Concurrent Neuroplastic and Behavioral Improvements Induced by Upper-Extremity Rehabilitation Post-Stroke

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Title:
Concurrent Neuroplastic and Behavioral Improvements Induced by Upper-Extremity Rehabilitation Post-Stroke
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english
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Corti, Manuela
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University of Florida
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Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Rehabilitation Science
Committee Chair:
Patten, Carolynn
Committee Members:
Behrman, Andrea L
Crosson, Bruce A
Triggs, William J

Subjects

Subjects / Keywords:
extremity -- neuroplasticity -- recovery -- rehabilitation -- stroke -- upper
Rehabilitation Science -- Dissertations, Academic -- UF
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Rehabilitation Science thesis, Ph.D.
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Abstract:
Stroke is the leading cause of adult disability worldwide, with the most persistent motor impairments affecting the upper-extremity (UE). Among survivors, 73-88% present with sensorimotor impairments affecting UE function and 55-75% present with difficulties using the arm for daily living activities. The related physical disability compromises these individuals’ autonomy, may affect their psychosocial functioning and contributes to depression and reduced quality of life. While this problem is well recognized, identification of effective approaches for rehabilitation of UE hemiparesis has been elusive. This knowledge gap points to an urgent, unmet need to better understand the neural mechanisms of UE motor recovery post-stroke and develop mechanism-based interventions that promote restoration of UE motor function. The long-term goal of this research is to restore UE motor function for persons post-stroke. The overall objective of this dissertation, which is the next step towards attainment of our long term goal, is to understand how therapeutic interventions for post-stroke hemiparesis affect key neural mechanisms that mediate motor recovery. The central hypothesis holds that an intervention that includes dynamic, high-intensity resistance training, induces positive changes at both behavioral and neurological levels by increasing central neural drive of the impaired hemisphere. This hypothesis is based on the notions that the most disabling impairments post-stroke are due to weakness in the affected limb, and also that dynamic resistance training post-stroke can help alleviate weakness through profound neural adaptations. Traditional clinical perspectives favor practice of functional tasks over resistance training because high-exertion activities were assumed to increase spasticity and impair motor performance. This dissertation includes four studies in persons post-stroke which demonstrate that interventions including resistance training are harmless and induce more significant improvements in strength, upper-extremity function, restoration of more normal movement patterns and neurophysiologic adaptations (including reflex and transcranial magnetic stimulation responses) compared to functional task practice performed in isolation.
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In the series University of Florida Digital Collections.
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Includes vita.
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Description based on online resource; title from PDF title page.
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This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Manuela Corti.
Thesis:
Thesis (Ph.D.)--University of Florida, 2012.
Local:
Adviser: Patten, Carolynn.
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RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2014-05-31

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1 CONCURRENT NEUROPLASTIC AND BEHAVIORAL IMPROVEMENTS INDUCED BY UPPER EXTREMITY REHABILITATION POST STROKE By MANUELA CORTI A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMEN T OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2012

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2 2012 Manuela Corti

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3 To my Mom and Dad who have always been right next to me

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4 ACKNOWLEDGMENTS I would like to a cknowled ge the people who directly he lp me with this dissertation and the people who have personally supported me through the PhD experience. I acknowledge the people that participated to these studies, which dedicated their time for the sake of others. Special thanks go out to all participan ts recovering from their stroke. I thank my mentor Dr. Carolynn Patten for her constant support from the beginning of my PhD journey and throughout my dissertation work. I thank all the members of my dissertation committee, Dr. Cros son, Dr. Behrman and Dr Triggs, for their advice and their availability. I thank all the members of Brain Rehabilitation Research Center. Each of them contributed to the realization of my dissertation work. I thank all the Pattenlab members : Dorian, Theresa, Martina, Ginny, Sh ilpa, Dave, Alicia, David, Alex, Albina, Krystina, Megan for making me feel always part of a great team. I am grateful to all my friends for being there always and without whom life w ould not have been half as fun. I finally would like to thank my wonderf ul family for their unconditional love throughout life. Special thanks go out to my parents, wh o provided me the tools to make this happen and an invaluable support despite the physical distance.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 9 LIST OF FIGURES ................................ ................................ ................................ ........ 10 ABSTRACT ................................ ................................ ................................ ................... 12 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 14 1.1 Upper Extremity Motor Dysfunction and Neural Mechanisms Post stroke ........ 14 1.1.1. Motor Dysfunctions Post stroke ................................ .............................. 14 1.1.1.1. What is spasticity? ................................ ................................ ........ 14 1.1.1.2. Dexte rity ................................ ................................ ........................ 16 1.1.1.3. Learned non use phenomenon ................................ ..................... 19 1.1.1.4. Muscle weakness ................................ ................................ .......... 22 1.1.2. Neural Mechanisms Post stroke ................................ ............................. 23 1.1.2.1. Activation impairment ................................ ................................ .... 24 1.1.2.2. Inter hemispheric inhibition (IHI) ................................ ................... 29 1.2. Strategies for Functional Improvement: Recovery versus Compensation ........ 31 1.2.1. Behavioral Recovery versus Compensation ................................ ........... 32 1.2.2. Neural Recovery versus Compensation ................................ ................. 33 1.2.3. Neural Strategies Supporting Functional Improvement .......................... 34 1.2.4. Appropriate Outcome Measures to Distinguish Recovery and Compensation ................................ ................................ ............................... 36 1.3. Neuroplasticity ................................ ................................ ................................ 39 1.3.1. Brief History and Key Concepts ................................ .............................. 39 1.3.2. Definition of Neuroplasticity ................................ ................................ .... 4 2 1.3.3. Use Dependent Neur al Plasticity in an Intact Nervous System: Motor Learning and Motor Experience ................................ ................................ .... 43 1.3.4. Use Dependent Neural Plasticity in an Injured Nervous System: a Relearning Process ................................ ................................ ....................... 46 1.3.5. Not All Plasticity is Good ................................ ................................ ........ 48 1.3.6. Plasticity is not only in the Brain ................................ ............................. 49 1.4. Neurorehabilitation induced Plasticity Post stroke ................................ ........... 50 1.4.1. Evolution of Neurorehabilitation ................................ .............................. 50 1.4.1.1. Evidence for n eurorehabiitation induced plasticity post stroke ..... 52 1.4.1.2. Behavioral interventions ................................ ................................ 53 1.4.1.3. Non invasive cortical stimulat ion ................................ ................... 55 1.5. Objective of this Dissertation ................................ ................................ ........... 63

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6 2 COMMON METHODS ................................ ................................ ............................ 67 2.1. Measures ................................ ................................ ................................ ......... 67 2.1.1. Clinical Evaluation ................................ ................................ .................. 67 2.1.2. Three dimensional Motion Analysis ................................ ........................ 67 2.1.2.1. General information about technique ................................ ............ 67 2.1.2.2. Data collection ................................ ................................ .............. 68 2.1.2.3. Data analysis ................................ ................................ ................ 69 2.1.3. Transcranial Magnetic Stimulation (TMS) ................................ ............... 69 2.1.3.1. General information about technique ................................ ............ 69 2.1.3.2. Data collection ................................ ................................ .............. 70 2.1.3.3. Data analysis ................................ ................................ ................ 71 2.1.4. Stretch Reflex ................................ ................................ ......................... 72 2.1.4.1. General information about technique ................................ ............ 72 2.1.4.2. Data collection ................................ ................................ .............. 73 2.1.4.3. Data analysis ................................ ................................ ................ 73 2.1.5. H reflex ................................ ................................ ................................ ... 74 2.1.5.1. General information about technique ................................ ............ 74 2.1.5.2. Data collection ................................ ................................ .............. 75 2.1.5.3. Data analysis ................................ ................................ ................ 76 2.2. Interventions ................................ ................................ ................................ .... 76 2.2.1. Functional Task Practice (FTP) ................................ .............................. 76 2.2.2. Constraint Induced Movement Therapy (CIMT) ................................ ..... 77 2.2.3. Power Training ................................ ................................ ....................... 77 2.2.4. Repetitive TMS (rTMS) ................................ ................................ ........... 77 3 DIFFERENTIAL EFFECTS OF POWER TRAINING VERSUS FUNCTIONAL TASK PRACTICE ON COMPENSATION AND RESTORATION OF ARM FUNCTION AFTER STROKE ................................ ................................ ................. 80 3.1. Background ................................ ................................ ................................ ...... 80 3.2. Methods ................................ ................................ ................................ ........... 83 3.2.1. Participants ................................ ................................ ............................. 83 3.2.2. Procedures ................................ ................................ ............................. 83 3.2.3. Measures ................................ ................................ ................................ 84 3.2.3.1. Clinical assessments ................................ ................................ ..... 84 3.2.3.2. Kinematics of functional reach to grasp: ................................ ....... 85 3.2.4. Therapeutic Intervention ................................ ................................ ......... 85 3.2.5. Kinematic Analysis ................................ ................................ ................. 86 3.2.6. Statistical Analysis ................................ ................................ .................. 87 3.3. Results ................................ ................................ ................................ ............. 88 3.3.1. Clinical Results ................................ ................................ ....................... 89 3.3.2. Kinematic Data ................................ ................................ ....................... 89 3.4. Discussion ................................ ................................ ................................ ....... 90 3.4.1. Compensation versus Restoration ................................ ......................... 90 3.4.2. Effect of Treatment Orde r ................................ ................................ ....... 91 3.4.3. Use of Kinematics to Investigate Motor Control ................................ ...... 91

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7 3.4.4. Neuroplasticity and Specificity of Training ................................ .............. 92 3.4.5. Limitations ................................ ................................ .............................. 94 3.4.6. Clinical Relevance ................................ ................................ .................. 96 4 POWER TRAINING ENHANCES ELBOW STRETCH REFLEX MODULATION POST STROKE ................................ ................................ ................................ .... 106 4.1. Background ................................ ................................ ................................ .... 106 4.2. Methods ................................ ................................ ................................ ......... 109 4.2.1. Participants ................................ ................................ ........................... 109 4.2.2. Procedure ................................ ................................ ............................. 110 4.2.3. Intervention ................................ ................................ ........................... 110 4.2.4. Evaluations ................................ ................................ ........................... 111 4.2.5. Stretch Reflex Analysis ................................ ................................ ......... 112 4.2.6. Statistical Analysis ................................ ................................ ................ 112 4.3. Results ................................ ................................ ................................ ........... 113 4.3.1. Treatment Effect ................................ ................................ ................... 113 4.3.2. Retention Effect ................................ ................................ .................... 114 4.3.3. Period Effect (Treatment Block by Group) ................................ ............ 114 4.3.4. Order Effect ................................ ................................ .......................... 115 4.4. Discussion ................................ ................................ ................................ ..... 115 5 UPPER EXTREMITY REHABILITATION REDUCES INTER HEMISPHERIC COMPETITION POST STROKE ................................ ................................ .......... 123 5.1. Backgr ound ................................ ................................ ................................ .... 123 5.2. Methods ................................ ................................ ................................ ......... 127 5.2.1. Subject Characteristics ................................ ................................ ......... 127 5.2 .2. Study Design ................................ ................................ ........................ 128 5.2.3. Measures ................................ ................................ .............................. 128 5.2.4. Intervention ................................ ................................ ........................... 131 5.2.4.1. Power training ................................ ................................ ............. 131 5.2.4.2. Functional Task Practice (FTP) ................................ ................... 132 5.3. Analysis ................................ ................................ ................................ ......... 132 5.3.1. Clinical Tests ................................ ................................ ........................ 132 5.3.2. Three Dimensional Motion Analysis ................................ ..................... 133 5.3.3. Transcranial Magnetic S timulation (TMS) ................................ ............. 134 5.3.3.1. Recruitment curve (RC) ................................ .............................. 134 5.3.3.2. Ipsilateral silent period (iSP) ................................ ....................... 135 5.3.4. Force Production. ................................ ................................ ................. 135 5.4. Results ................................ ................................ ................................ ........... 136 5.4.1. Clinical Tests ................................ ................................ ........................ 136 5.4.2. Kinematics ................................ ................................ ............................ 137 5.4.3. Transcranial Magnetic Stimulation (TMS) ................................ ............. 138 5.4.3.1. Recruitment curve (RC) ................................ .............................. 138 5.4.3.2. Ipsilateral silent period (iSP) ................................ ....................... 139 5.4.4. Force Measurements ................................ ................................ ............ 141

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8 5.5. Discussion ................................ ................................ ................................ ..... 142 6 POWER TRAINING POST STROKE ENGAGES NEURAL CIRCUITS AT SPINAL AND SUPRASPINAL LEVELS ................................ ................................ 162 6.1. Background ................................ ................................ ................................ .... 162 6.4. Research Design and Methods ................................ ................................ ...... 169 6.4.1. Inclusion and exclusion Criteria ................................ ............................ 169 6.4.2. Participant characteristics ................................ ................................ ..... 170 6.4.2. Experimental Design ................................ ................................ ............ 170 6 .4.3. Outcome Measures ................................ ................................ .............. 170 6.4.3.1. Behavioral measures ................................ ................................ .. 170 6.4.3.2. Neurophysiologic measures. ................................ ....................... 172 6.4.4. Therapeutic Interventions ................................ ................................ ..... 1 75 6.5. Analysis ................................ ................................ ................................ ......... 176 6.5.1. Clinical Tests ................................ ................................ ........................ 176 6.5.1. Three Dimensional Motion Analysis ................................ ..................... 176 6.5.2. H reflex ................................ ................................ ................................ 177 6.5.3. Tra nscranial Magnetic Stimulation (TMS) ................................ ............. 178 6.6. Results ................................ ................................ ................................ ........... 179 6.6.1. Clinical Tests ................................ ................................ ........................ 179 6.6.3. Kinematics ................................ ................................ ............................ 180 6.6.4. H reflex ................................ ................................ ................................ 180 6.6.5. Transcranial Magnetic Stimulation ................................ ........................ 181 6.6.5.1. Recruitment curve ................................ ................................ ....... 181 6.6.5.2. Silent period (SP) ................................ ................................ ........ 182 6.6.5.3. Ipsilateral s ilent period (iSP) ................................ ....................... 182 6.6.5.4. Short Intracortical inhibition (SICI) ................................ ............... 183 6.6.5.5. Suppression of voluntary contraction (SVC). .............................. 183 6.7. Conclusion ................................ ................................ ................................ ..... 183 7 CONCLUSIONS ................................ ................................ ................................ ... 204 APPENDIX A: REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION OF MOTOR CORTEX AFTER STROKE: A FOCUSED REVIEW .............................. 215 LIST OF REFERENCES ................................ ................................ ............................. 216 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 238

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9 LIST OF TABLES Table page 1 1 Definitions of recovery and compensation at the neural and behavioral levels. 65 1 2 Neural strategies supporting func tional improvements. ................................ ...... 65 2 1 Task based activities. ................................ ................................ ......................... 79 3 1 Participant characteristics. ................................ ................................ .................. 97 3 2 Clinical data. ................................ ................................ ................................ ....... 98 3 3 Kinematic data. ................................ ................................ ................................ 100 5 1 Wolf motor function test Number of improved and worse items ..................... 148 5 2 Clinical scales ................................ ................................ ................................ ... 149 5 3 Late life function and disability instrument ................................ ........................ 150 5 4 Functional task practice (FTP). ................................ ................................ ......... 151 6 1 POWER training. ................................ ................................ .............................. 191 6 2 Functional task practice (FTP) of HYBRID training. ................................ .......... 192 6 3 Clinical scales. Numbers in parenthesis indicate scores for non disabled. ....... 192 6 4 Muscle strength. ................................ ................................ ............................... 193 6 5 Neuromechanis ms. ................................ ................................ ........................... 194

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10 LIST OF FIGURES Figure page 1 1 Schematic diagram illustrating how experience dependent neural plasticity supports learning ................................ ................................ ................................ 66 3 1 Study design ................................ ................................ ................................ ..... 102 3 2 Treatment protocols ................................ ................................ .......................... 103 3 3 Key kine matic parameters of functional reach to grasp reveal effects of FTP and Power ................................ ................................ ................................ ........ 105 4 1 Study design. Summarizing the cross over design ................................ ........... 121 4 2 Passive stretch reflex ................................ ................................ ....................... 122 5 1 Study design ................................ ................................ ................................ ..... 152 5 2 POWER training ................................ ................................ ............................... 153 5 3 Wolf motor function test ................................ ................................ .................... 154 5 4 Key kinematic parameters of functional reach to grasp ................................ .... 155 5 6 Speed and index of curvature of functional reach to grasp. ............................. 156 5 8 Recruitment curve sl opes. ................................ ................................ ................ 157 5 9 Motor evoked potentials (MEPs). ................................ ................................ ...... 158 5 10 Ipisilateral silent period duration ................................ ................................ ....... 159 5 11 Laterality index for iSP duration. ................................ ................................ ....... 160 5 12 Force production. ................................ ................................ .............................. 161 6 1 Single subject design ................................ ................................ ....................... 190 6 2 Key kinematic parameters. ................................ ................................ ............... 195 6 4 H reflex recruitment curves and slopes. ................................ ........................... 197 6 5 Presynaptic or D1 inhibition. ................................ ................................ ............. 198 6 6 Post activation depression (PAD) ................................ ................................ ..... 198 6 7 TMS recruitment curve slopes. ................................ ................................ ......... 199

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11 6 8 Ipsilateral silent period (iSP) and laterality index (LI). ................................ ....... 200 6 9 Short intracortical inhibition (SICI). ................................ ................................ ... 201 6 10 Suppression of voluntary contraction (SVC .................... 202 6 11 Stimulus respon se (S R) curves of SP against stimulus intensity. .................... 203

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12 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CONCURRENT NEUROPLASTIC AND BEHAVIORAL IMPROVEMENTS INDUCED BY UPPER EXTREMITY REHABILITATION POST STROKE By Manuela Corti May 2012 Chair: Carolynn Patten Major: Re habilitation Science Stroke is the leading cause of adult disability worldwide, with the most persistent motor impairments affecting the upper extremity (UE) Among survivors, 73 88% present with sensorimotor impairments affecting UE function and 55 75 % present with diffi culties using the arm for daily living activities. The related physical disability compromises autonomy, may affect their psychosocial functioning and contributes to depression and reduced quality of life. While this pr oblem is well recognized, identification of effective approaches for rehabilitation of UE hemiparesis has been elusive. This knowledge gap points to an urgent, unmet need to better understand the neural mechanisms of UE motor recovery post stroke and devel op mechanism based interventions that promote restoration of UE motor function. The long term goal of this research is to restore UE motor function for persons post stroke. The overall objective of this dissertation, which is the next step towards attainme nt of our long term goal, is to understand how therapeutic interventions for post stroke hemiparesis affect key neural mechanisms that mediate motor recovery. The central hypothesis holds that an intervention that includes dynamic, high intensity resistanc e training, induces positive changes at both behavioral and neurological levels

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13 by increasing central neural drive of the impaired hemisphere This hypothesis is based on the notions that the most disabling impairments post stroke are due to weakness in th e affected limb, and also that dynamic resistance training post stroke can help alleviate weakness through profound neural adaptations. T raditional clinical perspectives fav or practice of functional tasks over resistance training because high exertion acti vities were assumed to increase spasticity and impair motor performance This dissertation includes four studies in persons post stroke which demonstrate that interventions including r esistance training are harmless and induce more significant improvement s in strength, upper extremity function, restoration o f more normal movement patterns and neurophysiologic adaptations (including reflex and transcranial magnetic stimulation responses) compared to functional task practice performed in isolation.

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14 CHAPTE R 1 I NTRODUCTION 1.1 Upper Extremity M otor D y s function and Neural M echanisms P ost stroke 1.1.1. Motor Dysfunctions P ost stroke Stroke is the leading cause of adult disability worldwide 1 According to the World Health Org anization, 15 million people suffer stroke each year, and fewer than 40 percent recover completely over the course of rehabilitation 1 The most persistent stroke related motor impairments affect the upper extremity 1 with approximately 80 percent of individuals presenting with sensorimotor impairments affecting arm function and about 65 percent presenting with persistent difficulties in using the affected arm for daily living activities such as eating, writing, bathing and dressing 2 The resulting autonomy 1, 3 may have detrimental effect s on their psychosocial functioning 4 and reduce their quality of life 1, 4, 5 The prevalence and persistence of these motor deficits point to an urgent need to develop effective rehabilitation interventions that promote restoration of normal upper extremity motor function. Hemiparesis is the m ost common consequence of stroke 6 and is characterized by lo ss of dexterity 7 ; spa s ticity which involves components of b oth hype r reflexia and hypertonia 8 ; weakness 9 and potentially learned non use 10 Here w e address the most important manifestations of upper extremity hemiparesis post stroke and seek to identify the mechanisms that contribute to these manifestations of motor dysfunction. 1.1.1.1. What is spasticity? Classically defined, spasticity is a velocity dependent resistance to passive muscle stretch 11 The phenomenon of spasticity involves two components: hypertonia

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15 increased mechanical resistance to stretch, and hyperreflexia exaggerated reflex activity in resting muscles. Krakauer 12 suggests the primary neural mechanism that contributes to spastic i ty is related to loss of cortical inhibitory control on brain stem motor nuclei and spinal monosynaptic reflex circuits Spast icity is comprised of increased resting muscle tone, hype r reflexia, and in some cases, clasp knife phenomenon from the loss of inhibition on flexor reflex afferents. Spastic signs are elicited at rest, but the degree to which spasticity plays a role durin g actual movement remains uncertain 12 Traditional perspective s in neurorehabilitation 13 held that spasticity imposed the gr eatest impairment to motor function and represented the most significant limitation to motor recovery. Moreover, because spasticity appeared to be exacerbated with exertion, any form of high effort activity was strictly proscribed in neurorehabilitation 13 Contrary to these beliefs, contemporary investigations have demonstrated first that spasticity is not a primary impairment to functional movement, mor e over acute bouts of effortful activity do not exacerbate spa sticity 14 16 Further, one contemporary review suggested evidence for the harmlessness of high exertion training, such as resistance training, in exacerbating muscle spasticity 16 Several studies have demonstrated the lack of a significant functional relationship between spasticity and functional motor performance 12 Thilmann et al. 17 studied the stretch induced EMG responses and found that, compared with controls, persons post stroke had increased resistance to limb displacement at rest but not when the arm was actively moving, suggesting that spastic i ty does not contribute to motor control abnormalities in hemiparesis. In another study, Thilmann et al. studied both the stretch induced EMG (hypereflexia) and torque

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16 (hypertonia) responses. They found that hypertonia was associated with muscle contracture rather than with reflex h ypere x citability, and detected no relationship between hypertonia and either weakness or loss of dexterity. Another study on 95 persons post stroke showed that severe functional disability occurred almost equally either in the presence or absence of spasti city. As mentioned, Patten et al. 18 compared hyperreflexic and hypertonic responses using passive stretches imposed under controlled velocity conditions after high intensity resistance training and functional task practice. The se authors showed that high intensity resistance t raining actually improved stretch reflex response modulation. In support of the importance of resistance training post stroke, a recent review 19 suggested that the presence of weakness post stroke could aggravate spasticity in many ways, including: reduced traffic in descending pathways responsible for voluntary movement; muscle fiber atrophy and contracture; changes in the spatial and temporal patterns of muscle activation, causing an inefficient EMG torque relationship; loss of functional motor units and changes in the properties of remaining units, p roducing a decrease in maximal force due to activation on a suboptimal portion of the force length relationship 20 25 Taken together, such observations shift the focus of neurorehabilitation away from spasticity t oward weakness as a prominent problem and introduce s the potential attention of neurorehabilitation to high intensity training. 1.1.1.2. Dexterity Dexterity is the ability to coordinate muscle activity to meet environmental demands and is not limited to t asks involving the hand 26 B ernstein defined dex terity as t quickly, rationally and deftly,

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17 where flexibility with respect to the changing environment is an important feature 27 Canning et al. 26 conducted a study to determine the relative contribution of strength and dexterity to function during recov ery after stroke and to determine the predictive value of initial strength, dexterity and function on long term function post stroke. Interestingly, the se authors found that strength and dexterity account for 71 percent of the variation in function in the six months post stroke. The largest contribution of function was made by the shared component of strength and dexterity, implying that strength and dexterity interact during the production of motor behavior. However, strength also made an additional separ ate contribution to function. The authors suggested that this additional contribution of strength was related to the fact that strength is a prerequisite of movement; without enough strength, it is not possible to function. Th is study suggested therefore that loss of strength, and not dexterity, is the major contributor to physical disability post stroke. Further, the study suggested that either strength and/or dexterity measured in the early stage can satisfactorily predict later function post stroke. The overall findings of this study suggested that, when significant weakness is present, exercise designed to increase strength will likely decrease disability 26 Several authors have attempted to study dexterity post stroke; however, most of the se used clinical assessments such as the Wolf Motor Function Test, the Fugl Meyer Asse s sment, the NIH Stroke Scale or the Purdue Pegboard, which are usually insufficient to explain the subtle deficits of dexterity 28 Thr ee dimensional motion analysis, including kinematic, electromyographic and kinetic variables, is a sensitive tool to characterize abnormal dexterity post stroke 7, 29, 30 For example, r each to grasp movements requi re accurate planning and execution of hand transport towards the

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18 objects and adjustment of Kinematic evaluations showed reach to grasp movements with the hemiparetic arm in stroke patients are slow er and less accurate than in healthy controls 31 The additional prerequisite for executing dexterous tasks is the ability to produce, maintain and modulate grip forces 7 Compared to healthy controls, grip forces post stroke are usually less coordinated and more variable in both the hemiparetic and non paretic arm 30 Nowak et al. quantified dexterity comprehensively at both hands using kinematic recording of finger and hand tapping, a reach to grasp movement, quantitative analysis of grip forces in a grasp lift task and clinical rating scale s The authors found that although most pronounced at the contralesional hand, the timing, accuracy and efficiency of reach to grasp and grasp lift movements were significantly impaired in both han ds. Also, the severity of impaired dexterity was not related to which hemisphere was affected and was similar for distal (grasping) and proximal (reaching) muscle groups of the arm, regardless of the performing hand. Finally, several performance deficits i n the timing, accuracy and efficiency of reach to grasp and grasp lift movements revealed strong correlations with clinical measures of hand function and sensory loss 30 Buma et al. 32 conducted a recent review o f serial imaging studies investigating recovery of dexterity within 6 months post stroke and identified trends in the association between task related brain activation patterns and funct ional upper limb recovery. Twenty two of the 869 studies identified met the inclusion criteria. One important point to the authors in selecting the studies was their internal validity. The authors excluded studies that did not specifically measure dexterit y of the paretic limb I mportantly, they did not consider clinical scales ( or activities of daily living ) as appropriate measures of

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19 dexterity. After stroke, motor task performance showed unilateral overactivation of motor and non motor areas, a posterior shift in activity in the primary motor cortex, and bilateral recruitment of associated motor and non motor areas. O veractivation appear ed to diminish longitudinally in parallel with neur al recovery, but not in all individuals 32 In add ition, the authors suggested the future research should : use outcomes that specifically measure dexterity of the paretic limb and control for the extent of white matter damage by using diffusion tensor i maging (DTI) and transcranial magnetic stimulation (TMS) to investigate changes in cortico spinal tract integrity 32 Further, they suggested that measure s of coordination dynamics shou ld accompany serial imaging studies relating to recovery and cortical activation patterns to separate behavioral compensation from behavioral recovery 32 Another study investigated the neural substrates of impaired finger tapping post stroke U sing a light accelerometer they evaluate d the regularity of index finger movements and generate d a regularity index. The authors found significant correlations between the affected hand regular ity index and the functional magnetic resonance imaging response within the contralesional dorsal premotor and prefrontal cort ices Decreased tapping regularity was associated with increased activation of both premotor areas and prefrontal areas, contrale sionally. The se findings suggest involvement of the contralesional dorsal premotor and prefrontal areas in affected hand functions post stroke, and consequently a possible involvement in recovery of dexterity. 1.1.1.3. Learned non use phenomenon The pheno menon referred as learned non use was described by Taub et al. (1966), and it probably corresponds to what Henry Meige (1904) descr ibed using the expression functional amnesia 33

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20 Tau use theory arose from experiments on deafferentation of a single forelimb in monkeys. Deafferented animals did not use of the forelimb spontaneous ly. However, restricting movement of the intact limb for several days could lead to spontaneou s use of the deafferented limb Furthermore, if the movement of the deafferented limb was prevented immediately after surgery and for the next 3 months, then u se of the deafferented limb did not reveal any overt residual consequences. Wolf 34, 35 proposed the use of this theory for the recovery of the upper l imb post stroke in human s E xtension of this theory from deafferented monkeys to stroke in humans does not have experimental verification, but it is supported b y clinical studies of constraint induced movement therapy (CIMT) in improving upper limb function post stroke 36 CIMT is a tre atment intervention in which the patient is strongly encouraged to use the affected arm while the unaffected arm is immobilized o r constrained This treatment is m eant to help patients overcome learned non use. Van der Lee 37 argued that CIMT is no more effective than an equal dose of bilateral therapy and that CIMT is most effective in individuals with sensory disorders/hemineglect. The author s argued also that our knowledge of the learned non use phenomenon in humans post stroke and the possible pathological mechanisms behind it is still poorly developed 37 Van der Lee conducted a review on the effect of CIMT post stroke includ ing four randomized clinical trials. Although the authors of all four studies reported positive results, the effect size calculated with out covariates yielded no statistically significant differences from the control intervention group In one of the studies a differential effect was found for patients with sensory disorders and hemineglect, leading to the hypothesis that learned non use m ay be related to sensory impairments. In addition,

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21 from a clinical relevance point of view, in studies that estimated the minimal clinically importance difference (MCID), the differences from the control intervention group were smaller than an MCID. These results are generally deafferentation observations. The author concluded that the learned non use theory requires further exploration. The evidence regarding the effectiveness of CIMT is not yet convincing 37 Sunderland et al. studied w hether hat CIMT is able to induce improvement in basic motor control. They suggested most of the studies implementing CIMT suf fered from some lack of clarity in what is meant by improvement in motor performance. Some might suggest that improvement could be the increased spontaneous use of the paretic arm during daily activities. However, increased use of the arm does not necessa rily mean that motor control of the arm is improved. Most of the studies with CIMT measured either gains in spontaneous use, such as tested by the Motor Activity Log or improvements in function such as tested by the Wolf Motor Function Test. Therefore, i n CIMT studies, it is difficult to discriminate between true behavioral recovery and the use of alternative compensatory strategies. One explanation for the improved arm function and arm use after CIMT may be that impaired motor control does not always dir ectly translate into functional losses because functional success (e.g., task completion) can be achieved using an abnormal movement pattern. The effect of CIMT may be the acquisition of compensatory skills in the use of the paretic arm 36 In addition, Sunderland et al. argued that the change in responsiv eness of a single muscle to TMS or fMRI activation during motor performance can be explained by both restoration of lost cortical representations and acquisition of new representations for adaptive learning. A

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22 clearer distinction between restitution and behavioral compensation will only be achieved by combining TMS or functional i maging with more detailed behavioral studies 36 1.1.1.4. Muscle weakness Weakness is defined as the inability to generate leve ls of muscle force under a specific set of testing conditions. Recent literature suggests that weakness is the major contributor to physical disability post stroke 9, 14, 16, 20, 27, 38 and that strength at early s tages post stroke can be used successfully to predict function 27 Several authors reported maximal grip force as a predictor of UE motor recovery and functional independence in acute stroke subjects 39, 40 In addition, other authors described a relationship between impaired reaching performance 15, 41 43 physical disability 26 and learned non use 15 A recent review of upper extremity strength training in stroke found that the technique caused no adverse effects 14 Further, Harris et al. 16 conducted a meta analysis of randomized controlled trials from 1950 through 2009 and found evidence that strength training can improve upper limb strength and function without increasing spasticity or pain in individuals with stroke. Nevertheless, controversy persists because traditionally, clinicians beli eve that strengthening the paretic upper limb may increase spasticity and impair motor performance 16 Weakness involve s both neural factors, which consist of the capacity of the nervous system to activate and modulate muscular activity, and muscular factors, which include the capacity of the muscle to generate force according to its phys iological cross sectional area. To generate force voluntarily, the motor areas of our brains must be able

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23 to communicate effectively with the motor neurons in the spinal cord that are Damage of the brain tiss ue following stroke reduces the communication of the corticospinal and other supraspinal pathways with the lower spinal levels. As a consequence of reduced neural information coming from higher levels, it has been proposed that the spinal cord undergoes a loss of motorneurons and impairment of the primary force control mechanisms 21, 24 However, disuse/non use and impaired muscle activation could also lead to atrophy and changes in the muscle fibers 44 which contribute to secondary weakness post stroke. The ability to accurately generate force depends on two strategies: recruitment of motor units and rate coding 45 48 Motor unit recruitment is the progressive activation of a muscle by successively recruiting motor units to accomplish increasing gradatio ns of contractile strength R ate coding consists of increasing the motor unit firing rate frequency to increase force production ( i.e. 45, 49 1.1.2. Neural Mechanisms P ost stroke Force control depends on the integrity of the sensorimotor system, and when injury to sensorimotor areas of the brain occurs, such as in stroke, control of force is impaired. People post stroke experience a range of force or motor control deficits, including exa ggeration of force, which is considered a compensatory strategy to maintain force when sensorimotor processes are affected. In addition, force control post stroke may exhibit timing deficits, such as impairment in the time required to release force as well as an abnormal time to achieve stable force. Last, even when the required force is achieved, force control post stroke may create difficulty in maintaining a constant force while executing a task 20, 50

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24 Because fu nctional muscle force is the product of both muscular and neural factors, damage to either of these factors may produce weakness. It is hypothesized that neural factors are the predominate cause of weakness in neurologic pathologies, including post stroke hemiparesis, because of the significant brain lesion. However, secondary inactivity and impaired muscle activation could also lead to atrophy and changes in the muscle fibers 44 1.1.2.1. Activation impairment Damage to the brain tissue following stroke reduces the communication of the corticospinal and other supraspinal pathways with the lower spinal levels. With reduced neural information coming from higher levels, the spinal cord undergoes a loss of connectivity to motorneurons and an impairment of the primary force control mechanisms 19 The l iterature 20 reveals several changes to the force control mechanisms post stroke that occur at the spinal level and include a change in motorneurons (i.e., a loss of motorneurons, or a change in th e recruitment order and firing rates of motor units) 20 nerve changes (i.e., a change in peripheral nerve conduction) 20 and muscle change (i.e., a change in the morphological and contractile proprieties of motor units and the mechanical proprieties of muscles) 20 It has been suggested that m ost of such motor unit rem odeling could occur between two and six months post stroke 20 Effect of strengthening in the presence of a healthy nervous system Resistance or strength training can increase muscular strength. Literature in the field has demonstrated that the physiological adaptations supporting increments in strength occur within the muscle itself 51 These adaptations consist of an increase in m uscle cross sectional area, called hypertrophy, which occurs 4 6 weeks after training begins

