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Gait and Postural Stability in Persons with Progressive Supranuclear Palsy

Permanent Link: http://ufdc.ufl.edu/UFE0045297/00001

Material Information

Title: Gait and Postural Stability in Persons with Progressive Supranuclear Palsy
Physical Description: 1 online resource (159 p.)
Language: english
Creator: Amano, Shinichi
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2013

Subjects

Subjects / Keywords: biomechanics -- gait -- gi -- parkinsonism -- pd -- posture -- psp
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: Progressive supranuclear palsy (PSP) is a chronic and progressive neurodegenerative disorder associated with early-onset and severe postural instability with frequent falls. Since many cardinal symptoms of PSP are overlapping those of Parkinson’s Disease (PD), PSP is frequently misdiagnosed as PD, making a negative impact of the patients’ quality of life. A review of literature suggests postural instability and gait disturbance(PIGD) can possibly differentiate PSP from PD; however, the knowledge regarding PIGD in PSP is still lacking. Thus, the objective of this study was to determine the underlying biomechanical characteristics of gait and static/dynamic postural control in PSP to gain more insight regarding PIGD in this population and its difference from PD. A total of 36 participants (12 PSP, 12 PD,and 12 age- and gender-matched healthy controls) were tested for static/postural control task, gait initiation (GI), and forward gait. Overall, the PIGD in PSP was more severely altered when compared to PD and healthy elderly peers. The results from static postural control indicated that persons with PSP had pronounced lateral postural instability than PD. Further, this lateral imbalance in PSP could be characterized as less adaptive and more stereotyped postural strategy due to the malfunctioned sensory integration process. The findings from the GI assessment, reduced step length and slower step during gait initiation in persons with PSP could result from the inability to execute anticipatory postural adjustments. Further, their compensatory GI strategy, shifting their center of pressure and center of mass together, was very distinct from PD, but paradoxically induced more lateral postural instability. Reduced cadence and gait velocity, along with increased asymmetry and step variability in PSP gait could stem from increased step width and double support time since persons with PSP preferred a larger safety margin to avoid falling. Given the motor control deficits in PSP worsened with movement, from static to dynamic postural control, assessing the GI performance could potentially help further differentiating PSP from PD. Clinicians and therapists should also emphasize the improvement of lateral postural control, in addition to anteroposterior control, to alleviate postural instability in this population.
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 Shinichi Amano.
Thesis: Thesis (Ph.D.)--University of Florida, 2013.
Local: Adviser: Hass, Christopher J.
Local: Co-adviser: Tillman, Mark D.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-05-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2013
System ID: UFE0045297:00001

Permanent Link: http://ufdc.ufl.edu/UFE0045297/00001

Material Information

Title: Gait and Postural Stability in Persons with Progressive Supranuclear Palsy
Physical Description: 1 online resource (159 p.)
Language: english
Creator: Amano, Shinichi
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2013

Subjects

Subjects / Keywords: biomechanics -- gait -- gi -- parkinsonism -- pd -- posture -- psp
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: Progressive supranuclear palsy (PSP) is a chronic and progressive neurodegenerative disorder associated with early-onset and severe postural instability with frequent falls. Since many cardinal symptoms of PSP are overlapping those of Parkinson’s Disease (PD), PSP is frequently misdiagnosed as PD, making a negative impact of the patients’ quality of life. A review of literature suggests postural instability and gait disturbance(PIGD) can possibly differentiate PSP from PD; however, the knowledge regarding PIGD in PSP is still lacking. Thus, the objective of this study was to determine the underlying biomechanical characteristics of gait and static/dynamic postural control in PSP to gain more insight regarding PIGD in this population and its difference from PD. A total of 36 participants (12 PSP, 12 PD,and 12 age- and gender-matched healthy controls) were tested for static/postural control task, gait initiation (GI), and forward gait. Overall, the PIGD in PSP was more severely altered when compared to PD and healthy elderly peers. The results from static postural control indicated that persons with PSP had pronounced lateral postural instability than PD. Further, this lateral imbalance in PSP could be characterized as less adaptive and more stereotyped postural strategy due to the malfunctioned sensory integration process. The findings from the GI assessment, reduced step length and slower step during gait initiation in persons with PSP could result from the inability to execute anticipatory postural adjustments. Further, their compensatory GI strategy, shifting their center of pressure and center of mass together, was very distinct from PD, but paradoxically induced more lateral postural instability. Reduced cadence and gait velocity, along with increased asymmetry and step variability in PSP gait could stem from increased step width and double support time since persons with PSP preferred a larger safety margin to avoid falling. Given the motor control deficits in PSP worsened with movement, from static to dynamic postural control, assessing the GI performance could potentially help further differentiating PSP from PD. Clinicians and therapists should also emphasize the improvement of lateral postural control, in addition to anteroposterior control, to alleviate postural instability in this population.
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 Shinichi Amano.
Thesis: Thesis (Ph.D.)--University of Florida, 2013.
Local: Adviser: Hass, Christopher J.
Local: Co-adviser: Tillman, Mark D.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-05-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2013
System ID: UFE0045297:00001


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1 GAIT AND POSTURAL STABILITY IN PERSONS WITH PROGRESSIVE SUPRANUCLEAR PALSY By SHINICHI AMANO 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 2013

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2 2013 Shinichi Amano

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3 To my mother, wife, and children

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4 ACKNOWLEDGMENTS First, I thank my mot her for her long term support to help me achieve my go als I also thank my wife and children fo r allowing me to leave them in Japan and to come to the University of Florida for my doctorate program in the United States. I could not have come this far without her unconditional support and their encouragement. I thank Dr. Chris Hass for his conti nuous support and mentorship during my academic career. I thank Dr. Nikolaus McFarland for giving me the opportunity to start my dissertation project and for his valuable suggestion s and comments based on his clinical ex pertise of progressive supranuclear palsy throughout my project I also thank my Committee Members, Dr. Mark Tillman and D r. Christopher Janelle for their patience and great feedback. I would like to thank Dr. Elizabeth Stegemoller and Amy Snyder for their time to recruit participants. I also would like to thank Dr. Nawaz Hack for helping me score patient s clinical characteristics. My project could not have been completed without help from Jared Skinner and Hyokeun Lee, who constantly help ed me recruiting subjects, collecting and processing data. Finally, I would like to thank all of my colleagues in the Biomechanics Laboratory and the Applied Neuromechanics Laboratory for their friendship, encouragement, and feedbacks throughout my time in Gainesville.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 8 LIST OF FIGURES ................................ ................................ ................................ .......... 9 LIST OF ABBREVIATIONS ................................ ................................ ........................... 13 ABSTRACT ................................ ................................ ................................ ................... 16 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 18 Background ................................ ................................ ................................ ............. 18 Objective of the Study ................................ ................................ ............................. 19 Specific Aims and Hypotheses ................................ ................................ ............... 20 Specific Aim 1 ................................ ................................ ................................ ... 20 Specific Aim 2 ................................ ................................ ................................ ... 21 Specific Aim 3 ................................ ................................ ................................ ... 21 2 REVIEW OF LITERATURE ................................ ................................ .................... 22 Progressive Supranuclear Palsy ................................ ................................ ............. 22 Epidemiology of PSP ................................ ................................ .............................. 22 Etiology and Patholog y of PSP ................................ ................................ ............... 23 Clinical F eatures of PSP ................................ ................................ ......................... 24 Diagnostic and Therapeutic Challenge in PSP ................................ ....................... 25 ................................ ................................ ............................... 27 Epidemiology of PD ................................ ................................ ................................ 28 Etiology and Pathology of PD ................................ ................................ ................. 28 Functional Anatomy Related to Gait and Postural Control ................................ ...... 29 Basal Ganglia ................................ ................................ ................................ ... 29 Thalamus ................................ ................................ ................................ .......... 31 Cerebellum ................................ ................................ ................................ ....... 32 Static P ostural I nstability in PSP and PD ................................ ................................ 35 Dynamic P ostural S tability in PSP and PD ................................ ............................. 40 Gait D isturbance in PSP and PD ................................ ................................ ............ 42 3 METHODS ................................ ................................ ................................ .............. 44 Participant Recruitment ................................ ................................ ........................... 44 Inclusion Criteria ................................ ................................ ............................... 44 Exclusion C riteria ................................ ................................ ............................. 45

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6 Equipment ................................ ................................ ................................ ............... 45 Clinical evaluations ................................ ................................ ................................ 46 Experimental Protocol ................................ ................................ ............................. 46 Methodology Designed to Achieve Specific Aim 1 ................................ ........... 46 Methodology Designed to Achieve Specific Aim 2 ................................ ........... 47 Metho dology Designed to Achieve Specific Aim 3 ................................ ........... 47 Data Processing and Outcome Measures ................................ .............................. 48 Aim 1 ................................ ................................ ................................ ................ 48 Mean COP velocity ................................ ................................ .................... 48 95% confidence e llipse a rea ................................ ................................ ...... 48 Approximate e ntropy ................................ ................................ .................. 49 Time to boundary ................................ ................................ ....................... 49 Frequency domain analysis ................................ ................................ ....... 51 Aim 2 ................................ ................................ ................................ ................ 51 Aim 3 ................................ ................................ ................................ ................ 52 Statistical Analyses ................................ ................................ ................................ 52 Aim 1 ................................ ................................ ................................ ................ 53 Aim 2 and 3 ................................ ................................ ................................ ...... 54 4 RESULTS ................................ ................................ ................................ ............... 57 Aim 1: Static Postural Control (EO and EC Condition) ................................ ........... 57 Mean COP Velocity ................................ ................................ .......................... 57 95% Confidence Ellipse Area ................................ ................................ ........... 57 Approximate Entropy ................................ ................................ ........................ 58 Time to Boundary ................................ ................................ ............................. 58 Frequency Domain Analyses ................................ ................................ ............ 60 Aim1: Static Postural Control (FOAM Condition) ................................ .................... 61 Mean COP Velocity ................................ ................................ .......................... 61 95% Confidence Ellipse Area ................................ ................................ ........... 61 Approximate Entropy ................................ ................................ ........................ 62 Time to Boundary ................................ ................................ ............................. 62 Frequency Domain Analyses ................................ ................................ ............ 62 Aim 2: Dynamic Postural Control ................................ ................................ ............ 63 Spatiotemporal Characteristics ................................ ................................ ......... 63 COP Characteristics ................................ ................................ ......................... 64 COPCOM Characteristics ................................ ................................ ................. 65 Aim 3: Gait ................................ ................................ ................................ .............. 65 5 DISCUSSION ................................ ................................ ................................ ....... 120 Aim 1: Static Postural Control ................................ ................................ ............... 120 Aim 2: Dynamic Postural Control ................................ ................................ .......... 127 Aim 3: Gait ................................ ................................ ................................ ............ 133 Limitations ................................ ................................ ................................ ............. 138 Conclusion ................................ ................................ ................................ ............ 139

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7 LIST OF REFERENCES ................................ ................................ ............................. 141 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 159

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8 LIST OF TABLES Table page 4 1 Demographic information and clinical characteri stics of each group ................ 107 4 2 Mean values (SD) of COP velocity and 95% confidence ellipse area of each group in Eyes open and Eyes closed conditions ................................ .............. 108 4 3 Mean values (SD) of approximate entropy of each group in Eyes open and Eyes closed conditions ................................ ................................ ..................... 109 4 4 Mean values (SD) of the Time to boundary measures of each group in Eyes open and Eyes closed conditions ................................ ................................ ..... 110 4 5 Mean (SD) relative power distribution in each frequency bandwidth in each group in Eyes open and Eyes closed conditions ................................ .............. 111 4 6 Mean values (SD) of COP velocity and 95% confidence ellipse area of each group in the FOAM condition ................................ ................................ ............ 112 4 7 Mean values (SD) of approximate en tropy of each group in the FOAM conditions ................................ ................................ ................................ ......... 113 4 8 Mean values (SD) of outcome measures of the Time to boundary analysis of each group in the FOAM condition ................................ ................................ ... 114 4 9 Mean (SD) relative power distribution in each frequency bandwidth in each group in the FOAM condition ................................ ................................ ............ 115 4 10 Spatiotemporal characteristics during gait i nitiation in each group ................... 116 4 11 COP characteristics during gait initiation ................................ .......................... 117 4 12 COPCOM distance during each phase of gait i nitiation ................................ .... 118 4 13 Spatiotemporal characteristics of forward gait in each group ........................... 119

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9 LIST OF FIGURES Figure page 3 1 Experimental s et up. A 10 camera motion capture system along with the three force platforms, and the orientation of the axes. ................................ ........ 55 3 2 Marker placement. The thirty five reflective markers was placed over in Gait model. ............................. 56 4 1 The mean and standard deviation of 95% confidence ellipse area (A95) in the .... 68 4 2 The mean and standard deviation of approximate entropy (ApEn) in the mediolateral direction in the EO and EC cond itions a significant difference ................................ ................................ ...................... 69 4 3 The mean and standard deviation of the number of inversed TTB peaks (numPeakTTBs) on LAS in the EO and EC conditions. a signi ficant ................................ ................................ ..... 70 4 4 The mean and standard deviation of the mean TTB in the posterior direction in the EO and EC conditions. ................................ ................................ ............. 71 4 5 The mean and standard deviation of the total number of inversed TTB peaks (numPeakTTBs) in the EO and EC conditions. a significant difference was observed ( p ................................ ................................ ............................. 72 4 6 The mean and standard deviation of the minimum TTB in the posterior direction in the EO and EC conditions. a significant difference was observed ( p ................................ ................................ ............................. 73 4 7 The mean and st andard deviation of the minimum TTB on MAS in the EO and EC conditions. a significant difference was observed ( p ................ 74 4 8 Average power spectra for each group of the frequency distribut ion of the COP trajectories in the anteroposterior direction for the EO condition. .............. 75 4 9 Average power spectra for each group of the frequency distribution of the COP trajectories in the medi olateral direction for the EO condition. ................... 76 4 10 Average power spectra for each group of the frequency distribution of the COP trajectories in the anteroposterior direction for the EC conditio n. ............... 77 4 11 Average power spectra for each group of the frequency distribution of the COP trajectories in the mediolateral direction for the EC condition. ................... 78

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10 4 12 The mean and standard deviation of the 95% power frequency (F95) in the mediolateral direction for each group in the EO and EC conditions .................... 79 4 13 The mean and standard deviation of distributed power in the frequency bandwidth (Bin1 5) in the mediolateral direction of each group in the EO and EC conditions. a significant difference was observed ( p ....................... 80 4 14 The mean and standard deviation of distributed power in the frequency bandwidths (Bin1 5) in the anteroposterior direction of each group in the EO and EC conditions. a significant difference was observed ( p ................ 81 4 15 The mean and standard deviation of the number of inversed TTB peaks (numPeakTTBs) in the posterior direction in the FOAM conditions a significant difference was observed ( p ................................ ..................... 82 4 16 Average power spectra for each group of the frequency distribution of the COP trajectories in the anteroposterior direction in the FOAM condition. ........... 83 4 17 Average power spectra for each group of the frequency distribution of the COP trajectories in the mediolateral direction in the FOAM condition. ............... 84 4 18 The mean and standard deviatio n of the 95% power frequency (F95) in the mediolateral direction for each group in the FOAM condition. A significant main effect for Group was observed ( p 0.05). § The post hoc Steel Dwass test detected a significant trend between the PSP and Control gro up ( p = 0.06). ................................ ................................ ................................ .................. 85 4 19 The mean and standard deviation of distributed power in the frequency bandwidths (Bin1 5) in the mediolateral direction of each group in the FOAM conditions. a signifi ............................. 86 4 20 The mean and standard deviation of distributed power in the frequency bandwidths (Bin1 5) in the anteroposterior direction of each group in the F .................. 87 4 21 The center of pressure (COP) and center of mass (COM) trajectories of the representative participants from each group during gait initiation. ...................... 88 4 22 The mean and standard deviation of step length in each group during gait ................................ 89 4 23 The mean and standard deviation of step velocity in each group during gait ................................ 90 4 24 The mean and standard deviation of step width in each group during gait initiation. ................................ ................................ ................................ ............. 91

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11 4 25 The mean and standard deviation of COP displacement in the S1 phase during gait initiation. Positive values in the anteroposterior direction represent anterior COP displacement and vice versa. Positive values in the mediolateral direction represent COP displacement toward initial trailing (ST) limb. a significant difference was observe ................................ ....... 92 4 26 The mean and standard deviation of COP displacement in the mediolateral direction during the S2 and in the anteroposterior direction during the S3 phase during gait initiat ion. Positive values in the anteroposterior direction represent anterior COP displacement and vice versa. Positive values in the mediolateral direction represent COP displacement toward initial trailing (ST) limb. a significant difference was observed (p ................................ ....... 93 4 27 The mean and standard deviation of COP velocity in the S1 phase during gait initiation. Positive values in the anteroposterior direction represent the anterior direction and vi ce versa. Positive values in the mediolateral direction represent the direction toward the initial trailing (ST) limb. a significant ................................ ................................ ..... 94 4 28 The mean and st andard deviation of anteroposterior COP velocity in the S3 phase during gait initiation. Positive values in the anteroposterior direction represent the anterior direction. a significant difference was observed ................................ ................................ ................................ ............. 95 4 29 The mean and standard deviation of anteroposterior, mediolateral and resultant COPCOM distance in each phase during gait initiation. a significant difference was observed ( p § a significant trend between the P SP and the PD group ( p <0.06). ................................ ................................ ........ 96 4 30 The mean and standard deviation of gait velocity during gait in each group. diff erence was observed ( p ................................ ................................ ..... 97 4 31 The mean and standard deviation of step length during gait in each group. difference was observed ( p 5). ................................ ................................ ..... 98 4 32 The mean and standard deviation of step duration during gait in each group. ................................ ... 99 4 33 The mean and standard deviation of cadence during gait in each group. a significant difference was observed ( p § A significant trend between the PSP and Control group was observed ( p <0.06). ................................ ........ 100 4 34 The mean and standard deviation of step width during gait in each group. Step width was normaliz difference was observed ( p ................................ ................................ ... 101

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12 4 35 The mean and standard deviation of double support time during gait in each group. Double support time significant difference was observed ( p ................................ ................... 102 4 36 The mean and standard deviation of gait asymmetry during gait in each group. Gait asymme try index was calculated based on swing time of both limbs. a significant difference was observed ( p ................................ ... 103 4 37 The mean and standard deviation of coefficient of variation (CV) of step length on MAS and LAS during gait in each group. a significant difference was observed ( p ................................ ................................ .................... 104 4 38 The mean and standard deviation of coefficient of variation (CV) of step duration on MAS and LAS during gait in each group. a significant difference was observed ( p ................................ ................................ .................... 105 4 3 9 The mean and standard deviation of coefficient of variation (CV) of d ouble support time durin g gait in each group. a significant difference was observed ( p § a significant trend between the PSP and the PD group was observed ( p <0.06). ................................ ................................ .................... 106

