THE CIRCUITRY OF THE HUMAN SPINAL CORD: SPINAL AND CORTICOSPINAL MECHANISMS OF MOVEMENT

Transcription

1 THE CIRCUITRY OF THE HUMAN SPINAL CORD: SPINAL AND CORTICOSPINAL MECHANISMS OF MOVEMENT Studies of human movement have proliferated in recent years. This greatly expanded and thoroughly updated reference surveys the literature on the corticospinal control of spinal cord circuits in human subjects, showing how different circuits can be studied, their role in normal movement and how they malfunction in disease states. Chapters are highly illustrated and consistently organised, reviewing, for each pathway, the experimental background, methodology, organisation and control, role during motor tasks and changes in patients with central nervous system lesions. Each chapter concludes with a helpful résumé that can be used independently of the main text to provide practical guidance for clinical studies. The final four chapters bring together the changes in transmission in spinal and corticospinal pathways during movement and how they contribute to the desired movement. This book is essential reading for research workers and clinicians involved in the study, treatment and rehabilitation of movement disorders. Emmanuel Pierrot-Deseilligny is Emeritus Professor of Clinical Neurophysiology and Rehabilitation at the Université Pierre et Marie Curie, Paris. David Burke is the Bushell Professor of Neurology at Royal Prince Alfred Hospital and Associate Dean (Research), Sydney Medical School, The University of Sydney.

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3 THE CIRCUITRY OF THE HUMAN SPINAL CORD Spinal and Corticospinal Mechanisms of Movement Emmanuel Pierrot-Deseilligny Université Pierre et Marie Curie David Burke The University of Sydney

4 CAMBRIDGE UNIVERSITY PRESS Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo, Delhi, Mexico City Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York Information on this title: / , 2012 This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published 2012 Printed in the United Kingdom at the University Press, Cambridge A catalogue record for this publication is available from the British Library ISBN Hardback Additional resources for this publication at / Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third-party Internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate.

5 Contents Acknowledgements Preface List of abbreviations page xvi xvii xxi 1 General Methodology 1 H Reflex and Tendon Jerk 1 Basic Methodology (H reflex) 4 H and M Recruitment Curve 7 Tendon Jerk 8 Random Alternation of Control and Conditioned Reflexes 8 Time Resolution of the Method 8 Recovery Cycle of the H Reflex 9 Threshold Tracking of the H Reflex 11 Mechanisms Acting on the Afferent Volley 11 Alterations in the Excitability of Ia Afferents 11 Presynaptic Inhibition of Ia Terminals 11 Homosynaptic Depression 12 Curtailment of the Compound EPSP by a Disynaptic Ib IPSP 12 Pool Problems 15 Non-linearity in the Input Output Relation 15 Changes in the Recruitment Gain of the Motoneurone Pool 16 Plateau Potentials and Amplification of Synaptic Input 17 Quantitative Data 20 Clinical Value 21 The F wave 21 Modulation of the On-Going EMG Activity 24 Underlying Principles and Methodology 24 Discrepant Changes in the On-Going EMG and in the H Reflex 26 Advantages, Limitations and Conclusions 27 Investigations on Single Motor Units 28 v

6 vi Contents Post-stimulus Time Histograms (PSTHs) 28 Underlying Principles 28 Basic Methodology 30 Timing of the Changes in Firing Probability 31 Size and Significance of the Peaks and Troughs in the PSTH 32 Critique: Limitations, Advantages and Conclusions 33 Post-stimulus Time Frequencygrams (PSFs) 34 Unitary H Reflex 35 Stimulation of the Motor Cortex 36 Caveats in Interpreting Studies Using Transcranial Stimulation 38 Transcranial Stimulation by Single Pulses 39 Paired-Pulse Stimulation of the Motor Cortex 44 Short-Interval Intracortical Inhibition (SICI) 44 Long-Interval Intracortical Inhibition (LICI) 45 Cortical Silent Period 45 Short-Interval Intracortical Facilitation (SICF) 45 Long-Interval Intracortical Facilitation (LICF) 46 Interhemispheric Interactions 46 Combined Peripheral and Cortical Stimulation 46 Prolonged Stimulation of the Motor Cortex (rtms, TBS, tdcs) 47 Spatial Facilitation 48 Underlying Principles 48 Spatial Facilitation in the PSTH 48 Spatial Facilitation of Monosynaptic Reflexes 50 Coherence Analyses and Motor Control 51 Résumé 52 References 59 2 Monosynaptic Ia Excitation, Homosynaptic Depression and Transcortical Ia Excitation 65 Monosynaptic Ia Excitation of Motoneurones 65 Background from Animal Experiments 65 Methodology 67 Homonymous Monosynaptic Ia Excitation 67 Heteronymous Monosynaptic Ia Excitation 69 Range of Electrical Thresholds and CV of Ia Afferents 74 Organisation and Pattern of Connections 76 Homonymous Monosynaptic Ia Excitation 76 Heteronymous Ia Connections in the Lower Limb 77 Heteronymous Ia Connections in the Upper Limb 78 Equivocal Data Obtained with Conditioning Tendon Taps 80 Motor Tasks and Physiological Implications 80 Short-Latency Ia Spinal Stretch Reflex 80 Heteronymous Connections in the Lower Limb 82 Heteronymous Connections in the Upper Limb 84 Studies in Patients and Clinical Implications 84 Homosynaptic Depression (HD) 85 Background from Animal Experiments 85 Methodology 85 Organisation and Physiological Implications 87 Strength of HD at Different Synapses 87 HD during Voluntary Contraction 88 Use-Dependent Plasticity 89 Functional Significance 89 HD in Patients 90 Spasticity 90 Parkinson s Disease 90 Transcortical Ia Excitation 90 History of Transcortical LLSRs in Humans 91 Denouement 93 Patients with Mirror Movements 93 Motor Cortex Stimulation 93 Transcortical LLSRs in the Upper Limb 94 LLSRs in Distal and Proximal Muscles 94 Overlap with Voluntary M3 Response 94 Group II Medium-Latency Responses 95 Sensory Pathway of M2 Responses 95 Functional Significance 96 Transcortical LLSRs in the Lower Limb 96 Evidence for Transcortical LLSRs 96 Functional Significance 98 Résumé 99 References 103

