Exercise and the Brain: Why Physical Exercise is Essential to Peak Cognitive Health 3031139232, 9783031139239

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

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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 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

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 preventing and treating common neurological symptoms and diseases. The book is also a comprehensive guide to the safety and efficacy of different types of physical activity needed to sustain a healthy brain throughout one’s life span. Given the importance 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 different 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 following 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 decisions 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 cardiovascular 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

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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 concludes: “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 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 functioning. 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 controlled trials and meta-analyses of these trials is also described in detail.

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Foreword 2

The emphasis is on scientific data, but the material is presented in a straightforward 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 ancestors 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 advancement in society. Leaders were selected on the basis of their physical, not their mental, 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 purchase 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 longstanding interest in the history of medicine, particularly the history of exercise in medicine. 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 neurological topics. I have personally supervised several large NIH-funded research ix

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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 committees focused on improving public health and brain health. In 1990, I submitted a research proposal to the National Institute of Aging entitled 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 subjects 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 longevity, we were cautious about conclusions but this chance observation was a key motivating 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 childhood 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 movement 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 developing 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.

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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 exercise. 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 overview and historical background for understanding why physical activity is so important 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 prevention and treatment of common neurological disorders including depression, chronic pain, strokes, and dementia. Finally, I conclude with an overview chapter that summarizes the current World Health Organization (WHO) recommendations for physical 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.

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Contents

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 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

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 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

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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

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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

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 Exercise, the Elixir for Learning������������������������������������������������������������   89 Physical Education and Learning��������������������������������������������������������������   89 Basic Mechanisms of Learning������������������������������������������������������������������   93

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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 References��������������������������������������������������������������������������������������������������  127

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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 References��������������������������������������������������������������������������������������������������  144

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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

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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 References��������������������������������������������������������������������������������������������������  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 References��������������������������������������������������������������������������������������������������  182

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 References��������������������������������������������������������������������������������������������������  199 11 Overview ��������������������������������������������������������������������������������������������������  201 World Health Organization (WHO) Guidelines����������������������������������������  202 Infants 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 obesity. 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 completely 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 overweight 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 muscle that is rapidly depleted. Aerobic physical activity uses fuel much more efficiently 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 maximize oxygen content in the blood you breathe faster and deeper and the heart rate

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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 exercise 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 improving brain function. So which type of exercise is best for you? The simple answer is probably a combination 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 obvious 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, however, 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 characterized by brief heavy resistance strength exercises such as lifting near maximum weight barbells while at the other end of the continuum is aerobic exercise characterized 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 nervous system manages the blood redistribution by relaxing the smooth muscles in the walls of the small arteries supplying working muscles while constricting the muscles 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 expiration. 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 cardiovascular 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 available 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 minute. However, just as with maximum oxygen uptake, maximum heart rate varies greatly with cardiovascular fitness and age so the best way to determine the maximum 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 maximum heart rate achieved during maximum performance.

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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 approximately 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 exercises, 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 individual’s fitness level. With any physical activity there are three variables, intensity, duration and frequency 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 benefit than increasing duration, but at some point further increases in intensity are less beneficial than increasing duration. Furthermore, it is important to spread the physical 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 percentage 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

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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 baseline 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 particular 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 cardiac 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 physical 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

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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.

References 1. British statesman, Edward Stanley the 15th Earl of Derby, made this statement in ones of his speeches in 1873. 2. Sallis RE.  Exercise is medicine and physicians need to prescribe it! Br J Sports Med. 2009;43:3–4. 3. Casperson CJ, Powell KE, Christenson GM.  Physical activity, exercise, and physical fitness: definitions and distinctions for health related research. Public Health Rep. 1985;100:126–31. 4. Ricketson S. Means of preserving health: founded principally on an attention to air and climate, drink, food, sleep, exercise. New York: Collins, Perkins; 1806. p. 152. 5. Warren JC. Physical education and the preservation of health. Boston: William D. Ticknor; 1846. p. 90. 6. Mitchell SW. Wear and tear or hints for the over worked. 5th ed. Philadelphia: Lippincott; 1891. 7. Mitchell SW. Fat and blood: an essay on the treatment of certain forms of neurasthenia and hysteria. Philadelphia: Lippincott; 1889. 8. Earnest ES. Weir Mitchell, novelist and physician. Philadelphia: University of Pennsylvania Press; 1950. 9. White JW. A physicians view of exercise and athletics. New York, Lippincott. 1887;39:1033. 10. Sargent HJ. Health, strength and power. Boston: HM Caldwell; 1904. 11. McKenzie RT.  Exercise in education and medicine. Philadelphia: WB Saunders; 1909. p. 12. 12. Berryman JW, Thomas K.  Cureton, Jr.: pioneer researcher, proselytizer, and proponent for physical fitness. Res Q Exerc Dance. 1996;67:1–12. 13. Williams RL, editor. The healthy life: how diet and exercise affect your heart and vigor. New York: Time Life Books; 1966. 14. Berryman JW.  Exercise is medicine: a historical perspective. Curr Sports Med Rep. 2010;9:195–201. 15. Kennedy JF. Sport at the new frontier: the soft American. Sports Illustrated. 1960;13:14–7. 16. Michener JA. Sports in America. New York: Random House; 1976. p. 67–8. 17. Cooper KH. Aerobics. New York: M. Evans and Company; 1968. 18. Barker L. 50 years after writing ‘aerobics,’ Dallas’ Dr. Kenneth Cooper isn’t slowing down. The Dallas Morning News April 16, 2018. 19. Thompson H. Walk don’t run. Texas Monthly, June 1995. 20. Paffenbarger RS, Hyde RT, Wing AL, Hsieh CC.  Physical activity, all-cause mortality and longevity of college alumni. N Engl J Med. 1986;314:605–13. 21. Pearce J, Paffenbarger RS Jr., 84, Epidemiologist, Dies. New York Times, July 14, 2007. 22. Paffenbarger RS, Olsen E.  LifeFit: an effective exercise program for optimal health and a longer life. Champaign, IL: Human Kinetics; 1996. 23. Blair SN, Kohl HW, Paffenbarger RS, et al. Physical fitness and all-cause mortality: a prospective study of healthy men and women. JAMA. 1989;262:2395–401. 24. Blair SN, Kohl HW III, Barlow CE, et al. Changes in physical fitness and all-cause mortality: a prospective study of healthy and unhealthy men. JAMA. 1995;273:1093–8. 25. Stofan JR, DiPietro L, Davis D, et al. Physical activity patterns associated with cardiorespiratory fitness and reduced mortality: the aerobics center longitudinal study. Am J Public Health. 1998;88:1807–13. 26. Blair SN. Physical inactivity: biggest public health problem of the 21st century. Br J Sports Med. 2009;43:1–2.

