of a hemorrhagic stroke. Although relatively rare, subarachnoid hemorrhage
is the most lethal of all strokes with about half of patients dying within 3 months.
Most subarachnoid hemorrhage strokes are caused by rupture of an arterial aneu-
rism (a bulge in an artery) allowing blood to flow into the space surrounding the
brain increasing intracranial pressure and decreasing cerebral blood flow.
Although there has been concern that intense exercise might potentially cause an
aneurysm to rupture, a recent study in Finland suggests that regular exercise actu-
ally decreases the risk of developing a subarachnoid hemorrhage [5]. The study
followed a cohort of 70,000 Finns and found that as little as half an hour of light
exercise per week reduced the risk of subarachnoid hemorrhage by about 5% while
a 30 min walk or bike ride 4 days a week reduced the risk by about 20% regardless
of age or gender. The study found that smoking was the number one risk factor for
developing subarachnoid hemorrhage and that the benefit of exercise was greater in
smokers than in non-smokers.
Ischemic strokes can be further divided into large vessel and small vessel strokes.
Blockage of the large arteries outside the brain substance, typically cause large
areas of infarction with higher morbidity and mortality compared to blockage of
small arteries within the brain substance. Small infarcts that develop from blockage
of the small arteries penetrating deep within the brain substance are often called
lacunar infarcts.
As noted in the introduction of the chapter, large arteries are most commonly
blocked by atherosclerosis while small arteries by arteriosclerosis. A third less fre-
quent mechanism of arterial blockage is embolic when a clot formed in the heart or
large artery breaks off and moves downstream to block an artery. Although all stroke
mechanisms have common risk factors (e.g. obesity, type 2 diabetes and inactivity)
the main risk factor for atherosclerosis is an increase in blood lipids and for arterio-
sclerosis, high blood pressure. Exercise decreases the risk of developing all types of
ischemic strokes.
Exercise and Stroke Prevention
Since most of the risk factors for heart attacks are the same as the risk factors for
stroke, it is not surprising that physical activity is beneficial in the prevention of
both disorders. However, there have been far fewer studies and the amount and
Exercise and Stroke Prevention 171
types of physical activity have been less well documented in stroke studies com-
pared to heart attack studies.
The first large meta-analysis on the effects of physical activity on stroke preven-
tion was published in 2003, composed of 23 studies reported between 1966 and
2002 [6]. Subjects were divided into three groups based on physical activity level:
highly active, moderately active and low active. Highly active individuals had a
27% lower risk of having a stroke and moderately active individuals a 20% lower
risk of having a stroke compared to low active individuals. These findings held for
men and women and for both ischemic and hemorrhagic strokes.
A second meta-analysis of studies of physical activity and stroke published a
year later divided physical activities into recreational and occupational and found
that both types of physical activity had roughly the same benefits in lowering the
risk of having a stroke [7]. The magnitude of the risk reduction was similar to that
reported in the 2003 meta-analysis.
Two prospective longitudinal studies of the effect of physical activity on stroke
prevention deserve mention because of the size and duration of follow up. The rela-
tionship between baseline aerobic fitness and stroke mortality was investigated in
16,878 healthy men between the ages of 40 and 87 years using the Cooper Institute
database [8]. Over an average of 10 years of follow-up, men in the moderate- and
high-fitness categories had a 63% and 68% lower risk of stroke death respectively
compared to men in the low-fitness group at baseline. This inverse association
between aerobic fitness and stroke mortality continued to be present even after sta-
tistical adjustment for smoking, alcohol use, body mass index, high blood pressure,
diabetes and a family history of coronary artery disease.
Investigators in Finland followed 47,721 individuals without a history of stroke
or heart attack at baseline over 19 years and compared the level of recreational
physical activity (exercise) with risk of having a stroke. In a nutshell individuals
(men and women) who exercised regularly had a 24% lower relative risk of isch-
emic stroke than those who did not exercise regularly [9].
In addition to the potential benefit of physical activity in lowering the risk of
developing a stroke, physical activity can ameliorate the amount and severity of
damage from a stroke if one occurs. A series of studies in the early 2000s showed
that physical activity prior to a stroke led to milder strokes and a better long-term
prognosis. In these studies, large groups of patients with ischemic stroke were fol-
lowed from months to years and functional recovery was correlated with self-reports
of frequency and intensity of physical activity prior to the stroke. Those who
reported high levels of physical activity had faster and more complete recovery than
those who reported low levels of physical activity.
In one study specifically designed to assess the protective effect physical activity
on stroke recovery, 159 patients with similar ischemic strokes were followed for 3
months and those who reported regular physical activity prior to the stroke had
milder stroke severity, smaller final infarct size and better functional outcome than
those who reported no regular physical activity [10]. Furthermore, regular physical
activity prior to stroke was associated with better arterial recanalization rate in
patients who were treated with intravenous thrombolytic agents (drugs for dissolv-
ing blood clots).
One possible mechanism for the beneficial effect of exercise on stroke outcome
is increased production of vascular endothelial growth factor (VEGF). The research-
ers measured blood VEGF levels on admission and 1 week later and the incremental
increase in production of VEGF and the exercise level prior to stroke independently
predicted a good functional outcome at 3 months.
In animal models of stroke, having the animal exercise regularly before inducing
a stroke leads to a less severe stroke with smaller areas of infarction along with bet-
ter and more rapid recovery. One study in mice found that voluntary running on a
wheel or forced running on a treadmill for 3 weeks prior to an induced ischemic
stroke markedly decreased the infarct size and functional deficits after an induced
stroke [11]. The blockage was produced by injecting a nylon monofilament coated
with a silicone resin into the middle cerebral artery on one side and after an hour
removing the blockage allowing for reperfusion of the damaged area.
The investigators convincingly showed that one of the mechanisms for the pro-
tective effect of exercise was increased production of the vascular endothelial
enzyme nitric oxide synthase (eNOS) induced by the regular running. Nitric oxide
is a potent dilator of small arteries and the enzyme that produces nitric oxide, eNOS,
is critical for modulating cerebral microcirculation. After the stroke, the exercise
induced increase in eNOS improved cerebral blood flow to the damaged area. To
confirm that increased production of eNOS was the mechanism of the protective
effect of exercise, the researchers genetically engineered mice so that they could not
produce eNOS and showed that exercising these mutant mice did not protect them
against stroke damage.
Vascular endothelial growth factor (VEGF) is known to increase production
eNOS so the well documented increase in VEGF with exercise may be the trigger
for increased eNOS production and the vascular dilatation caused by exercise.
Interestingly, in the same mouse model of stroke, the cholesterol lowering drugs,
statins (e.g. atorvastatin, Lipitor) produced a similar effect on eNOS as exercise.
Prophylactic treatment with a statin increased production of eNOS and protected
the mice against stroke damage and the protective effect did not occur in mice
genetically altered so that they could not produce eNOS.
Statins are among the most widely prescribed classes of drugs in the world and
side effects are common. Exercise may be an attractive alternative for these drugs
without the risk of side effects. Two other growth factors known to increase with
exercise, IGF-1 and BDNF, also likely contribute to the neuroprotective effect of
exercise on stroke damage.
Exercise and Rehabilitation After Stroke
As suggested earlier, strokes can present with a wide variety of symptoms depend-
ing on where in the brain the damage occurs. Since a large part of the brain is
involved in initiating and controlling body movement, abnormalities in voluntary
movements are part of most strokes. When a cerebral hemisphere is involved, the
impairment is usually on one side, the side opposite the stroke, since each
Exercise and Rehabilitation After Stroke 173
hemisphere controls movement of the extremities on the opposite side. If the dam-
age is in the brainstem both sides can be involved since the fiber tracts carrying
movement signals for the extremities on both sides are close together.
One of the most common stroke profiles is one-sided weakness called hemipare-
sis. Large strokes involving a major artery to a cerebral hemisphere often present
with hemiparesis accompanied by other neurological symptoms including language
and cognitive impairment whereas small strokes involving small penetrating arter-
ies deep within the brain can selectively damage the fiber tract carrying movement
signals to the opposite side producing an isolated hemiparesis.
Most studies on the benefit of exercise on rehabilitation after a stroke have
focused on patients with hemiparesis since it is common and the logic for using
exercise to improve strength is compelling. However, it must be kept in mind that
nearly all strokes whether involving hemiparesis or not markedly diminish physical
fitness and neuroplasticity is a key component in the repair process after all strokes.
By improving physical fitness and augmenting neuroplasticity, exercise is beneficial
for rehabilitation after all strokes regardless of the symptom complex.
Beginning in the latter part of the twentieth century, it became apparent that patients
with strokes particularly those with hemiparesis had markedly increased energy
demands to perform routine activities yet they had impaired exercise capacity; they
were physically unfit. Studies that measured maximum oxygen uptake capacity with
treadmill walking in stroke patients (mostly with hemiparesis) found values in the
10–15 ml/kg/min range compared to 25–30 ml/kg/min in age-matched people who
were physically inactive but otherwise healthy (see Chap. 1 for details) [12–14].
These low levels of aerobic physical fitness are below those required for per-
forming most routine daily activities. This means that stroke patients must work to
near exhaustion just to complete routine daily activities such as brushing their teeth
or walking to the kitchen. Even modest increases in physical fitness could allow
them to perform these activities without becoming exhausted.
Traditionally, the disability associated with a stroke has been attributed to brain
injury and the associated loss of central neural drive. But secondary changes in
peripheral tissues play an equally important role in the loss of physical fitness.
Loss of muscle bulk and increased muscle fat, changes in the immune system
and insulin resistance contribute to the decrease in physical fitness after a stroke. At
the microscopic level, individual muscle fibers shrink and shift from aerobic to
anaerobic metabolism, particularly on the hemiparetic side. These changes in mus-
cle fibers result in a more fatigable muscle that is more insulin resistant.
One of the mechanisms for the muscle atrophy and increased insulin resistance
after a stroke is an increase in the level of inflammatory cytokines in muscle. The
increase is greatest on the hemiparetic side but is also present on the opposite side.
Similar increases in cytokines are seen in people with age related muscle atrophy
and people with muscle atrophy associated with lack of activity (disuse atrophy).
These cytokines can block insulin signaling and produce insulin resistance.
Studies show that exercise training can reduce the level of muscle cytokines and
improve muscle strength in frail older people and in people with heart failure. One
would expect a similar result with exercise after stroke.
The prevalence of insulin resistance and abnormal glucose metabolism in non-