7 Contents vii 3 Fusimotor Mechanisms, Muscle Spindles and Their Role in the Control of Movement 110 Background 110 Methodology 114 Comparisons of Tendon Jerk and H Reflex 114 Nerve Blocks 115 Microneurography 115 Exploiting the Thixotropic Properties of Intrafusal Fibres 117 Critique of the Tests to Study Fusimotor Drive 117 Organisation and Pattern of Connections 118 Background Drive to Relaxed Muscles 118 Discharge Rates 118 Effect of Muscle Vibration on Human Spindles 119 Reflex Activation of Fusimotor Neurones 121 Supraspinal Activation of Fusimotor Neurones 123 Motor Tasks and Physiological Implications 123 Remote Muscle Contraction 123 Motor Preparation and Imagery 124 Deliberate Voluntary Effort 125 Isometric (Restrained) Contractions 125 Concentric and Eccentric Contractions 127 Activation of γ and β Motoneurones 127 Natural Unrestrained Movements 127 Possible Role of the Fusimotor System during Movement 128 Studies in Patients and Clinical Implications 129 Spasticity 129 Parkinson s Disease 130 Résumé 130 References Recurrent Inhibition 138 Background from Animal Experiments 138 Methodology 140 Arguable Techniques 140 The Paired H Reflex Technique 141 Underlying Principles 141 Conditioning Reflex and H Test Reflex 142 Evidence for Recurrent Inhibition 142 Validation 146 Critique: Limitations, Cautions, Conclusion 146 Heteronymous Recurrent Inhibition 147 Underlying Principles 147 Orthodromic (Reflex) Discharge 148 Antidromic Motor Volley 148 Evidence for Recurrent Inhibition 148 Critique: Limitations, Conclusions 152 Organisation and Pattern of Connections 152 Homonymous Recurrent Inhibition 152 Heteronymous Recurrent Inhibition in the Lower Limb 153 Heteronymous Recurrent Inhibition in the Upper Limb 154 Projections to Ia Inhibitory Interneurones 155 Cortical Control 157 Peripheral Control 157 Motor Tasks and Physiological Implications 158 Voluntary Contractions of the Test Muscle 158 Methodology 158 Various GS Voluntary Contractions 158 Mechanisms Underlying the Changes in H 160 Heteronymous Recurrent Inhibition 161 Conclusions and Functional Implications 162 Contraction of the Antagonistic Muscle 163 Co-contraction of Antagonistic Muscles 163 Stance 165 Homonymous Recurrent Inhibition 165 Heteronymous Recurrent Inhibition 165 Heteronymous Recurrent Inhibition during Gait 167 Studies in Patients and Clinical Implications 169 Spasticity: Recurrent Inhibition at Rest 169 Stroke and Spinal Cord Injury 169 Progressive Spastic Paraparesis 169 Spasticity: Changes in Recurrent Inhibition during Motor Tasks 170 Patients with Other Movement Disorders 170 Résumé 170 References Reciprocal Ia Inhibition 178 Background from Animal Experiments 178 Methodology 180

8 viii Contents Methods to Investigate Reciprocal Ia Inhibition at Hinge Joints 180 Inhibition of the Monosynaptic Reflex 180 Modulation of the On-going EMG 181 PSTHs for Single Units 181 Evidence for Reciprocal Ia Inhibition 181 Evidence for Ia-Induced Inhibition 181 Evidence for Disynaptic Transmission 184 Recurrent Inhibition of the Relevant Interneurones 185 Critique of the Tests to Study Reciprocal Ia Inhibition 185 Organisation and Pattern of Connections 187 Pattern and Strength of Reciprocal Ia Inhibition at Rest at Hinge Joints 187 Other Inputs to Ia Interneurones 188 Cutaneous Facilitation of Reciprocal Ia Inhibition 188 Corticospinal Facilitation of Reciprocal Ia Inhibition 190 Vestibulospinal Facilitation of Reciprocal Ia Inhibition 190 Absence of True Reciprocal Ia Inhibition at Wrist Level 190 Inhibition at Wrist Level Does Not Fulfil the Criteria for Reciprocal Ia Inhibition 190 Convergence of Group I Afferents from Several Different Muscles 192 Homosynaptic Depression 193 Motor Tasks and Physiological Implications 193 Voluntary Contraction of the Antagonist 194 Soleus H Reflex Depression 194 Reciprocal Ia Inhibition during Voluntary Ankle Dorsiflexion 194 Mechanisms Underlying Changes in Reciprocal Ia Inhibition 197 Functional Implications 198 Use-Dependent Plasticity 198 Voluntary Activation of the Agonist Muscle 199 Reciprocal Ia Inhibition during Co-contraction of Antagonistic Muscles 200 Postural Activity 202 Gait 204 Studies in Patients and Clinical Implications 204 Spasticity 205 Stroke 205 Spinal Cord Lesions 205 Underlying Mechanisms 206 Cerebral Palsy 206 Hyperekplexia 206 Parkinson s Disease 206 Résumé 206 References Ib Pathways 214 Background from Animal Experiments 214 Methodology 217 Methods to Investigate Ib Inhibition 217 Inhibition of the H Reflex at Rest 218 Inhibition in the PSTHs for Single Units 218 Evidence for Ib Inhibition 218 Evidence for a Ib Conditioning Input 218 Evidence for Disynaptic Transmission 221 Ib vs. Reciprocal Ia Inhibition 223 Short Duration 223 Oligosynaptic Group I Excitation 224 Critique of the Tests to Reveal Ib Effects 224 Organisation and Pattern of Connections 225 Pattern and Strength of Ib Inhibition 225 Homonymous Ib Inhibition 225 Heteronymous Ib Inhibition 225 Oligosynaptic Group I Excitation 226 Convergence with Ia Afferents 227 Effects of Low-Threshold Cutaneous Afferents 227 Cutaneous Suppression 227 Cutaneous Facilitation 229 Facilitation of Ib Inhibition by Joint Afferents 230 Effects from Nociceptive Afferents 230 Descending Effects 232 Convergent Inputs 232 Motor Tasks and Physiological Implications 234 Voluntary Contraction of the Agonist 234 Evidence for Suppression of Ib Inhibition 234 Possible Mechanisms 234 Possible Functional Role of Ib Inhibition 237 Facilitation by Other Afferent Discharges 237 Ib Inhibition to Motoneurones not Involved in the Voluntary Contraction 238

