Principles of Exercise Neuroscience

Principles of Exercise
Neuroscience
Principles of Exercise
Neuroscience
Edited by
Dawson J. Kidgell and Alan J. Pearce

Principles of Exercise Neuroscience
Edited by Dawson J. Kidgell and Alan J. Pearce
This book first published 2020
Cambridge Scholars Publishing
Lady Stephenson Library, Newcastle upon Tyne, NE6 2PA, UK
British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library
Copyright © 2020 by Dawson J. Kidgell and Alan J. Pearce and

contributors
All rights for this book reserved. No part of this book may be reproduced,
stored in a retrieval system, or transmitted, in any form or by any means,
electronic, mechanical, photocopying, recording or otherwise, without
the prior permission of the copyright owner.
ISBN (10): 1-5275-5813-4

ISBN (13): 978-1-5275-5813-7
TABLE OF CONTENTS
Preface ...................................................................................................... xii

Dawson J. Kidgell, PhD and Alan J. Pearce, PhD
Acknowledgements ................................................................................. xiv
Chapter 1 .................................................................................................... 1
The Nexus between Neuroscience and the Science of Exercise
Alan J. Pearce, PhD
1. Background ....................................................................................... 1
1.1 The neuroscience of human movement........................................... 2
1.2 What is ‘motor control’? How does motor control relate within
the larger discipline of exercise science? ........................................ 4
1.3 Motor learning and skill acquisition: similarities and contrasts
to motor control ............................................................................... 6
1.4 The challenge of translating neuroscience to exercise science ....... 8
1.5 How to get the best from this book ................................................. 8
References............................................................................................. 9
Chapter 2 .................................................................................................. 10
Levels of Motor Control
Dawson J. Kidgell, PhD and Alan J. Pearce, PhD
2. Background ..................................................................................... 10
2.1 Structural arrangement of the brain contributing to movement .... 11
2.1.1 Structure of the cerebral cortex ............................................ 11
2.1.2 The brain stem ...................................................................... 12
2.2 Transmission of cortical motor signals ......................................... 13
2.3 Motor functions of the cerebellum ................................................ 13
2.3.1 Anatomical and functional organisation of the cerebellum .... 14
2.3.2 Afferent and efferent pathways of the cerebellum ............... 15
2.4 Motor functions of the spinal cord ................................................ 16
2.4.1 Organisation of the spinal cord............................................. 17
2.5 Types of reflex pathways .............................................................. 18
2.5.1 Skeletal muscle reflexes ....................................................... 19
2.6 Hierarchical organisation of motor control ................................... 21
vi Table of Contents
2.7 Motor units, fibre types, and recruitment physiology ................... 23

2.7.1 The motor unit ...................................................................... 23
2.7.2 Physiological classification and recruitment ........................ 24
2.8 Principle of motor unit recruitment ............................................... 25
2.9 Motor unit synchrony .................................................................... 26
2.9.1 Quantifying the degree of motor unit synchrony .................. 27
2.9.2 Motor unit synchronization and human motor control ......... 27
2.9.3 Motor unit synchronization in upper and lower limb
muscles .................................................................................... 28
2.10 Summary ..................................................................................... 29
References........................................................................................... 29
Chapter 3 .................................................................................................. 32
Techniques Contributing to the Understanding of Neuroscience
in Exercise
Alan J. Pearce, PhD and Dawson J. Kidgell, PhD
3. Background ..................................................................................... 32
3.1 Electroencephalography (EEG) .................................................... 33
3.2. Magnetoencephalography (MEG) ................................................ 34
3.3 Transcranial magnetic stimulation (TMS) .................................... 35
3.3.1 Single-pulse TMS ................................................................. 36
3.3.2 Paired-pulse TMS ................................................................. 38
3.4 Voluntary activation and neural drive ........................................... 40
3.4.1 Interpolated twitch and VATMS ............................................. 40
3.4.2 H-reflex ................................................................................ 42
3.4.3 V-wave ................................................................................. 44
3.5 Summary ....................................................................................... 45
References........................................................................................... 46
Chapter 4 .................................................................................................. 53
Principles of Neuroplasticity in Exercise
Dawson J. Kidgell, PhD and Ashlyn K. Frazer, PhD
4. Neuroplasticity ................................................................................ 53
4.1 Mechanisms of neuroplasticity ..................................................... 53
4.2 Short and Long-term potentiation ................................................. 54
4.2.1 NMDA receptor activation and synaptic plasticity .............. 54
4.2.2 Brain-derived neurotrophic factor and neuroplasticity ......... 55
4.3 Experimentally-induced neuroplasticity ....................................... 56
4.3.1 Transcranial direct current stimulation and neuroplasticity .... 57
4.3.2 NIBS and functional connectivity ........................................ 58
Principles of Exercise Neuroscience vii
4.4 Is the induction of neuroplasticity via NIBS important for motor

performance? ................................................................................. 60
4.4.1 Is the magnitude of neuroplasticity and motor performance
improvement related to the BDNF polymorphism?................. 63
4.5 Is homeostatic plasticity important for motor performance? ........ 64
4.6 Use-dependent neuroplasticity ...................................................... 67
4.7 Summary ....................................................................................... 68
References........................................................................................... 69
Chapter 5 .................................................................................................. 76
Non-invasive Brain Stimulation and Exercise Performance
Shapour Jaberzadeh, PhD and Maryam Zoghi, PhD
5. Introduction ..................................................................................... 76
5.1 Transcranial Direct Current Stimulation ....................................... 77
5.2 The mechanisms behind tDCS effects during stimulation
(online effects) .............................................................................. 78
5.3 The mechanisms behind tDCS effects after the termination
of stimulation ................................................................................ 79
5.4 Montages for application of tDCS: The conventional montage .... 80
5.4.1 HD-tDCS montage ............................................................... 80
5.4.2 Other tDCS montages........................................................... 81
5.5 tDCS as a stand-alone technique ................................................... 82
5.6 tDCS as a priming technique ........................................................ 82
5.7 Halo sport tDCS device ................................................................ 82
5.8 The effects of tDCS on EP ............................................................ 83
5.9 Ethical considerations for the use of tDCS for enhancement
of EP .............................................................................................. 85
5.10 Summary ..................................................................................... 86
References........................................................................................... 86
Chapter 6 .................................................................................................. 92
Neural Control of Lengthening and Shortening Contractions
Jamie Tallent, PhD and Glyn Howatson, PhD
6. Background ..................................................................................... 92
6.1 Shortening and Lengthening Contractions .................................... 92
6.1.1 Benefits of lengthening contractions .................................... 93
6.2 Motor control of lengthening and shortening muscle contractions . 93
6.2.1 Muscle .................................................................................. 94
6.2.2 Spinal.................................................................................... 94
6.2.3 Cortico-Spinal ...................................................................... 95
6.3 Adaptations to shortening and lengthening resistance training ..... 97
viii Table of Contents
6.4 Summary ..................................................................................... 100

References......................................................................................... 101
Chapter 7 ................................................................................................ 107

Neural Adaptations to Strength Training
Dawson J. Kidgell, PhD
7. Background ................................................................................... 107
7.1 Acute neural responses to strength training ................................ 107
7.2 Using TMS to assess the neural responses to strength training ..... 108
7.3 MEPs are acutely facilitated following a strength training
session ......................................................................................... 109
7.4 Intracortical facilitation is acutely enhanced following a strength
training session ............................................................................ 110
7.5 Why does strength training increase corticospinal excitability
and intracortical facilitation of the motor cortex? ....................... 111
7.6 Long-term neuroplastic adaptations to strength training ............. 114
7.7 Changes in strength following 2-8 weeks of strength training .... 116
7.8 Long-term strength training does not affect motor threshold or
MEP amplitude............................................................................ 117
7.9 Long-term strength training reduces motor cortex mediated
inhibition ..................................................................................... 118
7.10 Changes in spinal cord plasticity with strength training ........... 120
7.11 Changes in H-reflex and V-wave amplitude following strength
training ........................................................................................ 120
7.12 Changes in motor unit activity following strength training ...... 122
7.12.1 Single motor unit behaviour following strength training.. 123
7.12.2 Motor unit synchronization following strength training ... 124
7.13 Summary ................................................................................... 125
References......................................................................................... 125
Chapter 8 ................................................................................................ 133

Neuromuscular Responses to Fatiguing Locomotor Exercise
Callum Brownstein, PhD and Kevin Thomas, PhD
8. Background ................................................................................... 133
8.1 The role of exercise intensity and duration on neuromuscular
responses to fatiguing exercise .................................................... 135
8.2 Neuromuscular responses to “all-out” exercise .......................... 136
8.3 Neuromuscular responses to severe intensity, short-duration
exercise........................................................................................ 139
8.4 Neuromuscular responses to sustained exercise below critical
power ........................................................................................... 141
Principles of Exercise Neuroscience ix
8.5 Neuromuscular responses to high-intensity intermittent

exercise........................................................................................ 144
8.6 The effect of exercise modality on neuromuscular responses
to locomotor exercise .................................................................. 146
8.7 Effect of exercise duration and intensity on recovery ................. 148
8.8 Origin of prolonged impairments in contractile function ............ 151
8.9 Origin of prolonged impairments in voluntary activation ........... 152
8.10 Summary ................................................................................... 153
References......................................................................................... 153
Chapter 9 ................................................................................................ 160

Sex Differences in Neuromuscular Function and Fatigability
Paul Ansdell, PhD and Stuart Goodall, PhD
9. Introduction ................................................................................... 160
9.1. A brief history of the scientific study of sex and performance .. 160
9.2. Sex differences throughout the motor pathway.......................... 161
9.2.1. Pre-motor processes .......................................................... 162
9.2.2. Intracortical and corticospinal neurons.............................. 163
9.2.3. Motor unit properties ......................................................... 164
9.2.4. Contractile apparatus ......................................................... 165
9.3. Functional neuromuscular sex differences ................................. 165
9.3.1. Maximal force production ................................................. 165
9.3.2. Force steadiness and accuracy ........................................... 166
9.3.3. Fatigability ........................................................................ 166
9.4. Female-specific neuromuscular function ................................... 169
9.4.1. The influence of hormones in vitro ................................... 169
9.4.2. In-vitro evidence ............................................................... 169
9.4.3. Functional changes across the menstrual cycle ................. 170
9.5. Summary .................................................................................... 173
9.5.1. What do we know already? ............................................... 173
9.5.2. Where do we go from here? .............................................. 174
References......................................................................................... 174
Chapter 10 .............................................................................................. 185

Motor Control Responses following Exercise-Induced Muscle Damage
Carlos Hermano Pinheiro, PhD and Alan J. Pearce, PhD
10. Background ................................................................................. 185
10.1 How does DOMS occur? .......................................................... 186
10.2 Functional outcomes affected by DOMS .................................. 188
10.3 Neuromuscular and motor control changes following DOMS .. 189
10.4 Neurophysiological studies in DOMS ...................................... 191
x Table of Contents
10.5 Summary ................................................................................... 192

References......................................................................................... 192
Chapter 11 .............................................................................................. 196

Neuromuscular Alterations and Motor Performance in Healthy Aging
Jakob Škarabot, PhD
11. Background ................................................................................. 196
11.1 Alterations in the central nervous system with advancing age .... 197
11.1.1 Alterations at the level of motor unit ................................ 197
11.1.2 The influence of synaptic inputs from spinal and
supraspinal centres ................................................................. 197
11.1.3 Reflex inputs to motoneurons........................................... 198
11.1.4 Cortical inputs to motoneurons ........................................ 199
11.2 Reduction in motor performance in healthy aging adults ......... 200
11.2.1 Motor performance during maximal contractions ............ 200
11.2.2 Control of muscle force output during submaximal tasks .. 204
11.2.3 Fatigability ....................................................................... 206
11.3 Summary ................................................................................... 208
References......................................................................................... 209
Chapter 12 .............................................................................................. 222

Cross-education
Ashlyn K. Frazer, PhD and Dawson J. Kidgell, PhD
12. Background ................................................................................. 222
12.1 Evidence of cross-education ..................................................... 222
12.2 Exercise prescription parameters .............................................. 223
12.3 Mechanisms of cross-education ................................................ 225
12.4 Interventions to enhance the cross-education effect.................. 228
12.4.1 Transcranial direct current stimulation and cross-
education................................................................................ 228
12.4.2 Electromyostimulation during cross-education ................ 229
12.4.3 Whole-body vibration (WBV) training and cross-
education ................................................................................ 230
12.5 Cross-education and neuromuscular injury ............................... 231
12.6 Summary ................................................................................... 232
References......................................................................................... 232
Principles of Exercise Neuroscience xi
Chapter 13 .............................................................................................. 237

Using Electrophysiology to Understand Responses following Concussion
and Mild Brain Injury
Alan J. Pearce, PhD and Michael E. Buckland, MBBS PhD
13. Background ................................................................................. 237
13.1 The definition of concussion ..................................................... 238
13.2 Current standard to diagnose concussion .................................. 239
13.3 Objective measures to assess concussion .................................. 239
13.4 Electrophysiology to assess concussion .................................... 240
13.5 Electroencephalography (EEG) ERPs in concussion research .. 241
13.5.1 Visual and vestibular evoked potentials ........................... 242
13.6 Transcranial Magnetic Stimulation (TMS) EPs and concussion
research ....................................................................................... 243
13.6.1 Studies in acute concussion .............................................. 244
13.6.2 Studies in retired athletes with history of concussion
and head trauma ..................................................................... 245
13.6.3 Studies in persistent post concussion symptoms .............. 246
13.7 Combined electrophysiological modalities to assess
neurophysiology .......................................................................... 246
13.9 Summary ................................................................................... 248
References......................................................................................... 249
PREFACE
DAWSON J. KIDGELL, PHD

AND ALAN J. PEARCE, PHD
Over the last 30 years, there has been a significant rise in research and
teaching interest that has examined the neuromuscular responses to different
types of exercise interventions. Two fields of research, neuroscience and
exercise science, have merged to provide evidence for how the nervous
system responds to exercise. An important component of exercise science,
but one area that is less recognised, although used ubiquitously through
other topics within exercise science, is the study of motor control. Motor
control is primarily concerned with the neurophysiological mechanisms that
contribute to human movement. Motor control is at the very heart of
exercise and sport science. Motor control drives how we program
appropriate exercise in health, injury and disease. Motor control is what
underpins this book we call Principles of Exercise Neuroscience.
This textbook introduces the key concepts that emphasise human motor
control and its application to exercise science and rehabilitation. The topics
covered integrate research, theory and the clinical applications of Exercise
Neuroscience that will support students, researchers and clinicians to
understand how the nervous system responds, or adapts to physical activity,
training, rehabilitation and disease. Exercise Neuroscience uses a mix of
neuromuscular physiology, electrophysiology and muscle physiology to
provide a synthesis of current knowledge and research in the field of
exercise neuroscience that specifically examines the effects of exercise
training, injury and rehabilitation on the human nervous system.
It is never easy writing a textbook like this from scratch. Indeed, this
textbook came about from the initial teaching notes to assist tertiary students
with some difficult learning concepts within the motor control subjects
taught at our respective universities. As time progressed, the lecture notes
developed into full chapters that eventually evolved into this textbook.
Further, through our international collaborative network, we were able to
draw upon international experts who were very happy to contribute and
provide their extensive knowledge and experience to develop our initial
Principles of Exercise Neuroscience xiii
chapters into state of the art reviews. Our guest authors are leaders in their
respective areas of enquiry and provide the latest research findings in three
key areas: principles of motor control; neuroscience of exercise
performance; and clinical exercise neuroscience (injury and neuro-
rehabilitation). We sincerely thank each of them for their time and efforts
in helping us complete this book.
This is the first text devoted solely to the emerging topic of Exercise
Neuroscience. It aims to assist readers in identifying current research
findings and provide new avenues to explore the benefits of exercise on the
human nervous system. We thoroughly enjoyed writing this and we hope
that you find this text useful for your learning and professional development.
Dawson J. Kidgell, Monash University, Melbourne, Australia.

Alan J. Pearce, La Trobe University, Melbourne, Australia
June, 2020
ACKNOWLEDGEMENTS
A text such as Principles of Exercise Neuroscience is not the effort of just

two authors. This text brings together the contributions of many research
scientists who have examined the changes that occur in the human nervous
system. We would like to especially thank Dr Eric Frazer for his assistance
in providing suggestions for revisions to this book, in particular his attention
to detail and endless editing. We would also like to acknowledge the
contributions of all the authors, in particular Professor Glyn Howatson, who
has established and leads a remarkable program of Applied Neuromuscular
Research at Northumbria University; many former PhD students from this
laboratory have contributed to this text.
CHAPTER 1
THE NEXUS BETWEEN NEUROSCIENCE

AND THE SCIENCE OF EXERCISE
ALAN J. PEARCE, PHD
1. Background
The past thirty years have seen a significant rise in the disciplines of
neuroscience and exercise science. However, within the last ten years we
have seen these two disciplines become intersected. While neuroscience has
been an area of research for over a century, it is only in the last 20-30 years
that neuroscience has transformed from an interdisciplinary speciality under
the umbrella of neurology, psychiatry and psychology, to a stand-alone
discipline, and is now the fifth largest field of study in the sciences (Rosvall
and Bergstrom, 2010). Particularly in the last decade, with advancements in
technologies such as neuroimaging and electrophysiology, neuroscience has
captured the imagination of the wider community. In particular, the concept
of neuroplasticity, where evidence has demonstrated that the brain has the
ability to reorganise and readapt over the lifespan, has ignited a huge interest
across many unrelated fields. This has, of course, been both positive, with
advances in our understanding of the brain and nervous system, but also
negative where we are seeing the rise in what some call “neurobabble”, the
phenomenon whereby neuroscientific explanations of cognitive and motor
behaviour are more persuasive simply because they sound more technical
and authoritative (Varazzani, 2017). Despite this, continued advances in
neuroscience research will improve the lives of everyday people, as well as
contributing to improved athletic performance.
In parallel, exercise science has also emerged from the discipline of physical
education. Since the early 1990s, when the first exercise science courses
were beginning to be established in Australia, the growth in exercise science
has been so rapid that physical education can now be regarded as one of the
areas under the broader discipline of exercise science (along with exercise
physiology, strength and conditioning, biomechanics, nutrition, functional
2 Chapter 1
anatomy, skill acquisition and psychosocial determinants of health). Indeed,

many exercise science graduates will continue their learning, pursuing
postgraduate studies in education and developing courses in sport and
exercise science in secondary schools.
It should be no surprise then that the maturing disciplines of exercise science

and neuroscience have overlapped. Significant interest and growth in
research and application have occurred in the role of exercise on brain health,
neural function and neuroplasticity. Conversely, greater understanding of
clinical neurological disease has impacted on advancing exercise
programming, with studies testing the efficacy of various exercise
interventions on brain and neural integrity. Taken together, the
understanding of human motor control occurs through exploring and
investigating neural and neuromuscular function.
1.1 The neuroscience of human movement.

It is important to note that neuroscience has many different areas of research
and study. Notwithstanding animal models of neuroscience, just focusing
on the neuroscience of human nervous systems can traverse a wide
continuum of study areas (Figure 1.1).
Figure 1.1. Continuum of general areas of study within neuroscience
It is not uncommon that neuroscientists from different research areas will

not necessarily understand each other’s work. For example, there are those
who investigate the neuroscience of a single cell under physiological or
pharmacological interventions. Conversely, there are others who are
interested in neuroimaging of the healthy or diseased brain. In between, we
have various levels of neuroscientific inquiry that can overlap but are
specific sub-disciplines in their own right. Further, like exercise neuroscience
or neurophysiology, various other combined disciplines exist such as
neuroanatomy, neurochemistry, neuropsychology and the like (see Table
1.1 for a list with definitions).
The Nexus between Neuroscience and the Science of Exercise 3
Table 1.1. List of combined areas of study within neuroscience.

Neuroanatomy Study of anatomy of neurons and neural
structures
Neurochemistry Study of the compounds that generate
physiological functioning in and between neurons
Neuroendocrinology Study of the interaction between the endocrine
and nervous systems
Neurodermatology Study of the neural structures within the skin
contributing to not only neural health but also
sensory reception.
Neurogenetics Study of the role of genetics in the development
and function of the nervous system
Neuroimmunology Study of the interaction between the immune and
nervous systems
Neurooncology Study of cancers of the brain and nervous system
Neuroopthamology Study of the interaction between the visual system
and nervous system
Neurotology Study of the neural contribution to vestibular
function
Neurophysiology Study of the functioning of the nervous system
Neuropsychology Study of the nervous systems influence in a
person’s cognition and behaviour
Of course, as this book will be focusing on aspects of exercise science and

human movement, the aim will be to synthesize and translate the growing
research output specific to human motor control. The result is that this text
narrows itself to the neural basis of human movement. Pathways, structures,
neurophysiological principles and application of these principles are
discussed but always in the context of human function and movement.
The scientific study of the neuroscience of movement is termed motor

behaviour. Motor behaviour is an umbrella term that encompasses a range
of sub-disciplines that overlap:
Motor control – the study of the underlying neurophysiological mechanisms

that contribute to movement;
Motor learning and skill acquisition – understanding the optimal

environments to practice and refine specific, purposeful movements
progressing the individual towards an accomplished level of expertise; and
Motor development – the study of movement across the lifespan; how

children develop and learn fundamental motor skills, through to
4 Chapter 1
understanding the mechanisms by which older adults decline in motor

control.
1.2 What is ‘motor control’? How does motor control

relate within the larger discipline of exercise science?
As teachers in motor control for over 15 years, this is usually the first
question that pops up from students. This is because motor control, as a term,
is rather indistinct. Indeed, as the term ‘motor control’ is becoming used
more widely, it has also been used and taken on slightly different meanings
to different professionals within the exercise and sport science domain. For
example, biomechanists discuss motor control in terms of physics being
applied on, or from within, the body during proficient performance of a
movement. Sport psychologists reference motor control in terms of actions
having an emotional or cognitive basis, for example, the use of motor
imagery to assist with rehabilitation of function or to improve on sports
skills. Physiotherapists discuss motor control in the rehabilitation setting,
with patients focusing on reducing “abnormal” movement and increasing
movement patterns that are less likely to cause injury (or re-injury).
Exercise physiologists may discuss the reduction in motor control
performance when an individual experiences fatigue. Strength and
conditioning and personal trainers need to consider motor control issues
when prescribing correct technique and resistance, to optimise strength
improvements and reduce likelihood of injury.
However, the core of motor control centres on the neuroscience that

underpins neuromuscular movement of the human body. It goes without
saying that people’s lives are filled with movement (Latash, 2008). As
undergraduates studying exercise science and related fields, human
movement is the core focus: using movement to improve strength and
muscle mass; using movement to improve skills; using movement to help
people lose weight; and using movement to assist people back to functional
daily activities.
Undergraduate study in exercise science will have motor control embedded

within course content across a number of subjects, or as a ‘stand-alone’
course. As exercise neuroscientists, we may have a bias here (who doesn’t!)
but it is quite easy to illustrate how elements of motor control permeate
throughout the curriculum of the major or core subjects areas taught in
exercise science courses (Table 1.2).
Table 1.2. Interrelationship between motor control and other areas within
the discipline of exercise science.
Study area Relationship to Example

motor control
Anatomy (neuroanatomy) Study of the Damage to primary
structure and motor cortex leading
function of the to motor dysfunction.
brain and nervous
system.
Biomechanics/movement Study of efficient Relationship of
analysis voluntary sequential limb
movement. movement for a
specific motor task.
Exercise/sport physiology Study of The role of the brain
biochemistry and in fatiguing exercise.
physiological
systems adapting
to exercise and
sport.
Psychology of exercise and Study of Mood disorder
sport psychological influencing loss in
influences in motivation to
determining exercise.
exercise behaviour, Motor imagery to
as well as improve movement
psychological traits efficiency in sport.
required in high
performance sport.
Nutrition Study of nutrients Gut/brain interaction,
in food, how the how food intake can
body uses affect movement
nutrients, and the (interrelationship
relationship with exercise
between diet, physiology).
health, and disease.
Strength and conditioning Study of methods Neural adaptations
to induce with strength or
resistance for resistance training
training modalities.
adaptations.
6 Chapter 1
So, where does this lead us in terms of establishing what motor control
actually is? The common denominator in all these areas is the interaction of
the brain and muscle to provide meaningful (Latash, 2008) goal-directed
movement (Enoka and Stuart, 2005). Therefore, it can be argued that motor
control has a basis in neuroscience. Motor control is concerned with the
neurophysiological processes that allow movements to become more
efficient (which may also include improvement in skills, movement
efficiency, and strength). Similarly, motor control investigates how
movements can be retrained after an injury. These scenarios now have a
well-described term, neuroplasticity (Doidge, 2007), which will be
discussed later and throughout the text.
1.3 Motor learning and skill acquisition:

similarities and contrasts to motor control.
Historically, physical education courses have focussed on the understanding
of the learning and teaching of motor skills (or motor learning). For example,
understanding the development of fundamental motor skills (FMS) such as
running, jumping, and throwing are important when teaching children these
lifelong skills. These fundamental skills are the foundation for more advanced
motor skills, particularly specific skills for sporting excellence. Teaching
motor skills effectively is ingrained within the cognitive/psychological
domain, whereby the teacher is creating an optimal learning environment.
However, with the increased interest in the study of motor development (see
section 1.4), exploration of FMS now sits within the development and
changes of skills and motor actions across the lifespan, providing motor
learning and skill acquisition the opportunity to have its own definition,
succinct from motor control and motor development.
Figure 1.2 addresses not only similarities, but also differences, between the
sub-disciplines of motor control and motor learning. Motor learning, it can
be suggested, is aimed at how people learn and acquire expertise at motor
skills. What are the environments that best optimise learning? For example,
should athletes practice the same movement action in an unchanging setting
repeatedly in a series of blocks to reinforce motor pathways? Or, should
athletes randomise the environment with the intention of learning a
particular skill but retaining the motor memory? Is it better for individuals
to learn implicitly through discovery, or have an external source (such as a
teacher or instructor) providing feedback on how their attempt was executed?
In reality, motor learning and skill acquisition are part of memory formation
and, therefore, it can be argued that this sits within the domain of cognitive
psychology. Motor learning is creating motor memory, similar to other

forms of learning (e.g., content knowledge) that leads to memory retention.
Figure 1.2. Differences and overlap between motor control and motor learning/skill
acquisition.
Motor development focuses on the stages and underlying processes that

allow children to gain motor skills. Traditionally, within the domain of
developmental psychology, the study of motor development has taken a
‘back seat’ compared to other developmental science areas such as cognitive,
social, language, personality, perceptual and emotional development (Adolf
and Robinson, 2015). However, there has been a resurgence of interest in
studying motor development due to its advantage in direct observation and
translation to the psychological sciences. Moreover, with increased
understanding of neuroplasticity, the study of motor development allows for
the understanding of neurophysiological processes, providing a foundation
for how adults learn new motor skills and retain motor memory.
Whilst motor development is primarily focussed in children and adolescents,

it is also important to understand changes as people age, and the
consequences of these. Our society is ageing, with significant increases in
the number of people who will be aged 65 and older in the coming decades.
Understanding the neuromuscular and motor control changes with ageing is
important for current students, particularly in thinking of career opportunities
8 Chapter 1
upon graduating. As part of the Allied Health sector, exercise science

students have a unique set of skills allowing application of their
neuroscience knowledge to, for example, exercise programming for older
people, or biomechanics to understand how to prevent falls. These will be
key areas in the near future to which exercise science can make a unique
contribution (if not already).
1.4 The challenge of translating neuroscience

to exercise science
So, why does neuroscience cause such difficulty to the majority of exercise
science students? The simple reason is because the neuromuscular system
is complex. It has a number of levels contributing to meaningful movement
that work at the conscious and subconscious levels, spinal and supraspinal
levels, and between sensory interactions with the motor response. Further,
it also may not necessarily have anything to do with exercise. Motor control
is as concerned with how an individual can create a pincer grip to control a
pen during writing, as it is concerned with how a person can increase
strength without muscle hypertrophy, or how the central nervous system
controls movement as it also responds to fatiguing exercise. It is also
concerned about how control can be lost, through degeneration, or how
control is lost after a brain injury and, in some cases, how it can be regained.
With the links between neuroscience and exercise becoming closer, it is

important that exercise scientists have a competent understanding of the
brain, and how it controls the neuromuscular pathways. Moreover, it is
important that exercise scientists who may practice in related fields are able
to constructively critique new developments in the area, and to confidently
determine good neuroscience from neurobabble. With unprecedented
access to news and information on a daily basis and the rise of pop-science,
it is important that, as practitioners in the field, you will be able to advise
your clients/patients what has been demonstrated using the scientific
method, and what has not been supported (despite comprehensive spin). The
contents in this book are based upon evidence-based research; however,
each chapter aims to translate the findings allowing students to learn new
concepts confidently.
1.5 How to get the best from this book

The topics in this book have come from our teaching of motor control to
students over the last 15 years. While the topics can and do overlap, each
chapter can be read independently and in any order. For some, all chapters
will be of interest. For others, specific chapters will be helpful for personal
and professional development. As the chapters are research based, our aim
is to guide students through each chapter with the most robust concepts, but
also some insights into future areas of enquiry. For some students, this text
may serve as a pathway to a career as an exercise science research student,
as much as it may inform students moving towards a practitioner career.
Either way, we hope that students find this book engaging, but also
challenging, in attaining future knowledge through scientific enquiry.
References
1. Adolph KE, Robinson SR. Motor Development, 2015.
2. Doidge N. The Brain That Changes Itself: Stories of Personal
Triumph from the Frontiers of Brain Science. 2007.
3. Enoka RM, Stuart DG. The contribution of neuroscience to exercise
studies. 1985.
4. Latash ML. Neurophysiological Basis of Movement. 2008.
5. Rosvall M, Bergstrom CT. Mapping change in large networks. 2010.
6. Varazzani C. The risks of ignoring the brain. 2017.
CHAPTER 2
LEVELS OF MOTOR CONTROL

2. Background
Understanding motor control is through learning the macro and the micro
arrangement of the nervous system. In this chapter, we will focus on the
macro: structural, functional and hierarchical organisation of movement. In
chapters four and five, we will discuss how motor control occurs through
neuromodulation and neuroplastic changes. The study of neuroscience
dictates that we need to learn the structural, functional and hierarchical
anatomical arrangement of the nervous system in order for us to appreciate
how individuals improve their movement, whether it be for sport, music,
jobs requiring fine skills or, alternatively, how patients relearn and regain
movement after an injury.
The chapter will start with the basics: the major structures identified in the
central nervous system. Where appropriate, and in keeping with the
objective of this textbook, we will focus examples and discussion on how
the region contributes to movement and motor control. Bear in mind which
cognitive functions, such as attention and decision-making, can and do
influence motor output. From there, we will outline the functional
arrangement of motor control. Here, we will focus on topographic
arrangement of motor functions and, in later chapters, how their
arrangement allows for adaptation and re-organisation. Finally, we will
discuss the hierarchical levels of motor control where we will incorporate
structural and functional understanding on how movement is planned and
executed.
Levels of Motor Control 11
2.1 Structural arrangement of the brain contributing

to movement
In simplistic terms, the brain can be divided into three parts: the cerebrum,
brain stem, and the cerebellum. Each of these structures makes important
contributions to the regulation of movement.
The cerebrum is the large ‘dome’ of the brain that is divided into right and
left cerebral hemispheres. The most superficial layer of the cerebrum is the
cerebral cortex, which is composed of tightly arranged neurons. The cortex
performs three important motor functions: (1) the organization of complex
movements; (2) the storage of learned experiences; and (3) the reception of
sensory information. For the purpose of this chapter, we will limit our
discussion to the role of the cortex in the organization of movement.
However, to appreciate this, some information about the structure of the
cerebral cortex is required.
2.1.1 Structure of the cerebral cortex

The cerebral cortex is well endowed with neurons, neuroglia, and blood
vessels. The structural organisation of the three types of cells that populate
the cortex, being pyramidal cells, stellate neurons and fusiform neurons,
enables the classification of the cortex into three types: allocortex,
mesocortex and the neocortex. The allocortex is the oldest region and is
composed of only three layers and is located in the limbic system. The
mesocortex is younger and is composed of three to six layers and is
predominantly located in the insula and cingulate gyrus. The neocortex is
the youngest region of the cortex and is composed of six layers that
comprise the bulk of the cerebral cortex (Rothwell 1994). Whilst the
cerebral cortex is structurally organised into layers, it also has organisation
through functional connections. Most corticospinal output is mediated
through pyramidal neurons and stellate (or granule) cells. The cellular
organisation of pyramidal and stellate cells within the cortex gives it a
characteristic layered or laminar appearance that can be identified as six
distinct layers:
I. Molecular layer. A layer lying immediately inferior to the pia matter and
containing very few cell bodies.
II. External granular layer. A layer of densely packed small cells

including small pyramidal and stellate cells.
12 Chapter 2
III. External pyramidal layer. A layer consisting of medium to large-sized

pyramidal cells.
IV. Internal granular layer. This layer is predominantly composed of

densely packed stellate and pyramidal cells.
V. Ganglionic layer. This layer contains large pyramidal cells (Betz cells).
VI. Multiform layer. This layer is relatively thin and mostly composed of
densely packed, spindle-shaped cells, many with axons leaving the cortex.
Layer 1 contains mainly long horizontal dendrites and axons in deeper

layers as well as thalamic afferents. The medium to large pyramidal cells in
layers III and V contain long cortico-cortical connections. In addition,
pyramidal cells in layer V also project to sub-cortical areas such as the basal
ganglia, brain stem and to the spinal cord. Layers II and IV receive afferent
inputs, with inputs from the thalamus generally terminating in layer IV.
Layer VI contains small pyramidal cells which exhibit greater morphologic
variability than the pyramidal cells located in other layers and have cortico-
cortical and cortico-thalamic projections. Layers II through VI all contain
stellate cells, some of which form excitatory connections onto pyramidal
cells and some of which form inhibitory synapses.
2.1.2 The brain stem

The brainstem is located inside the base of the skull just superior to the
spinal cord and is essentially an extension of the spinal cord. It is composed
of a series of complicated neural tracts and nuclei (groups of neurons). The
major structures of the brain stem include the medulla, pons and midbrain.
In addition to these structures, a complex neuronal network known as the
reticular formation resides in the brainstem. The brainstem performs motor
and sensory functions for the face and head (i.e., cranial nerves) along with
providing support to the body against gravity. For example, muscles of the
spinal column and the extensor muscles of the legs maintain the body
against gravity. These muscles are under the control of specific brainstem
nuclei, in particular the pontine reticular nuclei, which excite activity in the
antigravity muscles, and the medullary reticular nuclei, which inhibit the
activity of antigravity muscles. Importantly, the medullary reticular nuclei
receive collateral input from the corticospinal pathway, rubrospinal
pathway, and other motor pathways. These systems can activate the
inhibitory action of the medullary reticular nuclei and counterbalance the
signals from the pons.
2.2 Transmission of cortical motor signals

The spinal cord is under the control of a number of neurons that descend
from the primary motor cortex (M1). The largest of these are the
corticospinal neurons that have their origins in layer V of the cerebral cortex
and extend to form the bulk of the corticospinal or pyramidal tract (Porter
1985). Although corticospinal neurons are located within six cortical
regions, the M1 has the largest concentration (Porter, 1985). Within the M1,
these corticospinal neurons are functionally organised to project to
motoneurons that control specific muscle groups (He et al. 1993), thus they
are somatotopically organised. Corticospinal neurons that arise within the
M1 descend through the internal capsule, brainstem, and medulla oblongata
and continue to descend in the dorsolateral funiculi of the spinal cord
(Alawieh et al. 2017). As the corticospinal neurons leave the M1 and
descend to the medulla, they are organised somatotopically. At the
medullary spinal junction, approximately 85-90% of the corticospinal
neurons cross the midline to form the motor pyramidal decussation
(Alawieh et al. 2017), where they continue as the dorsolateral funiculi of the
spinal cord and converge onto motoneurons within the ventral horn of the
spinal cord that innervate limb muscles (Alawieh et al. 2017). Anatomical
mapping studies reveal that the connectivity of the corticospinal tract
suggests that the remaining uncrossed ipsilateral corticospinal tract fibres
descend primarily in the dorsolateral lateral or ventral funiculi of the spinal
cord (Alawieh et al. 2017).
A small proportion of corticospinal tract fibres do not crossover at the

pyramidal decussation at the medulla; rather, they project to ipsilateral
spinal motoneurons, where they could alter the excitability of ipsilateral
pathways (Porter and Lemon 1993, Carson 2005). In the clinical
neurophysiology literature, it has been suggested that increased utilisation
of the ipsilateral pathway may provide a viable method for re-establishing
motor control of upper-limb muscles following lesions to the M1 (Alawieh
et al. 2017, see Chapter 11 for more detail). There is now good evidence for
a functional role of the corticospinal system in the control of the upper limb
and changes in its functional organisation following different forms of
exercise training (Frazer et al. 2018).
2.3 Motor functions of the cerebellum

For a long time, the cerebellum has been referred to as the silent area of the
brain mainly because electrical stimulation of the cerebellum does not
14 Chapter 2
evoke any conscious sensation or movement. However, intriguingly,

removal of the cerebellum causes highly abnormal human movement.
Although it is difficult to study the function of the cerebellum in a conscious
person, it is generally accepted that the cerebellum is vital for rapid motor
actions which include cycling, running, playing the piano and talking.
Because the cerebellum does not cause muscle contraction per se, its main
function is to assist in the sequencing of motor actions and to monitor and
correct movements whilst they are being executed. The ability to adjust
motor sequences during movements enables the M1 and other parts of the
brain to ensure that the intended movements are performed correctly.
The cerebellum continuously receives updated information about the

intended/desired sequence of muscle activity from specific motor control
centres of the cortex. It receives sensory information from peripheral
receptors such as muscle spindles and Golgi tendon organs, thus allowing
corrective adjustments to be sent to the motor system to increase or decrease
the level of muscle activation of specific muscle groups. A critical function
of the cerebellum is to assist the cerebral cortex to plan the next series of
sequential movements in advance whilst the initial movement is still being
performed. This essentially enables movements to transition smoothly from
one movement to the next. The cerebellum also learns to correct movement,
via special cerebellar nuclei (the deep cerebellar nuclei) that can adjust
motor output. The cerebellum is able to perform these functions because of
its anatomical and functional organisation.
2.3.1 Anatomical and functional organisation of the cerebellum

The cerebellum is divided into three lobes: 1) anterior lobe, 2) posterior lobe
and 3) flocculonodular lobe and two deep cerebellar fissures. The cerebellar
hemispheres are separated along the longitudinal axis by a narrow band
called the vermis. The vermis plays an important role in controlling muscle
activity of the axial body, shoulders and head. To either side of the vermis,
are cerebellar hemispheres, whereby each hemisphere divides into an
intermediate and lateral zone. The intermediate zone controls motion of
distal portions of upper and lower limbs especially the hands and feet, whilst
the lateral zone controls sequencing movements of muscles including
timing and coordination of muscle activity. The vermis and intermediate
zones contain a topographical representation of the body, similar to that
observed in the sensory cortex, motor cortex, basal ganglia, red nucleus and
the reticular formation. The topographical regions of the vermis and lateral
zones receive afferent projections from all respective parts of the body, as
well as from corresponding topographical motor areas from the cerebral
cortex. The lateral zone of the cerebellar hemisphere is not topographically

organized, rather, it receives input signals from the cerebral cortex that
enable the cerebellum to assist the motor pathways to organise and plan
movement.
2.3.2 Afferent and efferent pathways of the cerebellum

Several neural tracts from the cerebral cortex to the cerebellum regulate
human movement. For example, the corticopontocerebellar pathway
originates from motor and premotor areas of the cerebral cortex and
somatosensory cortex and send their axons to mainly the lateral zone of the
cerebellar hemisphere. In addition, neural tracts from the brainstem, such as
the olivocerebellar tract, vestibulocerebellar tract (vestibular apparatus),
and reticulocerebellar tract, terminate predominately in the vermis. The
dorsal spinocerebellar tract transmits information mostly from muscle
spindles but also from Golgi tendon organs, tactile, and joint receptors in
the periphery to the cerebellum. Thus, it appraises the brain of the
momentary status of muscle contraction, muscle tension and limb position
and forces acting on the body surface. The other afferent pathway is the
ventral spinocerebellar tract that is mainly excited by motor signals that
arrive at the ventral horn of the spinal cord from the brain via the
corticospinal tract and from the internal motor pattern generators of the
spinal cord itself.
The main efferent pathways that exit the cerebellum include the
fastigioreticular tract and the cerebellothalamocortical tract, along with the
cerebellar nuclei. The fastigioreticular tract works in close association with
the equilibrium apparatus and brainstem nuclei to control balance and works
with the reticular formation of the brainstem to control postural stability.
The cerebellothalamocortical tract is extremely complex and passes
through many neuronal structures to finally terminate at the level of the
motor cortex, whereby it coordinates the reciprocal contractions of agonist
and antagonist muscles in the limbs; thus, it is involved in the turning ‘on’
and ‘off’ of muscle activity.
In addition to the efferent neural pathways located deep in the cerebellum,

on each side are three deep cerebellar nuclei, the dentate, interposed and
fastigial nuclei. The deep cerebellar nuclei all receive input signals from the
cerebellar cortex and the deep sensory afferent tracts to the cerebellum. The
primary source of motor output from the cerebellum is via the deep nuclear
cells. Every time an input signal is sent to the cerebellum, the afferent
signals go directly to the deep cerebellar nuclei and to the corresponding
16 Chapter 2
area of the cerebellar cortex overlying the deep nucleus. Once the input
signal has been received by the deep nuclei, an inhibitory output signal from
the deep nuclei is generated. Simplistically, all afferent signals to the
cerebellum end in the deep nuclei as excitatory signals followed a few
milliseconds later by inhibitory signals. These inhibitory signals from the
deep nuclei exit the cerebellum via efferent pathways described above.
2.4 Motor functions of the spinal cord

The spinal cord is about 45 cm long
and approximately 14 mm in width. It
has a laminar structure (i.e., flows
down from the brain without any
abrupt changes). Transection of the
spinal cord reveals a characteristic
butterfly picture, consisting of gray
matter (cell bodies of spinal neurons)
and the remaining white matter
(neural tracts that transmit
information to and from the brain)
constitutes the rest of the spinal cord
(Figure 2.1).
The spinal cord is protected by the

spinal vertebra and each vertebra has
two pairs of horns. The dorsal horns
Figure 2.1. Gross anatomy
(closer to the back) serve as an input of the human spinal cord.
pathway for sensory information from
peripheral receptors. As you can see in Figure 2.2, the cell bodies of the
receptors are located in spinal ganglia just outside of the spinal cord (i.e.,
the dorsal root ganglion). These cell bodies have T-shaped axons where
their distal branches travel to sensory endings located in the periphery and
their proximal branches enter the spinal cord via the dorsal horn. The axons
of many different peripheral receptors (e.g., muscle spindles, golgi tendon
organs) form a dorsal root and enter the spinal cord through the same dorsal
horn. In contrast, the ventral horns are the major output pathway of neural
signals to peripheral structures, in particular muscles (the axons of Į-motor
neurons) and the muscle spindles (the axons of gamma-motor neurons). The
axons of these neurons form the ventral roots. Most of the neurons within
the spinal cord are not motor neurons, rather they are interneurons. These
neurons receive information from both afferent and efferent fibres and
axons of neurons within the central nervous system (CNS), to generate

action potentials that are transmitted to other interneurons or motoneurons.
Figure 2.2. Cross-sectional anatomy of the spinal cord.
2.4.1 Organisation of the spinal cord

The nervous system enables sensory information to be integrated and, once
integrated, an appropriate motor response is generated that generally begins
in the spinal cord via reflexes. More complex processing will eventually
extend to the brainstem and cerebral cortex, whereby complex and intricate
motor skills are performed. There are many neural circuits in the spinal cord
that are vital for the control of movement and the spinal cord is organised
in a specific manner, as briefly discussed above; however, here we will go
into some specific detail.
Anterior motor neurons are located at each spinal segment level of the anterior
horn of the spinal gray matter (Figure 2.2). Each anterior horn contains several
thousand specialised neurons that are about 50-100% larger in size than other
neurons found in the nervous system; these are called anterior motoneurons.
Anterior motoneurons give rise to the nerve fibres that exit the spinal cord via
the anterior roots to directly innervate skeletal muscle. There are two types of
neurons, Į- motoneurons and gamma-motoneurons.
18 Chapter 2
Alpha motoneurons are large type A Į- motor neurons with a large diameter
that have many fibre branches as they enter and stimulate skeletal muscle.
A single Į- motoneuron and the muscle fibres it innervates are known as a
motor unit (see below). Transmission of nerve impulses into skeletal
muscles occurs by activating motor units, which in turn stimulate muscle
cells, which produce muscle force.
In contrast, gamma motor-neurons transmit nerve impulses through much

smaller type A gamma motor nerve fibres, which target the intrafusal fibres
of skeletal muscle. These fibres comprise the middle of the muscle spindle,
which helps control muscle tone via the stretch reflex.
In order to facilitate the ongoing control of movement and all of the

information that flows into the spinal cord, interneurons are present in all
areas of the spinal cord. Interneurons are small, highly excitable neurons
that have many interconnections with one another and many of them
synapse directly onto anterior motoneurons, enabling the integrative
function of the spinal cord to occur. This integrative process occurs via
spinal reflex activity. All reflexes commence with a stimulus that is of
sufficient intensity to activate a sensory receptor. Once activated, the
sensory receptor will discharge action potentials through sensory afferent
neurons to the CNS. The CNS, which includes the brain and spinal cord, is
the major integrative centre that processes and evaluates all incoming
(afferent) information and then coordinates an appropriate response. The
appropriate response results in a series of action potentials in efferent
neurons that then synapse onto an effector organ, such as a muscle to cause
a response. This whole process is referred as the reflex arc.
2.5 Types of reflex pathways

The common reflex pathways in the CNS consist of a network of neurons
that link sensory receptors to muscles and glands. Because of this, reflexes
can be classified in different ways, e.g., somatic reflex, spinal reflex,
autonomic, etc. The most relevant classification for human movement is
somatic and spinal reflexes. A somatic reflex involves the activation of
somatic motor neurons and skeletal muscle, whilst spinal reflexes are
reflexes that are integrated at the spinal level, but modulated by higher input
from the brain. Reflexes can also be classified by the number of neurons
within that reflex pathway. For example a monosynaptic reflex has a single
synapse between an afferent neuron and an efferent neuron, whilst a
polysynaptic reflex involves two or more synapses.
2.5.1 Skeletal muscle reflexes

Nearly every movement that we perform involves skeletal muscle reflexes.
We have specialised receptors throughout the musculoskeletal system that
sense changes in joint movement (position), muscle tension, and muscle
length. These receptors provide the CNS with this information, which then
responds in one of two ways. First, if the appropriate response is muscle
contraction, the CNS will stimulate somatic motor neurons in the ventral
horn to activate skeletal muscle or, if a muscle needs to relax, the CNS will
activate inhibitory interneurons and inhibit the activity of somatic motor
neurons. The specific reflex pathways for these responses are derived from
Golgi tendon organs and muscle spindles.
2.5.1.1 Muscle spindles
Muscle spindles are stretch sensitive receptors that propagate action

potentials to the spinal cord and muscle, which inform the CNS about
muscle length and the changes in muscle length that occur during movement.
Each muscle spindle is enclosed in a connective tissue capsule that is
infolded by a small group of muscle fibres known as intrafusal fibres.
Figure 2.3. Monosynaptic reflex arc.