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25 and is called the hypertrophic phase of strengthening. However, resistance training also induces change within the nervous system 52 Enoka 53 described phenomena that show evidence of the presence of neural adaptation in response to strengthening, such as an changes in the untrained con tralateral limb contralateral, and specificity of strength adaptations to the training movements. The neural phase of strength ening occurs over the first 1 6 weeks of training and is characterized by rapid gains in strength, negligible changes in muscle cr oss sectional area, a cross transfer effect to an untrained homologous limb and increased agonist muscle activation 54 Carroll et al. 51 suggested that in an undamaged brain, resistance training is associated with an increase in short term motor unit synchrony, which is argued to result from changes in synaptic efficacy within the motoneuron pool. This implies that, after resistance training, the number or the strength o f the connections to the motoneurons of trained muscles may increase. This suggests that resistance training may improve the synaptic efficacy between the cortico spinal cells and spinal motoneurons. Further, i n an experimental study with healthy volunteer s, Carroll et al. 55 investigated whether resistance training had the capacity to cause adaptations in the motor cortex. Specifically, they determined the effects of resistance training on the magnitude of responses to transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES). Their results demonstrated that a program of resistance training that increases strength alters the input output proprieties of the corticospinal pathway. The magnit ude of the EMG responses to both fo rms of transcranial stimulation was smaller following resistance training. Since the same effect of training occurred in

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26 response to both TMS and TES stimulations, and knowing that TES is less influenced by cortical excit ability, the authors concluded that the training effect was due to a change in the functional proprieties of the circuitry within the spinal cord. Specifically, they suggested that a corticospinal input of a given magnitude activated fewer motoneurons with greater synaptic efficacy during muscle contraction than prior to training. Therefore, they excluded the effect of training in the reorganization of the motor cortex 55 Other authors used TMS evaluations to demons trate neural adaptive effects of resistance training with equivocal results. Griffin et al. 56 demonstrated that four week s of isometric tibialis anterior training increased MEP amplitude by 32 percent, while Jensen et al. 57 demonstrated a depression in cortical excitability measured by decrease d recruitment curve slope s However, re cently Falvo et al. 58 demonstrated that three weeks of resistance training elicited significant strength gains which were accompanied by neural adaptation at the level of the cortex. The authors were able to demonstrate supraspinal adaptations using movement related cortical potentials (MRCP). MRCP s consist of surface negative potentials, detected a t the scalp via electroencephalography (EEG) during voluntary movement. Following training, the authors found MRCP amplitude was attenuated at several scalp sites overlying motor related cortical areas and the onset of MRCP was anticipated (2% earlier) In conclusion, the 3 week training protocol in study elicited significant strength gains which were accompanied by neural adaptations at the level of the cortex. The authors interpreted their findings of

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27 attenuated cortical demand for submaximal volu ntary movement as evidence for enhanced neural efficiency as a result of resistance training 58 Effect of strengthening post stroke As previously mentioned, although weakness is one of the most disabling factors post stroke and strengthening has been shown to be both harmless and effective, strengthening is not yet part of routine neurehabilitation programs. A recent review suggested that first, strength training increase s grip strength with a large effect size 0.95 Since grip strength is a predictor of disability and mortality in older adults 59 remediation of low grip strength by strength training should be an important aspect of treatment post stroke. Second, the review supported the e ffectiveness of strength training for all levels of upper limb motor impairment. Specifically, it reports an effect size of 0.45 for stroke with moderate impairment and an effect size of 0.2 for stroke with mild impairment. These findings suggest that stre ngth training may be important for people with moderate impairment post stroke, while people with mild impairment may benefit more from functional training 16 Kokotilo et al. 50 conducted a systematic review of neuroimaging studies that examined reorganization of brain function during force production and force modulation after stroke. Their review includes a number of imaging modalities, including functional magnetic resonance (f MRI), TMS, electroencephalography (EEG) and magnetoencephalography (MEG). They conclude that motor reorganization occurs with respect to force generation and modulation after stroke. Key findings across studies were that during force production, increased activation in motor areas, including the undamaged contralesional hemisphere, occurred in people with more severe stroke,

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28 and recruitment of these motor areas often diminished as recovery improved. With respect to force modulation, increased activation in motor areas occurred with greater force generation in people with stroke, and those with more severe stroke showed greater activation with increasing force production levels. This review, as the author suggested, provided evidence of reduced recruitment of secondary motor areas during force production as a function of time since stroke. Last, brain activation can be shifted by certain rehabilitative interventions in people post stroke. Our research team has conducted a set of studies that contribute e viden ce that resistance training as an intervention post stroke that can induce restoration of both the neural circuitry and movement patterns. First, Patten et al. 60 conducted a randomized clinical trial of upper extremity rehabilitation to compare the effects of functional task practice, and a hybrid intervention of functional task practi ce combined with dynamic high intensity resistance training post stroke. Further, Patten et al. compared the effects of high intensity resistance training and hybrid training on stretch reflex modulation. The findings of this study suggested that first, up per extremity rehabilitation involving high exertion activity did not exacerbate either the hyperreflexic or hypertonic components of spasticity in adults post stroke. Second, they illustrate d that high intensity resistance training promoted a more appropr iate modulation of stretch induced EMG responses. These neurophysiologic adaptations were associated with upper extremity motor function improvement evaluated with the Wolf Motor Function Test Functional Ability Scores (FAS). Subsequently Corti et al 61 compared power training (i.e dynamic high intensity resistance training) with functional task practice training on a battery of clinical scales

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29 and kinematics of reaching. As previous mentioned, k inematic analysis is more objective than clinical scales and offers a better understan ding of the mechanics of arm movement 62 Kinematics describe movements of the body through space and time, including linear and angular displacement s v elocities and accelerations. T hree dimensional motion capture is therefore a powerful mea sure for studying upper extremity kinematics during motor performance in hemiparetic persons 5 This measurement approach affords a sensitive, quantitative and reproducible assessment that allows differentiati o n between compensatory and recovery strategies, which standard clinical scales do not. 1. 1.2.2. Inter hemispheric inhibition (IHI) Following stroke, activity in the affected hemisphere (AH) is disrupted; not only by the infarct itself, but also by inhibition from the unaffected hemisphere (UH) which further reduces the excitability of the AH. As first described by Ward and Cohen 63 and 64 hypothesis of inter hemispheric competition post stroke, the primary motor cortex (M1) of the UH becomes disinhibited and exerts exaggerated inhibition onto the M1 of the AH Decreased excitability of the ipsilesional cort ex has been observed after stroke by using electrophysiological recordings 65 cortical stimulation 66 and functional neural imag ing studies 67 This decreased cortical excitability has been attributed to da mage from glutamate receptor expression from neurons in the infarct zone. As a consequence, it is argued that there is reduced inter hemispheric inhibition (IHI) via transcallosal pathways from the AH to the UH 68, 6 9 Consequently, the UH becomes disinhibited, creating additional inhibition on the affected hemisphere. Indeed, the magnitude of transcallosal inhibition exerted from the UH is positively correlated with the

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30 severity of the functional impairment of the a ffected hand 64 It is possible that inter hemispheric competition contribute s to weakness after stroke. Mechanisms for rebalancing inte r hemisphere competition after s troke Accordingly, the inter hemispheric competit ion hypothesis suggests that balancing excitability between the AH and UH may improve functional behavior in people post stroke 64, 70 75 Among several innovative, non invasive techniques for improving motor recov ery post stroke, repetitive transcranial magnetic stimulation (rTMS) shows considerable promise 73 rTMS involves focused magnetic s timulation applied to the skull to target a particular brain area 75 In healthy adults, rTMS at frequencies less than 1Hz can suppress motor cortex excitability causing an inhibitory effect, while at higher frequencies (e.g., > 1Hz) rTMS can increase cortical excitability, causing facilitation 7 2 The capacity for rTMS to influence cortical excitability contributes to the rationale for its use as a therapeutic adjuvant that may enhance the efficacy of rehabilitation for persons post stroke 64, 76 Asymmet ric cortical excitability resulting from stroke may promote maladaptive neuromotor strategies. Repeated use of maladaptive, compensatory motor strategies will disrupt normal physiological activity in transcallosal pathways producing an imbalance in the mut ual inhibitory projections between hemispheres 63, 64 Further, m odulation of cortical excitability with rTMS may induce synaptic plasticity and promote physiologic activity in transcallosal pathways which taken t ogether, will potentially limit development of maladaptive neural strategies 63, 64 In this context, rTMS has been also been proposed as a theoretical approach to restore the balance of inter hemispheric inhibition post stroke (e.g., reduce inter hemispheric competition) 63, 64

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31 The current literature reveals positive effects of rTMS post stroke including: modulation of cortical excitability (e.g., MEP amplitude, recruitment curves, motor threshold) towards decreased excitability of the unaffected hemisphere (UH) and increased excitability of the affected hemisphere (AH ) However, it is important to note that no studies to date have directly investigated the effects of rTMS o n IHI. Thus, support for the theoretical explanation that rTMS rebalances inter hemispheric inhibi tion remains to be demonstrated This current working hypothesis holds that inhibitory rTMS ove r the UH reduces transcallosal inhibition from the unaffected t o the affected/ipsilesional hemisphere and facilitatory rTM S over the AH increases excitability of the AH and increases transcallosal inhibition from the affected to the unaffected/contralesional hemisphere. Consistent with effects noted in healthy individ uals, rTMS (trains of stimuli sepa rated by inter train intervals) has been used in two ways in persons post stroke: low reduce hyper excitability of the contralesional hemisphere, or high frequency (e.g., >1 Hz) stimulation of the AH to incr ease excitability of the ipsilesional hemisphere 70 A more recent form of stimulation is Theta Burst Stimulation (TBS), which employs repeating bursts of very low intensity, combined frequency rTMS 77 Each burst consists of three stimuli (delivered at 50 Hz) repeating at 5 Hz. TBS is also used in two ways: a continuous train of 100 bursts (300 stimuli) (cTBS) is used to suppress corticospinal excitability; while an intermitt ent pattern (20 trains of 10 bursts, varied ISI, total 600 pulses) (iTBS) is used to enhance corticospinal excitability. 1.2. Strategies for Functional Improvement: Recovery versus C ompensation The terms motor compensation and motor recovery have been used somewhat inconsistently among clinicians and researchers across several disciplines 78 This

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32 imprecise use of important terms has caused misunderstanding in the definition of goals and motor outcomes of rehabilitation interventions. There is a need for definitions that allow neuroscientists and clinicians to use a common language and that encompass the underlying aspects of a mechanism in order for the terms to be meaningful for neu rorehabilitation. Clear definition of these terms will allow for the development of more effective rehabilitation strategies that focus on enhancing compensation and/or recovery 78, 79 In the past, there ha s been a lack of consistency among researchers and clinicians in the use of terminology that describes changes in motor ability following neurological injury 78 Specifically, the t erms motor compensation and motor recovery have been used in different ways. The lack of clear definitions for these terms is a potential barrier to interdisciplinary communicatio n. Commonly, the term recovery has been used to refer simultaneously to the r estitution of damaged structures or functions and to describe clinical improvements regardless of how these may have occurred. Recently, Levin et al. (2008) 78 provided unambiguous definitions of recovery and compensation at the neural and behavioral levels. These d efinitions are provided in T able 1 1 1.2.1. Behavioral Recovery versus C ompensation Behavioral recovery involves the reappearance of motor patterns present prior to strok e 78 while behavioral compensation is the appearance of new motor patterns, including substitution with different, impaired motor components 78 Determining whether upper extremity motor improvements result from recovery is a fundamental issue for developing appropriate rehabilitative interventions that induce restoration strategies. Reinforcing a pattern of compe nsatory movements, also termed learned baduse may over time re inforce either substitution or learned nonuse of the affected arm 80

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33 Compensatory patterns may induce processes of recruitment and retraining even in those situations when the nerv ous system could be capable of higher levels of plasticity including restoratio n 81 84 At the behavioral level, Levin et al. distinguish between body function (impairment) and a ctivity (function) levels. For body function, the emphasis is on the motor control of movement regardless of task accomplishment. Recovery corresponds to the reappearance of movement patterns present prior to the injury, including normalization of muscle tone, electromyographic activation, movement kinematics and temporal and spatial coordination. Compensation would be associated with the appearance of alternative movement patterns during the accomplishment of the task 5, 85 For example, a individual post stroke may improve the excursion of his arm by using exaggerated trunk displacement instead of using elbow extension and shoulder flexion 86 At the activity level recovery corresponds to execution of the task using the same end effectors and joints in the same movement patterns typically used by nondisabled people. Compensation is associated with substitution, which means the person accomplishes the task using dif ferent end effectors. For example, stroke patients may be able to open a jar only by stabilizing it against the chest and using only the unaffected hand instead of both hands. 1. 2 .2 Neural Recovery versus C ompensation Neural recovery is characterized by reactivation in brain areas previously non activated by the ischemic event and corresponds to restitution or repair of structures to their original state. When one population of neurons dies at the site of injury, it cannot be reactivated and remains in th at dead the areas surrounding the injury may be inactivated, but these areas may be reactivated

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34 by spontaneous recovery or by appropriate intervention. R eactivation of these residual areas is the metaphor of neural restoration. On the other hand, neural compensation is defined as the processes by which residual brain areas take on new or adapted functions to make up for functions of the lost tissue. Neural restoration is characterized by activation in alterna tive brain areas not normally observed in nondisabled individuals 78 If we recall the definition of plasticity an observable change in neuron al structure or function then both neural recovery and neural compensation are examples of neuroplasticity 81 84 The functional integrity of residual neural circuits are either restored (recovery) or adapted (compensation) through changes in the sy naptic connections within these circuits 81 84 1. 2 .3 Neural Strategies S upport ing Functional I mprovement Different neural strategies can be identified that involve neural recovery and/or compensation and take adva ntage of the inherent functional redundancy within the brain. These strategies include Restoration Recruitment and Retraining (T able 1 2) 81 84 Since these strategies may occur concurrently during rehabilitation, it is not trivial to dissociate them, especially in human studies. Kleim 1 uses another analogy to explain how differently these neural strategies may work: If a subset of the violin players had been removed, the remaining violin players may simply stop pla ying because without their comrades the music nonuse). There are several ways that the orchestra can adapt to improve the sound of their music. First, the remaining violin players cou ld be asked to continue to play (restoration). The other string instrument players could also be asked to take on a larger role and play their instruments louder or differently (recruitment) to make the music sound more like the original 1 Kleim JA. Neural plasticity: Foundation for neurorehabilitation. Unpublished manuscript.

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35 score. In neither case are the musicians being asked to play a new instrument; they simply use their existing talents to compensate for the reduced number of violin players. The final strategy might be to ask the other musicians to learn to play the violin and even switch i nstruments at certain points in the score (retraining). This is a very different kind of strategy and certainly has limits. Cello players might be more readily capable of making that switch than flute players The interpretation of this analogy suggests th at a person following stroke may have a lesion due to the infarct, which causes neural tissue affected by the injury to be lost. In addition, perilesional tissue areas are also compromised since they were originally connected to the lost tissue area. These areas may re activate spontaneously or by specific pharmacological treatment to solve secondary effects such as inflammation and edema (restoration). It is possible that they will stay deactivated for ill compensate for the function lost (recruitment or retraining). The brain may engage new residual areas that are capable of contributing to the same behavior as the lost tissue (recruitment), or it may engage remote areas to perform the lost function (re training). These neural strategies may be facilitated by the use of adequate electrical stimuli or particular rehabilitation interventions based on principle s of neuroplasticity. While restoration of the neural circuits and brain areas to their pre stroke condition constitutes neural recovery, recruitment and retraining strategies both correspond to neural compensation. Determining the relation between neural and behavioral recovery and compensation and dissociating the neural strategies from one another is not trivial since they may occur simultaneously. However, identifying these strategies and relating them to functional improvement are the challenges of neurorehabilitation. Meeting these challenges will help to tailor treatment and to enhance the effecti veness of neurorehabilitation intervention s 81 84

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36 1.2.4 Appropriate Outcome Measures to Distinguish Recovery and C ompensation M isinterpretation of the concepts of restoration and compensation among clinicians and researchers may be due in part t o the selection of outcome measures 87 91 The s electi on of appropriate outcome measures is problematic. Selection depends on several factors, such as the various etiologies of stro ke, heterogeneity of symptoms, variability of severity, and the possibility of spontaneous recovery after stroke 87 91 In addition, another essential factor in selecting outcome measures is establishing which doma in of motor function needs to be evaluated 87 91 In the past, clinical outcomes scales meant to measure improvement mainly focused on task accomplishment and were not qualitatively sensitive enough to discriminate improvement in task performance 78 Therefore, with the emphasis placed on task accomplishment, there was little attention paid to the motor control aspects of movement. W ithout at tention to motor control, it was not possible to distinguish between recovery and compensation 78 Recently, some authors tried to classify outcome measures in stroke rehabilitation summarizing aspects of measurement theory that are pertinent for evaluation measures 87 91 Neural measures Neural measurements correspond to imaging and neurophysiologic techniques 78 These techniques allow us to distinguish the neural strategies underlying functional improvements and therefore to distinguish between neural recovery and compensation. There are a variety of imaging approa ches, each offering advantages and disadvantages with respect to spatial and temporal resolution, interpretability, practicability and cost 92 Neural i maging approaches include : computed axial tomogra phy (CAT), diffuse optical imaging (DOI), electroencephalography (EEG), functional magnetic resonance imaging (fMRI), posit ron emission tomography (PET)

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37 magnetoencephalography (MEG), diffusion weighted imaging (DWI) diffusion tensor imaging (DTI) and tra ctography Neurophysiologic approaches include transcranial magnetic stimulation (TMS), transcranial direct current stimulation ( tDCS) electroencephalography, electromyography (EMG) and reflex probes ( i.e. stretch reflex and H reflex techniques ) Used co ncurrently with behavioral probes, t hese measures allow us to better understand the relationship between behavior and the central nervous system, including the brain and spinal cord. Behavioral measures. In order to distinguish between behavioral recovery and compensation, we need to distinguish between impairments and activity measures. Upper limb impairment measures incl ude clinical scales such as the Modified Ashworth Scale (MAS) 25 F ugl Meyer Upper Extremity Motor Score (UEFMMS) 93 and the shoulder elbow portion of the UEFMMS (30 points) 94 the European Stroke Scale (ESS) 95 the Chedoke McMaster Hand and Arm Inventory (CMHAI) 96 and the Reaching Performance Scale 78 Other motor deficits may be quantified in terms of active joint range of motion, muscle strength, and ability to perform movem ents of individual joints 1 More detailed kinematic analysis of motor patterns during the performance of functional tasks would provide even more relevant information about movement patterns and motor compensations 78 Measures of impairment appear to be closely related to the volume of brain loss and are probably the best markers of prognosis 91 H owever the extent to which measures of impairment relate to the volume of brain loss is not totally apparent. Impairment scales may be most sensitive to change and may have the greatest capacity to d ifferentiate between treatments 91 However, for clinical significance, it is

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38 important to relate changes in impairment to changes in activity. Activi ty measures are the most frequently used primary outcome measure in rehabilitation research However, most evaluation specifies neither how the task is accomplished nor which compensatory movements were used 78 Difficulties arise in interpretation of studies that use such clinical and functional tests to indicate recovery because improved scores on these tests may be due to either improvement of the appropriate motor pattern or enha ncement of compensatory strategies. On the other hand, activity measurements generally focus on basic activities of daily life (ADLs) 91 A portion o f the stroke population sustains complete recovery in ADL s. Thus, measures of ADL exhibit a ceiling effect and may not show a difference in outcome between groups. Other significant limitations, which may reveal differential effects of treatments, may not be captured 91 A challenge is activity measures are not directly correlated with pathology or impairment, and other factors may influence the outcome (e.g. depression, psychological and social conditions, etc.) M ore detailed kinematic analysis of motor patterns during the performance of functional tasks would provide more relevant information about movement pattern and motor compensations Kinematic a nalysis is a more objective method than clinical scales and offers a better understanding of the mechanic s of arm movement 62 Kinematics describe movements of the body through space and time, including linear and angular displacement, veloci ties and accelerations. T hree dimensional motion capture is therefore a powerful measure for studying upper extremity kinematics during motor performance in hemiparetic persons 5 This measurement approach affords a sensitive, quantitative and reproducible assessment

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39 that allows us to discern betwee n compensatory and recovery strategies, which standard clinical scales do not. 1.3. Neuroplasticity 1.3.1 Brief History and Key C oncepts The word plasticity entered the English language in the 18th century in the vocabulary of materials science, possibly from French or German 81, 97 By the middle of the 19th century, it was starting to appear in the language of biology to refer to the adaptability of an organism to changes in its environment. The use of the term in this context continued into the 20th century and remains to this day 81, 97 .The roots of the term plasticity in reference to the structure of the nervous system currently remain unclear 98 However, some argue that the psychologist William James was the first to use the term to describe the nervous system in his classic textbook Principle s of Psychology (1890) 99 He stated: Plasticity, then, in the wide sense of the word, means the possession of a structure weak enough to yield to an influence, but strong en ough not to yield all at once. Each relatively stable phase of equilibrium in such a structure is marked by what we may call a new set of habits. Organic matter, especially nervous tissue, seems endowed with a very extraordinary degree of plasticity of thi s sort; so that we may without hesitation lay down as our first proposition the following, that the phenomena of habit in living beings are due to plasticity of the organic materials of which their bodies are composed In contrast to the scholar ly view th at the adult brain is immutable, James argued that as neural pathways are repeatedly engaged, they become deeper, wider, stronger, like ruts in a well travelled country road 99 In 1896, the Belgian Jean Demoor published La neurones crbraux (Arch. Biol., Paris, 14: 723 752) 100 Since Dem oor did not claim the novel use of this word, some say Santiago Ramn y Cajal was the first to use it in

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40 Europe 100 Cajal had indeed used the term plastic ity in the transactions of the International Medical Congress held in Rome in 1894 98 Cajal applied the words dynamism, fo rce of inter nal differentiation, adaptations [of the neurons] to the con dition among others, to describe the potential of the brain to adapt to the environment 100 Marinesco in Bucarest and Jean Nageotte in Paris, along with Aldo Perroncito in and Cajal himself, were the most important early contributors in the field of neuroplasticity 97 However, it was not for another 50 years that the Oxford English Dictionary 97 recognized the use of plasticity in relation to the nervous system. The current edition of the dictionary attributes the first use to a 1978 article published in Nature on the developing visual system 97 However, there were numerous references to plas ticity of the nervous system in English prior to 1978. Indeed, in 1949, Donal d Hebb, whose theory is o ften summarized by the phrase, cells that fire toget her, wire together, proposed a form of synaptic plasticity driven by temporal contiguity of pre and post synaptic activity; that is, an increase in synaptic efficacy arises from the pre post synaptic cell 101, 102 This prediction was verified decades late r with the discovery of long term potentiation (LTP), which is the theoretical basis of some of the current rehabilitation therapies 101, 102 or cell assembly theory and state s: Let us assume that the persistence or repetition of a reverberatory activity (or trace) tends to induce lasting cellular changes that add to its repeatedly or persistently takes part in firing it, some growth process or

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41 as one of the cells firing B, is increa sed. (Hebb, DO. 1949. The organization of behavior, New York: Wiley) Similarly, in 1953, Jo hn Eccles de voted a chapter to P lasticity in the Nervous System in The Neurophysiological Bases of Mind 97 Eccles described alteration in the synaptic efficacy of group Ia afferent synapses on spinal motoneurons subjected to various manipulations such as t e tanic stimulation and deaffere ntation 97 Eccles p ostulated the likelihood of similar plastic changes at higher levels of the nervous system, suggesting the phenomena of memory and learning 97 In The Physiology of Synapses (1964), Eccles suggested that plastic alterations in synaptic efficacy underlying learning should be a ccompanied by morphological changes 97 Through the 1960s, the term plasticity appeared frequently and in different cerebral lesions, anatomical plasticity as a growth of dendrites in resp onse to environmental enrichment and chemical plasticity as alteration of level of neurotransmitters and metabolites 97 cognitive abilities observed in rats raised in enriched environments were ac companied by increased number and strength of synapses in the cerebral cortex. In addition, these studies demonstrated that more specific behavioral training paradigms induced the same kind of changes in neuron structure in a variety of organisms, includin g : insects, birds and primates 81 The se findings suggested that plasticity is a fundamental property of all nervous tissues and that it has an important property for the sake of rehabilitation: it is experience dependent 79, 97 Today, the terms plasticity and neuroplasticity have

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42 entered the everyday scientific vocabulary B ut the lack o f clear and precise definitions has led to inappropriate use of the terms 79, 97 1. 3 .2 Definition of Neuroplasticity The term neuroplasticity has been so overused without a specific definition that some argue that it has become uninformative 81 I t has been used to mean anything from behavioral adaptations to new situations to alteration s in the efficacy of individual synapses 97 Jones writes, and Kleim argues that it is a term that neuroscientists like to invoke when discussing phenomena they vaguely understand 81 While there is no universally agreed upon definition of neuroplasticity, Kleim 2 recently offered this one: Any change in neuron structure or function that is observed either directly from measures of individual neurons or inferred from measures taken across populations of neurons 81 By specifying a measurable change in neuron structure o r function, changes in behavior are not, on their own, a measure of neuroplasticit y. Behavioral changes may certainly be mediated by neural plasticity, but measures of behavior are not per se direct measures of neural plasticity. Behavioral measures alone do not give information regarding mechanisms that control adaptation of the nervou s system to a new environment or to treatment. Similarly, measures of neuroplasticity by themselves do not directly tell us about behavior al adaptations occurring in a new environment or under a new treatment 81 The essential issue for new rehabilitation scientists is to understand how behav ior and neuroplastic processes are interconnected. Our research team think that the connection between neuroplasticity and behavior is bidirectional. Specifically, we are 2 Kleim JA. Neural plasticity: Foundation for neurorehabilitation Unpublished manuscript

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43 interested in how neuroplasticity supports behavioral chan ges to induce recovery of n ormal function, and, vice versa, in how behaviors support neuroplastic processes that induce recovery of neural structure. 1. 3 .3 Use Dependent Neural Plasticity in a n Intact Nervous System: Motor L earning and M otor E xperience In this section, we will sho w how learning in the intact nervous system is supported by neuroplasticity. For the sake of simplification, we will refer to research literature that focuses on motor learning; however, similar neuroplastic changes are observed across all forms of learnin g (such as sensory or cognitive learning) but occur within different neural circuits, depending on the behavior being learned. Most research showing neuroplastic change s after motor learning uses rat models. Rats can be trained to reach through a slot to retrieve a food pellet located on a ledge outside the training cage. To successfully retrieve the pellet, the rat has to learn to control the reaching movement. Animals trained on the reaching task show changes at the synaptic level, such as dendritic grow n 103 synaptogenesis 104 and enhanced synaptic responses 105 at the forelimb motor cortex. Further, after training, rats show an expansion of wrist and digit movement representations in the motor cortex map derived by brain microelectrode stimulation 106 Similar studies using monkeys performing a pellet retrieving task showed similar effects After weeks of training, monkeys 107 Studies using transcranial magnetic stimulation (TMS) have demonstrated that short term activity may induce changes in the human motor cortex. Acquis ition of a fine motor skill through sustained practice over a period of several weeks of complex movements (a five finger sequence of keystrokes on piano) induced expansion of the

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44 motor cortical map and a decrease in motor threshold of practicing muscles 108 In addition, the training led to a functional behavioral gain as evidenced by improved motor precision ( e.g., fewer mistakes while performing the task) 108 Simila r results were reported for the leg motor area. A 32 minute period of skilled ankle training in healthy humans induced an increased recruitment curve of the tibialis anterior muscle, suggesting that the training increased motor cortical excitability 109 In addition short interval intracortical inhibition, as measured by a paired pulse TMS technique, was reduced, while no changes were observed in intracortical facilitation 109 A few TMS studies have demonstrated that motor skills highly developed over several years are also associated with long term changes in cortical reorganization. Motor cortical maps of the first dorsal interosseous muscle in the reading hand of proficien t Braille readers are significantly larger than those of the non reading hand 110 while the motor cortical representation of the abductor digiti minimi muscle was reduced. Interestingly, the cortical map in proficient Braille readers correlates with the amount of daily practice 111 Indeed, several days of non reading induced a dramatic reduction in the size of the reading finger cortical map. A group of people who play racquet sports 112 with many years of high level experience showed an increase in MEP amplitude, a decrease in resting motor threshold and inter hemispheric asymmetry in cortical map location 112 Thus, the results may indicat e that practiced, skilled motor performance could be associated with long term plasticity of the motor cortex. Similarly, another study investigated interhemispheric inhibition measured by paired pulse TMS in professional musicians who began musical trai ning at an early age 113 Condition ed TMS was applied to the hand area of the motor cortex of one hemisphere, followed 4 16

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45 ms later b y a test stimulus applied to the contralateral hemisphere. Tests were performed in two conditions: 1) at rest, and 2) with the first dorsal interosseous muscle contralateral to the condition ed hemisp here voluntarily active. C ompared to control subjects c o ndition ed TMS in musicians was 29 percent less effective at reducing the size of the test MEP at rest, and 63 percent less effective in the active condition 113 These results may imply that these differences in IHI have functional relevance; however, mechanisms of functional relevance that correlate with reduced interhemispheric inhibition in musicians are still unclear 113 Magnetic resonance imaging studies show augmented activity within premotor cortex 114 and cerebellar co rtex during the early stages of learning 115 while a study of the later stages of learning 116 showed augmented activation of the primary motor cortex. Studies of musicians demonstrated structural plastic changes within motor brain areas with highly developed motor skills. One study 117 showed the cortical representation of the digits of the left hand of string players was larger than controls. The effect was smallest for the left thumb, while the right hand did not show differences in the digit representation. The amount of cortical reorganization of the finger digits was correlated with the age at wh ich the subject began to play an instrument Another study showed that amateur and professional keyboard players have greater gray matter volume within motor and premotor cortexes and cerebellum than non musicians. In addition, the differences in gray matt er volume correlated with musical status. Indeed, professional musicians had greater volume than amateurs, who had greater volume than non musicians. The development of motor skills through years of keyboard playing is

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46 sufficient to induce cortical growth. Most likely, translating the knowledge derived from animal studies, gray matter in musicians reflects dendritic and synaptic growth 81 84 A study 118 using an inno vative imaging technique, diffusion tensor imaging (DTI), supports and advances evidence of activity dependent plasticity in the human brain. DTI showed differences in white matter architecture between musicians and non musicians 118 Musicians displayed greater functional anisotropy (FA) (the most used indicator of white matter organization at the microstructure level) in the genu of corpus callosum, which the authors hypothesized is the result of the cogni tive processes of musical study 118 Musicians displayed lower FA in the corona radiata and the internal capsule, which the authors hypothesized as being due to the effects of intensive motor training 118 The results of the paper supported the notion that intensive activity (the musical training) leads to distinct plastic changes in white matter architecture. Findings of all these studies demonstrate that a healthy central nervous system (in animals and humans) is able to adapt to the environment and to activity through plastic changes. Every time we acquire a new motor skill, the nervous system encodes the skill as enduring neurobiological changes. Th is is c alled learning dependent or activity dependent neural plasticity 81 84 1. 3 .4 Use Dependent Neural Plasticity in an Injured Nervous S ystem: a Relearning P rocess The functional improvement in an injured nervous s ystem can be associated with a relearning process. Within this perspective, through rehabilitation, patients are guided to re acquire the ability to produce behavior lost as a result of injury. As such, the nervous system should rely on the same fundamenta l neurobiological mechanisms it used to acquire the behaviors initially when the nervous system was intact 81 84

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47 However, the neural environment after injury may be different and may negatively affect the mechanis ms underlying learning. First, secondary changes associated with the injury, such as edema and inflammation, may affect the normal functioning of the residual tissue. Further, the neural structure remote to the lesion and without a specific function may s ubstitute for damaged structure through compensatory strategies 81 84 In addition to complications within the neural environment, the behavioral signal coming from the hemiplegic body to the inju red nervous system also may be abnormal as a consequence of the motor impairments. For example, to maintain function, movement may be performed using compensatory strategies. Appropriate afferent information is one of the fundamental drivers of positive plasticity 81 84 Therefore, the neural circuits receiving aberrant afferent information may negatively influence plastic changes. Following injury of the nervous system, therefore, both the changes in the neural and behavioral environm ents must be considered in the new learning process. D espite the added complexities associated with injury, Kleim 81 84 suggested that the same fundamental neural and behavioral signals that drive neural plasticity and support functional change should still be functioning (Figure 1 1 ). Kleim (unpublished manuscript) elegantly summarized the relearning process in an injured CNS using an orchestra analogy: Teaching cello players to play music written for the violin is very different from teaching violin players to simply play new violin music. If all brain area s could adapt and perform all functions then rehabilitation would be much easier. In fact we would not need formal therapy as patients could simply relearn the l ost behaviors in the same way they learned them in the first way; by interacting normally during daily lives. This is not how the CNS functions. Spec ific structures are evolutionally designed to perform certain functions and become more and more specialize d through life. So there are limits to the capacity for the CNS to acquire new function after injury. Relearning is much harder than learning because we are forced to use a

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48 compromise d set of circuits or circuits that may not have been designed to perform the relearned function. No t surprisingly then, the relearning curve will not be as steep as the initial learning curve. Small gains in performance requ ire large amounts of training. 1.3.5. Not All Plasticity is G ood Although neuroplasticity usually has a positive connotation corresponding to changes in the central nervous system that promote functional improvement in development or after injury, neuroplasticity may sometimes support maladaptive changes 119 These changes can result from abnormalities in the neural and beh avioral signals that drive plasticity. One example is dystonia. Dystonia may develop in persons who perform repetitive movements, such as musicians, artists and athletes 120 122 Electromyographic analysis of dyston ic movements reveals loss of inhibition between agonist and antagonist muscles, excessive finger activation and inability to release muscle contraction 121 Neuroimaging studies of the somatosensory cortex show alte rations in the representations of the hand and fingers. These changes represent a maladaptive cortical plasticity in which the brain is not able to represent the overused fingers distinctly. Specifically, the somatotopic representation of the hand shrinks and enlarges its receptive fields, which extend across multiple digits 123 Neuroimaging studies in monkeys after excessive repetitive movements show similar findings 124 In the context of neurorehabilitation post stroke, it is important to keep in mind that rehabilitation itself can induce plastic changes that are counterproductive. Many patients de velop compensatory strategies (bad habits ) that are easi er to perform than more difficult but ultimately more effective strategies 81 84 These compensatory strategies may induce maladaptive plasticity. The compensatory strategies and the associated neuroplastic changes may reduce the level of functional improveme nt that can be

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49 achieved. Since true behavioral and neural recovery is not always possible, neurorehabilitation needs to focus on maximizing a balance between compensation and recovery to elicit the maximal funct ional improvement possible 81 84 1.3.6 Plasticity is not o nly in the B rain Traditionally, plasticity was thought to take place only at the brain, but recently clinical and experimental observations indicate that p lasticity is ubiquitous in the central nervous system 125 including the spinal cord. Inputs from the periphery or from the brain can cause lasting changes in the spinal cord that affect its output 126 125 Beside s the obvious damage a t the brain site following stroke, the spinal cord also may undergo secondary damage 81 84 This damage may depend on the lost/impaired inhibition coming from the supraspinal structures and on the lost/impaired affe ren t information secondary to disuse/non use and/or anesthesia conditions. Commonly used measures of the spinal cord circuitry are the stretch reflex (produced mainly by the monosynaptic pathways composed of the primary afferent from the muscle spindle, it s synapse on the motor neuron, and the motor neuron 125 ), and its electrical analogue, the H reflex techniques, evoked by direct electrical stimulation of the primary afferent s 125 However, while the pathway is spinal, it is subjected to descending influences from the brain that act directly on the motor neuron and on the primary afferen t connection, which can affect the stretch and H reflexes 125 Using these techniques, several authors have suggested that post stroke, the spinal circuitry undergoes plastic changes i n both the paretic 127 130 and non paretic side s 68 A few articles have reported that neurointervention post stroke might induce changes of both stretch 18 and H reflex responses 131, 132 One i mportant finding in relation to neurointervention induced plasticity comes from a recent study on healthy subjects 133 In contrast to the traditional view that the paired