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13 LIST OF ABBREVIATIONS A95 95% confidence ellipse area ADNP activity dependent neuroprotective protein ANOVA a nalysis of variance AP anteroposterior APA anticipatory postural adjustment ApEn approximate entropy BOLD blood oxygenation level dependent BOS base of support COG center of gravity COM center of mass COP center of pressure COPCOM distance between center of pressure and center of mass COPDisp center of pressure displacement COPVel center of pressure velocity CV coeffic ient of variation DBS deep brain stimulation DSCT dorsal spinocerebellar tract EC eyes closed EMG el ectromyography/electromyographic EO eyes open FFT Fast Fourier Transform FOAM on a compliant foam GC gait cycle GI gait initiation

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14 GPe external globus pallidus GPi in ternal globus pallidus GRF ground reaction force IEED involuntary emotional expression dis order LAS less affected side LB Lewy body LL leg length M1 primary motor (area) MANOVA multivariate analysis of variance MAS more affected side meanTTB mean of peak time to boundary values minTTB minimum peak time to boundary value ML mediolateral MMSE min i mental status exam MNP mean normalized power NFT neurofibrillary tangle NINDS the National Institute of Neurological Disorders numPeakTTBs number of inversed peak TTBs PBA pseudobulbar affect PD Parkinson s disease PDQ 39 e 39 PFC prefrontal cortex PIGD postural instability and gait disturbance PM premotor PPN pedunculopontine nucleus

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15 PSP progressive supranuclear palsy PSPRS progressive supranuclear palsy rating scale QOL quality of life rCGM regional cerebral glucose metab olism RQA recurrent quantification analysis SCP superior cerebellar peduncle SDA stabilogram diffusion analysis SMA s upplementary motor area SN substantia nigra SNpc substantia nigra pars compacta SNpr substantia nigra pars reticulate SPSP Society for Prog ressive Supranuclear Palsy ST stance/trailing stdTTB standard deviation of peak time to boundary values STN subthalamic nucleus SW swing/stepping TTB time to boundary UPDRS unified Parkinson s disease rating scale VA ventralanterior VLm ventrolateral pars medialis VLo ventrolateral pars oralis VSCT ventral spinocerebellar tract

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16 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 Philoso phy GAIT AND POSTURAL STABILITY IN PERSONS WITH PROGRESSIVE SUPRANUCLEAR PALSY By Shinichi Amano May 2013 Chair: Chris Hass Cochair: Mark Tillman Major: Health and Human Performance Progressive supran uclear palsy (PSP) is a chronic and progressive neurod egenerative disorder associated with early onset and severe postural instability with frequent falls Since many cardinal symptoms of PSP are overlapping those of impact of t he A review of literature suggests postural instability and gait disturbance (PIGD) can possib ly differentiate PSP from PD ; however, t he knowledge regarding PIGD in PSP is still lacking. Th us, t he objective of this study was to determine the underlying biomechanical characteristics of gait and static/dynamic postural control in PSP to gain more insight regarding PIGD in this population and i ts difference from PD A total of 36 participants (12 PSP, 12 P D, and 12 age and gender matched healthy controls) were tested for static postural control task, gait initiation (GI) and forward gait Overall, the PIGD in PSP was more severel y altered when compared to PD and healthy elderly peers. The results from static p ostural control indicated tha t persons with PSP had pronounced lateral postural instability than PD F urther, this lateral imbalance in PSP could be characterized as less adaptive and more stereotyped

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17 postural strategy due t o the malfunctioned sensory integration process. The finding s from the GI assessment reduced step length and slower step during gait initiation in persons with PSP could result f rom the inability to execute anticipatory postural adjustm ent s. F urther, t heir compensatory GI stra tegy shifting their center of pressure and center of mass together, was very distinct from PD but paradoxically induced more lateral postural instability. R e duced cadenc e and gait velocity along with increased asymmetry and step variability in PSP gait could stem from increased step width and double support time since persons with PSP preferred a larger safety margin to avoid falling Given the motor control deficits in PSP worsened with movement, from static to dy namic postural control assessing the GI performance could potentially help further differentiating PSP from PD. C linicians and therapists should also emphasize the improvement of lateral postural control in ad dition to anteroposterior control, to alleviate postural instability in this population

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18 CHAPTER 1 INTRODU C TION Background Progressive supranuclear palsy (PSP) is a chronic, progressive neurodegenerative disorder associated with early onset and severe postural instability with frequent falls axial rigidity, vertical gaze palsy, supranuclear ophthalmoplegia, pseudobulbar affect (PBA), involuntary emotional expression disorder (IEED), and cognitive dysfunction. The incidence o f PSP is rare; however it is the most common form of atypical parkinsonism, constituting up to 10% of all cases of Parkinsonism [ 1 2 ] quality of life (QOL). One of the most reliable diagnostic tool s for PSP is neuroimaging, but it creates a n extra financial burden for patients and their family and is not always available in some clinics Therefore, diagnosis of PSP in clinical sites currently relies on subjective clinical evaluations. To improve the sensitivity of the clinical diagnosis of PSP, the National Institute of Neurological Disorders and Stroke (NINDS) and the Society for Progressive Supranuclear Palsy, Inc. (SPSP) developed the standardized diagnostic criteria, NINDS SPSP. According to this criteria, the clinical diagnosis of PSP requires both the presence of the vertical supranuclear palsy and prominent postural instability with falls in the first year of disease onset [ 3 ] Despite the develop ment of the clinical diagnostic criteria, the diagnosis of PSP is still difficult and challenging since many PSP cases are more divers e and since the diagnostic criteria might be still robust and subjective. Therefore, more proper and objective assessment of PSP may be neces sary to correctly diagnose PSP

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19 Currently, treatments for PSP are based on neu rotransmitter replacement and palliative care, but these approach es show disappointing results with only partial and transient effects due to lack of understanding of the pathophysiology [ 4 ] Given the fact that no effective cure or treatment is available for persons with PSP, it is necessary to develop a rehabilitation paradigm that can alleviate the disabling symptoms and maintain their QOL. Moreover, early and accurate assessment of the primary disabling features is essential to provide adeq uate rehabilitations that might help them maintain ing their QOL One of the major clinical features that can possib l y differentiate PSP from PD is postural instability and gait disturbance (PIGD) Unlike PD, persons with PSP mostly exhibit postural instab ility and experience falls within first year of symptom onset [ 4 ] In fact, Litvan and colleagues [ 5 ] suggested that unstable gait can be the one of the attributes that separates PSP from PD, along with absence of tremor and response to lev odopa. Given the fact that the gait assessment is typically done in the clinic using insensitive motor scales (scale of 0 4 in this previous study ) we speculated that biomechanical gait assessment can further identify the difference between PSP and PD. Ul timately, understanding biomechanical characteristics of postural control and gait in PSP and comparing to those in PD may help clinicians to correctly classify PSP and PD at early stage. Objective o f t he Study The objective of this study wa s to determine the underlying biomechanical characteristics of gait and static/dynamic postural control in PSP to gain more insight regarding PIGD in persons with PSP and its difference from persons with PD

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20 Specific Aims a nd Hypotheses Specific Aim 1 S pecific aim 1 wa s t o determine the underlying biomechanical characteristics of static postural control in persons with PSP and to determine the difference between PSP and PD. Hypothesis 1 First, we hypothesize d that persons with PSP and PD would exhibit postural instabi lity when compared to the age and gender matched healthy elderly individuals. T his would be evidenced by alternation of postural sway char acteristics including : (1) larger, but reduce d complexity in sway variability (2) reduced sensitivity of spatiotempo ral proximity relative to limit of stability and (3) lower frequency of postural control in both pathological populations (i.e., PSP and PD) when compared to their healthy counterparts Second r egarding the difference between PSP and PD, w e also hypothes ize d that persons with PSP would show more severe postural instability during quiet standing due to the combined deficits of all af ferent systems contributing to postural control (i.e., proprioception, visual and vestibular system s ) compared to persons wi th PD whose deficits are usually limited in their proprioceptive system This difference would be evidenced by : (1) more pronounced reduction of complexity in sway variability, (2) the power shift from the higher frequency to the lower frequency regions i n persons with PSP and (2) more pro minent delay to detect spatiotemporal proximity relative to limit of stability, under the conditions in which the afferent information (i.e., visual or somatosensory) is removed or manipulated

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21 Specific Aim 2 S pecific aim 2 was t o determine the underlying biomechanical characteristics of dynamic postural control in persons with PSP and to determine th e difference between PSP and PD Hypothesis 2 First, we hypothesized that both persons with PSP and PD would exhibit more d ynamic postural instability during gait initiation (GI) in comparison with the age and gender matched healt hy elderly individuals. Second w e also hypothesize d that persons with PSP would exhibit more severe dynamic postural instability compared to person s with PD. These differences w ould be evidenced by: ( 1 ) more pronounced impairments in feed forward postural control during planning phase of GI, (2) more pronounced inefficiency in generating required forward momentum prior to step initiation during GI a nd (3) more pronounced alternation of spatiotemporal parameters during GI Specific Aim 3 Specific aim 3 wa s t o determine the underlying biomechanical characteristics of gait in persons with PSP and to determine the difference between PSP and PD. Hypothesi s 3 We hypothesize d that persons with PSP have more severe gait dysfunction when compared to persons with PD. This will be evidenced by more pronounced alteration in spatiotemporal parameters (e.g., step length, gait velocity, double support time).

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22 CHAPT ER 2 REVIEW OF LITERATURE Progressive Supranuclear Palsy Progressive supranuclear palsy (PSP) is a chronic, progressive neurodegenerative disorder associated with severe postural instability, vertical gaze palsy, supranuclear ophthalmoplegia, pseudobulbar affect (PBA), involuntary emotional expression disorder (IEED), and cognitive dysfunction [ 4 6 7 ] This disease was named progressive supranuclear palsy, referring to the progressive degeneration of the brain structures localized superior to the oculomotor nuclei, causing palsy and eventual paralysis of ocular m ovements [ 8 ] It is also called, but not as often as PSP, Steele Richardson Olszewski syndrome [ 9 ] PSP is the most common form of atypical p arkinsonism constituting up to 10% of all cases of parkinsonism [ 1 2 ] Sin ce the symptoms of PSP resemble th ose of Parkinson s disease (PD), pat ients with PSP are often misdiagnosed as PD, resulting in delay of correct therapeutic and pharmacological treatments. Epidemiology of PSP The average age of onset for PSP is estimated 60 65 years; however early onset PSP cases are also documented [ 10 12 ] The mean survival time is approximately 6 years and very few patients with PSP can survive more than 15 years [ 13 ] The incidence of PSP is rare f or instance, Golbe and colleagues reported a rare occurrence of 1.39 cases per 100,000 people in New J ersey [ 10 ] The other state based epidemiological study conducted in Olmsted County in Minnesota reported the annual incident rate of PSP between 1976 and 1990 was 5.3 per 100,000 while the prevalence of PSP in London, UK was 6.4 per 100,000 [ 7 ] However, these estimates are likely to

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23 low due to under diagnosis and misdiagnosis of PSP [ 7 14 ] Although PSP does not appear to favor any geographi cal, ethnic, racial, or occupational factors, males are slightly more susceptible than females, evidenced by male to female ratio as 1.5:1 [ 15 ] Etiology and Pathology of PSP PSP is characterized by neurode ge neration, gliosis, and the abnormal accumulation of tau proteins in various regions of the central nervous system ( CNS ) such as basal ganglia, brain stem, thalamus, prefrontal cortex and cerebellum [ 8 16 ] The tau protein abundantly exists in the central nervous system to stabilize the axonal microtubules in the cytoskeleton of neurons [ 17 ] Microtubules are crucially important to maintain cell structure and functioning as the pathway for intracellular protein transport. Normally, tau protein is soluble and binds reversibly to microtubules. However in the neurodegenerative disorders, such as Alzheimer's disease and PSP, tau protein becomes resistant to proteolysis and partially crystallized creating abnormal amounts of tangled fibers (Neurofibrillary tangles: NFTs). It will eventually result in cellular death in an affected region [ 18 ] The brain diseases due to the abnormal accumulation of tau deposits in a human brain are called tauopathy. Although a growing evidence suggested oxidative stress and m itochondrial dysfunction are associated with NFT formation and cell death, the mechanisms of NFT formation and following cell death are not still fully understood [ 17 ] .Tufted astrocytes are also frequently present in motor cortex and striatum in PSP [ 19 ] Additionally, post mortal b rains in persons with PSP showed unique features such as mild atrophy in frontal region, midbrain, and basal ganglia. The substantia nigra (SN) is smaller than normal and it sometimes shows loss of pigment [ 20 ] T he basal ganglia and the cerebell um are involved in control of voluntary

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24 movements [ 21 ] Specifically, basal ganglia disorders are manifested by an inability to initiate voluntary movements, an inability to suppress involuntary movements, an abnorma lity in the velocity and amount of movement, and an abnormal muscle tone. Gait disturbances are also a major symptom for persons with basal ganglia disorder, such as PD [ 22 23 ] Therefore, the lesion in those regions could result in the various symptoms observed in persons with PSP, such as postural instability, emotional disorder, and cognitive dysfunction. Cli nical F eatures of PSP The cardinal clinical features of PSP are supranuclear gaze palsy, and early onset postural instability and gait d isturbance (PIGD) with fall s Persons with PSP have profound impairment of downward gaze, but impairment of upward and/o r horizontal gaze are also common. Slowing of saccades and hypometric saccades may precede the supranuclear limitation of vertical gaz e [ 24 ] Dysfunction of voluntary eyelid movements is often observed in PSP, leading to voluntary eyelid motility impai rment in late stage [ 25 ] Photophobia or painful oversensitivity of light is also common; thus many persons with PSP prefer to wear sunglasses during wak ing hours Behavioral disturbance, such as apathy, depression, and anxiety are often observed in persons with PSP. However, of its cardinal features, PIGD are the most disablin g symptoms which significantly reduce individuals mobility and QOL Postural i nstability in persons with PSP is severe, and it can be described as poor balance or feeling dizzy Gait in persons with PSP can be described as drunken sailor or dancing bear manifesting large lateral deviations and step asymmetry [ 3 17 ] However, freezing is less common when compared to persons with PD. When turning, persons with PSP tend to pivot with ab normally small steps.

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25 Although frequent backward falls and severe immobility is a hallmark of PSP, only a few studies investigated the biomechanical mechanism underlying PIGD in persons with PSP, and it still remains largely unknown. Diagnostic and Therap eutic Challenge in PSP Due to its rarity and resemblance to PD in terms of symptoms, persons with PSP are frequently misdiagnosed as PD [ 5 26 ] A previous study reported that less than half of PSP patients have received the correct diagnosis, and approximately 20% will have had a different diagnosis at the time of death [ 27 ] One of the most reliable diagnostic tools for PSP is neuroimaging, such as magnetic resonance imagin g [ 28 29 ] and transcranial brain parenchyma sonography [ 30 31 ] However, it is not always available to clinics and creates additional financial burden to patients. Therefore, diagnosis of PSP in clinical sites curren tly relies on subjective clinical evaluations. Progressive Supranuclear Palsy Rating Scale ( PSPRS ) [ 32 ] and the revised National Institute of Neurological Disorders and Stroke Society for Progressive Supranuclear Palsy workshop criteria ( NINDS SPSP ) [ 3 ] are most frequently used clinical ratin g scales to assess the level of impairments of PSP patients. Although is designed for assessment of PD, its motor section has been reported to be valid for patients with PSP as well [ 33 ] Despite the existence of these well known diagnostic criteria, the diagn osis of PSP is still difficult and challenging, which results in the frequent misdiagnosis of PSP as PD. Indeed, Santacruz and colleagues [ 34 ] reported that one third of the PSP cases had been misdiagnosed as PD. There is the other previous study which reported that PSP is correctly diagnosed onl y 75% of its cases in the United States [ 35 ] The possible reasons of this misdiagnosis are robustness and subjectivity of diagnostic criteria for

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26 PSP, as well a s inexperience of clinicians to diagnose PSP. Therefore, more proper and objective assessment of PSP independent o n clinicians is necessary to correctly and feasibly diagnose PSP. Currently, treatments for PSP are based on neurotransmitter replacement pharmacological therapy and palliative care, but these approach es show disappointing results with only partial and transient effects due to lack of understanding of the pathophysiology [ 4 ] Use of antiparkinsonian medications was mostly ineff ective and even caused adverse effects to the persons with PSP [ 36 ] The pharmacological industry recently proposed a davunetide treatment to persons with PSP [ 37 ] Davunetide is the fr agment of activity dependent neuroprotective protein (ADNP) that might be able to slow down the neurodegeneration of cytoskeletons in the tauopathies. In an animal study, the 5 month daily davunetide treatment to transgenic mice successfully reduced the le vels of hyperphosphorylated tau and NFTs [ 38 ] Thus, davunetide can be a candidate for the treatment of tau o pathies, including PSP. Unfortunately, davunetide is still in a Phase II clinical study of patients with cognitive impairments and there is no clinical study of persons with PSP to date. Given the fact that no effective cure or treatment is currently available for persons with PSP, it is necessary to devel op a rehabilitation paradigm that can alleviate the disabling symptoms and maintain ing their QOL Moreover, early and accurate diagnosis is essential to provide adequate rehabilitati ons programs for this pathological population In spite of the need of eff ective physical therapies in PSP, the re is a paucity of stud ies objectively and quantitatively evaluating postural control and gait abilities in

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27 this population Until we fully understand their decrements, we cannot devise evidenced based therapy protocols One of the major clinical features that can possi bly differentiate PSP from PD is PIGD Unlike PD, persons with PSP mostly start experienc ing postural instability and falls within first year of symptom onset [ 4 ] In fact, Litvan and colleagu es [ 5 ] used the logistic regression, as well as classification and regression tree analysis, to differentiate various types of neurological disorders including PSP and PD. They suggested that unstable gait can be the one of the attributes that separates PSP from PD, along with absence of tremor and response to levodopa. Also, the recent imaging study showed that gait/midline sub score of PSPRS was strongly correlated with the imaging measures, such as the total brain volume, and midbrain volume [ 39 ] This findings further strengthen s our postulation that the gait and balance performance could be a very sensitive measure to aid in the differential diagnose s of PSP. Given the fact that t he gait assessment used in Litvan s logistic regression study was subjective and unsophisticated (scale of 0 4) we speculated that biomechanical gait assessment can further identify the difference between PSP and PD. Ultimately, understanding biomechanica l characteristics of gait in PSP and comparing to that in PD may help clinicians to correctly classify PSP and PD at early stage. Parkinson s Disease Parkinson s disease (PD) is a chronic and progressive neurodegenerative disorder characterized by a varie ty of motor and non motor features that hugely impacts patients daily life [ 40 ] The cardinal symptoms of PD include resting tremor, rigidity bradykinesia, and postural instability [ 41 ] which means some of the cardinal symptoms are overlapped with those of PSP. The non motor symptoms that may appear in the

