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Sensori-Motor Effects of Three Locomotor Training Variables: Body Weight Support, Walking Environment, and Armswing

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Title:
Sensori-Motor Effects of Three Locomotor Training Variables: Body Weight Support, Walking Environment, and Armswing
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PHADKE, CHETAN P. ( Author, Primary )
Copyright Date:
2008

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Subjects / Keywords:
Body weight ( jstor )
Electromyography ( jstor )
Gait ( jstor )
Legs ( jstor )
Locomotion ( jstor )
Physical trauma ( jstor )
Spinal cord ( jstor )
Treadmills ( jstor )
Unloading ( jstor )
Walking ( jstor )

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University of Florida
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University of Florida
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Copyright Chetan P. Phadke. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
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8/31/2016

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SENSORI-MOTOR EFFECTS OF THREE LOCOMOTOR TRAINING VARIABLES: BODY WEIGHT SUPPORT, WALK ING ENVIRONMENT, AND ARMSWING By CHETAN. P. PHADKE A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2006

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Copyright 2006 by Chetan. P. Phadke

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This document is dedicated to the giants on whose shoulders stand all researchers.

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ACKNOWLEDGMENTS I wish to thank my advisor, Dr. Andrea. L. Behrman, for training and encouraging me through her own example. I deeply appreciate Dr. Floyd Thompson for his invaluable guidance through the last 5 years. My other two committee members, Dr. John Rosenbek and Dr. Steven Kautz, have been instrumental in helping me improve the quality of the experiments. I sincerely appreciate all members of the locomotor training/intervention laboratory for their assistance. I wish to thank the Department of Physical Therapy for its support of my research activities and the College of Public Health and Health Professions for a grant to support this dissertation project. I also wish to thank members of the Human Motor Performance Lab, BRRC, Malcolm Randall VA Medical Center. I wish to extend my sincere thanks to all my friends and well-wishers in supporting me through the years. I wish to thank the Bahai community of Gainesville for their love and support. A special note of thanks also goes to Dr. Sam Wu for his help with data analysis. Finally, I wish to thank my parents in India and my sister and her family in Quincy, IL, for their unwavering support and unconditional love. It would have been extremely difficult to reach this milestone without them. I thank them. iv

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TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................iv LIST OF TABLES ...........................................................................................................viii LIST OF FIGURES ...........................................................................................................ix ABSTRACT .......................................................................................................................xi CHAPTER 1 INTRODUCTION........................................................................................................1 Walking Rehabilitation: A Paradigm Shift...................................................................1 Measurement of Neurophysiological Response to Training Conditions......................4 Training Conditions/Variables: Leg Load, Walking Environment, and Armswing....5 Summary.......................................................................................................................6 2 BACKGROUND AND SIGNIFICANCE....................................................................8 Conventional Views on Spinal Cord and Recovery.....................................................8 Neuroplasticity..............................................................................................................9 Role of Spinal Cord in Walking.................................................................................11 Central Pattern Generators (CPGs).............................................................................12 Walking-related Neuroplasticity at the Spinal Cord Level.........................................16 Specificity of Sensory Input.......................................................................................19 Neurobiological Control of Walking..........................................................................20 Influence of Sensory Inputs on Stepping Pattern Post-SCI........................................20 Influence of Sensory Inputs on EMG Activity Post-SCI............................................22 Sensory Inputs Can Alter Stepping Pattern................................................................22 Human Application of Basic Science Research: Step Training.................................23 Soleus H-reflex as an Outcome Measure....................................................................24 Taskand Phase-specificity of H-reflex Response.....................................................24 Soleus H-reflex Post-SCI............................................................................................25 Normalization of H-reflexes With Training...............................................................26 Methodological Issues................................................................................................27 Body Weight Support System (BWS) and Rehabilitation..........................................28 BWS and Standing..............................................................................................28 Posture and Leg Loading.....................................................................................29 v

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Effect of Leg Unloading on Soleus H-reflex.......................................................30 Leg Unloading Using BWS..........................................................................30 Leg Unloading Using Buoyancy..................................................................31 Unloading of Legs Using Parabolic Flight...................................................31 Leg Unloading Post-SCI......................................................................................32 Locomotor Training with TM/BWS/trainers Post-SCI..............................................32 Two Contrasting Walking Environments: TM vs. OG.......................................32 Effect of BWS on Walking..................................................................................33 Benefits of Walking in the TM Environment......................................................34 Soleus H-reflex Modulation in Walking Post-SCI..............................................36 H-reflex Modulation and Training Adaptations..................................................37 Armswing...................................................................................................................38 Speed Related Armswing Patterns......................................................................38 Evolution of Armswing.......................................................................................39 Propriospinal Interneurons...........................................................................39 Role of Arm Swing..............................................................................................41 Neurological Connections between Arm and Leg...............................................42 CPGs for Armswing.....................................................................................43 Interlimb Reflexes........................................................................................44 Mechanical Coupling of Arms and Legs.............................................................46 Arm to Leg Frequency Ratio........................................................................46 Center of Mass Movements with Armswing................................................47 Can Armswing Drive Leg Movements in Walking?...........................................48 3 EXPERIMENT I: SOLEUS H-REFLEX MODULATION IN RESPONSE TO CHANGE IN PERCENTAGE OF LEG LOADING IN STANDING AFTER INCOMPLETE SPINAL CORD INJURY.................................................................50 Introduction.................................................................................................................50 Methods......................................................................................................................51 Results.........................................................................................................................54 Discussion...................................................................................................................56 Limitations..................................................................................................................59 Conclusion..................................................................................................................60 4 EXPERIMENT II: COMPARISON OF SOLEUS H-REFLEX MODULATION POST-INCOMPLETE SPINAL CORD INJURY IN TWO WALKING ENVIRONMENTS: TREADMILL AND OVERGROUND.....................................61 Introduction.................................................................................................................61 Methods......................................................................................................................64 Results.........................................................................................................................69 Modulation in Persons with I-SCI..............................................................................69 Soleus H-reflex Modulation I-SCI vs. Non-injured Controls.....................................70 Modulation in Non-injured Controls..........................................................................72 Discussion...................................................................................................................72 Effect of BWS on H-reflex.........................................................................................76 vi

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Effect of Walking Environment on H-reflex..............................................................77 Neural Adaptations with LT.......................................................................................78 Limitations..................................................................................................................80 Conclusions.................................................................................................................80 5 EXPERIMENT III: SOLEUS H-REFLEX MODULATION DURING STANCE PHASE OF WALKING IS INDEPENDENT OF ARMSWING PATTERNS IN HEALTHY NON-INJURED SUBJECTS..................................................................82 Introduction.................................................................................................................82 Methods......................................................................................................................84 Results.........................................................................................................................86 Discussion...................................................................................................................87 Central Control of Locomotion in Healthy Non-injured Subjects..............................89 Effect of Perceived Threat to Balance........................................................................90 Effect of Peripheral Sensory Inputs on H-reflex in Static Posture.............................91 Spinal Cord Injury and Soleus H-reflex Modulation..................................................92 Conclusion..................................................................................................................93 6 SUMMARY AND FUTURE DIRECTIONS.............................................................94 Body Weight Support in Standing..............................................................................94 Walking Environment.................................................................................................94 Armswing Patterns in Walking...................................................................................95 Summary.....................................................................................................................96 LIST OF REFERENCES...................................................................................................97 BIOGRAPHICAL SKETCH...........................................................................................119 vii

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LIST OF TABLES Table page 3-1. Demographic data: Persons with i-SCI.....................................................................52 3-2. EMG root mean square values recorded 100 ms prior to electrical stimulation.......56 4-1. Demographic data: Persons with i-SCI.....................................................................65 4-2. EMG activity recorded 100 ms prior to electrical stimulation and H/M ratio..........71 5-1. Mean EMG activity 100 ms prior to electrical stimulation.......................................87 5-2. Mean EMG activity in anterior and posterior deltoid muscles..................................88 viii

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LIST OF FIGURES Figure page 2-1. Model of control of walking.....................................................................................21 2-2. Flow chart of the experiments..................................................................................28 3-1. Standing: i-SCI vs. non-injured control; Comparison of H/Mmax values between the two BWL conditions in non-injured subjects and subjects with i-SCI; Standard error bars shown........................................................................................54 3-2. Raw data: M and H waves evoked in soleus; LTA=left tibialis anterior, LS=left soleus, RTA=right tibialis anterior, RS=right soleus, mV=millivolts, ms=milliseconds.......................................................................................................55 3-3. H-M recruitment curves. A typical recruitment curve in a non-injured subject and a subject with i-SCI. Current intensity was steadily increased for successive stimulations (1 to 122) from below the threshold of H wave up to the appearance of stable Mmax (5 mA minimum – 50 mA maximum); mA = milliamperes..........55 4-1. Person with i-SCI walking in two environments......................................................68 4-2. Comparison of mean H/M ratio in persons with i-SCI in the two walking conditions OG and TM; OG = overground, TM = treadmill; * Significantly different (p<0.05); Standard error bars shown.........................................................70 4-3. Persons with i-SCI: % decrease in H/M ratio while walking in TM environment compared to OG environment; Secondary y-axis: Walking speed (miles per hour). In subjects # 3, 4 the H/M ratio increased in stance phase and in subjects # 2, 5 the H/M ratio did not change in the swing phase of walking in the TM environment..............................................................................................................71 4-4. H/M ratio in non-injured persons in two walking conditions OG and TM; Standard error bars shown........................................................................................72 4-5. Raw soleus H-reflex data from one non-injured control and on person with i-SCI tested in two walking phases: stance and swing. The H-reflex in the swing phase is almost completely depressed in the non-injured subjects. In comparison, the H-reflex in the swing phase is not depressed in the swing phase of OG walking, but is completely depressed in the swing phase of TM walking environment in this person with i-SCI. Also note the decrease in H-reflex in the stance phase of ix

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walking in the TM compared to OG walking in this person with i-SCI; ms = millisecond; mV = millivolt.....................................................................................73 5-1. Two armswing conditions while walking over the treadmill at 2.4 miles per hour (mph)........................................................................................................................86 5-2. Mean H/M ratio in two walking conditions; Standard error bars shown.................87 x

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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 SENSORI-MOTOR EFFECTS OF THREE LOCOMOTOR TRAINING VARIABLES: BODY WEIGHT SUPPORT, WALKING ENVIRONMENT, AND ARMSWING By Chetan. P. Phadke August 2006 Chair: Andrea. L. Behrman Major Department: Rehabilitation Science Spinal cord injury (SCI) is highly prevalent with over 11,000 new cases per annum. With emergence of new therapies, walking rehabilitation is undergoing a paradigm shift from compensation-driven to physiologically-based. Locomotor training (LT) is a new strategy based on basic science evidence of plasticity as a result of repetitive task-specific sensory inputs to the injured spinal cord. It utilizes a treadmill (TM) and body weight support (BWS) and has been reported to improve walking in subjects with incomplete SCI (i-SCI). The aim of this project was to investigate the neurological mechanisms underlying LT variables in persons with i-SCI. Specifically, the effects of three walking-related inputs (leg load in standing, training environment, and armswing) on soleus H-reflex were examined. In the first experiment, the soleus H-reflex was tested in two standing conditions: with and without 40% BWS in non-injured and SCI subjects. The results suggest that the H-reflex was significantly greater in SCI compared to the non-injured subjects, but was not affected by 40% BWS in both groups. Although BWS is xi

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known to assist with standing, the underlying mechanism likely does not involve change in the H-reflex excitability. In the second experiment soleus H-reflexes were compared in two speed-matched walking environments: TM and OG. The TM environment consisted of a TM, BWS, and manual stepping assistance, whereas in the OG environment, subjects walked unassisted. Walking in the TM environment produced greater modulation of soleus H-reflex and the H-reflex was significantly greater in amplitude in SCI compared to non-injured subjects. It appears that the improvement in walking pattern in the TM environment is partly related to improvement in H-reflex modulation. In the third experiment, the soleus H-reflexes while walking at 2.4 mph with reciprocal armswing pattern were compared to actively restrained armswing condition. The results show that afferent information in the form of armswing does not affect H-reflex excitability in healthy non-injured subjects. The normal control mechanisms are impaired after SCI and the role of armswing must be investigated in the SCI population. In summary, it appears that LT environment has the potential to assist in normalization of reflex modulation post-SCI. xii

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CHAPTER 1 INTRODUCTION Walking Rehabilitation: A Paradigm Shift Walking is a highly specialized motor function orchestrated by the central nervous system using feedback from a confluence of sensory inputs. Injury to the central nervous system, supraspinal and spinal, may disrupt the flow and assimilation of sensory feedback leading to walking dysfunction. In particular, disruption of neural pathways of the spinal cord results either in the inability to walk or an impaired walking ability. The desire to walk is prominent after spinal cord injury with only 25-33% of the population regaining some degree of walking ability (Barbeau et al., 1999). Persons with incomplete spinal cord injury (i-SCI) may have greater potential for such recovery compared to complete SCI (Raineteau and Schwab, 2001). Traditional rehabilitation approaches for persons post-SCI use compensatory strategies for irremediable deficits of voluntary movements, strength, balance, and coordination to achieve functional abilities (i.e., wheelchair mobility, transfers, standing, walking). The assumption guiding the compensation-based approach is that the nervous system cannot repair itself, cannot be repaired, and is incapable of relearning lost functions (Harkema, 2001). Such an approach minimizes functional limitations by providing external walking aids and braces and teaching alternative movement strategies to achieve mobility (Somers, 1992; Atrice et al., 1995; Melis et al., 1999; Bateni and Maki, 2005). However, research studies both in animals and humans over the last two decades have provided new insights about the recovery processes after neurologic injury 1

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2 and the neurobiology of walking (Barbeau et al., 1987; Barbeau and Rossignol, 1987; Barbeau and Blunt, 1991; Barbeau et al., 1993; Dobkin, 1993; Blanger et al., 1996; Calancie et al., 1996; Edgerton et al., 1997; Edgerton et al., 1997; Basso, 1998; Chau et al., 1998; Barbeau et al., 1999; De Leon et al., 1999; Behrman and Harkema, 2000; Barbeau, 2003; Bem et al., 2003; Behrman et al., 2005). The term neuroplasticity has emerged from this body of research literature, which emphasizes the inherent potential of the adult nervous system to learn motor tasks in response to sensory stimulation. Activity dependent neuroplasticity is a lasting change in spinal cord function produced as a result of peripheral and/or descending inputs (Wolpaw and Tennissen, 2001). The underlying construct is that a change in sensory input can shape motor output (Grillner et al., 2000; Wolpaw and Tennissen, 2001; Zehr, 2005). Evidence from basic science has demonstrated that the spinal cord plays a predominant role in generating the reciprocal pattern of walking independent of supraspinal input (Grillner and Zangger, 1975; Andersson et al., 1978; Grillner and Rossignol, 1978; Grillner, 1979; Grillner, 1985; Barbeau and Rossignol, 1987; Conway et al., 1987; Grillner and Dubuc, 1988; de Guzman et al., 1991; De Leon et al., 1998; Bem et al., 2003). This evidence has challenged a hierarchical model for the control of walking and has been a catalyst for emerging rehabilitation therapies that maximize neuroplasticity and the inherent biological mechanisms that generate locomotion. Thus, rehabilitation of walking after SCI is undergoing a paradigm shift from a compensation-driven approach to a physiologically-based strategy to improve walking recovery (Behrman et al., 2005). Locomotor training (LT), a new training strategy that is based on evidence of plasticity in the injured spinal cord from basic science research, incorporates use of

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3 treadmill (TM) and body weight support (BWS) to promote practice of walking while minimizing compensation. LT features simulation of normal walking by providing appropriate walking related sensory inputs to evoke rhythmic stepping. To preclude compensation, BWS, a TM, and manual assistance are employed as the key components of LT. This approach is gaining widespread application for re-training walking in persons post-SCI (Wernig and Muller, 1992; Behrman and Harkema, 2000; Protas et al., 2001; Dietz and Harkema, 2004). Post SCI, walking is impaired and the sensory experience related to walking is different from normal walking. For example, walking post-SCI may feature use of walking aids and orthoses, slow speed, abnormal kinematics and kinetics, shift in loading from the legs to the arms for weight-bearing, and inappropriate activation of leg muscles (Visintin and Barbeau, 1994; Harkema et al., 1997; Melis et al., 1999; Behrman and Harkema, 2000; Maegele et al., 2002; Bateni and Maki, 2005). In contrast, the sensory experience of walking provided during LT aims to provide a complete sensory picture of normal walking to stimulate motor output in the form of improvement in walking behavior (Behrman and Harkema, 2000; Behrman et al., 2005). Several studies have reported LT related improvements in walking in subjects with i-SCI (Wernig and Muller, 1992; Dietz, 1995; Wernig et al., 1995; Gardner et al., 1998; Trimble et al., 1998; Behrman and Harkema, 2000; Protas et al., 2001; Wirz et al., 2001; Behrman et al., 2005; Effing et al., 2005; Field-Fote, 2005; Hicks et al., 2005; Dobkin et al., 2006), though with varying degrees of benefit. To further improve this therapy evidence is needed to understand the mechanism of recovery. Answering four key questions will advance the scientific evidence for clinical decision-making for locomotor training: 1) Who will benefit? 2) What is being provided? (The intervention), 3) When is

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4 the best time to deliver the intervention? and 4) How do persons benefit? (i.e., mechanisms of recovery to outcomes). The proposed studies will address two of these four questions. First, what are the optimal training parameters (i.e., treadmill speed and percentage of BWS) (Field-Fote, 2005; Hidler, 2005) necessary to maximize recovery of locomotor function? Second, what are the neurophysiological mechanisms of reported improvement? To devise and refine this intervention, there is a need to understand the effect of various training variables on motor output of stepping and the neurophysiological mechanisms accounting for the response (Cote and Gossard, 2004; Ferris et al., 2004). The primary aim of this project was to investigate the neurological mechanisms underlying the training variables of the locomotor training intervention in persons with i-SCI. In this three-part project, the soleus H-reflex was employed to examine the effect of three specific walking-related sensory inputs: leg load in standing, training environment (over ground or TM), and armswing. Measurement of Neurophysiological Response to Training Conditions Soleus H-reflex testing is a non-invasive, easy to evoke method of studying the excitatory and inhibitory effects of various sensory inputs on motorneuronal activity (Misiaszek, 2003). The spinal cord monitors and adjusts the soleus H-reflex amplitude in response to change in sensory inputs to suit the needs of the task of walking (Zehr, 2002; Misiaszek, 2003). H-reflex amplitude is increased post-SCI and normalization of reflex amplitudes has been associated with functional improvements (Fung and Barbeau, 1994; Hiersemenzel et al., 2000; Cote and Gossard, 2004; Kiser et al., 2005; Reese et al., 2006). Thus H-reflex is a sensitive tool to assess the effects of change in sensory input on the motor output of standing and stepping (Zehr, 2002; Misiaszek, 2003).

