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Effect of Low Frequency Bilateral Deep Brain Stimulation of the Subthalamic Nucleus on Balance and Gait in Parkinson Disease

Permanent Link: http://ufdc.ufl.edu/UFE0042090/00001

Material Information

Title: Effect of Low Frequency Bilateral Deep Brain Stimulation of the Subthalamic Nucleus on Balance and Gait in Parkinson Disease
Physical Description: 1 online resource (206 p.)
Language: english
Creator: Vallabhajosula, Srikant
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: balance, dbs, disease, gait, initiation, parkinson, stimulation, stn, subthalamic
Applied Physiology and Kinesiology -- Dissertations, Academic -- UF
Genre: Health and Human Performance thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: EFFECT OF LOW FREQUENCY BILATERAL DEEP BRAIN STIMULATION OF THE SUBTHALAMIC NUCLEUS ON BALANCE AND GAIT IN PARKINSON DISEASE High frequency subthalamic nucleus (STN) deep brain stimulation (DBS) surgery alleviates disabling symptoms like tremor and rigidity for Parkinson s disease (PD) patients. However, postural stability and gait seem to worsen with time after this surgery. A review of the literature suggests that low frequency stimulation of STN might be beneficial for certain motor activities. However, the effects of low frequency STN stimulation on posture and gait in PD have not been specifically studied. The purpose of the present study is to examine the acute effects of low frequency STN-DBS on postural stability and gait in PD. Ten participants with bilateral STN-DBS participated in the study. The participants were tested on two days while they were not on their prescribed medication. On day-1, four testing conditions were employed at baseline (currently used) voltage and pulse-width in a randomized manner: stimulator switched off (OFF-STIM), 30Hz, 60Hz and baseline frequency (130-185Hz). On day-2, four more testing conditions were randomly presented: 30Hz-HV, 30Hz-MV, 60Hz-HV and 60Hz-MV. HV referred to an increase of 1.5V from baseline and MV was the maximum tolerable voltage for each participant. Participants were then evaluated for static and dynamic postural control and gait performance. Unified Parkinson s Disease Rating Scale (UPDRS) Part-III was also administered in all the conditions. Overall, the low frequency conditions (30Hz and 60Hz) at baseline voltage significantly differed with the OFF-STIM condition (P < 0.05) but not with the baseline frequency. Specifically, differences were apparent for locomotion aspects of gait initiation and gait but not for static posture. The total UPDRS Part-III, bradykinesia and rigidity scores were improved when the stimulator was on, but speech worsened. Increasing the voltage at low frequency yielded minimal beneficial effects. Specifically, an increase in voltage at 30Hz seemed to benefit posture and an increase in voltage at 60Hz proved beneficial for locomotion. The acute effects of low frequency stimulation seemed to be equivalent to those by high frequency stimulation for posture and gait in individuals with PD. Hence, low frequency could be used in situations where high frequency DBS could cause an undesirable effect like decline in verbal fluency. Long-term effects of low frequency stimulation need to be evaluated.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Srikant Vallabhajosula.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: Tillman, Mark D.
Local: Co-adviser: Hass, Christopher J.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2011-02-28

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0042090:00001

Permanent Link: http://ufdc.ufl.edu/UFE0042090/00001

Material Information

Title: Effect of Low Frequency Bilateral Deep Brain Stimulation of the Subthalamic Nucleus on Balance and Gait in Parkinson Disease
Physical Description: 1 online resource (206 p.)
Language: english
Creator: Vallabhajosula, Srikant
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: balance, dbs, disease, gait, initiation, parkinson, stimulation, stn, subthalamic
Applied Physiology and Kinesiology -- Dissertations, Academic -- UF
Genre: Health and Human Performance thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: EFFECT OF LOW FREQUENCY BILATERAL DEEP BRAIN STIMULATION OF THE SUBTHALAMIC NUCLEUS ON BALANCE AND GAIT IN PARKINSON DISEASE High frequency subthalamic nucleus (STN) deep brain stimulation (DBS) surgery alleviates disabling symptoms like tremor and rigidity for Parkinson s disease (PD) patients. However, postural stability and gait seem to worsen with time after this surgery. A review of the literature suggests that low frequency stimulation of STN might be beneficial for certain motor activities. However, the effects of low frequency STN stimulation on posture and gait in PD have not been specifically studied. The purpose of the present study is to examine the acute effects of low frequency STN-DBS on postural stability and gait in PD. Ten participants with bilateral STN-DBS participated in the study. The participants were tested on two days while they were not on their prescribed medication. On day-1, four testing conditions were employed at baseline (currently used) voltage and pulse-width in a randomized manner: stimulator switched off (OFF-STIM), 30Hz, 60Hz and baseline frequency (130-185Hz). On day-2, four more testing conditions were randomly presented: 30Hz-HV, 30Hz-MV, 60Hz-HV and 60Hz-MV. HV referred to an increase of 1.5V from baseline and MV was the maximum tolerable voltage for each participant. Participants were then evaluated for static and dynamic postural control and gait performance. Unified Parkinson s Disease Rating Scale (UPDRS) Part-III was also administered in all the conditions. Overall, the low frequency conditions (30Hz and 60Hz) at baseline voltage significantly differed with the OFF-STIM condition (P < 0.05) but not with the baseline frequency. Specifically, differences were apparent for locomotion aspects of gait initiation and gait but not for static posture. The total UPDRS Part-III, bradykinesia and rigidity scores were improved when the stimulator was on, but speech worsened. Increasing the voltage at low frequency yielded minimal beneficial effects. Specifically, an increase in voltage at 30Hz seemed to benefit posture and an increase in voltage at 60Hz proved beneficial for locomotion. The acute effects of low frequency stimulation seemed to be equivalent to those by high frequency stimulation for posture and gait in individuals with PD. Hence, low frequency could be used in situations where high frequency DBS could cause an undesirable effect like decline in verbal fluency. Long-term effects of low frequency stimulation need to be evaluated.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Srikant Vallabhajosula.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: Tillman, Mark D.
Local: Co-adviser: Hass, Christopher J.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2011-02-28

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0042090:00001


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1 EFFECT OF LOW FREQUENCY BILATERAL DEEP BRAIN STIMULATION OF SUBTHALAMIC NUCLEUS ON BALANCE AND GAIT IN PARKINSON DISEASE By SRIKANT VALLABHAJOSULA A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2010

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2 2010 Srikant Vallabhajosula

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3 To my lovely family

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4 ACKNOWLEDGMENTS I thank my parents for their blessings and constant support to help me achieve my goals. I thank my brother for his constant words of encouragement and critical reasoning. I also thank my parents in law for their love, affection and support in the short time that I have known them. I thank my advis or Dr. Mark Tillman for being always there when I needed to advice on anything and everything. Dr. Chris Hass has been instrumental to guide me with all my projects during my doctoral work and his constant guidance even on personal front has helped me imme nsely to complete my work. I thank him for being my mentor. I would also like to acknowledge Dr. Michael Okun for sharing his incredible excitement and knowledge with me throughout my dissertation work He has helped me appreciate the clinical aspects of m y work. I would like to thank Dr. Mark Bishop for agreeing to be my external committee member as well as for his immediate availability to help me with my dissertation. My special thanks to Dr. John Chow and Dr. Beverly Roberts for supporting me in different phases of my doctoral work. My work would not have been able to complete without help from Dr. Nelson Hwynn who consistently helped in recruitment for the study and ensured that the project was completed in reasonable time. My special thanks to my colleagues in the Biomechanics lab and my friends who have helped in various ways during the course of my dissertation. Last but not the least; I thank my wife for incredibly being there when I needed her the most. Her presence helped me concentrate on my work and complete it in timely manner. I am grateful to her for the patience and unconditional support she has shown.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................. 4 LIST OF TABLES ............................................................................................................ 7 LIST OF FIGURES .......................................................................................................... 8 LIST OF ABBREVIATIONS ........................................................................................... 11 ABSTRACT ................................................................................................................... 13 CHAPTER 1 INTRODUCTION .................................................................................................... 15 Purpose of the Study .............................................................................................. 17 Specific Aims and Central Hypotheses ................................................................... 17 Specific Aim 1: .................................................................................................. 17 Central Hypothesis 1: ....................................................................................... 17 Specific Aim 2: .................................................................................................. 17 Central Hypothes is 2: ....................................................................................... 17 2 REVIEW OF LITERATURE .................................................................................... 18 Parkinson Disease .................................................................................................. 18 Epidemiology of P arkinson Disease (PD) ............................................................... 18 Structural Anatomy of the Basal Ganglia ................................................................ 19 Motor Circuit of the Basal Ganglia .......................................................................... 20 Motor Symptoms of PD ........................................................................................... 21 Prevalent Therapies for PD ..................................................................................... 22 Deep Brain Stimulation ........................................................................................... 26 Mechanism of Action of D eep Brain Stimulation (DBS) .......................................... 27 Therapeutic Effects of DBS ..................................................................................... 28 3 METHODS .............................................................................................................. 39 Participants ............................................................................................................. 39 Experimental Protocol ............................................................................................. 40 Evaluations ............................................................................................................. 41 U nified Parkinsons Disease Rating Scale (UPDRS) ........................................ 41 Static balance ................................................................................................... 41 Dynamic Balance and Gait ............................................................................... 42 Data Processing ..................................................................................................... 42 Data Analyses ......................................................................................................... 44

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6 4 RESULTS ............................................................................................................... 51 Effect of Low Frequency ......................................................................................... 51 Static Balance (Eyes Open and Eyes Closed Trials) ........................................ 51 Dynamic Balance (G ait Initiation) ..................................................................... 52 Gait Evaluation ................................................................................................. 53 UPDRS Part III ( Total Score and SubScores) ................................................. 54 Effect of Low Frequency and Higher Voltage .......................................................... 54 Static Balance (Eyes Open and Eyes Closed Trials) ........................................ 55 Dynamic Balance (Gait Initiation) ..................................................................... 55 Gait Evaluation ................................................................................................. 55 UPDRS (Total Sco re and SubScores) ............................................................. 56 Correlations with Total Electrical Energy Delivered (TEED) per Second ................ 57 Static Balance (Eyes Open and Eyes Closed Trials) ........................................ 57 Dynamic Balance (Gait Initiation) ..................................................................... 57 Gait Evaluation ................................................................................................. 58 UPDRS (Total Score and SubScores) ............................................................. 58 Non motor Symptoms and Observations ................................................................ 58 Subjective Feedback Scale ..................................................................................... 58 5 DISC USSION ......................................................................................................... 94 Static Balance (Eyes Open and Eyes Closed Trials) .............................................. 94 Gait Initiation ........................................................................................................... 99 Gait Evaluation ..................................................................................................... 108 UPDRS Part III ( Total Score and SubScores) ..................................................... 116 Correlations with Total Electrical Energy Delivered (TEED) per second ............... 119 Non motor Symptoms and Observations: ............................................................. 121 Subjective Feedback Scale ................................................................................... 121 Limita tions ............................................................................................................. 122 Conclusion ............................................................................................................ 122 Future Considerations ........................................................................................... 124 APPENDIX: STATISTICAL ANALYSES TABLES ....................................................... 125 LIST OF REFERENCES ............................................................................................. 195 BIOGRAPHICAL SKETC H .......................................................................................... 206

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7 LIST OF TABLES Table page 4 1 Baseline characteristics of the participants ......................................................... 83 4 2 Baseline characteristics of the right stimulator of the participants ...................... 83 4 3 Baseline characteristics of the left stimulator of the participants ......................... 84 4 4 Non motor symptoms and observations including participant feedback during data collection .......................................................................................... 83 4 5 Subjective Feedback scale ................................................................................. 90

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8 LIST OF FIGURES Figure page 2 1 Structural Anatomy of the Basal Ganglia. ........................................................... 37 2 2 Motor Circuit of the Basal Ganglia. ..................................................................... 38 2 3 The Activa D eep Brain Stimulator System and its components. ...................... 38 3 1 Flowchart of testing procedures for day 1 .......................................................... 47 3 2 Flowchart of testing procedures for day 2 .......................................................... 48 3 3 Biomechanics Lab Set Up.. ................................................................................ 49 3 4 Marker placement. ............................................................................................. 50 4 1 A nterior Posterior (AP) Center of Pressure (CoP) range for eyes open trial related to specific aim 1. ..................................................................................... 59 4 2 AP CoP velocity in S3 phase of gait initiation related to specific aim 1.. ............ 59 4 3 AP CoPC enter of Mass (CoM) distance in S3 phase of gait initiation related to specific aim 1. ................................................................................................. 60 4 4 Stance leg step length during gait initiation trials related to specif ic aim 1. ....... 60 4 5 Swing leg step length during gait initiation trials related to specific aim 1.. ........ 61 4 6 Swing leg step velocity during gait initiation trials related to specific aim 1.. ...... 61 4 7 Stance leg step velocity during gait initiation trials related to specific aim 1. ...... 62 4 8 Time to swing leg toeoff during gait initiation trials related to specific aim 1. ..... 62 4 9 Time to stance leg toe off during gait initiation trials related to specific aim 1. ... 63 4 10 C oefficient of Variation (CV) of swing leg step time during gait initiation trials related to specific aim 1.. .................................................................................... 63 4 11 C V of swing leg step velocity during gait initiation trials related to specific aim 1.. ................................................................................................................ 64 4 12 Walking speed d uring gait trials related to specific aim 1.. ................................. 64 4 13 Opposite foot contact during gait trials related to specific aim 1.. ....................... 65 4 14 CV of Opposite foot contact during gait trials related to specific aim 1.. ............. 65

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9 4 15 T otal score of U nited Parkinsons Disease Rating Scale (UPDRS) Part III evaluation related to specific aim 1. ................................................................... 66 4 16 Bradykinesia sub score of U PDRS Part III evaluation related to specific aim 1.. ....................................................................................................................... 66 4 17 Rigidity sub score of U PDRS Part III. evaluation related to specific aim 1.. ........ 67 4 18 Speech subscore of U PDRS Part III evaluation related to specific aim 1.. ....... 67 4 19 Frequency main effect of s way area during eyes closed trials related to specific a im 2. ..................................................................................................... 68 4 20 Fre quency main effect of AP CoP displacement in S2 phase during gait initiation trials related to specific aim 2. .............................................................. 68 4 21 Frequency main effect of AP CoP displacement in S3 phase (cm) during gait initiation trials related to specific aim 2.. ............................................................. 69 4 22 Frequency main effect of AP CoP velocity in S3 phase (cm) during gait initiation trials related to specific aim 2 .............................................................. 69 4 23 Frequency main effect of Swing leg step length during gait initiation trials related to specific aim 2.. .................................................................................... 70 4 24 Frequency main effect of S tance leg step length during gait initiation trials related to specific aim 2. ..................................................................................... 70 4 25 Frequency main effect of Swing leg step time during gait initiation trials related to specific aim 2. ..................................................................................... 71 4 26 Frequency main effect of CV o f stance leg step velocity during gait initiation trials related to specific aim 2.. ........................................................................... 71 4 27 Frequency main effect of Walking speed during gait trials related to specific aim 2.. ................................................................................................................ 72 4 28 Frequency main effect of Stride length during gait trials related to specific aim 2.. ................................................................................................................ 72 4 29 Frequency main effect of Step length at during gait tri als related to specific aim 2. ................................................................................................................. 73 4 30 Voltage main effect of Opposite foot contact during gait trials related to specific aim 2. ..................................................................................................... 73 4 31 Coefficient of Variation of opposite foot off during gait trials related to specific aim 2 .. ................................................................................................................ 74

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10 4 32 Frequency main effect of C V of opposite foot contact during gait trials related to specific aim 2. ................................................................................................. 74 4 33 Speech subscore during U PDRS Part III evaluat ion related to specific aim 2. .. 75 4 34 Tremor subscore during U PDRS Part III e valua tion related to specific aim 2. .. 75 4 35 C orrelation between T otal Electrical Energy Delivered (TEED) and M edio Lateral (ML) CoP Range during eyes open trial .................................................. 76 4 36 C orrelation between TEED and AP CoP Range during eyes open trial .............. 76 4 37 C orrelation between TEED and CoP Sway Area during eyes o pen trial ............. 77 4 38 Correlation between TEED and ML.CoP Range during eyes closed trial .......... 77 4 39 Correlation between TEED and AP.CoP Range during eyes closed trial .......... 78 4 40 Correlation between TEED and CoP Sway Area during eyes closed trial ......... 78 4 41 Correlation between TEED and ML CoP displacement during S2 phase of gait initiation ........................................................................................................ 79 4 42 Correlation between TEED and M aximum resultant C oP C oM distance during S3 phase of gait initiation ......................................................................... 79 4 43 Correlation between TEED and M aximum AP CoP CoM distance during S3 phase of gait initiation ........................................................................................ 80 4 44 Correlation between TEED and Swing leg step velocity during gait initiation ..... 80 4 45 Correlation between TEED and CV of stance leg step length during gait initiation .............................................................................................................. 81 4 46 Correlation between TEED and double support time during gait evaluation. ...... 81 4 47 Correlation between TEED and balance subscore on the U PDRS Part III evaluation ......................................................................................................... 82

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11 LIST OF ABBREVIATION S ANOVA Analyses of Variance AP AnteroPosterior BDI Becks Depression Index BF Baseline Frequency BV Baseline Voltage CoM Center of Mass CoP Center of Pressure CV Coe fficient of Variation DBS Deep Brain Stimulation EMG Electromyography GI Gait Initiation GPi Globus Pallidus Internus/Internal Segment GPe Globus Pallidus Externus/External Segment HV Higher Voltage LEDD Levodopa Equivalent Daily Dose MANOVA Multi variate Analyses of Variance ML MedioLateral MLR M idbrain Locomotor Region MMSE Mini Mental Status Examination MV Maximum tolerable Voltage OFF MED Without Medication OFF STIM Without Stimulation ON MED Under the influence of medication ON STIM With stimulator sw itched on

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12 PD Parkinson disease PFS Parkinsons Fatigue Scale PPN Pedunculopontine Nucleus R/L Right/Left RMS Root Mean Square SMA Supplementary Motor Area SNc Substantia Nigra pars compacta SNr Substantia Nigra pars reticulate STN Subthalamic Nucleus TEED Total Electrical Energy Delivered UPDRS Unified Parkinsons Disease Rating Scale

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13 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 EFFECT OF LOW FREQUENCY BILATERAL DEEP BRAIN STIMULATION OF THE SUBTHALAMIC NUCLEUS ON BALANCE AND GAIT IN PARKINSON DISEASE By Srikant Vallabhajosula August 2010 Chair: Mark Tillman Major: Health and Human Performance High frequency subthalamic nucleus (STN) deep brain stimulation (DBS) surgery alleviates disabling symptoms like tremor and rigidity for Parkinsons disease (PD) patients. However, postural stability and gait seem to worsen with time after this surgery. A review of the literature suggests that low frequency stimulation of STN might be beneficial for certain motor activities. However, the effects of low frequency STN stimulation on posture and gait in PD have not been specifically studied. The purpose of the present study is to examine the acute effects of low frequency STN DBS on postural stability and gait in PD. Ten participants with bilateral STN DBS participated in the study. The participants were tested on two days while they were not on their presc ribed medication. On day 1, four testing conditions were employed at baseline (currently used) voltage and pulse width in a randomized manner: stimulator switched off (OFF STIM), 30Hz, 60Hz and baseline frequency (130 185Hz) On day 2, four more testing conditions were randomly presented: 30Hz HV, 30Hz MV, 60Hz HV and 60Hz MV. HV referred to an increase of 1.5V from baseline and MV was the maximum tolerable voltage for each participant. Participants were then evaluated for static and dynamic postural contr ol

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14 and gait performance. U nified Parkinsons Disease Rating Scale (U PDRS ) Part III was also administered in all the conditions. O verall, the low frequency conditions (30Hz and 60Hz) at baseline voltage significantly differed with the OFF STIM condition ( P <0.05) but not with the baseline frequency. Specifically, differences were apparent for locomotion aspects of gait initiation and gait but not for static posture. The total UPDRS Part III, bradykinesia and rigidity scores were improved when the stimulator was on, but speech worsened. Increasing the voltage at low frequency yielded minimal beneficial effects. Specifically, an i ncrease in voltage at 30Hz seem ed to benefit posture and an increase in voltage at 60Hz proved beneficial for locomotion. The acu te effects of low frequency stimulation seemed to be equivalent to those by high frequency stimulation for posture and gait in individuals with PD. Hence, low frequency could be used in situations where high frequency DBS could cause an undesirable effect like decline in verbal fluency. Longterm effects of low frequency stimulation need to be evaluated.

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15 CHAPTER 1 INTRODUCTION Parkinson disease (PD) is the second most common neurodegenerative movement disorder, after essential tremor. This hypokinetic movement disorder is characterized cardinally by resting tremor, rigidity, akinesia (or bradykinesia) and postural instability (Alves et al., 2008). The clinical diagnosis of PD requires the presence of at least two of the four cardinal symptoms, unilateral onset, a strong clinical response to Levadopa, and absence of other neurologic disorders specific features (Ebadi and Pfeiffer, 2004). Many symptoms of this basal ganglia disorder result from the lack of dopamine, a chemical messenger, in the brain. Dopam ine depletion in the striatum is caused by the progressive degeneration of the dopaminergic neurons present in the substantia nigra. Motor deficits also include poverty of articulated speech, dysphagia, micrographia and others. Persons with PD exhibit shuf fling gait characterized by smaller and quicker steps. Sometimes, individuals in the advanced stage experience freezing of gait especially during activities like gait initiation, turning and passing through narrow precincts. Additionally, several nonmot or symptoms like sleep disturbances, urinary difficulties, anxiety, depression and cognitive decline are prominent among different stages of PD. Therapeutic options include administering medicines like Levodopa during early stages and using surgical procedures during advanced stages of PD. Deep brain stimulation (DBS) is a surgical procedure used to improve a variety of debilitating symptoms of PD such as tremor, rigidity, stiffness and slowed movement. The procedure uses a lead that is implanted into deep brain structures such as the subthalmic nucleus (STN) or globus pallidus (GPi) (Fernandez et al. 2007). The lead is

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16 connected to a battery operated neurostimulator through an extension passed under the skin of the head, neck, and shoulder. The neurostim ulator is usually implanted under the skin near the collarbone and sends electrical signals to the targeted areas in the brain that control movement. The settings on the neurostimulator are programmed based on the individuals needs and include the pulse width, frequency, and amplitude (measured in voltage). One of the primary benefits of the DBS procedure is the programmability of the neurostimulator. Once programmed to a particular setting, in case of any adverse effects, the settings can always be re pr ogrammed to a different setting or could be restored to the original settings in order to negate the undesirable effects. Currently high frequency (>130Hz) and low voltage settings are the most commonly used stimulator combinations. It is well accepted that high frequency DBS has positive impact on several cardinal features including reductions in tremor, dyskinesia and rigidity. However equivocal findings or even adverse effects have been observed in some symptoms such as freezing, postural instability, f alls and verbal fluency (Marconi et al. 2008). In fact, Moreau et al., (2008) mentioned an increase in the number of freezing episodes at a higher frequency (130Hz) and usual voltage compared to a lower frequency (60Hz) and higher voltage. Increasing the v oltage at a lower frequency was done to maintain equivalent electrical energy transmitted by the stimulators. Also, Wojtecki et al., (2006) reported a decline in cognitive performance at frequencies higher than 130Hz compared to low frequency (10Hz) and us ual voltage stimulation. However, few studies have been designed to examine the effects of altering

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17 the stimulation frequency and voltage (energy) on balance and gait in individuals with PD. Purpose of the Study The purpose of this study was to evaluate t he effects of altering the stimulation parameters (frequency and voltage) on motor aspects (tremor, rigidity, balance and gait) and determine if any particular setting provides a comprehensive beneficial effect for persons with PD. Specific Aims and Central Hypotheses Specific Aim 1 To determine if the motor characteristics of individuals with PD improve at a lower frequency with respect to the baseline (currently used) value while keeping the voltage and pulse width constant at the baseline (currently used) value. Central Hypothesis 1. At constant baseline pulse width and voltage, there will be an overall improvement in the motor aspects (tremor, rigidity, balance and gait) as the frequency is decreased from the baseline. Specific Aim 2 To determ ine if the motor characteristics of individuals with PD improve at a low frequency by increasing the voltage while keeping the pulse width constant Central Hypothesis 2. At constant pulse width and low frequency, t here will be an overall improvement in the motor aspects ( tremor, rigidity, balance and gait) as the voltage is increased from the baseline.

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18 CHAPTER 2 REVIEW OF LITERATURE Parkinson Disease Parkinson disease (PD) is the second most common and progressive neurodegenerative disease (Tanner and Aston 2000). Considered as a prevalent movement disorder, PD is typically identified by its cardinal symptoms: resting tremor, rigidity, akinesia and postural instability (Kanthasamy et al., 2005; Alves et al., 2008). This chronic basal ganglia disorder i s often characterized by nigrostriatal cell loss and presence of intracellular synuclein positive inclusions called Lewy bodies. Dopamine depletion in the striatum is caused by the progressive degeneration of the dopaminergic neurons present in the subst antia nigra. This dopamine depletion in the striatum further results in the decreased stimulation of the motor cortex by the basal ganglia. As the disease progresses, persons with PD display a wide range of motor and nonmotor deficits like akinesia, freez ing of gait, sleep dysfunction, depression and others. These deficits often lead to poorer quality of life (Schrag et al., 2000). Epidemiology of P D The average age of onset for PD is estimated around 60 and the disease affects about 1 to 2% of adults age d 65 or above and about 3 to 5% of those 85 years and older (Elbaz et al., 2002; Fahn 2003; Alves et al., 2008). Around 5 to 10% of the population develops PD symptoms before the age of 40 and are categorized as the Youngonset Parkinson Disease group. Slower progression of the disease coupled with more dystonic and psychiatric disturbances are characteristics of this young onset group. Also, individuals who develop PD symptoms before the age of 20 are commonly referred to as having Juvenile Onset Parkinso n Disease with 75% of the cases due to

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19 variation in the Parkin mutation. Gender based research reveals that the disease is more preponderant in males with ratio of about 6065% as compared to females ( Elbaz et al., 2002; Grimes, 2004) PD has been found to be rife among all ethnic groups. Van Den Eeden and colleagues (2003) reported higher incidences of the disease in Hispanics followed by nonHispanic Whites, Asians and Blacks. However in another study, the incidence was found to be greatest among Whites followed by Hispanics and Afro Americans (Dahodwala et al., 2009). Although PD may not directly cause death, the secondary consequences of PD like aspiration and falls due to motor dysfunction may lead to higher mortality rates in PD compared to healthy age matched individuals (Uitti et al., 1993; Ebadi and Pfeiffer, 2004). Structural Anatomy of the Basal Ganglia Basal ganglia refer to a group of nuclei located in the deeper parts of the cerebrum. The caudate nucleus and the lentiform nucleus, together termed as the corpus striatum constitute a pair of nuclear masses The caudate nucleus lies superior to the thalamus and medial to the internal capsule where as the lateral lentiform nucleus cons ists of a medial globus pallidus and a lateral putamen. The globus pallidus is further sub divided into an external segm ent (GPe) and internal segment (GPi) Along with the striatum, the subcortical subthalam ic nucleus (STN) is the other principal input nucleus of the basal ganglia. Other subcortical nuclei inclu de substantia nigra, and pedunculopontine nucleus (PPN). The substantia nigra is further classified into substantia nigra pars compacta (SNc) and substantia nigra pars reticulate (SNr). The structural locations of these constituent parts are s hown in F igure 2 1.

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20 Motor Circuit of the Basal Ganglia The striatum is the primary afferent structure in the basal ganglia receiving an excitatory glutametergic input from the cerebral cortex (Galvez Jiminez 2005). The cortico striatal projections exhibit both convergence and divergence properties within the striatum. While a projection from a cortical area diverges in the striatum, it also converges with the projections from other areas enabling the integration of sensory and motor information from different areas of the cortex. Cortical projections also input signals to the STN (F igure 22) Excitatory and inhibitory inputs to the striatum also exist from the SNc. The efferent nuclei of the basal ganglia include GPi and SNr. These output nuclei receive their affer ent signals through two converse pathways. The inhibitory D1 pathway carries the neuronal flow directly from striatum to the output nuclei. However a secondary pathway D2 having a net inhibitory effect on GPi and SNr projects from the striatum through the GPe and STN. The output neurons from the GPi and SNr are inhibitory in nature and project directly into the thalamus. The f unction of these two pathways is best exemplified through inspection of the motor loop of the basal ganglia. Motor neurons from the thalamus project to the areas associated with motor functioning in the cortex like the primary motor cortex and supplementary motor area. However, the flow of these neurons is inhibited by the action of the output from GPi and SNr. So when a motor action has to be performed there has to be a disinhibition of output from the basal ganglia. This inhibition of the output from GPi and SNr is achieved through the D1 pathway which sends inhibitory signals to GPi and SNr thereby causing them to send reduced inhi bitory signals to the thalamus hence enabling excitatory signal flow from thalamus to the cortical motor areas. On the other hand, when movement needs to be restrained, the basal ganglia need to send more

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21 inhibitory signals to the thalamus to restrict the outflow to the motor areas of the cortex. This is achieved through the D2 pathway which inputs excitatory signals to the GPi and SNr, thus enabling them to release more inhibitory signals to the thalamus as desired for slowing down the movement. Thus a com bined action of D1 and D2 pathways regulates the movement in a desired manner. This joint action between the direct and indirect pathways is in turn regulated by the amount of dopamine released by the SNc. More dopamine released into the striatum causes increased signal transmission through the D1 pathway and diminished movement through the D2 pathway. The overall effect of an augmented activity in the direct pathway and a decreased activity in the indirect pathway is reduction in the inhibitory output from the basal ganglia and hence more movement. Conversely, the depletion of dopaminergic neurons in the striatum results in reduced movement through enhanced output from the GPi and SNr (DeLong and Wichmann, 2007). The poverty of movement in people with P D i s often associated with th e paucity of dopamine levels in basal ganglia structures. Motor Symptoms of PD Among the motor symptoms of PD, tremor is the most observable symptom and more often occur s unilaterally. This 4 to 6Hz involuntary rhythmic oscillation is seen primarily in fingers and also in legs, jaws and tongue. Though the tremor starts unilaterally, it spreads bilaterally on an average of six years after the onset of symptoms (Scott et al., 1970; Ebadi and Pfeiffer, 2004). Sometimes postural or act ion tremor coexists with this resting tremor, thereby leading to more perceived social embarrassment. Another cardinal motor symptom of persons with PD is bradykinesia. Defined as generalized slowness of movement, bradykinesia is a prominent cause of dis ability in PD. In many of the diagnosing criteria for PD, presence of bradykinesia is

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22 considered mandatory. Bradykinesia may involve a delay in initiating movements, difficulty in swallowing, softer voice (hypophonia) with words spoken that are hard to understand, face masking and others. Night time drooling may result due to dysphagia and also handwriting gets smaller and less legible (micrographia). Persons with PD also experience difficulties performing some activities of daily living like tying shoe lac es, and buttoning shirts. As the disease progresses, noticeable reduction in arm swing, difficulty initiating gait, and smaller but quicker steps (called shuffling gait) are markedly visible. During advanced stages of the disease, individuals with PD exper ience freezing of gait Freezing involves sudden stopping and difficulty initiating gait while walking. This condition is particularly seen when a person with PD walks through narrow space s like doorways or while turning. Freezing can often lead to ins tability and increases the risk of falling in this population. Rigidity is defined as a hypertonic state of the muscle where the clinician can feel an unvarying increased resistance within the range of passive movement at a joint (Deuschl and Goddemeier 1 998; Ebadi and Pfeiffer, 2004 ). The Cogwheel type of rigidity is particularly prevalent in persons with PD where resistance of the palpated muscle increases in a periodic manner during passive movement. The stooped posture among PD is often attributed thei r rigidity. Postural instability, the fourth cardinal motor symptom, usually occurs in the later stages of the disease and often leads to gait difficulties and falls among PD. Given its unresponsiveness to anti Parkinsonian medications like Levodopa, postural instability is considered the least treatable motor symptom (Koller, 1989; Ebadi and Pfeiffer, 2004 ). Prevalent Therapies for PD Different modes of therapy including pharmacological therapy, physiotherapy, occupational therapy, music therapy, genetic therapy, surgical therapy and others have

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23 been employed to alleviate the motor complications. For example, researchers investigated music therapy as an alternative to address concerns of motor complications among people with PD. Music therapy involves addr essing the emotional, social and physical well being of a patient by p articipation in singing, playing instruments, or listening to music ( Yu et al., 2009) Pacchetti et al. (2000) showed beneficial effects of music therapy on bradykinesia measured through the Unified Parkinson's Disease Rating Scale ( UPDRS) score. But recently, Brown and colleagues (2009) reported no specific improvements among people with PD during gait performance combined with concurrent music during both single and dual tasks. M edicinal therapy and surgical therapy have been the most prevalent. Drug treatments include administering anti parkinsonian drugs like Levodopa or Carbidopa. Levodopa treatment has particularly been shown to be effective in relieving some of the cardinal symptoms of PD. In 1938, Peter Holtz discovered that dopamine could be produced by Levodopa in mammalian tissue (Hornykiewicz, 2002). Carlsson and Hornykiewicz highl ighted the effectiveness of the pharmacological intervention by demonstrating that a reversal of parkinsonian features could be accomplished by using substances that can directly stimulate the postsynaptic dopamine receptors in the striatum (LeWitt, 2008). When a dministered orally, only a small quantity of Levodopa reaches the brain from the upper small intestine to produce dopamine. This allowance of limited quantities of Levodopa has been explained due to the blood b rain barrier (Nutt and Fellman, 1984). Certain drugs like Carbidopa and Selegiline, when co administered, efficiently regulate the dopamine production by Levodopa. Additionally, Levodopa is used not only as a

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24 medication but also as a diagnostic tool. People with PD often show significant improv ements in speech and gait inside 15 to 30 minutes of oral dosage of Levodopa. However, the Levodopa treatment has also been shown to have a negative effect on some cardinal symptoms. Schrag and Quinn (2000) attributed the development of motor fluctuations to disease duration and dosage of Levodopa with patients who started Levodopa early showing more motor complications. They also ascribed the incidences of dyskinesias with duration of the Levodopa treatment. Fahn and colleagues (2005) showed that the effectiveness of Levodopa varies with its dosage levels and may slow down the rate of progression of the disease. However, they also pointed out that Levodopa could rapidly deteriorate the integrity of the dopamine transporter in the nigrostriatal nerves. Though their study mentioned some beneficial effects like reduction of freezing episodes with Levodopa, development of dyskinesias and quicker wearingoff of medicine after at least 5 months were also revealed. Higher doses of Levodopa have also been associat ed with an increase in dyskinesias and non motor symptoms (Fahn et al., 2004; Nutt, 2001 ). Radad and colleagues (2005) also mentioned the prevalence of psychiatric problems along with the dyskinesias due to long term Levodopa treatment. Holloway and collea gues (2004) reported lower occurrences of freezing episodes and better UPDRS scores but higher frequencies of dyskinesias and wearing off of Levodopa medicinal effects compared to another medicine (Praximpexole). In summary, the cost effective Levodopa provides good symptomatic relief but with certain longterm negative side effects. These sideeffects include shorter periods of relief particularly at peak dosages of medication (ON state), fluctuations between these ON and OFF (with Parkinsonian symptom s resurfacing)