20 Chapter 2
The intrafusual fibres are organised in such a manner that the ends are the
contractile component, whilst the central region is enclosed with sensory
nerve endings that respond to muscle stretch. The contractile components
of the muscle spindle are innervated by gamma motoneurons. Even at rest,
the central region of the muscle spindle is stretched enough to activate the
sensory nerve endings, which in turn discharge action potentials that arrive
at the spinal cord and synapse directly on Į- motoneurons innervating the
muscle in which the muscle spindle lies, producing a classic monosynaptic
reflex (Figure 2.3). This neural process occurs in order to maintain muscle
tone (i.e., a resting muscle will still a have particular level of tension).
During movement, muscle stretch activates muscles spindles, which
produce the synonymous stretch reflex via gamma motoneuron activation.
When Į-motoneurons discharge (due to muscle spindle input), the muscle
will contract, which releases the stiffness on the capsule of the muscle
spindle. In order to ensure normal spindle activity, gamma motoneurons
innervate the contractile ending of the spindle by discharging action
potentials at the same time as the central region discharges. The gamma
motoneuron causes the muscle to contract and, thus, shorten via stimulating
the intrafusal fibres. In simple terms, the discharge of the central regions
leads to Į- motoneuron activation (via the monosynaptic stretch reflex
pathway) and gamma motoneuron activation (which keeps the muscle
spindle active) simultaneously via a process called alpha-gamma co-
activation.
2.5.1.2 Golgi tendon organs (GTO)
GTOs are specialised sensory receptors located at the junction of tendons

and muscle fibres. GTOs respond to muscle tension during the isometric
phase of a muscle contraction, thus they detect the amount of motor unit
activity within a muscle.
The discharge rate of GTOs increases as a function of increasing force

production. Excitation of GTOs leads to an inhibitory reflex known as the
results inverse myotatic reflex (Figure 2.4).
Figure 2.4. Inverse myotatic reflex loop.

When a skeletal muscle contracts, it results in muscle tension that stimulates
the GTOs in the tendon attached to the skeletal muscle. Activation of GTOs
leads to the propagation of action potentials to the spinal cord by afferent
neurons. Within the spinal cord, the afferent neuron synapses with an
inhibitory interneuron and an excitatory Į- motoneuron. Because there is an
inhibitory synapse (via an interneuron) with an Į- motoneuron that
specifically innervates the muscle attached to the tendon, the inhibitory
synapses lead to the relaxation of the contracted muscle, whilst the
antagonist muscle is activated (e.g., autogenic inhibition). Thus, the GTO
reflex pathway is a safety mechanism to ensure that the agonist is not
producing too much force that could lead to tearing the muscle/tendon.
2.6 Hierarchical organisation of motor control

Further to structural and functional divisions of the central nervous system,
which provide an anatomical organisation of the brain and spinal cord,
understanding of how movement is integrated and controlled can also be
explained using a hierarchical approach.
22 Chapter 2
Whilst it is logical to assume structural levels of arrangement being cortical,

subcortical and spinal cord, the hierarchical approach arranges motor
control in terms of interactions between the structures and their
contributions to the final motor output. Each level of the hierarchy has a
specific function in motor control (Figure 2.5).
Figure 2.5. Hierarchical organisation of human motor control.
In order to commence a movement, such as elbow flexion with a dumbbell,

“an intention” to commence the movement is generated at the highest level
of the hierarchy (e.g., cerebral cortex, premotor areas, etc.). The exact
cortical regions involved in these “intentions” are not completely known,
but likely involve the pre-motor cortex, motor cortex and sensory cortex.
As Figure 2.5 shows, “motor commands” will then descend from the higher
motor-output centre “command neurons” to specific regions of the brain
that constitute the middle level of the motor control hierarchy. Such regions
include the brainstem, cerebellum, thalamus, sensoricortex and basal
ganglia. All these structures form strong functional connections to the motor
cortex. The main role of the middle level is to specify what postures and
movement are required in order to carry out the intended motor action. The
neurons located in the structures of the middle level receive their input from
neurons in the higher level centres simultaneously as they receive afferent
input from receptors in muscles, tendons, joints, skin, the vestibular system
and visual system. The afferent input relays this information to the middle-
level neurons, which provide important information about the starting
position of the body, posture and muscles to be recruited or activated to

enable the movement to occur. These neurons also integrate all afferent
information with the “command neurons” to develop a motor program (i.e.,
the pattern of neural activity required to perform a movement correctly).
The information determined by the motor program (i.e., starting position,
muscles to recruit, etc.) is then transmitted to the major descending motor
pathways (corticospinal tract) to the lowest level of the motor control
hierarchy, the brainstem and spinal cord. The lowest level (or local level)
includes motor neurons and interneurons within the spinal cord. It is the
final common pathway and it determines which motoneurons will be
activated in order to achieve the desired movement. In addition, this level
will also determine how many motor units will be recruited and what degree
of muscle activation is required.
2.7 Motor units, fibre types, and recruitment physiology

2.7.1 The motor unit
A motor unit is the functional unit of neural control for muscular activity.
Motor units consist of a cell body,
a Į-motoneuron, and all of the
muscle fibres innervated by the Į-
motoneuron (Figure 2.6; Enoka and
Fuglevand, 2001). Motor units
convert synaptic input received by
Į-motoneurons into mechanical
output by the muscle (Fang et al.
1997). The number of muscle fibres
per motor unit varies and, to a
certain extent, determines the
motor performance of the muscle.
The number of muscle fibres per
motor unit can vary from as little as
four for ocular muscles, 100 for
small muscles involved in fine Figure 2.6. Functional organisation of
motor performance, to as many human motor units.
as a 1000 or more for larger
muscles involved in gross motor patterns (Duchateau et al. 2006).
24 Chapter 2
2.7.2 Physiological classification and recruitment

A group of Į-motoneurons located in the ventral horn of the spinal cord and
the muscle they innervate are known as a motor unit pool. The motor units
that form a motor unit pool are diverse in regard to the intrinsic properties
of the Į-motoneurons and the muscle fibres that they innervate (Duchateau
et al. 2006). A Į-motoneuron is typically characterised by its structure,
excitability and distribution of synaptic input, whilst muscles fibres are
classified based upon their contractile speed, force generating capacity, and
resistance to fatigue (Burke et al. 1973). Most muscles in the human body
contain muscle fibres that have differing contractile speeds. Given that all
muscle fibres comprising a single motor unit have identical metabolic
properties, muscles that have different contractile speeds belong to a
different type of motor unit subtype. Experimental data confirm that motor
units have specific physiological and biochemical properties, and therefore
can be categorised based upon these properties (Kernell et al. 1999). The
most generally accepted physiological classification for motor unit types are:
slow contracting, fatigue resistant (S); fast contracting, fatigue resistant (FR);
and fast contracting, fast to fatigue (FF) (Figure 2.7).
Figure 2.7: Twitch contraction profile of human motor units (fatigue resistant (S);
fast contracting, fatigue resistant (FR); and fast contracting, fast to fatigue (FF).
Based upon this classification, it has been identified that S units have slow
contraction times (i.e., time to peak force), produce a relatively small
amount of tension, are recruited earlier, have slow conducting motor axons
and have a greater resistance to fatigue, whilst the FR units have
intermediate properties, for example, have a fast twitch, produce moderate
tension, are recruited later, have faster conducting motor axons and are
resistant to fatigue. In contrast to the S and FR unit properties, FF units have

a fast twitch, develop large tension, and are vulnerable to fatigue (Bigland-
Ritchie et al. 1998).
In addition to this classification, motor unit subtypes have also been

classified based upon their histochemical, biochemical, and molecular
properties of the muscle fibres that they innervate (Enoka and Fuglevand
2001). For example, histochemical analysis has identified three types of
muscle fibres: type I, type IIa and type IIx (Kernell et al. 1999). Type I fibres
are often referred to as slow-twitch fibres, whilst type II are fast-twitch
muscle fibres; however, they can be further categorised as Type IIa and IIx
(Brooke and Kaiser 1974).
2.8 Principle of motor unit recruitment

The recruitment of motor units is governed by the “size principle” which
was first proposed by Henneman and colleagues in 1974. In the simplest
elements, the size principle of motor unit recruitment states that the smallest
Į-motoneurons (and motor units) are recruited first and orderly recruitment,
relative to size, occurs thereafter. This appears to be a good strategy,
because the smaller motor units which are recruited first are also the ones
that are the most difficult to fatigue and thus can withstand long contraction
durations. When gradually increasing force production, most muscles
completely recruit all available motor units between 50 and 95% of
maximum force production. During fast or ballistic contractions, the level
of force required to recruit a specific motor unit is lowered. In other words,
larger (the so-called high-threshold) motor units are recruited at a lower
force level (i.e., more readily recruited) when the contraction is performed
as fast as possible rather than during a slow contraction. Force production
is also regulated by the rate at which a motor unit is activated. This simply
means how often an electrical discharge passes along the Į-motoneuron (i.e.,
motor unit action potential). This is known as rate of motor unit firing (also
known as discharge rate, firing frequency or rate coding). It has been
demonstrated during gradually increasing force contractions (the so-called
ramp contractions), already recruited motor units increase their firing rate
as the force level increases. Firing rate patterns appear to be reversed during
fast contractions, showing an initial burst of high firing rate followed by
lowered rates once a certain level of force is attained, but recruitment still
follows the size principle. Differences in the interaction between motor unit
recruitment and firing rate may be dependent upon the type of muscle, with
small muscles seemingly more reliant on firing rate to modulate force
26 Chapter 2
production while large force-producing muscles rely more on recruitment.

Nevertheless, ultimately, neural control of force production is reliant upon
motor unit recruitment and firing rate whose combination determines the
final signal presented to the muscle.
2.9 Motor unit synchrony

In some instances, depending on the motor task being performed, motor
units may be recruited in a synchronous manner. Motor unit synchronisation
is a time domain measure of the correlated activity of pairs of active motor
units (Sears and Stagg 1976). Motor unit synchronisation provides
information on the strength of branched common input to Į-motoneurons
that is modulated by the corticospinal pathway (Figure 2.8) (Nordstrom et
al. 1992).
Figure 2.8: Mechanism of motor unit synchronisation (Adapted from Semmler

2002).
The most direct method used to determine motor unit synchronisation in

humans is cross-correlation analysis of individual discharge times from
pairs of concurrently active motor units (Griffin et al. 2009). This procedure
requires identifying the discharge time of one motor unit, which is used as
a reference, and a histogram is constructed of the peri-event discharge times
of a second motor unit (Farmer et al. 1997). If a tendency towards
synchronisation exists, there will be a peak in the cross-correlation
histogram around the time of firing of the reference motor unit (Moore et al.
1966). The presence of a peak in the histogram is due to common input from
branched corticospinal axons of single last-order neurons (Farmer et al.
1997) and represents the common input strength (CIS) (Wiegner and
Wierzbicka 1987). This common input is thought to increase the probability
of simultaneous discharge in the motor units sharing these inputs (Datta and
Stephens 1990).
The presence of correlated activity (i.e., synchronisation) appears as a peak

in the centre of the histogram. The size of the peak in the histogram reflects
the amount of common input that is shared between the neurons (Farmer et
al. 1997) whilst the width of the peak is used to distinguish between direct
and indirect common input onto Į-motoneurons (Farmer et al. 1997). Direct
common input produces a narrow peak in the cross-correlation histogram
and is known as short-term synchronisation of motor units (Moritz et al.
2005). In contrast, indirect common input produces a broader peak in the
histogram and is known as broad-peak synchronisation (Lowery et al. 2007).
As a result, the width of the peak can be used to discriminate between direct
cortical connections to Į-motoneurons and those with an interposed neuron.
Experimental recordings in humans suggest that the histogram peaks
usually encompass a mixture of direct and indirect common inputs (Farmer
et al. 1997).
2.9.1 Quantifying the degree of motor unit synchrony

Motor unit synchronisation is quantified by applying the cumulative-sum
technique to identify statistically significant peaks, as well as significant
peak widths within the cross-correlation histogram (Wiegner and
Wierzbicka 1987). Once peaks have been identified in the cross-
correlogram, synchronisation indices can be calculated for all peaks within
the histogram (Nordstrom et al. 1992). For example, the K index is defined
as the ratio of total counts in the peak region to chance in the cross-
correlogram (for review see Nordstrom et al. 1992). It has been shown that
this synchronisation index tends to be smaller with higher motor unit
discharge rates, therefore making it a sensitive measure for quantifying
motor unit synchronisation at high force levels. The common input strength
(CIS) is another index often used to measure the magnitude of motor unit
synchronisation. CIS is estimated from the cross-correlogram as the number
of extra counts in the synchronous peak above that expected by chance.
Therefore, the CIS is a representation of the frequency of synchronised
motor unit discharges. Another index used includes the E index. The E index
quantifies the magnitude of motor unit synchronisation by counting the
28 Chapter 2
number of synchronous events normalised to the number of discharges of

the reference motor unit (Datta and Stephens 1990).
2.9.2 Motor unit synchronization and human motor control

Using cross-correlation analysis, several studies have demonstrated that
motor unit synchronisation is modulated by the motor task performed
(Semmler and Nordstrom 1998; Fling et al. 2009). For example, motor unit
synchronisation is less during index finger flexion, but greater during index
finger abduction (Bremner et al. 1991). Further, synchronisation is 35%
greater during eccentric contractions compared to isometric and concentric
(Semmler 2002). There is also evidence to suggest that the strength of motor
unit synchronisation is modulated by regular physical activity. However,
how motor unit synchronisation is altered following motor training is not
clear. In light of this, Semmler and Nordstrom (1998) demonstrated that the
strength of motor unit synchronisation was largest for the dominant and
non-dominant hands in weightlifters, and was the lowest in both hands of a
group of highly-skilled musicians. Fling et al. (2009) demonstrated that the
strength of motor unit synchronisation was greatest in the first dorsal
interosseous (FDI) and biceps brachii (BB) in weightlifters compared to a
control group. It must be noted that, as no training intervention was
performed in these studies, it is not known if the differences in
synchronisation are related to some aspect of muscle strength, or more
closely associated with skilled motor performance. Whilst there is limited
data that has examined the effect of strength training on motor unit
synchronisation, it is a common impression that increases in motor unit
synchronisation lead to an increase in strength.
2.9.3 Motor unit synchronization in upper and lower limb muscles

Given that the general line of evidence for motor unit synchronisation stems
from last-order common pre-synaptic input from descending corticospinal
neurons to Į-motoneurons (Farmer et al. 1997), the degree of synchronisation
between muscles varies (Fling et al. 2009). Motor unit synchronisation is
greater in the FDI, compared to the more proximal BB and the vastus
medialis muscles, suggesting that the strength of motor unit synchronisation
is influenced by the type of muscle (i.e., gross vs. fine). Recently, Fling et
al. (2009) assessed the magnitude of motor synchronisation of the BB and
FDI in a group of strength-trained participants. These results are in
accordance with previous research (Semmler and Nordstrom 1998),
demonstrating that the magnitude of motor unit synchronisation was greater
in the FDI when compared to the BB. A possible mechanism that may
account for this difference in motor unit synchronisation is that it may
simply be a result of differences in the physiological strength of the
corticospinal pathways monosynaptic connections onto the spinal
motoneuron pool that controls the FDI being stronger compared to the BB
(Kim et al. 2001, Fling et al. 2009). Furthermore, McKiernan et al. (1998)
demonstrated that individual cortico-motoneuronal cells have more
recurrent and more effective terminal connections onto the Į-motoneuron
pools of distal muscles compared to proximal muscles. Support for a
corticospinal origin for motor unit synchronisation has stemmed from
research in patients with corticospinal lesions (Semmler 2002). In patients
with amyotrophic lateral sclerosis, which is a progressive degenerative
disease affecting large diameter corticospinal cells, motor unit
synchronisation is almost absent (Schmied et al. 1999).
2.10 Summary
The control of voluntary movement is complex and requires the cooperation
of many areas within the CNS, including supraspinal and spinal structures.
In order to perform a voluntary movement, both cortical and subcortical
structures propagate descending volleys to the spinal cord via the
cerebellum and basal ganglia, which in turn recruit the appropriate type and
number of motor units to perform the given movement. Feedback to the
CNS is derived from muscle receptors, which allows for the ongoing
modification of the descending motor command, if required.
References
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Preclinical and Clinical Evidence on Ipsilateral Corticospinal
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2. Bigland-Ritchie, B., A. J. Fuglevand and C. K. Thomas (1998).
Contractile properties of human motor units: Is man a cat?
Nueroscientist 4: 240-249.
3. Bremner, F. D., J. R. Baker and J. A. Stephens (1991). Effect of task
on the degree of synchronization of intrinsic hand muscle motor units
in man. J Neurophysiol 66: 2072-2083.
4. Brooke, M. H. and K. K. Kaiser (1974). "The use and abuse of
muscle histochemistry." Annals of the New York Academy of
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5. Burke, R. E., D. N. Levine, P. Tsairis and F. E. Zajac (1973).

Physiological types and histochemical profiles in motor units of the
cat gastrocnemius. J Physiol 234: 723-748.
6. Carson, R. G. (2005). Neural pathways mediating bilateral
interactions between the upper limbs. Brain Res Brain Res Rev 49:
641-662.
7. Datta, A. K. and J. A. Stephens (1990). Synchronization of motor
unit activity during voluntary contraction in man. J Physiol 422: 397-
419.
8. Duchateau, J., J. G. Semmler and R. M. Enoka (2006). Training
adaptations in the behaviour of human motor units. J Appl Physiol
101: 1766-1775.
9. Enoka, R. M. and A. J. Fuglevand (2001). Motor unit physiology:
some unresolved issues. Muscle Nerve 24: 4-17.
10. Fang, J., B. T. Shahani and D. Graupe (1997). Motor unit number
estimation by spatial-temporal summation of single motor unit
potentials. Muscle Nerve 20: 461-468.
11. Farmer, S. F., D. M. Halliday, B. A. Conway, J. A. Stephens and J.
R. Rosenberg (1997). A review of recent applications of cross-
correlation methodologies to human motor unit recording. J
Neurosci Methods 74: 175-187.
12. Fling, B. W., C. Anita, A. and G. Kamen (2009). Motor unit
synchronization in FDI and biceps brachii muscles of strength-
trained males." J electromyography kinesiol 19: 800-809.
13. Griffin, L., P. Painter, A. Wadhwa and W. Spirduso (2009). Motor
unit firing variability and synchronization during short-term light-
load training in older adults. Exp Brain Res 197: 337-345.
14. He, S. Q., Dum, R. P., and Strick, P. L. (1993). Topographic
organization of corticospinal projections from the frontal lobe: motor
areas on the lateral surface of the hemisphere. J Neurosci 13: 952.
15. Kernell, D., Bakels, R., and Copray, J. C. (1999). Discharge
properties of motoneurones: How are they matched to the properties
and use of their muscle units? J Physiol 93: 87-96.
16. Kim, M.S., Masakado, Y., Tomita, Y., Chino, N., Pae, Y.S., and Lee,
K. (2001). Synchronization of single motor units during voluntary
contractions in the upper and lower extremities. Clin Neurophysiol
112: 1243-1249.
17. Lowery, M. M., Myersm L. J., and Erim, Z. (2007). Coherence
between motor unit discharges in response to shared neural inputs. J
Neurosci Meth 163: 384-391.
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analysis and functional interpretation of neuronal spike data. Annu
Rev Physiol 28: 493-522.
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Coherence at 16-32 Hz can be caused by short-term synchrony of
motor units. J Neurophysiol 94: 105-118.
20. Nordstrom, M. A., Fuglevand, A. J., and Enoka, R. M. (1992).
Estimating the strength of common input to human motor neurons
from the cross-correlogram. J Physiol 453: 547-574.
21. Porter, R. (1985). The corticomotoneuronal component of the
pyramidal tract: corticomotoneuronal connections and functions in
primates. Brain Res 357: 1-26.
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Voluntary Movement. New York, USA, Oxford Science Publications.
23. Rothwell, J. C. (1994). Control of Voluntary Human Movement.
London, Chapman & Hall.
24. Schmied, A., Pouget, J., and Vedel, J. P. (1999). Electromechanical
coupling and synchronous firing of single wrist extensor motor units
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Neurosci Meth 22: 125-131.
CHAPTER 3
TECHNIQUES CONTRIBUTING
TO THE UNDERSTANDING OF NEUROSCIENCE
IN EXERCISE
ALAN J. PEARCE, PHD

AND DAWSON J. KIDGELL, PHD
3. Background
The ability to examine the human central nervous system (CNS) has
developed remarkably over the last 30 years. Imaging techniques, such as
functional Magnetic Resonance Imaging (fMRI) and positron emission
topography (PET), indirectly measure the changes in blood flow associated
with neural activity while participants perform a particular motor task
(Jenkins et al. 1994). A number of investigations have demonstrated
modifications in cortical activity during various movements. For example,
there is a strong relationship between isometric force production, pre-
movement activity and actual movement execution that results in increased
cortical activity in the M1, supplementary motor area (SMA) and the dorsal
portion of the anterior cingulate cortex (Dettmers et al. 1995; Thickbroom
et al. 1999b; Farthing et al. 2007). Although these studies demonstrate
changes in blood flow during movement preparation and execution, they do
not provide any objective data concerning the excitatory and inhibitory
synaptic events specific to the M1 during movement. Alternatively,
transcranial stimulation techniques are able to produce excitatory and
inhibitory interactions within the M1, and provide an objective measure of
the strength and function of corticospinal cell projections (Hallett 2000).
Transcranial electrical stimulation (TES) was initially utilised to assess
neurophysiological function, however its painful and invasive nature
prompted the development of transcranial magnetic stimulation (TMS),
which is now widely used to quantify various corticospinal measures that
are subject to both use-dependent and experimentally-induced neuroplasticity
Techniques Contributing to the Understanding of Neuroscience 33
in Exercise
(Chapter 4) (Barker et al. 1985; Hallett 2000). The aim of this chapter is to
provide an overview of the non-invasive techniques that are used to assess
neurophysiological function in humans during exercise.
3.1 Electroencephalography (EEG)

The most well-established electrophysiological technique, EEG provides
valuable insight into cortical electrical behaviour that is based as a function
of time (Wallace et al. 2001). The waveforms resulting from EEG can
provide neuroscientists with data regarding normal and abnormal brain
activity, allowing for diagnostic capacity for various conditions including
epilepsy, sleep disorders, or tumours.
Compared to neuroimaging technologies such as fMRI and PET, EEG is

relatively inexpensive and can be administered conveniently, recording
over multiple regions of the brain simultaneously. With multiple regions to
analyse from, montages were created to measure various patterns of the
electrical activity between two or more channels. Over time, the 10-20
system was developed and became the International Standard of electrode
placement, allowing for relative comparison of electrical activity across
different head regions (Wallace et al. 2001).
Traditional EEG waveforms are separated into specific bands qualitatively

based on shape and range of frequency for clinical applications. These
generally occur within the limits of 0.1 – 35 Hz and include alpha, beta,
delta, and theta waves (Wallace et al. 2001). Waveforms at frequencies of
8 – 13 Hz, known as Alpha waves, are thought to originate in the posterior
region of the brain. Alpha waves are generally observed in the parietal,
occipital, and posterior temporal areas. These waves are best detected when
an individual is mentally sedentary, and are observed while awake but
relaxed in an environment stimulus free. Beta waves include all frequencies
greater than 13 Hz but have low amplitudes limited to less than 20 ȝ9
Whilst beta waves can exist simultaneously throughout the cortex at various
low amplitude frequencies, they are most commonly seen in the frontal and
central head regions in nearly all healthy adults. Delta rhythms consist of
low frequency (0.5 – 4 Hz), high-amplitude waveforms (20-200 ȝ9 Delta
waves can be seen in the posterior regions of the head, and/or they can occur
on either side of the temporal region. However, they are most often recorded
over the left cerebral cortex. These rhythms are produced by thalamo-
cortical neurons and are virtually absent in the EEGs of normal alert
individuals. Delta waves are associated with periods of unconsciousness,
typically appearing in cerebral monitoring during sleep, coma, or after
34 Chapter 3
pathophysiological conditions such as traumatic brain injury (TBI) (Rumpl

et al. 1979). Theta waves measure from 4 – 8 Hz and have low amplitudes
(~10 ȝ9 (Shenal et al. 2001). They are presumed to originate in the
thalamus and are associated with the hippocampus and limbic system. Theta
rhythms can be recorded in the frontal, temporal, central, and posterior head
regions and are rarely the predominant waveform, being frequently mixed
with alpha and beta waves.
Quantitative EEG (qEEG) is an extension of EEG that provides a greater

depth of analysis using the EEG technique. Specifically, EEG waveforms
reflect an electrophysiological signature indicative of “normal” individuals
(Shenal et al. 2001). Consequently, qEEG measures that determine waveform
activation patterns inconsistent with these established norms may provide a
useful indicant of cortical dysfunction. For example, an individual
demonstrating increased delta wave amplitudes localized at the temporal
lobe following head trauma may indicate dysfunction associated with a
lesion within this region (Rumple et al. 1979).
The development of qEEG technology has, as suggested by some (Shenal

et al. 2001; Kanda et al. 2009), created some controversy and debate,
specifically around its clinical utility. As argued initially by Nuwer (1997),
issues surround reliability and validity of the technique via operator
expertise and clinical experience, as well as using qEEG as an adjunct to
traditional EEG. The arguments around this are due to disparities in
techniques between laboratories as well as post-processing of data
producing different interpretations based upon the algorithms employed
(Nuwer 1997). Despite progress in a number of areas of research, including
qEEG for concussion and post-concussion syndrome (Duff 2004), there is
continued debate about the diagnostic validity of qEEG, and it is suggested
that further studies are required to corroborate and refine data collection and
post-processing methods (Haneef et al. 2013).
3.2. Magnetoencephalography (MEG)

In 1972, the first magnetoencephalogram was measured using a superconducting
quantum interference device (SQUID) (Cohen 1972) by quantifying the
magnetic fields emitted by the brain. Similar to EEG, MEG signals are
derived from the net effect of ionic currents generated from neuronal
dendrites during transmission that produce a quantifiable magnetic field.
Generation of detectable spatial signals requires a neuronal bundle of
approximately 50,000 active neurons (Okada 1983). Therefore, conceptually,
the two are similar directly sampling the electromagnetic fields instantaneously
in Exercise
generated by neuronal activity, giving both techniques excellent temporal

resolution compared to neuroimaging. The sub-millisecond temporal
resolution of MEG and EEG is noticeably superior to the temporal
resolution of functional neuroimaging techniques, such as fMRI (hundreds
of ms) or PET (min) (Lee and Huang 2014).
Commercial whole-head MEG units were developed in the mid-1990s. An

advantage of MEG lies in the difference in methods of measurement.
Magnetic fields can pass undisturbed through human tissue, unlike electric
fields which can be distorted by various tissues such as skull bone and scalp
skin, and the underlying dura, vascular tissue and blood, as they pass from
the brain to the sensors (Lee and Huang 2014). Further advantages of MEG
over EEG are seen in better spatial localization of neuronal sources using
MEG (mm) compared to EEG (cm). Comparative studies using a skull
phantom between MEG and EEG showed that the signal-to-noise ratio of
EEG was better than that of MEG, but the localisation error of MEG was
significantly less than that of EEG (3 mm versus 8 mm, respectively)
(Leahy et al. 1998). Disadvantages of MEG versus EEG are that the brain’s
magnetic fields are extremely weak compared to other magnetic signals
such as the earth’s magnetic field, as well as magnetic fields generated by
other organs, such as the heart. In addition, it is often difficult or impossible
to uniquely determine the sources of neuronal current which generates the
MEG signals measured at the surface of the head (Lee and Huang 2014).
Finally, the typical cost of an MEG unit, including its shielded room, is
roughly the same as a high-field magnetic resonance imaging (MRI)
scanner. Therefore, MEG units are not commonly found (for example, there
are four MEG units in Australia).
3.3 Transcranial magnetic stimulation (TMS)

TMS is a non-invasive brain stimulation technique that utilises the
principles of electromagnetic induction to probe, assess and modulate
corticospinal activity (Barker et al. 1985). Operating via a coil placed over
the scalp, TMS generates magnetic pulses that painlessly penetrate the skull
to reach the cortex with very little mitigation (Kobayashi and Pascual-Leone
2003). When placed over the motor cortex, the resulting depolarisation of
underlying pyramidal cells produces a series of action potentials which
synapse with lower motoneurones and consequently activate target muscles
(Weber and Eisen 2002). The subsequent muscle twitch directly
corresponds to the site of stimulation on the motor cortex (Koboyashi and
Pascual-Leone 2003). TMS can generate single pulses, paired pulses or
36 Chapter 3
repetitive pulses to assess the excitability of the intracortical circuitry of the

motor cortex.
3.3.1 Single-pulse TMS

There are a number of basic TMS techniques that allow the assessment of
the motor cortex and corticospinal tract (CST). The muscle activity
generated by TMS can be captured by electromyographic (EMG)
techniques in the form of a motor evoked potential (MEP, see Figure 3.1).
Figure 3.1: Single-pulse TMS; The depolarisation of underlying cortical nerurons

causes a MEP; which is followed by the silent period (SP) duration, which reflects
the absence of muscle activity following an active MEP.
The MEP is comprised of descending volleys generated by direct (D-waves)

and indirect, synaptic (I-waves) activation of pyramidal cells (Di Lazzaro
et al. 2002). Importantly, the muscle activity generated by TMS is
dependent on neuronal excitability in both the M1 and spinal cord, and is
thus typically considered a measure of corticospinal excitability (Kobayashi
and Pascual-Leone 2003). Consequently, the MEP is frequently used to
assess the neural adaptations to exercise (Kidgell et al. 2017, Mason et al.
2019).
As MEP amplitude increases with increasing stimulus intensity (Siebner

and Rothwell 2003), a common technique to assess corticospinal excitability
is to construct a stimulus-response curve/recruitment curve. This technique
is considered a comprehensive assessment of corticospinal excitability for
a given muscle (Siebner and Rothwell 2003). A change in MEP amplitude
at a given stimulus intensity following an intervention reflects alterations
in excitability of the CST, which may be an important mechanism
in Exercise
underpinning improvements in motor performance following exercise

(Rogasch et al. 2009). In other words, an increase in the size of the MEP
indicates that motoneurons are providing more output for a given synaptic
input. High stimulation intensities recruit predominantly high-threshold
motor units, whereas low stimulation intensities recruit mainly low-
threshold units (Classen and Benecke 1995).
Immediately following the MEP, there is a period of non-activity on the

EMG trace which is termed the corticospinal silent period, more recently
referred to as the silent period (Škarabot et al. 2019, see Figure 3.1B). The
silent period, only occurring in an active muscle, is mediated by the
neurotransmitter gamma-aminobutyric acid-B (GABAB) (McDonnell et al.
2006), and indicates an interruption in volitional drive from the M1 and the
removal of descending input to the spinal motoneuron pool (Škarabot,
Mesquita et al. 2019). Increases in the duration of the silent period reflect
greater levels of inhibition in the CST, with contributions arising from
cortical and spinal levels (Rogasch et al. 2014).
Although TMS is regarded as the gold standard for assessing corticospinal

excitability, there are a number of factors that need to be controlled in order
to ensure that changes in corticospinal excitability following single- pulse
TMS are robust. For example, considerable inter- and intra-trial MEP
variability exists, likely due to factors such as muscle activation and coil
position and orientation (Weber and Eisen 2002). These limitations are
circumvented by a range of strategies, including averaging MEP values
across a number of trials, and using co-ordinates to replicate motor cortex
hotspots between testing sessions. The MEP amplitude is particularly
variable in relaxed muscles (Burke et al. 1995); however, increasing the
probability of the motoneuron pool discharging via a low-level contraction
of the target muscle can substantially reduce this variability (Kiers et al.
1993). Recent developments have also indicated the appropriate stimulus
intensities and volume of stimuli for various measures to produce consistent
measurements (Temesi et al. 2017), leading to an increase in reliability. A
further single-pulse technique designed to assess the level of voluntary drive
to the motoneuron pool of the target muscle is TMS-voluntary activation
(VA TMS), which reflects how the motor cortex drives the recruitment of
motor units that are used in muscle contraction and force generation (Lee et
al. 2008). Given the proximity of motor units to the peripheral site, and their
direct influence over muscle contraction, VATMS is capable of providing
important insight as to how the motor cortex may adapt following different
modes of exercise (e.g., aerobic versus anaerobic).
38 Chapter 3
Changes in single-pulse TMS assessments do not necessarily reflect

changes in motor cortex as MEPs and the duration of the silent period are
influenced by several factors along the entire neuroaxis (Di Lazzaro and
Rothwell 2014). For example, MEP amplitude is influenced by the
excitability of the intrinsic circuitry of the spinal cord, the efficacy of the
corticospinal motoneuronal synapses, and changes in MEP amplitude may
be produced at a spinal level without motor cortical input (Di Lazzaro and
Ziemann 2013). Consequently, single-pulse TMS is unable to reveal the site
of neural adaptation following exercise (Carroll et al. 2011). Two main
techniques have been used to overcome the limitation of single-pulse TMS:
1) a range of paired-pulse TMS techniques; and 2) cervicomedullary motor
evoked potentials (CMEPs).
The analysis of CMEPs is an emerging single-pulse technique designed to

establish the spinal output to the motoneuron pool (Taylor and Gandevia
2004). It is generated at the cervicomedullary junction and instigates a
single descending volley (Berardelli et al. 1991) which, like the MEP, is
measured with EMG. Due to the subcortical delivery of the stimulus, the
amplitude of the CMEP removes the influence of the M1 and assesses
excitability at a spinal level. Through the combined analysis of CMEPs and
MEPs, it is possible to more precisely determine the site driving changes in
excitable input to the motorneuron pool (Nuzzo et al. 2016, Nuzzo et al.
2017).
3.3.2 Paired-pulse TMS

Paired-pulse TMS uses a sub-threshold conditioning stimulus (70-80%
motor threshold) delivered 2-4 ms prior to a supra-threshold test stimulus
and this results in a suppressed paired-pulse MEP compared to a baseline
single-pulse MEP (Rothwell et al. 2009). This protocol allows the
estimation of the excitability of GABAA-ergic circuits within the motor
cortex by calculating the ratio between the conditioned and unconditioned
MEPs, which is known as short-interval intracortical inhibition (SICI). SICI
is synaptic in origin and mediated by the activation of low-threshold
inhibitory circuits that have a presence of GABAA receptors from the sub-
threshold conditioning stimulus (Kujirai et al. 1993). Paired-pulse TMS
enables the measurement of synaptic efficacy of inhibitory neural networks
detectable at the level of the M1 following different exercise interventions.
The presence of low-level voluntary contraction causes a significant
reduction in SICI, indicating that investigation of cortical inhibition via
paired-pulse TMS is ideally performed either in resting conditions, or with
close monitoring of background muscle activity during testing (Ridding et
in Exercise
al. 1995). Most studies examining SICI have focused on the intrinsic
muscles of the hand, where inhibition seems to be greatest, possibly due to
the fine nature of motor performance (Dettmers et al. 1995). However, SICI
is also measurable in proximal arm muscles such as the biceps brachii (BB),
flexor carpi radialis (FCR) and extensor carpi radialis (ECR) (Abbruzzese
et al. 1999, Rantalainen et al. 2013). Intracortical facilitation (ICF) occurs
when a conditioning stimulus is delivered 6-20 ms prior to a test stimulus,
causing a net increase in cortical output (Kujirai et al. 1993, Ziemann et al.
1996). A detailed investigation into ICF and SICI found that they are likely
to be mediated by different mechanisms, due to the higher intensity of
conditioning stimulus required to obtain ICF (80% of predetermined motor
threshold or greater), and the observation that ICF is dependent on current
direction, while SICI is not (Figure 3.2, Ziemann et al. 1996).
Figure 3.2: Paired-pulse (TMS) paradigms: (Top left) Short-interval intracortical

inhibition, (Top right) Intracortical facilitation and (Bottom left) long-interval
cortical inhibition.
It was concluded that separate populations of inhibitory and excitatory

interneurons, most likely within the superficial layers of the motor cortex,
influence the net cortical output by acting either before or directly on to
pyramidal cells (Ziemann et al. 1996).
40 Chapter 3
In a similar manner, when a supra-threshold TMS pulse is applied at ISIs of

50-200 ms, MEPs are significantly reduced and are referred to as long-
interval intracortical inhibition (LICI) which is representative of a slow-
phase inhibitory circuit (Valls-Solé et al. 1992). Similar to the corticospinal
silent period, LICI is thought to reflect GABAB-mediated cortical inhibition.
3.4 Voluntary activation and neural drive

To generate maximal muscle force, the central nervous system must drive
all motor neurons that innervate contributing motor units at a rate sufficient
to produce tetanus. If this does not occur, the maximal voluntary contraction
(MVC) is less than the maximal force-generating capacity, and voluntary
activation (VA) is considered to be incomplete. In most muscle groups, VA
is typically high, but incomplete, and can be comprised during exercise as
result of central and or peripheral fatigue. The conventional method for
assessing VA involves the application of a single supramaximal electrical
stimulus to the motor nerve (peripheral nerve stimulation, PNS) during an
MVC. VA is calculated by determining the extra force evoked by the PNS
during contraction, which is referred to as the superimposed twitch. The
extra forced evoked is expressed as a percentage of the force produced by
the same, supramaximal stimulus at rest, which is known as the resting
twitch. There are several approaches to measuring VA, which include the
interpolated twitch technique and VATMS. The magnitude of VA is thought
to represent the level of ‘neural drive’ to the motoneuron pool controlling
the motor units of the target muscle. Neural drive can also be measured by
applying an electrical stimulus during an MVC and recording the
corresponding surface electromyographic response, a procedure known as
the V-wave.
3.4.1 Interpolated twitch and VATMS

The interpolated twitch technique (ITT) is commonly used to assess the
completeness of muscle activation during voluntary contractions. The
ability to quantify the level of VA is important when considering the effects
of exercise, as it can be used to assess the magnitude of neural drive
following exercise. When a supramaximal electrical stimulus is applied to
a peripheral nerve of an active muscle during voluntary contraction, any
motor units that have not been recruited will respond by generating a twitch
response. As expected, as the level of muscle activation increases, there will
be fewer motor units available for recruitment, the twitch response begins
in Exercise
to diminish and the superimposed twitch becomes smaller, and eventually

is eliminated during a MVC (Figure 3.3).
Figure 3.3: Superimposed twitch-like responses obtained during an MVC.
Early experiments revealed the progressive occlusion of the ITT by

voluntary contraction, suggesting that muscle groups could be activated
completely by voluntary command (Denny-Brown and Sherrington 1928).
Following this, several authors indicated that, in most healthy individuals,
complete activation of most muscles to which ITT was applied could be
achieved. Based upon these studies and the negative linear relationship
between evoked and voluntary force production, the extent of inactivation
can be quantified by expressing the interpolated twitch force as a percentage
of the twitch force evoked in a relaxed muscle, thus determining voluntary
activation (VA) of the stimulated muscle:
Voluntary activation (%) = [1-(superimposed twitch/control twitch)]