diabetic people after a stoke is as high as 50% and more than 80% in those with
long-standing hemiparesis. This along with obesity, also common after stroke,
makes this population more susceptible to atherosclerosis and blood clotting disor-
ders leading to recurrent stroke or heart attack.
But how much can one reasonably expect to improve cardiovascular fitness after
a stroke? Current day post stroke rehabilitation typically concentrates on the first
3–6 months post-stroke period, targeted at basic mobility and recovery of daily
activity skills. On average, outpatient physical therapy consists of about 10 visits
over 1–6 months after discharge. Individual sessions are usually very low intensity
with less than 3 min per session at even modest intensity exercise (i.e. above 50%
maximum heart rate).
Most stroke patients are discharged from physical therapy without complete
recovery and about 50% lose mobility in the first year after the stroke. Early studies
suggested that the maximum expected gain in cardiovascular fitness (maximum
oxygen uptake) during stroke rehabilitation was about 15% varying with different
training protocols. More recently studies in Germany and the United States show
that it is possible to increase maximum oxygen uptake by 30–35% in chronic stroke
patients using a high intensity treadmill protocol (up to 80% maximum heart rate)
[15, 16]. Although more studies are need to evaluate the benefit of increased cardio-
vascular fitness on functional outcome, at a minimum, one would expect an improve-
ment in cardiovascular risk factors and overall brain health similar to that seen in
healthy adults of the same age.
Illustrative Case
Anne was 62 years of age when she suffered her stroke [17]. I still recall the night
she presented to our emergency room (ER). I was on-call for the in-patient neurol-
ogy service and I received a call from our neurology resident saying he was in the
ER with a woman who likely had a stroke. She was paralyzed on the right side and
although she spoke very little she appeared to be aware of the circumstances and
was obviously frightened by the sudden change in her health status.
This was in the early 1990s, before the routine use of intravenous tissue plas-
minogen activator (tPA) was introduced to dissolve clots with an acute stroke, so
our main goal was to try to find out the cause of the stroke and to stabilize her medi-
cally so that she could begin the recovery process. We agreed to order an emergency
MRI of the brain and cerebral arteries and I left for the hospital to meet him
in the ER.
My first impression on seeing Anne in the ER was that she was anxious and
depressed but overall athletic in appearance. She could speak but did so slowly with
some difficulty finding words and was extremely frustrated that she could not move
her right side. There was also some slight drooping of the right side of her lower
face but she had no trouble swallowing. All of the neurological findings and the
MRI results were consistent with infarction within the left cerebral hemisphere and
Illustrative Case 175
MR angiography (special MRI study that visualizes the arteries) confirmed a block-
age of the left middle cerebral artery near its origin.
Anne’s husband confirmed that she had been an avid tennis player (college star)
for much of her life but had cut back in recent years because of increasing work
responsibilities. She was not doing any regular exercise but did go for leisurely
walks on the weekend. Her primary care physician had suggested beginning medi-
cation for elevated cholesterol and blood pressure but Anne preferred not to take
medications so she tried to work on her diet. Her father had died of a heart attack in
his late 40s.
The likely cause of Anne’s stoke was atherosclerosis with narrowing of the mid-
dle cerebral artery ultimately leading to thrombosis and blockage of the artery.
Another possibility was a clot originating from the heart or large arteries, breaking
off and lodging in the middle cerebral artery (embolism) but imaging of the heart
and large arteries did not identify a likely source of a clot. She did have elevated
“bad lipids” and high blood pressure during her hospitalization and was started on
medications for both lowering lipids and blood pressure.
Within a day she began to develop slight movements of her fingers and toes but
recovery of strength on the right side was slow and even after 3 days on the neuro-
logical ward and a week in the hospital neurological rehab unit she continued to
have severe weakness and could not walk without support. Fortunately her speech
recovered more rapidly and at the time of discharge she had only slight word finding
difficulty. Anne was scheduled for a series of standard outpatient rehab appoint-
ments and a return outpatient visit with me in a month.
When Anne returned for her first outpatient visit it was immediately apparent
that she was frustrated at her lack of progress. She had regularly attended her outpa-
tient rehab visits but was making relatively little progress and could only walk a
short distance using a cane. She didn’t think that the rehab was of much use. “They
just tell me to be patient.”
She said very little spontaneously but on questioning it was apparent that her
language skills were largely intact. She was clearly depressed. As we began to get
to know each other, I was impressed that Anne was a strong willed woman who had
achieved a great deal in both her private and professional life. We began to talk
about our mutual interest in tennis and the pleasure of the competition and the exhil-
arating feeling of utter exhaustion after a good match.
Anne thought that she could do more in her rehab sessions but the therapist urged
her to stick to the protocol. At the time, I was becoming more and more convinced
of the value of exercise for recovery after any type of brain injury and we decided
that it was time to get creative and try something new. Since our main goal was to
get her back to walking normally and improve physical fitness, I suggested that she
identify a round-trip mile walking distance near her home with an initial goal of
walking the mile with her cane no matter how long it took.
Anne had had an extensive cardiac work-up during her hospitalization and her
cardiologist saw no restrictions for vigorous exercise. For her weakness and loss of
dexterity of the right hand, I suggested that she try to use her right hand as much as
possible even if the process took much longer than using her left hand.
When Anne returned for a second follow-up visit a month later the most obvious
change was her mood. She was more animated and spontaneous and even smiled a
few times. She reported that after 2 weeks she was able to walk a mile with her cane
although the process was slow and tedious. It took her more than 3 h to make the
mile round-trip and initially she was self-conscious that people were staring at her
shuffling along with tiny steps.
But she remained determined and with time a few neighbors became “cheer lead-
ers” supporting her effort. I suggested that she might cut back to 4 days a week but
she was determined to continue with the daily routine and she saw no reason why
she couldn’t continue to improve her mile time.
When she returned for her next clinic visit 2 months later, her improvement in
walking was obvious as she entered the exam room. Although she still required a
cane, her steps were larger and she was much more confident with turning. The
strength in her right hand improved but there were still problems with fine move-
ments of the fingers and writing was slow and tedious.
Anne reported that she could make a mile in about an hour so she decided to
increase her daily walks to 2 miles which she was able to do in about 2½ h. I asked
her if she was becoming bored with the long daily walks and she replied that it was
better than sitting at home thinking about her stroke. Besides, even on days when it
was extremely difficult to force herself to complete the walk she persevered because
she knew she would feel better after the walk and a shower and it was very impor-
tant to her to be actively participating in her recovery.
I last saw Anne 3 years after her stroke and her recovery was near complete. She
still had some mild weakness on the right side compared to the left but she walked
without a cane and she reported that her best time for walking 2 miles was 48 min.
She had returned to most normal activities but did not return to tennis since she just
wasn’t competitive with her prior playing partners.
It can be dangerous to base medical decisions on anecdotal reports, but numerous
studies over the subsequent years have shown that current day standard physical
rehabilitation programs are not intensive or targeted enough to prevent the profound
cardiovascular and muscular deconditioning that occurs with a stroke. As a rule,
physical endurance and aerobic fitness are low on discharge and even those who
show some improvement in walking are not confident enough to walk indepen-
dently outside the house.
There is now general agreement that in order to meet the goal of regaining
independence and aerobic fitness, more active and intensive rehabilitation is
needed. In a met-analysis of randomized controlled trials of augmented exercise
therapy on walking and walking-related activities compared with standardized
rehabilitation within the first 6 months after a stroke, the authors identified 14 tri-
als with 725 participants conducted between 1990 and 2010 which they consid-
ered moderate to high quality studies [18]. Despite the fact that there was a wide
range in the types, frequency and duration of augmented exercise, compared with
the control groups, the augmented exercise significantly improved walking abil-
ity, comfortable walking speed, maximum walking speed and extended activities
of daily living.
How Does the Brain Recover from a Stroke 177
The key remaining questions are what type, frequency and duration of aug-
mented exercise is most beneficial. Most agree that the rehabilitation program
should focus on overall aerobic fitness and the physical activity most in need of
improving, i.e. walking and fine hand movements in the case of hemiplegia.
How Does the Brain Recover from a Stroke
After a stroke, the damaged area of the brain can recover function by a variety of
mechanisms although neuroplasticity is by far the most important mechanism [19].
There are trillions of connections between neurons in the brain and after a stroke,
neurons die and connections between neurons are destroyed. For example, people
struggle with mobility after a stroke because many of the neural connections that
control movement are either lost or damaged by the stroke.
Through the process of neuroplasticity the brain can form new neural pathways
and connections and potentially transfer functions that were previously controlled
by the damaged area to healthy areas of the brain. The same healthy areas of the
brain that learn to play a musical instrument or hit a golf ball can learn to take over
for the area damaged by the stroke. All the brain needs is practice.
It is even possible for new brain cells to form and for the new neurons to be inte-
grated into repair process. Neural stem cells located in the sub-ventricular zone can
migrate out to the damaged area where they differentiate into new neurons and
glial cells.
Although some people who suffer a stroke fully recover, the majority do not. The
most rapid recovery occurs in the first 3–4 months after a stroke but recovery can
still occur years after the event (see below). The degree of recovery depends on the
area of the brain damaged, the size of the damage and the efficiency of the repair
process. High intensity aerobic exercise and rehabilitation exercise aimed specifi-
cally at the patient’s deficits can improve neuroplasticity and neurogenesis and help
recovery. This should be started as soon as possible after the stroke [20].
Degeneration of neurons in the area damaged by a stroke triggers a series of
regenerative processes that promote the growth of new connections among surviv-
ing neurons. Normally, in the healthy adult brain, growth inhibitory molecules limit
axonal plasticity so that once major connections are established they are relatively
stable. However, after a stroke, these growth inhibitory molecules are diminished
allowing surviving neurons to sprout new axon collaterals to re-innervate neurons in
nearby surviving areas that have lost connections. New synapses tend to be overpro-
duced followed by a process of selective synapse pruning and maturation.
The neuronal changes are integrated with glial, vascular and extracellular matrix
remodeling producing a new brain area with new connections and altered excitatory
and inhibitory patterns. As with the developmental process, the environment includ-
ing the level of physical activity play a key role in determining the patterns and
functional benefit of this reorganization process [21].
Animal models of ischemic strokes have provided important insights into the
process of re-innervation and rehabilitation after a stroke [22, 23]. One of the most
studied models is infarction of the primary motor cortex after occlusion of the mid-
dle cerebral artery in rodents. After the stroke, neurons in the primary motor cortex
on the healthy side and remaining neurons on the damaged side sprout new axons
that re-innervate subcortical and spinal cord neurons that lost input from the stroke.
For example, remaining neurons on the damaged side that previously controlled
facial movement might sprout new axons that supply subcortical and spinal neurons
to the leg. The balance of re-innervation from the two sides obviously depends on
the number of remaining neurons on the damaged side but also on the behavioral
experience during the post-stroke rehabilitation. The vascular and glial remodeling
is also highly sensitive to behavioral experience.
A surprising finding in mice after a middle cerebral infarction is that although
both sides contribute to the re-innervation process the functional outcome is most
dependent on re-innervation and remodeling on the damaged side. In fact, when
projections from the healthy side predominate the re-innervation, recovery may
actually be impaired due to the development of abnormal muscle synergies in the
weak limbs. The wrong muscles are re-innervated so the muscle contractions are not
properly coordinated.
Sprouting of functionally useful axons can be increased by forced use of the
paretic limbs as soon as possible after the stroke. Preferential use of the non-paretic
limbs can potentially increase sprouting on the healthy side of the brain and inter-
fere with the rehabilitation process. In other words, learning new skills with the
non-paretic extremities while disusing the paretic extremities can be deleterious to
the compensation process.
In the mouse stroke model, the deleterious effects of predominately using the
normal side after a stroke, was minimized by forced involvement of the weak side
in all skilled activities. In patients with stroke, constraint-induced movement ther-
apy (CIMT) was developed to improve the recovery of the paretic extremities after
a stroke [24]. CIMT typically involves constraining the normal extremities during
intense rehabilitative training of the weak extremities.
The theory is that with CIMT, synapses that are more effective in activating the
right post-synaptic neurons are selectively maintained and matured at the expense
of less active ones. Constraining the healthy limbs reduces activity at synapses that
would have been created in response to using the limbs in the rehab process. In
essence, CIMT provides a competitive edge at the synaptic level for experiences of
the weak limbs over those of the paretic limbs. Several controlled clinic trials pro-
vide strong support for the use of CIMT for improving recovery of function in a
paretic extremity after stroke.
Delayed Recovery
There is a general consensus in the field of stroke rehabilitation that the majority of
recovery from a stroke occurs in the first 6 months after the stroke. Although this is
true there are examples of delayed improvement even many years after the stroke
particularly in younger patients.
Delayed Recovery 179
A case report published in 2017 by a group of Canadian neuroscientists provides