9 Contents ix Inactive Synergists 238 Voluntary Contraction of Antagonists 238 Changes in Ib Inhibition during Walking 238 Studies in Patients and Clinical Implications 241 Ib Inhibition 241 Spasticity 241 Hyperekplexia 241 Parkinson s Disease 241 Restless Leg Syndrome, Supranuclear Palsy 241 Mechanisms Underlying the Decreased Ib Inhibition 241 Ib Excitation in Spastic Patients 242 Résumé 242 References Group II Pathways 249 Background from Animal Experiments 249 Methodology 252 Underlying Principles 252 Stretch-Induced Homonymous Group II Excitation 252 Responses in Standing Subjects 252 Responses in Subjects Reclining Supine 254 Electrically Induced Heteronymous Group II Excitation 254 Late High-Threshold H Reflex Facilitation 254 PSTHs of Single Units 254 Modulation of the On-going EMG 254 Evidence for Muscle Group II Excitation 257 Late Excitation is not Due to Motor or Fusimotor Axon Stimulation 257 Evidence for Slowly Conducting Afferents 257 Differential Effects of Vibration 257 Pharmacological Validation 260 Origin of Group II Afferents 260 Critique of the Tests Used to Reveal Group II Actions 260 Contamination by Group I Effects 260 Contamination by Transcortical Long-Latency Responses 261 Other Limitations 261 Organisation and Pattern of Connections 261 Peripheral Pathway 261 Conduction Velocity of Group II Afferents 261 Group II Ia Ratio 262 Central Pathway of Group II Excitation 262 Estimates of the Central Delay 262 Rostral Location of the Relevant Interneurones 263 Distribution of Group II Excitation 264 Stretch-Induced Responses in Ipsilateral and Contralateral Muscles (Lower Limb) 264 Heteronymous Group II Excitation (Lower Limb) 264 Group II Excitation in the Upper Limb 264 Convergence with Other Peripheral Afferents 265 Group I Afferents 265 Absence of Evidence for Cutaneous Projections 266 Peripheral Inhibitory Input to Interneurones 266 Absence of Group II Inhibition of Motoneurones 266 Corticospinal Control of Group II Excitation 267 Corticospinal Facilitation of Group II Excitation 267 Corticospinal Control of Inhibitory Interneurones 267 Motor Tasks and Physiological Implications 270 Voluntary Contractions 270 Postural Tasks 271 Homonymous Group II Excitation 271 Heteronymous Group II Excitation in Postural Tasks 273 Monoaminergic Control System? 273 Functional Implications 274 Gait 274 Contribution to Soleus Activation 274 Contribution to Quadriceps Activation 276 Group II-Mediated Responses to External Perturbations 276 Studies in Patients and Clinical Implications 279 Peripheral Neuropathies 279 Spasticity 279 Increased Propriospinally Mediated Group I Group II Excitation 279 Possible Underlying Mechanisms 280 Is Increased Group II Excitation Sufficient to Cause Spasticity? 282

10 x Contents Parkinson s Disease 282 Dystonia 284 Résumé 284 References Presynaptic Inhibition of Ia Terminals 292 Background from Animal Experiments 292 Methodology 295 H Reflex vs. MEP 295 Assessing the Excitability of PAD Interneurones 297 Flawed Technique: Prolonged Vibration of the Homonymous Tendon 297 Short Vibration of a Heteronymous Tendon 298 Electrically Induced D1 and D2 Inhibitions 298 Critique 299 Assessing Monosynaptic Ia Facilitation of the H Reflex 300 Experimental Paradigm 300 Validation 300 Critique 302 Techniques Using Single Motor Units 302 Opposite Changes in Ia Facilitation and Heteronymous Inhibition 302 Organisation and Pattern of Connections 302 Projections to Different Motoneurone Types 302 Organisation of PAD INs in Subsets 303 Peripheral Projections to PAD INs 304 Excitatory Effects 304 Depression from Tactile Cutaneous Afferents 304 Corticospinal Projections 304 Vestibulospinal Projections 307 Tonic Level of Presynaptic Inhibition of la Terminals 307 Sensitivity of Stretch-Induced Ia Volleys to Presynaptic Inhibition 307 Motor Tasks and Physiological Implications 308 Ia Terminals on Voluntarily Activated Lower Limb Motoneurones 308 Evidence for Decreased Presynaptic Inhibition 308 Changes during Various Contractions 310 Origin and Functional Implications 312 Use-Dependent Plasticity 313 Ia Terminals on Motoneurones of Inactive Synergists 313 Evidence for Increased Presynaptic Inhibition 313 Origin and Functional Implications 314 Ia terminals to Motoneurones of Antagonists 314 Selective Contraction of the Antagonist 314 Co-contraction of Antagonists 314 Functional Implications 316 Contraction of Remote Muscles 316 Ia Terminals on Upper Limb Motoneurones 317 Active Standing 317 Walking 319 Running 320 Bicycling 321 Studies in Patients and Clinical Implications 321 Changes in Tests Assessing Presynaptic Inhibition with Ageing 321 Spasticity 322 Over-interpretation of Decreased Homonymous Vibratory Inhibition 322 Patients with Spinal Cord Lesions 322 Stroke Patients 322 Changes during Voluntary Movement 323 Parkinson s Disease 323 Dystonia 324 Résumé 324 References Cutaneomuscular, Withdrawal and Flexor Reflex Afferent ( FRA ) Responses 334 Background from Animal Experiments 334 Cutaneous Responses through Private Pathways 335 FRA Pathways 337 Methodology 339 Underlying Principles 339 Stimulation 340 Electrical Stimuli 340 Mechanical Stimuli 340 Assessing the Effects of Cutaneous Stimuli 341 Responses Recorded at Rest 341 Modulation of Motoneurone Excitability 343