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25 states and motor complications including dyskinesias. Hence, the search for therapies that alternate or supplement the medication based therapy gained prominence to counteract the debilitating effects of medications like Levodopa. Certain do pamine agonists are also used to supplement the action of drugs like Levodopa. While Levodopa has been linked with enhanced motor performance, the dopamine agonists have been associated with fewer motor fluctuations and dyskinesias. Kondo (2002) suggested that the dopamine agonists could be used for therapy during the initial stages with the introduction of Levodopa during the advanced stages of the disease to combat the motor complications. Kondo attributed the effectiveness of the dopamine agonists to the longer half life of their plasma. Similar reports were reviewed elsewhere further suggesting that the dopamine agonists could be used in conjunction with Levodopa during the advanced stages to hinder the development of motor complications (Watts, 1997; Radad et al., 2005; Ransmayr, 2005). Radad and colleagues (2005) also mentioned that the dopamine agonists like Bromocriptine, Pergolide, Cabergoline and others are frequently used by young onset Parkinsonians in their de novo (OFF MED) state before embarkin g on to Levodopa therapy. However, even though the dopamine agonists could reduce the disabling sideeffects of Levodopa, the monotherapy of the dopamine agonists or the adjunct therapy along with Levodopa has had limited success clinically. Poewe (1998) m entioned that the monotherapy of dopamine agonists was successful in only about 30% of the PD patients even after 3 years and that there was no ideal agonist with features matching the efficacy and longer actingperiod of Levodopa. Dopamine agonists are also used mostly in Parkinsonians younger than 75 years due to their side effects. Hence in

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26 people with advanced stage of PD, the need for an alternate treatment to complement Levodopa and dopamine agonists persists. During advanced stages of the disease, use of surgical therapies like thalamotomy, deep brain stimulation of subcortical structures have been suggested and studied to possibly alleviate the negative effects or lack of response to anti parkinsonian medication (Weiner, 2006; Giroux, 2007) Deep Brain Stimulation Deep brain stimulation is a surgical intervention aimed at ameliorating the effect of symptoms associated with P D DBS also serves as a reversible procedure as opposed to permanent neuroablative procedures like thalamotomy and pallidotomy. DBS entails passage of electrical impulses to subcortical areas through external means. DBS system has several components. For example, a commercially available Activa DBS system (Figure 2 3) comprises of the following: 1. Neurostimulator Supplies the power to the system by generating electrical pulses through a programmed computer chip 2. DBS Lead An insulated wire with four electrode contact s that are precisely implanted in the brain. 3. Extension A wire that connects the electrodes to the stimulator. This insu l ated wire is placed u nder the scalp and runs behind the ear, down the neck, and into the chest below the collarbone to the pulse generator. 4. Neurostimulator control magnet A patient control magnet that allows the patient to regulate the pulse generator between different settings when held over the power source system Sometimes the pulse generator is also turned on or off through radio frequency based device. Additional components include a console programmer and a software cartridge to alter the electrical parameters In DBS surgery, an electrode is placed stereotactically into a subcortical area of the brain like the STN or GPi or the thalamus. Initially, the effectiveness of the surgical

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27 treatment is assessed by temporarily connect ing the inserted electrode to a transcutaneous cable for short term stimulation. After several days, the temporary transcutaneous cable is replaced surgically by a permanent subcutaneous cable. One electrode on each side is used during bilateral stimulati on procedure where as during unilateral stimulation; a single electrode is placed contralaterally in the brain corresponding to the most affected side. The utility of the DBS procedure is highlighted by the reversible and noninvasive programming of its neuro stimulator. After the final surgical procedure, the stimulator is optimally adjusted between symptomatic control and emergence of undesirable side effects like dysarthria or dyskinesia. DBS has not only been used for symptomatic relief in PD but also in other movement disorders like dystonia and essential tremor (Kluger et al., 2009). Three principal components determine the nature of electrical impulses that are transmitted to the brain: frequency, voltage and pulse width. The frequency of the neurostimulator establishes the rate at which electrical impulses are generated. Voltage, the second parameter, determines the difference in electrical potential. And pulse width gives the time interval between two electrical pulses. Aforementioned, the program mable nature of the neurostimulator lends to its versatile usage. Programming the stimulator involves varying these three parameters. Typically in P D patients, highfrequency DBS is employed. Mechanism of A ction of DBS Though DBS is a prevalent surgical t herapy for persons with PD, little is known about the mechanism of action of the procedure. Hammond and colleagues (2008) discussed two possible mechanisms in their review. First, they questioned if the high

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28 frequency stimulation suppresses the stimulated neurons thereby producing effects similar to a lesion in the region. However, they also examined if the electrode stimulation establishes new activity in the basal ganglia network. Hammond et al. observed that the high frequency long duration STN DBS intro duces new neuronal activity that decreases spontaneous pathological patterns. These observations supported the work of Benazzouz and Hallett (2000) who mentioned that though the reduction in tremor among Parkinsonians with DBS mimicked a lesionlike effect STN DBS also resulted in increased release of glutamate in the substantia nigra and dopamine in striatum. Contrastingly, Liu et al. (2008) proposed that the STN DBS acts like a lesion by interrupting an abnormal pattern of firing in cortico basal gangliathalamocortical loops that cause symptomatic PD. Briet et al., (2004) elucidated this lesion like inhibitory effect of high frequency DBS mainly hypothesizing either depolarization blocking of the neuronal transmission by inactivating ionchannels by alt ering the voltage or by hindering the information flow by releasing efferent (out going) signals through external stimulation. Vitek (2002) commented the possibility of inhibition of the neurons at the stimulation site as well as increase in output from the stimulated structure through activation of the axonal elements exiting the stimulated structure. However the effects of the stimulation for other combinations of parameters have not been highlighted. Therapeutic Effects of DBS DBS has been often associat ed with reduction in anti parkinsonian medication levels like Levodopa and also reduce the dyskinesias in the OFF MED state due to long term Levodopa dosage levels Several researchers reported ameliorating effects of the DBS on axial symptoms which are nonresponsive to anti parkinsonian medications

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29 In the 29 Japanese PD participants that Yamada et al. (2008) tested before and after three months of DBS surgery, mean Levodopa dosage levels decreased by 27%. The response of indiv idual axial symptoms like falling, freezing, gait and postural instability was evident in some participants after STN DBS but not before the surgery. But this response was measured based on qualitative UPDRS scores. Kumar and colleagues (1998) studied seve n people with PD after six to 12 months post STN DBS. They reported improved UPDRS motor subscores for akinesia (58%), rigidity (52%), tremor (82%), and gait and postural stability (49%) during OFF MED and stimulator on (ON STIM) state compared to OFF MED stimulator off ( OFF STIM ) state. Further they reported a decrease in the OFF MED dyskinesias and drugdosage levels. In a larger group study of 72 participants, Tabbal and colleagues (2007) observed that after three to 12 months of STN DBS, in de novo co ndition, the total UPDRS motor score during ON STIM was lower by 47% when compared to the OFF STIM. Further, they reported an improvement in the UPDRS motor subscores for resting tremor (74%), rigidity (58%), bradykinesia (37%), pull test (35%), gait (44% ), axial signs (42%) and speech (13%). Similar results were also published by Karimi et al., (2008) with a 49% improved gait and 56% improved postural stability based on UPDRS rating. Hamani and colleagues (2008) reviewed the OFF MED and ON MED UPDRS score s for 471 bilateral STN DBS participants across 38 studies in 34 neurosurgical centers and 13 countries. They reported that the motor scores during OFF MED condition improved by 50% after six months, 56% after 12 months, 51% after two years, and 49% after five years of stimulation. Also, post 12 months STN DBS surgery, the UPDRS scores reduced for tremor (81%), rigidity (63%), bradykinesia (52%), gait (64%), and postural

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30 instability (69%) when compared with the OFF MED scores before the surgery. Further, d uring ON MED state, 94% reduction in dyskinesias, 52% reduction in Ldopa dosage levels after 12 months of STN DBS. One observation from these results is that the greatest improvements due to STN DBS occurred for tremor where as gait, axial signs and speec h benefitted the least, albeit measured qualitatively and subjectively. Few researchers have quantified the balance and gait characteristics using methods in conjunction with the UPDRS scores. Nilsson et al., (2005) used the Berg balance scale and UPDRS I II scores to quantify a 70% improvement in balance and postural stability scores during ON STIM compared to OFF STIM condition, in 31 PD participants after 1012hours without medication and six to 12 months post STN DBS. Estimating more objectively, Rocchi and colleagues (2002) measured center of pressure (CoP) characteristics like root mean square ( RMS ) displacement and sway area of six PD participants after at least six months of STN DBS and compared them with healthy older adults during one minute standi ng trials with eyes open. They estimated larger RMS and sway area values for persons with PD in their OFF MED, OFF STIM condition as compared to control participants. Interestingly, they also observed that the CoP based values increased further in ON MED a nd OFF STIM condition, hinting at some of the negative effects of Levodopa medication on postural balance. Additionally, Rocchi and colleagues also found much smaller and hence better values with the stimulator turned on and the medication off. However dur ing ON MED, ON STIM condition, the RMS displacement and sway areas CoP were intermediate to values from individual treatments highlighting plausible interaction effects of medications and high frequency STN DBS treatments. Furthermore, Guehl et al., (2006)

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31 found beneficial effects, three months after bilateral STN DBS on seven persons with PD with their postural control measures. After surgery, they found reduced CoP displacement under both STN DBS and the influence of Levodopa monotreatments. However, though the sway area values under STN DBS alone condition decreased, the corresponding values increased when the participants were under the influence of medication alone. S eparately, Liu and colleagues (2006) quantitatively studied the effects of STN DBS on gait initiation for 11 people with PD who had undergone bilateral surgery at least six months prior. Important observations were that in both OFF MED and ON MED states, the STN DBS increased the amplitude of the anticipatory postural phase, amplitude of the propulsive shear forces on both feet, and amplitude of CoP in both anterior posterior and medial lateral directions. Beneficial effects of bilateral STN DBS on gait initiation among PD were also studied by Crenna et al., (2006). With 10 PD participants i nitiating gait in ON STIM OFF MED condition, Crenna and colleagues showed an improvement in the vertical alignment of the trunk, larger backward and lateral displacement of the CoP in the anticipatory phase, shortening of the imbalance phase, shortening of swing phase of the stepping limb and an increase in initial step length. More characteristics of gait initiation can be studied from the CoP trace in the weight shifting phase and locomotion phase and also from its relationship with the center of mass (CoM). Using alternate methods, Colnat Coulbois et al. (2005) conducted static and dynamic posturography tests on 12 PD participants before and after six months of the bilateral STN DBS surgery. The results of their static test revealed an improvement in post ural control precision after surgery, during both eyes open and eyes closed standing trials. Also, using their dynamic tests, Colnat Coulbois

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32 and colleagues mentioned a decreased number of falls and the ability of the patients to develop more appropriate s ensorimotor strategies when stimulated. However all these tests were conducted in ON MED state and hence the individual treatment effect of STN DBS could not be elucidated. Several researchers have also studied the effects of STN DBS on gait performance i n PD. While testing their eight PD participants in the OFF MED condition, Johnsen et al., (2009) compared gait performances during ON STIM and OFF STIM conditions. One of their main findings was that improvements in stride length and velocity but not cadence were observed when the stimulator was turned on. Similar results were found in a more elaborate study by Liu et al. (2005) who tested 11 persons with PD with at least six months post STN DBS under all combinations of ON/OFF MED and ON/OFF STIM. They al so found an increase in walking velocity without any influence on cadence while immune to the influence of medication. Interestingly, Liu and colleagues mentioned that STN DBS did not improve balance during static quiet standing or transient gait initiation tasks. Comparable methodology was used by Lubik and colleagues (2006) who tested 12 PD participants at least after six months post bilateral STN DBS. Lubik et al. found that the best values for UPDRS motor scores and the walking speed and step length wer e found for ON M ED and ON STIM condition. During either monotherapy, the UPDRS motor scores were similar whereas better values for gait parameters (walking speed and step length) were found during ON MED alone compared to ON STIM alone. In another study i nvolving 10 PD participants 3 28 months post STN DBS surgery, analogous results were observed with similar walking speed values for individual therapies of medication and surgery and better additive

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33 effects for combined therapy (Carpinella et al., 2007). D uring self selected and fast gait, Chastan et al. (2009) mentioned an increase in step length and velocity with levodopa treatment alone or along with STN DBS for seven individuals with PD after about 2 years of STN DBS compared to OFF MED and OFF STIM con dition. However, these gait parameters increased only in the ON STIM and OFF MED condition during fast walking but not at usual walking speeds. Similar to other studies, the UPDRS III motor scores improved greatest with combination therapy than single ther apies compared to no therapy. Using different measurement techniques compared to other studies, Salarian et al., (2004) mentioned that their 10 OFF MED OFF STIM PD participants with minimum of 17 years post bilateral STN DBS demonstrated an slower stride velocity (52%), shorter stride length (60%), longer gait cycle time (40%), longer stance (11%) and longer double support time (59%) as compared to 10 agematched healthy individuals. However, with the stimulator on, persons with PD displayed an increase in stride velocity (31%), stride length (26%), stance (6%), and double support time (26%) compared to their OFF STIM state. However, the authors fail to mention if the tests were done in OFF /ON MED state, making it hard to compare with results from other stu dies. Correlation of some of these gait parameters with UPDRS motor scores was also mentioned. Thus these studies exhibit the limited effectiveness of STN DBS on gait parameters when compared to the effectiveness of Levodopa alone. Also, though few gait parameters are enhanced through STN DBS, the beneficial effect on postural stability is minimal. The negative effects of STN DBS on balance and gait in individuals with PD have also been indicated by researchers. In their review article, Benatru and colleagu es

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34 (2008) mentioned a lack of improvement in axial symptoms like postural stability compared to distal motor aspects like tremor after DBS at the STN. These views were echoed by several researchers including Lozano and Snyder (2008) who observed more inconsistency and less durability of the enhancements in gait and postural instability after STN DBS procedure among persons with PD. In fact, in a long term study, Krack and colleagues (2003) observed a degradation of postural instability and gait after five y ears of the STN stimulation with the negative trend seen after the first year. Using the motor part of UPDRS (UPDRS III), similar results have been reported elsewher e (Rodriguez Oroz et al., 2005; Schubpach et al., 2005; van Nuenen et al., 2008). Also, aft er five years of stimulation, an increase in the total electrical energy delivered with slight improvements in the UPDRS score related to axial symptoms has been observed (Romito et al., 2009). Elsewhere, researchers reported small improvements in postural stability and gait compared to the improvements in cardinal symptoms (Gervais Bernard et al., 2009; Gan et al., 2007). High frequency stimulation also has negative effects on cognitive effects like verbal fluency (Marconi et al., 2008; Okun et al. 2009; Z ahodne et al., 2009). All the studies reported above were performed at high frequency (> 100Hz) settings. However, few researchers have compared the effect of different stimulation settings on posture, gait and verbal fluency. Moreau and colleagues (2008 ) evaluated gait performances and UPDRS scores at low frequency (60Hz) and high frequency (130Hz) while maintaining an equivalent amount of electrical energy. Results of this study indicated that the number of freezing episodes decreased at 60Hz (highvolt age/equivalent energy) and increased in high energy conditions (130Hz high

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35 voltage). Additionally, there was no significant improvement in gait performance measured subjectively by means of a StandWalk Sit test or UPDRS III. Tagliati (2008) further purpor ted these results but exercised caution to generalize them. Later, Brozova et al. (2009) reported a significant increase in UPDRS II sub items relative to speech, falling and gait and UPDRS III sub items relative to speech and gait when their participants were stimulated at 60Hz after 4 years of high frequency stimulation. Though, they mentioned a considerable improvement in speech in some of their patients, a worsening of gait and postural stability in two participants at low frequency stimulation was also observed subjectively. However, adv erse effects of low frequency stimulation have also been reported. Timmermann et al. (2004) mentioned adv erse effects of low frequency stimulation (10Hz) with worsened motor symptoms compared to offstimulation and high frequency (>= 130Hz) settings. Further, Moro et al. (2002), also established worsening of akinesia at 5Hz. Interestingly, Moro and colleagues also mentioned that the combination of higher voltages combined with narrow pulse width as the most effective sett ing to improve the UPDRS III scores. Using a different methodology to measure movement characteristics, Eusebio et al. (2008), noted a detrimental finger tapping rate at 5Hz and 20Hz frequency settings when compared to no stimulation. Evaluating a different target site, Pereira et al. (2008) mentioned improvement in motor functioning for nonhuman primate after PPN DBS at low frequency. Comparing different target sites, Stefani and colleagues (2007) established a greater improvement in UPDRS score for STN DBS (130 185Hz: 54%) compared to PPN DBS (25Hz: 32%) condition in an OFF MED state. Also, they observed that during the ON MED state,

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36 combination of STN DBS and PPN DBS was more effective than STN DBS or PPN DBS alone in terms of improving the motor scores and performance of activities of daily living. Further, Bejjani et al. (2000) observed myoclonus and irregular jerky tremor in the upper limb contralateral to the site of stimulation in their study of effect of GPi stimula tion on PD and Essential Tremor p articipants at 15Hz. Adverse effects of high frequency stimulation have also been reported for cognitive tasks like verbal fluency among persons with PD. Wojtecki et al. (2006) mentioned a significantly better performance of the verbal fluency task at a f requency setting of 10Hz compared to the high frequency (130Hz) and no stimulation settings. Stefani et al. (2009) reported that the stimulation of PPN at low frequency (25Hz) had beneficial effects on the quality of sleep and executive functioning among people with PD, compared to STN DBS. However, using subjective testing, they also mentioned poorer improvement in motor scores suggesting inclusion of both the targets (PPN and STN) for stimulation. The effects of low frequency DBS stimulation has also bee n researched in populations other than PD. Kupsch et al. (2003) reported improvement in quality of life (63%) and severity of dystonic symptoms (43%) at 130Hz of GPi DBS compared to no stimulation. Also, they reported an improvement of clinical scores at h igher frequencies (between 180250Hz) against worsening at lower frequencies (5 and 50Hz). Contrastingly, in their case study, Alterman and colleagues (2006) mentioned that the high frequency (130 185Hz) GPi stimulation on their patient with Dystonia, produced side effects which were absent during s timulation at 80Hz. Additionally they also found a dramatic improvement functionally after one year of stimulation at 80Hz. However, the results reversed at 60Hz where the dystonic symptoms worsened.

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37 The studies discussed so far clearly present a lack of consensus on the ameliorating effects of STN DBS on balance and gait. Moreover, the electrode stimulation procedure seems to impart contrasting therapeutic effects based on different stimulation settings. Hence it is unclear if there is an optimal setting that could yield the best results together for balance and gait performance of an individual with PD. This optimal setting could be achieved by lowering the frequency and possibly increasing the voltage level based on the currently used values of a person with PD. Figure 21 Structural Anatomy of the Basal Ganglia ( Source: http://thebrain.mcgill.ca/flash/a/a_06/a_06_cr/a_06_cr_mou/a_06_cr_mou.ht ml Last accessed June, 2010).

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38 Figure 22 Motor Circuit of the Basal Ganglia. (Source: DeLong and Wichmann, 2007) Figure 23 T he Activa DBS System and its components ( Source: http://www.neurocirugi a.com/instrumental/index.php?m=10&y=07&entry=entr y071029 123203. Last accessed June, 2010). Green Excitatory Red Inhibitory Neurostimulator Extension

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39 CHAPTER 3 METHODS Participants Ten participants with Parkinson disease (PD) who had bilateral Deep Brain Stimulation (DBS) surgery at least six months prior to testing were recruited for the study. Each participant read and signed an informed consent form approved by the Universitys institutional review board. The inclusion criteria included : a. Idiopathic PD diagnosed by a movement di sorders specialist. The diagnosis w as based on the presence of at least two of three cardinal motor signs of PD: bradykinesia, resting tremor and rigidity, and a demonstrated good response to levodopa medication therapy. A good response to Levodopa w as defined as a 30% improvement in parkinsonian motor signs. This motor score improvement was based on the U nified Parkinsons Disease Rating Scale (UPDRS) motor examination subscore, following the administration of levodopa (1.5 times their typical dose) during their screening neurological examination. Such an inclusion criteria w as necessary to exclude patients with Parkinson's plus syndromes (such as progressive supranuclear palsy, multiple system atrophy, striatonigral degeneration, corticobasal degeneration, and Lewy body disease). b. Hoehn and Yahr stage II or worse when in the off medication condition. c. Age between 4585 years. d. A DBS device implanted for PD bilaterally The exclusion criterion for the study w as : Evidence of secondary/atypical movement disorder as suggested by presence of any of the following: 1. History of stroke(s) 2. Exposure to toxins or neuroleptics 3. History of encephalitis 4. Neurological signs of upper motor neuron disease, supranuclear gaze palsy, or significant orthostatic hypotension

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40 Experimental Protocol Unified Parkinson's Disease Rating Scale, balance and gait testing w ere conducted on two consecutive days. A pre test washout period of at least 12 hours off medication w as employed for both testi ng days. Also, the participants were asked to turn off their stimulators at least 12 hours prior to testing on the first day. The participants w ere tested on both days while they were off their medications (OFF MED). On the first day, the frequency settings of the stimulators w ere altered. Each participant w as tested in four different conditions. In the initial condition both the stimulators w ere switched off (OFF STIM). Later, both stimulators w ere turned on (ON STIM) and the participants w ere tested at three frequency settings in a random order : 30Hz, 60Hz and baseline frequency (BF). During these ON STIM conditions for day 1, for each participant, baseline voltage (BV) and pulse width values w ere maintained. These baseline values represented their clinically optimized therapy/ management. Also after the stimulators were tuned to a particular frequency, a 10 minute time period was allowed for habituation prior to testing at that setting. As no previous researchers have validated the most effective washout time period, we used the 10 minute interval keeping in mind, the longevity of testing protocol on both the days. The entire procedure day 1 is presented in Figure 31. On the second day, participants were tested under four combinat ions of frequency and voltage settings as described below. The following combinations were used in a random order : 30Hz + HV 30Hz + M V 60Hz + HV, 0Hz + MV. HV was set to 1.5 volts + BV and MV was deemed as the maximum voltage that the part icipant tolerate d While increasing the voltage, the movement disorders specialist observed signs like excessive tremor or dystonia or sweating to determine the tolerance level for

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41 the participant. The same pulse width value was used on both the testing days. Also similar to day 1, a 10mintue waiting time was employed when the stimulators were adjusted to a new setting. For both the days, at the beginning and end of each testing condition, the participants were asked about their overall well being using a subjective feedback scale. T he entire procedure for day 2 is presented in Figure 32. Kinematic data were collected at 120Hz using a 10camera motion capture system (Vicon, Lake Forest, CA). Kinetic data were collected using two embedded force platforms (B ertec Corp., Columbus, OH) at 360Hz (Figure 3 3 ). Thirty five retro reflective markers were placed over anatomical bony landmarks according to the Vicons Plugin Gait marker system. Markers were placed bilaterally on the 2nd metatarsophalangeal joint head, he el, ankle, tibia, knee, thigh, anterior superior iliac spine posterior superior iliac spine, shoulder, elbow, radial wrist, ulnar wrist, 2nd finger, forehead, and posterior head. Single markers were placed on the jugular notch, inferior sternum, C7, T 10, and the right scapula (Figure 3 4 ). Evaluations UPDRS A movement disorders trained neurologist conducted a video taped UPDRS III evaluation of the motor part for each participant during all conditions on both days. This UPDRS evaluation was done before other evaluations. A second neurologist blinded to the settings scored each participant using the recorded video tape. Static balance Static balance testing w as performed in all the conditions on both days. During te sting the participants stood quietly with a narrow stance width of 10cm for one minute with a foot on each force plate. The narrow stance width was deemed as a challenging

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42 position to maintain upright posture. Two trials with eyes open and two trials with eyes closed w ere performed by each participant at each setting. Dynamic B alance and Gait Dynamic balance was evaluated using the task of gait initiation. Participants initiate d gait in the forward direction at their self selected pace. Five experimental t rials w ere conducted in each stimulation condition on both days. Positioning of the feet and the initial stepping limb w ere self selected and subsequently maintained for consistency. Data collection began while the participants st ood in a relaxed position with their feet in a forward direction. Upon hearing a verbal ready signal, the participants paused momentarily and then initiated movement towards a target (at eye level). Each participant practiced the task till they beca me confident with the procedures prior to data collection. Kinematic gait evaluation included each participant perform ing five walking trials at their selfselected speed across an 8m walkway during each condition on both the days. Data Processing For balance measures, ground reaction forces and moments from each force platform w ere used to calculate the instantaneous center of pressure (CoP) on that force platform. T he CoP data from both force platforms w ere combined to obtain the net CoP (Termoz et al., 2008) U sing these values of the net CoP the following variables related to CoP characteristics during static balance testing w ere computed during both eyes open and eyes closed trials: range of CoP movement in anterior posterior (AP) and mediolateral (ML) directions, CoP sway area (product of AP and ML range) and root mean square (RMS) of the CoP displacement and velocity in AP and ML directions. Given the oscillating nature of the CoP movement, the RMS values of displacement and

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43 velocities were also calculated. The RMS values indic ate a better measurement of the CoP movement focusing on its magnitude change rather than the direction change. Data processing for dynamic balance testing involving gait initiation was done using the Vicon Nexus. All the trials w ere analyzed from the start of gait initiation (GI) to the first heel strike of the initial stance limb. The start of GI w as marked manually for all the trials as the time point from where the vertical ground reaction f orces for both the limbs starts to deviate from each other (Vaugoyeau et al., 2006). The gait initiation cycle w as divided into three distinct phases (S1, S2, S3) based on the CoP trace, as described previously in the literature (Hass et al., 2004). Briefly, the S1 phase (postural phase) was defined from the start of GI to the time point where the CoP undergoes maximum posterior and lateral displacement towards the swing limb. The S2 phase (weight shifting phase) was marked from the end of S1 phase to the time point of the swing limb toeoff. The S3 phase (locomotion phase) was identified from the end of the S2 phase to the timepoint of stance leg toeoff. During each phase, the following dependent variables related to CoP characteristics during dynamic balance testing w ere computed: the displacement and mean velocit y of CoP in the ML and AP directions, the maximum separation distance between the CoP and Center of Mass (CoM) in the ML, AP and resultant directions. This separation distance between CoP and CoM will henceforth be referred as the CoP CoM moment arm Als o, the whole body CoM location w as computed as the weighted sum of each body segments CoM from a 15 segment biomechanical model using Dempsters Anthropometric tables (Dempster, 1955). Apart from the CoP and CoM related variables, spatiotemporal variables like t he step length, step velocity and step time, the time to heel off and toe off of both the limbs

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44 from start of gait initiation for both the limbs w ere computed. All the dependent variables for the gait initiation trials w ere calculated using custom M ATLAB code (MathWorks Inc., Novi, MI) For kinematic gait evaluation, multiple toe off and heel strike events w ere marked manually for both feet and the following gait cycle parameters w ere calculated: cadence, walking speed, stride time, stride length, st ep time, step length, percentage of singlesupport time and doublesupport times using Vicon Nexus ( Vicon, Lake Forest, CA ). Also variability measures in terms of coefficient of variation were calculated for the spatiotemporal measures of gait initiation and the gait. The UPDRS evaluation was scored under eight components: Speech (score from question 18), Facial expression (score from question 19), Tremor (sum of scores from questions 20 and 21), Rigidity (score from question 22), Bradykinesia (sum of scor es from questions 23, 24, 25, 26, 27, and 31), Posture (score from question 28), Gait (score from question 28) and Balance (score from question 30). All the components except the rigidity were taken from the blinded investigators ratings and added to obta in a total UPDRS score. The rigidity subscore however was taken from the nonblinded investigators ratings. The electrical energy of each stimulator was calculated based on the values of the frequency, voltage, pulse width and impedance values at each c ondition on both the days (Koss et al., 2005). The electrical energy of both stimulators was added to obtain the total electrical energy delivered (TEED) per second. Data Analyses For the dependant variables, the mean individual values from the consecutive trials within a condition w ere used for analysis. The Kolmogorov Smirnov test w as us ed to establish that the data were normally distributed. For specific aim 1 the performance

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45 during the OFF STIM condition w as compared to performance at 30Hz, 60Hz and BF. More specifically, in order to observe the frequency effect f or the first specific aim, a oneway repeated measures multivariate analys i s of variance (MANOVA) w as performed for each of the following sets of variables: a. Static balance: CoP cha racteristics related to static balance testing with separate MANOVA for eyes open and eyes closed conditions b. Dynamic balance: CoP characteristics and Spatio temporal variables related to dynamic balance testing c. Gait: All gait cycle parameters For specifi c aim 2 the four conditions from day 2 were combined with two conditions (30Hz and 60Hz at BV) of day 1 to determine the effect of increasing the voltage at a low frequency A 2(frequency: 30Hz,60Hz) x 3(voltage: BV, HV, MV) repeated measures MANOVA w as p erformed for the same set of dependent variables mentioned earlier for specific aim 1. A tra ditional level of significance was 0.05). MANOVA w as conducted to control for Type I error. SPSS 13.0 for Windows w as used to perform all statistical calc ulations (Statistical Package for Social Sciences, Chicago, IL). When the variables were significantly correlated separate univariate analyses of variance (ANOVA) for each dependent variable w ere performed. Also, oneway repeated measures ANOVA were perfor med for the UPDRS related scores to estimate the frequency effects. To determine the voltage effect at low frequency, 2(frequency: 30Hz,60Hz) x 3(voltage: BV, HV, MV) repeated measures ANOVA for the UPDRS total score and subscores were performed. For esti mating the effect of low frequency, t he repeating factor for ANOVA was the frequency setting with four levels (OFF STIM, 30Hz, 60Hz and BF). F ollow up testing (Bonferroni) was used to determine the individual di fferences among the frequencies and voltages.

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46 Correlation analyses were performed to see the effect of TEED on each dependant variable. A Pearson correlation coefficient was used to determine the strength of correlation for all the dependent variables except the UPDRS related variables. For the nomi nal UPDRS scores, Spearmans correlation coefficient was used to gauge the nature of the relationship between each dependent variable and TEED. A tra ditional level of significance was for these tests as well

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47 Figure 31 Flowchart of testing procedures for day 1 Different frequency settings at constant baseline voltage and pulse width and OFF Medication End of testing on day 1: The participant took his/her medicine and the movement disorders specialist set their stimulators at their original daily used (bli) tti Condition 4 : BF/30Hz/60Hz UPDRS evaluation Static and Dynamic Balance Testing and Gait Evaluation Changed the stimulators to the last frequency among 30Hz/60Hz/BF, followed by a 10 minute waiting time Changed the stimulators to the next frequency among 30Hz/60Hz/BF, followed by a 10 minute waiting time Condition 3 : 60Hz/BF/30Hz UPDRS evaluation Static and Dynamic Balance Testing and Gait Evaluation Condition 2 : 30Hz/60Hz/BF UPDRS evaluation Static and Dynamic Balance Testing and Gait Evaluation Turned the stimulators ON at a frequency of 30Hz/60Hz/BF, followed by a 10 minute waiting time where BF refers to the baseline frequency that is being currently used by the participant on a daily basis Condition 1 : OFF STIM UPDRS evaluation Static and Dynamic Balance Testing and Gait Evaluation Previous night, 12 hours prior t o testing, the participant turned off his /her medication and stimulator s

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48 Figure 32 Flowc hart of testing procedures for day 2 Randomized combinations of low frequency and high voltage settings at baseline pulse width and OFF Medication At the start of day 2, the frequency for both the stimulators was decreased from its baseline value while the voltage was increased. The frequency was set at 30/60Hz and the voltage was set at HV/MV where HV = Baseline Voltage used on day 1 + 1.5V) and MV = Maximum Voltage the participant could tolerate. Once ON STIM, a 10 it iti ti d End of testing: The participant took his/her medicine and the movement disorders specialist set their stimulators at their original daily used (baseline) settings Changed the stimulators to the last combination of frequency (30/60Hz) and voltage (HV/MV) followed by a 10 minute waiting time Condition 4 : 60Hz+MV/30Hz+HV/30Hz+MV/60Hz+HV UPDRS evaluation Static and Dynamic Balance Testing and Gait Evaluation Condition 3 : 60Hz+HV/60Hz+MV/30Hz+HV/30Hz+MV UPDRS evaluation Static and Dynamic Balance Testing and Gait Evaluation Changed the stimulators to the next combination of frequency (30/60Hz) and voltage (HV/MV) followed by a 10 minute waiting time Conditi on 2 : 30Hz+MV/60Hz+HV/60Hz+MV/30Hz+HV UPDRS evaluation Static and Dynamic Balance Testing and Gait Evaluation Changed the stimulators to the next combination of frequency (30/60Hz) and voltage (HV/MV) followed by a 10 minute waiting time Condition 1 : 30Hz+HV/30Hz+MV/60Hz+HV/60Hz+MV UPDRS evaluation Static and Dynamic Balance Testing and Gait Evaluation Previous night, 12 hours prior t o testing, the participant turned off his /her medication

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49 Figure 33 Biomechanics Lab Set U p A 10 camera motion capture system along with the three force plates, and the orientation of the axes. Force plate Camera X Y Z Force plates amplifier Camera Hub Host Computer

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50 Figure 34 Marker placement. Front, Back and Side views of the thirty five retro reflective marker placement over anatomical bony landmarks according to Vicons Plugin Gait. Side View Back View Front View

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51 CHAPTER 4 RESULTS The descript ive characteristics of the participants a re listed in Table 41. The baseline characteristics including the frequency, voltage and pulse width values that were optimized for each patient after the deep bran stimulation (DBS) surgery have been tabulated under Tables 4 2 and 4 3. Effect of Low Frequency The following section lists the results precise to answering specific aim 1, i.e. to determine if lower frequency stimulation improves static balance, dynamic balance, gait and Unified Parkinsons Disease Rat ing Scale ( UPDRS) based performance of people with Parkinson disease (PD) The Kolmogorov Smirnov test revealed normality for all the dependent variables. The M ultiple Analyses of Variance (M ANOVA) tests showed significant result for the gait initiation (GI) spatiotemporal measures relative to specific aim 1 ( P = 0.026; Table A 1). However, the MANOVA tests failed to show any significance for all other sets of variables (Table A 1). Static Balance ( E yes Open a nd E yes Closed Trials) The data for the eyes open and eyes closed trials are shown in Tables A 1 and A 2 respectively. During the eyes open trial the frequency modulation a ffected the AnteroPosterior (AP) range ( P = 0.038). Further, the post hoc tests revealed that the participants reduced AP sway during the 60Hz stimulation compared to the OFF condition, though the difference was highlighted only by a statistical trend ( P =0.056, Figure 41). While t he other six C enter of Pressure (CoP) related balance measures did not differ significantly among th e four conditions, the lowest values were observed predominantly at the 30Hz stimulation (Table A 2 ). For the eyes closed trial none of the

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52 dependent measures showed significant differences among the four conditions (Table A 3 ). Dynamic Balance (Gait Init iation) The outcomes of dynamic balance testing involving GI were classified into CoP center of mass (CoM) characteristics (Tables A 4 and A 5) and spatiotemporal measures (Tables A 6 and A 7) Significant differences among the CoP and CoM related measures during GI were found for two outcome measures First, the forward movement of the CoP in the locomotion (S3) phase was faster at 30Hz stimulation compared to the 60Hz condition ( P = 0.015; Figu re 4 2 ). Second, significant effect was seen for the maximum AP CoP CoM moment arm ( P = 0.012). However, the post hoc tests failed to reveal differences between any two frequency settings. The greatest separation distance was observed at 60Hz and the least during OFF state ( Figure 4 3 ). Several spatio temporal outcomes during GI differed significantly under the four frequency settings ( Table A 6 ). Compared to the OFF condition, the participants executed a longer initial step with their stance leg at both 30Hz ( P = 0.003) and 60Hz ( P = 0.006, Figure 44 ). Also, the initial swing leg step length was longer at 60Hz than the OFF state albeit the difference was emphasized only with a statistical trend ( P = 0.059, Figure 45 ). Faster execution of these initial s teps with both the legs was seen with the stimulator on. Compared to the OFF condition, the s wing leg step velocity was greater at 30Hz ( P = 0.003), 60Hz ( P = 0.007) and baseline setting ( P = 0.007, Figure 46 ). Similarly, the stance leg step velocity was also greater at 30Hz ( P = 0.019), 60Hz ( P = 0.015) and baseline setting ( P = 0.032) compar ed to the OFF condition (Figure 4 7). S ignificant main effects were also seen for the time to swing leg toe off ( P = 0.030, Figure 48 ) and time to stance leg toeoff ( P = 0.027, Figure 49 ) But the Bonf erroni

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53 tests did not detect further betweenfrequency setting differences. A statistical trend for the time to stance leg heel rise ( P = 0.067) was also observed. An inspection of the values showed that the values for these three timebased measures were least for the lower frequencies (30Hz and 60Hz) compared to the baseline frequency and OFF STIM conditions (Table A 6) The stance width, swing and stance legs st epping times and the time to swing leg heel rise did not vary among the four frequency conditions. However, significant variability was observed in swing leg step time ( P = 0.027, Figure 4 10) and swing leg step velocity ( P = 0.005, Figure 4 11 ). Though the post hoc tests did not detect significant differences between any particular frequency settings, the participants exhibited lower variability for both these outcomes at the low frequency settings (30Hz and 60H z) compared to the OFF condition (Table A 7) Gait Evaluation Significant results for gait evaluation parameters were found for gait sp eed ( P = 0.0 29) and opposite foot contact parameter which denotes the instance in gait cycle when the swing leg strikes the ground ( P = 0.031) Bonferroni post hoc tests revealed a statistical trend for the gait speed results where the participants walked faster at 60Hz condition compared to OFF stimulation condition ( P = 0.052, Figure 412). However the post hoc tests did not project any significant differences for the o pposite foot contact parameter (Figure 4 13) Further no significant differences were found for other measures ( Table A 8 ). Data for gait variability in terms of Coefficient of variability is presented in Table A 9. Si gnificant differences were se en only for the Coefficient of variation of the opposite foot contact parameter ( P = 0.017). Particularly, participants showed low variability at

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54 60Hz when compared to the OFF stimulation condition ( P = 0.021) and low variability at 60Hz with a statistic al trend when compared to 30Hz ( P = 0.07 Figure 4 14). UPDRS Part III (Total Score and Sub Scores) The UPDRS part III total score along with the component subscores (except rigidity) evaluated by a blinded investigator were used for analyses. The rigidit y sub score was not included in the computation of the total score and was used directly from the rater who was not blinded to the settings. Significant main effects were seen mainly for the total UPDRS score ( P = 0.038), bradykinesia ( P = 0.046), speech ( P = 0.020) and rigidity ( P = 0.006) subscores (Table A 10 ). Bonferroni post hoc tests revealed a further differences among the frequency conditions only for the total score where a statistical trend showed that the participants performed marginally better at 30Hz compared to the OFF stimulation condition ( P = 0.066, Figure 415). For bradykinesia and rigidity subscores, participants had low scores with the stimulator switched on compared to the OFF STIM state (Figures 416, 4 17). However for the speech component, an opposite trend was observed with lower scores recorded during the OFF STIM condition compared to other three conditions (Figure 418). Effect of Low Frequency and Higher Voltage The following section lists the results precise to answering spec ific aim 2, i.e. to determine if the performance of persons with PD during static balance, dynamic balance, gait and UPDRS evaluations, improves at a low frequency by increasing the voltage. The Kolmogorov Smirnov test revealed normality for all the depend ent variables. The MANOVA tests did not show any significant results for any set of variables ( P > 0.05; Table A 11).