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28 later stage of PSP, such as depressi on, apathy, anxiety, and cognitive dysfunction, often occur the early stages of PD [ 42 44 ] Although its progression is slower than PSP, the wide range of both motor and non motor symptoms of PD also negatively impacts individuals QOL as the disease progresses [ 45 ] Epidemiology of PD S i milar to PSP, PD is a neurologic al disorder of later life. The average age of onset is estimated approximately 60 to 65 years [ 46 ] Early onset of PD is rare, approximately 4% of persons with P D developed the sign of PD prior to the age of 50 years [ 47 ] About 1 to 2 % of the population over age of 65 is affected by this disease, and the proportion increases with age. The annual incidence rate in the United States is ranged from 11 to 20 per 100,000 [ 48 51 ] As a result of remarkable increase in life expectancy due to the advance of medicine, more incidence of PD in the future is expected. Previous research estimated that approximately one million people have PD in the Unite d States [ 52 ] and t h e projected number of PD cases is likely to be drastically increased by 2030 [ 53 ] The mean survival time in PD is 12.8 years, which is about twice longer as that of PSP [ 54 ] Although, PD is not the direct cause of death, respiratory diseases (mostly pneumonia), dementia, and multiple failing organ functions, all of which can be the secondary consequences of PD, are the major causes of death for persons with PD. [ 54 55 ] Immobilization due to the frequent falls can also substantially shorten life expectancy for persons with PD [ 56 ] Etiology and Pathology of PD PD can be pathologically characterized by nigrostriatal dopaminergic cell loss; however a variety of PD symptoms, including dementia, sleep behavioral d isorders indicates widespread involvement of PD pathology. Although PSP and PD are

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29 symptomatically somehow similar, these pathologies are quite different. While PSP is a tauopathy affecting tau proteins, PD is a synucleinopathy affecting synucleins, gene rally localized in presynaptic terminals [ 57 ] A lthough the role of synucleins remains unclear, the recent study suggested that they play a key role in protecting nerve terminals and preventing neurodegeneration [ 58 ] The synucleins are normally soluble and unstructured, but in PD, they aggregate and form insoluble and round intracellular inclusions, called Lewy Bodies (LBs). Although, the mechanism underlying the formation of LBs is not completely understood yet, the pre sence of LBs is the consequence of impaired ability to clear the aggregated synucleins in a PD brain, and strongly associated with neurodegeneration in PD [ 59 ] Fun ctional Anatomy Related to Gait and Postural Control Basal G anglia Basal ganglia are a group of interconnected subcortical nuclei located in cerebrum, diencephalon, and midbrain and they strongly connect with cerebral cortex, thalamus and other brain areas [ 60 ] Basal ganglia consist of two primary input nucl ei, striatum and subthalamic nuclei (STN), and two primary output nuclei, the internal globus pallidus (GPi) and substantia nigra pars reticulate (SNpr). The striatum receive the excitatory inputs from various cortical areas, including primary motor (M1), supplementary motor area (SMA), p remotor (PM), and prefrontal cortex (PFC). From the striatum, two principal pathways, direct and indirect pathways, project to the output nuclei (i.e., GPi and SN p r) of the basal ganglia. The direct pathway st ems from D1 r eceptor s in the striatum, sending inhi bitory signal to GPi and SNpr. The dopamine from substantia nigra pars compacta (SNpc) acts at the D1 receptors to facilitate the postsynaptic activities, which inhibit the output

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30 nuclei of the basal ganglia. The outpu t nuclei then inhibit thalamus that send s excitatory signals back to cortical areas ; t hus, the main role of the direct pathway is the inhibit i on of the output nodes of basal ganglia resulting in disinhibition of thalamus. On the other hand, the indirect pathway originates from the D2 receptors in the striatum, The D2 receptors receives dopamine from SNpc, sending inhibitory signal to the external globus pallidus ( GPe ). Then GPe inhibits the activity of STN. The connection between STN and the output nuclei is excitatory; thus the indirect pathway increases the activity of the output nuclei of basal ganglia. Therefore the main role of the indirect pathway is to inhibit thalamic excitatory activity to the cortical area. The hyperdirect pathway is anatomicall y and functionally different from these two pathways mentioned above Though the hyperdirect pathway, t he frontal cortical area send s the excitatory signal directly to STN. Thus, the hyperdirect pathway, same as the indirect pathway, is to inhibit thalamus resulting in less excitation of the cort ex. T he hyperdirect pathway is the faste r than the direct pathway; therefore, these pathways provides fast, widespread and divergent excitation of the output nuclei through the STN, followed by slow and focused inh ibition through striatum. To initiate a voluntary movement, the hyperdirect pathway initially inhibits to thalamus so that the desired output can be created and sent to the targeted cortical areas Finally to creat e the optimal performance output. Thus, the net result of basal ganglia activity is the combination of the inhibition of competing motor patterns a nd focused facilitation from the selected voluntary movement pattern. However, the dopaminergic neuronal loss in

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31 SNpc that is observed in PD causes increased inhibition to the thalamus through the direct pathway, and decreased disinhibition to the thalamus thought the indirect pathway. As a result, the excessive inhibition of components of the motor circuit in the thalamus occurs [ 61 ] Therefore, persons with PD often manifest subsequent reduction in movement, such as akinesia or bradykinesia as a consequence of the dysfunction of basal ganglia [ 60 ] Thalamus Thalamus is a group of 50 60 nuclei located in the diencephalon and consisting of four groups, hypothalamus, epithalamus, the ventral thalamus and the dorsal thalamus [ 62 ] It is considered as a relay center subserving both sensory and motor mechanisms. The thalamus also plays a key role in processing sensory infor mation. In fact, most nuclei in the thalamus project to one or a few cortical areas, and multiple cortical areas also send information back to multiple thalamic nuclei forming the thalamocortical interconnection [ 63 ] Along with basal ganglia and the cerebral cortex, t h e thalamus forms the cortico basal thalamic circuit, which controls motor behaviors. The anterior parts of the thalamus, the ventrolateral pars oralis and medialis (VLo and VLm), ventralanterior (VA ) along with its pars magnocellularis (VAmc), receive afferents from the basal ganglia [ 21 ] Thus, these basal ganglia recipient thalamic nuclei, along with the basal ganglia, play a key role in controlling internally generated movements. Besides, the recent study by McFarland and colleagues [ 64 ] showed that the basal ganglia recipie nt thalamic nuclei also aid the cortico cortical communication. Although the previous studies already revealed the importance of the localized thalamic nuclei (basal ganglia recipient nuclei) as a relay station to the motor cortical areas when

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32 initiating i nternally generated movements, much more neurophysiological investigations are needed to understand to what extent the thalamus modifies the signals [ 65 ] A r ecent imaging stud y showed that the reduced glucose metabolism in the thalamus was strongly related with postural instability and falls in patients with PSP [ 66 ] They also found that during imagined standing, decreased blood oxyg enation level dependent (BOLD) signal change in the mesencephalic brainstem tegmentum, midline cerebellum, thalamus, and caudate nucleus were strongly correlated with the frequency of falls. In addition to the basal ganglia recipient nuclei, they speculate d that the dysfunction of the mesencephalic brainstem thalamus loop, where neuronal loss occurs early in the course of PSP, but late in the course of PD, seems to be the key factor for early onset and severe postural instability in persons with PSP [ 67 71 ] Cerebellum The cerebellum frequently affected in PSP, play an important role in control and adaptation of balance and gait [ 72 ] The previous research has shown that cerebellar damage impairs postural control as cerebellar patients demonstrated larger postural sway and impaired responses to postural perturbations [ 73 ] G ait ataxia, often described as a drunken gait and characterized by widened base of support, large step to step variability and abnormal inter joint coordination patterns is al so frequently observed as a result of cerebellar deficits [ 72 74 ] The cerebellum receives many projecti ons from variou s areas of the central nervous system including frontal and parietal area s of cortex (via the pontine nuclei), the vestibular nuclei and the inferior olive of the brain stem, and spinal cord The cerebellum also maintains a series of outputs throughout di fferen t motor systems, involving such areas as the P M and primary M1 areas as well as the brain stem. It can

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33 be functionally divided into the following different regions based on afferent and efferent connectivity : the central vermis located in the most m edial zone of the cerebellum, and the lateral and intermediate zones in each hemisphere, and flocculonodular lobe [ 75 ] The vermis often called spinocerebellum and the interm ediate region of the cerebellum receives vestibular information from the vestibular afferents and vestibular nuclei in addition to the somatosensory information from the spinal cord via dorsal (DSCT) and ventral (VSCT) spinocerebellar tracts. In turn, these cerebellar regions project to cortical and brainstem regions primarily vestibular and reticular nuclei [ 72 ] The previous animal studies demo nstrated that the lesion of these area s led to balance deficits with frequent falls backward and toward the lesion side [ 76 79 ] T he primary locomotor function of this region appears to be its influence over control of extensor to ne to maintain upright posture and stance during gait [ 80 81 ] Further, these regions of the cerebellum also play an important role in modulating th e rhythmic flexor and extensor muscle activation of vestibular and reticular nuclei during gait [ 82 ] The f locculonodular lobe is alternatively called vestibulocerebellum since its afferent and efferent connections are mainly with the vestibul ar nuclei in the brain stem. I ts function is limited to controlling bal ance and eye movements [ 83 84 ] This region is affected in PSP; therefore the flocculonodular involvement in PS P may lead to PIGD and vertical gaze palsy [ 85 ] The projection to the Intermediate zone is originated from th e DSCT and VSCT, reticular nuclei and cerebral cortical regions. The intermediate zone of the cerebellum projects to the red nucleus and to the cerebral cortex via the thalamus T he role of this zone in postural control and gait appears to be different fro m that of more medial region

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34 (i.e., vermis) but remains somewhat unclear Given that the impairments in spatiotemporal control during treadmill or ladder walking (e.g., swing stance phase ratio, and swing phase hypermetria) with little or no changes in ov erground walking and balance in animals with the lesions of this region has been observed in the previous studies [ 77 78 86 87 ] the intermediate region appears to contribute to modulation of limb movement under the condition in which more than the usual amou nt of precision is required. The l ateral zone, often called cerebrocerebellum receives inp uts from various cortical areas, including M1, PM, prefrontal, primary somatosensory, temporal and posterior parietal area, via pontine nuclei [ 88 90 ] The cerebell ar outputs from the dentate nucleus in this region project to the red nucleus and many cortical regions: M1, PM, parietal and prefrontal areas [ 91 95 ] Regarding gait and postural control, this region appears to contribute to voluntary adjustment s of gait patterns in novel contexts [ 72 96 ] The connections between cerebellum and other parts of the nervous system occur by three cerebellar peduncles: superior, middle and inferior cerebellar peduncles. The superior cerebellar peduncle (SCP) is the efferent pathway originati ng from deep cerebellar nuclei, such as dentate and interposed nuclei, and projecting to the contralateral VL thalamic nucleus via the red nucleus The red nucleus sends the cerebellar outputs to the inferior olives to provide the feedback on a major cereb ellar input, while VL thalamus sends the outputs to the various cortical areas, such as the M1 PM area and o culomotor cortex Some of the SCP fibers project inferiorly to brain stem reticular and vestibular nuclei The p revious imaging studies demonstrat ed that the SCP

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35 is affected in PSP, and the severity of its atrophy was significantly worse than the other neurodegenerative disorders including multiple system atrophy, and PD [ 97 99 ] Thus, the lesion of some SCP fibers in PSP may result in severe PIGD and gaze palsy, all of which are its cardinal features [ 3 ] Static P ostural I nstability in PSP and PD Postural instability in PD is well documented in clinical tests of balance, in computerized posturography, and in paradigms utilizing complex multi directional surface perturbations [ 100 110 ] These studies have identified several distinguishing postural abnormalities in patients with PD including ; abnormally sized automatic leg muscles; inability to modulate the response magnitude to different postural demands; delayed initiation o r reduced scaling of voluntary postural responses; and abnormal execution of compensatory stepping movements. As mentioned above, postural control in PD has been extensively studied and compared to age matched controls, while there is only few stud ies tha t quantitatively investigated postural control in PSP. Ondo and colleagues [ 111 ] compared balance performance in patients with early PSP to early PD utilizing co mputerized posturography They reported that persons with PSP showed severely decreased limit of stability overreliance of visual information, and abnormal short latency electromyographic ( EMG ) response, compared to p ersons with PD. These findings might i ndicate the severe central vestibular dysfunction and spinal cord involvement in postural control of PSP. Ganesan and colleagues [ 112 ] also utilized similar methodology to investigate postural control in persons with PSP. T heir finding s were consistent with Ondo s study an d confirmed postural stability in persons with PSP was

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36 severely affected in the posterior direction. On the other hand, they also found functional asymmetry in their postural stability, evidenced by preserved balance in some non dominant side directions. T h ese stud ies had shed light on the possibility of objective balance assessment to differentiate early PSP and early PD ; however, information regarding how differently persons with PSP control their balance in time series when compared to both their peers a nd patients with PD and the mechanism causing more severe balance impairment in persons with PSP when compared to PD are still limited. Despite the importance of postural instability in parkinsonian individuals and a large number of previous studies focus ing on this impairment in this population, knowledge about the underlying mechanisms causing postural instability remains limited. One of the major reasons is that linear measures have been widely used to quantify postural instability in laboratory setting s. For instance, sway area, which is one of the most widely used outcome measures in posturography, is the summary statistic measuring the magnitude of center of pressure (COP) variability. Traditionally, movement variability has been interpreted as a nois e or error superimposed on a signal; hence, increased variability in a movement pattern is thought to indicate an inefficient execution of a given movement pattern [ 113 ] I n fact, larger sway area has been considered as more unstable balance. However, it only provide s little insight into the structural na ture of how movement is controlled since standard averaging procedures mask the dynamical property of time series COP data [ 113 115 ] This limitation of tradi tional linear measures in posturography analysis might lead to the contradictory

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37 findings in previous PD studies; some have found reduced postural sway variability in PD [ 105 110 ] but the others did not [ 108 109 ] To more substantially evaluate postural sway dynamics, nonlinear analyses has recently gained an attention. Unlike the conventional linear measures that quantify magnitude of variation, nonlinear analyses can capture the variation in how post ural sway/fluctuation emerges in time series. They have been proved to be effective in detectin g subtle difference and change in temporal pattern of time series COP data. Recently, an effort to further understand the underlying mechanism causing postural i nstability in persons with PD has also begun, utilizing various types of nonlinear dynamics approaches including, but not limited to, stabilogram diffusion analysis ( SDA ) [ 116 ] and rec urrent quantification analysis ( RQA ) [ 117 118 ] For instance, Mitchell and colleagues [ 119 ] utilize d the SDA to gain insight regarding PD associated postural instability during quiet standing. They found that the postural sway dynamics in the mediolateral direction in persons with PD were altered when control strategy was implemented both with and witho ut feedback. They speculated that this altered activity in the mediolateral direction might be compensation strategy for impaired movement in the anteroposterior direction that has been previously reported. Nevertheless, their study first reported the alt ered postural dynamics in the mediolateral direction in persons with PD. Maurer and colleagues [ 120 ] used the same approach and found that persons with PD exhib ited ~1Hz oscillation of postural sway unlike age matched neurologically healthy peers. Additionally, combining their findings from SDA approach and a simple time delay sensory feedback model simulation, they concluded that persons with PD exhibited a high er level of neuromuscular noise and higher motor

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38 loop gain. Although the methodology of SDA has been receiving some criti cisms [ 121 123 ] these studies clearly demonstrated the p romise and need of nonlinear analyses to further understand the postural control mechanism in persons with PD. Unfortunately, postural control research in PSP has just begun and these measures have not been utilized to further our underst anding of postural control in PSP Of these various proposed nonlinear approaches, approximate entropy (ApEn), which was first introduced by Pincus [ 124 ] is one of the widely used techniques in postural control researches in various populations including, but not limited to: healthy young individu als, collegiate athletes after cerebral concussions, and healthy elderly individuals [ 125 128 ] ApEn was de signed to quantitatively evaluate regularity of time series physiological signal (More details including its mathematical methodology are described in Chapter 3). Generally, more predictable time series physiological signal (i.e., lower entropy value) indi cates loss of efficiency, adaptive capability, or automaticity of postural control due to various possible reasons, such as progression of disease and aging [ 129 130 ] which is called the loss of complexity hypothesis [ 131 ] Previous studies demonstrated a promise of ApEn as an effective approach to detect a previously unrecognized and subtle physiological difference and/or changes induced by manipulation of afferent s, disease or injuries [ 127 ] For instance, Cavanaugh and colleagues [ 128 ] investigated postural control system change after sports related cerebral concussion in collegiate athletes. They measured COP oscillation during quiet standing from collegiate athletes at preseason, less than two d ays after concussion, and two to four days after concussion. ApEn and range of COP oscillation were calculated and compared across three different time periods to determine the effect of injury on

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39 postural control and how long change in postural control ca used by concussion would persist. They concluded that the impact of cerebral concussion on postural control appears to persist longer even after any signs of their postural unsteadiness disappear since ApEn values remained significantly lower than the pres eason values, while the range of sway oscillation has been recovered to the preseason level after three to four days after concussion. Hong and colleagues [ 132 ] examined the effect of somatosensory or visual afferent information in postural sw ay variability of healthy young individuals under different stance conditions. They showed that sway dynamics (i.e., ApEn) was affected by withdrawal of visual information but not by somatosensory information, while sway magnitude (i.e., sway area) was aff ected by withdrawal of both types of afferent information. Also, they found that postural sway dynamics could be influenced by task difficulty (or demand), evidenced by the observed contrasting effect of visual information withdrawal (i.e., decreased ApEn value during normal stance but increased value during tandem stance). These studies demonstrated that ApEn analysis could provide more insights regarding postural control mechanism that the traditional linear analyses could elucidate Frequency domain ana lyses have been successful in detecting postural instability caused by various factors, including, but not limited to, visual impairment [ 133 ] ischemic blocking of leg afferents [ 134 ] and tension type headache [ 135 ] and in differentiating elderly individuals with high and low risk of falling [ 136 ] These previous studies showed that frequency domain analyses can be a useful methodology in identifying the underlying mechanisms regarding postural instability in persons with PSP.