11 Contents xi Critique of the Tests to Study Cutaneous Effects 343 Withdrawal Reflexes 344 Afferent Pathway of Withdrawal Reflexes 344 Parallel between Pain Sensation and the RIII Reflex 344 Afferent Volleys Involved in the RIII Reflex and Pain 346 Central Pathway of Early Withdrawal Responses 347 Central Delay 347 Conclusion 349 Functional Organisation of Early Withdrawal Reflexes 349 Trunk Skin Reflexes 349 Plantar Responses 351 Other Withdrawal Responses in the Lower Limb 352 Withdrawal Responses in the Upper Limb 353 Late Withdrawal Responses 353 Late Withdrawal Responses in Patients with Complete SCI 355 Late Responses in Normal Subjects 357 Interactions between Different Inputs 358 Painful Homonymous Cutaneous Volleys 358 Effects of Other Peripheral Inputs 359 Descending Effects 359 Changes during Motor Tasks 361 Voluntary Contraction 361 Postural Tasks 362 Gait 362 Cutaneomuscular Reflexes Evoked by Non-noxious Stimuli 362 The Different Responses 362 RII Reflex at Rest 362 Cutaneomuscular Reflexes during Voluntary Contraction 363 Modulation of the Monosynaptic Reflex 363 Afferent Pathway 365 Central Pathway of Early Responses 365 Spinal Origin of the Early Effects? 365 Oligo- or Poly-synaptic Spinal Pathways? 367 Private Pathway or Changes in Transmission in Another Pathway? 367 Presynaptic Inhibition of Ia Terminals 368 Central Pathway for Long-Latency Effects 368 Pattern of the Facilitation of Monosynaptic Reflexes 368 Latencies of the Responses 369 Observations in Patients 369 Maturation 369 Which Supraspinal Pathway in Lower Limbs? 369 Which Supraspinal Pathway in Upper Limbs? 371 Projections to Different Types of Motoneurones 372 Functional Role of Cutaneomuscular Responses 374 Cutaneomuscular Responses in the Upper Limb 374 Cutaneomuscular Responses in the Lower Limb 376 Interlimb Cutaneomuscular Responses 377 Gait 377 Changes in Patients and Clinical Implications 379 Complete Spinal Transection 380 Upper Motoneurone Lesions Other Than Complete SCI 380 Abolition of Normal Cutaneous Reflexes 380 Babinski Response 381 Withdrawal Reflexes in the Lower Limb 381 Flexor Spasms 381 Withdrawal Reflexes in the Upper Limb 382 Cutaneomuscular Responses 382 Grasp Reflex 382 Parkinson s Disease 382 Restless Leg Syndrome 382 Cerebellar Patients 383 Peripheral Neuropathies 383 Diagnostic Uses 383 Résumé 383 References Propriospinal Transmission of Descending Motor Commands 395 Background from Animal Experiments 395 The C3 C4 Propriospinal System in the Cat 395

12 xii Contents The C3 C4 Propriospinal System in the Monkey 397 Methodology 398 Propriospinally Mediated Peripheral Excitation 398 Cutaneous Suppression of Descending Excitation 400 Rostral Location of the Relevant Interneurones 400 Organisation and Pattern of Connections 401 Excitatory Inputs to Propriospinal Neurones 401 Peripheral Excitatory Input 401 Corticospinal Excitation of Propriospinal Neurones 402 Feedback Inhibition of Propriospinal Neurones 405 Peripheral Inhibition of Propriospinal Neurones 405 Corticospinal Excitation of Feedback Inhibitory Interneurones 407 Possible Existence of Inhibitory Propriospinal Interneurones 408 Interaction between Excitatory and Inhibitory Inputs 408 Propriospinal Neurones and Inhibitory Interneurones 408 Can Transmission via Segmental Interneurones Explain the Results? 408 Cervical Activity Visualised with BOLD fmri 410 Explanation for the Conflicting Conclusions 410 Natural vs. Artificial Activation of Corticospinal Projections 411 Organisation of the Cervical Propriospinal System 411 Organisation in Subsets 411 Convergence and Divergence 411 Projections to Different Types of Motoneurones 412 Motor Tasks and Physiological Implications 412 Transmission of a Part of the Descending Command 414 Underlying Principles 414 Evidence for Disfacilitation 414 Site of Disfacilitation 416 Effect on Various Motor Nuclei 416 Quantitative Aspects of the Cutaneous Suppression 416 Changes during Muscle Fatigue 417 Propriospinal Excitation during Simple Tasks 418 Reflex Facilitation at the Onset of Contraction 418 Descending Facilitation of Propriospinal Neurones 418 Factors Limiting the Increase in Reflex Facilitation 418 Further Insights on the Organisation of the System 419 Handedness-Related Asymmetry 419 Task-Dependent Changes 420 Grip 420 Reach-to-Grasp Movements 420 Grip Lift Task 422 Functional Implications 422 Integration of Group I and Descending Inputs 422 Cutaneous Suppression of the Descending Command 423 In Which Movements Is the Propriospinal System Involved? 425 Studies in Patients and Clinical Implications 425 Lesion at the Junction C6 C7 Spinal Level 425 Stroke Patients 427 Cutaneous Suppression of the On-Going EMG 427 Correlation with Recovery from Hemiplegia 429 Parkinson s Disease 430 Dystonia 431 The Lumbar Propriospinal System 431 Background from Animal Experiments 431 Methodology 431 Rostral Location of the Relevant Interneurones 432 Organisation and Pattern of Connections 432 Peripheral Excitatory Input 432 Peripheral Inhibitory Inputs 433