encouragement for the potential of late recovery even years after a stroke and insight
into how widespread neuroplasticity in the brain can be [25]. In 1979, a 15 years old
boy suffered a stroke that caused paralysis of his left side. He traveled by train from
Windsor to Toronto Canada to meet his parents and after carrying a heavy suitcase
for a long distance in the train station and loading it in the trunk of his parent’s car
he abruptly lost consciousness.
The young boy was found to have a rare cause for the stroke, an extra rib in his
neck that pinched the main artery that goes to the brain and arm on the right side.
The external pressure on the artery caused a clot to form that subsequently sent
pieces of clot into the arteries supplying the right arm and right side of the brain.
Presumably, carrying the heavy suitcase pulled the collar bone down onto the extra
rib pinching the artery in between.
When the boy regained consciousness he had severe weakness of his left extrem-
ities and imaging of the brain documented a large area of infarction involving the
right frontal and parietal cortex. Although initially the right arm had impaired circu-
lation, with time collateral circulation developed and the arm returned to normal. He
gradually regained function in the left leg and some use of the left shoulder and
elbow but the left hand was completely nonfunctional.
Four months after the stroke, he was able to walk without support and returned
to school. He had no movement at all in his left hand for the next 23 years during
which he used his right hand for all activities. In 2001, he took up swimming on a
regular basis primarily because he was gaining weight and a year later he noted
slight movements in his left fingers for the first time. Based on this promising find-
ing he was started in an intensive physiotherapy program using a spring-loaded
mechanical glove (the SarboGlove) that supports finger extensors and provides
resistance to finger flexors. With this program he showed gradual return of function
of his left hand and after a few years he was able to hold objects and pick up coins
and paperclips with his left hand.
To better understand the mechanism of his recovery, the researchers per-
formed functional magnetic resonance imaging (fMRI) of the brain as he
moved the fingers first in his right hand and then the left hand. This technique
measures changes in neuronal activity in different parts of the brain based on
changes in blood flow to the area during the movement. As expected, with use
of his intact right hand there was activation of motor and sensory areas in the
opposite cerebral cortex whereas with use of the left hand there was more
widespread activation including the motor and sensory cortex and cerebellum
on both sides.
What was the mechanism of this delayed recovery and why didn’t it occur during
the initial 6 months after the stroke? One possibility is that exercise (swimming)
initiated enhanced neuroplasticity to start the process going and the subsequent
focused training of the right hand accelerated the recovery. It is also possible that
combining shoulder movements during swimming with sensory stimulation of the
affected hand in the water initially facilitated the reorganization of the sensorimotor
connections in the cortex.
His initial rehabilitation program did not include regular aerobic exercise or
forced use of the paralyzed hand. Even though there was dramatic improvement in
the use of his right hand, the movements remained slow and at times awkward sug-
gesting that that widespread activation seen on fMRI could not compare with the
prior normal innervation pattern.
Factors that Influence Recovery After Stroke
A variety of factors have been shown to increase the odds of a poor functional
recovery after a stroke including: older age, diabetes, stroke severity, and the type
and timing of rehabilitation training [26].
Exercise training after a stroke is generally well tolerated without any documented
adverse effects [27]. Typically exercise consists of walking on a treadmill or riding a
stationary bicycle and strengthening weak muscles often using an isokinetic machine.
Strength training in the legs should emphasize the large extensor muscles in the
upper legs since these muscles are critical for support and balance during walking.
Studies in patients with severe gait abnormalities have shown that the goal of
improving strength without working on walking can be counterproductive. It is
important that post-stroke training focuses on repetitive practice of the function that
needs improvement. Regarding the timing of the start of rehabilitation training,
although few in number, controlled treatment trials suggest that beginning rehabili-
tation early in the first few days can aid long-term recovery of hemiplegia and lan-
guage function.
In a recent randomized controlled trial of two different rehabilitation techniques
begun either immediately after stroke or the standard 5 days after stroke through 6
months post-stroke, Italian researchers found that regardless of the training method,
beginning early led to a significantly better long-term functional recovery at 12
months (but not 3 months) than beginning later [28].
The early rehabilitation program consisted of approximately 1 h in and out of
bed sessions with passive and active movements daily. They used common simple
scales for assessing functional outcome that included measures of disability and
performance on activities of daily living. Beginning rehabilitation training early had
no observable adverse affects and was unrelated to increased morbidity or mortality.
The effect of the early rehabilitation training on daily living activities was greater in
those who were younger, with less severe strokes and without diabetes.
As suggested earlier in the chapter, exercise in stroke patients can usually
increase aerobic fitness just as with normal healthy subjects. Improved cardiovascu-
lar fitness has multiple benefits independent of whether or not there is residual neu-
rological damage.
One of the most common causes of death after a stroke is a heart attack since
atherosclerosis tends to be generalized. If there is atherosclerosis in the cerebral
arteries there is a good chance it is also present in the coronary arteries. Inactivity
associated with a stroke can accelerate atherosclerosis increasing the risk of devel-
oping a heart attack.
Goals for Stroke Rehabilitation 181
Improving cardiovascular fitness in a stroke survivor can enhance glucose regu-

lation, decrease body weight and fat stores, decrease total cholesterol, triglycerides
and low-density lipoproteins (“bad lipids”) and increase high-density lipoproteins
(“good lipids”). These changes promote atherosclerotic plaque stability and favor-
able changes in vascular wall function decreasing the likelihood of a recurrent
stroke or heart attack.
Researchers at Emory University in Atlanta, Georgia conducted a prospective
randomized controlled clinical trial of a home exercise training program on cardiac
function and blood lipids on 88 men with coronary artery disease and physical dis-
ability, two thirds of whom were stroke survivors with hemiplegia (most of the
remaining subjects were amputees). Subjects had to have one functioning normal
upper extremity [29].
After random assignment subjects in the treatment group were provided with a
wheelchair ramp with rollers that could essentially transform their wheelchair into
a stationary wheelchair ergometer. They were also given a telephone electrocardio-
graphic recording device that could store 30-s ECG recordings immediately after
exercise and transmit the recordings to the researchers. These recordings served as
a measure of safety and also a measure of compliance with the exercise routine.
Subjects in the treatment group were instructed to exercise 5 days/week for
20 min for a total of 100 min each week. Subjects in the control group were
instructed to follow activity guidelines provided by their regular health team. Both
groups received dietary instructions and were requested to follow a fat-controlled
diet. Echocardiography for cardiac function and blood tests for lipids were per-
formed at baseline and at 6 months.
After 6 months of home exercise training the treatment group had significantly
improved cardiac function measurements and decreased resting heart rate and total
serum cholesterol compared to the control group. These findings are similar to those
seen in normal healthy people after exercise. The study demonstrates that it is pos-
sible to get patients with coronary artery disease and stroke to participate in a regu-
lar exercise program even in those with persistent hemiplegia and that the exercise
can be beneficial in improving heart function and blood lipids that decrease the risk
of recurrent heart attack and stroke.
Goals for Stroke Rehabilitation
In addition to improving neurological recovery, rehabilitation training after a stroke

can prevent complications of inactivity due to the stroke, help prevent recurrent
strokes and improve skills and efficiency of self-care. All of these goals can be
achieved by a combination of aerobic exercise and task-specific exercise tailored to
the neurological impairment caused by the stroke.
The rehabilitation training should begin as soon as possible after the stroke with
the ultimate goal of improving aerobic fitness and regaining pre-stroke levels of
activity. Although the greatest recovery occurs within the first few months, there
really is no time limit to the benefit of rehab training.
It is important to get the patient up sitting, standing and walking with support
during the first few days after the stroke and passive and active range of motion
exercises are tolerated by patients with nearly all stroke types. Simply exposing
patients to the orthostatic stress associated with sitting and standing can decrease
the risk of developing complications such has venous thrombosis during
hospitalization.
After discharge from the hospital, a wide variety of exercise programs are avail-
able based on the type and severity of the stroke. Walking on a treadmill is a major
component of most rehab programs whether or not there is hemiplegia since it
involves a task required for most daily activities, it can be performed safely with
hand rails or specialized harnesses that effectively decrease the person’s weight and
the exercise intensity can be customized by changing speed and incline. Most rehab
programs also include upper body exercises and resistance training particularly in
patients with upper extremity hemiparesis.
Exercises are accompanied by range of motion exercises to prevent contractures
and increase routine activities of living. The frequency and duration of rehab ses-
sions is determined by multiple factors including availability but should be at least
3 times per week initially with 2 h sessions and later with 1 h sessions. There are
ways to exercise even in patients with profound hemiparesis.
One of the goals of rehabilitation training is to improve aerobic fitness but there
have been relatively few studies that have actually measured changes in aerobic fit-
ness after the training is complete and the results are mixed. Heart rate monitoring
during rehabilitation training shows that the heart rates in stroke patients are often
in the target heart rate range (>50% of estimated maximum heart rate) for achieving
improved aerobic fitness so it should be possible to improve aerobic fitness if the
exercise-induced tachycardia is maintained long enough.
With regard to safety, ECG monitoring during exercise should be performed ini-
tially evaluating heart rate, rhythm and possible cardiac symptoms along with blood
pressure measurements. This is most commonly done with a treadmill (with or
without weight support) but can also be performed using arm cycle ergometry or
one-sided leg cycle ergometry.
Once the exercise capacity is determined an optimal program can be developed
depending on the subject’s needs and limitations. Aerobic training modes typically
aim to reach 50–80% peak oxygen consumption or peak heart rate. Intermittent
training programs (e.g. 10 min bouts) may be necessary during the initial weeks
because of the extreme deconditioned level of most convalescent stroke patients.
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Dementia
10
Dementia is quite unlike cancer or heart disease or any of those other conditions where you
bargain with God for a cure or even just a bit more time. Laurie Graham [1]
Dementia is not a disease but rather a general term for impaired cognitive and mem-
ory function that occurs later in life after normal development. As discussed in
Chap. 6, cognitive and memory impairment can be part of normal aging but as a rule
the impairment is mild and not severe enough to interfere with daily life. Dementia
refers to more severe cognitive and memory impairment that does have a major
impact on daily life.
An intermediate condition called mild cognitive impairment (MCI) can interfere
with some daily activities but as a rule is not incapacitating [2]. About 50% of
people with MCI will go on to develop dementia but currently there is no reliable
way to determine who will and who will not develop dementia.
Dementia is associated with a wide variety of neurological conditions from com-
mon disorders such as head trauma, stroke and Parkinson disease to rare disorders
such as dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP)
and frontotemporal dementia (FTD). In a few disorders, like Alzheimer Disease,
dementia is the main clinical feature but even in these cases other neurological
symptoms may occur.
Alzheimer disease is by far the most common cause of dementia (60–80% of all
cases) and the incidence is rapidly increasing around the world [3]. The second most
common cause is vascular dementia either resulting from a stroke, a series of small
strokes or a generalized vascular disease that causes gradual decrease in blood flow
to the brain. Although it can be very difficult to differentiate between Alzheimer
disease and vascular dementia, symptoms of vascular dementia tend to involve
thinking and problem solving early and can develop as a series of downward steps
compared to the early memory loss with a steady downward decline typical of
Alzheimer disease.
https://doi.org/10.1007/978-3-031-13924-6_10
186 10 Dementia
Aging is the leading risk factor for developing Alzheimer disease and vascular
dementia and as we will see there is overlap in pathology of the aging brain,
Alzheimer disease and vascular dementia. Other common risk factors include the
APOE4 gene allele, elevated “bad lipids”, obesity, hypertension, type II diabetes,
smoking and inactivity. At the present time, there is no effective treatment for any
of the causes of dementia and management focuses on controlling risk factors with
regular exercise being the single best way to prevent dementia.
Alzheimer Disease
Given the fact that an estimated 95 million people in the world will develop
Alzheimer disease by the year 2030, there is naturally a global race to find the cause
and develop effective treatments for the disorder [4]. Since the original description
of the disease by Alzheimer in 1906, the presence of amyloid plaques and neurofi-
brillary tangles in the brain have been considered the hallmark for the diagnosis of
Alzheimer disease (Fig. 10.1) [5].
Subsequent research has shown that amyloid plaques are made up of pieces of
protein called beta-amyloid, the result of breaking down of a much larger protein
called amyloid precursor protein by two different enzymes [6]. The plaques are
hard, insoluble clumps of beta-amyloid located between nerve cells. Neurofibrillary
tangles are made up of abnormally shaped tau, a protein that normally binds to and
stabilizes microtubules, structures key for transporting nutrients within nerve cells.
Disease related chemical changes cause tau to detach from the microtubules and
clump together, forming threads that eventually join to form tangles inside the
nerve cells.
Neurofibrillary
a b tangles
Normal neurons
Amyloid
plaques
Fig. 10.1 Pathology of Alzheimer disease. (a) microscopic section from normal brain; (b) section
from brain of patient with Alzheimer disease showing amyloid plaques and neurofibrillary tangles
Alzheimer Disease 187
The problem is, even though accumulation of beta amyloid plaques and neurofi-
brillary tangles are considered hallmarks of Alzheimer disease, their presence does
not clearly separate normal from abnormal aging brains. The brains of some normal
older people who have no signs of dementia prior to death can have high levels of
plaques and tangles [7].
Despite extensive research, the causal role of plaques and tangles for the onset
and progression of Alzheimer disease is only partially understood. Currently, beta
amyloid and tau accumulation in the brain can’t be measured with a blood test or
seen on routine MRI and CT scans of the brain. However, Positron emission tomog-
raphy (PET) scans along with molecular imaging agents (tracers) can identify and
estimate the amount of either of these two disease-related proteins.
Amyloid PET scan tracers have been around for years and several are already
FDA approved but their usefulness in diagnosing Alzheimer disease has been disap-
pointing [8]. PET studies show that amyloid deposits in the brain build up early,
years before symptoms of dementia, and are not very good for measuring progres-
sion of disease. Furthermore, as with postmortem studies, some older people with
normal cognition can have high levels of amyloid deposits in the brain.
PET studies have been most useful as an objective measure in treatment trials but
unfortunately even though several drugs have been shown to be effective in remov-
ing amyloid deposits from the brain of patients with Alzheimer disease the patients
do not show significant clinical improvement. Either amyloid deposition is not the
cause of Alzheimer disease or the damage is already done by the time symptoms
and signs of dementia have developed. The drugs may need to be given before the
amyloid deposits develop. This hypothesis is currently being tested by giving the
drugs to people with a high genetic risk of developing Alzheimer disease before
they show evidence of clinical dementia.
PET scans using tracers for tau protein have only recently become available but
they show promise because the spread of tau is better correlated with Alzheimer
symptoms and disease progression than amyloid protein [9]. Unlike amyloid, whose
deposition peaks early in the clinical course, tau continues to accumulate throughout
the course of the disease. Tau accumulation begins in the hippocampus and entorhi-
nal cortex two key brain areas for episodic memory, a process that allows a person to
remember where and when a distinct sequence of events occurred in the past.
Tau continues to accumulate as the memory impairment progresses and the total
amount of tau in the brain appears to be linked to disease stage and severity [10].
Remarkably, abnormal tau can move from neuron to neuron across synapses and
spread throughout the brain. In addition to Alzheimer disease, there are several
other severe dementing disorders associated with abnormal tau proteins including
post traumatic encephalopathy, vascular dementia, progressive supranuclear palsy
(PSP) and frontotemporal dementia (FTD). Although tau accumulation occurs with
all of these disorders, the clinical course, the location and type of neurons affected
and the nature of the tau abnormalities are different for each disease (see below).
The end stage of all types of dementia is loss of neurons and brain atrophy.
Considering the overlap in patterns of cognitive decline and neuronal loss that
occurs with dementia and normal aging (see Chap. 6) it has been difficult to separate
188 10 Dementia
normal aging from pathological aging. The hippocampus is a critical hub for the
distributed cortical memory network and early hippocampal atrophy tends to be a
common feature of normal aging and most types of dementia particularly Alzheimer
disease. There are two possible explanations:
1. Alzheimer disease is an acceleration of normal aging.