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50 associative stimulation ( PAS ) induced plasticity is cortical in origin, Meunier et al. demonstrated that PAS induces parallel changes in corti cal a n d spinal excitability 133 These findings may be uti lized to induce and measure spinal cord plasticity after stroke or spinal cord injury. 1. 4. Neurorehabilitation induced Plasticity P ost stroke 1.4.1 Evolution of N eurorehabilitation Historically, the management of patients post stroke involved bed rest and convalescence 134 Using 1778) words, the role of the physician is to entertain his patient while nature takes it course 134 The concept of physical therapies developed through the early to mid 1900s to help world war and polio survivors 134 The branch of medicine focusing on active rehabilitation was created and wa s associated with a shift from do nothing to do something 134 Advances in understan ding neurological dysfunction and the observation that patients tolerated and benefitted from physical exercise influenced the rehabilitative interventions. The observation that patients had better mot or outcomes when exposed to an enriched envir onment r ather than bed rest became even more reported and accepted 134 However, the critical aspect that characterized the enriched experience remained unresolved. Distinct appr oaches to rehabilitation practice emerged in parallel to increasing understanding of the human nervous system and the response to physical interve ntion. The debate evolved from do something to do something specific 134 The questions became, what is the most effective type of therapy? What dosage? Which intensity? 134 Presently, these q uestions remain unanswered. However, we do know that neural plasticity is a key neurobiological factor in determining functional improvement after injury of the nervous system 81 84 The challenge now for neurehabil itation is to figure out

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51 how to identify the critical behavior al and neural signals that drive plasticity within specific neural circuits in order to select or develop novel, more effective therapeutic interventions. Important issues in meeting this challe nge are : 1) to appropriately quantify plasticity, and 2) to appropriately quantify behavioral recovery. A number of innovative methods have been studied during the past 10 years that show promise in restoring upper extremity function post stroke. Some of t hese methods are : robotic therapy 135 electrica l stimulation (FES) 136 task oriented and repetitive training 137 constraint induced movement therapy (CIMT) 138 power training (or dynamic resistance training) 9, 50 and non invasive brain stimulation, such as repetitive transcranial stimulation (rTMS) 139 theta burst stimulation 140 transcranial direct current stimulation (TDCS) 64 and paired associative stimulation (PAS) 141 Despite greater evidence of neurorehabi litation induced plasticity post stroke in animal models, few studies have demonstrated the effects of the above listed therapies in inducing neuroplastic changes in humans. The majority of human studies were not able to show whether the therapy was actual ly inducing plastic changes since the measurement used was not intended to detect neuroplasticity but rather changes in motor behavior 81 84 As mentioned, while it is true that behavioral changes are most likely m ediated by neural plasticity, measures of behavior are not themselves direct measures of neural plasticity 81 84 Technological evolution within the past decade led to the introduction of new functional neuroimagin g and electrophysiological techniques that have provided substantial insight into the adaptive changes of cerebral networks associated with plasticity and recovery post stroke. Some recent studies t ake advantage of these non

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52 invasive tools to measure neuro plasticity in humans post stroke. Therefore, here we present studies from both animal and human literature that support neurorehabilitation induced plasticity by using appropriate techniques to measure and quantify neuroplasticity. 1. 4 .1.1 Evidence for ne urorehabiitation induced plasticity post stroke Examples in animal research A series of studies on monkeys demonstrated processes of motor cortex reorganization following stroke injury. In monkeys not receiving post injury behavioral training, the remaini ng, undamaged hand representation decreased in size 107 In contrast, monkeys that received post injury behavioral training showed retention of the hand representation 142 In some cases, the hand territory expanded in to the elbow and shoulder representation 142 Similar examples of restoration occurred after small lesions in monkey somatosensory cortex with rehabilitative training. After training, m onkeys showed a reemergence of the representation of the fingertips in areas outside of the infarct where representations were initially lost 143 Other studies in the rat m otor cortex showed that injury post stroke results in a loss of motor limb representation 144 The loss of movement representation was accompanied by a loss of synapses and forelimb motor impairments as the rats ha d difficulties reaching for food. However, with several days of training on a forelimb reaching task, both synapses and the movement representations could be restored 144 The studies demonstrated that rehabilitatio n training that encourages use of the affected arm or forelimb can re engage the impaired neural circuits 143 144 Examples in human research As mentioned, few studies have shown evidence for neurorehabilitation induc ed plasticity in humans. However, traditional (i.e. functional MRI), innovative neuroimaging (DTI), and electrophysiological techniques (TMS) have

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53 opened a window on the human nervous system that may allow us to understand and measure plastic changes post stroke. The following rehabilitation techniques have shown some evidence for neuroplasticity in humans 1.4.1.2 Behavioral interventions Although many factors affect the phenomenon of neuroplasticity, one of the most important modulators is behavioral exp erience 145 Importantly, Xerri et al. suggested that motor maps undergo plastic changes through motor skill acquisition more than through repetitive use alone 143 Further, compensatory approaches at critical time periods may have a cost in terms of recovery of function 143 R elatively few studies have investigated whether the training implemented induc ed neuroplasticity in addition to behavioral functional improvements. The following will present findings of intervention approaches that inclu ded both behavioral and neurobiological outcomes. Constrain t induced movement therapy (CIMT) Constraint induced movement therapy (CIMT) forces use of the affected side by restraining the unaffected side. With naffected arm in a sling and /or a mitt The patient then uses his or her affected arm repetitively and intensively for two weeks generally 138 A functional MRI study demonstrated that two weeks of CIMT in people post stroke could induce a reduction of contralesional primary cortex activation. Also, th e laterality index ( LI ) 3 correlated with the Wolf Motor Function Test 146 Liepert et al. 147 3 LI=(contralateral ipsilateral)/(contralateral+ipsilateral); contralateral and ipsilateral activation to the hand movement LI ranges from 1 (all ipsilateral activation) to 1 (all contralateral activation).

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54 studied intracortical inhibition with TMS and brain activation with functional MRI after two weeks of CIMT post stroke. After treatment, the authors did not find any change in intracortical inhibition in either hemisphere, although, interestingly, ipsilesional activation was reduced 147 Another study demonstrated that CIMT was able to improve scores in the Motor Activity Log and that these improvements were associated with a reduction of overactivation in the ipsilesional hemisp here and an increase in motor map size 148 Kim et al. showed that two weeks of CIMT improved motor function as evaluated with Fugl Meyer, and the 9 hole peg test, induced an increase in ipsilesional brain activatio n in three subjects and of contralesional brain activation in four subjects 149 Repetitive task training One study used positron emission tomography (PET) during passive elbow movement to study training induced brain plasticity in severe stroke and demonstrated that task oriented arm training ind uced greater activation of the ipsilesional somatosensry cortex than no treatment 150 Bilateral training Luft et al. 151 demonstrated that bilateral arm training with rhythmic auditory cueing (BATRAC) increased activation of the ipsilesional cerebellum and contr alesional primary motor and somatosensory cortices Bra i n activation was studied with functional MRI during elbow movements. The au thors did not find differences in motor functional outcomes between BATRAC a nd standard intervention group. Motor learning Carey et al. 152 studied hand movement recovery (Box and Block score and tracking accuracy) and cortical reorganization (functional MRI) in people with chronic stroke after an intensive fin ger movement tracking prog ram. After treatment,

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55 stroke patients showed an improved laterality index (LI) and increased activation of the ipsilesional motor and somatosensory areas and premotor cortex 152 Functional training combined with h igh intensity resistance training Patten et al. 18 demonstrated that an intervention of combined upper extremity functional task practice and high intensity resistance training promoted more appropriate modulation of stretch reflex responses than functional task practice alone This neurophysiologic improvement was associated with upper extremity motor recovery. Despite the fact that these studies suggest intervention facilitated recovery, most of them offer no evidence for i ntervention induced neuroplasticity. Most have a smal l number of subjects and often do not provide an appropriate control condition 153 Further, t he se studies cannot definitely answer the question d oes specific motor training induce neuroplastic changes in persons post stroke? Importantly, a common feature of the training programs that showed behavioral and neurobiological improvement is high intensity training 154 156 Intensity and repetitio n are important principles driving plasticity, an idea that supported by several studies in animals but also in humans (studies on musician s ) 153 1.4.1.3 Non invasive cortical st imulation Repetitive TMS (rTMS). rTMS consists of regularly repeated stimulation of the cerebral cortex by trains of magnetic pulses 157 rTMS can modulate the excitability of the motor cortex beyond the period of stimulation 157 By convention, stimulating frequencies greater than 1 Hz are referred to as high frequency rTMS and have been shown to increase corticospi nal synaptic excitability, while stimulating frequencies lower than 1 Hz are referred to as low frequency rTMS and have been shown to decrease

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56 corticospinal synaptic excitability 158 Mechanisms similar to LTP and long term depression (LTD) are thought to be involved in the generation of these effects 158 rTMS after stroke is mainly used as an attempt to restore balance to the interhemispheric inhibition after it has been disrupted by an infarct. In the stroke population, the affected hemisphere (AH) is disordered not only by the infarct itself, but also by the resulting asymmetric inhibition of the unaffected hemisphere (UH), which further reduces the excitability of the AH. In stroke rehabilitation, low frequency rTMS is applied t o the UH to reduce excitability of the contralesional hemisphere, and high frequency stimulation of the AH is applied to increase excitability of the ipsilesional hemisphere 157 (A ppendix A) Application of a single session of constant high frequency rTMS t o the AH 159 162 demonstrated the possibility of inducing plastic changes in the excitability of the motor cortex post stroke. Kim et al. 160 applied 10Hz stimulation with an intensity of 80% resting motor threshold (RMT) and evaluated behavioral changes in finger motor tasks and corticomotor e xcitability before and after the intervention. They found that real rTMS resulted in larger improvements in MEP amplitude, movement accuracy and speed. Their results suggested that motor learning was dramatically amplified after high frequency rTMS in the AH. Similarly, Ameli et al. 159 applied 10Hz with an intensity of 80% RMT. Interestingly, they found different effects of high frequency rTMS in people with only subcortical stroke and in people with additional cort ical stroke. In subcortical stroke, rTMS was associated with improved kinematics of the index finger and hand tapping; these improvements were associated with reduced activity of the contralesional primary motor cortex (M1) measure d with functional MRI. I n people with additional

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57 cortical stroke, rTMS was associated with deteriorated kinematics of the affected hand; these effects were associated with a widespread bilateral recruitment of primary and secondary motor areas 159 These changes were revealed after stimulation of M1 and not after stimulation over the vertex (sham condition). This study suggested that the effectiveness of facilitatory rTMS applied over ipsilesional M1 depends on the functional integrity of t he stimulation site and/or the dimension s of the brain area affected by the stroke. Yozbatiran et al. 162 also studied the effects of higher frequency rTMS, but their study concentrated only on behavioral effects, w hich do not tell us about plastic changes that may occur in the nervous system. Further, five multiple session studies 163 167 assessed whether the effects from a single session of high frequency rTMS accumulate, i nducing longer lasting functional improvement and neuroplastic changes. In a single blinded longitudinal, randomized, sham controlled study, Khedr et al. 164 applied rTMS at 3Hz frequency and 120% RMT over the AH fo r 10 consecutive days. They found that real rTMS resulted in larger improvements on the Scandinavian Stroke Scale, the NIH Stroke Scale (NIHSS) and the Barthel Index (BI) compared to sham rTMS up to 10 days after stimulation 164 However, single pulse TMS did not show any changes in cortical excitability. More recently, Khedr et al. performed two single blinded, longitudinal, randomized, sham controlled studies. One study 163 co mpared 1Hz rTMS applied with continuous stimulation f or 15 minutes at 100% RMT and 3 Hz rTMS at 130% RMT. Both treatment groups underwent one session every day for five days. Each real rTMS group experienced greater improvements in keyboard tapping, p egboar d NIHSS and BI than the sham group. These improvements were g reater in the 1Hz than the 3 Hz group at

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58 three months after stimulation 163 In terms of cortical excitability, 1Hz rTMS induced an increase in MEP amplitud e and a decrease of active motor threshold (AMT) in the AH, and a decrease in amplitude of MEP and an increase of AMT in the UH. 3Hz rTMS induced only an increase in amplitude of MEP and a decrease of AMT in the AH. In the other study, Khedr et al. 165 compared 3 Hz rTMS at 130% RMT w ith 10Hz rTMS at 100% RMT. R eal rTMS produced greater improvements in muscle strength and grea ter alleviation of disability than sham stimulation, and these improvements were evident even at one year follow up 165 In addition, in the real rTMS groups, the AH experienced a decrease in both RMT and AMT, which was associated with an increase in MEP amplitude 165 The authors did not find significant differences between 3Hz and 10Hz stimulation, although 3Hz seemed to produce greater changes. Mally et al. 167 examined whether active movement could be ind uced by rTMS even several years after stroke and investigated which hemisphere would be the best location for stimulation in order to attenuate spasticity and develop movement in the paretic arm. However, the study did not evaluate whether rTMS induc ed neu roplasticity. Malcolm et al. 166 tested the potential adjuvant effect of rTMS in people undergoing constraint induced movement therapy (CI M T) for upper limb hemiparesis. Stroke participants underwent one session per day for 10 consecutive days of 20Hz rTMS at 90% RMT followed im mediately by CI M T. The study failed to show significant differential effects on the Wolf Motor Function Test (WMFT), the Motor Activity Log (MAL) and Box and Block test (BBT). However, in most of the measures, the rTMS group showed greater improvement eve n six months after intervention with rTMS Moreover, the rTMS group showed a significantly greater

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59 reduction of RMT after treatment, which indicates that some neural changes occurred at the cortical level. Other studies investigated the application of low frequency rTMS on the contralesional hemisphere to reduce transcallosal inhibition and to assess whether low frequency rTMS may induce changes in cortical excitability. Mansur et al. 168 and Liepert et al. 169 showed that inhibition of UH by low frequency rTMS resulted in a substantial gain of functi on, but neither of these studies measured any neuroplastic change. Two double blind studies involving single session s of real versus sham low frequency rTMS on the UH 69, 170 demonstrated that rTMS reduced both the amplitude of RMT in the UH and the duration of interhemipsheric inhibition ( IHI ). IHI was evaluated with ipsilateral silent period 170 These improvements were associated with an improvement in pinch acceleration of the affected hand. In addition, this improvement in motor function was significantly correlated with a reduced IHI duration. Similarly, Nowak et al. 171 applied low frequency rTMS on the UH for 10 minutes in subcor tical stroke patients. rTMS improved the kinematics of finger and grasp movements in the affected hand. At the neural level, functional MRI demonstrated that rTMS reduced over activity in the contralesional primary and non primary motor areas. Fregni et al conducted a five session study applying low frequency rTMS on the UH in chronic stroke 172 rTMS resulted in a significant improvement in motor function performance measured with the Jebsen Taylor hand function te st and Purdue Pegboard test in the affected hand. Corticospinal excitability decreased in the rTMS stimulated UH and increased in the AH. In addition, the author showed a significant correlation between motor function improvement and corticospinal excitabi lity change in the AH.

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60 T he se findings suggest that both low frequency and high frequency rTMS may induce functional improvement and these improvements are associated with neuroplastic processes in the brain. Theta burst stimulation (TBS). Theta burst stimu lation (TBS) is a novel form of rTMS that consists of repea ting bursts of stimuli 173 Each burst consists of three stimuli repeati ng at 50 Hz; bursts are repeated at 5 Hz. The intensity of stimulation is set at 80% of active motor threshold (AMT). In normal individuals, a continuous train of 100 bursts, named cTBS, can suppress corticospinal excitability. With an intermittent pattern (iTBS), corticospinal excitability is enhanced cTBS is therefore used to suppress the UH and iTBS to facilitate the AH in people post stroke 173 Talelli et al. 77 tested a group of stroke patients under three conditions: excitatory TBS over the stroke he misphere (iTBS), inhibitory TBS (cTBS) over the intact hemisphere and sham stimulation. iTBS consisted of 20 trains of 10 bursts at 5Hz with an intensity of 80% of AMT, while the cTBS i consisted of continuous trains of 100 bursts with an intensity of 80% o f AMT. After iTBS there were improvements in simple reaction time in the paretic hand, which remained shorter throughout the testing period compared to the sham stimulation. No effect in peak grip force was revealed. The amplitude of the MEPs at rest and d uring active muscle activation, and the area under the input output curves, also increased on the lesioned side. cTBS did not affect speed and peak grip force of the contralateral hand although it suppressed MEPs evoked in the healthy but not in the pare tic hand. This study suggested that TBS is safe and that iTBS transiently improve s motor behavior and cortical spinal output in the paretic hands. Similarly, Di Lazzaro et al. 140 compared the application of iTBS a nd cTBS. In contrast to

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61 the previous study, they found that both the facilitatory TBS on the affected motor cortex and the inhibitory TBS on the unaffected motor cortex produced a significant increase in the amplitude of MEPs evoked by the stimulation of t he AH. RMT decreased in the AH and increased in the UH, while MEP amplitude increased in the AH and decreased in the UH respectively The authors concluded that TBS could enhance excitability of the lesioned motor cortex and could be useful in re establis hing the balance of excitability between the two hemispheres. In a more recent study, Di Lazzaro et al. 174 correlated changes produced by iTBS (using the same parameters as in their previous study) to outcomes at a six month follow up. They found that iTBS produced increased MEP amplitude in the AH, which correlate d with recovery measured at follow up by the Modified Rankin Score (a scale for measuring the degree of disability or dependence) 174 This study showed for the first time in humans that the level of long term potentiation (LTP) in the AH was correlated with the long term recovery of functional activity 174 These findings demonstrate that both iTBS and cTBS may induce mot or recovery and plastic changes in cortical excitability. Paired associative stimulation (PAS). Paired associative stimulation ( PAS ) consists of a paradigm for repetitive, low frequency, single pulse electrical nerve (usually median) stimulation or a trai n of electrical stimuli applied to the motor points of muscles, followed by TMS over the contralateral motor cortex 175 It is based on the principles of associative LTP in experimental animals and the Hebbian concept o f spike timing dependent plasticity, with two inputs paired to arrive at a single neuron at approximately the same time 176 PAS induced changes in cortical excitability share a number of physiological propert ies with LTP and LTD. In humans, it takes about 20

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62 milliseconds for the fastest sensory impulses from the median nerve to reach the sensory cortex. The integration of the information from sensory cortex to motor cortex takes about 2 5 milliseconds 177 If the TMS is applied 25 milliseconds (PAS25) after median ner ve stimulation, motor cortex neurons are synchronously activated by the afferent input (presynaptic) and TMS (postsynaptic activation). Repeated pairings then result in an increase in the net efficiency with which subsequent TMS pulses can activate cortico spinal neurons 177 Repeated pairs of PAS25 lead to enhance d motor cortex excitability (LTP). In contrast, repeated pairs of PAS10 (TMS pulse given 10 milliseconds after median nerve stimulation) reduce the motor cortex excitability (LTD) since the postsynaptic activation (TMS) precedes the presynaptic activation (afferent input) at the motor cortex 178 In a recent study involving a single session, PAS protocol was applied at 5 and 12 months post stroke. PAS induced facilitation of the extensor carpis radialis MEP on the pa retic side 5 months after stroke, a fraction of which was still present 12 months after stroke 141 These effects were associated with clinical improvement measured with the Fugl Meyer motor scale and dynamometry of wrist extension 141 Another recent study applied inhibitory PAS (120 pairs at 0.5Hz) in stroke patients 179 with stimulation of the common peroneal nerve innervating the nonparetic tibialis anterior muscle followed by TMS of the contralesional motor cortex. As expected, this slightly decrease in excitability of the contralesi onal motor cortex was accompanied by increased motor cortical excitability of the lesioned side assessed during walking. This effect may be achieved through decreasing the interhemispheric inhibitory drive from the contralesional to the ipsilesional primar y motor cortex 179 While t hese findings suggest

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63 that the PAS technique has promise, furth er studies are needed to gather evidence that PAS induces functional improvements that are associated with neuroplastic processes 179 1. 5. Objective of this Dissertation Studies cited above have demonstrated that the most disabling impairments post stroke are due to weakness in the affected limb, and also that resistance training post stroke can help alleviate weakness Resistance trainin g is harmless and induces improvement s in strength, upper extremity function, restoration of more normal movement patterns during reaching tasks and neurophysiologic adaptations in stretch reflex modulation. In contrast, studies suggest that both function al task practice and CIMT induce improvement of arm function not by alleviating weakness or restoring normal movement patterns, but by encouraging compensatory strategies. Therefore, we propose that future research needs to focus further on the relationsh ip between motor behavioral recovery and nervous system reorganization to determine whether strengthening effectively induces behavioral and neurophysiological recovery. In addition, brain stimulation may be used as adjuvant to training protocol s in person s post stroke to enhance its effects 139 Recent studies suggest that rTMS has the potential to modulate cortical excitability. rTMS may therefore be used in an attempt to restore balance of interhemispheric competition post stroke 70 in association with resistance training. The overall objective of this dissertation is to improve recovery of upper extremity function post stroke and to improve our understanding of mechanisms underlying recovery by using a multim odal method of investigation that provides insight into the

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64 dynamic relationship between neurophysiology and motor behavior and pays particular attention to the selection of measures that distinguish between recovery and compensation. The following are th e main questions this dissertation attempts to answer: 1) Treatment efficacy at the behavioral level: What are the behavioral effects of functional training and high intensity resistance training for the upper extremity post stroke? Do the therapeutic inte rvention s induc e compensation or recovery of normal movement pattern s ? Does training intensity affect the efficacy of the treatment ? 2) Treatment efficacy at the neural level: Do the therapeutic intervention s induc e neuroplastic changes ? 3) Locus of thera peutic induced neuroplasticity Are the neuroplastic changes at the supraspinal spinal or both levels? Are the neuroplastic changes ipsi or contra lateral to the lesion ? Chapter 3, 4, 5 and 6 of this dissertation describe the individual studies we perform ed as an attempt to answer these research questions.

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65 Table 1 1. Definitions of recovery and compensation at t he neural and behavioral levels Recovery Compensation Neural Restoring function in neural tissue that was initially lost due to injury or d isease Residual neural tissue takes over a function lost due to injury or disease. Behavioral: Body Function (Impairment) Restoring the ability to perform movements in the same manner as it was performed prior to injury or disease. Performing movement in a manner different from how it was performed prior to injury or disease. Behavioral: Activity (Function) Restoring the ability to perform a task in exactly the same manner as it was performed prior to injury. Performing a task in a manner different from how it was performed prior to injury or disease. Note: Adapted from 1.Kleim JA. Neural plasticity and neurorehabilitation: Teaching the new brain old tricks. J Commun Disor 2011;44:7 84 Table 1 2. Neural strategies sup porting functional improvements Restoratio n Recruitment Compensation Strategy Re engaging residual brain areas initially dysfunctional after injury or disease. Engaging new residual brain areas. Training residual brain areas to perform new functions. Functional platform Internal and external r edundancy. External redundancy. Internal and external redundancy. Neural mechanism Recovery. Compensation. Compensation. Note: Adapted from 1.Kleim JA. Neural plasticity and neurorehabilitation: Teaching the new brain old tricks. J Commun Disor 2011;44 :7 84

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66 Figure 1 1 Schematic diagram illustrating how experience dependent neural plasticity supports learning 4 There are key behavioral signals that are inherent to any learning experience that serve to drive specific neural signaling systems that in turn induce end uring neuroplastic changes within those brain areas (sensory, motor, cognitive) engaged during training. This neural plasticity serves to encode the training experience and improves future performance of the trained behavior 4 Kleim JA. Neural plasticity: Foundation for neurorehabilitation Unpublished manuscript

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67 CHAPTER 2 COMMON METHODS 2. 1 Measures In this dissertation we suggest a multimodal method of investigation that explores the complex and dynamic relationship between neurophysiology and motor behavior and pays particular attention to the selection of measures that distinguish betwe en recovery and compensation. The multimodal assessment include s : 2.1.1. Clinical E valuation We use d Wolf Motor Function Test (WMFT) to investigate the behavioral motor function. In this test participants are timed as they complete 15 activities that invo lve progressively more difficult arm movements and interactions with objects. The WMFT is classified as an activity measure in the International Classification of Functioning, Disability and Health (ICF) and is one of the most used clinical test s to evalua te UE function post stroke The c linometric properties of the WMFT have been established, shown to have high interrater reliability (intraclass corre t 180 2.1.2. Three dimensional Motion A nalysis 2.1.2.1 General information about technique We use d three dimensional motion analysis to study motor behavior. This measur ement approach allows us to distinguish between behavioral compensation and recovery. It affords a sensitive, quantitative and reproducible assessment of abnormal movements 62, 181 Three dimensional motion analysis include d kinematic and electromyographic evaluation. Kinematics enable d us to study movement patterns used during the accomplishment of the task 5, 85 ; for example, the exaggerated use of trunk

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68 movements to compens ate for reduced elbow and shoulder flexion 86 Electromographic evaluation enabl e d us to study the abnormal patterns of muscle activation during movement performance; for example, potential coactivation of b iceps and triceps brachii muscles during active extension of the elbow, which is argued to be a frequent manifestation of hemiplegia 2.1.2.2 Data collection Motion analysis was performed using a functional reach to grasp task with the affected arm. Kinem atic data were recorded with a 8 camera motion analysis system 5 and using 26 reflective markers positioned at: C7, sternal notch, right and left acromion, lateral epicondyle, radial and ulnar styloid processes, third dorsal metacarpal phalangeal joint, dor sal interphalangeal joint of the index finger, and triads were placed on the superior thirds of the upper arm and forearm. Static trials included an additional marker on the medial epicondyle to create the kinematic model. Surface electromyography (EMG) wa s recorded using pre amplified electrodes 6 placed over the muscle bellies of the anterior deltoid, posterior deltoid, infraspinatus, major pectoris, biceps brachii, the long head of the triceps, extensor carpi radialis, and flexor carpi radialis muscles of the affected arm Kinematic and EMG data were recorded simultaneously. Subjects were seated on a backless stool with the affected arm placed immediately lateral to the affected thigh and were asked to reach and grasp a soda can and a pencil placed at 80 p ercent of their arm length at self selected speed. 10 trials of the reaching movement were recorded. Additional EMG data were recorded during 5 Copyright Vicon 612, Oxfor d Metrics, Oxford, UK 6 Copyright 2012 Motion Lab Systems, Inc, Baton Rouge, LA, USA

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69 maximal voluntary isometric contractions (MVIC) of each muscle group using standard manual muscle techniques 182 2.1.2.3 Data analysis We used custom designed MATLAB 7 programs to analyze and extract kinematic and EMG data. From the kinematic trajectories, we calculate d parameters commonly used in the literature: M EAN VELOCITY A measure of movement speed corresponding to the average of d during the entire movement. R EACH PATH RATIO AND SUB MOVEMENTS Ratio of the act ual wrist path and an ideal straight line between the start and end positions. Sub movements were defined as the number of times the hand velocity exceeds 5 percent of peak velocity. R ANGE OF MOTION AT SH OULDER AND ELBOW Difference in degrees between the maximum and minimum joint angles achieved. T RUNK DISPLACEMENT D isplacement of the sternum markers in the sagittal plane. From the EMG data, we calculate d parameters of mag nitude and timing. Intensity was expressed as the relative (percentage MVIC) amount of muscle activation. It was defined as the peak envelope value during the reaching trial divided by the peak activation was expressed as a percentage of movement duration. 2.1.3 Tran scranial Magnetic S timulation (TMS) 2.1.3.1 General information about technique We use d TMS to study cortical excitability. This measurement approach allow ed us to test whether th e intervention induced neuroplastic changes at the brain. TMS 7 MathWorks Inc., Massachusetts USA

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70 influences ongoing brain activity by generating weak electrical currents in brain tissue through electromagnetic induction 183 These electrical potentials are strong enough to depolarize neurons and affect normal electrical processes in nearby brain tissue. TMS causes action potent ials directly or indirectly in descending corticospinal motor neurons 183 The effects of TMS can be measured by recording EMG in the arm, hand, mechanisms: single and paired pulse stimulation. We use d both, single and paired pulse stimulation to study the hemispheric cortical excitability, inter hemispheric inhibition (IHI) and intracortical inhibitory circuits. M otor threshold, MEP amplitude and recruitment curve (RC) slope were used to study hemispheric cortical excitability 244 Ipsilateral silent period (iSP) 253 wa s used to study IHI. Co rtical silent period (cSP) 236 technique 184 and short lat ency intracortical inihibition (SICI) 1 85 were used to study the intracortical inhibitory circuits. 2. 1. 3.2. Data c ollection During TMS testing, participants were seated comfortably in a semi reclined chair. Stimulation was delivered using one or two Magstim 200 2 8 stimulators connected throu gh a Bi stim module to a figure eight coil while recording MEPs from the contralateral first dorsal interosseous (FDI) muscle by means of pre amplified EMG electrodes 9 The coil was placed tangentially over the scalp, with the handle pointing backwards and laterally at a 45 angle away from the midline, inducing a posterior anterior current in the target hemipshere For each subject, we firs t identified the optimal 8 The Magstim Company LTD Copyright 2011, Whitland, Wales, UK 9 Copyright 2012, Motion Lab Systems, Inc, Baton Rouge, LA, US A

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71 scalp location for induction of the largest MEPs in the contralateral FDI. The target site wa s marked as the hot spot on a tightly fitting cap worn by the subjects and on the neuronavigation system All the following measures were recorded for both hemispheres: The resting motor threshold (rMth) is the lowest stimulation intensity able to elicit Recruitment curve (RC) is generated by stimulation over the motor threshold hotspot at progressively increasing intensities. Testing proceeds by placing the coil at the hotspot and recording 10 stimuli in 5% increments beginning at an intensity of 10% below motor threshold. Data collection for the RC is terminated when a plateau of the sigmoidal curve is observed 224 ; Co rtical SP (cSP) and ipsilateral (iSP) are obtained using single pulse TMS delivered at 150% of motor threshold while the participant produces a sustained, submaximal contraction (~50% maximal effort) of the FDI muscle contralateral (cSP) or ipsilateral (iSP) to the stimulation 253 236 sion) reveals suppression of EMG in the limb contralateral to stimulation by subthreshold (about 20% below motor threshold) TMS, without any prior excitatory response 184 SICI is studied using paired pulse stimula tion, in which an MEP evoked by a suprathreshold test stimulus (~120% of motor threshold) is preceded at variable interstimulus intervals (ISIs) by a subthreshold conditioning stimulus (~80% of motor threshold). At ISIs ranging from 1 to 6 ms, the paired s timulations induce a short intracortical inhibition (SICI reduced MEP). 2.1.3.3 Data analysis We use d custom designed MATLAB programs to analyze TMS data and construct calculate iSP. EMG data were band pass filtered (5 1000 Hz) and not ch filtered (60 Hz). Recruitment curve (RC): Peak amplitude and area of the averaged MEP signal are calculated at each stimulus intensity. We considered the presence of MEP if the peak to defined as the last crossing of the mean baseline EMG level before the MEP peak and the MEP offset as the first crossing of the mean baseline EMG level after the MEP peak. The peak to peak amplitude and the area under the MEP

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72 are calculated at each stimulation intensity. For construction of the RC, MEP amplitude and area are normalized to both Mth and maxi mum MEP amplitude. A non linear fit of the data to Boltzmann Equation is performed, followed by a linear regression fit of the modeled data in the steepest portion of the range. The slope of th is range is determined. Motor threshold is established as the s timulation intensity at which the regression line fitting the steepest portion of the RC intersects the abscissa. Co rtical (cSP), ipsilateral silent period (iSP) and EMG suppression (a.k.a. over multi ple stimuli at a given stimulus intensity The mean and the standard (SD) deviation of the baseline EMG level for 100 ms before TMS stimulus is determined from the averaged signal. We considered the presence of an MEP (either ipsilateral or contralateral) if the post stimulus EMG exceeded the pre stimulus mean baseline stimulus mean baseline EMG before the MEP peak and the MEP offset as the first crossing of the pre stimulus mean ba seline EMG after the MEP peak. MEP area is calculated between the MEP onset and offset (MEP duration). Similarly, we considered the presence of an iS if the post stimulus EMG fell below the pre is defined as the first crossing of the pre stimulus mean baseline EMG after the MEP peak and the MEP offset as the first crossing of the pre stimulus mean baseline EMG after the iSP onset for at least 5 ms 186 The iSP duration i s the time between the onset and the offset values. We defined the silent period area as the area between the pre stimulus mean baseline EMG and the EMG signal during the silent period duration. The percent of inhibition is calculated as the percent of the total area under the pre stimulus mean baseline EMG during the silent period duration. SICI: For each ISI, signal averaging of multiple stimuli is performed. The peak amplitude is calculated and normalized as percent of the single pulse ME P amplitude. 2.1.4 Stretch Reflex 2.1.4.1 General information about technique The s tretch reflex is common ly used in assessment of spasticity, a motor disorder characterized by a velocity dependent increase in tonic stretch reflexes with exaggerated ten don jerk 11, 130 The stretch reflex (myotatic) is the muscle contraction in response to stretching within the muscle. It is a monosynaptic reflex, which provides regulation of skeletal muscle length and rate depend ent changes in muscle length When muscle lengthens,

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73 the muscle spindle is stretched and the activity incre ases leading to increased alpha motoneuron activity, muscle contraction and reduction of muscle length, which reduces muscle spindle activity 130 2.1.4.2. Data c ollection Stretch reflex modulation at the elbow was studied by imposing ramp and hold stretches Participants were positioned on the Biodex 10 dynamometer chair while the device is used to passively imp os e elbow extensions. Following each stretch the elbow was held in extension for 5 s before being passively returned to the starting position, and held in fle x ion for 10 s. EMG was recorded from the biceps brachii, brachiradialis and triceps brachii using pre amplified electrodes. Torque, position and EMG data were collected before and during passive elbow extension stretches. Two conditions were performed: the first passive, in which subjects were instructed to relax as the limb was moved through the full range of elbow motion by the dynamometer; the second, preloaded, in which the subjects performed an isometric contraction of elbow flexor muscle at 20% of MVIC before and during passive elbow extension stretches. Data were collected at four criterion spee ds (i.e., 90 o /s, 150 o /s, 210 o /s and 270 o /s). To quantify passive joint torques, two additional trials will be performed at 10 o /s. The reliability of both EMG and torque responses has been established for ramp and hold stretches o btained using this paradig m 218 2.1.4.3 Data analysis Torque, position and EMG data were analyzed using MATLAB The slow (10 deg/s) passive torque response at each position was subtracted from the torque 10 Copyright 2012, Biodex Biomedical System 3.2, Shirley, NY, USA