13 Contents xiii Peripheral Inhibition of Motoneurones 433 Corticospinal Control 434 Motor Tasks and Physiological Implications 434 Résumé 436 References Spinal and Corticospinal Pathways in Different Movements 446 Complex Limb Mechanics in Multi-joint Movements 447 Spinal Pathways in Voluntary Isometric Contractions 448 Recruitment of Motoneurones 448 Spinal Mechanisms Help Maintain Contractions 450 PIC-Induced Plateau Potentials in Motoneurons 450 Fusimotor-Driven Inflow from Spindle Endings 450 FRA Hypothesis 451 Propriospinally Mediated Excitation 451 Cutaneomuscular Responses 451 Suppression of Transmission in Inhibitory Pathways 451 Control of Different Features during the Contraction 452 Contribution of Spinal Pathways 452 Timing of the Effects 453 Spinal Pathways in Flexion Extension Movements 453 Afferent Discharges 453 Shortening and Lengthening Contractions 454 Differences in Muscle Activation 454 Recruitment Order of Motor Units 456 Presynaptic Inhibition of Ia Terminals? 456 Decreased Excitability of Motoneurones 456 Which Mechanism? 457 Movements Involving Hinge Joints 458 Pathways Contributing to Inhibition of the Antagonists 458 Absence of Redundancy 459 Movements Involving Ball Joints 460 Human Spinal Circuitry at Wrist Level 460 Non-reciprocal Group I Inhibition during Movements 462 Presynaptic Inhibition of Ia Terminals during Movements 464 Recurrent Inhibition during Movements 464 Propriospinal Pathways during Movements 465 Different Strategies for Proximal and Distal Movements 465 Rapid Concentric Movements 465 Coordinated Activation of Various Synergies 466 The Case for and against Muscle Synergies 467 Rationale 467 Arguments for the Hypothesis 467 Arguments against the Hypothesis 467 Conclusion 468 Where Are Motor Synergies Laid Down? 468 Spinal Origin? 468 Hierarchical Control Schema 469 Synergies Based on Hardwired Spinal Connections 469 State-Dependent Modulation of Spinal Pathways 470 CPG 471 C3 C4 Propriospinal System 471 Co-contraction of Antagonists 472 Changes in Spinal Pathways 472 Hinge Joints 472 Ball Joints 473 Control of the Decreased Inhibition between Antagonists 473 Spinal Mechanisms 473 Specific Corticospinal Drive for Co-contractions 474 Joint Stiffness 475 Control of the Stretch Reflex at Hinge Joints 475 Control of the Excitation at Ball Joints 475 Involvement of Transcortical Reflexes in Movement 476 Task-Dependent Responses 476 Postural Responses 476 Co-ordinated Functional Responses 478 LLSRs vs. Volitional Activity and Group II-Mediated Responses 478 Voluntary Intent and Single Joint LLSRs 478

14 xiv Contents Flexion Extension and Supination Pronation at Elbow Level 478 Elbow Wrist Coupling 479 Elbow Shoulder Coupling 479 Conclusion 481 Efference Copy and Internal Models 481 Efference Copy 481 Concept 481 Evidence for Efference Copy in Limb Movements 482 Where Are Efference Copy Signals Generated? 484 Internal Models 484 Concept 484 Optimal Feedback Control and Minimal Intervention Principle 485 C3 C4 Propriospinal System 485 Involvement of the Primary Motor Cortex (M1) in Voluntary Movements 486 Changes in Excitability of Corticospinal Neurones 486 Change in Corticospinal or Motoneurone Excitability? 486 Inactivity 486 Isometric Tonic Contractions 487 Phasic Contractions 488 Motor Resonance 490 Isometric Sinusoidal Contractions 490 Lengthening Contractions 491 Period Preceding the Contraction 491 Contraction of the Antagonists 492 Cortical Reciprocal Inhibition 493 Task-Related Changes in Motor Cortex Excitability 493 Conclusions 494 Changes in Short-Interval Intracortical Inhibition (SICI) 494 Changes in SICI during Contraction 494 Period Preceding Movement 495 Termination of Movement 495 Conclusion 495 Spinal and Supraspinal Factors in Human Muscle Fatigue 496 Methodology 496 Evidence for Central Fatigue 496 Which Mechanisms? 497 Conclusion 497 Résumé 497 References Spinal and Corticospinal Pathways in Stance and Gait 515 Bipedal Stance 515 Quiet Standing 515 The Inverted Pendulum 515 Multi-Sensory Feedback 516 Intrinsic Stiffness of the Ankle 517 Stretch Reflex 517 Paradoxical Muscle Movement 518 Predictive Response 518 Conclusion 520 Unstable Postures Requiring Prolonged Contractions 520 Responses to Fast Transient Perturbations in the Pitch Plane 520 Reflex Responses in Ankle Muscles 520 Ankle and Hip Strategies 522 Change in Support Strategy 523 Responses to Fast Transient Pitch Roll Perturbations 523 Changes with Training and with Ageing 524 Gait 525 Characteristics of Human Walking 525 Biomechanical Characteristics 525 Is There a CPG in Humans? 526 Pattern of Muscle Activation 527 Spinal Pathways in Unperturbed Walking 527 Contribution of Different Spinal Pathways 527 Mechanisms Operating at Ankle Level 528 Stabilisation of the Knee 528 Transition 529 Reactions to External Perturbations 529 Stretch-Induced Responses 529 Cutaneous Reflexes 531 Responses in or from Upper Limbs 531 Complex Responses 531 Conclusions 532 Running, Hopping, Landing 532 Résumé 533 References 537