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55 Static Balance (Eyes Open and Eyes Closed Trials) No significant interaction or main effects were seen for any of the measures for eyes open trials ( Tables A 12, A 13, and A 14 ). However, there was a frequency main effect for sway area during eyes closed trial with the participants producing lower sway area during 30Hz conditions compared to the 60Hz conditions ( P = 0.012, Figure 4 19). Fur ther, no significant interaction or main effects were found for other measures (Tables A 15, A 16 and A 17). Dynamic Balance (Gait Initiation) F requency main effects were noted for the anterior displacement of the CoP in the weight transfer (S2) phase wher e the participants produced longer CoP movements during the 60Hz conditions compared to the 30Hz conditions ( P = 0.053, Figure 420). Further, frequency main effects were also recorded for the CoPs forward displacement ( P = 0.023) and velocity ( P = 0.003) during the locomotion (S3) phase. For both these measures, t he values averaged across the 30Hz conditions were greater than the values averaged across the 60Hz conditions (Figures 421 and 4 22) No other measures including the CoP CoM separation distances showed either significant interaction or any of the main effects (Tables A 18 to A 23 ). Gait Evaluation F requency main effects were observed for walking speed ( P = 0.037), stride length ( P = 0.022) and step length ( P = 0.042). Participants walked faster with longer stride and step lengths when stimulated at 60Hz compared to 30Hz (Figures 4 27, 428, 429) Also, a voltage main effect was seen for the opposite foot contact parameter ( P = 0.028). Though the post hoc tests did not show significant d ifferences between any two particular voltage settings, the stance leg foot strike seemed to occur later during the

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56 gait cycle as voltage increases ( Figure 430). Among the outcomes representing gait variability an interaction between the frequency and vol tage settings was observed for the parameter opposite foot off which represents the instance in gait cycle when the toe off event of the swing leg occurs ( P = 0.035). The variability of the occurrence of the swing legs toeoff event seemed to higher at 30Hz while the voltages used were either baseline ( BV) or maximum tolerable ( MV ) values. However, at an intermediate high voltage ( HV ), the variability was greater for 60Hz compared to 30Hz (Figure 4 31 ). Also, a frequency main effect was seen in the varia bility in the opposite foot contact measure ( P = 0.029) with higher coefficient of variation during 30Hz conditions compared to 60Hz conditions ( Figure 432). No other gait related outcomes differed significantly (Tables A 30 to A 35). UPDRS (Total Score a nd Sub Scores) The data for UPDRS total score and sub scores is presented in Tables A 36 to A 38. Interaction between the frequency settings and voltage settings was observed for the speech component of the UPDRS Part III (Motor) evaluation ( P = 0.025; F igure 433). Subsequent paired sample t tests showed similar scores at both the frequency settings for baseline voltage. But, when the voltage was increased to a higher value, the participants perform ed poor ly at 60Hz compared to 30Hz ( P = 0.037). However, a further increase of voltage to the maximum tolerable value seemed to nonsignificantly worsen the performance at 30Hz compared to 60Hz. Also a frequency main effect of the tremor subscore revealed an aggravation of tremor at the 30Hz conditions compared to the 60Hz conditions particularly at higher voltage settings ( P = 0.027; Figure 434).

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57 Correlations with Total Electrical Energy Delivered (TEED) per s econd Static Balance (Eyes Open and Eyes Closed Trials) During the eyes open condition, negative corr elation w as observed between the TEED and the mediolateral (ML) range of motion ( r = 0.2 8 P = 0.019, Figure 4 35 ). Negative correlation was also observed between the AP range of motion and the TEED ( r = 0.3 3 P = 0.005, Figure 4 36). The CoP sway area also exhibited negative correlation with the TEED ( r = 0.3 1 P = 0.009, Figure 437). Correlation analysis results for the eyes closed trials replicated those for the eyes open standing trials. TEED negatively correlated with ML CoP range ( r = 0.2 5 P = 0.036, Figure 438), AP CoP range ( r = 0.24, P = 0.041, Figure 439 ), and sway area ( r = 0.2 7 P = 0.024, Figure 440 ). The other dependent measures that did not correlate significantly with the TEED are tabulated in Table A 39. Dynamic Bala nce (Gait Initiation) TEED correlated with the ML CoP displacement in the S2 phase (r = 0.2 7 P = 0.0 15, Figure 441). Higher values of TEED resulted in higher values of maximum resultant CoP C oM separation distance s during S3 phase with a positive correl ation between the two variables ( r = 0.2 5 P = 0.0 27 Figure 442 ) A positive correlation was also found between the TEED and the maximum AP CoP CoM separation distance during S3 phase ( r = 0.2 6 P = 0.0 24, Figure 4 43) Among the spatiotemporal parameters during GI, only the swing leg step velocity positively correlated with the TEED ( r = 0.2 3 P = 0.0 42, Figure 444 ) As the TEED values increased, the variability associated with stance leg step length decreased thus ex hibiting a negative correlation (r = 0.2 4 P = 0.0 36 Figure 4 45). Data pertaining to nonsignificant correlations of

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58 other dependent variables with TEED are shown in Table A 40. Effect of TEED was observed iThe anticipatory postural phase Gait Evaluation Among the gait parameters, the double support time negatively correlated with the TEED (r = 0.2 3 P = 0.0 39, Figure 446). None of the variables pertaining to gait variability correlated significantly with TEED. All the gait evaluation related dependent variables that did not significantly correlate with TEED are shown in Table A 41. UPDRS (Total Score and Sub Scores) The balance related subscore of the UPDRS Part III (Motor) evaluation correlated significantly with the TEED ( P = 0.038, Spearmans Rho = 0.23, Figure 447). Other variables which showed nonsignificant correlation with TEED have been tabulated in Table A 42. Non motor Symptoms and Observations Table 4 4 shows the qualitative data including the non motor symptoms, remedial actions and observations made during data collection. Table 44 also lists details about the participants feedback regarding some of their settings. Subjective Feedback Scale At th e beginning and end of testing of each stimulation condition, the participants were asked about their state of well being. Specifically, they were asked to answer the following question: On a scale of 1 to 10, with 10 being very good and 1 being very bad, how do you feel right now? Table 45 lists the responses for each testing condition. The testing order of the conditions is also presented in the table in order to compare the feeling of well being with the order of testing.

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59 Figure 41 Mean and standard error of Anterior posterior range (cm) of Center of Pressure at different frequency conditions during e yes o pen trials related to specific aim 1. Statistical t rend (0.05 <= P <= 0.07) ; Hz Hertz, cm centi meter Figure 42 Mean and standard error of Anterior posterior velocity of Center of Pressure (c m/s ) in S3 phase at different frequency conditions during gait initiation trials related to specific aim 1. S ignificant difference ( P < 0.05) ; Hz Hertz, cm centimeter s second. 0 1 2 3 4 5 6 Off 30 60 Baseline cmFrequency (Hz) 0 5 10 15 20 25 30 Off 30 60 Baseline cm/sFrequency (Hz)

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60 Figure 43 Mean and standard error of Anterior posterior Center of PressureCenter of Mass moment arm (cm) in S3 phase at different frequency conditions during gait initiation trials related to specific aim 1 Post hoc tests did not show any significant differences between any two conditions ( P >= 0.05 ) ; Hz Hertz, cm centimeter. Figure 44 Mean and standard error of Stance leg step length (cm) at different frequency conditions during gait initiation trials related to specific aim 1. Significant difference ( P < 0.05) ; Hz Hertz, cm centimeter. 0 5 10 15 20 25 Off 30 60 Baseline cmFrequency (Hz) 0 20 40 60 80 100 120 Off 30 60 Baseline cmFrequency (Hz)

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61 Figure 45 Me an and standard error of Swing leg step length (cm) at different frequency conditions during gait initiation trials related to specific aim 1. Statistical t rend (0.05 <= P <= 0.07) ; Hz Hertz, cm centimeter. Figure 46 Mean and standard error of Swing leg step velocity (cm/s) at different frequency conditions during gait initiation trials related to specific aim 1. Significant difference ( P < 0.05) between OFF condition and each of the other three conditions ; Hz Hertz, cm centimeter s second. 0 10 20 30 40 50 60 Off 30 60 Baseline cmFrequency (Hz) 0 20 40 60 80 100 120 Off 30 60 Baseline cm/sFrequency (Hz)

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62 Figure 47 Mean and standard error of Stance leg step velocity (cm/s) at different frequency conditions during gait initiation trials related to specific aim 1. Significant difference ( P < 0.05) between OFF condition and each of the other three conditions ; Hz Hertz, cm centimeter s second. Figure 48 Mean and standard error of Time to swing leg toeoff (s) at different frequency conditions during gait initiation trials related to specific aim 1. Post hoc tests did not show any significant differences between any two conditions ( P >= 0.05 ) ; Hz Hertz s second 0 20 40 60 80 100 120 140 160 180 Off 30 60 Baseline cm/sFrequency (Hz) 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 Off 30 60 Baseline sFrequency (Hz)

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63 Figure 49 Mean and standard error of Time to st ance leg toeoff (s) at different frequency conditions during gait initiation trials related to specific aim 1. Post hoc tests did not show any significant differences between any two conditions ( P >= 0.05 ) ; Hz Hertz s second Figure 410. Mean and standard error of Coefficient of Variation of swing leg step time (%) at different frequency conditions during gait initiation trials related to specific aim 1. Post hoc tests did not show any significant differences between any two conditions ( P >= 0.05 ) ; Hz Hertz 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 Off 30 60 Baseline sFrequency (Hz) 0 2 4 6 8 10 12 14 16 18 20 Off 30 60 Baseline %Frequency (Hz)

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64 Figure 411. Mean and standard error of Coefficient of Variation of swing leg step velocity (%) at different frequency conditions during gait initiation trials related to specific aim 1. Statistical t rend (0.05 <= P <= 0.07) ; Hz Hertz Figure 412. Mean and standard error of Walking speed (cm/s) at different frequency conditions during gait trials related to specific aim 1. Statistical t rend (0.05 <= P <= 0.07) ; Hz Hertz cm centimeter, s second. 0 5 10 15 20 25 Off 30 60 Baseline %Frequency (Hz) 0 20 40 60 80 100 120 Off 30 60 Baseline cm/sFrequency (Hz)

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65 Figure 413. Mean and standard error of Opposite foot contact (%) at different frequency conditions during gait tria ls related to specific aim 1. Post hoc tests did not show any significant differences between any two conditions ( P >= 0.05) ; Hz Hertz Figure 414. Mean and standard error of Coefficient of Variation of Opposite foot contact (%) at different frequency conditions during gait trials related to specific aim 1. Significant difference ( P < 0.05 ) Statistical t rend (0.05 <= P <= 0.07) ; Hz Hertz 0 10 20 30 40 50 60 Off 30 60 Baseline %Frequency (Hz) 0 0.5 1 1.5 2 2.5 3 3.5 4 Off 30 60 Baseline %Frequency (Hz)

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66 Figure 415. Mean and standard error of Total score at different frequency conditions during blinded Unified Parkinsons Disease Rating Scales Part III (Motor) evaluation related to specific aim 1. This total score does not include rigidity sub score. Statistical t rend (0.05 <= P <= 0.07); Hz Hertz. Figure 416. Mean and standard error of Bradykinesia subscore at different frequency conditions during blinded Unified Parkinsons Disease Rating Scales Part III (Motor) evaluation related to specific aim 1. Post hoc tests did not show any significant differences between any two conditions ( P >= 0.05 ) ; Hz Hertz 0 5 10 15 20 25 30 Off 30 60 Baseline Frequency (Hz) 0 2 4 6 8 10 12 14 16 18 20 Off 30 60 Baseline Frequency (Hz)

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67 Figure 417. Mean and standard error of Rigidity sub score at different frequency conditions during unblinded Unified Parkinsons Disease Rating Scales Part III (Motor) evaluation related to specific aim 1. Post hoc tests did not show any significant differences between any two conditions ( P >= 0.05 ) ; Hz Hertz Figure 418. Mean and standard error of Speech sub score at different frequency conditions during blinded Unified Parkinsons Disease Rating Scales Part III (Motor) evaluation related to specific aim 1. Post hoc tests did not show any significant differences between any two conditions ( P >= 0.05 ) ; Hz Hertz 0 2 4 6 8 10 12 Off 30 60 Baseline Frequency (Hz) 0 0.5 1 1.5 2 2.5 Off 30 60 Baseline Frequency (Hz)

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68 Figure 419. Me an and standard error of Sway area (square cm) at 30Hz and 60Hz frequency settings combined across the three voltage levels during eyes closed trials related to specific aim 2 Significant difference ( P < 0.05) ; Hz Hertz cm centimeter. Figure 4 20. Mean and standard error of Anterior Posterior Center of Pressure displacement in S2 phase (cm) at 30Hz and 60Hz frequency settings combined across the three voltage levels during gait initiation trials related to specific aim 2 Statistical t rend (0.05 <= P <= 0.07) ; Hz Hertz cm centimeter. 0 5 10 15 20 25 30 60 square cmFrequency (Hz) 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 30 60cmFrequency (Hz)

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69 Figure 421. Mean and standard error of Anterior Posterior Center of Pressure displacement in S3 phase (cm) at 30Hz and 60Hz frequency settings combined across the three voltage levels during gait initiation trials related to specific aim 2 Significant difference ( P < 0.05 ) ; Hz Hertz cm centimeter. Figure 422. Mean and standard error of Anterior Posterior Center of Pressure velocity in S3 phase (cm/s) at 30Hz and 60Hz frequency settings combined across the three voltage levels during gait initiation trials related to specific aim 2 Significant difference ( P < 0.05) ; Hz Hertz cm ce ntimeter, s second. 0 2 4 6 8 10 12 14 16 18 30 60 cmFrequency (Hz) 0 5 10 15 20 25 30 30 60 cm/sFrequency (Hz)

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70 Figure 423. Mean and standard error of Swing leg step length (cm) at 30Hz and 60Hz frequency settings combined across the three voltage levels during gait initiation trials related to specific aim 2 Significant difference ( P < 0.05) ; Hz Hertz cm centimeter. Figure 424. Mean and standard error of Stance leg step length (cm) at 30Hz and 60Hz frequency settings combined across the three voltage levels dur ing gait initiation trials related to specific aim 2 Statistical t rend (0.05 <= P <= 0.07) ; Hz Hertz cm centimeter. 0 10 20 30 40 50 60 30 60 cmFrequency (Hz) 0 20 40 60 80 100 120 30 60cmFrequency (Hz)

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71 Figure 425. Mean and standard error of Swing leg step time (s) at 30Hz and 60Hz frequency settings combined across the three voltage levels during gait initiation trials related to specific aim 2 Statistical t rend (0.05 <= P <= 0.07) ; Hz Hertz s second. Figure 426. Mean and standard error of Coef ficient of variation of stance leg step velocity (%) during gait initiation trials related to specific aim 2 Significant difference between 30Hz and 60Hz at a particular voltage condition ( P < 0.05) ; Hz Hertz BV Baseline voltage, HV H igh voltage, MV M aximum tolerable voltage. 0 0.1 0.2 0.3 0.4 0.5 0.6 30 60 sFrequency (Hz) 0 2 4 6 8 10 12 BV HV MV%Voltage condition 30Hz 60Hz

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72 Figure 427. Mean and standard error of Walking speed (cm/s) at 30Hz and 60Hz frequency settings combined across the three voltage levels during gait trials related to specific aim 2 Significant difference ( P < 0.05) ; Hz Hertz cm centimeter, s second. Figure 428. Mean and standard error of Stride length (cm) at 30Hz and 60Hz frequency settings combined across the three voltage levels during gait trials related to specific aim 2 Significant difference ( P < 0.05 ) ; Hz Hertz cm centimeter. 0 20 40 60 80 100 120 30 60 cm/sFrequency (Hz) 0 20 40 60 80 100 120 140 30 60cmFrequency (Hz)

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73 Figure 429. Mean and standard error of Step length (cm) at 30Hz and 60Hz frequency settings c ombined across the three voltage levels during gait trials related to specific aim 2 Significant difference ( P < 0.05 ) ; Hz Hertz cm centimeter. Figure 430. Mean and standard error of Opposite foot contact (%) at BV, H V and MV voltage conditions combined across the two frequency settings during gait trials related to specific aim 2 Post hoc tests did not show any significant differences between any two voltage conditions ( P > 0.05) ; BV Baseline voltage, HV H igh vol tage, MV M aximum tolerable voltage. 0 10 20 30 40 50 60 70 30 60 cmFrequency (Hz) 0 10 20 30 40 50 60 BV HV MV%Voltage condition

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74 Figure 431. Mean and standard error of Co efficient of Variation of opposite foot off during gait trials related to specific aim 2. Post hoc tests did not show any significant differences between the two frequency settings at any particular voltage condition ( P > 0.05) ; Hz Hertz, BV Baseline voltage, HV H igh voltage, MV M aximum tolerable voltage. Figure 432. Mean and standard error of Coefficient of variation of opposite foot contact (%) at 30Hz and 60Hz frequency settings combined across the three voltage levels during gait trials related to specific aim 2 Significant difference ( P < 0.05) ; Hz Hertz 0 2 4 6 8 10 12 14 16 18 BV HV MV %Voltage Condition 30Hz 60Hz 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 30 60 %Frequency (Hz)

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75 Figure 433. Mean and standard error of Speech sub score during Unified Parkinsons Disease Rating Scales Part III (Motor) evaluation related to specific aim 2 Significant difference ( P < 0.05); Hz Hertz, BV Baseline voltage, HV High voltage, MV Maximum tolerable voltage. Figure 434. Mean and standard error of Tremor subscore during Unified Parkinsons Disease Rating Scales Part III (Motor) evaluation related to specific aim 2 Significan t difference ( P < 0.05) ; Hz Hertz 0.0 0.5 1.0 1.5 2.0 2.5 BV HV MV Voltage condition 30Hz 60Hz 0 0.5 1 1.5 2 2.5 3 3.5 4 30 60 Frequency (Hz)

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76 Figure 435. Significant c orrelation between total electrical energy delivered per second ( Joules ) and MedioLateral Range (cm) of Center of Pressure during Eyes Open trial ( P < 0.05 ); r Pearson Correlation Coefficient cm centimeter Figure 436. Significant c orrelation between total electrical energy delivered per second ( Joules ) and Antero Posterior Range (cm) of Center of Pressure during Eyes Open tria l ( P < 0.05); r Pearson Correlation Coefficient cm centimeter r = 0.28 P = 0.019 0 2 4 6 8 10 12 0 100 200 300 400 500 600cmJoules r = 0.33 P = 0.005 0 1 2 3 4 5 6 7 8 9 10 0 100 200 300 400 500 600cmJoules

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77 Figure 437. Significant c orrelation between total electrical energy delivered per second (Joule s) and Sway Area (sq.cm) of Center of Pressure during Eyes Open trial ( P < 0.05); r Pearson Correlation Coefficient sq. cm square centimeter Figure 438. Significant c orrelation between total electrical energy delivered per second (Joule s) and Medio Lateral Range (cm ) of Center of Pressure during Eyes Closed trial ( P < 0.05); r Pearson Correlation Coefficient cm centimeter. r = 0.31 P = 0.009 0 10 20 30 40 50 60 70 80 0 100 200 300 400 500 600sq. cmJoules r = 0.25 P = 0.036 0 1 2 3 4 5 6 7 8 9 0 100 200 300 400 500 600cmJoules

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78 Figure 439. Significant c orrelation between total electrical energy delivered per second (Joule s) and Antero P osterior Range (cm) of Center of Pressure during Eyes Closed trial ( P < 0.05); r Pearson Correlation Coefficient cm centimeter. Figure 440. Significant c orrelation between total electrical energy delivered per second (Joule s) and Sway Area (sq.cm) of Center of Pressure during Eyes Closed trial ( P < 0.05); r Pearson Correlation Coefficient, sq. cm square centimeter. r = 0.24 P = 0.041 0 1 2 3 4 5 6 7 8 9 0 100 200 300 400 500 600cmJoules r = 0.27 P = 0.024 0 10 20 30 40 50 60 70 0 100 200 300 400 500 600sq.cmJoules

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79 Figure 441. Significant c orrelation between total electrical energy de livered per second (Joule s) and M edio Lateral Center of Pressure displacement (m) during the S2 phase of gait initiation ( P < 0.05); r Pearson Correlation Coefficient m meter. Negative values on the Y axis indicate the movement of the Center of Pressu re in the medial direction with respect to the initial stepping leg. Figure 442. Significant c orrelation between total electrical energy delivered per second (Joule s) and maximum resultant Center of PressureCenter of Mass separation distance (cm) duri ng S3 phase of gait initiation (P < 0.05) ; r Pearson Correlation Coefficient cm centimeter. r = 0.27 P = 0.015 0.18 0.16 0.14 0.12 0.1 0.08 0.06 0.04 0.02 0 0 100 200 300 400 500 600mJoules r = 0.25 P = 0.027 0 5 10 15 20 25 30 35 40 0 100 200 300 400 500 600cmJoules

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80 Figure 443. Significant c orrelation between total electrical energy delivered per second (Joule s) a nd maximum A nterior Posterior Center of PressureCenter of Mass separation distance (cm) during S 3 phase during gait initiation ( P < 0.05) ; r Pearson Correlation Coefficient, cm centimeter. Figure 444. Significant c orrela tion between total electrical energy delivered per second (Joule s) and swing leg step velocit y (m/s) during gait initiation ( P < 0.05); r Pearson Correlation Coefficient m/s meters per second. r= 0.26 P = 0.027 0 5 10 15 20 25 30 35 0 100 200 300 400 500 600cmJoules r = 0.23 P = 0.042 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 0 100 200 300 400 500 600m/sJoules

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81 Figure 445. Significant c orrelation between total electrical energy delivered per second (Joule s) and coefficient of variation of s tance leg step length (m) during gait initiation ( P < 0.05); r Pearson Correlation Coefficient. Figure 446. Significa nt cor relation between total electrical energy delivered per second (Joule s) and doubl e support time (s) during gait evaluation ( P < 0.05); r Pearson Correlation Coefficient s second. r = 0.24 P = 0.036 0 5 10 15 20 25 0 100 200 300 400 500 600%Joules r = 0.23 P = 0.039 0 0.1 0.2 0.3 0.4 0.5 0.6 0 200 400 600sJoules

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82 Figure 447. Significant c orrelation between total electrical energy delivered per second (Joule s) and balance related subscore (Question 30) on the Unified Parkinsons Disease Rating Scales Part III (Motor ) evaluation Form ( P < 0.05); Spearman Rho. = 0.23 P = 0.038 0 1 2 3 0 100 200 300 400 500 600 Joules

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83 Table 41 Baseline characteristics of the participants Person Gen der Age (yrs) Height (cm) Mass (kg) DD (yrs) Date of Implantation in months (R/L) LEDD (preop/ postop) Baseline MMSE Baseline BDI 1 M 56 176.5 62.1 17 25/47 no record/ no meds 30 4 2 M 69 182.9 104.8 8 19/25 800.04/ 750 30 3 3 F 63 153.7 52.4 19 58/70 1250/ 1000 28 10 4 M 73 173.4 84.1 12 21/34 833.4/ 1200 30 17 5 M 68 172.7 96.8 10 19/48 600/ 450 28 11 6 M 66 174.6 103.9 10 47/76 800.25/ 1050 30 20 7 M 69 182.9 82.8 13 27/35 1676.5/ 200 29 12 8 F 43 163.8 131.5 10 6/16 900/ 800 29 12 9 M 55 175.3 85.3 13 38/47 1200/ 150 28 14 10 M 70 182.9 88.9 10 6/29 1650/ 1150 30 1 Mean (SD) 63.20 (9.23) 173.9 (9.2) 89.3 (22.3) 12 (3.5) 29 (1) 10 (6) Range 43 73 153.7 182.9 52.4 131.5 8 19 28 30 1 20 cm centimeter, kg kilogram, R Right, L Left, DD Disease Duration, LEDD Levodopa Equivalent Daily Dose, MMSE Mini Mental Status Examination, BDI Becks Depression Index, meds medications, SD Standard deviation, M Ma le, F Female Table 42 Baseline characteristics of the right stimulator of the participants Person Electrode contact Case of the pulse generator Baseline voltage (V) Baseline pulse width (s) Baseline frequency (Hz) Baseline Mean PFS 16 Score (SD) 1 1 C+ 3.2 90 135 2.88 (1.50) 2 1 3+ 2.6 90 135 3.69 (1.01) 3 1 3+ 2.5 120 185 3.00 (1.03) 4 2 C+ 2.4 90 160 3.56 (0.81) 5 1 2 C+ 3.5 90 185 4.25 (0.45) 6 1 3 C+ 2.5 90 160 7 1 C+ 3.2 90 135 3.44 (0.63)

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84 Table 42. Continued Person Electrode contact Case of the pulse generator Baseline voltage (V) Baseline pulse width (s) Baseline frequency (Hz) Baseline Mean PFS 16 Score (SD) 8 2 C+ 2.8 90 135 4.31 (0.48) 9 2 3+ C+ 3.0 90 135 2.38 (0.96) 10 1 C+ 2.4 90 135 2.56 (1.50) V Volts, s Micro seconds, Hz Hertz, PFS Parkinson Fatigue Scale Table 43 Baseline characteristics of the left stimulator of the participants Person Electrode contact Case of the pulse generator Baseline voltage (V) Baseline pulse width (s) Baseline frequency (Hz) 1 1 C+ 3.2 90 135 2 2 C+ 2.2 90 135 3 2 C+ 2.3 90 135 4 1 C+ 2.6 60 160 5 1 2 C+ 3.1 90 185 6 1 2+ 3.3 90 135 7 2 C+ 2.5 120 160 8 2 C+ 2.9 90 185 9 1 2+ 3.2 120 185 10 2 C+ 2.8 90 160 V Volts, s Micro seconds, Hz Hertz.

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85 Table 4 4 Non motor symptoms and observations including participant feed back during data collection Person R/L Baseline Frequency (Hz) R/L Baseline Voltage (V) R/L Frequency (Hz) Observation Resulting Adjustment R/L Voltages (Condition) and observations 1 (The participant takes medications only occasionally) 135/135 3.2/3.3 OFF/OFF Multiple freezing episodes. 30/30 Developed quivering right eye when stimulated at 5.4V on right side Tested at 5.3/6.0 V (30Hz MV condition). Multiple freezing episodes. 60/60 at HV setting 60HV condition seemed to be the setting the participant liked the best. Participant felt his speech was improved dramatically. Excessive sweating. After the final testing session, the participant tried this new setting for three days and went back to his baseline settings. 60/60 at MV setting Excessive sweating. 2 135/135 2.6/2.2 60/60 Internal capsule when stimulated at 4.8V on right side and 3.8V on left side Tested at 4.1/2.6 V (60Hz MV condition). Dyskinesia. 60/60 Stimulation induced dyskinesia when stimulated at 3.5V on left side Tested at 3.3/3.5 V (60Hz HV condition) 30/30 Stimulation induced dyskinesia when stimulated at 5.1V on right side and stimulation induced mood changes when stimulated at 4.1V on left side Tested at 5.0/4.0 V (30Hz MV condition)

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86 Table 44. Continued Person R/L Baseline Frequen cy (Hz) R/L Baseline Voltage (V) R/L Frequency (Hz) Observation Resulting Adjustment R/L Voltages (Condition) and observatio ns 3 180/135 2.5/2.3 OFF/OFF Dystonia 30/30 at baseline voltage Dystonia especially in the left arm 60/60 Dizziness when stimulated at 4.2V on right side Tested at 4.1/2.6 V (60Hz MV condition) 4 160/160 2.4/2.6 30/30 Dizziness, Sweating (Autonomic symptom) when stimulated at 5.5V on right side Tested at 5.5/6.0 V (30Hz MV condition) 60/60 Stimulation induced tremor when stimulated at 4.4V on right side and 3.7V on left side Tested at 4.3/3.6 V (60Hz MV condition) 5 185/185 3.6/3.1 30/30 Diplopia when stimulated at 4.6V on right side and Oscillopsia when stimulated at 5.3V on left side Tested at 4.5/5.2 V (30Hz HV condition) 60/60 Pulling eyes (Capsule) when stimulated at 4.8V on right side and Eyes Twitching when stimulated at 4.8V on left side Tested at 4.7/4.7 V (60Hz HV condition) 60/60 Oscillopsia when stimulated at 4.2V on right side Tested at 4.1/6.1 V (60Hz MV)

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87 Table 44. Continued Person R/L Baseline Frequency (Hz) R/L Baseline Voltage (V) R/L Frequency (Hz) Observation Resulting Adjustment R/L Voltages (Condition) and observatio ns 6 (Participant experience s falls often. Last fall was 3 weeks back while lifting a propane tank) 160/135 2.5/3.3 30/30 Oscillopsia when stimulated at 3.8V on right side and when stimulated at 4.4V on left side Tested at 3.7/4.3 V (30Hz HV condition) 60/60 Pulling on left side of the face when stimulated at 4V on right side Tested at 3.9/4.8 V (60Hz HV condition) 7 (Participa nt said he would not recomme nd any of the low frequency (30/60HZ ) and high voltage (HV/MV) settings) 135/160 3.2/2.5 60/60 Autonomic symptoms and dyskinesia when stimulated at 5.1V on right side and when stimulated at 4.2V on left side Tested at 5.1/4.2 V (60Hz MV condition). Excessive sweating and feeling of stiffness in legs 30/30 Autonomous symptoms like excessive sweating, increased tremor and dyskinesia seen at the 30HV condition 30/30 Stimulation induced tremor when stimulated at 4.9V on right side Tested at 4.8/4.3 V (30Hz MV condition). Excessive stimulation induced euphoria

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88 Table 44. Continued Person R/L Baseline Frequency (Hz) R/L Baseline Voltage (V) R/L Frequency (Hz) Observation Resulting Adjustment R/L Voltages (Condition) and observatio ns 8 135/185 2.8/2.9 OFF/OFF Dyskinesia and aggrandized movements 135/185 at baseline voltage External tremor absent but the participant felt internal tremor 60/60 Heaviness in fingers when stimulated at 5.1V on left side Tested at 6.5/5.0 V (60Hz MV condition). Participant liked this setting (60MV) a lot as she feels she has more clarity of thinking. She is satisfied mentally with this setting but not so much physically as her lower back hurts may be because of fatigue 30/30 Heaviness in fingers when stimulated at 5.7V on left side Tested at 6.5/5.6 V (30Hz MV condition)

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89 Table 44. Continued Person R/L Baseline Frequency (Hz) R/L Baseline Voltage (V) R/L Frequency (Hz) Observation Resulting Adjustment R/L Voltages (Condition) and observatio ns 8 (contd) 135/185 2.8/2.9 30/30 at HV setting Participant didnt like this setting at all. She felt her voice is raspy, emotionally down, with slight breathlessness. Not many aggrandized movements. Participant was talking a lot before this setting but during this entire trial, she was absolutely silent. After trial she said she was on the verge of crying. At the end, the participant compared how she felt with baseline settings vs. 60MV by getting set at both the settings (baseline settings and 60MV). She left to home with the 60MV setting as she felt lesser internal tremor. 9 135/185 2.4/2.8 OFF/OFF Freezing observed 30/30 at baseline voltage setting Some freezing observed 60/60 Stimulation induced tremor when stimulated at 3.9V on right side and pulling in the right hand when stimulated at 6V on left side Tested at 3.8/5.9 V (60Hz HV conditio n) 30/30 Stimulation induced tremor when stimulated at 4.8V on right side and tightness in the right hand when stimulated at 5.7V on left side Tested at 4.7/5.6 V (30Hz MV conditio n) 30/30 at HV setting Participant feels tight in this setting. Festination.