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40 In addition to current knowledge regarding postural instability in PD and PSP derived from linear meas ures, understanding dynamic property of postural sway utilizing novel methodologies, including nonlinear approach and frequency domain analysis, can fill a gap in postural control mechanisms and provide further insights into differential diagnosis of PD an d PSP Dynamic P ostural S tability in PSP and PD Gait Initiation (GI) is the beginning of locomotion and involves transition from a stationary stable double limb support to a dynamic unstable single limb support. The characteristics of GI include the abil ity to separate the c enter of p ressure (COP) and c enter of m ass (COM) to initiate gait and their subsequent movement relative to each other. Dynamic postural stability is required to successfully achieve this integrated task; therefore these characteristic s have been studied extensively [ 137 141 ] These researchers showed that at the start of GI, the COP moves posteriorly and towards the swing leg. This COP move a t start of GI is responsible for an efficient way to generate momentum during GI as it causes the COM to move anteriorly and towards the stance leg known as anticipatory postural adjustments [APAs [ 141 ] ] For the elderly population, several researchers have observed a decreased posterolateral movement of COP during the beginning stages of GI [ 138 140 142 ] Further, Winter [ 143 ] proposed that the separation distance between COP and COM is directly proportional to the horizontal acceleration of the body based on the inverted pendulum model. Multiple studies ha ve revealed a reduction in momentum generation in older adults by observing a reduced distance between COP and COM especially during the stance leg toe off event [ 139 144 ]

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41 Persons with PD often ha ve difficulty in GI even when they have no problems with normal walking, possibly leading to falls [ 139 145 ] .Indeed, more reduced COPCOM uncoupling and reduced APAs during GI were observed in persons with PD when compared their age matched counterparts, which is p ossibly their compensatory strategy to minimize unbalanced single limb support time [ 140 146 148 ] This co uld be resulted from abnormal patterns of EMG activity in the lower extremities including tibialis anterior, gastrocnemius, and soleus [ 149 151 ] Besides, Hass and colleagues [ 137 ] found that the COP COM uncoupling was significantly reduced in more balance disabled PD individuals than less disabled PD individuals, proving biomechanically evaluating GI with absence of EMG can still detect a subtle change in dynamic postural stability among individuals w ith various degree of balance impairment. GI in PSP was also studied by Welter and colleague s [ 152 ] They reported no anticipatory braking against the center of gravity (COG) fall occurred before the swing limb hit the ground after initiating gait They claimed that inability to control the fall of COG could re sult in postural instability during gait. Although Welter and colleague demonstrated the impaired control of antigravity braking of the swing limb in PSP the characteristics of dynamic postural control (i.e., COPCOM uncoupling) during GI in PSP remains un clear. Given that kinematic outcome of GI (i.e., COPCOM uncoupling) can differentiate PD with and without balance impairment [ 137 ] more extensive investigation of GI could potentially help us to further understand the underlying mechanism that causes postural instability in persons with PSP that might not be ob served in balance and gait and to differentiate PSP and PD

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42 Gait D isturbance in PSP and PD Gait disturbance is one of the cardinal and the most disabling symptom in both PSP and PD. Regarding the gait in persons with PD, they clinically display features o f bradykinesia, reduced stride length, and increased duration of double limb support. Reductions in gait velocity stem from diminished stride length in persons with PD, while cadence is usually maintained [ 153 154 ] Diminished stride length is considered as a compensatory strategy to limit the COM movement within the base of support (BOS) [ 155 156 ] Gait festination, characterized by rapid and hypometric steps to minimize displacement of COM relative to the BOS and to increase double limb support time is often observed in persons with PD [ 157 ] This compensatory strategy is generated since person with PD are unable to control motor proce sses that simultaneously require regularity, rhythmicity, and symmetry in movements between limbs to create coordinated gait patterns [ 158 ] Indeed interlimb coordination during gait is disrupted in PD, evidenced by increased gait asymme try, diminished bilateral coordination, and high stride to stride variability [ 158 160 ] The r ecent 3 D analyses of PD gait have reported reduced movement ampl itude across all lower limb joints and reduced ankle push of power and hip pull off power [ 161 162 ] As the disease progresses, these gait disorders become more pronounced limiting QOL [ 161 ] Additionally, a bnormal gait variability has been also demonstrated in all stages of the disease and appears to increase with dise ase severity [ 149 159 ] On the other hand, the t ypical gait in PSP is characterized as clumsy, and it resembl es [ 8 17 27 ] As the disease progresses walking is no longer independent, and patients are unable to stand without assistance requiring the use of a wheelchair [ 163 ] Although many clinical studies

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43 reported gait dysfunction in PSP, quantitative studies of PSP gait are still lacking. To diagnose PSP at early st age and to refer them to appropriate therapeutic option, understanding balance and gait performance in PSP as well as quantitatively differentiating PSP and PD, is imperative. In summary, PSP is the second most common parkinsonism and impact patients qu ality of life even more than PD mainly due to more progressiv e and early onset PIGD when compared to PD. Due to the symptomatic resemblance to PD and lack of feasible and precise diagnostic tool for PSP, misdiagnosis of PSP frequently occurs, resulting in delay of correct therapeutic and pharmacological treatments. From both clinical and patients perspective, there is a dire need to investigate the underlying mechanisms causing more severe and early progressed PIGD in persons with PSP and to develop a diff erential diagnosis of PSP and PD, based on this cardinal and first recognizable symptom in most case, to provide an appropriate therapeutic cares to persons with PSP at their early disease stage. Conducting an integrated, objective and biomechanical study capturing multi aspects of PIGD, including static postural control, gait initiation, gait termination, and gait is imperative to build up a biomechanical information base regardin g PIGD in PSP and fully understand what causes it.

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44 CHAPTER 3 METHODS Part icipant Recruitment W e conduct ed a cross sectional case control study to investigate balance and gait performance in persons with PSP in comparison to individuals with PD and healthy controls. W e recruit ed a total of 36 subjects, including 12 ambulatory pa tients meeting clinical diagnostic criteria for PSP [ 3 ] 12 patients with a clinical diagnosis of PD (Hoehn and Yahr scale [ 164 ] between 1 and 3 .5), and 12 age and gender matched healthy control subjects. Recruitment methods for PD and PSP patients include d : identification of qualifying candidates by the Center for Movement Disorder and Neurorestoration database administrators (UF IRB 416 2002) and neurologists, and word of mouth. All participants that were recruited outside of th e Movement Disorders Center receive d a neur o logic evaluation by the collaborating neurologists to confirm a diagnosis of idiopathic PD or PSP Interested i ndividuals with either PSP or PD under went screenin g tests including the UPDRS, PSPRS the revised NINDS SPSP [ 3 ] and the Modified Mini Mental Status Exam (MMSE). For those who were recru ited by word of mouth, they visit ed U niversity of F lorida Center for Movement Disorder & Neurorestoration for require d screening. Inclusion Criteria PSP : All p articipants with PSP were diagnosed with probable PSP according to the NINDS SPSP and their age must be between 35 and 80. They were ambulatory and also capable of providing informed consent and complying with the trial procedures.

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45 PD: All p articipants with PD had clinical diagnosis of idiopathic PD (H &Y stages 1 to 3.5) and their age must be between 35 and 80. They were ambulatory and also capable of providing informed consent and complying with the trial procedu res. Healthy adults Control Subjects : Participants had no history of neurological or orthopedic problems that could impair walking function and be ambulatory wi thout assistance. Their age were between 35 and 80 and each of them was gender and age matche d with a neurologically impaired individual 2 years. They were also capable of providing informed consent and complying with the trial procedures. Exclusion C riteria T he e xclusion criteria applied to all groups were : Failure to meet the inclusion criteri a. L oss of vision, peripheral neuropathy, vestibular dysfunction, or those taking medications affecting balance or alertness /attention. Presence of active unstable medical or psychiatric conditions, diabetes, or any orthopedic condition that would preclu de their ability to participate in the exercises. Presence of active or unstable/untreated cardiovascular disease. Presence of any recent changes in mental and/or physical condition that might affect gait and balance Dementia, as defined by the Modified M ini Mental Status Exam (MMSE< 2 1 ) Equipment Kinematic data w ere collected at 120Hz using a 10 camera motion capture (VICON, Oxford, UK) Kinetic data w ere collected at 360 Hz using three embedded force platforms (Bertec Corp., Columbus, OH) aligned conse cutively on an 8 meter wa lkway. The experimental setup is described in Figure 3 1. A ccording to the modified Helen Hayes marker se t t hirty five reflective markers w ere placed on the anatomical

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46 bony landmarks : metatarsophalangeal joint head, heel, ankle, t ibia, knee, thigh, anterior superior iliac spine, posterior superior iliac spine, shoulder, elbow, radial wrist, ulnar wrist, finger, forehead, and posterior head (all bilaterally), the jugular notch, inferior sternum, C7, T10, and the right scapula ( Figur e 3 2 ) Clinical evaluations The c linical measures to be used in this study include d : 1) data about fall history, age, gender, and medical conditions; 2) clinical neurological examination ( PSPRS and/or UPDRS); 3) a idence of balance [ the Activities specific Balance Confidence (ABC) scale ; [ 165 ] ] and 4) PD related QOL [ Parkinson s Disease Questionnaire 39 ( PDQ 3 9 ) ; [ 166 167 ] ] The clinical evaluations w ere administered to each participant prior to biomechanical eval uations. The U PDRS and PSPRS w ere video taped and be evaluated by an experienced neurologist blinded to patient diagnosis Experimental Protocol Each participant c a me to the Applied Neuromechanics l aboratory for gait and balance assessment. All participants w ere tested on their usual anti movement disorder medication. Prior to evaluation, t he purpose of this study was explain ed to a participant and we provide d a participant enough time to review and sign the informed consent. Methodology Designed to Achieve Specific Aim 1 Participants st ood barefoot on the force platform with their arms on their side while looking straight at the fixed target placed at their eye level Participants perform ed three trials under three experimental conditions: (1) E yes open (EO): participan ts st ood quietly with their eyes open, and with their heels 10cm apart from each other, for a period of 30 seconds (2) Eye s closed (EC): participants perform ed under the same

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47 condition as (1), except with their eyes closed for a period of 30 seconds, and ( 3) on a compliant foam (FOAM): participants stood with their eyes open, on a compliant foam for 30 seconds. Methodology Designed to Achieve Specific Aim 2 Participants perform ed five GI trials at a self selected speed. The starting po sition for each GI tr ial w as established on the force platform located in the center of the walkway so that subsequent foot strikes c ould be measured by the two other force platforms anterior to the starting position. T he initial stepping (SW) limb and the positioning of the f eet w ere self selected and subsequently maintained for consistency. Data collection beg a n while the participants were standing in a relaxed position. Upon ready signal, participants pause d momentarily before initiating movement towards a target placed at the eye level. P articipant s were allowed to practice the tasks until they bec a me confident with the procedures prior to data collection. Extreme care w as given to avoid subject targeting of the pl atforms and participants w ere guarded unob trusively during their walking for increased safety. Methodology Designed to Achieve Specific Aim 3 Participants perform ed ten walking trial s at a self selected speed toward a visual target placed at the end of an 8 meter walkway. The starting posi tion fo r each walking trial was established so that individual foot strikes c ould be measured from the three force platforms located in center of t he walkway. Extreme care w as given to avoid subject targeting of the pla tforms and participants were guarded unobtru sively during their walking for increased safety.

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48 Data Processing and Outcome Measures Aim 1 Ground reaction force (GRF) and moments from the force platform w ere used to calculate the in stantaneous CO P Time series COP data w ere then low pass filtered at 2 0 Hz using the second order Butterworth filter. The following five components of outcome measures regarding COP variability will be computed by the customized MATLAB program (The MathWorks, Inc, Natick, MA) Mean COP velocity The mean COP velocity ( ) was calculated as: where N is the total number of the data points, and t is a time interval between each data point. 95% confidence e llipse a rea The 95% confidence ellipse area (A95) is the area of the 95% bivariate confidence ellipse enclosing approximately 95% of the data points on the COP trajectory. The A95 has been used to quantify the magnitude of COP variability. The details regarding the p rocedure to calculate the A95 is described in the previous literature [ 168 ] : w here F .05[2,N 2] i s the F statistic at a 95% confidence level for a bivariate distribution with N data points, s 2 AP and s 2 ML are the standard deviations of the anteroposterior (AP) and mediolateral (ML) time series, respectively, and s 2 APML is the covariance.

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49 Approximate e ntropy Approximate entropy (ApEn) is the nonlinear mea sure of system complexity, which was first introduced by Pincus [ 169 ] to quantitatively evaluate the complexity of the physiological time series signals, including heart rate, respiratory rate, electroencephalography, and electromyography [ 170 173 ] This measure has been also utilized to detect th e subtle change in the structure of COP variability in postural control, which can be viewed as a reflection of the reorganization of the motor system output due to either change in postural strategy, sensory modulation, or disease [ 125 126 174 ] ApEn can be computed by the following equation: where m is the length of the recurrence vector, r is a tolerance range, C m (r) and C m +1 (r) are the probabilities of the recurrence of vectors of length m and m+1 within a range of r respectively, and i s time delay. Consistent with t he previous literature in which the optimal parameter setting s for ApEn calculation in human postural control have been examined, m =2, r =0.2 of the standard deviation of the given time series signal, and = 18 w ere used i n this study [ 175 177 ] Time to boundary Time to boundary (TTB), which is derived from instantaneous velocity, acceleration, and COP displacement r elative to the BOS predicts the time it would virtually take the COP to reach the limits of the BOS. Thus, lower TTB measures are associated with greater postural instability. The algorithm to compute TTB is based on the previous literature [ 178 ] BOS will be determined from the tips of the toe, the most lateral parts of the foot, and

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50 heel reflective markers, r espectively. The distance from the instantaneous COP position to the limit of BOS at time t=t i in AP and ML direction, d AP (t i ) and d ML (t i ) respectively, can be estimated: w here P AP and P ML are the limit of BOS in AP and ML direction, respectively, COP AP (t i ) and COP ML (t i ) are the instantaneous COP position in AP and ML direction at time t = t i respectively. Thus, the TTB ( = ) at the moment t = t i can be obtained by solving the equations below: where v AP (t i ) and v ML (t i ) are the instantaneous velocity in AP and ML direction at time t = t i respectively, and a AP and a ML are the instantaneous acceleration in AP and ML at time t = t i respectively. A typical TTB time series is a sequence of multiple inversed peaks. These inversed peaks represent the moment when the instantaneous COP reaches the closest, in the time domain, to a limit of the BOS. Each inversed peak of TTB time series data w as detected by the MATLAB pre defined function. The ou tcome measures are: (1) The absolute minimum peak TTB (minTTB), (2) m ean of peak TTBs (meanTTB), (3) standard deviation of peak TTBs (stdTTB) and (4) number of inversed peaks detected (numPeakTTB). These outcome measures for each BOS border (anterior, po s terior, more affected side (MAS) and less affected side (LAS) ), as well as overall directions, were calculated and used for the statistical analyses. T o compare

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51 pathological with the healthy elderly group, the dominant and non dominant side w ere alternativ ely used as LAS and MAS for the Control group, respectively Frequency domain analysis Before converting the time series COP data to the frequency domain, a Hanning window function w as applied to minimize the influence of abrupt amplitude change at the edg es of the sample. After zero padding the time series COP data to 16384 (=2 14 ) data points and detrending it, Fast F ourier Transforms (FFTs) w ere used to obtain power spectra from 0Hz to 20Hz. Thus, the frequen cy resolution in this study was 0.02 2Hz. Each power spectrum w as normalized to the total signal power, log transformed and divided into five bandwidths: <.5Hz, .5 1Hz, 1 5Hz, 5 15Hz, and >15Hz (Bin1 5, respectively). Due to skewed distribution, mean normalized power s (MNPs) in each bandwidth were log transformed for further statistical analyses. The median and 95% power frequency (F95) were also measured and compared across the group. Aim 2 For estimating the COP chara cteristics, the GI cycle w as divided into three distinct phases (S1, S2, and S3) base d on the COP trajectory, as described previously in the literature [ 142 ] Briefly, the S1 phase is de fined 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 is marked from the end of S1 phase to the time point of the swing limb toe off. The final S3 phase is ident ified from the end of the S2 phase to the time point of stance leg toe off. The p rimary outcome variables w ere : 1. spatiotemporal parameters, such as step length, step width, step duration, and step velocity of both initial swing (SW) and trailing /stance (ST) limb,

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52 2. displacement of COP in both AP and ML direction during each phase (S1COPDisp, S2COPDisp, S3COPDisp, respectively), 3. mean velocity of COP in AP and ML direction during each phase (S1COPVel, S2COPVel, S3COPVel, respectively), and 4. maximum separation di stance between the COP and COM in AP, ML and resultant directions during each phase (S1 COPCOM S2 COPCOM and S3 COPCOM respectively). The step length and width were normalized by individuals leg length (LL) These outcome variables are susceptible to cha nge in dynamic postural control and stability [ 141 142 179 180 ] All outcome measures w ere computed by the customized MATLAB program. Aim 3 The gait cycle (GC) was defined as time interval between initial heel strike of the supporting limb and subseq uent heel strike of the same limb. The primary spatiotempora l gait outcome variables w ere : (1) cadence, (2) gait velocity, (3) step length, (4) step width, ( 5 ) step duration, ( 6 ) double lim b support time and (7) gait asymmetry based on swing time calcula ted using the standard definitions based on the marker data [ 181 182 ] The step length and width were n ormalized by individuals LL and step duration and double limb support time were normalized by individuals GC T he coeffic ient of variation (CV) of step length, step duration, step width for the MAS and LAS side, and double limb support time were also ca lculated to describe within subject inter step variability during gait and compared across the groups Statistical Analyses For the dependent variables, the mean individual values from the consecutive tr ials within a condition w ere used for analysis. The Shapiro test w as performed

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53 to determ ine whether data were normally distributed. All statistical analyses were performed using IBM SPSS statistics version 20 ( IBM Corp. Armonk, NY ). Aim 1 A 3 ( Group: PSP, PD, and Control) 2 (Condition: EO and EC ) two way mixed univariate anal ysis of variance (ANOVA) w as performed with Group as a between subject factor and Condition as a within subject factor for mean COP velocity and A95 A 3 (Group: PSP, PD, and Contr ol) 2 (Condition: EO, EC ) two way mixed multi variate analysis of variance ( M ANOVA) w as performed with Group as a between subject factor and Condition as a within subject factor for the rest of components (i.e., ApEn, TTB and frequency domain analyses). If any of assumption of M ANOVA (for each compone nt analysis) or ANOVA (for each dependent variable) was violated, univariate ANOVA or Kruskal Wallis test would be alternatively performed for each condition respectively A tradition al level of significance w as use d ( p 0.05). I n case that a si gnifican t differenc e was found, multiple comparisons ( Tukey s test for a parametric test and Steel Dwass test for a nonparametric test) w ere conducted as post hoc tests to determine the individual differences among the groups and the conditions when necessary. Sin ce six out of 12 participants with PSP in this study could not complete the trial i n FOAM condition, we separately analyze d FOAM condition to maximize the sample size in the main statistical analyses (i.e., EO and EC) Regarding FOAM condition, a one way A NOVA w as performed with Group (PSP, PD, and Control) as a between subject factor for mean COP velocity and A95 A one way M ANOVA w as performed with Group (PSP, PD, and Control) as a between subject factor for the rest of components (i.e., ApEn, TTB and fre quency domain analyses). The subjects in the PD and Control group included in th ese analys e s were those who were gender and age

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54 matched with the subjects with PSP who completed the trials under FOAM conditions. A tradition al level of significance w as used ( p 0.05) I n case that significant difference was found, a n appropriate Post hoc test w as used to determine the individual differences amon g the groups when necessary. If any of assumption of ANOVA was violated, Kruskal Wallis test would be alternativel y performed to compare across the group. Aim 2 and 3 S ince one of 12 PSP participants could not perform the GI task in Aim 2 a nd t wo PSP participants could not complete the gait assessment in Aim 3 the PD and Con trol participants who were matched to thes e PSP participants were excluded from the analyses in each aim. For each type of evaluation (GI and Gait), A one way multivariate analysis of variance ( M ANOVA) w as performed with Group ( three level: PSP, PD, and Control) as a between subject factor A sub sequent one way ANOVA w as performed for each outcome variable if overall main effect of Group is observed Additionally for Aim 3 to control for the effect of gait velocity an analysis of covariance (ANCOVA) with gait velocity as a covariate was performe d to assess differences among the groups. A tradition al level of significance w as used ( p 0.05). If any of assumption of ANOVA /MANOVA is violated, Kruskal Wallis test would be alternatively performed for each variable. In case that a significant difference is found, multiple comparisons Dwass test for a nonparametric test) were conducted as a post hoc test to determine the individual differences among the groups when necessary.