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5 Training Conditions/Variables: Leg Load, Walking Environment, and Armswing In the first experiment the effect of partial leg unloading in standing was examined. Standing is of inherent significance to walking recovery post-SCI. Use of BWS encourages independent standing by providing stability and reducing the fear of falling, thus assisting with retraining standing post-SCI. Even though BWS has been reported to be useful in retraining walking (Visintin and Barbeau, 1989; Visintin and Barbeau, 1994) and has been widely used in gait rehabilitation research, the neurological effect of BWS post-SCI is not well understood. Walking and standing are two unique tasks, and training in one task does not generalize to improvements in the other task (Edgerton et al., 1997). Hence, understanding the mechanism of change in soleus H-reflex excitability with a change in leg load in standing is critical. The purpose of the second experiment was to examine the effect of training environments, namely overground (OG) and TM/BWS/manual assistance (TM environment), on soleus H-reflex excitability. Disruption of the spinal cord circuits regulating locomotion results in slow and uncoordinated walking following i-SCI. In contrast, the TM environment incorporates training over TM with the help of BWS and trainers to simulate and facilitate normal walking kinematics. Thus, walking speed and kinematics closely resemble normal walking and are deemed as desirable for relearning walking post-SCI (Grillner and Rossignol, 1978). Along with walking deficits post-SCI, the soleus H-reflex excitability is also impaired and the reflex amplitudes are greater compared to normal healthy individuals while walking overground. Since the TM environment enables persons with i-SCI to generate a more normal stepping pattern (Visintin and Barbeau, 1994; Dietz, 1995; Harkema et al., 1997; Maegele et al., 2002), it may exert beneficial neurophysiological changes on the nervous system (Kiser et al.,

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6 2005). To further understand the effect of the therapeutic training environment, this study compared soleus H-reflex excitability while walking overground to responses while walking on the treadmill. The purpose of the third experiment was to test the effect of armswing, while walking on a TM, on soleus H-reflex excitability. Evidence from literature shows that armswing assists in propulsion and balance (Eke-Okoro et al., 1997), and inhibition of armswing leads to lower propulsion and decreased walking speed (Eke-Okoro et al., 1997; Marks, 1997). In addition, sensory input of upperlimb origin is carried to the spinal cord to modulate leg reflexes (Delwaide et al., 1977; Baldissera et al., 1998; Hiraoka and Nagata, 1999; Dietz et al., 2001; Hiraoka, 2001; Frigon et al., 2004), but none of these studies have tested these interlimb reflex effects while walking. There is lack of clear evidence in scientific literature that shows that armswing is beneficial to walking, and as a result several researchers continue to use parallel bars while training patients with neurologic injuries over the treadmill (Visintin and Barbeau, 1994; Field-Fote, 2005). Examining the sensory-motor effects of armswing on leg reflexes in walking will guide clinical decision-making for incorporating armswing with LT in subjects with neurologic injuries. Summary Overall, this dissertation project examined the sensory experience of 1) standing leg load during standing, 2) training in TM environment, and 3) armswing while walking on soleus H-reflex excitability. In the subsequent sections I will elaborate upon 1) the limitations of conventional walking rehabilitation approaches and the emergence of scientific literature on neuroplasticity of the spinal cord, 2) neuroplasticity of the spinal cord related to walking behavior and provide a framework for the neurobiological control

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7 of walking, 3) the evidence for benefits of retraining walking after SCI in the TM environment, 4) the merits of using the soleus H-reflex as a quantitative, neurophysiological measure for response to sensory input under varying conditions in both non-injured and spinal cord injured individuals, and 5) the state-of-the-evidence for each of the three sensori-motor conditions engaged in retraining standing and walking: BWS during standing, training environment (OG vs.TM), and armswing while walking. In the process I will identify gaps in our current knowledge that serve as the basis for this dissertation inquiry and the significance of this study for the advancement of the scientific evidence guiding locomotor rehabilitation.

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CHAPTER 2 BACKGROUND AND SIGNIFICANCE The aim of this dissertation was to understand the effect of sensory inputs on recovery processes after SCI-a highly prevalent injury type with over 11,000 new cases with SCI reported annually in United States ((NSCISC), 2005). About 52% of these injuries are incomplete as patients recover partial control of muscles and sensations below the level of injury ((NSCISC), 2005). Only 25-33% of this population regains some degree of walking ability and the desire to walk is prominent post-SCI (Barbeau et al., 1999). Majority of people with motor incomplete SCI (i-SCI) do not recover functional walking; yet, therapies for ambulation, except use of orthotic and assistive devices, have changed little over the last 20 years (Frankel et al., 1969; Ford, 1974; Guttman, 1976; Burke et al., 1985; Daverat et al., 1988; Somers, 1992; Knutsdottir, 1993). Conventional Views on Spinal Cord and Recovery Conventional rehabilitation primarily provides compensatory strategies for accomplishing mobility and strengthening above the level of the lesion (Somers, 1992; Atrice et al., 1995). Compensatory strategies include use of assistive devices such as walker, crutches, and canes which result in a forward-flexed posture and slow walking speed (Melis et al., 1999). Such an approach is based on conventional views that the spinal cord serves as a conduit for supraspinal input and reflexes. This hierarchical approach assumes that processing of sensory information, plasticity, and learning after SCI occur in the supraspinal structures rather than in the spinal cord (Harkema, 2001). In 8

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9 fact a long-held view was that spinal cord circuits are hard-wired and incapable of neuroplasticity (Forssberg and Svartengren, 1983; Wolpaw and Tennissen, 2001). Consequently, after the loss of supraspinal input and no possibility of re-growth across the injured spinal cord, recovery of locomotion has been considered unattainable following a severe or clinically complete SCI even after conventional therapy (Harkema, 2001). Thus, current conventional rehabilitation techniques are insufficient in assisting these patients in speeding and sustaining recovery of walking. Such an approach has been challenged by emergence of a plethora of literature about neuroplastic properties of both mammalian and human spinal cord. Neuroplasticity A simple interpretation of neuroplasticity would be plasticity related to the nervous system. The term neuroplasticity refers to all kinds and levels of reactionary change that occurs throughout the nervous system and includes both structural and functional change (Wolpaw and Carp, 2006). Neuroplasticity has been reported to affect function in diverse areas as visual systems (Fox and Wong, 2005; Hensch, 2005), speech generation (Neumann et al., 2005), auditory systems (Gil-Loyzaga, 2005), hippocampus (Lledo et al., 2006), motor cortex (Sur and Rubenstein, 2005), sensory cortex (Feldman and Brecht, 2005), and synapses (Ying et al., 2005). Sensory experience, either developmental or therapeutic, influences neural reorganization and is the underlying principle of neuroplastic changes seen across diverse sites in the central nervous system (Buonomano and Merzenich, 1998). Developmental plasticity using a unilateral vision deprivation rodent model is reported to cause a reactionary shrinkage in the somatosensory axons, thus indicating the critical role of sensory experience during vision maturation (Fox and Wong, 2005). In patients with

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10 persistent developmental stuttering, speech impairment may be related to compensatory brain hyperactivity; however, speech therapy induces a reorganization of communications between the brain areas associated with speech generation (Neumann et al., 2005). Apart from maturing nervous system, evidence of neuroplastic changes in the adult auditory receptors and related neural pathways is another example of diverse sites of neuroplastic changes in the fully matured nervous system (Gil-Loyzaga, 2005). Neurogenesis, the generation of new neurons, commonly occurs in the newborns and has been reported to occur throughout life in adult human hippocampus region (Eriksson et al., 1998). Brain is a highly plastic structure and Lledo et al. (2006) summarize, “cell-level renovation is not static or merely restorative; instead, adult neurogenesis constitutes an adaptive response to challenges imposed by an animal’s environment and/or its internal state” (Lledo et al., 2006 page-179). Using functional neuroimaging techniques, motor and sensory cortical maps have been recorded and their change in response to learning or injury corresponds with function in human beings (Sur and Rubenstein, 2005). Historically, Hlustic et al. (2006) noted, “Early notions of adult motor system plasticity date back to Sherrington’s observation of the ‘instability of the motor point’ when mapping the primate motor cortex with electrical surface stimulation.” (Hlustik et al., 2001 page-34). Owing to advances in imaging techniques, better construction of motor maps was possible; however, it is now known that representations in the primary motor cortex for different body parts overlap and are not clearly defined (like in primates), but have been reported to be distinct in their organization (Beisteiner et al., 2001). These maps are pliable and reorganize in response to an environmental change in the form of either motor learning or recovery after injury

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11 (Buonomano and Merzenich, 1998; Hlustik et al., 2001). Repetitive stimulation of muscle specific proprioceptive inputs can induce increase in the excitability of corticospinal projections to the target muscles (Miles, 2005). Much like the motor cortex, the sensory cortex maps also alter in response to sensory overuse or deprivation in a functionally distinct manner (Feldman and Brecht, 2005). It should be noted, however, that these cortical representations are not fixed and continuously modified in response to environmental changes and learning (Buonomano and Merzenich, 1998). Neuroimaging techniques have also been used to demonstrate experience-dependent neuroplasticity as a result of a change in behavioral states. A recent study reported that meditation practice induced structural brain changes in the form of increased thickness of cortical areas related to attention, introspection, and sensory processing (Lazar et al., 2005). Thus, plasticity occurs in response to injury, experience, or learning and is associated with learning both in healthy non-injured states and after neurologic injury (Wolpaw and Tennissen, 2001). The review below focuses on the locomotor neuroplasticity, particularly in the spinal cord, in response to injury. Role of Spinal Cord in Walking Wolpaw and Tennissen (2001) defined activity dependent neuroplasticity as a lasting change in the spinal cord function in response to a change in peripheral and/or descending inputs (Wolpaw and Tennissen, 2001).” Substantial evidence in spinal animals suggests that activity-dependent plasticity of spinal neuronal circuits modifies the sensory-motor function of the adult mammalian spinal cord (Barbeau and Rossignol, 1987; De Leon et al., 1998; de Leon et al., 1998; De Leon et al., 1999; Ying et al., 2005). The spinal cord plays a predominant role in generating the reciprocal pattern of walking independent of supraspinal input (Grillner and Zangger, 1975; Andersson et al., 1978;

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12 Grillner and Rossignol, 1978; Grillner, 1979; Grillner, 1985; Barbeau and Rossignol, 1987; Conway et al., 1987; Grillner and Dubuc, 1988; de Guzman et al., 1991; De Leon et al., 1998; Bem et al., 2003). Although supraspinal structures provide the drive for stepping, postural control, and goal directed behavior, the network of interneurons in the spinal cord is primarily responsible for stepping pattern generation (Rossignol, 1996; Grillner et al., 2000). These oscillating interneuronal circuits are also referred to as central pattern generators. Central Pattern Generators (CPGs) Central pattern generators are a network of neurons capable of independent activity without supraspinal or afferent input (MacKay-Lyons, 2002). The CPGs controlling respiration and mastication are located in the brain stem (Nakamura and Katakura, 1995; Marder and Rehm, 2005), whereas those controlling locomotor movements are located in the spinal cord (Grillner et al., 2000). Historically, Sherrington (1910) first reported the presence of stepping like movements in decerebrate cats (Sherrington, 1910) and later Brown (1911) observed that such stepping like rhythmic movements in decerebrate cats were also seen after additional deafferentation of the hind limbs (Brown, 1911). It appeared that presence of sensory information or supraspinal input was not essential for rhythmic pattern generation (Delcomyn, 1980). Grillner and Zangger (1979) reported that rhythmic firing of hind limb motor neurons was elicited even after all afferent feedback from peripheral nerves was pharmacologically abolished (Grillner and Zangger, 1979). This alternate firing of flexors and extensors was observed in one leg only, suggesting that there is at least one CPG network for each limb (Grillner and Zangger, 1979). Although sensory feedback from hind limbs is not causally related to CPG motor output

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13 (Grillner and Zangger, 1984), afferent information is critical for production of patterned movement (MacKay-Lyons, 2002). The importance of afferent feedback to CPG output was demonstrated by Giuliani and Smith (1987). In spinalized cats after spontaneous air stepping had emerged, one hind limb was deafferented (Giuliani and Smith, 1987). As a result, interlimb coordination was disrupted between the two hind limbs and it never recovered. In addition, it was observed that the deafferented limb could not produce rhythmic firing of muscles; however, the hind limb with normal afferentation recovered alternating firing of the flexors and extensors. Interestingly, when air stepping was associated with micturition or tail pinching, interlimb coordination temporarily recovered. A similar pattern was observed in treadmill locomotion and the deafferented limb (in contrast with the afferented limb) did not adapt to changing treadmill belt speed and landed on the dorsum of the paw during the stance phase (Giuliani and Smith, 1987). Bouyer and Rossignol (2003) further investigated this issue by studying the role of percentage of intact cutaneous inputs to locomotion in spinalized cats (Bouyer and Rossignol, 2003). They sequentially dissected the various cutaneous nerves and their data suggests that the percentage of cutaneous inputs is correlated with locomotor deficits. Thus it appears that some form of afferent information is necessary for a coordinated CPG output. This issue is further addressed below in relation with to the locomotor recovery under the heading – “specificity of sensory input”. It has been hypothesized that CPGs consist of reciprocally inhibiting half centers on each side of the spinal cord consisting of a pool of neurons within the neuronal network (Brown, 1911). These half centers consist of flexor and extensor halves for

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14 activating extensors and flexors of the hind limbs respectively (Eke-Okoro, 1991; Gossard et al., 1994; MacKay-Lyons, 2002). Later research, however, a more refined view of the CPGs emerged. The CPGs controlling the leg movements, for example, are now seen as a network of neurons distributed throughout the lumbar region of the spinal cord (Kiehn and Kjaerulff, 1998). As components of the CPG network, the concept of burst generators controlling single joint or muscle has evolved (Kiehn and Kjaerulff, 1998). Regardless of their organization, the neurons in the CPGs have special features like calcium channels and calcium dependent potassium channels which are regulated by a variety of modulatory mechanisms (both of supraspinal and intraspinal origin) to produce rhythmic movements (Grillner et al., 2000). A number of neuromodulators through GABAergic actions and inputs from variety of descending and ascending sources work through G-proteins to control the activity of the interneurons in the CPG network (Grillner et al., 2001). These characteristics result in regulation of the CPG function through both afferent feedback and descending inputs (Whelan, 1996; Zehr, 2005). Even thought the exact location of the CPGs in the transverse plane of the spinal cord is still unclear, the CPG for hind limbs is in the lumbar enlargement and CPGs for forelimbs is known to be in the cervical enlargement of the spinal cord (Kiehn and Kjaerulff, 1998). Genetic approaches are increasingly being adopted to locate neurons specific to various aspects of locomotion such as speed (Gosgnach et al., 2006). In humans, however, the exact location or anatomical evidence is impractical, but there is evidence suggesting the presence of CPGs in the human spinal cord (Zehr and Duysens, 2004). The evidence of CPG presence is indirect because of current limitations in studying the human spinal cord. Calancie et al. (1994) reported that involuntary rhythmic

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15 leg movements could be elicited in supine lying in a subject with chronic incomplete spinal cord injury (Calancie et al., 1994). They claimed that it was the first evidence of CPGs in human spinal cord; however, a few years earlier, Bussel et al. (1988 and 1989) had reported a case of complete spinal cord injured man who showed reciprocal alternating leg movements elicited with the stimulation of the flexor reflex afferents (Bussel et al., 1988; Bussel et al., 1989). In another study it was reported that epidural electrical stimulation of the posterior lumbar cord elicits rhythmic stepping like movements in the lower limbs (Minassian et al., 2004), suggesting the presence of CPGs in human lumbar spinal cord (Dimitrijevic et al., 1998). The evidence of CPGs also comes from healthy humans; a vibratory stimulus applied to either thigh or shank evoked rhythmic stepping like movements (Gurfinkel et al., 1998). Studies on stepping behavior in human infants suspended over a moving treadmill belt provide further support to the theory of human locomotor CPGs. It is, however, not yet clear if there are innate functional corticospinal connections responsible for infant locomotion (Lamb and Yang, 2000). Infants, age 2-11 months, have been suspended on a treadmill and as a result, a stepping pattern has been reported to have emerged (Lamb and Yang, 2000). Interestingly, the muscle patterns adapted to a gradual change in treadmill speed and walking direction, thus suggesting that even though natural locomotion is not yet manifest in these infants, the CPGs are innate in the human spinal cord (Lamb and Yang, 2000). Work from animal models shows that the rudimentary CPGs seen in new born animals need to developed and matured a process that requires sensory inputs from the periphery as well as the descending inputs (Marder and Rehm, 2005).

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16 A large body of research studies over the past 15 years using step training post-SCI has provided further indirect evidence of CPGs in human spinal cord. After SCI, the CPGs below the level of lesion remain anatomically intact and undergo structural reorganization (Nacimiento et al., 1995). Such a reorganization is reflected in selective depression of specific cutaneous afferent discharge related to ground contact within the task of stepping (Cote and Gossard, 2004). Thus, the important role of spinal cord has come to the forefront and the underlying neuroplasticity has been tapped predominantly by basic scientists to study the recovery of locomotor skills in persons with SCI. Walking-related Neuroplasticity at the Spinal Cord Level Neuroplasticity in the spinal cord has been extensively studied using the walking behavior. Scientists have observed that cats, with surgically complete mid-thoracic transection, could be trained to walk with training regimen consisting of repetitive stepping on a treadmill using a suspended sling for trunk support and manual assistance (Lovely et al., 1986; Barbeau and Rossignol, 1987; Lovely et al., 1990; Rossignol and Barbeau, 1995; Edgerton et al., 1997; de Leon et al., 1998; Barbeau, 2003). Use of trunk support and manual guidance encourages rhythmic loading and unloading of the limbs (Conway et al., 1987) and appropriate limb kinematics (Andersson et al., 1978; Grillner and Rossignol, 1978; Andersson and Grillner, 1983). After several weeks of training, the cats were able to step independently with little or no trunk support and assistance in moving the hind limbs. This recovery of stepping has been attributed to CPGs housed in the lumbo-sacral spinal cord that interact with phasic sensory input (Forssberg, 1979; Grillner, 1979; Grillner, 1985; Pearson and Rossignol, 1991). This plasticity is potentially a result of activity-dependent strengthening of the spinal cord circuitry (Muir, 1999).

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17 Such an assumption is based on the findings that stepping recovery occurred independent of change in muscle properties (Roy et al., 1999). It should be noted that although the above studies have focused on the plasticity occurring at spinal cord level, a number of other studies point towards generalized plasticity including at the supraspinal level associated with walking recovery. Neurectomy of ankle nerves done before or after spinalization in cats revealed different patterns of recovery (Carrier et al., 1997; Bouyer et al., 2001) suggesting that adaptive plasticity was distributed in the nervous system involving both spinal and supraspinal structures. The adaptive plasticity in the cortical areas was reflected in increased magnitude of hindlimb EMG responses to cortical electrical stimulation (Bretzner and Drew, 2005). As the severity of the low thoracic spinal lesion in cats increased, the compensation and duration of locomotor recovery also increased (Brustein and Rossignol, 1998). Compensation involved increased propulsive activity in the spared forelimbs of the severely spinalized cats (Brustein and Rossignol, 1998). Thus, the authors concluded that the spared corticospinal tracts had a certain limit beyond which, the compensatory plasticity was insufficient to restore locomotion (Brustein and Rossignol, 1998). The reason for widespread neuroplastic changes in the spinal cord and supraspinal structures is likely because walking behavior is a result of a well-orchestrated activity in both spinal and supraspinal systems. Wolpaw and Carp (2006) succinctly summarized, “the brain shapes spinal cord plasticity during early development and throughout life, and that, as a result, behavior is a combined function of the brain and spinal cord plasticity” (Wolpaw and Carp, 2006 page-248). Up to this point, the research literature focused on

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18 the role of different systems and their effect on the behavior of walking. Knowledge of function at the cellular level within the neurons is now available that provides insight into the walking behavior. Much like the historical views about the spinal cord, the motorneuron dendrites were once thought to be passive conduits for synaptic transmission (Heckman et al., 2005). A better understanding of the role of persistent inward currents (PICs) generated in dendritic region of the motorneuron has added another layer of understanding the motor function and motor control. The PICs are currents generated by voltage channels that are resistant to closing, thus the term persistent applies. The PICs are crucial because they enhance the synaptic input several times thereby enhancing the firing of motorneurons (Heckman et al., 2005). The PICs can be neuromodulated by monoaminergic inputs from the brainstem, thus allowing a control system to adjust and adapt the sensitivity of the motorneuron dendrites and eventually motor function (Heckman et al., 2005). Parallel with observations of spinal shock and loss of muscle tone, the PICs are also depressed, but the PICs have been reported to steadily rise over a period of a few weeks post-SCI resulting in hyperexcitable reflexes and clinical signs of spasticity (Li and Bennett, 2003; Heckman et al., 2005). The PICs are probably enhanced post-SCI in the absence of normal descending monoaminergic neuromodulatory drive from the brainstem. Thus, along with studies of neural pathways and clinical signs, cellular level studies demonstrate the importance of descending input on function at the spinal cord level. Orlovsky (1991) has described the role of supraspinal inputs as: 1) activating the CPGs, 2) controlling the intensity of CPGs, 3) adapting step movements to the environment, and 4) coordinating locomotion with other movements (Orlovsky, 1991).