or
2. Alzheimer disease represents a change from normal to abnormal aging?
There is a subtle difference between these two explanations and in either case, it is
important to identify the factor or factors that trigger the acceleration or the change
from normal to abnormal aging.
Currently, gene variants are the best example of a trigger for the onset of
Alzheimer disease [11]. Mutations in the genes for amyloid precursor protein and
the two enzymes that break it down and in the gene for tau protein all produce
Alzheimer disease at an early age (as early as the 40s and 50s). The mutations in
these genes are dominant meaning if you have the mutation you will get Alzheimer
disease if you live long enough. Mutations in these genes, however, have not been
found in most patients with late-onset Alzheimer disease so other factors must be
involved.
As discussed in Chap. 2, the presence of the APOE4 gene allele markedly
increases the risk of developing late-onset Alzheimer disease although some people
with the allele live to an old age without developing Alzheimer disease. The APOE
protein is the principal lipid transport vehicle and controls the production and depo-
sition of amyloid protein in the brain and the APOE4 allele increases the likelihood
of developing cerebrovascular disease and early onset amyloid deposition. Both
properties could accelerate the conversion from normal aging to dementia.
Research studies also suggest an important role for the immune system in the
change from normal aging to dementia [12]. Low-grade chronic inflammation is
common during aging. Activation of microglia (brain immune cells) in the aging
brain increases expression of pro-inflammatory cytokines that can accelerate mem-
ory impairment. Generalized systemic inflammation with aging can also trigger the
release of cytokines that enter the brain via the circulation.
Cytokines such as interleukin (IL) and tumor necrosis factor alpha (TNFα) sup-
press BDNF expression and neuroplasticity and accelerate beta amyloid and tau
protein production, factors known to induce dementia. Several recent studies have
found that exercise alleviates IL and TNFα expression and increases BDNF produc-
tion and attenuates memory impairment and cognitive decline in patients with mild
cognitive impairment and early Alzheimer disease [13].
Exercise and Alzheimer Disease Pathology
Although there is still controversy regarding the cause of Alzheimer disease, as

discussed in the prior section, there is agreement that deposition of beta amyloid
and tau proteins is the hallmark pathology for Alzheimer disease. Furthermore, it
Exercise for Prevention of Alzheimer Disease 189
appears that beta amyloid deposition is the initial step that is required for the tau
protein changes and neurofibrillary tangles to occur. Beta amyloid is cleaved from
the amyloid precursor protein by two protease enzymes and as noted earlier genetic
mutations in these enzymes lead to increased beta amyloid deposition and early
onset Alzheimer disease [11].
What effect does exercise have on the deposition of beta amyloid and tau protein
in the brain? Animal studies suggest that exercise decreases deposition and improves
clearance of beta amyloid in the brain [14, 15]. Mice can be made susceptible to
early development of cognitive impairment and Alzheimer pathology by inserting
genetic mutations in the protease enzymes that control beta amyloid production
known to cause Alzheimer disease in humans.
Exercise on a treadmill protects these mice from developing amyloid deposition
and associated cognitive impairment and can even clear beta amyloid that has
already been deposited. At the same time exercise reduces the number of activated
microglia and increases BDNF production in the hippocampus protecting the hip-
pocampus from cell loss and atrophy typical of Alzheimer disease.
Early studies on the effect of exercise on beta amyloid deposition in human sub-
jects have so far produced conflicting results and researchers agree that more studies
in larger populations of older people are needed. For example, in a cross sectional
study of 54 cognitively normal older adults (ages 55–88), those who reported regu-
lar exercise over the prior 10 years had markedly lower beta amyloid deposition on
PET scans compared to those who did not exercise regularly [16]. On the other
hand, a 52 week randomized controlled trial in 110 underactive older people (mean
age 73) found no significant difference in brain beta amyloid deposition in those
who performed 150 min of supervised exercise per week versus those who just
received educational intervention [17].
Both studies had important limitations and a large multiyear prospective study of
the effect of exercise on beta amyloid deposition is currently underway. There is
general agreement that regular exercise throughout life decreases the risk of devel-
oping Alzheimer disease and the associated deposition of beta amyloid but there is
less agreement on whether exercise late in life can reverse beta amyloid deposition
once it has occurred. The situation is analogous to the explanation for why drugs
that decrease beta amyloid deposition so far have not been effective for treating
Alzheimer disease. It may be too late to reverse the process once there is significant
beta amyloid deposition.
Exercise for Prevention of Alzheimer Disease
Many of the studies on prevention of dementia have looked at all-cause dementia