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90 Table 44. Continued Person R/L Baseline Frequency (Hz) R/L Baseline Voltage (V) R/L Frequency (Hz) Observation Resulting Adjustment R/L Voltages (Condition) and observations 10 135/160 2.4/2.8 60/60 Nausea and sweating when stimulated at 2.7V on right side and nausea and paresthesia in the contralateral hand when stimulated at 3.4V on left side Tested at 2.6/3.3 V (60Hz MV condition) 30/30 Autonomic symptoms when stimulated at 5.6V bilaterally (on both right side and left side) Tested at 5.5/5.5 V (30Hz MV condition) R Right, L Left, Hz Hertz, HV High Voltage (Baseline voltage + 1.5V), MV Maximum tolerable Voltage Table 45 Subjective Feedback scale (1 very bad to 10 very good) to rate the participants state of well being Person Day Condition Testing Order Beginning of testing End of testing 1 1 OFF 1 3 3 30BV 2 7 8 60BV 3 7 8 Baseline Frequency 4 8 7 2 30HV 1 2 3 60HV 2 7 9 30MV 3 1 1 60MV 4 3 6 Table 45. Continued

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91 Person Day Condition Testing Order Beginning of testing End of testing 2 1 OFF 1 9 9 30BV 2 9 9 60BV 3 9 7 (feels tired and wearing down) Baseline Frequency 4 7 5 2 30HV 3 9 9 60HV 2 8 8.5 30MV 4 8 7 60MV 1 7 5 3 1 OFF 1 8 4 30BV 4 8 7 60BV 3 8 8 (getting tired) Baseline Frequency 2 9 8 2 30HV 2 4 3 60HV 1 3 4 30MV 3 4 5 60MV 4 4 5 4 1 OFF 1 3 5 30BV 3 6 5 60BV 4 5 4 Baseline Frequency 2 4 6 2 30HV 2 6 (feeling weaker) 5 60HV 3 6 6 30MV 1 7 7 60MV 4 7 (Ankle and foot are hurting) 7

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92 Table 45. Continued Person Day Condition Testing Order Beginning of testing End of testing 5 1 OFF 1 10 10 30BV 3 10 10 60BV 2 10 10 Baseline Frequency 4 10 10 2 30HV 1 10 10 60HV 2 10 10 30MV 3 10 10 60MV 4 10 10 6 1 OFF 1 4 4 30BV 3 4 4 60BV 4 5 5 Baseline Frequency 3 4 5 2 30HV 1 4 4 60HV 3 4 5 30MV 4 5 5 60MV 2 3.5 4 7 1 OFF 1 8 8 30BV 2 8 8 60BV 4 6 6 Baseline Frequency 3 8 6 2 30HV 1 4 4 60HV 3 9 8 30MV 4 6 7 60MV 2 8 8 8 1 OFF 1 3 4 30BV 2 6 7 60BV 4 8 8 Baseline Frequency 3 8 8 2 30HV 4 7 4 60HV 2 6 6 30MV 1 6 6 60MV 3 7 8

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93 Table 45. Continued Person Day Condition Testing Order Beginning of testing End of testing 9 1 OFF 1 6 7 30BV 3 8 8 60BV 4 8 8 Baseline Frequency 2 8 8 2 30HV 2 6 6.5 60HV 1 6 7 30MV 3 7 6 60MV 4 5 6 10 1 OFF 1 4 8 30BV 2 7 7 60BV 4 5 7 Baseline Frequency 3 6 7 2 30HV 3 3 3 60HV 4 5 8 30MV 2 4 5 60MV 1 6 8 BV Baseline voltage, HV High Voltage (Baseline voltage + 1.5V), MV Maximum tolerable Voltage

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94 CHAPTER 5 DISCUSSION High frequency (> 100Hz) subthalamic nucleus (STN) deep brain stimulation (DBS) among individuals with Parkinsons disease (PD) has been show to have beneficial effect on some of the cardinal symptoms like tremor and rigidity. However its effect on postural stability and gait has been limited if not negative. The purpose of this stud y was to see the immediate efficacy of low frequency stimulation for postural stability and locomotion. Particularly, the acute effects of low frequency stimulation on static postural stability, anticipatory postural stability, dynamic postural stability and locomotion have been presented in the following sections. In each section, the influence of low frequency stimulation at baseline voltage is first discussed. Next, the effect of increasing the voltage at low frequency on the posture and locomotion is el aborated. Last, the response of all the outcome variables with changes in Total Electrical Energy Delivered (TEED) per second and the qualitative data are discussed. The absence of significant differences in stance width among different conditions eliminates the possibility of a wider base of support in explaining some of these results. Static Balance ( E yes O pen and E yes C losed T rials) Results from the evaluation of static balance trials involving eyes open and eyes closed bipedal standing showed that the C enter of Pressure (CoP) based parameters did not alter to a great extent with either frequency or voltage alteration. Specific aim 1 results showed that the stimulation at 60Hz produced smaller Antero posterior (AP) oscillation of the CoP compared to the OFF condition during the eyes open trials. Specific aim 2 results illustrated lower sway area across the three voltages levels for 30Hz compared to 60Hz. Based on these results, increasing the voltage did not seem to

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9 5 effect the standing postural control. P ostural control during quiet standing involves ability to minimize CoP movement. Winter et al. (1996) discussed how the central nervous system regulates the CoPs AP movement through the ankle plantar flexors and dorsiflexors and its Medio lateral (ML) mov ement through the hip muscles, in response to the position of the center of gravity during bipedal standing. The improvement in AP sway observed during 60Hz condition could be due to enhanced central regulation of postural control muscles or reduced stiffness of postural control muscles peripherally or a combination of both. Though the post hoc tests did not reveal a significant difference for the U nified Parkinsons Disease Rating Scale (UPDRS) b ased rigidity score between the 60Hz condition and the OFF co ndition, scores were about 38% lower with the stimulator ON. This lower score at 60Hz when compared to OFF STIM condition could therefore represent diminished rigidity and hence better postural muscle control ultimately resulting in reduced AP sway. Rigidi ty could depend on the contractile properties of the muscle or supraspinal regulation. Hufschmidt et al., (1991) showed that the contractile properties of lower leg muscles are normal in PD patients thus suggesting that rigidity could be primarily control led by central regulation. Based on the immediate effect of DBS on reduction of rigidity researchers have suggested that rigidity is regulated by supraspinal regions of the central nervous system rather than peripheral sources (Maurer et al., 2003; Levin et al., 2009). One counter argument to exhibiting better postural control because of reduction in rigidity was given by Termoz and colleagues (2008). They postulated that an increase in rigidity would reduce the sway among PD and would act as a compensator y mechanism for the loss of sensory inputs due to dopamine depletion in the striatum. However, in the

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96 present study, there was a concomitant decrease in rigidity along with AP sway at a low frequency (60Hz) suggesting that better postural control could hav e been achieved through better regulation of sensory inputs. Rocchi and colleagues (2002) also noted that the CoP oscillations could be influenced by the resting tremor present in arms, leg and trunk muscles. However, in the current study, participants exhibited greater tremor sub score but smaller sway area during eyes closed trials at 30Hz compared to 60Hz. This opposite trend could be due to a combination of resting and postural tremor during quiet stance. Sensorimotor strategies play a pivotal role in bipedal standing. In addition to muscle tone as discussed previously, stance motor control is also influenced by the vertical alignment of the body, and postural tone. Alignment refers to the positions of different body segments within the base of support in order to maintain equilibrium. PD patients are known to have stooped posture with considerable forward trunk flexion. Crenna et al. (2006) observed improvement of vertical alignment of trunk among people with PD after high frequency STN DBS. Though not directly measured, lower AP sway at 60Hz compared to OFF STIM condition during eyes open trial and lower sway area across the three voltage levels for the 30Hz condition compared to the 60Hz condition during eyes closed trial could have produced a more erect posture. Electromyography (EMG) measurements during standing trials could highlight changes in postural tone by detecting changes in the activity of postural control muscles. Postural tone is also affected by the visual, vestibular, and somatosensory inputs. The sway area under the 30Hz conditions decreased 19% compared to the 60Hz conditions across different voltages during eyes closed trials. However these differences did not appear during the

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97 eyes open trial. Pastor and colleagues (1993) established t he intactness of the vestibular input among PD. Hence, in the eyes closed condition, with no visual input, the 30Hz condition seemed to enhance the use of proprioceptive inputs for postural regulation among PD patients. Based on the differences observed between Ldopa and high frequency stimulation, Rocchi and colleagues (2002) also mentioned the possibility of DBS acting on nondopaminergic pathways from the basal ganglia to the brain stem to improve the proprioception among individuals with PD. Whether any of the visual, vestibular or proprioceptive sensory inputs were enhanced causing reduced rigidity and improved postural control at 30Hz/60Hz warrants further examination. Colnat Coulbois and colleagues (2005) observed lower values of ML CoP movement for their study cohort performing similar tasks of static posturography. However, these conflicting results could be attributed to two differences. First, their participants were in medicated state and hence the authors perceived a synergistic positive effect of DBS and medications on the postural control mechanisms in their PD patients. Since the present study was focused on evaluating the effects of low frequency DBS alone (without medication), the synergistic effect of low frequency DBS with medications cannot be commented on. Second, the trial duration was 20s in their study as compared to 60s in the current study Rocchi and colleagues (2002) demonstrated significant differences in postural measures between the OFF STIM state and high frequency stimulation during eyes open trials, while the patients were not under the influence of their medications. However, the results of the present study failed to identify these differences. One plausible explanation for these disparate results as supported by Burn (2002) could be that all the patients in the present study had their

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98 DBS at STN whereas in the study by Rocchi et al. (2002), only three out of six patients had STN DBS while the remaining underwent G lobus Pallidus Internus (GPi) DBS. Also differences in the wai ting time after turning on the stimulator (10 minutes in the present study vs. 20 minutes in the Rocchi and colleagues (2002) study) as well as differences in the methodology involving determining the ON STIM state could have lead to dissimilar results. M aurer and colleagues (2003) found contrasting results with an increase in sway area after high frequency STN stimulation compared to the OFF STIM condition and smaller CoP based outcome measures compared to present study. A younger mean age (48.1 years) and an early onset of PD (34.8 years) of their study cohort could probably contribute to some of these differences. Previous researchers have postulated that the postural control mechanisms are centrally regulated by nondopaminergic pathways compared to the motor control mechanisms regulated through dopaminergic pathways (Colnat Coulbois et al. 2005). This is often explained based on the therapeutic effects of Ldopa medication on distal symptoms like tremor and rigidity but mild improvements to even worsening of postural stability among PD (Bejjani et al. 2000; Beuter et al., 2008; OSuilleabhain 2001 ; Rocchi et al., 2002 ). Some of these nondopaminergic pathways that help in regulation of posture have been attributed to the pathway between the basal ganglia and the P edunculopontine Nucleus (PPN) of the Mesencephalic region. Takakusaki et al. (2009) postulated the role of basal ganglia in postural control via GABAergic inputs to the PPN. Lower frequency PPN stimulation has been found to generate ameliorating effects among the PD population (Stefani et al., 2009) and central integration for postural control could be due to the diffusion of low intensity currents to the PPN. Moreover

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99 results of high frequency STN stimulation also followed the trend of som e of the works of earlier investigators who did not see any marked improvements in postural stability after high frequency stimulation (Nilsson et al., 2009). A lack of other observable therapeutic DBS effects on postural control during these bipedal stand ing trials could partly be attributed to a minor role of the basal ganglias degraded dopaminergic circuits in the deficient proprioception among PD (Mongeon et al., 2009). Though the current study cannot pinpoint the exact neural substrates and mechanisms involved, some of the observed effects could be due to the enhanced activity between the STN stimulated at low frequency (30Hz and 60Hz) and the mesopotine tegmentum which plays a part in the postural regulation (Takakusaki et al., 2003). Low frequency st imulation (30Hz and 60Hz) seemed to deliver equivalent and/or better results for regulating standing posture compared to high frequency and OFF STIM conditions. Decrease in rigidity combined with increased proprioceptive input processing could be attributed to enhanced postural control. These ameliorating results at low frequencies (30Hz and 60Hz) could be due to an increased activation of nondopaminergic pathways connecting basal ganglia and brain stem possibly through PPN. Increasing the voltage had no effect on any of the measures related to postural control while bipedal standing. Gait Initiation Frequency modification resulted in changes only in the locomotion (S3) phase of gait initiation (GI) S ignifican t changes were seen for the CoP anterior velocity and its maximum separation distance from C enter of Mass (CoM) in the AP direction. CoP anterior velocity was greatest under the 30Hz condition and was significantly more than the value at the 60Hz condition. Though, not significantly dif ferent, the velocity was least

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100 during the OFF STIM condition. Faster CoP forward movement at 30Hz compared to 60Hz was further reinforced by a significant frequency main effect for results answering specific aim 2. Indeed, even the CoP anterior displacement was significantly longer at 30Hz compared to 60Hz across the three voltage conditions. However, a change in voltage did not affect these balance based measures; there were no interaction or voltage main effects. The forward CoP displacements and velociti es in the S3 phase for different conditions were similar to previous studies evaluating GI performance in transitionally frail adults and people with PD (Hass et al., 2004, 2008). Liu and colleagues (2006) found significant differences for the ML and AP CoP displacements in the S1 phase between the OFF STIM and baseline frequency conditions. However large values of their standard errors could highlight some of the significance of their results. Also the average time to swing leg toe off in the current study (1.6s) was slightly longer than that of the Liu et al. (2006), study (1.1s). Likewise, Crenna et al. (2006), showed significant improvement in the ML and AP displacement of the CoP with both the stimulators on, compared to OFF STIM condition. These dispa rities could be attributed to the differences in the methodology of testing in terms of waiting time for testing after setting the stimulator to a particular condition (10 minutes vs. 30 60 minutes). Absence of significant results in the anticipatory postu ral phase and weight shifting phase in the current study could highlight lack of limited effect of low frequency stimulation (30/60Hz) on the pathways involved in planning of voluntary movements. The greatest CoP CoM moment arm in the AP direction was found for the 60Hz condition and the least value was found for the OFF STIM condition with the post hoc tests failing to detect significant difference between any two conditions. Also there was

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101 no effect of voltage variation on this dependent measure. The AP CoP COM moment arm is one component of the resultant CoP COM moment arm which has often been reported in the literature. This resultant separation distance did not differ significantly among the conditions for both the specific aims. However, the values obtained fall in the continuum of those reported previously in the literature (16 30cm) for older adults with disability and PD (Chang and Krebs, 1999, Martin et al., 2002, Hass et al., 2005). In fact, the values obtained for the ON STIM conditions matched t he values found by Chang and Krebs (1999) for healthy older adults probably suggesting an ameliorating effect of STN DBS for PD patients. Also, the present study is the first to report these dynamic stability measures comparing ON STIM and OFF STIM conditi ons. The locomotion phase is similar to the stance phase of gait cycle where the CoP traverses forward under the stance foot. During this phase, the plantar flexors of the stance leg contract to enable a forward displacement of the CoP. Greater values of C oP velocity during 30HZ condition could thus be due to increased activity of the Triceps Surae muscles of the stance leg. However the use of tools that record muscle activity like the EMG recordings could provide better insight into the role of muscles for the faster CoP movement. Faster translation of the CoP during this single limb support phase could be attributed to faster stepping of the swing leg. But results showed the fastest movement for the swing leg while taking the first step occurred during the 60Hz condition. Hence, one possible explanation could be an incoherent postural control of the stance leg and swing leg. Quicker CoP translation during the 30Hz condition without a corresponding faster movement of the contralateral leg could also indicate a greater toe clearance during the lower frequency condition. In fact, Halliday and colleagues

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102 (1998) showed significantly lower ratio of step height and swing leg step length among persons with PD compared to healthy older and young adults. Computation of this stepping height could provide further insight into the CoPs forward velocity based results. The locomotion phase of GI is also considered as the most challenging phase owing to the single limb support during gait initiation. Maximizing the resulta nt CoP CoM moment arm has two effects: greater momentum generation due to greater torque exerted by the ground reaction force on the CoM and greater demand for postural control because of the increased moment of the body weight vector relative to the joint centers. Balancing between these two factors of momentum generation and postural control could thus impart insight into the challenging aspects of an activity like GI. The peak resultant CoP CoM separation distance has thus being used often as an indicator of the dynamic postural stability during transition tasks. Special populations like PD have been reported to generate a lesser value and hence have a declined postural stability during GI (Martin et al., 2002). Hass and colleagues (2005) suggested that shorter peak CoP CoM separation during this locomotion phase could indicate a voluntary reduction of mechanical and postural demands of initiating gait. Martin et al., (2002) highlighted that the impaired postural control could result in emphasizing stabili ty over momentum generation in the PD population. Given this background work on the peak resultant CoP CoM moment arm, whether these features translate even for its anterior component needs further exploration. The resultant CoP CoM moment arm represents the acceleration vector of the body. During the locomotion phase, its components are oriented anteriorly and medially

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103 (towards the swing leg). As the direction of motion is forward, the anterior component plays a dominant role in momentum generation as wel l as postural control. Significant differences only for the forward component instead of the resultant component could be a result of the consistently used narrow stance width while initiating gait. Though non significant, greater peak CoP CoM separation distance at the 60Hz condition could indicate better tolerance of postural instability as well as momentum generation in forward direction when compared to other conditions. The longer CoP CoM moment arm at 60Hz in spite of lesser CoP translation velocity in the S3 phase compared to 30Hz could indicate a longer forward displacement of the CoM in the 60Hz condition. Amalgamation of multiple sensory and motor pathways helps the central nervous system regulate different phases of gait initiation (Hass et al., 2005). Lack of differences in the anticipatory postural phase and weight shifting phase in contrast to the locomotion phase and results from the static balance tests probably highlight that the frequency alteration during DBS mainly affects the pathways r esponsible for dynamic postural control and locomotion rather than static and anticipatory postural control. The effect on locomotion is further highlighted by the spatiotemporal differences observed at different conditions. Significant spatio temporal outcome measures of the GI task explicit to specific aim 1 consistently revealed that the participants performed worst under the OFF condition and best under the 60Hz condition. Though, not significant, the results also indicated that the performance under l ow frequency conditions (30Hz and 60Hz) were better than the performance under baseline (high) frequency condition. Though no effects of voltage change were noted for the spatio-

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104 temporal parameters during GI, a greater swing leg step length was observed fo r 60Hz conditions compared to 30Hz conditions across all the voltages. Some of the spatiotemporal results like the swing leg step length and velocity mimicked the results of Crenna and colleagues (2006), who showed significantly greater values with the s timulators on and set at a high frequency. In the current study, there was a significant improvement in the swing leg step velocity and a nonsignificant improvement in the swing leg step length from the OFF STIM condition to the baseline condition. Moreov er, the values of both these variables were even greater for the low frequency conditions (30Hz and 60Hz). Breniere and Do (1991) proposed that the step length and the CoMs velocity at the end of first step depend on the propulsive forces generated before heel rise of the swing leg. However lack of differences among the different conditions in the anticipatory postural phase probably suggest an alternate mechanism for better step length of both the legs during 60Hz. Viton and colleagues (2000) further stat ed that the kinematics and kinetics governing balancing of posture and movement could either be affected by a neurological or peripheral deficit. Though the mechanism of action is still unclear, it is well known that DBS alters the functioning of the components of the basal ganglia either through inhibition of the neuronal activity of the stimulated nucleus and/or through increased output of the stimulated structure (Vitek 2002). Hence a neurological correction imparted by switching on the stimulator coul d be attributed for an improvement in spatiotemporal parameters. Also, after 30/60Hz stimulation, the motor programs devoted to the locomotion part of the GI could have been enhanced for each leg as well as the coordination between both the legs while initiating gait. This enhancement could override a pathophysiological deficit of

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105 improper scaling of motor programs that is prominent among PD patients while initiating gait (Crenna et al., 2006). Use of EMG techniques could verify the aforesaid assumption. On a peripheral level, reduced rigidity for the ON STIM conditions compared to the OFF STIM condition, could also contribute to better movement characteristics. Measuring the regional cerebral blood flow, Jahanshahi and colleagues (1995) reported underac tivation of the supplemental motor area (SMA) among PD patients while performing self initiating movements. An increase in blood flow to the SMA region after high frequency STN stimulation has been reported previously (Limousin et al. 1997; Ceballos Baumann et al. 1999) Perhaps, similar ameliorating effects occurred during stimulation at 60Hz frequency providing more output to the SMA region from the basal ganglia, resulting in an improved performance of GI. The premotor cortex and the SMA play an active role during anticipatory postural activities and preplanning motor actions. Hence assumption of increased activity between basal ganglia output and these higher cortical structures should be interpreted carefully owing to the presence of substantial resul ts only for the locomotion phase of GI compared to the anticipatory postural phase. Takakusaki et al. (2009) proposed that during voluntary movement tasks like GI, the output from basal ganglia to the spinal cord regulates postural control through the PPN region and locomotion through the midbrain locomotor region. Excessive GABAergic output from the GPi and the substantia nigra pars reticulata to midbrain locomotor region has been observed for a person suffering from PD (Alexander and Crutcher, 1990; Delong, 1990; Takakusaki et al., 2009). Based on the results of the current study, low frequency stimulation (30/60Hz) could have caused an

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106 inhibition of STN, which in turn would have caused less excitatory signals to be sent to the output nuclei of the basal ganglia. This would have caused the GPi and substantia nigra signals to send less inhibitory signals to the mesencephalic locomotor region enabling better locomotion. Better performance at lower frequency settings (30Hz and 60Hz) was also evident in the outcomes relative to variability of spatio temporal parameters during GI. Significant differences among the frequency conditions were seen for variability for swing leg stepping time and velocity. Particularly, the variability for swing leg step time was greatest during the OFF STIM condition and exceeded the average variability during ON STIM conditions by 65%. Moreover, greater differences in the variability scores were observed for the swing leg stepping velocity. The coefficient of variation (CV) for the speed of first step during the baseline frequency condition exceeded that of the low frequency conditions (30Hz and 60Hz) by 48%. An even greater difference was observed between the OFF STIM condition and the low frequency conditions where the coefficient of variation during the OFF STIM condition was double the value at low frequency conditions. The only effect of increasing the voltage was seen for the coefficient of variation of stance leg velocity. The change in voltage seemed to alter the variability m ore at 30Hz than 60Hz. For instance, when the voltage was changed from B aseline Voltage (BV) to H igh Voltage (HV) the variability decreased by 53% at 30Hz and increased by 50% at 60Hz. Yet, when the voltage was further increased from HV to M aximum Voltage (MV) the variability for stance leg step velocity increased by 57% compared to only 9% decrease at 60Hz. Though there was a considerable difference at BV and HV, the coefficient of variation of stance leg velocity was similar at MV for both

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107 the low frequency conditions. Aforesaid differences in CV scores between conditions suggest that low variability and hence better performance prevailed at 60Hz followed by 30Hz compared to OFF STIM and baseline frequency. Lesser variability could indicate better step i nitiating characteristics. Indeed, Mbourou and colleagues (2003) reported that the variability of swing leg step length during GI was two times greater for elderly fallers compared to agematched nonfallers concluding that this variability could be an imp ortant predictor for postural problems and stepping responses during fall recovery. Though no significant differences were found for the swing leg step length variability in the current study, the values at low frequency conditions (30Hz and 60Hz) were low er than the values at OFF STIM and high frequency conditions. Swing leg step length is a product of the step velocity and time. Hence lower variability at low frequency conditions (30Hz and 60Hz) for these variables might indicate better postural control at low frequency stimulations. Interestingly, the coefficient of variability for initial step length at 30Hz and 60Hz conditions were similar to the values for younger adults in Mbourou et al. (2003) study (~8%). Also the current studys cohort of mean age (63 years) had a swing leg step length of 10.4% during the OFF STIM condition, while the values for elderly non fallers (mean age: 73 years) and fallers (mean age: 80 years) were 12% and 45.3% respectively. Thus, there appears to be a continuum of increase in initial step length variability with age. Differences in the magnitude or rate of force production or the firing pattern of the plantar flexors of the swing and stance legs may explain the differences in variability (Mbourou et al. 2003). The differenc es in variability relative to swing leg step velocity could also be attributed to the differences in the mean swing leg step velocity values. Wittwer et al. (2008) presented that energy analysis of GI

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108 highlights three stages. In stage1, the stepping with the swing leg thrusts the body from a static state to a dynamic state. Then the stance leg stepping increases the bodys energy state close to steady state which is normally attained at the end of the stance leg step or the second step of the swing leg (Mi ller and Verstraete 1996). Thus greater variability during OFF STIM and baseline frequency conditions for swing leg step velocity could indicate greater inefficiency to produce the required power during the initial step. Similarly more variability or its associated changes related to stance leg stepping velocity could highlight the differences in power production across different frequency voltage combinations required for the stance leg step. The results of the current study also agree with the results of previous studies which showed greater variability for the spatiotemporal parameters during GI compared to gait trials. Thus results for GI based outcome measures revealed a consistent pattern of better locomotion characteristics at low frequency conditi ons (primarily 60Hz). However, no observable effects of low frequency stimulation (30/60Hz) were observed in the anticipatory postural phase and weight shifting phase. Additionally, increase in voltage at low frequency showed no substantial benefits. Gait Evaluation Compared to static balance and dynamic balance results, more observable effects of altering the frequency and voltage were seen for gait analysis. Specific aim 1 results highlighted that participants walked slowest with the stimulator off and their gait velocity increased the most (9%) when stimulated at 60Hz. Gait was faster across all the voltage levels at 60Hz compared to 30Hz by 4.5%. Also, across all the voltage levels, stride and step lengths at 60Hz were about 3% longer than corresponding values at 30Hz. A significant frequency effect (for specific aim 1) and voltage main effect (for specific aim -

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109 2) was seen for the opposite foot contact parameter which denotes the percentage of gait cycle when the swing leg strikes the ground. However the values for this contralateral heel strike parameter at different conditions denoted negligible differences (<1%) to justify a biomechanical improvement in stepping characteristics. Outcomes pertaining to gait analyses from the current study were comparab le to results from earlier studies (Johnsen et al., 2009, Liu et al., 2005). For instance the walking speed during the OFF STIM condition fell in the range reported in the literature (48cm/s to 98cm/s). Similarly the gait speed at high frequency also fell within the observed range (95cm/s to 111cm/s). Johnsen and colleagues (2009) found significantly better performance at the baseline frequency condition compared to OFF STIM for walking speed, stride length and opposite foot contact parameter whereas the pr esent study highlighted better performance at 60Hz. This contrast could be due to a difference in the waiting time (3 hours vs. 10 minutes) between switching the stimulator on and performing gait evaluation. However, the randomized approach described in the current study should account for some of these differences. The order of the conditions tested was randomized along with the order of trials during each testing condition. Thus the gait trials were performed after different times after switching the stim ulator on. This time range varied between 15 minutes to 30 minutes. Researchers have found significantly faster walking speed during high frequency stimulation compared to the OFF STIM condition (Liu et al., 2005, Carpinella et al., 2007). Absence of such difference in the current study could be due to the higher value of walking speed during OFF STIM (91cm/s) compared to aforementioned studies (58 68 cm/s). This difference during the OFF STIM condition could be attributed to different patient characteristi cs or

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110 difference in methodologies. Besides, the present studys cohort could be relatively more functionally ambulant. Notably, the value of walking speed at 60Hz in the present study was nonsignificantly greater than the walking speed at baseline frequency in all the studies. However, the cadence values were similar across all the conditions in the present study and the study by Liu and colleagues (2005). Previously, researchers have attributed the increase in walking velocity due to high frequency STN DB S to either increase in stride length (Faist et al., 2001), cadence (Stolze et al., 2001) or step length (Allert et al., 2001). The significantly faster velocity at 60Hz compared to 30Hz across the three voltage levels could be concomitant to significantly longer stride and step lengths. No such propositions about faster gait speed at 60Hz could be made to the results relative to specific aim 1. However, the stride length, cadence and step length nonsignificantly increased at 60Hz compared to the other conditions. Allert and colleagues (2001) mentioned that differences in cadence between OFF STIM and ON STIM are more visible for GPi stimulation compared to STN stimulation. Faist and colleagues (2001) mentioned that in PD patients, stride length could increase to the values of their age matched healthy peers by visual cues or attentional strategies for at least two hours but regresses after one day. Validity of this explanation in the context of present study is speculative as increases in stride length were found only for results pertaining to second day of testing rather than first day. Each day included about four hours of testing time and the difference between the last condition on the first day and first condition on the second day was about 20 hours. A smaller sample size in the current study could explain some of the nonsignificant results. Also, different patient characteristics (mean age) and/or methodologies (post operation testing time/waiting

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111 period after stimulator was switched on/data collection/analyses procedure) could highlight some of the differences observed in the previous studies between the OFF STIM condition and baseline frequency condition and the absence of those results in the current study In spite of these differences, 60Hz stimulation seems to be the most fruitful stimulating frequency for walking among this subset of people with PD. Calculations of gait variability for specific aim 1 showed that during the 60Hz condition, the participants had the least variability concerning the opposite foot contact parameter. A similar result ensued during analyses related to specific aim 2. Frequency main effects showed low variability across the 60Hz conditions compared to the 30Hz conditions. The percentage of time during the gait cycle when t he swing leg strikes the ground is a summation of the double support phase before the swing leg takes off and the single limb support phase of the stance leg. However, neither of these variables including their coefficients of variation was significantly d ifferent among the four conditions. Moreover, these values were averaged across both the legs. An independent observation of these variables for both the legs could provide more insight into the performance of the effected side leg and unaffected side leg. Calculations of gait variability for specific aim 2 showed that interaction for variability of opposite foot off parameter. However, the change in values among the three conditions at both the low frequencies (30Hz and 60Hz) seemed too small (<5%) for biomechanical consideration. The opposite foot off parameter denotes the instance in gait cycle when the contralateral foot takes off for the next step. Before the opposite foot off event happens, the body is in double stance phase. Hence an increase in variability for the opposite foot off parameter could indicate an increase in the corresponding double support phase.

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112 Since there are two double support phases in each gait cycle, an individual analysis of this parameter for each leg could give evaluate the tim e spent in each double support phase. Previous researchers have mentioned that stride time variability is a consistent feature of Parkinsonian gait and is associated with falls among people with PD ( Nieuwboer et al., 2001; Hausdorff et al., 2003; Schaafsma et al., 2003; Frenkel Toledo et al., 2005; Baltadjieva et al., 2006). Separately, Hausdorff and colleagues (2009) recorded reduced gait variability and lower UPDRS score during ON STIM, ON MED condition but failed to detect a parallel reduction of gait variability in spite of lower UPDRS scores during ON STIM, OFF MED condition compared to OFF STIM/OFF MED condition. There was no change in stride time variability with frequency or voltage stimulation in the current study. However, the present studys cohort showed larger stride time variability values but similar swing time variability values compared to Hausdorff et al., (2009). Difference in methodologies including longer gait trial and waiting time after switching on the stimulator could explain part of the distinction between the results of Hausdorff et al., (2009) and results of the present study. Mbourou and colleagues (2003) associated falls among PD with a stride length variability greater than 7%. Though stride length variability in the cur rent study neither changed significantly with frequency nor with voltage, a borderline (close to 7%) high coefficient of variation for stride length was observed during the OFF STIM condition (6.9%). With the stimulator ON, lower values were observed for baseline frequency (5.5%), 30Hz (4.4%) and 60Hz (4.1%). Further, use of maximum tolerable voltage seemed to have a deteriorating effect on the stride length variability with the values

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113 exceeding 7% during both 30Hz and 60Hz conditions with the deteriorating effect more pronounced at 30Hz. Better gait performance at 60Hz observed in the present study also echoed some of the previous findings by Moreau and colleagues (2008) who used the Stand Walk Sit test to ascertain their results in terms of time taken and number of steps required for task completion. Though the physiological mechanisms behind the functioning of DBS are still being studied, researchers have speculated the effect of proximity and role of the PPN to the STN target. The PPN is located within a distance of 5mm from the STN and has projections into the basal ganglia nuclei. Along with the dopaminergic cell loss in the substantia nigra, people with PD also experience cell loss in the PPN. Several researchers have theorized that the PPN receives GA BAergic inhibitory input in the aminobutyric acid from GPi and substantia nigra (Stolze et al., 2001; Takakusaki et al., 2009). These subnuclei in turn receive excessive excitatory glutamergic input from the STN in PD. STN DBS would cause less excitation of GPi and substantia nigra and consequent disinhibition of PPN. Indeed, Breit et al. (2001) used 6OHDA lesioned rats to demonstrate normalization of overactive PPN activity after lesioning the STN. Also earlier studies have shown the propensity of this PPN to positively respond to low frequency stimulation (< 25Hz) in terms of motor performance (Stefani et al., 2007; Pereira et al., 2008). One theory put forth is that when high stimulation frequencies are used for STN, it produces negative effec ts of distribution of current to the surrounding areas including PPN. Hence s ome of the positive effects of 60Hz stimulation on gait performance could be explained using activity near PPN. However, when using 30Hz frequency at STN, presumably not enough c urrent is being

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114 discharged to PPN to produce similar ameliorating effects of gait. Some researchers observed improvement in gait parameters only during ON STIM/OFF MED condition but not during OFF STIM/ON MED condition (Allert et al., 2001). Based on this, they suggested the possible action of STN stimulation on non dopaminergic pathways. Garcia Rill (1986) reviewed the role of the basal ganglia and motor cortex in postural control and locomotion through their projections into the PPN and Midbrain Locomotor Region (MLR) They proposed that the descending output of the PPN/MLR could be cholinergic in nature and could directly be under the influence of STN. The MLR is also known to modulate spinal locomotion oscillators which play an active role for the automation of the rhythmicity of locomotion (GarciaRill, 1986; Dietz et al., 1994). The presence of pathways from STN to PPN/MLR as well as the functional role of these regions in posture and locomotion could highlight the influence of DBS through nondopaminer gic pathways. In fact, the role of basal ganglia in motor control was discussed elaborately by Morris and colleagues (1996). They observed that the basal ganglia nuclei relay messages to the SMA prior to initiation of movement. Once the movement starts, th ere appears to be a cessation of neuronal activity inside the SMA and subsequent periodic outputs from basal ganglia to SMA were found at the end of sequential submovements (Mushiake et al., 1990; Brotchie et al., 1991a, b) Brotchie and colleagues (1991a, b) also observed this phenomenon for sub movements of well learned activities but not for novel tasks. Impairment in this periodic outburst from basal ganglia to SMA could thus lead to an abnormal phasic execution of submovements like cadence during ga it and the therapeutic effect of DBS could partly restore the normalcy of such neuronic outputs from basal ganglia to SMA. Aziz et al. (1998) suggested that

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115 cadence could be monitored by locomotor regions of the midbrain and spinal regions. Morris and col leagues (1996) also discussed an alternate mechanistic action of basal ganglia through motor control of whole gait sequence as opposed to periodic outputs to SMA. Reduced spatial parameters like stride length have been attributed to this second mechanism. Faist and colleagues (2001) mentioned that the restoration of stride length to normal values with attentional or visual cues among PD might suggest the intactness of alternate pathways monitoring the spatial features of gait. They also postulated that STN stimulation might reduce the disturbances to these alternate pathways, thus enabling patients to execute longer strides and steps. Hence, the action of low frequency STN stimulation at 60Hz seems to affect multiple efferent outputs of basal ganglia. DeLong and Wichmann (2007) mentioned that the features seen in PD could partly be attributed to reduced neuronal discharge rate from basal ganglia and/or band (10 to 25 Hz). However, Brown and Williams (2005), mentioned that with Levodopa or high frequency DBS, these neuronal oscillations increased to 60 to 80Hz. Similarly, the 60Hz DBS stimulation may have produced altered pattern changes in the neuronal output of the STN. Thus results of the present study for gait analysis show a therapeutic advantage of using 60Hz stimulation. This was particularly highlighted by a faster gait velocity and reduced stride length variability scores at 60Hz compared to other conditions. Efferent pathways from basal ganglia nuclei to different regions like SMA, PPN and midbrain locomotor region seem to regulate the locomotion and its rhythmic nature better at 60Hz compared to the baseline condition and the OFF STIM condition. Voltage variation