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27. Blair SN, Sallis RE. Exercise therapy—the public health message. Scand J Med Sci Sports. 2012;22:e24-28. 28. Garber CE, Blissmer B, Deschenes MR, et al. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidelines for prescribing exercise. Med Sci Sports Exerc. 2011;43:1334–59. 29. Lee DC, Sui X, Blair SN. Does physical activity ameliorate the health hazards of obesity? Br J Sports Med. 2009;43:49–51. 30. Shiroma EJ, Lee I-M.  Physical activity and cardiovascular health. Circulation. 2010;122:743–52. 31. Hargreaves M, Spriet LL. Exercise Metabolism. Champaign IL: Human Kinetics; 2006. 32. Hill A, Lupton H. Muscular exercise, lactic acid, and the supply and utilization of oxygen. Int J Med. 193(62):135–71. 33. Kramer A. An overview of the beneficial effects of exercise on health and performance. In: Xiao J, editor. Physical exercise for human health, advances in experimental medicine and biology. Singapore: Springer; 2020. p. 3–21. 34. Ketelhut S, Ketelhut RG.  Type of exercise training methods. An overview of the beneficial effects of exercise on health and performance. In: Xiao J, editor. Physical exercise for human health, advances in experimental medicine and biology. Singapore: Springer; 2020. p. 25–42.

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Physical Activity and Brain Evolution

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 industrialization 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 developed 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 animals 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 speculated that survival into the 70s and beyond can be explained based on the benefits of

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 R. W. Baloh, Exercise and the Brain, https://doi.org/10.1007/978-3-031-13924-6_2

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Orangutans

Common ancestor

Gorillas

Bonobos

Chimpanzees

Hunter gatherers

Homo Sapiens

~ 16 million years ago

~ 6 million years ago

~ 2 million years ago

~ 300,000 years ago

Fig. 2.1  Evolution of the human species

having grandparents who possess knowledge of cultural traditions and hunting techniques. 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 survival 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 societies. 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 potentially confounding influences, anthropologists have consistently found that modern day hunter-gatherer societies are much more physically active on a daily basis compared 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

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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 contemporary 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 sapiens 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 preservation. 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 routine 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, berries 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.

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From the start researchers were impressed with the lack of chronic medical illnesses 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 uncommon 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 ranchers 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 estimated 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 animals 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 additional 12 miles a day.

Physical Activity in Hunter-Gatherers As noted in Chap. 1, a simple but reliable technique to document the level of physical 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 running 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 positions 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 associated with squatting and kneeling is less than that associated with moderate to vigorous 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 important 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.

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The obvious implication of these studies is that 30 minutes to an hour of moderate 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 continuous 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 living 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 foraging 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 physical 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 common 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 contributed 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 geographically isolated deep within the Amazon, the Yanomami were already influenced by western culture for centuries using iron tools long before any anthropologists visited the region. Earlier in the twentieth century local governments gave permission 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 numbers 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 insulinresistant 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.

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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 consistently 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 lifestyle 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 deposition 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 inflammatory 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

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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 predominant 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 agricultural 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, politics 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 degenerative spine disease consistent with intense physical labor. Furthermore, the average 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

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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 raising 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 communities 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 expenditure in current day hunter-gatherer and agricultural societies found that energy expenditure in men was about the same but agricultural women expended significantly 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 consisting 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 ritualized and periodic only available for special occasions. Furthermore, natural fermentation 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 seasonally 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 impressive 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 societies? As a rule, there are major outbreaks of infectious disease, increased obesity and increased incidence of chronic diseases such as type 2 diabetes and

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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 transportation. White-collar jobs replaced hunting and fishing as their only means of subsistence. 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 educating 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 published a provocative article about the switch from hunter-gatherer lifestyle to agricultural 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

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Based on detailed descriptions of the modern day remnants of these primitive hunter-gatherer societies by anthropologists and lay people alike, they were surprisingly 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 similar 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 similarly low opinion of the European invaders finding them regimented, grim and joyless 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.

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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 controlled 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 illustrated 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 lifestyle 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 happiness 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 concluded 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 modern 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 activity, 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

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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 provided by infrequent recreational and leisure activities. For the first time in human existence exercise, a planned physical activity carried out with the goal of improving 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 improvement 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, hypertension and associated vascular disease are risk factors for these chronic neurological conditions.

Physical Inactivity and Chronic Diseases The notion that inactivity could decrease longevity became known in the mid twentieth 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 sedentary 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

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office. Not only did the physically inactive workers have more coronary artery episodes their symptoms were more severe than the physically active workers. Study after study in the latter half of the twentieth century showed that the mortality rate associated with the most common noninfectious causes of death (coronary 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 education 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 combination 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 variations occurred millions of years ago when early humans lived in a completely different 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 huntergatherers 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

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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 diabetes 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 environmental factors but the rapid recent epidemic is primarily due to environmental factors, 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 complex 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 physical 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 atherosclerosis, 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 polyunsaturated 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 polyunsaturated 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 physical 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.

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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 primitive 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 neurodegenerative 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 considered 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 manipulations. 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 determined 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 neurodegenerative diseases. Since diseases like type 2 diabetes, atherosclerosis, Alzheimer disease and Parkinson disease are relatively rare in primitive populations and extremely common in industrialized societies, they are sometimes called diseases of modern civilization, 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

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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.

References 1. Dobzhansky T.  Nothing in biology makes sense except in the light of evolution. Am Biol Teach. 1973;35:125–9. 2. Freese J, Klement RJ, Ruiz-Nunez B, et al. The sedentary (r)evolution: have we lost our metabolic flexibility? F1000Res. 2018;6:1787. 3. Cordain L, Gotshall RW, Eaton SB, Eaton SB III. Physical activity, energy expenditure and fitness: an evolutionary perspective. Int J Sports Med. 1998;19:328–35. 4. Marlowe F.  The Hazda: hunter-gatherers of Tanzania. Berkeley CA: Univ of California Press; 2010. 5. Hill K, Hurtado AM.  Aché life history: the ecology and demography of a foraging people. New York: Aldine de Gruyter; 1996. 6. Gurven M, Arave A, Hill K, Hurtado M. “It's a wonderful life”: signaling generosity among the Aché of Paraguay. Evol Human Behav. 2000;21:263–82. 7. Pontzer H, Raichlen DA, Wood BM, et  al. Energy expenditure and activity among Hadza hunter-gatherers. Am J Hum Biol. 2015;27:628–37. 8. Neel JV. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet. 1962;14:353–62. 9. Chagnon NA. Yanomamö: the fierce people. New York: Holt, Rinehart & Winston; 1968. 10. Lizot J.  Tales of the Yanomami: daily life in the Venezuelan Forest. Translated by Ernest Simon. Paris: Cambridge Univ. Press; 1985. 11. Tierney P.  Darkness in El Dorado: how scientists and journalists devastated the Amazon. New York: WW Norton; 2000. 12. Wang G, Speakman JR.  Analysis of positive selection at single nucleotide polymorphisms associated with body mass index does not support the "thrifty gene" hypothesis. Cell Metab. 2016;24:531–41. 13. Raichlen DA, Alexander GE. Adaptive capacity: an evolutionary-neuroscience model linking exercise, cognition and brain health. Trends Neurosci. 2017;40:408–21. 14. Menzel H-J, Kladetzky R-G, Assmann G.  Apolipoprotein E polymorphism and coronary artery disease. Arteriosclerosis. 1983;3:310–5. 15. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer’s disease. Neurology. 1993;43:1467–72. 16. Fullerton SM, et  al. Apolipoprotein E variation in the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism. Am J Hum Genet. 2000;67:881–900. 17. Raichlen DA, Alexander GE. Exercise, APOE genotype, and the evolution of the human lifespan. Trends Neurosci. 2014;37:247–55. 18. Price DT, Gabauer AB. New perspectives on the transition to agriculture. In: Price DT, Gabauer AB, editors. Last Hunters-First Farmers. Santa Fem NM: School of American Research Press. p. 3–20.