×100).
The superimposed twitch is the force increment obtained during a MVC at

the time of stimulation and the control twitch is the force evoked in a relaxed
muscle. Although interpolated twitch data obtained via PNS quantifies the
completeness of voluntary drive, this procedure provides no indication of
the site of failure within the CNS when neural drive is incomplete.
Consequently, a method of twitch interpolation using TMS was developed
to estimate “cortical” voluntary drive. This measure provides information
regarding the net motor output from the motor cortex (i.e., TMS voluntary
activation) and identifies sites of neural drive impairment (Todd et al. 2003,
Todd et al. 2004). To quantify submaximal motor cortex output, the level
of neural drive to the muscle is determined by the presence of a
superimposed twitch force that is produced by single-pulse TMS during a
MVC (Lee et al. 2008). The superimposed twitch represents the single-pulse
42 Chapter 3
TMS eliciting extra force from the muscle during a MVC due to
submaximal motor output from the motor cortex, while the absence of a
superimposed twitch suggests maximal output from the motor cortex (i.e.,
maximal neural drive) (Todd et al. 2004, Todd et al. 2007, Lee et al. 2008,
Goodall et al. 2009) (Figure 3.4).
Figure 3.4: (A) Raw force traces for three levels of wrist flexor voluntary
contraction force taken from a representative subject in a typical testing trial. TMS
was delivered over the contralateral motor cortex during 100%, 75% and 50% MVIC.
(B) Raw traces of the superimposed twitches produced by cortical stimulation during
100%, 75% and 50% MVIC. (C) Raw EMG responses (MEPs) produced by cortical
stimulation during 100%, 75% and 50% MVIC.
TMS has been shown to be a reliable and valid measurement of VA in the

human wrist extensor, knee extensor and elbow flexor muscle (Todd et al.
2004, Todd et al. 2007, Lee et al. 2008, Goodall et al. 2009, Sidhu et al.
2009).
3.4.2 H-reflex
There has been some attempt to investigate changes in reflex physiology
following exercise, providing evidence for changes in spinal cord
excitability/inhibition. The Hoffman’s or H-reflex can be used to evaluate
motoneuron excitability and the efficacy of 1a afferent synapses. The neural
circuitry underlying the H-reflex is characterized by monosynaptic
projections from group 1a afferents onto the corresponding motoneuron
pool. When a peripheral nerve is stimulated percutaneously by very brief
in Exercise
low-intensity electric currents, action potentials elicited within sensory 1a

afferents propagate to the spinal cord where they produce an excitatory
postsynaptic potential and synapse with alpha motor neurons. Activation of
the alpha motor neurons elicits action potentials which travel towards the
muscle, where they are recorded at the muscle as the H-reflex response
(Figure 3.5).
Figure 3.5: Neural circuitry of the H-reflex.
An inherent limitation to the H-reflex is that the magnitude of the H-reflex

response is influenced by the level of presynaptic inhibition, which limits
the interpretation of this technique as a quantifiable measure of motor
neuron excitability. Irrespective of this, the H-reflex is commonly used to
examine the effect of exercise, particularly strength training, on motor
neuron excitability. H-reflex amplitudes recorded during background
muscle activity are inconsistent, with some studies reporting increased H-
reflex amplitudes (Aagaard et al. 2002, Lagerquist et al. 2006, Holtermann
et al. 2007, Duclay et al. 2008), and other studies reporting no changes (Del
Balso and Cafarelli 2007, Fimland et al. 2009) following resistance training.
A recent systematic review demonstrated that resistance training has no
effect on the excitability of the motoneuron pool (Figure 3.6, Siddique et al.
2020).
44 Chapter 3
Figure 3.6: Pooled effect of resistance training on the excitability of the motoneuron
pool.
3.4.3 V-wave
The volitional or V-wave is an electrical variant of the H-reflex which is
recorded during a MVC. In contrast to the H-reflex, which uses submaximal
electrical stimulation, the V-wave is evoked by supramaximal electrical
stimulation of a peripheral nerve during a MVC. The supramaximal
stimulus produces a series of action potentials (antidromic) in all the motor
axons and in all group 1a afferents. In the motor axons that are involved in
the voluntary contraction, there is a collision between the voluntary
descending action potentials (i.e., orthodromic) and the electrically-evoked
action potentials (i.e., antidromic), thus leaving the axons to produce a
reflex response in the muscle (Mcneil et al. 2013).
As with most reflexes, the amplitude of the V-wave is influenced by a range

of factors, such as the level of muscle activation in which the reflex is
recorded. When the V-wave is obtained during a MVC, the amplitude is
thought to reflect or indicate the level of descending drive to the motoneuron
pool; thus, an increase in the V-wave indicates an increase in the discharge
rate and recruitment of motoneurons. This would suggest that there is an
increase in supraspinal input to the motoneuron; however, this should be
in Exercise
interpreted with caution, because the discharge rate of motoneurons reflects

all inputs which arrive at the motor neuron, not just supraspinal inputs. Thus,
the cause of any increase in the V-wave is undefined. There have been
several resistance training studies that have reported increases in V-wave
amplitude, suggesting exercise increases efferent drive and enhances
activation of the motoneuron pool (Figure 3.7).
Figure 3.7: Pooled effect of resistance training on the neural drive.
There has also been an inclination to attribute increases in motoneuron

activation as an adaptation that occurs at a supraspinal level, particularly
when V-wave changes are observed in parallel with H-reflexes (Aagaard et
al. 2002). However, a caveat to this interpretation is that the V-wave is an
indirect measure of the potential role of cortical mechanisms contributing
to efferent neural drive. In addition, the amplitude of the V-wave is
influenced by several factors, including the number and firing rate of
motoneurons that are involved in the voluntary contraction, the responsiveness
of the motoneurons, and the efficacy of synaptic transmission between 1a
afferents and the motoneurons. Because the V-wave, like the H-reflex, is
largely a monosynaptic reflex circuit from the 1a afferents to motoneurons,
any change in V-wave amplitude could simply be due to a change in
synaptic transmission (either 1a excitation or disynaptic inhibition)
(Aagaard et al. 2002).
3.5 Summary
There are several electrophysiological assessment techniques that are now
available to measure the neural responses and adaptations to exercise. Of
particular importance, these techniques enable the assessment of the entire
46 Chapter 3
neuroaxis (i.e., cortex to motor neuron pool), allowing the locus of

adaptation within the CNS to be identified.
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CHAPTER 4
PRINCIPLES OF NEUROPLASTICITY
IN EXERCISE

AND ASHLYN K. FRAZER, PHD
4. Neuroplasticity
Neuroplasticity represents the ability of the central nervous system (CNS)
to change in response to experience, use, or environmental demands, and is
understood to be a neural substrate for skill acquisition and recovery from
brain injury (Classen et al. 1998). Neuroplasticity can be induced via
experimental non-invasive brain stimulation techniques (NIBS) or by use-
dependent mechanism, such as exercise. The purpose of this chapter is to
describe the mechanisms of neuroplasticity and the ways in which plasticity
of the human motor system can be induced. In this regard, we will discuss
experimentally induced plasticity and use-dependent plasticity as models to
understand the neural adaptations to exercise.
4.1 Mechanisms of neuroplasticity

There are several physiological mechanisms that contribute to neuroplasticity,
however, the most attractive cellular mechanisms include synaptic plasticity,
which involves long-term potentiation (LTP), Short-term potentiation (STP)
and Long-term depression (LTD), unmasking of latent neural connections
due to changes in Gamma-aminobutyric acid (GABA) mediated inhibition
and N-methyl-D-aspartate (NMDA)-mediated activation. The removal of
local inhibition within neural circuits that control voluntary movement
underpins neuroplasticity. Modulation of inhibition is usually achieved as a
result of synaptic plasticity (i.e., each neuron has the capacity to adapt
dynamically), which results in up and down regulation of synaptic efficacy
in response to external stimuli (including exercise). Although synaptic
plasticity exists in many forms, LTP and LTD (e.g., lasting modifications
54 Chapter 4
in synaptic strength) are most relevant to exercise-induced changes in

synaptic plasticity.
4.2 Short and Long-term potentiation

Enhancement of synaptic plasticity can involve STP, which lasts 5-20
minutes, and LTP, which can last from 30 minutes, hours or days (Bliss &
Collingridge 1993). LTP is an activity-dependent process that results in the
long-lasting enhancement of synaptic transmission (i.e., efficacy) that
provides the basis for information storage within the cerebral cortex (Bear
& Malenka 1994, Hess et al. 1996).
LTP is characterised by three distinct properties including cooperativity,

associativity and input-sensitivity (Bliss & Collingridge 1993). Cooperativity
refers to the range of threshold intensities required for the induction of
activity-dependent potentiation. The threshold necessary for the induction
of LTP is dependent on the interaction between intensity and pattern of
tetanic stimulation. Unless stimulation is ‘strong’, LTP will not be triggered,
resulting in STP and post-tetanic potentiation (PTP) being induced
(McNaughton et al. 1978, Malenka 1991). Importantly, LTP is associative,
meaning a weak input can only be potentiated if it is active at the same time
as a strong input (McNaughton et al. 1978, Collingridge & Bliss 1987).
These three properties are mediated by the NMDA receptor which is located
on the post-synaptic dendrites of excitatory synapses (Collingridge & Bliss
1987).
4.2.1 NMDA receptor activation and synaptic plasticity

NMDA is an essential molecule for regulating neuroplasticity in humans
and operates as the channel responsible for LTP (Castro-Alamancos et al.
1995). To trigger the induction of LTP, two processes must occur involving
the NMDA receptor channel complex (Bliss & Collingridge 1993). First,
post-synaptic depolarization releases glutamate, resulting in the activation
of post-synaptic NMDA receptors. This event reduces the voltage-
dependent block of the NMDA receptor channel by magnesium (Mg2+),
allowing the influx of calcium (Ca2+) into the post-synaptic dendritic spine.
The level of depolarization will consequently determine whether the
cooperativity threshold will be enough to induce LTP. Failure to induce LTP
is a result of inadequate reduction of the Mg2+ block, rather than the
insufficient release of glutamate to activate the NMDA receptors (Bliss &
Collingridge 1993).
Principles of Neuroplasticity in Exercise 55
Bliss and Collingridge (1993) demonstrated the necessity of NMDA

receptor activation for the induction of LTP. This finding prompted
investigation into the potential relationship between NMDA receptor
activation and the induction of experimental and use-dependent neuroplasticity
(Liebetanz et al. 2002, Nitsche et al. 2003a). Using pharmacological agents,
Butefisch (2000) demonstrated that use-dependent plasticity of the hand
area of the primary motor cortex (M1) following motor training was
significantly reduced when the NMDA receptor was blocked. Similarly, the
necessity of NMDA receptor activation for the induction of experimentally-
induced plasticity was confirmed when the administration of the NMDA
receptor antagonist, dextromethorphan was found to inhibit the long-lasting
effects of transcranial direct current stimulation (tDCS) (Liebetanz et al.
2002). Collectively, these findings show that the NMDA receptor is an
important operating mechanism in the formation of use-dependent and
experimentally-induced neuroplasticity via activating LTP processes. In
addition, other cellular mechanisms involving neurotrophic factors (i.e.,
neurotrophins, glial cell-line derived neurotrophic factor family ligands, and
neuropoietic cytokines) that interact with the NMDA receptor and the
induction of LTP have also been recognized in shaping neuroplasticity.
4.2.2 Brain-derived neurotrophic factor (BDNF) and

neuroplasticity
Although the mechanisms that underpin neuroplasticity have been
described within the literature, the extent of neuroplasticity appears to be
influenced by genetic factors. BDNF is a neurotrophin which is involved in
a variety of CNS functions including but not limited to cell survival,
proliferation and synaptic growth (Antal et al. 2010). In humans, a naturally
occurring single nucleotide polymorphism results in the substitution of
valine to methionine at codon 66 (val66met), which has been associated
with reduced episodic memory and increased risk of neuropsychiatric
disorders (Bath & Lee 2006). The distribution of the polymorphism varies
widely between regions and ethnicities, with approximately 30-50% of
people worldwide identified as either heterozygous (Val/Met) or homozygous
(Met/Met) for the Met substitution. Expression of the Met allele is more
commonly found among Asian (51% in Japan) compared to Caucasian
populations (30% in America) (Shimizu et al. 2004) with evidence
suggesting those of Caucasian descent have larger associated cognitive and
behavioural consequences (Bath & Lee 2006). Abnormal cortical morphology
is a shared characteristic among carriers of the Met variant form of BDNF
(Bath & Lee 2006). Smaller hippocampal volumes and poorer performance
56 Chapter 4
on memory tasks have been revealed, determining the anatomical and

functional consequences of the BDNF polymorphism (Pezawas et al. 2004).
More recently, neurotrophic factors, particularly BDNF, have been identified

as critical molecules involved in the regulation of neuroplasticity in the
human brain (Bath & Lee 2006). Evidence from hippocampal in vitro
studies has demonstrated the modulatory role of BDNF on NMDA receptor-
dependent LTP and LTD (Woo et al. 2005). The facilitation of LTP because
of BDNF secretion suggests the importance of BDNF in regulating
experimentally-induced and use-dependent neuroplasticity (Gottmann et al.
2009). However, the interaction between BDNF and LTP processes has yet
to be investigated beyond a theoretical model. In addition, it is unclear what
modulatory effect the BDNF polymorphism may have on experimentally
induced and use-dependent neuroplasticity.
4.3 Experimentally-induced neuroplasticity

Several NIBS methods have been used to assess the potential underlying
mechanisms and regulators of neuroplasticity, including tDCS, theta burst
stimulation (TBS), paired associative stimulation (PAS), I-wave periodicity
TMS (iTMS) and repetitive transcranial magnetic stimulation (rTMS)
(Nitsche et al. 2003b, Siebner & Rothwell 2003, Sale et al. 2007). Such
NIBS techniques have been shown to modify levels of neuroplasticity that
have been attributed to LTP and LTD. More recently, tDCS has emerged as
a common NIBS technique used to modulate neuroplasticity with the aim
of modifying motor behaviour in both healthy and clinical populations
(Ridding & Ziemann 2010). More specifically, tDCS has been used in
combination with motor training, which has evolved into a popular
paradigm known as ‘motor priming’. Motor priming is thought to facilitate
motor learning and involves the application of tDCS either prior or during
motor learning (Stoykov & Madhavan 2015). Two established priming
theories have been proposed which include gating and homeostatic
plasticity (Siebner 2010). Gating occurs concurrently with motor training
(i.e., tDCS while training), while homeostatic plasticity involves
modulating the resting state of neurons prior to training (i.e., tDCS applied
before motor training).
Despite extensive research examining the indices of neuroplasticity of the

stimulated M1 following anodal tDCS (Bastani & Jaberzadeh 2012), little
is understood about the bilateral effects (i.e., non-stimulated M1) of uni-
hemisphere stimulation. Given that other NIBS techniques have been shown
to modulate not only the intended stimulated tissue but also distal areas of
the brain including the contralateral hemisphere (Gilio et al. 2003), it would
appear evident that the bilateral effects of anodal tDCS must be explored to
ensure the feasibility of tDCS as a priming method for inducing homeostatic
plasticity prior to motor training. Furthermore, individual corticospinal
responses to anodal tDCS are highly variable and the expression of the
BDNF polymorphism has been identified as a potential contributing factor
(Antal et al. 2010). Differential modulation of neuroplasticity between
different BDNF genotype carriers is of interest when examining the
induction of LTP, which is an essential physiological process involved in
neuroplasticity and motor learning (Cirillo et al. 2012). Therefore, the
following discussion will examine the induction of homeostatic plasticity
following tDCS, the use of tDCS in the absence of motor training and prior
to motor training (motor priming) to enhance motor performance, and the
potential regulatory role of the BDNF polymorphism.
4.3.1 Transcranial direct current stimulation and neuroplasticity

In contrast to other NIBS techniques, tDCS does not rely on rapid
depolarisation resulting in the induction of action potentials to stimulate
neuroplasticity (Nitsche et al. 2008). Rather, this method is considered to be
a ‘neuromodulator’, whereby a weak electrical current is passed through
electrodes placed on the scalp resulting in polarity specific changes of the
M1 (Nitsche & Paulus 2000). A number of parameters have been shown to
influence the efficacy of tDCS including current strength, electrode size,
stimulation duration and orientation of the electrode field (Nitsche et al.
2008). Orientation includes the position and polarity of electrodes, which
determines the direction of modulation (increase/decrease corticospinal
excitability, Figure 4.1). Anodal stimulation (positively charged electrode)
results in neuronal depolarisation and an increase in corticospinal
excitability (inducing LTP). Cathodal stimulation has the opposite effect
whereby hyperpolarization of neurons occurs leading to decreased
corticospinal excitability (LTD) (Nitsche & Paulus 2000).
Two common electrode arrangements used to modulate neuroplasticity in

healthy and clinical populations are uni-hemisphere and dual-hemisphere
tDCS. Uni-hemisphere tDCS, where the anode is placed over the M1 of
interest, has been shown to increase corticospinal excitability for up to 90
min post stimulation (Nitsche & Paulus 2001). In contrast, dual-hemisphere
tDCS involves simultaneously applying anodal tDCS to one hemisphere and
cathodal tDCS to the other. This arrangement leads to inhibitory effects in
one hemisphere and increased excitability in the opposite (Di Lazzaro et al.
2012a). Interestingly, the immediate and time-course effects of tDCS appear
58 Chapter 4
to be mediated by different mechanisms. Initially, tDCS is thought to

modify corticospinal excitability primarily through altering the resting
membrane potential (Nitsche & Paulus 2000, Nitsche et al. 2008). However,
the longer-lasting effects of tDCS appear to be dependent upon NMDA
receptor function, indicating that changes in corticospinal excitability are
likely due to LTP-like mechanisms (Liebetanz et al. 2002, Nitsche et al.
2004a, Nitsche et al. 2004b, Ridding & Ziemann 2010). At present, the
consensus is that anodal tDCS induces focal changes in corticospinal
excitability and inhibition of the M1 (Nitsche & Paulus 2000, Nitsche et al.
2008). However, it has recently been shown that NIBS techniques,
including tDCS, not only exert a neuro-modulatory effect over the
stimulated region, but also distal areas connected to the region of
stimulation (Gilio et al. 2003, Lang et al. 2004).
Figure 4.1: Uni-hemipshere anodal-tDCS, with the anode placed over the left
primary motor cortex and the cathode placed over the contralateral orbital region.
4.3.2 NIBS and functional connectivity

Emerging evidence from transcranial magnetic stimulation (TMS) studies
has revealed that NIBS techniques modulate not only the intended
stimulated tissue but also distal connecting tissue and structures, as well as
the opposite non-stimulated hemisphere (Gilio et al. 2003, Lang et al. 2004).
This concept is termed “functional connectivity” and is based upon the
working hypothesis that changes in localised brain activity can influence
distant, but functionally related, areas which is an essential function of the
healthy brain (Sale et al. 2015). Functional connectivity has evolved from
the parallel use of neuroimaging techniques (i.e., fMRI) and NIBS methods
(i.e., TMS, tDCS etc.) with the aim of understanding the interaction between
distant neural structures caused by activity of interconnected brain zones
(Sale et al. 2015). Previously, tDCS of the motor association cortex was
shown to induce inhibitory effects in the M1 (Kirimoto et al. 2011), and
stimulation of the premotor cortex facilitated the M1 by reducing SICI
(Boros et al. 2008). Critically, the limited number of TMS studies
examining the bilateral effect of uni-hemisphere stimulation have shown
highly diverse findings regarding the direction of excitability of the non-
stimulated hemisphere following various NIBS techniques (Gilio et al. 2003,
Lang et al. 2004, Di Lazzaro et al. 2011). For example, various protocols
using iTBS have shown increases in corticospinal excitability of the
stimulated hemisphere and a decrease in corticospinal excitability of the
non-stimulated hemisphere (Di Lazzaro et al. 2008, Di Lazzaro et al. 2011).
rTMS and PAS have been shown to increase excitability of both the
stimulated and non-stimulated M1 (Shin & Sohn 2011) and decrease
interhemispheric inhibition (IHI) between the left and right M1 (Gilio et al.
2003). Likewise, Lang et al. (2004) found that 10 min of anodal and
cathodal tDCS at 1 mA modulated transcallosal inhibition. Interestingly,
this finding was not accompanied by a bilateral increase in M1 excitability,
with only an increase in MEP amplitude seen in the stimulated M1.
Importantly, it should be highlighted that a key methodological component
of the studies investigating NIBS techniques and the concept of functional
connectivity is that many used a dominant M1 arrangement whereby the
stimulated hemisphere was the dominant M1 (left) and non-stimulated
hemisphere was the non-dominant M1 (right). Notably, it has previously
been shown that a hemispheric imbalance exists (dominant vs non-dominant)
as demonstrated by the non-dominant hemisphere having a lower motor
threshold, higher MEPs (De Gennaro et al. 2004) and shorter cortical silent
period durations (Priori et al. 1999). A potential difference in hemispheric
baseline characteristics poses an interesting question as to whether the
magnitude of bilateral neuroplasticity is affected by the direction of
stimulation (dominant vs non-dominant M1 stimulated), and if there is a
greater scope for the induction of corticospinal plasticity of the non-
dominant hemisphere.
60 Chapter 4
4.4 Is the induction of neuroplasticity via NIBS important

for motor performance?
There is promising evidence that the induction of homeostatic plasticity
following a single session of anodal tDCS (i.e., increase in corticospinal
excitability and inhibition) in the absence of training can also facilitate fine
motor performance and increase muscle strength (Boggio et al. 2006, Vines
et al. 2006, Kidgell et al. 2013, Frazer et al. 2016). For example, following
a single session of tDCS (in the absence of motor training), improved motor
performance in tasks such as the Jebson Taylor Test (JTT), maximal
strength of the elbow flexors and knee extensors, the Purdue pegboard test,
maximal pinch force, reaction time, and tests of motor sequencing tasks
have all been reported (Boggio et al. 2006, Vines et al. 2006, Kidgell et al.
2013).
In healthy adults, accumulated bouts of anodal tDCS have been shown to

improve motor performance with retention lasting up to three months
following stimulation (Boggio et al. 2007, Reis et al. 2009). Although the
underlying physiological changes were not examined, the induction of LTP
has been suggested to underlie the improvement in motor performance (Reis
et al. 2009). Previously, changes in corticospinal excitability have been
examined over a five-day period whereby participants were exposed to daily
anodal tDCS stimulation (Alonzo et al. 2012). Corticospinal excitability
was shown to significantly increase but, unfortunately, no motor
performance outcome was used to assess any functional effects of the tDCS
intervention. A recent study investigating the effect of repeated sessions of
anodal tDCS demonstrated an increase in corticospinal excitability
accompanied by an increase in muscle strength (Frazer et al. 2016).
Interestingly, there was no change in shorti-interval intracortical inhibition
(SICI), however a reduction in cortical silent period was reported suggesting
that accumulated bouts of anodal tDCS appear to modulate GABAB rather
than GABAA neurons (Frazer et al. 2016). Because the cortical silent period
that follows the excitatory MEP is caused by activation of long-lasting
GABAB mediated inhibition and reflects the temporary suppression in
motor cortical output (Werhahn et al. 2007), it appears that cumulative bouts
of anodal tDCS specifically target neural circuits that use GABAB as their
neurotransmitter (Frazer et al. 2016, Figure 4.2), resulting in the release of
pyramidal tract neurons from inhibition (Floeter & Rothwell 1999).
Therefore, a reduction in the temporary suppression of motor cortical output
may be a putative neural mechanism underlying the changes in strength.
Figure 4.2: Mean (± SE) changes in MEP amplitude following four consecutive
sessions of (A) sham tDCS and (B) anodal tDCS. (C) Changes in MEP amplitude
before and after four consecutive sessions of anodal tDCS in healthy subjects with
different BDNF genotypes. *significant to sham tDCS; † significant to baseline.
To date, the TMS literature has primarily focused on the acute effects of
tDCS modulating corticospinal excitability and the subsequent change in
motor performance. Although these studies have provided valuable insight
into possible acute physiological mechanisms, motor output from the M1
can also be quantified via TMS voluntary activation which provides further
insight into the mechanisms regulating corticospinal plasticity and the
expression of strength. The level of neural drive to a muscle during exercise
is commonly termed ‘voluntary activation’ (Gandevia et al. 1995) and can
be estimated by interpolation of a single supramaximal electrical stimulus
to the motor nerve during an isometric voluntary contraction (Merton 1954).
Although twitch interpolation assesses neural drive to a muscle during
62 Chapter 4
exercise, it cannot provide insight into the precise location of any neural
drive impairment (cortical or sub-cortical) (Lee et al. 2009, Carroll et al.
2011). In light of this, TMS has been employed to measure net motor output
from the M1 (i.e., TMS voluntary activation) identifying potential sites of
neural drive impairment (Todd et al. 2003, Todd et al. 2004). This technique
can provide additional information regarding corticospinal efficiency
following anodal tDCS by demonstrating changes in motor cortical output
via the recruitment of motor units used in force generation.
At present, studies have concentrated on the reliability and validity of TMS

to measure TMS voluntary activation in various muscle groups (Todd et al.
2003, Todd et al. 2004, Lee et al. 2008, Sidhu et al. 2009). However,
translation of this technique into applied research settings, such as assessing
changes in corticospinal plasticity following accumulated bouts of anodal
tDCS, has been only examined once (Frazer et al. 2016). Interestingly, an
increase in TMS voluntary activation and strength was observed, suggesting
that accumulated bouts of anodal tDCS modulate synaptic efficacy, which
improves the net descending drive (i.e., increased motor cortical drive) to
the motor neuron pool, representing as an increase in muscle strength
(Frazer et al. 2016, Figure 4.3).
Figure 4.3: Mean (± SE) changes in MVIC strength of the right wrist flexors
following four consecutive sessions of sham and anodal tDCS. * significant to sham
tDCS; † significant to baseline. Anodal tDCS stimulation resulted in an 8% increase
in isometric wrist flexor strength compared to 3% following sham tDCS. Figure on
the right displays the mean (± SE) changes in TMS voluntary activation following
four consecutive sessions of sham and anodal tDCS. * significant to sham tDCS; †
significant to baseline.
At a minimum, these data show that just the induction alone of

neuroplasticity can have a positive effect on motor performance. This
finding shows that the use of tDCS to induce homeostatic plasticity (i.e.,
modify corticospinal excitability) and improve motor performance is well
established (Nitsche et al. 2008, Vines et al. 2008, Kidgell et al. 2013, Frazer
et al. 2016), but the efficacy of tDCS may also be influenced by individual
genetic variations such as the BDNF polymorphism (Antal et al. 2010, Puri
et al. 2015, Frazer et al. 2016). Therefore, it appears vital to identify
individual variants that may impact on the effectiveness of tDCS protocols
to experimental-induce neuroplasticity.
4.4.1 Is the magnitude of neuroplasticity and motor performance

improvement related to the BDNF polymorphism?
Corticospinal responses to various NIBS techniques have been shown to
differ significantly between individuals (Chang et al. 2014, Hwang et al.
2015). Genetic factors, including the role of BDNF, have been reported as
potential contributors to the variability of results observed within the
literature. Evidence using TMS to evaluate the efficacy of NIBS techniques
generally suggests that the presence of the BDNF polymorphism
significantly impacts corticospinal plasticity and motor performance. This
is highlighted by the response of Met allele carriers being different to
Val66Val individuals following several NIBS protocols (Cheeran et al. 2008,
Cirillo et al. 2012, Chang et al. 2014, Hwang et al. 2015). For example,
Cheeran et al. (2008) found individuals that expressed the BDNF
polymorphism demonstrated altered corticospinal responses to continuous
and intermittent TBS, PAS and cathodal tDCS followed by rTMS compared
to those without the BDNF polymorphism. Using a larger sample size and
classification of three genotypes (Val/Val, Val/Met, Met/Met), Cirillo et al.
(2012) confirmed the important role that BDNF plays in PAS-induced
plasticity. Similarly, the influence of the BDNF polymorphism on the
induction of homeostatic plasticity following rTMS has been further
demonstrated in both healthy and clinical populations (Chang et al. 2014,
Hwang et al. 2015). However, the influence of BDNF on NIBS protocols is
not always consistent with some studies showing no difference in
corticospinal plasticity between Val66Val and Val66Met carriers following
rTMS and iTBS (Li Voti et al. 2011, Nakamura et al. 2011). Importantly, it
should be noted that the protocol duration used in these studies may not
have been sufficient to activate cellular processes of activity-dependent
BDNF secretion (Li Voti et al. 2011, Nakamura et al. 2011).
Interestingly, only a limited number of studies have investigated the impact

of the BDNF polymorphism on corticospinal plasticity induced by anodal
tDCS in young and older adults (Antal et al. 2010, Puri et al. 2015, Frazer
et al. 2016). One study found that carriers of the BDNF Met allele (Val/Met)
displayed enhanced corticospinal responses to a single session of anodal
tDCS compared to the Val/Val genotype (Antal et al. 2010). Antal and
64 Chapter 4
colleagues (2010) concluded that this finding was due to tDCS modifying
the transmembrane neuronal potential compared to the other NIBS
techniques which act upon LTP mechanisms. However, given that long-
lasting changes in motor behaviour associated with repeated tDCS
stimulation are likely to occur as a result of LTP-like mechanisms
(Liebetanz et al. 2002), it was not unexpected that a recent study found that
carriers of the BDNF Met allele displayed reduced corticospinal responses
to accumulated bouts of anodal tDCS (Frazer et al. 2016). Given the
evidence that the corticospinal responses to NIBS techniques are largely due
to LTP mechanisms and the interaction between BDNF secretion and
LTP/LTD processes, it is highly likely that BDNF is involved in the
regulation of corticospinal plasticity and, potentially, subsequent changes in
motor performance. However, further study is required to establish the
impact that the BDNF polymorphism may have in mediating different forms
of experimentally-induced plasticity and specifically what mechanisms are
involved. Furthermore, given the BDNF polymorphism has been shown to
shape an individual’s responsiveness to both experimentally-induced (i.e.,
tDCS) and use-dependent (i.e., motor skill training) plasticity protocols
(Kleim et al. 2006, Cheeran et al. 2008, Antal et al. 2010), it would be
critical to identify whether this genetic factor may also influence the
effectiveness of using tDCS as a priming protocol prior to motor training to
augment the corticospinal responses to a single bout of strength training.
4.5 Is homeostatic plasticity important for motor

performance?
Historically, tDCS has been used as a NIBS technique to modulate
neuroplasticity and modify motor behaviour (Ridding & Ziemann 2010).
However, in an effort to further explore the efficacy of tDCS to enhance
motor performance, the technique has evolved into a popular paradigm of
motor priming which is believed to facilitate motor learning (Stoykov &
Madhavan 2015). Motor priming involves the application of tDCS before
or during motor training, with the working hypothesis that enhanced neural
activity within the M1 will facilitate the mechanisms associated with LTP
or LTD (Ziemann & Siebner 2008). Two theories have been proposed to
underlie the response of corticospinal output neurons following priming
protocols including gating and homeostatic plasticity (Siebner 2010). The
theory of gating occurs instantaneously and describes the influx of calcium
ions to the targeted corticospinal neurons resulting in the disinhibition of
intracortical inhibitory circuits (Ziemann & Siebner 2008, Siebner 2010).
Gating is attained concurrently with motor training and has been shown to
facilitate motor performance tasks such as hand function using the JTT,
maximal strength, movement speed, reaction time and speed-accuracy
trade-off (Nitsche et al. 2003d, Boggio et al. 2006, Galea & Celnik 2009,
Hunter et al. 2009, Reis et al. 2009, Stagg et al. 2011, Hendy & Kidgell
2014). For example, Christova et al. (2015) showed a significant reduction
in SICI following the application of anodal tDCS during grooved pegboard
training. However, it appears that the efficacy of priming during training
may be limited to fine motor skill training tasks (i.e., pegboard). In support
of this notion, Hendy et al. (2013) investigated the use of anodal tDCS
applied to the active M1 during training to enhance maximal voluntary
strength (Figure 4.4). Interestingly, there was no difference in strength gain
between conditions, suggesting that strength training appeared to have a
powerful effect on modulating mechanisms associated with LTP, therefore,
potentially limiting further corticospinal responses induced by anodal tDCS.
Figure 4.4: The effect of using anodal-tDCS during strength training (exploiting the
plasticity principle of gating) on the percentage change in 1RM wrist extension
strength (mean ± SD). The ST + sham group wrist extension force increased by 11%
following the intervention, while the ST + a-tDCS group increased by 14%. The
increase in strength for both the ST + sham and ST + a-tDCS group was significantly
greater than the control group, which did not change. * represents a significant time
effect (P < 0.05). † represents a significant difference from the control group (group
by time interaction, P < 0.05).
66 Chapter 4
The principle of homeostatic plasticity whereby the resting state of

corticospinal neurons is altered prior to training (increased/decreased level
of excitability following a low/high level of synaptic activity) due to
changes in postsynaptic glutamate receptor activity (Ziemann & Siebner
2008, Siebner 2010) is also an emerging NIBS technique that can be used
to facilitate motor learning. Importantly, the lack of interactions observed
between conditions by Hendy et al. (2013, 2014) suggests that a critical
consideration to maximise the effectiveness of anodal tDCS as a M1
priming technique is the timing of application (i.e., during or prior the
training). Given that anodal tDCS has been shown to modulate NMDA
receptors, and subsequently produce a shift in the resting membrane
potential (Nitsche & Paulus 2000), it would be conceivable that anodal
tDCS is a promising priming tool to increase synaptic activity prior to a
single bout of strength training to further augment the acute neuroplastic
responses to strength training. Recently, it has been reported the M1
responses to strength training increase when anodal-tDCS is applied during
training due physiological mechanisms associated with gating. An
additional approach to improve the M1 responses to strength training, which
has not been explored, is to use anodal-tDCS to prime the M1 before a bout
of strength training. Frazer et al. (2019), using a randomized double-blinded
cross-over design, measured the changes in isometric strength, corticospinal
excitability and inhibition using TMS, when participants were exposed to
20-min of anodal and sham-tDCS prior to a single bout of strength training.
The experimental design exploited the mechanism of homeostatic plasticity,
with the hypothesis that priming the M1 and subsequently inducing
neuroplasticity would enhance the neuroplastic effects of the following
strength training session. TMS revealed a 24% increase in corticospinal
excitability following anodal-tDCS and strength training, but this increase
was not different between conditions, which was similar to the previous
findings by Hendy and Kidgell (2014). However, there was a 14% reduction
in corticospinal inhibition when anodal-tDCS was applied prior to strength
training when compared to sham-tDCS and strength training (all P < 0.05,
Figure 4.5).
Figure 4.5: The effect of homeostatic plasticity on the corticospinal responses to

strength training. The AURC obtained prior to anodal-tDCS + ST intervention is
shaded in white. The additional area enclosed by the recruitment curve obtained
following anodal-tDCS + ST is shaded in grey. The AURC was calculated from
corticospinal inhibition curves for 13 participants in the anodal-tDCS + ST condition
whereby the silent period was plotted against stimulus intensity. * indicates
significant within-condition-effect. # Indicates significant difference to sham + ST
(between-condition-effect).
These findings suggest that priming anodal-tDCS had a limited effect in

facilitating corticospinal excitability following an acute bout of strength
training. Interestingly, the interaction of anodal-tDCS and strength training
appears to affect the excitability of intracortical inhibitory circuits of the M1
via non-homeostatic mechanisms.
4.6 Use-dependent neuroplasticity

Use-dependent plasticity underlying improvements in motor performance
occurs as a series of overlapping and complementary events rather than a
single, measurable process. However, the acquisition of a novel motor skill
is characterised by distinct early and late stages that are driven by separate
mechanisms of neuroplasticity (Floyer-Lea and Matthews 2005; Kleim et
al. 2004; Kleim et al. 2006; Rosenkranz et al. 2007; Karni et al. 1998; Dayan
& Cohen 2011). The duration of these stages is highly specific to the
demands of the training task involved, such as the complexity and sensory
feedback involved (Karni et al. 1995; Doyon & Benali 2005). Further,
adaptations to motor skill training can occur online during training or offline
in the period between training sessions (Dayan & Cohen 2011).The earliest
mechanisms of neuroplasticity are restricted to existing structures, and
68 Chapter 4
occur through a selective release of inhibition that unmasks latent synaptic

connections, which improves synaptic efficacy (Hess et al. 1996; Hess &
Donoghue 1994; Rioult-Pedotti et al. 1998; Rioult-Pedotti et al. 2000). This
rapid improvement in synaptic efficacy likely occurs at first exposure to a
novel task and is therefore likely present online during motor training
because of mechanisms associated with STP (Muellbacher et al. 2002;
Coxon et al. 2014). For example, evidence of use-dependent plasticity has
been observed following associated ballistic motor skill training
(Muellbacher et al. 2001, Selvanayagam et al. 2011). Ballistic motor skill
tasks share similar characteristics to strength training and other forms of
motor training, as both require the repeated generation of high force
production and movement repetition (Carroll et al. 2008, Hinder et al. 2013).
In regards to a strength task, the requirements (muscle recruitment, timing
of muscle activation between agonists and antagonists, joint positioning)
indicate that a level of skill and learning is necessary for the successful
completion of the movement (Carroll et al. 2001b). Due to the similarity
between training paradigms, the notion that motor performance gains are
mediated by mechanism associated with use-dependent neuroplasticity
likely explains the rapid improvement in strength and motor skill function
that is commonly observed in the literature (Mason et al. 2019).
In the temporal space between training sessions, substantial offline

adaptations may occur which reflect consolidation of a skill so it can be
retained for future performance upon recall (Muellbacher et al. 2002;
Roberston, Pascual-Leone & Miall 2004; Fischer et al. 2005; Reis et al.
2009; Romano et al.2010). Structural plasticity, such as synaptogenesis, and
persistent reorganisation in M1 movement representations are likely to
occur offline in the late stage of motor skill acquisition (Mednick et al. 2011;
Kleim et al. 2004). Ultimately, an interaction between online and offline
mechanisms of neuroplasticity contributes to long-lasting improvements in
motor performance (Romano et al. 2010). Importantly, the rapid increases
in synaptic efficacy that occur as a result of motor training are considered a
mediating step in determining LTP and long-term structural adaptations
such as synaptogenesis and motor map expansion (Jacobs & Donoghue
1991, Ziemann, Hallett & Cohen 1998; Kleim et al. 2004). Thus, there is
now good evidence for this progression of neuroplasticity throughout the
acquisition of motor skills as a result of use-dependent neuropalsticity
(Kleim et al. 2004; Rosenkranz et al. 2007; Kleim et al. 2006; Adkins et al.
2006).
Use-dependent neuroplasticity typically involves both “online” and “off-

line” mechanisms of plasticity. Online adaptations refer to those corticospinal
responses during and immediately following a session of motor training or

strength training, in reference to their elevation being an immediate result
of the preceding activity. Further, ‘offline’ usually refers to adaptations
occurring following the cessation of one session and the commencement of
the next; however, ‘offline’ also represent changes that fall outside the
training period and occur in the temporal space following the transient
effects of the prior training session, thus occurring between training sessions
(Mason et al. 2019).
Although the concepts of online and offline adaptations and, in particular,

early and late phases of neuroplasticity, are well established in context of
skill acquisition (Floyer-Lea and Matthews 2005; Kleim et al. 2004; Kleim
et al. 2006; Rosenkranz, Kacar & Rothwell 2007; Karni et al. 1998; Dayan
& Cohen 2011), similar frameworks describing the neuroplastic processes
underlying the development of muscular strength (because of use-
dependent mechanisms) are relatively absent. However, in Chapter 5 and 7,
we present experimental evidence for both on-line and off-line use-
dependent neuroplasticity following skill and strength training.
4.7 Summary
Neuroplasticity can be induced by experimental techniques involving NIBS
and following different types of exercise. The degree of plasticity is
dependent upon specific genetic polymorphisms, with BDNF being the
most studied neurotrophic factor that shapes neuroplasticity. Both motor
skill training and strength training are two common techniques of use-
dependent plasticity. Combining NIBS with use-dependent plasticity results
in differing levels of neuroplasticity and motor function, depending on the
timing of NIBS application relative to the timing of exercise.
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CHAPTER 5
NON-INVASIVE BRAIN STIMULATION

AND EXERCISE PERFORMANCE
SHAPOUR JABERZADEH, PHD

AND MARYAM ZOGHI, PHD
5. Introduction
Exercise performance (EP) is affected by a number of factors including
physical, physiological, and psychological factors (Figure 5.1) (McCormick
et al. 2015; Neumayr et al. 2003). Physical factors refer to physical
attributes of the body such as height, weight, body mass index, level of body
fat and muscle mass. Psychological factors include lifestyle, personality
characteristics, arousal, motivation and stress level. Physiological factors
involve muscle strength, skill, energy production (anaerobic and aerobic),
muscle fatigue and fibre type.
Boosting EP was the focus of huge research during the last century to affect
one or a combination of the aforementioned factors (Schubert and Astorino
2013). During the last two decades, the focus has shifted to the brain and
how it could boost EP. Literature indicates that the brain is crucially taking
part in the foundation of fatigue and, therefore, EP (Noakes 2011, 2012,
Gandevia 2001, Van Cutsem et al 2017). In addition, literature also indicates
the boosting effects of some centrally-acting performance modifiers on EP
(Noakes 2012; Van Cutsem et al 2017). Non-invasive brain stimulation
(NIBS) techniques, including transcranial direct current stimulation (tDCS),
were also used as a priming technique for enhancement of EP. In this
chapter, we offer an overview of tDCS for the enhancement of EP. tDCS is
a NIBS technique with an excellent safety record which is well tolerated,
relatively inexpensive and readily available.
Non-invasive Brain Stimulation and Exercise Performance 77
Figure 5.1. Factors affecting exercise performance.
5.1 Transcranial Direct Current Stimulation

tDCS is a neuromodulatory technique in which a subthreshold direct current,
with an intensity of up to 2mA, is applied to the scalp through surface
electrodes for tens of minutes to induce cortical excitability changes
(Nitsche and Paulus 2001; Nitsche et al. 2003) and changes in spike rates
(Bogaard et al. 2019). Traditionally, it was assumed that the effect of tDCS
on neuronal excitability was polarity dependent. Accordingly, placement of
the anode electrode over the target brain area (a-tDCS) increases while
application of the cathode over this area (c-tDCS) decreases neuronal
excitability (Nitsche and Paulus 2001; Nitsche et al. 2003). Due to a non-
linear dose-response relationship, this notion is considered very simplistic
and is not supported by new literature. New literature indicates that, under
certain circumstances, a-tDCS can decrease and c-tDCS can increase neural
excitability (Esmaeilpour et al. 2018; Jamil et al. 2017; Batsikadze et al.
2013). Having said that, we adopt the conventional anodal and cathodal
terminology for the purpose of this chapter. Commonly, research indicates
that the effects of tDCS remain beyond the completion of the stimulation
session for up to two hours (Nitsche and Paulus 2001; Nitsche et al. 2003).
78 Chapter 5
5.2 The mechanisms behind tDCS effects during

stimulation (online effects)
Early animal studies showed that tDCS of the cerebral cortex induces
changes in resting membrane potentials (Purpura and McMurtry 1965). A-
tDCS of the cortex increases while c-tDCS reduces spontaneous neuronal
activity (Bindman et al. 1964; Creutzfeld et al. 1962; Purpura and McMurtry
1965). This effect is not uniform throughout the cortex and may depend on
the types of neurons which may have different modulation thresholds,
location of the neurons within the cortex and also their orientation relative
to the electrical fields (Purpura and McMurtry 1965).
Figure 5.2. The physiological mechanisms underlying the effects of tDCS during
stimulation.
Results from human studies using pharmacological approaches showed that

the effects of tDCS during stimulation are mainly dependent on changes in
the resting membrane potential. These findings are also supported by the
findings in animal studies (Purpura and McMurtry 1965; Jackson et al.
2016). Research also suggested redistribution of polarization across the
cellular axis (one dendritic branch versus another) as the mechanism

underlying tDCS effects during stimulation (Fritsch et al. 2010; Rahman et
al. 2013; Arlotti et al.; 2012; Kabakov et al. 2012).
5.3 The mechanisms behind tDCS effects after

the termination of stimulation
Pharmacological studies indicate that the after-effects of tDCS are mainly
mediated by modification of NMDA-receptor sensitivity (Liebantz et al.
2002; Nitsche et al. 2006). It is also proposed that the after-effects of tDCS
may be mediated by changes in the concentration of intracortical
neurotransmitters such as GABA or glutamate (Stagg et al. 2009). In line
with this effect, literature also indicates the regulation of a broad variety of
other neurotransmitters, including dopamine, acetylcholine and serotonin as
the mechanisms behind neuroplastic changes following application of tDCS
(Nitsche et al. 2006; Kuo et al. 2007; Monte Silva et al. 2009).
tDCS after-effects may also rely on non-synaptic mechanisms (Ardolino