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74 measured during st retches imposed at all speeds. EMG activity was evaluated as the mean amplitude calculated over a 100 ms sliding window. For each trial, EMG was defined as active when the mean amplitude exceeded threshold (i.e., mean baseline, resting EMG plus 2.5 standard deviations). Data were used to obtain the following par ameters indicative of stretch reflex modulation : EMG B URST D URATION T he percentage of the movement time during which EMG activity was present. P OSITION T HRESHOLD The joint angle, expressed in degrees of elbow flexion, at which muscle activity was first identified. B URST I NTENSITY The mean amplitude of EMG activity when the muscle was active minus the baseline resting activity. T ORQUE The average torque calculated over a 100 ms window centered a t 40 degrees of elbow flexion. 2.1.5 H reflex 2.1.5.1 G eneral information about technique The H reflex ( or Hofmann reflex ) is an involuntary reaction of muscles after electrical stimulation of sensory fibers (Ia afferent s stemming from muscle spindles) and is the electrical analogue of the monosynaptic stretch reflex 187, 188 The H reflex is evoked by low intensity electrical stimulation of the afferent nerve, rather than a mechanical stretch of the muscle spindle, that results in monosynaptic excitation of the alpha mo toneurons. The H reflex bypasses the muscle spindle and the fusimotor activity that may influence the sensitivity of the Ia afferents to engage a reflex circuit. The r esponse is usually a wave, called H wave, occurring 28 35 ms after the stimulus. The elec trical stimulation of the mixed peripheral nerve produces two responses in the muscle, an M wave (short latency direct motor response due to stimulation of motor axons) and an H reflex. At supra maximal stimulation, the H reflex is absent due to

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75 collision of the antidromic motor volley with the orthodrom ic afferent volley and the M wav e is maximum 187, 188 2.1.5.2 Data collection Participants were positioned in sitting with the wrist positioned in neutral flexion/ extension; forearm in mid prone; elbow at 45 o flexion; shoulder abduction and flexion at 15 o ; and neutral shoulder rotation. H reflexes was evoked bilaterally A custom fabricated forearm splint was used to provide stabilization and maintain the forearm in mid prone. H and M waves were electrically evoked using a constant current stimulator 11 triggered by a second stimulator (S8800 Stimulator, Grass technologies, West Warwick, RI, USA) at a frequency of 0.2 Hz (to minimize homonymous or paired reflex depres sion 189 EMG was recorded on the Flexor Carpi Radi alis (FCR) muscle at a sampling frequency of 10kHz. The stimulating electrode was placed in the medial bicipital groove to stimulate the median nerve and the position was adjusted to evoke FCR H reflexes (in absence of M wave). A stimulus location was cho sen where at least 10 H reflexes were evoked at increasing stimulus intensities without an M wave. This procedure was used to assure capture of H reflex responses on the ascending limb of the recruitment curve 188 Once the stimulation site was located, stimulation intensity was sequentially increased (typically by 0.05 mA increments) from a sub H refl ex threshold intensity to the point when H reflex amplitude reache d the maximum and begins to decline. 11 Copyright 1998, Digitimer DS7A, Digitimer Ltd., Hertfordshire, England

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76 Thereafter, current intensity was increased at a faster rate (0.2 1 mA) until a maximum M wave (Mmax) was elicited. 2.1.5.3 Data analysis The peak to peak amplitude of both, H and M waves in each recruitment curve was normalized to the Mmax of the same recruitment curve. The H slope (Hslp) was calculated on the ascending limb of the H reflex recruitment curve defined as a range from 10 85% of maximum H wave amplitude Similarly, the M slope (Mslp) was calculated for the M wave recruitment curve. On the ascending limb of the H reflex recruitment curve, both H and M waves rise in a relatively linear fashion, thus allowing calculation of the slope of a l inear regression line through the data points representing H and M waves in this range of stimulation intensities. Finally, Hslp was normalized to Mslp, expressed as the ratio Hslp/Mslp. This ratio has been reported to be the most effective way to detec t changes in spinal excitability 187 The peak to peak H reflex and M wave amplitude was calculated from five maximal responses and averaged. H reflex and M wave thresholds (HTH and MTH, respectively) were determined using the minimal stimulation intensity at which a visually discernible reflex response is elicited 3 out 5 times. 2. 2. Interventions 2.2.1 Functional Task P ractice (FTP) One on one treatments were delivered by a licensed physical therapist. From a list of upp er extremity activities the treatment therapist ch o se 7 activities that were 61 Treatment was delivered in three sessions per week each lasting 90 minutes. Each session was comprised of 5 15 minutes of stretching (depending o

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77 followed by 60 70 minutes of task based activity therapy. Five activities were performed per session (10 15 minutes per activity) and each activity was incorporated into therapy twice per week ( Figure 2 1 ). 2.2.2 Constra int Induced Movement Therapy (CIMT) CIMT intervention consist ed of the classical CIMT protocol described by Wolf 138 : 6 hours per day of massed practice of the affected arm combined with shaping, behavioral contracts and constraint of the unaffected arm for 90% of waking ho urs for two weeks. 2.2.3. Power T raining We deliver ed dynamic, high intensity resistance exercise for the shoulder, elbow and wrist using an isokinetic dynamo meter (Biodex System 3.0 Pro). The treatment protocol involved 7 exercises (shoulder flexion, sho ulder abduction, shoulder external rotation, elbow flexion/extension, wrist flexion/extension), 3 sets of 10 repetitions of each exercise. The speed of movement was progressively adjusted upward over the duration of training for each study 61 2.2.4. Repetitive TMS (rTMS) Inhibitory rTMS was administered over the contralesi onal M1 corresponding to the hot spot for the ipsilesional/non paretic muscle representation. In addition, participants wore a tight fitting lycra swim cap. Skin mounted surface electromyogram preamplifier was pla ced over the FDI muscle contralateral to the stimulated hemisphere. Subjects were seated in a Biodex chair adjusted such that hips, knees and ankles were maintained at 90 degrees and were asked to relax. MEP threshold was measured before and after each rTM S session using a figure 8 coil centered at the scalp vertex and connected to a Magstim Rapid 2 high power magnetic stimulator (Magstim Ltd,

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78 UK). Stimulations were delivered at an intensity of 100% motor threshold, 1 Hz frequency, biphasic waveform and 12 00 stimulations in a single, continuous train lasting 20:00 172

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79 Table 2 1. Task based a ctivities Monday Wednesday Friday Activities 1,2,3,4,5 Activities 3,4,5,6,7 Activities 5,6,7,1,2 1. Catch & release/sp ort. 2. Water task. 3. Laundry task. 4. Board games/cards. 5. Computer/keyboarding. 6. Tool task. 7. Drawing/painting/writing. 8. Feeding/cooking/food preparation.

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80 CHAPTER 3 DIFFERENTIAL EFFECTS OF POWER TRAINING VE RSUS FUNCTIONAL TASK PRACTICE ON COMPE NSATION AND RESTORAT ION OF ARM FUNCTION AFTER STROKE 3.1. Background Current debate centers on whether therapeutically induced improvements in upper extremity function in persons post stroke reflect acquisition of compensatory movement strategies or resto ration of more normal movement patterns 78 Restoration involves reappearance of motor patterns present prior to stroke 78 while compensation involves appearance of new motor strategies, including substitution with different, atypical components 78 Although compensatory movements may enable task performance in the short term, these may be detrimental to overall outcome in the long term by contributing to problems including pain and reduced range of joint motion 7 8 Moreover, the use and reinforcement of atypical movement components may interfere with attainment of normal upper extremity motor patterns and thus limit genuine recovery. Compensatory strategies may also have a detrimental psychosocial impact. Both th e self perception and appearance of aberrant movement to others 4 contribute to depression and, ultimately, avoidance of using the impaired arm 4 These problems underscore the compelling need to discriminate between compensation and restoration in neurorehabilitation. This distinction is critical to development of effective r ehabilitation interventions that promote restoration of motor func tion present prior to stroke. Published in Neurorehabil Neural Repair Corti M, McGuirk TE, Wu SS, Patten C. Differential Effects of Power Tra ining Versus FunctionalTask Practice on Compensation and Restoration of Arm Function After Stroke. Neurorehabil Neural Repair 2012 Feb 22. [Epub ahead of print]

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81 Kinematic analysis of upper extremity (UE) motor performance enables sensitive, quantitative and reliable 62 assessment of abnormal movements 190 and thus may facilitate discrimination between compensation 78 and restoration of arm function post stroke 62, 191 To date, the majority of UE kinematic studies in persons post stroke have been cross sectional investigations of reaching 2, 5, 43, 62, 191 196 or grasping tasks 86, 193, 197 which reveal: slowness, spatial coordina tion deficits, temporal joint dy scoordination and compensatory movements that interfere with normal performance 2, 5, 43, 62, 86, 191 197 Investigations of intervention related changes in UE motor performance using kinematics have focused on evaluating the effects of: constraint induced movement therapy 192, 198 and functional unilateral 86, 197, 199, 200 or bilateral 201 repetitive task training. These therapeutic approaches are believed to facilitate ne ural plasticity through repetitive execution of functional movements. Although weakness is recognized as a major factor contributing to disability post stroke 15, 43, 44 strengthening is not typically included as a neurorehabilitation technique. Historical clinical perspectives cautioned against high exertion activities for neurologic populations because they were assumed to increase spasticity and impair motor performance 44 More recently it has been argued that remediation of impairments (i.e., weakness) does not generalize to functional tas k performance. To date, only two studies have directly compared UE strengthening and functional task practice with kinematics 199 Both studies utilized resistive therapeutic ba nds and concluded that strengthening does not improve paretic UE motor function. On careful review, however, the methods lack any rationale assuring either sufficient intensity or means for progression of the strengthening activities, thus it is likely the se studies failed to offer sufficient overload 202 Additionally, the importance of positioning,

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82 specifically trunk stabilization, has been confirmed by demonstration of greater improvements in UE movements following treatment activitie s performed with external trunk stabilization 86 203 These studies positioned participants in a standard chair, which may not provide optimal trunk stabilization an d may even enable acquisition of compensatory movements. Taken together, these factors may explain the failure of this paradigm to produce meaningful effects on either s trength or paretic UE function. While there is now considerable evidence that systemati c high intensity progressive resistance training increases strength, improves activity and produces behavioral improvements in the hemiparetic UE without increasing spasticity 14, 16 the majority of the literature reports effects of combined strengthening and functional task practice. Therefore, the behavioral effects of resistance tra ining alone remain unclear. Here we compared two forms of UE rehabilitation for persons post stroke: 1) functional task practice (FTP ) and 2) dynamic high intensity resistance training, or power training (POWER). Our primary aim was to compare these two interventions using a battery of standardized clinical evaluations and kinematics of goal directed UE movements. This approached enable d concurrent investigation of changes in function, as understood by commonly used clinical tools, and movement strategies used by persons post stroke during reaching tasks. We hypothesized that following POWER behavioral motor improvements would reveal res toration of motor patterns more similar to healthy individuals while following FTP behavioral changes would reveal compensatory movement strategies. Our secondary aim was to determine the effects of treatment order. We hypothesized that FTP preceded by POW ER would reveal greater

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83 behavioral motor improvements because FTP would be more effective following restoration of neuromechanical function. 3.2. Methods 3.2.1. Participants This study was a single center, randomized controlled trial 12 Participants includ ed fourteen persons with UE hemiparesis post stroke meeting the following inclusion criteria: single, unilateral stroke within 6 26 months of enrollment (confirmed by diagnostic imaging); voluntary movement in the major shoulder and elbow agonists in the horizontal plane (e.g., gravity eliminated) 204 ; active wrist extension, thumb abduction and extensio n of any two digits. Exclusion criteria were: presence of significant UE joint pain, limitations in passive range of motion (ROM) or prop rioception deficits at the elbow or shoulder joint; lesions involving the brain stem or cerebellum, cognitive deficits affecting the ability to follow 3 step commands and conditions involving any unstable cardiovascular, orthopedic or neurological impairme nt precluding exercise. All procedures were approved by the Stanford University panels on human subjects research. 3.2.2. Procedures After providing written informed consent, all participants were enrolled in a two stage cross over design (Figure 3 1). Pa rticipants were randomized to either: 1) POWER or FTP, followed by 2) the alternate therapy. Each treatment block lasted ten weeks and involved 30 sessions (i.e., 3 90 minute sessions per week), thus each participant received a total of 90 hours of one on one treatment with a licensed physical 12 This work was conducted at the Rehabilitation R&D Center at the VA Palo Alto Health Care Sy stem

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84 therapist. The treatment blocks were separated by a two week evaluation period. Clinical and kinematic assessments were conducted by blinded assessors: 1) at baseline, 2) following the first and 3) second treatment bl ocks. To assure baseline equivalence between treatment orders, the shoulder elbow components of the upper extremity Fugl Meyer Motor evaluation 62, 94 functioning (<20/30 points) individuals. Separate randomization orders were prepared, allocated to sealed envelopes and stored by the study coordinator in a locked drawer. Following baseline clinical assessment the blinded evaluator drew a sequentially numbered sealed envelope from the appropriate grouping (i.e., higher vs. lower) and provided it to the treating physical therapist who broke the seal to reveal assignment to either treatment Order A (FTP followed by POWER) or B (POWER followed by FTP). Participants were b linded to their randomization. 3.2.3. Measures 3.2.3.1. Clinical assessments Clinical outcomes were assessed using tools for which: 1) validity and reliability have previously been established in individuals post stroke, and 2) represent assessment across all levels of the ICF 205 Specifically, this clinical battery included: the Modified Ashworth Scale (MAS) 25 Fugl Meyer Upper Extremity Motor Score (UEFMMS) 93 and the shoulder elbow portion of the UEFMMS (30 points) 94 and European Stroke Scale (ESS) 95 to characterize impairment; the Chedoke McMaster Hand and Arm Inventory (CMHAI) 96 to characterize activities; and the Reintegration to Normal Living index (RNL) 206 to characterize participation.

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85 3.2.3.2. Kinematics of functional reach to grasp: Kinematics were obtained dur ing performance of self paced functional reach to grasp. Participants were seated in a straight back chair with the paretic UE resting on the ipsilateral thigh, the shoulder in neutral flexion/extension and internal rotation, the elbow in 75 90 degrees of flexion with the wrist resting in pronation, and instructed to 180 ). Two trials were obtained. A 7 camera Motion Capture System 13 recorded (120 Hz) displacements of 16 reflective markers, which were used to reconstruct three dimensional movements of the arm, forearm and trunk. During dynamic trials, markers were positioned at: C7, sternal notch, right and left acromion, lateral epicondyle, radial and ulnar styloid proce sses, third dorsal metacarpal phalangeal joint, dorsal interphalangeal joint of the index finger, and triads were placed on the superior thirds of the upper arm and forearm. Static trials included an additional marker on the medial epicondyle to create the kinematic model. A 2.2 cm wide piece of reflective tape on the superior border of the soda can identified the reaching target. 3.2.4. Therapeutic I ntervention The treatment algorithms have been previously described in detail 54 (in which the two interventions were combined in a HYBRID therapy). Here, all participants received both forms of intervention in separate bouts to allow comparison of individual treatment effects. FTP i nvolved practice of functional tasks using a progression of six therapeutic goals and nine activity categories. Specific therapeutic tasks were chosen from these 13 Copyright 2011, Qualisys North America Inc, Charlotte, NC

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86 activity categories based on participant specific goals and baseline functional level and prac ticed on a structured rotation within the framework of the overriding therapeutic goals. POWER involved five reciprocal upper extremity movements: shoulder abduction/adduction, shoulder flexion/extension, shoulder external/internal rotation, transverse pla ne elbow flexion/extension and wrist flexion/extension, which were trained using a commercially available dynamometer 14 Custom designed attachments to enable participants with impaired grasp to engage the dynamometer, were used by all participants. POWER i nvolved a standardized progression in which movement speed and the number of training sets (i.e., 10 repetitions each) were adjusted to maintain a constant period of active muscle work 202 within each session. Both the FTP and Power prog r ams are elaborated in Figure 3 2. 3.2.5. Kinematic Analysis Marker data were identified using Qualisys Track Manager 15 modeled using Visual3D 16 and kinematic trajectories analyzed using custom written MATLAB 17 scripts. Kinematic data were low pass filter ed (12 Hz cutoff) using a bi directional 4 th order Butterworth filter. The start of movement (SOM) was defined as the first point at which the velocity of the marker on the third metacarpalphalangeal joint exceeded 5% peak velocity and the end of movement (EOM) as the last point at which velocity of this marker fell below 5% peak 43 14 Copyright 2012, Biodex Biomedical System 3.2, Shirley, NY, USA 15 Copyright 2011, Qualisys Qualisys, North America Inc, Charlotte, NC 16 Copyright 2010 C Motion, Version 4.00.19, Inc C Motion, Germantown, Maryland 17 MathWorks Version 7.0, Inc., Massachusetts USA Natick, Massachusetts

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87 The following parameters were calculated from the kinematic trajectories: i) mean velocity to quantify movement speed; ii) reach path ratio (RPR) and sub mo vements to quantify movement accuracy; iii) time to peak hand velocity, time to max shoulder flexion and time to max elbow extension to quantify motor coordination; iv) shoulder and elbow range of motion and trunk displacement to quantify movement exe cution. Movement time was defined as the time between SOM and EOM. Maximum hand velocity was defined as the maximum tangential linear velocity of the marker on the third during the entire movement. Sub movements were defined as the number of peaks in the hand velocity profile as defined by SOM and EOM, described above 5, 43, 191, 207, 208 Time to peak hand velocity, time to max shoulder flexion and time to max elbow extension were defined as the time between SOM and maximum hand velocity, maximum shoulder flexion and maximum elbow extension, respectively. Range of motion (ROM) was calculated for shoulder flexion and elbow extension as the difference between the maximum and minimum joint angle achieved. Trunk displacement was defined as the sagittal plane displacement of the sternum marker. 3.2.6. Statistical A nalysis Statistical analysis was performed with MATLAB Data were tested for no rmality using the Kolmogorov Smirnov test. Kinematic data revealed normally distributed data (p >.05), while clinical scores were significantly non normal (p<.05). Hence, Wilcoxon Rank Sum and Signed Rank tests were used to test clinical variables, while t wo sample and paired t tests were used for kinematic variables. Paired t tests were used to test for differences between the two trials in kinematic parameters. Significant differences were

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88 not revealed between trials, thus the mean value for each paramete r was carried forward for group analysis. Three sets of comparisons were performed for both clinical and kinematic data: the first two evaluated treatment specific changes between FTP and POWER, while the third tested the treatment order (A=FTP>POWER vs. B =POWER>FTP). The full set of comparisons included: The primary treatment effect, characterized by comparing Block1 chang e scores between FTP and POWER. To probe for a potential period effect, the difference in magnitude of Block1 and Block2 change scores w as compared within each treatment order (i.e., (POWER minus FTP) for Order A vs. ( FTP minus POWER) for Order B). If FTP and POWER produced equivalent effects, this comparison would be non significant since both between blocks differences would reveal a pot ential period effect. However, a non zero difference between Orders A and B would reveal additional information regarding differential treatment effects for FTP vs. POWER 209 The effect of treatment order was determined by comparing the overall change between baseline and end of Block2 (i.e., sum of Block1 and Block2 change scores for ea ch group (Order A vs. Order B). P n procedure 210 Unless otherwise noted, statistical significance was set at p <.05. Onl y effects that retained significance after correction are reported in text. All effects and corresponding p values are reported in Table 3 2 and Table 3 3 Effect sizes, calculated using the mean difference divided by the pooled standard deviation, are rep orted for each clinical or kinematic measure. 3.3. Results Individual subject characteristics are summarized in Table 3 1. At baseline, participants revealed a mean age of 59.8(15.0) years (2 female), 15.22(6.7) months post stroke and UEFMM score of 33.7 1(9.6) points. Concealed allocation resulted in

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89 eight and six participants randomized to treatment orders A and B, respectively. Clinical characteristics revealed no significant difference s between groups at baseline. 3.3.1. Clinical Results Results and e ffect sizes for all clinical measures are summarized in Table 3 2. Treatment e ffect ( FTP vs. Power). The primary treatment effect revealed a significant difference from 0 in the CMHAI for both treatments, and in Fugl Meyer Shoulder/Elbow score for Group A only. Between group differences, approaching statistical significance, were revealed only in the Fugl Meyer Shoulder/Elbow score. Following correction for multiple comparisons, no significant within or between group differences remained. Thus, based on cli nical assessments, our results indicate that both groups improved without differential treatment effects. Period e ffect (FTP vs. POWER) Marginal between group differences were revealed only in the Fugl Meyer Shoulder/Elbow score and MAS for wrist flexion However, following correction for multiple comparisons, no significant differences remained either within or between groups for any of the clinical scales. Treatment o rder effect The overall treatment effect for both Order A and B was significantly diff erent from 0 in the CMHAI and UEFMMS. Marginal differences between groups were revealed only in the CMHAI. However, following correction for multiple comparisons, no significant differences were revealed either within or between groups for any of the clin ical scales. 3.3.2. Kinematic D ata Results and effect sizes for kinematic variables are summarized in Table 3 3. Treatment e ffect. (FTP vs. POWER) The primary treatment effect revealed significant differences from 0 in: time to max elbow extension, time t o max shoulder

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90 flexion, shoulder flexion ROM, sub movements and trunk displacement. Between group differences were revealed in elbow extension ROM and trunk displacement (Figure 3) indicating that following Block1, POWER revealed greater improvements in el bow extension ROM and reduced trunk displacement. These comparisons retained statistical significance following corre ction for multiple comparisons. Period e ffect. (FTP vs. POWER). Differential treatment effects were revealed in several parameters. Mean ve locity and peak hand velocity time improved more after FTP, while maximum elbow extension time maximum shoulder flexion time, elbow extension ROM, shoulder flexion ROM and trunk displacement improved more after POWER. Following correction for multiple comp arisons, between group differences in mean velocity and trunk displacement retained statistical significance to reveal greater improvements in mean velocity following FTP, while trunk displace ment improved more after POWER. Treatment order e ffect. The over all treatment effect differed significantly from 0 in: time to max shoulder flexion, time to peak hand velocity and trunk displacement. Between group differences were revealed in trunk displacement indicating that participants randomized to treatment Order B (POWER>FTP) revealed greater improvements in trunk displacement (i.e., reduced trunk displacement). These effects retained statistical significance following correc tion for multiple comparisons. 3.4. Discussion 3.4.1. Compensation versus Restoration Her e we investigated concurrent clinical and kinematic changes following two UE rehabilitation treatments, functional task practice (FTP) and power (POWER) training, with the primary aim of understanding whether improved UE function post stroke results

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91 from u tilization of compensatory movements or restoration of more normal movement patterns. As hypothesized, behavioral motor improvements (e.g., kinematics) post POWER reveal restoration of more normal movement function. In contrast, behavioral changes post FTP reveal compensatory movement strategies. While mean reaching velocity increased post FTP, this apparent improvement involved concurrent reductions in shoulder flexion and elbow extension ROM, and increased trunk displacement changes indicating reinforce ment of compensatory movement strategies 5 Following POWER, participants increased shoulder flexion and elbow extension ROM, reduced associated trunk displacement and also demonstrated greater improvements in time to max shoulder flexion and elbow extension, parameters contributing to normal inter joint coordination. As revealed by a shift toward normal across numerous kinematic parameters 62 motor patterns more similar to healthy individuals were revealed following POWER. These b ehavioral manifestations can be attributed to rest oration or true motor recovery. 3.4.2. Effect of Treatment O rder We addressed our secondary aim, understanding the effect of treatment order, using a crossover design. As hypothesized, our data reveal that POWER followed by FTP produced greater improvements, primarily significantly reduced trunk displacement, indicating a marked reduction of compensatory movements. Notably, this reduced compensation was accompanied by reappearance of normal patterns of shoul der and elbow mov ement present prior to stroke. 3.4.3. Use of Kinematics to Investigate Motor C ontrol It is important to note that clinical assessments of motor function revealed similar improvements after both POWER and FTP. Clinical scales focus on gross indicators of

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92 task accomplishment (i.e., success or failure of task completion, assistance required, time to task completion) but are unable to discern differences in actual movement performance. This focus on task completion ignores that individual subje cts may adopt unique approaches. Indeed, comparable change scores may result from utilization of wholly different movement strategies involving either adoption of compensatory movements or acquisition of normal movement patterns. In this light, results of the present study emphasize the important contribution of kinematics 191 to understanding the effects and ef ficacy of neurorehabilitation. The goal of rehabilitation is not only to facilitate behavioral improvem ent at the level of task completion, but to promote neural 211 Accurate evaluation of motor dysfunction is therefore fundamental to developing rehabilitation interventions with the capacity to produce neural recovery that manifests in improved behavioral function. In contrast to the cli nical assessments, our results illustrate that UE kinematics 43, 62, 191, 199 discriminate between normal and compensatory movement strategies and therefore reveal the actual effects of rehabilitation interventions. While the therapeutic goal in this study was not specifically to train to normal 212 our kinematic data reveal differential intervention responses with reacquisition of many features of n ormal movement following POWER. 3.4.4. Neuroplasticity and Specificity of T raining The capacity for neural p lasticity after stroke is now well recognized and may include different degrees of physiologic recovery. Current evidence suggests that in both animal and human models with and without stroke, neural recovery and reorganization of neuronal function are not only spontaneous processes but are strongly influenced and modulated by activity (e.g., activity dependent plasticity) 213 Because

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93 recent studies demonstrate that neural plasticity is task specific 83 task related practice is considered essential for driving neuroplasticity 83 However, as Daly suggests, a central assumption of motor learning is that the neural structures controlling movement are required to adap t to constraints that are imposed by: the structure of the musculoskeletal system, the physical laws governing movement, and the impairments that are present 136 Building on these assumptions, the constraints impos ed on the individual in a given motor task must be incorporated into a successful treatment plan. For example, an individual impaired by weakness may be unable to reach and grasp a soda can, thus performance (e.g., completion) of this task would necessaril y involve compensation with other body segments or utilization of motor strategies not typically involved in the movement. Rehabilitation using repetitive task practice would reinforce these abnormal movements and the motor skill acquired would not be the one desired. Latash 212 has proposed that the choice of a particular movement pattern is based on priorities and that under atypical conditions (i.e., structural or biomechanical changes within the neuro musculo skeletal system post stroke), the CNS may reweight its priorities for movement execut ion leading to altered movement patterns. This perspective suggests that therapeutic approaches directed toward remediation of underlying impairments may reduce the need for reweighting movement priorities. Weakness is one of the most significant impairmen ts post stroke 14, 15, 43, 44 Results of the present study indicate that therapeutic intervention directly addressing weakness effectively restores motor control in the hemiparetic UE. Our results also suggest that an effective therapeutic approach most likely involves multiple stages, each with a specific goal. The present study design reflects

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94 two such stages: i) remediation of hemiparetic weakness by training the individual to recruit and control the requisite fo rce for task execution, followed by ii) utilization of this enhanced neuromechanical capacity in repetitive practice of close to normal movements. Therefore, our results are consistent with contemporary principles of neuroplasticity 83 First, force production is a neurologic phenomenon and there is conside rable evidence that strengthening elicits profound adaptations at both supraspinal and spinal levels in non disabled 51, 53, 56, 58, 214 and neurologically impaired populations 50 Moreover, the neural phase of strengthening is argued to involve motor learning 215, 216 Second, weakness contributes to impaired movement patterns 43, 217, 218 and functional motor performance 219 while changes in critical movement parameters are demonstrate d post strengthening 220, 221 Finally, repetitive practice of close to normal movements is an important aspect of training specificity. Our results suggest that functional outcomes are enhanced when therapeutic in terventions train the capacity of the motor system prior to engagi ng in repetitive task practice. 3.4.5. Limitations We acknowledge limitations of the present study. First, FTP did not provide trunk stabilization, while POWER provided some stabilization fr om the dynamometer chair and chest strap. Other authors have suggested 203 that implicit feedback provided by trunk stabilization may be influential in re learning of normal motor strategies. Important in this regar d is our use of a crossover design and its capacity to monitor differential treatment responses in the same individuals. While all participants received both FTP and POWER, our results reveal a significant order effect when POWER preceded FTP. If the prima ry affordance of POWER training was the trunk restraint, it is unlikely to have been retained throughout the FTP treatment, which reintroduced the opportunity to

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95 utilize and practice with compensatory trunk movements. Second, while not an explicit limitati on, both treatments were based on systematic approaches for intensity and progression; however the physical and physiological demands of POWER were indeed more intense than FTP. Consistent with the literature which indicates that better functional outcomes are associated with higher treatment intensity 202, 222 our data suggest that FTP in isolation may lack the requisite intensity to stimulate the appropriate neuroplastic processes underlying recovery of normal mo vement patterns. Third, heterogeneity in lesion location among our participants precludes our ability to make direct associations between lesion location and functional outcome. There is a need for further research to analyze the relationship between CST i nvolvement and individual responses to interventions. Finally, our kinematic analysis is based on two trials of each movement. There is no consensus regarding the appropriate or optimal number of behavioral trials to sample. Some investigators capture mult iple trials to understand the variability/consistency over repeated trials of a movement 191 however in studying individuals with severely compromised motor function our primary concern was to avoid inducing a confounding effect of fatigue. By current standards of clinical rehabilitation in the United States, 60 sessions of one on one treatment delivered over twenty weeks may not readily translate to clinical practice. However, our findings offer an opportunity for reconsideration of appropriate rehabilitation practice models. Importantly, participants in this study presented with lower functional status than in many currently reported studies 54, 223 yet substantial UE i mprovements were revealed across levels of measurement. Our results suggest that our approach of 90 minute treatments thrice weekly for an extended period enables

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96 incorporation of progressive, incremental physiological and behavioral changes into movements encountered in the course of daily life 224 An additional consideration for rehabilitation practice models is that the systematic power training component of this intervention could be incorporated in the outpatient or community settings where multiple individuals can participate simultaneously. 3.4.6. Clinical R elevance Here we directly compared two intervention approaches with the aim of demonstrating dif ferential mechanisms of motor recovery. Our findings demonstrate that POWER promotes restoration of normal movement patterns, which may result from increased neural drive from the impaired hemisphere. Importantly, our results demonstrate that it is possibl e to correct compensatory movement strategies in persons post stroke and confirm the lack of deleterious effects of high intensity activities in persons with neurological disorders 14, 15 Taken together, our result s offer novel insight for identifying effective UE rehabilitation interventions that promote restoration of normal motor function. Further experimental studies are necessary to identify the physiological mechanisms that underlie restoration of normal movem ent.

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97 Table 3 1. Participant c haracteristics. Group Upper extremity Fugl Meyer motor score (66 points total) Gender Affected Side Premorbid Laterality Age, years Time since onset, months Mechanism of stroke Lesion Location Group A 24 F R R 61.1 25.2 occlusion cortical Group A 36 M R L 64.5 11.8 infarct subcortical Group A 14 M L R 47.7 13.2 ischemic cortical Group A 26 M R R 66.1 19.8 embolic subcortical Group A 29 M R L 62.3 13.6 infarct cortical Group A 33 F L R 82.3 10.6 hemorrhagic subco rtical Group A 48 M R R 22.0 6.8 infarct cortical Group A 38 M L L 46.3 23.9 embolic cortical Mean 31 ( 10.2) 56.53 ( 17.9) 15.61 ( 6.6) Group B 39 M R R 61.1 24.4 infarct cortical Group B 29 M L R 64.5 18.5 infarct subcortical Group B 34 M L R 47.7 20.2 infarct cortical Group B 44 M L R 66.1 11.1 dissection cortical Group B 49 M R R 62.3 6.8 hemorrhagic subcortical Group B 29 M R R 82.3 7.2 ischemic cortical Mean 37.33 (8.2) 64.16 (9.8) 14.7 (7.4) Cohort Mean 33.71 (9. 6) 59.80 (15.0) 15.22 (6.7) Note: Participants were randomly assigned to Groups A or B, reflecting treatment order, where A = FTP followed by POWER and B = POWER followed by FTP. Baseline equivalence b etween groups was confirmed for Upper Extremi ty Fugl Meyer motor score, age and time since stroke onset (all ps>0.05). Mechanism of stroke was determined from review of medical records and lesion location by confirmatory neuroimaging.

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98 Table 3 2. Clinical d ata. Clinical Variable Mean (SD) Wilcoxon Rank Sum Wilcoxon Signed Rank Effect Size (Order A) (Order B) P Value (Order A) (Order B) Primary Treatment Effect (Difference Following Treatment 1 (Eval1)) Chedoke McMaster 1 4.83 (7.93) 9.43 (7.18) 0.284 0.031 0.016 0.714 European Stroke scale 2.86 (2.41) 3.167 (4.1) 0.772 0.031 0.062 0.093 Fugl Meyer Shol/Elbow Score (30 pts) 3.57 (1.99) 1.43 (4.12) 0.062 0.016 0.531 0.663 Fugl Meyer Motor Score (66 pts) 7.00 (9.09) 6.71 (4.40) 0.564 0.156 0.031 0.040 MA Elb Ext 0.29 (1.25) 0.29 (0.76) 0.3 89 1.000 0.625 0.552 MA Elb Flex 0.71 (1.11) 0.29 (0.95) 0.477 0.250 0.750 0.414 MA Sh Abd 0.29 (0.76) 0.14 (0.70) 1.000 1.000 1.000 0.197 MA Sh Ext 0.86 (1.21) 0.14 (0.38) 0.229 0.250 1.000 0.794 MA Sh Flex 0.00 (0.63) 0.00 (0.58) 1.000 1.00 0 1.000 0 MA Wrist Ext 0.29 (0.76) 0.71 (1.11) 0.393 1.000 0.250 0.451 MA Wrist Flex 0.29 (0.76) 0.57 (1.13) 0.110 1.000 0.500 0.890 RNL 1.57 (7.14) 0.86 (6.54) 0.481 0.844 0.594 0.355 Period Effect (Differences between Eval1 and Eval2 (Eval2 Eva l1)) Chedoke McMaster 0.67 (18.22 ) 1.86 (14.27) 0.667 0.073 European Stroke scale 3.29 (1.70) 3.00 (3.58) 0.263 0.102 Fugl Meyer Shol/Elbow Score (30 pts) 3.14 (2.29) 0.14 (5.01) 0.063 0.844 Fugl Meyer Motor Score (66 pts) 3.86 (15.82 ) 4.43 (5.22) 0.335 0.049 MA Elb Ext 0.43 (1.51) 0.14 (1.57) 0.388 0.370 MA Elb Flex 0.71 (1.50) 0.43 (0.98) 0.119 0.905 MA Sh Abd 0.29 (1.25) 0.00 (1.00) 0.881 0.252 MA Sh Ext 0.86 (1.68) 0.14 (0.38) 0.502 0.588 MA Sh Flex 0.17 (0.98) 0.14 (0.69) 0 .870 0.028 MA Wrist Ext 0.14 (1.21) 1.14 (2.03) 0.493 0.597 MA Wrist Flex 0.71 (1.25) 1.14 (2.27) 0.066 1.014 RNL 1.86 (6.28) 2.57 (10.22) 0.898 0.084

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99 Table 3 2. Continued Clinical Variable Mean (SD) Wilcoxon Rank Sum Wilcoxon Signed Rank E ffect Size (Order A) (Order B) P Value (Order A) (Order B) Order Effect (Overall Difference (Eval3)) Chedoke McMaster 30.33 (7.12) 20.71 (9.74) 0.053 0.031 0.016 1.127 European Stroke scale 2.43 (3.73) 3.33 (4.88) 1.000 0.172 0.188 0.208 Fugl Meyer Shol/Elbow Score (30 pts) 4.00 (2.30) 3.00 (4.00) 0.517 0.016 0.109 0.306 Fugl Meyer Motor Score (66 pts) 10.14 (4.34) 9.00 (5.80) 0.948 0.016 0.016 0.223 MA Elb Ext 0.14 (1.57) 0.43 (0.98) 0.547 1.000 0.500 0.436 MA Elb Flex 0.71 (0.95) 1.00 (1.41) 0.736 0.250 0.188 0.237 MA Sh Abd 0.29 (0.49) 0.29 (0.49) 1.000 0.500 0.500 0 MA Sh Ext 0.86 (0.9) 0.14 (0.38) 0.099 0.125 1.000 1.035 MA Sh Flex 0.17 (0.41) 0.14 (0.69) 1.000 1.000 1.000 0.042 MA Wrist Ext 0.43 (1.13) 0.29 (1.25) 0.7 81 0.500 0.500 0.120 MA Wrist Flex 0.14 (0.90) 0.00 (0.00) 1.000 1.000 NA 0.225 RNL 1.29 (8.38) 4.29 (4.72) 0.141 0.922 0.094 0.819 Note: Table describes m ean change (SD) in clinical scores, p values and effect sizes for comparisons as described in m ethods. Abbreviations: MA Modified Ashworth Scale; RNL Reintegration to normal living index.

