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Vestibulo-ocular Reflex Function in Autism Spectrum Disorders

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Title:
Vestibulo-ocular Reflex Function in Autism Spectrum Disorders
Creator:
Carson, Tana B
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[Gainesville, Fla.]
Florida
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University of Florida
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english
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1 online resource (175 p.)

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Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Psychology
Committee Chair:
LEWIS,MARK HENRY
Committee Co-Chair:
DEVINE,DARRAGH P
Committee Members:
VOLLMER,TIMOTHY RAYMOND
HASS,CHRISTOPHER J
REYNOLDS,STACEY E
SCHUBERT,MICHAEL C
Graduation Date:
12/13/2013

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Subjects / Keywords:
Asperger syndrome ( jstor )
Autistic disorder ( jstor )
Eye movements ( jstor )
Intelligence quotient ( jstor )
Nystagmus ( jstor )
Pathologic nystagmus ( jstor )
Stress tests ( jstor )
Time constants ( jstor )
Velocity ( jstor )
Vestibulo ocular reflex ( jstor )
Psychology -- Dissertations, Academic -- UF
autism -- cerebellum -- motor -- oculomotor -- reflex -- sensory -- vestibular -- vestibulo-ocular
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bibliography ( marcgt )
theses ( marcgt )
government publication (state, provincial, terriorial, dependent) ( marcgt )
born-digital ( sobekcm )
Electronic Thesis or Dissertation
Psychology thesis, Ph.D.

Notes

Abstract:
Autism spectrum disorders (ASD) are characterized by social and communication skill deficits and excessive restricted/repetitive behaviors (APA, 2000; DSM-IV TR). Additional features commonly noted in ASD are deficits in sensory processing and motor control. Some motor control differences reported in ASD include decreased postural stability, decreased muscle tone, altered vestibulo-ocular reflexes (VORs) and delayed motor milestones (Fournier et al., 2010; Ben-Sasson et al., 2009; Bhat et al., 2011;Ornitz et al., 1985). These deficits may share a common dependence upon processing of vestibular sensory input. Therefore a better understanding of the extent to which vestibular sensory processing and related motor control is compromised in ASD would be beneficial for studying the underlying neurobiology of ASD. The VOR is useful for studying vestibular related sensory motor processing in this population as it involves a relatively simple reflex system, am enable to study in very young children. The rotational vestibulo-ocular reflex (rVOR)functions to maintain stable vision by generating oculomotor responses to angular rotation head movements. Our understanding of these VOR differences in ASD is currently hindered by a paucity of studies investigating this reflex. In the current studies, children ages 6 – 12 diagnosed with autism spectrum disorders observed three main differences in rVOR metrics including: (1)increased time constant of decay of post-rotary nystagmus during velocity step tests in the dark and with fixation suppression (Chapter 2); (2) increased per-rotary nystagmus gain during velocity step tests in the dark and increased gain during sinusoidal harmonic acceleration (SHA) tests in the dark as well as fixation suppression (Chapter 2 and 3 respectively); and (3) increased phase lead during SHA tests at 0.5Hz frequency cycle (Chapter 3). Several functional measures were found to correlate with rVOR time constant differences in ASD such as: adaptive skills and balance deficits(Chapter 4). Additional aberrations in the quality of rVOR such as increased slow phase irregularities are described and methods for further analysis of these differences are discussed(Chapter 5). The current findings suggest vestibular processing deficits in the rVOR that are consistent with reports of cerebellar deficits in the ASD population and warrant further study. ( en )
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In the series University of Florida Digital Collections.
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Includes vita.
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Includes bibliographical references.
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Description based on online resource; title from PDF title page.
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This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Thesis:
Thesis (Ph.D.)--University of Florida, 2013.
Local:
Adviser: LEWIS,MARK HENRY.
Local:
Co-adviser: DEVINE,DARRAGH P.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-12-31
Statement of Responsibility:
by Tana B Carson.

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Embargo Date:
12/31/2015
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LD1780 2013 ( lcc )

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1 VESTIBULO OCULAR REFLEX FUNCTION IN CHILDREN WITH AUTISM SPECTRUM DISORDERS By TANA BLESER CARSON 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 Tana Bleser Carson

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3 T o my cousin, Cheryl, my friend and inspiration

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4 ACKNOWLEDGMENTS It is with gratitude that I acknowledge the m entorship of my committee chair, Mark Lewis, PhD. His instruction in grant writing made it possible to obtain funding to support this research and his guidance throughout the writing and data analysis process made it possible for me to complete this disser tation I would also like to thank my dissertation committee (in alphabetical order): Dr. Darragh Devine, Dr. Chris Hass, Dr. Stacey Reynolds, Dr. Michael Schubert and Dr. Timothy Vollmer for their critical reviews and support Additional thanks go to Dr. Schubert for his mentorship in vestibular testing methods and interpretation of my research results. I am indebted to s everal graduate and undergraduate students whose hard work and assistance with either designing testing equipment, data analysis methods or testing participants made this study possible including: Bradley Wilkes, Jill Welsh, Kunal Patel, Sridhar Srinivasan and Subrat Nayak. I would also like to thank Brittany Jesewitz and Ashley Giddings for their assistance in mak ing testing enjoyable fo r the children participating. I would also like to thank John Bac om and Erika Espinosa for work designing and building the original pediatric rotary platform and Alex Keiderman at Neurokinetics, LLC. for understanding our vision for a n updated pediatric ro tary platform and helping to make it a reality. Thank you to Philip Teitelbaum, PhD, Osnat Teitelbaum, PhD, Theresa Dourado, PT, Rose Marie Rine, PT, PhD and Kathy Berger, PT, PhD for their support Special thanks to my cousin, Cheryl Eisnor for all of he r love, friendship and inspiration. Finally, and most importantly, I would like to thank my family, particularly my parents, Rob and Sandra Bleser, my step mother Linda and my husband, Wyatt Carson, for their encouragement, love and suppor t.

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5 TABLE OF CONT ENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 9 LIST OF FIGURES ................................ ................................ ................................ ........ 10 LIST OF ABBREVIATIONS ................................ ................................ ........................... 13 ABSTRACT ................................ ................................ ................................ ................... 14 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 16 Vestibular Sensorimotor Processing in Autism Spect rum Disorders ....................... 16 The Vestibulo ocular Reflex ................................ ................................ .................... 17 Vestibulo ocular Reflex Studies in Autism ................................ .............................. 20 Specific Aims ................................ ................................ ................................ .......... 22 Overview of Studies Presented in this Dissertation ................................ ................ 24 General Methods ................................ ................................ ................................ .... 25 Participants and Recruitment ................................ ................................ ........... 25 General Procedure ................................ ................................ ........................... 26 Innovation ................................ ................................ ................................ ............... 28 2 EFFECT OF VISUAL CONDITIONS ON ROTATIONAL VESTIBULO OCULAR REFLEX FUNCTION IN AUTISM SPECTRUM DISORDERS ................................ 37 Methods ................................ ................................ ................................ .................. 40 Participants and Recruitment ................................ ................................ ........... 40 Neuropsychological Testing and Standardized Rating Scales ......................... 41 Testing Equipment ................................ ................................ ........................... 42 Procedure ................................ ................................ ................................ ......... 43 Statistical Methods ................................ ................................ ........................... 46 Results ................................ ................................ ................................ .................... 47 Demographics and Neuropsychological and Rating Scale Assessments ......... 47 Oculomotor Screening ................................ ................................ ...................... 48 Velocity Step Tests ................................ ................................ ........................... 49 Gain ................................ ................................ ................................ ........... 49 Time Constant of Decay. ................................ ................................ ........... 50 Discussion ................................ ................................ ................................ .............. 51 Neuropsychological Tests and Standardized Rating Scales ............................ 51 Oculomotor Scr eening ................................ ................................ ...................... 52 Velocity Step Test: Per rotary rVOR ................................ ................................ 53 Velocity Step Test: Post rotary rVOR ................................ ............................... 54

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6 Summary ................................ ................................ ................................ .......... 56 Future Studies ................................ ................................ ................................ .. 57 3 SINUSOIDAL HARMONIC ACCELERATION TESTS OF VESTIBULO OCULAR FUNCTION IN A UTISM SPECTRUM DISORDERS ................................ ............... 73 Methods ................................ ................................ ................................ .................. 77 Participants and Recruitment ................................ ................................ ........... 77 Testing Equipment ................................ ................................ ........................... 77 Procedure ................................ ................................ ................................ ......... 78 Statistical Methods ................................ ................................ ........................... 79 Results ................................ ................................ ................................ .................... 79 Oculomotor Screening ................................ ................................ ...................... 79 Sinusoidal Harmonic Acceleration (SHA) ................................ ......................... 80 SHA dark testing ................................ ................................ ........................ 80 SHA suppression testing ................................ ................................ ............ 81 Discussion ................................ ................................ ................................ .............. 82 SHA in the Dark ................................ ................................ ................................ 82 SHA with Fixation Suppression Testing ................................ ........................... 83 Summary ................................ ................................ ................................ .......... 83 Limitations and Future Studies ................................ ................................ ......... 84 4 FUNCTIONAL CORRELATES OF THE VESTIBULO OCULAR REFLEX IN AUTISM SPECTRUM DISORDERS ................................ ................................ ....... 90 Methods ................................ ................................ ................................ .................. 92 Participants and Recruitment ................................ ................................ ........... 92 Testing Equipment ................................ ................................ ........................... 92 Procedure ................................ ................................ ................................ ......... 93 General procedure ................................ ................................ ..................... 93 Neuropsychological assessments ................................ .............................. 93 VOG system calibration ................................ ................................ ............. 96 Oculomotor screening ................................ ................................ ................ 97 Velocity step testing general procedure ................................ ..................... 97 Data Analysis ................................ ................................ ................................ ... 97 Results ................................ ................................ ................................ .................... 98 Dark Condition rVOR Time Constants ................................ .............................. 99 Fixation Suppression Condition rVOR Time Constants ................................ .... 99 Associations among Neuropsychological and Standard Rating Scale Assessments ................................ ................................ ................................ 99 Discussion ................................ ................................ ................................ ............ 100 Vestibular Function Measures: rVOR Time Constants, PANESS Balance Errors and Sensory Profile Vestibular Processing Subscale ....................... 101 Vestibulo ocular and vestibulo spinal function ................................ ......... 101 Parent report of vestibular processing and direct measures of vestibular fun ction ................................ ................................ ................................ 101 IQ and vestibular function ................................ ................................ ........ 103

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7 Intercorrelations among Neuropsychological and Standardized Rating Scale Assessments ................................ ................................ ............................... 104 Symptom severity: ADOS, SCQ and RBS R ................................ ............ 104 Functional ability: Leiter Brief IQ and Vineland II Adaptive Scales ........... 107 Summary ................................ ................................ ................................ ........ 108 Limitations and Future Studies ................................ ................................ ....... 109 5 ABNORMAL QUALITY OF THE ROT ATIONAL VESTIBULO OCULAR REFLEX IN AUTISM SPECTRUM DISORDERS ................................ ................................ 122 Number of Nystagmus Beats ................................ ................................ .......... 122 Slow Phase Irregularity ................................ ................................ ................... 123 Vertical Eye Movement Intrusions ................................ ................................ .. 123 Methods ................................ ................................ ................................ ................ 125 Participants and Rec ruitment ................................ ................................ ......... 125 Testing Equipment ................................ ................................ ......................... 125 Procedure ................................ ................................ ................................ ....... 126 Data Analysis ................................ ................................ ................................ 127 Methods for analyzing number of post rotary nystagmus beats ............... 127 Development and testing of a quantitative method for analyzin g temporal dynamics of slow phase irregularity and vertical intrusions .... 128 Results ................................ ................................ ................................ .................. 130 Number of Post rotary Nystagmus Beats ................................ ....................... 130 Slow Phase Irregularity ................................ ................................ ................... 130 Vertical Eye Movement Intrusions ................................ ................................ .. 131 Preliminary Results from Temporal Dynamics Analysis ................................ 132 Discussion ................................ ................................ ................................ ............ 133 Number of Post rotary Nystagmus Beats ................................ ....................... 133 Slow Phase Irregularity ................................ ................................ ................... 134 Vertical Eye Movement Intrusions ................................ ................................ .. 135 Future Studi es ................................ ................................ ................................ 138 Summary ................................ ................................ ................................ ........ 141 6 CONCLUSIONS ................................ ................................ ................................ ... 153 Objective ................................ ................................ ................................ ............... 153 Summary of Results ................................ ................................ .............................. 153 Fixation Suppression and Smooth Pursuit Deficits in ASD: Chapters 2 and 3 153 Neuropsychological Correlates to rVOR in ASD: Chapter 4 ........................... 156 rVOR Qualitative Differences in ASD: Chapter 5 ................................ ............ 157 Implications ................................ ................................ ................................ ........... 157 Limitations ................................ ................................ ................................ ............. 160 Future Studies ................................ ................................ ................................ ...... 161 Gener al Summary ................................ ................................ ................................ 162 APPENDIX: GLOSSARY OF TERMS RELATED TO VESTIBULO OCULAR REFLEXES ................................ ................................ ................................ ........... 164

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8 LIST OF REFERENCES ................................ ................................ ............................. 166 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 175

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9 LIST OF TABLES Table page 2 1 Summary of Group Mean (SD) for Demographics and Neu ropsychological Assessments ................................ ................................ ................................ ...... 60 2 2 Summary of Smooth Pursuit Comparisons for Phase (degrees) ........................ 61 4 1 Pearson Correlation Summary Table for Neuropsychological Assessments and rVOR Time Constant of Decay in the Dark and with Fixation Suppression 112 4 2 Pearson Correlation Summary Table for Neuropsychological Assessments. ... 113 5 1 Summary of Post Rotary Nystagmus Number of Beats for Velocity Step Test 142

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10 LIST OF FIGURES Figure page 1 1 Basic circuitry of the rVOR. ................................ ................................ ................ 31 1 2 Illustration of a Nystagmus Beat. ................................ ................................ ........ 32 1 3 Illustration of Velocity Step Rotary Chair Motion Profile.. ................................ ... 33 1 4 Illustration of SHA Rotary Chair Motor Profile. ................................ .................... 34 1 5 General Lab Procedure Schematic. ................................ ................................ .... 35 1 6 rVOR Testing Session Schematic. ................................ ................................ ..... 36 2 1 Pediatric Rotary Chair. ................................ ................................ ....................... 59 2 2 Saccade Gain. ................................ ................................ ................................ .... 62 2 3 Saccade Latency. ................................ ................................ ............................... 63 2 4 Horizontal Smooth Pursuit Gain ................................ ................................ ......... 64 2 5 Horizontal Smooth Pursuit Phase. ................................ ................................ ...... 65 2 6 Vertical Smooth Pursuit Gain. ................................ ................................ ............. 66 2 7 Vertical Smooth Pursuit Phase. ................................ ................................ .......... 67 2 8 Gaze Evoked Nystagmus Mean Eye Excursion. ................................ ................ 68 2 9 Velocity Step Test Per Rotary rVOR Gain. ................................ ......................... 69 2 10 Velocity Step Test Per rotary rVOR TCD. ................................ .......................... 70 2 11 Velocity Step Test Post Rotary rVOR Gain. ................................ ....................... 71 2 12 Velocity Step Test Post rotary rVOR TCD. ................................ ......................... 72 3 1 Mean gain for each group during SHA testing in the dark condition at cycle frequencies of (1) 0.05Hz, (2) 0.1H z and (3) 0.5Hz. ................................ ........... 86 3 2 Mean phase for each group during SHA testing in the dark condition at cycle frequencies of (1) 0.05Hz, (2) 0.1Hz and (3) 0.5Hz. ................................ ........... 87 3 3 Mean gain for each group during SHA testing with fixation suppression LED at cycle frequencies of (1) 0.05Hz, (2) 0.1Hz and (3) 0.5Hz. .............................. 88