2005) such as changes in transmembrane proteins or electrolysis-related
changes in [H+] induced by exposure to a constant electric field (Rae et al.
2013).
Figure 5.3 The mechanisms behind tDCS effects after termination of stimulation.
80 Chapter 5
5.4 Montages for application of tDCS:

The conventional montage
This montage involves the application of a subthreshold direct current via
two surface electrodes placed over the scalp of a participant. In this montage,
one electrode is known as the active electrode and is placed over the target
cortical area. The other is known as the return electrode and is usually
placed over the contralateral supraorbital area. During stimulation, the
applied current flows from the anode which passes through the cortical
tissue toward the cathode to complete the circuit.
Figure 5.4. Conventional montage. Anodal tDCS of left primary motor cortex (C3).
This montage includes an active electrode (i.e., anode) which is connected to a return
electrode (i.e., cathode). The current density under the return electrode is equal to
the density under the active electrode. Electrical field intensities throughout the brain
are modelled using a finite-element-method approach.
5.4.1 HD-tDCS montage

HD-tDCS is a novel montage for application of tDCS. In this montage,
smaller electrodes are used to minimise spread of the applied current outside
of the target area (Datta et al. 2009). For a-tDCS, using a 1 x 4 ring electrode
configuration, the positive central electrode (anode) could be located on the
area of interest (i.e., left dorsolateral prefrontal cortex [DLPFC], F3 based
on the international 10–20 EEG system), while it is surrounded by four
negative electrodes (cathode) on adjacent electrode sites such as F5, AF3,

F1, FC3 (based on the international 10–20 EEG system). In this montage,
the electrodes are usually kept in place by using plastic holders mounted
into an EEG cap. Modelling studies have shown that HD-tDCS stimulates
more focally and therefore induces neuromodulatory changes within the
area of interest.
Figure 5.5 HD-tDCS montage includes a central active electrode (i.e., anode) over
the brain target area which is surrounded by a number of return electrodes (i.e.,
cathodes). The current density under each return electrode is 25% of the density
under the active electrode. Electrical field intensities throughout the brain are
modelled using a finite-element-method approach.
5.4.2 Other tDCS montages

To stimulate two parallel cortices (i.e., left and right primary motor cortex),
the electrodes may be applied “bihemispherically” (e.g., the parietal cortices)
(Benwell et al. 2015). In this montage, the aim is to purposefully upregulate
one brain region using a positive electrode (anode) while downregulating
another region using a negative electrode (cathode) (Lindenberg et al. 2010).
82 Chapter 5
5.5 tDCS as a stand-alone technique

tDCS can be used as a stand-alone technique in the absence of a concurrent
intervention. This technique has a promising potential particularly for the
management of pain and reduction of symptoms in multiple neurological
and psychiatric conditions. Due to the fact that the effect of tDCS on cortical
excitability is cumulative, these interventions typically include the
application of multiple tDCS sessions over succeeding days ranging from
one to a number of weeks (Alonzo et al. 2012; Galvez et al. 2013).
Methodological considerations for the use of tDCS as a stand-alone
technique require careful consideration of: 1. Number and intervals between
the treatment sessions; 2. Stimulation duration, current intensity/density and
montage; 3. Stimulation site (Brain target) for induction of the desired
effects; 4. Standardised patient’s activity during the stimulation sessions;
and 5. Control for potential brain state effects during application of
stimulation.
5.6 tDCS as a priming technique

In this technique, tDCS is an adjunct technique which is combined with
other therapeutic interventions such as pharmacotherapy, other NIBS
techniques, or behavioural interventions such as exercise or other forms of
training or rehabilitative strategies. In all of these combined applications,
tDCS is used to prime, or precondition prior to application of the second
intervention (i.e., homeostatic plasticity, see Chapter 4, Stagg and Nitsche
2011). Animal studies indicate that the presence of ongoing background
activity is essential for the induction of long-term neuroplastic changes in
the brain (Fritsch et al. 2010). A critical consideration in the use of this
technique is the timing of tDCS application relative to the execution of the
behavioural intervention. Literature indicates the superiority of the online
(concurrent) application of the combined techniques compared to their
offline applications, i.e., application of tDCS prior to or after completion of
the behavioural task (Stagg et al. 2011; Martin et al. 2014).
5.7 Halo sport tDCS device

Halo Sport is a brain stimulator device which was introduced for the first
time in 2017 by Halo Neuroscience (San Francisco, CA, United States). It
is indeed a tDCS device which is incorporated into a self-contained headset
similar in appearance to an audio headphone (Figure 5.6). The electrical
contact with the scalp is provided through three wet studded foam electrodes.
These electrodes are connected to a direct current battery-operated

generator. The current intensity of maximum 2.2 mA is controlled by an
application using a mobile phone or iPad.
The device works by applying a small electric current (1-2 mA) to the area
of the brain that controls movement (Figure 5.6) to boost athletic
performance. The headset emits direct current to the brain via rubber pads.
The current modulates the motor cortex and induces neuroplasticity
(Chapter 3). Depending on the site of stimulation, it can improve both
mental and physical performance.
Figure 5.6. Halo Sport headset could be easily used by individuals to modulate
primary motor cortex for both upper and lower limbs in left and right sides of the
body.
This technology mainly works by priming the training effects for

enhancement of EP. The protocol includes a 20-min Halo Sport session at
rest which is followed by a normal 60 minutes training session. A recent
study by Huang et al. (2019) indicated that application of tDCS with the
Halo Sport device improved repeated sprint cycling power output and
Stroop performance.
5.8 The effects of tDCS on EP

Numerous brain mechanisms are involved in the regulation of EP which
indicates the contribution of different areas of the brain in this process.
Excellence in EP requires not only physical and motor capabilities, but also
sensory-cognitive skills (Moscatelli et al. 2016). Considering the
neuromodulatory effects of tDCS on the motor, sensory and cognitive
regions of the brain, tDCS was extensively used for enhancement of EP.
84 Chapter 5
Due to its driving role in the control of muscle activity during exercise,
targeting the primary motor area with tDCS has been used to improve EP.
tDCS can be used to compensate for the reduction in corticospinal
excitability (CSE) following central fatigue exercise (Cogiamanian et al.
2007).
Exercise-induced pain also plays a significant role in the regulation of EP

(Mauger 2013). Therefore, due to the connections between the M1 to insula
and thalamus, modulation of pain perception is another reason for
stimulation of this area to improve EP (Vaseghi et al. 2014).
Vitor-Costa (2015) showed that bilateral a-tDCS (2 mA) of M1 for lower

limb muscles increased exercise tolerance in a cycling-based, constant-load
exercise test, performed at 80% of peak power. In another study,
Abdelmoula et al. (2016) investigated the effects of a-tDCS on neuromuscular
fatigability and concluded that 10 minutes a-tDCS of M1 significantly
reduced fatigue. Similarly, Cogiamanian et al. (2007) applied a-tDCS over
the M1 of the elbow flexors and showed improved muscle endurance and
reduced muscle fatigue in both healthy participants and patients with
pathological conditions.
Because of its role in top-down control of exercise-related internal and

external cues (Robertson and Robino 2016), a-tDCS of the DLPFC can also
be used to improve EP. A systematic review of the literature indicated that
reduced endurance performance was associated with increased cognitive
load (Van Cutsem et al. 2017). Therefore, the application of tDCS over the
DLPFC could improve the function of this area in the maintenance of the
volitional drive to the motor cortex and therefore improve EP.
The temporal and insular cortex (TC, IC), regions of the brain involved in
autonomic control of the cardiorespiratory system, are other targets for the
use of tDCS to improve EP. Literature indicates the role of the right and left
IC in sympathetic and parasympathetic activity (Oppenheimer and Cechetto
1990; Oppenheimer et al. 1992; Napadowe al 2008). Okano et al. (2015)
concluded that the application of a-tDCS over the TC modulates the activity
of the autonomic nervous system. This modulation delayed muscular
fatigue by increasing the time exercising with a lower cardiovascular load.
In addition, Okano et al. (2013), in a tDCS study on trained cyclists, showed
that 20 minutes of a-tDCS (2 mA) over the left TC significantly reduced
both heart rate and rating of perceived exertion during submaximal exercise
levels. These authors also reported a significant increase in peak power
output during a stepwise maximal exertion test. Due to the large size of the
electrodes used, the stimulation may also have an affect on the IC, which is
involved in the awareness of different parts of the body related to an
athlete’s perception of physical exertion during exercise, and parts of the
frontal lobe (Craig 2003; Williamson et al. 1999).
In line with these findings, Cogiamanian et al. (2007) demonstrated

increased time-to-exhaustion following a-tDCS (1.5 mA, 10 minutes) of the
motor cortex during an isometric arm endurance task. Similarly, Tanaka et
al. (2009) also reported that a-tDCS (2 mA, 10 min) of the lower leg motor
cortex significantly increased maximal pinch force in the lower leg. In
another study, Angius et al. (2015) investigated the effects of tDCS (2 mA,
10 min) on exercise-induced pain and reported improved pain tolerance
during a cold pressor test.
Unlike the studies with enhancing effects of tDCS on EP, there are also a
number of others studies which have failed to show any positive effects on
EP (Barwood et al. 2016; Kan et al. 2013; Muthalib et al. 2013; Angius et
al. 2015). The mixed findings could be caused by the methodological
differences in these studies. Therefore, future double-blinded randomized
controlled studies, using larger sample size and protocols that are more
robust, are required to shed light in this area of research.
5.9 Ethical considerations for the use of tDCS

for enhancement of EP
Fairness and the ethics of tDCS use for enhancement of EP were also subject
of a number of opinion articles in the literature (Davis 2013; Banissy and
Muggleton 2013; Colzato et al. 2017; Park 2017). In these articles, tDCS is
considered as a technique which potentially can become a “neuro-doping”
agent for enhancement of EP. The authors in these articles argued that tDCS
is associated with physical, behavioral and ethical risks for its users and
should be banned because it is a new doping technique.
It should be noted that the use of tDCS is not a banned substance/modality

by the World Anti-Doping Agency (WADA) (Stewart et al. 2013). These
articles suggest there is a need to develop anti-doping regulations by sports
governing bodies, to consider the prohibition of tDCS application for the
enhancement of EP.
86 Chapter 5
5.10 Summary
The focus of research for enhancement of EP during the last two decades
has shifted from physical, physiological, and psychological factors towards
the brain. The main reason behind this shift is the development of centrally-
acting performance modifiers and also the development of NIBS techniques
such as tDCS. This is a technique with an excellent safety record which is
well tolerated, relatively inexpensive and readily available. Research
indicates that, while a large number of studies are in support of using tDCS
for enhancement of EP, there are also a number of other studies which have
failed to show any positive effects. The mixed findings could be caused by
the methodological differences in these studies. Therefore, future double-
blinded randomized controlled studies, using larger sample size and
protocols that are more robust, are required to shed light in this area of
research.
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CHAPTER 6
NEURAL CONTROL OF LENGTHENING

AND SHORTENING CONTRACTIONS
JAMIE TALLENT, PHD

AND GLYN HOWATSON, PHD
6. Background
It is well accepted that the performance capacity of skeletal muscle is
different between shortening and lengthening contractions, which suggests
that the neural control strategy must also differ. The purpose of this chapter
is to detail and compare the activation strategies used by the nervous system
to control muscle force during shortening and lengthening contractions. The
chapter will also compare the neural adaptations to lengthening and
shortening contractions performed during resistance training.
6.1 Shortening and Lengthening Contractions

Shortening (concentric) muscle contractions occur when the muscle’s
contractile apparatus shortens, whilst lengthening (eccentric) muscle
contractions occur as the muscle’s contractile apparatus lengthens, usually
under tension (Asmussen, 1953). Lengthening muscle contractions consist
of resisting load, such as lowering a weight and walking downhill, whilst
shortening muscle contractions overcome external resistance, such as lifting
a weight or climbing stairs; however, both are critical for everyday human
movement (Isner-Horobeti et al. 2013). It has long been established that
lengthening muscle contractions can produce and withstand greater forces
compared to shortening contractions (Crenshaw et al. 1995; Doss and
Karpovich, 1965; Westing et al. 1991; Westing and Seger, 1989). Early
reports have demonstrated up to an 80% higher force generating capacity of
lengthening when compared to shortening muscle contractions (Rodgers
and Berger, 1974), although smaller differences have also been reported
(Aagaard et al. 2000). As a result, the increased stimulus provided by
Neural Control of Lengthening and Shortening Contractions 93
lengthening compared to shortening contractions during resistance training

has the potential for greater gains in muscle mass and strength (Roig et al.
2009). Another unique and advantageous characteristic of lengthening
contractions is the lower metabolic cost when compared to shortening
actions at the same absolute load (Okamoto et al. 2006; Vallejo et al. 2006).
Collectively, these characteristics make lengthening actions a potentially
powerful exercise stimulus for numerous groups ranging from clinical
through to elite athlete populations; therefore, an understanding of the
neural control and acute and chronic responses to resistance training is
essential in maximising rehabilitation and performance programmes.
6.1.1 Benefits of lengthening contractions

Muscle contractions provide a key part of rehabilitation and resistance
training programmes for both clinical and athletic populations. For example,
high intensity lengthening muscle contractions have been shown to increase
strength in Parkinson’s patients (Hirsch et al. 2003) and consequently
improve physical capacity, such as walking (Scandalis et al. 2001). Resistance
training that incorporates lengthening contractions has also been shown to
have a greater influence on strength changes in stroke patients when
compared to shortening contractions (Engardt et al. 1995). Furthermore, the
addition of lengthening resistance training in an exercise programme
augmented an increase in lean tissue in type II diabetes patients (Marcus et
al. 2008) and has been shown to be an effective tool to increase strength in
cardiovascular disease patients (Meyer et al. 2003). In an athletic population,
overloading lengthening contractions has resulted in a reduction in
hamstring injuries (Askling et al. 2003) and an enhancement in explosive
power (Clarka et al. 2005). Furthermore, lengthening contractions have
been shown to reduce the risk of falls in the elderly (LaStayo et al. 2003).
Whilst this list is not exhaustive, it provides multiple examples that illustrate
the benefits of lengthening contractions. The apparent superiority of
lengthening muscle contractions to optimise rehabilitation and the responses
to resistance training are likely, at least in part, to be due to their unique
neurological control strategies which are subsequently presented.
6.2 Motor control of lengthening and shortening muscle

contractions
During voluntary contractions, there is a large body of evidence showing
lower surface electromyography (EMG) amplitude in lengthening
compared to shortening muscle contractions (Aagaard et al. 2000; Amiridis
94 Chapter 6
et al. 1996; Duclay et al. 2011; Komi et al. 2000; Benjamin et al. 2000;
Teschet al. 1990) (Figure 6.1) even though a higher force producing
capacity for lengthening muscle contractions is often observed (Crenshaw
et al. 1995; Westing et al. 1991; Westing and Seger, 1989). For any given
force, there is also a reduction in oxygen cost (Bigland-Ritchie and Woods,
1976) indicating a more metabolic efficient contraction. Furthermore, the
greater force twitch during maximal voluntary contracts (MVCs) further
demonstrates unique neurological qualities during lengthening contractions
(Löscher and Nordlund, 2002). This section will describe the differences in
the motor control of lengthening and shortening contractions at the muscle,
spine and motor cortex.
6.2.1 Muscle
Early evidence suggested that the recruitment order of motor units is altered
during lengthening contractions (Howell et al. 1995; Nardone et al. 1989).
Type II higher threshold motor units are selectively recruited in preference
to lower threshold type I motor units (Howell et al. 1995; Nardone et al.
1989). Because the EMG activity is lower, it could be assumed that fewer
motor units are required for the same level of force; however, this is not a
widely supported idea (Bawa and Jones, 1999; Pasquet et al. 2006; Stotz
and Bawa, 2001). The lower EMG values recorded during lengthening
compared to maximal shortening contractions might be due to increased
inhibition during a lengthening action (Aagaard et al. 2000). Specifically,
during a maximal lengthening contraction, Golgi organs excite the Ib
afferents that activate inhibitory interneurons, thus resulting in less muscle
activity (Aagaard et al. 2000). It has been reported that the Golgi organs
inhibit muscle activity to act as a protective mechanism during lengthening
contractions (Tomberlin et al. 1991), although the evidence for this
proposed protective mechanism from damage is unclear (Chalmers 2002).
Finally, synchronization could also influence the EMG signal; a greater
synchronization of motor units has been reported during lengthening muscle
contractions when compared to shortening contractions (Semmler et al.
2002).
6.2.2 Spinal
Differences between lengthening and shortening muscle contractions at a
spinal level are often assessed through the Hoffman Reflex (H-reflex). The
H-reflex is a reflex that excludes gamma motor neurons spindle discharge

(Zehr, 2002) and requires low intensity, short duration electrical stimulation
of the peripheral nerve to be evoked. Volitional drive (V-wave) is an EMG
variant response of the H-reflex recorded during maximal voluntary
contractions (Aagaard et al. 2002). To elicit a V-wave, supramaximal
stimulation is applied to the peripheral nerve during a maximal contraction
and consequently represents modulations in efferent output during maximal
contractions (Aaggard et al. 2002). These techniques will be referred to in
this section to discuss differences in motor control strategies between
shortening and lengthening contractions.
In a rested state, a reduction in lengthening compared to shortening H-reflex

amplitude has been demonstrated in numerous studies (Duclay and Martin,
2005; Nordlund et al. 2002; Pinniger et al. 2001). Specifically, an increased
presynaptic inhibition and increased post-activation depression have been
reported as the specific mechanisms for a reduction in the H-reflex during
passive lengthening contractions (Duclay and Martin, 2005; Hultborn et al.
1987; Rudomin and Schmidt, 1999). There is also evidence of a reduction
in H-reflex amplitude during active lengthening compared to shortening
contraction (Duclay and Martin, 2005; Duclay et al. 2011), with no change
in volitional drive (Duclay et al. 2008; Hahn et al. 2012). The information
presented here strongly suggests that supraspinal drive is inhibited at a
spinal level during lengthening contractions and may be a contributor for
the reduced EMG activity at the muscle. As discussed earlier, lengthening
contractions generate a greater force compared to shortening contractions.
It is also plausible that afferent feedback from the Golgi organs might
contribute to the reduction of muscle activity recorded at the muscle during
a lengthening contraction (Aagaard et al. 2000). Due to the H-reflex being
a Ia afferent reflex, presynaptic inhibition of the Ia afferents appears an
equally likely mechanism in reducing EMG activity recorded at the muscle
during lengthening contractions (Duclay and Martin, 2005). More recently,
recurrent inhibition has been shown for the first time to increase during
lengthening compared to shortening maximal contractions (Barrue-Belou et
al. 2018) and it may also be a key regulating or protective mechanism at the
level of the spinal cord circuitry. In summary, it appears that no single
mechanism is responsible for the suppression of EMG at the muscle and,
hence, there are likely to be a multitude of inhibitory factors.
6.2.3 Cortico-Spinal
Transcranial Magnetic Stimulation (TMS) (Duclay et al. 2011; Löscher and
Nordlund 2002) and electroencephalogram (EEG) (Fang et al. 2001; 2004)
96 Chapter 6
studies have investigated differences in motor control between lengthening

and shortening muscle contractions at a cortical level. Fang et al. (2001)
investigated movement related cortical potentials (MRCP) from EEG
recordings and showed them to be higher during lengthening contractions
compared to shortening contractions. The authors concluded that
lengthening contractions are processed and planned differently to
shortening contractions due to the complexity of the movement. Therefore,
the greater MRCP might be a result of a greater cortical activity to process
the amount of sensory feedback immediately prior and during lengthening
muscle contractions (Fang et al. 2001; Fang et al. 2004). There appears to
be greater supraspinal activity during lengthening muscle contraction and
reduced activity at a spinal level which results in a lower EMG response.
Interestingly, during maximal contractions, the majority of previous work

has reported no difference in corticospinal excitability of lengthening and
shortening muscle contractions (Duclay et al. 2011; Löscher and Nordlund,
2002); however, there is evidence to suggest motor evoked potentials (MEP)
are reduced during lengthening contractions when recorded during MVCs
(Duclay et al. 2011). The reduction in corticospinal excitability during
muscle lengthening appears to be more evident at submaximal contraction
intensities (Abbruzzese et al. 1994; Sekiguchi et al. 2001), however the
exact mechanisms why this might happen remain unclear. The MEPs reflect
the balance between excitability and inhibition along the brain to muscle
pathway (Hallett, 2000). Consequently, an increase in cortical excitability
might occur, but heightened spinal inhibition (as discussed in the previous
section) could reduce the EMG response seen at the muscle. No change in
cervicomedullary motor evoked potential (CMEP) has previously been
reported between lengthening when compared to shortening contractions
(Hahn et al. 2012), though this is not consistant in the literature. Gruber et
al. (2009) investigated the ratio of MEPs evoked at the primary motor cortex
and the CMEP to determine the control mechanisms of lengthening and
isometric contractions at a cortical level. Lengthening contractions showed
lower CMEP and MEP amplitude than isometric contractions, however the
MEP-to-CMEP ratios increased. This information further suggests that
there is heightened cortical activity and spinal inhibition during lengthening
compared to isometric contractions. More specifically, this section suggests
that spinal inhibition occurs further up the spinal tract in additional to at a
reflex level.
The amount of neural drive to the muscle during a maximal muscle

contraction is defined as voluntary activation (Gandevia et al. 1995) and has
been used to investigate changes in the neurological control strategies of
shortening and lengthening contractions. More specifically, lengthening

contractions showed a voluntary
activation of only 79% compared to
92% during shortening muscle
contractions. Figure 6.1 shows an
example individual trace showing the
large interpolated twitch response from
a maximal lengthening contraction
compared to isometric and shortening
contractions. The data indicate that,
during maximal contractions, excitation
of the motoneuron pool is lower. This,
in addition to the unique control
strategies presented in previous
sections, may suggest that lengthening
contractions have the potential for
greater adaptation to resistance training.
This will be explored in the next section.
6.3 Adaptations to shortening

and lengthening resistance
training
As described in the previous section,
motor control strategies of lengthening
and shortening muscle contractions
differ from the motor cortex to the
muscle (Duchateau and Enoka, 2008). Figure 6.1. Representative torque
Given the pool of literature investigating traces, isometric (A), shortening (B),
and lengthening (C) maximal voluntary
the neurological differences between contractions for knee flexion with
shortening and lengthening contractions, it superimposed twitch. Timing of
is surprising that relatively few studies superimposed twitch is indicated
have investigated nervous system through the arrow. Adapted
adaptations from lengthening and from Beltman, Sargeant, van Mechelen,
shortening contractions, particularly at & de Haan (2004).
multiple levels of the central nervous
system (CNS).
98 Chapter 6
Hortobagyi et al. (1996) showed a 3.5-fold increase in strength that was

accompanied by a 7-fold increase in EMG. The large increase in strength
was attributed to a greater recruitment (from the CNS) of type II muscle
fibres. Further evidence has also reported a preferential recruitment of type
II muscle fibres during lengthening contractions (Nardone et al. 1989).
Whilst Hortobagyi et al. (1996) showed an increase in neural drive from
lengthening resistance training, Seger and Thorstensson (2005) did not
detect changes in EMG between shortening and lengthening resistance
training, which is likely attributable to the very small sample size (n = 5 per
group) that were moderately trained. Trained individuals have been shown
to have a lower superimposed twitch force compared to untrained (Amiridis
et al. 1996), suggesting a reduction in the neural inhibitory mechanism
discussed in the previous section (Aagaard et al. 2000; Webber and
Kriellaars, 1997). Even though Higbe et al. (1996) found a significant
increase in EMG from pre to post training in both the shortening and the
lengthening muscle contraction groups, there was no difference in post
training EMG between groups.
Variability of EMG can play a significant role in the lack of findings in

some studies. For example, Blazevich et al. (2008) did not detect any
changes in EMG pre to post and post to detraining in shortening or
lengthening training groups despite changes in the rate of force development
(RFD) and MVC. Whilst experimenters make every effort to reduce
variability, the nature of EMG can make detecting changes difficult. Factors
such as phase out cancellation and high within-subject variability are two
significant limitations of this technique (Farina et al. 2014). Assessing
adaptation during a dynamic muscle contraction further adds to the potential
variability of EMG testing. EMG signals recorded at the muscle belly are
highly susceptible to small muscle movements (Rainoldi et al. 2000) over
skin-mounted electrodes. The emergence of high-density surface EMG has
the potential to reduce some of these limitations and is able to detect the
specific behaviour associated with exercise-induced alterations in individual
motor units (Sleutjes et al. 2018). Furthermore, the segmental assessment
of changes in the motor cortex to muscle has allowed for a greater insight
into neurological changes than a volitional EMG measure alone.
Lengthening contractions have been coupled with shortening contractions

in a dynamic task to investigate the effects on volitional drive and spinal
excitability (Ekblom, 2010). Participants that performed calf raises to raise
(shortening) and lower (lengthening), respectively showed no differences in
H-reflex during rest or high intensity muscle contractions (HSUP), although
an increase in V-wave was evident during shortening and lengthening
contractions (Ekblom, 2010). In this study (Ekblom, 2010), it was difficult

to separate the influence that lengthening resistance training had on
adaptations to the nervous system because the lengthening training was
coupled with shortening contractions. Therefore, the remainder of this
section will focus on isolated muscle actions performed during resistance
training.
Only a couple of studies have appropriately isolated lengthening and

shortening resistance training. Duclay et al. (2008) used peripheral nerve
stimulation to investigate the effect of solely lengthening resistance training
on H-reflex and V-wave during lengthening and shortening muscle
contractions. H-reflex and V-wave were assessed in the soleus and medial
gastrocnemius with differing results. No changes were found in the resting
H-reflex regardless of muscle contraction; however, in contrast, an increase
in HSUP was found during lengthening, shortening and isometric muscle
contractions in the medial gastrocnemius, but only during lengthening in
the soleus. As HSUP is recorded during maximal contractions, it can be
suggested that adaptations in spinal excitability/inhibition appear to be
intensity specific from lengthening resistance training. Furthermore,
differences between the two studies (Duclay et al. 2008; Ekblom, 2010)
might be due to the lack of kinematic specificity to the conditions HSUP
was assessed under and the resistance training procedure. Ekblom (2010)
performed dynamic resistance training whilst the assessment was conducted
on an isokinetic dynamometer, so arguably, this would have had less
transfer compared to Duclay et al. (2008) who conducted training and
assessment on the isokinetic dynamometer. Furthermore, a faster angular
velocity (20°/s) was used by Duclay et al. (2008) compared to 5°/s by
Ekblom (2010), which most likely resulted in a higher level of presynaptic
inhibition during fast compared to slow lengthening contractions. Further,
Ekblom (2010) suggested that the faster lengthening contraction used by
Duclay et al. (2008) allowed for a greater potential to reduce presynaptic
inhibition. Presynaptic inhibition was highlighted earlier in this chapter as
being higher in lengthening compared to shortening contractions and thus a
greater potential for modification. An increase in volitional drive was also
found post resistance training in all muscle contractions and in both muscles,
apart from during maximal shortening contractions (Duclay et al. 2008).
The data suggested that increased maximal force during lengthening muscle
contractions could be due to an enhanced supraspinal volitional drive and
increased excitability coupled with reduced presynaptic and post-synaptic
spinal inhibition. Differences in findings between muscles within the same
study (Duclay et al. 2008) might be due to the specific neural mechanisms
100 Chapter 6
that influence spinal excitability of each muscle (Meunier and Pierrot-

Deseilligny, 1998).
More recently, work from our laboratory (Tallent et al. 2017) has segmentally
assessed neurological adaptations following a 4-week shortening or
lengthening resistance-training intervention. Shortening and lengthening
resistance training improved MVCs in a task-specific manner (i.e.,
lengthening training improved eccentric strength more than shortening).
Interestingly, V-wave showed an increase of 57% following lengthening
resistance training during maximal lengthening contractions compared to
an increase of 23% in maximal shortening contractions following
shortening resistance training. Changes were independent of any alterations
in muscle mass. These data suggest that the superiority of lengthening
contractions in enhancing strength may be, in part, due to the enhancement
of volitions drive. However, it must be noted that this study did not find a
superiority of lengthening contractions in enhancing strength. For
practitioners, there appears to be an advantage of using lengthening
resistance training in enhancing strength through neurological adaptations.
The exact mechanisms are probably due to improved volitional drive and a
reduction in inhibition at a spinal level, though further research is required.
6.4 Summary
Lengthening muscle contractions consist of resisting load, and key
locomotion activities such as walking downhill or stairs. In an athletic
population, lengthening contractions decelerate the body which is a critical
physical attribute in many sports. Lengthening contractions are a fundamental
part of rehabilitation programmes and performance programmes.
Consequently, researching optimal strategies for modifying the neurological
system and enhancing force generating capacity of the muscle is a vital area
for exercise-science research. The neural control of shortening and
lengthening contractions appears to differ at a cortical, spinal and muscle
level. At a cortical level, it appears that there is an increase in cortical output
that is likely reflective of the complexity of the movement, through a
potential decrease in corticospinal inhibition. Spinal inhibition through
actions of the Golgi organs exciting Ib afferents could cause a reduction in
muscle activity. This may be a contributing factor in the dampening of the
neurological response at the muscle. Force generating capacity of the
muscle appears to increase to a greater extent following lengthening
compared to shortening training. Adaptions appear to be associated with a
greater increase in volitional drive and decrease in inhibition at a spinal

level.
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CHAPTER 7
NEURAL ADAPTATIONS
TO STRENGTH TRAINING
7. Background
The purpose of this chapter is to introduce the acute and long-term effects
of strength training on the function of the neuromuscular system. It is
important to consider that the neuromuscular system (i.e., the interaction
between nerves and muscles) functions as an interactive unit. The terminal-
point of the nervous system is the neuromuscular junction (the point where
motoneurons and muscle fibres are inter-digitated). The commencement of
the nervous system is difficult to define, however, for simplicity; it can be
regarded as the primary motor cortex (M1) and the corticospinal pathway.
Consequently, it is preferable to consider the interaction of the nervous and
muscular system as a continuum rather than in isolation; thus, structures
between the M1 and the muscles are likely to undergo subtle changes
following strength training. Keeping this in mind, the following sections
will discuss the effect of strength training on M1 plasticity and changes in
corticospinal activity, including spinal cord plasticity and changes in motor
unit behaviour.
7.1 Acute neural responses to strength training

The nervous system is able to modify its function in response to activity or
experience (Sanes 2003). This response has been termed ‘plasticity’ and
involves reorganisation of neural circuits that control movement. In
particular, the M1 can experience plasticity following various types of
physical activity. Although plasticity can be stimulated in a variety of ways,
recently, it has been reported following various types of strength training
(Kidgell et al. 2017).
108 Chapter 7
Muscle strength is the maximal force or torque that can be developed by the
muscles while performing a specific movement (Enoka 1988), and changes
in the nervous system play an important role in force production and
strength development (Kidgell et al. 2017). Muscles increase in strength by
being forced to contract at relatively high tensions. Strength training uses
specific equipment (free weights and machines) to increase specific tension
in the trained muscles. Experimental data now shows that specific
neurological factors contribute to the development of muscle strength
(Siddique et al. 2020). These studies have used a variety of neuromuscular
assessment techniques which include peripheral measures such as surface
electromyography (sEMG), evoked spinal-reflex recordings and single
motor-unit recordings (Aagaard 2003; Kidgell et al. 2006) to identify the
neural mechanisms that contribute to force production. However, other lines
of enquiry include using functional magnetic resonance imaging (fMRI)
and transcranial magnetic stimulation (TMS) to examine the acute and long-
term neural responses to strength training (Frazer et al. 2018; Mason et al.
2019).
7.2 Using TMS to assess the neural responses to strength

training
TMS has emerged as the leading candidate to provide insight into the
synaptic activity of the cortico-cortical circuitry of the M1. When single-
pulse TMS is applied over the M1, a number of physiological variables can
be determined that represent M1 excitability, such as motor threshold (MT)
and motor-evoked potential amplitude (MEP). When a MEP is recorded
during voluntary muscle activation, there is a pause in the ongoing sEMG
signal, which is termed the corticospinal silent period; this is a measure of
intracortical inhibition. The corticospinal silent period is mediated by the
neurotransmitter gamma-aminobutyric acid-B (GABAB) and indicates an
interruption in volitional drive from the M1 (i.e., neural drive) and
withdrawal of descending input to the spinal motoneuron pool (Yacyshyn
et al. 2016). The corticospinal silent period can be used as a proxy measure
for M1 excitability, particularly when reductions are observed following an
intervention (Kidgell and Pearce 2010). Although single-pulse TMS is used
to determine synaptic efficacy of the M1 and corticospinal tract, it does have
limitations as it is unable to examine the excitability of the intracortical
micro-circuits of the M1 (Burke and Pierrot-Deseilligny 2010).
Neural Adaptations to Strength Training 109
Paired-pulse TMS allows for an assessment of the physiology of the

intrinsic intra-cortical connections within the M1 following strength
training (Kidgell et al. 2017). Depending on the inter-stimulus interval
between the conditioning and test pulse, the excitability of the intracortical
inhibitory (e.g., 2-5ms) and long intracortical inhibition (e.g., 100-150ms)
and intracortical facilitatory circuits (e.g., 8-15ms) of the M1 can be
examined, providing important information about the effects of strength
training on the GABA-ergic system (Hanajima et al. 2003).
The acute neural responses from strength training likely arise from changes
in synaptic efficacy along the corticospinal pathway and in the intrinsic
circuitry of the M1. However, because TMS is limited in that it cannot
identify the precise location of synaptic modification following strength
training, stimulating the axons of corticospinal fibres assists in identifying
the level of synaptic modification. For example, cervicomedullary motor
evoked potentials (CMEPs) can be generated subcortically via electrical
stimulation at the cervicomedullary junction. When an electrical current
passes through electrodes positioned on the mastoid processes, it evokes a
descending volley which, like TMS, is captured using sEMG (Nuzzo et al.
2018). Importantly, because cervicomedullary stimulation is delivered
inferior to the level of the M1, it is regarded as a measure of spinal
excitability (Taylor and Gandevia 2004; Taylor 2006). By comparing
changes in CMEP and MEP amplitudes following strength training,
researchers are able to infer whether increases in excitability occur at a
cortical or spinal level, or both.
7.3 MEPs are acutely facilitated following a strength

training session
There are several TMS studies that have examined changes in the
excitability of the M1 following a single session of strength training
(Selvanayagam et al. 2011; Hendy and Kidgell 2014; Brandner et al. 2015;
Leung et al. 2015; Latella et al. 2017; Latella et al. 2018; Latella et al. 2018;
Mason et al. 2019). Leung et al. (2015) showed that a single session of
heavy-load elbow flexion strength exercise increased MEPs evoked by
single-pulse TMS (Figure 7.1).
110 Chapter 7
Figure 7.1. Change in corticospinal excitability following a single bout of heavy-

loaded elbow flexions. MEP amplitude increased by 95% following the strength
training. Adapted from Leung et al. (2015).
More recently, Latella et al. in 2017and 2018 reported increased MEP

amplitude following a single session of both heavy-loaded and hypertrophy-
based strength training. However, in contrast, Latella et al. (2016) and
Selvanayagam et al. (2011) reported reduced MEP amplitude following a
single session of strength training. Because of these inconsistent findings,
Mason et al. (2019) systematically examined the pooled effect of a single
session of strength training on M1 excitability and confirmed that strength
training increases M1 excitability (effect size, 1.26). Although the pooled
effect was strong, there was a high degree of heterogeneity across studies.
Nonetheless, the available data suggest that an acute bout of strength
training increases M1 excitability.
7.4 Intracortical facilitation is acutely enhanced following

a strength training session
Beyond measuring the excitability of corticospinal excitability with single-
pulse TMS, paired-pulse TMS is also capable of assessing intracortical
facilitation (ICF), which estimates cortical excitability evoked by a
conditioning stimulus followed by a test stimulus. There is now preliminary
evidence to suggest that a single bout of strength training affects the
excitability of the intracortical micro-circuitry of the M1 towards
facilitation (Figure 7.2; Latella et al. 2016; Latella et al. 2017; Latella et al.
2018; Latella et al. 2018).
Figure 7.2. Acute increase in the excitability of the intracortical facilitatory micro-
circuitry of the M1 following hypertrophy strength training. Hypertrophy training
increased the size of the conditioned TMS induced MEP by 142%. Adapted from
Latella et al. (2018).
This finding is now confirmed by systematic evidence that shows strength

training specifically targets the facilitatory intracortical neurons of the M1
that use glutamate. Specifically, the acute responses to strength training
revealed a large pooled effect for increased intracortical facilitation (effect
size, 1.6).
7.5 Why does strength training increase corticospinal

excitability and intracortical facilitation of the motor
cortex?
Recent data, from the systematic review by Mason et al. (2019), show that
the overall pooled estimate obtained from the nine eligible studies reveals a
large effect size (SMD, 1.26, 95% CI 0.88, 1.63, P < 0.0001) for increased
MEP amplitude in the period immediately following a single session of
strength training. This enhancement of MEP amplitude is reasonably
consistent between studies and extends across a range of muscle groups that
have been trained, including biceps brachii (Leung et al. 2015) and wrist
flexors (Nuzzo et al. 2018). Although this finding is interesting, it remains
unclear whether similar acute neural responses occur in the lower limb. In
fact, to date, only one study has examined the acute neural responses
112 Chapter 7
following lower-limb strength training (Latella et al. 2017). Despite this,

increased MEP amplitude is a consistent finding across different types of
muscle actions, with both isometric (Nuzzo et al. 2016; Nuzzo et al. 2018),
isotonic (Brandner et al. 2015; Leung et al. 2015; Latella et al. 2017),
concentric and eccentric (Latella et al. 2018) strength training eliciting an
increase. At a fundamental level, these findings show that there is a rapid
increase in MEP amplitude following a single strength training session,
which may simply be a transient response closely resembling those
associated with motor learning (Butefisch et al. 2000).
Interestingly, following a single bout of motor learning, MEP amplitude is

also rapidly and transiently elevated (Cirillo et al. 2011) suggesting that
neural processes associated with ‘early consolidation of learning a motor
skill’ begin within M1 from the first exposure to a new task (Muellbacher
et al. 2002). In novice strength trainers, first exposure to a loaded strength-
training stimulus may also be akin to motor learning processes, with MEP
amplitude increasing as an early ‘neural’ response in order to acquire and
consolidate the strength-training task. In addition, the acute increase in MEP
amplitude following a single session of strength training could also be a
mechanism to attenuate muscle fatigue that is generated through the
strength-training task (Latella et al. 2017; Latella et al. 2018). Strength
training-induced fatigue is accompanied by a number of physiological
responses which are known to modify the acute chemical environment,
subsequently modulating changes in MEP amplitude and the intrinsic
micro-circuitry of the M1 (Goodall et al. 2018). Strength training is also
sufficient to induce increases in lactate which is associated with increased
MEP amplitude (Coco et al. 2010).
In addition to changes in MEP amplitude, strength training increases ICF

showing that strength training is a clinically useful tool to modulate
intracortical micro-circuits involved in motor control. Overall, strength
training targets glutamatergic neuronal populations located specifically in
the M1, revealing that the intracortical circuits of the M1 become facilitated,
and this could be an important neural response that contributes to longer-
term strength development (Di Lazzaro and Ziemann 2013).
Change in the duration of the corticospinal silent period is a ‘primary’

mechanism that underlies motor performance (Kidgell and Pearce 2010).
Increased corticospinal silent period duration reflects greater levels of
inhibition in the corticospinal pathway, thus reducing neural drive to the
trained muscles, with contributions arising from both cortical and spinal
levels (Yacyshyn et al. 2016). Reductions in the duration of the
corticospinal silent period have been observed to accompany changes in

muscle strength following strength training (Latella et al. 2012; Christie and
Kamen 2013; Hendy and Kidgell 2013; Mason et al. 2017; Mason et al.
2018). However, the evidence regarding changes in the duration of the
corticospinal silent period following a single session of strength training is
limited. Recent experimental findings show that the duration of the
corticospinal silent period is reduced immediately following both heavy-
load and hypertrophy-based strength training (Figure 7.3, Latella et al. 2016;
Latella et al. 2017; Latella et al. 2018); this is in conflict with earlier
findings which suggest increases in corticospinal silent period duration
occur throughout and immediately following a single session of strength
training (Ruotsalainen et al. 2014).
Figure 7.3. The effect of hypertrophy strength training on the duration of the silent
period, a measure of inhibition within the corticospinal pathway, mediated by
GABA-B.
Similar to the corticospinal silent period, some studies have assessed the
effect of strength training on short-interval cortical inhibition (SICI, Figure
7.4).
There is now good evidence to show that SICI is reduced following a single
session of strength training (Latella et al. 2012; Hendy and Kidgell 2014;
Leung et al. 2015; Latella et al. 2016; Latella et al. 2017; Latella et al. 2018).
These experiments reveal that, at a minimum, strength training increases the
MEP amplitudes from the test response of a SICI-inducing protocol,
confirming that strength training affects the excitability of the intracortical
inhibitory micro-circuits of the M1. This clearly shows that strength training
targets/recruits corticospinal cells that use both GABAA and GABAB which
collectively act to reduce the withdrawal of descending inputs to the spinal
114 Chapter 7
motoneuron pool, which in turn increases motor unit activation (Griffin and
Cafarelli 2007) via increased neural drive.
Figure 7.4. Changes in SICI following heavy-load strength training of the elbow
flexors. There was a 34% reduction in inhibition, showing that strength training
increases the size of the conditioned MEP, which shows that strength training
reduces the excitability of the intracortical inhibitory neurons. Adapted from Leung
et al. (2017).
Long-interval intracortical inhibition (LICI) can be assessed using longer

inter-stimulus intervals of 50 to 200 ms, and is used to measure GABAB-
mediated cortical inhibition within M1 (Opie et al. 2017). SICI and LICI
are modulated by independent cell populations (Sanger et al. 2001) and
could exhibit unique responses to strength training. Unlike measures of
corticospinal excitability and inhibition, there is limited experimental data
that have examined LICI following strength training. There are only three
studies that have examined LICI following strength training (Latella et al.
2016; Latella et al. 2017; Manca et al. 2018). All three studies showed that
the long-latency inhibitory networks remain unchanged following strength
training. At this point, it is unclear how strength training may affect the
long-latency inhibitory micro-circuits of the M1.
7.6 Long-term neuroplastic adaptations to strength