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55 Figure 3 1. E xperimental s et up A 10 camera motion capture system a long with the three force plat forms and the orie ntation of the axes

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56 Figure 3 2. Marker placement The thirty five reflective markers was placed over anatomical landmarks based on Vicon s Plug in Gait model.

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57 CHAPTER 4 RESULTS The demographic information and clinical scores of each group are show n in Table 4 1 No significant differences among groups were reported in any demographic variable : age, height, and mass (all p s > 0 .05 ; Table 4 1 ) We observed a main effect of Group in MMSE. T h e post hoc Tukey s test confi rmed that persons with PSP exhib ited a significant reduction of cognition in general, when compared to the PD ( p = 0.02) and the Control group ( p = 0.01). With regard to self reported confidence about balance, a significant difference was observed among the groups ( p < 0.01). Specificall y, the persons with PSP reported significantly lower confidence about balance than both the PD and the Control group s (both p s <0.01). The UPDRS total and motor scores and PDQ39 scale index significantly differed between PSP and PD, indica ting persons wit h PSP exhibited more severe neurological disability (UPDRS total: p < 0.01 UPDRS motor: p < 0.01) and reduced QOL than persons with PD ( p < 0.01) Aim 1: Static Postural C ontrol (EO and EC C ondition) Mean COP V elocity T he Kruskal Wallis t est was performe d to compare across the groups in each condition. No significant Group difference for mean COP velocity was observed in either condition ( EO: p = 0.83 and EC: p = 0.3 8 ; Table 4 2 ) 95% Confidence Ellipse A rea T he Kruskal Wallis t est was performed to compar e across the groups in each condition. N o s ignificant difference among group s for A95 was observed in the EO condition ( p = 0. 14 ) while a significant group difference was observed in the EC condition ( p < 0.01; Table 4 2). Specifically, the post hoc Steel Dwass test confirmed

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58 that the PSP group exhibited significantly larger A95 value than the Control group ( p < 0. 01), but they did not differ from the PD group ( p = 0.33 ; Figure 4 1 ). N o significant difference b etween the PD and Control group was observed ( p = 0.08 ; Figure 4 1 ) Approximate Entropy The Kruskal Wallis t est found no significant difference among the groups in the AP direction in either condition ( EO: p = 0.23, EC: p = 0.38; Table 4 3 ). In the ML direction, however, a significant diffe rence amo ng groups was observed in both EO ( p = 0. 02) and EC ( p = 0. 03) conditions (Table 4 3). T he post hoc Steel Dwass test confirmed t hat the PSP group exhibited significantly lower ApEn value when compared to both the PD ( p = 0.05 ) and the Control ( p = 0.04 ) gr oup s in the EO condition ( Figure 4 2 ) In the EC condition, the PSP group exhibited significantly lower ApEn value in comparison with the Control group ( p = 0.04 ) but not to the PD group ( p = 0.18 ; Figure 4 2 ) The PD group did not differ from the Control group in either conditions ( EO: p = 1.00 EC: p = 0. 55 ; Table 4 3 ) Time to B oundary The TTB characteristics of each group in the EO and EC condition are shown in Table 4 4 According to the distribution of the data sets in this component, either MANOVA ( for the variables that were normally distributed in both EO and EC conditions), univariate ANOVA (for the variables that were normally distributed in either one of the two conditions) or Kruskal Wallis t est for individual condition (for the variables that were not normally distributed ) w ere performed for statistical comparisons We observed significa nt difference s in several outcome variables in this component.

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59 First, t he 2 3 two way MANOVA revealed significant overall effects for both G roup ( p = 0.04) and C ondition ( p = 0.04) for the TTB components that were normally distributed ( Table 4 4 ). N o significant Group C ondition interaction was found ( p = 0.80) The subsequent univariate tests confirmed a significant difference among the groups for the numPeakT TB in the LAS direction ( p = 0.03). Specifically, the PSP group perceived and corrected their postural challenge toward the LAS direction significantly fewer than the Control group in the EO condition ( p = 0.0 2), while this difference between PSP and C ontr ol group did not reach the statistically significant level in the EC condition ( p = 0.0 8 ; Figure 4 3 ). No significant difference between the PSP and PD group was observed in either condition ( EO: p = 0.82 EC: p = 1.00). Similarly, t he PD group did not sign ificantly diffe r from the Control group in either condition ( EO: p = 11 EC: p = 0. 07). The meanTTB value in the posterior direction differed among group s but it did not reach the statistically significant level ( p = 0.06 ; Figure 4 4 ). The Kruskal Wallis test revealed that the numPea kTTB in all directions in the EC condition differed among the groups ( p = 0.0 1 ), while the difference among the groups in the EO condition did not reach the statistically significant level ( p = 0.0 8 ). The subsequent multiple co mparisons for the EC condition confirmed that the numPeakTTB value in the PSP group did not differ from either the PD ( p = 0.27 ) or the Control group ( p = 0. 54 ) Conversely, a significant reduction for the numPeakTTB in the PD group was observed when compa red to the Control group ( p < 0.0 1 ; Figure 4 5 ). The Kruskal Wallis test also showed that t he minTTB values in the posterior direction differed across the group s in the EO condition ( p = 0.0 3). Conversely we failed to observe a significant difference amo ng the groups for the minTTB in the EC condition

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60 ( p = 0.0 9). The post hoc Steel Dwass test for the EO condition confirmed that the posterior minTTB value in the PSP group was significantly diminished when compared to the Control group ( p = 0.0 3), but not t o the PD group ( p = 0. 27 ; Figure 4 6 ). The PD group did not differ significantly from the Control group ( p = 0. 55 ) Regarding the main effect of Condition the following univariate tests revealed that the minTTB in the MAS direction and num Peak TTB s in the LAS direction significantly differed between the conditions ( p = 0.02 and <0.01, respectively) Specifically, the minTTB value in the MAS direction in the PSP group was significantly decreased in the EC condition when compared to the EO conditions ( p = 0.0 4 ; Figure 4 7 ). The num Peak TTB s values in the LAS direction in both the PD and the Control group s significantly decreased in the EC conditions in comparison with the EO condition ( p <0.01 and =0.03 respectively ; Figure 4 3 ) Frequency Domain A nalyse s The median frequency and F95 are shown in Table 4 5, and the relative power distribution in each frequency bandwidth for each group in the EO and EC condition are shown from Figure 4 8 to Figure 4 11 The univariate one way ANOVAs and Kruskal Wallis tests rev ealed that t he medi an frequency in either direction did not differ among the groups in either condition ( EO: p = 0. 10 and 0.17 ; EC: p = 0. 62 and 0. 23, respectively ) Similarly, the F95 in the AP direction did not differ among the groups in either condition ( EO: p = 0. 09 and EC: p = 0 .99). I n the ML direction, a significant difference among groups was detected for the F95 in the EO condition ( p = 0. 05), whereas no significant group difference s w ere observed in the EC condition ( p = 0. 15; Table 4 5). Although PSP exhibited lower F95 value than the PD group ( p = 0.19 ) and Control group ( p = 0. 10) in the EO condition, the

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61 pos t hoc Steel Dwass multiple comparisons fail ed to detect any significant difference s between PSP and the other two groups (Figure 4 12 ) Th e MNP distribution in Bin1 in the ML direction significantly differed among groups in the EO condition ( p = 0.05). While the PSP group exhibited the highest relative power distribution in Bin1 in the EO condition of the three groups, the post hoc Steel Dwa ss multiple comparisons failed to detect any significant differences between the PSP and the PD ( p = 0.14) or between the PSP and the Control group ( p = 0. 12; Figure 4 13 ). In Bin2 in the ML direction, a significant trend for Group ( p = 0.06) was observed Indeed, the post hoc Tukey s test showed that the PSP group exhibited significantly lower power distributed in this bandwidth when compared to the Control group ( p = 0.06), but not to the PD group ( p = 0.27, Figure 4 13 ) The MNP in Bin2 in the AP direct ion also significantly differed among groups in the EO condition ( p = 0.14). Specifically, the PSP and PD group exhibited lower relative power than the Control group ( p = 0.02 and 0.05, respectively), while there was no significant difference between the P SP and PD group ( p = 0.92; Figure 4 1 4 ) Aim1: Static Postural Control (FOAM C ondition) The means and standard deviation of all dependent measures in t he FOAM condition are listed in Table 4 3 Mean COP V elocity T he Kruskal Wallis t est revealed n o signif icant Group difference s for mean COP velocity in the FOAM condition ( p = 0.68; Table 4 6 ). 95% Confidence Ellipse A rea T he Kruskal Wallis t est was alternatively performed to compare acr oss the groups No significant Group differ ence s for A95 was observed ( p = 0.20; Table 4 6 ).

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62 Approximate Entropy The Kruskal Walli test revealed no significant difference s amon g the groups for either direction in the FOAM condition (AP: p = 0.41 ML : p = 0.10; Table 4 7 ). Time to B oundary The TTB characteristic s of each group in the FOAM condition are shown in Table 4 8 The one way MANOVA (for the variables that were normally distribut ed ) revealed no significant overall difference among the groups The Kruskal Wallis test revealed that the numPeakTTBs in the posterior directi on significantly differed among groups ( p = 0.02). Specifically, the numPeakTTBs in the PSP group was significantly larger than the Control group ( p = 0.01 ; Figure 4 11 ). On the other hand, t here was no significant difference between the PSP and the PD ( p = 0.13) or between the PD and the Control group ( p = 0.70; Figure 4 1 5 ). Frequency Domain A nalyses The median frequency, F95 are shown in Table 4 9, and the relative power distribution in each frequency bandwidth for ea ch group in the AP and ML direction are shown from Figure 4 16 and Figure 4 17, respectively The one way MANOVA (for the variables that were normally distribut ed ) revealed that there was a n overall significant main effect for Group ( p = 0.04). The univariate one way ANOVAs revealed that th e median frequency in either the AP or the ML direction did not differ among the groups ( p = 0. 17 and 0.92, respectively ) Conversely, there was a significant difference among the groups for F95 in the ML direction ( p = 0.04). Although the PSP group exhibi ted the highest F95 value, the post hoc pairwise comparisons using Steel Dwass test failed to detect a significant difference (PSP vs. PD: p = 0.18, PSP vs. Control: p = 0.06, and PD vs. Control: p = 0 50; Figure 4 1 8 ).

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63 The post hoc univariate tests also c onfirmed that Bin2 and Bin 3 in the ML direction differed across groups ( p = 0.05 and 0.02).We also observed a significant trend ( p = 0.07) in Bin1 in the ML direction. The post hoc multiple comparisons revealed that the PSP group exhibited lower MNP value than the Control group in both Bin2 and Bin3 ( p = 0.05 and 0.02, respectively; Figure 4 1 9 ). The Kruskal Wallis test revealed a significant difference among the groups for Bin1 in the AP direction ( p = 0.05). Specifically, the PSP group exhibited signific antly higher MNP than the Control group ( p = 0.04), while the PSP group did not significantly differ from the PD group ( p = 0.25; Figure 4 20 ). Aim 2: Dynamic Postural Control The representative COP and CO M trajector ies during GI in each group are shown i n Figure 4 21 The one way MANOVA confirmed a significant main effect of Group ( p < 0.01 ). Spatiotemporal Characteristics The spatiotemporal characteristics of each group during GI are shown in Table 4 10 The ANOVA s revealed that the step length and veloc ity for both SW and ST side significantly differed among the groups (all p s<.0 1 ) Specificall y, when compared to PD and Control participants, the PSP participants exhibited significantly shorter SW ( both p s < 0.01 ) and ST step length ( both p s < 0.01 ; Fi g ure 4 22 ). Also, the PSP participants exhibited slower SW ( both p s < 0.01 ) and ST step velocity ( both p s < 0.01 ) than PD and Control participants (Figure 4 23 ). A significant trend for Group was also observed for step width ( p < 0.06 ; Figure 4 24 ). We d id not observe any significant difference between PD and Control in any spatiotemporal characteristics during GI (Table 4 10)

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64 COP Characteristics The COP characteristics du ring GI are shown in Table 4 11 The ANOVA and Kruskal Wallis test revealed that S 1COPDisp in both the AP and ML direction, S2COPDisp in the ML direction, and S3COPDisp in the AP direction significantly differed among the groups (all p s < 0 .0 1 ). S1COPVel and S3COPVel in the AP direction and S1COPVel in the ML direction significantly di ffered among the groups (all p s < 0 .0 1 ). First, t he post hoc pairwise comparisons using Tukey s test s and Steel Dwass test confirmed that t he PSP group significantly shifted their COP more anteriorly and toward the ST limb during the S1 phase, while the P D and Control group s shifted in the opposite direction: posteriorly and toward the SW limb (AP: p = 0.01 and < 0 01 ML: p = 0 01 and < 0 0 1 r espectively ; Figure 4 25 ). Moreover, a significant reduction of S1COPDisp in the AP direction was observed in the PD group when compared to the Control group ( p = 0.04), but not in the ML direction ( p = 0.55 ; Figure 4 25 ). It was also confirmed that S2COPdisp in the ML direction and S3COPDisp in the AP direction were significantly reduced in the PSP group when compare d to the PD (both p s = 0.01) and the Control group s ( both p s < 0.01; Figure 4 26 ) Regarding COP velocity during GI, t he PSP group exhibited signi ficantly reduced S1COPVel in both AP and ML directions when compared to the PD ( both p = 0 .0 2 ) and Control g roup s (both p s < 0.01 ; Figure 4 2 7 ) T he PD group exhibited significantly reduced S1COPVel in the AP direction than the Control group ( p = 0 .0 2 ), but not in the ML direction ( p = 0 22; Figure 4 2 7 ). S3COPVel in the AP direction in the P SP group was signif icantly reduced when compared to both the PD and Control group s ( p = 0 02 and < 0 0 1 respectively ; Figure 4 2 8 ).

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65 COPCOM Characteristics The COPCOM characteristics of each group during GI are shown in Table 4 12 T h e ANOVA and Kruskal Wallis test revealed that S1COPCOM, S2COPCOM, and S3COPCOM in the AP direction ( all p s < 0. 01 ) and S1COPCOM ( p = 0. 05 ) and S3COPCOM ( p < 0. 01 ) in the resultant direction differed signif icantly among the groups The post hoc multiple comparison s procedure using Tuke s test o r Steel Dwass test confirmed that the PSP group exhibited signifi cantly reduced COPCOM moment arm in the AP direction at all phases (from S1 to S3) when compared to the Control group ( all p s < 0. 01 ; Figure 4 2 2 ). E ven compared to the PD group, the COPCOM moment arm in the AP direction at the S2 and S3 phase for the PSP group were significantly diminished ( both p s < 0. 01 ; Fig ure 4 2 9 ) Similarly, AP moment arm during all phases were also smaller in the PD group, but these reductions failed to reach a signi ficant level when compared to the HOA group (S1: p < 0.06, S2: p < 0. 41, and S3: p < 0. 84 ; Figure 4 29 ) S3COPCOM in the resultant direction in PSP was significantly reduced when compared to both the PD and Control groups ( both p s < 0 .01 ; Figure 4 2 9 ). Al though the main effect for Group was observed, t he post hoc Tukey s test failed to detect a significant difference between any of two groups for S1COPCOM in the resultant direction. Aim 3: Gait The spatiotemporal characteristics during for ward gait are sho wn in Table 4 13 The one way MANOVA confirmed a significant overall main effect of Group ( p < 0.01 ) The following univariate ANOVA s tests revealed all spa tiotemporal gait characteristic s significantly differed among the group s (all p s < 0 .05). Specific ally, The post hoc multiple comparisons using Tukey s test confirmed that in comparisons with the PD and Control group, the PSP group exhibited significantly reduced gait velocity

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66 ( both p s < 0.01 ; Fig ure 4 30 ) step length ( p = 0.04 and < 0.01 respectiv ely; Fig ure 4 31 ) and step duration ( p < 0.01 and = 0.02 respectively; Fig ure 4 32 ). Cadence in the PSP group was also significantly reduced in comparison with the PD group ( p = 0.03). We also observed a significant trend between the PSP and the Control group indicating the cadence of PSP was also lower than the Control group ( p < 0.06; Figure 4 33 ). Meanwhile, the PSP group exhibited significantly wider step width ( both p s < 0.01 ; Fig ure 4 34 ) and longer double support time ( p = 0.01 and 0.02 respecti vely; Fig ure 4 35 ) than both the PD and the Control group s Moreover, swing time during gait in PSP was significantly more asymmetric evidenced by larger gait asymmetry value, than both the PD and the Control groups ( both p s < 0.01 ; Fig ure 4 36 ) When co rrected for gait velocity, the ANCOVA revealed significant differences among the groups in step width ( p = 0.01), but not in the other spatiotemporal variables. W e did not observe a significant difference in any spatiotemporal gait characteristics between the PD and Control groups. S tep variability o n both MAS and LAS described as the CV of step length and duration was significantly altered in PSP (CV of step length: both p s < 0.01 CV of step duration: both p s < 0.01 ; Table 4 13 ). Specifically, the ste p length variability on the MAS for the PS P group was significantly larger than the PD and Control group ( both p s < 0.01; Figure 4 3 7 ) Similarly on the LAS, the step length variability in the PSP group was significantly larger than both t he PD and the Co ntrol group s ( both p s < 0.01; Figure 4 3 7 ) The step dur ation variability on both MAS and LAS was also increased in the PSP group when compared to both the PD and the Control group s ( all p s < 0.01 on both sides; Fig ure 4 3 8 ). Stride to stride var iabilit y of double support time significantly

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67 differed across the group s ( p < 0.01). Specifically, the PSP group exhibited significantly larger stride to stride variabilit y when compared to the Control group ( p < 0.01 ; Figure 4 3 9 ) T he double support time inter stride variability in PSP also appeared to be larger than PD, evidenced by a significant trend between these two group s ( p < 0.0 6). Between the PD and the Control groups, no significant difference s in gait variability w ere observed in the present study.