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11 3 4 Mean phase for each group during SHA testing with fixation suppression LED at cycle frequencies of (1) 0.05Hz, (2) 0.1Hz and (3) 0.5Hz. ...................... 89 4 1 Scatterplots of age (in months) and time constant of decay (in secon ds) in the dark condition and fixation suppression condition. ................................ ..... 114 4 2 Scatterplots of Leiter R Brief IQ (composite scores) and time constant of decay (in seconds) in the dark condition and fix ation suppression condition. ... 115 4 3 Scatterplots of Vineland II Adaptive Behavior Scales (composite scores) and time constant of decay (in seconds) in the dark condition and fixation suppress ion condition. ................................ ................................ ...................... 116 4 4 Scatterplots of Autism Diagnostic Observation Schedule (ADOS) composite scores and time constant of decay (in seconds) in the dark condition and fixation suppression con dition. ................................ ................................ .......... 117 4 5 Scatterplots of Social Communication Questionnaire (SCQ; total score) and time constant of decay (in seconds) in the dark condition and fixation suppression condition. ................................ ................................ ...................... 118 4 6 Scatterplots of Restricted Repetitive Behavior Scale Revised Stereotypy Subscale Total Score and time constant of decay (in seconds) in the dark condition and fixation suppression condition. ................................ ................... 119 4 7 Scatterplots of Sensory Profile (SP) Vestibular Processing Subscale Score and time constant of decay (in seconds) in the dark condition and fixation suppression condition. ................................ ................................ ...................... 120 4 8 Scatterplots of Physical and Neurological Exam of Soft Signs (PANESS) ....... 121 5 1 videos of rVOR from three ASD and three TD participants ................................ ................................ 143 5 2 Example of Post Rotary Nystagmus Slow Phase Regularity in the TD Group 144 5 3 Example of Post Rotary Nystagmus Slow Phase Irregularity in the ASD Group. ................................ ................................ ................................ .............. 145 5 4 Vertical and Horizontal Eye Movements during Post Rotary Nystagmus in the TD Group. ................................ ................................ ................................ ......... 146 5 5 Vertical and Horizontal Eye Movements during Post Rotary Nystagmus in the ASD Group. ................................ ................................ ................................ ...... 147 5 6 Approximate entropy (ApEn) of horizon tal rVOR during velocity step testing in the dark presented for one ASD participant and one typically developing control. ................................ ................................ ................................ .............. 148

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12 5 7 Spectral plot comparison of horizontal eye movements during a single trial of velocity step testing in the dark for one ASD and one TD participant. .............. 149 5 8 Spectral plot comparison of vertical eye movements during a single trial of velocity step testing in the dark for one ASD and one TD participant. .............. 150 5 9 Peak frequency of horizontal and vertical rVOR measured in one ASD and one TD participant during velocity step testing in the dark ............................... 151 5 10 Comparison of the f95 or the frequency that accounts for 95% of the total power spectrum for one ASD and one TD participant during velocity step testing in the dark. ................................ ................................ ............................ 152

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13 LIST OF ABBREVIATIONS ASD autism spectrum disorders EOG e lectro oculography HFA high functioning autism IDD intellectual developmental disability IQ Intelligence quotient PANESS physical and neurological exam of subtle signs PDD NOS perv asive developmental disorder not otherwise specified RBS R restricted repetitive behavior scale revised SCQ social communication questionnaire SHA sinusoidal harmonic acceleration SP sensory profile TD typically developing TCD time constant of decay VN G video nystagmography VOG video oculography goggles VOR vestibulo ocular reflex rVOR rotational vestibulo ocular reflex tVOR torsional vestibulo ocular reflex

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14 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy VESTIBULO OCULAR REFLEX FUNC TION IN CHILDREN WITH AUTISM SPECTRUM DISORDERS By Tana Bleser Carson December 2013 Chair: Mark Lewis Major: Psychology Aut ism spectrum disorders (ASD) are characterized by social and communication skill deficits and excessive restricted/repetitive behaviors (APA, 2000; DSM IV TR). Additional features commonly noted in ASD are deficits in sensory processing and motor control. Some motor control differences reported in ASD include decreased postural stability, decreased muscle tone, altered vestibulo ocular reflexes (VORs) and delayed motor milestones ( Fournier et al., 2010; Ben Sasson et al., 2009; Bhat et al., 2011; Ornitz et al., 1985). T hese deficits may share a common dependence upon processing of vestibular sensory input. Therefore a better understanding of the extent to which vestibular sensory processing and related motor control is compromised in ASD would be beneficial for studying the underlying neurobiology of ASD The VOR is useful for studying vestibular related sensory motor processing in this population as it involves a relatively simple reflex system, amenable to study in very young children. The rotational vestib ulo ocular reflex (rVOR) function s to maintain stable vision by generating oculomotor responses to angular rotation head movements. Our understanding of these VOR differences in ASD is currently hindered by a paucity of studies investigating this reflex. I n the current studies, children ages 6 12 diagnosed

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15 with autism spectrum disorders observed three main differences in rVOR metrics including: (1) increased time constant of decay of post rotary nystagmus during velocity step tests in the dark and with fi xation suppression (Chapter 2); (2) increased per rotary nystagmus gain during velocity step tests in the dark and increased gain during sinusoidal harmonic acceleration ( SHA ) tests in the dark as well as fixation suppression (Chapter 2 and 3 respectively) ; and (3) increased phase lead during SHA tests at 0.5Hz frequency cycle (Chapter 3) Several functional measures were found to correlate with rVOR time constant differences in ASD such as: adaptive skills and balance deficits (Chapter 4). Additional aberr ations in the quality of rVOR such as increased slow phase irregularities are described and methods for further analysis of these differences are discussed (Chapter 5). The current findings suggest vestibular processing deficits in the rVOR that are consis tent with reports of cerebellar deficits in the ASD population and warrant further study.

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16 CHAPTER 1 INTRODUCTION Vestibular Sensorimotor Processing in Autism Spectrum Disorders Abnormal sensory processing and motor control have been frequently reported i n autism spectrum disorders (ASD ). Motor deficits include reports of decreased postural stability, decreased muscle tone, and delayed motor milestones (see Fournier et al., 2010; Ben Sasson et al., 2009; B hat et al., 2011 for reviews). Acquisition of such motor skills as the ability to maintain upright posture, the development of skeletal muscle tone and coordination of locomotion are dependent on normal vestibular function (Phillips & Backous, 2002). Studi es of dynamic posturography, a sensory selective method for evaluating the functional integration of these systems, have shown that maintaining postural stability is significantly more difficult for children with ASD, particularly when vision is occluded a nd proprioceptive cues are diminished, forcing participants to rely on vestibular sensation (Minshew et al., 2004; Molloy, Dietrich & Bhattacharya, 2003). The vestibular system contributes to a body centered spatial coordinate system onto which sensory mod alities such as proprioception and vision are mapped in the posterior parietal cortex (Anderson, 1997). Therefore, successful maintenance of posture is dependent on sufficient integration of vestibular, visual, and proprioceptive sensory input with appropr iate motor output via brainstem, cerebellum, and parietal lobe circuitry and may be deficient in individuals with ASD. Recent imaging, histological, and behavioral studies show abnormalities in these regions of the brain in individuals with ASD (see DiCicc o Bloom et al., 2006 for review), which also correlate with sensory processing deficits observed in this population (Jou et al., 2008). In summary, abnormal processing of vestibular sensory

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17 input could contribute to several of the sensory motor processing deficits commonly observed in ASD. The Vestibul o ocular Reflex In addition to postural responses, the vestibular system also drives oculomotor responses known as vestibulo ocular reflexes (VORs). VORs are important for maintaining stable vision during mov ement of the head and body and have been very well studied in both intact and lesion ed animal experiments and human studies The VORs are compensatory eye movements that occur in response to head movement (see diagram in Figure 1 1 for an example of the si mplest form of VOR circuitry). Several forms of VOR exist including translational and rotary. Translational VOR (tVOR) produces compensatory eye movements in response to otolith stimulation from linear motion of the head in the forward aft, side to side or up and down directions. Ocular counter roll, a second type of VOR occurs in response to the otolith organs sensing a change in the static relationship between the head and gravity. For example when the head is tilted to one side t he VOR allows the eye to counter roll or roll in the opposite direction of head movement in order to compensate for static head tilt (Leigh & Zee, 2006) The current study will focus on rotational VOR (rVOR) a compensatory eye movement that occurs in response to angular rotation of the head in one of three planes of movement: yaw, pitch or roll (see Appendix A for related glossary of terms) For example, when the head rotates in yaw to the left, the vestibular system translates information about that movement such as the accelera tion and direction and commands a compensatory eye movement to occur in the opposite direction (i.e., yaw to the right). This oculomotor response to head movement allows maintenance of stable visual fixation during movement of the head/body.

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18 After prolong ed rotation of the head (e.g., when a child spins continuously on a merry go round), the oculomotor response is prolonged and occurs in the form of repetitive eye movements or nystagmus. Vestibular n ystagmus eye movements are composed of two phases: a slow phase eye movement occurs in the opposite direction center. These two phases occur in a repetitive, oscillating fashion (Figure 1 2) Two methods of rVOR testing will b e used in the current study: velocity step tests and sinusoidal harmonic acceleration tests (SHA) For the current studies, these tests will be conducted with chair rotations about an earth vertical axis, providing rotational vestibular stimulation in the yaw plane (Figure 1 3). Velocity step tests include a rapid for a set duration of time followed by a rapid deceleration to stop ( see Figure 1 4 for an illustration of this type rotary chair motion profile; see Chapter 2 for detailed methods ) SHA testing includes side to side, oscillating rotations back and forth with a set peak velocity. This test included several trials conducted at a range of frequency cycles of rotation (see Figure 1 5 for an i llustration of this type of rotary chair motion profile; see Chapter 3 for detailed methods). There are two types of vestibular nystagmus that occur as a result of the continuous rotation of the head and body en bloc ( i.e., when spinning the whole body) ; per and post rotary nystagmus During rotation, the slow phase moves in the opposite direction of head rotation followed by a quick/fast phase in the same direction of head rotation thus resetting the eye to center. This nystagmus that occurs during rot ation is called per rotary nystagmus. For example, during clock wise yaw rotation, the slow

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19 phase moves counter clock wise to compensate for moving away from the previous visual stimuli and the fast phase moves clock wise to quickly reset the eye to center As rotation reaches a constant velocity, t he cerebellum stores this velocity information in an effort to increase the efficiency of the rVOR response during low frequency stimulation such as this and prolongs per rotary nystagmus for a measurable amount of time known as the time constant of decay (TCD; Raphan, Matsuo & Cohen 1979) After rotation has stopped a second form of nyst agmus called post rotary nystagmus will occur A lthough the body and head have stopped rotating the fluid in the semicircular canals continues to move until friction against the membrane of the canals eventually slows the fluid down Therefore, the vestib ular system is excited in the opposite direction and when visual cues are omitted, may give the individual the perception that he/she is now spinning in the opposing direction even though he/she is stationary at this time Post rotary nystagmus also has a measurable time constant of decay. The TCD reflects the (Waespe & Henn, 1977; Raphan et al., 1979) Normative data for TCD in children have been reported to range from 13 to 17 seconds in children ages 4 12 years (Horak et al., 1988; Casselbrant et al., 2010). Another meas urable feature of rVOR is the gain. Gain is a measure of the accuracy of the rVOR system reactions t o changes in head position To do so, the rVOR must compens ate for head movements with eye movements that are equally matched in velocity to head movements in order to prevent instability of the retinal image. Therefore gain is measured as the ratio of peak eye velocity to peak head velocity. If eye and head velo city are perfectly matched the rVOR gain is 1.0. If there is an error in

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20 this system as small as 2 degrees / second, cerebellar modulation of the vestibular nuclei will detect and correct such errors by modifying vestibular nuclei output. For example, a he ad movement of 100 degrees/second would require that the rVOR gain must be at least 0.98 to prevent retinal image slip and blurred vision ( Hain and Helminski, 2007 ). In individuals with cerebellar deficits (Thurston et al., 1987) g ain may be increased ref lecting the inability for the cerebellum to detect and correct for differences between eye and head velocity Since cerebellar deficits have been one of the most consistent neurobiological findings in ASD, gain is certainly a measure of interest in the ASD population. The rVOR is an excellent example of sensory and motor processing that holds considerable promise for studying such processes in ASD. The extensive body of literature outlining both healthy and aberrant rVOR function provides an excellent plat form from which to study aberrations in brainstem, cerebellar and cortical sensorimotor processing in ASD. However, the number of studies that have systematically investigated the characteristics of rVOR in this population is very limited. Vestibulo ocula r Reflex Studies in Autism Three studies have reported aberrations in rVOR in ASD (Ritvo et al., 1969; Ornitz et al., 1974; Ornitz et al., 1985) and two studies have reported some typical characteristics of rVOR in this population (Ornitz et al., 1985; Gol dberg et al., 2000). According to these reports, aberrations include: (a) decreased duration of post rotary nystagmus when tested in conditions where light and/ or visual stimuli are available (Ritvo et al., 1969; Ornitz et al., 1974), (b) decreased frequen cy of post rotary nystagmus beats (Ornitz et al., 1985, Ornitz et al., 1974), (c) differences in per and post rotary time constants of decay (Ornitz et al., 1985), (d) increased incidences of

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21 abnormal slow phase excursion (Ornitz et al., 1985) and (e) inc reased within subjects variability in the frequency of rVOR nystagmus beats as a function of the duration of rVOR (Ornitz et al., 1974 ) compared to typical controls. T wo characteristic s of rVOR in ASD have been shown to be no different from controls The first characteristic is gain On ly one study examined gain in ASD (Ornitz et al., 1985) and found no difference between ASD and typical controls on this measure when tested in the dark Healthy gain suggests that the peripheral vestibular organ itself is f unctioning properly in ASD and that other aberrant characteristics of rVOR observed in the study were likely attributable to central nervous system rather than peripheral pathology. The second typical feature of rVOR examined in the ASD population is t il t suppression Tilt suppression is a phenomenon that results in a decrease in rVOR time constant of decay in response to a change in head position (i.e., tilting or leaning forward) after continuous rotation I n a s tudy of children with high functioning au tism (HFA) there was no differen ce between HFA and typical controls (Goldberg et al., 2000). Normal tilt suppression in HFA suggests that vestibulo cerebellar function in this sub group of ASD may be spared. However, u p to 68% of individuals with ASD have been estimated to have intellectual disability ( Yeargin Allsopp et al., 2003) and tilt suppression in individuals who are lower functioning has not been investigated. Q uestions remain as to whether or not cerebellar related tilt suppression deficits may ex ist in the lower functioning individuals with ASD. Thus the nature of and the neural mechanisms responsible for rVOR abnormalities in ASD and whether or not these aberrations exist in ASD as a whole or

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22 within sub groups with low IQ only remains unclear There are several advantages to studying rVORs in an effort to answer such questions First, rVOR s are well studied i n both human and animal models and provide a wealth of normative data as well as clinical data for comparison. Second, rVOR s can be measure d in low functioning individuals as well as young infants; thus this reflex lends itself well to being studied across the spectrum of functional levels under the umbrella of ASD diagnoses as well as offering potential biobehavioral markers for further stu dy in young children at risk for ASD Third, rVORs are highly modifiable so by better characterizing rVOR dysfunction in ASD, we may be better able to development rVOR sensorimotor interventions for this population Specific Aims The overall objective of the present studies was to provide a comprehensive, detailed and systematic evaluation of rVOR function from the horizontal semicircular canals via rotational stimuli in children with ASD. T he studies describe d in Chapters 2, 3, 4 and 5 were developed to achieve the following specific aims: Specific Aim 1: To identify alterations in function from the horizontal semicircular canals via rotational stimuli in ASD. We aimed to replicate and extend previous findings of horizontal rVOR aberrations including de creased frequency of nystagmus beats and increased slow phase eye movement aberrations in children with ASD compared to typically developing c ontrols. T wo standard rotary chair tests were conducted : (1) velocity step test and (2) sinusoidal harmonic accele ration (SHA) tests Velocity step tests have be en conducted in ASD previously; however, those studies did not use a video o culography goggle (VOG) system therefore, our studies aimed to extend previous findings with the use of these methods (see Chapter 2 for detailed methods)

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23 SHA has never been studied in ASD and were conducted to explore whether aberrations in SHA measures exist in the ASD population (see Chapter 3 for detailed methods) Hypotheses: Velocity step test s will show significantly altered r VOR response in ASD as evidenced by decreased number of nystagmus beats and increased frequency of s low phase errors. SHA tests will be explored for possible differences in gain phase and symmetry between groups. Based on preliminary results, it is expect ed that ASD groups will exhibit increased frequency of vertical slow phase eye movements in both tests. Specific Aim 2: To determine differences in fixation suppression of rVOR in ASD and TD groups. Children with ASD have previously demonstrated greater than normal suppression o f rVOR time constants when experiencing velocity step testi ng in a lighted room (Ritvo et al., 1969) or when presented with various visual stimulus conditions after rotation (Ornitz et a l., 1974). To replicate and extend these fin dings v elocity step tests were conducted in light, dark and fixation suppression conditions. The f ixation s uppression condition visual stimulus was provided by an LED visual stimulus within the VOG system during and after rotation to test whether children with ASD exhibit any differences in fixation suppression of rVOR. Fixation suppression during SHA tests have never been conducted in ASD and were conducted to explore possible differences between groups in fixation suppression for this test Hypothesis: B ased on previous findings, it is expected that children with ASD will demonstrate significantly greater rVOR suppression compared to controls as evidenced by significantly decreased time constants of decay in both the light and fixation suppression conditi ons and no difference in time constants in the dark conditions. Specific Aim 3: To identify correlations between rVOR and functional measures in ASD. If alteration s in rVOR are correlated with functional ability (i.e., IQ) or other