training
Longer-term strength training results in changes in muscle strength that are
accompanied by adaptive alterations in the neuromuscular system,
particularly during the early phases (i.e., 2-8 weeks of training) (Carroll et
al. 2002; Duchateau and Enoka 2002; Jensen et al. 2005; Lee et al. 2009).
Most of the available evidence for changes in the nervous system following
strength training has been provided by studies that have used sEMG, evoked
spinal reflex recordings, and via single motor unit recordings (Duchateau et
al. 2006; Del Balso and Cafarelli 2007). Changes in the amplitude of the
sEMG signal have, by default, been interpreted as increases in neural drive,
therefore contributing to the increase in force production (Sale 1988; Griffin
and Cafarelli 2007; Coombs et al. 2016). Measurement of evoked spinal
reflexes, such as the Hoffman reflex and volitional drive (V-wave), have
also been shown to increase following a period of strength training, possibly
contributing to training-related increases in strength (Aagaard et al. 2002;
Fimland et al. 2010).
There are now many training studies that have used TMS to investigate the
neural adaptations to strength training. In healthy untrained participants,
Carroll et al. (2002) observed that strength training of a hand muscle
increased muscle strength; however, corticospinal excitability remained
unchanged at rest, but decreased significantly at higher force levels (50%
of maximal voluntary contraction [MVC]). Similarly, Jensen et al. (2005)
also reported a significant reduction in the size of the maximal MEP and
slope of the stimulus-response curve at rest following four weeks strength
training of the biceps brachii muscle in healthy untrained participants. Lee
et al. (2009) observed that four weeks strength training of the wrist
abductors did not modify the size of the TMS-evoked MEP. More recently,
Coombs et al. (2016) showed that three weeks of wrist extensor strength
training had no effect on corticospinal excitability, despite significant
increases in muscle strength. However, in contrast, Griffin and Cafarelli
(2007) observed a 32% increase in MEP amplitude following isometric
strength training of the tibialis anterior. Other relatively recent contributions
show that strength training of both the upper and lower limbs, paced to an
audible metronome, increases MEP amplitude following isotonic strength
training in untrained participants (Kidgell et al. 2010; Goodwill et al. 2012;
Weier et al. 2012; Leung et al. 2017; Mason et al. 2017; Mason et al. 2019;
Mason et al. 2019).
Whilst the MEP amplitude has provided equivocal findings, changes in

corticospinal inhibition appear to be more consistent. This suggests that an
important neural adaptation that might underpin the rapid increase in
strength following strength training could be a reduction in corticospinal
inhibition. Several studies in both healthy untrained younger and older
adults have reported that the duration of the cortical silent period is reduced
following isometric and isotonic strength training (Kidgell and Pearce 2010;
Hendy and Kidgell 2013; Latella et al. 2017; Mason et al. 2017; Latella et
al. 2018; Mason et al. 2019). At the very least, these results are suggestive
116 Chapter 7
that strength training targets specific populations of intracortical neurons

that are GABAB sensitive, which manifests as an increase in the activation
of the spinal motoneuron pool of the trained muscle. In a similar manner, a
reduction in SICI may also represent an important neural adaptation to
strength training (Weier et al. 2012; Manca et al. 2018; Mason et al. 2019).
For example, several strength-training studies have now reported reduced
SICI, which shows that the amplitude of MEPs from the test response of the
SICI inducing protocol is facilitated (Weier et al. 2012; Leung et al. 2017;
Mason et al. 2019). Therefore, it is feasible that strength training affects the
low-threshold inhibitory circuits that use the neurotransmitter GABAA,
which reduces the efficacy of inhibitory circuits within the M1 (Kidgell et
al. 2017).
7.7 Changes in strength following 2-8 weeks of strength

training
The early muscle-strength gains that occur after strength training predominantly
involve neural adaptations; however, the exact site of adaptation within the
nervous system has eluded scientists. Despite this, several experimental
studies have reported changes in motor unit behavior, such as increased
sEMG amplitude, increased discharge rate, doublet firing of motor units,
reduced co-activation of antagonists and increased neural drive (i.e.,
changes in V-wave amplitude), representing neural changes at multiple
points along the neuroaxis (Sale 1988). However, keeping in focus of the
current chapter, the specific role of the M1 underpinning strength training
remains more elusive (Kidgell et al. 2017).
In an attempt to explain why strength increases in a rapid manner, there have

been recent suggestions that the concept of use-dependent cortical plasticity
of neural networks (see Chapter 4 for more details) may be similar between
skill training and strength training (Leung et al. 2017; Mason et al. 2019)
and that this may be the mechanism underpinning strength gain. As an
example, neural adaptations have been shown to be the preliminary step that
improves the acquisition of motor skills (Pascual-Leone et al. 1995).
Particularly in humans, long-term potentiation (LTP) is considered to occur
at existing synapses during the early stages of skill acquisition (Rosenkranz
et al. 2007). In a similar manner, strength training also leads to LTP, and
these changes in synaptic activity within the M1 underpin rapid strength
gain (Kidgell et al. 2017; Siddique et al. 2020). However, to date, it is
unclear whether the neural adaptations that occur following strength
training involve a similar mechanism to skill training (Leung et al. 2017;
Mason et al. 2019), which predominantly involves increased M1

excitability.
7.8 Long-term strength training does not affect motor

threshold or MEP amplitude
One potential site of neural adaptation that could underpin the rapid gain in
muscle strength is the M1. Certainly, motor skills that require greater
dexterity have consistently demonstrated cortical plasticity within the M1,
with increased MEP amplitudes and a reduction in intracortical inhibition
(Classen et al. 1998; Garry et al. 2004). Conversely, relatively few studies
have examined the training-related M1 responses to strength training
(Kidgell and Pearce 2010).
Recent experimental evidence now confirms that long-term strength

training only has a borderline affect for increasing M1 excitability (Kidgell
et al. 2017). Unlike motor skill training, strength training does not alter
motor threshold (Pascual-Leone et al. 1995), therefore, strength training
does not affect membrane excitability of corticospinal neurons and
interneurons within the M1. Given that motor threshold is a representative
measure of synaptic efficacy of presynaptic neurons within the M1, the
evidence suggests that strength training does not alter membrane
excitability. Interestingly, Kidgell et al. (2017) systematically appraised the
available evidence to show that strength training has no effect on overall
M1 excitability. This finding is in contrast to the acute neural responses to
strength training which strongly show there are specific neurons targeted
during acute strength training. This systematic finding is interesting because
there are several TMS strength-training studies that have reported increased
M1 excitability (Griffin and Cafarelli 2007; Kidgell et al. 2010; Goodwill
et al. 2012; Weier et al. 2012; Hendy and Kidgell 2013; Leung et al. 2017;
Mason et al. 2017; Latella et al. 2018; Mason et al. 2019; Mason et al. 2019).
However, when these data are pooled together, the overall effect on
corticospinal excitability is inconsistent because of high levels of
heterogeneity (Kidgell et al. 2017). For example, to date, four studies have
reported increased M1 excitability, one study reported a decrease and the
remaining 14 studies showed no change in corticospinal excitability, with
the overall pooled effect being borderline (P = 0.054). This pooled effect,
in essence, supports the previous inconsistencies in the literature. It seems
that these inconsistent findings are mostly related to the different strength-
training tasks performed during training (static vs. dynamic, tonic vs.
ballistic, etc.), the duration of the training intervention, and/or different
118 Chapter 7
methodological techniques used to determine M1 excitability. The biggest

issue seems to be related to TMS-evoked MEPs being assessed at rest,
which are likely to be insensitive to detecting changes as the state of the M1
(increased excitability with increased force) is not being assessed under the
same conditions in which the strength training is being performed. Based
upon the current literature, the overall conclusion is that long-term strength
training does not alter M1 excitability or the efficacy of neural transmission
along the peripheral motor pathway.
7.9 Long-term strength training reduces motor cortex

mediated inhibition
Experimental evidence indicates that long-term strength training reduces
the corticospinal silent period duration and SICI. Therefore, strength
training reduces the synaptic efficacy of inhibitory networks within the M1
and corticospinal pathway, representing an important, reproducible neural
adaptation to strength training (Kidgell et al. 2017). Because the duration of
the silent period is modulated by GABAB-mediated inhibition (Yacyshyn et
al. 2016) confined within the M1, strength training specifically targets
intracortical inhibitory neurons that collectively act to increase neural drive
to the spinal motoneurone pool, which increases muscle strength.
Figure 7.5. The area under the recruitment curve obtained prior to the strength-
training intervention is shaded in grey. The additional area enclosed by the
recruitment curve obtained following 3 weeks of strength training is the right biceps
brachii patterned. Inhibition reduced by 17.5%, showing that strength training
targets neurons in the M1 that use GABA-B. AMT, active motort hreshold. Adapted
from Frazer et al. (2019).
In addition to reductions in silent period duration, a reduction in SICI, a

measure of GABA-ergic inhibition within intracortical micro-circuits of the
M1, is also important for strength gain. It has been known for some time
that cortico-cortical cells increase their discharge rate in a linear manner
with increasing force production (Ashe 1997). It has been shown that the
M1 is a critical determinant of muscle strength (Kidgell and Pearce 2010;
Goodwill et al. 2012; Weier et al. 2012) because several experiments that
have used a model of immobilization have reported an increase in cortico-
cortical inhibition and a reduction in muscle strength (Clark et al. 2010;
Clark et al. 2014); however, strength training seems to attenuate the
prolongation of the cortical silent period (Pearce et al. 2013). At a minimum,
strength training reduces cortical inhibition (cortical silent period and short-
interval intracortical inhibition) which releases the cortical representation
of the trained muscles from inhibition and increases the subsequent
excitatory drive to produce the intended movement (Floeter and Rothwell
1999). Overall, strength training causes a reduction in the responsiveness of
intracortical inhibitory neurons because of training. It is likely strength
training targets neurons that use GABAA and GABAB, which leads to
reduced synaptic efficacy of their synapses onto corticospinal neurons, thus
increasing the recruitment of cortico-motoneuron cells.
Figure 7.6. Significant decrease in strength (45%) and a significant increase in

cortical inhibition (13.5%) following limb immobilization (Adapted from Pearce et
al. 2013).
120 Chapter 7
7.10 Changes in spinal cord plasticity with strength

training
Reflex responses in the spinal cord can be produced by electrical stimulation
of peripheral nerves. Such a technique has the potential to contribute
important information about the sites and mechanisms of neural adaptation
to strength training. There are two common reflexes that are evoked to
determine the contribution of the spinal cord to increases in strength
following a training period. Both the Hoffman reflex, or H-reflex, and
volitional wave, or V-wave, are produced by electrical stimulation of a
mixed nerve. Both reflexes are modulated by the monosynaptic circuit from
1a afferent fibres to motoneurons. When an electrical stimulus is applied to
a mixed nerve, it produces an afferent volley that causes a synchronous
discharge of the spinal motoneurons. With the H-reflex, this response
gradually increases with stimulation intensity as the afferent volley
increases in size, but, it progressively falls to zero as the intensity of
electrical stimulation approaches levels that are supramaximal for activating
motor axons. The V-wave is predominantly produced by supramaximal
electrical stimulation that is applied during a voluntary contraction, usually
a MVC. The cancellation of action potentials that diminish the H-reflex at
high stimulus intensities is inhibited in some motoneurons by action
potentials that are produced by volution during the MVC. Thus, in some
motoneurons, a voluntary action potential will collide with the antidromic
action potential that is produced by the electrical stimulus. In general, the
overall size of the reflex will depend on the responsiveness of the
motoneurons and the efficacy of synaptic transmission between the
afferents and the motoneurons themselves. Although these reflexes do
provide important information about the efficacy of the 1a afferent pathway
and the output from the motoneuron pool during voluntary contraction, they
are not without their limitations; however, there is evidence to suggest that
strength training may alter this pathway.
7.11 Changes in H-reflex and V-wave amplitude following

strength training
Over the last 40 years, there have been several investigations into the
underlying changes in reflex physiology following strength training. Over
this time, there have been no reports of an increase in H-reflex amplitude at
rest following strength training (Scaglioni et al. 2002; Holtermann et al.
2007; Duclay et al. 2008; Fimland et al. 2009; Fimland et al. 2009; Fimland
et al. 2010). However, a handful of studies have reported increased V-wave
amplitude in lower-limb muscles following strength training (Sale et al.

1983; Aagaard et al. 2002; Gondin et al. 2006; Ekblom 2010). H-reflex
amplitudes recorded during background muscle activity are inconsistent
following strength training. Some studies have reported increased H-reflex
amplitudes (Lagerquist et al. 2006; Duclay et al. 2008), whilst other studies
report that, it remains unaffected following strength training (Beck et al.
2007; Del Balso and Cafarelli 2007; Figure 7.7).
Figure 7.7. Effect of strength training on H-reflexes (Adapted from Siddique et al.
2020).
Increases in V-wave amplitude following strength training have been

frequently cited as evidence of increased motoneuron activation. There has
also been an inclination to attribute increases in motoneuron activation as
an adaptation that occurs at a supraspinal level, particularly when V-wave
changes are observed in parallel with H-reflexes (Aagaard et al. 2002).
While an increase in neural drive to motoneurons is a plausible explanation
for increased V-wave amplitudes, there are numerous alternative
possibilities that should not be discounted (i.e., changes in the excitability
of intrinsic neuronal circuits of the M1). Irrespective of this, there is
evidence to suggest that strength training increases motoneuron activation
by multiple mechanisms associated with increased descending neural drive
(Figure 7.8; Siddique et al. 2020).
122 Chapter 7
Figure 7.8. Effect of strength training on V-wave amplitude (Adapted from

Siddique et al. 2020).
7.12 Changes in motor unit activity following strength

training
The basic function of a motor unit is to transform synaptic input received
by the motoneurons into mechanical output activity by skeletal muscle. It is
not uncommon to measure the strength of a muscle as the peak force
achieved during a maximal voluntary contraction. Any changes in MVC
following a strength training intervention could be as a result of adaptations
in the activation of the involved motor units. In studying the neural effects
of strength training on motor unit activity, a common approach is to assess
the maximum strength of a contraction using sEMG. The amplitude of the
sEMG signal is inferred as a measure of motor-unit recruitment and firing
rate (rate coding), with increases in sEMG amplitude and rate coding being
an indication of neural adaptation to strength training. For several decades,
many studies have reported increased sEMG amplitudes during maximum
force production in untrained individuals (Hakkinen and Komi 1983;
Häkkinen et al. 1993; Aagaard et al. 2002; Duchateau et al. 2006). Several
lines of evidence also show that strength training increases the rate of rise
of EMG amplitude (or average EMG) over the initial period of force
production during ballistic contractions (Van Cutsem et al. 1998; Patten and
Kamen 2000; Patten et al. 2001; Kamen and Knight 2004), suggesting
increased neural drive and rate of force development (Aagaard et al. 2002).
However, because there are significant limitations with the sEMG technique,
it is likely that other central mechanisms account for the increases in EMG
amplitude following strength training (Farina et al. 2014; Del Vecchio et al.
2019). One approach to overcome this limitation is to record single motor
unit behaviour with indwelling EMG.
7.12.1 Single motor unit behaviour following strength training

Single motor unit behaviour can be recorded by using a fine-wire electrode
that is inserted into the muscle of interest. The fine-wire electrode can
record the discharge of identifiable single motor units because the fine wire
is inserted in only a few muscle fibres. Therefore, it is able to provide
information on the discharge characteristics of motoneurons in the spinal
cord due to transmission of each action potential to the muscle being
innervated. However, similar to sEMG, there are technical difficulties
associated with single motor unit recordings but, despite this, there is good
evidence to show that strength training alters the behaviour of single motor
units. For example, Kamen and Knight (2004) reported a 33% increase in
force production following six weeks of strength training the knee extensor.
They reported increased motor unit discharge rates in both young (by 15%)
and older adults (by 49%). This finding was also supported by Van Cutsem
et al. (1988) following 12 weeks of ballistic strength training of the tibialis
anterior. In this study, rate of force development and sEMG increased,
which were associated with increases in the instantaneous discharge rate for
the first four action potentials in single motor units. Although the
recruitment order of motor units remained unchanged following training,
the average instantaneous discharge rate increased from 69 to 96 pulses per
second with training. Furthermore, strength training caused a significant
increase in the number of motor units (from 5 to 33%) that discharged with
brief interspike intervals (<5 ms). Thus, the increase in the rate of force
development appears to have been achieved by an adaptation in motor unit
discharge rate.
Figure 7.9. Motor unit discharge rates are shown for young and older adults after
two baseline tests (1 week apart) and 6 weeks of strength training in young adults.
Data presented is the motor unit discharge rate obtained during an MVC at day 1, 8,
22 and 50 of training.
124 Chapter 7
7.12.2 Motor unit synchronization following strength training

Over the last three decades, discussions on the neural adaptations to training
have inevitably included a role for motor unit synchronization in the rapid
gains in strength during the first few weeks of a strength-training program
(Milner-Brown et al. 1975). The rationale for this is based upon the seminal
study by Milner-Brown et al. (1975) who provided indirect evidence from
the sEMG showing that strength training of a hand muscle enhances motor
unit synchronization. However, it has been shown that the indirect method
of estimating synchronization from the surface EMG has several limitations
which restricts its usefulness as an index of synchronization during
voluntary contractions in humans (Yue et al. 1995). Although a change in
motor unit synchronization is regarded as one of the most significant
adaptations that occur in the nervous system in response to training, the use
of the sEMG index by Milner-Brown et al. (1975) casts some doubt on the
conclusions drawn from their data (Kidgell et al. 2006).
The most direct method to quantify motor unit synchronization in humans

is by the cross-correlation of individual discharge times from pairs of
concurrently active motor units, where the discharge times of one motor
unit are used as a reference and a histogram is constructed of the peri-event
discharge times of the other motor unit. If a tendency towards
synchronization exists, there will be a peak in the cross-correlation
histogram around the time of firing of the reference motor unit that arises
from common inputs from branched axons of single last-order neurons that
increase the probability of simultaneous discharge in the motor units sharing
these inputs. Because of the tedious nature of recording motor unit
synchronization, very few studies have examined the effect of strength
training on motor unit synchrony. However, a recent study found that
significant strength gains after four weeks of training were not accompanied
by increases in synchronization between pairs of concurrently active motor
units in an intrinsic hand muscle (Kidgell et al. 2006).
This finding is consistent with computer simulation studies which show that
the degree of synchronization does not influence the maximum amount of
force a muscle can produce. Therefore, the overall conclusion suggests that
a change in motor unit synchronization is not a central mechanism that
increases the force generating capacity of a muscle.
Figure 7.10. Maximal voluntary contraction force (right) and strength of motor unit
synchronisation (left) measured before and after strength training. Data show a 54%
increase in index finger abduction force and a 20% reduction in mean strength of
motor unit synchronisation following four-weeks of strength training (Adapted from
Kidgell et al. 2006).
7.13 Summary
There are several experimental techniques that can be used to assess the
acute and long-term neural responses to strength training. The neuromuscular
system controls force production through an intricate and complex system
that has many levels of control (cortico-cortical, corticospinal, spinal, etc.).
Each element of this system is capable of increasing (i.e., facilitating) or
decreasing (i.e., inhibiting) force output, but is dependent on whether the
strength training is acute or long-term. Performing a single session of
strength training will challenge various elements of the nervous system
leading to acute modifications in the ability of the system to recruit motor
units and increase their firing rate. However, as this chapter highlights, there
is still work to be done in order to fully understand which parts of the
nervous system are modified during a single strength training session and
which parts adapt during longer-term training. At present, there seems to be
an initial increase in the excitability of the nervous system that is then, over
time, taken over by a reduction in inhibition, with both facilitation and
inhibition being neural responses that increase motor unit recruitment and
force output. However, the overall conclusion would suggest that strength
training affects multiple components of the neuroaxis from the cerebral
cortex to the recruitment and activation of motor units.
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CHAPTER 8
NEUROMUSCULAR RESPONSES
TO FATIGUING LOCOMOTOR EXERCISE
CALLUM BROWNSTEIN, PHD

AND KEVIN THOMAS, PHD
8. Background
In sport and exercise, the ability of the muscle to exert force is imperative
to successful performance. During high-intensity or prolonged exercise, the
force generating capacity of the muscle is progressively reduced. This
reduction in muscle force during exercise is an integral contributor to
fatigue, defined as a sensation of tiredness and weakness which is
underpinned by a myriad of physiological and psychological processes
(Brownstein et al. 2017). In turn, impairments in neuromuscular function
are responsible for declines in the force generating capacity of the muscle,
and thus have a negative impact on performance and injury risk.
Consequently, understanding the neuromuscular responses to fatiguing
exercise and the factors contributing towards declines in muscle force is a
pertinent area of research.
Impairments in the force generating capacity of the muscle can potentially

occur at any step along the neuromuscular pathway, from brain to muscle
(Figure 8.1). Most commonly, maximum voluntary contractions (MVCs)
are measured during isometric contractions to assess alterations in muscle
function during and/or following exercise (Thomas et al. 2015; Tomazin et
al. 2017; Temesi et al. 2014). Using neurostimulation techniques, including
electrical nerve and transcranial magnetic stimulation (TMS), it is possible
to differentiate between the peripheral and central contributors to
impairments in neuromuscular function and muscle force generating
capacity during exercise. Peripheral contributors to reductions in muscle
force involve perturbations at sites at or distal to the neuromuscular junction
and can be assessed by measuring involuntary evoked responses to
134 Chapter 8
electrical stimulation at rest. Central contributors to fatigue involve

processes occurring proximal to the neuromuscular junction, resulting in an
impairment in the capacity of the central nervous system (CNS) to
voluntarily activate the muscle, and can be examined through evoked
responses to electrical and magnetic stimulation during voluntary
contractions. While these techniques permit the assessment of neuromuscular
function at a segmented level, it should be noted that the peripheral and
central contributors to impairments in neuromuscular function are not
mutually exclusive. Indeed, changes occurring within the muscle influence
the activation signal discharged by motoneurons during voluntary
contractions, while sensory feedback transmitted from the muscle by group
III/IV afferents travel to various sites within the CNS, and can influence the
integration of synaptic input by spinal motoneurons and contribute to
perceptions of pain during exercise (Enoka and Duchateau, 2016).
Nevertheless, these neurostimulatory techniques have advanced knowledge
on the aetiology of fatigue and the neuromuscular responses to exercise.
Figure 8.1. The chain of command involved in voluntary force production.

Impairments in the force generating capacity of the muscle can potentially occur at
any step along the brain-to-muscle pathway. Adapted from Hunter (2018).
Neuromuscular Responses to Fatiguing Locomotor Exercise 135
A common approach when studying neuromuscular responses to fatiguing

exercise is to assess changes in neuromuscular function using electrical and
magnetic stimulation during fatiguing single-limb, isometric exercise
protocols, such as sustaining a given level of submaximal force for as long
as possible (Taylor et al. 2006; Kennedy et al. 2016). This approach is
convenient because participants are not required to manoeuvre between the
designated apparatus for the fatiguing task (i.e., the equipment used to
measure isometric force) and the neuromuscular assessment, thus
permitting the immediate assessment of neuromuscular function during
and/or immediately following fatiguing protocols. These studies have
demonstrated that the aetiology of impairments in neuromuscular function
is dependent on the intensity, duration and the nature of the task (i.e.,
intermittent or sustained) (Gandevia, 2001). While studies using isometric
protocols have furthered scientific understanding on the aetiology of fatigue,
the “real-world” applicability of the findings from these studies is
questionable due to the lack of ecological validity. That is, the type of
exercise being performed differs substantially from that performed in a
sport and exercise environment, where dynamic, locomotor exercise is
performed with multiple limbs, and the systemic and local responses are
considerably different to that of isometric exercise. Given the well-
established importance of task dependency in determining the aetiology of
exercise-induced fatigue (Enoka, 1995), it is inappropriate to extrapolate
the findings concerning the neuromuscular responses to fatiguing exercise
from isometric to locomotor tasks. As such, an increasing number of studies
have documented neuromuscular responses to locomotor exercise of
varying intensities, durations and modes, both during and in the recovery
period following exercise. This chapter will provide a summary of current
literature concerning the neuromuscular responses to fatiguing locomotor
exercise.
8.1 The role of exercise intensity and duration on

neuromuscular responses to fatiguing exercise
Research has demonstrated that the intensity and duration of locomotor
exercise have a profound influence on the aetiology of impairments in
neuromuscular function (Thomas et al. 2016; Thomas et al. 2015; Black et
al. 2017). Exercise intensity during locomotor exercise can be categorised
into distinct domains demarcated by physiological thresholds. Specifically,
four intensity domains have so far been established: moderate (power output
below lactate threshold, defined as the intensity at which lactate production
exceeds its clearance); heavy (power output between lactate threshold and
136 Chapter 8
critical power, defined as the asymptote of the relationship between power

and time, and the maximum sustainable exercise intensity); severe (power
output above critical power than can be sustained until VO2max is reached);
and extreme (supra-severe intensity in which exercise intensity is such that
VO2max cannot be reached before exhaustion) (Burnley et al. 2012). Each
intensity domain is characterised by differences in VO2 kinetics, muscle
metabolic and blood acid-base responses (Jones et al. 2008). In turn, the
exercise intensity domain and the distinct physiological responses are
proposed to influence the mechanisms responsible for impairments in
neuromuscular function.
8.2 Neuromuscular responses to “all-out” exercise

Short-duration, high-intensity exercise (30-60 s), in which there is
maximum effort and a considerable decrease in performance, is referred to
as ‘all-out’ exercise (Bishop, 2012). This form of exercise is commonplace
during high-intensity and sprint interval training, which is regularly
implemented as a means of improving health (Whyte et al. 2010) and sports
performance (Gibala et al. 2006), as well as the Wingate and athletic events
such as 400 m track running. Despite the relatively brief nature of this mode
of exercise, there is a substantial and progressive decrease in the force
generating capacity of the muscle. Following a 30 s all-out cycle sprint,
Fernandez-del-Olmo et al. (2013) demonstrated a 16% reduction in
isometric MVC strength of the knee extensors. It is widely believed that the
decrease in performance during this form of exercise is due to perturbations
occurring within the muscle. Indeed, following 30 s all-out cycling exercise,
a 36% reduction in the maximal evoked resting twitch response was
demonstrated, indicating the presence of considerable impairments within
the contractile machinery (Fernandez-del-Olmo et al. 2013). The substantial
reduction in the ability of the muscle to produce force in response to neural
input during all-out exercise is likely due to the high rate of energy
liberation and considerable perturbations to peripheral homeostasis.
Specifically, limitations in energy liberation and an accumulation of
metabolites which impair excitation-contraction coupling are thought to be
the primary causes of impaired muscle function during all-out exercise
(Green, 1997; Allen et al. 2008). In regards to energy supply, phosphocreatine
(PCr), the primary energy source during maximal-intensity exercise, is
rapidly depleted from exercise onset, and has been reported to be
approximately 35-55% of resting values following 6 s of maximal sprint
cycling exercise (Gaitanos et al. 1993; Dawson et al. 1997). Furthermore,
the accumulation of inorganic phosphate (Pi) and H+ ions occurring due to
the creatine kinase reaction and anaerobic glycolysis, respectively, could

interfere with the excitation-contraction coupling process and/or the ability
to derive ATP from glycolysis (Allen et al. 2008; Bishop, 2012). Thus,
perturbations to metabolism within the muscle are likely the main cause of
fatigue during all-out exercise.
Discrepancies exist in the literature in regard to the effect of maximal

intensity exercise on voluntary activation. For example, following two 30 s
all-out sprint cycles, Fernandez-del-Olma (2013) found a 34% reduction in
voluntary activation, whereas Kruger et al. (2019) found no reduction in
voluntary activation following a similar exercise task. Studies assessing
neuromuscular responses to intermittent maximal intensity exercise, such
as repeated running (Goodall et al. 2015) or cycle sprints (Hureau et al.
2016), have demonstrated post-exercise reductions in voluntary activation
of around 10% (Figure 8.2).
The mechanisms which contribute to impaired voluntary activation

throughout maximal intensity exercise are unclear, but could be related to
an increase in inhibitory afferent feedback from group III and IV afferents,
which are sensitive to metabolites associated with high-intensity exercise
(e.g., H+ and extracellular K+). Indeed, group III and IV afferents ascend to
multiple areas within the motor pathway at both the motor cortical and
spinal level, and are known to exert an inhibitory influence at the motor
cortical cells and spinal motoneurons (Gandevia, 2001).
Concurrent with measures of voluntary activation following maximal

intensity exercise, studies have utilised TMS in order to assess the
responsiveness of the corticospinal pathway which represents the primary
conduit of human movement (Weavil and Amann, 2018). Specifically,
TMS delivered over the motor cortex pre- and post-exercise can determine
the effect of exercise on the excitability of the motor pathway through
changes in the amplitude of the motor evoked potential (MEP). Following
intermittent cycling (Girard et al. 2013) and running sprints (Goodall et al.
2015), no changes in MEP amplitude were found. While these findings
suggest that the responsiveness of neurons involved in motor cortical output
is not altered during short duration, maximal intensity exercise, the MEP
amplitude can be altered as a consequence of changes at both the motor
cortical and motoneuronal level. For example, an increase in spinal
excitability could mask or offset any decrease in supraspinal excitability
that occurs throughout maximal intensity exercise. By delivering electrical
stimulations at the spinal level concurrent with TMS, it is possible to
examine the excitability of the motor pathway at the motor cortical and
138 Chapter 8
motoneuronal level. Using

these techniques following
repeated arm sprint cycling,
Pearcy et al. (2016) found
that supraspinal excitability
was decreased, while spinal
excitability, assessed through
the cervicomedullary evoked
potential (CMEP), was
increased. The mechanisms
responsible for these
adjustments in the motor
pathway in response to
maximal intensity exercise
are unclear and warrant
further investigation.
Decreases in the excitability
of neurons at the supraspinal
level could be due to
perturbations in the activity
of intracortical inhibitory and
facilitatory interneurons
which regulate motor cortical
neurons involved in motor
output (Kennedy et al. 2016),
or alterations in afferent
feedback in response to
exercise (Blain et al. 2016).
At the spinal level, the
increase in motoneuron
excitability could be due to a
Figure 8.2. Neuromuscular responses to
number of mechanisms, such
repeated sprint exercise measured during and
as a decrease in voltage after 12 × 30 m sprints with 30 s recovery.
threshold for action potential,
activation of persistent inward currents, or activation of the monoaminergic
system during exercise which can influence motoneuron excitability (Pearcey
et al. 2016). Thus, while reductions in muscle force during all-out exercise
are primarily a result of perturbations within the muscle, it is evident that
this form of exercise might exert an influence on the motor pathway at both
the supraspinal and spinal level.
8.3 Neuromuscular responses to severe intensity,

short-duration exercise
Many sporting activities are characterised by short-duration, high-intensity
locomotor exercise, such as middle-distance running (i.e., 800-5000 m) or
track cycling events lasting ~2-20 mins. The exercise intensity associated
with these events falls within the ‘severe’ domain, i.e., above the maximum
sustainable exercise intensity, known as ‘critical power’. Exercise in the
severe domain is associated with a progressive loss of muscle homeostasis,
such as a reduction in PCr and pH, and an increase in Pi (Black et al. 2017).
These disturbances occurring at the peripheral level impair the capacity of
the muscle to produce force in response to neural stimulation. Evidence
suggests that disturbances within the muscle are the primary contributor to
impairments in muscle force during severe-intensity exercise (Temesi et al.
2017; Thomas et al. 2015; Thomas et al. 2016). For example, Thomas et al.
(2016) had participants perform constant-load cycling within the heavy and
severe exercise intensity domains. The results showed that contractile
impairments were greater in response to severe intensity exercise, with a
higher reduction in evoked twitch force at intensities within the severe
domain compared with the heavy domain. These results corroborated the
findings from a previous study conducted by the same group which
demonstrated that impairments in contractile function were more evident
during short-duration, self-paced cycling time-trials (4 km) compared with
longer durations (20 and 40 km) (Thomas et al. 2015). Similarly, Black et
al. (2017) assessed the metabolic and neuromuscular responses to constant-
load cycling in the moderate, heavy and severe intensity domains until task
failure. Exercise within the severe intensity domain was associated with
substantial perturbations to metabolic homeostasis, such as an increase in
Pi and plasma K+ concentration, and a decrease in muscle pH and ATP, with
a concomitant reduction in M-wave amplitude indicative of a decrease in
muscle excitability. These metabolic perturbations were greater than those
observed during heavy or moderate intensity exercise.
Impairments in voluntary activation are also evident during high-intensity

short-duration exercise, though the decrease appears to be modest. For
example, following short-duration cycling in the severe domain at the
power associated with VO2max, in which the limit of tolerance was reached
after ~3 mins, Thomas et al. (2016) reported a 3% reduction in voluntary
activation, with similar reductions following severe intensity exercise to
exhaustion, albeit with a longer exercise duration (~7 mins) (Weavil et al.
2016). Studies assessing motor cortical and motoneuronal excitability
140 Chapter 8
during and following this form of exercise have frequently displayed no

change in either variable in response to severe-intensity exercise. While
these findings could suggest that severe-intensity exercise does not alter
motor cortical or motoneuronal excitability, there are caveats to this
conclusion. For example, during severe-intensity exercise, there is a
progressive increase in motor unit recruitment, likely as a compensatory
mechanism to maintain force production despite impairments in the muscles’
capacity to produce force (Lepers et al. 2002). An increase in motor unit
recruitment, as demonstrated through an increase in EMG activity, is known
to increase corticospinal excitability during non-fatiguing exercise (Weavil
et al. 2015). Thus, the lack of increase in corticospinal excitability, despite
the increase in EMG activity, could suggest a disfacilitation or inhibitory
influence of severe-intensity exercise on the corticospinal pathway. This
was aptly displayed by Weavil et al. (2016) who compared corticospinal
(MEP), motoneuronal (CMEP) and cortical excitability (MEP/CMEP ratio)
during fatiguing and non-fatiguing cycling with a similar increase in EMG
activity. Their study demonstrated no change in motor cortical or
motoneuronal excitability during fatiguing cycling exercise and an increase
in corticospinal and motoneuronal excitability during non-fatiguing cycling.
Specifically, during the fatiguing task, there was no change in MEPs,
CMEPs, or the MEP/CMEP ratio, whereas the non-fatiguing cycling
resulted in a ~40% increase in both MEP and CMEP, thus causing no
change in the MEP/CMEP ratio. This indicates that the increase in motor
unit recruitment during the non-fatiguing task increased motoneuron
excitability, and that this increase in motoneuron excitability was supressed
during the fatiguing task. It was suggested that the decreased excitability of
the motoneuron pool during fatigue could be due to alterations in
motoneuronal membrane potential, activation of extrasynaptic serotonin
receptors, or insufficient release or depletion of neurotransmitters as a
consequence of repetitive activation (Weavil et al. 2016). Nevertheless,
while recent studies suggest a greater effect of severe-intensity exercise on
the CNS than had been previously thought, the modest decrease in voluntary
activation and large decrease in resting twitch force indicate that
impairments in contractile function are the primary culprits causing
reductions in muscle force during high-intensity exercise.
8.4 Neuromuscular responses to sustained exercise below

critical power
Exercise between lactate threshold and critical power is classified as heavy-
intensity exercise, while exercise below lactate threshold is termed
moderate intensity (Burnley et al. 2012; Black et al. 2017). At these
intensities, perturbations in muscle metabolism are much more limited than
with exercise in the severe domain, with steady-state values of PCr, pH and
Pi achieved within the first few minutes of exercise (Black et al. 2017).
Consequently, the contribution of impairments in contractile function
towards decreases in the force generating capacity of the muscle is reduced,
though not abolished. For example, during self-paced exercise, Thomas et
al. (2015) showed that the reduction in evoked twitch force was less
following 40 km (29%) and 20 km (31%) time-trials compared with a 4 km
(40%) time-trial. Thus, during lower intensity, longer duration locomotor
exercise, impairments in contractile function occur without significant
metabolic disturbance. The mechanisms, which might contribute to
impaired contractile function following moderate- or heavy-intensity
exercise, include glycogen depletion and increased production of reactive
oxygen and nitrogen species, both of which impair the release of Ca2+ within
the muscle in response to neural input, and thereby inhibit the excitation-
contraction coupling process (Cheng et al. 2017). These events likely occur
within lower threshold motor units that are recruited during the exercise task
(Allen et al. 2008).
In both studies by Thomas et al. during self-paced (2015) and fixed-intensity

exercise (2016), the reduction in MVC was similar post-exercise
irrespective of the intensity or duration; despite this fact, the reductions in
evoked twitch force were less after more prolonged, lower-intensity
exercise. This suggests that reductions in the capacity of the CNS to activate
the muscle play an increasingly important role as exercise duration
progresses. Indeed, during fixed-intensity cycling, the reduction in
voluntary activation measured through motor nerve stimulation following
exercise to exhaustion in the heavy-intensity domain was greater (9%)
compared with exercise to exhaustion in the upper severe-intensity domain,
where the decrease in voluntary activation was modest (3%) (Thomas et al.
2016). Similarly, the reduction in voluntary activation was greater
following 20 km (11%) and 40 km (10%) time-trial cycling compared with
4 km (7%; Figure 8.3) (Thomas et al. 2015). The findings that reductions in
voluntary activation are more pronounced during longer-duration exercise
142 Chapter 8
is in line with findings from studies utilising prolonged isometric

contractions (Enoka, 1995).
Studies examining the neuromuscular responses to very long duration

exercise, such as marathon and ultra-endurance events, have provided
further evidence for the importance of impairments in voluntary activation
in contributing towards reductions in muscle force. For example, Ross et al.
(2007) investigated neuromuscular responses in the tibialis anterior muscle
in response to marathon running, reporting a 14% reduction in voluntary
activation when assessed post-exercise. Moreover, following an extreme
mountain ultra-marathon lasting 166 km, Millet et al. (2011) reported a 19%
reduction in knee extensor voluntary activation. Investigations into the
time-course and kinetics of voluntary activation during prolonged fatiguing
exercise suggest that impairments in voluntary activation manifest towards
the end of the exercise bout. Place et al. (2004) investigated the effects of 5
h of treadmill running at 55% of maximum aerobic speed on neuromuscular
function, with measurements taken at 1 h intervals. It was demonstrated that
reductions in voluntary activation occurred only towards the end of the
exercise bout, with a 12% reduction following 4 h of running and 16%
reduction following 5 h. Similar results have been found following
prolonged cycling exercise (i.e., 4 h), with statistically significant
reductions in VA manifesting only after 5 h of exercise (Lepers et al. 2002).
The impact of prolonged exercise on the excitability of the motor pathway

is unclear. When measured with the muscle at rest, studies have
demonstrated reductions in MEP amplitude following prolonged exercise
ranging from 20 km cycling (Thomas et al. 2015), marathon running (Ross
et al. 2007), and a simulated Tour de France (Ross et al. 2010). However,
changes in MEP amplitude at rest may not reflect alterations in corticospinal
excitability that occur during contractions. When corticospinal excitability
has been assessed pre- and post-prolonged exercise during isometric
contractions, conflicting findings exist, with studies reporting an increase
(Temesi et al. 2014), decrease (Ross et al. 2007; Ross et al. 2010), or no
change in MEP amplitude (Thomas et al. 2015; Thomas et al. 2016; Hollge
et al. 1997).
Figure 8.3. Pre-to-post changes in MVC (A), potentiated twitch force (B), and
voluntary activation measured with electrical nerve (C) and TMS (D) following 4
km, 20 km and 40 km cycling time-trials. From Thomas et al. (2015).
These conflicting findings could be the result of the substantial

heterogeneity in the exercise challenges, such as the modalities and the
duration of the task, as well as methodological differences such as
stimulation intensities and the contraction intensities at which corticospinal
144 Chapter 8
excitability is measured, both of which can influence the change in MEP in

response to exercise (Temesi et al. 2014; Aboodarda et al. 2019). Further
work is required to elucidate the effects of prolonged exercise within the
moderate- and heavy-exercise domains on the corticospinal pathway at both
the supraspinal and spinal level. In summary, it is evident that the
mechanisms underpinning impairments in neuromuscular function and
voluntary force production after continuous exercise are intensity- and
duration-dependent, with impairments in the capacity of the CNS to activate
the muscle becoming more apparent during prolonged fatiguing exercise
compared with severe-intensity exercise.
8.5 Neuromuscular responses to high-intensity

intermittent exercise
While an increasing number of studies have assessed neuromuscular
responses to continuous locomotor exercise during tasks such as cycling
and running, many team sports, such as association football (soccer), rugby
league, and hockey, are characterised by bouts of high-intensity exercise
interspersed with prolonged periods of low-to-moderate intensity activity.
In addition, team-sport players also complete numerous explosive actions
throughout competitive matches, such as jumping, changing direction,
tackling and kicking, which are often performed with incomplete recovery.
Consequently, high-intensity intermittent team sports are associated with a
high physiological and neuromuscular demand, resulting in substantial
fatigue and impairments in neuromuscular function (Goodall et al. 2017b).
During team sports such as soccer and hockey, fatigue manifests through
transient reductions in work-rate following the most demanding periods of
a match, and cumulative reductions in work-rate towards the end of a match
(Mohr et al. 2005). In addition, fatigue is thought to increase the risk of
sustaining an injury during match-play, with players more susceptible to
sustaining injuries towards the later stages of a match (Ekstrand et al. 2011).
In order to better understand the physiology underpinning the symptom of
fatigue experienced during match-play, studies have examined the
neuromuscular responses to simulated and competitive high-intensity
intermittent team sport activity.
Using a simulated soccer-match protocol designed to replicate the physiological

demands of soccer match-play, Goodall et al. (2017b) investigated
neuromuscular function before, at half-time (i.e., 45 mins), full-time (i.e.,
90 mins) and following a period of extra time (i.e., 120 mins). An interesting
finding from this study was that, while the simulated soccer match induced
reductions in MVC and impairments in both contractile function and

voluntary activation (measuring using the neurostimulation techniques
described previously), the reduction in contractile function demonstrated a
plateau after half-time (Figure 8.4).
Figure 8.4. Maximum voluntary contraction (a), potentiated knee-extensor twitch

force (b) and voluntary activation measured with motor nerve (VA, white dot
symbol), and motor cortical (TMSVA) stimulation (c) at pre-exercise, half time (HT),
full time (FT), and following extra time (ET) of a simulated soccer match. From
Goodall et al. (2017b).
It was hypothesised that this plateau was due to the early fatigue of higher-
threshold motor units, which are more susceptible to fatigue, within the first
half. In the second half, the lower reduction in contractile function was
suggested to be a result of the recruitment of more fatigue-resistant motor
units, which exert a smaller reduction in the size of evoked twitch responses.
In contrast to the nadir in contractile function, impairments in voluntary
activation increased progressively, with a voluntary activation lower at half-
time compared with pre-match, and lower at the end of extra-time compared
with half-time. These impairments in neuromuscular function were
concurrent with increases in perceptions of effort and impairments in
146 Chapter 8
voluntary physical performance (sprint speed and jump height) measured in

a companion study (Harper et al. 2016). Following competitive match-play,
studies have similarly demonstrated substantial impairments in contractile
function and voluntary activation (Rampinini et al. 2011; Brownstein et al.
2017), resulting in a 11-14% reduction in knee extensor MVC, concurrent
with decreases in jump height, reactive strength and sprint speed
(Brownstein et al. 2017). The limited number of studies examining
corticospinal and intracortical responses following simulated (Thomas et al.
2017) and competitive match-play (Brownstein et al. 2017) have shown no
changes post-exercise, though further research is required to assess the
effect of high-intensity intermittent exercise on motoneuronal excitability.
Thus, during prolonged high-intensity intermittent exercise such as soccer
match-play, neuromuscular function is impaired both at the peripheral and
central level, with peripheral perturbations appearing to be more prevalent
in the earlier stages of exercise, and impairments in voluntary activation
more apparent as exercise progresses. These disruptions in neuromuscular
function likely contribute to the decline in physical performance known to
occur following the most-demanding periods of match-play and towards the
end of a match.
8.6 The effect of exercise modality on neuromuscular

responses to locomotor exercise
One of the central themes surrounding research into the neuromuscular
responses to fatiguing exercise is task dependency. In addition to the
influence of exercise intensity and duration discussed earlier, exercise
modality, or the type of locomotor exercise being performed, can have a
profound influence on the demands placed on the neuromuscular system.
Exercise modality can influence the contraction type in the prime movers
involved in locomotor exercise, as well as contraction duration or time
under tension, the active skeletal muscle mass, mechanical efficiency and
muscle recruitment strategy. All of these factors can in turn influence the
metabolic and mechanical stress imposed on the muscle and the
mechanisms underpinning decrements in neuromuscular function during
exercise.
While several different modes of locomotor exercise exist (e.g., running,

cycling, rowing, skiing), systematic comparisons delineating the neuromuscular
responses to different exercise modes are scarce. However, studies by
Lepers et al. (2002) and Place et al. (2004) assessed the neuromuscular
responses to cycling and running exercise, respectively, at the same relative
intensity (55% maximal aerobic power or velocity) and duration (5 h).