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68 Figure 4 1. The mean and standard deviation of 95% c onfidence e llipse a rea (A95) in the EO and EC conditions a significant difference was observed ( p 0.05)

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69 Figure 4 2 The mean and standard deviation of approximate entropy (ApEn) in the mediolateral direction in the EO and EC conditions a significant difference was observed

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70 Figure 4 3. The mean and standard deviation of the number of inversed TTB peaks (numPeakTTBs) on LAS in the EO and EC conditions a significant difference was observed (p 0.05)

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71 Figure 4 4. The mean and standard deviation of the mean TTB in the posterior direction in the EO and EC conditions

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72 Figure 4 5. The mean and standard deviation of the total number of inversed TTB peaks (numPeakTTBs) in the EO and EC conditions a significant difference was observed ( p 0.05)

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73 Figure 4 6 The mean and standard deviation of the minimum TTB in the posterior direct ion in the EO and EC conditions a significant difference was observed ( p 0.05)

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74 Figure 4 7 The mean and standard deviation of the minimum TTB on MAS in the EO and EC conditions a significant difference was observed ( p 0.05)

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75 Figure 4 8. Aver age pow er spectra for each group of the frequency distribution of the COP trajec tories in the anteroposterior direction for the EO condition.

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76 Figure 4 9. Average pow er spectra for each group of the frequency distribution of the COP trajec tories in the mediolateral direction for the EO condition.

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77 Figure 4 10. Average pow er spectra for each group of the frequency distribution of the COP trajec tories in the anteroposterior direction for the EC condition.

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78 Figure 4 11. Average pow er spectra for each g roup of the frequency distribution of the COP trajec tories in the mediolateral direction for the EC condition.

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79 Figure 4 12 The mean and standard deviation of the 95% power frequency (F95) in the mediolateral direction for each group in the EO and EC c ondition s

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80 Figure 4 13 The mean and standard deviation of distributed power in the frequency bandwidth ( Bin1 5 ) in the mediolateral direction of each group in the EO and EC conditions a significant difference was observed ( p 0.05)

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81 Figure 4 1 4 The mean and standard deviation of distributed power in the frequency bandwidth s (Bin1 5) in the anteroposterior direction of each group in the EO and EC condition s a significant difference was observed ( p 0.05)

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82 Figure 4 1 5 The mean and standard deviation of the number of inverse d TTB peaks (numPeakTTBs) in the posterior direction in the FOAM conditions a significant difference was observed ( p 0.05)

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83 Figure 4 16 Average pow er spectra for each group of the frequency d istribution of the COP trajec tories in the anteroposterior direction in the FOAM condition.

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84 Figure 4 17 Average pow er spectra for each group of the frequency distribution of the COP trajec tories in the mediolateral direction in the FOAM condition.

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85 F igure 4 1 8 The mean and standard deviation of the 95% power frequency (F95) in the mediolateral direction for each group in the FOAM condition A significant main effect for Group was observed ( p 0.05). § The post hoc Steel Dwass test detected a significant trend between the PSP and Control group ( p = 0.06).

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86 Figure 4 1 9 The mean and standard deviation of distributed power in the frequency bandwidths (Bin1 5) in the mediolateral direction of e ach group in the FOAM conditions a significant difference was observed (p 0.05)

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87 Figure 4 20 The mean and standard deviation of distributed power in the frequency bandwidths (Bin1 5) in the anteroposterior direction of each group in the FOAM condit ions a significant difference was observed (p 0.05)

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88 Figur e 4 21 The center of pressure (COP) and center of mass (COM) trajectories of the representative participants from each group during gait initiation.

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89 Figure 4 22 The mean and stan dard de viation of step length in each group during gait initiation a significant difference was observed (p 0.05)

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90 Figure 4 23 The mean and standa rd deviation of step velocity in each group during gait initiation a significant difference was observed (p 0.05)

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91 Figure 4 24 The mean and standard deviation of step width in each group during gait initiation

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92 Figure 4 25 T h e mean and standard deviation of COP displacement in the S1 phase during gait initiation. Positive values in the anteroposterior direction represent anterior COP displacement and vice versa. P ositive values in the mediolateral direction represent COP displacement toward initial trailing (ST) limb. a significant difference was observed (p 0.05)

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93 Figure 4 26 T h e mean and standa rd deviation of COP displacement in the mediolateral direction during the S2 and in the anteroposterior direction during the S3 phase during gait initiation. Positive values in the anteroposterior direction represent anterior COP displacement and vice vers a. P ositive values in the mediolateral direction represent COP displacement toward initial trailing (ST) limb. a significant difference was observed (p 0.05)

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94 Figure 4 2 7 T h e mean and standard deviation of COP velocity in the S1 phase during gait initiation. Positive values in the anteroposterior direction represent the anterior direction and vice versa. Positive values in the mediolateral direction represent the direction toward the initial trailing (ST) limb. a significant difference was observed (p 0.05)

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95 Figure 4 2 8 T h e mean and standard deviation of anteroposterior COP velocity in the S3 phase during gait initiation. Positive values in the anteroposterior direction represent the anterior direction. a significant difference was observed (p 0.05)

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96 Figure 4 2 9 T h e mean and standard deviation of anteroposterior mediolateral and resultant COPCOM distance in each phase during gait initiat ion. a significant difference was observed ( p 0.05) § a significant trend between the PSP and the PD group ( p < 0.06).

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97 Figure 4 30 T h e mean and standard deviation of gait velocity during gait in each group. Gait velocity was normalized by participant s leg length. a significant difference was observed ( p 0.05)

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98 Figure 4 31 T h e mean and standard deviation of step length during gait in each group. Step length was normalized by participants leg length. a significant difference was observed ( p 0 .05)

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99 Figure 4 32 T h e mean and standard deviation of step duration during gait in each group. Step duration was normalized by participants gait cycle.

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100 Figure 4 33 T h e mean and standard deviation of cadence during gait in each group. a signifi cant difference was observed ( p 0.05) § A significant trend between the PSP and Control group was observed ( p <0.06).

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101 Figure 4 34 T h e mean and standard deviation of step width during gait in each group. Step width was normalized by participants leg length. a significant differen ce was observed ( p 0.05)

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102 Figure 4 35 T h e mean and standard deviation of double support time during gait in each group. Double support time was normalized by participants leg length a significant difference was observed ( p 0.05)

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103 Figure 4 36 T h e mean and standard deviation of gait asymmetry during gait in each group. Gait asymmetry index was calculated based on swing time of both limbs. a significant difference was observed ( p 0.05)

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104 Figure 4 37 T h e mean and standard deviation of coefficie nt of variation (CV) of step length on MAS and LAS during gait in each group. a significant difference was observed ( p 0.05)

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105 Figure 4 3 8 T h e mean and standard deviation of coefficient of variation (CV) of step duration on MAS and LAS during gait in each group. a significant difference was observed ( p 0.05)

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106 Figure 4 3 9 T h e mean and standard deviation of coefficient of variation ( CV) of d ouble support time during gait in each group. a significant difference was observed ( p 0.05) § a significa nt trend between the PSP and the PD group was observed ( p <0.06).

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107 Table 4 1. Demographic information and clinical characteristics of each group Group PSP PD Control p value N 12 12 12 M /F 5/7 5/7 5/7 Age (years) 66 (8) 64 (7) 67 (7) 0.65 Height (cm) 164.9 (11.4) 169.8 (12.7) 168.1 (11.8) 0.62 Mass (kg) 77.4 (14.9) 78.4 (15.3) 72.1 (12.5) 0.54 MMSE a ,b 27.4 (2.7) a 29.5 (0.8) b 29.8 (0.6) <0.01 ABC a ,b 44.1 (29.7) a 89.9 (8.7) b 90.5 (11.2) <0.01 Disease Duration (years) 6.5 (4.9) 7.8 (7.1) 0.61 HY scale 3 5 1.5 3 PDQ39 SI a 37.6 (13.4) a 13.4 (7.1) <0.01 UPDRS total a 71.3 (15.6) a 33.9 (8.2) <0.01 UPDRS motor a 49.6 (10.4) a 23.5 (8.5) <0.01 PSPRS 37.3 (9.3) Note: a significant main effect of G roup was observed in both conditions ( p 0.05) a ,b, a significa nt difference between two groups was observed ( p 0. 05 )

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108 Table 4 2 Mean values (SD) of COP velocity and 95% confidence ellipse area of each group in Eyes open and Eyes closed conditions Condition EO EC Group PSP PD Control P SP PD Control COP Velocity (cm/s) 1.28 (0.80) 1.30 (0.65) 1.15 (0.37) 1.23 (0.52) 1.49 (0.52) 1.09 (0.34) A95 (cm 2 ) 5.49 (6.39) 3.38 (2.48) 2.10 (1.07) a 5.02 (3.13) 3.43 (2.10) a 1.80 (1.06) Note: a significant main effect of G roup was observed in E C condition ( p 0.05 ) a ,b a significant difference between two groups was observed ( p 0.05)

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109 Table 4 3 Mean values (SD) of approximate entropy of each group in Eyes open and Eyes closed conditions Condition EO EC Group PSP PD Control PSP PD Control AP directio n 0.31 (0.12) 0.37 (0.23) 0.39 (0.14) 0.30 (0.11) 0.40 (0.28) 0.38 (0.16) ML direction a ,b 0.26 (0.11) a 0.37 (0.10) b 0.39 (0.13) b 0.26 (0.14) 0.38 (0.16) b 0.40 (0.10) Note: a significant main effect of G roup was observed in both conditions ( p 0. 05) a ,b a significa nt difference between two groups was observed ( p 0. 05 )

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1 10 Table 4 4 Mean va lues (SD) of the Time to boundary measures of each group in Eyes open and Eyes closed conditions Condition EO EC Group PSP PD Control PSP PD Control Overa ll minTTB (s) 0.30 (0.08) 0.32 (0.06) 0.33 (0.04) 0.31 (0.06) 0.33 (0.07) 0.35 (0.05) meanTTB (s) 0.63 (0.11) 0.67 (0.08) 0.70 (0.10) 0.66 (0.06) 0.66 (0.09) 0.70 (0.09) stdTTB (s) 0.15 (0.02) 0.16 (0.02) 0.16 (0.03) 0.16 (0.02) 0.15 (0.01) 0. 16 (0.03) EC numPeakTTBs 1144 (228) 1134 (122) 1227 (60) 1172 (124) c 1109 (140) c 1234 (57) Anterior minTTB (s) 0.42 (0.11) 0.42 (0.08) 0.41 (0.06) 0.43 (0.09) 0.41 (0.08) 0.41 (0.07) meanTTB (s) 0.71 (0.14) 0.73 (0.09) 0.74 (0.11) 0. 74 (0.09) 0.71 (0.10) 0.75 (0.10) stdTTB (s) 0.14 (0.02) 0.16 (0.02) 0.16 (0.02) 0.15 (0.01) 0.16 (0.02) 0.16 (0.03) numPeakTTBs 239 (43) 245 (31) 279 (58) 250 (63) 247 (31) 284 (71) Posterior EO minTTB (s) b 0.32 (0.10) 0.37 (0.08) b 0 .41 (0.07) 0.33 (0.10) 0.37 (0.08) 0.41 (0.06) meanTTB (s) 0.59 (0.12) 0.64 (0.10) 0.70 (0.11) 0.61 (0.08) 0.63 (0.10) 0.70 (0.10) stdTTB (s) 0.14 (0.02) 0.14 (0.02) 0.15 (0.03) 0.14 (0.02) 0.14 (0.01) 0.15 (0.03) numPeakTTBs 192 (57) 183 (43) 170 (34 ) 226 (79) 184 (44) 174 (34) MAS + minTTB (s) % 0.33 (0.09) 0.34 (0.08) 0.39 (0.05) % 0.35 (0.09) 0.36 (0.08) 0.39 (0.05) meanTTB (s) 0.62 (0.12) 0.66 (0.09) 0.71 (0.09) 0.63 (0.09) 0.65 (0.09) 0.70 (0.09) stdTTB (s) 0.14 (0.02) 0.15 (0.01 ) 0.15 (0.03) 0.15 (0.02) 0.15 (0.01) 0.15 (0.03) numPeakTTBs 384 (115) 384 (105) 373 (66) 393 (111) 354 (123) 347 (63) LAS minTTB (s) 0.35 (0.10) 0.40 (0.06) 0.36 (0.05) 0.38 (0.04) 0.39 (0.06) 0.36 (0.05) meanTTB (s) 0.66 (0.09) 0.69 (0.07) 0.69 (0.10) 0.69 (0.05) 0.67 (0.07) 0.68 (0.09) stdTTB (s) 0.14 (0.02) 0.15 (0.02) 0.15 (0.03) 0.15 (0.02) 0.15 (0.01) 0.15 (0.03) EO + numPeakTTBs b 317 (117) % 338 (84) b % 428 (68) 315 (104) % 309 (97) % 406 (75) Note: § a significant trend ( p = 0.06 ) for Gro up was observ ed + a significant main effect for Condition was observed ( p 0. 05 ) EO, *EC a significant main effect of Group in EO or EC condition wa s observed ( p 0. 05 ) b ,c a significa nt difference between two groups was observed ( p 0. 05 ) % a significant difference between two conditions was observed within a group ( p 0. 05 )

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111 Table 4 5 Mean (SD) relative power distribution in each frequency bandwidth in each group in Eyes open and Eyes closed conditions Condition EO EC Group PSP PD Control PSP PD Control AP direction Median (Hz) 0.10 (0.04) 0.11 (0.06 ) 0.15 (0.06) 0.14 (0.06) 0.12 (0.05) 0.12 (0.07) F95 (Hz) 0.71 (0.31) 0.70 (0.45) 0.91 (0.35) 0.70 (0.28) 0.74 (0.32) 0.78 (0.40) Bin1 0.04 (0.02) 0.04 (0.03) 0.07 (0.04) 0.05 (0.04) 0.05 (0.03) 0.06 (0.04) EO Bin2 b 1.30 (0.17) c 1.40 (0.38) b ,c 1.05 (0.24) 1.28 (0.38) 1.22 (0.27) 1.23 (0.29) Bin3 1.67 (0.32) 1.75 (0.46) 1.52 (0.37) 1.67 (0.32) 1.67 (0.38) 1.64 (0.42) Bin4 3.46 (0.51) 3.26 (0.46) 3.39 (0.50) 3.48 (0.48) 3.23 (0.32) 3.49 (0.52) Bin5 4.99 (0.34) 4.99 (0.48) 4.90 (0.30) 5.08 (0.37) 5.02 (0.33) 4.92 (0.24) ML direction Median (Hz) 0.14 (0.08) 0.13 (0.05) 0.19 (0.06) 0.14 (0.08) 0.17 (0.07) 0.21 (0.11) EO F95 (Hz) 0.57 (0.32) 0.66 (0.14) 0.88 (0.37) 0.62 (0.35) 0.65 (0.18) 0.86 (0.35) EO Bi n1 0.03 (0.04) 0.05 (0.02) 0.08 (0.06) 0.04 (0.05) 0.05 (0.04) 0.09 (0.09) Bin2 a 1.44 (0.42) 1.16 (0.25) a 1.02 (0.38) 1.39 (0.58) 1.19 (0.33) 1.06 (0.37) Bin3 1.99 (0.46) 1.76 (0.15) 1.64 (0.49) 2.03 (0.61) 1.78 (0.28) 1.60 (0.53) B in4 3.32 (0.62) 3.02 (0.44) 3.25 (0.43) 3.40 (0.61) 3.05 (0.37) 3.23 (0.43) Bin5 4.32 (0.73) 4.21 (0.55) 4.10 (0.34) 4.47 (0.58) 4.26 (0.50) 4.08 (0.38) Note: All Bin values are described as log transformed relative power distribution in each frequency bandwidth. § a significant trend ( p = 0.06 ) for Group was observed. EO a significant main effect of Group in the EO condition was observed ( p 0. 05 ) a b a significa nt difference between two groups was observed ( p 0. 05 )

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112 Table 4 6 Mean values (SD) of COP velocity and 95% confidence ellipse area of each group in the FOAM condition Group PSP PD Control COP Velocity (cm/s) 2.68 (1.00) 2.36 (0.71) 2.75 (1.00) A95 (cm 2 ) 16.86 (7.05) 11.26 (6.98) 11.11 (6.75)

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113 Table 4 7. Mean values (SD) o f approximate entropy of each group in the FOAM conditions Group PSP PD Control AP direction 0.37 (0.14) 0.40 (0.06) 0.45 (0.17) ML direction 0.30 (0.08) 0.35 (0.07) 0.41 (0.10)

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114 Table 4 8. Mean values (SD) of outcome measures of the Time to boundary analysis of each group in the FOAM condition Group PSP PD Control Overall minTTB (s) 0.308 (0.058) 0.325 (0.042) 0.303 (0.063) meanTTB (s) 0.661 (0.086) 0.684 (0.050) 0.631 (0.108) stdTTB (s) 0.154 (0.020) 0.161 (0.014) 0.144 (0.019) numPeakT TBs 1123 (142) 1073 (50) 1133 (103) Anterior direction minTTB (s) 0.363 (0.081) 0.356 (0.037) 0.351 (0.094) meanTTB (s) 0.681 (0.125) 0.698 (0.033) 0.650 (0.116) stdTTB (s) 0.154 (0.018) 0.173 (0.023) 0.151 (0.015) numPeakTTBs 290 (89) 280 (36) 279 (20) Posterior direction minTTB (s) 0.313 (0.092) 0.350 (0.048) 0.351 (0.071) meanTTB (s) 0.624 (0.118) 0.673 (0.043) 0.638 (0.108) stdTTB (s) 0.150 (0.018) 0.167 (0.017) 0.138 (0.021) numPeakTTBs a 216 (16) 157 (50) a 172 (29) MAS minTTB (s) 0.345 (0.080) 0.370 (0.067) 0.364 (0.050) meanTTB (s) 0.673 (0.080) 0.684 (0.064) 0.661 (0.102) stdTTB (s) 0.151 (0.021) 0.152 (0.008) 0.141 (0.015) numPeakTTBs 310 (71) 322 (68) 295 (39) LAS minTTB (s) 0.299 (0.153) 0 .367 (0.038) 0.306 (0.061) meanTTB (s) 0.676 (0.071) 0.690 (0.052) 0.614 (0.090) stdTTB (s) 0.152 (0.020) 0.158 (0.018) 0.142 (0.015) numPeakTTBs 308 (111) 313 (47) 386 (70) a significant main effect for Group was observed ( p 0. 05 ) a a signific a nt difference between two groups was observed ( p 0. 05 )

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115 Table 4 9. Mean (SD) relative power distribution in each frequency bandwidth in each group in the FOAM condition Group PSP PD Control AP direction Median (Hz) 0.22 (0.06) 0.19 (0.10) 0. 20 (0.08) F95 (Hz) 0.74 (0.48) 0.81 (0.14) 1.17 (0.69) Bin1 a 0.045 (0.030) 0.079 (0.034) a 0.106 (0.053) Bin2 1.239 (0.337) 0.954 (0.244) 0.926 (0.350) Bin3 1.799 (0.361) 1.554 (0.110) 1.428 (0.485) Bin4 4.209 (0.563) 3.605 (0.287) 3.98 6 (0.826) Bin5 5.735 (0.364) 5.624 (0.348) 5.504 (0.447) ML direction Median (Hz) 0.17 (0.08) 0.18 (0.09) 0.23 (0.08) F95 (Hz) 0.51 (0.21) 0.68 (0.16) 0.82 (0.19) § Bin1 0.034 (0.036) 0.050 (0.035) 0.087 (0.042) Bin2 a 1.442 (0.404) 1.156 (0.288) a 0.939 (0.267) Bin3 a 2.119 (0.405) 1.792 (0.231) a 1.574 (0.223) Bin4 3.999 (0.438) 3.402 (0.239) 3.749 (0.522) Bin5 5.379 (0.480) 5.149 (0.373) 5.027 (0.221) Note: All Bin values are described as log transformed relative p ower distribution in each frequency bandwidth. a significant main effe ct of Group was observed ( p 0 .05). a a signific ant difference between PSP and Control group was observed ( p 0.05)

PAGE 116

116 Table 4 10. Spatiotemporal characteristics during gait initiation in each group Group PSP PD Control Initial Swing (SW) Step length (%LL) a,b 38.30 (15.35) a 5 5.66 (7.96) b 60.30 (7.80) Step duration (s) 0.63 (0.16) 0.58 (0.06) 0.60 (0.21) Step velocity (m/s) a,b 0.56 (0.22) a 0.89 (0.16) b 0.96 (0.18) Step width (%LL) 17.78 (4.11) 14.81 (2.01) 15.10 (2.51) Initial Stance (ST) Step length (%LL) a,b 71.21 (30.32) a 112.99 (13.31) b 121.92 (15.89) Step duration (s) 0.76 (0.19) 0.76 (0.13) 0.74 (0.10) Step velocity (m/s) a,b 0.86 (0.36) a 1.41 (0.27) b 1.50 (0.26) Note: a significant main effe ct of Group was observed ( p 0 .05) a,b a significa nt difference between two groups was observed ( p 0 .05). § a significant trend ( p < 0.06 ) for Group was observed.