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24 measures of sensory/mo tor function, then rVOR may hold promise as an early marker or risk factor for the development of ASD. Hypothesis : We predict that functional measures such as: ( 1 ) the severity of ASD symptoms,(2) functional ability ( intelligence quotients and adaptive s cales), ( 3 ) vestibular processing measures may be correlated with alterations of rVOR performance in ASD. Overview of Studies Presented in this Dissertation Chapter 2 : Effect of Visual Conditions on Rotational Vestibulo ocular Reflex Function in Autism S pectrum Disorders Chapter 2 reports the results of v elocity step testing results conducted in three conditions including: light, dark and fixation suppression in ASD compared to TD controls. This study addresses two of the specific aims listed above as fo llows: (1) to identify alterations in function from the horizontal semicircular canals via rotational stimuli in ASD and (2) t o determine differences in fixation suppression of rVOR in ASD and TD groups. Chapter 3 : Sinusoidal Harmonic Acceleration (SHA) Tests of Vestibulo ocular Reflex Function in Autism Spectrum Disorders Chapter 3 d escribes the results of SHA testing conducted in dark and fixation suppression conditions in ASD compared to TD controls This study addresses two of the specific aims liste d above as follows: (1) to identify alterations in function from the horizontal semicircular canals via rotational stimuli in ASD and (2) to determine differences in fixation suppression of rVOR in ASD and TD groups. Chapter 4 : Functional Correlates of t he Vestibulo ocular Reflex in Autism Spectrum Disorders Chapter 4 describes correlation analyses between time constant of decay during velocity step test results in the dark and suppression conditions and other measures such as intelligence, autism severi ty and vestibular processing. This

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25 study addresses specific aim (3): t o identify correlations between rVOR measures and functional measures in ASD. Chapter 5 : Abnormal Quality of the Rotational Vestibulo Ocular Reflex in Autism Spectrum Disorders Chapter 5 describes qualitative differences in rVOR between groups and provides a preliminary analysis of methods for comparing the temporal dynamics of rVOR between ASD and TD groups. This study addresses specific aim (1): t o identify alterations in horizontal rV OR in ASD General Methods Participants and Recruitment For the studies presented in Chapters 2 5 16 children with ASD and 17 typically developing (TD) children, ages 6 12 were recruited to participate in functional assessments including ASD diagnostic assessments, neuropsychological assessments, as well as assessments of sensory processing and motor function in addition to tests of rVOR function Data from the same children with ASD and TD children are presented across all chapters; therefore, the part icipant data presented in each chapter do not represent different sets of subjects or repeated testing. Participants were recruited from the University of Florida Center for Autism and Related Disabilities as well as local community resources such as schoo ls and medical centers within Alachua county, Florida. The ASD group included individuals with one of the following diagnoses: Autism Disorder Not Otherwise Specified. Diagnoses were confirmed by a clinica l neuropsychologist. Exclusionary criteria include diagnoses of Fragile X, Rett Syndrome, tuberous sclerosis, seizure disorder or fetal cytomegalovirus infection. Exclusionary criteria for control participants included parent report of any current or past history of

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26 psychiatric or neurologic disorder or any immediate family with a history of autism, schizophrenia, developmental disorder, mood disorder or anxiety disorder, or if they were taking any psychiatric medications. These exclusionary criteria were s elected in an effort to minimize confounding variables and to better define the ASD and TD groups by excluding disorders with known etiologies such as Fragile X, Rett Syndrome, tuberous sclerosis, and fetal cytomegalovirus infection and to reduce the risk of any harm to participants as seizures have been reported to be elicited by vestibular stimulation. Since children with ASD frequently take psychiatric medications for concurrent disorders, medication status and concurrent disorders were documented for pa rticipants in the ASD group for subsequent analyses. All demographic and neuropsychological test results are presented in Chapter 2, Table 2 1. General Procedure All four studies were conducted using the same study paradigm (Figure 1 5 ) composed of three main steps. Each of the four studies (Chapters 2, 3, 4 and 5) present data collected on the same cohort of children with the exception of a few participants that completed some, but not all tests. Data are presented for those studies that participants were able to complete; therefore a minor difference in the number of subjects exists for each study. The entire study required that participants attend the lab for 2 to 3 testing sessions, as needed to complete all tests. During Step 1 of the general study (F igure 1 5 ; Step 1) participants were recruited through community centers with flyers. I nterested p arents called or emailed the lab and were asked to complete a phone screening questionnaire to assess whether or not the ir child was eligible to participate in the studies (see Participants and Recruitment section above for inclusion/exclusion criteria).

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27 If the child was eligible to participate they were scheduled to attend their first testing session ( Figure 1 5 ; Step 2 ). During the first testing session, e ach child participated in neuropsychological testing and oculomotor screening For neuropsychological testing children from both groups participated in the following two assessments: (1) the Leiter International Performance Scale R evised (Leiter R) Brief IQ test (Roid, Miller, & Leiter, 1997), a non verbal intelligence assessment that allows children to indicate their responses through gestures or manual selection and (2) the Physical and Neurological Examination for Soft Signs (PANESS), a standardized pe diatric neurological assessment of motor control ( Denckla, 1974 ) where children completed motor tasks such as rapid finger tapping or walking heel to toe. Children from the ASD group only participated in the Autism Diagnostic Observation Schedule (ADOS; Lo rd et al., 2000), a semi structured play based assessment of social and communication skills and restricted repetitive behaviors. During these assessments, parents/guardians of participants in both groups completed the following questionnaires: the Repetit ive Behavior Scale Revised (RBS R; Bodfish et al. 2000), the Sensory Profile Caregiver Questionnaire ( Dunn 1999 ) and the Vineland II Adaptive Scales (Sparrow & Cicchetti, 1985; Sparrow, Cicchetti, & Balla, 2005). Parents from the ASD group also completed the Social Communication Questionnaire (SCQ; Rutter, Bayley & Lord, 2003) a diagnostic screening tool for ASD. The combination of ADOS and SCQ was used to confirm diagnoses of children recruited into the ASD group. A combination of Vineland II Adaptive Sc ale and Leiter R IQ results was used to determine presence or absence of intellectual disability. The final part of Step 2 included calibration of the VOG system and oculomotor screening for each participant (see Chapter 2 for

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28 methods). This first testing session took approximately 60 to 120 minutes to complete depending on group assignment, participant compliance and endurance for tests. If participants were able to successfully complete the first testing session (i.e., if there was no aversion to wearing the VOG goggles, no gross oculomotor impai rments and no behavioral or compliance barriers to participation ) they were scheduled to return to the lab within 1 to 8 weeks for a second testing session (Figure 1 5 ; Step 3). The second testing session include d velocity step and SHA tests of VOR function (see Figure 1 6 for schematic of rVOR testing sequence) Velocity step tests were conducted first and included 2 trials (one in each direction) within 3 conditions as follows: (i) light, (ii) dark, and (iii) fi xation suppression (see Chapter 2 for detailed methods) resulting in a total of 6 trials of velocity step tests. SHA tests followed velocity step testing and were conducted within two conditions, first in the dark condition, then in the suppression conditi on. Within each condition one trial was conducted at each of 3 frequency cycles as follows: 0.05, 0.10 and 0.50Hz resulting in a total of 6 trials of SHA testing (see Chapter 3 for detailed methods). The rVOR testing session took approximately 90 to 120 mi nutes to complete. Several children in the ASD group required the vestibular testing session to be broken up into two shorter sessions. In this case, these children attended the lab for a total of 3 testing sessions in order to complete all tests. Upon com pletion participants were provided with a $ 50 gift card to Wal Mart or Target stores for their participation whether they completed all tests or not Innovation Conceptual Innovation. It is clear that the neural processes which result in autism spectrum disorders (ASD) occur very early in development before the presentation of the classic symptoms of the disorders such as deficits in

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29 social/communication skills and excessive restricted, repetitive behaviors. If the abnormal eye movements observed in this study are specific to ASD, they could provide a novel as well as simple and reliable, early identifier of risk for ASD. In addition, this aberrant reflex could provide a novel approach to patient treatment matching for specific balance and visual rehabilit ation treatment methods. Finally, if these eye movement abnormalities are present in only a sub group of ASD, then rVOR may be a novel way to differentiate among sub groups on the autism spectrum. Methodological Innovation. Although sinusoidal harmonic ac celeration (SHA) tests and SHA tests with fixation suppression are standard rVOR assessments, these have not been evaluated in ASD to date. SHA fixation suppression testing may help improve our understanding of the large effect of significantly decreased p ost rotary nystagmus in ASD when tested when visual feedback is presented (Ornitz et al., 1974). It is possible that visual hyper vigilance observed in children with ASD may allow them to visually suppress nystagmus to a greater extent compared to typicall y developing children. Conducting SHA tests with a controlled visual stimulus such as the light emitting diode (LED) stimulus provided in the fixation suppression tests represents an innovative method to better understand this phenomenon in ASD. Technical Innovation. The novel pediatric rotary chair equipment developed for the current study is a combination of a customized pediatric chair designed in our lab specifically for use with children with ASD and a standardized videonystagmography and computer cont rolled motor system from NeuroKinetics, LLC., an international manufacturer of high quality clinical vestibular assessment equipment. The customized pediatric chair was designed in our lab to allow children with ASD to be tested

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30 independently, rather than requiring these children to sit on an adult s lap. The chair was also designed to resemble a flight chair for a space mission theme to increase compliance and comfort for children with the testing procedures. The lab environment, rotary chair and testing p rotocol have been integrated into a space themed mission with graded activities during breaks to keep children engaged and to minimize anxiety.

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31 Figure 1 1 Basic circuitry of the rVOR. This image illustrates rVOR slow phase eye movement response to clock wise head rotation in the yaw plane S ensory hair cells within the two s emicircular canals (top of image) are stimulated when the fluid lags the head rotation. This stimulation sends an ipsilateral (right sided) excitatory signal to the vestibular nuclei. Excitatory neurons project to the contralateral abducens nucleus which signals the right oculomotor nucleus to initiate contraction of the right media l rectus muscle as well as the left eye lateral rectus, thus counter rotating the both eyes to the left in order to compensate for the clock wise yaw head rotation The left semicircular canal provides an inhibitory response along the parallel pathway and inhibiting the opposing ocular muscles and allowing the slow phase eye movement to occur and maintain a stable visual field. Figure provided by User: Mikael Hggstrm (Image:ThreeNeuronArc.png) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC BY SA 3.0 ( http://creativecommons.org/licenses/by sa/3.0/)], via Wikimedia Commons on July 11, 2013.

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32 A B C D Figure 1 2. Illustration of a Ny stagmus Beat. If the subject is facing you and rotating his/h er head in the yaw plane to the left, their eye would exhibit a slow phase eye movement to the right (A C) followed by a quick/fast phase eye movement to the left (D) The tracing below the eye diagram is an example of the eye movement tracing provided by video oculography where in the software tracks the pupil as it moves through this nystagmus beat. The tracing is labeled according to the eye movement diagram above (A D). Rightward eye movements are reflected as a positive or upward change in position and leftward eye movements are reflected as negative or downward change in position. A B C D Head movement

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33 Figure 1 3. Illustration of Velocity Step Rotary Chair Motion Profile. This diagram depicts the motion of the rotary chair during a velocity step testing trial. The ch air begins at 0/sec and rapidly accelerates rotation in one direction (clock wise or counter clock wise) to a constant velocity (e.g., 100/sec) which is maintained for a set duration of time, followed by rapid deceleration back to 0/sec Per rotary nyst agmus is observed during this constant velocity rotation and post rotary nystagmus is observed after rotation has stopped.

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34 Figure 1 4. Illustration of SHA Rotary Chair Motor Profile This diagram depicts the motion of the rotary chair during a single SHA testing trial. The chair begins at 0/sec and accelerates rotation in one direction to a set peak velocity (e.g., 60/sec) followed by deceleration back to 0/sec This s ame acceleration and deceleration profile is then repeated in the opposite direct ion, resulting in a sine wave velocity profile and a back and forth motion experience by the participant.

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35 Figure 1 5 General Lab Procedure Schematic Step 1: Participants were recruited and parents participated in a phone screener to evaluate whethe child was eligible to participate in the current studies; Step 2: Participants attended the lab for testing session 1 where the child participated in neuropsychological testing and oculomotor screening while parents completed questionnair es; Step 3: Participants returned to the lab within 1 to 8 weeks to complete VOR tests and including velocity step tests and sinusoidal harmonic acceleration tests

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36 Figure 1 6. rVOR Testing Session Schematic. rVOR testing included two types of tests: Velocity Step and SHA tests. Velocity step tests were conducted in 3 conditions (light, dark and fixation suppression) with one trial each of clock wise and counter clock wise rotation completed in each condition for a total of 6 trials of velocity step t esting. SHA tests were conducted in two conditions (dark and fixation suppression) with one trial at each of the 3 frequency cycles (0.05, 0.10 and 0.50 Hz) for a total of 6 trials of SHA testing.

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37 CHAPTER 2 EFFECT OF VISUAL CONDITIONS ON ROTATIONAL VESTIB ULO OCULAR REFLEX FUNCTION IN AUTISM SPECTRUM DISORDERS The rotational vestibulo ocular reflex (rVOR) is an oculomotor response to angular vestibular stimulation (i.e., rotation of the head) and is required to maintain stable vision during head movement. The rVOR response is modulated by brainstem and cerebellar structures, two areas consistently reported to have neurobiological differences in ASD (Amaral, Schumann & Nordahl, 2008) and may provide useful insights as to the function of these structures in A SD. Rotary chair testing is considered the gold standard for assessing rVOR function. Velocity step tests, one method of rotary chair testing, involves the participant seated on a motorized rotary chair that provides a step in acceleration to a constant v elocity in order to provide continuous whole body rotational vestibular stimulation. The rVOR is characterized by nystagmus beats or repetitive sequences of slow followed by quick eye movements that occur in response to continuous rotation. During rotary c hair tests, eye movements are recorded during and after rotation to assess three primary measures used in evaluating rVOR function: gain, symmetry and time constant of decay. Gain is the ratio of head movement to eye movement and reflects the peripheral se nsory organ and eighth cranial nerve function. Time constant of decay, the time it takes the rVOR post rotary nystagmus response to decrement to 37% of its peak velocity, is a measure of the velocity storage mechanism or central processing of rVOR includin g brainstem and cerebellar function. Symmetry is a measure comparing the response of the eyes to leftward and rightward rotation (i.e., stimulating left and right vestibular systems respectively) to test for unilateral deficits (Brey, McPherson & Lynch, 20 08).