Comparisons between the results of those studies show that, despite the
similar exercise intensity and duration, the reduction in knee extensor
strength was greater following running (28%) compared with cycling
exercise (18%). The greater reduction in MVC was likely due to the greater
reduction in voluntary activation following running (16%) compared with
cycling (8%). In a study directly comparing cycling and running exercise,
Tomazin et al. (2017) had participants perform three sets of 5 × 6 s repeated
sprints with the sprints performed on a treadmill and a cycle ergometer. The
study found that the reduction in MVC was greater during and following
running sprints compared with cycling. In addition, the reduction in MVC
was accompanied by a reduction in VA throughout the running protocol
which was not seen during cycling. Following ~3 h of running (Millet et al.
2003a) and skiing exercise (Millet et al. 2003b), a significant reduction in
voluntary activation (8%) was only observed following running-based
exercise. Thus, it appears that perturbations to central nervous system
function and consequent impairments in muscle strength are greater
following running-based exercise compared with other locomotor exercise
modes. This is likely a result of the muscle damage associated with running-
based exercise, and the lower mechanical demands imposed during exercise
such as cycling and skiing. Specifically, running-based exercise involves
multiple stretch shortening cycles and associated eccentric contractions
likely to elicit considerable muscle damage, whereas cycling- and skiing-
based exercise impose a high metabolic stress but a substantially lower
mechanical stress. Furthermore, muscle damage elicited by eccentric
exercise protocols has been shown to elicit substantial impairments in
voluntary activation which can persist for several days post-exercise
(Goodall et al. 2017a), further suggesting that muscle damage sustained
during running-based exercise contributes to the greater reduction in
voluntary activation compared with cycling.
At the peripheral level, studies have reported a greater reduction in

contractile function during and following cycling compared with running
(Rampinini et al. 2016; Lepers et al. 2002; Place et al. 2004). For example,
following 5 × 6 s cycling and running sprints, Rampinini et al. (2016)
demonstrated a significantly greater reduction in knee extensor peak twitch
force following cycling (~55% reduction) compared with running (~35%).
Similarly, Lepers et al. (2002) reported a significant reduction in knee
extensor peak twitch during every hour throughout 5 h of cycling, whereas
Place et al. (2004) showed no change in quadriceps contractile properties
throughout 5 h of running exercise. The higher perturbations at the
peripheral level in response to cycling could be a consequence of the
148 Chapter 8
differences in the involved muscle mass. For example, during weight-

supported sports such as cycling, the overall active muscle mass involved
is lower than during running. It has been demonstrated throughout the
literature that, during tasks involving lower active muscle mass, the
reduction in twitch force is higher (Rossman et al. 2014; Rossman et al.
2012). This is likely because, during tasks involving a higher muscle mass,
there is a greater sensory input (e.g., from group III/IV afferents) from the
involved muscle mass, as well as a greater disruption to homeostasis in
other physiological systems (e.g., cardiovascular, respiratory) (Thomas et
al. 2018). Consequently, there is a greater contribution to fatigue and the
limit of tolerance from multiple physiological systems, whereas during
cycling the more local, less diffuse signal from the lower muscle mass
permits a greater level of perturbation within the muscle to be tolerated
(Thomas et al. 2018).
The perturbations within the neuromuscular system elicited by fatiguing

exercise can persist for prolonged periods following exercise cessation.
Much like the neuromuscular alterations which occur during exercise, the
magnitude, aetiology, and time-course of recovery of post-exercise
impairments in neuromuscular function are dependent on the intensity,
duration and mode of exercise. While few studies have attempted to
document the aetiology of fatigue and time-course of recovery as a function
of exercise intensity and/or duration (Carroll et al. 2017), a number of
studies have assessed recovery of maximal isometric force generating
capacity, voluntary activation, and/or contractile function following various
locomotor exercise challenges (Blain et al. 2016; Brownstein et al. 2017;
Ross et al. 2010). As such, some conclusions can be drawn on recovery of
neuromuscular function following different intensities, durations and
modes of locomotor exercise.
8.7 Effect of exercise duration and intensity on recovery

Following short-duration, high-intensity exercise, in which muscle function
is primarily limited by metabolic perturbations, there is a rapid initial
recovery due to clearance of intramuscular metabolites (i.e., Pi and H+)
(Allen et al. 2008, Hureau et al. 2016). For example, following high-
intensity dynamic knee extension (~6 mins) and cycling exercise (10 × 10 s
sprints), respectively, Froyd et al. (2013) and Hureau et al. (2016) found
rapid initial recovery of MVC force and Qtwpot within the first two minutes
of exercise cessation. However, both of these studies found incomplete
restoration of contractile function following six (Hureau et al. 2016) and
eight (Froyd et al. 2013) minutes of recovery, likely due to prolonged

impairments in Ca2+ handling (Allen et al. 2008; Edwards et al. 1977).
Following longer duration exercise, impairments in neuromuscular function
can persist for more prolonged periods (Sidhu et al. 2009; Booth et al. 1997).
For example, following prolonged cycling exercise at 75% VO2peak until
exhaustion (72 ± 4 mins), Booth et al. (1997) found that reductions in MVC
and evoked twitch force in the quadriceps persisted following 20 minutes
of recovery, and took 60 minutes to return to baseline. Following eight, five
minute bouts of cycling exercise at 80% of maximum workload, Sidhu et al.
(2009) found a 23% reduction in MVC and 10% reduction in voluntary
activation, which remained 12% and 10% below baseline following 45
minutes of recovery, respectively. Furthermore, the delayed recovery
following more prolonged cycling exercise was recently displayed by
Kruger et al. (2019) who compared a 30 s all-out maximal cycling test
(Wingate), 10 min severe-intensity exercise, and 90 min moderate-intensity
exercise. The study showed a slower recovery of knee extensor MVC and
peak twitch forces in response to paired electrical stimuli following 90 min
moderate-intensity exercise compared to the all-out and severe-intensity
trials. Thus, following locomotor exercise with a high metabolic demand,
such as cycling exercise, recovery is rapid following short-duration, high-
intensity tasks, likely due to the negligible impairments in voluntary
activation and the rapid dissipation of metabolic disturbances that
contribute to impaired contractile function throughout exercise. Following
more prolonged cycling exercise, recovery is delayed due to persistent
reductions in the capacity of the nervous system to activate the muscle and
prolonged disturbances within the contractile machinery, likely related to
altered Ca2+ handling (Allen et al. 2008).
Recovery of neuromuscular function is further complicated following

running-based exercise, which involves repetitious stretch-shortening
cycles (SSCs). The eccentric contractions involved in SSCs produce muscle
damage, which is known to interfere with neuromuscular function at both
the peripheral and central level, and can take several days to recover
(Goodall et al. 2017a). Following high-intensity intermittent team-sport
exercise, which involves numerous eccentric actions such as jumping and
landing, forceful decelerations, as well as player to player contacts, recovery
of neuromuscular function is delayed for several days post-exercise.
150 Chapter 8
Figure 8.5. Maximal voluntary contraction (A), voluntary activation measured with
electrical nerve (B) and TMS (C), and quadriceps potentiated twitch force (D)
measured pre-, post- and at 24, 48, and 72 h post- competitive soccer match-play.
Solid lines represent average data and circles represent individual responses.
Adapted from Brownstein et al. (2017).
For example, following competitive soccer match-play, Brownstein et al.

(2017) found that MVC force took 72 hours to return to baseline, while
voluntary activation and peak twitch force remained 5% and 6% below
baseline following 24 h recovery, before recovering at 48 h (Figure 8.5).
At the more extreme end of the exercise spectrum, Millet et al. (2011)
assessed neuromuscular function for up to 16 days following an ultra-
marathon. Their study found a 19% reduction in voluntary activation and
35% reduction in MVC post-exercise, with impairments in voluntary
activation recovering by 48 h, but MVC requiring nine days to return to
baseline. The prolonged reduction in MVC strength was likely due
prolonged disturbances at the peripheral level, with peak twitch force
remaining 5% below baseline following nine days of recovery. Accordingly,
recovery of neuromuscular function is hindered substantially at both the
central and peripheral level by damage incurred throughout locomotor
exercise involving eccentric contractions.
8.8 Origin of prolonged impairments in contractile

function
As alluded to earlier, the mechanisms contributing to prolonged impairments in
contractile function depend largely on the mode of exercise. When exercise
is metabolically taxing but has a low mechanical demand and consequently
elicits minimal muscle damage, prolonged impairments in contractile
function could be a consequence of glycogen depletion or increases in
reactive oxygen/nitrogen species. Reduced muscle glycogen has been
linked with impaired sarcoplasmic reticulum (SR) Ca2+ handling, thought
to occur due to preferential glycogen depletion in the region of the t-tubular-
SR junction (Gejl et al. 2014). Indeed, studies have clearly demonstrated
that when glycogen levels fall below critical levels (250-300 mmol·kgí
dw), SR Ca2+ handling is impeded (Gejl et al. 2014). In regards to reactive
oxygen/nitrogen species, increases in both chemical species occur during
metabolically demanding exercise due to increase in the efflux of
superoxide anion (O2-) from the mitochondria and an increase in production
of nitric oxide (NO) following increased nitric oxide synthase activity. A
number of studies have shown that ROS/RNS impede SR Ca2+ release,
thought to be due to redox modifications of ryananodine receptors (RyR)
which are integral in the excitation-contraction coupling process (Cheng et
al. 2016; Cooper et al. 2013; Cheng et al. 2017). Following exercise-
induced muscle damage, such as following running-based or team-sport
events, prolonged impairments in contractile function are likely a result of
‘primary muscle damage’, i.e., the initial damaging event induced by
eccentric contractions which causes myofibrillar damage and
disorganisation or sarcomeres, leading to a reduced ability of the contractile
machinery to produce force. In addition, mechanisms which occur
secondary to the initial damaging event, such as increases in inflammation
152 Chapter 8
and oxidative stress, can impede the excitation-contraction coupling and

muscle force through a number of mechanisms which can impair calcium
release, re-uptake and sensitivity, as well as cross-bridge cycling (Cheng et
al. 2017; Reid 2008). Accordingly, both metabolic and mechanical factors
associated with locomotor exercise can cause prolonged impairments in
contractile function through various mechanisms which are dependent on
the mode, intensity and duration of the task.
8.9 Origin of prolonged impairments in voluntary

activation
The mechanisms by which impairments in voluntary activation persist
following exercise cessation are unknown (Carroll et al. 2017). Reductions
in the capacity of the CNS to activate the muscle can occur anywhere along
the pathway from the motor cortex to the neuromuscular junction. Using
TMS, studies have assessed corticospinal excitability during the recovery
period following high-intensity intermittent exercise and shown that,
despite persistent impairments in voluntary activation, corticospinal
excitability was unaltered (Thomas et al. 2017; Brownstein et al. 2017).
However, no studies have assessed recovery of corticospinal excitability at
a segmented level using TMS and spinal stimulation, and this provides an
interesting area for future research. While it cannot be said conclusively
what causes prolonged impairments in voluntary activation, a number of
potential explanations could account for the residual activation deficit.
Previous work has shown that the occurrence of muscle damage following
eccentric-based exercise elicits prolonged reductions in VA which require
days to resolve (Goodall et al. 2017a). One commonly cited explanation for
the link between muscle damage and impaired VA is that ‘noxious’
biochemical substrates that infiltrate the muscle following exercise induced
muscle damage (EIMD) stimulate group III/IV muscle afferents, which
relay inhibitory afferent feedback to various sites within the CNS (Endoh et
al. 2005; Pitman and Semmler, 2012) Indeed, biochemical substrates such
as prostaglandins and bradykinins, and factors associated with inflammation
such as neuropeptides and histamines, have been shown to activate group
III/IV muscle afferents (Clarkson and Hubal; 2002, Smith, 1991). However,
evidence to suggest that afferent feedback directly affects motor output
from the CNS is equivocal and remains hotly debated (Marcora, 2010;
Amann and Secher, 2010). It is known that inflammatory cytokines
produced following damaging exercise are a potent effector of CNS
function (Carmichael et al. 2006). For example, increases in interleukin-1
beta (IL-ȕ concentrations within the brain have been displayed following
downhill running, concurrent with delayed recovery of running performance

in the 48 h post-exercise (Carmichael et al. 2006). Elevated concentrations
of these cytokines have also been linked with impaired behavioural
responses (Dantzer, 2004) and fatigue (Swain et al. 1998). Nevertheless,
whether or not increases in inflammatory cytokines within the brain
contribute to an impaired capacity of the CNS to activate the muscle is
unknown and warrants further investigation.
8.10 Summary
Locomotor exercise presents a substantial challenge to the neuromuscular
system and can require high and/or prolonged levels of neural drive, force
production, and energy turnover. The past two decades have seen an
increased emphasis on investigations into neuromuscular function in
response to fatiguing locomotor exercise. Research in these areas has
demonstrated the importance of task-dependency on impairments in
neuromuscular function, with exercise intensity, duration and mode all
influencing the aetiology of neuromuscular impairments. In general,
perturbations at the peripheral level predominate during high-intensity
exercise, while impairments in voluntary activation are more apparent after
prolonged exercise. From a recovery perspective, there is a more rapid
recovery following high-intensity exercise, whereas recovery is delayed
following more prolonged exercise, in particular that which causes muscle
damage. While the peripheral mechanisms which contribute to impaired
neuromuscular function are well-established, more research is required to
elucidate the aetiology of impairments in voluntary activation and central
nervous system function both during and in the recovery following
locomotor exercise.
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CHAPTER 9
SEX DIFFERENCES IN NEUROMUSCULAR

FUNCTION AND FATIGABILITY
PAUL ANSDELL, PHD

AND STUART GOODALL, PHD
9. Introduction
Considering sex as a biological variable has been promoted as an area of
importance for neuroscience research, highlighted by a series of review
articles (Cahill, 2006; Beery and Zucker, 2011; McCarthy et al. 2012;
Shansky and Woolley, 2016). The neuroscientific sex differences also
extend to exercise performance; all exercise requires coupling of the
nervous system with skeletal muscle(s), therefore sex differences at any
stage of the motor pathway have the potential to influence exercise
performance. Understanding how sex influences the neuromuscular system
in health and disease will enable practitioners to optimise the prescription
of exercise in athletic and clinical populations. This chapter aims to detail
the current scientific knowledge of sex differences in neuromuscular
function, whilst outlining areas for future research.
9.1. A brief history of the scientific study of sex

and performance
The anatomical and physiological differences between males and females
have been thought to determine the absolute limits to human performance
for centuries. The scientific understanding of this topic has developed
considerably over the past 150 years, mainly due to advances in technology.
However, in the 19th century, medical literature consisted mainly of
hypotheses and opinion. For instance, Dr Edward Clark published A Fair
Chance For The Girls in 1873 which suggested that, if women pushed
themselves to compete with males, they would experience nervous collapse
Sex Differences in Neuromuscular Function and Fatigability 161
and sterility. However, similar to other essays of that era, the conclusions
were not based on empirical data. The first to comprehensively study female
performance was Dr Mary Putnam-Jacobi, who studied a range of parameters
including muscle strength, pulse pressures and daily physical activity levels.
The data showed that menstruation did not hinder female performance, and
the essay was awarded Harvard University’s esteemed Boylston Prize in
1876. Despite the early work of Putnam-Jacobi, the inclusion of females in
the peer-reviewed literature has been an issue over the following ~150 years.
As Beery & Zucker (2011) outlined: in biological research the number of
male-only studies outnumbers female-only studies, particularly in neuroscience
(5.5:1) and physiology (3.7:1). Furthermore, in these two disciplines, when
studies included both sexes, only 20-30% of studies factored sex into their
analyses. The importance of understanding the influence of sex on
physiological outcomes is of vital importance; in the context of neuromuscular
physiology, there is a lack of understanding about how to optimise
performance and adaptation in training and rehabilitation in both sexes
across the lifespan.
9.2. Sex differences throughout the motor pathway

The process of muscle contraction begins with the planning of movement
in supra-cortical structures. Descending drive from the motor cortex, via the
corticospinal tract, innervates spinal motoneurons that results in the
excitation of motor axons and the recruitment of motor units, resulting in
excitation contraction coupling and force output (see Chapter 3 for more
detail). This chain of events is summarised in Figure 9.1, adapted from
Gandevia (2001), and contributes to neuromuscular performance during
maximal and submaximal muscle contractions. Conceptually, within an
individual, a modulation at any level of the motor pathway can affect the
net force output, whether this is an augmentation (e.g., strength training,
Weier et al. 2012), or an attenuation (e.g., exercise-induced fatigue, Sidhu
et al., 2017). Individual characteristics of the exercise performer can also
affect neuromuscular output, with sex causing differences at multiple levels
of the motor pathway.
162 Chapter 9
Figure 9.1: The aetiology of sex differences and menstrual cycle effects within the
motor pathway. Broken arrows refer to variables that are greater in males; unbroken
refers to variables that are greater in females; light unbroken arrow refer to variables
that experience changes across the menstrual cycle; the grey dashed arrow refers to
a sex difference that is not beneficial/detrimental to either sex. Adapted from
Gandevia (2001).
9.2.1. Pre-motor processes

Beginning at the top of the motor pathway (Chapter 2), sex differences in
brain structure and function are prevalent, including greater connectivity
between the sensory and motor cortices in males (Ritchie et al. 2018).
Techniques such as functional and structural magnetic resonance imaging
(MRI), positron emission tomography (PET), and single photon emission
computed tomography (SPECT) have identified sex differences in cerebral
blood flow and neurochemistry (Cosgrove et al. 2007), indicating that males
and females have distinct cerebral features that could contribute to sex
differences in a wide range of pathological developments. However, how
these differences relate to motor function is unclear, and whether these sex
differences are physiological or related to social factors remains undetermined.
Further, evidence supports the notion that a sex difference in cortical and
sub-cortical activation occurs during both simple and complex motor tasks
(Lissek et al. 2007). Whilst sensorimotor activation, assessed by functional

MRI (fMRI), has been implicated in the production of force (Cramer et al.
2002) and exercise-induced fatigue (Liu et al. 2003), the causal role of
interaction between brain areas on neuromuscular function during exercise
is still unclear (Robertson and Marino, 2016; Meeusen et al. 2016). As
suggested by Hunter (2014), the present challenge is to determine the
functional significance of sex differences in brain activity during motor
output.
9.2.2. Intracortical and corticospinal neurons

Another method of probing the contribution of the central nervous system
to neuromuscular performance is transcranial magnetic stimulation (TMS).
When the electromyographic (EMG) response to TMS is recorded,
excitability of the targeted tissue(s) can be assessed. Increased excitability
can facilitate the recruitment of motor units and reduce the amount of
synaptic input (neural drive) to produce force (Weavil and Amann, 2018).
Paired-pulse TMS can purportedly quantify the degree of intracortical
inhibition and facilitation (Kujirai et al. 1993). The physiological underpinnings
of these measures (i.e., GABAergic inhibition and glutamatergic facilitation)
are suggested to influence neuromuscular functions such as manual
dexterity (Rurak et al. 2019), motor learning (Perez et al. 2004), adaptation
to exercise (Weier et al. 2012), and neurorehabilitation (Johnstone et al.
2018). Therefore, understanding whether neurotransmitter systems might
differ between sexes can aid in optimising a wide range of processes. To
date, only one investigation has addressed this question directly, reporting
no sex difference in the resting first dorsal interosseous muscle (Cahn et al.
2003). However, as acknowledged by Kalmar (2018), excitability of
cortical and corticospinal structures is state, time, and task dependent,
therefore resting data should not be extrapolated to an active state. On this
note, cortical representations of different muscle groups also exhibit
different input-output properties in response to single- and paired-pulse
TMS (Chen et al. 1998). Thus, a comprehensive investigation into the
dynamics of intracortical properties in different muscle groups, during
different tasks, is required before conclusions can be made about sex
differences in these properties. This aspect of central nervous system
function cannot be mentioned without noting the potent effect of sex
hormones on intracortical properties, with the female menstrual cycle
eliciting large changes in responses to paired-pulse TMS (Smith et al. 2002;
Ansdell et al. 2019). This topic is covered in more detail below.
164 Chapter 9
At rest, the properties of the corticospinal tract in response to single-pulse

TMS are known to be similar between males and females (Pitcher et al.
2003; Rozand et al. 2019). Similarly, both sexes experience changes in
corticospinal excitability following fatiguing exercise (Hunter et al. 2006;
Senefeld et al. 2018), suggesting that responsiveness of this descending tract
is not responsible for any sex differences in aspects of neuromuscular
performance. However, to fully discern the aetiology of change in
corticospinal properties, direct subcortical stimulation must be delivered in
addition to TMS (e.g., Petersen et al. 2002; Martin et al. 2008; Škarabot et
al. 2019). To date, no studies exist comparing the contribution of cortical
and subcortical structures to indices of neuromuscular performance in
fatigued or non-fatigued states.
9.2.3. Motor unit properties

The motor unit is the final aspect of the nervous system’s contribution to
the motor pathway; as a result, the properties of the motor unit can directly
influence force production. For instance, Del Vecchio et al. (2018, 2019)
recently showed that discharge rate is strongly correlated with contractile
speed, and can predict ~80% of force fluctuations during oscillatory,
submaximal contractions. A variety of techniques exist to assess motor unit
discharge properties, however, there is a lack of literature directly
comparing sex differences. Higher discharge rates have been observed in
males compared to females at low (15%) contraction intensities (Harwood
et al. 2014), possibly due to the fact that males have a lower proportion of
low-threshold motor units (Kukulka & Clamann, 1981). These factors,
amongst others, are suggested to contribute to a sex difference in force
steadiness (Jakobi et al. 2018), although the authors concluded that, despite
a clear sex difference in steadiness, the underlying mechanisms are unclear.
One potential avenue for exploration of this phenomenon could be with the
use of high-density EMG. Whilst recordings from intramuscular electrodes
can provide information about the action potentials discharged by single
motor units, they provide limited information about the activity of the
whole-muscle (Enoka, 2019). High-density EMG permits the assessment of
large numbers of motor units (Muceli et al. 2015; Farina and Holobar, 2016)
over repeated sessions (Martinez-Valdes et al. 2017). This relatively new
technology has assumptions and limitations (Enoka, 2019), but does
provide a promising technique to investigate how the nervous system
controls movement. Indeed, a recent investigation using high-density EMG
(Pereira et al. 2019) demonstrated no differences in discharge rate, but
rather, showed that females experienced greater oscillations in the common
synaptic input to motor units. This greater coefficient of variation (CV) in

the common synaptic input has been associated with the CV of force during
sustained submaximal contractions (Farina and Negro, 2015). The present
challenge is to assess how the interaction between sex, motor unit firing
properties, and force steadiness affects functional tasks, rather than low-
intensity isometric contractions which, as suggested by Jakobi et al. (2018),
is a challenging task.
9.2.4. Contractile apparatus

Whilst the focus of this chapter/book is not on the contractile apparatus of
the exerciser, it must be acknowledged that this differs between sexes.
Principally, the proportion of type I fibres is greater in females compared to
male counterparts in certain muscles such as the knee-extensors (Simoneau
and Bouchard, 1989; Staron et al. 2000; Roepstorff et al. 2006; Welle et al.
2008). This leads to greater capillarisation (Roepstorff et al. 2006) and,
when combined with a greater vasodilatory response to exercise (Parker et
al. 2007), allows for a greater perfusion of oxygenated blood during exercise.
Similarly, because of differential fibre type proportions, females exhibit
slower contractile properties due to slower calcium (Ca2+) kinetics within the
sarcoplasmic reticulum (Harmer et al. 2014). Collectively, these sex
differences in contractile properties lead to greater female fatigue resistance
during certain tasks (Hunter et al. 2004; Wüst et al. 2008; Ansdell et al. 2018).
For a more detailed overview of sex differences in metabolic and contractile
properties of skeletal muscle, the interested reader should see Hunter (2014).
9.3. Functional neuromuscular sex differences

9.3.1. Maximal force production
Sex differences in the motor pathway can lead to functional differences, the
most obvious of which is maximal force production, where males routinely
exceed female counterparts by approximately a third (Hannah et al. 2012;
Ansdell et al. 2018). This difference is likely almost entirely related to
differences in muscle mass (Abe et al. 2003) and fibre type (Simoneau and
Bouchard, 1989; Staron et al. 2000; Roepstorff et al. 2006; Welle et al.
2008). Such variations lead to males outperforming females in tasks
involving high-force contractions (i.e., sprinting and vertical jumps) when
the data are considered in absolute terms (Winter et al. 1991; Perez-Gomez
et al. 2008). Despite this, when the data are normalised to an index of lean
mass (e.g., fat free mass, or lean leg volume), the sex difference is reduced,
166 Chapter 9
suggesting that muscle quantity accounts for a large proportion of the sex
difference in maximal instantaneous exercise performance.
9.3.2. Force steadiness and accuracy

As mentioned previously, force steadiness during submaximal contractions
is typically poorer in females compared to males (Harwood et al. 2014;
Pereira et al. 2015; Almuklass et al. 2016). Steadiness is thought to reflect
a combination of neural, muscular and tendon-related factors, and is
suggested to be associated with the sensorimotor system’s ability to regulate
efferent drive and afferent feedback (Jakobi et al. 2018). Similarly, females
have demonstrated poorer spatial accuracy during goal-directed movements
(Casamento-Moran et al. 2017). This index of neuromuscular function has
been assessed in ‘real-world’ scenarios such as throwing and catching a ball
(Watson and Kimura, 1991; Moreno-Briseño et al. 2010), which demonstrated
a sex difference independent of physique or athletic experience (Watson
and Kimura, 1991). A more controlled environment to study spatial
inaccuracies is during single-joint movements in a dynamometer, such as
the setup used by Casamento-Moran et al. (2017). Using the tibialis anterior
muscle, participants were instructed to perform dorsiflexion towards a
target position (9° vertical displacement) at a particular time (180 ms
following a visual cue). The results demonstrated that females had a greater
positional error compared to males independent of differences in maximum
strength, with altered antagonist muscle activation purported to explain this
difference. As suggested by Jakobi et al. (2018), discerning the underlying
mechanisms of force fluctuation is a necessary step which will allow
practitioners to target interventions to improve steadiness and accuracy in
clinical and athletic populations.
9.3.3. Fatigability
The sex difference in fatigability is relatively well researched in comparison
to other indices of neuromuscular function (for review see Hunter 2009,
2014, 2016); however, many factors remain undetermined that could help
to explain why females demonstrate greater fatigue resistance than males
during specific tasks. During sustained isometric contractions at the same
relative intensity, females outlast males (Hunter and Enoka, 2001; Clark et
al. 2005; Hunter et al. 2006), with the difference negatively correlated with
contraction intensity (Hunter, 2009). The sex difference during these
particular exercise tasks is thought to be related to blood flow occlusion
within the working muscle, as the difference is negated at higher contraction
intensities where both sexes experience reduced skeletal muscle perfusion

(Hunter, 2009, 2014). At lower contraction intensities, the sex difference is
magnified because males produce greater absolute force than females,
causing increased intramuscular pressures (Russ & Kent-Braun, 2003).
During contractions where blood flow is not a limiting factor to exercise

(e.g., intermittent contractions), females still demonstrate greater fatigue
resistance (Hunter et al. 2004; Ansdell et al. 2018, Figure 9.2).
Figure 9.2: Adapted from Ansdell et al. (2018) demonstrating a slower rate of force
loss, EMG increase in females during an intensity matched (50% MVC),
intermittent (3 s on, 2 s off), isometric fatiguing task compared to males.
In these situations, the sex difference in fibre type proportions (see above)
is thought to contribute to a reduced rate of accumulation of deleterious
metabolites within the working muscles of females (Hunter, 2014). Such an
accumulation of metabolites impairs contractile function of the exercised
muscle (Allen et al. 2008; Fitts, 2008). In the context of the nervous system,
a build-up of metabolites activates molecular receptors on group III/IV
neurons, which project to spinal and supraspinal sites within the nervous
168 Chapter 9
system (Amann and Light, 2015). This afferent feedback is thought to have
inhibitory effects throughout the nervous system, diminishing motoneuronal
excitability (Weavil et al. 2016) and increasing intracortical inhibition
(Sidhu et al. 2018), with the net effect being a reduced capacity of the
nervous system to voluntarily activate the working muscle (Sidhu et al.
2017). Given that voluntary activation (VA) involves the integration of
synaptic input from descending pathways, spinal interneurons, and
peripheral afferent neurons (Enoka, 2012), it is perhaps unsurprising that in
a non-fatigued state, males and females are able to equally activate skeletal
muscle (Hunter et al. 2006; Keller et al. 2011; Molenaar et al. 2013).
However, the menstrual cycle is an exception to this altered synaptic input
to descending tracts as it is known to modify the ability of the nervous
system to activate skeletal muscle (Ansdell et al. 2019). Following fatiguing
tasks involving the lower limbs, a greater reduction in VA has been
observed in males compared to females (Russ and Kent-Braun, 2003;
Martin & Rattey, 2007). This observation would align with the hypothesis
that females experience a lesser/slower accumulation of nociceptive
metabolites during exercise suggesting that, as a result, they also experience
a lesser degree of group III/IV afferent neuron activation (Hunter, 2014).
Interestingly, the metaboreflex, an increase in the cardiovascular response
to activation of sensory neurons by metabolites (Kaufman and Hayes, 2002),
is attenuated in females compared to males during isometric fatiguing tasks
in the upper (Hunter and Enoka, 2001) and lower limbs (Ansdell et al.
unpublished data). No data currently exists directly comparing activation of
metabo-sensitive afferent neurons during exercise in males and females.
Therefore, it could be equally plausible that the activation of these neurons
has disparate effects within the projecting areas of the central nervous
system in males and females. Understanding this potential sex difference is
of importance as diseases such as heart failure, chronic fatigue syndrome,
and fibromyalgia have all been purported to have maladaptive effects on
this neural system. Therefore, improving our understanding could lead to
tailored exercise/pharmacological intervention to optimise the treatment
processes.
Fatigability is an amalgamation of a myriad of factors, and is specific to the

task(s) performed (Hureau et al. 2018; Thomas et al. 2018), therefore,
findings from single-limb studies do not necessarily translate into whole-
body locomotor activities. Research studying the sex difference in
fatigability during locomotor tasks is relatively minimal. Studies
investigating long-duration cycling (Glace et al. 2013) and trail-running
(Temesi et al. 2015) demonstrate a reduced disruption in contractile
function in females compared to male counterparts. Similarly, female
military recruits experienced a lesser decline in maximal force production

following a 9.7 km loaded march compared to males (O’Leary et al. 2018).
Despite these studies, Boccia et al. (2018) demonstrated no differences in
CNS or contractile dysfunction following a half-marathon. One
consideration about the aforementioned studies is that all employed self-
paced exercise which, whilst being ecologically valid in terms of exercise
performance, limits the physiological insights into the mechanisms of
fatigability. Accounting for metabolic thresholds by discerning exercise
intensity domains (i.e., the power-duration relationship) has been suggested
to be the most valid way of modelling fatigue and its physiological
underpinnings (Burnley and Jones, 2018).
9.4. Female-specific neuromuscular function

9.4.1. The influence of hormones in vitro
Sex differences cannot be discussed without acknowledging the potent
effects of sex hormones on neural function. Throughout the female lifespan,
women experience changes in sex hormone concentrations from menarche
to menopause (Brown and Thomas, 2011). These sex hormones can
modulate activity within the nervous system, which has led researchers to
refer to them as ‘neurosteroids’ (Paul and Purdy, 1992). The effects of these
hormones can be simplified into net excitatory or inhibitory, with the
amalgamation of all hormonal concentrations at a given time point creating
a ‘dynamic ecosystem’ within the nervous system (Tenan, 2016). Typically,
oestrogens have excitatory effects as they attenuate the release of Ȗ-
aminobutyric acid (GABA, Schultz et al. 2009); these effects lead to
decreased firing thresholds and increased discharge frequency of cerebral
neurons (Smith et al. 1989; Wong and Moss, 1992). On the contrary,
progesterone and its metabolites have a net inhibitory effect on the nervous
system, as the activity and effects of GABA are potentiated, leading to
decreased neuronal discharge rate (Smith et al. 1989) and, in an animal
model, increased inhibition of pyramidal neurons (Hsu and Smith, 2003).
Collectively, this in-vitro evidence suggests human neuronal function could
be affected; however, in-vivo studies are relatively sparse in comparison.
9.4.2 In-vitro evidence

Research employing TMS to investigate the neurosteroidal effects of these
hormones often use the menstrual cycle to study changes. Smith et al. (1999)
first demonstrated the inhibitory effects of progesterone by assessing short-
170 Chapter 9
interval intracortical inhibition (SICI) in the resting hand muscles during

the follicular (low progesterone) and luteal (high progesterone) phases. The
authors reported greater inhibition in the luteal phase, which supported the
notion that progesterone potentiated GABAergic processes (Smith et al.,
1989; Hsu and Smith, 2003). The authors then built on their findings by
demonstrating that in the late follicular phase (high oestrogen, low
progesterone) oestrogen reduced intracortical inhibition and increased
facilitation (Smith et al. 2002). These changes have since been suggested to
cause modifications in motor unit firing properties across the menstrual
cycle (Tenan et al. 2013); specifically, a lower initial firing rate at
recruitment was observed in the early follicular phase, when hormone
concentrations are lowest. Similarly, inhibition in other locations of the
nervous system has been shown to be modulated by hormones. Using TMS,
Hausmann et al. (2006) demonstrated that ipsilateral silent period, an index
of transcallosal inhibition (Ferbert et al. 1992), was reduced in the late
follicular phase. Furthermore, lower in the motor pathway, presynaptic
inhibition of sensory 1a axons is reduced concurrently with elevated
oestrogen concentrations (Hoffman et al. 2018). This theme of inhibitory
pathways being modulated by sex hormones is evidently common within
the nervous system, however no effect is observed on descending motor
pathways. Corticospinal tract (Ansdell et al. 2019) and motoneuron pool
excitability (Hoffman et al. 2018) have been shown not to change across the
menstrual cycle. These data could suggest that GABAergic inhibition is
mainly modulated by sex hormones, rather than descending transmission of
motor signals.
9.4.3 Functional changes across the menstrual cycle

The aforementioned neuronal changes have been purported to elicit
functional consequences too, for instance, a body of literature suggests that
females can produce greater maximal force around the late follicular phase,
when intracortical inhibition is reduced (Sarwar et al. 1996; Birch & Reilly,
2002; Tenan et al. 2016). Despite this, there is an equal abundance of studies
showing no difference in strength across the menstrual cycle (Dibrezzo et
al. 1991; Janse De Jonge et al. 2001; Elliott et al. 2003; Kubo et al. 2009;
Ansdell et al. 2019).
Figure 9.3: Data from Ansdell et al. (2019) demonstrating the increased time to task
failure of an open-ended, intermittent, isometric fatiguing task (60% MVC, 3s on 2s
off) in the luteal phase of the menstrual cycle. Day 2 (D2): early follicular; Day 14
(D14): late follicular; Day 21 (D21): luteal phase.
During submaximal contractions, force steadiness is decreased in the mid-

luteal phase (Tenan et al. 2016), with the authors suggesting this could
potentially be due to reduced motor unit synchronisation; however, this
mechanistic index of neuromuscular function is yet to be examined across
the menstrual cycle. Discrepancies between studies could be caused by
factors such as the identification and confirmation of menstrual cycle phases
(e.g., counting days since menstruation vs. obtaining serum hormone
concentrations); time of day (Birch and Reilly, 2002); and variability in the
cycle phases durations (Fehring et al. 2006). However, efforts are now being
made to reduce ambiguity in study designs involving females (Elliott-Sale
et al. 2013; Sims and Heather, 2018), which should be used as guidelines
for researchers planning these types of investigations.
Prompted by the heterogeneity in the literature, and the fact that the majority
of mechanistic studies focus on resting hand muscles, our laboratory
recently investigated the effects of the menstrual cycle on neuromuscular
function and fatigability of the knee-extensors (Ansdell et al. 2019). As
mentioned, intracortical and corticospinal excitabilities are known to be task
and muscle specific (Kalmar, 2018), thus, it was necessary to combine the
mechanistic measures with performance measures in a functionally-relevant
muscle group. Furthermore, the importance of considering measurement
error in neurostimulation studies has recently been emphasised (Furlan and
Sterr, 2018). Therefore, repeatability of the techniques was discerned in
monophasic oral contraceptive pill users who present a constant hormonal
profile.
172 Chapter 9
Figure 9.4: Data from Ansdell et al. (2019) demonstrating the changes in SICI
across the three phases of the menstrual cycle. Day 2 (D2): early follicular; Day 14
(D14): late follicular; Day 21 (D21): luteal phase.
The data showed that, during the late follicular phase, intracortical
inhibition was lowest (Figure 9.4), which was associated with a greater VA
in the knee-extensors. This occurred concurrent with a rise in oestrogen,
whilst progesterone remained low. Contrary to our hypothesis, maximum
strength was not augmented at this time point, perhaps suggesting a ‘ceiling
effect’ within the nervous system where additive motor units could not be
recruited by TMS despite a similar level of background force. More than
likely, however, the null finding in strength change is due to the larger
measurement error compared to the mechanistic measures. This would also
explain why consistent mechanistic changes are shown across the menstrual
cycle (i.e., nervous system inhibition), whereas performance measures
display some heterogeneity.
Seven days later, in the luteal phase, the rise in progesterone caused an
increase in intracortical inhibition and a parallel decrease in VA, again
without a change in strength. The increase in SICI that occurred alongside
the rise in progesterone was of a similar magnitude to GABA-agonist
pharmacological interventions (Ziemann et al. 1996). When fatigability was
considered, performance in the luteal phase was also remarkable. The study
employed an open-ended, intermittent, isometric fatiguing task (60% MVC,
3s on 2 s off), and demonstrated a 23% and 36% increase in time to task
failure compared to the early and late follicular phases, respectively. As is
widely acknowledged, fatigability has both physiological and psychological
components that interact to determine exercise tolerance (Enoka and
Duchateau, 2016). Therefore, due to the fact that no additive neuromuscular
fatigue was experienced in the luteal phase, and participants were simply
able to exercise in a state of fatigue for longer, we speculated that the anti-
nociceptive, analgesic effects of augmented GABAergic inhibition were in
effect (Jasmin et al. 2003; Enna and McCarson, 2006). This enabled the
participants to continue exercising in fatigued states, potentially processing
the nociceptive afferent feedback from the exercising muscles differently.
Indeed ‘luteal analgesia’ is a phenomenon recently described by Vincent et
al. (2018), suggesting that functional connectivity within the emotional
regulation network is altered by progesterone in a way that reduces the
affective response to pain. This notion, of course, requires further
experimental inquiry into the effects of augmented GABAergic inhibition
on aspects of fatigability and exercise performance.
The aforementioned modulations in neuromuscular function were displayed

in eumenorrheic females; no such response was observed in monophasic
oral contraceptive pill users (Ansdell et al. 2019). Whilst comparisons
between pill users and eumenorrheic females were not made in this study,
the effects of hormonal contraceptives on neural function remain unclear.
As suggested by the title of a recent review by Pletzer & Kerschbaum (2014)
‘50 years of hormonal contraception - time to find out what it does to our
brain’, this is an under-investigated area of female neurophysiology.
Synthetic hormones act upon the receptor sites of endogenous hormones
throughout the body (Africander et al. 2011); this has been linked with
alterations in brain structure (Pletzer et al. 2010), cognitive function
(Mordecai et al. 2008; Wharton et al. 2008) and emotional processing
(Oinonen and Mazmanian, 2002). How these changes relate to brain
chemistry and neurotransmission is unknown and, within the motor
pathway, it remains unclear whether synthetic hormones are neuroactive.
This is a pertinent area for future research as usage of hormonal
contraceptives in athletic populations is ~50% (Martin et al. 2018).
Therefore, the information gained from assessing how chronic
downregulation of endogenous hormones affects neuromuscular function is
of vital importance to practitioners.
9.5. Summary
9.5.1. What do we know already?
Biological sex mediates the neuromuscular pathway in complex ways. In
non-fatigued states, the differences within the nervous system are subtle,
mainly involving the functional activation of brain areas during motor tasks.
Insufficient evidence exists to completely rule out differential activation of
intracortical and/or corticospinal neurons during movement whereas, at the
motor unit level, evidence is emerging to suggest there are differences in
synaptic input and firing properties between sexes. The final level of the
174 Chapter 9
motor pathway, skeletal muscle, is a location where large differences occur

between sexes. Females exhibit greater relative proportions of ‘slow-twitch’
type I fibres across several muscle groups. Collectively, these differences
in neuromuscular properties lead to functional performance differences;
males are capable of producing greater absolute forces, mainly due to
muscle quantity and limb size. However, during submaximal contractions,
females display poorer steadiness and accuracy, which could be related to
the differences in the properties of motor units. During exercise that
involves sustained or repeated contractions, females demonstrate a greater
resistance to fatigue compared to males.
9.5.2. Where do we go from here?