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19. Page AE, Viguier S, Dyble M, et al. Reproductive trade-offs in extant hunter-gatherers suggest adaptive mechanism for the neolithic expansion. ONAS. 2016;113:4694–9. 20. Dounias E, Froment A. When forest-based hunter-gatherers become sedentary: consequences for diet and health. Unasylva. 2006;224:26–33. 21. Bassett DR, Schneider PL, Huntington GE. Physical activity in an old order Amish community. Med Sci Sports Exerc. 2004;36:79–85. 22. Hsueh W-C, Mitchell BD, Aburomia R, et al. Diabetes in the old order Amish. Diabetes Care. 2000;23:595–601. 23. Holder J, Warren AC. Prevalence of Alzheimer’s disease and apoprotein E allele frequencies in the old order Amish. J Neuropsych. 1998;10:100–2. 24. Akande VO, Ruiter RAC, Kremers SPJ. Environmental and motivational determinants of physical activity among Canadian Inuit in the artic. Int J Environ Res Public Health. 2019;16:2437. 25. Diamond J. The worst mistake in the history of the human race. Discover Magazine. 1987; 26. Kidd TS, Hankins B. Baptists in America. A history. New York: Oxford Univ. Press; 2015. 27. Lumholtz CS. Unknown Mexico: A Record of Five Years Exploration Among the Tribes of the Western Sierra Madre; in the Tierra Caliente of Tepic and Jalisco; and among the Tarascos od Michoacin. New York: Charles Scribner’s Sons, volume I, 1902. 28. Oxendine JB. American Indian sports heritage. Omaha NB: Univ. Nebraska Press; 1995. 29. Suzman J. Affluence without abundance: what we can learn from the world’s most successful civilization. New York: Bloomsbury; 2017. 30. Chakravarthy MV, Fw B. Eating, exercise and “thrifty” genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases. J Appl Physiol. 2004;96:3–10. 31. Szreter S. Industrialization and health. Br Med Bull. 2004;69:75–86. 32. Morris JN, Kagan A, Pattison DC, et al. Incidence and prediction of ischaemic heart-disease in London busmen. Lancet. 1966;2:553–9. 33. Morris JN, Chave SP, Adam C, et al. Vigorous exercise in leisure-time and the incidence of coronary heart-disease. Lancet. 1973;1:333–9. 34. Booth FW, Roberts CK, Laye MJ.  Lack of exercise is a major cause of chronic diseases. Compr Physiol. 2012;2:1143–211. 35. U.S Department of Transportation. Summary of Travel Trends. National Household Travel Survey. Washington, D. C: Federal Highway Administration; 2001. p. 2004. 36. Ponzer H, Raichlen DA, Wood BW, et al. Hunter-gatherer energetics and human obesity. PLoS One. 2012;7:e40503. 37. Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus— present and future perspectives. Nat Rev Endocrinol. 2012;8:228–36. 38. Eaton SB, Konner MJ, Shostak M. Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Am J Med. 1988;84:739–49. 39. Thompson RC, Allam AH, Lombardi GP, et al. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Lancet. 2013;381:1211–22. 40. Fox M. Evolutionary medicine perspectives on Alzheimers’s disease: review and new directions. Ageing Res Rev. 2018;47:140–8. 41. Pacholko AG, Wotton CA, Bekar LK. Poor diet, stress, and inactivity converge to form a “perfect storm” that drives Alzheimer’s disease pathogenesis. Neurodegener Dis. 2019;19:60–77. 42. Di Liegro CM, Schiera G, Proia P, Di Liegro I. Physical activity and brain disease. Genes. 2019;10:720. 43. Hidaka BH. Depression as a disease of modernity: explanations for increasing prevalence. J Affect Disord. 2012;140:205–14.

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A Healthy Body for a Sound Mind

I say the best of all exercises are not only those which are able to exercise the body vigorously, 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 maintaining 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 important 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).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 R. W. Baloh, Exercise and the Brain, https://doi.org/10.1007/978-3-031-13924-6_3

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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 introduced 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 tolerated 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 understanding 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 farming and teaching martial arts [5, 6]. The Chen style which was practiced and gradually 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 discoveries teaching just to people in their village mostly relatives.

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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 traditional 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 separate from the military self-defense benefits. The Wu style is characterized by a forward 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.

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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 disciplined 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

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regulated breathing and periods of relaxation and meditation. Asanas played a relatively 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 liberation 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 oligarchic 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 sponsored special fitness programs designed to make them physically fit to become soldiers. 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 euthanized. 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 decision 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 training 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 entertainment. The boys were organized into squads according to age for their gymnastic

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training which included swimming, wrestling, running, jumping and throwing the javelin and discus. The squads were combined into companies for military exercises, 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 spectacular 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 influence 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 gymnasium 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 purgatives, 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 exercise 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 religion 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

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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 concluding 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 digestion 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 outside 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 revolutionize 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 princess. 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

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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 consumption 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 participants. 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 neglecting 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 comply 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.

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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 gymnasia 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 provided a transient unification of Greek society. Before the Games messengers traveled 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 completion 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 ceremonial 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

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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 anything 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 meager 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 typically including sword, lance, helmet, greaves and shield. Second and third class soldiers were ordinary citizens who were provided with weapons but were less

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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 weapons 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 interested 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 during his speeches. The popularity of the Greek outdoor gymnasium never took hold in Roman society. 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 converse and read poetry.

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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 maintained [3, 21]. Galen was born in the ancient city of Pergamon the son of a wealthy Greek architect 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.

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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 exercise 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 breathing 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 medication 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-exercising 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 contests 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 gladiators. 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 noting 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 experience. 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 relatively 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

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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 pleasure so that people would enjoy exercising. Galen was opposed to what he considered 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 development 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 dramatic 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 feelings 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

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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 experiences 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, astronomy and music. Sports or play of any kind was frowned upon as wasteful and potentially 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 chivalry 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

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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 dismounting 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 tournaments 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 roundtable. 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 persisted 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 interest 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

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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 universale), 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 fencing. 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 second half of the book he focuses on the medical benefits of exercise both for preventing 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

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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 devastated 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 implemented 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 treatments. People with symptoms were allowed to move freely throughout the city. Plague can be spread by respiratory droplets with coughing or sneezing which typically 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 philosopher 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 philosophy 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

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government. Locke later also fled to Holland with his only crime being his association 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 education 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 courageous. 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 education, 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 exercising 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.

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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 outdoors 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 education 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 understanding 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 children. 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 education 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.”

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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 seminary with the thought of becoming a priest. Rousseau had been an indifferent student 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 seamstress in Paris and all were given to a Foundling Hospital as newborns. The seamstress 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 entrusting them to a family ill brought up, to be still worse educated. The risk of the education 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.

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Rousseau began his treatise on Emile’s education by emphasizing the importance 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 business.” 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 movement. 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 continually 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 shuttlecock, 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 providing 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.

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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 without 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

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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 exercise” [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.