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100 Table 3 3 Kinematic d ata. Kinematic Variable Mean (SD) Between group comparisons Within group comparisons Effect size (Order A) (Order B) P Value Ord er A Order B Treatment Effect (Difference Following Treatment 1 (Eval1)) RPR 0.22 (1.70) 1.82 (1.38) 0.078 0.740 0.013 1.031 Max_Elbow_Ext_time 21.14 (31.34) 8.3 (4.48) 0.048 0.125 0.003* 1.315 Max_Shoulder_Flex_time 6.55 (10.87) 20.08 (7.48) 0. 019 0.162 0.000* 1.451 Mean_Velocity 3.86 (4.21) 2.67 (6.99) 0.056 0.051 0.351 1.133 Peak_Hand_Vel_time 4.51 (15.53) 23.24 (26.24) 0.033 0.471 0.058 1.287 ROM_Elbow_Ext 8.83 (11.26) 22.52 (20.33) 0.004* 0.083 0.026 1.907 ROM_Shoulder_Flex 2.42 (1 0.44) 11.88 (7.78) 0.013 0.563 0.007* 1.552 Submovements 0.71 (4.43) 2.79 (1.38) 0.085 0.685 0.002* 1.066 Trunk_displacement 3.79 (0.97) 3.62 (1.81) <0.001* <.000 0.002* 5.094 Period Effect (Testing Differences between Eval2 and Eval1 (Eval2 Eval1) ) RPR 0.40 (2.28) 2.05 (2.54) 0.082 1.014 Max_Elbow_Ext_time 27.29 (38.62) 7.66 (6.98) 0.054 1.259 Max_Shoulder_Flex_time 6.37 (9.59) 19.32 (10.67) 0.034 1.277 Mean_Velocity 6.26 (3.03) 12.49 (9.92) 0.002* 2.558 Peak_Hand_Vel_time 14.27 (1 1.98) 16.23 (28.03) 0.021 1.415 ROM_Elbow_Ext 12.03 (16.99) 18.83 (22.03) 0.012 1.569 ROM_Shoulder_Flex 3.22 (15.47) 13.38 (7.83) 0.026 1.354 Submovements 3.07 (7.32) 2.86 (3.36) 0.075 1.040 Trunk_displacement 6.84 (2.24) 2.47 (2.21) <.002* 4.181

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101 Table 3 3 Continued Kinematic Variable Mean (SD) Between group comparisons Within group comparisons Effect size (Order A) (Order B) P Value Order A Order B Order Effect (Over all Difference (Eval3)) RPR 0.85 (1.72) 1.59 (1.43) 0.4 00 0.240 0.026 0.466 Max_Elbow_Ext_time 14.98 (28.24) 8.94 (7.75) 0.068 0.210 0.022 1.155 Max_Shoulder_Flex_time 6.72 (15.48) 20.84 (8.71) 0.057 0.294 0.001* 1.124 Mean_Velocity 1.46 (7.20) 7.15 (7.28) 0.168 0.611 0.041 0.785 Peak_Hand_Vel_time 10 .96 (21.18) 37.87 (20.38) 0.032 0.220 0.003* 1.295 ROM_Elbow_Ext 5.62 (11.64) 26.20 (30.58) 0.034 0.248 0.064 1.376 ROM_Shoulder_Flex 1.61 (10.81) 10.37 (9.51) 0.048 0.706 0.028 1.177 Submovements 1.64 (5.3) 2.71 (2.40) 0.635 0.444 0.024 0.260 T runk_displacement 0.66 (2.44) 4.76 (2.82) 0.002* 0.503 0.004* 2.054 Note: Table describes m ean change (SD) in kinematic parameters, p values and effect sizes for comparisons as described in methods. Abbreviations: RPR reach path ratio; Max_Elbow_Ext_ti me time to maximum elbow extension; Max_Shoulder_Flex_time time to maximum shoulder flexion; Peak_Hand_Vel_time time to peak hand velocity time; ROM_Elbow_Ext elbow range of motion; ROM_Shoulder_Flex shoulder range of motion

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102 Figure 3 1 Stu dy design. Summariz ing the cross over design. Participants were evaluated three times: at baseline and after each treatment block. The treatment order for Group A was FTP followed by POWER and for Group B POWER followed by FTP.

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103 Figure 3 2. Treatment protocols. Sections A and B: Outline of the functional task practice (FTP) program. Consistent with our previous work, the FTP program addresse d six global therapeutic goals A). Therapeutic activities (B) were developed on the basis of the current therapeu tic goal, the nine activity categories listed in the sub table, the minute treatment session involved 15minutes of stretching and warm up, followed by practice of activities in each of th e 9 categories for 8minutes each. Specific examples of activities for high and low functioning individuals are provided. To assure consistency

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104 across all participants, treatment was advanced to the next therapeutic goal on the timeline specified, the nine activity categories were presented in rotation, and timing of each category was adhered to. Section C: Outline of the POWER training. Participants performed both concentric and eccentric actions for 10 consecutive weeks. Movement speed ranged from 30 to 90 degrees per second for eccentric and from 30 to 180 degrees per second for concentric actions. Each bar represents one set of 10 repetitions at the criterion speed noted on the Y axis. A primary goal of power training is to improve the capacity for force production in dynamic conditions. Therefore, the training prescription was progressed through advancement of the criterion movement speed. Because the neuromuscular active state differs with movement speed, the number of sets was adjusted to maintain a co nsistent work:rest ratio across the 10 week program. Referenced to Week 1 (3 sets of each exercise: Con 30 o /s, Con 60 o /s, Ecc 30 o /s), the work:rest averaged 1.07 (.08, range 0.97 1.27). E ach set involved 10 repetitions

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105 Figure 3 3 Key kinematic para meters of functional reach to grasp reveal effects of FTP and Power. Left panel describes Treatment effect (differences following treatment 1). Graphs describe mean and standard errors of mean velocity (Panel A), elbow extension ROM (Panel B) and trunk dis placement (Panel C) at baseline, and after first and second treatments. Group A (FTP followed by POWER) corresponds to white bars, Group B (POWER followed by FTP) to gray bars. Graphs show significant effect in elbow extension ROM (Left Panel B) and Trunk displacement (Left Panel C). Right panel describes Period effect ( difference in magnitude of Block1 and Block2 change scores ). Graphs describe change scores after first and second treatments. Results show significant effect in mean velocity (Right Panel A) and trunk displacement (Right Panel C).

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106 CHAPTER 4 POWER TRAINING ENHANCES ELBOW STRETCH REFLEX MODULATION POSTSTROKE 4.1. Background Between 20-40% of persons post-stroke experience spasticity225. Spasticity is a symptom of impaired motor control commonly observed in the upper-extremity226 which may interfere with normal movement post-stro ke. Classically defined, spasticity is a velocity-dependent involuntary resi stance to passive muscle stretch11. The phenomenon of spasticity involves two components: hy pertonia increased mechanical resistance to stretch, and hyperreflexia exaggerated re flex activity in resting muscles. Both hypertonia and hyperreflexia can be quantified using passive stretches imposed under controlled velocity conditions227, 228. Torques obtained from the passive stretch paradigm characterize hypertonia and provide information that parallels the clinical Ashworth Scale, while electromyographic re sponses (EMG) obtained concurrently with passive stretches characterize hyperreflexia228. Traditional clinical perspectives on neurorehabilitation13 argued that spasticity imposed the greatest impairment to motor func tion and represented the most significant limitation to motor recovery. Moreover, s pasticity appeared to be exacerbated with exertion, therefore, any form of high-effort activity, including muscle strengthening, was strictly proscribed in neurorehabilitation13 Corti M, Patten C. Power training enhances elbow stretch reflex modulation post-stroke. Neurorehabilitation and Neural Repair. In preparation.

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107 In contrast, some authors have demonstrated that weakness rather than spasticity, is the primary cause of dysfunctional movement post stroke 229 Several studies fail to demonstrate a significant func tional relationship between spasticity and functional motor performance 12 Thilmann et al. 17 studied stretch induced EMG responses and found that, compared with controls, persons post stroke had increased resistance to limb displacement at rest but not when the arm was actively moving, s uggesting that spasticity does not contribute to motor control abnormalities in hemiparesis. In another study, Thilmann et al. studied both the stretch induced EMG (hypereflexia) and torque (hypertonia) responses 17 68 They f ound that hypertonia was associated with muscle contracture rather than with reflex hypere x citability, and detected no relationship between hypertonia and either weakness or loss of dexterity. Another study on 95 post stroke patients showed that severe fun ctional disability occurred almost equally either in the presence or absence of spasticity 225 A contemporary review of evidence suggest s that high exertion training, such as resistance training, improve s upper lim b function without exacerbating muscle spasticity 16 In support of the importance of resistance training post stroke, a recent review 1 9 confirmed: 1) that the presenc e of weakness post stroke could aggravate spasticity in many ways including: reduced traffic in descending pathways responsible for voluntary movement; muscle fiber atrophy and contracture; changes in the spatial and tempo ral patterns of muscle activation, causing an inefficient EMG torque relationship; loss of functional motor units and changes in the properties of remaining units producing a decrease in maximal force due to activation on a suboptimal portion of the force length relationship 24 ; 2) that strengthening can positively increase strength,

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108 promote functional improvement and, potentially change quality of life without increasing spasticity 19 Our research team conducted a set of studies that contributes to the evidence that resistance training as an intervention post stroke can induce restoration of more normal movement patterns and promote appropriate activity in neural circuits 18 60 61 First, Patten et al. 60 conducted a randomized clinical trial of upper extremity rehabilitation to compare the effects of functional task practice, and a hybrid intervention of functional task practice combined with dynamic high intensity resistance training pos t stroke. Further, Patten et al. 18 compared the effects of high intensity resistance training and hybrid training during stretch reflex modulation. The findings of this study suggested that : first, upper extremity rehabilitation involving high exertion activity did not exacerb ate either the hyperreflexic or hypertonic components of spasticity in adults post stroke. Second, they illustrate that high intensity resistance training promoted a more appropriate modulation of stretch induced EMG responses. These neurophysiologic adapt ations were associated with upper extremity motor function improvement evaluated with the Wolf Motor Function Test Functional Ability Scores (FAS). In our previous work, we compared 61 power training (i.e. dynamic high intensity resistance training) with functional task practice tr aining on a battery of clinical scales and on kinematics during a reaching task. We demonstrated that, although clinical evaluation did not reveal any differential effect of treatment, kinematic improvements following power training revealed a restoration of more normal movement patterns, while improvement after functional task practice suggested reinforcement of

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109 compensatory strategies. Specifically, following functional task practice, hemiparetic participants demonstrated increased mean velocity during re aching, but reduced shoulder flexion and elbow extension range of motion, which were compensated by increased trunk displacement. In contrast, following power training, participants increased shoulder flexion and elbow extension range of motion and reduced associated trunk displacement. This study showed that power training is effective in inducing behavioral recovery; however it did not evaluate neural adaptation of power training 61 Here, we compare the effects of POWER and FTP on stretch reflex modul ation. The aims of this study ar e: 1) to test the differential effects of POWER and FTP intervention s, and 2) to test the effect of treatment order on stretch reflex modulation We hypothesize that POWER will reveal greater improvements in stretch reflex modulation due to increased corti cal drive and that the treatment order of FTP prece ded by POWER would reveal greater behavioral motor improvements because FTP would be more effective following restoration of neuromechanical function. 4.2. Methods 4.2.1. Participants The study population was comprised of sixteen participants (mean age 59.80 15.01 yrs 2 female ) who suffered a single stroke (time since onset 15.22 6.67 months ) Inclusion criteria for the parent study 61 involved: clinical presentation of a single, unilateral stroke; freedom from significant upper extr emity joint pain, range of motion limitations, or major sensory deficits as evidenced by absent proprioception at the elbow or shoulder joints. Additionally, participants were required to demonstrate: 1) ability to move the elbow and shoulder in the horizo ntal plane corresponding to a poor

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110 (2/5) manual muscle test grade 204 in the major shoulder and elbow agonists, 2) at least 10 o of active wrist extension, 10 o active thumb abduction, and 10 o active extension of any two digits, three times within one minute 230 and 3) ability to relax the biceps brachii (i.e., silent EMG) with the arm positioned in elbow flexion out of the plane of gravity. Participants were screened using the Neurobehavioral Cognitive Status Exam ( Cognistat) 231 to assess their capacity to comprehend and follow three step commands. All aspects o f the study described here were approved by the Stanford University panel on human participants in medical research and all participants provided informed consent in accordance with the Declaration of Helsinki. 4.2.2. Procedure After providing written inf ormed consent, all participants were enrolled in a two stage cross over design (Figure 4 1). Participants were randomized to either treatment Order A (FTP followed by POWER) or B (POWER followed by FTP). Each treatment block (either FTP or POWER) lasted te n weeks and included 3 (90 minutes) sessions per week. Thus, each participant received a total of 60 sessions (i.e. 180 hours) of one on one treatment delivered by a licensed physical therapy. The treatment blocks were separated by two weeks of inactivity. Participants underwent to four evaluations: 1) at b aseline, 2) after the first and 3) second treatment blocks and 4) at 6 months follow up (retention). Both, the participants and the assessors were blinded to the order randomization. 4.2.3. Intervention The treatment algorithms have been previously described in detail 61 All participants received either FTP or POWER i ntervention s in separate bouts to allow comparison of individual treatment effects. FTP involved practice of functional tasks

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111 using a progression of six therapeutic goal s and nine activity categories. Specific therapeutic tasks were chosen from these activity categories based on participant specific goals and baseline functional level and practiced on a structured rotation within the framework of the overriding therapeuti c goals. POWER involved five reciprocal upper extremity movements: shoulder abduction/adduction, shoulder flexion/extension, shoulder external/internal rotation, transverse plane elbow flexion/extension and wrist flexion/extension, which were trained using a commercially available dynamometer. Custom designed attachments to enable participants with impaired grasp to engage the dynamometer were used by all participants. POWER involved a standardized progression in which movement speed and the number of train ing sets (i.e., 10 repetitions each) were adjusted to maintain a constant period of active muscle work 202 within each session. 4.2.4. Evaluations Stretch Reflex testing was performed using ramp and hold elbow extensions applied using a comm ercially available dynamometer 18 operat ed in passive mode Surface electromyography ( EMG ) was recorded from the biceps brachii using pre amplified electrodes 19 Elbow extensions covered a 100 degree range ending at the of motion Each trial was comprised of four phases: a 10 second static hold in elbow flexion; passive elbow extension at criterion speed; a 5 second static hold in full extension; and a passive return to elbow flexion at 30 o /s. Two conditions were perform ed: passive, in which subjects were instructed to relax as the 18 Copyri ght 2012, Biodex Biomedical System 3.2, Shirley, NY, USA 19 Copyright 2012 Motion Lab Systems, Inc, Baton Rouge, LA, USA

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112 limb was moved through the full range of elbow motion by the dynamometer; and preloaded, in which the subjects sustained an isometric contraction of elbow flexor muscle at 20% of MVIC before an d during passive elbow extension stretches. Data were collected at four criterion speeds (i.e., 90 o /s, 150 o /s, 210 o /s and 270 o /s). To quantify passive joint torques, two additional trials were performed at 10 o /s. The reliability of both EMG and torque resp onses was already been established for ramp and hold stretch es obtained using this paradigm 228 4.2.5. Stretch Reflex Analysis The slow (10 deg /s) passive torque response at each position was subtracted from the torque measured during st retches imposed at all speeds. EMG activity was evaluated as the mean amplitude calculated over a 100 ms sliding window. For each trial, EMG was defined as active when the mean amplitude exceeded threshold (i.e., mean baseline, resting EMG plus 2.5 standard deviations). EMG d ata were used to obtain the following parameters indicative of stretch reflex modulation : EMG B URST D URATION The percentage of the movement t ime during which EMG activity will be present. P OSITION T HRESHOLD The joint angle, expressed in degrees of elbow flexion, at which muscle acti vity will be first identified. B URST I NTENSITY The mean amplitude of EMG activity when the muscle will be acti ve minus the baseline resting activity. 4.2.6. Statistical Analysis For each parameter (i.e. EMG burst duration, position threshold and burst intensity) comparisons were performed to evaluate treatment specific changes between FTP and POWER the treatmen t order (A=FTP>POWER vs. B=POWER>FTP) (Figure 4 1) and the retention effect We calculated the difference scores between :

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113 B ASELINE AND B LOCK 1 EVALUATIONS To test the first block treatment effect, either POWER or FTP, depending on treatm ent order (Order A vs. Order B). B LOCK 1 AND B LOCK 2 EVALUATIONS To test the second block treatment effect. B LOCK 2 AND B LOCK 3 EVALUATIONS To test the retention effect, at 6 month follow up B LOCK 3 AND BASELINE EVALUAT IONS To test the order effect. Statistical analys is was performed with JMP 9 software 20 Kolmogorov Smirnov test revealed normally distributed data (p >.05). We performed analysis of variance including the following factors: orders (i.e. Order A or Order B), condition (i.e., Passive or Preloaded), block ( i.e., 1, 2, or 3), treatment (i.e., FTP, POWER and Retention) and speed (i.e., 90 o /s, 150 o /s, 210 o /s and 270 o /s). We evaluated the interactions between the factors for each stretch reflex parameter (i.e. EMG burst duration, position threshold and burst in tensity). Unless otherwise noted, statistical significance was set at p <.05 P values were corrected for multiple comparisons using a Bonferroni correction 4.3. R esults We did not find differences among reflex responses across criterion velocities (p>0. 05) for all three stretch reflex parameters. Therefore, data from all four criterion velocities were co llapsed Further, we did not find differences between passive and preloaded conditions (p>0.05). 4.3.1. Treatment E ffect POWER produced significantly gr eater improvement in stretch reflexes modulation in all three parameters (all p values < 0.01) (Figure 4 3 Top row). POWER produced a 350 ms (SD 30 ) decrease in burst duration, 21.73 ( SD 3.89 ) decrease in position 20 Copyright 2011, JMP 9.0.2 2010 SAS Institute Inc.

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11 4 threshold (i.e. EMG onset occurred at greater elbow extension by 21.73 ) and 89.62 ms (SD 21.08 ) increase in EMG onset latency. In contrast FTP produced only 10 ms (SD 20 ) decrease in burst duration, 4.30 ( SD 2.97 ) dec rease in position threshold and 1.49 ms (SD 15.87 ) increase in EMG latency. 4.3.2. Retention E ffect In general, at retention, improvements in stretch reflex modulation were partially maintained: 10 ms (SD30) increase in burst duration, 11.17 (SD4.26) d ecrease in position threshold and 25.11 ms ( SD 18.43) increase in EMG onset latency ((Figure 4 3 Top row). 4.3.3. Period E ffect ( Treatment Block by G roup) Independently of its position in the treatment order, POWER produced significantly greater improvem ents in stretch reflex modulation in all three parameters (all p values < 0.01) (Figure 4 3 Middle row). After POWER, burst duration decreased of 450 ms ( SD 40) in the first block treatment and 240 ms (SD 50 ) in the second block treatment I nstead after FTP, burst duration decreased by 80 ms (SD 20 ) in the first block treatment and increased (i.e. worsening) by 60 ms (SD 40 ) in the second block treatment. After POWER, position threshold decreased 33.02 ( SD 4.88 ) in the first treatment block and 10.24 ( SD 5.73 ) in the second treatment block. After POWER, EMG onset latency increased by 152 .78 ms ( SD 34.31 ) in the first treatment block and of 26.47 ms (SD 21.71 ) in the second treatment block After FTP, EMG onset latency increased by 18.30 ms (SD 22.72 ) in the first treatment block, but decreased (i.e. worsening) in the second treatment block.

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115 4.3.4. Order E ffect When POWER was followed by FTP (Group B), overall outcomes were significantly greater for burst duration and latency (p values < 0.05) (Figure 4 3 bottom row) Overall, burst duration decreased by 410 ms (SD 50 ) in Group B but only 290 ms (SD 50 ) in Group A; position threshold decreased by 30.10 ( SD 8.30 ) in Group B and only 20.31 ( SD 5.56 ) in Group A; EMG onset latency increased by 136.36 ms (S D 34.03 ) in Group B and only 41.46 ms (SD 24.13 ) in Group A 4.4. Discussion Primary effects. W e compare d the effects of POWER and FTP training on stretch reflex modul ation. The primary aims of this study were to test: 1) the differential effects of POWE R and FTP intervention s, and 2) the effect of treatment order on stretch reflex modulation We hypothesized that POWER would reveal greater improvements in stretch reflex modulation due to enhanced afferent regulation and that the treatment order FTP proce eded by POWER would reveal greater behavioral motor improvements because FTP would be more effective following restoration of neuromechanical function. As hypothesized, POWER produced greater improvements of stretch reflex modulation than FTP for all par ameters : EMG burst duration, position threshold and burst intensity. These findings indicate that POWER constitutes a potent form of neuromotor training. Beside s adaptation in the muscle itself, profound neural adaptations after resistance training are wel l recognized 51 53 The primary mechanisms for force production and force control reside supraspinally and in the spinal circuitry. Findings of this study suggest that POWER induces restoration of mechanisms

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116 control ling spinal motoneuron e discharge 17 68 187 189 These mechanisms are likely mediated by improved descending (supraspinal) control of pre synaptic Ia inhibition 187 and enhanced post activation (spinal) depress ion 187 189 We a ddressed our secondary aim, understanding the effect of treatment order, using a crossover design. As hypothesized, our data reveal that POWER followed by FTP produced greater improvements, most significantly for EMG burst duration and EMG latency. Changes in position threshold failed to reach statistical significance difference between treatment Order A and B. Influence of voluntary activation and speed The study design included passive and preloaded conditions with the attempt to discriminate between s upraspinal and spinal adaptations. The preloaded condition was implemented to stimulate the voluntary supraspinal descending control by mean s of an isometric contraction of elbow flexor muscle before and during passive elbow extension stretches 232 In an intact nervous system, one of the major inhibitory circuitry regulating the excitability of the spinal motoneurons i s the Ia inhibitory interneuron pool 232 These interneurons receive input from Ia afferent and supraspinal center and are responsible for reciprocal inhibition of antagonist muscle 232 Therefore, as a consequence of antagonist contraction, we were expecting a reduction of the stretch reflex responses by increase of d i synaptic reciprocal inhibition and pre synaptic inhibition of I a afferents. In contrast to our hypothesis, our data suggest that the post intervention adaptation effects did not differ between the two conditions in any of the stretch reflex parameters. Th is lack of differential effects between passive and preloaded co nditions may suggest that both the passive and pre loaded conditions are testing the same neurophysiologic function or

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117 that participants of this study had an inappropriate depression of the inhibitory mechanisms controlling the stretch reflex 232 Further, this study evaluated stretch reflex modulation at different velocities ( i.e., 90 o /s, 150 o /s, 210 o /s and 270 o /s). Our findings suggest that treatment effects did not differ between velocities Previous work also found that stretch reflex responses are weakly dependent on stretch reflex velocity. Wolf et al 233 demonstrated that position threshold is not affected by speed (1.0 radian/s) in post stroke individuals and suggested that the speed used in their study may not have been fast enough to induce a speed effect. Further, Powers et al 227, 234 demonstrated that the stretch evoked torque was not dependent on stretch reflex velocity. The authors suggested that the individual stretch reflex threshold m ay influence the relationship between the stretch reflex responses and the stretch speed. Thus, failure to detect a statistically significant effect does not necessary indicate a lack of speed effect. Further research should address the relationship betwee n individual stretch reflex threshold and a wider range of speeds. Neuromechanisms. Many spinal pathways control the excitability of the stretch reflex and a malfunction in any of them could theoretically produce an exaggeration of the stretch reflex incl uding Ib inhibition, recurrent inhibition, disynaptic reciprocal Ia inhibition and presynaptic mechanisms However, the main two mechanisms that have been postulated to influence the stretch reflex modulation post stroke are: 1) impaired (decreased) presyn aptic Ia inhibition 184 129, 187, 232 and 2) decreased post activation depression (homosynaptic depression) 184 129, 187, 232 The argument that presynaptic Ia i nhibition may be decreased spastic individuals, emerges from observation of decreased H reflex depression induced by tonic vibration applied to the antagonist

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118 tendon 184 129, 187, 232 The fact that the depression is associated to a motor discharge (the tonic vibration response) authors suggested that it must have a presynaptic influence. However, when to nic vibration was applied to the homonymous tendon, it also induced H reflex depression due to post activation depression evoked by repetitive synaptic activation Post activation depression also contributes to the vibratory induced depression of the refle x and it can be attributed to the repetitive activation of the Ia motoneurone synapses 235 It is well recognized that resistance training induces change within the nervous system 52 However, the argument for whether these changes affect both the spinal and the supraspinal circuitries is still open. Enoka 53 described phenomena that show evidence of neural adaptation after strengthening in non disabled adaptations, strength changes in t he limb contralateral to the trained muscle, and specificity of strength adaptations to the training movements (citation) Carroll et al. 51 suggested that resistance training is associated with an increase in short term motor unit synchrony, which is argued to result from change s in synaptic efficacy within the motoneuron pool. Th e s e observations impl y that after resistance training the number or the strength of the connections to the motoneurons of trained muscles may increase which suggests that resistance training may improv e the synaptic efficacy between the cortico spinal cells and spinal motoneurons. However recently Falvo et al. 58 demonstrated that three weeks of resistance training elicited significant strength gains which were accompanied by neural adaptation at the level of the cortex. The authors were able to demonstrate supraspinal adaptations using movement r elat ed cortical potentials (MRCP). Following training, the authors found MRCP amplitude was

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119 attenuated at several scalp sites overlying motor related cortical areas and the onset of MRCP was anticipated Furthermore, Kokotilo et al. 50 conducted a systematic review of neuroimaging studies that examined reorganization of brain function during force p roduction and force modulation after stroke. Their review includes a number of imaging modalities, including functional magnetic resonance (fMRI), TMS, electroencephalography (EEG) and magnetoencephalography (MEG). They conclude that motor reorganization o ccurs with respect to force generation and modulation after stroke. Key findings across studies were that during force production, increased activation in motor areas including the undamaged contralesional hemisphere, occurred in people with more severe s troke, and recruitment of these motor areas often diminished as motor function recover ed With respect to force modulation, increased activation in motor areas occurred with greater force generation in people with stroke, and those with more severe stroke showed greater activation with increasing force production levels. One of the purposes of this study was to evaluate the potential effect of POWER training on the descending cortical drive. The preloaded condition was implemented to evaluate the presynapt ic descending cortical influence and the passive condition was implemented to evaluate the putative monosynaptic spinal reflexes. In contrast to our hypothesis, our data did not allow us to discriminate between spinal and supraspinal (presynaptic) influen ces by using the preloaded condition. Future studies with more sophisticated techniques such as transcranial magnetic stimulation (TMS) and H reflex should further investigate the origin of neuroadapations after resistance training These techniques will a llow to study the supraspinal involvement and to explore the relative

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120 contributions of presynaptic Ia inhibition and postactivation depression to the malfunction of the arc reflex post stroke Our hypothesis is that POWER induces neuroadaptations at spina l (including pres synaptic and monosynaptic inhibitory pathways) and supraspinal levels. Specifically, it increases the central neural drive leading to enhanced recruitment of the spinal circuitry and consequent improved control of the force required for e xecution of complex multi segmental tasks. Relevance. We directly compared two intervention approaches with the aim of demonstrating differential mechanisms of neuromotor recovery. Our findings demonstrate that POWER promotes greater improvements of stret ch reflex modulation and better retention of these improvements at follow up six months following intervention Further, POWER followed by FTP induced greater improvement in stretch reflex parameters than vice versa, which may result from increased neural drive from the impaired hemisphere. Importantly, our results confirm the lack of deleterious effects of high intensity activities in persons with neurological disorders 14, 15 Taken together, our results offer nove l insight for identifying effective UE rehabilitation interventions that promote restoration of normal motor function including stretch reflex modulation post stroke. Further experimental studies are necessary to 1) better identify the physiological mech anisms that underlie improved reflex modulation, such as the contribution of pre synaptic and monosynaptic inhibitory pathways after POWER training and 2) explore the effect of POWER training on the impaired cortical descending inhibitory control.

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121 Fig ure 4 1. Study design. Summarizing the cross over design. Participants were evaluated 4 times times: at baseline, after each treatment block and at 6 months follow up The treatment order for Group A was FTP followed by POWER and for Group B POWER followe d by FTP.

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122 Figure 4 2 Passive stretch reflex. Top row shows treatment effects. Middle row shows group by block effect. Bottom Raw shows Order effect. Black columns indicate FTP treatment, gray columns indicate POWER treatment and light gray columns in dicate retention. Black columns with gray borders indicate FTP preceded POWER (Order A). Gray columns with black borders indicate POWER preceded FTP (Order B).

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123 CHAPTER 5 UPPER EXTREMITY REHABILITA TION REDUCES INTER HEMISPHERIC COMPETITION POST STROKE 5 .1. Background L imited recovery of upper extremity function continues to be one of the greatest challenges faced in neurorehabil itation for persons post stroke As a result, there is an urgent unmet need to identify effective approaches to drive upper ext remity (UE) recovery. Contemporary approaches to motor rehabilitation are based on evidence that practice and experience drives cortical reorganization following neural injury 100, 236 Current UE treatment approach es focus on repetitive execution of functional movements, ostensibly to facilitate neural plasticity 237 However, while these therapeutic methods show promise in improving UE function post stroke, most of the work to date documents improvements through clinical or gross behavioral measure s, which emphasize task accomplishment more than motor control or neuroplastic changes 36 Thus, there remains a significant kn owledge gap between means required to induc e positive neuro biological and behavioral change that constitutes functional recovery in humans post stroke This discrepancy suggests that repetitive execution of functional movements alone may not be sufficient to drive the necessary cortical reorganization and effect functional improvement following stroke. Therefore, there is a clear need to augment or potentiate the behavioral effects derived from experience driven therapies for this clinical population. Corti M, N aik, S McGuirk T E Triggs W J Patten C. Upper extremity rehabilit ation reduces inter hemispheric competition post stroke. Brain Research i n preparation.

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124 Trad itionally, UE behavioral treatment approaches have focused on repetition of functional movements (i.e. task practice), which is argued to facilitate neural plasticity 237 Despite the presence of profound weakness, strengthening has been proscribed in neurorehabilitation because it is assu med to exacerbate spasticity and impair motor performance 13 M ainstream therapeutic interventions, such as constraint induced movement therapy (CIMT) 237 and functional task practice (FTP) 237 show promise at promoting improved UE function, however the metrics of improvement are gauged by clinical scales or gross behavioral measures that emphasize task accomplishment over reacquisit ion of appropriate motor strategies or neuroplastic changes 36 Importantly, assessing task completion fails to distinguish com pensatory (i.e. maladaptive) strategies from restoration (i.e. strategies used by non disable d individuals ) at either the behavioral or neural levels 78 Our research team has com pleted a set of studies demonstrating that high intensity resistance training (i.e. POWER training), performed either in isolation or in combination with FTP (i.e. HYBRID training) 61 can induce restoration of more normal movement by improving neuromechanical function. These positive outcomes can most likely be attributed to profound, well recognized neural adaptations that occur at the level of the spinal cord and motor cortex 53 While our studies to date demonstrate that POWER is an effective treatment at the behavioral level, we have not had the opportunity to m easure neuroplastic changes that may occur in the brain, or elsewhere in the neuraxis, concurrently with behavioral and neuromechanical recovery.

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125 Following stroke, activity in the affected hemisphere (AH) is disrupted; not only by the infarct itself, but a lso by inhibition from the unaffected hemisphere (UH) which further reduces the excitability of the AH. As first described by Ward and Cohen 63 and 64 hypothesis of inter hemispheric competition post stroke, the primary motor cortex of the UH becomes disinhibited and e xerts exaggerated inhibition onto the primary motor cortex of the AH Among several innovative, non invasive techniques for improving motor recovery post stroke, repetitive transcranial magnetic stimulation (rTMS) shows considerable promise 73 rTMS involves focused magnetic stimulation applied to the skull to target a particular brain area 75 In healthy adu lts, rTMS at frequencies less than 1Hz can suppress excitability of the motor cortex, causing an inhibitory effect, while at higher frequencies (e.g., >1Hz) rTMS can increase cortical excitability, causing facilitation 72 The capacity for rTMS to influence cortical excitability contributes to the rationale for its use as a therapeutic adjuvant that may improve the efficacy of rehabilitation strategies for persons post stroke 64, 76 Modulation of cortical excitability with rTMS may induce synaptic plasticity and potentially limit d evelopment of maladaptive neural strategies 63, 64 Asymmetric cortical excitability resulting from stroke may enable maladaptive neuromotor strategies, disrupting physiological activity in transcallosal pathways an d producing an imbalance in the reciprocal inhibitory projections between hemispheres 63, 64 In this context, rTMS has been also been proposed as a theoretical approach to restore the balance of inter hemispheric i nhibition post stroke (e.g., reduce inter hemispheric competition) 63, 64 63, 64, 73

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126 The current literature reveals positive effects of rTMS post stroke including: modulat ion of cortical excitability (e.g., MEP amplitude, recruitment curves, motor threshold) suggesting improved inter hemispheric balance. However, it is important to note that no studies to date have directly investigated the effects of rTMS on IHI. Thus, sup port for the theoretical explanation that rTMS rebalances inter hemispheric inhibition remains to be demonstrated. The current working hypothesis holds that inhibitory rTMS over the unaffected hemisphere (UH) reduces transcallosal inhibition from the unaff ected to the affected/ipsilesional hemisphere and facilitatory rTMS over the affected hemisphere (AH) increases excitability of the AH and increases transcallosal inhibition from the affected to the unaffected/contralesional hemisphere. Consistent with eff ects noted in he althy individuals, constant high frequency rTMS (trains of stimuli separated by inter trains intervals) has been used in two ways in persons post stroke: low excitability of the contralesional h emisphere, or high frequency (e.g., >1 Hz) stimulation of the AH to increase excitability of the ipsilesional hemisphere 70 Some investigators favor low frequency rTMS to the UH over high frequency rTMS to the AH b ecause of its wider toleration and fewer potential risks of inducing seizures 61 although review of the current literature does not support t hese concerns (A ppendix A). This study addressed the gap between inducing neurobiological and behavioral change that constitutes functional rec overy by examining combined behavioral and neurobiological approaches that represent potential drivers of cortical reorganization.