15 Contents xv 13 Plasticity in Spinal and Corticospinal Pathways 541 The H Reflex: A Tool to Study Synaptic Plasticity 541 Spinal Cord Plasticity 542 Evidence for Spinal Plasticity 543 Spinal Fixation in Animal Experiments 543 Training and Disuse 543 H Reflex Operant Conditioning 543 Maturation and Spinal Plasticity 546 Data from Animal Experiments 546 Human Cutaneous Reflexes 546 Proprioceptive Reflexes 547 Stance and Gait 547 Spinal Plasticity in the Elderly 548 Monosynaptic Reflex 548 Transmission in Spinal Pathways 548 Training Corrective Balance Reactions 548 Short-term Spinal Plasticity 549 Disuse 549 Specific Training 549 From Short- to Long-term Spinal Plasticity 550 Long-term Spinal Plasticity 551 Long-term Spinal Plasticity following CNS Lesions 552 Spontaneous Plasticity after SCI 552 Changes in Transmission in Spinal Pathways after CNS Lesion 552 Which Protocol for Rehabilitation of SCI? 552 Corticospinal Plasticity 553 Short-term Motor Cortex Plasticity 553 Use-Dependent Plasticity of the Motor Cortex 553 TMS-Induced Plasticity of the Motor Cortex 553 Peripheral-Induced Plasticity of the Motor Cortex 554 Corticospinal Plasticity Induced by Disuse or Specific Training 555 Long-term Motor Cortex Plasticity 555 Skill-Related Long-term Motor Cortex Plasticity 555 Reorganisation of the Motor Cortex Representation 555 Age-Related Changes 556 Brain Plasticity after Lesions 556 Take-over by the Ipsilateral Hemisphere? 556 Affected Hemisphere 557 Résumé 557 References Contribution of Spinal Pathways to the Pathophysiology of Movement Disorders 565 Spinal Pathways in Spasticity 565 What Is Spasticity? What Is not? 565 Definition 565 Spasticity vs. Animal Decerebrate Rigidity 566 Spasticity vs. Contracture 566 Contribution to Motor Impairment 566 Spinal Pathways at Rest 567 Why Do Spinal Pathways Malfunction? 570 Changes in Spinal Pathways during Movement 571 Spasticity after Cerebral Lesions 572 Affected Side of Stroke Patients 572 Unaffected Side of Stroke Patients 572 Synkinetic Movements 572 Cerebral Palsy 572 Spasticity after Spinal Lesions 573 Spinal Pathways in Parkinson s Disease 573 Possible Mechanisms Underlying Parkinsonian Rigidity 573 Increased Passive Muscle Stiffness 573 Exaggerated Long-Latency Responses to Stretch 574 Transmission in Spinal Pathways at Rest 574 Transmission in Spinal Pathways during Motor Tasks 575 Spinal Pathways in Dystonia 575 Résumé 576 References 577 Index 580

16 Acknowledgements This book is dedicated to the memory of Anders Lundberg, whose work and personal support have provided the inspiration behind most of the research described here. Writing this book would not have been possible without the understanding, life-long support and benign tolerance that we have received throughout our careers from Evelyne and Katre, who have allowed us to pursue our interests even when the demands placed on them were unreasonable and who have, in recent year, put much on hold while we completed this work. Geneviève Bard and Mary Sweet have provided us with invaluable assistance in collating references and getting the text into presentable order. We are grateful for the friendship, loyalty and meticulous attention to detail that has characterised their association with us over more than two decades. The studies reported here represent the intellectual achievements of collaborators, colleagues and students. We are grateful to everyone whose work is reported here, and to our colleagues and collaborators and their publishers who have allowed us to reproduce figures from their original work. Finally, we are indebted to L Institut National de la Santé et de la Recherche Médicale (INSERM) and the National Health & Medical Research Council of Australia (NHMRC) for recognising the value of research into human motor control and its disorders. xvi

17 Preface This book is the direct descendant of our book entitled The Circuitry of the Human Spinal Cord: Its Role in Motor Control and Movement Disorders, published in 2005 by Cambridge University Press. A revised and updated edition was needed because in 7 years new and more recent data have changed views about the role of the spinal cord in the control of limb movement. This revised edition also takes into account the development and rapid uptake of investigations using transcranial stimulation of the motor cortex. Thus, much more attention has been put on the corticospinal control of movement and transcortical pathways. Neural plasticity, whether underlying learning a new skill by healthy subjects or compensatory mechanisms for the neural changes associated with ageing or disease, has also been the subject of many recent investigations that deserve to be considered. The book is dedicated to Anders Lundberg ( ). Anders Lundberg is rightfully seen as the father of modern spinal cord neurophysiology, on how spinal circuitry is mobilised by descending commands and how feedback modifies the command at spinal cord level. Anders Lundberg was an outstanding leader, an intense and focused researcher, a tough critic, a good listener and inspiring mentor. He and his students provided much of the background data from animal experiments for the human studies which this book attempts to summarise. Above all, not only did he lead the world in the definition of interneuronal mechanisms in the spinal cord but he also developed hypotheses about how these mechanisms would be used in the intact organism. In later years, having defined the C3 C4 propriospinal system in the cat, he undertook behavioural experiments to confirm its role xvii