often with no attempt to differentiate between the different causes of dementia
[18]. Since Alzheimer disease is by far the most common cause of dementia one
can assume that most of these studies are applicable to Alzheimer disease. There
are two ways that an intervention might prevent Alzheimer disease: by prevent-
ing the disease from developing or by delaying the onset of disease. Although
delaying onset may seem to be much less desirable than preventing the disease,
190 10 Dementia
it has been estimated that delaying the onset by 1 year would reduce worldwide
cases by 11% whereas delaying the onset by 5 years would reduce worldwide
cases by 30%.
Delaying the onset of disease decreases the number of years living with the dis-
ease and reduces the public health costs of caring for patients with the disease. The
only proven way to delay the onset of Alzheimer disease is to reduce the risk factors
for developing the disease. There are two types of risk factors for developing
Alzheimer disease: modifiable and non-modifiable. The main non-modifiable risk
factors are age and genes; the modifiable risk factors include physical inactivity, low
educational achievement, smoking, midlife obesity, midlife high blood pressure,
diabetes mellitus and depression. Of these seven modifiable risk factors, exercise
reduces five of them.
In the late 1970s when I was beginning my academic career in Neurology, I came
across an article that had a major impact on my thinking about the role of exercise
on brain function [19]. Researchers in Austin, Texas conducted a simple experi-
ment; often the most impactful experiments are simple. They compared reaction
time measurements in a group of young men (ages 20–30) with those from a group
of older men (ages 60–70). Two thirds of subjects in each group were physically
active running or playing racket sports at least four times a week while one third
were physically inactive.
Interestingly, they noted that they had a hard time finding physically active older
subjects and had to canvas many areas of Texas in order to recruit enough physically
active older subjects. The study found that reaction times were significantly shorter in
the physically active subjects in both young and older groups compared to the physi-
cally inactive subjects. Although the young physically active subjects had quicker
reaction times than the older physically active subjects the reaction times of the older
physically active subjects were comparable to the younger physically inactive subjects.
Reaction times are among the most basic of all neurological function measure-
ments. They represent the time in milliseconds for a subject to react to a stimulus
such as a light flash (simple reaction time) or a choice of one of several light flashes
(complex reaction time) with a motor response such as pressing or releasing a but-
ton. Numerous studies had shown that reaction times increase with aging and with
a variety of environmental factors including alcohol and tranquilizers.
Reaction times are also prolonged in a wide variety of neurological conditions
including all causes of dementia particularly Alzheimer disease. Although nonspe-
cific, the implications of prolonged reaction times are obvious for most daily activi-
ties particularly activities such as driving an automobile. It was impressive that
older people who exercised regularly had reaction times equal to those of young
people who did not exercise regularly. This suggested that regular exercise might
counteract age-related decline in overall brain function.
In the latter part of the twentieth century, numerous epidemiological studies con-
cluded that regular exercise decreased the risk of developing Alzheimer disease but
most of these studies were retrospective studies subject to recall bias. For example,
information about exercise patterns in Alzheimer patients was obtained from family
members or other proxies.
Exercise for Prevention of Alzheimer Disease 191
One of the first large prospective studies on exercise and Alzheimer disease per-
formed in the late twentieth century received a great deal of notoriety not so much
for its findings regarding exercise but for other behaviors that might protect one
from developing Alzheimer disease. The Canadian Study of Health and Aging
enrolled 6434 subjects nationwide, aged 65 years or older who were cognitively
normal in 1991 when they completed an entry risk factor questionnaire [20]. Those
still alive were reassessed for cognitive impairment 5 years later in 1996 at which
time 194 subjects had Alzheimer disease and 3894 remained cognitively normal.
Not surprisingly, increasing age, fewer years of education and presence of the
APOE4 gene allele were associated with a significantly increased risk of developing
Alzheimer disease. On the other hand, wine consumption, coffee consumption, use
of non-steroidal anti-inflammatory drugs and regular exercise were associated with
a significantly decreased risk of developing Alzheimer disease. Wine consumption
decreased the risk by 50%, non-steroidal anti-inflammatory drugs by 35% and cof-
fee consumption and exercise by 31%. These modifications of Alzheimer disease
risk were not altered by age or APOE4 status.
Surprisingly, there was no significant relationship between depression, head
trauma, smoking, high blood pressure, heart disease or stroke with the risk of devel-
oping Alzheimer disease. The researchers acknowledged that considering the large
number of variables studied and the relatively small number of Alzheimer disease
cases some of the findings may have been the result of random chance but the pro-
tective effect of wine, non-steroidal anti-inflammatory drugs and particularly exer-
cise had been observed in several prior studies. Regardless, older Americans could
feel good about their wine, non-steroidal anti-inflammatory drug and coffee con-
sumption and not worry too much about their lack of physical activity.
The number of prospective studies on the effect of physical activity on the risk of
developing Alzheimer disease markedly increased in the early twenty-first century
so that we now have compelling evidence that increasing physical activity signifi-
cantly decreases the risk of developing Alzheimer disease. Several meta-analyses of
these studies found that moderate to high regular physical activity decreases the risk
of developing Alzheimer disease in the range of 30–40%.
One meta-analysis review looked at all prospective studies of the affect of physi-
cal activity on the risk of developing cognitive decline, all-cause dementia,
Alzheimer disease, and vascular dementia conducted up until April 2016 [21]. The
studies had to have well-defined inclusion and exclusion criteria and follow up of at
least a year. The total sample size from all included studies was 117,410 with follow
up between 1 and 28 years. The protective effect of physical activity was greatest for
Alzheimer disease, 38% for high levels of physical activity and 29% for moderate
levels of physical activity. Probably, the main limitation of these studies was the
lack of detailed information on the type, duration and intensity of physical activity.
One of the largest studies followed 803 cognitively normal Japanese individuals
over the age of 65 for 17 years [22]. During the follow up 291 developed all-cause
dementia with 165 diagnosed with Alzheimer disease. Physical activity status was
defined as participating in exercise at least one or more times a week. People were
divided into two groups: active or inactive based on whether they exercised at least
192 10 Dementia
once a week or not. People in the physically inactive group were 41% more likely
to develop Alzheimer disease than those in the physically active group. This data
suggests that exercising as little as once a week can significantly decrease the risk
of developing Alzheimer disease.
Exercise for Treating Alzheimer Disease
Current evidence indicates that exercise may be an effective treatment for mild cog-
nitive impairment but not for Alzheimer disease once it has developed. As noted in
the introduction mild cognitive impairment may be an early stage of dementia.
There are two types of mild cognitive impairment: amnestic mild cognitive impair-
ment characterized by early memory loss that is most likely to transition to
Alzheimer disease and non-amnestic mild cognitive impairment (for example lan-
guage and visual spatial impairment) most likely to transition to other types of
dementia.
People with both types of mild cognitive impairment have about a 15% chance
of transitioning to dementia within 2 years. Although studies have been limited
because of small sample size, short periods of observation and lack of standardized
neuropsychological testing most have found a significant effect of exercise on
delaying the onset of dementia in people with mild cognitive impairment [23]. In
their practice guidelines the American Academy of Neurology concluded that exer-
cise is a promising non-pharmacological treatment to improve cognitive function in
people with mild cognitive impairment [24]. Although more long-term trials are
needed the key is to begin exercise as early as possible in the course of mild cogni-
tive impairment.
While there is no evidence that exercise can reverse the cognitive decline of
Alzheimer disease once it has developed, there are studies that indicate that regular
exercise can improve the quality of life in some patients with Alzheimer disease.
One might reasonably ask how can anyone with dementia have a good quality of
life? The answer is that it depends on the stage of the disease.
Early in the disease process people can maintain meaningful relationships and
participate in hobbies and recreational activities as they did before the disease. How
long this last varies greatly. Late in the disease, however, they typically require 24 h
care and are unable to participate in any meaningful relationships or activities. In
patients with Alzheimer disease, impaired physical function, slowed reaction times
and loss of muscle strength go hand in hand with cognitive decline. So these patients
are at a high risk for falls and fall related injuries.
Exercise can speed up reaction times, improve muscle strength and improve
overall physical function. In one prospective study, 54 patients with mild Alzheimer
dementia and 26 with moderate Alzheimer dementia were divided into two groups,
exercise and no exercise and followed for 2 years [25]. The exercise group had sig-
nificantly better strength, aerobic endurance, balance and agility and less unex-
plained hospitalizations that the no exercise group. But this was only seen in patients
with mild dementia not later dementia.
Exercise and Vascular Disease Pathology 193
Vascular Dementia
Vascular dementia is the second most common cause of dementia after Alzheimer
disease. Complicating matters, there is overlap in the brain changes associated with
these two conditions and 25–30% of patients with dementia may have a combina-
tion of vascular and Alzheimer dementia.
Traditionally, vascular dementia was thought to result from a series of small
strokes, each stroke damaging more brain volume so that over time the patient
developed dementia. The clinical course was characterized by step-wise progres-
sion involving a combination of cognitive and motor symptoms based on the areas
of the brain damaged by the strokes.
With the development of better brain imaging techniques as discussed in Chap.
6, it became apparent that white matter hyperintensities on MRI of the brain are
associated with an increased risk of developing dementia with aging. While white
matter hyperintensities are thought to be due to small vessel disease in the brain, the
clinical course is a gradual slow progression not the step-wise progression of multi-
stroke dementia. Furthermore, it can be impossible to separate patients with severe
white matter hyperintensities from those with Alzheimer disease and many of the
patients with severe white matter hyperintensities on MRI have typical Alzheimer
pathology on post mortem examination.
White matter hyperintensities are either a cause of Alzheimer disease or a risk
factor for developing Alzheimer disease. Some have suggested that there may be
two different types of white matter hyperintensities, one due to small vessel disease
and associated with vascular dementia and the other due to aging and associated
with Alzheimer disease. If that is the case, currently it is impossible to separate the
two by clinical or imaging features.
Exercise and Vascular Disease Pathology
As discussed in Chap. 9, strokes result from blockage of large arteries from athero-
sclerosis or blockage of small vessels from arteriosclerosis. Both processes are
made worse by physical inactivity and improved by exercise. Other risk factors
include obesity, type II diabetes, hypertension, stress and increased “bad lipids” all
of which are diminished by exercise. As described in the prior chapter, numerous
studies have shown that controlling these risk factors can decrease the risk of an
initial stroke or recurrent stroke.
The role of exercise in slowing down or reversing white matter hyperintensities
on MRI is controversial since research studies have lead to conflicting results [26,
27]. Studies of patients with white matter hyperintensities and stroke or Alzheimer
disease have found that controlling vascular risk factors can slow the progression of
white matter hyperintensities but this does not change the course of the underlying
disease. Studies focusing on younger individuals where exercise and physical fit-
ness are carefully quantified have found the most consistent benefit for exercise for
diminishing white matter hyperintensities. But even in longitudinal studies,
194 10 Dementia
exercise/physical fitness and white matter hyperintensities have typically been mea-
sured at a single point in time for a process that is known to very slowly progressive
over many years.
Exercise for Preventing Vascular Dementia
Surprisingly, despite the convincing evidence that exercise can decrease the risk of
stroke (see Chap. 9), there is relatively little evidence that exercise can decrease the
risk of developing vascular dementia. In several meta-analysis of research studies
on the benefit of exercise for decreasing the risk of developing all-cause dementia,
the benefit for preventing Alzheimer dementia was dramatic compared to the benefit
for preventing vascular dementia [21]. The majority of studies found little or no
benefit for exercise in preventing vascular dementia. Possible explanations for the
negative finding include, the small number of studies and patients with vascular
dementia compared to those with Alzheimer disease and inconsistency in criteria
for the diagnosis of vascular dementia.
Exercise for Treating Vascular Dementia
As with Alzheimer disease, there is no evidence that exercise can reverse the course
of vascular dementia although maintaining physical fitness can decrease the risk of
falls and unanticipated hospitalizations and at least in the early stages improve the
quality of life.
Lewey Body/Parkinson Disease Dementia
Next to Alzheimer disease, Parkinson disease is the second most common neurode-
generative disease [28]. Although Parkinson disease is generally recognized as a
movement disorder characterized by tremor, stiffness and slowness of movements,
dementia is also very common particularly late in the disease course. About 25% of
patients with Parkinson disease develop dementia and it has been estimated that
more than 80% of patients with Parkinson disease would develop dementia if they
survive 20 years with the disease.
Like amyloid and tau deposition with Alzheimer disease, Parkinson disease is
associated with deposition of a protein called alpha-synuclein either in clumps
within the neurons (Lewey bodies) or filaments in nerve fibers (Lewey neurites)
[29]. Also similar to amyloid and tau gene mutatioins in Alzheimer disease, muta-
tions in the alpha-synuclein gene result in familial Parkinson disease. Alpha-
synuclein is normally heavily expressed at neuronal synapses where is plays a
critical role in the packaging and release of neurotransmitters. It is currently unclear
what causes the protein to clump and whether Lewey bodies are toxic or protective
to the neurons.
Exercise and Lewey Bodies 195
There is a spectrum of Lewey body disorders with Parkinson disease at one end
of the spectrum and a condition called dementia with Lewey bodies at the other end
of the spectrum. At the middle is a condition called Parkinson dementia that has
features of both movement disorder and dementia early on. Each condition appears
to be determined by where the Lewey bodies are initially found. With Parkinson
disease Lewey bodies are seen early in deep nuclei such as the substantia nigra, rich
in dopamine and important in movement control, whereas in dementia with Lewey
bodies, the Lewey bodies are seen early in the cerebral cortex in regions important
for cognitive function. With Parkinson dementia the Lewey bodies are widely dis-
tributed from the onset.
Patients that have dementia in the Lewey body spectrum can have memory loss,
and trouble with alertness and paying attention just like patients with Alzheimer
disease but there are clinical differences that can help differentiate the two types of
dementia [30]. The presence of an associated movement disorder, vivid hallucina-
tions early in the course and a condition called REM sleep behavioral disorder all
suggest dementia with Lewey bodies.
REM sleep behavioral disorder is a dramatic clinical disorder whereby people
act out their dreams often with violent movement of the extremities that can injure
their bed partner. They are asleep so they are usually unaware of the events but the
bed partner recalls them vividly. These sleep related symptoms can precede the
onset of Lewey body symptoms by as long as 10–15 years, an important warning
sign when physicians are considering preventive treatment such a exercise [31].
Exercise and Lewey Bodies
Although there is a concerted effort to develop PET tracers for alpha-synuclein so

that Lewey bodies can be imaged in patients, at present no such tracers are available.
All of the data regarding exercise and Lewey body deposition have been obtained
from the study of rodent models. Mice can be made to produce Lewey bodies with
clinical features of Parkinson disease and dementia by injecting the neurotoxin
MPTP into the brain or by introducing a mutant form of the human alpha-synuclein
gene producing transgenic animals.
MPTP was initially discovered to produce a Parkinson-like syndrome in humans
when drug addicts in California inadvertently injected themselves with street drugs
contaminated with MPTP. Subsequently, the toxin has been used to produce models
of Parkinson disease in a range of animals from rodents to primates. Movement and
cognitive symptoms develop in concert with deposition of alpha-synuclein. Several
studies in mice given MPTP found that vigorous treadmill exercise can diminish
symptoms and decrease alpha-synuclein deposition compared to animals that do not
exercise [32].
Typically transgenic mice with the human alpha-synuclein mutation remain
asymptomatic until about a year of age when they begin developing movement and
cognitive symptoms. In one study, running wheels were set up in the cages of pre-
symptomatic animals at 12 months of age and in controls the wheels were locked
196 10 Dementia
[33]. After 3 months, both cognitive and motor performance measured with water
maze and rotating rod tests were significantly better in running animals compared to
transgenic mice with locked running wheels. Running mice had significantly less
alpha-synuclein aggregation in the brain compared to non-running mice.
Interestingly, the improvement correlated with increases in BDNF levels in the
brain raising the possibility that the well known effect of exercise on BDNF (see
Chap. 6) was a mechanism for the improvement.
Exercise for Prevention of Parkinson Disease
As with Alzheimer disease, most but not all prospective cohort studies have found
that physical activity earlier in life can decrease the risk of developing Parkinson
disease with an overall risk reduction of about 35%. The first published report fol-
lowed up 50,002 male college students who graduated between the years 1916 and
1950 from Harvard and the University of Pennsylvania and found that playing var-
sity sports or exercising regularly in college significantly reduced the risk of devel-
oping Parkinson disease by 36% and 17% respectively. Subjects who engaged in
exercise later in adulthood slightly decreased the risk of developing Parkinson dis-
ease but not to a significant level [34].
Several studies found that high intensity exercise was more effective in prevent-
ing Parkinson disease than low intensity exercise. In the Health Professionals
Follow-Up Study, men had a 30% lower risk of developing Parkinson disease in the
highest quintile of physical activity compared to those in the lowest quintile.
In the Cancer Prevention Study II Nutrition Cohort, 143,325 people were fol-
lowed from 1992 to 2001 and 413 developed Parkinson disease [35]. Physical activ-
ity was estimated at baseline by reporting the number of hours per week spent
performing physical activities from light (walking, dancing) to vigorous (running,
lap swimming, tennis). Men and women who performed vigorous exercise were
40% less likely to develop Parkinson disease than those who performed light exer-
cise. To rule out the possibility that the reason the subjects were not exercising was
because they had early unrecognized Parkinson disease, several studies removed
subjects that developed Parkinson disease in the first several years of the follow up
but the results were unchanged.
Exercise for Treating Parkinson Disease
Remarkably, there is more than 50 years of extensive research showing that exercise
can improve physical fitness, walking speed, balance and strength in patients with
Parkinson disease [28, 36]. Research studies of exercise on non-motor symptoms
such as cognition and mood are less frequent although there is some suggestion that
these symptoms can also be improved with exercise.
Two recent studies that focused on aerobic exercise with treadmill walking
found significant improvement in balance, walking speed and distance and fear of
Dementia due to Tau Protein Aggregation 197
falling in patients with mild to moderate Parkinson disease compared to controls.