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116 again seemed futile for improvem ent in gait characteristics at a low frequency (30/60Hz). UPDRS Part III (Total Score and Sub Scores) Modification of frequency and voltage resulted in substantial change in the total UPDRS motor score (excluding rigidity) and some of its components. Diff erences between the OFF STIM and ON STIM conditions were along the expected lines with the participants performing poorly with the stimulator off. Though no major differences for the total UPDRS motor score were spotted between the three frequency settings (for specific aim 1), the scores during ON STIM conditions were on an average only 9% lower than the total score during the OFF STIM state. Bradykinesia forms a major part of this total UPDRS motor score. The subscores of bradykinesia were highest (worst ) for the OFF STIM condition. Participants exhibited slightly lesser bradykinetic movement at the 60Hz stimulation compared to the other two ON STIM conditions. Though not significant, the bradykinesia subscore dropped by about 14% from OFF STIM condition to 60Hz condition. Evaluated by an investigator who was not blinded to the settings, greater rigidity scores were seen during the OFF STIM condition compared to the three similar ON STIM conditions (by about 27%). Interestingly, the scores for the speech component showed opposite trend as they increased from OFF STIM condition to low frequency conditions (30Hz and 60Hz) to the high frequency baseline condition. Results for the functions of the cephalic body segments signaled a worsening of performance as t he frequency was increased at baseline voltage. However, at 30Hz, when the voltage was increased to HV, the speech subscore improved to the OFF STIM speech subscore. A corresponding increase in voltage at 60Hz from BV to HV resulted in further worsening of the speech subscore. When the voltage was increased

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117 from HV to MV, the speech score worsened at 30Hz. Conversely, at 60Hz, a voltage increase from HV to MV resulted in the lowest (best) speech subscore among results of both specific aims. These result s suggest that speech modulation depends on both frequency and voltage parameters of STN DBS. Results related to specific aim 2 showed increased (worsened) tremor subscore for the 30Hz conditions. Further inspection of values showed that the tremor worsened at a combination of 30Hz and MV. Among the non significant outcome measures, the subjective UPDRS rating showed poor postural stability scores for the 60Hz condition when compared to the other three conditions. However an opposite trend was seen in the objective analysis using eyes open and eyes closed conditions. This contrast further highlights the importance of objective analyses in clinical settings when possible to implement. UPDRS is vastly used as the primary assessment tool for people with PD. However, the UPDRS evaluation is subjective in nature and could vary between observers. One way to counter this subjectivity is to introduce objective ways of evaluating the PD patients. However, due to the limitation of the time factor involved in clinical settings, the objective evaluation methods are seldom employed. In comparison to previous studies (Kumar et al., 1998; Tabbal et al., 2007; Karimi et al., 2008) limited improvement in especially in the tremor, bradykinesia, rigidity, gait and postural stability during ON STIM states of the present study could be attributed to a relatively high functional study cohort during OFF STIM condition. This is also in line with the static balance, dynamic balance and gait analyses results. By seeing the effect of c hanging the electrical parameters on UPDRS motor scores, Moro et al. (2002) stated that the combination of highest voltage and narrowest pulsewidth was the most important factor. The results of

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118 the present study differed from this idea. This could be due to differences in the methodology of different waiting times for stimulation and formula used for calculating higher voltage to maintain equivalent TEED. Karimi et al., (2008) proposed that an increase in blood flow to the thalamus correlated to improvement in bradykinesia and a decrease in blood flow correlated to improvement in rigidity after high frequency STN DBS. Similar studies using PET studies could highlight the effect of low frequency stimulation as well. Also, t hough not measured in th e current study, higher scores of rigidity and bradykinesia during the OFF STIM condition would have resulted in improper upper and lower limb coordination and/or interlimb coordination during steady state gait (Winogro dzka et al., 2005; Carpinella et al., 2007). Usi ng the quantitative outcome of work, Shapiro and colleagues (2007) showed the beneficial effects of STN DBS on reducing rigidity when compared to OFF STIM condition with no medication. Delwaide and colleagues (1991) suggested that the important mechanism for rigidity at spinal level is the reduction of autogenic inhibition via the Spinal Ib interneurons. These interneurons have been shown to be present in the descending pathways from tegmentum and reticular formation and irregular functioning of the basal ganglia in PD has been hypothesized to indirectly influence the functioning of these interneurons (Delwaide et al., 2000). Shapiro et al. (2007) further elaborated that the STN DBS has been shown to reduce this rigidity as well as restore the abnormally r educed autogenic inhibition. However the absence of any correlation between the reduction in rigidity and reduction in autogenic inhibition highlights the uncertain neural mechanisms produced by the stimulation (Potter et al., 2004; Shapiro et al., 2007). This appears to hold for high frequency as well as low

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119 frequency stimulation owing to the lack of rigidity subscore differences between the three frequency settings. Greater scores for speech component during UPDRS testing could indicate hypophonia and/or dysarthria. Previous researchers have also observed a negative effect of high frequency stimulation on hypophonia and dysarthria among PD patients (Volkmann et al., 2001; Romito et al., 2003). In fact, Romito and colleagues (2003) associated hypophonia wi th Levodopa retraction owing to the improvement in the symptom with increase in medication. Low frequency stimulation (30Hz or 60Hz) seems to have an intermediate effect when compared to OFF STIM and high frequency. While the subscores of rigidity and br adykinesia seemed to be the least at 60/30Hz, the subscores for speech were greater when compared to OFF STIM. However, positive effects of increasing the voltage at low frequency conditions were visible for improving the speech component. Correlations with Total Electrical Energy Delivered (TEED) per second Significant correlations of dependent measures from static balance, dynamic balance, gait with TEED showed one common theme: better performance with an increase in the TEED. For instance, among the static balance variables, lower values of ML CoP range, AP CoP range and sway area under both eyes open and eyes closed trials were observed for higher energy levels. Among the GI related variables, longer medial CoP displacement during weight shifting phase, maximum AP and resultant CoP CoM moment arm in locomotion phase, faster swing leg step velocity and minimal coefficient of variation of stance leg step length resulted for higher energy levels. Among the gait parameters, the double support time decreased with an increase in TEED. Shorter duration of double support time could indicate faster movement as well as longer single support time which are indicators for better postural control during gait.

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120 For most of the variables, the 60Hz/30Hz stimulations at baseline voltage showed the most beneficial effect. Negligible improvements were recorded with an increase in voltage at these frequencies. The TEED is a function of the frequency, pulse width, square of the voltage and inverse of the impedance. In spite of being directly related to the square of voltage, feeble changes in the outcome measures with voltage alteration was contrary to the expectations. However, the weak to mild significant correlations with TEED for different measures probably shows that an inc rease in pulse width and/or decrease in impedance resulting in an increase in the TEED could also highlight some better postural and locomotion characteristics. Moro and colleagues (2002) mentioned that while an increase in pulse width could enhance tremor control, it could also result in more sideeffects. So using more TEED per second could come at an economic expense dealing with shorter battery life of the transmitters and frequent replacements. Recently, Isaias and colleagues (2009) reported that using low stimulation energy for DBS of GPi was associated with longer battery life among patients with primary generalized dystonia. Stimulation energy was lowered through a combination of lower frequency and shorter pulse width. Also, the ineffectiveness of h igh energy stimulation to significantly improve the clinical outcomes among dystonia patients on a long term basis have been previously reported (Alterman et al., 2007; Vercueil et al., 2007; Isaias et al., 2009). Though the present study dealt with the PD population, similar limited effect of TEED was observed on the clinical UPDRS part III related scores. Moreau et al. (2008) showed that high voltage at high frequency (i.e. high stimulation energy level) negatively impacted the gait among PD patients who underwent STN DBS. They also showed a positive effect of using high voltage at 60Hz on reduction of freezing

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121 episodes. The high voltage that Moreau and colleagues (2008) used was based on matching the total electrical energy delivered during baseline condi tion. The current study did not focus on freezing among PD and hence cannot comment on similarity of observations with Moreau et al. (2008) study. In summary, low frequency stimulation of either 30Hz or 60Hz seems to impart equivalent effects of high frequ ency stimulation and could possibly help in enhancing the longevity of the internal pulse generator used in DBS. Non motor S ymptoms and Observations: Autonomic symptoms like excessive sweating, diplopia, oscillopsia were observed mainly when the voltage was tuned just beyond the maximum tolerable level. After the final testing session, two out of the ten participants volunteered to try new low frequency settings outside the laboratory. While one participant tried the new low frequency setting that helped hi m to be more vocal, he returned after two days to go back to his baseline settings owing to some disabling motor symptoms affecting his activities of daily living. However, the other person who also tried the new low frequency setting is still currently us ing those stimulation parameters as she perceived that it gave her clarity of thought. Thus, nonmotor symptoms also need greater attention while evaluating PD patients using low frequency STN DBS. Subjective Feedback Scale The subjective feedback scale did not show pronounced variations among ON STIM settings. As expected, most of the participants felt worst during OFF condition. Values in the scale also suggest that the general feeling during most of the ON STIM conditions remained the same for each participant.

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122 Limitations 1. A review of literature shows the possibility of the effect of optimal electrode placement on motor features among individuals with PD. Herzog and colleagues (2004) suggested that the dorsolateral border zone of the STN was the most efficient site for DBS stimulation. Johnsen et al. (2010) further purported this by showing superior gait performance in people whose dorsal STN was stimulated as compared to ventral STN. The influence of localization of electr ode placement on the results of the current study is unknown. However, the focus of this study has been to evaluate the efficacies of using low frequency stimulation. Once the effectiveness of low frequency stimulation is established, localization of elec trode placement can act as a future evaluation step. 2. The waiting time of 10 minutes between each condition could have had a carry over effect of the previous condition. However, due to the longevity of the protocol (four hours each day for two days), this waiting time was adopted in order to minimize the effect of fatigue on the performance of the participants. Also, apart from UPDRS, the other tasks were randomly performed in order to neutralize such carry over effects. Though Temperli et al. (2003) postul ated a 3 hour waiting time for the effects of DBS to fade off, absence of a gold standard methodology may explain some of the variability in the results of different studies. 3. Changes in many variables in the current study showed statistical trend. This could have been partly due to a smaller sample size of this study. However, sample size of the current study was justified based on the sample size used in some of the previous studies which focused on evaluating the effects of DBS. 4. Analyses of the results of current study and comparison with earlier studies indicate that the present study cohort was more functional in their OFF STIM/OFF MED state, thus leading to the absence of commonly observed differences between OFF STIM and ON STIM conditions. Conclusio n Researchers have demonstrated the prominence of spinal level movement centers in generating rhythmic successive movements while the amplitude of those movements have been associated with higher cortical levels (Plotnik et al., 2007). Activities like the locomotion phase of gait initiation, gait and hand movements to test bradykinesia involve repetitive rhythmic movements of certain body parts. Results from the spatiotemporal parameters of gait initiation, gait and UPDRS bradykinesia subscore could

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123 poss ibly indicate better communication and activation of pathways between the higher cortical levels and the spinal centers at 60Hz stimulation. Crenna and colleagues (2006) suggested that the effect of high frequency (> 100Hz) stimulation was more evident for locomotion based motor tasks which are predominantly controlled by lower hierarchical levels of the central nervous system. Results from the current study seemed to support or extend this observation for lower frequency stimulation of 60Hz as well with more significant results seen during the dynamic gait initiation and gait compared to the static and anticipatory postural control. Results from the current study also show the efficacy of 60Hz stimulation in enhancing postural control and locomotion. In mos t cases, the values of the outcome measures at 60Hz stimulation were equal if not better than the baseline (high) frequency condition. Though the best results werent always obtained, use of 60Hz stimulation might optimize the performance across various domains as well as optimize the usage of the stimulator in terms of its battery life. Longterm effects of 60Hz stimulation need to be verified for full scale implementation.

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124 Future Considerations 1. The synergistic effect of combining Levodopa medication and low frequency (< 100Hz) stimulation could be evaluated. High frequency stimulation has been shown to restore some of the negative effects of Levadopa on postural control (Rocchi et al., 2002). Whether such ameliorating effects are possible when low frequency stimulation is combined with L dopa medication warrants further examination. This would also help to ascertain if low frequency DBS also influences nondopaminergic pathways. 2. Entropy based estimations of CoP during bipedal standing could perhaps shed m ore light onto the effects of these low frequency stimulations at different voltages 3. Change in motor programs during activities of bipedal standing, initiation of gait and gait with low frequency stimulation and at different voltages could be studied usi ng EMG techniques. This has the potential to elaborate more on the neuromuscular interpretations of some of the results observed in the current study. 4. In spite of acute amelioration of gait performance following high frequency STN DBS, several studies have reported degradation of performance in longterm (Krack et al., 2003; Rodriguez Oroz et al., 2005; Schubpach et al., 2005; van Nuenen et al., 2008). Sustenance of these acute beneficial effects of low frequency stimulation over longterm has to be pursued. 5. The effect of low frequency stimulation on the dorsal STN border in terms of gait and postural stability can be evaluated as a low frequency of 60Hz seems to have more beneficial effect s on these motor aspects compared to currently used high frequency st imulation. 6. Micro electrode recordings during STN DBS using low frequency stimulation could offer some insight into the probable mechanisms of DBS. Though the low frequency stimulation showed equivalent if not better results compared to high frequency stimulation, examining the neuronal activity could reveal either better neuronal firing rates or reduced irregular oscillatory pattern of neuronal activity in STN. 7. Studies evaluating long term effects of low frequency stimulation need to be performed to estimate its effectiveness in improving the quality of life among people with PD. Further, its effect on nonmotor symptoms also needs to be evaluated.

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125 APPENDIX: STATISTICAL ANALYSES TABLES Table A 1 MANOVA test results of frequency main effect for trials related to Specific Aim 1. Trial Dependent Variable(s) Effect Statistical Parameters Eyes Open AP and ML range, Sway area, RMS AP and ML displacement, RMS AP and ML velocity Frequency Main Effect F (21.00,60.85) = 1.52, P = 0.110 Eyes Closed AP and ML range, Sway area, RMS AP and ML displacement, RMS AP and ML velocity Frequency Main Effect F (21.00,60.85) = 0.84, P = 0.660 GI (CoP measures) CoP displacement and velocity in AP and ML directions, in the three phases (S1, S2, S3) Frequency Main Effect F (36.00,48.00) = 1.36, P = 0.160 GI (CoP CoM measures) Maximum CoP CoM separation distance in AP, ML and resultant directions in directions, in the three phases (S1, S2, S3) Frequency Main Effect F (27.00,56.13) = 1.60, P = 0.069

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126 Table A 1. Continued Trial Dependent Variable(s) Effect Statistical Parameters GI (Spatiotemporal measures) Step length, step velocity, step time, time to heel rise, toe off and heel strike of swing and stance legs. Frequency Main Effect F (33.00,50.79) = 1.83, P = 0.026* GI (Variability of Spatiotemporal measures) CV of Step length, step velocity, step time, time to heel rise, toe off and heel strike of swing and stance legs. Frequency Main Effect F (33.00,50.79) = 1.07, P = 0.403 Gait (Spatiotemporal measures) Cadence, walking speed, stride and step time, opposite foot off, opposite foot contact, foot off, single support and double support time, stride and step length Frequency Main Effect F (33.00,50.79) = 1.08, P = 0.399 Gait (Variability of Spatiotemporal measures) CV of Walking Speed, Cadence, stride and step time, opposite foot off & contact, foot off, single & double support time, stride & step length Frequency Main Effect F (33.00,50.79) = 1.15, P = 0.320

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127 Table A 1. Continued Trial Dependent Variable(s) Effect Statistical Parameters UPDRS Part III Tremor, bradykinesia, posture, gait, balance, speech, facial expression, total score, rigidity Frequency Main Effect F (24.00,58.61) = 1.68, P = 0.055 Significant difference ( P < 0.05); AP Anterior Posterior direction, ML MedioLateral direction, RMS Root Mean Square, CoP Center of Pressure, CoM Center of Mass, CV Coefficient of Variation, UPDRS Unified Parkinson Disease Rating Scale, MANOVA Multiple Analyses of Variance Table A 2 Descriptive statistics and Univariate test results for Center of Pressure related balance measures from Eyes Open trials related to Specific Aim 1. Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power Medio lateral range (cm) Off 3.1 (0.7) F(3,27) = 0.20 0.895 0.02 0.08 30Hz 3.4 (0.5) 60Hz 3.4 (0.6) Baseline 3.2 (0.5) Antero posterior range (cm) Off 5.0 (0.5) F(3,27) = 3.22 0.038 0.26 0.68 30Hz 4.1 (0.4) 60Hz 4.0 (0.4) Baseline 4.3 (0.5) Sway area (square cm) Off 17.74 (5.99) F(3,27) = 0.17 0.956 0.01 0.07 30Hz 15.72 (3.84) 60Hz 16.25 (4.71) Baseline 15.76 (4.36) RMS medio lateral displacement (cm) Off 0.23 (0.03) F(3,27) = 1.43 0.256 0.14 0.34 30Hz 0.24 (0.03) 60Hz 0.25 (0.03) Baseline 0.25 (0.03) RMS antero posterior displacement (cm) Off 0.35 (0.07) F(3,27) = 0.55 0.652 0.06 0.15 30Hz 0.35 (0.07) 60Hz 0.39 (0.08) Baseline 0.38 (0.08)

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128 Table A 2. Continued Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power RMS medio lateral velocity (cm/s) Off 81.4 (11.1) F(3,27) = 1.47 0.244 0.14 0.35 30Hz 83.9 (10.1) 60Hz 89.4 (11.5) Baseline 89.5 (11.7) RMS antero posterior velocity (cm/s) Off 24.0 (3.8) F(3,27) = 0.45 0.720 0.05 0.13 30Hz 24.1 (4.1) 60Hz 26.6 (4.7) Baseline 25.4 (4.7) Significant difference ( P < 0.05); Statistical Trend (0.05 <= P <= 0.07); SE Standard Error, RMS Root Mean Square, cm centimeter, s second, Hz Hertz Table A 3 Descriptive statistics and Univariate test results for Center of Pressure related balance measures from Eyes Closed trials related to Specific Aim 1. Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power Medio lateral range (cm) Off 3.3 (0.6) F(3,27) = 0.36 0.780 0.04 0.11 30Hz 3.2 (0.5) 60Hz 3.7 (0.5) Baseline 3.5 (0.6) Antero posterior range (cm) Off 5.3 (0.4) F(3,27) = 1.08 0.375 0.11 0.26 30Hz 4.7 (0.3) 60Hz 4.8 (0.4) Baseline 5.0 (0.4) Sway area (square cm) Off 18.93 (4.64) F(3,27) = 0.34 0.956 0.04 0.11 30Hz 16.05 (3.22) 60Hz 19.04 (3.56) Baseline 19.54 (5.55) RMS medio lateral displacement (cm) Off 0.23 (0.03) F(3,27) = 2.62 0.071 0.23 0.58 30Hz 0.23 (0.03) 60Hz 0.25 (0.03) Baseline 0.26 (0.03)

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129 Table A 3. Continued Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power RMS antero posterior displacement (cm) Off 0.35 (0.06) F(1.57,14.15) = 0.55 0.550 0.06 0.17 30Hz 0.36 (0.07) 60Hz 0.39 (0.08) Baseline 0.39 (0.08) RMS medio lateral velocity (cm/s) Off 80.6 (10.8) F(3,27) = 2.56 0.076 0.22 0.57 30Hz 83.4 (10.2) 60Hz 89.8 (11.6) Baseline 91.3 (11.5) RMS antero posterior velocity (cm/s) Off 23.9 (3.4) F(1.56,13.99) = 0.46 0.591 0.05 0.11 30Hz 24.5 (4.2) 60Hz 26.2 (4.6) Baseline 26.4 (4.6) No significant differences for any measures; SE Standard Error, RMS Root Mean Square, cm centimeter, s second, Hz Hertz Table A 4 Descriptive statistics and Univariate test results for Center of Pressure related measures during Gait Initiation related to Specific Aim 1. Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power Medio lateral displace ment in S1 phase (cm) Off 1.3 (0.4) F(3,27) = 0.06 0.982 0.01 0.06 30Hz 1.3 (0.2) 60Hz 1.3 (0.2) Baseline 1.2 (0.2) Antero posterior displace ment in S1 phase (cm) Off 1.2 (0.4) F(3,27) = 0.11 0.954 0.01 0.07 30Hz 1.2 (0.2) 60Hz 1.3 (0.3) Baseline 1.4 (0.4) Medio lateral displace ment in S2 phase (cm) Off 10.2 (0.6) F(1.46,13.13) = 0.40 0.613 0.04 0.12 30Hz 10.7 (0.6) 60Hz 10.1 (0.9) Baseline 10.4 (0.7)

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130 Table A 4. Continued Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power Antero posterior displace ment in S2 phase (cm) Off 0.6 (0.6) F(3,27) = 0.20 0.899 0.02 0.08 30Hz 0.4 (0.8) 60Hz 0.5 (0.6) Baseline 0.8 (0.7) Medio lateral displace ment in S3 phase (cm) Off 0.7 (0.5) F(3,27) = 2.33 0.097 0.21 0.52 30Hz 0.2 (0.5) 60Hz 0.0 (0.5) Baseline 0.2 (0.5) Antero posterior displace ment in S3 phase (cm) Off 14.3 (0.9) F(3,27) = 1.87 0.159 0.17 0.43 30Hz 15.2 (1.3) 60Hz 14.8 (1.1) Baseline 14.1 (1.2) Medio lateral velocity in S1 phase (cm/s) Off 5.0 (1.1) F(3,27) = 0.22 0.884 0.02 0.09 30Hz 4.9 (0.7) 60Hz 4.4 (0.7) Baseline 4.9 (0.8) Antero posterior velocity in S1 phase (cm/s) Off 4.9 (1.2) F(3,27) = 0.59 0.627 0.06 0.16 30Hz 4.2 (1.0) 60Hz 4.7 (0.8) Baseline 5.6 (1.4) Medio lateral velocity in S2 phase (cm/s) Off 17.0 (2.4) F(1.48,13.31) = 3.24 0.083 0.27 0.46 30Hz 20.5 (2.5) 60Hz 19.8 (2.5) Baseline 14.4 (3.6)

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131 Table A 4. Continued Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power Antero posterior velocity in S2 phase (cm/s) Off 0.2 (1.1) F(3,27) = 0.02 0.998 0.00 0.05 30Hz 0.0 (1.5) 60Hz 0.2 (1.2) Baseline 0.2 (1.1) Medio lateral velocity in S3 phase (cm/s) Off 1.1 (0.8) F(3,27) = 1.30 0.294 0.13 0.31 30Hz 0.4 (0.8) 60Hz 0.2 (0.8) Baseline 0.4 (0.8) Antero posterior velocity in S3 phase (cm/s) Off 20.1 (1.9) F(1.65,14.86) = 4.64 0.033 0.34 0.64 30Hz 25.4 (2.4) 60Hz 23.4 (2.3) Baseline 23.5 (2.6) Significant difference ( P < 0.05); SE Standard Error, cm centimeter, s second, Hz Hertz; negative value indicates movement in either posterior or medial direction

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132 Table A 5 Descriptive statistics and Univariate test results for Center of Pressure (CoP) and Center of Mass (CoM) related measures during Gait Initiation related to Specific Aim 1. Table A 5. Continued Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power ML CoP CoM distance in S1 phase (cm) Off 1.6 (0.3) F(3,27) = 0.12 0.945 0.01 0.07 30Hz 1.6 (0.2) 60Hz 1.6 (0.3) Baseline 1.7 (0.2) AP CoP CoM distance in S1 phase (cm) Off 1.5 (0.4) F(3,27) = 1.88 0.157 0.17 0.43 30Hz 1.6 (0.4) 60Hz 1.8 (0.4) Baseline 2.0 (0.4) Resultant CoP CoM distance in S1 phase (cm) Off 2.2 (0.5) F(3,27) = 1.02 0.401 0.10 0.25 30Hz 2.4 (0.4) 60Hz 2.4 (0.5) Baseline 2.7 (0.5) ML CoP CoM distance in S2 phase (cm) Off 5.0 (0.4) F(1.09,9.80) = 1.90 0.200 0.17 0.25 30Hz 7.3 (1.4) 60Hz 5.3 (0.4) Baseline 5.4 (0.5) AP CoP CoM distance in S2 phase (cm) Off 5.0 (0.8) F(3,27) = 2.29 0.101 0.20 0.51 30Hz 6.1 (0.6) 60Hz 6.1 (0.9) Baseline 6.6 (1.0) Resultant CoP CoM distance in S2 phase (cm) Off 7.2 (0.7) F(1.26,11.31) = 2.02 0.183 0.18 0.28 30Hz 9.8 (1.3) 60Hz 8.2 (0.7) Baseline 8.6 (0.9)

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133 Significant difference ( P < 0.05); SE Standard Error, ML MedioLateral, AP Antero Posterior, cm centimeter, Hz Hertz Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power ML CoP CoM distance in S3 phase (cm) Off 11.0 (1.0) F(1.32,11.83) = 1.71 0.220 0.16 0.25 30Hz 12.1 (1.7) 60Hz 9.9 (1.1) Baseline 10.3 (1.2) AP CoP CoM distance in S3 phase (cm) Off 15.5 (2.2) F(3,27) = 4.41 0.012 0.33 0.82 30Hz 17.2 (1.9) 60Hz 18.5 (2.3) Baseline 18.1 (2.1) Resultant CoP CoM distance in S3 phase (cm) Off 19.5 (2.0) F(3,27) = 1.99 0.139 0.18 0.46 30Hz 22.1 (1.6) 60Hz 21.5 (2.0) Baseline 21.1 (2.0)

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134 Table A 6 Descriptive statistics and Univariate test results for SpatioTemporal measures during Gait Initiation related to Specific Aim 1. Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power Swing leg step length (cm) Off 37.5 (4.0) F(3,27) = 4.62 0.010 0.34 0.84 30Hz 43.5 (3.6) 60Hz 44.7 (4.5) Baseline 42.4 (4.3) Stance leg step length (cm) Off 79.8 (6.2) *+ F(3,27) = 9.95 <0.001 0.53 0.99 30Hz 92.1 (6.0) 60Hz 94.4 (7.2) + Baseline 90.6 (6.4) Swing leg step time (s) Off 0.55 (0.02) F(3,27) = 2.42 0.088 0.21 0.54 30Hz 0.50 (0.02) 60Hz 0.51 (0.03) Baseline 0.51 (0.03) Stance leg step time (s) Off 0.69 (0.03) F(3,27) = 1.11 0.363 0.11 0.27 30Hz 0.66 (0.03) 60Hz 0.65 (0.03) Baseline 0.66 (0.03) Swing leg step velocity (cm/s) Off 71.2 (9.4) *+^ F(3,27) = 1 5.13 < 0.001 0.63 1.00 30Hz 89.1 (8.4) 60Hz 90.5 (10.3) + Baseline 85.6 (9.7) ^ Stance leg step velocity (cm/s) Off 121.7 (12.9) *+^ F(3,27) = 11.94 < 0.001 0.57 1.00 30Hz 144.4 (13.5) 60Hz 149.2 (15.1) + Baseline 140.9 (13.1) ^ Stance width (cm) Off 16.7 (0.4) F(3,27) = 1.37 0.273 0.13 0.32 30Hz 16.6 (0.4) 60Hz 17.5 (0.3) Baseline 17.5 (0.7) Time to swing leg heel rise (s) Off 0.87 (0.08) F(3,27) = 2.22 0.109 0.20 0.50 30Hz 0.83 (0.06) 60Hz 0.81 (0.08) Baseline 0.97 (0.10)

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135 Table A 6. Continued Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power Time to swing leg toe off (s) Off 1.62 (0.11) F(3,27) = 3.46 0.030 0.28 0.71 30Hz 1.43 (0.08) 60Hz 1.43 (0.10) Baseline 1.58 (0.12) Time to stance leg heel rise (s) Off 1.00 (0.08) F(3,27) = 2.68 0.067 0.230 0.59 30Hz 0.94 (0.07) 60Hz 0.93 (0.08) Baseline 1.10 (0.10) Time to stance leg toe off (s) Off 1.90 (0.14) F(3,27) = 3.57 0.027 0.28 0.73 30Hz 1.68 (0.10) 60Hz 1.69 (0.11) Baseline 1.84 (0.13) *+^ Significant difference ( P < 0.05); Statistical Trend (0.05 <= P <= 0.07); SE Standard Error, cm centimeter, s second, Hz Hertz

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136 Table A 7 Descriptive statistics and Univariate test results for Coefficient of Variation (CV) of the SpatioTemporal measures during Gait Initiation related to Specific Aim 1. Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power CV of swing leg step length (%) Off 10.43 (2.22) F(3,27) = 1.62 0.207 0.15 0.38 30Hz 8.02 (1.74) 60Hz 7.78 (1.50) Baseline 11.70 (3.14) CV of stance leg step length (%) Off 8.57 (2.00) F(3,27) = 1.95 0.145 0.18 0.45 30Hz 6.36 (0.95) 60Hz 4.93 (0.72) Baseline 6.14 (1.50) CV of swing leg step time (%) Off 14.59 (2.99) F(3,27) = 3.56 0.027 0.28 0.72 30Hz 8.44 (1.62) 60Hz 8.22 (1.35) Baseline 9.91 (1.64) CV of stance leg step time (%) Off 8.69 (1.73) F(3,27) = 0.44 0.728 0.05 0.13 30Hz 7.14 (1.22) 60Hz 7.08 (1.13) Baseline 6.84 (1.14) CV of swing leg step velocity (%) Off 16.66 (2.65) F(3,27) = 5.28 0.005 0.37 0.89 30Hz 8.48 (1.44) 60Hz 8.08 (1.36) Baseline 12.29 (2.12) CV of stance leg step velocity (%) Off 12.04 (2.59) F(1.61,14.49) = 3.25 0.076 0.27 0.48 30Hz 7.84 (0.79) 60Hz 5.85 (0.78) Baseline 8.04 (1.41) CV of stance width (%) Off 10.03 (5.17) F(1.74,15.63) = 0.30 0.714 0.03 0.09 30Hz 5.73 (0.94) 60Hz 8.43 (2.13) Baseline 11.92 (7.15)

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137 Table A 7. Continued Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power CV of time to swing leg heel rise (%) Off 29.83 (5.84) F(3,27) = 0.28 0.838 0.03 0.10 30Hz 26.73 (2.24) 60Hz 24.68 (4.48) Baseline 29.62 (5.62) CV of time to swing leg toe off (%) Off 18.65 (3.04) F(3,27) = 0.86 0.472 0.09 0.21 30Hz 15.53 (1.32) 60Hz 13.86 (2.01) Baseline 18.53 (3.20) CV of time to stance leg heel rise (%) Off 25.87 (4.17) F(3,27) = 0.25 0.863 0.03 0.09 30Hz 25.21 (2.33) 60Hz 21.75 (3.24) Baseline 25.43 (4.85) CV of time to stance leg toe off (%) Off 16.69 (2.88) F(3,27) = 0.70 0.563 0.07 0.18 30Hz 13.95 (1.42) 60Hz 12.84 (1.83) Baseline 16.69 (2.90) Significant difference ( P < 0.05); Statistical trend ( 0.05 <= P <= 0.07 ); SE Standard Error, Hz Hertz

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138 Table A 8 Descriptive statistics and Univariate test results for SpatioTemporal measures during Gait related to Specific Aim 1. Measure Frequency Seting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power Cadence (steps/minut e) Off 101 (3) F(3,27) = 1.83 0.165 0.17 0.42 30Hz 102 (3) 60Hz 105 (2) Baseline 105 (3) Walking speed (cm/s) Off 91.4 (7.6) F(3,27) = 3.49 0.029* 0.28 0.71 30Hz 96.3 (7.6) 60Hz 100.3 (7.2) Baseline 98.5 (6.8) Stride time (s) Off 1.20 (0.04) F(1.41,12.66) = 2.12 0.167 0.19 0.31 30Hz 1.18 (0.03) 60Hz 1.15 (0.02) Baseline 1.15 (0.03) Step time (s) Off 0.60 (0.02) F(1.41,12.67) = 1.75 0.213 0.16 0.26 30Hz 0.59 (0.02) 60Hz 0.58 (0.01) Baseline 0.58 (0.02) Opposite foot off (%) Off 16.87 (0.83) F(3,27) = 0.98 0.416 0.10 0.24 30Hz 16.44 (0.75) 60Hz 16.22 (0.55) Baseline 16.79 (0.63) Opposite foot contact (%) Off 50.20 (0.11) F(3,27) = 3.44 0.031 0.28 0.71 30Hz 49.76 (0.13) 60Hz 49.79 (0.15) Baseline 50.10 (0.14) Foot off (%) Off 66.99 (0.84) F(3,27) = 1.06 0.383 0.11 0.25 30Hz 66.50 (0.74) 60Hz 66.19 (0.54) Baseline 66.87 (0.62) Single support time (s) Off 0.40 (0.01) F(3,27) = 2.33 0.097 0.21 0.52 30Hz 0.39 (0.01) 60Hz 0.39 (0.01) Baseline 0.38 (0.01)

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139 Table A 8 Continued Measure Frequency Setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power Double support time (s) Off 0.41 (0.03) F(3,27) = 1.20 0.329 0.12 0.29 30Hz 0.39 (0.02) 60Hz 0.38 (0.02) Baseline 0.39 (0.02) Stride length (cm) Off 107.6 (6.6) F(3,27) = 1.96 0.144 0.18 0.45 30Hz 111.3 (6.2) 60Hz 113.7 (5.9) Baseline 111.9 (5.2) Step length (cm) Off 54.0 (3.3) F(1.81,16.32) = 1.82 0.196 0.17 0.31 30Hz 55.8 (3.0) 60Hz 57.1 (2.9) Baseline 56.2 (2.4) Significant difference ( P < 0.05); Statistical trend ( 0.05 <= P < 0.07); SE Standard Error, cm centimeter, s second, Hz Hertz

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140 Table A 9 Descriptive statistics and Univariate test results for Coefficient of Variation (CV) of Spatio Temporal measures during Gait related to Specific Aim 1. Measure Frequency Setting Mean (SE) Statistical Test F value P PES Observed Power CV of cadence (%) Off 4.27 (0.63) F(3,27) = 1.50 0.238 0.14 0.35 30Hz 4.20 (0.64) 60Hz 3.09 (0.43) Baseline 3.62 (0.34) CV of walking speed (%) Off 8.14 (2.09) F(1.21,10.86) = 1.82 0.208 0.17 0.25 30Hz 5.78 (0.79) 60Hz 4.57 (0.47) Baseline 6.29 (0.89) CV of stride time (%) Off 4.44 (0.91) F(3,27) = 1.13 0.354 0.11 0.27 30Hz 4.02 (0.54) 60Hz 3.10 (0.43) Baseline 3.61 (0.34) CV of step time (%) Off 5.19 (0.95) F(3,27) = 1.29 0.299 0.13 0.30 30Hz 4.95 (0.49) 60Hz 3.88 (0.59) Baseline 5.03 (0.54) CV of opposite foot off (%) Off 11.96 (3.06) F(1.27,11.41) = 0.47 0.554 0.05 0.10 30Hz 10.78 (1.27) 60Hz 9.25 (1.04) Baseline 10.22 (1.11) CV of opposite foot contact (%) Off 3.00 (0.29) F(3,27) = 4.03 0.017 0.31 0.78 30Hz 3.22 (0.19) 60Hz 2.28 (0.30) Baseline 2.80 (0.30) CV of foot off (%) Off 3.26 (0.79) F(1.42,12.74) = 0.95 0.382 0.10 0.16 30Hz 2.53 (0.21) 60Hz 2.35 (0.18) Baseline 2.82 (0.36) CV of single support time (%) Off 7.71 (1.43) F(3,27) = 1.68 0.195 0.16 0.39 30Hz 6.98 (1.04) 60Hz 5.33 (0.81) Baseline 5.69 (0.77)

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141 Table A 9. Continued Measure Frequency Setting Mean (SE) Statistical Test F value P PES Observed Power CV of double support time (%) Off 13.70 (5.51) F(1.14,10.28) = 0.57 0.489 0.06 0.11 30Hz 9.46 (1.17) 60Hz 9.60 (1.09) Baseline 9.81 (1.12) CV of stride length (%) Off 6.85 (2.30) F(1.43,12.85) = 1.04 0.356 0.10 0.17 30Hz 4.44 (0.85) 60Hz 4.12 (0.52) Baseline 5.46 (0.97) CV of step length (%) Off 8.04 (2.34) F(1.10,9.75) = 0.91 0.373 0.09 0.14 30Hz 6.32 (1.27) 60Hz 4.27 (0.54) Baseline 15.97 (10.24) Significant difference (P < 0.05); Statistical trend ( 0.05 <= P <= 0.07 ); SE Standard Error, Hz Hertz PES Partial Eta Squared

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142 Table A 10 Descriptive statistics and Univariate test results for Unified Parkinsons Disease Rating Scales Part III (Motor) evaluation subscores and total score related to Specific Aim 1. Measure Frequency Setting Mean (SE) Statistical Test F value P PES Obser ved Power Tremor sub score Off 2.4 (0.7) F(3,27) = 1.61 0.211 0.15 0.37 30Hz 2.3 (0.9) 60Hz 2.3 (1.2) Baseline 1.3 (0.7) Bradykinesia sub score Off 16.8 (1.8) F(3,27) = 3.04 0.046 0.25 0.65 30Hz 15.1 (1.3) 60Hz 14.5 (1.4) Baseline 15.1 (1.3) Posture sub score Off 0.9 (0.2) F(3,27) = 1.54 0.227 0.15 0.36 30Hz 0.8 (0.2) 60Hz 1.1 (0.2) Baseline 0.9 (0.2) Gait sub score Off 1.5 (0.3) F(3,27) = 1.00 0.408 0.10 0.24 30Hz 1.3 (0.2) 60Hz 1.3 (0.2) Baseline 1.3 (0.2) Balance sub score Off 0.5 (0.2) F(3,27) = 1.50 0.237 0.14 0.35 30Hz 0.1 (0.1) 60Hz 0.2 (0.1) Baseline 0.4 (0.2) Speech sub score Off 1.3 (0.3) F(3,27) = 3.86 0.020 0.30 0.76 30Hz 1.6 (0.3) 60Hz 1.6 (0.3) Baseline 1.8 (0.3) Facial Expression sub score Off 1.2 (0.2) F(3,27) = 0.64 0.594 0.07 0.17 30Hz 1.3 (0.2) 60Hz 1.2 (0.1) Baseline 1.3 (0.2) Total UPDRS Part III score Off 24.6 (2.5) F(3,27) = 3.23 0.038 0.26 0.68 30Hz 22.5 (2.1) 60Hz 22.2 (2.5) Baseline 22.1 (2.3)

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143 Table A 10. Continued Measure Frequency Setting Mean (SE) Statistical Test F value P PES Observed Power Rigidity sub score Off 9.1 (1.0) F(3,27) = 5.09 0.006 0.36 0.88 30Hz 6.6 (1.0) 60Hz 6.7 (1.0) Baseline 6.6 (0.8) Significant difference ( P < 0.05); Statistical trend ( 0.05 <= P <= 0.07 ); SE Standard Error, Hz Hertz, PES Partial Eta Squared, UPDRS Unified Parkinsons Disease Rating Scales Part III (Motor evaluation); All the subscores (except rigidity) and the total UPDRS score are from an investigator who was blinded to the settings. Also, total score does not include rigidity sub score.