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38 Children with ASD have been reported to demonstrate significantly greater ability to suppress their rVOR response after rotary chair velocity step testing compared to typically developing controls. Ritvo et al. (1969) tested horizontal rVOR in a samp le of with surroundings visible to the participant and (2) in the dark with surroundings not visible to the participant (i.e., children were blindfolded). In the li ght, the children with autism showed significantly decreased duration of post rotary nystagmus compared to typically developing children, whereas in the dark, there was no difference in the duration of post rotary nystagmus between the two groups (Ritvo et al., 1969). The authors suggested that children with autism were able to use optokinetic feedback for inhibiting post rotary nystagmus to a greater extent than the typically developing children and further suggested that aberrations in brainstem or cortic al input may be responsible for this difference. A subsequent study exploring the effects of various visual fixation stimuli on rVOR in ASD failed to replicate this finding of decreased post rotary nystagmus in the light (Ornitz et al., 1974). They also r eported no difference between ASD and controls when tested in the dark. They did report significantly decreased post rotary nystagmus response in ASD, however, when various visual fixation stimuli were provided after rotation in the dark including: (i) a s tandard visual field with a fixation object, (ii) a pinpoint of red light in otherwise complete darkness, (iii) frosted goggles that admitted light but prevented fixation and (iv) frosted goggles with lower light intensity to further prevent fixation (Orni tz et al., 1974). These reports, although contradictory in the light

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39 condition, suggest that individuals with ASD respond differently than controls to visual fixation suppression of rVOR. Ornitz et al., (1985) reported increased time constants of decay du ring per rotary nystagmus in the dark (Ornitz et al. 1985). These results, combined with those reported by Ritvo et al. (1969) and Ornitz et al. (1974) indicate that aberrations in rVOR may arise in regions of the central nervous system that modulate rVOR and oculomotor control such as the brainstem nuclei and cerebellar velocity storage modulation of rVOR. Visual fixation suppression testing provides information regarding midline cerebellum and vestibular nuclei modulation of rVOR (Brey et al., 2008b). A previous study by Ornitz et al. (1974) attempted to determine visual suppression differences in ASD, however, they did not provide fixation stimuli during rotation. They conducted velocity step tests in the dark and after rotation stopped, participants we re provided with visual fixation stimuli. To date, fixation suppression testing with fixation stimuli provided during and after rotation has not yet been conducted with children with ASD and may help to improve our current understanding of visual fixation suppression of rVOR and may shed light on brainstem and cerebellar function in this population. The objective of the current study was to replicate and extend the earlier findings of Ritvo et al. (1969) and to determine differences in fixation suppression of rVOR in ASD and TD groups using pediatric rotary chair tests. Significantly greater than normal suppression of rVOR in ASD has been demonstrated during velocity step testing in a lighted room (Ritvo et al., 1969) and with various visual fixation stimul i (Ornitz et al., 1974). Velocity step tests will be conducted in light and dark conditions to replicate and

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40 extend previous findings. Based on previous findings, it is expected that children with ASD will demonstrate significantly greater rVOR fixation su ppression (i.e., decreased time constants of decay in the light and visual fixation suppression conditions) and increased time constants of decay in the dark condition compared to controls. Methods Participants and Recruitment For this study, 16 children with ASD and 17 typically developing children ages 6 12 were recruited from the University of Florida Center for Autism and Related Disabilities (UF CARD), schools and medical centers within Alachua county. This lower age limit was selected for the current study to be confident in the diagnosis of ASD (Table 2 1). Participant medical history was obtained by parent report at the time of informed consent. The ASD group included individuals with one of the following ervasive Developmental Disorder Not Otherwise Specified. Diagnoses were confirmed by the Autism Diagnostic Observation Schedule (ADOS; Lord et al., 2000) and the Social Communication Questionnaire (SCQ; Rutter, Bayley & Lord, 2003). Children were exclude d from the study if they had a diagnosis of Fragile X, Rett Syndrome, tuberous sclerosis, seizure disorder or fetal cytomegalovirus infection. Control participants were excluded if parents reported any current or past history of psychiatric or neurologic d isorder or related medications. These exclusionary criteria were selected in an effort to minimize confounding variables and to better define the ASD and TD groups by excluding disorders with known etiologies such as Fragile X, Rett Syndrome, tuberous scle rosis, and fetal cytomegalovirus infection and to reduce the risk of any harm to participants as seizures

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41 have been reported to be elicited by vestibular stimulation. Demographic data are presented in Table 2 1. Neuropsychological Testing and Standardize d Rating Scales Children in the ASD group participated in the Autism Diagnostic Observation Schedule (ADOS; Lord et al., 2000). The combination of ADOS and SCQ scores were used to confirm ASD diagnoses. The ADOS is a semi structured play based assessment o f social and communication skills and restricted repetitive behaviors. During Neuropsychological testing, both groups were administered the Leiter International Performance Scale Revised (Leiter R) Brief IQ test (Roid, Miller, & Leiter, 1997), a non verb al intelligence assessment where children are allowed to indicate their responses through gestures such as pointing or manual selection. Both groups also participated in the Physical and Neurological Examination for Soft Signs (PANESS; Denckla, 1974), a st andardized pediatric neurological assessment of motor control where children were asked to complete motor tasks such as rapid finger tapping or walking heel to toe while being video recorded for later scoring. The PANESS sum of balance errors subscale has been previously shown to distinguish typically developing children from children with ASD (Jansiewicz et al., 2006), therefore this subscale was chosen as a variable of interest for the current study. While children participated in the assessments listed above, parents/guardians from both ASD and TD groups completed four questionnaires as follows: (1) the Repetitive Behavior Scale Revised (RBS R; Bodfish et al. 2000), a parent report measure that is used to index the range of these behaviors in ASD, (2) t he Sensory Profile Caregiver Questionnaire (Dunn, 1999), a parent report of non adaptive behavioral responses to various vestibular sensory stimuli encountered in daily activities

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42 and (3) the Vineland II Adaptive Scales (Sparrow & Cicchetti, 1985; Sparrow, Cicchetti, & Balla, 2005), a measure of communication, daily living, socialization and motor skills for daily living. Parents/caregivers from the ASD group were also asked to complete the Social Communication Questionnaire (SCQ; Rutter, Bayley & Lord, 200 3), a parent report measure of social and communication skills The RBS R includes 6 subscales as follows: (1) stereotyped behavior, (2) self injurious behavior, (3) compulsive behavior, (4) ritualistic behavior, (5) sameness behavior and (6) restricted be havior. Each item within these subscales is rated on a 4 point Likert scale from 0 (behaviors do not occur) to 3 (behaviors do occur and are a severe problem ).The sum of all six subscales was used for comparison between groups. The Sensory Profile includes statements of non adaptive responses to sensory stimuli. Parents rate these statements on a Likert scale of 1 (always) to 5 (never) occurring for their child The higher the Sensory Profile score the more adaptive the behavior and the lower the score the less adaptive. The adaptive behavior composite score of the Vineland II Adaptive Scales was used for the current study. T he combination of ADOS and SCQ was used to confirm diagnoses of children recruited into the ASD group and a combination of Vineland II Adaptive Scale and Leiter R Brief IQ results was used to determine presence or absence of intellectual disability in both groups. The entire neuropsychological testing session took approximately 90 to 120 minutes for the ASD group to complete and 60 to 90 minutes for the TD group to complete. Testing Equipment Our lab used a computer controlled, motorized rotary chair and video oculography goggle (VOG) system for VOR tests The motor, controls, VEST TM 6.8 Software and VOG I Portal TM Video Oculography Goggl e (VOG) System were

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43 manufactured by Neuro Kinetics Inc. (NKI) and are comparable to commercially produced NKI vestibular assessment systems used in clinics around the world. On top of the rotary platform we added a seating system specifically for use in pe diatrics including: an enlarged rotary platform, a small chair, safety harnesses, and a head stabilizing system (Figure 2 1). Procedure VOG System Calibration. Prior to testing each participant, calibration of the VOG system was completed. For both calibr ation and oculomotor testing, a laser visual stimulus was provided via an NKI motor controlled laser mounted below the rotary chair projecting a small moving laser onto a smooth black screen. The black screen had a 60 arc with a radius of 76.5 inches so t hat movement of the laser was congruent with the arc of eye movement rotation that occurs when tracking the laser. During calibration, the participant was seated on the rotary chair, wearing the VOG head set, with their head fixed by the head stabilizing s ystem. The rotary chair remained stationary and the participant was asked to visually track a laser visual stimulus in complete darkness as the laser moved + 10 from center first to the left, then to the right, then up and finally downward. This process w as repeated two times and results were averaged for calibration. This same calibration value was later used for the oculomotor tests as well as vestibular tests. Oculomotor Screening. Since the behavior of interest in rVOR is the oculomotor response to ve stibular stimluli, it was important to screen for oculomotor deficits prior to interpreting rVOR oculomotor responses. Therefore, oculomotor assessments were conducted as a screening tool to rule out the confounding variable of oculomotor disorders such as spontaneous nystagmus or gross oculomotor differences

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44 not previously reported in ASD Additionally, children who could not tolerate wearing the goggles or remaining seated in the rotary chair for calibration of the VOG system or oculomotor screening tests were not asked to return for vestibular testing. Three oculomotor assessments were conducted as follows: saccade, smooth pursuit and gaze evoked nystagmus test. Each oculomotor test was explained to the child prior to testing so that he/she understood th e requirements of each task. Children were instructed to follow the red glowing dot with their eyes. Saccade tests were completed using a laser stimulus moved horizontally and vertically to elicit 30 horizontal and 30 vertical saccades with pseudo randomly assigned location and timing of each trial ranging from 0 to 24 for target locations and 1 to 2 second delays between trials. Smooth Pursuit testing included moving the laser stimulus in the horizontal plane and in the vertical plane at two different fr equencies and velocity profiles as follows: at a frequency of 0.1Hz and 4 /second and at a frequency of 0.5Hz and 20/second. Gaze Evoked Nystagmus testing included presenting the laser visual stimulus at 10 in the horizontal plane for 5 seconds and the n turned off while the participant was instructed to continue to focus on that spot for 15 seconds. This process was repeated at +10 in the horizontal plane, and then again the entire process was repeated +/ 10 in the vertical plane. The average slow ph ase velocities of eye movements as they drift away from the target location were recorded. Velocity Step Testing. an d between each trial. Participants completed a 3 part battery of velocity step tests in three different conditions as follows: (1) in the light with the goggle cover off and room

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45 lights on, (2) in the dark with the goggle cover on to prevent visual stimula tion and with room lights off and (3) with a fixation suppression LED turned on inside the goggle cover in the dark with room lights off. Participants were asked to count aloud with researchers to prevent drowsiness and control for attention to task and w ere monitored for signs of drowsiness such as excessive blinks. Trials where participants indicated feeling drowsy were repeated. Each trial was followed by a short break (1 2 minutes) including activities to increase alertness such as a variety of games a nd activities with varying levels of difficulty Velocity step test trial s were completed in both clock wise and counter clock wise directions in each condition with a ramp up time of 1.2 seconds and a peak velocity of 100/ second. Per rotary recordings w ere taken for 60 seconds, followed by post rotary recordings that lasted as long as nystagmus was occurring up to 60 seconds. Each test was completed once in each direction. If one of these two trials was disrupted by excessive blinking, talking, head move ment or the child requesting a break, was presented first because young children are often fearful of the dark, thus, presenting the velocity step test in the light i nitially helped the children to become accustomed to this testing protocol and decrease anxiety. After the light condition, the dark condition was introduced. Finally, velocity step testing was conducted in the suppression condition (in the dark with suppr ession LED on inside the VOG). During suppression testing, the participants were instructed to keep their eyes focused on the preference for the space theme) as they are ridi vestibular testing session lasted approximately 60 minutes.

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46 Statistical Methods Oculomotor screening. For oculomotor screening tests of saccades, smooth pursuit and gaze evoked nystagmus tests, group means comparisons wer e conducted using independent samples t tests with Bonferroni corrections for experiment wise alpha using IBM SPSS Statistics software v. 21. Saccade test group means were compared for four measures including: vertical and horizontal saccade latency as wel l as vertical and horizontal saccade gain. Smooth pursuit test group means were compared for eight measures including: vertical and horizontal gain at frequencies of 0.1Hz and 0.5Hz in each direction as well as vertical and horizontal phase at frequencies of 0.1Hz and 0.5Hz in each direction. Finally, gaze evoked nystagmus test group means were compared for eight trials with target conditions including target LED Velocity step test rVOR analysis. Comparisons of rVOR metrics for both per and post rotary nystagmus including gain, symmetry, and time constant of decay were conducted with mixed ANOVAs using IBM SPSS Statistics software v. 21 with group (ASD or TD) as a between subjects factor s, and visual condition: (i) light, (ii) dark and (iii) fixation suppression conditions as within subjects factors. No difference was found between symmetry comparisons (i.e., clock wise vs. counter clock wise trials) of gain and time constant of decay for both groups for per rotary or post rotary nystagmus. Therefore, clock wise and counter clock wise values for time constants and gain were averaged for each participant.

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47 Results Demographics and Neuropsychological and Rating Scale Assessments Table 2 1 p rovides a summary of participant demographics including age and gender as well as neuropsychological and standardized rating scale assessment results. One control participant demonstrated spontaneous vertical nystagmus during oculomotor screening and was t hen excluded from the study. Independent samples t tests were run to determine if there were differences in demographic or assessment data between groups. There was no significant difference in age (months) between the ASD group and controls, t (31) = .41, p = .69 (means and SDs are presented in Table 2 1). There was also no significant difference in Leiter Brief IQ score between ASD and controls, t (31) = .59, p = .56. There were statistically significant between group differences for all other neuropsychol ogical and rating scale assessments as follows: Vineland II Adaptive Scores were lower in ASD compared to controls, M = 20.62, 95% CI [ 30.83, 10.43], t (37.998) = 4.12, p < .005; SCQ scores were higher in the ASD group compared to controls, M = 18.66, 95 % CI [14.48, 22.84], t (31) = 10.07, p < .005; Vestibular processing subsection scores from the Sensory Profile were lower in the ASD group compared to controls, M = 7.92, 95% CI [ 11.60, 4.24], t (31) = 4.40, p < .005; RBS R scores were higher in the ASD g roup compared to controls, M = 33.65, 95% CI [21.15, 46.16], t (31) = 5.87, p < .005; and PANESS balance sum of error scores were higher in the ASD group, M = 3.57, 95% CI [1.74, 5.40], t (31) = 4.11, p = .001. The ADOS was only conducted as a diagnostic asse ssment for participants with ASD, therefore, no comparison tests were conducted between groups on this measure. Homogeneity of variance was assessed by Levene's Test for Equality of Variances for each measure. There was homogeneity of variances for age ( p = .90), Leiter Brief IQ

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48 scores ( p = .22), Vineland II Adaptive Scales ( p = .63) and Vestibular Processing subsection scores from the Sensory Profile ( p = .18). Homogeneity of variances was violated for SCQ scores ( p < .005), RBS R scores ( p < .005) and PANES S balance sum of error scores ( p = .001), so for these measures separate variances and the Welch Satterthwaite correction were used. Oculomotor Screening Saccade gain. There was no significant difference in saccade gain between groups in either direction, horizontal, t = 1.62, p = 0.120 or vertical, t = 0.45, p = 0.657 based on a Bonferroni adjusted experiment wise alpha of 0.025 for the two comparisons completed within this test (Figure 2 2). Saccade latency. The ASD group demonstrated significantly gre ater horizontal saccade latency ( M = 260ms, SD = 60) than the TD group ( M = 210ms, SD = 40) t = 2.65, p = 0.012. No significant difference was observed between groups for vertical saccade latency, t = 0.85, p = 0.405, however. These results are based on a Bonferroni adjusted experiment wise alpha of 0.025 for the two comparisons completed within this test (Figure 2 3). Smooth pursuit gain. No significant difference was observed in smooth pursuit gain between groups at any of the movement frequencies (0.1 H z or 0.5 Hz) or directions (horizontal or vertical) as follows: 0.1Hz horizontal, t = 0.38, p = 0.704; 0.5Hz horizontal, t = 0.67, p = 0.511; 0.1 Hz vertical, t = 0.42, p = 0.680 and 0.5Hz vertical, t = 1.32, p = 0.200. These results were based on a Bonf erroni adjusted experiment wise alpha of 0.0125 for the four comparisons completed within this test (Figures 2 4 and 2 6).