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19 Thus supraspinal inputs are a critical aspect of locomotion and neuroplasticity in the spinal cord is associated with plasticity changes throughout the nervous system. Specificity of Sensory Input The CPGs respond to walking specific peripheral sensory information to produce a coordinated locomotor pattern in the absence of supraspinal influence (Lovely et al., 1986; Barbeau and Rossignol, 1987). It was demonstrated that this specific sensory input was incorporated and interpreted by the spinal cord neural circuitry to generate a coordinated stepping pattern (Rossignol and Barbeau, 1995; Barbeau, 2003). Several subsequent studies have reported the importance of the specificity and repetitive nature of this peripheral sensory input to induce recovery of stepping (Edgerton et al., 1991). Viala et al. (1986) reported that spinalized rabbits trained to move the hindlimbs together did not exhibit alternating stepping movements (Viala et al., 1986). The lumbo-sacral spinal cord of the cat could function to execute stepping (de Leon et al., 1998) or standing (De Leon et al., 1998) more successfully if that particular task was specifically practiced (Edgerton et al., 1997). There was little carry over from one task to another; when stand training alone was practiced, stepping ability did not recover (de Leon et al., 1999). Observations in spinal cats (Edgerton et al., 1997; De Leon et al., 1999) and to a certain extent in humans (Edgerton et al., 1991; Dobkin, 1993; Muir and Steeves, 1997; Wirz et al., 2001; Dietz and Muller, 2004) also indicate that if the training of a motor task is discontinued, the performance of that task deteriorates. These results show that repetitive motor training provides sufficient stimulation of specific neural pathways to facilitate functional reorganization within the spinal cord and improve motor output. Furthermore, appropriate sensory input during training is of

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20 critical importance to achieve an optimal motor output of the spinal neuronal circuitry (Kawashima et al., 2005). Neurobiological Control of Walking Based on research findings reviewed above a new model of walking control has emerged. Figure 2-1. depicts a model adapted from previous works (Whelan, 1996; Zehr, 2005). The model demonstrates the role of spinal networks which synthesize afferent information for motor output of stepping. The pattern generation as a result of spinal interneuronal network or CPG activity provides the foundation for walking behavior. This pattern generation is regulated by descending input as well as ascending afferent inputs. The descending input, for e.g. the decision to begin walking, is conveyed to the spinal cord and the task of rhythmic pattern generation is relegated to the CPGs (Zehr, 2005). The afferent inputs, namely, proprioceptive muscle afferents from flexor and extensor muscles and cutaneous inputs are the key to rhythmic stepping pattern. The sensory input arrives at the spinal cord as soon as stepping begins and orients the CPGs to the local conditions and thus assists in polishing the motor output of stepping (Zehr, 2005). Particularly post-SCI, the dependence on afferent information increases as reflected in increased dorsal root projections concurrent with recovery of walking (Helgren and Goldberger, 1993). Influence of Sensory Inputs on Stepping Pattern Post-SCI Task-specific sensory input is known to be crucial to movement recovery. Muir and Steeves (1995) reported that spinalized chicks provided with phasic cutaneous stimulation at the foot were able to recover leg movement and retain the newly learned movement (Muir and Steeves, 1995).

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21 CPGs Supraspinal Structures Sensory Input Motor Output CPGs Supraspinal Structures Sensory Input Motor Output Figure 2-1. Model of control of walking In comparison, the chicks that were not provided with cutaneous stimulation could not recover the leg movement. In addition, chicks that were trained to walk overground were able to recover leg movement, whereas chicks trained to swim could not recover the leg movement (Muir and Steeves, 1995). Similarly, spinalized cats trained to stand did not improve walking and cats trained to walk did not improve standing performance (Edgerton et al., 1997). Sensory stimulation in the form of step training post-SCI is known to elicit improved locomotor patterns (Lovely et al., 1986; Barbeau and Rossignol, 1987; de Leon et al., 1998; Rossignol et al., 2002). Sensory inputs during walking occur in a patterned fashion of alternating flexion-extension or loading unloading; such a task specific afferent feedback is known to induce short term plastic changes in the spinal cord and may be crucial to recovery post-SCI (Perez et al., 2003). Afferent information arising from variety of sources is carried up to the spinal cord neurons that monitor and adapt the motor output of walking. For example, initiation of swing phase of walking depends on

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22 the hip position and contralateral step cycle phase (Grillner and Rossignol, 1978). This sensory feedback is crucial to eliciting specific aspects of walking like weight bearing in the stance phase and foot placement (Bouyer and Rossignol, 2003). Influence of Sensory Inputs on EMG Activity Post-SCI Sensory input originating in the ankle extensors contributes 30-60% of the extensor torque produced during normal walking (Yang et al., 1991; Sinkjaer et al., 2000) and inputs like load directly influence the extensor muscle EMG (Harkema et al., 1997). Such reflex changes in extensor EMG activity are most likely of spinal origin because of low response latencies like 40ms (Gorassini et al., 1994) and 64ms (Sinkjaer et al., 2000). Afferent feedback such as proprioception arising from ankle and knee contributes to knee and ankle muscle activity during the task of walking (Hiebert and Pearson, 1999). Elimination of afferent feedback has been reported to decrease extensor EMG by ~50% in decerebrate cats (Hiebert and Pearson, 1999) and conversely increased limb loading increases the EMG activity in the extensor muscles (Timoszyk et al., 2002). Interestingly, unilateral loading of the leg induced a similar increase in unilateral extensor EMG without disrupting interlimb coordination (Timoszyk et al., 2002). Sensory Inputs Can Alter Stepping Pattern There is an increase in extensor EMG activity from afferent stimulation during extension, but resetting of locomotor pattern to extensor activity occurs if this feedback is provided during flexion (Conway et al., 1987; Pearson et al., 1998; Schomburg et al., 1998). The afferent feedback arising from hip flexors also has a similar effect of prolonging the swing phase and increasing flexor activity (Lam and Pearson, 2001). Stimulation of afferent nerves in the stance phase of walking delays the beginning of swing phase and prolongs the stance phase (Whelan et al., 1995). Thus walking specific

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23 sensory inputs related to loading, and cutaneous and proprioceptive inputs are all able to shape and modify the motor output in the form of rhythmic stepping movements (Muir and Steeves, 1995). Human Application of Basic Science Research: Step Training Based on the above model and mammalian and human research, new research therapies are continually being pursued to understand the mechanisms of recovery after SCI. Researchers have adapted information from basic science to rehabilitation science for the development of effective and evidence-based rehabilitation strategies for the recovery of walking after neurologic injury in humans (Edgerton et al., 1991; Rossignol and Barbeau, 1995; Barbeau et al., 1999; Barbeau, 2003). Barbeau et al. (1987 & 1993) first reported suspending a human over a treadmill to assess feasibility of walking retraining (Barbeau et al., 1987; Barbeau et al., 1993); subsequently researchers and clinicians have increasingly adopted the use of a body weight support (BWS) system in human locomotor research and clinical practice respectively (Behrman et al., 2005). Numerous studies have reported locomotor training (LT) related improvements in walking in subjects with i-SCI (Wernig and Muller, 1992; Dietz, 1995; Wernig et al., 1995; Gardner et al., 1998; Trimble et al., 1998; Behrman and Harkema, 2000; Protas et al., 2001; Wirz et al., 2001; Behrman et al., 2005; Effing et al., 2005; Field-Fote, 2005; Hicks et al., 2005; Dobkin et al., 2006) with varying degrees of benefit. The rationale behind this locomotor training (LT) strategy that utilizes treadmill (TM), BWS, and manual assistance, is that a repetitive sensory input in the form of rhythmic stepping movements can evoke motor output of walking (Behrman et al., 2005). Thus, the rationale for the use of TM/BWS/Trainers environment in LT has a sound platform, but more information is needed to understand the mode of recovery that follows

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24 post-SCI and the role of specific parameters of training (Field-Fote, 2005; Hidler, 2005). More specifically, there is a need to understand the neurological effect of walking specific sensory inputs or a combination of sensory inputs related to LT (Little et al., 1999). Knowledge of the neuronal mechanism that underlies locomotor recovery after i-SCI is important for evidence-based practice. Use of soleus H-reflex as a tool is proposed to study the neurological effects of variable sensory inputs during walking. Soleus H-reflex as an Outcome Measure Outcome measures that are sensitive to small changes and reflect functional recovery are critical to examining the effects of various therapies and training variables. H-reflex amplitude as an outcome measure is widespread in research for understanding the neural control of movements. The relatively direct anatomical synaptic connections between the Ia afferents and alpha-motorneurons and the ease of evoking this reflex gives researchers a chance to examine the changes in the motorneuron excitability (Zehr, 2002). H-reflex, an electrically elicited reflex, is equated with a simple stretch reflex or tendon jerk. However, in contrast to a stretch reflex, electrical stimulation of nerves by-passes the effects of muscle spindle (a receptor that senses muscle stretch) and thus allows a measure of excitability of neurons independent of muscle spindle sensitivity (Misiaszek, 2003). Moreover, electrical stimulation of a nerve, to evoke H-reflex, generates a relatively synchronous activation of the alpha motorneuronal pool and thus subtle changes in the H-reflex excitability can be effectively identified (Misiaszek, 2003). Taskand Phase-specificity of H-reflex Response Soleus H-reflex behavior has been studied extensively in normal subjects and is known to be modulated in a task-specific and walking phase-specific manner (Capaday and Stein, 1986; Capaday and Stein, 1987; Llewellyn et al., 1990; Edamura et al., 1991;

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25 Koceja et al., 1993; Stein, 1995; Sinkjaer et al., 1996; Garrett et al., 1999; Simonsen and Dyhre-Poulsen, 1999; Chalmers and Knutzen, 2000; Simonsen et al., 2002; Ethier et al., 2003). The soleus H-reflex amplitude is relatively smaller in standing compared to sitting (Hayashi et al., 1992; Mynark et al., 1997; Kawashima et al., 2003) and prone position (Koceja et al., 1993; Angulo-Kinzler et al., 1998) and relatively smaller in stance phase compared to standing and almost completely depressed in the swing phase of walking (Capaday and Stein, 1986; Sinkjaer et al., 1996; Garrett et al., 1999; Simonsen and Dyhre-Poulsen, 1999; Simonsen et al., 2002). Changes in sensory inputs to the spinal cord from as distant origins as arms (Baldissera et al., 1998; Hiraoka and Nagata, 1999; Kawanishi et al., 1999; Hiraoka, 2001; Frigon et al., 2004) and contralateral leg can change the soleus H-reflex excitability and thus makes H-reflex a useful tool in understanding the effects of certain sensory inputs individually or in a combination. Soleus H-reflex Post-SCI Study of H-reflexes in soleus muscle has offered insights into altered patterns of reflex excitability following SCI (Yang et al., 1991) as well as providing sensitive probes of changes induced by specific therapeutic regimen (Yang et al., 1991; Fung and Barbeau, 1994; Trimble et al., 1998). Following SCI, the development of spasticity has been temporally correlated to specific changes in excitability patterns of soleus H-reflex (Hiersemenzel et al., 2000). H-reflex can be elicited normally and is depressed (similar to non-injured people) immediately post-SCI (Leis et al., 1996), but steadily increases over the period of first few weeks (Leis et al., 1996) and months (Hiersemenzel et al., 2000). It appears that during the spinal shock period, even though there is paralysis of muscles because of disruption of supraspinal inputs, the H-reflexes are normally elicitable. Thus it appears that supraspinal inputs to the spinal cord reflex centers are not exclusively

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26 inhibitory in nature. There is a generalized down regulation of neuronal activity following SCI and subsequently, over the next few weeks immediately post-SCI, there is a generalized upregulation of synaptic activity leading to greater excitability of H-reflexes. After the initial spinal shock is over and spasticity emerges, decreased modulation and significantly greater H-reflex amplitudes compared to healthy controls are observed (Ishikawa et al., 1966; Yang et al., 1991; Fung and Barbeau, 1994; Trimble et al., 1998; Trimble et al., 2001; Kawashima et al., 2003). Therefore, these abnormal reflexes appear to be significant contributors to spasticity (Okuma et al,. 2002; Crone et al., 2003; Kiser et al., 2005) and walking related impairments like clonus (Yang et al., 1991). Normalization of H-reflexes With Training Soleus H-reflexes are greater post-SCI (Stein et al., 1993) and a decrease in H-reflex amplitude may be correlated with recovery. Trimble et al. (2001) reported an increase in walking speed in subjects with i-SCI with a decrease in soleus H-reflex amplitude after a single bout of locomotor training (Trimble et al., 2001). During recovery post-SCI, training programs such as passive bicycling and walking over a treadmill have been reported to result in normalization of H-reflex modulation. Skinner et al. (1996) reported normalization of H-reflex rate depression following 3 months of passive bicycling in completely spinalized rats (Skinner et al., 1996). Kiser et al. (2005) reported in their case study that 13 weeks of passive bicycling resulted in habituation of H-reflex and decrease in spasticity (Kiser et al., 2005). In a similar study in spinalized rats, Reese et al. (2006) reported that passive bike training can normalize H-reflexes immediately post-SCI for a period of up to 3 months post-injury (Reese et al., 2006). Trimble et al. (1998) reported in a single subject that normalization of H-reflex

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27 modulation occurred after 4 months of training over a treadmill (Trimble et al., 1998). H-reflexes can also be operantly conditioned to either increase or decrease and can alter function in lower limbs (Wolpaw et al., 1989). In addition, Chen et al. (2005) reported that conditioning of soleus H-reflex can improve locomotion in spinalized rats (Chen et al., 2005). Methodological Issues H-reflex is highly sensitive to various inputs including posture (Paquet and Hui-Chan, 1999), joint position (Zehr, 2002), reciprocal and recurrent inhibition (Pierrot-Deseilligny and Mazevet, 2000), behavioral state (Honore et al., 1983; Bonnet et al., 1997), and muscle activity (Funase and Miles, 1999). However, if the above factors are sufficiently controlled, then H-reflex can provide information of the state of the reflex arc. It has immense value as an indicator of adaptation in the central nervous system (Misiaszek, 2003). In fact, Pierrot-Deseilligny and Mazevet (2000) emphasized that H reflex is probably the only available technique affording investigation of changes in transmission in the spinal pathways during motor tasks (Pierrot-Deseilligny and Mazevet, 2000). Thus, soleus H-reflex may serve as an important indicator of a change in walking function. Furthermore, since the means to examine the neural control of movements are limited in human beings compared to animals, H-reflex is widely used as a human neural probe (Misiaszek, 2003). In the subsequent sections I will review pertinent literature related to sensory inputs during LT (see Figure 2-2. below); specifically, leg load using BWS (A), stepping pattern during walking in the TM environment (B), and armswing patterns (C).

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28 Figure 2-2. Flow chart of the experiments Body Weight Support System (BWS) and Rehabilitation A BWS system provides support of a select percentage of a person’s body weight via a suspension device and harness, thus achieving partial unloading of legs. BWS and Standing The BWS system was first introduced in the rehabilitation setting in 1987 by Hugues Barbeau (Barbeau et al., 1987). The purpose of this modality was to support a person’s body weight and assist with stepping post-SCI. Such BWS systems are gaining prominence in clinical settings and have been used in conjunction with a treadmill for gait retraining, particularly in people following SCI (Wernig and Muller, 1992; Behrman and Harkema, 2000; Protas et al., 2001; Dietz and Harkema, 2004) or stroke (Visintin and Barbeau, 1989; Wernig and Muller, 1992; Behrman and Harkema, 2000; Sullivan et al., 2002). The majority of interest in the neurological effects of BWS over the last fifteen years, barring two recent studies (Ali and Sabbahi, 2000; Field-Fote et al., 2000), has been focused on walking. However, BWS system can also be employed to retrain standing following SCI. Stand training in spinalized cats has been reported to

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29 significantly increase standing performance and EMG activity (De Leon et al., 1998) and the spinal cord can respond to the repetitive sensory input of loading. Even though standing normally is the predecessor to walking, they are both quite different tasks. Standing is the position one needs to start from before proceeding to walk or during gait retraining; thus, training to stand and walk go hand-in-hand. BWS has been reported to facilitate better stepping pattern over the TM (Visintin and Barbeau, 1989) and has been used in several studies to date (Wernig and Muller, 1992; Behrman and Harkema, 2000; Protas et al., 2001; Sullivan et al., 2002; Dietz and Harkema, 2004). However, ability to step does not translate to standing in spinalized cats (Edgerton et al., 1997; Edgerton, 1997) and the effect of BWS needs to be studied separately in both tasks. H-reflex is known to be task-specific and decreases with a change in posture from sitting to standing (Capaday and Stein, 1986). It is not clear if it is a change in posture or a change in leg loading that leads to changes in H-reflex excitability. Past studies to understand the effect of unloading of legs on the soleus H-reflex modulation show that unloading the legs while standing does not change the soleus H-reflex amplitude in non-injured subjects (Ali and Sabbahi, 2000; Field-Fote,, Hufford et al,. 2000); however, the neurological effect of leg loading is still unclear in the SCI population. BWS alters leg loading; studying the change in soleus H-reflex with a change in BWS will help understand the mechanism of recovery of standing post-SCI. Posture and Leg Loading Soleus H-reflex amplitude is reported to be greater when recorded during non-weight bearing positions such as prone-lying (Koceja et al., 1993; Angulo-Kinzler et al., 1998) and sitting (Hayashi et al., 1992; Mynark et al., 1997; Kawashima et al., 2003) compared to those recorded during a weight-bearing position such as standing. In contrast

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30 to non-weight bearing postures, standing requires more postural control and legs are fully loaded in this position. However, it is unclear if the H-reflex modulation is caused by a change in posture or a change in leg loading. Since soleus H-reflex modulation is task specific in nature (Capaday and Stein, 1986), the modulation of H-reflex may result due to change in posture. This issue has been studied in normal healthy subjects using different ways of unloading the legs. Effect of Leg Unloading on Soleus H-reflex Several studies have reported the effects of leg unloading on H-reflex excitability in healthy subjects using parabolic flight, BWS, or water buoyancy to unload the legs. Leg Unloading Using BWS Ali et al. (2000) used 25% BWS to study the effect of leg unloading on H-reflex in healthy subjects. They used a harness to symmetrically unload the legs and found that soleus H-reflex did not change with leg unloading (Ali and Sabbahi, 2000). Similarly, Field-Fote group (2000) used BWS system to provide unloading (25% and 50% BWS); they found that motor neuron excitability did not change with a change in leg weight bearing load in healthy subjects (Field-Fote et al., 2000). Locomotor training studies using BWS and TM have typically used 40% BWS (Wernig and Muller, 1992; Wernig et al., 1995; Protas et al., 2001; Dobkin et al., 2003) to train individuals with leg paralysis. It has been reported that using greater than 50% BWS (Finch et al., 1991) leads to significant change in gait parameters and a decrease in mean EMG amplitudes. Thus, a BWS percentage in the range of 25-50% appears to clinically relevant. In their studies, Ali et al. (2000) and Field-Fote et al. (2000) used clinically relevant BWS percentage (25-50%) and reported no change in H-reflex amplitude. However, using a higher than 50% BWS may cause depression of H-reflex amplitude.

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31 Leg Unloading Using Buoyancy Nakazawa and colleagues used tank water submerging as a means to unload the legs and found that in healthy subjects the H-reflex was suppressed when the legs were unloaded (Nakazawa et al., 2004). The contrasting results between the studies by Nakazawa et al. (2004) and Field-Fote et al. (2000) are probably because of the percentage of leg loading used; in the Field-Fote study the lowest leg loading allowed was 50% body weight and in the Nakazawa study the leg loading allowed was 20% body weight. In a similar study, Egawa et al., (2000) reported that soleus H-reflex amplitude was significantly greater when legs were unloaded compared to standing with full body weight load bearing (Egawa, al., 2000). They used water tank buoyancy to unload the legs by up to 95%, thus leaving the legs loaded with only 5% of body weight. From the above four studies it appears that 25-50% BWS support does not cause a change in soleus H-reflex amplitude, but 80-95% BWS causes suppression of the H-reflex amplitude. Unloading of Legs Using Parabolic Flight Miyoshi et al., (2003) used a parabolic flight to artificially create a condition with decreased and increased gravity and tested soleus H-reflexes, but their results were inconclusive (Miyoshi et al., 2003). They found that both the gravity conditions showed greater H-reflex amplitude compared to normal gravity standing, but no difference was found between increased and decreased gravity standing (Miyoshi et al., 2003). In summary, the studies done in healthy subjects show that soleus H-reflex modulation does not change with a change in leg unloading of up to 50% body weight; however, this issue has not been sufficiently addressed in subjects with SCI.