One used 8 weeks of training on a treadmill with load bearing for 30 min sessions
[37] while the other 6 weeks of supervised treadmill walking 3 times a week for
40 min [38].
Some studies suggest that forced aerobic exercise where the patient works with
a trainer is more effective than individual training. In one study, two groups ped-
aled on a cycle ergometer for 1 h, 3 times a week for 8 weeks [39]. One group
exercised on their own and was told to maintain their heart rate between 60 and
80% maximum while the other group pedaled on a double bicycle with a trainer
that monitored heart rate to be sure they were in the correct range. The group
assisted by a trainer maintained a 30% higher heart rate during cycling and had a
35% greater improvement in motor symptoms than the group that exercised on
their own.
Recent studies suggest that strength training in patients with Parkinson disease
can increase muscle strength and size and improve bone density just as in normal
subjects. Strength training combined with aerobic exercise appears to be ideal for
maintaining independence in daily living.
Dementia due to Tau Protein Aggregation
As noted earlier in the chapter, aggregation of amyloid and tau proteins in the brain
as plaques and tangles is characteristic of Alzheimer disease. Several rare dementia
syndromes, known as tauopathies, are associated with accumulation of tau tangles
in neurons and glial cells throughout the brain [40]. The cause is unknown and cur-
rently there are no known medical treatments.
There can be overlap in the symptoms of these syndromes and not infrequently
patients can evolve from one syndrome to another. Frontotemporal dementia (FTD)
is one of the most devastating of all dementia syndromes. Early symptoms typically
include antisocial behavior along with speech and language impairment. Patients
lose social skills and are perceived to be insensitive and rude often acting impul-
sively with complete loss of normal inhibitions. Pick’s disease overlaps with FTD
also beginning with compulsive and inappropriate behavior causing conflicts at
work and at home. There are sudden changes in mood and patients often lose inter-
est in social interactions and daily activities.
Chronic traumatic encephalopathy is a tauopathy caused by repetitive traumatic
brain injuries. Initially identified in boxers and called “dementia pugilistica”, more
recently it has been diagnosed in a large number of American football players.
Clinical features and tau pathology overlap with Alzheimer disease and frontotem-
poral dementia and currently there is no reliable test to distinguish between these
different disorders.
With corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP)
motor symptoms often predominate early in the course of the dementing illness.
Patients experience difficulty with balance and coordination, muscle jerking and
stiffness and abnormal postures with some Parkinson-like features. Both disorders
198 10 Dementia
have abnormal eye movements but with PSP there is a characteristic difficulty with
vertical eye movements. Because of difficulty looking down patients often trip over
objects and have great difficulty going down stairs.
Exercise for Preventing and Treating Tauopathies
Because of the rarity and difficulty diagnosing the tauopathy dementia syndromes,
there have been no controlled treatment trials of exercise in patients with these dis-
orders. However, there have been several case reports suggesting that exercise is
beneficial at least in managing the motor symptoms of these disorders. More con-
vincing are research studies in animal models with transgenic tauopathies showing
that exercise can improve symptoms and decrease aggregation and deposition of tau
in neurons and glial cells.
Late in the twentieth century, researchers identified several mutations in the tau
gene that produced an early onset familial dementia. For example, in one family
with a P301S mutation in the tau gene, the father developed frontotemporal demen-
tia and the son corticobasal degeneration in the third decade both with rapid pro-
gression [41]. This family illustrates how a single gene defect could produce two
different taopathy clinical syndromes. Postmortem examination of the father’s brain
showed characteristic tau neurofibrillary tangles and biochemical studies showed
that the tau protein with the P301S mutation had reduced ability to form microtubules.
When the human P301S mutation was introduced into mice, the mice developed
progressive impairment of motor function and exploratory behavior beginning at
about 6 months age. In one study, researchers subjected 7-month old P301S tau
transgenic mice to a 12-week forced treadmill exercise regimen that had previously
been found beneficial in a Parkinson mouse model [42]. Compared to control mice,
exercise improved motor and exploratory activity and resulted in significantly less
tau aggregation in the spinal cord and hippocampus. Exercise did not cure the dis-
order but delayed the onset and diminished symptoms.
These findings are consistent with clinical reports of the beneficial effects of
exercise in patients with late onset tauopathies. For example, at age 60, a dentist
began noticing problems with walking and hand coordination and at age 66 he was
diagnosed with corticobasal degeneration [43]. The clinical syndrome gradually
evolved and at age 72 he was also diagnosed with progressive supranuclear palsy.
He began a therapist-led community exercise program for people with Parkinson
disease at age 70. The program consisted of forward and backward treadmill walk-
ing, trunk and lower extremity stretching and muscle strengthening and balance
exercises. He participated twice a week for 1 h on a regular basis for 10 years.
Compared to his performance before starting the exercise program he had fewer
falls and improved balance and endurance and at 10 years he continued to walk on
his own although requiring a walker for support. Granted, although case reports can
be misleading, at the very least a regular exercise program can provide hope and
physical benefits for patients with these devastating conditions.
References 199
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Overview
11
In this book, I have provided what I consider convincing evidence that people who
are physically active are healthier than people who are not physically active. The
need for physical activity is written in our genes that evolved over millions of years.
The brain is uniquely dependent on physical activity for optimal performance and
physical activity, whether planned (exercise) or part of one’s daily routine, can pre-
vent and treat many chronic neurological disorders.
There remain many unknowns in our understanding of the complex biology of
exercise and physical fitness but there is general agreement in the clinical and
research community that the positive effects of exercise and the negative effects of
physical inactivity on health are clear enough to warrant widespread promotion.
There is some disagreement on how this promotion can be achieved.
One area of debate is whether it is best to emphasize the benefits of increasing
physical activity or the risks of inactivity. Since the emphasis on benefits hasn’t
worked so well, it might be better to focus on physical inactivity, emphasizing that
this population is abnormal and at high risk of developing a variety of diseases.
Some have compared physical inactivity to smoking and even suggested the slogan
“sitting is the new smoking”. Overall we have done a reasonably good job of con-
vincing people that smoking is bad for their health but not such a good job of con-
vincing them that sedentary behavior is bad for their health.
One problem is the definition of physical inactivity. Some use the term for any-
body who does not reach the recommended 150 min per week of the World Health
Organization (WHO) while others restrict the term for those who exhibit sedentary
behavior, people who spend most of their day sitting. Some consider physical inac-
tivity to be just the opposite of physical activity while others consider sedentary
behavior to be biologically and physiologically different from physical activity.
Another problem is the lack of a universally accepted questionnaire for surveillance
of physical activity worldwide. These are problems that can be solved and there are
examples where campaigns to increase physical activity and decrease sedentary
behavior have been successful [1].
https://doi.org/10.1007/978-3-031-13924-6_11
202 11 Overview
World Health Organization (WHO) Guidelines
In 2010 the WHO published guidelines for recommended levels of physical activity
for older children and adults based on a review of published data by a team in inter-
national experts [2]. These initial recommendations were straightforward and
broadly applicable. In a nutshell: Children and adolescents should average 60 min/
day of moderate to vigorous intensity physical activity (mostly aerobic); Adults
should average at least 150 min per week of moderate intensity or 75 min of vigor-
ous intensity aerobic physical activity or some equivalent combination of the two;
Children and adults should also combine muscle-strengthening activities with their
regular physical activity as much as possible. The term physical activity was used
rather than exercise to emphasize that all types of physical activity were effective
whether specifically planned, recreational or part of one’s daily routine. These
guidelines became widely adopted by countries around the world in part because of
their simplicity.
Subsequently it became apparent that the initial guidelines needed to be
expanded to be applicable for different age groups and circumstances and to
include new research data that had accumulated in the early twenty-first century. In
2019, the WHO published recommendations for physical activity, sedentary behav-
ior and sleep for infants under age 5 years [3] and in 2020 they published recom-
mendations for physical activity and sedentary behavior for children over age 5
years, adolescents, adults, older adults, pregnant women and people with disabili-
ties [4]. Rather than focusing just on physical activity or sedentary behavior, the
guidelines addressed both equally. Definitions of WHO terms are summarized in
Table 11.1.
With these new guidelines there is no minimum physical activity require-
ment. For everyone, some physical activity is better than none. Even brief peri-
ods of physical activity can have health benefits particularly in people who are
sedentary. Such individuals should start with small amounts of physical activity
and gradually increase frequency, intensity and duration over time. Any poten-
tial risk of increasing physical activity is greatly outweighed by the potential
benefits.
With regard to medical evaluation prior to starting exercise, this was generally
thought not to be necessary. For those who are sedentary, they can begin low
intensity physical activity without medical clearance and for those who are already
physically active they can gradually increase from moderate to vigorous activity
without needing to consult a healthcare provider. Of course, should they develop
new symptoms with increase in physical activity they should contact a healthcare
provider.
Infants <5 Years of Age 203
Table 11.1 WHO definition of terms

Physical activity—Bodily movement produced by skeletal muscles that requires energy
expenditure. Physical activities can be undertaken in various domains, including one of more of
the following: leisure, occupation, education, home and/or transport.
Physical inactivity—Insufficient physical activity level to meet present physical activity
recommendations.
Metabolic equivalent of task (MET)—The metabolic equivalent of task, or simply metabolic
equivalent, is a physiological measure expressing the intensity of physical activities. One MET
is the energy equivalent expended by an individual while seated at rest or the resting metabolic
rate (RMR), usually expressed as mL O2/kg/min.
Sedentary behavior—Any waking behavior characterized by an energy expenditure of 1.5
METs or lower while sitting, reclining or lying. Most desk-based office work, driving a car and
watching television are examples of sedentary behaviors; these can also apply to those unable
to stand, such as wheelchair users.
Light-intensity physical activity—On an absolute scale, light intensity refers to physical
activity that is performed between 1.5 and 3 METs. On a scale relative to an individual’s
personal capacity, light-intensity physical activity is usually a 2–4 on a rating scale of perceived
exertion scale of 0–10. Examples include slow walking, bathing or other incidental activities
that do not result in a substantial increase in heart rate or breathing rate.
Moderate-intensity physical activity—On an absolute scale, moderate-intensity refers to the
physical activity that is performed between 3 and <6 times the intensity of rest (METs). On a
scale relative to an individual’s personal capacity, MPA is usually a 5 or 6 on a rating scale of
perceived exertion scale of 0–10.
Vigorous-intensity physical activity—On an absolute scale, vigorous intensity refers to
physical activity that is performed at 6.0 or more METs. On a scale relative to an individual’s
personal capacity, VPA is usually a 7 or 8 on a rating scale of perceived exertion scale of 0–10.
Multicomponent physical activity—Multicomponent physical activity are activities that can
be done at home or in a structured group or class setting and combine all types of exercise
(aerobic, muscle strengthening and balance training) into a session, and this has been shown to
be effective. An example of a multicomponent physical activity program could include walking
(aerobic activity), lifting weights (muscle strengthening) and could incorporate balance
training. Examples of balance training can include walking backwards or sideways or standing
on one foot while doing an upper body muscle-strengthening activity, such as bicep curls.
Dancing also combines aerobic and balance components.
Infants <5 Years of Age
The WHO recommendations for physical activity, sedentary behavior and sleep in
infants under the age of 5 are outline in Table 11.2. Key features include: gradually
increasing physical activity with age; even babies need to be physically active with
at least 30 min of tummy time per day; at least 180 min a day of physical activity for
infants age 1–5; restraining infants of any age should be kept to minimum; no screen
time before age 2 and no more than an hour a day from ages 2 to 5; reading and story
telling are encouraged for all ages.
These guidelines were developed based on the knowledge that the period from
birth to age 5 years is critical for physical and cognitive development. Active play
204 11 Overview
Table 11.2 WHO recommendations for physical activity, sedentary behavior and sleep in infants
Age Physical activity Sedentary behavior Sleep
<1 year Several times a day in a Never restrain for more than an 0–3 months to
variety of ways, more is hour (stroller, high chair or 14–17 h, 4–11
better, at least 30 min in strapped to back), reading and months to 12–16 h
prone position (tummy time) story telling but no screen time of good quality
sleep including naps
1 and 2 At least 180 min of physical Never restrain for more than an 11–14 h of good
years activity including some hour, no sedentary screen time quality sleep,
moderate and vigorous for 1-year-olds and no more than including naps, with
intensity activity spread 1 h for 2-year-olds. Reading and regular sleep and
throughout the day, more is story telling encouraged. wake-up times.
better
3 and 4 At least 180 min of physical Never restrain for more than an 10–13 h of good
years activity of which at least hour. Sedentary screen time no quality sleep, which
60 min is moderate to more than 1 h. Reading and may include a nap,
vigorous intensity spread story telling encouraged. with regular sleep
throughout the day, more is and wake-up times.
better.
with both structured and unstructured physical activity improves motor skills and
exploration of the physical environment. Furthermore, habits formed as a child can
influence the level and pattern of physical activity manifested throughout the child’s
lifetime.
Children and Adolescents Ages 5–17 years
For children and adolescents the WHO recommended at least 60 min of moderate to
vigorous physical activity per day (Table 11.3). Compared to the 2010 recommen-
dations, “at least” 60 min per day was changed to “an average” of 60 min per day
thought to more accurately reflect the reported evidence and the way physical activ-
ity is usually measured. There was evidence that aerobic activity improved cardio-
respiratory fitness and muscle-strengthening activities improved muscle strength
and some evidence that doing both was more beneficial than doing either alone but
it was not felt that the evidence was strong enough to recommend a specific exercise
routine.
The relationship between sedentary behavior and adverse health outcomes in
children and adolescents was considered strong particularly for television viewing
and recreational screen time. However, the evidence was insufficient to set an exact
threshold or cut-off for the amount of sedentary or recreational screen time.
The WHO concluded that there is an urgent need to increase physical activity and
decrease sedentary behavior in adolescents since recent global estimates suggest
that four fifths of adolescents did not meet the 2010 recommendations for aerobic
exercise.
Children and Adolescents Ages 5–17 years 205
Table 11.3 WHO recommendations for physical activity and sedentary behavior for children,
adolescents, adults, older adults and pregnant women
Physical activity Sedentary behavior
Children and • Children and adolescents should do at • Children and adolescents
adolescents (aged least an average of 60 min/day of should limit the amount of
5–17 years), moderate-to-vigorous intensity, mostly time spent being sedentary,
including those aerobic, physical activity, across the particularly the amount of
living with week recreational screen time.
disability • Vigorous-intensity aerobic activities, as
well as those that strengthen muscle
and bone should be incorporated at
least 3 days a week.
Adults (aged 18–64 • Adults should do at least 150–300 min • Adults should limit the
years) including of moderate-intensity aerobic physical amount of time spent being
those with chronic activity, or at least 75–150 min of sedentary. Replacing
conditions and vigorous-intensity aerobic physical sedentary time with physical
those living with activity, or an equivalent combination activity of any intensity
disability of moderate-intensity and vigorous- (including light intensity)
intensity activity throughout the week provides health benefits
for substantial health benefits
• Adults should also do muscle- • To help reduce the
strengthening activities at moderate or detrimental effects of high
greater intensity that involve all major levels of sedentary behaviour
muscle groups on two or more days a on health, adults should aim
week, as these provide additional to do more than the
health benefits. recommended minimal levels
of moderate-to-vigorous
physical activity.
Older adults (aged Same as adults, plus Same as adults
65 years and older) • As part of their weekly physical
including those activity, older adults should do varied
with chronic multicomponent physical activity that
conditions and emphasises functional balance and
those living with strength training at moderate or greater
disability intensity on 3 or more days a week, to
enhance functional capacity and to
prevent falls.
Pregnant and • Undertake regular physical activity • Pregnant and postpartum
postpartum women throughout pregnancy and post partum women should limit the
• Do at least 150 min of moderate- amount of time spent being
intensity aerobic physical activity sedentary. Replacing
throughout the week for substantial sedentary time with physical
health benefits activity of any intensity
• Incorporate a variety of aerobic and (including light intensity)
muscle-strengthening activities. provides health benefits.
Adding gentle stretching may also be
beneficial
206 11 Overview
Adults Ages 18–64 Years
The new guidelines are based on the assumption that most of the benefits of physical
activity are obtained with an average weekly volume of 150–300 min of moderate
intensity or 75–150 min of vigorous intensity, or an equivalent combination of the
two types of physical activity (Table 11.3). This is a distinct change from the 2010
guidelines that recommended 150 min of moderate or 75 min of vigorous physical
activity per week. Health benefits definitely occur below the minimal recommended
level so some is better than none and likely there are health benefits with physical
activity above the maximum recommended level so more is usually better than less
but the activity level where health benefits diminish, stop or even possibly reverse is
currently unknown. If such a level exists it likely varies amongst individuals and
with different health conditions.
The new guidelines emphasized the dangers of sedentary behavior in adults and
the need to replace sitting time as much as possible with periods of physical activity
even if just light physical activity. People whose jobs include high levels of seden-
tary time need longer and more intense periods of physical activity than people who
are physically active on the job.
Older Adults Ages 65 Years and Older
In addition to the recommended 150–300 min of moderate-intensity or 75–150 min