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49 Smooth pursuit phase. No significant difference was observed between groups for smooth pursuit phase for any of the movement frequenc ies (0.1 Hz or 0.5 Hz) or directions (horizontal or vertical), based on a Bonferroni adjusted experiment wise alpha of 0.0125 for all four comparisons completed (Figures 2 5 and 2 7). However, a noteworthy and systematic trend was observed with the ASD sho wing higher smooth pursuit phase lag than the TD group, particularly during vertical smooth pursuit ( p < 0.03; see Table 2 2 for a summary of t test statistics). Gaze Evoked Nystagmus. The gaze evoked nystagmus tests were the most challenging for childr en as they required compliance to more complex instructions than the other two tests. Therefore, only 9 participants in the ASD group and 16 in the TD group were able to complete this portion of the oculomotor screening battery. There was no statisticall y significant difference in mean eye movement excursion between 8) and no nystagmus was elicited by the gaze evoked nystagmus test in any subjects included in this study. Velocity Step Tests Gain Per rotary nystagmus gain. For per rotary nystagmus, there was a statistically significant main effect of condition on per rotary nystagmus gain, F (1,31) = 374.55, p < 2 = .924, with both groups displaying lower gain in the suppression condition and higher gain in the dark condition. The main effect of group showed that there was a statistically significant difference in per rotary gain between groups F (1, 31) = 11.158, p 2 = .265, with the ASD group showing higher gain than the TD group. There was no statistically significant group by condition (i.e., light, dark, and

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50 fixation suppression) interaction for per rotary nystagmus gain, F (1,31 ) = .450, p < .508, 2 = .014 (Figure 2 9). Post rotary nystagmus gain. There was a statistically significant main effect of condition on post rotary nystagmus gain, F (2,62) = 90.69, p 2 = .745, with lower gain for both groups in th e light and suppression conditions and higher gain in the dark condition (Figure 2 10). N o statistically significant difference in post rotary gain was found between groups F (1, 31) = 1.734, p 2 = .053. No statistically significant group b y condition interaction for post rotary nystagmus gain was observed, F (2,62) = .520, p 2 = .016. Time Constant of Decay. Per rotary nystagmus time constant of decay. For per rotary nystagmus, there was a main effect of condition on per ro tary time constant of decay, F (1, 31) = 4.32, p 2 = .122, with both groups demonstrating lower per rotary time constants during the suppression condition and higher time constants in the dark condition (Figure 2 11). N o statistically signi ficant difference in per rotary time constant of decay was observed between groups F (1, 31) = 3.453, p 2 = .100. There was no statistically significant group by condition interaction for time constant of decay, F (1,31) = .328, p = .571, pa 2 = .010. Post rotary nystagmus time constant of decay. There was a statistically significant main effect of condition, F (2,62) = 5.919, p 2 = .592, where both groups demonstrated lower time constants in the light condition and high er time constants in both dark and suppression conditions. There was a statistically significant group by condition interaction for post rotary time constant of decay, F (2,62) = 5.919, p 2 = .160. There was a significant difference between groups for post

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51 rotary time constant of decay in both the dark condition, F (1,31) = 6.195, p = .018, 2 = .167 and suppression condition, F (1, 31) = 20.125, p 2 = .394, with the ASD group demonstrating higher time constants in bo th conditions. There was no significant difference, however, between groups for post rotary time constant in the light condition, F (1, 31) = .379, p 2 = .012 (Figure 2 12). The greatest difference between groups was in the suppression cond ition. Discussion Neuropsychological Tests and Standardized Rating Scales There was no significant difference in age or IQ scores between the ASD group and controls, indicating that the samples were relatively well matched for age and IQ. Every effort was made to recruit high functioning children into the ASD group to better match the two samples; however, one out of the 16 ASD participants had IQ below 70, whereas none of the 17 TD group participants had IQ below 70. As expected, based on previous studies of these measures in ASD, the ASD and TD groups differed significantly on all other neuropsychological measures. Vineland II Adaptive Scores compared to controls. T he Social Communication Questionnaire (SCQ) was used in combination with the ADOS to confirm diagnoses for the ASD group, but was also conducted to screen for any ASD characteristics in the TD group (SCQ scores > 15 are clinically relevant for ASD). SCQ sc ores were significantly higher in the ASD group and well above the ASD cut off score compared to controls, wh ose scores were well below the ASD cut off, indicating that there were no significant ASD characteristics of concern in the TD group.

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52 The ASD grou p demonstrated significantly lower scores on the vestibular processing subscale of the Sensory Profile than the TD group, indicating less adaptive behavioral responses to vestibular stimuli. According to the scoring form for the Sensory Profile Caregiver Q definite The PANESS Physical and Neurological Exam for Subtle Signs ( PANESS; Denckla 1974) is a motor assessme nt that is useful for pediatric assessment of neuromotor control deficits. The PANESS has been shown to be useful for distinguishing differences in motor control between children with ASD and typically developing children as well as in distinguishing high functioning children with autism subscore presented in this study was found, as expected, to be significantly different between groups, with the ASD group having a higher score, indicating greater number of errors made such as loss of balance during the balance assessments. Oculomotor Screening Oculomotor control deficits have been well documented in the ASD population. In the current study we observed significantly increased h orizontal saccade latency in the ASD group compared to typically developing controls, but no difference in gain between groups. These findings are inconsistent with previous findings of no difference between horizontal saccade latency (Takarae, Minshew, Luna & Sweeney, 2004). Previous studies have also shown that individuals with high functioning autism show increased deficits in horizontal saccade accuracy, but no difference in saccade metrics such as gain o r latency (Johnson et al., 2012).

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53 Additionally, we observed a noteworthy trend in ASD towards increased smooth pursuit latency, particularly in the vertical direction ( p < 0.03). Although this was not statistically significant based on the Bonferroni adjus ted experiment wise alpha ( p < 0.0125) used in the current study, this was an interesting systematic pattern worthy of note. Increased vertical smooth pursuit latency has not been previously reported in ASD. However, increased horizontal pursuit latency in ASD has been previously observed in subgroups of ASD without a history of language delay. Those with and without a history of language delay have been shown to make a greater number of catch up saccades during pursuit tasks (Takarae et al., 2008), indicat ing that regardless of language development, some level of horizontal smooth pursuit deficit does exist in ASD. Our study extends these previous findings to suggest the possibility that vertically directed smooth pursuit eye movements may also display incr eased latency in this population and could contribute to functional visual deficits. Velocity Step Test: Per rotary rVOR Per rotary Gain For per rotary nystagmus, both groups displayed a trend of lower per rotary rVOR gain during the suppression conditio n and higher gain in the dark condition. This effect of condition is expected due to the suppressive effect of the fixation stimulus provided in the fixation suppression condition but lacking in the dark condition. This change in gain for both groups sugge sts that both groups were attending to the fixation suppression visual target during rotation and benefitted from the suppression effects. Even though the ASD group demonstrated the same trend of decreasing gain and time constants in the suppression condit ion compared to the dark condition, in both conditions the ASD group demonstrated significantly higher per rotary

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54 nystagmus gain compared to controls. This may indicate possible deficits in cerebellar inhibitory modulation of rVOR in ASD. Per rotary Time Constant of Decay For per rotary nystagmus, there was no difference in TCD between groups This is inconsistent with the findings reported by Ornitz et al. (1985) of increased per rotary TCD in children with ASD. It is not clear why we observed no differe nce in TCD during rotation, but did observe a difference after rotation and why Ornitz et al. (1985) found the opposite pattern of increased TCD in their participants. Velocity Step Test: Post rotary rVOR Post rotary Gain For both groups the light and f ixation suppression conditions resulted in the lowest gain and the dark condition resulted in higher gain (approaching 1.0) This suppression of rVOR gain in the light and fixation suppression conditions is likely due to the visual fixation stimuli provide d by the visible surroundings after rotation has stopped in the light condition as well as the fixation suppression target stimuli provided both during and after rotation in the fixation suppression These visual fixation stimuli provide visual feedback us eful for suppressing nystagmus gain Again, this effect of condition and decrease in gain for both groups suggests that both groups were attending to the visual fixation stimuli available in both the light condition and the fixation suppression condition a fter rotation and benefitted from the suppression effects. There was no difference between groups ; however, for post rotary nystagmus gain in any of the three conditions (light, dark or suppression). Post rotary Time Constant of Decay The ASD group exhibi ted significantly increased post rotary TCD in the dark and fixation suppression conditions compared to typically developing controls but no difference in the light condition. Based on previous

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55 studies reporting decreased duration of post rotary nystagmu s in the light (Ritvo et al., 1969) and with visual fixation stimuli provided after rotation (Ornitz et al., 1985), it is surprising that the ASD group showed no difference in TCD in the light and increased TCD in the fixation suppression condition in the current study Neither of the previous studies provided visual fixation stimuli both during and after rotation; therefore, the difference in methods and presentation of visual fixation stimuli may have resulted in the differences observed in the current st udy. Since both groups demonstrated a n effect of condition where gain was decrease d in the light and fixation suppression condition compared to the dark condition, it is reasonable to assume that the ASD group was able to follow directions during the supp ression condition and was attending to the visual target after rotation. Therefore, it is reasonable to suspect that these results reflect a true difference in rVOR function between groups rather than a difference merely in ability to follow directions or attend to fixation stimuli. The time constant of decay serves to increase the efficiency of the rVOR response to low frequency stimulation, as was provided in the current study. This is accomplished through vestibulo cerebellar modulation of the velocity storage mechanism in the brainstem (Leigh & Zee, 2006). Lesions in the nodulus and uvula (i.e., velocity storage mechanism of the cerebellum) can result in increased time constant of decay (Waespe et al., 1985). Such increases in time constant of decay hav e been observed in ASD previously when tested in the dark (see Chapter 3; Ornitz et al., 1985) and are consistent with the current findings. The differences between the visual stimuli in the fixation suppression condition and light condition may be key to understanding why these differences occurred in the

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56 suppression condition but not in the light condition for the ASD group. First, during the visual fixation condition, an LED visual target stimulus is presented in the right eye piece of the videooculogra phy goggle. This visual stimulus follows the participant as they rotate and places demands on both the smooth pursuit system as well as the brainstem neural integrator circuitry for maintaining gaze stability and fixation. In the light condition, during ro tation the full field visual stimuli of the surrounding environment remains fixed as the participant rotates creating retinal slip and providing optokinetic visual feedback that should facilitate per rotary nystagmus. When rotation stops, this full visual field also provides visual feedback that motion has ceased and helps to inhibit post rotary nystagmus. Second, during the visual fixation task, the participant was asked to fixate on the visual LED target, therefore the target is present within the foveal visual field; whereas, in the light condition the visual stimuli is presented within the full visual field including both foveal and peripheral visual fields. Therefore, there may be a difference between these two conditions based on differing requirements of smooth pursuit and optokinetic systems. Summary Taken together, these results of increased time constant of decay in the dark and during fixation suppression conditions suggest that there may be deficits in cerebellar modulation of velocity storage a s well as visual fixation. The increased gain during per rotary nystagmus and increased time constant of decay of post rotary nystagmus in the dark indicates a lack of inhibition from the cerebellum to the brainstem velocity storage system in ASD. This lac k of inhibition may be related to similar findings of pre natal and post natal neuropathological processes suspected in the cerebellum in ASD such as Purkinje cell loss ( Ritvo et al., 1986; Bailey et al., 1998; Kemper & Bauman, 2002;

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57 Purcell et al., 2001; Lee et al., 2002; Palmen et al., 2004) The increased time constant of decay for post rotary nystagmus during visual fixation suppression suggests that there is a possible deficit in visual fixation or smooth pursuit Although no significant difference was found in the smooth pursuit oculomotor screening tests, there was a consistent trend toward higher smooth pursuit latencies in the ASD group. The current study may not have had enough statistical power to identify significant differences in this measure. Additionally, the individuals with ASD recruited into the current study were relatively high functioning and therefore, may have more subtle differences in oculomotor results. Oculomotor differences within ASD have been previously shown to depend on presen ce or absence of language delay, which was not recorded in this sample (Takarae et al., 2004; Takarae et al., 2008). Future Studies Optokinetic nystagmus (OKN) and optokinetic after nystagmus (OKAN) are repetitive eye movement responses to visual motion stimuli rather than vestibular stimuli as with per and post rotary nystagmus is to rVOR. Like rVOR however, both OKN and OKAN are also dependent upon normal functioning of the nodulus and uvula. Horizontal OKAN is prolonged with damage to these structures (Angelaki & Hess, 1994; Wearne et al., 1998). OKN and has been briefly described in the literature to differ from controls in one oculomotor study (Scharre & Creedon, 1992). However, these tests were conducted by visual observation of OKN only and actual measurements of gain and time constant of decay were not possible. The authors reported that 83% of the ASD seconds, duration of the response less than 5 seconds, gaze av oidance, and/or

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58 phenotype rather than OKN such as stereotypic behavior and gaze avoidance and there may have been some bias towards the ASD population to exhibit these types o f was due to abnormal OKN responses or ASD related behaviors. OKAN has not been studied in this population to date. Since horizontal rVOR is prolonged in ASD, it is rea sonable to expect that OKAN might also be prolonged in this population and may further provide evidence for deficits in nodular/uvular function in ASD. condition and fixation suppression condition, possible differences may exist in the ability of individuals with ASD to process central/foveal vs. full field vision for optokinetic feedback for gaze stabilization. Rotary chair testing with OKN full visual field used as the fixat ion suppression stimulus during rotation (Brey, McPherson & Lynch, 2008b) may help to determine whether or not there are differences in visual processing of full field vs. foveal fixation suppression of rVOR in ASD.

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59 A. C. Figure 2 1. Pediatric Rotary Chair. A) child seated in rotary chair wearing goggles themed rotary chair secured to motorized platform, armrests equipped with video oculography goggle system and goggle cover. B.

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60 Table 2 1. Summary of Group Mean (SD) for Demographics and Neuropsychological Assessments ASD (n = 16) Controls (n = 17) Mean SD n Mean SD n t p Age (months) 106.63 24.51 16 110.06 23.76 17 .409 0.69 Leiter Brief IQ 100.19 24.23 16 104.24 14.61 17 .585 0.56 Vineland II Adaptive Score 81.31 13.68 16 101.94 14.97 17 4.12 <0.005 ADOS 10.25 5.39 16 N/A N/A 17 N/A N/A SCQ 20.60 7.43 15 1.94 1.71 17 9.50 <0.005 Vestibular Proce ssing (SP) 42.75 6.03 16 50.67 3.60 15 4.40 <0.005 RBS R 36.13 23.15 16 2.47 4.78 17 5.70 <0.005 PANESS Balance errors 4.69 3.11 16 1.12 1.73 17 4.04 0.001 N/A = ADOS testing only conducted with the ASD group.

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61 Table 2 2. Summary of Smooth Purs uit Comparisons for Phase (degrees) Target condition Group n M SD T Sig. Horizontal 0.1 Hz ASD 14 4.25 9.53 TD 17 0.85 1.42 1.37 0.193 Horizontal 0.5 Hz ASD 15 6.71 8.11 TD 17 4.32 4.22 1.06 0.296 Vertical 0.1 Hz ASD 15 10.03 9.94 TD 17 3.37 5.86 2.32 0.028 Vertical 0.5 Hz ASD 15 14.93 13.71 TD 17 6.30 8.00 2.34 0.029 Results based on a Bonferroni adjusted p value of p < 0.0125 for the four comparisons made in this test

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62 Figure 2 2. Saccade Gain. There was no statisticall y significant difference between groups in saccade gain for either horizontal or vertical saccades.

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63 Figure 2 3. Saccade Latency. The ASD group showed significantly increased horizontal saccade latency N o difference was observed between groups for v ertical saccade eye movement latency ( error bars indicate standard deviations; p < 0.025).

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64 Figure 2 4. Horizontal Smooth Pursuit Gain. No difference in horizontal smooth pursuit gain between groups at either frequency of target movement (error ba rs indicate standard deviations).

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65 Figure 2 5. Horizontal Smooth Pursuit Phase. No statistically significant difference in horizontal smooth pursuit phase between groups ; however, there is a noteworthy increase in the phase lead in the ASD group at bo th movement frequencies. There is also a noteworthy difference in variability between groups, with the ASD group showing greater variability (error bars indicate standard deviations).

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66 Figure 2 6. Vertical Smooth Pursuit Gain. No significant differe nce in vertical smooth pursuit gain between groups at either frequency of target movement (error bars indicate standard deviations).

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67 Figure 2 7. Vertical Smooth Pursuit Phase. No statistically significant difference in vertical smooth pursuit phase b etween groups; however, there is a noteworthy increase in the phase lag in the ASD group at both movement frequencies. There is also a noteworthy difference in variability between groups, with the ASD group showing greater variability (error bars indicate standard deviations).

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68 Figure 2 8. Gaze Evoked Nystagmus Mean Eye Excursion. No significant difference between groups in any direction of target movement or with target on/off. Also, no nystagmus beats were elicited by this test, which is normal (e rror bars indicate standard deviations)

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69 Figure 2 9. Velocity Step Test Per Rotary rVOR Gain. Both groups displayed decreased mean gain in the suppression condition, as expected, due to the suppression effects of fixation during and after rotation. However, the ASD group showed higher per rotary nystagmus gain in both dark and fixation suppression condition s (error bars indicate standard deviations; ** p < 0.01). * *

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70 Figure 2 10. Velocity Step Test Per rotary rVOR TCD Both groups displayed decreas ed time constant of decay in the suppression condition, as expected, due to the suppression effects of fixation during and after rotation. There was no difference between groups in either condition.