The next steps for researchers interested in the neuromuscular systems of
males and females is to gain a comprehensive understanding of how
different neuronal networks behave during motor tasks in both sexes. If this
information can be discerned, practitioners can begin to prescribe exercises
that target specific populations of neurons during neurorehabilitation and
athletic training. The question that then arises is whether neural adaptation
to exercise, or neuroplasticity, is different between sexes. Furthermore,
current understanding is that the menstrual cycle modulates neurotransmitter
activity within the motor pathway, which could be considered a sex
difference in itself. Once more, what is unknown is how these hormones
affect neuroplasticity, and how different forms of hormonal contraceptives
affect neural function in acute and chronic scenarios. Regardless, enough
evidence is known to confirm that females are not simply smaller versions
of males, and that sex differences in neuromuscular function must be taken
into account when considering exercise performance.
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CHAPTER 10
MOTOR CONTROL RESPONSES FOLLOWING

EXERCISE-INDUCED MUSCLE DAMAGE
CARLOS HERMANO PINHEIRO, PHD

10. Background
It is well described that strenuous, unaccustomed exercise that involves
eccentric (lengthening) contractions results in the phenomena of delayed
onset muscle soreness (DOMS) (Nosaka et al., 1991). DOMS results in
protracted loss in strength, shortening of the muscle, increased discomfort,
and associated increases in circulating muscle proteins such as creatine
kinase (CK) (Ebbeling and Clarkson, 1989).
DOMS is classified as a ‘type I’ muscle strain injury and presents with

localised tenderness or stiffness upon palpation and/or movement (Gulick
and Kimura, 1996). Although the pathophysiology associated with DOMS
is generally subclinical (Armstrong and Warren, 1993), the disparity of
sensations experienced with this injury can vary from muscle stiffness to
severe debilitating pain (Cheung et al., 2003). The intensity of discomfort
increases within the first 24 hours following cessation of exercise, peaks
between 24 and 72 hours, subsides and eventually disappears by 5–7 days
post-exercise (Pearce et al. 1998).
Tenderness associated with DOMS is usually situated in the distal portion

of the muscle (Cheung et al. 2003). It has been suggested that the region of
pain can be attributed to a high concentration of muscle nociceptors (pain
receptors) found in the connective tissue of the myotendinous junction
(Newham et al. 1982). This junction is characterised by a continuous,
extensively folded membrane interlocked within skeletal muscle tissue
(Noonan and Garrett, 1992). This particular arrangement of the fibres
adjacent to the myotendinous junction reduces the ability for muscle to
186 Chapter 10
withstand high-tension forces (Noonan and Garrett, 1992; Cheung et al.

2003). As a result, the contractile elements of the muscle, particularly in the
myotendinous junction, are vulnerable to microscopic damage affecting
force and strength. However, from a motor control perspective, this damage
can also affect the quality of voluntary movements. This chapter will focus
on and discuss the neurophysiology and associated motor control outcomes
following eccentric exercise resulting in DOMS. This includes strength and
power loss and regain, impairment of function and motor skill changes.
10.1 How does DOMS occur?

The exact causative mechanisms of DOMS are not fully elucidated.
Currently, the consensus is that there is no one theory to explain DOMS,
however there is a model that involves a sequence of events that contribute
towards DOMS. Various hypotheses have been put forward to explain the
pain stimulus associated with DOMS including the Lactic Acid Theory,
muscle fibre cell damage, intramuscular connective tissue damage,
inflammation, muscle spasm and enzyme efflux theories (Cheung et al.
2003).
When trying to understand the biological factors that cause DOMS, it is

important to keep in mind that it is an uncomfortable, possibly painful,
sensation that is experienced between 24 and 48 hours after eccentric
exercise (Cheung et al. 2003; Nosaka, 2011). Thus, the association between
measurements and the temporal window of painful sensation is of great
importance to determine etiological factors of DOMS.
One of the etiological theories of DOMS is the Lactic Acid Theory. It has
been assumed that the production of lactic acid would persist during the
post-exercise period and the accumulation of this metabolite would
stimulate nociceptive receptors and cause the sensation of pain. However, it
was well established that blood lactic acid levels generally return to pre-
exercise values after one hour following an exercise bout (Schwane et al.
1983). Other evidence against this theory is the absence of similar painful
sensation following high-intensity exercise involving concentric
contractions when compared to eccentric exercise (Asmussen, 1956).
Among the factors involved in the cascade of physiological changes that

would provoke DOMS are both damage to intramuscular connective tissue
and to skeletal muscle fibres. The Theory of connective tissue injury
[causing DOMS is supported by the evidence of an increase in the
concentration of hydroxyproline in the urine after the exercise bout,
Motor Control Responses following Exercise-Induced Muscle Damage 187
suggesting a process of overuse or degradation of the extracellular matrix

due to the stretching of the tissue during eccentric exercise (Perdelli et al.
2000; Nogueira et al. 2011). There is evidence that urinary hydroxyproline
excretion is greater after eccentric exercises than concentric exercises
(Nogueira et al. 2011). However, a study by Horswill et al. (1988) has
shown that an acute session of weight training which produced muscle
soreness did not increase the urinary excretion of hydroxyproline.
The Theory of Muscle Damage initially proposed by Hough at the turn of

the 20th century (Hough, 1902) emphasizes the mechanical disruption of
the sarcomeric microstructure at the level of the Z-line after eccentric
exercise. Another theory, The Enzyme Efflux Theory, involving muscle
injury, was proposed by Gulick and Kimura (1996) and suggests the
accumulation of calcium in the sarcoplasm after damage to the sarcolemma
of muscle fibre is due to the repetitive stretching in eccentric contractions.
The theory of muscle damage after the exercise bout has been supported by
strong evidence of increased blood levels of CK (Newham et al. 1983). As
a biochemical marker of muscle injury, pre-exercise concentration is ~100
IU/L, but can reach as high as 82,000 IU/L in the post-exercise period
(Newham et al. 1983; Kim et al. 2013). It is also important to highlight
changes in metabolic homeostasis, oxidative stress and fatigue as factors
involved in muscle damage induced by contractile activity in skeletal
muscle (Bassit et al. 2010; Pinheiro et al. 2012; Lantier et al. 2014).
However, there is a discrepancy between the peak of blood CK levels and
the peak of muscle soreness, as evidenced by several studies reviewed by
Cheung et al. (2003). It is important to know that, with DOMS, the
unpleasant sensations after unaccustomed strenuous exercise are not
necessarily due to a single biological phenomenon such as muscle damage
or inflammatory process.
The Theory of Inflammation suggests that the damage created by eccentric

exercise creates an inflammatory process contributing to DOMS. This
theory is supported by evidence of the oedema formation and the presence
of an inflammatory infiltrate in the muscle tissue after eccentric exercise
(Cheung et al. 2003; Nosaka, 2011; Dupuy et al. 2018). The peak of muscle
oedema is more associated with DOMS than the inflammatory infiltrate
itself, although there is a hypothesis that substances released locally by
macrophages could stimulate the nerve endings of the tissue provoking the
sensation of pain (Cheung et al. 2003).
Finally, the Muscle Spasm Theory proposes that high muscle activity
observed after eccentric exercise would cause ischemia inciting an
188 Chapter 10
accumulation of substances that would provoke a nociceptive stimulus

locally (Armstrong and Warren, 1993).
In summary, the model involves DOMS resulting from high-tensile forces

produced from eccentric muscle contractions. Eccentric muscle contractions
are more than just ‘lengthening’ of the muscle (such as extension of the
forearm), but rather lengthening of the tissue during muscle contractions,
for example, during a bicep curl when resisting a weight that is too heavy.
Similarly, DOMS can result from isometric contractions when the limb is at
near-full extension, placing the muscle at long muscle length (Jones et al.
1989; Clarkson et al. 1992). Both situations place excessive strain of the
connective tissue at the myotendinous junction and adjacent muscle fibres
(connective tissue damage and muscle damage theories). As a result,
damage to the sarcolemma increases calcium release inhibiting cellular
metabolism, inhibiting adenosine triphosphate (ATP) production and
interrupting calcium homeostasis. This disruption affects the proteins
troponin and tropomyosin which are integral in muscle contraction function
(enzyme efflux theory) causing inflammation and cellular necrosis
(inflammation theory). The immune response, resulting in increased
pressure from tissue oedema and local temperature, activates nociceptors
(pain receptors) resulting in a dull, localised muscle pain (inflammation
theory). The soreness can be exacerbated with movement due to increased
intramuscular pressure creating a further mechanical stimulus for already
activated nociceptor excitability (palpation also increases pain due to
similar mechanisms) (Cheung et al. 2003; Nosaka, 2011).
10.2 Functional outcomes affected by DOMS

The painful sensation in DOMS is characterized by its appearance during
contraction, stretching or when pressure is applied on the muscle which is
not at rest. It is important to highlight that both the soreness and the tissue
damage can alter muscle performance and joint mechanics during exercise.
The functional outcomes following eccentric, or lengthened isometric,

contractions include: pain, muscle weakness and fatigue, reduced exercise
economy and strength, and affected range of joint motion. These effects
usually peak in the first 24 hours, but may extend to 72 hours, with acute
effects disappearing by five to seven days (Armstrong, 1984; Nosaka et al.
1991; Nosaka, 2011).
10.3 Neuromuscular and motor control changes

following DOMS
Relative to other aspects of this area of research and investigation, there are
fewer studies that have investigated the neurophysiological responses
following DOMS. Similarly, few studies have also quantified time-course
motor control changes after DOMS. While understanding the functional
outcomes, such as changes in strength, pain and range of motion is
important, investigating the central nervous systeme responses (CNS)
responses and the ability to control a movement allows for the
understanding of the complex interactions between various regions of the
brain, efferent motor neurons, and afferent receptors such as those in muscle
and tendons (Saxton et al. 1995). Moreover, understanding this relationship
has applications to a number of areas including athlete-training programs,
exercise rehabilitation and motor skill acquisition (Pearce et al. 1998).
Early studies by Saxton et al. (1995) reported that eccentric-exercise-

induced DOMS resulted, in addition to increases in CK and reduction in
voluntary force production, in increased muscular tremor and impairment
of joint position sense and perception of force, peaking at ~3 d, when
compared to the unexercised arm that was used as a reference. Similar
findings were demonstrated by Brockett et al. (1997) who showed that, 4 d
after eccentric exercise with a position matching task, the exercised arm of
participants was more extended than the non-exercised arm at a given
position, suggesting that participants estimated that the muscle was shorter
than it actually was. Further, in a force-matching task, the exercised arm
consistently ‘undershot’ the target at 10% of maximal voluntary contraction
(MVC). These authors concluded that, as eccentric exercise is associated
with damage to muscle fibres, this in turn leads to disturbance in muscle
spindle and tendon organs that may contribute to impaired motor control.
Further understanding the relationship between force loss and motor control,
Pearce et al. (1998) investigated time-course changes in motor control
properties of the biceps brachii following eccentric exercise. Results
showed that, following the bout of exercise (7 sets of 5 eccentric
contractions at 30°/s), there was a significant increase in CK and a decrease
in strength, peaking at 1 d and 7 d (Pearce et al. 1998). Similar to strength,
the greatest error in force-tracking was observed at 1 d (Figure 10.1), with
the loss in strength and increased tracking error showing a significant
correlation (r2 = 0.724; p <0.001) (Pearce et al. 1998).
A further interesting observation was reported with regards to familiarisation,

190 Chapter 10
as a proxy of learning, of the task. Participants who completed the eccentric

exercise were compared to a control group who did not undertake the
exercise intervention (Figures 10.1 and 10.2).
Figure 10.1. Tracking task trace showing increased error (particularly over-shooting
when changing direction) 1 d post eccentric exercise (trace from author’s own collection).
While the eccentric exercise group showed improvement in the task from
the 7 d mark, when compared to the control group who also showed
improvements until the 7 d mark, the exercised group never reached the
accuracy of the control group who plateaued at 14 d. Even 28 d post exercise,
the mean accuracy of the intervention group never achieved the accuracy of
the control group. A follow up study by Pearce et al. (2009) re-confirmed
these findings by showing error rate returning to pre-intervention levels at
7d, but still not reaching similar levels of accuracy to non-exercised controls.
Figure 10.2. Time course changes in motor skill tracking performance. Dark line
with improvement in performance is control. The lighter line is the eccentrically
exercised group. Increased numbers on y-axis indicate greater error (from the
author’s own collection).
10.4 Neurophysiological studies in DOMS

Another aspect of DOMS that is currently poorly researched is
neurophysiological mechanisms contributing to poor movement control.
One question regarding DOMS is the contribution of the CNS following
eccentric exercise. In one of the first studies to address this topic, Miles et
al. (1997) asked the question if changes in motor control following eccentric
exercise were due to central or peripheral mechanisms. These authors used
electrophysiology, in particular electromyography (EMG), to measure
neuromuscular activity.
It is well known that agonist/antagonist contractions work cooperatively to

ensure smooth motor control (Wierzbicka et al. 1986). For example, when
using EMG to record elbow flexion, the EMG pattern consists of a primary
EMG ‘burst’ of the biceps brachii muscle to commence flexion of the elbow,
followed by an EMG ‘burst’ of the antagonist triceps brachii muscle to
moderate the flexion movement, and finally a secondary EMG ‘burst’ of the
biceps brachii muscle to offset the antagonist triceps muscle and ‘clamp’
the limb in the targeted stopping position. This characteristic pattern is
reflective of central motor programming (Miles et al. 1997).
Following 50 eccentric contractions and daily measures up to 5 d post

exercise, Miles et al. (1997) demonstrated a disruption of the tri-phasic
pattern between agonist and antagonist muscles groups following eccentric
exercise of the elbow flexors. Specifically, they found key elements of the
EMG burst patterning including onset of EMG burst (termed onset of motor
time), time to peak EMG activity, EMG burst duration and latency between
biceps and triceps burst patterns lengthened post exercise and persisted for
the full five days. Further, functional measures, such as CK efflux, were
significantly increased and kinematic variables, such as total movement
time and time to peak velocity, were compensated. These authors concluded
that high-force eccentric exercise resulting in DOMS caused prolonged
alterations in neuromuscular control that were reflective of disruption of
skeletal muscle contractile properties.
The notion of central changes following DOMS has also been explored by
transcranial magnetic stimulation (TMS), albeit to a limited extent. In the
only known study to date, Pearce (1995) reported increases in motor-evoked
potential (MEP) amplitude at one and three days post exercise returning to
baseline levels by seven days. While intracortical inhibition was not
measured, the TMS-mapping technique employed showed a medial shift in
the optimal site for the representation of the biceps brachii muscle. While
192 Chapter 10
the area of the maps did not change, the shift in the representation, combined
with the increased MEP amplitude, demonstrated that central mechanisms
were affected with DOMS, supporting the work of Miles et al. (1997).
10.5 Summary
The effect of eccentric exercise that induces DOMS is well known and well
described in the literature. While research is aiming to focus on diminishing
the effect of eccentric exercise, such as the utilization of pre-conditioning
isometric exercise, (Chen et al. 2012a; Chen et al. 2012b) additional
research should aim to explore the neurophysiological properties
contributing to neuromuscular control. Indeed, understanding motor control
outcomes has application across many areas of exercise science such as
impacts on motor learning, skill acquisition, exercise programming and
prescription.
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CHAPTER 11
NEUROMUSCULAR ALTERATIONS AND MOTOR

PERFORMANCE IN HEALTHY AGING
JAKOB ŠKARABOT, PHD
11. Background
Healthy aging is characterised by many neuromuscular and performance
decrements associated with alterations in both the muscular and neural
systems. These alterations can occur even in the absence of acute or chronic
pathological conditions and despite maintenance of physical activity levels.
The most apparent age-related biological remodelling is sarcopenia, which
is the loss of muscle mass and strength with advancing age. Sarcopenia is
induced by the loss of skeletal muscle fibres, apoptosis of motor neurons
and incomplete reinnervation of remaining muscle fibres, resulting in fewer,
but larger, motor units (Doherty, 2003). Since the first description of the
phenomenon about 30 years ago (Rosenberg, 1989), the definition of
sarcopenia has been extended to encompass the age-related decrements in
the central nervous system (CNS) function, hormonal status, inflammation
and nutritional intake (Doherty, 2003). The focus of this chapter will be
placed on age-related alterations in the neuromuscular system,
encompassing alterations at the level of the motor unit, i.e., the alpha
motoneuron and the muscle fibres it innervates, and the synaptic inputs the
motor neurons receive from the CNS. These alterations have a profound
effect on motor performance, as will be described in the second portion of
this chapter. Whilst the definitions vary across the literature, people are
usually considered as “aging” between 60 and 65 years of age (Hunter et al.
2016; McNeil and Rice, 2018).
Neuromuscular Alterations and Motor Performance in Healthy Aging 197
11.1 Alterations in the central nervous system

with advancing age
11.1.1 Alterations at the level of motor unit
Healthy aging is accompanied by a progressive loss of motor units (MUs)
(McNeil et al. 2005), which might be a precursor for many neuromuscular
adaptations in older age (McNeil and Rice, 2018). Due to the adaptive
nature of the neuromuscular system, following the loss of MUs, the process
of collateral reinnervation occurs, with nearby surviving motor axons
sprouting to reinnervate the denervated muscle fibres. This results in larger
MUs, with surviving motor neurons now innervating a greater number of
muscle fibres. However, reinnervation leads to greater oxidative stress to
motoneurons, which could lead to their death, as well as instability of the
neuromuscular junction (Deschenes, 2011; Hepple and Rice, 2016). The
process of sprouting appears to be finite, with individual motor neurons
being limited in the number of muscle fibres they can sustain (Rafuse et al.
1992). The latter might explain the greater success rate of collateral
sprouting in older compared to very-old adults (Gilmore et al. 2018;
Piasecki et al. 2018). Overall however, studies indicate that reinnervation
leads to a reduction in the estimated number of MUs (Gooch et al. 2014) in
older populations (Gilmore et al. 2017; McNeil et al. 2005; Piasecki et al.
2018; Power et al. 2016a). The rate of reduction in the estimated number of
MUs is ~1% per year between the third and sixth decades, but thereafter
accelerates to ~2% a year (Campbell et al. 1973; McNeil et al. 2005;
Tomlinson and Irving, 1977).
Despite the process of reinnervation, its finite nature might eventually lead
to the death of motoneurons, which has been suggested to preferentially
occur in motoneurons innervating fast-twitch muscle fibres (Kanda and
Hashizume, 1989). The latter might potentially explain the reduction in MU
discharge rates and the slowing of contractile properties. Indeed, discharge
rates of MUs during moderate- and high-intensity contractions have
consistently been shown to be lower in older compared to younger adults
(Dalton et al. 2010; Kirk et al. 2018; Klass et al. 2008).
11.1.2 The influence of synaptic inputs from spinal

and supraspinal centres
Whilst the actions of the muscles are dependent on the output from
motoneurons, the activity of the latter is dependent on the synaptic inputs
198 Chapter 11
that they receive. Thus, the age-related changes at the level of the MU are
determined by the gain of the neuromuscular system, i.e., the ratio of the
output to the input (Hunter et al. 2016). The synaptic inputs to the
motoneurons originate from numerous sites in the CNS. This section will
focus on the reflex responses that alter motoneuron excitability through the
afferent pathway, as well as inputs originating from the supraspinal centres
emphasising those related to the primary motor cortex.
11.1.3 Reflex inputs to motoneurons

Aging has been associated with a concomitant reduction in responses from
the afferent sensory receptors to spinal motoneurons. The H-reflex has been
shown to be lower in amplitude in older adults when compared to young
(Figure 11.1), and has often been related to increased presynaptic inhibition
(Kallio et al. 2010; Morita et al. 1995; Sabbahi and Sedgwick, 1982;
Scaglioni et al. 2002). There is also a reduction in peripheral nerve
conduction velocity with advancing age (Dorfman and Bosley, 1979;
Rivner et al. 2001), possibly stemming from the loss of large-diameter
axons (Kawamura et al. 1977), smaller density of both myelinated and
unmyelinated neurons as well as reduced internodal length (Doherty and
Brown, 1993; Jacobs and Love, 1985; Metter et al. 1998; Scaglioni et al.
2002), resulting in a general slowing of responses. Based on the prolonged
latencies of the H-reflex, but no change in the latency of direct motor
response with advancing age, it has been suggested that aging might affect
sensory afferent axons to a greater extent than efferent motor axons
(Scaglioni et al. 2002). However, further investigation, employing a more
robust measure of conduction velocity by calculating conduction times
(Udupa and Chen, 2013), indicates that it is actually the motor axons that
seem to be more affected in older age, compared to sensory axons and
conduction capacity of central structures (Škarabot et al. 2019).
Figure 11.1. The difference between maximal H-reflex during an isometric

submaximal contraction in a young and an older adult. The downward pointing
arrows denote the point of stimulus. Data from Škarabot et al. (2019a).
11.1.4 Cortical inputs to motoneurons

Unlike the loss of spinal motoneurons, the number of cortical neurons
appears to be unchanged in older populations (Salat et al. 2004). However,
aging is accompanied by reductions in the size of cortical neuronal cell
bodies (Ward, 2006), and reduced white (Marner et al. 2003) and grey
(McGinnis et al. 2011; Salat et al. 2004) matter volume, which have been
associated with decreases in motor performance (Kennedy and Raz, 2005).
Furthermore, instability of neuromuscular transmission has been observed
in aging adults (Power et al. 2016a). With regards to the latter, latencies of
motor evoked potentials have been shown to be longer in older individuals,
which might stem from age-related alterations in temporal characteristics of
interneuronal circuitry (Opie et al. 2018).
Aging has been associated with decreased interhemispheric inhibition

(Mattay et al. 2002; Ward, 2006), shorter transcranial magnetic stimulation-
induced silent periods (Oliviero et al. 2006; Sale and Semmler, 2005) and
reduced intracortical inhibition (Heise et al. 2013; Marneweck et al. 2011;
Opie and Semmler, 2016). This decreased inhibition could result in
inappropriate activation of motor units leading to unnecessarily greater
muscle activation and reduced motor control (Johnson et al. 2017; Seidler
et al. 2010), particularly during fine motor tasks (Shinohara et al. 2003).
However, the findings pertaining to the indices of corticospinal excitability,
such as the size of motor evoked potentials and the slope of the input-output
relationship of transcranial magnetic stimulation have been equivocal
(Bhandari et al. 2016), with studies showing similar (Hassanlouei et al. 2017;
Smith et al. 2011; Stevens-Lapsley et al. 2013) or reduced (Oliviero et al.
2006; Pitcher et al. 2003; Sale and Semmler, 2005; Škarabot et al. 2019)
corticospinal excitability in older adults compared to young. Similarly,
results from paired-pulse stimulation measures, such as intracortical
inhibition and facilitation, have been mixed (Bhandari et al. 2016).
Furthermore, the duration of the silent period has been found to be
unchanged (Hunter et al. 2008; Rozand et al. 2017; Škarabot et al. 2019;
Stevens-Lapsley et al. 2013) or shorter (Oliviero et al. 2006; Sale and
Semmler, 2005) in older adults. These discrepancies could be multifactorial
(Hassanlouei et al. 2017), ranging from biological sex, contractile state
(relaxed vs. active) and the muscle investigated (upper vs. lower limb).
Whilst most of the aforementioned studies have assessed responses in
isometric tasks or at rest, a recent investigation suggests that corticospinal
responses in older adults are not dependent on contraction type (Škarabot et
al. 2019).
200 Chapter 11
Interestingly, the age-related changes in intracortical inhibition, which

reflect the state of neurotransmitters in the brain (McGinley et al. 2010;
Opie and Semmler, 2016), have been linked to the capacity for
neuroplasticity (Cash et al. 2016). As such, the latter might be reduced in
older adults (McNeil and Rice, 2018; Opie et al. 2018). Indeed, a recent
study indicates the age-related shift in temporal characteristics of the
interneuronal cortical circuitry could predict the ability to induce cortical
plasticity (Opie et al. 2018). Investigation of supraspinal responses in older
adults is thus not only important in elucidating the age-related changes in
corticospinal input that can alter synaptic input at the motoneuronal level,
but also in explaining the potential mechanisms of the neuroplastic response
to different types of exercise, which is crucial for informing clinical practice.
11.2 Reduction in motor performance in healthy aging

adults
As a result of neuromuscular alterations described in the preceding section,
aging adults exhibit reductions in motor performance during both maximal
and submaximal contractions. Within the population of older adults
however, there might be differences depending on age, with very old adults
(> 80 years old; Hunter et al. 2016) usually exhibiting significantly greater
decrements in motor performance compared to old adults (60-80 years old).
However, even when matched for age and sex, great heterogeneity of
responses is typically observed in older compared to young adults (Degens
and Korhonen, 2012; Rantanen et al. 1998; Vanden Noven et al., 2014).
Furthermore, older adults exhibit greater trial-to-trial variability (Degens
and Korhonen, 2012; Rantanen et al. 1998; Vanden Noven et al. 2014). The
origin of this greater heterogeneity has been ascribed to age-related changes
in the neuromuscular system (Hunter et al. 2016) and needs to be taken into
consideration when investigating motor performance. The purpose of this
section is to provide an overview of the age-related decrements and
variability in motor performance measures that are pertinent to exercise
performance as well as activities of daily living.
11.2.1 Motor performance during maximal contractions

Muscle strength
Aging is usually accompanied by a reduction in isometric strength (Doherty,

2003; Grabiner and Enoka, 1995; McNeil et al. 2005; Piasecki et al. 2018),
which parallels the age-related reduction in muscle mass (Frontera et al.
2000; Metter et al. 1999). Furthermore, aging adults exhibit lower specific
force, i.e., force per unit of cross-sectional area, which is explained by the
greater proportion of intramuscular fat and connective tissue (Goodpaster et
al. 2008; Schaap et al. 2013). Cross-sectional studies show that the average
age-related loss in isometric strength is ~10% per decade from ~50 years of
age onwards, with acceleration of this decline in very old adults (Hunter et
al. 2000; Lindle et al. 1997). However, longitudinal studies suggest that this
decline might be underestimated (Frontera et al. 2000; Metter et al. 1999).
The degree of age-related strength loss might also vary across different
muscle groups (Doherty, 2003), with bigger muscle groups such as knee
extensors often exhibiting a greater decline in strength compared to hand,
arm or lower leg muscles (Frontera et al. 2000; Hunter et al. 2000; Janssen
et al. 2000; Klass et al. 2011; Kwon et al. 2011). This could be explained by
variability in the rate of sarcopenia (Gilmore et al. 2017; Morat et al. 2016;
Piasecki et al. 2018) and the associated failure to expand the MU size to
compensate for a reduction in the number of MUs (Piasecki et al. 2018),
which might be related to the variability of use across muscles in activities
of daily living. Nevertheless, even when older adults might not present a
deficit in the generation of maximal force, underlying neural changes
associated with aging could still be present (McNeil et al. 2005; Škarabot et
al. 2019). The rate of strength loss could also differ between sexes, with
aging males possibly exhibiting a greater decline in isometric strength
compared to age-matched females (Ditroilo et al. 2010; Wu et al. 2016).
Similar to maximal isometric contractions, aging adults exhibit a reduction

in strength during shortening contractions compared to the young, with the
age difference being augmented by increased velocity of the contraction
(Raj et al. 2010). The latter might be related to reduced maximal shortening
velocity of fast-twitch fibres (Krivickas et al. 2001; Larsson et al. 1997),
altered muscle architecture (Thom et al. 2007) and possibly lower maximal
MU discharge rates (Klass et al. 2008). Conversely, strength during
lengthening contractions is better maintained in older age (Roig et al. 2010),
as evidenced by greater lengthening to isometric strength ratio irrespective
of contraction velocity (Figure 11.2; Power et al. 2015). This has largely
been attributed to muscle properties such as slower cross-bridge kinetics
and greater stiffness of the muscle-tendon unit, rather than age-related
alterations in the CNS (Klass et al. 2005; Larsson et al. 1997; Power et al.
2016b; Power et al. 2015).
202 Chapter 11
Figure 11.2. Age-related differences in the ratio of peak torque during lengthening
and isometric dorsiflexion at two different angular velocities. Data from Škarabot et
al. (2019a, 2019b).
Muscle power
Whilst muscle strength is typically used as an indicator of neuromuscular

adaptations with aging, muscle power tends to decline at a greater rate in
comparison with strength in older age (McNeil and Rice, 2007; Raj et al.
2010; Reid and Fielding, 2012; Thom et al. 2007), and this decline typically
increases as a function of contraction velocity (Callahan and Kent-Braun,
2011; Lanza et al. 2003; Reid and Fielding, 2012). This is particularly
relevant since muscle power seems to be a determinant of performance of
functional daily tasks (e.g., stair climbing, rising from a chair) and is a better
predictor of functional ability and limitations in older age (Reid and
Fielding, 2012).
The age-related loss in power is related to both neural and muscular

mechanisms. With regard to the latter, the age-related decline in muscle
power has been associated with reduction in muscle mass, alterations in
muscle architecture (Thom et al. 2007), and the number and size of type II
muscle fibres and their accompanied shortening velocity (Krivickas et al.
2001; Larsson et al. 1997) which occurs regardless of physical activity
levels (Power et al. 2016c). The rate at which an aging muscle can produce
force is reduced in both voluntary and electrically-evoked conditions
(Callahan and Kent-Braun, 2011; Hunter et al. 1999; Klass et al. 2008;
Molenaar et al. 2013). However, the age-related decline in rate of force
development during electrically-evoked contractions is less than in
voluntary contractions (Klass et al. 2008), suggesting that alterations in
neural drive are responsible for reduced rate of force production in older
age. Klass and colleagues have shown that the discharge rate of MUs
declines concurrently with the rate of force production in older adults and
that this is related to inability of older motor units to sustain a high discharge
rate during successive MU discharges (Klass et al. 2008). It has been
suggested that the duration of motoneuron afterhyperpolarisation, that
seems to continuously increase throughout the entire lifespan (Piotrkiewicz
et al. 2007), could at least partially explain the reduced ability to discharge
MUs at a fast enough rate in older age (Baudry et al. 2007).
Voluntary activation
The level of voluntary activation (VA), defined as the level of ability of the
CNS to activate the muscle, has been shown to be either lower (De Serres
and Enoka, 1998; Hunter et al. 2008; Morse et al. 2004; Shinohara et al.
2003; Yoon et al. 2008) or similar (Dalton et al. 2009; Jakobi and Rice, 2002;
Molenaar et al. 2013) in older compared to younger adults. However, a
critical consideration when performing measures of VA is adequate
familiarisation. This is corroborated by the ability to significantly improve
one’s VA in one practice session or even within a practice session, a finding
typical in older adults (Hunter et al. 2008; Jakobi and Rice, 2002). Indeed,
when sufficient practice is performed, older adults exhibit similar levels of
VA during maximal isometric contractions (Hunter et al. 2008; Jakobi and
Rice, 2002; Molenaar et al. 2013; Yoon et al. 2008), as well as during
maximal dynamic tasks (Klass et al. 2005; Rozand et al. 2017; Wilder and
Cannon, 2009).
The lack of difference in VA notwithstanding, older adults exhibit

significantly greater variability in VA levels across trials and among
individuals (Figure 11.3; Jakobi and Rice 2002; Hunter et al. 2008; Rozand
et al. 2017). This has been suggested to be of relevance to tasks of daily
living as they typically require only one attempt, thus resulting in inadequate
activation (Rozand et al. 2017).
204 Chapter 11
Figure 11.3. Variability in voluntary activation across ten trials in young and older
adults. Adapted from Hunter et al. (2008).
11.2.2 Control of muscle force output during submaximal tasks

Whilst most studies assess the effect of aging on motor performance via
some type of maximal performance measure (e.g., maximal strength, power
etc.), submaximal performance is considered less often (Bellew, 2002).
However, the latter may be of greater functional significance for the aging
population, given that functional issues (e.g., loss of balance) are more
likely related to attenuated control of muscular force than its maximal
capacity (Shepard et al. 1993).
There is a plethora of evidence suggesting that older individuals exhibit

greater difficulty in controlling the force output of the muscle during
submaximal contractions (Enoka et al. 2003). Control of force is quantified
by variability of force output about a mean value as standard deviation or
coefficient of variation (Enoka et al. 2003). Generally, the differences in
control of muscle force between young and older adults are influenced by
the contraction intensity, muscle group, contraction type, and physical
activity of the individual (Enoka et al. 2003). The absolute force variability
increases with increases in contraction strength regardless of age due to an
increase in MU activity with increased magnitude of contraction (Burnett et
al. 2000; Galganski et al. 1993; Keen et al. 1994; Laidlaw et al. 2000; Tracy
and Enoka, 2002). However, the variability appears to be a bigger challenge
for the elderly particularly during low (10% MVC) or higher (>50% MVC)
intensity isometric contractions (Graves et al. 2000; Tracy & Enoka, 2002).
Whilst the control of muscle force is generally compromised in older adults
compared to the young, this finding is not entirely consistent across muscle
groups, with some investigations in elbow flexor (Graves et al., 2000) and
knee extensor (Tracy and Enoka, 2002) muscles not showing a difference
between young and older individuals. However, older individuals exhibit

greater variability across trials when compared to their young counterparts
(Christou et al. 2001; Christou and Carlton, 2001), likely due to impaired
ability to reproduce timing characteristics of the contraction (Christou et al.
2002). Interestingly, there seems to be a lack of relationship between
maximal strength and torque variability during submaximal contractions in
older adults (Burnett et al. 2000).
Usually, older adults have a greater difficulty controlling the force output
during dynamic contractions, with the difficulty being greater at faster
contraction velocities (Burnett et al. 2000; Graves et al. 2000; Laidlaw et al.
2000, 2002; Christou et al. 2003). Interestingly, variability in submaximal
force production seems to be especially increased during lengthening
contractions in older people with a history of falling when compared to age-
matched peers without any history of falling (Carville et al. 2007).
Furthermore, lengthening contractions seem to be difficult to control by
older people during functional activities (Hughes et al. 1996; Moxley
Scarborough et al. 1999), and many falls seem to occur during such
activities (Jacobs, 2016; Startzell et al. 2000) suggesting that steadiness
during lengthening contractions is important for functional ability (Carville
et al. 2007). Force accuracy is also impaired with aging and is usually due
to overshooting the target force, making the movement uneconomical
(Hortobágyi et al. 2001). This difference suggests poorer ability of older
adults to exert a force with precision during isometric contractions and
greater variability of trajectory during movement (Tracy and Enoka, 2002),
possibly leading to greater incidence of falls (Bellew, 2002). As evidenced
by many investigations suggesting that either strength or skill (Kornatz et
al. 2005) training improves force steadiness, it is clear that muscle force
control is dependent on physical activity status of an individual.
The greater difficulty of controlling muscle force in aging adults is mainly

related to age-related alterations in the neuromuscular system. The loss of
skeletal muscle fibres, apoptosis of motoneurons and incomplete re-
innervation of remaining muscle fibres (Doherty, 2003), resulting in fewer,
but larger MUs producing larger and more variable MU action potentials
might be responsible for poorer control of muscle force in older individuals
(Galganski et al. 1993). The activity in supraspinal centres, such as cortical
and subcortical areas as well as frontal lobes (putamen, insula and
contralateral superior frontal gyrus; Yoon et al. 2014) has also been
associated with difficulty in controlling the muscle force output.
Furthermore, aging is associated with impairments in the sensory system,
such as joint-position sense, touch, kinesthesis and proprioception (Cole,
206 Chapter 11
1991; Desrosiers et al. 1996; Henningsen et al. 1995; Sathian et al. 1997;
Skinner et al. 1984), which could influence afferent feedback mechanisms
associated with force control (Hortobágyi et al. 2001). Recent investigations
indicate, however, that greater variability of MU discharge rates and
common synaptic input can largely explain greater variability of force
output in older age (Castronovo et al. 2018; Feeney et al. 2018).
11.2.3 Fatigability
Since performance fatigability is at least partially mediated by alterations in
different loci within the CNS, it seems reasonable to hypothesise that
fatigability will be affected by age. The greater variability in performance
in older adults is extended to repeated motor tasks (Hunter et al. 2008; Kent-
Braun et al. 2014; Senefeld et al. 2017; Vanden Noven et al. 2014) and
perhaps related to variability in VA (Hunter et al. 2016), suggesting a neural
contribution. However, in maximal and submaximal isometric tasks to
failure, older adults are usually less fatigable than young (Kent-Braun,
2009); this is apparent even when matched for strength (Hunter et al. 2005)
and occurs independently of biological sex (Hunter et al. 2004). The
mechanisms associated with greater fatigue-resistance in older adults, are
mainly constrained to the processes occurring within the muscle, such as
slower contractile properties, lower proportion of type IIa fibres, and less
dependence on the production of energy through the glycolytic metabolism
(Callahan et al. 2016; Hunter et al. 1999; Kent-Braun, 2009), leading to
lower accumulation of metabolic by-products (e.g., inorganic phosphate and
hydrogen ions) (Lanza et al. 2007). This behaviour seems to be dependent
on age such that, in very old adults, this apparent fatigue-resistance during
isometric tasks is diminished (Justice et al. 2014), perhaps due to
accelerated age-related alterations within the neuromuscular system. It has
been suggested that there might be a threshold at ~75 years of age when the
output of the neuromuscular system declines at a more rapid rate,
influencing, among others, fatigability (Hunter, 2018).
On the other hand, age-difference in fatigability is diminished (Callahan et

al. 2009; Dalton et al. 2012; Yoon et al. 2013) or even greater in older adults
(Dalton et al. 2010; McNeil and Rice, 2007; Sundberg et al. 2018; Wallace
et al. 2016) during dynamic tasks and appears to be dependent on
contraction velocity, but is independent of biological sex (Sundberg et al.
2018). These findings are somewhat dependent on the muscle studied
however, with lower compared to upper limb muscles seemingly becoming
more fatigable during dynamic contractions in older age (Senefeld et al.
2017), potentially due to greater degree of disuse and consequent greater
age-related reductions in strength and power (Hunter et al. 2000; Raj et al.
2010; Venturelli et al. 2015). The mechanisms responsible for greater
fatigability of older adults at higher contraction velocity might involve the
processes related to contractile velocity (Baudry et al. 2007; Callahan et al.
2009; Yoon et al. 2013) and muscle bioenergetics, resulting in greater
accumulation of metabolic by-products (Sundberg et al. 2019).
The processes within the CNS might still play a role in age-related
differences in fatigability, as evidenced by greater fatigability in older
compared to young adults when imposing a high cognitive challenge during
an isometric task to failure (Pereira et al. 2015). The mechanisms of this
behaviour are less understood, but imposition of a cognitive task has been
shown to result in greater variability of force output (Pereira et al. 2015;
Vanden Noven et al. 2014), which has been related to greater oscillations in
the common synaptic input to motoneurons (Pereira et al. 2019). The
increased fatigability in older adults during a high cognitive demand task
might have an important application in activities of daily living as those
regularly involve a dual-task challenge (Hunter et al. 2016).
11.3 Summary
Healthy aging is associated with many alterations in the neuromuscular
system ranging from the loss and adaptations of motor units, the synaptic
input the motoneurons receive from the somatosensory receptors as well as
the cortical areas, potentially influencing an individual’s ability to adapt to
new stimuli. These age-related modifications in the neuromuscular system
occur regardless of pathology but, can be, to an extent, slowed down with
higher levels of physical activity.
The age-related alterations in the neuromuscular system have a profound

effect on motor performance resulting in weaker and less-powerful maximal
contractions, reduced ability to control the force output during submaximal
contractions and more fatigable muscles, at least during dynamic tasks.
These performance decrements are exacerbated in very old adults. An
important consideration for exercise and activities of daily living is that
older individuals tend to exhibit greater variability in motor performance
across trials and greater heterogeneity of behaviour across individuals. This
variability is intensified when a cognitive task is imposed on a motor task
and leads to greater fatigability, which has implications for activities of
daily living that often include a dual-task scenario. Whilst changes in
maximal strength are often used to indicate the extent of age-related
alterations in the neuromuscular system, its relationship with functional
208 Chapter 11
performance remains elusive. On the other hand, the age-related loss of

maximal power, which is typically of greater magnitude than the decline in
maximal strength, is a good predictor of functionality and independence in
older age. A challenge for researchers in the future is to investigate the age-
related adaptations in the neuromuscular system using longitudinal study
designs that will likely provide greater insight into the mechanisms of age-
related decline in the output of the neuromuscular system and their effect
on performance during exercise and tasks of daily living.
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CHAPTER 12
CROSS-EDUCATION
ASHLYN K. FRAZER, PHD

AND DAWSON J. KIDGELL, PHD
12. Background
The purpose of this chapter is to introduce and discuss the phenomenon of
cross-education. Cross-education describes the strength gain in the opposite,
untrained limb following a unilateral strength training program. Since the
mid-19th century, compelling evidence has demonstrated the existence of
cross-education following a number of unilateral strength training
paradigms including isometric and dynamic training protocols in both the
upper and lower limb. Given the extensive interest of the research community
into this phenomenon, a number of methods have been employed to explore
the potential mechanisms underpinning the cross-education effect. This
includes surface electromyography (sEMG) recordings (Cannon and
Cafarelli 1987, 1992; Mason et al. 2017), electrical stimulation of peripheral
nerves (Fimland et al. 2009; Lagerquist et al. 2006), transcranial magnetic
stimulation (TMS) (Goodwill et al. 2012; Hortobágyi et al. 2011; Manca et
al. 2016; Mason et al. 2017) and functional magnetic resonance imaging
(fMRI) (Farthing et al. 2007; Palmer et al. 2013; Ruddy et al. 2017).
Currently, the physiological mechanisms that underlie the cross-education
phenomenon remain unclear. However, there is a consensus that the cross-
education of strength is a result of changes along the entire neuroaxis. In
light of this, adaptations within the central nervous system (CNS) that
involve both structural and functional changes within cortical motor and
non-motor regions will be discussed in this chapter.
12.1 Evidence of cross-education

Since the first documentation of cross-education in the 19th century
(Scripture et al.1894), there are now many published reports that have
Cross-education 223
established that the cross-education of muscle strength is a real phenomenon

(Manca et al. 2017). The magnitude of cross-education to the untrained limb
has been shown to be proportional to the strength gain of the trained limb
(see Figure 12.1 for experimental data example; Zhou 2000; Munn et al.
2005).
A recently published meta-analysis by Manca et al. (2017) revealed a pooled

cross-education effect on muscle strength of 11.9%. Following a
quantitative analysis of 31 studies which drew data from 785 subjects,
Manca et al. (2017) concluded that the cross-education effect was conducive
to the entire muscle action spectrum across both upper and lower limbs.
Furthermore, the cross-education effect was observed following various
strength training paradigms involving isometric, concentric, eccentric, and
isotonic-dynamic contraction types.
12.2 Exercise prescription parameters

Although the cross-education model evidently exists in both the upper and
lower limb, it appears that the cross-education effect is greater for the lower-
limb musculature with a 16.4% increase in contralateral strength reported
compared to 9.4% increase for the upper limb (see Figure 12.2).
224 Chapter 12
Within the upper limb cross-education studies, the hand/wrist muscles and
elbow flexors have predominantly been the focus, while the lower limb
literature has investigated the knee extensors and ankle musculature (Manca
et al. 2017). Interestingly, it should be highlighted that not only was the
magnitude of strength transfer less for the upper limb, but also the individual
responses to the unilateral strength training protocols were more variable. It
has been suggested that the notable difference in strength gains of the
untrained limb between the upper and lower body may be due to the
capacity to voluntarily activate these diverse muscle groups (Frazer et al.
2018). For example, given the functional requirements of the upper limb,
the capacity to increase strength may be limited to already high voluntary
cortical activation levels (Lee et al. 2009a) when compared to the lower
limb (Ross et al. 2007; Sidhu et al. 2009). Although the magnitude of cross-
education appears to be different between the upper and lower limbs,
contraction type (i.e., isometric, concentric, eccentric and isotonic) has also
been shown to influence the magnitude of cross-education (Farthing et al.
2005; Manca et al. 2017).
Despite all contraction types (isometric 8.2%; concentric 11.3%; eccentric

17.7%; isotonic-dynamic training 15.9%) significantly increasing contralateral
strength following unilateral strength training, it appears the magnitude of
strength transfer differs (see Figure 12.3).
Cross-education 225
At present, the majority of the cross-education literature has employed

isometric and concentric training paradigms (Carroll et al. 2006; Manca et
al. 2017; Munn et al. 2004). However, this particular exercise prescription
bias may change given that Manca et al. (2017) has demonstrated that
eccentric and dynamic contractions are more powerful mediators of strength
in the exercising and non-exercising limbs.
12.3 Mechanisms of cross-education