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32 Leg Unloading Post-SCI The studies mentioned above were all performed on healthy subjects, consequently, the information about the load related change in soleus H-reflex excitability post-SCI remains a gap in scientific literature. What we know thus far is limited to a study by Kawashima and colleagues, (2003), who reported that in subjects with complete SCI soleus H-reflex amplitude was greater when recorded during sitting compared to standing (Kawashima et al., 2003). This effect can either be explained by a change in posture or a change in leg loading. Since BWS is a modality used to retrain standing following SCI, examining the effect of BWS on soleus H-reflex in subjects post-SCI will provide information about how a change in sensory input of leg loading influences reflex activity. This information is vital to effective implementation of this therapy in a rehabilitation setting. Locomotor Training with TM/BWS/trainers Post-SCI Step training in the TM environment assists in producing a rhythmic and repetitive walking pattern which subjects with i-SCI are unable to generate unassisted overground. The EMG firing pattern of leg muscles, during LT, has been reported to be similar to the firing pattern in healthy subjects (Dietz, 1995). Practice of this rhythmic and repetitive stepping pattern is therefore deemed to be beneficial for relearning stepping after SCI (Behrman and Harkema, 2000). To assist with generating this stepping pattern, BWS, TM, and manual assistance are employed. Two Contrasting Walking Environments: TM vs. OG Walking overground involves unassisted movement of legs to generate stepping and use of an assistive device, particularly for balance. As a result, patients with SCI are unable to walk independently with normal kinematics, thus resulting in uncoordinated

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33 walking. In contrast, to tackle the problems encountered while walking overground, LT over TM utilizes specific measures like BWS and manual assistance. BWS system assists with maintenance of walking balance, thus removing the fear of falling (Behrman and Harkema, 2000). Compared to using assistive devices like walker when walking overground, BWS has been shown to be more effective in generating more appropriate EMG and lower limb kinematics both in humans (Visintin and Barbeau, 1994) and animals. Using BWS and manual assistance, during LT over TM, induces a more normal EMG pattern similar to that seen in able-bodied controls (Harkema et al., 1997) and a more reciprocal activity of agonist and antagonist muscles (Maegele et al., 2002). The TM provides the option of adjusting walking speed and manual assistance to guide the limbs and pelvis, which encourages good walking kinematics, namely: phase specific leg movements and timing and duration of the swing and stance phases. The use of elements like BWS, TM, and manual assistance (TM environment), together, induce a better walking pattern in terms of kinematics and leg muscle EMG firing patterns. Thus, the sensory experience of walking during LT over TM is quite different than walking overground unassisted. Effect of BWS on Walking It is generally accepted that body weight unloading is essential to facilitate leg movements during locomotor training in patients with SCI (Dietz et al., 2002). In their classic study Visintin and Barbeau (1989) reported the benefit of training spastic paretic subjects to walk over TM with BWS. The group that trained with BWS (compared to the group that trained without BWS) showed significant increases in overground speed, endurance, balance, and motor recovery (Visintin and Barbeau, 1989). Walking with 40% BWS also facilitates more normal EMG and decreases clonus in spastic paretic subjects,

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34 compared to walking with 0% BWS (Visintin and Barbeau, 1994). Using BWS while walking over TM is known to generate straighter trunk and better knee alignment, increases in stride length and single limb support time, and decrease in double limb support time (Visintin and Barbeau, 1989). Thus, partial unloading of legs, using BWS, seems to be a crucial factor to generate good walking pattern. Following SCI, walking is unstable, slow and uncoordinated and BWS appears to facilitate relearning of normal walking pattern over the TM. However, it is unclear whether BWS per se is responsible for the benefits of training. Even after a spinal cord injury, Leg load appears to modulate EMG activity in the ankle plantar flexor muscle post-SCI (Harkema et al., 1997). Harkema et al (1997) showed that human spinal cord interprets loading sensation and EMG output during walking may be closely related to peak limb load than muscle-tendon stretch (Harkema et al., 1997). Benefits of Walking in the TM Environment A number of studies using this TM/BWS/trainers strategy have shown promising improvements in persons with SCI (Wernig and Muller, 1992; Wernig et al., 1995; Behrman and Harkema, 2000; Sullivan et al., 2002). Wernig et al. (1995) used LT to train 89 patients with i-SCI and reported significant improvements in walking ability (from being wheelchair bound to ambulatory), walking speed and endurance, and ability to walk over the staircase (Wernig et al., 1995). These improvements were striking since these patients had completed conventional rehabilitation therapy before starting the locomotor training protocol. Several other studies with smaller number of participants have also reported gains in walking speed, endurance, balance, muscle strength, oxygen consumption, and EMG activity.

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35 Gardner et al. (1998) reported effects of LT on one participant, seven months post-injury, who showed an increase in self-selected velocity from 1.22 to 1.36 mph, and also showed improvements in fastest comfortable speed, stride length, and resting HR (Gardner et al., 1998). Behrman and Harkema, (2000) reported the effects of LT over TM in four subjects with mean post-injury time of six months. The subjects with i-SCI improved overground walking and walking speed on the treadmill and demonstrated improvements in gait endurance and balance (Behrman and Harkema, 2000). In 2001, Protas et al. reported three subjects who improved in gait speed, endurance, oxygen costs, and muscle strength (Protas et al., 2001). Wernig at al., (1992) found improvement in both speed and endurance in a chronic population (n=8) in which 5/8 had “functional paralysis” and were previously unable to walk (Wernig and Muller, 1992). In 1995, Dietz et al. showed that, leg muscle EMG activity during LT in patients with SCI was modulated in a similar manner to that in healthy subjects (Dietz, 1995). In 1998, Colombo et al. used TM and BWS to train patients with SCI and reported improved timing and grading of the EMG responses (Colombo et al., 1998). Wirz et al. (2001) have reported similar increase in extensor EMG activity and improved locomotor ability post LT that was maintained at 3 years after the intervention was stopped (Wirz et al., 2001). This maintenance of locomotor gains however was only seen in subjects with i-SCI that walked consistently. Hicks et al. (2005) in another study on effect of long term locomotor training report gains in walking speed and satisfaction with life. Their study was of 12 months duration and a follow up of 8 months post training revealed maintenance of locomotor gains (Hicks et al., 2005). These studies demonstrate the potential and promise of LT over conventional gait training overground.

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36 In summary, the strategy to train stepping in the TM environment appears to be beneficial; however, the specific neurological mechanisms underlying the improvements seen in this environment are not known. The second experiment of this project aims to investigate the sensori-motor effects of training in the TM environment. Soleus H-reflex Modulation in Walking Post-SCI Alongside walking deficits post-SCI, the soleus H-reflex excitability is also impaired and the reflex amplitudes are greater compared to healthy controls while walking overground. Normally, soleus H-reflex is strongly modulated during the walking cycle; it is greater in the stance phase and very small in swing phase in healthy subjects (Capaday and Stein, 1986; Edamura et al., 1991; Sinkjaer et al., 1996; Garrett et al., 1999; Simonsen and Dyhre-Poulsen, 1999; Chalmers and Knutzen, 2000; Ethier et al., 2003). Thus, H-reflex modulation is walking phase specific and commensurate to the needs of walking, but post-SCI reflex activity in the lower limbs is impaired; stretch reflex (Sinkjaer et al., 1996), cutaneous reflexes (Jones and Yang, 1994; Cote and Gossard, 2004), and soleus H-reflexes (Fung and Barbeau, 1994) evoked during walking are all impaired. The impaired soleus H-reflex modulation is reflected in higher reflex amplitudes in both the stance and swing phases of walking compared to healthy subjects (Yang et al., 1991; Trimble et al., 2001). H-reflex modulation is known to be impaired post-SCI both while walking over the TM (Yang et al., 1991) and walking overground (Trimble et al., 2001). Walking impairment post-SCI may be related to impaired modulation of soleus H-reflex (Yang et al., 1991; Trimble et al., 1998). This impaired modulation is also seen in subjects with chronic SCI, who have completed rehabilitation suggesting that modulation does not improve with conventional rehabilitation techniques. These abnormal reflexes

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37 may be responsible for walking related impairments like clonus (Yang et al., 1991). Visintin et al. (1994) reported that using BWS decreased clonus associated with walking (Visintin and Barbeau, 1994). LT enables persons with i-SCI to generate a better stepping pattern over TM (Visintin and Barbeau, 1989). Visintin & Barbeau (1989) reported that using 40% BWS to walk over a TM in patients with i-SCI (without manual assistance) produced a straighter trunk and better knee alignment, increased single support time and stride length, and decreased the double support time. They also reported instances of appropriate EMG timing during the gait cycle (Visintin and Barbeau, 1989). Such an improvement in walking pattern may induce clinically beneficial changes in soleus H-reflex excitability (Trimble et al., 1998). Low frequency rate depression of soleus H-reflex has also been reported to improve by 35% in a subject with i-SCI post LT (Trimble et al., 1998). After a single bout of LT, the soleus H-reflex was found to be depressed significantly while walking overground (Trimble et al., 2001); however in the above study, H-reflex was tested in overground walking after the session of LT over the TM. H-reflex Modulation and Training Adaptations Schneider et al. (2003) reported that soleus H-reflex modulation can adapt and change if systematic training is provided (Schneider and Capaday, 2003). In their study they trained normal subjects to walk backwards on a treadmill and after just 10 days of training the H-reflex decreased in amplitude. The reflex amplitude increased again when subjects walked with eyes closed. Similarly, the H-reflex depressed significantly when subjects walked while holding on to hand rails. Post-SCI the soleus H-reflex has been reported to be modulated by external means like electrical stimulation (Fung and Barbeau, 1994). A couple of studies also demonstrate a neurophysiological change in the form of increase in soleus H-reflex modulation while walking immediately post LT

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38 (Trimble et al., 2001) and increase in low frequency rate depression (in a semi-reclined position) post-training over a TM (Trimble et al., 1998). However, Trimble (1998) also reported no change in H/M ratios (while walking) post-training over TM in one subject with i-SCI (Trimble et al., 1998). In the above study, the subject walked independently over the TM without BWS or manual assistance. This result suggests that use of BWS and manual assistance may be crucial to induce a neurophysiological change while a person is walking over a TM. LT strategy using the TM environment is gaining popularity and is increasing in prevalence and application in clinics; thus there is an urgent need to understand how the benefits of LT are achieved. It is crucial to understand the effect of altered sensory input in the TM/BWS/Trainer walking environment on reflex excitability. This information will assist in modifying and adapting the application of this therapeutic intervention in the clinical setting. In the second experiment we tested the soleus H-reflex modulation while walking overground unassisted and while walking over a TM with BWS and manual assistance, at matched walking speeds. Armswing Arm swing is the reciprocal and rhythmic movement pattern of the arms coordinated with legs and is walking-speed dependent. Speed Related Armswing Patterns Arm swing during walking is qualitatively dynamic. At slow walking speeds the arms swing back and forth in unison; at speeds above ~1.9 mph, the arms move in-phase with the contralateral legs (Webb et al., 1994; Wagenaar and van Emmerik, 2000; Donker et al., 2002). Such a speed dependent relationship suggests that the arm muscles are

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39 recruited, to match reciprocal arm swing with leg movement, only at normal walking speeds (~2.8 mph). Evolution of Armswing Animal evidence: Understanding of the armswing phenomenon is limited to a very few studies that directly address this issue (Eke-Okoro et al., 1997; Marks, 1997). The reason for the dearth in studies related to arm swing is partly because of the myth that arm swing was a passive phenomena and its casual coexistence with walking was viewed to be insignificant. Recently however, there has been a renewed interest in arm swing and its neurological and biomechanical connections with walking. Studies on quadrupedal locomotion serve as a basis for understanding the fundamentals of locomotion related interlimb coordination. Locomotor pattern generating mechanisms in the spinal cord coordinate forelimbs and hindlimbs (Cazalets and Bertrand, 2000) via the intra-spinal connections between the sacral and cervical segments (Krutki et al., 1998). It is thought that these animal linkages were preserved as humans adopted an upright stance and developed hand dexterity. Evidence of persistence of these linkages is seen in humans, for e.g. frequency of arm-leg coordination in activities like creeping, swimming, and walking (Wannier et al., 2001). The linkages between forelimbs and hindlimbs are the propriospinal interneurons connecting various segments of the spinal cord. Propriospinal Interneurons It is this wealth of animal research that we must draw upon and compare with human systems before systematically studying arm swing in humans. In cats, the interlimb pathways connecting cervical and lumbar enlargements in the spinal cord have been thought to be responsible for coordinating foreand hindlimbs during locomotor activities (Milleret al., 1975). The interlimb pathways consist predominantly of

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40 propriospinal neurons connecting the lumbar and cervical enlargements of the spinal cord. These neurons (long and short) synapse with the segments in the spinal cord controlling forelimb and hindlimb movements during locomotion (Krutki et al., 1998; Mrowczynski et al., 1998; Juvin et al., 2005). The presence of propriospinal system has also been shown in human spinal cord (Nathan et al., 1996; Nicolas et al., 2001). This system consists of spinal interneurons connecting different spinal segments and receives convergent inputs from descending systems and from peripheral sources; their anatomical presence assists the spinal cord to serve as an integrating center. They are termed propriospinal because they are intrinsic to spinal cord with axons that cross a number of spinal segments (Burke, 2001). Propriospinal neurons are intact and potentially functional below the level of lesion after spinal cord transection. Baxendale and Ferrell (1985) showed that in decerebrate cats with intact innervation of the foreand hind limbs and reported that the flexion reflexes were most easily elicited in forelimb muscles when the hindlimb was extended, and hindlimb flexion reflexes were most easily elicited when the forelimbs were extended (Baxendale and Ferrell, 1985). After intra-articular injection of local anesthetic, this modulation of reflex excitability was abolished. Thus, in addition to their known segmental effects, joint afferents also exert significant ascending and descending effects on motorneuron excitability (Baxendale and Ferrell, 1985), most likely through the propriospinal system of neurons. It is questioned if animal findings can be extrapolated to humans, since arms have dissociated from being predominantly used for supporting/propelling function, to skilled manipulation (Dietz, 2002). Evidence from basic science and human studies suggests that

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41 the neural interconnections between forelimbs and hindlimbs of quadrupeds may have been preserved and modified in man (Dietz, 2002). The presence of arm swing during walking is one of the purported signs of such preserved interlimb connections. It was historically believed that arms swing passively like a pendulum during walking, but later it was shown that arm muscles actively contract during walking (Jackson et al., 1983; Eke-Okoro et al., 1997). Arm swing and walking appear to be related in a task-specific manner. Even when the upper limbs are restrained (either actively or passively), the arm musculature continues to contract rhythmically (Buchthal and Fernandez-Ballesteros, 1965). There is a coordinated firing of the arm and leg muscles during walking (Buchthal and Fernandez-Ballesteros, 1965) and this coordination has been linked to evolution from quadrupeds. If such interlimb linkages are preserved in man, then it is crucial to study them during human walking. The information gained will provide evidence for the therapeutic use of armswing while walking. Unlike the role of forelimbs in propulsion and weight support in quadrupedal gait, the upper limbs serve a different function in a bipedal gait. Role of Arm Swing The rhythmical oscillation of arms provides counter rotational forces to the trunk, which supports balance, maintains posture, and contributes to propulsion during gait (Eke-Okoro et al., 1997). Thus, arm swing prevents uncoordinated gait patterns (Jackson et al., 1983) and a natural consequence of restriction of reciprocal arm swing is disruption of walking kinematics. Restriction of arm swing also shows depression of leg to arm interlimb reflexes (Dietz et al., 2001). It appears that restriction of arm swing causes both kinematic and neurological changes.

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42 Restriction of arm swing while walking alters symmetrical rotation of the trunk, disrupts lower limb joint trajectories, decreases gait velocity, and shortens stride length (Eke-Okoro et al., 1997; Marks, 1997). Arm swing restriction is also known to induce changes in the trunk kinetics and kinematics. Trunk and pelvis are the anatomical units connecting the arms and legs and much like arm swing, pelvic rotation is also walking speed dependent. Study of pelvic-thorax coordination during human gait showed a shift from in-phase pattern to anti-phase as walking speed increased (Lamoth et al., 2002). The pelvis moves forward along with the swing leg and at higher speeds (above 2.2 mph) this pelvic rotation is counterbalanced by opposite (anti-phase) thoracic rotation. The control of postural muscle tone and stepping behavior may not be different (Grasso et al., 2000). In fact in animal models, the movements of trunk are synchronized and controlled together with limb movements via the CPGs (Bem et al., 2003). Restriction of arm swing increases the EMG activation of trunk muscles required for rotation and decreases the axial trunk rotation (Callaghan et al., 1999). Arm swing assists in trunk rotation and absence of arm swing can limit trunk movements; limited trunk movements can decrease walking speed, both in normal and post-stroke subjects (Wagenaar and Beek, 1992). The functional role of arm swing and the effects of arm restriction together suggest that arms and legs are neurologically and biomechanically connected. Neurological Connections between Arm and Leg The movement of the arms during walking is due to muscular activity and is not simply a passive pendular movement (Jackson et al., 1983; Gutnik et al., 2005). Such a rhythmic coordinated muscle activity of the legs and arms must necessarily need a controlling center. Circuits in the spinal cord are most likely involved in this role. It is unlikely that higher centers in the brain are involved in coordination of arms and legs

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43 specific to the task of walking. Near-infrared spectroscopic topography reveals that there is little brain activation in presumed arm areas of primary sensorimotor cortex during human walking (Miyai et al., 2001). In fact, active arm swinging during standing activated cortical areas not activated during gait (Miyai et al., 2001). Moreover walking with or without arm swing did not change the activation pattern in the brain, thus suggesting that control of arm swing may be achieved predominantly through the spinal cord centers. CPGs for Armswing Recently, Zehr (2005) proposed a model of control of all rhythmic movements (Zehr, 2005). According to this model, rhythmic movements like movements of arms and legs during locomotion bicycling, swimming etc. are all controlled by CPGs and are dependent on and modulated by peripheral sensory and supraspinal inputs. Just like other animals, humans may also have CPGs to generate and coordinate walking (Dimitrijevic et al., 1998). CPGs control interlimb coordination in human walking (Haridas and Zehr, 2003) and arms and legs may be coordinated at least partially through the propriospinal tracts (Haridas and Zehr, 2003). Several studies have used cutaneous and H-reflex modulation and have suggested that the neural control of rhythmic arm movement (Zehr and Kido, 2001; Zehr et al., 2003; Zehr and Haridas, 2003) is very similar to the control of rhythmic leg movement. Thus, arm swing may be controlled by CPG activity (Carroll et al., 2005). A recent study by Frigon et al. (2003) found facilitation of soleus H-reflex with a rhythmic arm cycling task. Their results suggest that the neural networks coupling the leg and arm movements may be active during rhythmic movement of arms. Arm swing during walking, like arm cycling, is also a rhythmic task and can modulate the soleus H