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71 Figure 2 11. Velocity Step Test Post Rotary rVOR Gain. Both groups displayed decreased mean gain in the light and suppression conditions, as expected, due to the suppression effects of visual stimuli after rotation. There was no difference between groups in any of the three conditions (error bars indica te standard deviations).

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72 Figure 2 12. Velocity Step Test Post rotary rVOR TCD The typically developing (TD) control group displayed decreased time constant of decay in the light and suppression condition, as expected, due to the suppression effects of visual stimuli during and after rotation. However, the ASD group demonstrated a significantly increased post rotary time constant of decay in the fixation suppression condition, which is unexpected. The ASD group also displayed a higher post rotary time constant of decay in the dark condition (error bars indicate standard deviations; p < 0.05; ** p < 0.01). *

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73 CHAPTER 3 SINUSOIDAL HARMONIC ACCELERATION TESTS OF VESTIBULO OCULAR FUNCTION IN AUTISM SPECTRUM DISORDERS Rotary chair tests are considered the gold standard for rotational vestibulo ocular reflex (rVOR) assessments (Fife et al., 2000) A rotary chair assessment battery typically includes at least two types of tests: the velocity step test and the s inusoidal harm onic acceleration test (SHA). Velo city step testing has been previously reported to be abnormal in children with autism spectrum disorders (ASD; Ritvo et al., 1969; Ornitz et al., 1974; Ornitz et al., 1985) ; however, SHA tests have never been conducted in this population. The rationale be hind SHA testing is that the horizontal rVOR can be challenged by a range of frequencies of rotation at a moderate velocity of 50 60 degrees/second Typically, throughout everyday movement, head movements occur between 0.5 and 5.0Hz (Leigh & Zee, 2006) The frequency range tested during SHA is anywhere from 0.01Hz to 0.64Hz; sometimes up to 2 Hz, depending on the type of testing equipment. Therefore, another benefit to SHA testing is that it can be conducted at higher frequencies (0.5 2 Hz) that more cl osely approximate natural ranges of motion than other forms of testing (Brey, McPherson & Lynch, 2008b). The ability to test at a range of frequencies is important because deficits in rVOR responses at high or low frequencies can be useful in determining the origin of vestibular symptoms (i.e., whether they are the result of central vs. peripheral dysfunction). The rVOR is a remarkably fast reflex with just 7 15 ms latency that responds most efficiently to high frequency acceleration stimuli, such as th at resulting from quick rotational movements of the head. Abnormal responses to high frequency cycle SHA

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74 testing can reflect peripheral horizontal semicircular canal dysfunction. In order to maintain the efficiency and accuracy of this compensatory oculomo tor response at lower frequencies the velocity storage mechanisms in the brainstem and cerebellum work together to prolong the raw vestibular signal from the peripheral vestibular organ into what is known as the time constant of decay thus making rVOR re sponses to low frequency stimuli more efficient (Leigh & Zee, 2006) Therefore, deficits in the rVOR response to low frequency cycles of stimulation may reflect differences in the velocity storage mechanism of rVOR. SHA testing can also be useful for dete rmining whether or not there is a unilateral neurological deficit or lesion. Three primary measures are obtained from SHA testing including : gain, phase and symmetry. Gain is the ratio of head and eye velocity. Gain is an excellent indicator of how well th e peripheral vestibular system is responding to angular acceleration. Phase is the timing relationship between the initiation of head movement and subsequent compensatory eye movement. Abnormally increased phase lead may be due to either central nervous sy stem damage to vestibular nuclei or peripheral damage to vestibular organ nerve (Shepard & Telian, 1996). Symmetry is the comparison of slow phase velocity between the two directions of movement (i.e., to the right vs. to the left) and indicates whether on e or the other peripheral vestibular systems is not functioning properly. SHA testing is typically conducted in the dark to prevent any visual fixation during rotation. However, a f ixation s uppressio n condition can also be conducted in combination with SHA protocols to evaluate the ability for visual fixation during oscillation to inhibit rVOR eye movements. For this test of visual suppression, an LED

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75 visual stimulus is provided within the video oculography goggle (VOG) system and the participant is directe d to maintain visual fixation on the stimulus while they are rotating back and forth. This visual stimulus during rotation provides a target for visual fixation that moves with the subject and, in healthy subjects, should suppress rVOR gain during rotation dampen the amplitude of nystagmus beats and allow the eye to remain fixed on the visual target. This response relies on a healthy connection between the primary vestibular processor or vestibular nuclei of the brainstem and the adaptive processor, the m idline cerebel lar structures ( Hain & Helminski, 2007; Brey et al. 2008b). Previous studies of velocity step tests have reported findings of significant differences in rVOR responses in ASD compared to typically developing controls when visual stimuli in various forms are made available to the participant s at different times during rotary chair velocity step testing (i.e., during or after rotation) Ritvo et al. ( 1969 ) found that children with ASD have significantly decreased rVOR post rotary nystagmus res ponse when provided full field standard visual surroundings during and after rotation however, this effect was not replicated in a recent study of children with ASD that displayed no difference in time constant of decay when tested in the light (see Chapt er 2 of current studies) Ornitz et al. (1974) reported that children with ASD show no difference in rVOR post rotary nystagmus response compared to controls when provided a blank, white visual field after rotation in the dark When a visual fixation suppr ession target is provided via VOG goggles both during and after rotation (current studies, Chapter 2) the ASD group demonstrated increased time constants of decay W hereas, if they rotated in the dark and then were presented with the visual fixation suppr ession target after rotation has ceased, they exhibit ed decreased post rotary

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76 n ys tagmus duration compared to controls (Ornitz et al., 1974). Since each of the above studies provide visual stimuli at different time points during testing, questions remain as to the consistency of rVOR fixation suppression deficits in ASD. Furthermore, questions remain as to the source of rVOR deficits in ASD, whether they are of peripheral or central origin. To date, no SHA testing has been reported in ASD with or without a f ixation suppression condition. The current study aimed to determine whether peripheral or central VOR processing deficits exist in ASD by conducting SHA tests in the dark over a range of high and low frequency cycles of rotation The second aim of the cur rent study was to explore the possibility that visual fixation suppression stimuli provided during SHA tests would produce differences in rVOR gain or phase in the ASD group. S ymmetry is expected to be typical in children with ASD, as there is no evidenc e of unilateral deficits in ASD in any of the previous studies of rVOR function mentioned previously The SHA fixation suppression testing will provide the LED suppression stimulus both during and after rotation, since this is the classic method for conducti ng this test and will allow comparisons to a wealth of basic science as well as clinical rVOR literature for interpreting any abnormal responses. Based on previous studies conducted by the authors (Chapter 2), it is expected that the fixation suppression w ill affect gain of rVOR for both groups, but there may not be a difference in fixation suppression gain between groups. Since phase has not been previously explored in this population, it is exploratory as to any differences that may arise between groups i n the phase of rVOR in ASD. However, if central velocity storage deficits in this population exist, it is conceivable that phase differences will be observed in the ASD group.

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77 Methods Participants an d Recruitment For this study, 15 children with ASD and 17 typically developing children ages 6 12 were recruited from the University of Florida Center for Autism and Related Disabilities (UF CARD), Alachua County elementary and middle schools and pediatric therapy centers within Alachua county. ASD diagnoses i ncluded: A syndrome, or Pervasive Developmental Disorder Not Otherwise Specified and were confirmed by the Autism Diagnostic Observation Schedule (ADOS; Lord et al., 2000) and the Social Communication Questionnaire (SCQ; Rutter, Bayley & Lord, 2003). Exclusionary criteria include diagnoses of Fragile X, Rett Syndrome, tuberous sclerosis, seizure disorder or fetal cytomegalovirus infection. Exclusionary criteria for control participants included parent report of any current or past history of psychiatric or neurologic disorder or any immediate family with history of autism, schizophrenia, developmental disorder, mood disorder or anxiety disorder, or if they were taking any psychiatric medications. These exclusionary criteria were selected i n an effort to minimize confounding variables and to better define the ASD and TD group s by excluding disorders with known etiologies such as Fragile X, Rett Syndrome, tuberous sclerosis, and fetal cytomegalovirus infection and to reduce the risk of any ha rm to participants as seizures have been reported to be elicited by vestibular stimulation. Testing Equipment A computer controlled, motorized rotary platform, I Portal TM Video Oculography Goggle (VOG) System and VEST 6.8 Software were used to record eye movement s during sinusoidal harmonic acceleration testing On top of the rotary platform, padding,

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78 a chair, safety harnesses, and a head stabilizing system were added by the authors to adapt seating for pediatric use (Figure 2 1, Chapter 2). Procedure V OG System Calibration. The VOG system was calibrated prior to testing each participant. A laser visual stimulus was projected onto a black screen with a 60 arc 76.5 inch radius so that movement of the laser was congruent with the arc of eye movement. The laser visual stimulus was projected onto the screen in complete darkness at + 10 from center first to the left, then right, then up and down This process wa s repeated tw ice and results were averaged. Oculomotor Screening. Oculomotor screening tests inc luded : saccade, smooth pursuit and gaze evoked nystagmus test s Participants were instructed to follow the red glowing dot through a series of movements for each specific test (see methods section in Chapter 2 for further detail) Sinusoidal H armon ic A cce leration (SHA) in the Dark. SHA tests were conducted under two conditions as follows: (1) in the dark with goggle cover on and room lights off and (2) with fixation suppression LED turned on inside goggle cover in the dark with room lights off. During SHA testing in the dark condition, the participant experience d acceleration to a peak velocity of 60/sec followed by decelerat ion to 0/sec in one direction, after which, the same acceleration and deceleration profile was repeated in the opposite direction, resulting collectively in a back and forth motion experience by the participant. T his procedure has been performed with children age 3 to 9 previously with a freq uency cycle profile of 0.02Hz, 0.05Hz, 0.1Hz and 0. 5 Hz ( Casselbrant, 2010 ) Howeve r, the 0.02 H z condition takes up to (1/0.02) 50 seconds per cycle. Generally, a minimum of 3 cycles are completed and averaged at each frequency

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79 (Brey, McPherson & Lynch, 2008a). Therefore, the 0.02Hz frequency trial takes 150 seconds or 2.5 minutes to complete 3 rota tions. This is a very slow movement and it rotating slowly. Therefore, it is not uncommon for studies to drop this frequency from their protocol. Thus only 0.05, 0.10 and 0.50 Hz frequencies were conducted in this study Sinusoidal Harmonic Acceleration (SHA) with Fixation suppression SHA testing in the fixation suppression condition was conducted as above with the addition of an illuminated fixation LED present ed on the inner surface of the right eye view in the goggle cover This LED provide d a visual fixation stimulus during and after rotation and allow ed visual feedback to inhibit the duration of the per and post rotary VOR Statistical Methods Comparison s of rVOR metrics including gain, phase, symmetry, and an estimated time constant of decay were conducted with m ixed ANOVAs using IBM SPSS Statistics software v. 21 with group ( e.g., ASD or TD) as a between subjects factors, and visual condition: ( 1 ) light, ( 2 ) dark and ( 3 ) fixation suppression conditions as within subjects factors. Time constant of decay was estimated using an equation to calculate time constant during SHA testing at 0.05Hz as described by Brey et al. ( 2008 a ) Results Oculomotor Screening The results of the oculomotor screening revealed significantly greater horizontal saccade latency in the ASD group (Figure 2 2). No other significant differences between groups were discovered (refer to Chapter 2 Oculomotor Results). However, a

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80 systemati c trend of increased smooth pursuit phase was observed in ASD that is noteworthy and may be related to fixation suppression. Sinusoidal Harmonic Acceleration (SHA) SHA dark testing Gain. The assumption of homogeneity of variances was met for all analyses, as assessed by Levene's Test of Homogeneity of Variance at each of the three frequencies tested ( p > .05). The assumption of homogeneity of covariances was violated as assessed by Box's test of equality of covariance matrices ( p = .039). There was a stati stically significant main effect of frequency on SHA gain in the dark F ( 2,60) = 3.574, p = 2 = .106 where gain increased for both groups as the testing frequency increased for both groups There was also a significant main effect of group on SHA gain in the dark, F (1,30) = .196, p 2 = .106 where ASD participant s showed higher gain than TD participants at each of the three frequencies tested T here was no statistically significant interaction between group and frequency on SHA gain in the dark F (2,60) = 604, p = 2 = .020 (Figure 3 1) Phase. The assumption of homogeneity of variances was met for all analyses, as assessed by Levene's Test of Homogeneity of Variance at each of the three frequencies tested ( p > .05). The assumption of homogeneity of covariances was met, as assessed by Box's test of e quality of covariance matrices ( p = .094). There was a statistically significant main effect of frequency on SHA phase in the dark F (2,60) = 95. 361 p = .000, parti 2 = 761 where phase decreased as the frequencies of movement increased for both groups There was no significant main effect of group on SHA phase in the dark F (1,30) = 1.662 p = 207 2 = 053 as well as no statistically

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81 significant intera ction between group and frequency on SHA phase in the dark F (2,60) = .814 p = 448 2 = 026 (Figure 3 2 ). SHA suppression testing Gain. The assumption of homogeneity of variances was met for 0.1Hz ( p = .197) but not for 0.05 Hz ( p = .005) and 0. 5 Hz ( p=. 002), as assessed by Levene's Test of Homogeneity of Variance ( p > .05). The assumption of homogeneity of covariances was not met, as assessed by Box's test of equality of covariance matrices ( p = .025). There were no statistically significant mai n effects of frequency, F (2,60) = .124 p = 883 2 = 004 or group on SHA gain with fixation suppression, F (1,30) = 3.666 p = 065 2 = 109 There was also no statistically significant interaction between group and frequency on SHA gain with fixation suppression, F (2,60) = 1.753 p = 187 2 = 055 (Figure 3 3 ). Phase. The assumption of homogeneity of variances was met for all analyses, as assessed by Levene's Test of Homogeneity of Variance at each of the three frequencies tested ( p > .05).The assumption of homogeneity of c ovariances was met, as assessed by Box's test of equality of covariance matrices ( p = 761 ). There was a statistically significant main effect of frequency o n SHA phase with fixation suppression, F (2,60) = 14.23 p = 000 2 = 322, where phase de creased as frequency increased for both groups. There was no significant main effect of group on SHA phase with fixation suppression F (1,30) = .433 p = 515 2 = 014 T here was however, a statistically significant interaction between group and frequency on SHA phase with fixation suppression F (2,60) = 3.213 p = 047 2 = 097 where the ASD group exhibited increased phase lead compared to the TD group in the 0.50 Hz frequency condition only (Figure 3 4 ).