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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 mechanism 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 maintaining health developed. For the first time, a large segment of society was not getting 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 1. Galen. The exercise with the small ball. In: Galen: selected works (trans PN Singer). New York: 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 exercise 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. 6. Lam P.  History of Tai Chi. Sydney: Tai Chi Productions; 2007. https://taichiforhealthinstitute.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. 13. Tipton CM. The history of “exercise is medicine” in ancient civilizations. Adv Physiol Educ. 2014;38:109–2013. 14. Nutton V. Hippocratic theories; in ancient medicine. London: Routledge; 2004. 15. Reid HL. Plato’s gymnasium. Sport Ethics Philos. 2010;4:170–82. 16. Plato. Republic. Trans. Desmond Lee, Book 3, Harmondsworth: Penguin; 1987. 17. Kieran J, Daley A. The story of the Olympic Games. Philadelphia: Lippincott; 1961. 18. Keppie L. The making of the Roman Army. London: Anchor Brendon; 1984. 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. 21. Sarton G. Galen of Pergamon. Lawrence: University of Kansas Press; 1954. 22. Berryman JW. The art of medicine. Motion and rest: Galen on exercise and health. Lancet. 2012;380:210–1. 23. Randers-Pehrson JD.  Barbarians and romans: the birth struggle of Europe, AD 400-700. Norman, OK: University of Oklahoma Press; 1993. 24. McKitterick R.  Charlemagne: the formation of European identity. Cambridge: Cambridge University Press; 2008.

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25. Riley-Smith JSC.  The Oxford history of the crusades. New  York: Oxford University Press; 1999. 26. Hale J.  The civilization of Europe in the renaissance. New  York: Maxwell Macmillan International; 1994. 27. The age of the renaissance. London: Thames and Hudson; 1986. 28. Eliot CW, editor. English philosophers of the seventeenth and eighteenth centuries: Locke, Berkeley, Hume. New York: P. F. Collier & Son; 1910. 29. Locke J.  In: Grant RW, Tarcov N, editors. Some thoughts concerning education and of the conduct of the understanding. Indianapolis: Hackett Publishing Company; 1996. 30. Rousseau J-J.  Emile, or on education, trans with an intro by a bloom. New  York: Basic Books; 1979. 31. Einaudi M. Early Rousseau. Ithaca: Cornell University Press; 1968. 32. Kellar A. Colonial America: a compact history. New York: Hawthorn Books; 1971. 33. Boyd JP, editor. The papers of Thomas Jefferson, vol. 8, 25 February–31 October 1785. Princeton: Princeton University Press; 1953. p. 405–8. 34. Boyd JP, editor. The papers of Thomas Jefferson, vol. 6, 21 May 1781-March 1784. Princeton: Princeton University Press; 1953. p. 359–61. 35. Karolides NJ, Karolides M. Focus on fitness. Santa Barbara, CA: ABC-CLIO; 1993. 36. Willcox WB, editor. The papers of Benjamin Franklin, vol. 19, January 1 through December 31, 1772. New Haven: Yale University Press; 1975. p. 257–60.

4

The Developing Brain

It is notorious that man is constructed on the same general type or model with other mammals. 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 development 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 developing 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.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 R. W. Baloh, Exercise and the Brain, https://doi.org/10.1007/978-3-031-13924-6_4

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Link Between Upright Posture and Increasing Brain Size The development of upright posture in the human species nicely illustrates the gradual 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, freeing 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 leading 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, lengthening 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 activities 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 standing 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

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Human: 1,500 g, 86 billion neurons Chimpanzee: 380g 28 billion neuron

Cortex Parietal Occipital Frontal Temporal Cerebellum

~x3

~x15 ~x200

1 cm Macaque: 87g 6 billion neurons

Marmoset: 8g 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

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there was an increase in the energy content of the diet and improved aerobic capacity 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 functions 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 fontanelles 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 performance of complicated motor activities such as running, playing the piano or hitting 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

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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 awareness. 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 language 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 complete 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 positive and negative environmental factors to influence human brain development.

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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 cerebral 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 thickness 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 process 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 production and changed the “conditioning stimulus” from a lab coat to a loud noise, ringing 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 associated 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 neurons 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

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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 plasticity with environmental enrichment and physical activity. In the mid twentieth century the Canadian psychologist, Donald Hebb performed pioneering experiments 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 development. 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 information 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 particularly in animal studies [16]. Numerous studies in rodents show that wheel

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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 developmental 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 suggested earlier, during evolution early humans engaged in a variety of cognitive functions 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 theoretical concerns about the effects of physical activity on placental growth and potential 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 agricultural 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.

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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 regular 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 recommended 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 conducted 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 pregnancy 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

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potential confounding issues including, smoking, socioeconomic, education, marital 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 aerobics 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 during 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 pregnancy physical activity levels were highly correlated. It does raise the interesting possibility of a beneficial effect of exercise prior to pregnancy on the cognitive function 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 naturally 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

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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 phenomena 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 particularly 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 consistently shown a beneficial effect of exercise on brain function in pups at widely varying 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 previous 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 regardless 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 improvement 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 controls 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 correlated 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 learning (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

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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 impairment despite later returning to normal visual environment, Hubel and Wiesel performed 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 synapse formation in the visual cortex and led to permanent visual impairment. This explains why children born with congenital cataracts have permanent visual impairment 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 environment 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 activities 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.

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Physical Activity in Preadolescent Children Although a large number of studies have found a positive effect of exercise on cognitive function in preadolescent children, there are also studies with disparate findings 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 function. 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 socioeconomic status can all influence fitness independent of exercise. In order to interpret studies of physical fitness in children it is important to understand 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 sophisticated 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 during 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 measure 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 children 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 continues. 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 maximum lap score.

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As with heart rate, the maximum oxygen uptake can be estimated from the performance 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 obesity (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 fitness 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 fitness 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 measured 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 measurements with little change in muscle strength and flexibility measurements. For example, 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 academic 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 development 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

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the cerebral cortex. These functions include planning, working memory and inhibitory control as well as other processes under conscious control that help avoid making errors. Studies in preadolescent children (4–8 years of age) show that they have relatively 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 fitness (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 fitness was correlated with better performance on the test of executive function independent 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 published 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 average 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 elementary 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 performance 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

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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 individual specific and not due to shared environmental or genetic influences. Heritability explained less than 15% of the beneficial effect of cardiovascular fitness on cognitive 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 during 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

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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 additional 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 significantly increased in the experimental group with increased frequency and intensity 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 performed 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 studies 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 adolescents. 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

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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 neurotrophic 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 disorder affecting nearly 10% of children [36]. ADHD begins during preschool years and persists throughout adolescence and adulthood causing significant functional disability over a lifetime. The main neuropsychological symptoms of ADHD are hyperactivity, poor attention and impulsivity. Overall, Children with ADHD perform 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 consistent 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 behavioral 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

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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 treatments 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 children 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 available 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 hyperactivity 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 (noradrenalin 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 convincing one must keep in mind the limitations in comparing cognitive function measurements 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.

References 1. Darwin C. The descent of man: the evolution. VM eBooks; 2016. p. 4–5. 2. Rodman PS, McHenry HM.  Bioenergetics and the origin of hominid bipedalism. Am J Physical Anthropol. 1980;52:103–6. 3. Niemitz C.  The evolution of the upright posture and gait—a review and a synthesis. Naturwissenschaften. 2010;97:241–63.