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117 Table 4 11. COP characteristics during gait initiation Group PSP PD Control Displacement S1DispAP (cm) a,b 0.71 (1.55) a,c 1.14 (0.71) b ,c 2.61 (1.56) S1DispML (cm) a,b 2.46 (3.62) a 0.81 (1.03) b 1.85 (1.28) S2DispAP (cm) 1.04 (1.36) 0.61 (2.10) 0.25 (2.64) S2DispML (cm) a,b 5.65 (3.06) a 9.30 (2.26) b 10.17 (1.69) S3DispAP (cm) a,b 4.92 (2.44) a 7.84 (1.74) b 8.93 (2.18) S3DispML (cm) 0.01 (1.60) 1.10 (0.88) 1.06 (1.34) Velocity S1VelAP (cm/s) a,b 1.23 (2.99) a,c 3.76 (2.34) b ,c 9.00 (6.16) S1VelML (cm/s) a,b 7.09 (11.90) a 2.20 (3.85) b 5.50 (4.57) S2VelAP (cm/s) 4.36 (6.83) 0.11 (5.63) 0 .12 (8.87) S2VelML (cm/s) 20.08 (20.11) 22.08 (7.14) 31.70 (7.31) S3VelAP (cm/s) a,b 13.21 (5.96) a 20.27 (5.41) b 22.65 (5.98) S3VelML (cm/s) 2.41 (8.68) 2.68 (2.49) 2.75 (3.34) Note: a significant main effe ct of Group was observed ( p 0 .05). a b c a significant difference between tw o groups was observed ( p 0 .05). Positive values in the anteroposterior direction represent the anterior direction and vice versa. Positive values in the mediolateral direction represent the direction toward the initi al trailing (ST) limb.

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118 Table 4 12. COPCOM distance during each phase of gait initiation PSP PD Control S1COPCOM AP (cm) b 1.43 (0.94) § 2.32 (1.06) § b 3.65 (1.71) ML (cm) 2.84 (2.86) 1.85 (0.80) 2.66 (1.12) Resultant (cm) 3.27 (2.91) 3. 02 (1.22) 4.63 (1.88) S2COPCOM AP (cm) a, b 4.91 (1.89) a 7.69 (1.62) b 8.67 (1.87) ML (cm) 5.57 (2.92) 4.72 (1.16) 5.10 (0.74) Resultant (cm) b 7.67 (3.06) 9.08 (1.76) b 10.22 (1.54) S3COPCOM AP (cm) a, b 10.06 (3.76) a 17.39 (2.95) b 18.26 (4.19) ML (cm) 6.44 (2.33) 6.20 (1.72) 6.51 (1.10) Resultant (cm) a, b 12.30 (3.38) a 18.48 (2.89) b 19.56 (3.69) Note: a significant main effe ct of Group was observed ( p 0 .05). a b a significant difference between tw o groups was observed ( p 0 .05). § a significant trend ( p < 0.06 ) for Group was observed.

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119 Table 4 13 Spatiotemporal characteristics of forward gait in each group Group PSP PD Control Cadence (steps/min) a 99 (15) a 116 (16) 115 (12) Gait velocity (%LL/s) a,b 85.60 (3 3.68) a 123.40 (14.99) b 129.10 (14.83) Step l ength (%LL) a,b 49.20 (15.11) a 60.90 (6.90) b 65.10 (5.53) Step width (%LL) a,b 13.10 (4.28) a 6.60 (2.72) b 7.10 (1.20) Step duration (%GC) a,b 34.83 (3.98) a 38.85 (0.84) b 38.50 (1.98) Double s upport time (%GC) a,b 30.35 (7.96) a 22.95 (2.12) b 23.75 (3.47) C V of double support time ( % ) § b 13.90 (5.20) § 9.06 (3.54) b 8.36 (3.09) CV on MAS Step Length ( % ) a,b 13.58 (14.84) a 3.45 (1.15) b 2.82 (0.73) Step duration ( % ) a,b 8.4 2 (4.74) a 3.25 (1.17) b 2.71 (0.77) Step Width ( % ) 35.68 (22.81) 35.26 (14.31) 41.19 (15.36) CV on L AS Step Length ( % ) a,b 13.32 (15.25) a 3.46 (1.47) b 2.56 (0.77) Step duration ( % ) a,b 8.16 (5.43) a 3.16 (0.94) b 2.51 (0.56) Step Width ( % ) 33.30 (26.34) 43.19 (21.29) 37.85 (19.30) Gait asymmetry (a.u ) a,b 0.13 (0.10) a 0.02 (0.02) b 0.03 (0.02) Note: a significant main effe ct of Group was observed ( p 0 .05) a,b a significa nt difference between two groups was observed ( p 0 .05). § a significant trend ( p < 0.06 ) for Group was observed.

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120 CHAPTER 5 DISCUSSION The main objective of the present study was to determine the underlying biomechanical characte ristics of static/dynamic postural control and gait performance in PSP We evaluated: (1) static postural control, (2) dynamic postural control, and (3) gait in persons with PSP along with gender and age matched healthy elderly individuals and persons wit h PD In the present study, we found meaningful difference s in static postural control between PSP and PD as well as remarkable difference s in dynamic postural control and gait. This study is the first study to comprehensively report the underlying biomech anical characteristics of postural control and gait in persons with PSP in comparison to persons with PD and age and gender matched healthy elderly adults. Aim 1: Static Postural Control W e hypothesized that persons with PSP and PD would exhibit postural instability when compared to the age and gender matched healthy elderly individuals. This hypothesis was based on the deficits in proprioception, visual and vestibular systems, observed in these populations Additionally, we hypothesized that persons wit h PSP would exhibit impaired postural control with respect to persons with PD. To test th ese hypothes e s, five different components of an individuals postural sway were investigated in three different condit ions (EO, EC and FOAM). In addition to a signific ant difference among groups in the traditional m easure (i.e., A95) we detect ed significant differences among groups by using perhaps more sensitive nonlinear (i.e., ApEn) TTB, and frequency domain analyses.

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121 The mean velocity of COP in PSP did not signifi cantly differ from either PD or Control in any of the conditions. This is surprising since Prieto and colleagues [ 168 ] have reported sway velocity could be the one attribute associated with age related changes in postural control durin g both EO and EC conditions. In their study, mean COP velocity increased with age, and was greater when visual information was withdrawn. T he failure to observe significant difference s among groups indicated the potential limitation of the use of sway velo city to quantify sometimes subtle change s in an individual s postural control system W e observe d a significant difference among the groups for A95 in the EC condition The A95 represents the area enclosing approximately 95% of COP oscillation Genera lly abnormally large area (or magnitude) of postural sway has been associated with an ineffective / ineff i cient postural control system Although to date, no previous study has actually evaluated the magnitude of sway variability (i.e., A95) in persons with P SP, there has been one research comparable with the present results. Ondo and colleagues [ 111 ] have reported that the percentile equilibrium s core relative to th e limit of stability, in PSP was not significantly different from PD in the EO condition, while the ir score became worse than PD when visual and/or proprioceptive information were manipulated. They also observed larger score in PSP in comparison with PD wh en visual feedback was provided at an individuals center of sway. Yet, not statistically significant, a similar trend was observed in the present study : the persons with PSP exhibited relatively larger sway than PD in all conditions (Table 4 2 ) Further, the difference in A95 between these two groups appe ared to be magnified in the FOAM

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122 condition; specifically, A95 in PSP (16.8 7. 1 cm 2 ) was approximately 50% larger than PD ( 11 3 7.0 cm 2 ). When standing on a compliant foam pad (i.e., FOAM condition), somat osensory inputs are modulated; thus, appropriate reorganization of sensory priorities are required to efficiently maintain balance under this novel environment. The b asal ganglia, which are affected in both PSP and PD, play a crucial role in sensory reorga nization for postural adjustment under novel sensory environment s [ 183 185 ] N eurodegener ation of the subcortical areas, including basal ganglia and thalamus appear s earlier in the course of PSP than in PD [ 3 67 71 ] The strong association between postural instabili ty and brain atrophy in cerebral postural network is further supported by work of Zwergal and colleagues [ 66 ] They compared total sway path length with function al activation and regional cerebral glucose metabolism (rCGM) in the brain area s related to postural control. They revealed higher total sway path values w ere strongly related to decreased rCGM in the thalamus a nd its reduced activation during imag ery of q uiet standing. In the present study, the disease duration of PSP and PD participants were similar though (PSP: mean disease duration = 6 5 year s, PD: mean disease duration = 7 8 years p =0.61 ) Further, the PD participants exhibited only early to moderate stage disability (UPDRS motor : 23.5 p oin ts) when compared to PSP ( 49.6 p oin ts) Thus, it can be assumed that the absence of remarked alteration of A95 in PD and increased A95 in PSP, especially in a novel environment, could potentially reflect the severity of neural degeneration in basal ganglia and thalamus Since only six PSP participants could perform this task, further study with larger sample size is neces sary to confirm this postulation While no significant difference for A95 among the groups was obs erved in

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123 the FOAM condition, the other approaches (i.e., the TTB and the frequency domain analyses) could still explain significant differences and differentiate frail individuals (the PSP group) and non frail ones (the Control group). This possibly indic ate s a limitation in the sensitivity of the conventional linear measures of postural sway The present study clearly specified the need to consider integrating several different approaches to comprehensively elucidate individual s characteristics of postur al control T he analyses of TTB detect ed significant difference s among groups particularly in the lateral and posterior direction Briefly, the TTB quantifies the spatiotemporal stability margin in relati on to the individual s BOS [ 178 186 187 ] To maintain an adequate stability margin, indivi duals must perceive appropriate postural sensitivity from their afferent systems and counteract potential postural threats in a timely manner. Thus, TTB can provide relevant and more detailed information regarding individuals postural control system [ 178 ] than solely COP velocity or sway magnitude (e.g., A95). The significant reduction of minTTB value in the posterior direction in PSP observed in the present study is consistent with the previous study reporting frequent backward falls and direction specific postural deficits, especially the posterior direction in a limit of stability tas k [ 112 ] Indeed, y et not significant we also observed a significant trend for Group main effect in meanTT B ( p = 0.06), indicating that PSP exhibited delayed postural response when compared to the PD and Control (Figure 4 4). Moreover, the numPeak TTB s values in the posterior direction were larger than both the PD and the Control group s (EO: 4.9 % and 12.9 % resp ectively ; EC : 22.8 % and 29.9 % respectively ) Given that previous studies demonstrated that mean TTB value was associated with advancing age and postural instability [ 178 186 ] i t can be postulated

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124 that postural instability in the posterior direction frequently observed in person with PSP possibly could result from the inability to adequately respond t o perceived postural th reats In van Wegen and colleagues study [ 108 ] the ML mean TTB value was decreased in persons with PD when compared to healthy elderly individuals when standing quietly and leaning forward or backward. We could not confirm the difference between PD and healthy elderly adults, possibly due to the difference of the methodology. In van Wegen s study, TTB was calculated based on only the instantaneous distance between COP and BOS and velocity, while our study included instantan eous acceleration to calculate TTBs. Further, COP velocity in each direction was used and calculated TTB in the AP and ML direction separately in their study. In the present study, we used the resultant COP velocity to calculate TTBs based on current COP v elocity and extrapolated COP trajectory. This methodology was also used in the other previous study on human postural control [ 178 ] Since there is a possibi lity in which peak TTB in one direction becomes larger than the other direction at the same instant and since the acceleration term can reverse the direction of the current COP velocity in some cases, we believe our methodology more thoroughly capture s COP dynamics. Indeed, Haddad and colleagues [ 188 ] previously compared the effectiveness of the aforementioned two different TTB methodologies to assess postural control during quiet standing and induced sway conditions. They recommended our methodology rather than Wegen s methodology when ass essing postural control during quiet standing due to the inclusion of the acceleration term in the TTB calculation Therefore, to clarify the alteration of spatiotemporal stability margin in the ML direction

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125 in PD population and to determine whether PSP pr ofoundly affect individuals perception of spatiotemporal postural dynamics than PD, further large sample study utilizing our methodology is warranted We observed the decreased ApEn value in the M L direction in the EO condition for PSP when compared to t he PD and Control group. A significant reduction of ApEn value in EC condition in comparison with the Control group was also observed in the present study. The ApEn analysis quantifies complexity of given physiologic time series data. Low ApEn values in PS P rep resent a predictable time series signal, which is generally thought to correspond to loss of efficiency, adaptive capability, or automaticity of postural contro l [ 129 130 ] Given that the biological redundancy is necessary to prepare for any sudden change in a surrounding environment th ese findings could further support the aforementioned speculati on regarding postural instability related to the sensory reorganization deficit in PSP. In fact, the alteration of postural control in the ML direction during the limit of stability task has been previously reported [ 112 ] The ApEn analysis differentiated postural control in PSP from the other two groups and revealed the lack of adaptability in the ML direction in persons with PSP. Although not significant in the EC and FOAM condition the ApEn value s in the ML direct ion in PSP were substantially lower than PD (EO: 29.7 %, EC: 31.6 % and FO AM: 14.3 % ). The difference between these two pathological groups was not as large as the di fference between PSP and the age matched healthy elderly groups. This appeared to be consistent with our hypothesized continuum of the deterioration in postural stab ility. The present study identified significant alterations in frequency domain measures in the ML direction in persons with PSP in EO and FOAM conditions. Specifically,

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126 persons with PSP tended to predominantly control their upright posture in lower frequ ency regions, while the other two groups (PD and Control) tended to weight more toward higher frequency domains Indeed, the significant main effect of Group for F95 in the EO condition observed in the present study indicated that the frequency distributio n in PSP was more converge d in a lower region, when compared to the PD and Control groups. Briefly, the frequency domain analyses quantify the distribution of power in the ranges of low, middle and high frequencies which are thought to be influenced in va rying degrees by different afferent information [ 135 189 ] Specifically, lower frequency regions are p rimarily controlled by vestibular system [ 190 ] while region s of relatively higher frequencies are controlled by visual and proprioceptive system s [ 190 ] Considering these representations of frequency ranges, persons with PSP appeared to predominantly rely on their vestibular system. Meanwhile the vestibular deficits could be associated with postural instability in PSP sinc e Ondo and colleagues [ 111 ] demonstrated that postural control in PSP was markedly altered when both visual and proprioceptive inputs were manipulated. Thus, the reliance of the vestibular afferent system could be representing a malfunctioning postural strategy for this population. Furthermore, the increased reliance on vestibular information for postural control could indicate somatosensory loss in persons with P SP [ 191 ] Indeed, recent studies showed that the pedunculopontine nucleus (PPN), which is frequently affected in PSP [ 69 192 ] receives the direct som atosensory input [ 193 ] and might be involved in sensorimotor integration [ 194 ] Therefore, it can be speculated that increased contribution of the vestibular system in the postural control system is associated with potential somatosensory lo ss, possibly due to the neuronal degeneration of PPN

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127 Further study with larger sample size and statistical assessment of the interaction between sensory manipulations (e.g., change between the EO and FOAM condition) and gr oup is warranted to confirm our s peculations regarding the association between the overreliance of vestibular system and the proprioceptive deficits in PSP In summary, the combined findings from Aim 1 in the present study revealed the lateral postural dynamics in PSP were altered. In con junction with the previous literature, the observed alteration of postural control system may have resulted from neurodegeneration of basal ganglia, thalamus, and PPN. The underlyin g biomechanical characteristics of postural instability in PSP can be chara cterized as: (1) less flexible, adaptive and more stereotyped postural dynamics in ML direction (2) malfunctioned sensory integration strategy (i.e., profoundly relying on the vestibular system), possibly due to the proprioceptive loss and (3) the in adeq uate postural response when leaning toward the posterior direction, leading to the constantly unstable upright posture (i.e., small spatiotemporal stability margin toward the posterior limit of stability) More pronounced lateral instability could be indic ative of early sign of PSP and one of the differential clinical feature s of PSP from PD. Moreover, we can suggest clinicians and therapists should also emphasize the improvement of lateral postural control to alleviate postural instability and to reduce nu mber of falls. Aim 2: Dynamic Postural Control Specific aim 2 was t o determine the underlying biomechanical characteristics of dynamic postural control in persons with PSP and to determine the difference between PSP and PD. We hypothesized that both perso ns with PSP and PD would exhibit more dynamic postural instability when initiating gait in comparison with the age and gender matched healthy elderly individuals. Second, w e also hypothesize d that persons with

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128 PSP would exhibit more severe dynamic postur al instability compared to persons with PD. We confirmed our hypothes e s that persons with PSP exhibited more severe dynamic postural instability than controls and persons with PD, who were also found to be slightly worse th an healthy peers A nticipatory p ostural adjustments ( APAs ) during GI function to initially shift the COP posteriorly and laterally towards the SW limb (i.e., the initial stepping limb ) prior to an initial heel off of the SW limb namely S1 phase [ 141 ] P osterior COP movement during this phase generates forward momentum needed to initiate gait, whereas lateral movement aids in generation of the movement of the COM towards the ST limb in preparat ion for an initial step [ 141 ] Previous studies revealed that with advancing age and disability there is a reduction in the magnitude of the posterior and late ral C O P displacement during the S1 phase [ 180 195 ] A lso, Hass and colleagues [ 137 ] suggested that the COPCOM distance could provide sensitive para meters quantifying the impairment of dynamic postural control during GI. Thus, quantifying APAs and COPCOM distance during GI provide us more detailed insights of disease related deterioration of dynamic postural control in PSP and PD Regarding the COP ch aracteristics of GI, S1Disp in the AP direction in PSP were significantly reduced when compared to both the PD and the Control groups (Figure 4 18 ) Specifically, the typical profile of APAs (i.e., posterolateral COP shift during the S1 phase) was profound ly diminished (0. 71 cm anteriorly ) even when compared to persons with PD (1.1 cm posteriorly) and the Control group (2.6 cm posteriorly) or in some totally absent (Figure 4 15 ). Meanwhil e, the magnitude of the posterolateral COP displacement in the PD group was significantly less than the Control group (Figure 4 18),

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129 but the APAs were still present (Figure 4 15) Thus, the significant alteration of APAs in PSP and the limited change in persons with PD indicated the degree of impairment in dynamic postural co ntrol in P SP was more prominent than that of PD. Furthermore, Breniere and Do [ 196 ] suggested that step length and progressive velocity were related to the sum of gravitational and muscular propulsive forces acting on the body generated prior to an initial step. Thus, the significant reduction of posterior COP displacement during the S1 phase in PSP should lead to shorter step length and slower step velocity in comparison with PD and Control groups This postula tion was confirmed in our analyses (Table 4 10 ). The COP displacement in the ML direction during S1p hase also significantly differed among groups (Figure 4 1 8 ) While the subjects in the PD and the Control groups shifted their COP laterally toward the SW limb (PD: 0.8cm, Control: 1.9 cm) the subjects in the PSP group appeared to move their COP toward the ST limb (2.5 cm) Moreover, the COP velocity in the ML direction during S1 phase in PSP (toward the ST limb) was significantly faster than the other two groups (Figure 4 2 0) Considering these findings, in conjunction with the aforementioned reduction or a bsence of posterior COP displacement during S1, it can be speculated that persons with PSP shifted their weight directly toward the initial ST limb to lift up the initial SW limb, without preparing for the subsequent forward progression. This could be th e compensatory preparatory strategy for persons with PSP; however, abnormally fast COP velocity toward the ST side might indicate the inability to control the lateral lean of the body, which could induce potential postural imbalance in the following GI pha ses due to the lateral postural instability (see Aim 1).