18 xviii Preface in movement, and it remains the only carefully documented interneuronal system for which a functional purpose has been clearly identified. His enthusiasm and enormous intellect have provided an impetus for us to show how discoveries from animal experiments have benefited the human condition, despite the adaptations that are necessary to cater for the greater motor repertoire of human subjects. In the preface to our previous book, we wrote: Over recent years, reappraisal of the role of direct corticomotoneuronal projections in higher primates including humans has led to the view that the control of movement resides in the motor cortical centres that drive spinal motoneurone pools to produce the supraspinally crafted movement. This view belies the complex interneuronal machinery that resides in the spinal cord. It is a thesis of this book that the final movement is only that part of the supraspinally derived programme that the spinal cord circuitry deems appropriate. This statement remains, we believe, as true today as it was in 2005 and it is also a driving motivation behind this volume. As research interest shifts to the complexities of the cortical mechanisms in the control of movement, so too has the thrust of this new book shifted to encompass transcortical reflexes, motor cortex excitability and corticospinal mechanisms in greater detail. Nevertheless, it is timely to remind the reader that limb movements can be planned and their programs initiated by the brain but they cannot be performed without a spinal cord and they cannot be performed gracefully without the intricate feedback systems that reside within it. As mentioned above, there has been an explosion of literature on motor control over the past 7 years, much of it devoted to cortical mechanisms preceding and associated with movement, and even some that do not have any direct influence on spinal circuitry. However, even in the latter instance, the state of the spinal cord is important when the procedures involved in testing the cortical circuitry depend on the modulation of a response that is transmitted through spinal mechanisms. In reviewing the literature for this book, we have become concerned that so simple a fact has been so often ignored in publications, even in prestigious journals. However, the justification for a new book ultimately resides not in restating the obvious but in whether there is anything new to say, and accordingly it should be asked, precisely what is new in this book? To understand the influence of cortical mechanisms on the spinal motoneurone pools it is necessary to understand, first, how segmental mechanisms can modulate the command signal and, second, the limitations of techniques that can be used in human subjects to demonstrate appropriate changes. Accordingly, the structure of the initial chapters in this new book recapitulates that of the previous book but each has been updated to cover new findings, new techniques and new appreciations of advantages and disadvantages. In a new chapter, the largest in this volume, we focus more fully on the techniques (and their limitations) used to study cortical and corticospinal mechanisms in the control of movement and on the results of such studies. It thereby provides an overview that integrates spinal and cortical mechanisms so that those who work at one end of the neuraxis can appreciate the importance of the other. A further major advance over the last decade has been on the plastic changes in connectivity that occur with development, senescence, motor learning, disease and recovery from it. An understanding of how the nervous system can adapt to changed circumstances is the key to understanding, on the one hand, acquired differences in motor skill and, on the other hand, the compensations, sometimes dysfunctional, that occur when the nervous system is damaged. Accordingly appropriate data are highlighted in chapters focussed on specific circuits, and there is a new chapter that specifically addresses the short- and long-standing adaptations of the function of spinal and corticospinal circuits to altered demands and pathology. Organisation of Individual Chapters We have retained the same format as for the previous book, with consideration first of the different spinal pathways for which there are reliable and non-invasive

19 Preface xix methods of investigation. Accordingly, after an extensive chapter on Methodology, we consider spinal circuitry in Chapters 2 10 with, for each circuit: 1. A brief background from animal experiments. Human investigations are indirect and it is crucial to know the essential characteristics of each pathway described in animal experiments with recordings from motoneurones and/or interneurones. Caution should always be taken in extrapolating from data obtained in reduced preparations (anaesthetised, decerebrate or spinalised animals) to awake intact human subjects, but the validation of a technique for exploring a given pathway may require controls only possible in animal experiments, and the results in human subjects are more credible when there is a close analogy with animal experiments. 2. A critical description of the available method(s) that have been used to explore the relevant pathways selectively. For those who wish to know how methods and concepts have evolved over the years and why some interpretations were erroneous even if, at the time, influential, the methods are described in detail, with their limits and caveats, and the results obtained and their interpretation(s) are critically evaluated in each chapter. Because human studies are fraught with technical difficulties, much space has been allotted to methods and potential pitfalls. 3. The organisation and descending control (in particular corticospinal) of these pathways in human subjects. The basic organisation of each pathway may well be the same in humans and cats, but the strength of the projections of individual spinal pathways on different motoneurone pools and their descending control have been the subject of phylogenetic adaptations to different motor repertoires. For the human lower limb, more elaborate reflex assistance is required for bipedal stance and gait. That there has been this phylogenetic adaptation argues that spinal pathways have a functional role in human subjects and are not evolutionary relics. 4. The changes in transmission in these pathways during various motor tasks. How spinal reflex pathways are used in motor control cannot be deduced from experiments on reduced animal preparations. It requires experiments performed during natural movements, as can be done in humans. This has been one major contribution of human studies to the understanding of motor control physiology. Thus, even though many of the conclusions are speculative, this book gives a large place to the probable functional implications of the described changes in transmission in spinal pathways during movement. 5. Changes in transmission in these pathways in patients with various lesions of the CNS. This has provided new insights about the pathophysiology of the movement disorder in these patients. Overall Organisation of the Book We have again adopted much the same organisation as previously. Methodology. The general methodologies which are used for investigating pathways are considered in a first chapter with the advantages and disadvantages of each technique. There is a risk that starting with a technical chapter would dissuade the non-specialist reader from delving further into the book. However, this initial chapter is useful to understand the rationale, advantages and limitations of the different techniques used to investigate different pathways, and we consider it important for those who have no experience with a particular technique but wish to use it in human subjects. Nevertheless it is not essential for the comprehension of subsequent chapters. Résumés. For those who want to get to the gist of the matter reasonably quickly each chapter terminates with a résumé of its salient points. The résumés can be used on their own without reference to the detailed text. They give a practical recipe on the choice of the appropriate technique and its proper use in routine clinical studies, together with data on the possible functional role of the particular pathway in motor control and in the pathophysiology of movement disorders. Overviews. The final four chapters summarise and synthesise the changes in transmission in spinal and corticospinal pathways during movement, and how these changes contribute to motor control, and spinal