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4. Sockol MD, Raichlen DA, Pontzer H.  Chimpanzee locomotor energetics and the origin of human bipedalism. PNAS. 2007;104:12265–9. 5. Hofman MA. Design principles of the human brain: an evolutionary perspective. Prog Brain Res. 2012;195:373–90. 6. Allen JS. The lives of the brain: human evolution and the organ of mind. Cambridge, MA: Belknap Press; 2009. 7. Leigh SR. Brain ontogeny and life history in Homo erectus. J Hum Evol. 2006;50:104–8. 8. Coqueugniot H, Hublin J-J, Veillon F, et al. Early brain growth in Homo erectus and implications for cognitive ability. Nature. 2004;431:299–302. 9. Weaver AH.  Reciprocal evolution of the cerebellum and neocortex in fossil humans. PNAS. 2005;102:3576–80. 10. Van Essen DC, Donahue CJ, Glasser MF. Development and evolution of cerebral and cerebellar cortex. Brain Behav Evol. 2018;91:158–69. 11. Blakemore S-J, Choudhury S. Development of the adolescent brain: implications for executive function and social cognition. J Child Psychol Psychiatry. 2006;47:296–312. 12. Pavlov IP. Conditioned reflexes. An investigation of the physiological activity of the cerebral cortex (translated by Anrep GV). London: Oxford University Press; 1927. 13. Cajal SR. The Croonian lecture: the fine structure of the nervous system. Proc R Soc Lond Ser B. 1894;55:444–67. 14. Gomez-Robles A, Hopkins WD, Schapiro SJ, Sherwood CC. Relaxed genetic control of cortical organization in human brains compared with chimpanzees. PNAS. 2015;112:14799–804. 15. Hebb DO. The organization of behavior. New York: Wiley; 1949. 16. Gomes da Silva S, Arida RM. Physical activity and brain development. Exp Rev Neurother. 2015;15:1041–51. 17. Hamilton GF, Criss KJ, Klintsova AY. Voluntary exercise partially reverses neonatal alcohol-­ induced deficits in mPFC layer II/III dendritic morphology of male adolescent rats. Synapse. 2015;69:405–15. 18. Raichlen DA, Bharadwaj PK, Fitzhugh MC. Differences in resting state functional connectivity between young adult endurance athletes and healthy controls. Front Hum Neurosci. 2016;10:610. 19. Clapp JF III, Cram C. Exercise through your pregnancy. A compelling case for exercise during and after pregnancy. 2nd ed. Omaha, NE: Addicus Books; 2012. 20. Clapp JF III.  Morphometric and neurodevelopmental outcome at age five years of the offspring of women who continued to exercise regularly throughout pregnancy. J Pediatr. 1996;129:856–63. 21. Esteban-Cornejo I, Martinez-Gomez D, Tejero-Gonzalez CM, et al. Maternal physical activity before and during the prenatal period and the offspring’s academic performance in youth. The UP&DOWN study. J Matern Fetal Neonatal Med. 2015;29:1–7. 22. Robinson AM, Bucci DJ. Maternal exercise and cognitive functions of the offspring. Cogn Sci. 2012;7:187–205. 23. Parnpiansil P, Jutpakdeegul N, Chentanez T, Kotchabhakdi N.  Exercise during pregnancy increases hippocampal brain-derived neurotrophic factor mRNA expression and spatial learning in neonatal rat pup. Neurosci Lett. 2003;352:45–8. 24. Kandel ER.  An introduction to the work of David Hubel and Torsten Wiesel. J Physiol. 2009;587:2733–41. 25. Sibley BA, Etnier JL. The relationship between physical activity and cognition in children: a meta-analysis. Ped Exercise Sci. 2003;15:243–56. 26. Коlіmесhkоv Ѕ. Рhуѕісаl fіtnеѕѕ аѕѕеѕѕmеnt іn сhіldrеn аnd аdоlеѕсеntѕ: а ѕуѕtеmаtіс rеvіеw. Еur Ј Рhуѕ Еduс Ѕроrt Ѕсі. 2017;3:65–78. 27. Plowman SA, Meredith MD, editors. Fitnessgram/activitygram reference guide. 4th ed. Dallas, TX: The Cooper Institute; 2013. 28. Castelli D, Hillman C, Buck S, Erwin HE. Physical fitness and academic achievement in 3rd and 5th grade students. J Sport Exerc Psychol. 2007;29:239–52.

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29. Efrat M. The relationship between low-income and minority children’s physical activity and academic-related outcomes: a review of the literature. Health Educ Behav. 2011;38:441–51. 30. Hillman C, Buck S, Themanson JR, Pnontifex MB.  Aerobic fitness and cognitive development: event-related brain potential and task performance indices of executive control in preadolescent children. Dev Psychol. 2009;45:114–29. 31. Aberg MA, Pedersen NL, Toren K, et al. Cardiovascular fitness is associated with cognition in young adulthood. PNAS. 2009;106:20906–11. 32. Middleton LE, Barnes DE, Lui L-Y, Yaffe K.  Physical activity over the life course and its association with cognitive performance and impairment in old age. J Am Geriatr Soc. 2010;58:1322–6. 33. Ardoy DN, Fernandez-Rodriguez D, Jimenez-Pavon D, et  al. A physical education trial improves adolescent’s cognitive performance and academic achievement: the EDUFIT study. J Med Sci Sports. 2014;24:e52–61. 34. Herting MH, Chu X.  Exercise, cognition and the adolescent brain. Birth Defects Res. 2017;109:1672–9. 35. Hopkins ME, Nitecki R, Bucci DJ. Physical exercise during adolescence versus adulthood: differential effects on object recognition memory and brain-derived neurotrophic factor levels. Neuroscience. 2011;194:84–94. 36. Halperin JM, Healey DM. The influences of environmental enrichment, cognitive enhancement and physical exercise on brain development: can we alter the developmental trajectory of ADHD? Neurosci Biobehav Rev. 2011;35:621–34. 37. Sagvolden T, Borga E, Woien G, et al. The spontaneous hypertensive rat model of ADHD—the importance of selecting the appropriate reference strain. Neuropharmacology. 2009;57:619–26. 38. Robinson AM, Hopkins ME, Bucci DJ. Effects of physical exercise on ADHD-like behavior in male and female adolescent spontaneously hypertensive rats. Dev Psychobiol. 2011;53:383–90.

5

Exercise, the Elixir for Learning

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 environment. When we learn something, physical changes occur in our brains. Old connections 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 exercise improves learning and continues to be beneficial for learning long after brain development is complete. Based on empirical observations that students who exercise 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 physical 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

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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 students 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 summer, 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 gradually 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 functioning 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.

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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 physician 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 supporting 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 considered 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 techniques. 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.

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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 understand 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 gymnastic instructors in Stockholm where he was known for developing free calisthenics 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 disciples. Initially, the established Swedish medical community was suspicious of Ling’s

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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 mechanisms of brain plasticity, however, would require improvements in technology and molecular biology that only became available in the latter half of the twentieth century. 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 abdominal 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 neurons 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 magnification. He was able to penetrate the neurons with a glass pipet and maintain recordings 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 sensory 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 animal 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 neurotransmitter serotonin at synapses on the axon terminals of the sensory neurons. Serotonin receptors in the presynaptic membrane then activated a cascade of intracellular “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 longer 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

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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 neuronal 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 stable 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 experiences 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 important during retrieval of memories by monitoring the process to verify accuracy. The monitoring process allows a person to separate activated concepts based on information 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 hippocampus producing an anxiety/depression like state. By contrast, exercise increases hippocampal volume, improves neuroplasticity and neurogenesis and relieves anxiety and depression symptoms. Such animal studies suggest a central role for neuroplasticity 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.