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82 Discussion SHA in the Dark As the testing frequency increased from 0.05 to 0.5 Hz, the gain increased and phase lag decreased for both groups. The increase in gain indicates improved accuracy of the peripheral rVOR response and the decreased phase lag means that the eyes were able to b etter keep up with changes in head movement direction at higher frequencies. This improved efficiency of the rVOR at higher frequencies reflects healthy peripheral vestibular function in both groups since the rVOR responds best to high frequency cycle rota tion, similar to that experience d by daily head movements. Although both groups follow ed the same increasing trend in increasing gain over the increasing frequencies (increasing x 3) the gain in the ASD group was significantly higher than controls at each of the three frequencies tested. This increased gain may reflect decreased cerebellar modulation of rVOR and is consistent with velocity step test findings of increased per rotary gain and increased post rotary time constant of decay in both dark and supp ression conditions in ASD (see Chapter 2 of the current studies). There was no difference in phase between groups at each frequency Overall, in the dark, the ASD group followed the same trend as controls of improved efficiency of gain at higher frequencie s of rotation. T he significant increase in gain compared to controls in the dark however, may be related to hyper responsivity to vestibular stimulation in ASD or to a lack of inhibition from the cerebellum. The interpretation that this result reflects h yper responsivity has interesting implications for clinical use considering that children with ASD have been noted to either seek or avoid vestibular sensory stimuli to an extent that is different from age appropriate behavior (see Chapter 2) indicating ch ildren with ASD do not tend to

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83 respond adaptively to vestibular stimulation in their activities of daily living. It seems reasonable to suspect that the sample of participants that volunteered for the current study would have an affinity toward or toleranc e of vestibular stimuli. Therefore, it is surprising that these participants demonstrate such a heightened response during these tasks. SHA with Fi xation S uppression T esting There was no difference between groups on gain during fixation suppression SHA te sting at any of the frequencies tested and both groups demonstrated a reduction in gain compared to dark SHA tests. This reduction in gain across groups indicates that both groups were able to attend to the visual fixation stimulus and that both groups ben efited from visual fixation suppression of rVOR during rotation by being able to suppress their rVOR nystagmus. Again, for both groups p hase decreased as frequency increased. However, at the highest frequency tested (0.5Hz frequency), the ASD group exhibit ed increased phase lag compared to controls (Figure 3 4). Summary The ASD group exhibited significantly greater rVOR gain in the dark condition across all frequencies. Although this followed a typical trend, the increase in gain compared to controls indic ates abnormal SHA response in this population that may be indicative of a lack of cerebellar inhibitory control of rVOR in this group. There was no difference between groups for phase in the dark condition; however, the ASD group exhibited greater mean rVO R phase lead compared to the TD group at 0.5Hz (the higher frequency) during the fixation suppression condition. Increased phase lead may indicate either peripheral vestibular differences or central deficits at the brainstem level in vestibular nuclei func tion (Shepard & Telian, 1996). Further studies are warranted to

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84 discern whether these differences are due to perturbations in the peripheral or central nervous system. Limitations and Future Studies Several questions remain regarding rVOR performance dur ing SHA tests in this population. Typically time constant of decay is estimated only for SHA tests conducted with a peak velocity of 50 60 /sec at the slowest frequency cycle (usually 0.01 or 0.02Hz) B oth groups in the current study however, would not tolerate testing at 0.01 or 0.02Hz frequency cycles and were tested instead at 0.05 Hz as the lowest frequency cycle Although the current study provide d rotational stimuli at an appropriate peak velocity (60/sec ), the frequency cycle of 0.05 Hz was not low enough to calculate TCD from the current SHA test results Future studies should be conducted with SHA at 60 /sec peak velocity at a lo wer frequency cycle such as 0.01 or 0.02 Hz in order to estimate TCD for comparison in ASD. It would be beneficial to calculate the TCD during SHA tests both in the dark and in fixation suppression conditions to better compare the results of these tests to velocity step tests conducted in ASD. However, the TCD estimate for SHA testing is directly related to the SHA phase. Based on the current results increased phase lead in ASD at the 0.5Hz frequency cycle with fixation suppression indicates that at least f or that condition and frequency cycle, TCD in the ASD group may be decreased compared to controls This would be contradictory to velocity step test findings of increased TCD during fixation suppression in ASD. This contradictory finding is worthy of furth er investigation. To extend the current findings of differences in fixation suppression, SHA fixation suppression testing should be explored using a full visual field as the fixation suppression stim ulus during rotation (Brey et al. 2008b). A full visual field will stimulate

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85 the optokinetic nystagmus system and may help to determine whether or not there are further differences in visual processing for full field vs. foveal fixation suppression of rVOR in ASD. If differences arise in response to full field stimuli, it may be related to optokinetic system dysfunction; whereas, if differences with foveal fixation stimuli, differences may be related to gaze fixation or smooth pursuit deficits.

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86 Figure 3 1. Mean gain for each group during SHA testing in the dark condition at cycle frequencies of (1) 0.05Hz, (2) 0.1Hz and (3) 0.5Hz Gain was significantly higher for the ASD group across all frequencies ( p < 0.05). S inusoidal H armonic A cceleration Gain in the Dark

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87 Figure 3 2. Mean phase for each group during SHA testing in the dark condition at cycle frequencies of (1) 0.05Hz, (2) 0.1Hz and (3) 0.5Hz. There was no significant difference between groups across conditions; however, there was a main effect of condition with both groups exhibiting a decrease in phase as frequency conditions increas ed. S inusoidal H armonic A cceleration Phase in the Dark

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88 Figure 3 3. Mean gain for each group during SHA testing with fixation suppression LED at cycle frequencies of (1) 0.05Hz, (2) 0.1Hz and (3) 0.5Hz. It is important to note that the y axis scale for mean gain in the fixation suppression condi tion above (0.22 to 0.32) is much lower than that in the dark condition (0.55 to 0.75) illustrating that both groups demonstrated a reduction in gain with fixation target present. There was no significant difference between groups for SHA gain across all f requency conditions. S inusoidal H armonic A cceleration Gain with Fixation Suppression

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89 Figure 3 4. Mean phase for each group during SHA testing with fixation suppression LED at cycle frequencies of (1) 0.05Hz, (2) 0.1Hz and (3) 0.5Hz. The ASD group demonstrated increased phase lead at the 0.5Hz frequency cyc le condition only (* p < 0.05). S inusoidal H armonic A cceleration Phase with Fixation Suppression

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90 CHAPTER 4 FUNCTIONAL CORRELATES OF THE VESTIBULO OCULAR REFLEX IN AUTISM SPECTRUM DISORDERS Autism spectrum disorders (ASD) are developmental disorders characterized by deficits in communication skills, social skills a nd restricted repetitive behaviors (APA, 2000; DSM IV TR). Additional features commonly reported in ASD are deficits in vestibular processing related motor functions such as postural control (Minshew et al., 2004; Molloy, Dietrich & Bhattacharya, 2003) and vestibulo ocular reflex function (Ritvo et al., 1969; Ornitz et al., 1984; Ornitz et al., 1985). These sensory/motor deficits are of particular interest in ASD for both their functional implications, such as balance, motor planning/coordination, sensory p erception and visual stability, as well as their usefulness in pinpointing neural substrates for pathology in ASD. The most consistent finding of rotational vestibulo ocular reflex (rVOR) aberration in ASD is a significant increase in the time constant of decay of the rVOR post rotary nystagmus response following continuous rotation compared to typically developing controls (Ritvo et al., 1969; Ornitz et al., 1974; Ornitz et al., 1985; Chapter 2 of the current studies). The time constant is a prolongation of the nystagmus that occurs during rVOR. The time constant of decay functions to improve the efficiency of rVOR in response to low frequency stimulation and is dependent upon brainstem and cerebellar modulation of rVOR (Leigh & Zee, 2006). Both brainstem and cerebellar structural differences have been consistently noted in ASD ( Bauman &Kemper, 2005 ) and both structures are important for modulating vestibular sensory input and appropriate vestibulo spinal or vestibulo ocular motor output. It has been postul ated that there is a general vestibular processing difference in ASD (Maurer & Damasio, 1979; Ornitz et al., 1985; Kern et al., 2007) If there is, indeed some common level of central vestibular

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91 processing dysfunction in ASD, it is reasonable to suspect t hat there may be a correlation between vestibulo spinal (i.e., postural control/balance) and rVOR function as well as a relationship between vestibular function measures and parent reports of behavioral responses to vestibular stimuli in this population. rVOR time constant of decay differences in ASD were observed with the use of sophisticated laboratory testing equipment and provided an objective index of rVOR deficits Q uestions remain however, as to their functional significance and the relationship of th ese reflex measures to functional abilities and deficits in children with ASD. If deficits in rVOR responses reflect neurological deficits in ASD, they may also be correlated to other functional measures in ASD such as the severity of ASD symptoms and a bility measures. The current study aimed to determine whether relationships exist between aberrant rVOR findings reported in Chapter 2 of the current studies and other functional performance measures in ASD. Specifically, it was anticipated that the follo wing relationships would exist: (1) rVOR time constants of decay should be positively correlated with PANESS balance error measures indicating that a relationship exists between ve stibulo ocular and vestibulo spinal measures in ASD; (2) parent reports of v estibular processing via the Sensory Profile should be negatively correlated with direct tests of vestibular function such as rVOR time constant of decay and/or balance errors such that as parent reports of adaptive vestibular processing behaviors improves time constants and balance errors also improve; (3) Functional ability measures such as IQ and parent report of adaptive function should be negatively correlated with rVOR time constants in ASD such that as IQ and adaptive scales improve, rVOR time const ants

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92 will improve as well; and (4) If rVOR deficits are related to the symptoms of ASD, then rVOR time constants should be positively correlated with ASD symptom severity (i.e., as rVOR time constant increases ADOS, SCQ and RBS R scores will also increase) Methods Participants and Recruitment For this study, 16 children with ASD ages 6 12 were recruited from the University of Florida Center for Autism and Related Disabilities (UF CARD), Alachua County elementary and middle schools and pediatric therapy centers within Alachua county. Disorder Not Otherwise Specified and were confirmed by the Autism Diagnostic Observation Schedule (ADOS; Lord et al., 2000) and the Social Comm unication Questionnaire (SCQ; Rutter, Bayley & Lord, 2003). Exclusionary criteria include diagnoses of Fragile X, Rett Syndrome, tuberous sclerosis, seizure disorder or fetal cytomegalovirus infection. These exclusionary criteria were selected in an effort to minimize confounding variables and to better define the ASD group by excluding disorders with known etiologies and to reduce the risk of any harm to participants as seizures have been reported to be elicited by vestibular stimulation. Testing Equipmen t A Neuro Kinetics, Inc. (NKI) motorized, computer controlled, rotary system was adapted for pediatric use for the current study. The authors added a seating system attached to the top of the rotary platform that was designed specifically for use with this pediatric population. This seating system included: padding, a chair, safety harnesses, and a head stabilizing system (Figure 2 1 in Chapter 2). NKI I Portal TM Video

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93 Oculography Goggle (VOG) System and VEST 6.8 Software were used to record eye movement du ring whole body continuous rotation velocity step tests. Procedure General procedure Participants attended 2 3 testing sessions for participation in this study. For the first testing session, children and parents participated in various neuropsychologic al assessments. Some were conducted with direct observation of the child and others were questionnaires completed by parents/caregivers. At the end of the first testing session, participants were screened for gross oculomotor deficits and the videooculogra phy (VOG) goggle system was calibrated. VOR tests were conducted during the second session and third session, if needed. Each session lasted approximately 1 to 2 hours. Neuropsychological assessments Children participated in four assessments as follows: (1) the Autism Diagnostic Observation Schedule ( ADOS; Lord et al., 2000), (2) the Social Communication Questionnaire (SCQ; Rutter, Bayley & Lord, 2003) (3) the Leiter R Brief IQ test (Roid, Miller, & Leiter, 1997), and (4) the Physical and Neurological E xamination for Soft Signs (PANESS; Denckla, 1974). While children participated in the assessments listed above, parents/guardians completed three questionnaires as follows: (1) the Repetitive Behavior Scale Revised (RBS R; Bodfish et al. 2000), (2) the Se nsory Profile Caregiver Questionnaire (Dunn, 1999) and (3) the Vineland II Adaptive Scales (Sparrow & Cicchetti, 1985; Sparrow, Cicchetti, & Balla, 2005). For the current studies, t he combination of ADOS and SCQ was used to confirm diagnoses of children re cruited into

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94 the ASD group and a combination of Vineland II Adaptive Scale and Leiter R Brief IQ results was used to determine presence or absence of intellectual disability. Autism Diagnostic Observation Schedule. The Autism Diagnostic Observation Schedul e (ADOS; Lord et al., 2000) is a semi structured play based assessment of social and communication skills and restricted repetitive behaviors. The ADOS is considered the gold standard in ASD diagnostic assessments and provides a method for direct observati on and scoring of all three behavioral domains. The ADOS also provides a classification of autism, autism spectrum disorder and non spectrum and thus, a measure of severity of autism symptoms ranging between ASD cut off score (lower score, less severe) and autism cut off score (higher score, more severe). This assessment takes approximately 60 120 minutes to administer. Social Communication Questionnaire. The Social Communication Questionnaire (SCQ; Rutter, Bayley & Lord, 2003) is a parent report measure of social and communication skills. The SCQ is a valid first level screening tool for identifying school age children who are at risk for ASD and would benefit from further ASD diagnostic testing ( Eaves, Wingert, Ho & Mickelson, 2006; Chandler et al., 2007 ). In the current study, the SCQ was used in conjunction with ADOS scores to confirm diagnoses within the autism spectrum. Leiter International Performance Scale Revised (Leiter R) Brief IQ. The Leiter R Brief IQ test (Roid, Miller & Leiter, 1997) is a non verbal intelligence assessment that allows individuals age 2 to 21 years to indicate their responses through gestures or manual selection. It is generally recommended that the Leiter R be used for children with ASD due to deficits in communication that would preclude or prevent

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95 completion of other forms of intelligence testing ( Tsatsanis et al., 2003). This test takes approximately 60 minutes to administer. The Physical and Neurological Examination for Soft Signs (PANESS). The PANESS is a standardized pediatric neurological assessment of motor control where children complete motor tasks such as rapid finger tapping or walking heel to toe (Denckla, 1974). The PANESS includes a subset of measures of balance such as single leg stance and hopping on one foo t. The PANESS subscale sum of balance errors has been previously shown to distinguish typically developing children from children with syndrome (Jansiewicz et al., 2006). Bala nce is a measure of vestibulo spinal function, therefore, the balance sum of errors subscale from the PANESS was chosen as a variable of interest for the current study to compare with other measures of VOR function. This test takes approximately 20 minutes to administer. Repetitive Behavior Scale Revised: Stereotypy Subscale. The Repetitive Behavior Scale Revised (RBS R; Bodfish et al. 2000) is an index of restricted repetitive behaviors in ASD. The RBS R includes 6 subscales as follows: stereotyped behavi or, self injurious behavior, compulsive behavior, ritualistic behavior, sameness behavior and restricted behavior. Each item within these subscales is rated on a 4 point likert scale from 0 (behaviors do not occur) to 3 (behaviors do occur and are a severe problem ). The stereotyped behavior subscale of the RBS R was selected for the current study rather than total RBS R scores because 3 out of 5 of the questions in the stereotypy subscale include movement stereotypies that generate vestibular stimulation

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96 su ch as (1) body rocking or body swaying, (2) rolling, nodding, or turning the head and (3) turning in circles, whirling, jumping or bouncing. Sensory Profile: Vestibular Subscale. The Sensory Profile Caregiver Questionnaire (Dunn, 1999) is a tool for evalu respond adaptively to six sensory processin g domains including the domain of vestibular processing. The vestibular processing subsection of the Sensory Profile provides a parent report of non adaptive behavioral responses to various vestibular sensory stimuli encountered in daily activities. Questi on prompts include examples such behavior on a Likert scale of 1 (always) to 5 ( never). Thus, higher scores reflect more adaptive responses and the lower scores reflect less adaptive responses. Vineland II Adaptive Scales. The Vineland II Adaptive Scales (Sparrow & Cicchetti, 1985; Sparrow, Cicchetti, & Balla, 2005) is a measure of co mmunication, daily living, socialization and motor skills for daily living. The Vineland II is widely used clinically in combination with IQ to evaluate functional intelligence and has been shown to have test retest reliability, internal consistency (Sparr ow, Cicchetti & Balla, 2005) and concurrent validity (Perry et al., 1989). VOG system calibration The VOG system was calibrated prior to testing each participant using a laser stimulus projected onto a black screen (60 arc with 76.5 inch radius). The lase r provided a visual target that moved to specified locations + 10 from center (e.g., first

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97 10 to the left, then right, then up and then down). Results were averaged across two trials. Oculomotor screening Oculomotor screening tests were conducted to ru le out any neurological impairment related to ocu lo motor function that would preclude interpreting rVOR eye movements. These tests included: saccade, smooth pursuit and gaze evoked ts as they followed the red laser stimulus through a series of movements for each test (see methods section in Chapter 2 for further detail). Velocity step testing general procedure Velocity step tests were completed in both clock wise and counter clock w ise directions with a ramp up time of 1.2 seconds and a peak velocity of 100/sec. This protocol was repeated across two conditions: (1) in the dark with no visible surroundings and (2) in the dark with a visual fixation suppression LED target provided ins ide the VOG system during and after rotation. Per rotary recordings were taken for 60 seconds, followed by post rotary recordings that lasted as long as nystagmus was occurring up to 60 seconds. Each test was completed once in each direction. However, if one of these two trials was disrupted by excessive blinking, talking, head movement or Data Analysis Pearson product moment correlations were conducted using IBM SP SS Statistics software v. 21 to test for relationships between rVOR time constant in the dark condition or rVOR time constant in the fixation suppression condition and the following functional measures: (1) the Autism Diagnostic Observation Schedule (ADOS; Lord et al., 2000);