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127 We combined behavioral therapies that improve strength (POWER) and motor skill (FTP) with therapeutic inhibitory repetitive transcranial magnetic stimulation (rTMS). Specifically, the aims of this study were to: 1) test the hypothesis of inter hemispheric competition post stroke; 2) test whether it was possible to restore a balance of inter hemispheric competition; and 3) test whether rTMS combined with POWER training resulted in better functional, biomechanical and neurophysiological outcomes than rTMS combined with FTP. 64 assumption, we hypothesized that : 1) the p rimary motor cortex of the UH would be disinhibited and would exert exaggerated inhibition onto the primary motor cortex of the AH ; 2) inter hemispheric competition could be reduced ; and 3) based on our previous studies, the combination of inhibitory rTMS on the UH with POWER training of the affected arm would reveal reduced hemispheric competition and improved motor behavior. 5.2. Methods 5.2.1. Subject Characteristics Here we report two single case designs. Case 1. The patient was a 59 year old, left han d dominant, white male who was enrolled in the present study 6 months following a lacunar infarction of the right putamen and periventricular white matter with consequent left hemiparesis affecting both the upper and lower extremit ies Baseline clinical sc ores revealed low level of spasticity measured by Modified Ashworth Scale (MAS) 25 (composite score, 3 out of 32) a medium level of motor impairment measure by Fugl Meyer Upper Extremity

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128 Motor Score (UEFMMS) 93 (47 out of 66) and no sensor y impairment by the sensory portion of the UEFMMS 94 (12 out of 12). Case 2. The patient was a 70 year old right hand dominant, white female who was enrolled 11 months following a hemorrhage in the right putamen w ith consequent left hemiparesis affecting both the upper and lower extremities. Baseline clinical scores revealed low level of spasticity measured by MAS 25 (composite score, 1 out of 32) a medium level of motor impairment measure by UEFMMS 93 (48 out of 66) and a severe sensory impairment by the sensory portion of the UEFMMS 94 (6 out of 12). 5.2.2. Study Design The study consisted of a multiple baseline, A B case series design. Following repeated b aseline assessments (timing), p articipants performed 6 weeks of affected arm POWER training followed by 6 weeks of bilateral FTP. Each treatment session was preceded by 20 minutes of inhibitory rTMS t o the contr a lesional (unaffected) hemipshere. Assessment s were conducted at baseline after each treatment and following six months without additional intervention Th e study design is described in F igure 5 1. 5.2.3. Measures Our multimodal assessment approach provided insight into this dynamic relationship be tween neurobiology and motor behavior, and paid particular attention to the selection of measures that distinguish between compensation and recovery. The multimodal assessment included : clinical tests, three dimensional motion analysis, measure s of force p roduction and transcranial magnetic stimulation (TMS). Both

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129 participants underwent the same multimodal evaluation. Data from four healthy control volunteers (mean age 63.75 7.85 years, 1 female, all right hand dominant) were obtained to provide reference d ata for all measures. Wolf Motor Function Test (WMFT). Our primary clinical test was the WMFT, which is one of the most used clinical tests to evaluate UE motor function post stroke (citation) Clinometric properties of the WMFT have been established, shown to 180 In addition to the WMFT, we used a battery of clinical outcomes to represent a comprehensive assessment across all levels of the ICF 205 Specifically, this clinical battery included: the Modi fied Ashworth Scale (MAS) 25 Fugl Meyer Upper Extremity Motor Score (UEFMMS) 93 and the sensory portion of the UEFMMS 94 the Beck Depression Inventory 238 and the Late L ife F unction and D isability I nstrument 239 Three dimensional motion analysis. K inematics of the paretic UE w ere measured while participants were seated in a straight back chair with the paretic UE resting on the ipsilateral thigh (Start position). The shoulder was positioned in neutral flexion/extension and neutral internal rotation; the elbow in 75 90 degrees of flexion with the wrist resting in pronation. Participants were instructed to reach, grasp and ret rieve a 180 ). This functional reach to grasp task was selected as the study outcome task because of its status as a fundamental motor skill necessary for many daily activities. Participants comp leted 1 2 practice trials followed by three test trials. Three dimensional motion

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130 analysis data were collected using 53 reflective markers placed on the: anterior and posterior spines, base of sacrum, manubrium and body of sternum, 7 th cervical vertebra, 1 0 th thoracic vertebrae, and bilaterally on the acromion processes medial and lateral epicond y les ulnar and radial styloid processes, superior thirds of the upper arm and forearm (triads markers), hand and finger tips (set of 11 small size markers). Mark er d ata were recorded with a twelve camera motion analysis system (Vicon 612, Oxford Metrics Inc., Oxford, U.K.) at a sampling frequency of 200 Hz. The motion analysis system expressed output data as three dimensional, time dependent marker coordinates in relation to a laboratory coordinate system. Transcranial Magnetic Stimulation (TMS). We investigated inter hemispheric competition by studying the combination of hemispheric cortical excitability and inter hemispheric inhibition (IHI). Recruitment curves (RC) slopes were used to study cortical excitability 244 Ipsilateral silent period (iSP) was used to study IHI 253 RC was generated by stimul ation over the motor threshold hotspot at progressively increasing intensities recording 10 stimuli in 5% increment s beginning at an intensity of 10% below motor threshold. Data collection for the RC was terminated when a plateau of the sigmoidal curve wa s observed 240 The input output curve was measured for both ipsilesional and contralesional hemispheres. The ability to reconstruct RCs depended on the ability to evoke MEPs iSP was obtained using single pulse TMS delivered at 150% of motor threshold while the participant produced a sustained, submaximal contraction (50% maximal effort) of the FDI muscle ipsilateral to the stimulation 253 186 Twenty responses of iSP were obtained for each hemispheres.

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131 Measure of force production. We investigated force/torque production by using a commercially available dynamometer 21 during isometric and dynamic (i.e. isotonic and isokinetic) muscle co ntractions of elbow flexion extension in the hemiparetic side. Three trials were collected and then averaged. 5.2.4. Intervention One on one treatment session was delivered 3 days weekly. Both participants participated in 6 weeks (18 sessions) of power tra ining (POWER) and 6 weeks (18 sessions) of functional task practice (FTP). POWER was performed unilaterally with the paretic/affected arm, while functional task practice included activities typically performed bilaterally, but was emphasize practice and re petition with the paretic arm. Both POWER and FTP are described elsewhere 61 All treatments were preceded by inhibitory rTMS delivered to the contralesional hemisphere. 5.2.4.1. Power training We delivered dynamic, high intensity resistance exercise for the shoulder, elbow and wrist using an isokinetic dynamometer. The treatment protocol involved 7 exercises (shoulder flexion, shoulder abduction, shoulder external rotation, elbow flexion/extension, wrist flexion/extension), 3 sets of 10 repetitions of each exercise. The speed of move ment was progressively adjusted upward over the six weeks of training. Details of POWER intensity and progression are shown in Figure 5 2. 21 Copyright 2012, Biodex Biomedical System 3.2, Shirley, NY, USA

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132 5.2.4.2. Functional Task Practice (FTP) FTP involved practice of functional tasks using a progression of six therapeu tic goals and nine activity categories. Specific therapeutic tasks were chosen from these activity categories based on participant specific goals and baseline functional level and practiced on a structured rotation within the framework of the overriding th erapeutic goals ( Table 5 4 ). 5.2.4.3. Repetitive TMS (rTMS) Inhibitory rTMS was administered over the contralesional M1 corresponding to the hot spot for the ipsilesional/non paretic muscle representation. In addition, participants wore a tight fitting lycra swim cap. Skin mounted surface electromyogram preamplifier was placed over FDI muscle contralateral to the stimulated hemisphere. Subjects were seated in the dynamometer chair adjusted such that hips, knees and ankles were maintained at 90 degrees an d were asked to relax. MEP threshold was measured before and after each rTMS session using a figure 8 coil centered at the scalp vertex and connected to a Magstim 200 2 high power magnetic stimulator (Magstim Ltd, UK). Stimulation was delivered at an inte nsity of 100% motor threshold, 1 Hz frequency, biphasic waveform and 1200 stimulations in a single, continuous train lasting 20:00 172 5.3. Analysis 5.3.1. Clinical Tests For the 15 total items of the WMFT, we ca lculated the number of items that improved or worse ned Improvement was defined as at least 10% reduction in task

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133 execution time and worse ning was define d as at least 10% increase in task execution time. In addition, we calculated the change in the sum of task execution time for all tasks (Total Time) between baseline and the first block of intervention (or post POWER, i.e. rTMS+POWER), between the first and the second block of intervention (or post FTP, i.e. rTMS + FTP) and between the second block interve ntion and follow up (or Retention). For all other clinical tests, we reported the raw score at each evaluation (i.e. Baseline, post POWER, post FTP and Retention). 5.3.2. Three Dimensional Motion Analysis Marker data were labeled using Vicon Nexus 22 and mo deled using Visual3D 23 Kinematic trajectories, extracted from Visual3D, were analyzed using custom written MATLAB scripts 24 Kinematic data were low pass filtered (12 Hz cutoff) using a bi directional 4 th order Butterworth filter. The start of movement (S OM) was defined as the first point at which the velocity of the marker on the third metacarp o phalangeal joint exceeded 5% peak velocity and the end of movement (EOM) as the last point at which velocity of this marker fell below 5% peak 43, 181 Our primary kinematic outcomes were shoulder and elbow range of motion and trunk displacement to quantify movement execution. Total movement time and reach path ratio (RPR) were used as secondary outcomes to quantify speed an d movement accuracy. 22 Copyright Vicon 612, Oxford Metrics, Oxford, UK 23 Copyright 2010 C Motion, Version 4.00.19, Inc C Motion, Germantown, Maryland 24 MathWorks Inc., V ersion R2011b Massachusetts USA

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134 Range of motion (ROM) was calculated for shoulder flexion and elbow extension as the difference, in degrees, between the maximum and minimum joint angle achieved. Trunk displacement was defined as the displacement of the sternum marke r, in centimeters, in the sagittal plane. Movement time was defined as the time between SOM and EOM. Reach path ratio was defined as the ratio of the actual path and the direct path lengths of the hand marker. The actual path is defined as the three dimens ional displacement of the hand marker path during the reach task, and the direct path is defined as the three dimensional distance between the hand marker at onset and the hand marker at offset. 5.3.3. Transcranial Magnetic Stimulation (TMS) 5.3.3.1. Recru itment curve (RC) For each stimulus intensity t he average of 10 stimuli was evaluated Peak amplitude and area of the averaged MEP signal were calculated We considered th e presence of MEP if the peak to The MEP onset was defined as last crossing of the mean baseline EMG level before the MEP peak and the MEP offset as the first crossing of the mean baseline EMG level after the MEP peak. The area of the mean M EP was normalized to the maximal MEP area The data were fit using a non linear regression to the Boltzmann Equation followed by a linear regression fit to the modeled data in the steepest portion of the range. We report motor threshold (MT) as the stimulation level at which the slope of the fitted line intersects the abscissa

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135 5.3.3.2. Ipsilateral silent period (iSP) The EMG signal s w ere rectified and averag ed over 20 stimuli. The mean and the standard (SD) deviation of the EMG level for 100 ms prior to TMS stimulus were determined from the averaged signal. We considered the presence of an ipsilateral MEP (iMEP) if the post stimulus EMG exceeded the pre stimulus mean baseline EMG 186 iMEP onset was defined as the last crossing of the pre stimulus mean baseline EMG before the MEP peak and the iMEP offset as the first crossing of the pre stimulus mean baseline EMG after the iMEP peak. iMEP area was calculated betw een the iMEP onset and offset (iMEP dura tion). Similarly, we considered the presence of an iSP if the post stimulus EMG fell below the pre stimulus mean baseline stimulus mean baseline EMG after the MEP peak and t he iMEP offset as the first crossing of the pre stimulus mean baseline EMG after the iSP onset for at least 5 ms 186 The iSP duration was defined as the time between the onset and the offset values. We also calcula ted the laterality index (LI) for the iSP duration as (A B)/(B+A), where A corresponds to the dominant hemisphere (DH) for the healthy controls and to the unaffected hemisphere (UH) for the stroke participants, and B corresponds to the nondominant hemisphe re (NDH) for the healthy control and to the affected hemisphere (AH) for the stroke participants. 5.3.4. Force Production. For each contraction, peak torque (for isometric contractions) and peak power (for isotonic and isokinetic contractions) were calcul ated The average of three trials was

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136 reported for both elbow flexion and extension movements. During isometric contraction peak torques were calculated at 55 (for movements in flexion) and 75 (for movements in extension) starting from the fully extended position of the elbow (i.e. 0). During isotonic and isokinetic contractions peak powers were calculated during the range 0 120. 5.4. Results 5.4.1. Clinical Test s Case 1. The WMFT, after the first intervention block (post POWER), revealed a specific nu mber of improved and a specific number of worsened timed items in both, the affected (AA) and the unaffected (UA) arm s. C ompared to the second intervention block (post FTP) a greater number of improved items and fewer worsened items were detected followi ng POWER At follow up, there was a further increase of improved items and a further decrease of worsened timed items in both AA and UH (Table 5 1). Change revealed an improvement (decrease) in the sum of task execution time in the AA after the first inter vention block (post POWER) and a worsening (increase) in the sum of task execution time in the second intervention block (post FTP). However a similar improvement was revealed after both interventions and follow up in the UA (Figure 5 3). Case 2. The seco nd intervention block (post FTP) revealed a specific number of improved and a specific number of worsened timed items in both, the AA and the UA arms compared to the first intervention block (post POWER). At follow up, there were a

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137 lower number of improved items and a greater number of worsened timed items compared to the previous evaluation (Table 5 1). Change scores revealed an improvement (decrease) in task execution time in both the AA and UA after the second intervention block (post FTP) but an increas e d task execution time in both the AA and AU after the first block intervention (post POWER). At follow up there was a further improvement in the AA, while the UA did not show any change (Figure 5 3). R aw scores of Fugl Meyer Upper extremity scale score (U EFMMS) and its sensory portion, Beck Depression Inventory (BDI), Modified Ashworth Scale (MAS) and late life function and disability instrument f or both participants, are reported in Table 5 2 and 5 3. 5.4.2. Kinematics Case 1. Shoulder flexion and elbow extension range of motion increased post POWER (change score: 3.25 for shoulder and 6.09 for elbow), but decreased post FTP (change score: 4.36 (shoulder) and 3.31 (elbow). At follow up, both shoulder flexion and elbow extension increased (change sco res: 6.20 for shoulder and .90 for elbow). Trunk displacement decreased post POWER (change score: 3.65 cm) and continued to decrease post FTP (change score: 7.41 cm) and at follow up (change score: 6.50 cm (Figure 5 4). Case 2. POWER revealed unchang ed shoulder excursion and reduced elbow excursion (change score: 0.62 at the shoulder and 7.63 at the elbow), associated with a small reduction of trunk displacement (change score: 1.93 cm). Instead, FTP

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138 increased shoulder and elbow excursion (change score: 6.45 (shoulder) and 13.83 (elbow). At follow up, the shoulder ROM did not change (change score: 0.92) and the elbow ROM decreased (change score: 10). Further, trunk displacement reduced somewhat following both treatments, POWER (change score: 2.0 cm) and FTP (change score: 16.0 cm). However, trunk displacement was worse at follow up (change score: 20.21 cm) (Figure 5 4 ). T he secondary outcomes total movement time and index of curvature f or both participants, are described in Figure 5 5 5.4 .3. Transcranial Magnetic Stimulation (TMS) 5.4.3.1. Recruitment curve (RC) In healthy controls, the average of the recruitment curve slopes was 0.05 ( 0.006) for the dominant hemisphere and 0.03 ( 0.01) for the nondominant hemisphere. Case 1. At baseli ne (Figure 5 8), the recruitment curve slope was 0.01 for the UH In the AH, we stimulated up to 100% of stimulator output without elicit ing MEPs, therefore a recruitment curve could not be construct ed Post POWER, the recruitment curve slope shifted towar ds normal values, 0.05 for the UH. I n the AH there was an emergence of MEPs from which it was possible to construct a recruitment curve, which had slope of 0.05. Post FTP, the recruitment curve slope was 0.06 for the UH and was not possible to construct a recruitment curve for the AH since the MEPs were complex and below threshold (Figure 5 9). At follow up, it was possible to construct recruitment curves for both hemispheres with slopes of 0.05 for the unaffected hemisphere and 0.03 for the affected hemisp here.

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139 Case 2. At baseline (Figure 5 8), the recruitment curves for the two hemispheres were symmetrical and both slopes were 0.03. Post POWER, the slopes remained similar with a value of 0.04. Post FTP, the recruitment curve slope for the unaffected hemisp here remained at 0.04 However, the slope of the affected hemisphere dropped to 0.01. At follow up, both slopes increased reaching a value of 0.09 for the unaffected hemisphere and 0.04 for the affected hemisphere. 5.4.3.2. Ipsilateral silent period (iSP) In healthy controls, the average duration of ipsilateral silent period (iSP) from the dominant hemisphere (DH) to the nondominant hemisphere ( ND H) (iSP while stimulating the dominant hemisphere) was 37.92 ( 5.77) ms and the average duration of the ipsila teral silent period (iSP) from the NDH to the DH (iSP while stimulating the nondominant hemisphere) was 24.91 ( 0.9) ms (Figure 5 10). The laterality index for the iSP duration ((DH NDH)/(DH+NDH)) was 0.20 ( 0.72), indicating a slight predominance of inter hemispheric inhibition from the dominant hemisphere (Figure 5 11). Case 1. At baseline, the iSP duration from the AH to the UH (iSP while stimulating the affected hemisphere) was shorter (23.20 ms) than the healthy control s ; instead, the iSP duration from the UH to the AH (iSP while stimulating the unaffected hemisphere) was longer (91.13 ms) than healthy control s Post POWER, the duration of IHI from the AH to the UH increased (59.44ms) and from the UH to the AH decreased (71.66 ms). Post FTP, the duration of IHI from the UH to the AH continued to decrease (65 ms). We were unable to generate sufficient responses, therefore, d ata relative to

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140 interhemispheric inhibition from the affected hemisphere to the unaffected hemisphere were unavailable. At follow up, the duration of IHI from the AH to the UH continued to increase (65 ms) and the duration of the interhemispheric inhibition from the unaffected hemisphere to the affected hemisphere continued to decrease (48.85 ms) (Figure 5 10). The laterality index for t he iSP duration ((AH UH)/(AH+UH)) was 0.59 at baseline, 0.09 post POWER 1 post FTP and 0.14 at Follow up (Figure 5 11). Case 2. At baseline, the duration of IHI from the affected hemisphere to the unaffected hemisphere (iSP while stimulating the affected hemisphere) was longer (138.43 ms) than the healthy control s ; instead, the duration of the interhemispheric inhibition from the unaffected hemisphere to the affected hemisphere (iSP while stimulating the unaffected hemisphere) was shorter (60 ms) than the opposite hemisphere but longer than healthy control s Post POWER, the duration of the interhemispheric inhibition from the affected hemisphere to the unaffected hemisphere reduced (87.94 ms) and the duration of the interhemispheric inhibition from the unaf fected hemisphere to the affected hemisphere increased (93.64 ms). Post FTP, the duration of iSP from the affected hemisphere to the unaffected hemisphere continued to decrease (79.80 ms); the duration of the iSP from the affected hemisphere to the unaffec ted hemisphere remained stable (93.64 ms). At follow up, the duration of the iSP from the affected hemisphere to the unaffected hemisphere continued to increase (59.60 ms); the duration of the iSP from the unaffected hemisphere to the affected hemisphere c ontinued to increase (111.40 ms) (Figure 5 10). The laterality index for the iSP duration ((AH UH)/(AH+UH)) was 0.39 at baseline indicating a predominance of

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141 interhemispheric inhibition from the AH to the UH however it normalized in response t o interve ntion: 0.03 post POWER 0. 07 post FTP and 0.30 at Follow up (Figure 5 11) 5.4.4. Force Measurements Case 1. POWER improved torque/power improvements in all contraction mode s: isometric elbow flexion (change score: 7.82 0.04) and extension (change score: 10.16 1.44 ); isotonic elbow flexion (change score: 13.17 0.54 ) and extension (change score: 15.65 0 ); isokinetic elbow flexion (change score: 7.63 2.60 ) and extension (change score: 12.21 0.46 ). FTP improved all elbow flexion contractions: isometric (chang e score: 5.91 0.75 ), isotonic (change score: 11.34 1.08 ) and isokinetic (change score: 0.39 2.68 ). However, force production in all the extension contractions was worse after FTP: isometric (change score: 12.46 2.26 ), isotonic (change score: 6.4 6.68 ) an d isokinetic (change score: 5.84 2.14 ). At follow up, isometric elbow flexion (change score: 8.82 0.94 ), isotonic elbow extension (change score: 5.31), isokinetic elbow flexion (change score: 5.05 0.15 ) and extension (change score: 0.62 2.40) were wor se. Only isometric elbow extension (change score: 6.45 1.69) and isotonic elbow flexion (change score: 4.85 2.16) improved at follow up (Figure 5 12). Case 2. POWER showed torque/power improvements in all contraction mode s: isometric elbow flexion (change score: 0.97 0.62 ) and extension (change score: 3.49 0.19 ); isotonic elbow flexion (change score: 2.74 1.25 ); isokinetic elbow flexion (change score: 10.42) and extension (change score: 10.88 2.10) except for isotonic elbow extension (change score: 0.31 0 .45 ). FTP improved only isometric elbow flexion (change score: 0.97 0.62) and isokinetic elbow extension (change score: 1.28 0.58 ).

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142 Force production in a ll other contraction conditions was worse: isometric elbow extension (change score: 7.19 0.84), isoton ic elbow flexion (change score: 0.982.20) and extension (change score: 0.160.21) and isokinetic elbow flexion (change score: 13.43 0.01). At follow up, isometric elbow extension (change score: 4350.70), isotonic elbow flexion (change score: 1.060.70 ) and extension (change score: 2.170.05) and isokinetic elbow flexion (change score: 3.350.10) improved. Instead, isometric elbow flexion (change score: 0.480.10) and isokinetic elbow extension (change score: 0.622.40) worse (Figure 5 12) 5.5. Disc ussion This study aimed to address the gap between inducing neurobiological change and detecting positive behavioral change that constitutes functional recovery in persons post stroke. We examin ed combined behavioral and neurobiological approaches to bette r understand mechanisms of functional recovery. We combined behavioral therapies that improve strength, POWER, and motor skill, FTP, with inhibitory therapeutic repetitive transcranial magnetic stimulation (rTMS) to the UH Hypothesis of inter hemis p heric competition. Our first aim was to test the hypothesis of interhemispheric competition post stroke. A s we hypothesized at baseline Case 1 showed presence o f inter hemispheric competition hypothesis. I nterhemispheric competition was revealed as an imbalance in the iSP duration between the two hemispheres. The prolonged duration of the unaffected hemisphere iSP suggests that the unaffected hemisphere may be disinhibited and exerts exaggerated inhibition onto the affected hemisphere. T he exaggerated laterality

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143 index (LI) indicates the predominance of the unaffected hemisphere meaning of inter hemispheric competition as described by Nowak. In addition, at baseline we were unable to elicit MEPS in the AH in Case 1 The inability to evoke MEPs post stroke is considered a poor prognostic indicator 241 242 Our study however suggests that the presence or absence of MEPs as a prognostic indicator should not be u se d in isolation. Case 1 showed improvements of the cortical excitability (reappearance of MEPs and ability to reconstruct RC) and IHI even in absence of MEPs at baseline evaluation. Case 2 also, showed an imbalance of IHI Surprisingly, at baseline this imbalance Hemispheric competition was revealed as prolonged iSP duration from the affected compared to the unaffected hemisphere. The prolonged duration of the affected hemisphere iSP suggests that the affected h emisphere exerts greater inhibition onto the unaffected hemisphere. The negative laterality index (LI) indicates the predominance of the affected hemisphere. In contrast to Case 1, it was possible to elicit MEPs in both hemispheres at baseline evaluation i n Case 2 Moreover, at baseline evaluation recruitment curve slopes were similar between the two hemispheres, and close to normal values. An important note regarding the reversed inter hemispheric competition is that Case 2 had disputable hand laterality. T he participant revealed that she was naturally left handed, but was forced to right hand laterality during childhood. Th is forced laterality may have affected the direction of IHI and the LI at baseline. Of note in Case 1, the affected hemisphere was the dominant hemisphere and the LI showed predominance of the unaffected hemisphere.

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144 Restoring balance of inter hemispheric competition. Our second aim was to determine if it is possible to restore a balance of inter hemispheric competition. In Case 1, POWER training produced reduction of inter hemispheric competition as shown by balanced duration of iSP and normalization of the LI. In addition, POWER showed emergence of MEPs. This may indicate a normalization of the cortical excitability both within and betw een the two hemispheres. We cannot draw conclusions about IHI after FTP treatment since data were not available A lthough as suggested by disappearance of effective MEPs in the AH and increased recruitment curve slope in the UH it does appear that improv ements in cortical excitability revealed by POWER training were lost following FTP indicating a return to the baseline state In Case 2, POWER also showed reduction of inter hemispheric competition as shown by balanced duration of iSP between the two hemis pheres and normalization towards positive values of the LI. These results were maintained after FTP. POWER induced an increase of the recruitment curve slopes of both hemispheres, bringing the cortical excitability within the normal range Effects of POWE R training. Our third aim was to test whether rTMS combined with POWER training resulted in better functional, biomechanical and neurophysiological outcomes than rTMS combined with FTP. In Case 1, motor function, as indicated by WMFT, revealed a greater nu mber of improved and a lower number of worsened timed items in the affected hand post POWER training. Further, POWER induced improvement (decrease) in the WOLF score (e.g., sum of task execution time ) In addition, POWER produced improvements in joint exc ursion at the elbow and

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145 shoulder, associated with reduced trunk displacement. These outcomes are consistent with improved motor strategies in response to POWER demonstrated in our previous work 61 At the neurophysiologic level, POWER produced reduced inter hemispheric competition as s hown by balanced LI and positive changes in cortical excitability, including emergence of MEPs in the affected hemisphere. In summary, POWER showed positive behavioral and neural effects consistent with our hypothesis of increased central drive in the ipsi l esional hemisphere. Conversely, in Case 2 FTP showed improvements in the WOLF score as indicated by a greater number of improved and a lower number of worsened timed items in the affected hand. Further, FTP induced improvement (decrease) in the WOLF scor e (e.g., sum of task execution time ) In addition, FTP produced improvements in joint excursion at the elbow and shoulder, associated with reduced in trunk displacement. At the neurophysiological level, POWER produced normalization of inter hemispheric co mpetition as indicated by positive direction of the LI and FTP produced negative changes in cortical excitability as indicated by increased asymmetry in recruitment curve slopes. In summary, in Case 2 POWER did not appear to be as effective at the behav ioral level as it was for Case 1, however it still induced positive neural changes. It is important to note that the two individuals had similarity in clinical evaluation at baseline and lesion location. However, they had opposite responses in clinical and behavioral motor outcomes. One important clinical difference at baseline was that Case 2 had a sensory impairment as indicated by the sensory component of the UEFMMS (Table 5 2). The severe sensory impairment could have affected the potential benefit

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146 from POWER training. It has been described the negative association between sensory impairment and motor ability 243 Normal movement relies both on an intact motor system and also on sensory information 244 Carey et al 245 stated the primary importance of sensation is to provide the feedback needed to guide motor acts. It is possible that Case 2 had be nefit more from FTP than POWER because of the presence of visual feedback during the execution and accomplishment of functional tasks. Therefore, it could be possible that the motor output of Case 2 during POWER training was inadequate, as consequence of sensory impairment, and therefore ineffective to induce positive motor behavioral changes. Limitation s We recognize that this study included only two individuals, which are not enough to draw definitely conclusions about the heterogeneous post stroke population. However, th e purpose and the innovation of this case series were to demonstrate the possibility to induce neural changes at the supraspinal level as an effect of rehabilitation intervention. Another limitation of this study is the use of iSP as a measure IHI. IHI is usually studied by a paired pulse protocol with the conditioning stimulus delivered to one M1 and the test stimulus delivered to the other M1 10ms later (S IHI) 246 The activity in the M1 receiving the conditioning stimulus, facilitates inhibition of the MEP elic ited by the test stimulus. It has been suggested 246 that th is in hibition is produced at cortical level via transcallosal pathways. However, an alternative method used to study interhemipsheric inhibition involves a short attenuation or interruption of ongoing voluntary EMG activity induced by TMS of the ipsilateral M 1 247 This ipsilateral silent period (iSP) has a latency of 30 40ms post stimulus and lasts around 25m s.

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147 Meyer at al 248 indica ted that iSP is mediated by interhemipsheric cortico cortical inhibitory pathways including fibres passing through the posterior half of the trunk of the corpus callosum 248 Chen et al 186 suggested that iSP and S IHI are mediated by diffe rent neural mechanisms (i.e., pathways) For this reason, the iSP is currently considered as a measure that provides complementary, but not identical, information regarding interhemispheric inhibition compared to S IHI 249 However, several authors 250 252 have used the iSP instead of the S IHI to provide an estimation of IHI. The advantage of using the iSP in persons post stroke consists of the fact that it allows estimation o f IHI even in the absence of MEPs in the ipsilesional hemisphere when it would not be possible to induce S IHI. Conclusions. In general, our findings suggest that it is possible to induce neurobiological change associated with behavioral change that const itutes functional recovery. Our findings support our hypothesis that POWER promotes enhanced central neural drive in the ipsilesional hemisphere and may represent potential driver of cortical reorganization. Our results compel us to investigate these mecha nisms with future larger scale research studies, which may inform how individual characteristics interact with mechanisms of neural recovery.

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148 Table 5 1. Wolf motor function t est Number of improved and worse items Affected arm Unaffected arm Impro ved items Worse items Improved items Worse items Case 1 e study 1 Post POWER 11 4 10 5 Post FTP 4 11 5 10 Follow up 14 1 12 3 Case 2 Case study 2 Post POWER 5 10 4 11 Post FTP 13 2 10 5 Follow up 8 7 8 7

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149 Table 5 2. Clinical scales Fugl Meye r Upper Extremity Scale Motor (66) Fugl Meyer Upper Extremity Scale Sensory (12) BDI ( 63 ) MAS (32) Case 1 Baseline 47 12 3 3 Post POWER 55 12 4 2 Post FTP 49 12 4 4.5 Follow up 62 12 8 0 Case 2 Baseline 48 6 7 1 Post POWER 49 6 0 1 Post F TP 55 8 0 0 Follow up 58 9 2 0

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150 Table 5 3. Late life function and disability i nstrument Disability component Function component Total frequency dimension Total limitation dimension Total function dimension Upper extremity functioning domain C ase 1 Baseline Raw score 34 30 78 14 Scaled Score 35.96 40.61 43.13 41 SE 2.69 3.05 1.58 5.01 Post POWER Raw score 39 29 71 14 Scaled Score 39.42 39.63 40.98 41 SE 2.56 3.13 1.61 5.01 Post FTP Raw score 33 28 81 17 Scaled Sco re 35.23 38.59 44.03 47.67 SE 2.72 3.22 1.57 4.3 Follow up Raw score 38 33 93 22 Scaled Score 38.75 43.29 47.6 56.09 SE 2.58 2.85 1.57 3.86 Case 2 Baseline Raw score 31 47 92 21 Scaled Score 33.68 53.09 47.3 54.53 SE 2.81 2.46 1.56 3 .89 Post POWER Raw score 40 49 98 24 Scaled Score 40.07 54.34 49.1 59.21 SE 2.54 2.45 1.58 3.9 Post FTP Raw score 39 54 100 25 Scaled Score 39.42 57.43 49.7 60.81 SE 2.56 2.46 1.58 3.96 Follow up Raw score 38 53 88 26 Scaled Score 38 .75 56.81 46.11 62.49 SE 2.58 2.46 1.56 4.07

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151 Table 5 4. F unctional task practice (FTP). Timeline Therapeutic Goals Activity category Therapeutic activity 1 2 weeks Improve scapulo thoracic/humeral rhythm and stability Water Task Pour 1/2 cup of wate r into a bowl Incorporate gravity Pour into taller vessels. Elevate table surface 2 4 weeks Incorporate shoulder external rotation and stretch to long finger flexors Catch/Release Release ball into hoop using long reach Incorporate bilateral hand mov ement Alternate bounce/catch/release with both hands 4 6 weeks Incorporate reaching and manipulation through hand directed movements Feeding/Cooking Feed self with spoon Incorporate controlled elbow movement Grasp jars from table and place on shelf Note: Consistent with our previous work, the FTP program addressed six global therapeutic goals Therapeutic activities were developed on the basis of the specific therapeutic goal. There were nine activity categories: water tasks, catch release, feeding and cooking games, painting and drawing, laundry, sport, computer keyboarding and tool tasks. Each 90 minute treatment session involved 15minutes of stretching and warm up, followed by practice of activities in each of the 9 categories for 8minutes each. Table reports s pecific examples of activities. Difficulty of activities was adjusted based on level of function of each individual. To assure consistency across all participants, treatment was advanced to the next therapeutic goal on the timeline specified and the nine activity categories were presented in rotation

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152 Figure 5 1. Study design. Participants were evaluated 4 times times: at baseline, after 6 weeks of rTMS and POWER training; after 6 weeks of rTMS and FTP training and at 6 months follow up.

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153 Figure 5 2. POWER training. Participants performed both concentric and eccentric actions for 6 consecutive weeks. Movement speed ranged from 30 to 75 degrees per second for eccentric and from 30 to 180 degrees per second for concentric actions. Eac h bar represents two set s of 10 repetitions at the criterion speed noted on the Y axis. A primary goal of power training is to improve the capacity for force production in dynamic conditions.

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154 Figure 5 3. Wolf motor function t est. C hange score of task execution time (total time) between baseline and the fi rst block of intervention (post POWER), between the first and the second block s of intervention ( post FTP) and at retention Upward bars indicate worsening (increase) and downward bars indicate improve ment (decrease) in task execution time

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155 Figure 5 4. Key kinematic parameters of functional reach to grasp. Top chart describes range of motion (in degrees) of shoulder and elbow joints. Bottom chart describes trunk excursion (in millimeters). Baseline post POWER and post FTP evaluations are shown for case 1 and 2 Data from a healthy control are shown for comparison.