of vigorous physical activity per week, older adults should perform balance and
strengthening activities 3 or more days a week (Table 11.3). This multicomponent
program helps maintain cognitive function, muscle strength and bone density while
decreasing the risk of falls. Compared to the 2010 guidelines, multicomponent
activities are recommended for all older adults not just those with mobility prob-
lems. Just as in younger adults prolonged sitting without breaks should be avoided
even if the breaks just consist of light physical activity such as standing and mov-
ing about.
Pregnant and Postpartum Women
The new guidelines are based on strong evidence that physical activity during preg-
nancy is beneficial to both the mother and the fetus. There is also evidence that regu-
lar physical activity decreases delivery complications and the risk of developing
postpartum depression. These same benefits apply to pregnant women who are
overweight or obese. Unless there are medical contraindications, women should do
at least 150 min of moderate intensity physical activity along with muscle stretching
and strengthening activities weekly (Table 11.3). Women who prior to pregnancy
regularly performed vigorous intensity physical activity can continue the activity
during pregnancy and the postpartum period.
Future Directions 207
Just as with other adults pregnant women should avoid time spent being seden-
tary. Breaking up prolonged sitting time with even low intensity physical activity is
beneficial to health.
People Living with Chronic Disabilities
In the 2020 report, the WHO, for the first time, addressed physical activity recom-
mendations for people with chronic disabilities. They reviewed published evidence
for the benefits of physical activity in people diagnosed with multiple sclerosis,
spinal cord injuries, Parkinson’s disease, stroke, major clinical depression, schizo-
phrenia and attention deficit hyperactivity syndrome (ADHD). Where available they
identified the following outcomes: comorbidities, physical functioning, cognition
and quality of life.
First, they concluded that physical activity was safe and beneficial for people
living with disability without contraindications and that there were no major risks
when the physical activity was appropriate to the person’s current activity level,
health status and physical functioning level. Overall, it was felt that the guidelines
for adults without disability were applicable to people with disabilities. However,
people with some disabilities might need to consult with healthcare professionals
for guidance on the type and amount of physical activity appropriate for them.
While the data regarding the adverse effects of sedentary behavior on people
with disabilities is scarce, it was concluded that the adverse effects of sedentary
behavior seen in people without disabilities could be extrapolated to those with dis-
abilities. For those with low mobility or confined to a wheelchair, sedentary behav-
ior could be mitigated by performing low to high intensity physical activity that
does not involve the lower extremities.
Future Directions
Developing guidelines for increasing physical activity and decreasing sedentary

behavior in normal people and people with chronic disabilities is an important step
for reaping the benefits of physical activity on public health but much more needs to
be done. One thing that is clear from reading the literature cited as the basis for the
guidelines is the large gap in our knowledge regarding the positive effects of physi-
cal activity and the negative effects of physical inactivity in subgroups of the popu-
lation particularly those with chronic disabilities. Furthermore, although neurological
diseases dominate the list of chronic disabilities, clinical research on the benefits of
physical activity and the adverse effects of sedentary behavior on chronic neurologi-
cal diseases is relatively scarce.
Although it is reasonable to extrapolate evidence regarding the benefits of
increasing physical activity from the general populations to people with chronic
neurological diseases, the lack of specific details may limit the impact of the
208 11 Overview
recommendations. For example, there is relatively little information regarding the

optimal type, intensity, frequency, and duration of physical activity for people with
different neurological disorders. There is essentially no information regarding the
adverse effects of sedentary behavior on these disorders.
Regardless, the evidence that increasing physical activity improves health is so
compelling that the medical community can’t wait to coordinate efforts to dissemi-
nate the physical activity guidelines. This includes making a concerted effort to
reach underserved communities, particularly low-income and disadvantaged com-
munities. The goal is to achieve an environment conducive for increasing physical
activity in schools, workplaces and communities. For example, studies show that
access to parks and safe open spaces and providing transportation to and from such
areas can have a significant impact on an individual’s decision to increase physical
activity.
Finally, as discussed in Chap. 1, health care providers should routinely monitor
the level of physical activity and physicians need to regularly prescribe the “exercise
pill”. Neurologists, in particular, should be aware of the proven benefits of physical
activity for brain health and include a discussion of physical activity during patient
encounters. Both private and governmental health care systems need to reorganize
priorities to incentivize time spent monitoring the level of physical activity and
educating patients on the importance of regular physical activity for maintaining
good health.
References
1. Hallal PG, Pratt M. Physical activity: moving from words to action. Lancet Glob Health.
2020;8:e867–8.
2. World Health Organization. Global recommendations on physical activity for health. Geneva:
World Health Organization; 2010.
3. World Health Organization. Guidelines on physical activity, sedentary behaviour and sleep for
children under 5 years of age. Geneva: World Health Organization; 2019.
4. World Health Organization. Guidelines on physical activity and sedentary behaviour. Geneva:
World Health Organization; 2020.
Index
A Athens and the Greek gymnasium, 48, 49

Aerobics Atherosclerosis, 167
vs. anaerobic physical activity, 13, 14 Attention-deficit/hyperactivity disorder
exercise, 118, 121 (ADHD), 84, 85
and Kenneth Cooper, 7–9
training modes, 182
Age of chivalry, 55, 56 B
Aging, 186 Balfour, W., 160
brain Beard, G., 160
age related cognitive decline, 109 Bernard, C., 130
cognitive decline, 126, 127 Beta amyloid, 186, 189
early life experiences and, 111, 112 Body mass index (BMI), 114
energy consumption, 110 Bone density, 206
genes and cognitive aging, 113 Brain derived neurotrophic factor
muscular strength and, 120 (BDNF), 95, 124
physical activity and, 113, 114 Brain development
shrinkage of brain, 118, 119 exercise influence on, 83, 84
white matter abnormalities, 115–118 neuroplasticity and, 72, 73
temporary memory lapse, 109 physical activity and, 73
Agricultural communities, 30 Brain evolution, 69
Agricultural revolution, 29 Brain growth, 70
Alcoholic beverages, 30 Brain plasticity, 93
Alzheimer disease, 185, 187 Brain reserve theory, 122
amyloid PET scan tracers, 187 Brain size, 68, 69
exercise for prevention, 189, 190 Brain-derived neurotrophic factor (BDNF), 94,
exercise for treating, 192 122, 141
pathology, 189 Breathing exercises, 42
Alzheimer’s disease, 109, 110, 125 Brisk walking, 155
American Heart Association, 36 B-vitamins, 125
Animal models, 133
Antidepressant medication, 143, 155
Anxiety, 137 C
APOE gene, 28 Cannon, W.B., 130
APOE4 gene allele, 113, 188, 191 Cardiovascular disease, 13
Apolipoprotein E, 28 Cardiovascular fitness, 143
Arterial blockage, 170 Cellular changes, 110
Asanas, 45 Cellular homeostasis, 130
Asclepeions, 46 Centers for disease control (CDC), 114
Asclepius, 46 Cerebellar expansion, 70, 71
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer 209
Nature Switzerland AG 2022
R. W. Baloh, Exercise and the Brain, https://doi.org/10.1007/978-3-031-13924-6
210 Index
Cerebral blood flow, 168, 169 Emotional stress, 137, 138

Chignon, N., 26, 27 Endothelial enzyme nitric oxide synthase
Chinese martial arts, 41–43 (eNOS), 172
Chronic disabilities, 207 Energy metabolism, 13
Chronic pain Environmental stressors, 130
central sensitization and, 149, 150 Exercise
chronic low back pain, 152–154 and Alzheimer disease pathology, 188, 189
exercise for, 151 beginning exercise training, 18
and fear avoidance, 151 body-brain connection, 95–97
fibromyalgia, 160–162 in brain function, 2
headaches, 157–160 cerebral blood flow and, 168, 169
inflammation and, 151 during pregnancy, 75
neck pain, 155–157 early exercise equipment, 64, 65
opioids and, 148 and early neurology, 4
perception of, 148 effect of maternal exercise, 75–77
Chronic stress, 133 green exercise, 103
“Circle of Willis”, 169 for health in early America, 3, 4
Cognitive activity, 67 high, 99–102
Cognitive aging, 113 for improving cognition in older people,
Cognitive function, 109, 206 122, 124, 125
Cognitive performance, 83 on learning and memory, 97, 98
Cognitive reserve theory, 122 and Lewey bodies, 195, 196
Constraint-induced movement therapy physicians and “exercise pill”, 1, 2
(CIMT), 178 placebo effect of, 144
Cooper, K., 7–9 for preventing and treating tauopa-
Cortisol, 132 thies, 198
Cureton, T, 6 for prevention of falls in older
Cytokine levels, 133 people, 121
Cytokines, 188 prevention of Parkinson disease, 196, 197
and rehabilitation, 172–174
serotonin, emotions and learning, 104, 105
D and sleep, 98, 99
Darwin, C., 68, 148 and stroke prevention, 170–172
Darwin, E., 148 training for improving fitness, 16–18
Dementia, 1 for treating abnormal brain develop-
tau protein aggregation, 197 ment, 84, 85
vascular dementia, 193–195 for treating anxiety, 138, 139
Depression, 39, 139, 158 for treating depression, 143, 144
animal models of, 140–142 for treating PTSD, 136, 137
exercise for preventing, 142 Exercise muscles, 120
exercise for treating, 143, 144 Exercise training, 126
Diagnostic and Statistical Manual of Mental Exercise-induced fatigue, 104
Disorders (DSM) of the American
Psychiatric Society., 140
Diamond, J., 32 F
Diet and Cognitive Aging, 124 Fibromyalgia, 160
Disc protrusions, 153 The Finnish Geriatric Intervention Study to
Dopamine, 150 Prevent Cognitive Impairment and
Disability (FINGER), 126
Frontotemporal dementia (FTD), 187
E Fructose, 27
Early rehabilitation program, 180 Functional magnetic resonance imaging
Early-life stress, 141 (fMRI), 179
Emotional brain, 132 Functional MRI studies, 84
Index 211
G Low-grade chronic inflammation, 188