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144 Table A 11 MANOVA tes t results of frequency and voltage interaction and main effects for trials related to Specific Aim 2. Trial Dependent Variable(s) Effect Statistical Parameters Eyes Open AP and ML range, Sway area, RMS AP and ML displacement, RMS AP and ML velocity Interaction Frequency Main Effect Voltage Main Effect F (14.00,20.00) = 0.69, P = 0.758 F (7.00,2.00) = 4.39, P = 0.198 F (14.00,20.00) = 1.51, P = 0.194 Eyes Closed AP and ML range, Sway area, RMS AP and ML displacement, RMS AP and ML velocity Interaction Frequency Main Effect Voltage Main Effect F (14.00,20.00) = 1.48, P = 0.208 F (7.00,2.00) = 1.15, P = 0.540 F (14.00,20.00) = 1.38, P = 0.250 GI (CoP measures) CoP displacement and velocity in AP and ML directions, in the three phases (S1, S2, S3) Interaction Frequency Main Effect Voltage Main Effect F (24.00,14.00) = 0.53, P = 0.918 F (9.00,1.00) = 3.56, P = 0.391 F (24.00,14.00) = 0.43, P = 0.966 GI (CoP CoM measures) Maximum CoP CoM separation distance in AP, ML and resultant directions in directions, in the three phases (S1, S2, S3) Interaction Frequency Main Effect Voltage Main Effect F (18.00,16.00) = 0.84, P = 0.113 F (8.00,1.00) = 2.06, P = 0.494 F (18.00,16.00) = 0.56, P = 0.886

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145 Table A 11. Continued Trial Dependent Variable(s) Effect Statistical Parameters GI (Spatiotemporal measures) Step length, step velocity, step time, time to heel rise, toe off and heel strike of swing and stance legs. Interaction Frequency Main Effect Voltage Main Effect F (22.00,16.00) = 0.50, P = 0.934 F (9.00,1.00) = 2.53, P = 0.456 F (22.00,16.00) = 0.70, P = 0.782 GI (Variability of Spatiotemporal measures) CV of Step length, step velocity, step time, time to heel rise, toe off and heel strike of swing and stance legs. Interaction Frequency Main Effect Voltage Main Effect F (22.00,16.00) = 1.01, P = 0.500 F (9.00,1.00) = 67.27, P = 0.094 F (22.00,16.00) = 1.13, P = 0.405 Gait (Spatiotemporal measures) Cadence, walking speed, stride and step time, opposite foot off, opposite foot contact, foot off, single support and double support time, stride and step length Interaction Frequency Main Effect Voltage Main Effect F (22.00,16.00) = 1.20, P = 0.359 F (9.00,1.00) = 98.34, P = 0.078 F (22.00,16.00) = 0.75, P = 0.738 Gait (Variability of Spatiotemporal measures) CV of Cadence, walking speed, stride & step time, opposite foot off & contact, foot off, single & double support time, stride & step length Interaction Frequency Main Effect Voltage Main Effect F (22.00,16.00) = 1.22, P = 0.347 F (9.00,1.00) = 1.62, P = 0.548 F (22.00,16.00) = 0.74, P = 0.75

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146 Table A 11. Continued Trial Dependent Variable(s) Effect Statistical Parameters UPDRS Part III Tremor, bradykinesia, posture, gait, balance, speech, facial expression, total score, rigidity Interaction Frequency Main Effect Voltage Main Effect F (16.00,22.00) = 1.47, P = 0.199 F (8.00,2.00) = 5.64, P = 0.159 Wilks F (16.00,22.00) = 0.83, P = 0.646 No significant differences for any measures; AP Anterior Posterior direction, ML MedioLateral direction, RMS Root Mean Square, CoP Center of Pressure, CoM Center of Mass, CV Coefficient of Variatio n, UPDRS Unified Parkinson Disease Rating Scale

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147 Table A 12 Descriptive statistics and Univariate test results of interaction of frequency and voltage for Center of Pressure related balance measures from Eyes Open trials relat ed to Specific Aim 2. Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP ML range (cm) 30Hz BV 3.5 (0.5) F(1.23,9.80) = 0.05 0.866 0.01 0.06 HV 3.9 (1.0) MV 3.3 (0.5) 60Hz BV 3.5 (0.7) HV 4.0 (1.0) MV 3.2 (0.5) AP range (cm) 30Hz BV 4.3 (0.4) F(2,16) = 1.38 0.281 0.15 0.25 HV 4.6 (0.5) MV 4.2 (0.5) 60Hz BV 4.1 (0.5) HV 4.3 (0.5) MV 4.4 (0.4) Sway area (square cm) 30Hz BV 16.8 (4.1) F(1.14,9.09) = 0.04 0.872 0.01 0.05 HV 20.8 (7.2) MV 15.0 (4.2) 60Hz BV 17.0 (5.2) HV 19.6 (6.4) MV 14.4 (3.0) RMS ML displace ment (cm) 30Hz BV 0.24 (0.03) F(1.13,9.05) = 0.47 0.533 0.06 0.10 HV 0.30 (0.03) MV 0.31 (0.04) 60Hz BV 0.26 (0.03) HV 0.28 (0.03) MV 0.34 (0.06) RMS AP displace ment (cm) 30Hz BV 0.31 (0.06) F(1.20,9.58) = 0.04 0.889 0.01 0.05 HV 0.34 (0.06) MV 0.34 (0.07) 60Hz BV 0.35 (0.07) HV 0.39 (0.08) MV 0.38 (0.06) RMS ML velocity (cm/s) 30Hz BV 86.6 (10.9) F(2,16) = 1.04 0.378 0.12 0.20 HV 106.6 (10.2) MV 110.7 (13.2) 60Hz BV 92.7 (12.3) HV 100.5 (9.5) MV 109.1 (14.8)

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148 Table A 12. Continued Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP RMS AP velocity (cm/s) 30Hz BV 21.5 (3.6) F(2,16) = 0.20 0.821 0.02 0.08 HV 22.1 (3.6) MV 22.5 (4.2) 60Hz BV 24.0 (4.3) HV 25.5 (4.9) MV 26.8 (4.3) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, ML MedioLateral, AP AnteroPosterior, RMS Root Mean Square, cm centimeter, s second, Hz Hertz PES Partial Eta Squared, OP Observed Power

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149 Table A 13 Descriptive statistics and Univariate test results of Frequency Main Effect for Center of Pressure related balance measures from Eyes Open trials related to Specific Aim 2. Measure Frequency setting Mean (SE) Statistical Test F value P PES Observed Power ML range (cm) 30Hz 3.6 (0.6) F(1,8) = 0.01 0.923 0.00 0.05 60Hz 3.6 (0.6) AP range (cm) 30Hz 4.4 (0.5) F(1,8) = 0.19 0.671 0.02 0.07 60Hz 4.3 (0.4) Sway area (square cm) 30Hz 17.53 (4.77) F(1,8) = 0.07 0.80 0.01 0.06 60Hz 17.02 (4.02) RMS ML displace ment (cm) 30Hz 0.28 (0.03) F(1,8) = 0.22 0.648 0.03 0.07 60Hz 0.29 (0.02) RMS AP displace ment (cm) 30Hz 0.33 (0.04) F(1,8) = 1.25 0.296 0.14 0.17 60Hz 0.37 (0.05) RMS ML velocity (cm/s) 30Hz 101.3 (10.0) F(1,8) = 0.04 0.853 0.01 0.05 60Hz 100.8 (10.5) RMS AP velocity (cm/s) 30Hz 22.1 (2.8) F(1,8) = 3.73 0.089 0.32 0.40 60Hz 25.5 (3.7) No significant differences were found ( P > 0.05); SE Standard Error, ML MedioLateral, AP AnteroPosterior, RMS Root Mean Square, cm centimeter, s second, Hz Hertz PES Partial Eta Squared

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150 Table A 14 Descriptive statistics and Univariate test results of Voltage Main Effect for Center of Pressure related balance measures from Eyes Open trials related to Specific Aim 2. Measure Voltage setting Mean (SE) Statistical Test F value P PES Observed Power ML range (cm) BV 3.5 (0.5) F(2,16) = 0.57 0.576 0.07 0.13 HV 3.9 (1.0) MV 3.2 (0.5) AP range (cm) BV 4.2 (0.4) F(2,16) = 1.11 0.354 0.12 0.21 HV 4.5 (0.4) MV 4.3 (0.5) Sway area (square cm) BV 16.91 (4.02) F(2,16) = 0.89 0.430 0.10 0.18 HV 20.18 (6.74) MV 14.74 (3.30) RMS ML displacem ent (cm) BV 0.25 (0.03) F(1.21,9.69) = 1.94 0.175 0.20 0.34 HV 0.29 (0.03) MV 0.32 (0.04) RMS AP displacem ent (cm) BV 0.33 (0.07) F(1.06,8.46) = 0.13 0.740 0.02 0.06 HV 0.37 (0.07) MV 0.36 (0.04) RMS ML velocity (cm/s) BV 89.63 (11.23) F(2,16) = 2.23 0.140 0.22 0.39 HV 103.51 (9.53) MV 109.89 (13.71) RMS AP velocity (cm/s) BV 22.78 (3.81) F(1.07,8.56) = 0.10 0.781 0.01 0.06 HV 23.82 (4.21) MV 24.67 (4.02) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, ML MedioLateral, AP AnteroPosterior, RMS Root Mean Square, cm centimeter, s second PES Partial Eta Squared

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151 Table A 15 Descriptive statistics and Univariate test results of interaction of frequency and voltage for Center of Pressure related balance measures from Eyes Closed trials related to Specific Aim 2. Measure Frequency setting Volt age setting Mean (SE) Statistical Test F value P PES OP ML range (cm) 30Hz BV 3.2 (0.6) F(1.26,10.16) = 0.52 0.528 0.06 0.11 HV 3.2 (0.5) MV 3.4 (0.6) 60Hz BV 3.7 (0.5) HV 3.8 (0.6) MV 3.5 (0.5) AP range (cm) 30Hz BV 4.7 (0.4) F(2,16) = 2.21 0.142 0.22 0.39 HV 4.8 (0.3) MV 4.7 (0.3) 60Hz BV 4.9 (0.4) HV 4.9 (0.4) MV 5.4 (0.4) Sway area (square cm) 30Hz BV 16.39 (3.58) F(2,16) = 0.06 0.946 0.01 0.06 HV 16.08 (3.25) MV 17.01 (3.21) 60Hz BV 19.44 (3.95) HV 19.80 (4.20) MV 19.78 (3.38) RMS ML displace ment (cm) 30Hz BV 0.24 (0.03) F(2,16) = 1.39 0.279 0.15 0.25 HV 0.29 (0.03) MV 0.31 (0.04) 60Hz BV 0.26 (0.03) HV 0.28 (0.03) MV 0.30 (0.04) RMS AP displace ment (cm) 30Hz BV 0.31 (0.06) F(2,16) = 0.03 0.968 0.07 0.06 HV 0.34 (0.05) MV 0.35 (0.07) 60Hz BV 0.35 (0.07) HV 0.38 (0.08) MV 0.39 (0.07) RMS ML velocity (cm/s) 30Hz BV 85.88 (11.08) F(2,16) = 1.39 0.277 0.15 0.26 HV 105.46 (9.76) MV 110.00 (12.64) 60Hz BV 93.10 (12.39) HV 99.71 (9.40) MV 108.48 (14.26)

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152 Table A 15. Continued Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP RMS AP velocity (cm/s) 30Hz BV 21.67 (3.43) F(2,16) = 0.04 0.964 0.01 0.06 HV 22.20 (3.52) MV 23.03(4.67) 60Hz BV 23.59 (4.22) HV 24.98 (5.35) MV 25.10 (4.39) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, ML MedioLateral, AP AnteroPosterior, RMS Root Mean Square, cm centimeter, s second, Hz Hertz PES Partial Eta Squared, OP Observed Power

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153 Tab le A 16 Descriptive statistics and Univariate test results of Frequency Main Effect for Center of Pressure related balance measures from Eyes Closed trials related to Specific Aim 2. Measure Frequency setting Mean (SE) Statistical Test F value P PES Observed Power ML range (cm) 30Hz 3.3 (0.5) F(1,8) = 2.73 0.137 0.25 0.31 60Hz 3.6 (0.5) AP range (cm) 30Hz 4.8 (0.3) F(1,8) = 1.65 0.235 0.17 0.21 60Hz 5.1 (0.4) Sway area (square cm) 30Hz 16.49 (3.27) F(1,8) = 10.62 0.012 0.57 0.81 60Hz 19.68 (3.45) RMS ML displace ment (cm) 30Hz 0.28 (0.03) F(1,8) = 0.00 0.991 0.00 0.05 60Hz 0.28 (0.03) RMS AP displace ment (cm) 30Hz 0.37 (0.04) F(1,8) = 2.37 0.163 0.23 0.27 60Hz 0.37 (0.05) RMS ML velocity (cm/s) 30Hz 100.45 (9.70) F(1,8) = 0.00 0.994 0.00 0.05 60Hz 100.43 (10.40) RMS AP velocity (cm/s) 30Hz 22.30 (2.88) F(1,8) = 2.22 0.175 0.22 0.26 60Hz 24.56 (3.74) Significant difference ( P < 0.05); SE Standard Error, ML MedioLateral, AP Antero Posterior, RMS Root Mean Square, cm centimeter, s second, Hz Hertz PES Partial Eta Squared

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154 Table A 17 Descriptive statistics and Univariate test results of Voltage Main Effect for Center of Pressure related balance measures from Eyes Closed trials. Measure Voltage setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power ML range (cm) BV 3.5 (0.5) F(2,16) = 0.04 0.961 0.01 0.06 HV 3.5 (0.5) MV 3.4 (0.5) AP range (cm) BV 4.8 (0.4) F(2,16) = 0.72 0.504 0.08 0.15 HV 4.8 (0.3) MV 5.1 (0.3) Sway area (square cm) BV 17.91 (3.59) F(2,16) = 0.05 0.956 0.01 0.06 HV 17.94 (3.68) MV 18.40 (3.16) RMS ML displace ment (cm) BV 0.25 (0.03) F(2,16) = 2.20 0.147 0.21 0.38 HV 0.28 (0.03) MV 0.30 (0.04) RMS AP displace ment (cm) BV 0.33 (0.07) F(1.03,8.25) = 0.14 0.724 0.02 0.06 HV 0.36 (0.07) MV 0.37 (0.07) RMS ML velocity (cm/s) BV 89.49 (11.43) F(2,16) = 2.20 0.145 0.21 0.38 HV 102.58 (9.30) MV 109.24 (13.19) RMS AP velocity (cm/s) BV 22.63 (3.66) F(1.05,8.37) = 0.06 0.831 0.01 0.06 HV 23.59 (4.41) MV 24.07 (4.29) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, ML MedioLateral, AP AnteroPosterior, RMS Root Mean Square, cm centimeter, s second

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155 Table A 18 Descriptive statistics and Univariate test results of interaction of frequency and voltage for Center of Pressure related measures from Gait Initiation trials related to Specific Aim 2. Measure Frequency set ting Voltage setting Mean (SE) Statistical Test F value P PES OP ML displaceme nt in S1 phase (cm) 30Hz BV 1.3 (0.2) F(2,18) = 1.01 0.384 0.10 0.20 HV 1.6 (0.3) MV 1.4 (0.3) 60Hz BV 1.1 (0.2) HV 1.2 (0.3) MV 1.5 (0.3) AP displaceme nt in S1 phase (cm) 30Hz BV 1.2 (0.2) F(2,18) = 0.16 0.853 0.02 0.07 HV 1.4 (0.4) MV 1.3 (0.4) 60Hz BV 1.2 (0.3) HV 1.2 (0.3) MV 1.3 (0.3) ML displaceme nt in S2 phase (cm) 30Hz BV 10.7 (0.6) F(2,18) = 0.65 0.533 0.07 0.14 HV 11.0 (0.8) MV 10.7 (0.7) 60Hz BV 9.9 (0.8) HV 10.6 (0.6) MV 10.8 (0.7) AP displaceme nt in S2 phase (cm) 30Hz BV 0.4 (0.8) F(2,18) = 0.43 0.657 0.05 0.11 HV 0.5 (0.6) MV 0.6 (0.7) 60Hz BV 0.7 (0.8) HV 1.5 (0.8) MV 1.0 (0.5) ML displaceme nt in S3 phase (cm) 30Hz BV 0.2 (0.5) F(2,18) = 0.11 0.893 0.01 0.07 HV 0.0 (0.5) MV 0.0 (0.5) 60Hz BV 0.1 (0.5) HV 0.0 (0.5) MV 0.2 (0.5) AP displaceme nt in S3 phase (cm) 30Hz BV 15.2 (1.3) F(1.29,11.63) = 0.39 0.596 0.04 0.10 HV 14.7 (1.1) MV 14.5 (1.1) 60Hz BV 14.4 (1.3) HV 13.9 (1.1) MV 14.3 (1.1)

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156 Table A 18. Continued Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP ML velocity in S1 phase (cm/s) 30Hz BV 4.9 (0.7) F(2,18) = 1.28 0.301 0.13 0.24 HV 6.1 (1.4) MV 4.8 (1.2) 60Hz BV 4.0 (0.7) HV 5.0 (1.4) MV 5.4 (0.9) AP velocity in S1 phase (cm/s) 30Hz BV 4.2 (1.0) F(2,18) = 0 .14 0.870 0.02 0.07 HV 5.7 (1.6) MV 4.6(1.3) 60Hz BV 4.3 (0.9) HV 5.5 (1.5) MV 5.0 (1.2) ML velocity in S2 phase (cm/s) 30Hz BV 20.5 (2.5) F(2,18) = 0.43 0.657 0.05 0.11 HV 21.6 (3.1) MV 22.2 (3.9) 60Hz BV 18.6 (2.6) HV 19.3 (2.9) MV 22.6 (3.4) AP velocity in S2 phase (cm/s) 30Hz BV 0.0 (1.5) F(2,18) = 0.46 0.638 0.05 0.11 HV 0.6 (1.2) MV 0.7 (1.5) 60Hz BV 0.1 (1.2) HV 1.5 (1.3) MV 0.6 (1.1) ML velocity in S3 phase (cm/s) 30Hz BV 0.4 (0.8) F(2,18) = 0.11 0.895 0.01 0.06 HV 0.1 (0.7) MV 0.2 (0.9) 60Hz BV 0.2 (0.8) HV 0.0 (0.7) MV 0.0 (0.8) AP velocity in S3 phase (cm/s) 30Hz BV 25.4 (2.4) F(2,18) = 0.75 0.487 0.08 0.16 HV 23.9 (2.3) MV 25.4 (2.8) 60Hz BV 22.8 (2.5) HV 23.2 (2.9) MV 22.9 (2.4) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, ML MedioLateral, AP AnteroPosterior, cm centimeter, s second, Hz Hertz PES Partial Eta Squared, OP Observed Power; negative value indicates m ovement in either posterior or medial direction

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157 Table A 19 Descriptive statistics and Univariate test results of Frequency Main Effect for Center of Pressure related measures from Gait Initiation trials related to Specific Aim 2. Measure Frequency setting Mean (SE) Statistical Test F value P PES OP ML displacement in S1 phase (cm) 30Hz 1.4 (0.3) F(1,9) = 3.58 0.091 0.28 0.39 60Hz 1.3 (0.3) AP displacement in S1 phase (cm) 30Hz 1.3 (0.3) F(1,9) = 1.14 0.313 0.11 0.16 60Hz 1.2 (0.3) ML displacement in S2 phase (cm) 30Hz 10.8 (0.5) F(1,9) = 1.52 0.249 0.14 0.20 60Hz 10.4 (0.6) AP displacement in S2 phase (cm) 30Hz 0.5 (0.6) F(1,9) = 4.93 0.053 0.35 0.51 60Hz 1.1 (0.7) ML displacement in S3 phase (cm) 30Hz 0.1 (0.4) F(1,9) = 0.70 0.424 0.07 0.12 60Hz 0.1 (0.5) AP displacement in S3 phase (cm) 30Hz 14.8 (1.1) F(1,9) = 7.50 0.023 0.46 0.69 60Hz 14.2 (1.1) ML velocity in S1 phase (cm/s) 30Hz 5.3 (1.0) F(1,9) = 1.80 0.212 0.17 0.23 60Hz 4.8 (0.9)

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158 Table A 19. Continued Measure Frequency setting Mean (SE) Statistical Test F value P PES OP AP velocity in S1 phase (cm/s) 30Hz 4.8 (1.2) F(1,9) = 0 .10 0.765 0.01 0.06 60Hz 4.9 (1.1) ML velocity in S2 phase (cm/s) 30Hz 21.4 (2.9) F(1,9) = 2.06 0.185 0.19 0.25 60Hz 20.2 (2.8) AP velocity in S2 phase (cm/s) 30Hz 0.4 (1.3) F(1,9) = 0.39 0.548 0.04 0.09 60Hz 0.7 (1.1) ML velocity in S3 phase (cm/s) 30Hz 0.2 (0.7) F(1,9) = 0.50 0.497 0.05 0.10 60Hz 0.1 (0.7) AP velocity in S3 phase (cm/s) 30Hz 24.9 (2.4) F(1,9) = 17.12 0.003 0.66 0.96 60Hz 23.0 (2.6) Significant difference ( P < 0.05); Statistical Trend (0.05 <= P <= 0.07); SE Standard Error, ML MedioLateral, AP AnteroPosterior, cm centimeter, s second, Hz Hertz, PES Partial Eta Squared, OP Observed Power; negative value indicates movement in either posterior or medial direction

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159 Table A 20 Descriptive statistics and Univariate test results of Voltage Main Effect for Center of Pressure related measu res from Gait Initiation trials related to Specific Aim 2. Measure Voltage setting Mean (SE) Statistical Test F value P PES OP ML displacement in S1 phase (cm) BV 1.2 (0.2) F(2,18) = 0.66 0.529 0.07 0.14 HV 1.4 (0.3) MV 1.4 (0.3) AP displacement in S1 phase (cm) BV 1.2 (0.2) F(2,18) = 0.27 0.769 0.03 0.09 HV 1.3 (0.4) MV 1.3 (0.3) ML displacement in S2 phase (cm) BV 10.3 (0.6) F(2,18) = 0.48 0.624 0.05 0.12 HV 10.8 (0.6) MV 10.7 (0.6) AP displacement in S2 phase (cm) BV 0.5 (0.7) F(2,18) = 0.81 0.459 0.08 0.17 HV 1.0 (0.7) MV 0.8 (0.6) ML displacement in S3 phase (cm) BV 0.1 (0.5) F(2,18) = 0.27 0.763 0.03 0.09 HV 0.0 (0.5) MV 0.1 (0.5) AP displacement in S3 phase (cm) BV 14.8 (1.2) F(1.49,11.59) = 0.73 0.445 0.08 0.13 HV 14.3 (1.1) MV 14.4 (1.1) ML velocity in S1 phase (cm/s) BV 4.5 (0.5) F(1.53,11.46) = 1.06 0.344 0.11 0.17 HV 5.5 (1.4) MV 5.1 (1.0) AP velocity in S1 phase (cm/s) BV 4.2 (0.9) F(2,18) = 1.76 0.200 0.16 0.32 HV 5.6 (1.5) MV 4.8 (1.2) ML velocity in S2 phase (cm/s) BV 19.6 (2.4) F(2,18) = 1.91 0.177 0.18 0.34 HV 20.4 (2.9) MV 22.4 (3.5) AP velocity in S2 phase (cm/s) BV 0.1 (1.3) F(2,18) = 1.26 0.308 0.12 0.24 HV 1.0 (1.2) MV 0.7 (1.2) ML velocity in S3 phase (cm/s) BV 0.3 (0.8) F(2,18) = 0.23 0.797 0.03 0.08 HV 0.0 (0.7) MV 0.1 (0.8)

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160 Table A 20. Continued Measure Voltage setting Mean (SE) Statistical Test F value P PES OP AP velocity in S3 phase (cm/s) BV 24.1 (2.4) F(2,18) = 0.48 0.629 0.05 0.12 HV 23.5 (2.5) MV 24.2 (2.6) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, ML MedioLateral, AP AnteroPosterior, cm centimeter, s second PES Partial Eta Squared, OP Observed Power ; negative value indicates movement in either posterior or medial direction

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161 Table A 21 Descriptive statistics and Univariate test results of interaction of frequency and voltage for Center of Pressure (CoP) and Center of Mass (CoM) related measures from Gait Initiation trials related to Specific Aim 2. Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP ML CoP CoM distance in S1 phase (cm) 30Hz BV 1.7 (0.2) F(2,16) = 0.51 0.611 0.06 0.12 HV 1.9 (0.3) MV 1.8 (0.4) 60Hz BV 1.6 (0.4) HV 1.5 (0.3) MV 1.9 (0.4) AP CoP CoM distance in S1 phase (cm) 30Hz BV 1.7 (0.4) F(2,16) = 0.44 0.653 0.05 0.11 HV 2.0 (0.5) MV 1.9 (0.5) 60Hz BV 1.9 (0.5) HV 1.7 (0.4) MV 1.9 (0.5) Resultant CoP CoM distance in S1 phase (cm) 30Hz BV 2.5 (0.4) F(2,16) = 0.45 0.646 0.05 0.11 HV 2.8 (0.6) MV 2.7 (0.6) 60Hz BV 2.5 (0.6) HV 2.4 (0.5) MV 2.7 (0.6) ML CoP CoM distance in S2 phase (cm) 30Hz BV 7.3 (1.5) F(2,16) = 0.81 0.463 0.09 0.16 HV 7.4 (1.5) MV 5.9 (0.5) 60Hz BV 5.2 (0.5) HV 6.8 (1.1) MV 5.7 (0.5) AP CoP CoM distance in S2 phase (cm) 30Hz BV 6.3 (0.6) F(2,16) = 0.32 0.733 0.04 0.09 HV 6.6 (0.8) MV 6.6 (0.9) 60Hz BV 6.4 (0.9) HV 6.4 (0.7) MV 5.9 (0.9) Resultant CoP CoM distance in S2 phase (cm) 30Hz BV 10.0 (1.4) F(2,16) = 0.24 0.790 0.03 0.08 HV 10.3 (1.4) MV 9.0 (0.8) 60Hz BV 8.3 (0.8) HV 9.6 (1.0) MV 8.4 (0.8)

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162 Table A 21. Continued Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP ML CoP CoM distance in S3 phase (cm) 30Hz BV 11.7 (1.9) F(2,16) = 2.42 0.121 0.23 0.42 HV 11.4 (1.8) MV 11.8 (1.8) 60Hz BV 9.3 (1.0) HV 10.9 (1.4) MV 10.1 (0.7) AP CoP CoM distance in S3 phase (cm) 30Hz BV 17.5 (2.1) F(2,16) = 0.30 0.746 0.04 0.09 HV 18.2 (2.1) MV 18.3 (2.1) 60Hz BV 18.9 (2.5) HV 18.7 (1.7) MV 18.7 (2.2) Resultant CoP CoM distance in S3 phase (cm) 30Hz BV 22.2 (1.8) F(1.23,9.84) = 0.18 0.733 0.02 0.07 HV 22.4 (1.8) MV 22.6 (1.9) 60Hz BV 21.5 (2.2) HV 22.2 (1.6) MV 21.4 (2.1) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, ML MedioLateral, AP AnteroPosterior, cm centimeter, s second, Hz Hertz PES Partial Eta Squared, OP Observed Power

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163 Table A 22 Descriptive statistics and Univariate test results of Frequency Main Effect for Center of Pressure (CoP) and Center of Mass (CoM) related measures from Gait Initiation trials related to Specific Aim 2. Measure Frequency setting Mean (SE) Statistical Te st F value P Partial Eta Squared Observed Power ML CoP CoM distance in S1 phase (cm) 30Hz 1.8 (0.2) F(1,8) = 1.33 0.282 0.14 0.18 60Hz 1.7 (0.3) AP CoP CoM distance in S1 phase (cm) 30Hz 1.9 (0.4) F(1,8) = 0.90 0.372 0.10 0.13 60Hz 1.8 (0.4) Resultant CoP CoM distance in S1 phase (cm) 30Hz 2.7 (0.5) F(1,8) = 2.09 0.186 0.21 0.25 60Hz 2.5 (0.5) ML CoP CoM distance in S2 phase (cm) 30Hz 6.9 (1.1) F(1,8) = 0.632 0.450 0.07 0.11 60Hz 5.9 (0.4) AP CoP CoM distance in S2 phase (cm) 30Hz 6.5 (0.6) F(1,8) = 0.93 0.363 0.10 0.14 60Hz 6.2 (0.7) Resultant CoP CoM distance in S2 phase (cm) 30Hz 9.7 (1.0) F(1,8) = 0.78 0.404 0.09 0.12 60Hz 8.7 (0.5) ML CoP CoM distance in S3 phase (cm) 30Hz 11.6 (1.8) F(1,8) = 0.97 0.354 0.11 0.14 60Hz 10.1 (0.8)

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164 Table A 22. Continued Measure Frequency setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power AP CoP CoM distance in S3 phase (cm) 30Hz 18.0 (2.0) F(1,8) = 3.20 0.112 0.29 0.35 60Hz 18.7 (2.1) Resultant CoP CoM distance in S3 phase (cm) 30Hz 22.4 (1.2) F(1,8) = 0.20 0.663 0.03 0.07 60Hz 21.7 (1.9) No significant differences were found ( P > 0.05); SE Standard Error, ML MedioLateral, AP AnteroPosterior, cm centimeter, s second, Hz Hertz

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165 Table A 23 Descriptive statistics and Univariate test results of Voltage Main Effect for Center of Pressure (CoP) and Center of Mass (CoM) related measures from Gait Initiation trials related to Specific Aim 2. Measure Voltage setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power ML CoP CoM distance in S1 phase (cm) BV 1.7 (0.2) F(2,16) = 1.46 0.641 0.05 0.11 HV 1.7 (0.3) MV 1.8 (0.3) AP CoP CoM distance in S1 phase (cm) BV 1.8 (0.4) F(2,16) = 0.17 0.846 0.02 0.07 HV 1.9 (0.4) MV 1.9 (0.5) Resultant CoP CoM distance in S1 phase (cm) BV 2.5 (0.5) F(2,16) = 0.39 0.686 0.05 0.10 HV 2.6 (0.5) MV 2.7 (0.6) ML CoP CoM distance in S2 phase (cm) BV 6.3 (0.8) F(2,16) = 1.44 0.267 0.15 0.26 HV 7.1 (0.8) MV 5.8 (0.5) AP CoP CoM distance in S2 phase (cm) BV 6.3 (0.7) F(2,16) = 0.05 0.948 0.01 0.06 HV 6.5 (0.7) MV 6.3 (0.9) Resultant CoP CoM distance in S2 phase (cm) BV 9.1 (0.9) F(2,16) = 0.86 0.443 0.10 0.17 HV 9.9 (0.7) MV 8.7 (0.8) ML CoP CoM distance in S3 phase (cm) BV 10.5 (1.3) F(2,16) = 0.43 0.656 0.05 0.11 HV 11.2 (1.3) MV 10.9 (1.1) AP CoP CoM distance in S3 phase (cm) BV 18.2 (2.3) F(2,16) = 0.10 0.910 0.01 0.06 HV 18.4 (1.9) MV 18.5 (2.1) Resultant CoP CoM distance in S3 phase (cm) BV 21.8 (1.8) F(2,16) = 0.26 0.775 0.03 0.08 HV 22.3 (1.3) MV 22.0 (1.9) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, ML MedioLateral, AP AnteroPosterior, cm centimeter, s second