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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 hippocampus 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 semipermeable membrane called the blood brain barrier. Proteins particularly large

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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 capillary 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 complicated 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 during 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 messenger 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 metabolic requirements of contracting muscles. The hypothalamus activates the sympathetic division of the autonomic nervous system releasing noradrenalin and sending

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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 increasing 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 cortisol 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 hippocampus, 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 regardless 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 chapter) 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 learning 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

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regularly. They typically don’t smoke, eat better and have a higher socioeconomic status than people who do not exercise. It is even possible that a preexisting 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, running 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 durations 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 suggesting 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 outside 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 prefrontal cortex. Suppression of sleep (sleep deprivation) prior to learning tasks impairs acquisition 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

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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 transiently 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, exercise 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 quality 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

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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 complex interactions between primitive neuronal networks deep in the brain and more recently evolved networks in the cerebral cortex. Many of our emotions and behaviors 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 relaxation 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 dopamine within a neuronal network that became known as the motivation/reward network. 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 motivation/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 transmission 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.

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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 motivation/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 important 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, hippocampus and the amygdala are rich in endocannabinoid receptors and cannabinoid drugs such as cannabis bind to these receptors reducing stress and anxiety and promoting 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, endocannabinoids 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 endorphins 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 effervescence [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 compulsion 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

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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 measured 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 exertion/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 exercising 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 performed 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

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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 exercise. Another motivating factor that recently has received special attention is exercise 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 powers 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 better physical and mental health benefits [33, 34]. Furthermore, since green exercise is typically conducted in public outdoor spaces there is no need for costly equipment and indoor space. Simply walking outdoors is probably the easiest of all exercises to maintain adherence. In addition to motivating people to exercise, there is evidence that people perceive exercise as easier outdoors in a natural environment. When people walk outdoors 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 exercise 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 including 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

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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 amygdala 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 serotonin 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

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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 exercise group began with a 5-min warm up and then cycled for 30 min at their designated 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 correlation 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 inhibitors (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 improvement 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, escitalopram, given to healthy volunteers impaired learning and cognitive flexibility while improving impulse control compared to those given placebo [38]. The authors

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speculated that the results reflected a differential modulation of serotonin in different 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 produced 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 process 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 environment. 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 symptoms and signs of depression.

References 1. Bauer KD, Liou D. Physical activity. In: Nutrition counseling and educational skill development. 3rd ed. Boston, MA: Cengage Learning; 2016. p. 192. 2. Leonard FE.  The beginnings of modern physical training in Europe. Am Phys Ed Rev. 1904;9:89–110. 3. Leonard FE. History of physical education. In: McKenzie RT, editor. The physical education series. Philadelphia: Lea & Febiger; 1923. 4. Kandel ER. In search of memory. New York: WW Norton & Co; 2006. 5. Kempermann G, Gage FH, Aigner L, et al. Human adult neurogenesis: evidence and remaining questions. Cell Stem Cell. 2018;23:25–30. 6. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25:295–301. 7. Lindenberger U, Lovden M. Brain plasticity in human lifespan development: the exploration-­ selection-­refinement model. Annu Rev Dev Psychol. 2019;1:97–222. 8. McEwen BS. Structural plasticity of the adult brain: how animal models help us understand brain changes in depression and systemic disorders related to depression. Dialogues Clin Neurosci. 2004;6:119–33. 9. Voss MW, Vivar C, Kramer AF, van Praag. Bridging animal and human models of exercise-­ induced brain plasticity. Trends Cogn Sci. 2013;17:525–44. 10. Ratey JJ, Hagerman E. Spark. New York: Little Brown Co; 2008. p. 35–56. 11. Gejl AK, Enevold C, Bugge A, et  al. Association between serum and plasma brain-derived neurotrophic factor and influence of storage time and centrifugation strategy. Sci Rep. 2019;9:9655. 12. De la Rosa A, Solana E, Corpas R, et al. Long-term exercise training improves memory and modulates peripheral levels of BDNF and Cathepsin B. Sci Rep. 2019;9:3337. 13. Dinoff A, Herrmann N, Swardfager W, et al. The effect of exercise training on resting concentrations of peripheral brain-derived neurotrophic factor (BDNF): a meta-analysis. PLoS One. 2016;11:e0163037. 14. Pedersen BK, Akerstrom TC, Nielsen AR, Fischer CP.  Role of myokines in exercise and metabolism. J Appl Physiol. 2007;103:1093–8. 15. Kwon JH, Moon KM, Min K-W. Exercise-induced myokines can explain the importance of physical activity in the elderly: an overview. Healthcare (Basel). 2020;8:378. 16. Thomas AG, Dennis A, Bandetttini PA, Johansen-Berg H. The effects of aerobic activity on brain structure. Front Psychol. 2012;3:86.

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17. Patten AR, Yau SY, Fontaine CJ. The benefits of exercise on structural and functional plasticity in the rodent hippocampus of different disease models. Brain Plast. 2015;1:97–127. 18. Erickson KI, Voss MW, Prakash TS, et al. Exercise training increases size of hippocampus and improves memory. PNAS. 2011;108:3017–22. 19. Blomstrand P, Engvail J. Effects of a single exercise workout on memory and learning functions in young adults—a systematic review. Transl Sports Med. 4(1):115–27. https://doi. org/10.1002/TSM2.190. 20. Zagaar M, Dao A, Levine A, et  al. Regular exercise prevents sleep deprivation associated impairment of long-term memory and synaptic plasticity in the Ca1 area of the hippocampus. Sleep. 2013;36:751–61. 21. Reid KJ, Baron KG, Lu B, et al. Aerobic exercise improves self-reported sleep and quality of life in older adults with insomnia. Sleep Med. 2010;11:934–40. 22. Kline CE. The bidirectional relationship between exercise and sleep: implications for exercise adherence and sleep improvement. Am J Lifestyle Med. 2014;8:375–9. 23. Iftikhar IH, Kline CE, Youngstedt SD.  Effects of exercise training on sleep apnea: a meta-­ analysis. Lung. 2014;192:175–84. 24. Olds J, Milner P. Positive reinforcement produced by electrical stimulation of septal area and other regions of the rat brain. J Comp Physiol Psychol. 1954;47:419–27. 25. Wardie MC, Lopez-Gamundi P, LaVoy EC. Effects of an acute bout of physical exercise on reward functioning in healthy adults. Physiol Behav. 2018;194:552–9. 26. Merrer JL, Becker JAJ, Befort K, Kieffer BL. Reward processing by the opioid system in the brain. Physiol Rev. 2009;89:1379–412. 27. Gorzalka BB, Hill MN, Hillard CJ. Regulation of endocannabinoid signaling by stress: implications for stress-related affective disorders. Neurosci Biobehav Rev. 2008;32:11523–160. 28. Durkheim E. The elementary forms of religious life. New York: Free Press; 1912/1965. 29. Waller J. A forgotten plague: making sense of dance mania. Lancet. 2009;373:624–5. 30. Davis A, Taylor J, Cohen E. Social bonds and exercise: evidence for a reciprocal relationship. PLoS One. 2015;10:e0136705. 31. Tarr B, Launay J, Cohen E, Dunbar R. Synchrony and exertion during dance independently raise pain threshold and encourage social bonding. Biol Lett. 2015;11:20150767. 32. Wilson EO. Biophilia. Boston, MA: Harvard University Press; 1984. 33. Gladwell VF, Brown DK, Wood C, et al. The great outdoors: how a green exercise environment can benefit all. Extreme Physiol Med. 2013;2:3. 34. Glover N, Polley S. GOING GREEN: the effectiveness of a 40-day green exercise intervention for insufficiently active adults. Sports (Basel). 2019;7:142. 35. Ellaway A, Macintyre S, Bonnefoy X. Graffiti, greenery and obesity in adults: secondary analysis of European cross-sectional survey. Br Med J. 2005;331:611–2. 36. Nicastro TM, Greenwood BN. Central monoaminergic systems are a site of convergence of signals conveying the experience of exercise to brain circuits involved in cognition and emotional behavior. Curr Zool. 2016;62:293–306. 37. Zimmer P, Stritt C, Bloch W.  The effects of different aerobic exercise intensities on serum serotonin concentrations and their association with Stroop task performance: a randomized controlled trial. J Appl Physiol. 2016;116:2025–34. 38. Skandali N, Rowe JB, Voon V, et  al. Dissociable effects of acute SSRI (escitalopram) on executive, learning and emotional functions in healthy humans. Neuropsychopharmacology. 2018;43:2645–51.