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156 Figure 5 6 Speed and i ndex of curvature of functional reach to grasp

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157 Figure 5 8. Recruitment curve slopes.

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158 Figure 5 9 Moto r evoked potentials (MEPs) At baseline evaluation we were not able to induce MEPs in the ipsilesional hemisphere Top panel shows the reappearance of MEPs after POWER. MEPs are maintained after FTP and Follow up evaluations. However, after FTP we were not a ble to reconstruct a RC since the MEPs were complex and below threshold The MEP latency (~40 ms for all evaluations) looks most consistent at follow up. The scale is the same for all three evaluations.

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159 Figure 5 10. Ipisilateral silent period duration Duration of inhibition from the affected to the unaffected hemisphere (white columns) and from the unaffected to the affected hemisphere (black columns) at baseline, after first (Post POWER) and second (Post FTP) block of interventions and at follow up. Horizontal lines indicate average iSP duration in four healthy controls. Top line indicates inhibition from dominant to non dominant hemisphere and bottom line indicates inhibition from non dominant to dominant hemisphere.

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160 Figure 5 11. Laterality i ndex for iSP duration.

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161 Figure 5 12 Force production. Flexion movements (left column) and extension movements (right column) Top row illustrates isometric contractions, middle row describe isotonic contractions and bottom row isokinetic contractions (eccentric contraction at the speed of 120deg/s). Case 1 is represented in white and Case 2 is represented in black. Each plot represents the change in force/torque/power after POWER, after FTP and at follow up.

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162 CHAPTER 6 POWER TRAINING POST STROKE ENGAG ES NEURAL CIRCUITS AT SPINAL AND SUPRASPINAL LEVELS 6.1. Background Current upper extremity (UE) treatment approaches post stroke focus on repetitive execution of functional movements, ostensibly to facilitate neural plasticity. High intensity activities, especially strengthening, have traditionally been avoided because they are assumed to increase spasticity and impair motor performance in neurological disorders. Among the currently accepted therapeutic approaches are constraint induced movement therapy ( CIMT) 138 task or iented and repetitive training 137 and more recently, robotic therap ies 135 While these therapeutic methods show promise in improving UE function p ost stroke, most of the work to date documents improvements through clinical or gross behavioral measures, which emphasize task accomplishment more than motor control or neuroplastic changes 36 Due to the gross nature of discernment, these metrics are not able to distinguish restoration from compensatory movements at either the behavioral or the neural level. Our research team h as conducted a set of studies that contributes to the contemporary evidence that resistance training as an intervention post stroke can induce restoration of more normal activation in neural circuits and movement patterns. First, Patten et al. 18, 60 conducted a randomized clinical trial of UE rehabilitation to compare the effects of functional task practice (FTP), and a hybrid intervention of FTP combined with dynamic high intensity resistance training post stroke. This clinical trial revealed that the hybrid intervention produced more significant gains in both clinical Corti, M & Patten, C. Power training post stroke engages neural circuits at spinal and supraspinal levels. Clinical Neurophysiology. In preparation

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163 indicators of motor recovery and neuromechanical parameters, including: iso metric maximal voluntary force, dynamic isovelocity torques and neuromuscular activation, as revealed using EMG 18, 60 Further, Patten et al 18 com pared the effe cts of these two intervention approaches on stretch reflex modulation. Results of this study indicate: first, that UE rehabilitation involving high exertion activity does not exacerbate either the hyperreflexic or hypertonic components of spasticity in adu lts post stroke; second, dynamic, high intensity resistance training (e.g., power training) promoted more appropriate modulation of stretch induced EMG responses; third, these neurophysiologic adaptations were associated with improved UE motor function imp rovement as evaluated with the Wolf Motor Function Test Functional Ability Scores (FAS) F inally, clinical improvements in response to the 22.5 hours of hybrid intervention exceeded those in response to 60 hours of CIMT as reported from the ExCITE trial 230 Subsequently, Corti et al 61 compared power training performed in isolation against FTP on a battery of clinical scales and kinematics of unconstrained reaching. In contrast to clinical scales, UE kinematics obtained through 3D motion capture afford a sensitive, quantitative and reproducible assessment that enables discernment between compensatory and recovery strat egies 62 Although clinical eval uations conducted by Corti et a l 61 did not reveal differential treatment effects, kinematic improvements following POWER training revealed restoration of more normal movement patterns, while performance after FTP indicated refinement of co mpensatory movement strategies. Specifically, following FTP, hemiparetic participants demonstrated increased mean velocity during reaching, but reduced shoulder flexion and elbow extension range of motion, which were compensated with increased trunk displa cement. In contrast,

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164 following POWER training, participants increased shoulder flexion and elbow extension range of motion and significantly reduced associated trunk displacement. Further, the use of a crossover design revealed that these treatment effects were greater when POWER training preceded FTP training than vice versa These positive outcomes of POWER can most likely be attributed to: a) the well recognized and profound neural adaptations induced by resistance training 51, 53, 55 and capacity. Neural adaptations induced by resistance training occur: 1) at the level of the spinal cord, potentially including short term motor unit synchronization, which is caused by changes in synaptic efficacy within the motoneuron pool, and 2) at the supraspinal level, including adaptations within the cortical circuitry. While our combined work to date suggests that POWER and HYBRID are effective treatments and may induce neuromechanical changes we have not measured the effect of therapeutic intervention involving POWER training on neural circuits at the supraspinal level. T echnological developments have led to the introduction of electrophysiolo gical techniques that provide substantial insight into the adaptive changes of neurophysiologic networks associated with plasticity and recovery post stroke 92, 153, 253 255 These technologies include transcranial magnetic stimulation (TMS) and H reflexes which are two of these non invasive tools, to measure therapeutically induced neuroplasticity post stroke at supra spinal and spinal levels, respectively. The H reflex is the electrical analogue of the spinal str etch reflex and tests the monosynaptic reflex pathways and associated activity in the spinal circuitry 187 Literature suggests that H reflex amplitude and slope are greater in the paretic versus non paretic

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165 arm post stroke and the paretic arm versus non disabled group 256 Recently, the H ref lex has been used to selectively study spinal inhibitory pathways including: presynaptic Ia inhibition and post activation depression (PAD). Presynaptic Ia inhibition is responsible for a late inhibition (i.e. D1 inhibition) and is typically assessed usin g a conditioned H reflex. Presynaptic Ia inhibition of the flexor carpi radialis (FCR) is elicited by electrical stimuli applied to the nerve supplying antagonist muscles 184 129 PAD is explored by varying the time interval between repeated H reflexes 129 Aymard demonstrated that both D1 inhibition and PAD were reduced in the affected arm post stroke as comp ared to a group of non disabled individuals 184 TMS involves non invasive brain stimulation by magnetic field pulses that induce a flow of current in the tissue, leading to the excitation of neurons 257 Stimulation of the hand representation area of a healthy motor cortex induces motor evoked potentials (MEP) in the contralateral hand muscles, which manifest as muscle co ntractions or twitches. The recruitment curve (RC) obtained using TMS is a commonly used indicator of cortical excitability 258 Dec reased activity of the ipsilesional cortex has been observed after stroke by using electrophysiological recordings 65 cortical stimulation 66 a nd functional neural imaging studies 67 This decreased cortica l excitability has been attributed to damage from glutamate receptor expression from neurons in the infarct zone In the healthy brain, neural activity in the motor areas is equally balanced in terms of mutual inhibitory control between hemispheres 64 Movements of one hand are associated with enhanced neural activity in contralateral motor areas of the brain.

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166 Activated contralateral motor areas produce inhibition on homologous areas of the ipsilateral hemisphere. Stroke affects activity in this circuitry and disrupts this balance of IHI As a result, the primary motor cortex of the unaffected (contralesional) hemisphere becomes disinhibited and thus exerts exaggerated inhibition to the primary motor cortex of the affecte hypothesis of inter hemispheric competition post stroke 64 Murase et al. 259 demonstrated that the amount of inh ibition exerted from the unaffected to the affected hemisphere is positively correlated with the severity of the functional impairment of the affected hand as measured by finger tapping. One way to study IHI is by measuring the symmetry of inhibition betwe en the two hemispheres via the ipsilateral silent period (iSP) 250 252 The ipsilateral silent period refers to a reduction in background EMG in a contracting muscle ipsilateral to TMS stimulation following a supra threshold stimulus 250 252 E xperimental studies suggest that plastic changes usually require the down regulation of local inhibitory circuits within M1 and that local disinhibition can unmask latent intracortical c onnections contributing to cortical reorganization 252, 260 263 Three types of inhibitory phenomena involving cortical mechanisms are usually studied using TMS: 1) the cortical (contralateral) silent period (cSP) 262 2) suppression of voluntary 264 and 3) short intracortical inhibition (SICI) 265 The cSP refers to suppression of the voluntary muscle activity of the contralateral hand following suprathreshold TMS 262 cSP is commonly interpreted to result from inhibitory activity in intrac ortical circuits likely mediated by the inhibitory neurotransmitter GABA b 262 Recent studies suggest that cSP in the ipsilesional hemisphere is significantly

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167 prolonged when compared to either the unaffected hemisph ere of patients post stroke or to healthy control s 261, 266, 267 SVC refers to suppression of the voluntary muscle activity of the contralateral hand by sub threshold TMS without any prior ex citatory response (i.e., MEP) 264 Davey et al proposed that SVC activates corticofugal neurons, which, via collateral s, excite inhibitory inter neurons that inhibit corticospina l activity 264 Pathway s involved in SVC could include a longer route, such as the inhibitory loop via the thalamus, which would explain the longer latency of SVC compared to cSP Since SVC is evoked in response to subthreshold TMS, the structures responsible for the EMG suppression are likely superficial ( i.e. cortical surface, closer to the stimulating coil ) Indeed, Jones (1975) reported that inhibitory GABAergic neurons are l ocated predominantly in the most superficial layers of the motor cortex 264 Thus, EMG suppression induced by sub threshold TMS during motor activity is argued to confirm the pre sence of corticomotor involvement 268 SVC has never been studied in persons post stroke however Davey 184 studied SVC in spinal cord subjects and suggested that SVC has a longer latency compared to healthy control group 184 This phenomenon may reflect a weak or absent early component of cortical inhibition in the spinal cord injured population. SICI is commonly use d to test intracortical inhibitory circuits likely mediated by GABA a Studies investigating SICI in people with stroke have found reduced intracortical inhibition in the affected hemisphere 185 The effect of therapeutic intervention involving POWER training post stroke on excitatory and inhibitory networks at either spinal and supraspinal levels has never been addressed The refore, the overall objective of this single subject design was to impro ve

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168 our understanding of mechanisms underlying recovery post stroke by using a multimodal investigative approach that provides insight into the dynamic relationship between neurophysiology and motor behavior and pays particular attention to the selection of measures that distinguish betwee n recovery and compensation. This study evaluated the effect of 2 weeks of HYBRID training (POWER + FTP) using clinical tests and three dimensional motion analysis of functional task performance to measure motor control ; H reflex es to test the spinal circuitry and TMS to measure cortical networks (i.e. exci tatory and inhibitory), and IHI. Our central hypothesis was that an intervention involving POWER would increase central neural drive during functional voluntary movement, which would be revealed by improvements in both motor behavioral and neural outcomes. In this study, w e used TMS to study cortic al excitability, inter hemispheric inhibition (IHI) and cortical inhibitory networks The first aim of this study consisted of evaluating the effect of the HYBRID training at the behavioral level. To address this aim, we used clinical tests to measure motor impairment and activity levels, and three dimensional motion analysis of functional upper extremity tasks to measure behavio ral motor control. Consistent with our previous studies 61 we hypothesized that clinical tests would fail to detect differences after treatment, while kinematic s would reveal post treatment effects. The second aim of this study evaluate d the excitability and inhibitory networks at the spinal and supra spinal levels. At the spinal level, we hypothesized that HYBRID training would induce reduc ed exci tability of the affected upper limb motor pools as revealed by increased presynaptic inhibition (i.e., D1 inhibition) and post activation de pression (PAD) (i.e. homosynaptic depression). At the supraspinal level, we

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169 hypothesized that HYBR I D training would induce increased cortical excitability of the affected hemisphere and rebalancing of IHI. Further, we expected that HYBRID training would i nduce improved modulation of the inhibitory pathways, which would be revealed by shortened cSP duration, increased magnitude of SVC and increased SICI towards normal 6.4. Research Design and M ethods 6.4.1. Inclusion and exclusion Criteria The p articipa nt was included on the basis of the following inclusion and exclusion criteria : 1) clinical presentation of at least one, and no more than three, strokes on the same side of the brain (confirmed by CT or MRI); 2) demonstrated ability to move the upper extr emity in the horizontal plane corresponding to a poor (2/5) manual muscle test grade in the major shoulder and elbow agonists 3) at least 10 degree s of active wrist extension, 10 degree s of active abduction of the thumb, and 10 degree s of active extension of any two digits, three times within one minute 4) freedom from significant UE joint pain, passive range of motion limitations, and marked sensory deficits as evidenced by absent proprioception at the elbow or shoulder joints. The exclusion criteria were: 1) use of medications that may lower seizure threshold; 2) history of epilepsy, brain tumor, learning disorder, mental retardation, drug or alcohol abuse, dementia, major head trauma, or major psychiatric illness; 3) evidence of epileptiform activity on e lectroencephalography obtained prior to screening; 4) history or radiographic evidence of arteriovenous malformation, intracortical hemorrhage, subarachnoid hemorrhage, or bilateral cerebrovascular disease; 5) history of implanted pacemaker or medication p ump, metal plate in skull, or metal objects in the eye or skull;

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170 6) p regnancy; 7) inability to understand 3 step directions; 8) impaired corrected vision that would alter kinematics of reaching. 6.4.2. Participant characteristics Participant was 66 year old right hand dominant, white fe male who was enrolled in the present study 5 months following a venous infarction associated with cortical vein thrombosis involving the arm hand knob region and the subcortical posterior half of white matter (including th e corona radiata and posterior limb of internal capsule). The lesion resulted in left hemiparesis affecting mainly the upper extremity with absence of cognitive impairment. The p articipant was identified during acute inpatient rehabilitation at Brooks Reha bilitation Hospital in Jacksonville FL and she was enrolled in this study after discharge from all formal, supervised inpatient and outpatient rehabilitation. 6.4.2. Experimental D esign This single subject design involved two weeks of HYBRID (POWER + FTP) therapy at Brooks Center for Rehabilitation Studies in Jacksonville, FL. Prior to, immediately following and one month follow ing the participant underwent a multimodal evaluation at the VA Rehab R&D Brain Rehabilitation Research Center ( BRRC ) in Gainesvi lle FL (Figure 6 1). 6.4.3. Outcome M easures The multimodal evaluation included behavioral and neurophysiological measures. 6.4.3.1. Behavioral measures Behavioral measures include d clinical tests and three dimensional motion analysis. Clinical tests Clinical tests were comprised of the: 1) upper extremity subsection of the Fugl Meyer Assessment 93 (including the total score and its motor portion) to

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171 measure upper extremity motor impairment; 2) Modified Ashworth Scale (MAS) 269 for shoulder flexors/extensors, abd uctors/adductors, ext ernal /int e r n a l rotators, elbow and wrist flexor/extensor muscles to measure hypertonia; 3) Wolf Motor Function Test (WMFT) 270 to measure motor activit y; 4) muscle strength measurements of five reciprocal upper extremity movements using a hand held myometer 25 Three dimensional motion analysis K inematics of the paretic UE were measured while the participant w as positioned in sitting in a straight back chair with the paretic UE resting on the ipsilateral thigh (Start position). The shoulder was positioned in neutral flexion/extension and neutral internal rotation; the elbow in 75 90 degrees of flexion with the wrist resting in pronation. The p artic ipants w as instructed to reach, 180 ). This functional reach to grasp task was selected as the study outcome task because of its status as a fundamental motor skill necessary for many daily activities. Subjects completed 1 2 practice trials followed by three test trials. T hree dimensional motion analysis data were collected using 53 reflective markers placed on the: anterior and posterior spines, base of sacrum, manubrium and body of sternum, 7 th cervical vertebra, 10 th thoracic vertebrae, and bilaterally on the acromion processe s, medial and lateral epicond y les, ulnar and radial styloid processes, superior thirds of the upper arm and forearm (triads), hand and finger tips (set of 11 small size markers) Data were recorded with a twelve camera motion analysis system 26 (Vicon 612, Oxford Metrics Inc., Oxford, U.K.) at a sampling frequency of 200 Hz. The motion 25 Micro Fet model 01163, Lafayette Instrument Company, Lafayette, Indiana. 26

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172 analysis system expressed output data as three dimensional, time depen dent marker coordinates relative to a laboratory coordinate system. 6.4.3.2. Neurophysiologic measure s H re f lex We conducted three sets of experiments: 1) unconditioned H reflexes to establish a recruitment curve and slope for the flexor carpi radialis (FCR) 184 2) D1 inhibition, conditioning of the FCR H reflex with median nerve stimulation to study pre synaptic inhibition 184 ; and 3) repeated H reflexes at varying inters timulus intervals to study post activation or homosynaptic depression 184 In all sets of experiments, the participant was seated with the forearm pronated, with wrist in neutral flexion/extension position and elbow at 45 degrees flexion; shoulder was in neutral rotation and slightly abducted and flexed to allow access to the median nerve. H and M waves were electrically evoked using a constant current stimulator 27 Conditioning stimuli were delivered using a second st imulator ( Grass technologies, West Warwick, RI, USA). For the unconditioned H reflex and D1 inhibition, we used a surface electromyography electrode placed over the belly of the flexor carpi radialis to record the H and M wave and a stimulating bipolar ele ctrode placed in the medial bicipital groove to stimulate the media n nerve. For post activation depression (PAD), we used an additional electromyography electrode on the belly of the extensor carpi radialis and a stimulating electrode above and lateral to the elbow to stimulate the radial nerve. Data were collected at a sampl ing rate of 10kHz using a PowerLab analog to digital converter and LabChart Software 28 27 Digitimer DS7A, Digitim er Ltd., Hertfordshire, England 28 PowerLab analog to digital converter and LabChart Software Version 7.3, ADInstruments, Colorado Springs, CO, USA

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173 Once the stimulation site for the media n nerve was located, FCR H reflex recruitment curves were o btained. The stimulation intensity at the media n nerve was sequentially increased (typically by 0.5 mA increments) from sub H reflex threshold intensity to the point when H reflex amplitude reached the maximum and began to decline ; t hereafter, current inte nsity was increased at a faster rate (1 mA) until a maximum M wave (Mmax) was elicited. Pre synaptic Ia or D1 inhibition was performed by median nerve stimulation (unconditioned stimulus) preceded by a conditioning stimulus at the radial nerve (conditione d stimulus). Unconditioned responses were elicited at the stimulation intensity level that produced an M wave equal to 20% of Mmax (ascending curve of the M wave). The radial nerve conditioning stimulus was delivered at 0.95 motor threshold at an interstim ulus interval of 13 ms (conditioning stimulus preceded test by 13 ms). We performed 20 stimuli randomly alternating conditioned and unconditioned stimuli Post activation or monosynaptic depression (PAD) was tested by randomly stimulating the median nerve at interstimulus intervals (ISIs) between 1 12 seconds 184 Five stimuli were repeated at each ISI at an intensity level that produced an H wave equal to Hmax/2 184 T ransc ranial magnetic stimulation (TMS) We conducted four sets of experiments to study cortical excitability interhemispheric inhibition (IHI) and activity in cortical inhibitory networks D uring TMS testing, the participant was seated comfortably in a semi re clined chair. Stimulation was delivered using one or two Magstim 200 2 29 stimulators connected through a Bi stim module to a figure eight coil (Magstim ) while 29 The Magstim Company LTD, Whitland, Wales, UK

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174 recording MEPs from the contralateral first dorsal interosseous (FDI) muscle by means of pre ampl ified EMG electrodes (MA 311, Motion Lab Systems, Baton Rouge, LA, USA). The coil was placed tangentially over the scalp, with the handle pointing backwards and laterally at a 45 angle away from the midline, inducing a posterior anterior current in the ta rget hemisphere. We studied cortical excitability by calculating the slope of the active input output curve, also known as the active recruitment curve (RC). The slope of the RC provides a measure of the excitability of corti cal motor areas 258 Active RC was generated by stimulation over the motor threshold ho tspot during background contraction (10% of the maximal effort) of the first dorsal interosseous (FDI) Responses were elicited at progressively increasing intensities over a range from 10% below motor threshold until maximal MEP amplitude was obtained 240 10 stimuli were recorded at each intensity and stimulation intensity was increased in 5% increments The maximum FDI M wave was evok ed and the peak to peak amplitude used to normalize MEP amplitude for construction of the RC. RC was measured for both ipsilesional and contralesional hemispheres. We used the duration of ipsilateral silent period (iSP) to study inter hemispheric inhibiti on (IHI). iSP was obtained using single pulse TMS delivered at 150% of motor threshold while the participant produced a background contraction (10% of the maximal effort) of the FDI muscle ipsilateral to the stimulation. 10 trials of iSP were obtained for each hemisphere. We studied cortical inhibitory network s by measuring the cortical silent period (cSP), the suppression of voluntary contraction without an excitatory response (SVC or

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175 Davey's technique) and short intracortical inhibition (SICI). The cSP c onsists of suppression of the voluntary muscle activity of the contralateral hand by a supra threshold TMS after prior excitatory response (MEP). We studied the cSP simultaneously with MEP amplitude during the RC experiment. 10 cSP trials were obtained at each stimulus intensity for each hemisphere. The SVC, or Davey's technique, consists of suppression of the voluntary muscle activity of the contralateral hand by a sub threshold (i.e. ~ 20% below motor threshold) TMS without any prior excitatory response. 50 trial s of SVC were obtained for each hemisphere. SICI consists of a reduction in the amplitude of the excitatory response (MEP) to a suprathreshold test stimulus (intensity producing MEPs of ~1mV) by a subthreshold conditioning stimulus (80% of active motor threshold) at interstimulus intervals ranging from 1 to 6 ms. 5 paired pulse stimuli were delivered at each ISI to quantify SICI in each hemisphere. 6.4.4. Therapeutic I nterventions HYBRID intervention consisted of combined POWER training followed b y FTP for 3 hours daily, 5 days per week, for two weeks. The treatment algorithms was developed on the basis of the results of our previous studies 61 and adapted for a shorter treatment period 54 POWER in volved five reciprocal upper limb movements: shoulder abduction/adduction, shoulder flexion/extension, shoulder external/internal rotation, transverse plane elbow flexion/extension and wrist flexion/extension. All movements were trained using a commerciall y available dynamometer 30 and custom fabricated attachments to accommodate the hemiparetic upper extremity (Table 6 1) FTP involved practice of functional tasks using a progression of six therapeutic goals and 30 Biodex, Copyright 2012, Biodex Biomedical System 3.2, Shirley, NY, USA

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176 nine activity categories. Specific therapeutic tasks were chosen from a list of activity categories based on participant specific goals and baseline functional level and practiced on a structured rotation within the framework of the therapeutic goal (Table 6 2) 6.5. Analysis 6.5.1. Clinical Tests For MAS, we calculated the composite score for shoulder flexion / extension abduction / adduction ext e r n a l /int e r n a l rotation elbow and wrist flexion / extension For Fugl Meyer Assessment, we calculated the total score (total score) and the motor portion (motor score). For WMFT, we calculated the sum and the mean of the total execution time for both affected and unaffected sides. WMFT was compared to normal data 270 For mu scle strength measurements, we calculated the change score between baseline and post HYBRID and between post HYBRID and follow up for each UE movement. 6.5.1. Three Dimensional Motion Analysis Marker data were labeled using Vicon Nexus 31 and modeled using Visual3D 32 Kinematic trajectories, extracted from Visual3D, were analyzed using custom written Matlab 33 scripts. Kinematic data were low pass filtered (12 Hz cutoff) using a bi directional 4 th order Butterworth filter. The start of movement (SOM) was defin ed as the first point at which the velocity of the marker on the third metacarp o phalangeal joint 31 Vicon 612, Oxford Metrics, Oxford, UK 32 Copyright 2010 C Motion, Version 4.00.19, Inc C Motion, Germantown, Maryland 33 MathWorks Version R2011b, Inc ., Massachusetts USA

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177 exceeded 5% peak velocity and the end of movement (EOM) as the last point at which velocity of this marker fell below 5% peak 43, 181 Our primary kinematic outcomes were shoulder and elbow range of motion and trunk displacement to quantify movement execution. Reach path ratio (RPR) w as used as a secondary outcome to quantify movement accuracy. Range of motion (ROM) was calculated for shoulder flexion and elbow extension as the difference, in degrees, between the maximum and minimum joint angle achieved. Trunk displacement was defined as the displacement of the sternum marker, in millimeters in the sagittal plane. Reach path ratio was defined as the ratio of the actual path and the direct path length of the hand marker. The actual path is defined as the three dimensional displacement of the hand marker path during the reach task, and the direct path is defined as the thr ee dimensional distance between the hand marker at onset and the hand marker at offset. 6.5.2. H reflex The peak to peak amplitude of both, H and M waves were normalized to Mmax. Using the range of H and M responses, H and M recruitment curves were pl otted. Maximum values for H and M of the recruitment curves were calculated and the Hmax/Mmax ratio was assessed. Linear regressions were calculated for both H and M wave recruitment curves to obtain the H and M slope. The slope of the H reflex recruit ment curve (Hslp) was calculated on the ascending limb defined as a range from 10 85% of maximum H reflex amplitude Similarly, the M slope (Mslp) was calculated for the M wave recruitment curve. Hslp was normalized to Mslp, expressed as the ratio Hslp/M slp. This ratio has been reported as an effective and sensitive method to detect changes in spinal excitability 187, 256 For conditioned stimuli, the amplitude of the

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178 conditioned H reflex was expressed as relative to the unconditioned H reflex. The amplitude of the H reflex following repeated stimulation was expressed relative to H reflex amplitude at the 12 s ISI 184 6 .5.3. Transcranial Magnetic Stimulation (TMS) The area of the averag e, rectified MEP response was calculated at each stimulus intensity. MEP areas were normalized to M wave area and the stimulus response curve of MEP area against stimulus intensity (i.e. recruitment curve, RC) was constructed. A non linear reg ression fit of the data was performed using the Boltzmann Equation followed by a linear regression fit of the modeled data in the steepest portion of the range The slope of the fitted line was reported. For cortical silent period (cSP), ipsilateral sile nt period (iSP) and EMG suppression (a.k.a. ) : EMG data were rectified and averaged over multiple trials The mean and the standard (SD) deviation of the baseline EMG level for 100 ms before TMS stimulus was determined from the averaged si gnal. We considered the presence of an MEP (either ipsilateral or contralateral) if the post stimulus EMG exceeded the pre MEP onset was defined as the last crossing of the pre stimulus mean baseline EMG before the MEP peak and the MEP offset as the first crossing of the pre stimulus mea n baseline EMG after the MEP peak. MEP area was calculated between the MEP onset and offset ( MEP duration). Similarly, we considered the presence of an SP ( either cSP and iSP) if the post stimulus EMG fell below the pre for > 5 ms. The SP onset was defined as the first crossing of the pre stimulus mean baseline EMG after the MEP peak and the MEP offset as the first crossing of the pre stimul us mean baseline EMG after the SP onset for at least 5 ms 186 The SP duration was the time between the

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179 onset and the offset values. For each ISI, signal averaging of multiple stimuli was performed. The peak amplitude was calculated and normalized relative to the single pulse (unconditioned) MEP amplitude The stimulus response curve of cSP against stimulus intensity (i.e. recruitment curve, RC) was constructed using a non linear regression fit of the data to the Boltzmann Equation followed by a linear regression fit of the modeled data in the s teepest portion of the range The slope of the fitted line was reported. 6.6. Results 6.6.1. Clinical Tests Clinical tests are summarized in Table 6 3 and 6 4. At baseline, MAS indicated a slight increase in muscle tone in 5 out of 7 tested muscles (compo site score, 5). MAS improved progressively after HYBRID treatment (composite score, 2) and at follow up (composite score, 0). At baseline, Fugl Meyer assessment indicated a very mild impairment (total score, 118 out of 126 and motor score, 62 out of 66). A fter HYBRID, Fugl Meyer reached the maximum value for both total score and motor score (respectively 126 out of 126 and 66 out of 66), these scores were maintained at follow up. At baseline, Wolf motor function test for both the unaffected arm (sum, 25.49 1.19 and mean, 1.70 1.19 ) and affected arm (sum, 26.57 1.20 and mean, 1.771.20) were similar to normal data for the age match ed population (mean for right 1.300.3 and for left 1.300.3) 270 These values remained stable after HYBRID (sum for unaffected, 23.711.09 and for affected, 23.611.35) and at follow up (sum for unaffected, 24.701.02 and for affected, 23.930.99). At baseline, muscle strength measurements r evealed an asymmetry between unaffected (muscle strength average, 18.22lb) and affected (muscle strength average, 11.69lb) arms in favor of the unaffected arm. After

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180 HYBRID, there was a larger improvement in the affected arm (average change score, 4.81lb) versus the unaffected arm (average change score, 0.56lb. At follow up, the affected arm continued to improve (average change score, 1.59lb). 6.6.3. Kinematics Kinematics of the affected arm were compared to the unaffected arm during the same functional re aching task (Figure 6 2). At baseline, the affected arm had less range of motion at the shoulder and elbow (shoulder, 18.871.45 and elbow, 11.701.66 ) than the unaffected arm (shoulder, 22.461.01 and elbow, 21.821.39 ). After HYBRID range of motion of the affected arm had a small increase at s houlder flexion (change score: 2 0.9) and a greater increase at elbow extension (change score: 5.83 0.5). At follow up these improvements were lost at the shoulder (change score: 3.54 0.04 ) but maintained at the elbow (1 0.3 ). Trunk excursion during affected arm movement was lower (17 2.01mm) than during unaffected arm movement (20.25 1.22mm) at baseline and it increased progressively post HYBRID (19.51 2mm) and at follow up (25.14 1.28mm).The reach path rat io of the affected arm (1.03 0.09) did not differ from the reach path ratio of the unaffected arm (1.04 0.01) at baseline and remained constant at all the evaluations (Figure 6 2 ). 6.6.4. H reflex Unconditioned test. The H max /M max ratio at baseline was gre ater (0.77) than the value reported for non disabled older adults (~0.4) 256 and decreased progressively after HYBRID treatment (0.35) and at follow up (0.16) (Figure 6 2). Similarly, the H slope /M slope ratio was greater at baseline (0.74) than the value reported for non disabled older adults

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181 (~0.3) 256 and decreased progressively after HYBRID treatment (0.66) and at follow up (0.50) (Figure 6 2) Pre synaptic Ia or D1 inhibition (conditioned test) At baseline, the conditioned D1 test induced an abnormal facilitation of the H reflex response (154.46 2.7% of unconditioned value) instead of inhibition as observed in non disabled individuals 184 After HYBRID treatment, this abnormal facilitation was somewhat reduced (114.17 2.84% of unconditioned value ) and became inhibition at follow up (93.73 12.70 of unconditioned value ) (Figure 6 4). Homosynaptic or p os t activation depression (PAD) (repeated test) Figure 6 5 illustrates the post activation depression when the inter stimulus interval (ISI) was varied from 1 to 12 seconds. H reflex size at ISI of12 seconds was used as reference value (i.e. 100%) 184 At baseline, for ISIs ranging between 1 to 5 seconds, the amplitude of the H reflex increased when the ISIs increased with a similar pattern as observed in non disabled subjects 1 84 To quantify the total post activation depression, the area under the PAD curve at ISIs ranging between 1 and 12 seconds was calculated. At baseline the area (1005) was greater than after HYBRID training (890.30) and at follow up (580.50), indicating a progressive increase of total PAD. 6.6.5. Transcranial Magnetic Stimulation 6.6.5.1. Recruitment curve At baseline, the recruitment curve slope was greater in the unaffected hemisphere (9.07) than in the affected hemisphere (4.56) (Figure 6 7). After HYB RID treatment, the slope in the unaffected hemisphere decreased (5.36) and increased in the affected hemisphere (5.76). At follow up the slope in the unaffected hemisphere continued to decrease (2.55), while it remained stable in the affected hemisphere (5 .01). These

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182 results indicate a decreased excitability in the unaffected hemisphere and a concurrent increased excitability in the affected hemisphere. 6.6.5.2. Silent period (SP) We constructed the stimulus response (S R) curves of SP duration against stim ulus intensity (Figure 6 11). At baseline, the linear slopes in the steepest range of the sigmoidal curves were similar in the unaffected (7.52 0.16) and affected (6.07 0.28) sides. After HYBRID treatment, the slopes reduced in both sides (unaffected, 3.81 1.36 and affected, 3.43 1.30) and they both increased at follow up (unaffected, 12.42 3.08 and affected, 5.82 1.90). Further, the duration of the silent period decreased after HYBRID treatment, versus baseline, for stimulation intensities greater than 50% in the unaffected side and decreased after HYBRID and at follow up for stimulation intensities greater than 45% in the affected side (Figure 6 11). 6.6.5.3. Ipsilateral silent period (iSP) At baseline, IHI from the affected to the unaffected hemisphere (i SP duration while stimulating the affected hemisphere) was shorter than IHI from the unaffected to the affected hemisphere (iSP duration while stimulating the unaffected hemisphere) (34 and 42 ms, respectively). After HYBRID treatment, IHI from the affecte d to the unaffected hemisphere increased (42.99 ms) and from the unaffected to the affected hemisphere decreased (37.38 ms). At follow up, IHI was reduced in both hemispheres (from the affected to the unaffected hemisphere, 37.13ms and from the unaffected to the affected hemisphere, 26.38ms) and reached values of non disabled healthy controls (Figure 6 6). The laterality index for the iSP duration ( ( AH UH )/( AH+UH ) ) was 0.10 at baseline, 0.06 after HYBRID treatment and 0.16 at follow up (Figure 6 6).

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183 6.6. 5.4. Short Intracortical inhibition (SICI) At baseline, the affected hemisphere revealed less SICI compared to the unaffected hemisphere for ISIs less than 3ms. These data are consistent with previous work 265 Aft er HYBRID, SICI increased in the affected hemisphere and decreased in the unaffected hemisphere. SICI after HYBRID was greater in the affected versus the unaffected hemisphere for ISIs ranging 1 6ms. At follow up, SICI increased in both hemispheres and bec ame more symmetrical (Figure 6 7). 6.6.5.5. Suppression of voluntary contraction (SVC). We were able to show suppression of the voluntary contraction (SVC) after sub threshold TMS for both affected and unaffected sides (Figure 6 10). At baseline, the pe rcent of inhibition normalized to the prestimulus EMG in the affected FDI (22.07%) was slightly smaller than the unaffected hemisphere (30%). After Hybrid training, the % of inhibition remained constant in both affected (21.50%) and unaffected (25%) hemisp h e res At follow up, there was a slight decrease in inhibition in both affected (18.82%) and unaffected (19.15%). 6.7. Conclusion This study evaluated the effect of 2 weeks of HYBRID training (POWER + FTP) using clinical tests and three dimensional motio n analysis during a functional task to measure motor control, H reflex es to test spinal circuitry TMS to measure cortical networks (i.e. exci tatory and inhibitory), and IHI. Table 6 5 summarizes the results for each neurophysiologic technique and the corr esponding neurological pathways. Our central hypothesis was that an intervention involving POWER would increase central neural drive during functional voluntary movement, which would be revealed by improvements in both motor behavioral and neural outcomes.