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44 reflex. Soleus H-reflexes were depressed because of an arm cycling task (arm at 70 degree flexion and arm at 10 degree extension) in normal healthy subjects (Frigon et al., 2004). Their results suggested that much like in the leg muscles in walking, this modulation of soleus H-reflex was because of presynaptic inhibition. Apart from arm cycling, arm swing in standing also causes depression of the soleus reflex (Kawanishi et al., 1999; Hiraoka, 2001). Delwaide et al. (1977) determined that with right arm flexion and left arm extension the myotactic reflexes of the soleus and quadriceps of the right leg were facilitated (Delwaide et al., 1977). When the arm positions were reversed, the right lower extremity soleus and quadriceps reflexes were depressed and the biceps femoris reflex was facilitated. In addition, passive movement of the elbow joint (flexion/extension) was shown to facilitate (Hiraoka and Nagata, 1999) while arm swing depressed soleus H-reflex during walking (Kawanishi et al., 1999; Hiraoka, 2001). Thus, the evidence reviewed so far suggests that arm swing patterns influence the leg reflex activity. Interlimb Reflexes Interlimb reflex activity (ILR), elicited in arm muscles by sensory stimulus in the leg and vice versa, is further evidence of a linked neural network in humans. It is believed that since these reflexes have very short latencies (65-80 ms), reflex responses are unlikely to result from cortical mediation (Dietz et al., 2001). Interlimb reflex activity from 50 to 60 ms is likely confined to the spinal cord, while latencies of ~110 ms probably includes both spinal and supraspinal pathways (Calancie et al., 2002). The most likely pathway for these short latency reflexes then, is propriospinal system. Propriospinal connections found in several species including man (Nathan et al., 1996) may be responsible for direct coupling of the cervical and lumbosacral segments of

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45 the human spinal cord to convey afferent input from upper limbs during arm movement. Loss of normal fore-hindlimb coordination and the lack of its recovery in cats are correlated with damage to the central white matter that contains the long propriospinal pathways. The loss of descending long propriospinals is correlated with loss of normal fore-hind limb coordination (Anderson and Howland, 2001). Thus, in a cervical SCI, the probability of sparing of propriospinal neurons is very high. The presence of interlimb reflex responses post-SCI (Calancie et al., 2002; Calancie et al., 2005) provide further evidence that propriospinal pathways coupling the cervical and lumbosacral enlargements of the spinal cord contribute to interlimb coordination. Interlimb reflex activity has been extensively studied in healthy normals using diverse sensory stimuli. For example, rhythmic movements of the foot resulted in ipsilateral wrist flexor activity of short latency (Baldissera et al., 1998). The ILR are also observed in arm muscles in response to mechanical displacement of the ankle and tibial nerve stimulation during walking (Dietz et al., 2001). ILR appear to be phase dependent; they are depressed when the arm swing is restricted and completely absent during standing, standing with arm swing, and sitting (Dietz et al., 2001), thereby suggesting that the neurological connections between arms and legs are functional and specific to the task of walking. Thus it appears that the arms and legs are interconnected via neural communication networks in the spinal cord. Dietz et al. (1999) found that higher the level of lesion in the spinal cord (from thoracic to cervical), the more normal was the locomotor pattern exhibited on a treadmill (Dietz et al., 1999). Perhaps, this indicates that if this spinal cord circuitry [and propriospinal interneurons (Dimitrijevic et al., 1998)] is spared, as would

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46 be the case in incomplete spinal cord injury, higher cervical level spinal cord injury, and stroke, the capacity for locomotor recovery is greater. Spared spinal segments and their interconnections below the level of lesion coordinate better and may be the reason for better walking outcome. Since the arms and legs are linked normally as a part of a functional circuitry, swing of the arms may enhance locomotive abilities. Mechanical Coupling of Arms and Legs Apart from studies exploring the neurological connections between arms and legs, there are a number of kinematic studies demonstrating the biomechanical coupling of the arms and legs. Wannier et al. (2001) observed that the frequency of arm-leg coordinative patterns in creeping and swimming was remarkably similar to that of the arm to leg movement frequency observed in walking (Wannier et al., 2001). Efforts to disrupt this partnership by adding resistance to lower limbs (flippers) during swimming did not alter the arm to leg coordination. The individual adapted arm rhythm to match the new leg pattern and maintaining a locked ratio of arm to leg movement. Such a phenomenon was also reported by Donker et al. (2002); loading of one limb induced generalized reorganization in all body segments to maintain rhythm constancy and balance (Donker et al., 2002). Arm to Leg Frequency Ratio In walking humans, arm to leg coordination is a well-established phenomenon (Dietz et al., 2001). A ratio of 2:1 frequency coordination between arm and leg movements occurs at low walking velocities and the 1:1 frequency coordination occurs at higher walking velocities; it is a clear indication that interlimb coordination between upper and lower limbs exist (Donker et al., 2001; Kubo et al., 2004). Thus, the coordination pattern between the two limbs is dynamic in nature (Wagenaar and van

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47 Emmerik, 2000). Ipsilateral in-phase and out of phase movement of arms and legs is disrupted by passive movement of contralateral arm or leg (Serrien et al., 2001), also suggesting the coupling of all four limbs. Center of Mass Movements with Armswing Furthermore, reciprocal arm swing may also contribute to the effective movement of center of mass (COM). The COM goes through a sinusoidal movement during walking assisting the legs (like springs) to absorb the shock of weight acceptance from one leg to other. The lowest point of COM converges with the highest point of the ground reaction forces (under the foot) at midstance phase of walking. Thus the two curves are upside down; as the ground reaction forces rise, the COM lowers (Farley and Gonzalez, 1996). This occurs at mid-stance of either leg. Interestingly at mid-stance both the arms are by the side, one arm is on its way in extension and the other in flexion. Raising the arm causes the COM to rise and vice versa (Marigold et al., 2003; Lees et al., 2004). Put together, it seems that the raising of arms in either direction after mid-stance assists in raising the COM in preparation to lower and absorb ground reaction forces before the heel strikes. This coincidence of arm and COM movements provide further evidence of the connection between the arm swing and locomotion. Arm swing influences the kinetics of the lower limbs in a vertical and long jump by increasing respectively: the velocity and height of the jump (Lees et al., 2004) and the jumping distance (Ashby and Heegaard, 2002). Arm swing is known to generate energy which is then transferred to the rest of the body, thus enhancing the jump (Lees et al., 2004). However, while walking, arms do not swing in the same direction but in opposite directions and thus may be generating counter balancing forces to control lower limb kinematics and kinetics.

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48 Can Armswing Drive Leg Movements in Walking? Circuits in the spinal cord (CPGs) producing the overall pattern of walking are connected through the propriospinal tracts and one CPG may drive the other. Humans demonstrate natural frequency locking between upper limb movement and lower limb movement during walking, crawling, and swimming (Wannier et al., 2001). Arm and leg coordination during human locomotor activities and their frequency relationships corresponds with a system of two coupled oscillators (Wannier et al., 2001). Mrowczynski et al. (2001) showed in cats that the stimulation of sacral segments causes firing of neurons in the cervical enlargement (Mrowczynski et al., 1998). Arm swing being an integral component of walking, it is quite possible that assistance with arm swing can drive the legs. Incorporating arm swing makes the gait training more task specific, and may enhance recovery. It is possible that if arm swing is incorporated into locomotor training then one oscillator (arm swing CPG) could drive the other (leg CPG). Two separate circuits can be strongly entrained to produce synchronous outputs for inter-limb coordination and reflex modulation (Guadagnoli et al., 2000). Given that the nervous system has the ability to integrate the sensory input from lower limbs and modulate upper extremity reflex function, it is quite likely that arm swing may be an important factor in the recovery of walking (Delwaide et al., 1977). Calancie et al. (2005) reported signs of synaptic connections of ILR becoming stronger post SCI of duration of 1-2 years (Calancie et al., 2005). This suggests that plasticity of the neuronal connections post-SCI can also lead to strengthening of connections between cervical and lumbar spinal cord. Hiraoka (2001) showed that arm movement frequencies can alter soleus H-reflex modulation while standing (Hiraoka, 2001). A recent report suggests that rhythmic upper limb movements can enhance muscle activation in lower

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49 limbs (Huang and Ferris, 2004). Leg movements driven by upper limbs (lower limbs relaxed) compared to leg movements actively driven by upper and lower limbs together produced similar timing of EMG burst in lower limb muscles (Huang and Ferris, 2004). Haridas and Zehr (2003) reported that stimulation of the superficial nerve increased dorsiflexion of the ankle at the stance-swing transition phase (Haridas and Zehr, 2003). The above studies demonstrate that arms can influence leg muscle and reflex activity. The hypothesis that arm swing can drive the legs has been documented in the past. If the circuits in the spinal cord producing the overall pattern of walking are connected, then one may influence or drive the other (Delwaide et al., 1977). Behrman et al. (1998) demonstrated that instructions to increase the arm swing amplitude changed gait parameters resulting in faster walking velocity in subjects with Parkinson’s disease (Behrman et al., 1998). However, there are no other studies exploring the use of arm swing to alter gait parameters in a neurologically impaired patient population. The third experiment of this project was designed to specifically examine the effect of different patterns of arm swing on soleus H-reflex excitability. It is important to identify the specific neurological effects of a particular step-training parameter like armswing and this information will assist in effective application of armswing phenomena to walking rehabilitation.

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CHAPTER 3 EXPERIMENT I: SOLEUS H-REFLEX MODULATION IN RESPONSE TO CHANGE IN PERCENTAGE OF LEG LOADING IN STANDING AFTER INCOMPLETE SPINAL CORD INJURY Introduction Body weight support (BWS) systems are used in clinical settings, with applications for a variety of patient populations. A BWS system provides support of a selected percentage of a person’s body weight via a suspension device and harness, thereby, partially unloading the legs. As a relatively new therapeutic modality for rehabilitation, BWS systems are gaining widespread application for re-training standing and walking, particularly in people following spinal cord injury (SCI) (Wernig and Muller, 1992; Behrman and Harkema, 2000; Protas et al., 2001; Dietz and Harkema, 2004; Behrman et al., 2005). Although, BWS can provide stability and reduce fear of falling during standing rehabilitation, the possibility that it may also be producing a modulation of reflex excitability has not been specifically examined post-SCI. Soleus H-reflex amplitude in persons with complete SCI was reported as greater during sitting (leg unloading) compared to standing (leg loading) (Kawashima et al., 2003). However, it is not known if this modulation of H-reflex amplitude was produced by change in posture or a change in leg loading. Researchers have reported that unloading of legs with BWS does not affect the soleus H-reflex amplitude in standing in non-injured subjects (Ali and Sabbahi, 2000; Field-Fote et al., 2000; Grey et al., 2002). 50

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51 While there is a consensus that soleus H-reflexes are increased in amplitude following SCI in humans (Little and Halar, 1985; Trimble et al., 1998; Thompson et al., 2001; Trimble et al., 2001) and animals (Thompson et al., 1998), recent findings by Lee et al. (2005) (Lee et al., 2005), Schindler-Ivens (2004) (Schindler-Ivens and Shields, 2004), and others (Diamantopoulos and Zander Olsen, 1967; Ashby et al., 1974; Taylor et al., 1984; Boorman et al., 1991; Thompson et al., 1992; Calancie et al., 1993) have challenged this consensus. Questions, therefore, continue to arise regarding H-reflex excitability after acute and chronic SCI and the recorded responses specific to the testing and recording conditions. Since BWS is a modality that is frequently used in rehabilitation post-SCI, it is important to understand any potential contributions from this modality on soleus H-reflex modulation. Therefore, the purpose of this study was to further study reflex excitability in general, and to specifically evaluate the influence of leg loading using BWS on reflex excitability in persons with motor incomplete SCI (i-SCI) and non-injured subjects. Methods Eight persons with motor i-SCI {Mean age 50.25 years, SD 6.9 (Table 3-1.)} and 5 non-injured controls (Mean age 48.6 years, SD 4.6) signed the informed consent approved by the Institutional Review Board at University of Florida. All experiments were conducted in accordance with the Declaration of Helsinki and all procedures were carried out with the adequate understanding and written consent of the study subjects. The degree of motor and sensory impairment for persons with i-SCI was evaluated and classified according to the guidelines of the American Spinal Injury Association (ASIA) (Maynard et al., 1997).

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52 Table 3-1. Demographic data: Persons with i-SCI Spasticity Medication Subject AGE SEX ETHNICITY Months since injury ASIA LM score Mean 39/50 UM score Mean 39/50 Level of lesion Type Dose mg/d 1 43 Male Caucasian 35 D 35 23 Cervical 2 48 Male Caucasian 20 D 32 19 Cervical Baclofen 120 3 60 Male Caucasian 5 D 38 44 Cervical 4 58 Male Afric-Amer 26 D 37 50 Cervical 5 46 Male Caucasian 3 D 47 50 Cervical 6 49 Male Caucasian 5 D 46 42 Cervical 7 42 Male Caucasian 72 D 44 44 Cervical 8 56 Male Caucasian 3 D 35 38 Cervical Baclofen 10 LM= Lower limb motor score from ASIA scale, UM = Upper limb motor score from ASIA, Afric-Amer = African American, mg/d= milligrams per day, Standard deviation: LM = 5.6, UM = 11.7. To provide partial BWS, subjects wore a specialized harness (Robertson Harness, PO Box 90086, Henderson, NV 89009-0086) with one thoracic band, one pelvic band, and two thigh straps. The harness was then attached vertically overhead to a cross-bar and cable with body weight supported via air compressor regulation and monitored by a digital gauge (Neuro II Vigor Equipment Inc, 4915 Advance Way, Stevensville, MI 49127). We examined the effect of BWS (symmetrical unloading of legs) on the soleus H-reflex in both non-injured subjects and persons with i-SCI. As training protocols typically begin with 40% BWS, (Wernig and Muller, 1992; Wernig et al., 1995; Protas et al., 2001; Dobkin et al., 2003) we chose to compare 100% Body Weight Load (BWL; 0% BWS) with 60% BWL (40% BWS) to assess the effect of a standard BWS on soleus H-reflex amplitude. Soleus H-reflex in standing has high reliability for within-session (Handcock et al., 2001), test-retest, within-day (Ali and Sabbahi, 2001), and inter-session (Hopkins et al., 2000) testing. Subject preparation for H-reflex assessment: Soleus H-reflex was evoked, for the purpose of consistency, on the more involved side of persons with i-SCI (determined by

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53 ASIA-lower limb motor score) and on the non-dominant side of non-injured control subjects. Skin was shaved and cleaned for application of electrodes. A bipolar (2 cm inter-electrode distance) Ag–AgCl surface electrode (Therapeutics Unlimited) was placed longitudinally over the soleus muscle. Tibial nerve was stimulated to evoke H-reflexes; current pulses were delivered via a constant-current stimulator (Grass Instruments, model S8800 with a modified CCU1) using a 2 cm 1/2 sphere silver cathode placed in the popliteal fossa (Schindler-Ivens and Shields, 2000) and a 10 cm silver anode positioned just superior to the patella. Data were acquired at a sample rate of 10 kHz per channel and stored digitally using Data-Pac III software (Run Technologies) on a personal computer (Dell Systems, Intel Celeron). Protocol: Before the H-reflex was tested under the two loading conditions, H-M recruitment curves were recorded. The stimulus intensity was gradually increased from a level below H-wave threshold to a level where a stable maximum M-wave (Mmax) was elicited. These recordings determined the test stimulus intensity for both loading conditions. Subsequently, the test stimulus intensity was set at M-wave response of 10+3% Mmax (chosen based upon our experience that this range provides the minimum amplitude stable M-wave for standardizing stimulus intensity). During the testing, the M-wave was constantly monitored and if it changed then stimulus intensity was readjusted. Fifteen H-reflexes were recorded at 100% BWL and 60% BWL at 10+3% Mmax. Subjects were instructed to stand upright, steady, and with weight evenly distributed across both legs. Data Analysis: H-reflex values used in our analysis were normalized to Mmax (H/M ratio). To compare the non-injured control group with the i-SCI group, we

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54 conducted the Skillings-Mack test (Hollander and Wolfe, 1999) using rankings of H-reflex excitability within each BWL condition. This test statistic is the average of the squares of the two Wilcoxon rank sum test statistics obtained separately from the two loading conditions. The significance level was determined based on permutation method instead of large-sample approximation. In addition, Wilcoxon signed-rank tests were performed to compare the two loading conditions, separately for the non-injured and the i-SCI groups. Results H-Reflex Excitability in Non-injured Subjects and Subjects with i-SCI: The mean soleus H-reflex amplitude (H/M ratio) in the non-injured group was 0.24 0.10 recorded during standing at 100% BWL. By contrast, in the i-SCI group, the mean H/M ratio recorded during standing at 100% BWL was 0.64 0.22. These differences (Figure 3-1., 3-2., & 3-3.) were significant (Skilling-Mack test, p< 0.001). 00.10.20.30.40.50.60.70.8H/M Ratio Control 100% BWL i-SCI 100% BWL Control 60% BWL i-SCI 60% BWL Figure 3-1. Standing: i-SCI vs. non-injured control; Comparison of H/Mmax values between the two BWL conditions in non-injured subjects and subjects with i-SCI; Standard error bars shown.

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55 Figure 3-2. Raw data: M and H waves evoked in soleus; LTA=Left Tibialis Anterior, LS=Left Soleus, RTA=Right Tibialis Anterior, RS=Right Soleus, mV=millivolts, ms=milliseconds 00.20.40.60.811.211223344556677889100111122Stimulation Intensity (mA)H-reflex amplitude (normalized to Mmax) i-SCI-M/Max i-SCI-H/Max Non-Injured-M/Mmax Non-Injured-H/Mmax Figure 3-3. H-M recruitment curves. A typical recruitment curve in a non-injured subject and a subject with i-SCI. Current intensity was steadily increased for successive stimulations (1 to 122) from below the threshold of H wave up to the appearance of stable Mmax (5 mA minimum – 50 mA maximum); mA = milliamperes. Influence of Leg Loading on Reflex Excitability: In the non-injured control group, the mean H/M ratio obtained from recordings during 60% BWL (0.23 0.16) was not

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56 significantly different from the H/M ratio recorded at 100% BWL. In the i-SCI group, the mean H/M ratio obtained from recordings during 60% BWL (0.64 0.27) was identical to the H/M ratio obtained from recordings during 100% BWL. A Wilcoxon signed-rank test yielded a p-value of 0.64, indicating no significant difference between the two BWS conditions. Collectively, these observations indicated that a change in leg loading did not cause a significant change in H-reflex amplitude in either experimental group (Figure 3-1.). The EMG activity in tibialis anterior and soleus did not change systematically with a change in H/M ratio (Table 3.2.). Table 3-2. EMG root mean square values recorded 100 ms prior to electrical stimulation Subjects Soleus Tibialis Anterior H/M ratio # 0% BWS 40% BWS 0% BWS 40% BWS 0% BWS 40% BWS 1 0.04 0.04 0.05 0.02 0.84 0.89 2 N/A N/A N/A N/A 0.40 0.76 3 0.13 0.09 1.71 0.90 0.44 0.63 4 0.10 0.41 2.85 1.89 0.69 0.69 5 0.25 0.23 2.17 2.21 0.82 0.58 6 0.34 0.09 2.83 3.18 0.32 0.79 7 0.25 0.02 0.01 0.02 0.88 0.02 i-SCI 8 0.15 0.03 0.55 0.01 0.78 0.79 1 0.56 0.04 1.57 0.06 0.19 0.19 2 0.28 0.14 1.30 1.36 0.28 0.14 3 0.22 0.20 1.39 0.93 0.10 0.02 4 0.15 0.30 2.93 2.71 0.30 0.44 Non-injured 5 0.23 0.12 1.47 0.31 0.37 0.37 Discussion The main finding of this study was that while there was a two-fold difference in the amplitude of the soleus H-reflexes in i-SCI group (compared with non-injured subjects); no significant change in the respective H/M ratios was produced in either group as a function of 100% vs. 60% leg loading conditions. While these results in non-injured control subjects are in agreement with previous studies (Ali and Sabbahi, 2000; Field