Currently, the physiological mechanisms that underlie the cross-education
phenomenon remain unclear. A recent review by Frazer et al. (2018)
concluded that the neural adaptations mediating the transfer of muscular
strength most likely represents a continuum of change along the entire
neuroaxis, involving both structural and functional changes within cortical
motor and non-motor regions. Furthermore, these changes are likely to be
at both a cortical and subcortical level including increased corticospinal
excitability, reduced cortical inhibition, reduced interhemispheric inhibition,
changes in evoked twitch forces and new regions of cortical activation (see
Figure 12.4).
226 Chapter 12
Figure 12.4 Potential sites of neural adaptation to cross-education include (1)

changes in (A) supplementary motor area, (B) primary motor cortex, (C) middle
temporal gyrus, (D) inferior temporal gyrus, (E) occipital lobe, (F) cerebellum, (2)
changes in interhemispheric inhibition, (3) changes in TMS measures confined to
the ipsilateral “untrained” primary motor cortex (SICI), (4) changes along the
corticospinal tract ipsilateral to the trained limb (excitability and inhibition), (5)
changes in motoneurone excitability, and (6) changes in VATMS, raw EMG response
(MEP) produced by cortical stimulation during maximal contraction, as well as the
superimposed twitch produced by cortical stimulation during maximal contraction
(Adapted from Frazer et al. 2018).
At present, most studies have used TMS to explore the excitatory and
inhibitory circuits within the primary motor cortex (M1) to provide valuable
objective insights into the possible mechanisms of cross-education. Briefly,
single- and paired-pulse TMS can be used to measure various parameters of
corticospinal plasticity involving changes confined to the M1 and changes
along the corticospinal tract (see Chapter 3 for a comprehensive overview).
Recent evidence from TMS studies has highlighted the significant role of
the M1 ipsilateral to the training limb in mediating the cross-education
effect (Frazer et al. 2017; Hendy et al. 2015; Hortobágyi et al. 2011; Lee et
al. 2010). Specifically, cross-education studies have reported increased
corticospinal excitability (Kidgell et al. 2015), decreased corticospinal
inhibition (Coombs et al. 2016; Hendy et al. 2015), reduced interhemispheric
inhibition (IHI) (Hortobágyi et al. 2011; Zult et al. 2016) and increased
voluntary activation (Lee et al. 2009b) in the M1 ipsilateral to the training
limb (Numbers 2-6 in Figure 12.4). The considerable amount of evidence
gives rise to the consensus that the neural mechanisms mediating cross-
education appear to be related to bilateral cortical activity whereby, during
unilateral strength training, there is concurrent activation in both cerebral
Cross-education 227
hemispheres that are involved in motor output (Frazer et al. 2017; Hendy
and Kidgell 2014; Lee et al. 2010). Undoubtedly, it should be highlighted
that the extensive neural network between hemispheres via the corpus
callosum provides a platform to share neuromuscular adaptations obtained
by the trained side (Number 2 in Figure 12.4). However, given the breath of
TMS evidence, it appears that the ‘spill-over’ of neural drive from the
trained side to the untrained side resulting in corticospinal adaptations of
the untrained limb has become, at present, the most established theory of
cross-education (Frazer et al. 2018).
With advancing technologies, the use of neuroimaging techniques has

emerged as a promising technique enabling the investigation of new regions
of brain activation as potential sites of adaptation following cross-education
(Number 1 in Figure 12.4). Functional magnetic resonance imaging (fMRI)
has been used to provide evidence of the structural and functional
connectivity patterns within the brain following cross-education training.
For example, a recent acute cross-education study demonstrated that the
increase in performance of the untrained limb was 83% of that observed for
the trained limb, and that there was a significant increase in functional
connectivity in the resting motor network between the right and left
supplementary motor area (Ruddy et al. 2017). Two longer-term cross-
education studies have also used neuroimaging techniques to determine
potential sites and patterns of cortical activation (Farthing et al. 2007;
Palmer et al. 2013). Farthing et al. (2007) demonstrated an increase in
strength of the left untrained limb by 47% which was accompanied by an
increase in activation of the sensorimotor cortex and bilateral M1 following
a six-week unilateral strength-training intervention. This was followed by
Palmer et al. (2013) who examined the training-related effects of cross-
education on structural connectivity and patterns of cortical activation.
Following four-weeks of strength training of the lower limb, strength
training increased plantar flexion strength by 30% in the untrained limb;
however, this change was not accompanied by any structural cortical
changes. Unfortunately, a comprehensive explanation of the mediating
neural mechanisms of cross-education remains elusive suggesting that there
is a need to combine neuroimaging techniques with electrophysiological
techniques, such as single- and paired-pulse TMS and quantitative
electroencephalography, to determine the spatial and temporal effects of
cross-education (Frazer et al. 2018).
228 Chapter 12
12.4 Interventions to enhance the cross-education effect

Recently, there have been some innovative techniques used to enhance the
cross-education effect. There is now some preliminary evidence to show
that the cross-education of strength may be enhanced by using transcranial
direct current stimulation (tDCS, see Chapter 5), a simple and cost effective
technique whereby electrodes are placed over the M1 of a target muscle and
low levels of electricity are passed through to the underlying cortical
neurons (Frazer et al. 2017). Both acute and chronic studies now show that
the cross-education of strength is enhanced when tDCS is applied to the
ipsilateral M1 before or during the training intervention (Frazer et al. 2017;
Hendy and Kidgell 2014; Hendy et al. 2015). In a similar manner, applying
electrical stimulation over the training muscles (Hortobágyi et al. 1999) and
whole-body vibration training (WBV) have also been used to enhance the
cross-education effect (Goodwill and Kidgell 2012; Lapole et al. 2013).
12.4.1 Transcranial direct current stimulation

and cross-education
tDCS has emerged as a promising, non-invasive technique to improve motor
performance in both young and older adults (Goodwill et al. 2015; Kidgell
et al. 2013). The application of tDCS over the M1 induces transient,
polarity-specific changes in the neuronal resting membrane potential
(Nitsche et al. 2008), with increases in excitability and performance
improvements lasting up to 90 minutes following the cessation of
stimulation (Lang et al. 2005). However, similar to the TMS strength-
training studies (Kidgell et al. 2017), the reproducibility of neuroplasticity
inducing protocols, like tDCS, remains a challenge (Heroux et al. 2015;
Heroux et al. 2017). However, recently, tDCS has been used experimentally
to enhance the cross-education of muscle strength. For example, Hendy and
Kidgell (2014) reported an increase in maximal strength and cross-
activation of the contralateral untrained limb (left hand) following a single
session of anodal tDCS applied to the ipsilateral right M1 during strength
training of the right hand (Hendy and Kidgell 2014). In a follow-up study,
Hendy et al. (2015) applied anodal tDCS to the ipsilateral right M1 during
a two-week strength-training intervention and showed that the effects of
cross-education were prolonged, and that tDCS retained strength of the
untrained limb compared to sham tDCS and strength-training (Hendy et al.
2015).
Cross-education 229
Although this data is interesting and has potential applications in the clinical
environment, there is a greater need to identify the optimal timing of tDCS
to the ipsilateral M1 (i.e., before, during or after training). In an attempt to
address this, we recently demonstrated a substantial increase in maximum
strength of the untrained left biceps brachii when anodal tDCS was applied
to the ipsilateral M1 (right hemisphere), prior to a single bout of strength
training of the right arm only, exploiting the principles of homeostatic meta-
plasticity (Frazer et al. 2017). Although preliminary evidence indicates that
tDCS is a promising tool, the timing of application needs to be rigorously
investigated following both single-session and longer-term training periods
(>2 weeks). Undoubtedly, combining robust investigation techniques, such
as TMS and fMRI, would aid in quantifying the potential opportunity to
augment the cross-education of muscle strength.
12.4.2 Electromyostimulation during cross-education

Similar to voluntary contractions evoked during unilateral strength training,
there is good evidence to show that the application of electrostimulation
during strength training increases MVC force production of an untrained
homologous muscle following unilateral strength training (Bezerra et al.
2009; Hortobágyi et al. 1999). There are now several studies that have
revealed electrical stimulation of a muscle, compared with voluntary
contraction, evokes specific effects at the level of the cerebral cortex and
increases force in an untrained limb (Bezerra et al. 2009; Hortobágyi et al.
1999). Hortobágyi et al. (1999) reported that electrical muscle stimulation
induced a contralateral increase in strength of 21% following four-weeks of
isometric strength training, which was comparable to that induced by
voluntary isometric strength training alone. In addition, six weeks of
eccentric strength training with electrical muscle stimulation induced an
increase in strength of 104% compared to 23% for voluntary eccentric
training alone (Hortobágyi et al. 1999; Oakman et al. 1999). Interestingly,
electrical stimulation training is also more effective than voluntary strength
training when imparting a cross-education effect (Bezerra et al. 2009).
Because the cross-education effect following electrical stimulation training
is not associated with any changes in the cross-sectional area of the
contralateral untrained muscle (Bezerra et al. 2009), the physiological
mechanisms underpinning the changes in strength seem to reside within the
cerebral cortex. For example, when electrical muscle stimulation is used to
induce left-wrist flexion, both TMS induced MEPs and the H-reflex
increase in the right resting-wrist flexors (Hortobágyi et al. 2003). In a
similar manner, when electrical muscle stimulation is applied during
230 Chapter 12
voluntary contraction of the left-wrist flexors, TMS-induced MEPs are

increased, but the H-reflex in the right resting-wrist flexors is reduced
(Hortobágyi et al. 2003). These observations suggest that electrical muscle
stimulation and voluntary contractions are affected differently at a
supraspinal level in contralateral homologous muscles. This difference is
likely the result of increased sensory and nociceptive inputs that act at a
cortical level following electrical stimulation. Perhaps such inputs modify
motor output and interhemispheric pathways, which lead to an increase in
strength of the trained and untrained limb. Certainly, this hypothesis is
supported by changes in interhemispheric inhibition following unilateral
training (Hortobágyi et al. 2011; Howatson et al. 2011; Lee et al. 2010).
12.4.3 Whole-body vibration (WBV) training and cross-education

The recent emergence of WBV as a training technique has been of interest
to researchers due to its potential to improve neuromuscular function. Many
studies have reported increases in strength following an acute bout of WBV.
Similarly, increases in strength have also been demonstrated following a
period of strength training with the addition of WBV (Issurin 2005;
Nordlund and Thorstensson 2007; Rittweger 2010), suggesting that WBV
training may be an effective and alternative training technique for strength
development (Rittweger et al. 2003) and for enhancing cross-education
(Goodwill and Kidgell 2012). Given that the magnitude of strength gain in
the trained limb is an important proxy for strength transfer to the untrained
limb, we examined the effect of unilateral strength training with superimposed
WBV on the magnitude of cross-education (Goodwill and Kidgell 2012).
Healthy participants completed unilateral strength training, with or without
the application of WBV (35 Hz; 2.5 mm amplitude), three times per week
for three weeks. Strength increased by 41% in the trained limb following
strength training without WBV and by 55% with WBV. Interestingly, the
cross-transfer of strength was greater for the untrained limb (52%)
following WBV, with only a 35% transfer following training without WBV.
Further, after WBV training, there was an increase in corticospinal
excitability and a reduction in short-interval intracortical inhibition (SICI)
of the ipsilateral M1 suggesting that WBV training had a cortical effect
(Goodwill and Kidgell 2012). In a similar manner, 14 days of Achilles-
tendon vibration also increased the strength of a vibrated gastrocnemius and
the non-vibrated gastrocnemius muscle. The increase in strength of the non-
vibrated gastrocnemius was associated with a 41% increase in the volitional
wave (a measure of neural drive), but the H-reflex remained unchanged
(Lapole et al. 2013). These observations suggest that there could be
Cross-education 231
additional cross-education benefits following the application of vibration to

the training limb.
12.5 Cross-education and neuromuscular injury

Given the large body of evidence demonstrating the effect of cross-
education, the next step is to successfully translate this phenomenon into
clinical populations where, perhaps, the benefits of cross-education could
be best observed. As such, it has been postulated that the model of cross-
education may be a suitable candidate to attenuate the loss of function that
occurs with limb immobilisation. At present, five studies have investigated
the effects of cross-education in healthy participants undergoing a period of
immobilisation (Andrushko et al. 2018; Farthing et al. 2009, 2011;
Papandreou et al. 2013; Pearce et al. 2012, Figure 12.5).
Figure 12.5: The pooled data indicated that following unilateral resistance training,
muscular strength was attenuated (SMD 1.33, 95% CI 0.59, 2.08, P = 0.0005) in the
immobilized limb compared to the immobilized limb of the control group, with the
heterogeneity of results between the studies being high (I2 = 75%).
Interestingly, all studies have demonstrated attenuated strength loss, with

four of the investigations also displaying a sparing effect for muscle size.
Furthermore, Magnus et al. (2013) successfully translated the cross-
education model into a clinical population of women older than 50 years
who suffered a unilateral distal radius fracture, highlighting the promising
clinical effects of the cross-education model. Another highly plausible
application of cross-education is the restoration of bilateral limb symmetry
following stroke (Dragert and Zehr 2013). Indeed, preliminary evidence
from a recent meta-analysis has shown the positive effect of cross-education
on muscle strength in patients who have suffered a stroke (Ehrensberger et
al. 2016). Furthermore, this has given impetus to adapting the cross-
232 Chapter 12
education model for other clinical populations that may suffer from severely
weakened limbs due to various conditions such as multiple sclerosis (Frazer
et al. 2018).
12.6 Summary
A considerable amount of research has been dedicated to establishing the
phenomenon of cross-education and understanding the potential underlying
mechanisms. Strength training paradigms of both the upper and lower limb
using various contraction modes have shown promising results regarding
the increase in strength of the opposite, untrained limb. Consequently, the
focus of investigation has moved towards determining the prescription
parameters which result in the greatest strength gain of the opposite
untrained limb. Although there is strong TMS data demonstrating the role
of the ipsilateral M1 being a significant mediator of cross-education,
preliminary neuroimaging evidence also highlights the potential adaptations
of motor and non-motor regions of the brain contributing to this
phenomenon. Indeed, the existing cross-education literature is promising;
however, attention needs to shift beyond the focus of demonstrating a
transfer in strength to gains in functional tasks and recovery of motor
function in clinical populations.
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CHAPTER 13
USING ELECTROPHYSIOLOGY
TO UNDERSTAND RESPONSES FOLLOWING
CONCUSSION AND MILD BRAIN INJURY
ALAN J. PEARCE PHD

AND MICHAEL E. BUCKLAND MBBS PHD
13. Background
The international public health concern regarding the issue of mild
traumatic brain injury (mTBI) and concussion continues to grow.
Concussion in sport particularly has gathered notable interest. While it is
suggested that, short-term, a concussion injury increases risk of further
concussion (Guskiewicz et al. 2003), emerging evidence also points to
greater risk of musculo-skeletal injuries (Nordström et al. 2014; Herman et
al. 2016). Conversely, multiple concussions and repeated head trauma that
do not show overt signs or symptoms of concussion (known as sub-
concussion) increase the long-term risk of chronic neurological impairments
such as cognitive deficiencies and movement disorders (Ozolins et al. 2016),
and increased risk of neurodegenerative diseases, including Parkinson’s
disease, amyotrophic lateral sclerosis, dementias including Alzheimer’s
disease (Mackay et al. 2019), and chronic traumatic encephalopathy (CTE)
(McKee et al. 2014; McKee et al. 2016; Buckland et al. 2019).
As a result of this intensified concern, there has been an increase in the

exploration of the physiology of concussion. While physiological research
methods have focused on the metabolic changes post concussion (Giza and
Hovda 2001, 2014) and include neuroimaging, using electrophysiological
methods has several advantages. For example, electrophysiology provides
superior temporal resolution allowing for improved precision with neural
transmission and sensitivity to both functional and structural brain injury.
Further advantages include technologies that allow for point-of-care
238 Chapter 13
diagnostics, rapid acquisition, and ease of use with training, non-radiation

emitting and overall cost-effectiveness (Brooks et al. 2017).
This chapter will overview the functional injury definition of concussion,

then discuss the pathophysiology of concussion leading into the advantages
and disadvantages of the electrophysiological methods presented in this
chapter, and key variables measured in concussion/mTBI research. For in-
depth discussion about the basic principles of each technique, the reader is
directed to reviews by Bronzino (1995), Lee and Huang (2014), and Hallett
(2000). This chapter will also provide emerging evidence where
electrophysiological techniques have demonstrated value in quantifying the
time-course of acute concussion and recovery, as well as in studies
exploring the long-term effects of repeated concussions in contact sport
athletes.
13.1 The definition of concussion

Induced by biomechanical forces, a concussion may result following a
direct blow to the head, face, and/or the neck. However, a concussion can
also occur when a force of sufficient magnitude elsewhere on the body
transmits the impulse to the head (McCrory et al. 2013). A concussion
produces a complex pathophysiological process resulting in transient
abnormal functioning of the brain (Giza and Hovda 2001; McCrory et al.
2013) that can be observed with clinical signs and symptoms. However,
brain neuroimaging shows no signs of damage, thus concussion is currently
defined as a ‘functional injury’ (McCrory et al. 2017).
While the myth still prevails, loss of consciousness only occurs in 10-20%
of concussion injuries (Finch et al. 2013). Similarly, concussion does not
produce a stereotypical symptom response. While more common signs and
symptoms include one or more of the following: confusion, nausea,
headaches, postural instability, irritability or emotional labiality, amnesia,
blurred vision or inability to focus with eyes, slowed speech, and impaired
reaction times (Ropper 2008; McCrory et al. 2013), these symptoms may
vary between individuals, both in number and severity. Other less common,
but still noticeable, signs include sleep disturbance, anxiety and/or
depression (Finch et al. 2013; McCrory et al. 2013). Fatigue is also common,
but observed more as a symptom of chronic post-concussion symptoms
(Johansson and Rönnbäck 2014; Pearce et al. 2019b; Pearce et al. 2019c).
Using Electrophysiology to Understand Responses following 239
Concussion and Mild Brain Injury
13.2 Current standard to diagnose concussion

Standard clinical diagnoses in sport usually incorporate a head injury
assessment (HIA) instrument such as the Sports Concussion Assessment
Tool (SCAT). Currently, the latest version is the SCAT5 (Echemendia et al.
2017; McCrory et al. 2017). The SCAT5 is used as a sideline or pitch-side
HIA tool for suspected concussion. The SCAT5 can also be used as a
prognostic instrument, used in the clinic to assist in the decision for a player
to be deemed ‘clinically recovered’ and signed-off to return to training or
the next competitive event. Usually, this means that players are asymptomatic,
as determined by the clinician, and are also able to complete the various
subcategories contained within the evaluation tool. While still considered
the ‘gold-standard’ in diagnosis of concussion and decision on return to play
(McCrory et al. 2017), evaluations such as the SCAT can only be
administered by a clinician or ‘licenced health professional’ (McCrory et al.
2017) limiting return to play assessments to only elite or professionals teams
that have the financial ability to access a suitably qualified health or medical
practitioner. Despite this, there is growing apprehension that sideline
assessments are subjective, relying heavily on self-reporting or admission
of symptoms, and disparity in application of the evaluation between
practitioners (Brooks et al. 2017) leading to inconsistent decisions.
13.3 Objective measures to assess concussion

There are increased calls for a greater reliance on technologies to assist the
clinical diagnosis. Currently, standard clinical neuroimaging techniques
such as magnetic resonance imaging (MRI) and computerized tomography
(CT) scanning do not reveal abnormalities (McCrory et al. 2017).
Conversely, experimental neuroimaging techniques such as diffusion tensor
imaging (DTI) are able to determine changes in functional connectivity
between regions of the brain. Moreover, DTI has shown evidence of
disruption in white matter tract integrity following concussion injuries that
can be seen after one season (Merchant-Borna et al. 2016; Slobounov et al.
2017) or as a result of cumulative head trauma in retired football players
(Stamm et al. 2015). Additionally, magnetic resonance spectroscopy studies
have reported changes in brain metabolism following concussion (Vagnozzi
et al. 2010). Despite this emerging evidence, experimental neuroimaging
studies are expensive to complete and access to these technologies is limited,
making rapid point-of-care diagnostics and follow-up prognostic evaluations,
for return to play decisions, not feasible currently (Brooks et al. 2017).
240 Chapter 13
Brain physiology changes can also be detected via electrophysiology

techniques, and suggest the utility of electrophysiological biomarkers of
functional brain injury/concussion (Brooks et al. 2017; Pearce 2019).
Further, advances in these techniques now allow the added advantage of
portability for sideline or clubroom testing at the time of injury as well as
follow up in determining return to play decisions. To date, electrophysiological
techniques have been demonstrated to show disturbances and recovery in
brain activity following a concussion injury (Pearce et al. 2015), as well as
reflecting persistent alterations in brain function in those with a history of
concussions (De Beaumont et al. 2007b; De Beaumont et al. 2011a; Pearce
2017; Pearce et al. 2019b; Pearce et al. 2019c).
13.4 Electrophysiology to assess concussion

Electrophysiology covers a wide range of techniques available to study at
the micro level, such as the electrical properties of ion channels in a single
neuron, to macro level whole brain networks. Electrophysiology not only
allows for the understanding of how the brain works functionally, but also
provides an understanding of the physiological mechanisms associated with
neurological disorders and the potential effects and utility of pharmaceutical
interventions. However, for the purpose of this chapter, discussion on
electrophysiological techniques will be limited to non-invasive methods
that have been employed to study the brain following concussion. These
include electroencephalography (EEG), which includes quantitative EEG
(qEEG) which is also used to record visual and vestibular evoked potentials
(EPs), magnetoencephalography (MEG), and transcranial magnetic
stimulation (TMS). Generally speaking, these techniques directly sample
the electrical and electromagneteic fields instantaneously generated by
neuronal activity. This is in contrast to clinical neuroimgaging techniques
such as functional MRI (fMRI) that measures regional blood flow in the
brain, or positron emission tomography (PET) that scans regional brain
glucose metabolism or specific neuronal activity via radioactive tracer.
Whist useful in quantifying neuronal activity, fMRI and PET provide
indirect measurements of neuronal activity (Lee and Huang 2014).
While electrophysiology can measure ongoing electrical activity of the

brain and compare abnormal to healthy physiological activity, utilizing
event related potentials (ERPs) or evoked potentials (EPs) provides further
information on pathophysiological brain changes associated with
concussion injury. ERPs or EPs measure brain activity in response to a
stimulus event which may be cognitive, visual, vestibular, sensory or motor.

Many of these techniques are discussed in Chapter 3.
13.5 Electroencephalography (EEG) ERPs in concussion

research
EEG has been the most widely used electrophysiological method to assess
the neurophysiological impact of concussion and mTBI in humans. Early
EEG research reported electrical abnormalities in patients with TBI, 24
hours post injury, demonstrating that the more severe the injury symptoms,
the more severe and persistent abnormalities in the EEG (Dow et al. 1944).
Larsson et al. (1954) reported changes in cortical activity in frontal and
temporal lobes following bouts as quickly as 15 minutes post-injury in
boxers. Conversely, (Greenblatt 1943) showed abnormal EEG in post-
traumatic brain injury cases between two months and 10 years.
Interestingly, as early as 1940, Jasper and colleagues (Jasper et al. 1940;

Jasper et al. 1945) observed disparity in clinical resolution and EEG
recordings. For example, in a case-series study, Jasper et al. (1940) observed
that while the clinically observed severity matched EEG abnormalities,
there were disparities in time-course recovery of symptoms and electrical
activity of the cortex. These investigators suggested that more stringent
psychological examinations should be involved to support EEG findings,
given that others (e.g., Conkey 1938) had demonstrated chronic deficiencies
in psychological performance well after clinical symptoms had resolved.
However, the findings of a ‘lack of correlation’ were leveraged by others
(Blonstein and Clarke 1954) to dismiss using EEG as an objective marker
for post-traumatic brain injury recovery and maintain clinical examination
as gold standard.
More recent studies, and the emerging evidence, now suggest that this
disparity in electrophysiology and clinical symptoms is meaningful. For
example, Barr et al. (2012) comparing 59 concussed American football
players to 31 controls from time of injury to 45 days post-injury. They
showed significant abnormalities in qualitative EEG (qEEG, see section 3.1)
event related potentials (ERPs) at the time of the injury and at eight days
post concussion, when cognitive functioning and postural stability were no
different from controls. Further, while not statistically significant, the
authors reported that, at 45 days, the qEEG data showed noticeable
differences, suggesting that some athletes continued to exhibit alterations in
brain activity. The authors suggest that continued brain activity alterations
242 Chapter 13
may lead towards post-concussion syndrome and/or increase the susceptibility

to another injury (Barr et al. 2012). More recent qEEG studies by Brooks et
al. (2017) showed similar findings, with significant changes at 72 hours post
concussion and return to baseline by 45 days. Studies with longer time
frames (0 – 90 days) have reported alterations in amplitude in all frequency
bands across the EEG spectrum following a concussion (Thompson et al.
2005; McCrea et al. 2010). Similar to the findings of Barr et al. (2012),
changes reported outlasted clinical symptomology; initial qEEG changes
were associated with symptoms that resolved within 7 – 10 days, whereas
electrophysiological changes persisted to three months post injury
(Slobounov et al. 2002; Thompson et al. 2005; McCrea et al. 2010; Teel et
al. 2014).
13.5.1 Visual and vestibular evoked potentials

Visual evoked potentials (VEPs) and vestibular evoked myogenic potentials
(VEMPs) both reflect the neurophysiological response following an
electrical stimulus. For VEPs, a light stimulus is presented with EEG used
to record the evoked response, while VEMPs involve delivering a stimulus
via headphones or bone percussion with responses recorded using EMG
over the sternocleidomastoid muscles on the ipsilateral side of the stimulus
for cervical VEMP (cVEMP) or the inferior oblique muscle over the
contralateral orbit for ocular VEMP (oVEMP) (Papathanasiou et al. 2018).
13.5.1.1 Visual evoked potentials
Remarkably, despite VEPs being used in head-trauma research since the

1970s, the published research literature has shown mixed results in its
ability to determine mTBI/concussion. In studies in acutely concussed
patients, measuring the P100 waveform (where the peak positive phase
occurs at 100 ms post stimulus) showed no differences in mild brain injured
participants up to a fortnight post injury event (Werner and Vanderzant
1991). Similar findings have been reported by Papathanasopoulos et al.
(1994) who observed no differences in VEPs in patients up to 30 days post
mTBI compared with healthy controls. Further studies are required, as a
recent review of the literature did not produce any new studies in this area
(Papathanasiou et al. 2018). VEPs have been shown to differ in participants
with symptoms that do not resolve after the injury. In comparison to healthy
controls, patients with persistent post-concussion symptoms (PPCS) showed
P100 latencies and reduction in amplitude (Weinberg 2000; Moore et al.
2014).
13.5.1.2 Vestibular evoked myogenic potentials
It is well described that one of the most common, but debilitating, outcomes
of concussion is chronic dizziness, which includes the illusion of self-
motion (vertigo) and also imbalance. The frequency of reported dizziness in
the literature has been reported between 47 to 78% in patients (Papathanasiou
et al. 2018). While the symptoms of dizziness may be via a combination of
aetiologies, the most common cause appears to be paroxysmal positional
vertigo (PPV) which has been shown to affect half of acutely-concussed
patients with dizziness (Hoffer et al. 2004) and 30-40% of those with PPCS
(Arshad et al. 2017).
Unlike VEPs, VEMPs appear to be more rigorous in detecting

neurophysiological abnormalities that complement dizziness symptoms.
While still limited in sports concussion research, military studies have
shown abnormal VEMPs with dizziness and postural instability following
single (Scherer et al. 2011) and repeated blast exposures (Littlefield et al.
2016). In a case series by Gattu et al. (2016), three of four military veterans
complaining of chronic dizziness or unstable posture demonstrated VEMPs
that were reduced in amplitude or absent. Further, in one case, oculomotor
(eye movement) recordings showed increased latency for rightward
saccades, suggesting central nervous system pathophysiology.
Studies using VEMPs with oculomotor measures have reported similar

findings in acute concussion following blast injury. For example, in serving
military personal recovering from blast-related TBI comparing symptomatic
(n=12) to asymptomatic (n=12) patients, Scherer et al. (2011) showed that
half of the symptomatic patients demonstrated both reduced VEMP along
with abnormal nystagmus or oculomotor findings. Whilst the authors were
unable to suggest the precise cause of these findings, insofar as only 50%
of the symptomatic group showed abnormal VEMP and ocumomotor
findings, it was suggested that acute-blast effects played a role in affecting
the underlying pathophysiology in the symptomatic patients.
13.6 Transcranial Magnetic Stimulation (TMS) EPs

and concussion research
TMS is not a new technology; indeed, the technique of TMS was first
published in 1985 (Barker et al. 1985). However, TMS is a relatively more-
recent neurophysiological technique to be used in concussion research. In
single-pulse TMS, the twitch response, known as the motor evoked potential
(MEP), has two components. The first is the biphasic waveform response
244 Chapter 13
and represents excitation along the corticospinal tract. Following the

waveform, there is an immediate period of inactivity, known as the cortical
silent period (cSP), before the return of uninterrupted EMG. This represents
the cortical inhibitory pathways. With paired-pulse TMS, the interstimulus
interval can facilitate or inhibit the test MEP response representing
intracortical excitation or inhibition, respectively. (See Chapter 3 for further
discussion of the technique and example illustrations of the single- and
paired-pulse MEPs).
As a result of the versatility of TMS and its potential as a diagnostic

technique for concussion and head trauma, there are an increasing number
of published studies using TMS for concussion. Accordingly, TMS has now
been included in the 2017 Concussion in Sport Consensus statement as a
technique to quantify changes following concussion as well as for chronic
manifestation of multiple concussions (McCrory et al. 2017).
13.6.1 Studies in acute concussion

Studies have investigated short-term responses following both sub-
concussion (Di Virgilio et al. 2016; Di Virgilio et al. 2019) and concussion
injury (Christyakov et al. 2001; Bashir et al. 2012; Livingston et al. 2012;
Miller et al. 2014; Powers et al. 2014; Pearce et al. 2015; Edwards and
Christie 2017; Yasen et al. 2017), with the majority of published studies
presenting data on the MEP waveform amplitude and cSP. MEP amplitude
data have shown mixed results with two studies presenting decreased MEP
amplitude (Christyakov et al. 2001; Livingston et al. 2012), one study
showing increased MEP amplitude with the muscle at rest (Edwards and
Christie 2017), and two studies showing no change (Pearce et al. 2015; Di
Virgilio et al. 2016). This is not unexpected, however. A limitation of the
MEP amplitude from single-pulse TMS is that it reflects excitation of the
corticospinal pathway, which could suggest changes not only at the cortical
level but also at the spinal levels and possibly at the motor unit level.
Conversely, the corticospinal silent period (cSP) is a more robust measure
of inhibition at the cortical level. Indeed, all but one study showed increased
cSP inhibition post sub-concussion and concussion injury (Christyakov et
al. 2001; Miller et al. 2014; Pearce et al. 2015; Di Virgilio et al. 2016;
Edwards and Christie 2017; Yasen et al. 2017). One study observed a
reduction in cSP duration, but this was not reported as significant (Powers
et al. 2014).
Limited studies (three to date) have used paired-pulse measures. Three

studies (Bashir et al. 2012; Powers et al. 2014; Pearce et al. 2015) found no
difference in short intracortical inhibition (SICI) at either 2 ms inter-

stimulus interval (ISI) or 3 ms ISI post concussion. One study (Bashir et al.
2012) showed a significant absence of long intracortical inhibition (LICI) at
100 ms ISI in their case study at two weeks, returning to baseline, and no
difference to the control group by six weeks. Conversely, no differences in
LICI were observed by Powers et al. (2014). Two studies reported
intracortical factiliation (ICF). Bashir et al (2012) found increased ICF at
12-15 ms ISI compared to baseline and the control group, at both two and
six weeks post concussion injury. Conversely Powers et al. (2014) observed
an increased ICF in the control group compared to the concussed group.
13.6.2 Studies in retired athletes with history of concussion

and head trauma
To date, 13 studies have presented long-term data, with group mean time
post concussion ranging from 17 months (Davidson and Tremblay 2016) to
over 20 years (Pearce et al. 2014a; Pearce et al. 2018c), up to a maximum
of ~35 years (De Beaumont et al. 2009). Unlike acute studies, chronic TMS
studies have shown no differences in MEP amplitude between former
athletes and age-matched controls (De Beaumont et al. 2007b; De
Beaumont et al. 2009; Pearce et al. 2014b; Davidson and Tremblay 2016;
Meehan et al. 2017; Pearce et al. 2018b). Moreover, cSP duration variables
have been mixed. Five studies reported significant lengthening of the cSP
(De Beaumont et al. 2007b; De Beaumont et al. 2009; De Beaumont et al.
2011a; De Beaumont et al. 2011b; Tremblay et al. 2011), whereas two
studies reported significant shortening of the cSP (Pearce et al. 2014b;
Pearce et al. 2018b), and three studies presented no change (Tremblay et al.
2014; Davidson and Tremblay 2016; Lewis et al. 2017). Further studies are
required to elucidate cortical inhibitory changes that may reflect self-
reported symptoms. For example, limited data suggests that retired players
who self-report chronic fatigue and/or are diagnosed with depression appear
to have lengthened cSP; conversely, those who have been diagnosed with
post-traumatic epilepsy or anxiety have reduced cSP (Pearce et al. 2018a).
Paired-pulse TMS measures have been utilised in longitudinal studies. SICI

data have shown mixed results between the former retired players and age-
matched controls, with only three studies reporting differences (Pearce et al.
2014b; Meehan et al. 2017; Pearce et al. 2019c). However, seven of eight
studies showed significant differences in LICI between groups (De
Beaumont et al. 2011a; De Beaumont et al. 2011b; Tremblay et al. 2011;
Pearce et al. 2014b; Lewis et al. 2017; Pearce et al. 2018b; Pearce et al.
246 Chapter 13
2019c). ICF (12 and 15 ms ISI) was collected in two studies (De Beaumont
et al. 2007b; De Beaumont et al. 2009) but no differences were seen between
groups.
13.6.3 Studies in persistent post concussion symptoms

Little TMS research has focussed on patients with persistent PPCS. PPCS
occurs in a minority of people (~10%) who do not recover from a
concussion in a timely manner. Whilst the operational definition of PPCS is
mutable, generally speaking, PPCS is diagnosed in those with ongoing
symptoms for at least three months. It has also been assumed that PPCS is
psychological rather than physiological (Silverberg and Iverson 2011).
To date, only two studies have been published on the neurophysiology of

PPCS. Pearce et al. (2019a) studied 40 individuals who had suffered a
concussion in the previous 12 to 15 months. Twenty of these individuals
were diagnosed with PPCS, whereas twenty had been concussed but had
fully recovered. Both groups were compared to twenty age-matched
controls with no history of concussions. TMS data showed a significant
increase in cSP in the PPCS group which correlated to self-reported
symptoms of fatigue and related symptoms score (Johansson et al. 2009). A
follow-up study by the same research group (Pearce et al. 2019b) showed
that those who scored over the threshold for PPCS fatigue (n=38), as
determined by Johansson and colleagues (Johansson et al. 2009; Johansson
and Rönnbäck 2012, 2014), demonstrated slowed sensorimotor reaction
time and increased reaction time variability compared to asymptomatic
controls (n=43). Similarly, the PPCS group showed increased cortical
inhibition, which significantly correlated to reaction time and variability in
reaction time. These preliminary data demonstrate that PPCS, particularly
for those expressing chronic fatigue, may have altered neurophysiology
suggesting potential rehabilitation based on physical rehabilitation rather
than psychological counselling.
13.7 Combined electrophysiological modalities to assess

neurophysiology
A number of studies have used combined techniques to investigate the
underlying neurophysiology of concussion. While no studies have appeared
to use MEG to assess concussion exclusively (see section 13.4), MEG has
been used in multi-modality studies. For example, MEG studies have
reported alterations in slow wave in 20 individuals with persistent PCS that
were 65% sensitive in detecting symptomatic PCS compared to 25% with

EEG and 20% with MRI (Lewine et al. 1999). In a retrospective blinded
review, Lewine et al (2007) investigated 30 patients 12 months post injury
(blunt head trauma). In comparing MEG to neuroimaging (single-photon
emission tomography or SPECT, and MRI), Lewine and colleagues (2007)
found MEG abnormal slow-wave activity in 19 of 30 patients, compared to
abnormal results in 12 of 30 and 4 of 30 for SPECT and MRI, respectively.
Of interest, no associations were found with behavioural symptoms but, in
those with cognitive impairments, MEG was abnormal in 86% of
participants, compared to 40% and 18% for SPECT and MRI, respectively
Several studies have used evoked potentials via EEG and/or TMS to explore
cortical excitability in asymptomatic athletes with a history of repeated
concussions. For example, using ERPs with EEG, along with
neuropsychological tests, De Beaumont et al. (2007a) compared Canadian
college football athletes who had a history of multiple concussions (with
their last concussion sustained a mean 2.6 years previously) to those
reporting only a single concussion (mean 4.9 years previously) and control
athletes with no history of concussion. These authors found significantly
abnormal ERP activity in the group with multiple concussions compared to
the single concussion and control groups, despite no differences in
neuropsychological tests. A parallel study, using TMS, in the same groups
(De Beaumont et al. 2007b) reported increased corticomotor inhibition.
Taken together, these studies show that multiple sports-related concussions
result in cumulative electrophysiological abnormalities more so than a
single concussion event contributing to adverse long-term outcomes (De
Beaumont et al. 2007a; De Beaumont et al. 2007b).
Emerging evidence is also showing long-term neurophysiological changes

representative of chronic neurological impairments in athletes with a history
of head trauma and/or multiple concussions. Using a mixed cohort of former
college and professional athletes, De Beaumont et al. (2009) used EEG (P3
component) and TMS MEPs to investigate the effects of repeated
concussion injuries on cognitive and motor functions later in life. These
individuals (mean age 61 years) had reported their last concussion a mean
34.7 years previously and were compared to age-matched controls with no
history of concussion. Along with decreased neuropsychological performance
in memory and response inhibition and slowed movement velocity, EEG
ERP data showed delayed and suppressed P3 waveforms while TMS cSP
was significantly increased. More recent TMS-EEG studies by Opie et al.
(2019) have confirmed that inhibitory circuits involving GABA are
moderated after mTBI/concussion; paired-pulse measures suggest that
248 Chapter 13
maladapted neuroplasticity of inhibitory networks involving the GABAA

receptor subtype are more pronounced that GABAB.
13.9 Summary
This chapter has outlined electrophysiological techniques used in
quantifying the neurophysiological aspects of repeated head trauma and
concussion. As an emerging area of research, the use of electrophysiology
is increasing. To date, MEG and EEG/qEEG investigations have provided
evidence for dysfunction in concussed individuals compared to healthy
controls (Thompson et al. 2005; Gosselin et al. 2006; Lee and Huang 2014;
Teel et al. 2014). Similarly, TMS is also providing further evidence for
changes in cortical inhibition following a concussion as well as with chronic
manifestations of multiple concussions. However, for both qEEG and TMS,
their clinical significance has not yet been fully established and there is
hesitation surrounding the usefulness of EEG and TMS as a tool for
gradation of injury (Thatcher et al. 2001; Nuwer et al. 2005). Further,
methodological disparities undermine confidence in using these techniques
as objective markers for return to play decisions (Kamins et al. 2017).
Future research must incorporate streamlined protocols to fully assess their
efficacy in determining when an individual is fully recovered physiologically.
Despite these limitations, these techniques are now being recognized as

legitimate methods that can be used as part of the multi-modality approach
to assessing the short- and long-term effects of sports concussion. In
particular, the benefits of qEEG and TMS over neuroimaging techniques
are their simplicity of testing set up, ready availability at the point of care,
rapid acquisition, ease of use with limited training, nonradiation emitting,
and cost-effectiveness (Brooks et al. 2017).
Future explorations into the underlying electrophysiological mechanisms

following sports concussion are needed. Given that electrophysiological
techniques appear to be detecting abnormal changes in clinically
asymptomatic individuals, further research should aim to compare
differences between those with ongoing signs and symptoms versus those
who no longer report symptoms. As these techniques provide functional
measures of brain activity, sports concussion research should move towards
co-registration of these techniques with advanced neuroimaging in order to
elucidate relevant mechanisms and clarify the unique contribution each
modality can offer towards identifying markers of concussion diagnosis and
prognosis.
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Principles of Exercise Neuroscience

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Principles of Exercise

Dawson J. Kidgell and Alan J. Pearce

Edited by Dawson J. Kidgell and Alan J. Pearce

This book first published 2020

Cambridge Scholars Publishing

Lady Stephenson Library, Newcastle upon Tyne, NE6 2PA, UK

British Library Cataloguing in Publication Data

Copyright © 2020 by Dawson J. Kidgell and Alan J. Pearce and

ISBN (10): 1-5275-5813-4

Preface ...................................................................................................... xii

Acknowledgements ................................................................................. xiv

2.7 Motor units, fibre types, and recruitment physiology ................... 23

4.4 Is the induction of neuroplasticity via NIBS important for motor

6.4 Summary ..................................................................................... 100

Chapter 7 ................................................................................................ 107

Chapter 8 ................................................................................................ 133

8.5 Neuromuscular responses to high-intensity intermittent

Chapter 9 ................................................................................................ 160

Chapter 10 .............................................................................................. 185

10.5 Summary ................................................................................... 192

Chapter 11 .............................................................................................. 196

Chapter 12 .............................................................................................. 222

Chapter 13 .............................................................................................. 237

DAWSON J. KIDGELL, PHD

Dawson J. Kidgell, Monash University, Melbourne, Australia.

A text such as Principles of Exercise Neuroscience is not the effort of just

THE NEXUS BETWEEN NEUROSCIENCE

ALAN J. PEARCE, PHD

anatomy, skill acquisition and psychosocial determinants of health). Indeed,

It should be no surprise then that the maturing disciplines of exercise science

1.1 The neuroscience of human movement.

Figure 1.1. Continuum of general areas of study within neuroscience

It is not uncommon that neuroscientists from different research areas will

Table 1.1. List of combined areas of study within neuroscience.

Of course, as this book will be focusing on aspects of exercise science and

The scientific study of the neuroscience of movement is termed motor

Motor control – the study of the underlying neurophysiological mechanisms

Motor learning and skill acquisition – understanding the optimal

Motor development – the study of movement across the lifespan; how

understanding the mechanisms by which older adults decline in motor

1.2 What is ‘motor control’? How does motor control

However, the core of motor control centres on the neuroscience that

Undergraduate study in exercise science will have motor control embedded

Study area Relationship to Example

1.3 Motor learning and skill acquisition:

psychology. Motor learning is creating motor memory, similar to other

Motor development focuses on the stages and underlying processes that

Whilst motor development is primarily focussed in children and adolescents,

upon graduating. As part of the Allied Health sector, exercise science

1.4 The challenge of translating neuroscience

With the links between neuroscience and exercise becoming closer, it is

1.5 How to get the best from this book

LEVELS OF MOTOR CONTROL

DAWSON J. KIDGELL, PHD

2.1 Structural arrangement of the brain contributing

2.1.1 Structure of the cerebral cortex

II. External granular layer. A layer of densely packed small cells

III. External pyramidal layer. A layer consisting of medium to large-sized