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184 Behavioral level. Baseline evaluation for all clinical tests of the affected arm, with exception of muscle strength measurements, showed minimal motor impairment. Either after HYBRID or at follow up, MAS and Fugl Meyer Assessment reached the maximum scor es and WMFT reached normative values for age matched non disabled population (Table 6 3) 270 Strength measurements revealed asymmetry between arms in favor of the u naffected arm (~7lb difference). HYBRID training increased strength in all muscles of the unaffected arm except for wrist extensors. The greater strength improvements were at elbow flexors/extensors, shoulder internal rotators and flexors. Of note, baselin e evaluation revealed greater weakness in proximal relative to distal muscles, and this weakness was in accordance with the participant self report of motor impairment. T otal muscle strength in the affected arm progressively improved after HYBRID and at follow up, while muscle strength remained constant in the unaffected arm. Similarly to clinical tests, kinematic data indicated that the motor control strategy in the affected arm was very similar to the unaffected arm during UE reaching task. After HYBRI D, shoulder and elbow ROM and trunk displacement improved (reaching unaffected arm values); at follow up, these improvements were maintained at elbow ROM, but they were lost at shoulder ROM and trunk displacement. Spinal Circuits Baseline evaluation for both H max /M max and H slope /M slope ratios are in accordance with values reported previously for post stroke individuals 256 Our results reveal progressively reduced H max /M max and H slope /M slope ratios post HYBRID and at follow up. Interestingly, after HYBRID both these ratios reached values reported for non disabled older adult s 256 These findings suggest normalization of spinal excitability, whi ch is normally found to be increased in the affected upper limb post stroke 256

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185 Further, we evaluated presynaptic inhibition (i.e. D1 inhibition) and post activation depression (PAD) (i.e. homosynaptic depression). Both PAD and D1 increased progressively post HYBRID and at follow up. Therefore, o ur results suggest that HYBR ID training induces improved modulation of the spinal mechanisms controlling homosynaptic (PAD) and presynaptic (D1) pathways of the monosynaptic reflex arc. Improvements in modulation of the homosynaptic reflex arc (PAD) may suggest improvement in the eff icacy of the Ia fibre motoneurone synapse. Improvements in the presynaptic (D1) mechanisms may suggest improvement of the descending inhibitory control from supraspinal structures post stroke. Our results at spinal level, including both excitatory and inhi bitory pathways, are in accordance with our hypothesis of positive neural changes post HYBRID. Supraspinal level. First, we evaluated the slope of the stimulus response curve of MEP area vs. stimulus intensity, which offers information regarding the exci tability of the motor cortex and the strength and integrity of the corticospinal pathways 271, 272 Our data indicate that HYBRID increased RC slopes in the affected hemisphere and reduced RC slopes in the unaffecte d hemisphere. These findings suggest an increase of the cortical excitability in the affected hemisphere and a concurrent decrease of the cortical excitability in the unaffected hemisphere. Second, we evaluated interhemipsheric inhibition (IHI). IHI is co mmonly studied by a paired pulse protocol with the conditioning stimulus delivered to one M1 and the test stimulus delivered to the other M1 10ms later (S IHI) 246 Specifically, the activity in the M1 receiving the conditioning stimulus, facilitates inhibition of the MEP elicited by the

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186 test stimulus. Ferbert et al 246 suggest ed that the inhibition was produced at cortical level via transcallosal route. Beside s S IHI, interhemipsheric inhibition can also be studied by a short interruption of ongoing voluntary EMG activity induced by focal TMS of the ipsilateral M1 247 This ipsilateral silent period (iSP) has a latency of 30 40ms post stimulus and lasts around 25ms. Meyer at al 248 indicated that iSP re flects interhemipsheric cortico cortical inhibitory mechanisms mediated by fibres passing through the posterior half of the trunk of the corpus callosum 248 Chen et al 186 suggested that the neural mechanisms underlying the iSP differ from those responsible for S IHI. For this reason, the iSP is currently considered as a measure that provides complementary, but not identical, information on interhemispheric inhibition compared to S IHI 249 Several au thors 250 252 have used the iSP instead of the S IHI to provide an estimation of interhemispheric inhibition. The advantage of using the iSP in persons post stroke is that it allows estimation of IHI even in the abs ence of MEPs in the ipsilesional hemisphere. Our data indicate that HYBRID increased the iSP from the affected to the unaffected hemisphere, and reduced the iSP from the unaffected to the affected hemisphere. At follow up, the iSP in both affected and unaf fected hemispheres reduced and reached values of healthy control s These findings indicate rebalancing of IHI following therapeutic intervention 64 The laterality index of the iSP indicated a slight predominance of the unaffected hemisphere at baseline and a reversed condition in favor of the affected hemisphere after HYRBID and at follow up. We also evaluated the short intracortical inhibitory network (SICI). Consistent with previous studies 185 our results indicated reduced SICI in the affected hemisphere compared to the unaffected hemisphere at baseline After HYBRID, SICI increased in

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187 the affected hemisphere and reduced in the un affected hemisphere, resulting in greater intr acortical inhibition in the affected hemisphere. At follow up, SICI increased in both hemispheres and become more symmetrical. Some authors 185, 273 suggested that the asymmetry in SICI of the affected and unaffecte d hemispheres is a maladaptive process. It has been suggested that the reduced inhibition in the affected hemisphere could be due to persistent reduction in the intracortical inhibitory GABA a ergic circuits within M1 or to an increased excitability and lowe red threshold for activation of those interneurons responsible for the excitatory effects at short ISIs. Cincinelli 185 suggested there is an enhanced intracortical excitability of the affected hemisphere as a resu lt of reduced ( defective ) SICI. As the author suggested, it is important to clarify that there are different excitable elements in motor cortex, thus increased excitability to paired stimuli might reflect to reduced activity of inhibitory M1 intracortical circuits, and the decreased excitability to single stimuli is probably related to loss of excitable elements. Therefore, our findings suggest HYRBID training was able to improve the modulation of the GABA a ergic circuits within M1 or the interneurons respon sible for excitatory effects at short ISIs. These results are in accordance with our hypothesis. Lastly, we studied the suppression of voluntary contraction (i.e. technique). Our data did not indicate any changes in the depth of EMG suppre ssion after either HYBRID or follow up evaluations in either the affected and unaffected hemispheres. SVC reveals suppression of the ongoing EMG by a sub threshold TMS pulse and is known to occur as a result of activating superficial cortico cortical inhib itory interneurons, argued to be mediated by GABA B ergic receptors. The resulting EMG supression induced during motor activity reflect s the presence of corticomotor

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188 involvement 268 At all evaluations, we were able to elicit EMG suppression with sub threshold TMS pulse indicating corticomotor involvement in the voluntary FDI contraction (10% of MVIC). A visual analysis of EMG (Figure 6 10) could lead to the interpretation that H YBRID training increased SVC in both the affected and unaffected hemispheres. However, when the suppression is normalized to the prestimulus EMG activity, the magnitude of inhibition is similar It is possible that HYBRID treatment did not have any effect on the mechanisms controlling SVC, however it also possible that HYBRID did increase the amount of suppression as revealed by the EMG visual inspection and that the amount of inhibition as % of the prestimulus EMG cannot be interpreted as meaningful. In su pport of this interpretation, Barthelemy and Nielsen 274 suggested that the suppression of the EMG can only be used to pr ovide confirmation of the contribution of corticospinal drive to the ongoing EMG, but it cannot be used to draw conclusions regarding the magnitude of that drive, how significant it is for the EMG activity or for differences in the drive during two tasks. Taken together our findings support our hypothesis that POWER training promotes enhanced central neural drive in the ipsilesional hemisphere and may represent a potential driver of cortical reorganization including modulation of intracortical and interhem ipsherric inhibition. The intensity of the HYBRID treatment may have indirectly improved the impaired modulation of the cortical inhibitio ry pathways by engaging increased participation of the nervous system and eliciting greater voluntary cortical drive. Further, our data reveal that it is possible to induce concurrent neurophysiologic changes at spinal and supraspinal levels, associated with behavioral change that constitute s functional recovery. The positive outcomes of HYBRID training can most

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189 likely be attributed to: a) the well recognized and profound neural adaptations induced by POWER training, and b) therapeutic intensity, which promotes improvements by nervous system. This is the first study to address the effects of therapeutic intervention involving POWER training post stroke concurrently on spinal and on supra spinal excitatory and inhibitory networks. Our results compel us to investigate these mechanisms with futur e larger scale research studies, which may inform how individual characteristics interact with mechanism s of neural recovery.

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190 Figure 6 1 Single subject design. Participant underwent to two weeks of HYBRID (POWER + FTP) therapy and was assessed with a multimodal evaluation, including clinical tests behavioral and neurophysiologic measures p rior to and immediately following two weeks of treatment, and at one month follow up.

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191 Table 6 1. POWER training. Number of sets Speed s 30 45 60 75 30 60 90 120 150 180 Week 1 Shoulder flexion 2 2 0 0 2 2 2 2 0 0 Shoulder abduction 2 2 0 0 2 2 2 2 0 0 Shoulder extrarotation 2 2 0 0 2 2 2 2 0 0 Wrist flexion/extension 2 2 0 0 2 2 2 2 0 0 Elbow flexion/extension 2 2 0 0 2 2 2 2 0 0 Week 2 Shoulder flexion 2 2 2 2 1 0 2 2 2 2 Shoulder abduction 1 2 2 2 1 0 2 2 2 2 Shoulder extrarotation 1 2 2 2 1 0 2 2 2 2 Wrist flexion/extension 2 2 2 2 2 0 2 2 2 2 Elbow flexion/extension 1 2 2 2 1 0 2 2 2 2 Note: Table indicates number of sets performed for each movement during the two weeks of training. Monday, Wednesday and Friday training involved shoulder flexion and abduction, and wrist flexion/extension. Tuesday and Thursday training involved shoulder external rotation and elbow flexion/extension.

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192 Table 6 2. F unctional task practice (FTP) of HYBRID training Activity Key kinesiologic components Advancing therapy Therapeutic goal Laundry task Manipulation skills including grips, proximal stabilizati on/el evation required Begin by smoothing out and folding a towel, focus on app ropriate gleno humeral rhythm. Advance to tasks requiring proximal stabilization with simultaneous manipulation including buttoning, zipping, tying and folding of laundry. Wr ist/hand Writing/ drawing/ paint Gleno humeral rhythm & stabilization with elbow control This task can be advanced by raising the height and increasing the vertical angle of the work surface. Furthermore, more difficult patterns can introduced. Shoulder Note: Consistent with our previous work, the FTP program addressed six global therapeutic goals Therapeutic activities were developed on the basis of the specific therapeutic goal. There were nine activity categories: water tasks, catch release, feeding and cooking games, painting and drawing, laundry, sport, computer keyboarding and tool tasks. Each 90 minute treatment session involved 15minutes of stretching and warm up, followed by practice of activities in each of the 9 categories for 8minutes each. Table reports s pecific examples of activities. Difficulty of activities was adjusted based on level of function of each individual. To assure consistency across all participants, treatment was advanced to the next therapeutic goal on the timeline specifie d and the nine activity categories were presented in rotation Table 6 3. Clinical scales. Numbers in parenthesis indicate scores for non disabled. Baseline Post HYBRID Follow up Modified Ashworth Scale (0) 5.00 2.00 0.00 Fugl Meyer Assessment Total score (126) 118 .00 126.00 126.00 Motor score (66) 62.00 66.00 66.00 Wolf Motor Function Test Right unaffected (median) 25.49 1.19 23.71 1.09 24.70 1.02 Left affected(median) Right (mean) (1.30.3) Left (mean) (1.30.3) 26.57 1.20 1.701.1 9 1.771.20 23.61 1.35 1.581.09 1.711.66 23.93 0.99 1.651.02 1.600.99

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193 Table 6 4. Muscle strength. Change scores Right/Unaffected side Left/Affected side Movements Post HYBRID Follow up Post HYBRID Follow up Shoulder flexion (lb) 2.10 0.10 3. 20 3.20 Shoulder extension (lb) 0.10 0.90 0.10 1.60 Shoulder abduction (lb) 0.40 3.00 1.40 7.80 Shoulder adduction (lb) 0.70 1.20 1.40 3.70 Shoulder extrarotation (lb) 1.40 0.50 1.90 1.20 Shoulder intrarotation (lb) 0.70 1.00 7.40 0.60 Elbow ex tension (lb) 1.60 1.10 14.10 4.30 Elbow flexion (lb) 0.80 4.30 17.40 1.30 Wrist flexion (lb) 0.10 2.00 1.80 2.30 Wrist extension (lb) 0.70 1.20 0.60 5.30

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194 Table 6 5. Neuromechanisms. Pathways Technique Parameters Results Spinal excitability H reflex Hmax/Mmax ratio Reduced in the AA (Figure 6 3) Hslope/Mslope ratio Reduced in the AA (Figure 6 3) Presynaptic I a inhibition D1 inhibition Increased in the AA (Figure 6 5) Monosynaptic inhibitory reflex arc PAD Increased in the AA (Figure 6 6) Cortical excitability TMS RC slope of MEPs area Reduced in the UH; increased in the AH (Figure 6 7) Inter hemipsheric inhibitory pathways iSP duration Increase d from AH to the UH; decreased from the UH to the AH (Figure 6 8) Cortical inhibitory in terneurons (GABA B ) RC slope for cSP duration Decreased in AH and UH (Figure 11) Global Inhibitory pathway (GABA A ) SICI (%inhibition) Increased in the AH; decreased in the UH (Figure 6 9) Cortical inhibitory interneurons (GABA B ) SVC duration No chang e in e ither AH or UH (Figure 6 10)

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195 Figure 6 2 Key kinematic parameters. Horizontal lines indicate values for the unaffected arm (black line is shoulder ROM, dash line is elbow ROM).

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196 Figure 6 3 H max /M max and H slope /M slope

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197 Figure 6 4 H ref lex recruitment curves and slopes.

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198 Figure 6 5 Presynaptic or D1 inhibition. Values are expressed as percent of unconditioned reflex: Values greater than 100 correspond to facilitation and values smaller than 100 correspond to inhibition. Figure 6 6 Post activation depression (PAD). Values are expressed as percent of reflex at ISI of 12 seconds: Values greater than 100 correspond to facilitation compared to reflex at ISI of 12 seconds, and values smaller than 100 correspond to inhibition compared to reflex at ISI of 12 seconds.

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199 Figure 6 7 TMS r ecruitment curve slopes.

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200 Figure 6 8 Ipsilateral silent period (iSP) and laterality index (LI).

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201 Figure 6 9 Short intracortical inhibition (SICI)

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202 Figure 6 10 Suppression of voluntary co x axis are milliseconds and units for y axis are in microvolts.

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203 Figure 6 11 Stimulus response (S R) curves of SP against stimulus intensity.

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204 CHAPTER 7 CONCLUSIONS The overall objective of this dissertat ion was to improve our understanding of mechanisms underlying upper extremity recovery post stroke by using a multimodal method of investigation that provides insight into the dynamic relationship between neurophysiology and motor behavior and pays particu lar attention to the selection of measures that distinguish betw een recovery and compensation. Chapters 3, 4, 5 and 6 of this dissertation describe individual studies we performed as an attempt to answer our research questions Study 1. W e investigated co ncurrent clinical and kinematic changes following two UE rehabilitation treatments, functional task practice (FTP) and power (POWER) training, with the primary aim of understanding whether improved UE function post stroke results from utilization of compen satory movements or restoration of more normal movement patterns. According to our hypothesis behavioral motor improvements as demonstrated by kinematics reveal restoration of more normal movement function post POWER. In contrast, behavioral changes pos t FTP reveal ed compensatory movement strategies. While mean reaching velocity increased post FTP, this apparent improvement involved concurrent reductions in shoulder flexion and elbow extension ROM, and increased trunk displacement changes indicating re inforcement of compensatory movement strategies 5 Following POWER, participants increased shoulder flexion and elbow extension ROM, reduced associated trunk displacement and also demonstrated greater improvements in the time to max imum shoulder flexion and elbow extension, parameters contributing t o normal inter joint coordination. As revealed by a shift toward normal across numerous kinematic parameters 62 motor patterns more

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205 similar to healthy individuals were revealed following POWER. These behavioral manifestations can be attributed to rest oration or true motor recovery. By using a crossover design w e were able to address a secondary aim, understanding the effect of treatment order,. As hypothesized, our data reveal that POWER followed by FTP produced greater improvements, primarily significantly reduced trunk displacement, indicating a marked reduction of compensatory movements. Notably, this reduced compensation was accompanied by reappearance of normal patterns of shoulder an d elbow mov ement present prior to stroke 78 Taken together, these results offer novel insight for identifying effective UE rehabilitation interventions that promote restoration of n ormal motor function. Further experimental studies are necessary to identify the physiological mechanisms that underlie restoration of normal movement. Study 2 W e compare d the effects of POWER and FTP training i n stretch reflex modul ation. POWER produced greater improvements of stretch reflex modulation than FTP for all parameters (i.e. EMG burst duration, position threshold and burst Intensity). Again, by using a crossover design we were able to address a secondary aim of understanding the effect of trea tment order on stretch reflex modulation. As hypothesized from findings of our previous study our data reveal that POWER followed by FTP produced greater improvements, most significantly for EMG burst duration and EMG latency. Changes in the reflex positi on threshold were present but did not reach statistical significance. It is well recognized that resistance training induces change within the nervous system 52 However, the argument whether these changes affect both the spinal and the supraspinal circuitries is still open 52 This study design included passive and preloaded conditions with the at tempt to discriminate between supraspinal

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206 and spinal adaptations 232 The preloaded condition was implemented to stimulate the voluntary supraspinal descending control by mean s of isometric contraction of elbow flexor muscle s before and during passive elbow extension stretches. In contrast to our hypothesis, data suggest that the effects did not differ between the two conditions in any of the stretch reflex parameters. T he explanation for the lack of differential effects between passive and preloaded conditions may be that both these conditions are testing the same neurophysiologic function Findings of this study may suggest that POWER induces restoration of mechanisms controlling spinal motoneurone discharge. These mechanisms are likely mediated by improved descending (supraspinal) control of motor neuron excitability at the spinal level. Our hypothesis is that improvements at the spinal levels depend on improved regula tion of spinal and supraspinal mechanisms. S pecifically, we believe it can increases the central neural drive leading to enhanced recruitment of the spinal circuitry and consequent improved control of the force required for execution of complex multi segme ntal tasks. Future studies with more sophisticated techniques to study pre synaptic Ia inhibition, post activation depression and cortical excitability should be conducted to differentiate the locus of neur al adaptations after resistance training. Study 3 This study is based on the no tion that a symmetric cortical excitability resulting from stroke may enable maladaptive neuromotor strategies, disrupting physiological activity in transcallosal pathways and producing an imbalance in the mutual inhibitory p rojections between hemispheres 63, 64 Following stroke, activity in the affected hemisphere is disrupted; not only by the infarct itself, but also by inhibition from the unaffected hemisphere which further reduces the excitability of the affected

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207 hemisphere As first described by Ward and Cohen 63 and more recently stated by 64 hypothesis of inter hemispheric competition post stroke, the primary motor cortex of the unaffected hemisphere becomes disinhibited and exerts exaggerated inhibition onto the p rimary motor cortex of the affected hemisphere Specifically, the aims of this study were to: 1) test the hypothesis of inter hemispheric competition post stroke; 2) test whether it was possible to restore a balance of inter hemispheric competition; and 3) test whether repetitive transcranial magnetic stimulation ( rTMS ) combined with POWER training resulted in better functional, biomechanical and neurophysiological outcomes than rTMS combined with FTP. This study included two participants with lesions in similar locations (e.g., right putamen and contiguous white matter) with consequent similar left hemiparesis affecting both the upper and lower extremities The outcomes for Case 1 are consistent with our hypothesis that is formulated on our previous work 61 54 (i.e., better improvements after POWER training versus FTP, as revealed by increased force production in UE muscles, increased joint excursion at elbow and shoulder and associated reduction of compensatory trunk displacement.) At the neurophysiologic level, POWER produced reduced inter hemispheric competition as shown by restored balance of inter hemispheric inhibition (i.e., iSP laterality index). Further, it induced pos itive changes in cortical excitability characterized by emergence of MEPs in the affected hemisphere. In summary, POWER showed positive behavioral and neural effects consistent with our hypothesis of increased central drive from the ipsilesional hemisphere

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208 Conversely, Case 2 revealed better improvements after FTP in joint excursion at elbow and shoulder, associated with improvements in trunk displacement. Further, she did not reveal any change in force production of UE muscles after either POWER training or FTP. At the neurophysiological level, POWER produced normalization of inter hemispheric competition as indicated by positive direction of the iSP laterality index. In summary, in Case 2 POWER did not seem to be as effective at the behavioral level as it was for Case 1, however it still induced positive neural changes. We believe that the sensory impairment of Case 2 could have affected the potential benefit from POWER training. It is possible that Case 2 had benefit more from FTP training than POWER trai ning because of the presence of visual feedback during the execution and accomplishment of functional tasks and that the motor output of POWER training was inadequate, as consequence of sensory impairment, and therefore less effective for inducing positive motor behavioral changes. In support of this view, Van der Lee 37 showed that constrained induce movement therapy (CIMT), in which the patient is strongly encouraged to use only the affected arm while the unaffected arm is immobilized was more effective in people with hemineglect. In general, findings of this case series suggest that it is possible to induce change s in cortical exci tability and interhemispheric inhibition (IHI) associated with behavioral change that constitute functional recovery post stroke Our findings support our hypothesis that POWER promote s enhanced central neural drive in the ipsilesional hemisphere and may r epresent a potential driver of cortical reorganization. Our results compel us to investigate these mechanisms with future larger scale research studies,

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209 which may inform how individual characteristics interact with mechanisms of neural recovery. Study 4 T his single subject design evaluated the effect of 2 weeks of HYBRID training 54 (POWER + FTP) using clinical tests and three dimensional motion an alysis during a functional task to measure behavioral motor control ; H reflex es to probe the spinal circuitry ; transcranial magnetic stimulation ( TMS ) to measure physiological functioning of the cortical networks (i.e. excitatory and inhibitory), and inter hemispheric inhibition (IHI) Our central hypothesis was that an intervention involving POWER would increase the central neural drive during functional voluntary movement, which would be revealed by improvements in both motor behavioral and neural outcomes at both the spinal and supraspinal level s Our kinematic data suggest that HYBRID improved motor control during the functional reaching task. At the spinal level our findings strongly suggest normalization of spinal hyp e re xcitability and increased presyn aptic (e.g., supraspinal) and homosynaptic (spinal) inhibition of the reflex arc in the affected UE motor pools. TMS data at post HYBRID evaluation indicated: 1) increased recruitment curve slopes in the affected hemisphere and reduced recruitment curve sl opes in the unaffected hemisphere; 2) increased ipsilateral silent period from the affected hemisphere to the unaffected hemisphere, and reduced ipsilateral silent period from the unaffected hemisphere to the affected hemisphere indicating rebalancing of IHI; 3) reduced cortical silent period (cSP) duration and its RC slope in the unaffected hemisphere indicating improvement of intracortical inhibition mediated by GABA B receptors 252 ; 4) i ncreased SICI in the affected hemisphere and decreased SICI in the

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210 unaffected hemisphere indicating improvement of intracortical inhibition mediated by GABA A receptors 265 These positive outcomes of HYBRID training can most likely be attributed to: a) the well recognized and profound neural adapta tions induced by POWER training 53, 55, 58 and b) therapeutic intensity, which promotes improvement by challenging the level of the spinal cord, potentially including short term motor unit synchronization, whic h is caused by changes in synaptic efficacy within the motoneuron poo l 53 and 2) at the supraspinal level, including adaptations such as increased activation within the cortical circuit s 58, 154 Our results suggest that HYBRID training induces improved modulation of the spinal mechanisms controlling homosynaptic (PAD) and presynaptic (D1) pathways of the monosynaptic reflex. Improvements in homosynaptic reflex modulation (PAD) suggest improvement in the efficacy of the Ia fibre motoneurone synap se 184 Improvements in the presynaptic (D1) mechanisms suggest improvement of descending inhibitory control from higher cortical structures post stroke 184 TMS data confirm positive treatment effects on inhibitory and excitatory supraspinal pathways. The affected hemisphere improved its cortical excitability and its interhemispheric influence (i.e. inhibition) on the unaffected hemisphere. These findings together suggest an improved interaction between the two hemispheres. In addition, our results suggest improved modulation of the inhibitory pathways within the motor cortex mediated by GABA B (cSP) and GABA A (SICI) receptors. In accordance with previous studies, our study sh owed motor recovery associated with reduction of cSP duration, which is usually prolonged in the ipsilesional hemisphere post stroke, and increased

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211 SICI, which is usually reduced in the ipsilesional hemisphere post stroke. As we hypothesized, the HYBRID tr eatment may have indirectly improved the impaired modulation of the cortical inhibitory pathways by intensely eliciting more participation of the nervous system and engaging of voluntary cortical drive. The power of POWER training: intensity of training. Studies regarding the efficacy of intervention post stroke suggest that high intensity treatments result in better outcomes 222, 275 However, definitions of treatment intensity usually focus on the duration of the rapy or the number of repetitions 222, 275 Therefore, based on this definition, time seems to be an important variable in post stroke rehabilitation. However, as suggested by Wallace et al 27 5 equal time of therapy may not reflect equal intensity of treatment, particularly if there are differences in the content of therapy and severity of the stroke. Systematic reviews of strength training after stroke have provided evidence for efficacy in r educing impairments and a generalization of these effects to increased functional activities. To obtain improvements in strength post stroke, Patten et al recommended working at a minimum intensity of 60% of one repetition maximum 14, 16, 44, 276 using three sets of 8 10 exercises with load adjusted to maintained the minimum desired training target (60 80% of one repetition maximum). Kidgell and Pearce 154 demonstrated changes in cortical excitability and inhibitory cortical networks in non disabled subjects after strength training based on heavy resistive load, manipula tion of repetition and velocity. It appears that training intensity and the manner in which the repetitions are performed are important for increasing neural transmission via the corticospinal pathway 154 156 Lee e t al 277 Carroll et al 55 and Jensen et al 57 reported either a decrease or no change in corticospinal

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212 excitability after strength trainin g. However, these studies did not provide information regarding parameters of strength training program such as training load, repetition, speeds and progression. The consistent findings between studies using high intensity standardized strengthening proto col suggest that to maximize strengthening training via change in neural control, protocols need to focus on load, repetition and velocity. Based on these notions, we believe that positive outcomes of POWER training can most likely be attributed to the the rapeutic intensity, which promotes improvements by challenging POWER im proves the efficiency in descending neural pathways because of adjustments in the activation of ago nists and synergists and decreases in coactivation of antagonists. These adaptations after strength training occur at: a) the supraspinal level, involving changes in corticospinal excitability and inhibition and b) the spinal level, involving changes in s pinal motoneuron excitability and activity in inhibitory and excitatory interneurons 154 Significance I mpairments of UE function are among the most persistent and disabling effects of stroke. While the problem is well recognized, identification of effective therapeutic interventions that restore functional UE use remains elusive. While mainstream therapeuti c interventions, such as constraint induced movement therapy (CIMT) and functional task practice (FTP), show promise at promoting improved UE function post stroke, the metrics of improvement are gauged by clinical scales or gross behavioral measures which emphasize task accomplishment more than motor control or neuroplastic c hanges 36 Importantly, assessment at the level of task completion or failure does not distinguish restoration from compensation at either the behavioral or the

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213 neural levels. This dissertation contributes to the contemporary evidence that resistance training as an intervention post stroke can induce restoratio n of more normal activation in neural circuits and movement patterns. Conclusions and future research. Results of this dissertation support the idea that an intervention involving POWER facilitates restoration of impairments but also activates the process of true recovery at the behavioral and neural levels post stroke. However, future larger scale research studies need to be conducting to better identify the neurophysiological mechanisms that underlie restoration of normal movement. The relationship betwe en spinal and supraspinal facilitatory and inhibitory systems may be clarified by studying their interactions. The knowledge of how different cortical inhibitory and facilitatory circuits are related to each other would improve our understanding of the fun ctional reorganization of the motor cortex and would allow better interpretation of abnormalities post stroke and changes following therapy. Further, our studies suggest that besides impairment of the ipsilesional hemisphere, the contralesion al hemisphere may also be impaired after stroke. Specifically, the contralesional hemisphere may become disinhibited which could contribute to interhemispheric competition 64 Our studies suggest that POWER training may induce posit ive neural changes affecting the excitability of both hemispheres, which may facilitate a more balanced interhemispheric relationship. Based on these notions, future research should reference responses from non disabled healthy controls as comparison rathe r than from the contralesional hemisphere. Moreover, our findings suggest that individual characteristics (such as sensory impairments, depression or physical condition pre stroke) could interact with

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214 mechanism of recovery. Future studies should inform ho w individual characteristics (such as sensory impairment, depression, motivation etc.) interact with mechanisms of recovery, which would help the identification of those individuals who could benefit most from high intensive practice. Lastly, more investi gations need to be conducted to fully understand the effects of treatment intensity. It would be interesting to compare our 2 weeks of HYBRID training with one of the currently most applied therap eutic approaches for upper extremity hemiparesis, such as in duced movement therapy (CIMT). CIMT is a very onerous treatment in terms of both the care cost s During CIMT the patient is strongly encouraged to use only the affected arm while the unaffected arm is immobilized Classically, CI MT is administered for 6 hours/day over 2 weeks, resulting in a total of 60 hours of treatment. In contrast, the HYBRID intervention we proposed in this dissertation consists of 3 hours per day of therapy over two weeks resulting in a total of 30 hours of treatment. This comparison will give more insights regarding the relationship of duration and intensity of treatment.

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215 APPENDIX A REPETITIVE TRANSCRAN IAL MAGNETIC STIMULA TION OF MOTOR CORTEX AFTER STROKE: A FOCU SED REVIEW The following hyperlink gives ac current safety and efficacy of high frequency repetitive transcranial magnetic stimulation (rTMS) on the primary motor cortices (M1) of the affected hemisphere in adults post stroke (Click on OvidSP & Athe ns to access the article) http:/ /pt.wkhealth.com/pt/re/lwwgateway/landingpage.htm;jsessionid=P5GThTB3x7bhn WtWJTvzs3j6kcHvbtQLTQp3PTw1hm9GTG6gz1Gb! 459155671!181195629!8091! 1?issn=0894 9115&volume=91&issue=3&spage=254

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236 262. Kimiskidis VK, Papagiannopoulos S, Sotirakoglou K, Kazis DA, Kazis A, Mills KR. Silent period to transcranial magnetic stimulation: Construction and properties of stimulus response curves in healthy v olunteers. Exp Brain Res 2005;163:21 31 263. Reis J, Swayne OB, Vandermeeren Y, Camus M, Dimyan MA, Harris Love M, Perez MA, Ragert P, Rothwell JC, Cohen LG. Contribution of transcranial magnetic stimulation to the understanding of cortical mechanisms inv olved in motor control. J Physiol 2008;586:325 351 264. Davey NJ, Romaiguere P, Maskill DW, Ellaway PH. Suppression of voluntary motor activity revealed using transcranial magnetic stimulation of the motor cortex in man. J Physiol 1994;477 ( Pt 2):223 23 5 265. Wittenberg GF, Bastings EP, Fowlkes AM, Morgan TM, Good DC, Pons TP. Dynamic course of intracortical tms paired pulse responses during recovery of motor function after stroke. Neurorehabil Neural Repair 2007;21:568 573 266. Liepert J, Storch P, Fri tsch A, Weiller C. Motor cortex disinhibition in acute stroke. Clin Neurophysiol 2000;111:671 676 267. Brouwer BJ, Schryburt Brown K. Hand function and motor cortical output poststroke: Are they related? Arch Phys Med Rehabil 2006;87:627 634 268. Peterse n NT, Pyndt HS, Nielsen JB. Investigating human motor control by transcranial magnetic stimulation. Exp Brain Res 2003;152:1 16 269. Ansari NN, Naghdi S, Hasson S, Mousakhani A, Nouriyan A, Omidvar Z. Inter rater reliability of the modified modified ashwo rth scale as a clinical tool in measurements of post stroke elbow flexor spasticity. NeuroRehabilitation 2009;24:225 229 270. Wolf SL, McJunkin JP, Swanson ML, Weiss PS. Pilot normative database for the wolf motor function test. Arch Phys Med Rehabil 200 6;87:443 445 271. Abbruzzese G, Trompetto C. Clinical and research methods for evaluating cortical excitability. J Clin Neurophysiol 2002;19:307 321 272. Kiers L, Clouston P, Chiappa KH, Cros D. Assessment of cortical motor output: Compound mu scle action potential versus twitch force recording. Electroencephalogr Clin Neurophysiol 1995;97:131 139 273. Oh BM, Kim DY, Paik NJ. Disinhibition in the unaffected hemisphere is related with the cortical involvement of the affected hemisphere. Int J Ne urosci 2010;120:512 515 274. Barthelemy D, Nielsen JB. Corticospinal contribution to arm muscle activity during human walking. J Physiol 2010;588:967 979

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238 BIOGRAPHICAL SKETCH After earning her apy from the University of Insubria (Varese, Italy), Manuela Corti worked at San Raffaele Hospital in Milan as a physical therapist, researcher in the Movement Analysis Laboratory and teacher in the physical therapy program at the University Vita Salute Sa n Raffaele. In the hospital she worked with dozens of people with motor disabilities. Their heartbreaking stories and unflinching courage inspired her to dedicate her life to helping people with motor dysfunction. She eagerly learned about motor impairmen ts in people with neurological disorders and developed expertise with motion analysis W hile at San Raffaele she contributed to four peer reviewed and three non peer reviewed articles, which appear in the premiere rehabilitation medicine journal in Italy. After five years at San Raffaele, helping one patient at a time, she resolved to further her education in order to develop skills to conduct scientific research and position herself to make discoveries with broad impact for people with neuromotor dysfunct ion. To achieve her goals, Manuela Corti moved from her home in Italy to enroll in the University of Florida (UF) Rehabilitation Sciences Doctoral Program under the mentorship of Dr. Carolynn Patten. She dedicated her doctoral studies to understanding ne uromotor re covery by combining physiological and behavioral techniques including: transcranial magnetic stimulation (TMS), stretch and H reflexes, motion analysis and cl inical measures. She received her Ph.D from the University of Florida in the spring 20 12. Her curriculum includes course s in neurobiolog y, neurophysiolog y and m agnetic r esonance imaging and s pectroscopy in living systems.

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239 U ltimately she will pursue an academic position in clinical tra nslational science, directing and conducting neurologic al related research The overall objective of her research lies in investigating the neuromechanics and neurobiology of neurologic disorders. The long term goal of her research is to improve therapy and recovery for persons with neurological diseases.