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57 Fote et al., 2000), this is the first study to examine the effect of leg loading on soleus H-reflex in persons with i-SCI. Therefore, these results indicate that 60% BWL does not have an immediate effect of altering soleus H-reflex excitability in patients with i-SCI. Further, these results suggest that the change in soleus H-reflex, observed in subjects with complete SCI (Kawashima et al., 2003), sitting to standing, can most likely be attributed to a change in posture rather than a change in leg loading. Previous studies have evaluated H-reflex excitability during different loading conditions. However, in each of these studies, additional factors within the recording setting or the modality used for unloading added uncertainty to the interpretations. For example, soleus H-reflex amplitude is reported to be greater when recorded during non-weight bearing positions {(prone position (Koceja et al., 1993; Angulo-Kinzler et al., 1998)) and sitting (Hayashi et al., 1992; Mynark et al., 1997; Kawashima et al., 2003)} compared to those recorded during weight-bearing position such as standing (both in controls and subjects with SCI) (Kawashima et al., 2003). However, it has not been clear if change in the soleus H-reflex amplitude occurred due to change of posture or change in leg loading. Since no change in H-reflex amplitude was observed relative to leg loading in our subjects, the change in posture is more likely to account for the changes in soleus H-reflex excitability reported by previous investigators (Kawashima et al., 2003). Previous studies in non-injured persons that used parabolic flight (Miyoshi et al., 2003) to examine the effects of unloading changes in soleus H-reflex amplitude yielded inconclusive results. Using water buoyancy, investigators reported that significant increases in the H-reflex amplitude occurred during 80% (Nakazawa et al., 2004) or 95% (Egawa et al., 2000) leg unloading. In the above two studies, afferent input from

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58 mechanoreceptors and cutaneous receptors from sole of the foot may have been responsible for the increase in soleus H-reflex amplitude. However, neither we, nor others were able to replicate those results with 40%, 50% (Field-Fote et al., 2000), 30% (Grey et al., 2002), or 25% (Ali and Sabbahi, 2000) BWS. Thus, it appears that if the afferent input arising from unloading of the legs crosses a particular threshold (possibly between 50-80% leg unloading), it causes an increase in the H-reflex amplitude. Rehabilitation studies typically use ~40% BWS to initiate retraining standing and walking (Wernig and Muller, 1992; Wernig et al., 1995; Behrman and Harkema, 2000; Protas et al., 2001; Dobkin et al., 2003) (as was used in the current study); therefore, our results are pertinent to clinical use of this modality after i-SCI. The ability of the spinal cord to modulate sensory input and presynaptic inhibition are impaired post-SCI (Stein, 1995). Previous studies, have systematically reported that greater H/M ratios were recorded in post-SCI subjects (Little and Halar, 1985; Stein, 1995; Hiersemenzel et al., 2000) than recorded in non-injured controls. Our findings are in agreement with these and show that the amplitude of soleus H-reflex in standing is significantly greater post i-SCI than recorded in non-injured persons, for subjects with both acute and chronic injuries. H-reflex is depressed immediately post-SCI (Leis et al., 1996), but steadily increases over the period of first few weeks (Leis et al., 1996) and months (Hiersemenzel et al., 2000) and is reported to be greater in chronic SCI compared to non-injured controls (Nakazawa et al., 2006). In our study 4/8 subjects had chronic i-SCI (see Table 6-1.) and all subjects with i-SCI showed an increased H/M ratio compared to non-injured controls. In addition, the H/M ratios were comparable between the chronic and sub-chronic populations and in

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59 agreement with a recent report (Nakazawa et al., 2006). H/M ratios are reported as comparable in incomplete versus complete SCI (Nakazawa et al., 2006); however it should be noted that recently, Lee et al. (2005) reported in a rat model that the nature of change in H-reflex amplitude following experimental contusion injuries was dependent upon the severity of the injury (Lee et al., 2005). Future studies are needed to determine if H/M ratios are correlated with the severity of SCI in human population. On the other hand, Schindler-Ivens and Shields (2004) reported that soleus H-reflex amplitudes were not greater than non-injured controls (Schindler-Ivens and Shields, 2004). Although it is not known if the pharmacological history of the subjects accounts for the specific amplitude patterns, six out of 9 subjects in their study were on Baclofen and it is possible, as suggested by the authors, that this medication history could have contributed to the appearance of lower H-reflex amplitudes. In light of the potential interaction of drug therapy on H-reflex excitability, careful and complete reporting of the pharmacologic history of all subjects is highly recommended and instructive. Therefore, it appears that there is some controversy in the literature in regard to the influence of SCI on H-reflex excitability. However, as the specific issues of injury severity, duration, and pharmacologic treatment, which significantly influence H-reflex excitability, are carefully reported, these differences may be resolved. Limitations The H-reflex was located near the lowest part of the saturation curve – therefore, minimal inhibition would be observed to decrease the response amplitude. While these are saturated H-reflexes, the mean H/M ratio of 0.64 indicates a relative 36% of the motoneurons that could still be recruited to reveal facilitation.

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60 Our literature review (Kawashima et al., 2003; Nakazawa et al., 2004) suggests that statistically significant differences in the means of H-reflex amplitude would be 0.2 for i-SCI subjects and 0.1 for non-injured subjects, corresponding to effect sizes of 0.9 and 1.0 based on standard deviations estimated from our data. Thus, it should be noted that our study had low power with only 8 i-SCI subjects and 5 non-injured subjects. Conclusion Our findings suggest that non-injured persons and persons with i-SCI respond similarly to bilateral limb unloading (40% BWS) during standing with no significant change in H-reflex amplitude. It appears that although soleus H-reflex amplitude is significantly greater after SCI and is exhibited even during quiet standing, load does not alter soleus H-reflex excitability. Therefore, relevant to the therapeutic setting of rehabilitation using partial BWS, these results indicate that reflex excitability is not specifically altered by leg unloading during 40% BWS standing. As H-reflex activity is task-dependent, future studies will examine the effect of BWS on soleus H-reflex during the task of walking.

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CHAPTER 4 EXPERIMENT II: COMPARISON OF SOLEUS H-REFLEX MODULATION POST-INCOMPLETE SPINAL CORD INJURY IN TWO WALKING ENVIRONMENTS: TREADMILL AND OVERGROUND Introduction Generating an improved stepping pattern following repetitive sensory-stimulation specific to walking exemplifies the impact of activity-dependent plasticity in the human injured spinal cord (Behrman and Harkema, 2000; Behrman et al., 2005; Field-Fote, 2005). This physiological-based strategy for rehabilitating walking after SCI is founded in basic science research employing a treadmill, body weight support (BWS), and manual assistance to achieve repetitive stepping in animal models of SCI (Lovely et al., 1986; Barbeau and Rossignol, 1987; Lovely et al., 1990; de Leon et al., 1998). Based on this model, Hugues Barbeau first translated use of a treadmill and BWS to retrain walking post human SCI (Barbeau et al., 1987). Since then, the literature reporting benefits of training in this environment to overcome locomotor deficits following human motor incomplete spinal cord injury (i-SCI) has grown (Wernig and Muller, 1992; Dietz, 1995; Wernig et al., 1995; Behrman and Harkema, 2000; Behrman et al., 2005; Field-Fote, 2005). In contrast to conventional gait training provided overground, locomotor training (LT) utilizes a treadmill (TM), BWS, and manual assistance to provide a locomotor specific experience of walking. Several studies have reported improvements in locomotor ability following locomotor training of variable duration in persons post-SCI (Wernig and Muller, 1992; Hesse et al., 1999; Behrman and Harkema, 2000; Sullivan et al., 2002; Behrman et al., 2005). The nature of immediate neurophysiological changes 61

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62 related to walking in the TM environment (on a treadmill with BWS and trainers) are not yet fully understood. The study of mechanisms underlying locomotor recovery will assist in the analysis and selection of one modality or training environment over another. LT assists in producing rhythmic and repetitive stepping over the TM, to afford experience of a relatively normal walking pattern that persons with i-SCI are typically unable to generate unassisted overground (OG) (Visintin and Barbeau, 1989; Harkema et al., 1997). In conventional gait training, patients with i-SCI frequently use various devices to assist with walking balance; however, an assistive device may not directly improve walking kinematics. In contrast, subjects using a BWS system feel secured (by removing of the ‘fear of falling’ (Behrman and Harkema, 2000)) and produce more appropriate EMG and lower limb kinematics (Visintin and Barbeau, 1994). In addition, limb guidance provided by trainers assists with generation of appropriate walking kinematics, namely: walking phase specific leg movements and timing of the swing and stance phases (Behrman and Harkema, 2000; Behrman et al., 2005). A combined use of TM, BWS, and manual assistance during LT induces EMG patterns that are more similar to those recorded in healthy persons (Dietz, 1995; Harkema et al., 1997), particularly, more reciprocal activity of agonist and antagonist muscles (Maegele et al., 2002). Therefore, practice of this rhythmic and repetitive stepping pattern is proposed to provide critical therapeutic shaping of the locomotor neurobiology deemed essential to generate and relearn stepping after SCI (Behrman and Harkema, 2000). To study the locomotor neurobiology, soleus H-reflex testing offers a non-invasive method to examine the altered patterns of reflex excitability following SCI (Yang et al., 1991) and is a sensitive probe of changes induced by specific therapeutic regimen (Yang

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63 et al., 1991; Fung and Barbeau, 1994; Trimble et al., 1998). Following SCI, the development of spasticity has been temporally correlated to specific changes in excitability patterns of soleus H-reflex (Hiersemenzel et al., 2000). These changes include impaired modulation (Knikou, 2006) and significantly greater reflex amplitudes compared to healthy controls while walking overground (Yang et al., 1991; Fung and Barbeau, 1994). Therefore, these abnormal reflexes appear to be significant contributors to spasticity (Okuma et al., 2002; Crone et al., 2003; Kiser et al., 2005) and walking related impairments associated with clonus (Yang et al., 1991). Although LT enables persons with i-SCI to generate improved stepping patterns while walking on a TM, it is not clear to what extent these improvements in walking patterns are specifically correlated with clinically significant changes in soleus H-reflex excitability (Trimble et al., 1998). Trimble et al. (2001) reported that following a single bout of LT, a significant increase in the soleus H-reflex modulation was observed while walking overground (Trimble et al., 2001). Thus, it appears that LT can potentially increase soleus H-reflex modulation post-SCI, however, it is not known if the improved modulation is inherent to the TM environment. Therefore, in parallel with the development of LT as a therapeutic strategy, there is a need to study the underlying neural mechanisms that may be associated with walking recovery following i-SCI. We hypothesized that walking in the TM environment will induce a greater modulation of the soleus H-reflex compared to unassisted walking overground in persons with i-SCI. Since H-reflex modulation is reported to be impaired post-SCI (Little and Halar, 1985; Thompson et al., 1998; Trimble et al., 1998; Thompson et al., 2001; Trimble et al., 2001), an environment that affords greater H-reflex

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64 modulation would be viewed as providing a training experience consistent with normalizing the afferent experience deemed crucial to stepping recovery. We also hypothesized that the H-reflex amplitudes will be significantly greater in persons with i-SCI compared to non-injured controls. Our third hypothesis was that the walking environment will not affect H-reflex modulation in non-injured controls. The purpose of this experiment was to examine the immediate effect of two walking environments (TM and OG) on soleus H-reflex excitability in persons with i-SCI and non-injured controls. Methods Eight persons with motor i-SCI (Mean age 50.25 years, SD 6.9) and 8 non-injured controls (Mean age – 51.37 years, SD – 7.17) signed the informed consent approved by the Institutional Review Board at University of Florida (see Table 4-1.). All experiments were conducted in accordance with the Declaration of Helsinki and all procedures were carried out with the adequate understanding and written consent of the study participants. The degree of motor and sensory impairment for persons with i-SCI was evaluated and classified according to the guidelines of the American Spinal Injury Association (ASIA) (Maynard et al., 1997). All persons with i-SCI first walked using their customary assistive device on a level 25’ walkway (Gait Mat II EQ Inc. digitized mat with embedded micro-switches) at their self-selected walking velocity. Three trials of walking were recorded and comfortable walking velocity determined using GAIT MAT II software. All persons were then asked to walk overground and subsequently over the TM at this walking velocity.

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65 Table 4-1. Demographic data: Persons with i-SCI Afric-Amer = African American, RPW=Rolling Platform Walker, RW=Rolling Walker, R-AFO=Right Ankle Foot Orthosis, LM= Lower limb motor score from ASIA, UM = Upper limb motor score from ASIA,* Standard deviation: LM = 5.6, UM = 11.7, SS = self-selected # Age Sex Ethnicity Assistive Device Months since injury ASIA LM Score *Mean =39/50 UM Score *Mean =39/50 Level of lesion SS Walking Speed (mph) 1 43 M Caucasian RPW 35 D 35 23 C 6 0.29 2 48 M Caucasian RPW 20 D 32 19 C 5-6 0.22 3 60 M Caucasian Cane 5 D 38 44 C 7 1.07 4 58 M Afric-Amer RW 26 D 37 50 C 5 0.76 5 46 M Caucasian None 3 D 47 50 C 8, T 1 2.90 6 49 M Caucasian None 5 D 46 42 C 6-7 1.14 7 42 M Caucasian None 72 D 44 44 C 4-5 2.20 8 56 M Caucasian RW + R-AFO 3 D 35 38 C 5-6 0.43 The two testing conditions for this study were walking overground unassisted (no manual assistance, but with assistive device of their choice) and walking over a treadmill with body weight support (BWS) and manual assistance. BWS was provided using a specialized harness (Robertson Harness, PO Box 90086, Henderson, NV 89009-0086) with one thoracic band, one pelvic band, and two thigh straps. The harness was attached vertically overhead to a cross bar connected to pulleys, supporting the person’s body weight. The BWS system (Neuro II Vigor Equipment Inc, 4915 Advance Way, Stevensville, MI 49127) was used to pneumatically adjust the support to 40% of the subject’s body weight (Visintin and Barbeau, 1994; Harkema et al., 1997). We chose to provide 40% BWS to train the persons with i-SCI over the TM, since training protocols typically begin with 40% BWS (Wernig and Muller, 1992; Wernig et al., 1995; Protas et

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66 al., 2001; Dobkin et al., 2003) and greater than 50% BWS (Finch et al., 1991) has shown to cause significant change in gait parameters and a decrease in mean EMG amplitudes. A treadmill (Biodex Medical Systems, 20 Ramsay Road, Shirley, NY 11967-4704) with 0.1-mph speed increments was used for the TM walking condition. Trainers provided manual assistance when necessary to initiate or maintain good kinematics while stepping on the treadmill. As soon as an adequate stepping pattern over the TM was established, soleus H-reflex testing was initiated. Thus, a relatively immediate effect of walking in the TM environment was measured. Since H-reflex is prone to age related changes (Kido et al., 2004), the non-injured controls were age-matched to the persons with i-SCI and walked over the treadmill with 40% BWS. Subject preparation for H-reflex assessment: Soleus H-reflexes were evoked, on the more involved side of persons with i-SCI (determined by ASIA-Motor score) and on the dominant side of healthy controls. Skin was shaved and cleaned for application of electrodes. A bipolar (2 cm inter-electrode distance) Ag–AgCl surface electrode (Therapeutics Unlimited, Iowa City, Iowa) was placed longitudinally over the soleus muscle. Surface EMG electrodes were placed over the soleus and tibialis anterior muscle belly. The EMG data was used to examine if soleus H-reflex amplitude changed systematically with mean EMG activity. To evoke H-reflexes, current pulses were delivered via a constant-current stimulator (Grass Instruments, model S8800 with a modified CCU1) using a 2 cm 1/2 sphere silver cathode placed in the popliteal fossa (Schindler-Ivens and Shields, 2000) and a 10 cm silver anode positioned just superior to the patella. The tibial nerve was localized, in the popliteal fossa by the electrode placement, to evoke a soleus H-reflex at the least current intensity required. Data were

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67 acquired at a sample rate of 10 kHz per channel and stored digitally with a commercially available data acquisition system (Data-Pac III by Run Technologies) on a personal computer (Dell Systems, Intel Celeron). Protocol: All participants with i-SCI underwent soleus H-reflex testing under the two testing conditions: first when walking overground (Figure 4-1.A) and then with 40% BWS over the TM with manual assistance from three trainers (one each for the two legs and one at the hips; see Figure 4-1.B). Persons with i-SCI walked overground at self-selected speed and then this speed was matched over the TM whereas the non-injured persons walked overground at self-selected speed and over the treadmill at 2.8 mph (Van Emmerik et al., 2005). Non-injured controls were tested under similar conditions (overground and TM), but no manual assistance was provided over the TM. Before the H-reflex was tested under the two loading conditions, H-M recruitment curves were recorded. The stimulus intensity was gradually increased from a level below H-wave threshold to a level where a stable maximum M-wave (Mmax) was elicited. These recordings determined the test stimulus intensity for both walking conditions. Subsequently, the test stimulus intensity was set at M-wave response of 10+3% Mmax (chosen based upon our experience that this range provides the minimum amplitude stable M-wave for standardizing stimulus intensity) (Nakazawa et al., 2006; Phadke et al., 2006). During the testing, the M-wave was constantly monitored and if it changed, then stimulus intensity was readjusted. In all persons, 15 H-reflexes each were evoked in the mid-stance and mid-swing phases of walking (Garrett et al., 1999).

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68 A B Figure 4-1. Person with i-SCI walking in two environments; A: Overground (OG); B: Treadmill (TM) The mid-stance and mid-swing phases of walking were determined visually and confirmed using footfall data patterns from micro footswitches. H-reflex amplitude goes through a cyclic modulation during the walking cycle; the amplitude increases gradually during the stance phase before falling sharply at toe off, hence we chose midpoints of stance and swing phases for stimulation (Chalmers and Knutzen, 2000; Ethier et al., 2003). Data Analysis: H-reflex values were normalized to Mmax (H/M ratio). To compare the non-injured control group with the i-SCI group, we conducted the Skillings-Mack test (Hollander and Wolfe, 1999) using rankings of H-reflex amplitude within each walking condition. The test statistic is the average of the squares of the two Wilcoxon rank sum test statistics obtained separately from the two walking conditions. The significance level was determined based using a permutation method instead of large-sample approximation.

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69 In addition, Wilcoxon signed-rank tests were performed to compare the two walking conditions, separately for the non-injured and the i-SCI groups. The above analyses were conducted separately for the two phases of walking: stance and swing. Results The results in persons with i-SCI in the two walking environments, a comparison between the two subject populations, and the effects of the walking environment in healthy non-injured subjects is presented below in that order. Modulation in Persons with I-SCI The mean H/M ratio in the swing phase of persons with i-SCI (Figure 4-2.), while walking in the TM environment, was significantly smaller than walking overground (Wilcoxon Signed-rank test, p=0.0078). The mean H/M ratio in the stance phase of walking was not significantly different (Wilcoxon Signed-rank test, p=0.0781) between the two walking environments. The mean H/M ratio recorded during swing in the persons with i-SCI was approximately 50% smaller than those recorded during stance phase, both, for OG and TM walking environments. Examining individual data revealed that all persons with i-SCI showed a decreased H/M ratio in either swing or stance, or both phases of walking in the TM environment compared to OG environment (Figure 4-3.). In the TM walking environment, 4/8 persons with i-SCI showed a smaller H/M ratio in both the swing and the stance phase (Subjects # 1, 6, 7, 8 – Table 4-2.). In addition, it should be noted that in the i-SCI group, the H/M ratio decreased in the TM environment in 6/8 persons in the swing phase (Subjects # 1, 3, 4, 6, 7, 8) and 6/8 persons in the stance phase (Subjects # 1, 2, 5, 6, 7, 8 – see Table 4-2.).

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70 00.10.20.30.40.50.60.70.8H/M Ratio OG-stance TM-stance OG-swing TM-swing 00.10.20.30.40.50.60.70.8H/M Ratio OG-stance TM-stance OG-swing TM-swing Figure 4-2. Comparison of mean H/M ratio in persons with i-SCI in the two walking conditions OG and TM; OG = overground, TM = treadmill; * Significantly different (p<0.05); Standard error bars shown Out of the two persons with i-SCI who did not show a change in H/M ratio in the swing phase, one person already had a completely depressed H-reflex (Subject # 2). The EMG activity in the soleus and tibialis anterior muscles did not change systematically with the H/M ratio (Table 4-2.). Soleus H-reflex Modulation I-SCI vs. Non-injured Controls Skillings-Mack test comparing persons with i-SCI with healthy persons revealed that mean H/M ratio in persons with i-SCI walking overground was significantly greater than non-injured controls for both stance and swing phases of walking (p=0.0001 and p=0.0002, respectively). A second Skillings-Mack test revealed that the mean H/M ratio in persons with i-SCI and healthy persons was not significantly different in the TM walking environment for both stance and swing phases of walking (P>0.05).