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166 Table A 24 Descriptive statistics and Univariate test results of interaction of frequency and voltage for Spatiotemporal meas ures from Gait Initiation trials related to Specific Aim 2. Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP Swing leg step length (cm) 30Hz BV 43.5 (3.6) F(1.28,11.50) = 0.09 0.831 0.01 0.06 HV 42.8 (4.2) MV 44.1 (3.6) 60Hz BV 45.4 (4.5) HV 44.8 (3.2) MV 45.2 (3.6) Stance leg step length (cm) 30Hz BV 92.1 (6.0) F(1.30,11.68) = 0.34 0.630 0.04 0.09 HV 92.1 (7.0) MV 93.3 (6.4) 60Hz BV 95.5 (7.1) HV 94.1 (5.5) MV 93.6 (6.3) Swing leg step time (s) 30Hz BV 0.50 (0.02) F(2,18) = 0.67 0.526 0.07 0.14 HV 0.53 (0.03) MV 0.52 (0.04) 60Hz BV 0.51 (0.03) HV 0.54 (0.03) MV 0.54 (0.02) Stance leg step time (s) 30Hz BV 0.66 (0.03) F(2,18) = 1.07 0.364 0.11 0.21 HV 0.66 (0.03) MV 0.64 (0.02) 60Hz BV 0.65 (0.03) HV 0.68 (0.03) MV 0.66 (0.02) Swing leg step velocity (cm/s) 30Hz BV 89.1 (8.4) F(2,18) = 0.68 0.520 0.07 0.15 HV 84.8 (9.8) MV 91.0 (10.0) 60Hz BV 91.8 (10.4) HV 87.6 (9.4) MV 88.0 (9.5) Stance leg step velocity (cm/s) 30Hz BV 144.4 (13.5) F(1.30,11.74) = 1.24 0.305 0.12 0.19 HV 144.0 (13.9) MV 148.6 (13.2) 60Hz BV 151.3 (14.9) HV 143.5 (12.1) MV 144.6 (13.0)

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167 Table A 24. Continued Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP Stance Width (cm) 30Hz BV 16.6 (0.4) F(1.13,10.13) = 0.78 0.412 0.08 0.1 3 HV 17.4 (0.3) MV 17.5 (0.5) 60Hz BV 17.6 (0.3) HV 17.9 (0.7) MV 17.6 (0.5) Time to swing leg heel rise (s) 30Hz BV 0.83 (0.06) F(2,18) = 0.33 0.725 0.04 0.0 9 HV 0.81 (0.08) MV 0.83 (0.06) 60Hz BV 0.80 (0.08) HV 0.85 (0.07) MV 0.81 (0.07) Time to swing leg toe off (s) 30Hz BV 1.43 (0.08) F(2,18) = 0.18 0.835 0.02 0.0 7 HV 1.45 (0.10) MV 1.46 (0.08) 60Hz BV 1.43 (0.10) HV 1.48 (0.11) MV 1.45 (0.11) Time to stance leg heel rise (s) 30Hz BV 0.94 (0.07) F(2,18) = 0.18 0.836 0.02 0.0 7 HV 0.95 (0.09) MV 0.96 (0.06) 60Hz BV 0.92 (0.08) HV 0.97 (0.08) MV 0.93 (0.08) Time to stance leg toe off (s) 30Hz BV 1.68 (0.10) F(2,18) = 0.12 0.885 0.01 0.0 7 HV 1.70 (0.12) MV 1.69 (0.09) 60Hz BV 1.68 (0.11) HV 1.74 (0.12) MV 1.69 (0.12) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, cm centimeter, s second, Hz Hertz PES Partial Eta Squared, OP Observed Power

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168 Table A 25 Descriptive statistics and Univariate test results of Frequency Main Effect for Spatio temporal measures from Gait Initiation trials related to Specific Aim 2. Measure Frequency setting Mean (SE) Statistical Test F value P PES OP Swing leg step length (cm) 30Hz 43.5 (3.7) F(1,9) = 6.31 0.033 0.41 0.61 60Hz 45.1 (3.7) Stance leg step length (cm) 30Hz 92.5 (6.3) F(1,9) = 4.31 0.068 0.32 0.46 60Hz 94.4 (6.2) Swing leg step time (s) 30Hz 0.51 (0.03) F(1,9) = 4.39 0.066 0.33 0.47 60Hz 0.53 (0.03) Stance leg step time (s) 30Hz 0.65 (0.02) F(1,9) = 1.53 0.247 0.15 0.20 60Hz 0.66 (0.02) Swing leg step velocity (cm/s) 30Hz 88.3 (9.1) F(1,9) = 0.24 0.634 0.03 0.07 60Hz 89.1 (9.5) Swing leg step velocity (cm/s) 30Hz 145.7 (13.2) F(1,9) = 0.11 0.750 0.01 0.06 60Hz 146.5 (13.2)

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169 Table A 25. Continued Measure Frequency setting Mean (SE) Statistical Test F value P PES OP Stance width (cm) 30Hz 17.2 (0.4) F(1,9) = 3.21 0.107 0.26 0.36 60Hz 17.7 (0.3) Time to swing leg heel rise (s) 30Hz 0.82 (0.06) F(1,9) = 0.01 0.932 0.00 0.05 60Hz 0.82 (0.07) Time to swing leg toe off (s) 30Hz 1.45 (0.08) F(1,9) = 0.01 0.922 0.00 0.05 60Hz 1.45 (0.10) Time to stance leg heel rise (s) 30Hz 0.95 (0.07) F(1,9) = 0.07 0.798 0.01 0.06 60Hz 0.94 (0.08) Time to stance leg toe off (s) 30Hz 1.69 (0.09) F(1,9) = 0.06 0.817 0.01 0.06 60Hz 1.70 (0.11) Significant difference ( P < 0.05); Statistical trend (0.05 <= P <= 0.07); SE Standard Error cm centimeter, s second, Hz Hertz PES Partial Eta Squared, OP Observed Power

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170 Table A 26 Descriptive statistics and Univariate test results of Voltage Main Effect for Spatiotemporal measures from Gait Initiation tri als related to Specific Aim 2. Measure Voltage setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power Swing leg step length (cm) BV 44.5 (4.0) F(2,18) = 0.31 0.738 0.03 0.09 HV 43.8 (3.6) MV 44.6 (3.6) Stance leg step length (cm) BV 93.8 (6.5) F(2,18) = 0.10 0.902 0.01 0.06 HV 93.1 (6.1) MV 93.4 (6.3) Swing leg step time (s) BV 0.50 (0.03) F(2,18) = 1.44 0.263 0.14 0.27 HV 0.53 (0.03) MV 0.53 (0.04) Stance leg step time (s) BV 0.66 (0.03) F(2,18) = 0.90 0.424 0.09 0.18 HV 0.67 (0.03) MV 0.65 (0.02) Swing leg step velocity (cm/s) BV 90.4 (9.3) F(2,18) = 1.58 0.234 0.15 0.29 HV 86.2 (9.3) MV 89.5 (9.6) Stance leg step velocity (cm/s) BV 147.9 (14.1) F(2,18) = 1.14 0.341 0.11 0.22 HV 143.8 (12.7) MV 146.6 (12.9) Stance width (cm) BV 17.1 (0.3) F(2,18) = 1.02 0.382 0.10 0.20 HV 17.6 (0.4) MV 17.6 (0.4) Time to swing leg heel rise (s) BV 0.81 (0.07) F(2,18) = 0.06 0.939 0.01 0.06 HV 0.83 (0.07) MV 0.82 (0.05) Time to swing leg toe off (s) BV 1.43 (0.09) F(2,18) = 0.38 0.688 0.04 0.10 HV 1.47 (0.10) MV 1.45 (0.09) Time to stance leg heel rise (s) BV 0.93 (0.07) F(2,18) = 0.17 0.848 0.02 0.07 HV 0.96 (0.08) MV 0.94 (0.06)

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171 Table A 26. Continued Measure Voltage setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power Time to stance leg toe off (s) BV 1.68 (0.10) F(2,18) = 0.38 0.690 0.04 0.10 HV 1.72 (0.11) MV 1.69 (0.10) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, cm centimeter, s second Table A 27 Descriptive statistics and Univariate test results of interaction of frequency and voltage for Coefficient of Variation (CV) of Spatiotemporal measures from Gait Initiation trials related to Specific Aim 2. Measure Frequency setting Voltage setting Me an (SE) Statistical Test F value P PES OP CV of Swing leg step length (%) 30Hz BV 8.0 (1.7) F(2,18) = 0.03 0.969 0.00 0.05 HV 9.8 (3.3) MV 9.0 (2.0) 60Hz BV 7.8 (1.5) HV 8.8 (1.3) MV 8.3 (1.7) CV of Stance leg step length (%) 30Hz BV 6.4 (1.0) F(2,18) = 1.81 0.192 0.17 0.33 HV 5.0 (1.4) MV 5.9 (1.3) 60Hz BV 4.9 (0.7) HV 5.4 (0.9) MV 4.5 (1.0) CV of Swing leg step time (%) 30Hz BV 8.4 (1.6) F(2,18) = 0.28 0.756 0.03 0.09 HV 12.8 (3.1) MV 11.0 (2.6) 60Hz BV 8.2 (1.4) HV 10.2 (1.9) MV 9.5 (2.2) CV of Stance leg step time (%) 30Hz BV 7.1 (1.2) F(2,18) = 1.46 0.258 0.14 0.27 HV 5.1 (0.7) MV 6.1 (1.2) 60Hz BV 7.1 (1.1) HV 8.0 (1.1) MV 7.0 (0.9) CV of Swing leg step velocity (%) 30Hz BV 8.5 (1.4) F(2,18) = 0.63 0.547 0.07 0.14 HV 12.4 (2.8) MV 11.5 (2.7) 60Hz BV 8.1 (1.4) HV 9.4 (2.0) MV 7.9 (1.5)

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172 Table A 27. Continued Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP CV of Stance leg step velocity (%) 30Hz BV 7.8 (0.8) F(2,18) = 7.21 0.005 0.46 0.89 HV 5.1 (0.7) MV 8.0 (1.2) 60Hz BV 5.8 (0.8) HV 8.7 (1.0) MV 7.9 (1.7) CV of Stance width (%) 30Hz BV 5.7 (0.9) F(2,18) = 0.84 0.447 0.09 0.17 HV 4.1 (0.6) MV 4.9 (1.1) 60Hz BV 8.4 (2.1) HV 4.7 (1.6) MV 6.2 (2.2) CV of Time to swing leg heel rise (%) 30Hz BV 26.7 (2.2) F(2,18) = 0.17 0.844 0.02 0.07 HV 32.4 (5.6) MV 27.9 (3.8) 60Hz BV 24.7 (4.5) HV 29.6 (5.0) MV 29.2 (3.7) CV of Time to swing leg toe off (%) 30Hz BV 15.5 (1.3) F(2,18) = 0.11 0.899 0.01 0.06 HV 17.1 (2.9) MV 18.6 (3.1) 60Hz BV 13.9 (2.0) HV 17.2 (2.9) MV 17.0 (2.4) CV of Time to stance leg heel rise (%) 30Hz BV 25.2 (2.3) F(2,18) = 0.23 0.794 0.03 0.08 HV 25.9 (3.8) MV 25.8 (4.4) 60Hz BV 21.8 (3.2) HV 26.5 (4.1) MV 25.5 (3.7) CV of Time to stance leg toe off (%) 30Hz BV 14.0 (1.4) F(2,18) = 0.16 0.852 0.02 0.07 HV 15.0 (2.8) MV 16.4 (2.8) 60Hz BV 12.8 (1.8) HV 15.1 (2.4) MV 14.4 (2.0) Significant difference ( P < 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, Hz Hertz PES Partial Eta Squared, OP Observed Power

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173 Table A 28 Descriptive statistics and Univariate test results of Frequency Main Effect for Coefficient of Variation (CV) of Spatiotemporal measures from Gait Initiation trials related to Specific Aim 2. Measure Frequency setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power CV of Swing leg step length (%) 30Hz 8.9 (1.8) F(1,9) = 1.02 0.338 0.10 0.15 60Hz 8.3 (1.2) CV of Stance leg step length (%) 30Hz 5.7 (1.0) F(1,9) = 2.20 0.172 0.20 0.26 60Hz 5.0 (0.7) CV of Swing leg step time (%) 30Hz 10.7 (2.3) F(1,9) = 0.51 0.492 0.05 0.10 60Hz 9.3 (1.2) CV of Stance leg step time (%) 30Hz 6.1 (0.8) F(1,9) = 1.52 0.249 0.14 0.20 60Hz 7.3 (0.6) CV of Swing leg step velocity (%) 30Hz 10.8 (1.9) F(1,9) = 1.60 0.237 0.15 0.21 60Hz 8.5 (1.0) CV of Swing leg step velocity (%) 30Hz 7.0 (0.6) F(1,9) = 0.42 0.535 0.04 0.09 60Hz 7.5 (0.8) CV of Stance width (%) 30Hz 4.9 (0.6) F(1,9) = 1.72 0.222 0.16 0.22 60Hz 6.5 (1.6)

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174 Table A 2 8 Continued Measure Frequency setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power CV of Time to swing leg heel rise (%) 30Hz 29.0 (3.1) F(1,9) = 0.14 0.717 0.02 0.06 60Hz 27.8 (3.5) CV of Time to swing leg toe off (%) 30Hz 17.1 (2.0) F(1,9) = 0.27 0.619 0.03 0.08 60Hz 16.0 (1.9) CV of Time to stance leg heel rise (%) 30Hz 25.6 (2.9) F(1,9) = 0.11 0.748 0.01 0.06 60Hz 24.6 (2.7) CV of Time to stance leg toe off %) 30Hz 15.1 (2.0) F(1,9) = 0.27 0.615 0.03 0.08 60Hz 14.1 (1.6) No significant differences were found ( P > 0.05); SE Standard Error Hz Hertz

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175 Table A 29 Descriptive statistics and Univariate test results of Voltage Main Effect for Coefficient of Variation (CV) of Spatiotemporal measures from Gait Initiation trials related to Specific Aim 2. Measure Voltage setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power CV of Swing leg step length (%) BV 7.9 (1.5) F(2,18) = 0.29 0.749 0.03 0.09 HV 9.3 (2.2) MV 8.6 (1.6) CV of Stance leg step length (%) BV 5.6 (0.8) F(2,18) = 0.13 0.880 0.01 0.07 HV 5.2 (1.1) MV 5.2 (1.1) CV of Swing leg step time (%) BV 8.3 (1.4) F(2,18) = 2.07 0.156 0.19 0.37 HV 11.5 (2.1) MV 10.3 (1.7) CV of Stance leg step time (%) BV 7.1 (0.6) F(2,18) = 0.20 0.820 0.02 0.08 HV 6.6 (0.7) MV 6.5 (1.0) CV of Swing leg step velocity (%) BV 8.3 (1.2) F(2,18) = 1.00 0.388 0.10 0.20 HV 10.9 (1.8) MV 9.7 (1.8) CV of Stance leg step velocity (%) BV 6.8 (0.7) F(2,18) = 0.55 0.587 0.06 0.13 HV 6.9 (0.4) MV 8.0 (1.4) CV of Stance width (%) BV 7.1 (1.4) F(2,18) = 1.79 0.196 0.17 0.32 HV 4.4 (1.0) MV 5.6 (1.6) CV of Time to swing leg heel rise (%) BV 25.7 (2.8) F(2,18) = 1.91 0.177 0.18 0.34 HV 31.0 (4.1) MV 28.6 (2.8) CV of Time to swing leg toe off (%) BV 14.7 (1.5) F(2,18) = 1.74 0.204 0.16 0.32 HV 17.1 (2.1) MV 17.8 (2.1) CV of Time to stance leg heel rise (%) BV 23.5 (2.4) F(2,18) = 0.61 0.554 0.06 0.14 HV 26.2 (2.8) MV 25.7 (3.1)

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176 Table A 29. Continued Measure Voltage setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power CV of Time to stance leg toe off (%) BV 13.4 (1.5) F(2,18) = 0.95 0.410 0.10 0.19 HV 15.0 (1.9) MV 15.4 (1.9) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage

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177 Table A 30 Descriptive statistics and Univariate test results of interaction of frequency and voltage for Spatiotemporal measures from Gait trials related to Specific Aim 2. Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP Cadence (steps/min ute) 30Hz BV 102 (3) F(1.15,10.32) = 0.35 0.594 0.04 0.09 HV 106 (3) MV 110 (5) 60Hz BV 105 (2) HV 106 (2) MV 109 (2) Walking speed (cm/s) 30Hz BV 96.3 (7.6) F(1.13,10.17) = 0.31 0.614 0.03 0.08 HV 100.6 (8.4) MV 94.4 (7.9) 60Hz BV 100.3 (7.2) HV 103.6 (7.3) MV 100.4 (7.9) Stride time (s) 30Hz BV 1.18 (0.03) F(1.22,10.94) = 0.28 0.654 0.03 0.08 HV 1.13 (0.04) MV 1.12 (0.04) 60Hz BV 1.15 (0.02) HV 1.13 (0.02) MV 1.11 (0.02) Step time (s) 30Hz BV 0.59 (0.02) F(1.29,11.62) = 0.11 0.807 0.01 0.06 HV 0.57 (0.02) MV 0.56 (0.02) 60Hz BV 0.58 (0.01) HV 0.57 (0.01) MV 0.55 (0.01) Opposite foot off (%) 30Hz BV 16.44 (0.75) F(2,18) = 1.09 0.357 0.11 0.21 HV 17.03 (0.84) MV 17.74 (1.15) 60Hz BV 16.22 (0.55) HV 16.20 (0.64) MV 17.01 (0.95) Opposite foot contact (%) 30Hz BV 49.76 (0.13) F(2,18) = 0.29 0.749 0.03 0.09 HV 49.92 (0.10) MV 49.98 (0.10) 60Hz BV 49.79 (0.15) HV 50.03 (0.12) MV 50.15 (0.13)

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178 Table A 30. Continued Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP Foot off (%) 30Hz BV 66.50 (0.74) F(2,18) = 0.12 0.890 0.01 0.07 HV 66.73 (0.74) MV 67.42 (0.94) 60Hz BV 66.19 (0.54) HV 66.18 (0.54) MV 66.93 (0.90) Single support time (s) 30Hz BV 0.39 (0.01) F(1.10,9.90) = 1.50 0.252 0.14 0.21 HV 0.37 (0.01) MV 0.36 (0.02) 60Hz BV 0.39 (0.01) HV 0.42 (0.04) MV 0.36 (0.01) Double support time (s) 30Hz BV 0.39 (0.02) F(2,18) = 0.09 0.919 0.01 0.06 HV 0.39 (0.03) MV 0.39 (0.02) 60Hz BV 0.38 (0.02) HV 0.37 (0.02) MV 0.38 (0.02) Stride length (cm) 30Hz BV 1.11 (0.06) F(1.30,11.66) = 0.18 0.745 0.02 0.07 HV 1.12 (0.07) MV 1.06 (0.08) 60Hz BV 1.14 (0.06) HV 1.16 (0.06) MV 1.11 (0.08) Step length (cm) 30Hz BV 0.56 (0.03) F(1.24,11.14) = 0.08 0.829 0.01 0.06 HV 0.56 (0.04) MV 0.54 (0.04) 60Hz BV 0.57 (0.03) HV 0.58 (0.03) MV 0.55 (0.04) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, cm centimeter, s second, Hz Hertz, PES Partial Eta Squared, OP Observed power

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179 Table A 31 Descriptive statistics and Univariate test results of Frequency Main Effect for Spatio temporal measures from Gait trials related to Specific Aim 2. Measure Frequency setting Mean (SE) Statistical Test F value P PES OP Cadence (steps/minute) 30Hz 106 (2) F(1,9) = 0.11 0.744 0.01 0.06 60Hz 107 (2) Walking speed (cm/s) 30Hz 97.1 (7.7) F(1,9) = 5.95 0.037 0.40 0.59 60Hz 101.5 (7.1) Stride time (s) 30Hz 1.14 (0.02) F(1,9) = 0.93 0.361 0.09 0.14 60Hz 1.13 (0.02) Step time (s) 30Hz 0.57 (0.01) F(1,9) = 2.23 0.169 0.20 0.27 60Hz 0.56 (0.01) Opposite foot off (%) 30Hz 17.07 (0.82) F(1,9) = 3.94 0.078 0.30 0.43 60Hz 16.48 (0.63) Opposite foot contact (%) 30Hz 48.89 (0.10) F(1,9) = 1.34 0.277 0.13 0.18 60Hz 49.99 (0.10) Foot off (%) 30Hz 66.88 (0.73) F(1,9) = 3.62 0.090 0.29 0.40 60Hz 66.43 (0.56)

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180 Table A 31. Continued Measure Frequency setting Mean (SE) Statistical Test F value P PES OP Single support time (s) 30Hz 0.38 (0.01) F(1,9) = 1.54 0.245 0.15 0.20 60Hz 0.39 (0.01) Double support time (s) 30Hz 0.39 (0.02) F(1,9) = 3.63 0.089 0.29 0.40 60Hz 0.37 (0.02) Stride length (cm) 30Hz 109.9 (6.7) F(1,9) = 7.71 0.022 0.46 0.70 60Hz 113.5 (6.2) Step length (cm) 30Hz 55.2 (3.3) F(1,9) = 5.59 0.042 0.38 0.56 60Hz 56.8 (3.1) Significant difference ( P < 0.05); SE Standard Error cm centimeter, s second, Hz Hertz PES Partial Eta Squared, OP Observed Power

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181 Table A 32 Descriptive statistics and Univariate test results of Voltage Main Effect for Spatiotemporal measu res from Gait trials related to Specific Aim 2. Measure Voltage setting Mean (SE) Statistical Test F value P PES OP Cadence (steps/minute) BV 103 (2) F(1.14,10.26) = 2.15 0.172 0.19 0.28 HV 106 (2) MV 110 (3) Walking speed (cm/s) BV 98.3 (7.3) F(2,18) = 1.10 0.353 0.11 0.21 HV 102.1 (7.6) MV 97.4 (7.9) Stride time (s) BV 1.16 (0.03) F(2,18) = 2.27 0.132 0.20 0.40 HV 1.13 (0.03) MV 1.11 (0.02) Step time (s) BV 0.58 (0.01) F(2,18) = 2.96 0.077 0.25 0.50 HV 0.57 (0.01) MV 0.55 (0.01) Opposite foot off (%) BV 16.33 (0.64) F(1.07,9.60) = 1.30 0.286 0.13 0.18 HV 16.61 (0.71) MV 17.37 (1.04) Opposite foot contact (%) BV 49.77 (0.11) F(1.28,11.52) = 5.76 0.028 0.39 0.65 HV 49.98 (0.09) MV 50.06 (0.10) Foot off (%) BV 66.35 (0.62) F(1.13,10.17) = 1.16 0.316 0.11 0.17 HV 66.45 (0.60) MV 67.17 (0.91) Single support time (s) BV 0.39 (0.01) F(2,18) = 1.80 0.194 0.17 0.33 HV 0.40 (0.02) MV 0.36 (0.01) Double support time (s) BV 0.39 (0.02) F(2,18) = 0.25 0.781 0.03 0.08 HV 0.38 (0.02) MV 0.38 (0.02) Stride length (cm) BV 112.5 (6.0) F(1.22,10.99) = 1.14 0.324 0.11 0.17 HV 114.3 (6.5) MV 108.3 (8.0) Step length (cm) BV 56.5 (2.9) F(1.22,11.00) = 1.26 0.297 0.12 0.19 HV 57.2 (3.2) MV 54.4 (3.8)

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1 82 Significant difference ( P < 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, cm centimeter, s second, PES Partial Eta Squared, OP Observed Power Table A 33 Descriptive statistics and Univariate test results of interaction of frequency and voltage for Coefficient of Variation (CV) of Spatiotemporal measures from Gait trials relate d to Specific Aim 2. Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES Observed Power CV of Cadence (%) 30Hz BV 4.20 (0.60) F(1.10,9.87) = 0.95 0.363 0.10 0.15 HV 3.52 (0.50) MV 8.02 (4.00) 60Hz BV 3.09 (0.40) HV 3.31 (0.50) MV 3.96 (0.60) CV of Walking speed (%) 30Hz BV 5.78 (0.80) F(1.06,9.52) = 1.65 0.231 0.16 0.22 HV 5.35 (0.70) MV 14.2 (8.00) 60Hz BV 4.57 (0.50) HV 4.90 (0.90) MV 7.15 (2.90) CV of Stride time (%) 30Hz BV 4.02 (0.50) F(1.11,10.0 3) = 0.87 0.386 0.09 0.14 HV 16.67 (10.90) MV 8.15 (4.00) 60Hz BV 3.09 (0.40) HV 3.30 (0.50) MV 3.96 (0.60) CV of Step time (%) 30Hz BV 4.95 (0.50) F(1.05,9.45) = 1.05 0.334 0.11 0.21 HV 4.81 (0.60) MV 9.08 (3.80) 60Hz BV 3.88 (0.60) HV 4.07 (0.40) MV 4.48 (0.50) CV of Opposite foot off (%) 30Hz BV 10.78 (1.30) F(2,18) = 4.08 0.035 0.31 0.65 HV 9.05 (1.00) MV 12.99 (3.00) 60Hz BV 9.25 (1.00) HV 10.59 (1.90) MV 8.59 (1.20) CV of Opposite foot contact (%) 30Hz BV 3.22 (0.20) F(1.09,9.79) = 0.55 0.492 0.06 0.13 HV 3.04 (0.40) MV 4.84 (1.70) 60Hz BV 2.28 (0.30) HV 2.40 (0.30)

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183 MV 2.72 (0.30) Table A 33. Continued Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power CV of Foot off (%) 30Hz BV 2.53 (0.20) F(2,18) = 0.53 0.601 0.06 0.12 HV 2.85 (0.50) MV 3.56 (0.70) 60Hz BV 2.35 (0.20) HV 2.51 (0.40) MV 2.74 (0.40) CV of Single support time (%) 30Hz BV 6.98 (1.00) F(2,18) = 1.65 0.220 0.16 0.30 HV 6.75 (0.90) MV 14.60 (7.20) 60Hz BV 5.33 (0.80) HV 13.83 (6.90) MV 9.36 (2.30) CV of Double support time (%) 30Hz BV 9.46 (1.20) F(2,18) = 0.73 0.495 0.08 0.15 HV 7.02 (1.00) MV 8.76 (0.90) 60Hz BV 9.60 (1.10) HV 9.07 (1.20) MV 8.50 (1.00) CV of Stride length (%) 30Hz BV 4.44 (0.80) F(1.02,9.2 1) = 0.90 0.369 0.09 0.14 HV 4.58 (0.50) MV 15.01 (10.40) 60Hz BV 4.19 (0.50) HV 3.85 (0.50) MV 7.61 (3.10) CV of Step length (%) 30Hz BV 6.32 (1.30) F(1.07,9.6 3) = 0.39 0.562 0.04 0.09 HV 4.75 (0.50) MV 14.06 (8.40) 60Hz BV 4.27 (0.50) HV 4.47 (0.50) MV 9.49 (3.40) Significant difference ( P < 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, Hz Hertz

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184 Table A 34 Descriptive statistics and Univariate test results of Frequency Main Effect for Coefficient of Variation (CV) of Spatiotemporal measures from Gait trials related to Specific Aim 2. Measure Frequency setting Mean (SE) Statistical Test F value P PES OP CV of Cadence (%) 30Hz 5.2 (1.4) F(1,9) = 1.75 0.219 0.16 0.22 60Hz 3.4 (0.3) CV of Walking speed (%) 30Hz 8.4 (2.9) F(1,9) = 2.07 0.184 0.19 0.25 60Hz 5.5 (0.9) CV of Stride time (%) 30Hz 9.6 (3.6) F(1,9) = 2.74 0.132 0.23 0.32 60Hz 3.5 (0.3) CV of Step time (%) 30Hz 6.3 (1.3) F(1,9) = 3.05 0.115 0.25 0.35 60Hz 4.1 (0.4) CV of Opposite foot off (%) 30Hz 10.9 (1.4) F(1,9) = 1.37 0.271 0.13 0.18 60Hz 9.5 (1.0) CV of Opposite foot contact (%) 30Hz 3.7 (0.5) F(1,9) = 6.71 0.029 0.43 0.64 60Hz 2.5 (0.2) CV of Foot off (%) 30Hz 3.0 (0.3) F(1,9) = 2.41 0.155 0.21 0.29 60Hz 2.5 (0.2)

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185 Table A 34. Continued Measure Frequency setting Mean (SE) Statistical Test F value P Partial Eta Squared Observed Power CV of Single support time (%) 30Hz 9.4 (2.4) F(1,9) = 0.00 0.988 0.00 0.05 60Hz 9.5 (2.9) CV of Double support time (%) 30Hz 8.4 (0.7) F(1,9) = 0.56 0.472 0.06 0.10 60Hz 9.1 (0.7) CV of Stride length (%) 30Hz 8.0 (3.6) F(1,9) = 1.19 0.303 0.12 0.17 60Hz 5.2 (1.1) CV of Step length (%) 30Hz 8.4 (2.9) F(1,9) = 1.44 0.260 0.14 0.19 60Hz 6.1 (1.2) Significant difference ( P < 0.05); SE Standard Error Hz Hertz PES Partial Eta Squared, OP Observed Power

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186 Table A 35 Descriptive statistics and Univariate test results of Voltage Main Effect for Coefficient of Variation (CV) of Spatiotemporal measures from Gait trials related to Specific Aim 2. Measure Voltage setting Mean (SE) Statistical Test F value P PES OP CV of Cadence (%) BV 3.6 (0.4) F(1.09,9.81) = 1.23 0.299 0.12 0.18 HV 3.4 (0.4) MV 6.0 (2.2) CV of Walking speed (%) BV 5.2 (0.5) F(1.03,9.23) = 1.04 0.336 0.10 0.15 HV 5.1 (0.6) MV 10.7 (5.4) CV of Stride time (%) BV 3.6 (0.4) F(1.18,10.63) = 0.87 0.390 0.09 0.14 HV 10.0 (5.4) MV 6.1 (2.2) CV of Step time (%) BV 4.4 (0.5) F(1.08,9.69) = 1.24 0.298 0.12 0.18 HV 4.4 (0.4) MV 6.8 (2.1) CV of Opposite foot off (%) BV 10.0 (1.0) F(2,18) = 0.15 0.860 0.02 0.07 HV 9.8 (1.3) MV 10.8 (2.0) CV of Opposite foot contact (%) BV 2.7 (0.2) F(1.19,10.68) = 1.03 0.347 0.10 0.16 HV 2.7 (0.3) MV 3.8 (0.9) CV of Foot off (%) BV 2.4 (0.1) F(2,18) = 1.10 0.354 0.11 0.21 HV 2.7 (0.3) MV 3.1 (0.5) CV of Single support time (%) BV 6.2 (0.9) F(2,18) = 0.91 0.421 0.09 0.18 HV 10.3 (3.6) MV 12.0 (4.0) CV of Double support time (%) BV 9.5 (0.8) F(2,18) = 1.16 0.335 0.12 0.22 HV 8.0 (0.9) MV 8.6 (0.7) CV of Stride length (%) BV 4.3 (0.6) F(1.01,9.09) = 1.12 0.318 0.11 0.16 HV 4.2 (0.3) MV 11.3 (6.7)

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187 Table A 35. Continued Measure Voltage setting Mean (SE) Statistical Test F value P PES OP CV of Step length (%) BV 5.3 (0.8) F(1.02,9.21) = 1.46 0.259 0.14 0.19 HV 4.6 (0.4) MV 11.8 (5.7) No significant differences were found ( P > 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, PES Partial Eta Squared, OP Observed Power

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188 Table A 36 Descriptive statistics and Univariate test results of interaction of frequency and voltage for Unified Parkinsons Disease Rating Scales Part III (Motor) evaluation sub scores and total score related to Specific Aim 2. Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP Tremor sub score 30Hz BV 2.3 (0.9) F(2,18) = 2.51 0.109 0.22 0.44 HV 2.7 (1.0) MV 4.1 (0.9) 60Hz BV 2.3 (1.2) HV 2.4 (0.9) MV 2.3 (0.9) Bradykin esia sub score 30Hz BV 15.1 (1.3) F(2,18) = 0.04 0.957 0.01 0.06 HV 14.9 (1.5) MV 15.6 (1.1) 60Hz BV 14.5 (1.4) HV 14.6 (1.4) MV 15.4 (1.7) Posture sub score 30Hz BV 0.8 (0.3) F(2,18) = 2.14 0.146 0.19 0.38 HV 0.7 (0.3) MV 1.1 (0.2) 60Hz BV 1.1 (0.2) HV 1.0 (0.2) MV 0.9 (0.2) Gait sub score 30Hz BV 1.3 (0.2) F(2,18) = 0.00 1.000 0.00 0.05 HV 1.1 (0.1) MV 1.3 (0.2) 60Hz BV 1.3 (0.2) HV 1.1 (0.3) MV 1.3 (0.2) Balance sub score 30Hz BV 0.1 (0.1) F(2,18) = 0.64 0.537 0.07 0.14 HV 0.0 (0.0) MV 0.2 (0.1) 60Hz BV 0.2 (0.1) HV 0.1 (0.1) MV 0.1 (0.1) Speech sub score 30Hz BV 1.6 (0.3) F(2,18) = 4.56 0.025 0.34 0.70 HV 1.3 (0.3) MV 1.5 (0.3) 60Hz BV 1.6 (0.3) HV 1.7 (0.3) MV 1.2 (0.3)

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189 Table A 36. Continued Measure Frequency setting Voltage setting Mean (SE) Statistical Test F value P PES OP Facial sub score 30Hz BV 1.3 (0.2) F(2,18) = 0.34 0.717 0.04 0.10 HV 1.3 (0.3) MV 1.1 (0.1) 60Hz BV 1.2 (0.1) HV 1.4 (0.3) MV 1.2 (0.2) Total UPDRS Part III score 30Hz BV 22.5 (2.1) F(2,18) = 1.74 0.203 0.16 0.32 HV 22.0 (2.5) MV 24.9 (1.9) 60Hz BV 22.2 (2.5) HV 22.3 (2.3) MV 22.4 (2.6) Rigidity sub score 30Hz BV 6.6 (1.0) F(2,18) = 2.50 0.110 0.22 0.44 HV 6.9 (0.8) MV 8.0 (0.8) 60Hz BV 6.7 (1.0) HV 7.3 (1.0) MV 7.0 (1.0) Significant difference ( P < 0.05); SE Standard Error, BV baseline voltage, HV high voltage, MV maximum tolerable voltage, Hz Hertz, UPDRS Unified Parkinsons Disease Rating Scales Part III (Motor evaluation) PES Partial Eta Squared, OP Observed Power; All the sub scores (except rigidity) and the total UPDRS score are from an investigator who was blinded to the settings. Also, total score does not include rigidity subsc ore.

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190 Table A 37 Descriptive statistics and Univariate test results of Frequency Main Effect for Unified Parkinsons Disease Rating Scales Part III (Motor) evaluation subscores and total score related to Specific Aim 2. Measure Frequency setting Mean (SE) Statistical Test F value P PES OP Tremor sub score 30Hz 3.0 (0.8) F(1,9) = 6.98 0.027 0.44 0.65 60Hz 2.3 (0.9) Bradykinesia sub score 30Hz 15.2 (1.2) F(1,9) = 1.12 0.32 0.11 0.16 60Hz 14.8 (1.4) Posture sub score 30Hz 0.9 (0.2) F(1,9) = 1.71 0.223 0.16 0.22 60Hz 1.0 (0.2) Gait sub score 30Hz 1.2 (0.1) F(1,9) = 0.00 1.000 0.00 0.05 60Hz 1.2 (0.2) Balance sub score 30Hz 0.1 (0.1) F(1,9) = 0.31 0.591 0.03 0.08 60Hz 0.1 (0.1) Speech sub score 30Hz 1.5 (0.3) F(1,9) = 0.18 0.678 0.02 0.07 60Hz 1.5 (0.3) Facial sub score 30Hz 1.2 (0.1) F(1,9) = 0.18 0.678 0.02 0.07 60Hz 1.3 (0.2)

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191 Table A 37. Continued Measure Frequency setting Mean (SE) Statistical Test F value P PES OP Total UPDRS Part III score 30Hz 23.1 (2.0) F(1,9) = 2.34 0.161 0.21 0.28 60Hz 22.3 (2.3) Rigidity sub score 30Hz 7.2 (0.7) F(1,9) = 0.287 0.605 0.03 0.08 60Hz 7.0 (0.9) Significant difference ( P < 0.05); SE Standard Error Hz Hertz, UPDRS Unified Parkinsons Disease Rating Scales Part III (Motor evaluation) PES Partial Eta Squared, OP Observed Power; All the sub scores (except rigidity) and the total UPDRS score are from an investigator who was blinded to the settings. Also, t otal score does not include rigidity subscore.