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130 T he COPCOM distance represents the moment arm required to effectively create a forward propulsive acceleration during GI S eparating the COP from COM is required to efficiently create the forward mo mentum to initiate gait [ 197 ] However, at the same time, it also forces individuals to destabilize themselves while the COM is still in the base of support [ 198 ] Hass and colleagues [ 137 ] showed that the maximum COPCOM distance during S3 phase could be indicative of severity of disease in dynamic postural co ntrol. Ther efore, as suggested by Martin and colleagues [ 139 ] the redu ction of COPCOM distance reflect s the compensatory GI strategy to maintain individuals stability resulting from their balance impairment and/or inability to generate enough momentum using the pos terior COP shift during the preparatory phase (S1). In the present study, t he COPCOM characteristics during GI were also markedly altered in PS P (Figure 4 2 2 ). T he maximum AP COPCOM distance in PSP was significantly reduced in comparison with th e PD group both at the preparatory ( S2 ) and the locomotion ( S3 ) phases Similarly during the S2 phase the COPCOM dis tance in the AP direction in the PSP group was si gnificantly smaller than the PD group This is intriguing since Hass and colleagues [ 137 ] reported the significant difference between PD individuals with pos tural instability and without manifested only in the locomotion phase. This significant alteration could result fr om more pronounced dynamic postural instability in PSP, in comparison with PD. During the locomotion phase (S3) the AP COPCOM distance in PSP was approximately 60% smaller than both PD and Control groups. The present study also revealed that the resultant COPCOM distance in the S3 phase significantly differed among the groups Many previous studies demonstrated the COPCOM distance during GI cou ld identify persons with postural instability and fall risks

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131 [ 137 139 199 ] Hwa Ann and Krebs [ 199 ] previously suggested that the cutoff point of the resultant S3COPCOM value to identify the persons with dynamic postural instability was from 16 18cm In the present study, the mean S3COPCOM in the resultant directio n for the PSP group was 12.3cm, which is markedly smaller th an the aforementioned cutoff point Furthermore, approximately 34% difference between the PSP and the PD group observed in the present study was much larger than the value r eported by Hass and col leagues ( approximately 16% between PD subj ects with postural instability and without [ 137 ] ) Considering these findings, t he prominent alteration at both preparatory and locomot ion phases of GI could further imply that dynamic postural control is more disturbed in PSP than PD and that dynamic postural control wa s more severely impaired than static postural control in persons with PSP To initiate and regulate internally generated voluntary movements, like GI, the active involvement of SMA, basal ganglia and cerebellum are necessary [ 200 201 ] The SMA receives afferent projections from many brain areas, including basal ganglia and cerebellum (primarily from cere bellar dentate nucleus), and these inputs are relayed by different thalamic areas [ 21 202 204 ] I n persons with PD, s everal previous studies revealed both SMA and basal ganglia were affected [ 205 206 ] In PSP, neurodegeneration is also not limited to the basal ganglia. P revious studies reported more prominent deficits of thalamus, cerebellum including the flocculonodular lobe [ 85 ] the dentate nucleus [ 207 ] and superior cerebellar peduncle [ 98 208 ] in PSP [ 20 66 85 209 210 ] The dentate nucleus in cerebellum is thought to be responsible for motor planning, initiation and control of voluntary movement, and its output projects through the superior cerebellar pedunc le and reaches the M1 and PM area via thalamus.

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132 Further, the flocculonodular lobe of the cerebellum plays an important role in the postural control system. Hence it can be suggested that more widespread atrophy and dysfunction of cerebellum and/or thalamus in PSP, but not in PD, could be associated with more prominent deficits in dynamic postural control in PSP than PD. In summary, the results for Aim 2 of the present study showed that GI performance in persons with PSP was significantly altered when compared to both PD and Control groups, possibly due to their severely impaired d ynamic postural control. The biomechanical assessment of GI revealed that the profound reduction of the step length and slower step during GI in persons with PSP could result from the severe abnormality of APAs evidenced by the absence of posterolateral C OP displacement during S1 phase. Thus, the persons with PSP appeared to attempt to execute the compensatory strategy to initiate a first step by leaning toward the ST limb. However, this compensatory strategy could paradoxically result in more lateral post ural instability due to the lack of active control of lateral COP drift during the preparatory GI phase. This is to s ome extent consistent with the findings in Aim 1 in which the intrinsic static postural instability in the ML direction was presented. Gi ven that cerebellum, basal ganglia, and thalamus are thought to play important roles in postural control and gait, and they are often affected by PSP, these deficits in dynamic postural control could possibly stem from multi focal nature of neurodegenerati on commonly observed in PSP. From the clinical application perspective, the present study suggested, in conjunction with the previous studies by Hass and colleagues [ 137 ] and Hwa Ann and Krebs [ 199 ] the posterolateral COP displacement during S1 phase and the maximum COPCOM distance at S3 could be potential ly t wo sensitive factor s that might be able to quantify

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133 the severity of PSP associated with dynamic postural instability and to differentiate PSP from PD Aim 3: Gait The goal of Aim 3 was to determine the underlying biomechanical characteristics of gait in persons with PSP and to determine the difference among PSP PD and healthy elderly adults We hypothesized that persons with PSP have more severe gait dysfunction when compared to persons with PD. To evaluate this hypothesis, forward overground gait at their self selected speed was biomechanically assessed in each group and spatiotemporal gait characteristics were compared. Gait velocity was significantly slower in PSP (0. 76 m/s) when compared to the PD (1.1 5 m/s) and Control (1.1 6 m/s) groups. Moreover s tep length and cadence were significantly reduced in PSP (0.4 5 m and 99 steps/min, respectively) in comparison with th e PD (0.5 7 m and 11 6 steps /min) and Control groups (0.5 9 m and 11 5 step s/min respectively; Figure 4 24 and 4 26 ). Many previous studies in P D have reported that cadence in persons with PD was typical ly unaffected or slightly increased [ 23 154 211 212 ] except for one recent PD study which utilized the GaitRite system instead of motion capture [ 213 ] Increased cadence can be considered as the compensatory mechanism for the reduction of step length [ 214 ] G iven that gait velocity is proportional to step l ength and cadence, the pronounced reduction of gait velocity in PSP appeared to result from deteriorations of internal programming of both spatial and temporal motor outputs, unlike PD, whose deficits were relatively limited in spatial control. The person s with PSP exhibited signi ficantly larger step width ( 11.7 cm) th an the other two groups (PD: 6.10 cm, Control: 6.4 cm), possibly indicating they attempt to widen their BOS to increase postural stability during locomotion. Even w hen corrected

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134 for the effect o f gait velocity, step width in PSP was still significantly larger than the other two groups ( p = 0.01) indicating the observed change in step width was independent of change in gait velocity This observation appeared to be in agreement with the observed significant increase of double support time in PSP ( 30.4 % of GC) when compared to the PD (2 3 0 % of GC) and the Control (23. 8 %) group While increasing step width increases the spatial stability margin, it is less efficient since more metabolic cost is requ ired [ 215 ] To act ively control step width during gait, lateral balance must be stabilized by visual and vestibular feedback [ 216 ] R evisiting Aim 1 of the present study, we showed persons with PSP appeared to have lateral postural instability due to the malfunctioning sensory integration process Furthermore, persons with PSP reported less confidence of their balance, evidenced by significantly lower ABC score than the other two groups. Therefore, it is plausible to postulate that the wider step s during gait in PSP could be the compensatory strategy for lateral postural instability and fear of falling The present study revealed that gait asymmetry index in PSP was significantly higher than the PD and Control groups. The pronounced asymmetric gait pattern in PSP was intriguing since PSP has been thought to be more symmetric nature than that of PD [ 1 ] Given that the gait asymmetry index used in the present study wa s the log transformed ratio of the swing time of each limb side, higher values for this variable represent larger disassociation of the left and right (or MAS and LAS for PSP and PD groups) swing time [ 181 ] The less coordinated gait pattern in PSP, often described as ataxic, lurching, or drunken sailor gait, could be indicative of marked dysfunction of indirect locomotor pathway: the prefrontal cortex, basal ganglia (particularly STN), and

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135 the brainstem locomotor regions, such as PPN and cunei form nucleus. The indirect locomotor pathway is very important for modulation of the locomotor pattern [ 217 ] Indeed, Zwergal and colleagues [ 218 ] recently revealed that reduced metabolism in the se ar eas were associated with gait velocity, step length and PSPRS gait subscore which could support the aforemention ed postulation Meanwhile, r educed cadence and increase of the outcome measures associated with postural control during gait, such as step wid th, double support time, and step duration, could be the typical feature of cerebellar gait [ 219 ] While brainstem locomotor regions and the spinal cord generate basic locomot or patterns, the cerebellum contributes to modulations of timing, r ate and force of muscle activation [ 220 ] helping to generate highly rhythmic and stereotyped locomotor pattern. A recent study reported the increased activation of the cerebellum in persons with PSP who performed a 10 minute overground walking before a brain imaging procedure in comparison with control subjects [ 218 ] M o reover, the authors have reported that the increased activity in the cere bellum was associated with the degree of gait impairment, quantified by clinical gait scores gait velocity and step length. Indeed, the cerebellar hyperactivation and its association with defective basal ganglia have been suggested in PD [ 221 222 ] Thus, it can be postu lated that persons with PSP have similar compensatory mechanism to bypass the defective indirect locomotor pathway. W ithout any brain imaging evidences we could not conclude whether gait dys function in persons with PSP resulted from cerebellar hyperactivity or neurodegeneration ( or even both ). Nonetheless, the present study indicated that more severe anomaly in the cerebellum in comparison with PD, also appeared to be involved in alteration of gait characteristics in persons with PSP.

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136 The present study demonstrated that inter step step le ngth and duration variability in p ersons with PSP were profoundly altered when compared to PD and Control. Inter step variability measures have been used as markers of balance instability, fall risk and gait dysfunction. A recent study suggested that different gait variability measures could represent different aspects of gait performance [ 223 ] In particular, s tep length variability was strongly associated with ante roposterior trunk acceleration variability ; thus it could represent the degree of steadiness in propulsive acceleration Given that previous literature showed increased step length variability (>7%) was associated with high risk of falling [ 224 225 ] the present study further indicated that persons with PS P were at higher risk of falls than PD and Control group Moe Nilssen and colleagues also suggested that s tep duration variability was highly related to vertical trunk acc eleration variability. Considering this previous suggestion step duration variability could reflect individual s capability to control vertical fall a nd/or rise of COM during gait. This postulation can be supported by the previous findings by Welter and colleagues [ 152 ] who reported acti ve braking of the fall of COM prior to foot contact during GI was absent in persons with PS P. O n the basis of the previous findings by Welter and colleagues, the present stud y further suggested that persons with PSP appeared to be unable to consistently control vertical fall of COM during gait possibly causing unstable gait. Although the exact neural mechanism causing higher spatial (i.e., step length) and temporal (i.e. step duration) gait variability remains unknown the findings of the pre sent study further supported the aforementioned postulation that widespread deterioration in cortical, subcortical and cerebellar region s could affect gait dysfunction

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137 in this population. Some previous studies suggested that the basal ganglia particular l y GPi and STN, are mainly responsible for the control of amplitude of motor output s [ 226 228 ] and these nuclei, along with the cerebellum, SMA and PM area also play an important role in controlling temporal coordination [ 229 231 ] This postulation can be supported by the findings of Ebersbach and colleagues [ 232 ] who compared parkinsonian gait variability to that of persons with cerebellar ataxia They reported persons with cerebellar ataxia exhibited increased both spatial and temporal CV values (step length CV: 7.7%, s tride duration CV: 4.8%), while persons with PD (step length CV: 3.7%, stride duration: 2.4%) did not differ from their healthy peers (2.8% and 2.3%, respectiv ely ). When comparing to the present study, the PSP participants exhibited even higher step to ste p spatiotemporal variability (step length CV: 13.5%, step duration: 8.3%) than the cerebellar patients in the aforementioned previous study. The large difference between cerebellar patients and persons with PSP in gait variability appeared to indicate that the variab ility is likely due to a complex neurological dysfunction rather than solely attributable to cerebellum or basal ganglia in isolation The findings of the present study in conjunction with the previous neuroanatomical findings, suggest that mor e widespread and severe neuropatho logical deficits in basal ganglia cerebellum SMA and PM area could result in profound increase in gait variability in persons with PSP The present study first revealed many biomechanical aspects of gait dysfunction of PSP: (1) re duced cadence step length and gait velocity (2) increased balance related parameters (i.e., step width and doubl e support time), ( 3 ) temporally uncoordinated gait pattern (asymmetric gait) and (4) higher step to step and stride to

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138 stride var iability T he results in this aim showed that t hese alterations were significantly pronounced in comparison with PD. T he gait dysfunction of PSP could result from the combination of deficits in brainstem locomotor regions, basal ganglia, prefrontal area, a nd cerebellum, but further studies are needed to fill the gap between the underlying biomechanical characteristics of PSP gait and its neuropatholog ical mechanisms affecting gait. Limitations A review of literature showed persons with PD exhibited various alterations in static postural control [ 100 110 ] dynamic postural control [ 139 145 ] and spatiotemporal parameters of gait [ 153 154 ] when compared to healthy peers A lthough we did observe the stepwise deterioration among the groups (i.e., PSP is the worst, followed by the PD group, and the Control group was least affected) of static/dynamic postural control a nd gait performance, we could not find significant difference in many outcome variable s The possible explanation could be the combination of the retained motor capability in the PD subjects and the age related deterioration of motor control in healthy eld erly controls in the present study. For instance, p revious studies have determined that gait velocity of higher than 1 .0 for older a dults without disability [ 233 ] Other studies have shown that gait velocity of less than 0.8 m/s is pathological gait velocity [ 234 ] T he g ait velocity of both groups observed in this study (1.2 m/s) seeme d to be slower than expected for healthy elderly individuals, and faster for the persons with PD. Further, the self reported confidence about balance did not differ between the PD and the Control group. To rule out the possibility that the pronounced defic its in postural control and gait in PSP, in comparison with PD, resul t from the severity of general parkinsonian deficits affecting PIGD rather than specific

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139 PSP deficits the clear distinction between PD and the gender and age matched healthy peers in the performance outcomes is imperative. Nonetheless, the overall results of the present study showed that PIGD in PSP was more severely manifested when compared to PD and healthy elderly peers and that the PD group exhibited slightly worse performance tha n the Control group in most outcome measures in all tasks. Thus, we believe that further research is warranted, solving these limitation s by increasing sample size and more restricted inclusion/exclusion criteria of PSP and PD than the present study. Concl usion The results fr om the present study revealed that the PIGD in PSP was more severely manifested when compared to persons wit h PD and healthy elderly peers The widespread and profound neuronal degeneration resulting from PSP, particularly in the thalam us and PPN, could lead to more severe lateral postural instability than PD. T he overall results in Aim 1 indicated that this lateral imbalance in PSP could be characterized as less adaptive and more stereotyped postural strategy due to the malfunctioned se nsory integration process ( perhaps the overreliance of the vestibular system in a normal condition). Furthermore, dynamic postural control in persons with PSP was also profoundly altered in comparison with persons with PD and healthy elde r ly peers T he abn ormally shorter and slower step during GI in PS P could result from the inability to execute APAs while APAs were only moderately affected in PD Consequently, the compensatory strategy for step initiation in persons with PSP appeared to be very distinct f rom PD, but it paradoxically induced more lateral postural instability. The r educed cadence, gait velocity and step length along with increased asymmetry in PSP gait could stem from increased step width a nd double support time

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140 since per sons with PSP prefe r red a larger safety margin during gait because of their lateral instability and fear of falling The present study also suggested that t he combination of deficits in brainstem locomotor regions, basal ganglia, p re motor area, and cerebellum could result in the pronounce d gait disturbance in PSP S ince PSP gait features were also similar to those reported for cerebellar patients, th e cerebellar involvement could be more prominent in PSP than PD In conclusion, t his first extensive biomechanical investigatio n of gait and postural control in persons with PSP substantially advance d our knowledg e regarding gait and postural in stability in persons with PSP and aid clinicians and therapists to correctly and feasibly classify PSP from PD at early stage and to estab lish evidence based therapy protocols for this pathological population Given the motor control deficits in PSP worsened with movement, from static to dynamic postural control assessing dynamic postural control during GI could potentially help further dif ferentiating PSP from PD. From the therapeutic perspective, clinicians and therapists should emphasize the improvement of lateral postural control in addition to anteroposterior control, to alleviate postural instability and to reduce number of falls in t his population

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159 BIOGRAPHICAL SKETCH Shinichi Amano was born in Osaka, Japan. He received a Bachelor of Science in mechanical engineering from Kobe University, Japan in 2001. He came to the United States in 2002 and e arned a Bachelor of Science in k inesiology from Louisiana State University in 2006. He started his PhD program under the guidance of Dr. Chris Hass in 2007. To date, he has been involved in many research projects targeting pathological populations with gait dysfunction and postural instability. He received his PhD degree in May 2013.