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71 00.20.40.60.811.212345678Subjects% Decrease in H/M ratio00.511.522.533.5Walking Speed (mph) stance swing Speed Figure 4-3. Persons with i-SCI: % decrease in H/M ratio while walking in TM environment compared to OG environment; Secondary y-axis: Walking speed (miles per hour). In subjects # 3, 4 the H/M ratio increased in stance phase and in subjects # 2, 5 the H/M ratio did not change in the swing phase of walking in the TM environment Table 4-2. EMG activity recorded 100 ms prior to electrical stimulation and H/M ratio Soleus Tibialis Anterior H/M Ratio Subjects OG TM OG TM OG TM i-SCI Stance Swing Stance Swing Stance Swing Stance Swing Stance Swing Stance Swing 1 0.04 0.04 0.05 0.04 0.04 0.02 0.03 0.02 0.88 0.86 0.56 0.31 2 0.05 0.04 0.05 0.04 0.02 0.06 0.03 0.07 0.45 0.01 0.39 0.01 3 0.14 0.14 0.09 0.09 1.73 1.7 0.89 1 0.48 0.23 0.52 0.07 4 0.26 0.44 0.36 0.57 1.43 1.68 1.71 2.08 0.74 0.47 0.86 0.4 5 0.24 0.59 0.17 0.3 2.18 2.16 2.2 2.3 0.87 0.26 0.58 0.26 6 0.37 0.43 0.16 0.29 3.52 3.5 1.74 2.5 0.43 0.18 0.37 0.07 7 0.06 0.03 0.09 0.03 0.02 0.02 0.01 0.02 0.78 0.53 0.04 0.01 8 0.15 0.13 0.05 0.03 1.21 1.17 0.03 0.01 0.86 0.78 0.34 0.31 Control 1 0.36 0.31 0.29 0.27 0.07 0.07 0.07 0.08 0.29 0.04 0.23 0.02 2 0.12 0.13 0.12 0.10 0.06 0.08 0.07 0.07 0.41 0.05 0.06 0.06 3 0.10 0.10 0.14 0.10 0.03 0.04 0.04 0.05 0.35 0.02 0.49 0.05 4 0.40 0.46 0.26 0.30 0.10 0.11 0.10 0.09 0.26 0.18 0.49 0.13 5 0.22 0.23 0.22 0.23 0.07 0.10 0.09 0.09 0.04 0.01 0.06 0.01 6 0.10 0.10 0.14 0.19 0.07 0.09 0.06 0.08 0.27 0.07 0.33 0.07 7 0.08 0.07 0.08 0.08 0.06 0.05 0.07 0.07 0.29 0.03 0.24 0.03 8 0.19 0.15 0.22 0.20 0.05 0.06 0.09 0.08 0.02 0.00 0.02 0.01

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72 Modulation in Non-injured Controls The mean H/M ratio in the non-injured persons (Figure 4-4.) was not significantly different between the two walking conditions (OG and TM). The amplitude of the soleus H-reflex recorded during swing was approximately ~80% smaller than recorded during stance, both, for overground and treadmill locomotion (see Figure 4-4.). Figure 4-5. shows raw H-reflexes in the two walking conditions elicited during the stance and swing phases. 00.050.10.150.20.250.30.35H/M ratio OG-Stance TM-Stance OG-Swing TM-Swing Figure 4-4. H/M ratio in non-injured persons in two walking conditions OG and TM; Standard error bars shown Discussion The primary finding of this study was that mean H/M ratio was 33% (stance) and 56% (swing) smaller during walking on TM environment compared to overground walking in i-SCI group (Figure 4-2.). Even though 6/8 subjects showed a decrease in the H/M ratio in the TM environment, in contrast with swing phase, the stance phase H/M ratio was not statistically significant.

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73 Stance Swing Figure 4-5. Raw soleus H-reflex data from one non-injured control and on person with i-SCI tested in two walking phases: stance and swing. The H-reflex in the swing phase is almost completely depressed in the non-injured subjects. In comparison, the H-reflex in the swing phase is not depressed in the swing phase of OG walking, but is completely depressed in the swing phase of TM walking environment in this person with i-SCI. Also note the decrease in H-reflex in the stance phase of walking in the TM compared to OG walking in this person with i-SCI; ms = millisecond; mV = millivolt Trimble et al. (2001) reported that the overground walking speeds of the subjects with i-SCI increased by 26% after a single bout of locomotor training (Trimble et al., 2001). Furthermore, they found that concomitant H-reflexes were significantly depressed in the SCI subjects (28% decrease in stance, 34% decrease in swing) (Trimble et al., 2001). This change in H/M ratio was task specific, since it was observed only during walking, but the H/M ratio tested in standing remained unchanged after training. In the light of this report, the mean change of 33% (stance) and 56% (swing) that we report in this study appears to be a clinically significant change (Trimble et al., 2001; Okuma et OG TM OG TM i-SCI Control 10 mV 62.50 ms m H

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74 al., 2002; Crone, Johnsen et al., 2003). The two persons with i-SCI that did not show a decrease in H/M ratio in the stance phase of TM environment were both older (subject # 3 = 60 years, subject # 4 = 58 years) than the rest of the study sample (range 42-56 years; see Table 4-1.). The relatively older age of these two subjects may have affected the H-reflex response, consistent with previous reports that the H/M ratios are less likely to change in older compared to younger persons (Koceja et al., 1995; Tsuruike et al., 2003; Kido et al., 2004). The soleus H-reflexes are modulated in a phase-specific manner being greater in stance phase and completely depressed in the swing phase of walking in non-injured persons (Capaday and Stein, 1986; Capaday and Stein, 1987; Garrett et al., 1999; Simonsen and Dyhre-Poulsen, 1999; Chalmers and Knutzen, 2000; Simonsen et al., 2002; Ethier et al., 2003); however this ability is diminished post-SCI resulting in significantly greater soleus H-reflex amplitudes (Yang et al., 1991; Fung and Barbeau, 1994; Trimble et al., 2001). Persons with i-SCI in this study showed greater modulation of soleus H-reflex while walking in the TM environment. In the light of these findings, it appears that the injured spinal cord modulation of the H-reflex in a task-specific manner is enhanced in response to the sensory input provided in the TM environment (compared to OG environment). Since the phase-specific H-reflex modulation in the TM environment in persons with i-SCI more closely resembles the modulation pattern that occurs in the intact spinal cord, this enhancement is perceived as a particularly desirable asset of this type of intervention (Schneider and Capaday, 2003). A second finding of this study was that mean H/M ratio in persons with iSCI was significantly greater compared to non-injured persons. Examination of individual data

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75 revealed that two persons with i-SCI (Subjects # 2, 6), with a clinical presentation of impaired walking speed, showed good phase-specific modulation in the OG environment comparable to non-injured controls (Table 4-2.). Similar findings, suggesting that all subjects with SCI do not exhibit increased H-reflexes during walking, were also reported previously by Yang et al. (1991) (Yang et al., 1991). Apart from walking studies, few studies performed in static positions in humans and animals report that H-reflex does not increase post-SCI (Thompson et al., 1992; Schindler-Ivens and Shields, 2004; Lee et al., 2005). A large majority of studies, however, have reported that H-reflex modulation is impaired (seen as increase in reflex amplitude) post-SCI (Taylor et al., 1984; Little and Halar, 1985; Calancie et al., 1993; Thompson et al., 1998; Trimble et al., 1998; Thompson et al., 2001; Trimble et al., 2001). A recent study by Lee et al. (2005) indicates that the impairment of H-reflex modulation may be related to severity of SCI (Lee et al., 2005). Although our finding of increased mean H/M ratio in persons with i-SCI is consistent with a majority of past reports (Yang et al., 1991; Fung and Barbeau, 1994; Trimble et al., 1998; Trimble et al., 2001), it is important to document this observation since there remains an ongoing controversy over this issue of spinal cord injury and H-reflex excitability (Schindler-Ivens and Shields, 2004). The third finding was that H-reflex modulation in non-injured persons walking overground was identical to walking over the TM with 40% BWS; these results support previous findings by Ferris et al. (2001) (Ferris et al., 2001) and Miyoshi et al. (2006) (Miyoshi et al., 2006). The H-reflex modulation seen during walking (in both conditions) in the non-injured controls in our experiment was similar to the non-injured subject data

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76 reported in past experiments (Garrett et al., 1999; Chalmers and Knutzen, 2000; Ethier et al., 2003). The primary purpose of this study was to examine the behavior of soleus H-reflex during walking in the TM environment in comparison to overground walking. At matched walking speeds, our results suggest that the TM environment improves modulation of soleus H-reflex. In contrast to overground walking, training variables afforded in the LT environment include BWS (Harkema et al., 1997), TM speed (Beres-Jones and Harkema, 2004), and manual assistance and each of these factors may have an independent (Visintin and Barbeau, 1994) or perhaps even an interactive or cumulative effect on the resulting H-reflex modulation. Effect of BWS on H-reflex BWS is known to decrease lower limb muscle EMG amplitude in spastic paretic persons (Visintin and Barbeau, 1989), however, the mean EMG recorded in soleus and TA muscles in our study did not change systematically with the H-reflex amplitude (Table 2). Investigators have reported that soleus H-reflex modulation during walking depends on central mechanisms and is not affected by agonist or antagonist muscle activity, muscle stretch, or background muscle activity (Yang and Whelan, 1993; Schneider et al., 2000). Similarly, Ferris et al. (2001) reported that soleus and TA activity remained nearly identical during walking with up to 75% unloading of the body weight and H-reflex modulation was independent of muscle activity and BWS (Ferris et al., 2001). Moreover, lower limb kinematics while walking over the treadmill do not change with varying amounts of body weight support (from 0% to 95%) (Ivanenko et al., 2002) and thus the effect of BWS per se may not have caused the change in H-reflex modulation. The non-injured persons in this study also walked with 40% BWS over TM

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77 and the H-reflex modulation was identical to walking overground. This result again suggests that BWS is less likely to have been independently responsible for the modulation seen in persons with i-SCI. An increase in balance requirements during narrow beam walking have been reported to cause a depression of soleus H-reflex (Llewellyn et al., 1990). In our study 40% BWS was used to support balance and a secondary safety catch mechanism was also installed and each subject was informed about the safety of the system; thus it is unlikely that the person’s balance was threatened and thus cannot account for modulation of soleus H-reflex. Effect of Walking Environment on H-reflex Walking over TM and overground walking are not completely comparable in terms of lower limb kinematics. TM walking induces greater hip flexion and cadence, decrease in the stance time (Alton et al., 1998), and significantly different lumbar movements (Vogt et al., 2002) compared to walking overground. However, a familiarization interval ranging from 6 minutes in young healthy persons (Matsas et al., 2000) to 14 minutes in older healthy persons (Wass et al., 2005) is reported to generate identical walking patterns over a TM compared to overground. Persons in our study were offered a very short familiarization period (1-2 minutes) and data collection began as soon as the subject achieved a good stable walking pattern. Several previous studies have reported that knee angular velocity or range of motion or stretch (Garrett et al., 1999) does not alter soleus H-reflex excitability and it is more likely to be centrally mediated in the spinal cord (Schneider et al., 2000). Secondary results from our study show that the H-reflex modulation in non-injured persons was stable over the two walking environments: TM and overground. The H-reflex excitability was comparable across both conditions and it

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78 is unlikely that the soleus H-reflex amplitude is independently influenced by either overground or TM walking environments, though this is certainly a testable hypothesis. Neural Adaptations with LT The reflex pathways are known to demonstrate plasticity and can be modified (Wolpaw et al., 1989; Wolpaw and Tennissen, 2001), however the nature of these neuroplastic changes as walking improves post-SCI is not known (Cote and Gossard, 2004). The H-reflexes are exaggerated post-SCI (Trimble et al., 2001; Kiser et al., 2005; Lee et al., 2005; Nakazawa et al., 2006; Reese et al., 2006) and it may be possible to normalize these reflexes by training. There have been previous reports of normalization of reflex excitability post-SCI following training programs such as step training in humans (Trimble et al., 1998) and cats (Cote and Gossard, 2004), passive bike training in rats (Reese et al., 2006), and passive bicycling in humans (Kiser et al., 2005). In all the above training studies, the reflexes were tested during non-locomotor tasks. In contrast, to investigate the nature of neurophysiologic changes associated with training modalities, we chose to examine the H-reflex excitability within the task of walking. The reduced H/M ratio seen in our study during walking in the treadmill environment may be a precursor to ongoing plasticity of reflex pathways. Chen et al. (2005) used an H-reflex conditioning protocol (duration 50-day) to demonstrate that the size of the conditioned H-reflex is correlated with the size of the soleus EMG response (Chen et al., 2005). The soleus EMG activity (Pepin et al., 2003) and H-reflex amplitude (Yang et al., 1991) are both greater post-SCI and a decrease in soleus H-reflex amplitude and EMG may occur with training in the TM environment. Thus, it is possible that training in the TM environment over the period of time can condition the soleus H-reflex to decrease and may produce a concomitant decrease in soleus EMG.

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79 Neuroplasticity can cause immediate effects to occur and have been previously reported in post-SCI persons. Trimble et al. (2001) reported that a single bout of locomotor training produced immediate increases in walking velocity and acute neurophysiologic changes in persons with i-SCI (Trimble et al., 2001). Fung and Barbeau (1994) reported that using conditioning cutaneomuscular stimulation produced normal soleus H-reflex modulation while walking in patients with SCI (Fung and Barbeau, 1994). Thus it is plausible that the effects seen in this study were entirely because of methods used to train in the TM environment (40% BWS with assistance of manual trainers). Although a change in individual joint movements during walking does not alter soleus H-reflex excitability (Garrett et al., 1999; Schneider et al., 2000), LT probably induces a generalized change in sensory input to the spinal cord and may be significant for the spatial-temporal pattern of sensory input specific to walking. The reduced H/M ratios can be attributed to this overall change in range of motion, improvement in phase specific timing of muscle contractions, and interlimb coordination during walking in the TM environment (Stein et al., 1993; Muir and Steeves, 1995; Muir and Steeves, 1997; Hiebert and Pearson, 1999; Knikou and Conway, 2001; Lam and Pearson, 2001; Knikou and Rymer, 2002; Knikou, 2005). Using BWS while walking over TM is known to generate straighter trunk and better knee alignment, increases in stride length and single limb support time, and decrease in double limb support time (Visintin and Barbeau, 1989). In this study we did not record the lower limb kinematic data, but from visual observation and video recordings, persons with i-SCI were able to generate better stepping pattern during walking in the TM environment (see Figures 4-1.). Subjects’ posture was typically more

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80 vertical, greater hip extension was achieved, and limb excursion achieved a greater complement of flexion and extension range while walking in the TM environment. The trainers providing manual assistance in this study were experienced (Behrman and Harkema, 2000; Behrman et al., 2005). Level of loading on the lower limbs provides cues that enable the human lumbosacral spinal cord to modulate efferent output in a manner that may facilitate the generation of stepping after SCI (Harkema et al., 1997). Thus, it appears that a combination of all the above factors involved in the LT environment, i.e., TM, BWS, manual assistance, and acute neural adaptation were together instrumental in improving soleus H-reflex modulation. The effect of different combinations of variables overground or on the TM could certainly be tested; however, our interest was to examine these different variables as an ensemble of sensory information and a total experience, rather than as individual effects. Limitations First, we only examined the effect of training in the TM walking environment rather than individual components of the TM walking environment such as treadmill speed, BWS, and manual assistance. Separate investigation of the neurological effects of walking over a TM and the effect of BWS will yield information on the unique effects of these training variables and their contribution to the sensory experience for training. Second, an order effect cannot be ruled out since testing was always performed first in the overground walking environment. Conclusions Soleus H-reflex amplitude decreased significantly during the swing phase of walking in the TM environment compared to walking overground unassisted in persons with i-SCI. Training walking in a controlled environment where specific training

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81 parameters such as walking speed, BWS, and stepping pattern can be regulated will be important as considerations for development of training protocols such as robotics that incorporate these variables. Even though, we used self-selected walking speed to train in the TM environment, walking at faster speeds may elicit stronger reflex modulation post-SCI (Dobkin et al., 1995; Sullivan et al., 2002; Pepin et al., 2003; Beres-Jones and Harkema, 2004). The training speed and optimal level of BWS, during LT, remain an area of ambiguity and inconsistency among different training protocols (Behrman et al., 2005; Field-Fote, 2005; Hidler, 2005). The contribution of specific variables of the training such as: walking speed, walking kinematics, specifically the lower limb joint excursion and stance and step times, trunk posture, and BWS on soleus H-reflex modulation need to be further investigated in the SCI population. This study demonstrated the beneficial effect, within a single training experience of manually-assisted LT using a BWS and TM, on improved H-reflex modulation in persons with i-SCI. The long-term benefit of locomotor training to persons following i-SCI may in part be attributed to cumulative effects of a single bout experience in this environment on normalizing the soleus H-reflex.