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192 Table A 38 Descriptive statistics and Univariate test results of Voltage Main Effect for Unified Parkinsons Disease Rating Scales Part III (Motor) evaluation subscores and total score related to Specific Aim 2. Measure Voltage setting Mean (SE) Statistical Test F value P PES Observed Power Tremor sub score BV 2.3 (1.0) F(2,18) = 1.32 0.291 0.13 0.25 HV 2.6 (0.9) MV 3.2 (0.9) Bradykines ia sub score BV 14.8 (1.3) F(2,18) = 0.71 0.504 0.07 0.16 HV 14.8 (1.4) MV 15.5 (1.3) Posture sub score BV 1.0 (0.2) F(1.28,11.55) = 0.61 0.489 0.06 0.12 HV 0.9 (0.2) MV 1.0 (0.2) Gait sub score BV 1.3 (0.2) F(2,18) = 0.67 0.523 0.07 0.15 HV 1.1 (0.2) MV 1.3 (0.1) Balance sub score BV 0.2 (0.1) F(2,18) = 0.64 0.537 0.07 0.14 HV 0.1 (0.1) MV 0.2 (0.1) Speech sub score BV 1.6 (0.3) F(1.30,11.72) = 1.88 0.198 0.17 0.27 HV 1.5 (0.2) MV 1.4 (0.3) Facial sub score BV 1.3 (0.1) F(2,18) = 0.92 0.418 0.09 0.18 HV 1.4 (0.2) MV 1.5 (0.1) Total UPDRS Part III score BV 22.4 (2.2) F(2,18) = 1.19 0.326 0.12 0.23 HV 22.2 (2.3) MV 23.7 (2.1) Rigidity sub score BV 6.7 (1.0) F(2,18) = 0.88 0.431 0.09 0.18 HV 7.1 (0.9) MV 7.5 (0.8) No significant differences were found ( P > 0.05); SE Standard Error Hz Hertz, UPDRS Unified Parkinsons Disease Rating Scales Part III (Motor evaluation) PES Partial Eta Squared ; All the sub scores (except rigidity) and the total UPDRS score are from an investigator who was blinded to the settings. Also, total score does not include rigidity subscore.

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193 Table A 39 Correlation between total electrical energy delivered per second and Center of Pressure (CoP) related dependent variables during Eyes Open (EO) and Eyes Closed (EC) Standing trials P r CoP RMS ML Displacement during EO trial 0.656 0.053 CoP RMS AP Displacement during EO trial 0.332 0.116 CoP RMS ML Velocity during EO trial 0.634 0.057 CoP RMS AP Velocity during EO trial 0.368 0.108 CoP RMS ML Displacement during EC trial 0.595 0.064 CoP RMS AP Displacement during EC trial 0.321 0.119 CoP RMS ML Velocity during EC trial 0.584 0.066 CoP RMS AP Velocity during EC trial 0.358 0.110 No significant correlation was observed ( P > 0.05); RMS Root Mean Square, ML MedioLateral, AP Antero Posterior, r Pearson Correlation Coefficient Table A 40 Correlation between total electrical energy delivered per second (Joule) and dependent variables related to Gait Initiation P r CoP ML Displacement in S1 phase 0.111 0.180 CoP AP Displacement in S1 phase 0.256 0.129 CoP AP Displacement in S2 phase 0.235 0.134 CoP ML Displacement in S3 phase 0.672 0.048 CoP AP Displacement in S3 phase 0.587 0.062 CoP ML Velocity in S1 phase 0.155 0.160 CoP AP Velocity in S1 phase 0.109 0.180 CoP ML Velocity in S2 phase 0.076 0.200 CoP AP Velocity in S2 phase 0.371 0.101 CoP ML Velocity in S3 phase 0.801 0.029 CoP AP Velocity in S3 phase 0.275 0.123 Maximum ML CoP CoM distance in S1 phase 0.105 0.185 Maximum AP CoP CoM distance in S1 phase 0.122 0.176 Maximum Resultant CoP CoM distance in S1 phase 0.105 0.185 Maximum ML CoP CoM distance in S2 phase 0.595 0.061 Maximum AP CoP CoM distance in S2 phase 0.220 0.140 Maximum Resultant CoP CoM distance in S2 phase 0.311 0.116 Maximum ML CoP CoM distance in S3 phase 0.404 0.096 Swing Leg Step Length 0.066 0.207 Stance Leg Step Length 0.053 0.217 Swing Leg Step Time 0.134 0.169 Stance Leg Step Time 0.677 0.047 Stance Leg Step Velocity 0.137 0.168 Stance Width 0.094 0.197 Time to Swing Leg Heel Rise 0.816 0.026 Time to Swing Leg Toe Off 0.395 0.096 Time to Stance Leg Heel Rise 0.647 0.052 Time to Stance Leg Toe Off 0.384 0.099 Swing Leg Step Length Variability 0.449 0.086 Swing Leg Step Time Variability 0.117 0.177 Stance Leg Step Time Variability 0.305 0.116 Swing Leg Step Velocity Variability 0.109 0.181

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194 Table A 40. Continued P r Stance Leg Step Velocity Variability 0.303 0.117 Stance Width Variability 0.997 0.000 Time to Swing Leg Heel Rise Variability 0.512 0.074 Time to Swing Leg Toe Off Variability 0.853 0.021 Time to Stance Leg Heel Rise Variability 0.534 0.071 Time to Swing Leg Toe Off Variability 0.725 0.040 No significant correlation was observed ( P > 0.05); r Pearson Correlation Coefficient, CoP Center of Pressure, CoM Center of Mass, ML MedioLateral, AP AnteroPosterior Table A 41 Correlation between total electrical energy delivered per second (Joule) and dependent variables related to gait evaluation P r Cadence 0.068 0.205 Walking Speed 0.153 0.161 Stride Time 0.726 0.040 Step Time 0.057 0.214 Opposite Foot Off 0.109 0.180 Opposite Foot Contact 0.819 0.026 Foot Off 0.194 0.147 Single Support Time 0.872 0.018 Stride Length 0.281 0.122 Step Length 0.973 0.004 Variability in Cadence 0.866 0.019 Variability in Walking Speed 0.851 0.021 Variability in Stride Time 0.890 0.016 Variability in Step Time 0.812 0.027 Variability in Opposite Foot Off 0.931 0.010 Variability in Opposite Foot Contact 0.987 0.002 Variability in Foot Off 0.828 0.025 Variability in Single Support Time 0.943 0.008 Variability in Double Support Time 0.433 0.089 Variability in Stride Length 0.914 0.012 Variability in Step Length 0.772 0.033 No significant correlation was observed ( P > 0.05); r Pearson Correlation Coefficient. Table A 42 Correlation between TEED per second (Joule) and dependent variables related to the UPDRS Part III (Motor evaluation) P Tremor 0.378 0.100 Bradykinesia 0.591 0.061 Posture 0.757 0.035 Gait 0.503 0.076 Speech 0.346 0.107 Facial Expression 0.526 0.072 Total 0.262 0.127 Rigidity 0.063 0.209 No significant correlation was observed ( P > 0.05); Spearmans Rho Correlation Coefficient, TEED Total Electrical Energy Delivered, UPDRS Unified Parkinsons Disease Rating Scale

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195 L IST OF REFERENCES Al exander GE, Crutcher MD Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990; 13:267 271. Allert N, Volkmann J, Dotse S Hefter H, Sturm V, Freund HJ. Effects of bilateral pallidal or subthalamic stimulation on gait in advanced Parkinsons disease. Mov Disord 2001;16: 1076 1085. Alves G Forsaa E, Pedersen K, Dreetz Gjerstad M Larsen J. Epidemiology of Parkinson's disease. J Neurol. 2008 Sep;255 Suppl 5:1832 Alterman R, Shils J, Miravite J, Tagliati M. Lower stimulation frequency can enhance tolerability and efficacy of pallidal deep brain stimulation for dystonia. Mov Disord 2007;22(3):3668. Alterman RL, Miravite J, Weiss D, Shi ls JL, Bressman SB, Tagliati M. Sixty hertz pallidal deep brain stimulation for primary torsion dystonia. Neurology. 2007;69(7):681688. Aziz TZ, Davies L, Stein J, et al. The role of descending basal ganglia connections to the brain stem in parkinsonian akinesia. Br J Neurosurg 1998;12:245 249. Bejjani B, Arnulf I, Vidailhet M, Pidoux B, Damier P, Papadopoulos S et al. Irregular jerky tremor, myoclonus, and thalamus: a study using low frequency stimulation. Mov Disord 2000;15(5):919 24. Bejjani BP Gervai s D, Arnulf I, et al. Axial parkinsonian symptoms can be improved: the role of levodopa and bilateral subthalamic stimulation. J Neurol Neurosurg Psychiatry 2000; 68:595 600. Benatru I, Vaugoyeau M, Azulay J. Postural disorders in Parkinson's disease. Neurophysiol Clin 2008;38(6):459 65. Benazzouz A, Hallett M. Mechanism of action of deep brain stimulation. Neurology 2000;55(12 Suppl 6):S136. Beuter A, Hernndez R, Rigal R, Modolo J, Blanchet PJ. Postural sway and effect of levodopa in early Parkinson's disease. Can J Neurol Sci. 2008 Mar;35(1):65 8. Breit S, Bouali R, Benabid AL, Benazzouz A. Unilateral lesion of the nigrotriatal pathway induces an increase of neuronal activity of the pedunculpontine nucleus, which is reversed by the lesion of the subthal amic nucleus in the rat. Eur J Neurosci 2001;14: 1833 1842 Breit S, Schulz JB, Benabid AL. Deep brain stimulation. Cell Tissue Res 2004;318(1):27588.

PAGE 196

196 Breniere Y, Do MC. Control of gait initiation. J Mot Behav 1991;23:23540. Brotchie P, Iansek R, Home MK. Motor function of the monkey globus pallidus. 1. Neuronal discharge and parameters of movement. Brain 1991a; 114: 1667 83. Brotchie P, Iansek R, Home MK. Motor function of the monkey globus pallidus. 2. Cognitive aspects of movement and phasic neuronal activity. Brain 1991b; 114: 1685702. Brown LA, de Bruin N, Doan JB, Suchowersky O, Hu B. Novel challenges to gait in Parkinson's disease: the effect of concurrent music in singleand dual task contexts. Arch Phys Med Rehabil 2009;90(9):157883. Brown P, Williams D. Basal ganglia local field potential activity: character and functional significance in the human. Clin Neurophysiol 2005;116:2510 2519. Brozova H, Barnaure I, Alterman R, Tagliati M. STN DBS frequency effects on f reezing of gait in advanced Parkinson disease. Neurology 2009;72(8):770; author reply 1. Burn DJ The effects of deep brain stimulation and levodopa on postural sway in subjects with Parkinson's disease. J Neurol Neurosurg Psychiatry. 2002 Sep;73(3):240. Carpinella I, Crenna P, Marzegan A, Rabuffetti M, Rizzone M, Lopiano L, Ferrarin M Effect of L dopa and subthalamic nucleus stimulation on arm and leg swing during gait in Parkinson's Disease. Conf Proc IEEE Eng Med Biol Soc 2007;2007:6665 8. Chang H, K rebs DE. Dynamic balance control in elders: gait initiation assessment as a screening tool. Arch Phys Med Rehabil 1999;80:4904. Chastan N, Westby G, Yelnik J, Bardinet E, Do M, Agid Y et al. Effects of nigral stimulation on locomotion and postural stabili ty in patients with Parkinson's disease. Brain 2009;132(Pt 1):172 84. Colnat Coulbois S, Gauchard G, Maillard L, Barroche G, Vespignani H, Auque J et al. Bilateral subthalamic nucleus stimulation improves balance control in Parkinson's disease. J Neurol N eurosurg Psychiatry 2005;76(6):7807. Crenna P, Carpinella I, Rabuffetti M, Rizzone M, Lopiano L, Lanotte M et al. Impact of subthalamic nucleus stimulation on the initiation of gait in Parkinson's disease. Exp Brain Res 2006;172(4):51932. Dahodwala N Siderowf A Xie M Noll E Stern M Mandell DS Racial differences in the diagnosis of Parkinson's disease. Mov Disord. 2009 Jun 15;24(8):12005 Delong MR. Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990; 13:281 289

PAGE 197

197 DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch Neurol. 2007 Jan; 64(1):20 4. Delwaide PJ, Pepin JL, Maertens A, de Noordhout. Short latency autogenic inhibition in patients with Parkinsonian rigidity. Ann Neur ol 1991;30:83 9. Delwaide PJ, Pepin JL, De Pasqua V, de Noordhout AM. Projections from basal ganglia to tegmentum: A subcortical route for explaining the pathophysiology of Parkinsons disease signs. J Neurol 2000;247:II75 II81 Deuschl G, Goddemeier C. Spontaneous and reflex activity of facial muscles in dystonia, Parkinson's disease, and in normal subjects. J Neurol Neurosurg Psychiatry. 1998 Mar;64(3):3204. Ebadi M and Pfeiffer R, 2004. Parkinsons Disease Boca Raton, Florida, USA: CRC Press. Elbaz A Bower JH Maraganore DM McDonnell SK Peterson BJ Ahlskog JE Schaid DJ Rocca WA Risk tables for parkinsonism and Parkinson's disease. Clin Epidemiol. 2002 Jan;55(1):2531. Eusebio A, Chen C, Lu C, Lee S, Tsai C, Limousin P et al. Effects of low freq uency stimulation of the subthalamic nucleus on movement in Parkinson's disease. Exp Neurol 2008;209(1):12530. Fahn S. Description of Parkinsons disease as a clinical syndrome. Ann N Y Acad Sci 2003; 991:1 14 Fahn S. Does levodopa slow or hasten the rate of progression of Parkinson's disease? J Neurol 2005;252 Suppl 4:IV37 IV42. Faist M, Xie J, Kurz D, Berger W, Maurer C, Pollak P, L cking CH. Effect of bilateral subthalamic nucleus stimulation on gait in Parkinsons disease. Brain 2001;124: 1590 1600 F ernandez H Rodriguez R Skidmore F, Okun M, 2007. A Practical Approach to Movement Disorders : Diagnosis and Medical and Surgical Management. New York, New York, USA: Demos Medical Publishing Galvez Jimenez, 2005. Scientific Basis for the Treatment of Parkinson's Disease. Abingdon, Oxon, United Kingdom: Taylor & Francis Group Gan J, Xie Brustolin J, Mertens P, Polo G, Klinger H, Mollion H et al. Bilateral subthalamic nucleus stimulation in advanced Parkinson's disease: three years follow up. J Neurol 2 007;254(1):99106. Garcia Rill E. The basal ganglia and the locomotor regions. Brain Res. 1986 Mar;396(1):4763.

PAGE 198

198 Gervais Bernard H, Xie Brustolin J, Mertens P, Polo G, Klinger H, Adamec D, Broussolle E, Thobois S. Bilateral subthalamic nucleus stimulation in advanced Parkinson's disease: five year follow up. J Neurol. 2009 Feb;256(2):22533. Epub 2009 Feb 26. Giroux ML. Parkinson disease: managing a complex, progressive disease at all stages. Cleve Clin J Med 2007;74(5):313 4, 7 8, 20 2 passim. Grimes D, 2004. Parkinson's Stepping Forward. Toronto, Canada: Key Porter. Guehl D, Dehail P, de Sze M, Cuny E, Faux P, Tison F et al. Evolution of postural stability after subthalamic nucleus stimulation in Parkinson's disease: a combined clinical and posturometric study. Exp Brain Res 2006;170(2):206 15. Halliday SE, Winter DA, Frank JS, Patla AE, Prince F. The initiation of gait in young, elderly, and Parkinson's disease subjects. Gait Posture. 1998 Aug 1;8(1):814. Hamani C, Richter E, Schwalb J, Lozano A. Bilateral subthalamic nucleus stimulation for Parkinson's disease: a systematic review of the clinical literature. Neurosurgery 2008;62 Suppl 2:86374. Hammond C, Ammari R, Bioulac B, Garcia L. Latest view on the mechanism of action of deep brain stimulation. Movement Disorders 2008;23(15):211121. Hausdorff JM, Schaafsma JD, Balash Y, Bartels AL, Gurevich T., Giladi N. Impaired regulation of stride variability in Parkinsons disease subjects with freezing of gait Exp Brain Res 2003;149:187 194. Hausdorff JM Gruendlinger L, Scollins L O'Herron S Tarsy D Deep brain stimulation effects on gait variability in Parkinson's disease. Mov Disord. 2009 Aug 15;24(11):168892. Herzog J Fietzek U Hamel W Morsnowski A Steigerwald F Schrader B Weinert D Pfister G, Mller D Mehdorn HM Deuschl G Volkmann J Most effective stimulation site in subthalamic deep brain stimulation for Parkinson's disease. Mov Disord. 2004 Sep;19(9):10504. Holloway RG SI, Fahn S, et al. Pramipexole vs Levodopa as Initial Treatment for Parkinson Disease: A 4 Year Randomized Controlled Trial. Arch Neurol 2004;61(7):104453. Hornykiewicz O. Dopamine miracle: From brain homogenate to dopamine replacement. Movement Disorders 2002;17(3):5018. Hufschmidt A, Stark K, Lucking CH. Contractile properties of lower leg muscles are normal in Parkinsons disease. J Neurol Neurosurg Psychiatry 1991; 54: 457 60.

PAGE 199

199 Isaias IU Alterman RL, Tagliati M Deep brain stimulation for primary generalized dystonia: longterm outcomes. Arch Neurol. 2009 Apr;66(4):46570. Jahanshahi M, Jenkins IH, Brown RG, Marsden CD, Passingham RE, Brooks DJ. Self initiated versus externally triggered movements. I. An investigation using measurement of regional cerebral blood flow with PET and movement related potentials in normal and Parkinson's disease subjects. Brain. 1995 Aug;118 ( Pt 4):913 33. Johnsen E, Mogensen P, Sunde N, Ostergaard K. Improved asymmetry of gait in Park inson's disease with DBS: gait and postural instability in Parkinson's disease treated with bilateral deep brain stimulation in the subthalamic nucleus. Mov Disord 2009;24(4):5907. Johnsen EL, Sunde N Mogensen PH Ostergaard K MRI verified STN stimulat ion site gait improvement and clinical outcome. Eur J Neurol. 2010 Mar 22. [Epub ahead of print] Kanthasamy AG Kitazawa M Kanthasamy A Anantharam V Dieldrin induced neurotoxicity: relevance to Parkinson's disease pathogenesis. Neurotoxicology. 2005 A ug;26(4):70119. Karimi M, Golchin N, Tabbal S, Hershey T, Videen T, Wu J et al. Subthalamic nucleus stimulationinduced regional blood flow responses correlate with improvement of motor signs in Parkinson disease. Brain 2008;131(Pt 10):2710 9. Kluger BM, Klepitskaya O, Okun MS. Surgical treatment of movement disorders. Neurol Clin 2009;27(3):63377, v. Koller WC, Glatt S, Vetere Overfield B, Hassanein R. Falls and Parkinson's disease. Clin Neuropharmacol. 1989 Apr;12(2):98105. Kondo T. Initial therapy for Parkinson's disease: levodopa vs. dopamine receptor agonists. J Neurol 2002;249 Suppl 2:II259. Koss AM Alterman RL, Tagliati M Shils JL Calculating total electrical energy delivered by deep brain stimulation systems Ann Neurol. 2005 Jul;58(1):168; author reply 1689 Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C et al. Five year follow up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 2003;349(20):192534. Kumar R, Lozano A, Kim Y, Hutchison W, Sime E, Halket E et al. Doubleblind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson's disease. Neurology 1998;51(3):8505.

PAGE 200

200 Kupsch A, Klaffke S, Khn A, Meissner W, Arnold G, Schneider G. The effects of frequency in pallidal deep brain stimulation for primary dystonia. J Neurol 2003;250(10):1201 5. Levin J Krafczyk S Valkovic P Eggert T Claassen J Btzel K .. Mov Disord. Objective measurement of muscle rigidity in Parkinsonian patients treated with subthalamic stimulation. 2009 Jan 15;24(1):5763. Lewitt PA. Levodopa for the treatment of Parkinson's disease. N Engl J Med 2008;359(23):2468 76. Liu W, McIntire K, Kim S, Zhang J, Dascalos S, Lyons K et al. Quantitative assessments of the effect of bilateral subthalamic stimulation on multiple aspects of sensorimotor function for patients with Parkinson's disease. Park insonism Relat Disord 2 005;11(8):5038. Liu W, McIntire K, Kim S, Zhang J, Dascalos S, Lyons K et al. Bilateral subthalamic stimulation improves gait initiation in patients with Parkinson's disease. Gait Posture 2006;23(4):4928. Liu Y, Postupna N, Falke nberg J, Anderson ME. High frequency deep brain stimulation: what are the therapeutic mechanisms? Neurosci Biobehav Rev 2008;32(3):34351. Lozano A, Snyder B. Deep brain stimulation for parkinsonian gait disorders. J Neurol 2008;255 Suppl 4:301. Lubik S Fogel W, Tronnier V, Krause M, Knig J, Jost W. Gait analysis in patients with advanced Parkinson disease: different or additive effects on gait induced by levodopa and chronic STN stimulation. J Neural Transm 2006;113(2):16373. Marconi R, Landi A, Val zania F. Subthalamic nucleus stimulation in Parkinson's disease. Neurol Sci 2008;29 Suppl 5:S38991. Martin M, Shinberg M, Kuchibhatla M, Ray L, Carollo JJ, Schenkman ML. Gait initiation in community dwelling adults with Parkinson disease: comparison with older and younger adults without the disease. Phys Ther 2002;82:566 77. Maurer C Mergner T Xie J Faist M Pollak P Lcking CH Effect of chronic bilateral subthalamic nucleus (STN) stimulation on postural control in Parkinson's disease. Brain. 2003 May;126(Pt 5):1146 63. Mbourou GA, Lajoie Y, Teasdale N. Step length variability at gait initiation in elderly fallers and nonfallers, and young adults. Gerontology 2003 JanFeb;49(1):216. Miller CA Verstraete MC Determination of the step durati on of gait initiation using a mechanical energy analysis. J Biomech. 1996 Sep;29(9):1195 9.

PAGE 201

201 Mongeon D, Blanchet P, Messier J. Impact of Parkinson's disease and dopaminergic medication on proprioceptive processing. Neuroscience. 2009 Jan 23;158(2):426 40. E pub 2008 Oct 17. Montgomery EJ, Gale J. Mechanisms of action of deep brain stimulation(DBS) Neurosci Biobehav Rev 2008;32(3):388407. Moreau C, Defebvre L, Deste A, Bleuse S, Clement F, Blatt J et al. STN DBS frequency effects on freezing of gait in advanced Parkinson disease. Neurology 2008;71(2):804. Moro E, Esselink R, Xie J, Hommel M, Benabid A, Pollak P. The impact on Parkinson's disease of electrical parameter settings in STN stimulation. Neurology 2002;59(5):70613. Morris ME Iansek R Matyas TA Summers JJ Stride length regulation in Parkinson's disease. Normalization strategies and underlying mechanisms. Brain. 1996 Apr;119 ( Pt 2):55168. Mushiake H, Inase M, Tanji J. Selective coding of motor sequence in the supplementary motor area of the monkey cerebral cortex. Exp Brain Res 1990; 82: 20810. Nieuwboer A, Dom R, De WW, et al. Abnormalities of the spatiotemporal characteristics of gait at the onset of freezing in Parkinsons disease. Mov Disord 2001;16:1066 1075. Nilsson M, Trnqvist A, Rehncrona S. Deepbrain stimulation in the subthalamic nuclei improves balance performance in patients with Parkinson's disease, when tested without anti parkinsonian medication. Acta Neurol Scand 2005;111(5):301 8. Nilsson MH, Fra nsson PA, Jarnlo GB, Magnusson M, Rehncrona S. The effects of high frequency subthalamic stimulation on balance performance and fear of falling in patients with Parkinson's disease.J Neuroeng Rehabil. 2009 Apr 30;6:13. Nutt JG, Fellman JH. P harmacokinetics of Levodopa. Clinical Neuropharmacology 1984;7(1):35 49. Nutt JG. Motor fluctuations and dyskinesia in Parkinson's disease. Parkinsonism & Related Disorders; 2001 Oct;8(2):101 8. Okun M, Fernandez H, Wu S, KirschDarrow L, Bowers D, Bova F et al. Cognit ion and mood in Parkinson's disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial. Ann Neurol 2009;65(5):586 95. OSuilleabhain P Bullard J, Dewey RB. Proprioception in Parkinsons disease is acutely depr essed by dopaminergic medications. J Neurol Neurosurg P sychiatry 2001; 71:607 10.

PAGE 202

202 Pacchetti C, Mancini F, Aglieri R, Fundaro C, Martignoni E, Nappi G. Active music therapy in Parkinson's disease: an integrative method for motor and emotional rehabilitation. Psychosom Med 2000;62(3):38693. Pastor MA Day BL, Marsden CD. Vestibular induced postural responses in Parkinsons disease. Brain1993; 116 :1177 90. Pereira E, Muthusamy K, De Pennington N, Joint C, Aziz T. Deep brain stimulation of the pedunculopontine nucleus in Parkinson's disease. Preliminary experience at Oxford. Br J Neurosurg 2008;22 Suppl 1:S414. Plotnik M, Giladi N, Hausdorff JM. A new measure for quantifying the bilateral coordination of human gait: effects of aging and Parkinsons disease. Ex p Brain Res 2007;181:561 570. Poewe W. Adjuncts to levodopa therapy: dopamine agonists. Neurology 1998;50(6 Suppl 6):S236; discussion S44 8. Potter M, Illert M, Wenzelburger R, Deuschl G, Volkmann J. The effect of subthalamic nucleus stimulation on autog enic inhibition in Parkinson disease. Neurology 2004;63:1234 1239. Radad K, Gille G, Rausch WD. Short review on dopamine agonists: insight into clinical and research studies relevant to Parkinson's disease. Pharmacol Rep 2005;57(6):70112. Ransmayr G. [Th e role of dopaminagonists in the treatment of Parkinson's disease]. Praxis (Bern 1994) 2005;94(42):16338. Rocchi L, Chiari L, Horak F. Effects of deep brain stimulation and levodopa on postural sway in Parkinson's disease. J Neurol Neurosurg Psychiatry 2002;73(3):267 74. Rodriguez Oroz M, Obeso J, Lang A, Houeto J, Pollak P, Rehncrona S Kulisevsky J Albanes e A Volkmann J Hariz MI Quinn NP Speelman JD Guridi J Zamarbide I Gironell A Molet J Pascual Sedano B Pidoux B Bonnet AM Agid Y Xie J Benabid AL, Lozano AM Saint Cyr J Romito L, Contarino MF Scerrati M Fraix V Van Blercom N Bilateral d eep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow up. Brain 2005;128(Pt 10):2240 9. Romito LM, Scerrati M, Contarino MF, Iacoangeli M, Bentivoglio AR, Albanese A. Bilateral high frequency subthalamic stimulation in Park insons disease: Longterm neurological follow up. J Neurosurg Sci 2003; 47:119 128 Romito L, Contarino M, Vanacore N, Bentivoglio A, Scerrati M, Albanese A. Replacement of dopaminergic medication with subthalamic nucleus stimulation in Parkinson's disease : long term observation. Mov Disord 2009;24(4):557 63.

PAGE 203

203 Salarian A RH, Vingerhoets FJ, Dehollain C, Blanc Y, Burkhard PR, Aminian K. Gait assessment in Parkinson's disease: toward an ambulatory system for long term monitoring. IEEE Trans Biomed Eng. 2004 A ug;51(8):1434 43. Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson's disease. A community based study. Brain 2000;123 ( Pt 11):2297305. Schra g A, Jahanshahi M, Quinn N. What contributes to quality of life in patients with Parkinsons di sease? J Neurol Neurosurg Psychiatry 2000; 69:308 312. Scott RM, Brody JA, Schwab RS, Cooper IS. Progression of unilateral tremor and rigidity in Parkinson's disease. Neurology. 1970 Jul;20(7):7104. Schpbach W, Chastan N, Welter M, Houeto J, Mesnage V, Bonnet A et al. Stimulation of the subthalamic nucleus in Parkinson's disease: a 5 year follow up. J Neurol Neurosurg Psychiatry 2005;76(12):16404. Shapiro MB Vaillancourt DE Sturman MM Metman LV Bakay RA Corcos DM Effects of STN DBS on rigidity in Parkinson's disease. IEEE Trans Neural Syst Rehabil Eng. 2007 Jun;15(2):17381. Shivitz N, Koop M, Fahimi J, Heit G, BronteStewart H. Bilateral subthalamic nucleus deep brain stimulation improves certain aspects of postural control i n Park inson's disease, whereas medication does not. Mov Disord 2006;21(8):108897. Stefani A, Lozano A, Peppe A, Stanzione P, Galati S, Tropepi D Pierantozzi M Brusa L Scarnati E Mazzone P Bilateral deep brain stimulation of the pedunculopontine and subthal amic nuclei in severe Parkinson's disease. Brain 2007;130(Pt 6):1596 607. Stefani A, Roberto C, Livia B, Mariangela P, Alberto C, Salvatore G et al. Non motor functions in parkinsonian patients implanted in the pedunculopontine nucleus: Focus on sleep and cognitive domains. J Neurol Sci 2009. Stolze H, Klebe S, Poepping M, Lorenz D, Herzog J, HamelW, Schrader B, Raethjen J,Wenzelburger R, Mehdorn HM, Deuschel G, Krack P Effects of bilateral subthalamic nucleus stimulation on parkinsonian gait. Neurology 2001; 57: 144 146 Tabbal S, Revilla F, Mink J, Schneider Gibson P, Wernle A, de Erausquin G. Safety and efficacy of subthalamic nucleus deep brain stimulation performed with limited intraoperative mapping for treatment of Parkinson's disease. Neurosurgery 2 007;61(3 Suppl):11927; discussion 27 9. Tagliati M. Fine tuning gait in Parkinson dise ase. Neurology 2008;71(2):76 7.

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204 Takakusaki K, Habaguchi T, OhtinataSugimoto J, Saitoh K, Sakamoto T Basal ganglia efferents to the brainstem centres controlling postural muscle tone and locomotion: a new concept for understanding motor disorders in basal gangliadysfunction. Neurosci 2003; 119:293 308 Takakusaki K, Tomita N, Yano M. Substrates for normal gait and pathophysiology of gait disturbances with respect to the basal ganglia dysfunction. J Neurol 2008 Aug;255 Suppl 4:1929. Review. Tanner CM, Aston DA. Epidemiology of Parkinson's disease and akinetic syndromes. Curr Opin Neurol. 2000 Aug;13(4):427 30. Temperli P Ghika J Villemure JG Burkhard PR Bogousslavsky J Vingerhoets FJ How do parkinsonian signs return after discontinuation of subthalamic DBS? Neurology. 2003 Jan 14;60(1):7881. Te rmoz N, Halliday SE, Winter DA, Frank JS, Patla AE, Prince F. The control of upright stance in young, elderly and persons with Parkinson's disease. Gait Posture. 2008 Apr;27(3):463 70. Epub 2007 Jul 17. Timmermann L, Wojtecki L, Gross J, Lehrke R, Voges J Maarouf M et al. Ten Hertz stimulation of subthalamic nucleus deteriorates motor symptoms in Parkinson's disease. Mov Disord 2004;19(11):132833. Uitti RJ Ahlskog JE Maraganore DM Muenter MD Atkinson EJ Cha RH, O'Brien PC Levodopa therapy and survi val in idiopathic Parkinson's disease: Olmsted County project. Neurology. 1993 Oct;43(10):1918 26. Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, Nelson LM. Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. Am J Epidemiol. 2003 Jun 1;157(11):1015 22. van Nuenen BF, Esselink RA, Munneke M, Speelman JD, van Laar T, Bloem BR. Mov Disord. Postoperative gait deterioration after bilateral subthalamic nucleus stimulation in Parkinson's disease. 2008 Dec 15;23(16):24046. Vercueil L, Houeto JL, Krystkowiak P; et al, Spidy GROUP (French Pallidal Stimulation Group for Dystonia). Effects of pulse width variations in pallidal stimulation for primary generalized dystonia. J Neurol. 2007;254(11):15331537. Vitek JL Mechanisms of deep brain stimulation: excitation or inhibition. Mov Disord. 2002;17 Suppl 3:S6972. Viton JM, Timsit M, Mesure S, Massion J, Franceschi JP, Delarque A. Arch Phys Med Rehabil. Asymmetry of gait initiation in patients with unilateral knee arthritis. 2000 Feb;81(2):194200.

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205 Volkmann J, Allert N, Voges J, Weiss PH, Freund HJ, Sturm V: Safety and efficacy of pallidal or subthalamic nucleus stimulation in advanced PD. Neurology 2001; 56:548 551. Watts RL. The role of dopamine agonis ts in early Parkinson's disease. Neurology 1997;49(1 Suppl 1):S3448. Winter DA, Prince F, Frank JS, Powell C, Zabjek KF. Unified theory regarding A/P and M/L balance in quiet stance. J Neurophysiol. 1996 Jun;75(6):2334 43. Weiner WJ. Motor fluctuations in Parkinson's disease. Rev Neurol Dis 2006;3(3):1018. Winogrodzka, A., Wagenaar, R. C., Booij, J., and Wolters, E. C. Rigidity and bradykinesia reduce interlimb coordination in Parkinsonian gait. A rch.Phys.Med.Rehabil. Feb 2005;86 (2): 183 189. Wittwer JE, Andrews PT, Webster KE, Menz HB. Timing variability during gait initiation is increased in people with Alzheimer's disease compared to controls. Dement Geriatr Cogn Disord 2008;26(3):27783. Epub 2008 Oct 8. Wojtecki L, Timmermann L, Jrgens S, Sdmeyer M, Maarouf M, Treuer H et al. Frequency dependent reciprocal modulation of verbal fluency and motor functions in subthalamic deep brain stimulation. Arch Neurol 2006;63(9):12736. Yamada K, Goto S, Hamasaki T, Kuratsu J. Effect of bilateral subthalamic nucleus stimulation on levodopaunresponsive axial symptoms in Parkinson's disease. Acta Neurochir (Wien) 2008;150(1):15 22; discussion. Yu JY, Huang DF, Li Y, Zhang YT. Implementati on of MP3 player for music therapy on hypertension. Conf Proc IEEE Eng Med Biol Soc 2009;1:6444 7. Zahodne L, Okun M, Foote K, Fernandez H, Rodriguez R, Kirsch Darrow L et al. Cognitive declines one year after unilateral deep brain stimulation surgery in P arkinson's disease: a controlled study using reliable change. Clin Neuropsychol 2009;23(3):385405.

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206 BIOGRAPHICAL SKETCH Srikant Vallabhajosula was born and brought up in Hyderabad, India. After completing his bachelor s in m echanical e ngineering in Hyder abad in 2002, he pursued his m aster s in m echanical e ngineering at University of Cincinnati under Dr. Ronald Huston. It was there he started developing an interest in b iomechanics. To pursue further studies, he started his doctoral program at University of Florida and worked with Dr. John Chow, Dr. Mark Tillman and Dr. Chris Hass. Many of the projects he worked on involved studying geriatric population and people with Parkinson disease. His research interests cater towards studying the factors that affect t he quality of life including balance and locomotion among different populations and therapies to improve them.