Galen, 52, 53 Lumholtz, Carl, 33
Gene variants, 31, 188
Greek education system, 51
Greek gymnasium, 48, 49 M
GutsMuths, 91 Magnetic resonance imaging (MRI), 83,
115, 116
Medical community, 208
H Medical treatments, 46
Hatha Yoga, 44 Mediterranean diet, 125
Headaches, 157–160 Memory impairment progresses, 187
Heart attacks, 168 Metabolic equivalent of task (MET), 203
Helsinki Birth Cohort Study, 111 Migraine headaches, 157
Herodicus of Cnidos, 46, 47 Mild cognitive impairment (MCI), 124, 185
Hippocrates of Cos, 47, 48 Military drilling, 51
Human brain development, 71, 72 Mitchell, S.W., 4
Hunter-gatherer societies Moderate- intensity physical activity, 203
The Aché, 24, 25 Modern yoga, 44
vs. agricultural lifestyle, 29, 30 Monoamines, 150
The Amish, 31 Morgan, W., 142
APOE gene and late onset chronic Mouse stroke model, 178
diseases, 28, 29 Multicomponent physical activity, 203
Canadian Inuits, 31–34 Muscle electrical activity, 25
energy consumption in, 22, 23 Muscular strength, 120, 206
The Hadza, 23
industrial revolution, 34, 35
physical activity in, 25, 26 N
thrifty gene hypothesis, 26 National Health and Nutritional Survey
(NHANES), 114
National transportation surveys, 36
I Neel, J., 26
Industrial revolution, 34, 35 Neural stem cells, 177
Inhibitory neurotransmitter, 141 Neurogenesis, 94
Insulin-like growth factor 1 (IGF-1), 121 Neuroplasticity, 94, 123, 177
Interleukin (IL), 188 Neurotransmitters, 94
Neurotrophins, 94
NHANES study, 114
J Noradrenaline, 150
Jefferson, T., 63, 64 Normal aging, 123
Jones, D., 33
Julius Ceasar, 53
O
Obesity, 13
K Obstetric dilemma, 70
Kandel, E., 93 Olympic games, 49, 50
Kung Fu, 42
P
L Paffenbarger, R., 9
Light-intensity physical activity, 203 Pain signals, 149
Limbic system, 132 Physical activity, 2, 67, 203, 206
Locke, J., 58–60 in adolescent children, 81
Long term potentiation (LTP), 94, 149 in infants, 77, 78
Lothian Birth Cohort study, 112 in preadolescent children, 79
212 Index
Physical activity (cont.) Slight pressure, 161

vs. rest during pregnancy, 74, 75 Smythe, Hugh, 160
thrifty gene hypothesis, 27, 28 Social isolation, 120
WHO recommendations, 205 Statins, 172
WHO recommendations for, 203, 204 Stress
Physical education exercise and, 134, 135
and academic performance, 82, 83 financial or family health crisis, 129
early ideas on, 5, 6 and illness, 129
and learning, 89–92 neurobiology of, 132–134
and sports, 6, 7 posttraumatic stress syndrome, 135
Thomas Cureton and the science of, 6 Stress triggers, 131
Physical fitness, 2 Stretching, 42
and academic performance, 80–82 Strokes, 167
and longevity, 10, 11 brain recover from, 177, 178
oxygen utilization and, 14, 15 delayed recovery, 178, 180
sparta and, 45, 46 exercise and rehabilitation after, 172–174
Physical inactivity, 36, 203 factor, influence recovery of, 180
and chronic diseases, 35–38 prevention, 170–172
and poor health, 9 stroke rehabilitation, 181, 182
Public Health implications of, 11, 12 types of, 170
Plato, 48, 49 Stroops test, 105
Posttraumatic stress syndrome (PTSD), 135 Subarachnoid hemorrhage strokes, 170
PREDIMED study, 125 Swedish system, 92
Pregnant and postpartum women, 206
Primitive hunter gatherer societies, 111
Progressive supranuclear palsy (PSP), 187 T
Psychosocial factors, 154 Tai Chi, 42
Pulmonary ventilation, 169 Taoism, 42
Pyrrhic dance, 46 Ta Wu, 41
Telomeres, 113, 114
Tender points, 161
R Tension-type headaches, 158
Randomized controlled trials, 176 Tierney, P., 27
Religious beliefs, 54 Tissue plasminogen activator (tPA), 174
The Renaissance, 56–58 Tranquilizers, 155
Ricketson, S., 3 Transportation, 3
Rig-Veda, 44 Tumor necrosis factor alpha (TNFα), 188
Roman Empire, 54
The Romans, 50–52
Roosevelt, T., 5 V
Rousseau, Jean-Jacques, 60–63 Vascular dementia, 193–195
Vascular endothelial growth factor
(VEGF), 172
S Vedic yoga, 44
Sargent, D., 5 Vigorous-intensity physical activity, 203
Sedentary behavior, 203–205 VITACOG study, 125
Selective serotonin reuptake inhibitors Vitamin D, 122
(SSRIs), 105, 106
Selye, H., 132
Serotonin, 104, 150 W
Serotonin levels, 104 Warren, J.C., 3
Serotonin receptors, 93 White matter abnormalities, 115–118
Serum insulin, 37 White matter hyperintensities, 116, 117
Serum serotonin, 105 White, J.W., 5
Skeletal muscles, 120 Whitman, W., 5
Index 213
World Health Organization (WHO), 201, 202 Y

World War I, 6 Yanomami tribes, 26, 27
World War II, 6 Yoga, 44
X Z
X-ray computerized tomography, 115 Zues, 50

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Exercise and

Exercise and the Brain

ISBN 978-3-031-13923-9 ISBN 978-3-031-13924-6 (eBook)

The emphasis is on scientific data, but the material is presented in a straightfor-

Neurology, UCLA, Los Angeles, CA, USA Robert W. Baloh

Hunter-Gatherers didn’t Have it So Bad���������������������������������������������������� 32

How Exercise Improves Learning�������������������������������������������������������������� 94

Exercise for Treating Chronic Low Back Pain������������������������������������������ 154

Older Adults Ages 65 Years and Older������������������������������������������������������ 206

Physicians and the “Exercise Pill”

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 1

Exercise, Physical Activity and Physical Fitness

Exercise for Health in Early America

Exercise and Early Neurology

Early Ideas on Physical Education

In 1887, J William White, another Philadelphia physician, published an article for

Thomas Cureton and the Science of Physical Education

Physical Fitness and Sports

Kenneth Cooper and Aerobics

Physical Inactivity and Poor Health

Physical Fitness and Longevity

Public Health Implications of Physical Inactivity

Body Weight and Energy Metabolism

Physical Fitness, Obesity and Cardiovascular Disease

Aerobic Versus Anaerobic Physical Activity

Oxygen Utilization and Fitness

Exercise Training for Improving Fitness

Examples of moderate-intensity physical activities include:

• Walking at least 2.5 miles per hour

Examples of high-intensity physical activities include:

To improve cardiovascular fitness you need to gradually increase the amount

Beginning Exercise Training

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 21

Common ~ 16 million ~ 6 million ~ 2 million ~ 300,000

Fig. 2.1 Evolution of the human species

Energy Consumption in Primitive Societies

Physical Activity in Hunter-Gatherers

The obvious implication of these studies is that 30 minutes to an hour of moder-

The Thrifty Gene Hypothesis

Napoleon Chignon Popularizes Anthropology

Neel was first introduced to the Yanomami by anthropologist, Napoleon Chignon,

Physical Activity and the Thrifty Gene Hypothesis

The APOE Gene and Late Onset Chronic Diseases

The Agricultural Revolution

Around 12,000 BC, agriculture was introduced in human populations at several

Hunter-Gatherer Versus Agricultural Lifestyle

were widely available in agricultural communities consumption was still limited by

The Old Order Amish

The Canadian Inuits

Hunter-Gatherers didn’t Have it So Bad

Based on detailed descriptions of the modern day remnants of these primitive

The Industrial Revolution

Unlike the transition from hunter-gatherer to agricultural societies in which there

Physical Inactivity and Chronic Diseases

Depression is a neurological disease with characteristic neurological symptoms

Chinese Martial Arts

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 41

Fig. 3.1 Stretching and breathing exercises as performed in ancient China

Yoga and the Melding of the Mind and Body

Sparta and Physical Fitness

Neurology, UCLA, Los Angeles, CA, USA Robert W. Baloh

Hunter-Gatherers didn’t Have it So Bad�� 32

How Exercise Improves Learning�� 94

Exercise for Treating Chronic Low Back Pain�� 154

Older Adults Ages 65 Years and Older�� 206

Physicians and the “Exercise Pill”

Exercise, Physical Activity and Physical Fitness

Exercise for Health in Early America

Exercise and Early Neurology

Early Ideas on Physical Education

Thomas Cureton and the Science of Physical Education

Physical Fitness and Sports

Kenneth Cooper and Aerobics

Physical Inactivity and Poor Health

Physical Fitness and Longevity

Public Health Implications of Physical Inactivity

Body Weight and Energy Metabolism

Physical Fitness, Obesity and Cardiovascular Disease

Aerobic Versus Anaerobic Physical Activity

Oxygen Utilization and Fitness

Exercise Training for Improving Fitness

Beginning Exercise Training

Energy Consumption in Primitive Societies

Physical Activity in Hunter-Gatherers

The Thrifty Gene Hypothesis

Napoleon Chignon Popularizes Anthropology

Physical Activity and the Thrifty Gene Hypothesis

The APOE Gene and Late Onset Chronic Diseases

The Agricultural Revolution

Hunter-Gatherer Versus Agricultural Lifestyle

The Old Order Amish

The Canadian Inuits

Hunter-Gatherers didn’t Have it So Bad

The Industrial Revolution

Physical Inactivity and Chronic Diseases

Chinese Martial Arts

Yoga and the Melding of the Mind and Body

Sparta and Physical Fitness

Athens and the Greek Gymnasium

The Olympic Games

The Middle Ages and the Soul Rules the body

The Age of Chivalry

Early Exercise Equipment

Link Between Upright Posture and Increasing Brain Size

Brain Growth After Birth

Human Brain Development

Neuroplasticity and Brain Development

Physical Activity and Brain Development

Physical Activity Versus Rest During Pregnancy

Exercise During Pregnancy Is Beneficial to Mother and Child

Effect of Maternal Exercise on Fetal Brain Development

Physical Activity in Infants

Physical Activity in Preadolescent Children

Physical Fitness and Academic Performance

Physical Activity in Adolescent Children

Physical Fitness and Academic Performance in Adolescents

Physical Education and Academic Performance

How Does Exercise Influence Brain Development?

Exercise for Treating Abnormal Brain Development

Physical Education and Learning

Basic Mechanisms of Learning

How Exercise Improves Learning

Exercise and the Body-Brain Connection

Research Studies of Exercise on Learning and Memory

Sleep, Exercise and Learning

Serotonin, Emotions and Learning

Serotonin Drugs and Learning

Energy Consumption and the Aging Brain

Early Life Experiences and the Aging Brain

Genes and Cognitive Aging

Telomere Length, Physical Activity and Aging

White Matter Abnormalities with Aging

Shrinkage of the Brain with Aging

Muscular Strength and Aging

Exercise for Prevention of Falls in Older People

Exercise for Improving Cognition in Older People

activity-dependent secretion of BDNF and increase the likelihood of developing age

Combining Interventions to Prevent Cognitive Decline