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CHAPTER 5 EXPERIMENT III: SOLEUS H-REFLEX MODULATION DURING STANCE PHASE OF WALKING IS INDEPENDENT OF ARMSWING PATTERNS IN HEALTHY NON-INJURED SUBJECTS Introduction The understanding of ‘armswing in human walking’ is limited to a very few studies that directly address this issue (Eke-Okoro et al., 1997; Marks, 1997). The dearth of such studies may in part be due to a myth that armswing was a passive phenomena and its casual coexistence with walking insignificant. Later studies reported that armswing occurs as a result of rhythmic firing of arm musculature during walking (Jackson et al., 1983; Eke-Okoro et al., 1997) and these muscles continue to fire even when the upper limbs are restrained (Buchthal and Fernandez-Ballesteros, 1965). Recently however, there has been a renewed interest in armswing and its neurological and biomechanical connections with walking (Dietz et al., 2001; Dietz, 2002). Armswing occurs in synchrony with leg movements while walking and such arm-leg coordination is also seen in other human locomotor activities like running and swimming (Wannier et al., 2001), as well as in quadrupeds (Krutki et al., 1998; Mrowczynski et al., 1998; Juvin et al., 2005). The neurological connections responsible for interlimb coordination between all four limbs have been identified and described in animals (Duysens and Van de Crommert, 1998; Cazalets and Bertrand, 2000). Rhythmic swinging of arms during walking may be attributed to persistence of these neurological connections during evolution from quadrupedal to bipedal gait. Unlike quadrupeds, 82

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83 human upper limbs are not used for weight bearing, but instead, have a specific role in walking. (Dietz, 2002) Rhythmic armswing assists in impulsion, balance, and posture while walking (Eke-Okoro et al., 1997). As a result, inhibition of arm swing during walking leads to abnormal leg movements, decreased forward propulsion, and decrease in walking speed (Eke-Okoro et al., 1997; Marks, 1997). Natural arm swing pattern is walking speed specific; both arms swing in unison at walking speeds below ~1.9 mph and the arms swing reciprocally above the critical speed of ~1.9 mph (Webb et al., 1994; Donker et al., 2002). Armswing may have an important role to play during walking retraining after neurological injury. Persons with neurological injuries, needing walking assistance, are often not able to walk with a reciprocal armswing pattern. Armswing is often restricted when patients with neurological injuries walk with assistive devices. Bearing body weight through the arms while walking, though, is not a usual component of the task of walking. Walkers, crutches, and canes are introduced in rehabilitation to compensate for impaired balance, weakness, or incoordination (Bateni and Maki, 2005), but arm loading may promote the use of compensatory movements to achieve walking (Visintin and Barbeau, 1994). Even though the biomechanical effect of armswing on the walking pattern in normal healthy subjects is well studied, the neurological contribution of armswing to walking is largely speculative. Gaining a better understanding of the neurobiology of armswing on leg muscle reflex activity in normal healthy persons will assist us in developing strategies for gait rehabilitation in persons with neurological injury and understanding the neurological contribution of armswing to walking. Armswing during

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84 the task of standing was reported to induce significant depression of soleus H-reflex (Kawanishi et al., 1999; Hiraoka, 2001). Thus, sensory input provided by armswing may contribute to task-related adjustments in soleus H-reflex and the generation of coordinated walking (Hiraoka and Nagata, 1999; Hiraoka, 2001; Frigon et al., 2004). Therefore, the aim of this experiment was to understand how armswing affects leg reflex activity while walking. We specifically examined the effect of armswing pattern on soleus H-reflex excitability in non-injured persons while walking at 2.4 mph on a treadmill. Based on previous reports of rhythmic activities such as bicycling (Frigon et al., 2004; Zehr, 2005) and walking (Capaday and Stein, 1986) contributing to soleus H-reflex inhibition, we hypothesized that restraining the rhythmic armswing would increase the soleus H-reflex amplitude while walking. Methods Subjects: Eleven non-injured subjects with no history of neurological or orthopedic impairment of arms, legs, or trunk and no walking disability were recruited. An informed consent form approved by University of Florida-Institutional Review Board, was explained to and then signed by all subjects. Procedures: Stimulation and electrode placement: Skin was shaved and cleaned for application of surface electrodes. The tibial nerve was stimulated at the popliteal fossa using a button shaped silver electrode, strapped around the knee. Ground electrode was placed medial to the shin, between the surface EMG electrodes (Ag/AgCl Therapeutics Unlimited, Iowa City, Iowa) on soleus and tibialis anterior. EMG activity 100ms prior to electrical stimulation was recorded to examine if the H-reflex systematically changed with EMG activity. Surface EMG electrodes were also placed on the right anterior and posterior deltoid muscles. Stimulus was delivered using a Grass stimulator (Grass

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85 Instruments, model S88 with a modified CCU1. Astro-Med Industrial Park, 600 East Greenwich Avenue, West Warwick, RI-02893). Evoking soleus H-reflex: For the purpose of consistency, soleus H-reflex was tested on the dominant leg (determined by preferred kicking leg (Niemuth et al., 2005)). Subjects walked over the treadmill at 2.4 mph speed over two different conditions: reciprocal armswing and actively restrained armswing; the order was randomly chosen. All subjects wore a harness connected overhead to provide support in an event of a trip or fall. This harness, however, did not support the person’s body weight while walking. All subjects were then familiarized with the walking conditions for one minute each before recording H-reflex recruitment curve in mid-stance phase of walking. H-reflex recruitment curve was obtained by steadily increasing the stimulation intensity until the H-reflex was completely depressed and maximum M wave (Mmax) was obtained. The ascending limb of the recruitment curve was of interest in this experiment, since it reflects the behavior of H-reflex at a range of stimulation intensities. The ascending limb is the part of the curve when the H-reflex steadily increases, plateaus, and peaks as the stimulus intensity increases. The stimulation intensity was varied such that a majority of H-reflexes were at 4-6% of maximum M wave (Mmax) (Lagerquist et al., 2006). Duration between two consecutive stimulations ranged from 3-5 seconds. All subjects were given a 2 minute break between the testing conditions. Testing conditions were: 1) natural reciprocal armswing: Subjects walked naturally at 2.4 mph, a speed where reciprocal armswing is naturally present (Figure 5-1.A). No specific instructions were given; and 2) active restraint of armswing: Subjects walked at

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86 2.4 mph holding arms by the side of the trunk, thus actively inhibiting natural armswing (Figure 5-1.B). A B Figure 5-1. Two armswing conditions while walking over the treadmill at 2.4 miles per hour (mph); A: Natural reciprocal; B: Active restraint Data Analysis: The H-reflexes were normalized to Mmax in each testing condition. The mean of 10 H-reflexes in the range of 4-6% of Mmax was averaged for comparison between the two conditions (Lagerquist et al., 2006). Statistics: Paired t-test was used to compare mean H/M ratios between the two walking condition (p = 0.05). Results The mean H/M ratio was not significantly different between the two walking conditions (p>0.05). The mean H/M ratio was 0.18 in the natural reciprocal condition and 0.21 in the active restraint condition (Figure 5-2.). The mean EMG of soleus and tibialis anterior muscles 100 ms prior to the electrical stimulation was similar in both conditions (Table 5-1.). Mean EMG activity in both anterior and posterior deltoid was low and did not systematically change between the two conditions (Table 5-2.).

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87 00.050.10.150.20.250.30.350.4Armswing conditionH/M ratio Natural reciprocal Active restraint Figure 5-2. Mean H/M ratio in two walking conditions; Standard error bars shown Table 5-1. Mean EMG activity 100 ms prior to electrical stimulation Mean Soleus EMG Mean Tibialis Anterior EMG Subjects Natural reciprocal Active restraint Natural reciprocal Active restraint 1 0.14 0.17 0.11 0.07 2 0.31 0.30 0.07 0.07 3 0.14 0.13 0.06 0.05 4 0.12 0.10 0.08 0.08 5 0.13 0.10 0.04 0.04 6 0.26 0.27 0.07 0.07 7 0.26 0.24 0.08 0.07 8 0.14 0.13 0.06 0.06 9 0.10 0.11 0.03 0.04 10 0.08 0.08 0.07 0.06 11 0.18 0.17 0.07 0.07 Discussion Based on previous reports of rhythmic activities like bicycling (Zehr, 2005) and walking (Capaday and Stein, 1986) contributing to soleus H-reflex inhibition, we hypothesized that the soleus H-reflex amplitude would be greater while walking with

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88 restrained armswing; however, our results do not support this hypothesis and the soleus H-reflex amplitude (H/M ratio) remained unchanged. Table 5-2. Mean EMG activity in anterior and posterior deltoid muscles Mean Posterior Deltoid EMG Mean Anterior Deltoid EMG Subjects Natural reciprocal Active restraint Natural reciprocal Active restraint 1 0.05 0.05 0.06 0.06 2 0.04 0.04 0.05 0.05 3 0.10 0.04 0.05 0.05 4 0.05 0.04 0.05 0.05 5 0.04 0.04 0.05 0.05 6 0.04 0.05 0.05 0.05 7 0.03 0.03 0.05 0.05 8 0.03 0.03 0.05 0.05 9 0.04 0.03 0.05 0.04 10 0.04 0.03 0.05 0.05 11 0.04 0.04 0.05 0.05 The essential difference between the two walking conditions in this experiment was presence or absence of reciprocal armswing. Since, armswing-related peripheral afferent information did not alter the lower limb reflexes, it appears that this reflex modulation is centrally controlled and is independent of armswing in healthy non-injured subjects. The possibility of a central control of locomotion should, however, be viewed within the context of walking, since various peripheral sensory inputs are known to change the reflex amplitudes in non-locomotor tasks such as sitting and lying (Delwaide et al., 1977; Baxendale and Ferrell, 1985; Baldissera et al., 1998; Hiraoka and Nagata, 1999; Kawanishi et al., 1999; Hiraoka, 2001; Knikou and Conway, 2001; Knikou and Rymer, 2002a; Knikou and Rymer, 2002b; Frigon et al., 2004; Knikou, 2005). After an injury to the nervous system such as SCI, it is likely that the central control mechanisms are disrupted and modulation of reflexes can be influenced by peripheral sensory information

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89 (see results in Experiment II) (Misiaszek and Pearson, 1997; Schneider and Capaday, 2003). Central Control of Locomotion in Healthy Non-injured Subjects The findings of several studies in which knee range of motion (Garrett et al., 1999; Schneider et al., 2000), ankle muscle activity (Yang and Whelan, 1993), percentage of leg loading (Ferris et al., 2001; Miyoshi et al., 2006), walking environment (Crenna and Frigo, 1987; Simonsen et al., 1995; Ung et al., 2005), and conditioning of the H-reflexes (Capaday et al., 1995; Shoji et al., 2005) were manipulated, collectively, point towards the central control of locomotor reflex modulation. Garrett et al. (1999) and Schneider et al. (2000) reported that the soleus H-reflex amplitude did not change when the normal knee range of motion was eliminated via bracing (Garrett et al., 1999; Schneider et al., 2000). In the above two studies even though the peripheral sensory information originating from the legs while walking was disrupted, it did not change the phase-specific H-reflex modulation. It was proposed that the phase-specific reflex modulation during walking is centrally controlled and is not affected by peripheral events (Garrett et al., 1999; Schneider et al., 2000). Boorman et al. (1992) reported that passive bicycling did not induce H-reflex modulation seen during active bicycling (Boorman et al., 1992). In their study, the kinematics of bicycling motion was unchanged between the two modes of bicycling and supports the suggestion that reflex modulation is centrally controlled (Garrett et al., 1999; Schneider et al., 2000). Similarly in non-injured subjects, the phase-specific H-reflex modulation in walking was observed to be unaffected by tibialis muscle inactivity or soleus muscle activity during the swing phase of walking (Llewellyn et al., 1990; Yang and Whelan, 1993). Even different walking patterns that produce comparatively different amounts of

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90 ankle EMG activity (e.g. walking uphill, downhill, or on a level surface), did not change the amplitude of H-reflexes (Simonsen et al., 1995). Similar phase-specific soleus H-reflex modulation patterns were observed during single leg stepping on the treadmill and spot single leg stepping compared to bipedal walking on the treadmill (Crenna and Frigo, 1987; Lavoie et al., 1997). It was suggested that this desensitization to conditioning input during walking was produced by presynaptic inhibition (Yang and Whelan, 1993; Capaday et al., 1995), gating of afferent nerves, or saturation of the neuronal network (Capaday et al., 1995). Such an arrangement where peripheral inputs do not alter H-reflex amplitude is probably designed to maintain locomotion and afford flexibility during the task of walking. Similarly, the H-reflex amplitude (results from Experiment II) and gains (Ferris et al., 2001; Miyoshi et al., 2006) have been reported to remain unchanged at lower levels of leg load during walking. Peripheral afferent inputs influence soleus H-reflex amplitude in static tasks like standing or sitting, but during walking these same peripheral afferent inputs are most likely gated such that H-reflexes elicited during walking are not altered. H-reflex amplitude during the stance phase of walking is unaffected by a conditioning stimulus that normally depresses the H-reflex in standing (Capaday et al., 1995) or sitting (Shoji et al., 2005). Effect of Perceived Threat to Balance There are a few studies, however, that report a change in H-reflex excitability in response to a novel task of walking such as narrow beam walking and backward walking. Llewellyn et al. (1990) reported that walking on a narrow beam induces co-contraction of ankle musculature, decreases swing time, and decreases soleus H-reflexes in the stance phase (Llewellyn et al., 1990). Walking on the narrow beam probably required subjects to

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91 look at the walking surface and may have introduced the element of neck flexion during the walking trials. Head acceleration is known to cause depression of the H-reflexes (Paquet and Hui-Chan, 1999) and is a potential confound in the study by Llewellyn et al. (1990). In another study on backward walking task, it was reported that soleus H-reflex in the swing phase of walking was greater than the amplitude in the stance phase in healthy subjects untrained in the task of backward walking (Schneider and Capaday, 2003). When these same subjects walked backwards while holding on to side rails with their hands, the H-reflex amplitude in the swing phase was completely depressed; however the H-reflex amplitude increased again when the subjects were asked to walk backwards with eyes closed (Schneider and Capaday, 2003). The authors suggested that the high soleus H-reflex amplitude in the swing phase was related to fear of losing balance (Schneider and Capaday, 2003). In our study, we did not test H-reflexes in the swing phase of walking, but all subjects wore a safety harness attached overhead (with a sufficient slack to ensure that weight was not being pulled up) to assist with balance. Effect of Peripheral Sensory Inputs on H-reflex in Static Posture Thus, a large majority of studies report no change in H-reflex amplitude in response to a change in peripheral sensory inputs during the task of walking. In contrast to the locomotor studies, several studies performed in static leg positions report that arm movements influence soleus H-reflexes. Soleus H-reflexes were depressed because of an arm cycling task (arm at 70 degree flexion and arm at 10 degree extension) in normal healthy subjects (Frigon et al., 2004). Delwaide et al (1977) determined that with right arm flexion and left arm extension the myotactic reflexes of the soleus and quadriceps of the right leg were facilitated (Delwaide et al., 1977). When the arm positions were reversed right lower extremity soleus and quadriceps reflexes were depressed and the

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92 biceps femoris reflex was facilitated. In addition, active and passive arm movements and active armswing have been reported to depress soleus H-reflexes in standing (Hiraoka and Nagata, 1999; Kawanishi et al., 1999; Hiraoka, 2001); however, during the task of walking we report that the soleus H-reflexes were not affected by armswing. It appears that though the neuronal connections exist between arms and legs, these connections are gated during the task of walking. Even though the H-reflexes in walking are not sensitive to afferent input in non-injured healthy subjects, there appears to be a small window of time during learning of a new task when the H-reflex modulation is affected. Increase in soleus H-reflex amplitude has been associated with the phase of learning a new motor task (Hess et al., 2003); however, the H-reflex decreases back to pre-learning amplitude very quickly (Hess et al., 2003). The results from the above study suggest that even after various components of walking are altered in normal subjects with an intact nervous system, once the new task is learned, the H-reflex modulation is held constant at normal pre-learning level. Walking with actively restrained armswing is also a novel task; however, in our study we provided the subjects a chance to acclimatize to the new task of walking with restrained armswing before collecting H-reflex data. Thus, any increase in H-reflex amplitude associated with walking with restrained armswing may have normalized. Spinal Cord Injury and Soleus H-reflex Modulation Corticospinal tracts in the dorsal column of spinal cord are essential for H-reflex conditioning (Chen and Wolpaw, 1997). Cortical activity has been reported to increase as the animal adapts to the walking environment (Drew, 1993). Thus the corticospinal tracts may be responsible for presynaptic inhibition of Ia afferents (Ung et al., 2005). These

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93 tracts may be injured after SCI, leading to impaired presynaptic inhibition (Stein, 1995) and regulation of H-reflexes (Yang et al., 1991). Presynaptic inhibition is increased in afferent sources not related to the target muscle (Rudomin, 1999); thus afferent feedback arising from various sources may be gated during locomotion. After SCI, however, these mechanisms may be impaired. In a decerebrate cat model, a quadriceps stretch during the stance phase of locomotion depressed the soleus H-reflex (Misiaszek and Pearson, 1997). It was suggested that this response was most likely due to presynaptic inhibition of the afferents (Misiaszek and Pearson, 1997). In the above study, a comparison with normal cats as a control was not performed and it is not known if the quadriceps stretch suppressed the soleus H-reflex during locomotion. In summary, it appears that afferent input from the armswing could potentially be used to influence reflex modulation in the legs. Even though armswing restraint did not alter soleus H-reflex amplitude in our study of healthy non-injured subjects, there may be an effect seen in the population with injured spinal cord. Conclusion Reflex modulation appears to be centrally controlled and peripheral events such as armswing do not appear to affect H-reflex excitability during walking. The injury to the nervous system, however, can disrupt the central mechanisms regulating phase-specific reflex modulation, as reflected in impaired reflex modulation. The walking related sensory information may improve reflex modulation after a neurological injury. Some researchers suggest incorporating armswing into the practice of walking (Behrman and Harkema, 2000; Field-Fote, 2005). The effect of armswing on generating phase-specific reflex modulation in the task of walking needs to be systematically examined in persons with spinal cord injury and stroke.

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94 CHAPTER 6 SUMMARY AND FUTURE DIRECTIONS The purpose of this dissertation project was to examine three sensory aspects of locomotor training: BWS, walking environment, armswing. Below is a brief summary of the results from these experiments and future research directions. Body Weight Support in Standing We tested the effect of 40% BWS on soleus H-reflex amplitude in the standing position. The results, in both persons with i-SCI and non-injured controls, demonstrate that up to 40% BWS does not significantly alter soleus H-reflex amplitude (See Chapter 6). The use of BWS, however, is necessarily over a longer period of time in contrast to the cross-sectional usage in our study. Although our findings suggest that there is no immediate effect of 40% BWS on H-reflex, long term use of BWS to train standing in persons with i-SCI needs to be examined in the future. In addition, even though up to 40% BWS is a common support percentage used in research studies, it will be important to test the effect of higher percentages of BWS on soleus H-reflex in the future. Walking Environment In the second experiment the effect of the walking environment on soleus H-reflex excitability was examined. Two walking environments: walking overground unassisted (OG) and walking over the TM with 40% BWS and manual assistance (TM) we assessed. The results demonstrate that the mean soleus H-reflex amplitude in the TM environment was significantly smaller in the swing phase compared to the OG walking environment.

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95 Although the soleus H-reflex amplitude in the stance phase of walking was not significantly different between the two walking conditions, there was a trend toward a decrease in amplitude in the TM walking condition (See Chapter 7). The soleus H-reflex amplitude in the ageand speed-matched non-injured controls was significantly smaller compared to persons with i-SCI in the OG walking condition. In the TM walking environment, the soleus H-reflex amplitude in persons with i-SCI was not significantly different from the ageand speed-matched non-injured controls. Since the H-reflex amplitude in persons with i-SCI decreased in the TM walking environment, our results suggest that the TM walking environment induces a decrease in H-reflex amplitude, a sign of improved walking. The TM walking environment is employed to train persons with i-SCI to relearn walking. The locomotor training protocols vary from 3 weeks to 28 weeks (Behrman and Harkema, 2000; Behrman et al., 2005; Dietz et al., 1998; Dobkin et al., 2003; Gardner et al., 1998; Protas et al., 2001; Wernig and Muller, 1992; Wernig et al., 1995; Wirz et al., 2001). Future studies will examine the effect of long term training in the TM environment on the soleus H-reflex excitability. The next step is to examine if improvements in walking speed post locomotor training are correlated with decrease in H-reflex amplitude. Armswing Patterns in Walking In the third experiment, the impact of armswing pattern on soleus H-reflexes while walking on a treadmill at 2.4 mph was examined. The results show that armswing pattern did not affect soleus H-reflex excitability in non-injured healthy controls. These results are in contrast with studies done in static postures like standing and sitting. In static postures, arm position or armswing affects the excitability of soleus H-reflexes, however,

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96 while walking it appears that the nervous system adapts to a change in armswing and maintains the reflex amplitudes. Our results support earlier work suggesting reflexes are centrally controlled during walking. In the third experiment, we did not examine the change in reflexes in the acclimatization period of first minute or two. It is possible that the soleus H-reflexes were affected in the learning phase, but quickly normalized once the task of waling without armswing was mastered. Apart from cell death, injury to the spinal cord disrupts the normal connections between interneurons and the descending inputs. Thus, in the absence or reduction of cortical control of walking and walking specific reflexes, sensory inputs arising from the arm could be potentially utilized to compensate. Future studies may thus examine the immediate and long term effect of armswing restraint or assisted armswing on H-reflexes in persons with i-SCI and systematically examine the potential of armswing as a training variable to improve walking. The time course of training variables will be important to study whether an immediate effect is seen or if an extended training period is necessary for improvements to appear. Summary Locomotor training is a promising strategy to retrain walking after SCI and stroke. The aim of this dissertation was to specifically assess the effect of various locomotor training variables such as BWS, training environment, and armswing. Our results suggest: 1) BWS and armswing do not alter soleus H-reflex excitability in standing and walking respectively and 2) The TM training environment significantly normalized the H-reflex amplitude in the swing phase of walking. In light of these results, new experiments will be designed to carry forward the effort to understand the mechanisms of recovery and optimal delivery of the therapeutic intervention of locomotor training.

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BIOGRAPHICAL SKETCH Chetan. P. Phadke graduated from Chaitanya Medical Foundation’s College of Physiotherapy, with a Diploma in Rehabilitation (1993-1997). Subsequently, he was enrolled in the post-graduate program at the All India Institute of Physical Medicine and Rehabilitation and graduated with a Diploma in Rehabilitation for Physiotherapists (1998-1999). Chetan. P. Phadke returned to Chaitanya Medical Foundation’s College of Physiotherapy to complete a Bridge Course of 1-year duration to graduate with a Bachelor of Physiotherapy degree from the University of Pune (1999-2000). 119