20 xx Preface mechanisms underlying spasticity and motor impairment in patients with Parkinson s disease and dystonia. The physiological and pathophysiological roles of spinal and corticospinal pathways are presented using a different approach to that in the previous chapters. With respect to the previous book, these overviews have been greatly developed. A long chapter (Chapter 11) is focussed on purposeful movements and involves: (i) an overview of the contribution made by the different spinal pathways in various kinds of movement, (ii) an attempt to unravel the relationships between volitional control, afferent feedback (in particular through transcortical reflexes), and possible efference copy, (iii) a description of the changes in motor cortex excitability and short interval intracortical inhibition (SICI) during the different phases of various movement, and (iv) the role of spinal and supraspinal factors in muscle fatigue. Chapter 12 considers the contribution of spinal and transcortical pathways in unperturbed and perturbed stance and gait. Plastic changes in spinal and corticospinal circuits are considered in Chapter 13. In a brief summary, Chapter 14 collates data in preceding chapters on spinal mechanisms underlying spasticity and the motor impairment in patients with Parkinson s disease and dystonia.

21 Abbreviations Ach ACT ADM AG1 AG2 AHP ALS ANT APB APL BB BF BR CMEP CNS CoM CPG CPN CS CSP CSP CT CUSUM CV D-wave DPN E1 E2 ECR ECT ECU ED acetylcholine afferent conduction time abductor digiti minimi first agonist burst second agonist burst afterhyperpolarisation amyotrophic lateral sclerosis antagonist burst abductor pollicis brevis abductor pollicis longus biceps brachii biceps femoris brachioradialis cervicomedullary motor evoked potential central nervous system centre of mass central pattern generator common peroneal nerve corticospinal tract contralateral silent period cutaneous silent period conduction time cumulative sum conduction velocity direct wave of the corticospinal volley deep peroneal nerve early cutaneomuscular excitation late cutaneomuscular excitation extensor carpi radialis efferent conduction time extensor carpi ulnaris extensor digitorum xxi

22 xxii List of abbreviations EDB extensor digitorum brevis EDL extensor digitorum longus EEG electroencephalogram EHB extensor hallucis brevis EHL extensor hallucis longus EMG electromyogram EPSP excitatory post-synaptic potential FA fractional anisotropy FCR flexor carpi radialis FCU flexor carpi ulnaris FDB flexor digitorum brevis FDI first dorsal interosseous FDP flexor digitorum profundus FDS flexor digitorum superficialis FHB flexor hallucis brevis fmri functional magnetic resonance imaging FN femoral nerve FPL flexor pollicis longus FRA flexion reflex afferents GABA gamma-aminobutyric acid GL gastrocnemius lateralis GM gastrocnemius medialis GS gastrocnemius soleus GTO Golgi tendon organ H test reflex, paired H reflex technique for recurrent inhibition H1 conditioning H reflex, paired H reflex technique for recurrent inhibition HD homosynaptic depression H max maximal H reflex I-wave indirect wave of the corticospinal volley I1 cutaneomuscular inhibition Ia IN Ia inhibitory interneurone Ib IN Ib interneurone ICF intracortical facilitation IHI interhemispheric inhibition IN interneurone IPSP inhibitory post-synaptic potential ISI interstimulus interval isp ipsilateral cortical silent period L-Ac L-acetylcarnitine LAI long-latency afferent inhibition LICF long-interval intracortical facilitation LICI long-interval intracortical inhibition LL response LLSR Loc Coer LRN LTD LTI LTP M wave M1 M1 M2 M2 M3 MC MEP MLSR M max MN MS MT MU MVC NA NRM PAD PAD IN PAS PB PD PET PIC PL PM PN PSF PSP PSTH PT PTN PTP RC long-latency response long-latency stretch reflex locus coeruleus lateral reticular nucleus long-term depression linear-time-invariant long-term potentiation direct motor response primary motor cortex short-latency stretch response long-latency stretch response (upper limb) medium-latency stretch response (lower limb) long-latency stretch response musculo-cutaneous motor evoked potential medium-latency stretch response maximal direct motor response motoneurone multiple sclerosis motor threshold motor unit maximal voluntary contraction noradrenergic nucleus raphe magnus primary afferent depolarisation interneurone mediating primary afferent depolarisation paired associative stimulation peroneus brevis posterior deltoid positron emission tomography persistent inward current peroneus longus pectoralis major propriospinal neurone post-stimulus frequencygram post-synaptic potential post-stimulus time histogram perception threshold posterior tibial nerve post-tetanic potentiation Renshaw cell

23 List of abbreviations xxiii REM rapid eye movements TA tibialis anterior RF rectus femoris TBS theta burst stimulation rtms repetitive TMS tdcs transcranial direct current stimulation S1 conditioning stimulus, paired H reflex technique for recurrent inhibition TENS transcutaneous electrical nerve stimulation SAI short-latency afferent inhibition TES transcranial electrical stimulation SCI spinal cord injury TFL tensor fascia latae SD standard deviation TMS transcranial magnetic stimulation SEM standard error of the mean TN tibial nerve SICF short-interval intracortical facilitation Tri TT triceps brachii tendon jerk threshold SICI short-interval intracortical inhibition TVR tonic vibration reflex SLSR short-latency stretch reflex UMN upper motoneurone SM test stimulus, paired H reflex technique for recurrent inhibition V1 reflex response following M max during voluntary contraction SPN superficial peroneal nerve VL vastus lateralis SR superficial radial VM vastus medialis SSEP somatosensory evoked potential VS vestibulospinal tract ST semitendinosus VSCT ventral spinocerebellar tract