6

The Aging Brain

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 posture, skin becomes dry and brittle causing wrinkles, and eye sight and hearing deteriorate 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 balance 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 developing Alzheimer’s disease but just having a “senior moment”. But how do we differentiate 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 impairment with aging with blurred boundaries between the different degrees of impairment. 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 susceptible 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 concern. 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.

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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 maintained. 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 regularly used are pruned saving valuable energy as people age. It is interesting to compare 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 dementia. 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

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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 cognitive 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 supplement 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 possible 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 capability 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 starting point of the overall risk for developing age related cognitive decline and late onset neurodegenerative diseases including education, access to health care, physical 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 accelerates 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

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and later followed from 1971 onwards documenting adult health outcomes including 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 development predicted better performance on measures of muscle strength, muscle endurance, and aerobic fitness in adults. Of all the possible factors that predict cognitive ability in old age, cognitive ability 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 people. 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 relationship between cognitive performance and other variables such as socioeconomic status, 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 testing 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 consistent 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

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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 consistent 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 cognitive 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 (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 initially 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.

References 1. Confucius. The analects (Lau DC, Trans.). London: Penquin Books; 1998. 2. Ainslie PN, Barach A, Murrell C, et  al. Alterations in cerebral autoregulation and cerebral blood flow velocity during acute hypoxia: rest and exercise. Am J Physiol Heart Circ Physiol. 2007;2007(292):H976–83. 3. Hoiland RL, Bain AR, Rieger MG, et al. Hypoxemia, oxygen content, and the regulation of cerebral blood flow. Am J Physiol Regul Integr Comp Physiol. 2016;310:R398–413.

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4. Smith KJ, Ainslie PN. Regulation of cerebral blood flow and metabolism during exercise. Exp Physiol. 2017;102(11):1356–71. 5. Lindbohm JV, Rautalin I, Jousilahti P, et  al. Physical activity associates with subarachnoid hemorrhage risk—a population-based long-term cohort study. Sci Rep. 2019;9:9219. 6. Lee CD, Folsom AR, Blair SN.  Physical activity and stroke risk: a meta-analysis. Stroke. 2003;34:2475–81. 7. Wendel-Voss GC, Schuit AJ, Feskens EJ, et al. Physical activity and stroke. A meta-analysis of observational data. Int J Epidemiol. 2004;33:787–98. 8. Lee CD, Blair SN.  Cardiorespiratory fitness and stroke mortality in men. Med Sci Sports Exerc. 2002;34:592–5. 9. Hu G, Sarti C, Jousilahti P, et al. Leisure time, occupational and commuting physical activity and the risk of strike. Stroke. 2005;36:1994–9. 10. Ricciardi AC, Lopez-Cancio E, Perez de la Ossa N, et al. Prestroke physical activity is associated with good functional outcome and arterial recanalization after stroke due to large vessel occlusion. Cerebrovasc Dis. 2014;37:304–11. 11. Endres M, Gertz K, Lindauer U, et al. Mechanisms of stroke protection by physical activity. Ann Neurol. 2003;54:582–90. 12. Roth EJ, Harvey RL. Rehabilitation of stroke syndromes. In: Braddom RL, editor. Physical medicine and rehabilitation. 2nd ed. Philadelphia, PA: WB Saunders; 2000. p. 1117–63. 13. Gordon NF, Gulanick M, Costa F, et al. Physical activity and exercise recommendations for stroke survivors. Stroke. 2004;35:1230–40. 14. Ivey FM, Hafer-Macko CE, Macko RF.  Exercise rehabilitation after stroke. NeuroRx. 2006;3:439–50. 15. Globas C, Becker C, Cerny J, et al. Chronic stroke survivors benefit from high-intensity aerobic treadmill exercise: a randomized control trial. Neurorehabil Neural Repair. 2012;26:85–95. 16. Ivey FM, Stookey AD, Hafer-Macko CE, et al. Higher treadmill training intensity to address functional aerobic impairment after stroke. J Stroke Cerebrovasc Dis. 2015;24:2539–46. 17. Private patient of author, details slightly changed to protect privacy. 18. Veerbeek JM, Koolstra M, Ket JCF, et al. Effects of augmented exercise therapy on outcomes of gait and gait-related activities in the first 6 months after stroke: a meta-analysis. Stroke. 2011;42:3311–5. 19. Shepherd RB. Exercise and training to optimize functional motor performance in stroke: driving neural reorganization? Neural Plast. 2001;8:121–9. 20. Bernhardt J, Godecke E, Johnson L, Langhorne P. Early rehabilitation after stroke. Curr Opin Neurol. 2017;30:48–54. 21. Carr JH, Shepherd RB.  Enhancing physical activity and brain reorganization after stroke. Neurol Res Int. 2011;2011:515938. 22. Fluri F, Schuhmann M, Kleinschnitz C. Animal models of ischemic stroke and their application in clinical research. Drug Des Devel Ther. 2015;9:3445–54. 23. Sommer CJ.  Ischemic stroke: experimental models and reality. Acta Neuropathol. 2017;133:245–61. 24. Kwakkel G, Veerbeek JM, van Wegen EEH.  Constraint-induced movement therapy after stroke. Lancet Neurol. 2015;14:224–34. 25. Soros P, Teasell R, Hanley DF, Spence JD. Motor recovery beginning 23 years after ischemic stroke. J Neurophysiol. 2017;118:778–81. 26. Alawieh A, Zhao J, Feng W.  Factors affecting post-stroke motor recovery: implications on neurotherapy after brain injury. Behav Brain Res. 2018;340:94–101. 27. Pang MY, Eng JJ, Dawson AS, Gylfadottir S. The use of aerobic exercise training in improving aerobic capacity in individuals with stroke: a meta-analysis. Clin Rehabil. 2006;20:97–111. 28. Morreale M, Marchione P, Pili A, et al. Early versus delayed rehabilitation treatment in hemiparetic patients with ischemic stroke: proprioceptive or cognitive approach. Eur J Phys Rehabil Med. 2016;52:81–9. 29. Fletcher BJ, Dunbar MN, Felner JM, et al. Exercise testing and training in physically sidabled men with clinical evidence of corobary artery disease. Am J Cardiol. 1994;73:170–4.

Dementia

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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 memory 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 common 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.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 R. W. Baloh, Exercise and the Brain, https://doi.org/10.1007/978-3-031-13924-6_10

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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 neurofibrillary 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. a

b

Neurofibrillary 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

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The problem is, even though accumulation of beta amyloid plaques and neurofibrillary 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 tomography (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 disappointing [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 progression 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 removing 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 entorhinal 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

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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 deposition 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 memory 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) suppress 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 production 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

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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 hippocampus from cell loss and atrophy typical of Alzheimer disease. Early studies on the effect of exercise on beta amyloid deposition in human subjects 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 regular 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 developing 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 preventing 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,

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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 disease 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 experiment; 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 physically 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 measurements. 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 button. 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 nonspecific, the implications of prolonged reaction times are obvious for most daily activities 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 concluded 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.

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One of the first large prospective studies on exercise and Alzheimer disease performed 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 coffee 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 developing 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 protective effect of wine, non-steroidal anti-inflammatory drugs and particularly exercise had been observed in several prior studies. Regardless, older Americans could feel good about their wine, non-steroidal anti-inflammatory drug and coffee consumption 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 significantly 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 physical 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

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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 cognitive 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 impairment characterized by early memory loss that is most likely to transition to Alzheimer disease and non-amnestic mild cognitive impairment (for example language 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 exercise 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 cognitive 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 significantly better strength, aerobic endurance, balance and agility and less unexplained hospitalizations that the no exercise group. But this was only seen in patients with mild dementia not later dementia.

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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 combination 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 progression 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 atherosclerosis 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 fitness are carefully quantified have found the most consistent benefit for exercise for diminishing white matter hyperintensities. But even in longitudinal studies,

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exercise/physical fitness and white matter hyperintensities have typically been measured 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 neurodegenerative 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, mutations 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.

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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 distributed 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 hallucinations 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

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[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 followed 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 varsity sports or exercising regularly in college significantly reduced the risk of developing Parkinson disease by 36% and 17% respectively. Subjects who engaged in exercise later in adulthood slightly decreased the risk of developing Parkinson disease but not to a significant level [34]. Several studies found that high intensity exercise was more effective in preventing 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 followed from 1992 to 2001 and 413 developed Parkinson disease [35]. Physical activity 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 exercise. 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

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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 pedaled 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 currently 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 impulsively 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 interest 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 frontotemporal 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

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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 disorders. However, there have been several case reports suggesting that exercise is beneficial at least in managing the motor symptoms of these disorders. More convincing 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 dementia and the son corticobasal degeneration in the third decade both with rapid progression [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 disorder 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 walking, 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.

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22. Kishimoto H, Ohara T, Hata J, et al. The long-term association between physical activity and risk of dementia in the community: the Hisayama study. Eur J Epidemiol. 2016;31:267–74. 23. Gronek P, Balko S, Gronek J, et  al. Physical activity and Alzheimer’s disease: a narrative review. Aging Dis. 2019;10:1282–92. 24. Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update summary: mild cognitive impairment. Neurology. 2018;90:126–35. 25. Chen K-H, Chen H-H, Li L, et al. The impact of exercise on patients with dementia. A 2-year follow-up. Medicine. 2020;99:e20597. 26. Torrres ER, Strack EF, Fernandez CE, et al. Physical activity and white matter hyperintensities: a systematic review of quantitative studies. Prev Med Rep. 2015;2:319–25. 27. Smith CD, Johnson ES, Van Eldik JL, et al. Peripheral (deep) but not perventricular MRI white matter hyperintensities are increased in clinical vascular dementia compared to Alzheimer’s disease. Brain Behav. 2016;6:e00438. 28. de Carvalho AO, Sa Filho AS, Murillo-Rodriguez E, et al. Physical exercise for Parkinson’s disease: clinical and experimental evidence. Clin Pract Epidemiol Ment Health. 2018;14:89–98. 29. Miller KM, Mercado NM, Sortwell CE.  Synucleinopathy-associated pathogenesis in Parkinson’s disease and the potential for brain-derived neurotrophic factor. NPJ Parkinsons Dis. 2021;7:35. 30. Hanyu H, Sato T, Hirao K, et al. Differences in clinical course between dementia with Lewy bodies and Alzheimer’s disease. Eur J Neurol. 2009;162:212–7. 31. Inskip M, Mavros Y, Sachdev PS, Singh MAF.  Exercise for individuals with Lewey body dementia: a systematic review. PLoS One. 2016;11:e0156520. 32. Jang Y, Koo J-H, Kwon I, et al. Neuroprotective effects of endurance exercise against neuroinflammation in MPTP-induced Parkinson’s disease mice. Brain Res. 2017;1655:186–93. 33. Zhou W, Barkow JC, Freed CR. Running wheel exercise reduces α-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson’s disease. PLoS One. 2017;12:e0190160. 34. Sasco AJ, Paffenbarger RS, Gendre I, Wing AL. The role of physical exercise in the occurrence of Parkinson’s disease. Arch Neurol. 1992;49(4):360–5. 35. Thacker EL, Chen H, Patel AV. Recreational physical activity and risk of Parkinson’s disease. Mov Disord. 2008;23:69–74. 36. Crotty GF, Schwarzschild MA.  Chasing protection in Parkinson’s disease: does exercise reduce risk and progression? Front Aging Neurosci. 2020;12:186. 37. Cakit BD, Saracoglu M, Genc H, Erdem HR, Inan L.  The effects of incremental speed-­ dependent treadmill training on postural instability and fear of falling in Parkinson’s disease. Clin Rehabil. 2007;21:698–705. 38. Kurtais Y, Kutlay S, Tur BS, Gok H, Akbostanci C. Does treadmill training improve lower-­ extremity tasks in Parkinson disease? A randomized controlled trial. Clin J Sport Med. 2008;18:289–91. 39. Ridgel AL, Vitek JL, Alberts JL. Forced, not voluntary, exercise improves motor function in Parkinson’s disease patients. Neurorehabil Neural Repair. 2009;23(6):600–8. 40. Orr ME, Sullivan AC, Frost B. A brief overview of tauopathy: causes, consequences and therapeutic strategies. Trends Pharmacol Sci. 2017;38:637–48. 41. Bugiani O, Murrell JR, Giaccone G, et al. Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol. 1999;58:667–77. 42. Ohia-Nwoko O, Montazari S, Lau YS, et  al. Long-term treadmill exercise attenuates tau pathology in P301S tau transgenic mice. Mol Neurodegener. 2014;9:54. 43. Steffen TM, Boeve BF, Petersen CM. Long-term exercise training for an individual with mixed corticobasal degeneration and progressive supranuclear palsy features: 10-year case report follow-up. Phys Ther. 2014;94:289–96.

Overview

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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 prevent 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 convincing people that smoking is bad for their health but not such a good job of convincing them that sedentary behavior is bad for their health. One problem is the definition of physical inactivity. Some use the term for anybody 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 inactivity 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].

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 R. W. Baloh, Exercise and the Brain, https://doi.org/10.1007/978-3-031-13924-6_11

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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 international 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 vigorous 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 behavior and sleep for infants under age 5 years [3] and in 2020 they published recommendations for physical activity and sedentary behavior for children over age 5 years, adolescents, adults, older adults, pregnant women and people with disabilities [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 requirement. For everyone, some physical activity is better than none. Even brief periods 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 potential 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