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98 (2) the Social Communication Questionnaire (SCQ; Rutter, Bayley & Lord, 2003) ; (3) the Leiter R Brief IQ test (Roid, Miller, & Leiter, 1997); (4) the Physical and Neurological Examination for Soft Signs sum of balance errors (PANESS; D enckla, 1974); (5) the Repetitive Behavior Scale Revised (RBS R; Bodfish et al. 2000); (6) the Sensory Profile Caregiver Questionnaire vestibular processing subscale (Dunn, 1999) and (7) the Vineland II Adaptive Scales (Sparrow & Cicchetti, 1985; Sparrow, Cicchetti, & Balla, 2005). For the rVOR time constants in each of the conditions tested, data from both clock wise and counter clockwise trials were pooled for each ASD participant, since there was no significant difference between th ese conditions within subjects ( paired t tests, p > 0.05 ) Results A Pearson's product moment correlation was conducted to assess the relationship between neuropsychological assessments of autism severity, functional ability and vestibular function as well as the variables o f age and rVOR time constant of decay in two conditions: dark and fixation suppression. All variables included in the analyses were observed to be approximately normally distributed, as tested by Shapiro Wilk's test ( p > .05), except for three measures in cluding: (1) PANESS balance sum of errors ( p = 0.01) which displayed a somewhat bimodal distribution with scores falling between either 0 to 2 total errors or 5 to 8 total errors (see Figure 4 8) ; (2) rVOR TCD in the dark ( p = 0. 0 3) which was slightly posi tively skewed (i.e., skewed towards more errors and longer time constants) and (3) ADOS scores ( p < .05) which were slightly analysi s is somewhat robust to deviations from normality these variables were includ ed in the analysis, but deviations from normality are considered in the interpretation of related results. A summary of

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99 1. Figures 4 1 to 4 8 provide scatterplots of all neuropsychological and rating scale assessments to illustrate their relationships with time constant of decay in the dark condition as well as time constant of decay with fixation suppression. Dark Condition rVOR Time Constants The only neuropsychological assessment that demonstrat ed a significant relationship with rVOR time constant in the dark was the PANESS subscales for balance errors. There was a positive correlation between the sum of balance errors scores on the PANESS and time constant of decay for rVOR in the dark, r (14) = .587, p < .017. Fixation Suppression Condition rVOR Time Con s tants Only one significant association was observed between neuropsychological and rating scale measures and the time constant of rVOR in the fixation suppression condition. A s ignificant negat ive correlation was observed between rVOR time constants during fixation suppression and Vineland II Adaptive Scales, r (14) = .545, p = .029. Non significant but marginal correlations include d : (1) a negative correlation with Leiter Brief IQ, r (14) = .43 4, p = .093; (2) a negative correlation with RBS R Stereotypy Subscales, r (14) = .442, p = .099 and (3) a positive correlation with the sum of balance errors on the PANESS, r (14) = .445, p = .084. Associations among Neuropsychological and Standard Rating Scale Assessments Significant positive correlations were found between the three following pairs of neuropsychological assessments: (1) Sensory Profile and ADOS, r (14) = .546, p = .029; (2) Vineland II and IQ, r (14) = .597, p = .015; and (3) RBS R and SC Q, r (12) = .565, p =

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100 .035. Significant negative correlations were observed between the four following neuropsychological assessments: (1) Age and IQ, r (14) = .592, p = .016; (2) Vineland II and Age, r (14) = .587, p = .017; (3) RBS R and ADOS, r (13) = .5 34, p = .040 and (4) a very strong negative correlation between Sensory Profile and RBS R, r (13) = .835, p < .005. Vineland II and SCQ exhibit a marginal negative correlation that approaches but does not reach significance, r (14) = .470, p = .077; Discu ssion Laboratory tests of rVOR deficits (Ritvo et al., 1969; Ornitz et al., 1974; Ornitz et al., 1985; Chapter 2 of current studies) and postural control (i.e., vesitublo spinal) deficits (Minshew et al., 2004; Molloy, Dietrich & Bhattacharya, 2003) have b een reported in ASD. However, the implication of these findings and their relationship to other functional abilities of children with ASD remains unclear. For the current study, it was anticipated that significant relationships would be evident between la boratory test results of rVOR aberrations in ASD and the following functional measures: vestibulo spinal function tests of balance, parent report of vestibular processing and neuropsychological assessments of ASD symptom severity and functional ability. R e lationships were observed between rVOR time constant of decay and vestibulo spinal/balance function as well as measures of functional adaptive skills. These results indicate that there may be vestibular processing deficits in ASD that include vestibulo ocu lar as well as vestibulo spinal dysfunction and that these two functional deficits may be related in ASD. The current study also demonstrates that rVOR deficits in ASD may be related to other measures of functional ability such as adaptive function. It is interesting to note that rVOR time constant of decay in the dark and time constant of decay with fixation suppression were not correlated with one another in the current

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101 study. Furthermore, it is interesting to note that the fixation suppression time const ant was significantly correlated with Vineland II Adaptive Scales and marginally correlated with Leiter R Brief IQ, RBS R and the PANESS balance scores, whereas, the dark time constant was only significantly correlated with PANESS balance error scores with no marginal correlations to any of the other measures. This may indicate that the fixation suppression condition would be a better candidate for further study as a potential bio behavioral marker. Vestibular Function Measures: rVOR Time Constants, PANESS Balance Errors and Sensory Profile Vestibular Processing Subscale Vestibulo ocular and vestibulo spinal function The Physical and Neurological Exam of Soft Signs (PANESS; Denckla, 1974) is a pediatric measure of neurologic motor function. In the current study, PANESS balance error scores were strongly positively correlated with time constants of decay for rVOR in the dark condition and marginally positively correlated with time constant during fixation suppression testing. As PANESS balance errors increa sed so did the rVOR time constant of decay (i.e., increasing time constants indicate central rVOR processing deficits). This connection between measures of vestibulo spinal (i.e., PANESS balance errors) and VOR function (i.e., time constant of decay) in AS D indicate that there may be a global vestibular processing deficit affecting both the vestibulo ocular and vestibulo spinal function in ASD and may share a common neurobiological basis. Parent report of vestibular processing and direct measures of vestib ular function Often in pediatric rehabilitation, the first step for evaluating sensory processing deficits is One measure, the Sensory Profile Caregiver Questionnaire (Sensory Profile; Dunn, 1999), is

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102 commonly used as a screening tool to evaluate adaptive behavioral responses to sensory stimuli. The Sensory Profile provides an indication to therapists that sensory processing deficits exist and may warrant further testing. It is also used as a guide for sensory integration treatment planning. The Sensory Profile provides information about including the domain of vestibular processing. The vestibular proce ssing subscale of the Sensory Profile provides a parent report of non adaptive behavioral responses to various vestibular sensory stimuli encountered in daily activities. Since this is often the first step in evaluating sensory processing deficits, it woul d be useful to know if parent report of Sensory Profile is correlated with direct measures of vestibular function in children with ASD such as postural control/balance or VOR function. According to the Sensory Profile scoring package, the group mean for th e Although the sensory profile is a parent report, it is often used clinically in Occupational Therapy as the first screening too l or indication that a sensory processing deficit exists. Therefore, i t is surprising then that the current study found no statistically significant relationships between the vestibular processing subscale of the Sensory Profile and either of the rVOR meas ures or the balance measure Although not statistically significant, it is noteworthy that the vestibular processing subscale of Sensory Profile was slightly positively correlated with the following three vestibular function measures: (1) the PANESS balanc e error subscale, r (14) = .354, p = .178; (2) the rVOR time constant of decay in the dark, r (14) = .354, p = .179; and (3) the rVOR time constant of decay in the fixation suppression condition,

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103 r (14) = .373, p = .155. The lack of significant findings may h ave been due to a small sample size and lack of sufficient power to pick up on this relationship. However, in a previous study with the same sample of children all three of these vestibular processing related variables were significantly different between ASD and typically developing controls (Chapter 2). Additionally, a larger study with 103 children and adults age 3 to 43 with ASD showed a significant difference between ASD and typically developing controls on the vestibular processing subscale of the Sen sory Profile (Kern et al., 2007). Thus, it appears that although the vestibular subsection of the Sensory Profile is able to demonstrate differences between ASD and controls, it may not be related to direct measures of vestibular function in this populatio n. Further studies with a larger sample size should be conducted before ruling out the possible relationship between the vestibular subsection of the Sensory Profile and direct measures of vestibular function. IQ and vestibular function No significant corr elations between IQ and rVOR were found. However, although not significant, IQ was marginally negatively correlated with time constant of decay for rVOR fixation suppression. If such a relationship did exist, the direction of this correlation indicated tha t as IQ increased fixation suppression rVOR time constant decrease d meaning that as level of intelligence increase d the ability to use visual fixation to suppress rVOR post rotary nystagmus improve d This relationship may indicate that central processin g deficits in rVOR are related to defici ts in using higher order processing function in ASD. It is also possible that those participants with lower IQ have greater difficulty attending to task and therefore, fixating on the visual target. However, as pr eviously described in Chapter 2, there was no significant difference in gain between the two

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104 groups for this condition (i.e., both groups demonstrate d decreased gain during fixation suppression). Therefore, we are fairly confident that both groups were ind eed fixating on the visual target during testing, as such a decrease in gain would not occur otherwise. Intercorrelations among Neuropsychological and Standardized Rating Scale Assessments Symptom severity: ADOS, SCQ and RBS R Autism is diagnosed based on functional deficits within three behavioral domains: social skills, communication skills and restricted, repetitive behaviors. The ADOS is considered the gold standard for diagnosing ASD and the SCQ is often used as a parent report screening tool to aid i n the diagnosis of ASD. The SCQ and total score from the RBS R provide measures of the three diagnostic domains for ASD including: deficits in communication skills and social skills (SCQ) and excess restricted, repetitive behaviors (RBS R). In the current study, ADOS scores were negatively correlated with motor stereotypy subscale scores of the RBS R. Both measures provide scores that increase as an index of greater dysfunction and would be expected to be positively correlated (i.e., severity of ASD increa ses as motor stereotypies severity increases). However, in the current study, the negative correlation indicates that as the severity of ASD symptoms increases, the severity of stereotypies decreases. Similarly, ADOS scores were positively correlated with the vestibular subscale of the Sensory Profile. Higher Sensory Profile scores indicate more adaptive behavior (i.e., less dysfunction). Therefore, it is expected that as ASD severity increases, vestibular processing scores should indicate greater dysfunct ion (i.e., decrease). However, according to the positive relationship found in the current study, as autism severity

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105 increases, the parent report of adaptive behavioral responses to vestibular stimuli improves. These two unexpected directional relationshi ps are not consistent with the literature that suggests that children who are more severely affected display a greater incidence of stereotypic behaviors (Bodfish, Symons, Parker & Lewis, 2000; Michelotti, Charman, Slonims & Baird, 2002; Morgan, Wetherby & Barber, 2008). It may be possible that there is a distinction between ASD severity and movement related vs. cognitive related restricted, repetitive behavior. Additionally, these findings could be an artifact of only using stereotypy subscale scores of th e RBS R and Sensory Profile rather than the full scales. Additionally, the current study recruitment targeted high functioning somewhat older children with ASD; therefore, it is possible that motor stereotypy sub scales may be relatively low in this group compared to younger children with ASD. Among other things, this could lead to a truncated range for these subscales, which could possibly generate spurious correlations. Therefore, it is difficult to make any conclusions based on these results at this time Surprisingly, correlations between ADOS and SCQ scores were very low. It is unclear as to why a strong relationship between ADOS and SCQ was not observed since both of these diagnostic tools are primarily focused on the social and communication aspects of the ASD triad. Although the current study did not account for presence or absence of language delay, only 2 participants exhibited limited verbal communication skills. Therefore, it is possible that the current group was skewed towards the higher functi oning range and/or had a high percentage of children with It is also

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106 possible that the lack of correlation between these measures is related to the fact that the SCQ is a parent report o the lifespan and the ADOS research setting over a few hours of observation The RBS R and SCQ in combination provide information about al l three of the ASD core diagnostic behavioral domains including restricted repetitive behaviors and social/communication skills respectively. In the current study, the stereotypy subscale of the RBS R was found to be positively correlated with SCQ total sc ores, meaning that as movement stereotypies become more severe, so do social/communication skill deficits. These results may provide support for the combination of the RBS R stereotypy subscale and full scale SCQ as a potentially useful parent report batte ry to index the severity of ASD symptoms. It is unclear at this time whether or not these relationships would exist between the full scale RBS R and SCQ measures. The strongest correlation observed in the current study arose between the vestibular subscal e of the Sensory Profile and the stereotypy subscale of the RBS R. Since the stereotypy subscale of RBS R was designed to collect parent reports of restricted, repetitive behaviors specific to ASD, 3 out of 5 of which result in vestibular stimulation, it w as reasonable to assume that vestibular stimulating movement stereotypies would be related to some measure of vestibular function. However, the current study did not find any significant relationship between the stereotypy subscale of the RBS R and direct measures of vestibular function such as rVOR time constant or balance errors. It is possible that vestibular function has no bearing on these stereotypies and that these repetitive behaviors are propagated by another

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107 physiological process. There was, howev er, a significant positive relationship between the two parent report measures: the Sensory Profile vestibular subscale and the stereotypy subscale of the RBS R, demonstrating that there is some consistency within parent reports of vestibular related movem ent behavior in ASD. Taken together, these results suggest that the stereotypy subscale or the RBS R and the Sensory Profile vestibular processing subsection are more related to vestibular related restricted, repetitive behaviors rather than actual vestibu lar function in this group. This finding is consistent with the current use and interpretation of the RBS R stereotypy subscale, but is inconsistent with the current use of the Sensory Profile vestibular subscale as an indicator of vestibular sensory proce ssing function. Functional ability: Leiter Br i ef IQ and Vineland II Adaptive Scales Vineland II Adaptive Scores and Leiter Brief IQ scores were positively correlated meaning that as IQ increased, so did functional adaptive skills. This relationship betw een these two measures was expected since the combination of these measures is often useful for determining presence or absence of developmental delays and intellectual developmental disabilities Previous studies have also demonstrated a strong correlatio n between IQ and age with adaptive skills in ASD (Kanne et al., 2010). Age and IQ as well as Age and Vineland II Adaptive Scales were negatively correlated such that as age increased in these individuals with ASD, IQ and adaptive skills decreased. Althoug h not significant, the Vineland II Adaptive Scales and SCQ total scores also exhibited a moderate negative correlation. These relationships between the Vineland II and these two measures follow an unexpected pattern of social and communication skills incre asing while adaptive skills decrease. This unexpected pattern of findings may indicate that deficits in adaptive function fail to improve as development

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108 continues in this population or that the deficits in adaptive function are magnified as development con tinues in this population. This concept has been presented previously in a larger study of children with ASD and measures of Vineland II Adaptive Skills demonstrating that as age increases in ASD, the gap between mental age and adaptive skills increases; i .e., deficits become more apparent in this population (Kanne et al., 2010; Klin et al., 2007). Summary Taken together, the results of the current study indicate that there was a strong correlation between measures of vestibulo spinal (i.e., balance) defici ts and rVOR TCD (only in the dark condition) in ASD indicating that central vestibular processing dysfunction does exist in this population and that these two systems may share common central processing deficits. The current study further demonstrated tha t IQ and adaptive function are also related to deficits in rVOR fixation suppression in ASD and that rVOR suppression deficits may be related to higher order central processing deficits in ASD. A lack of any significant relationship between Sensory Profile vestibular processing subscales and direct measures of vestibular function is surprising and warrants further study. The RBS R movement stereotypy subscale however, d id appear to be related to direct measures of rVOR fixat ion suppression deficits in ASD. The results of the current study may inform pediatric clinical rehabilitative practices for screening and assessment of vestibular processing deficits in ASD as well as future research studies of the neurological mechanisms underlying vestibular processin g deficits in ASD. The results of the current study may help to provide direct assessments that can accompany and strengthen current parent report measures of assessing sensory

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109 processing in ASD. Alternatively, these finding s may help to develop a vestibu lar processing parent report questionnaire with revised prompts to improve predictive validity for direct measures of vestibular function. Limitations and Future Studies Questions remain as to whether increased rVOR time constant of decay during the dar k and visual fixation suppression conditions are specific to ASD as a whole, specific to subgroups within ASD, or specific to developmental disabilities in general. The current studies demonstrate that IQ and adaptive skills are positively correlated with both of these measures of deficits in rVOR function in ASD. Although the current study included one child with an IQ below 70, little is known about rVOR function in lower functioning individuals with ASD. It would be interesting to know whether lower func tioning individuals would further strengthen this correlation and demonstrate a greater increase in rVOR fixation suppression. One extension of the current findings could involve testing visual fixation suppression in lower functioning individuals with ASD The available physiological research literature in this subgroup of individuals with ASD is limited, likely due to the added methodological challenges and reduced compliance associated with this population. Many of these challenges are due to communicati on deficits, however, and with added precautions can be ameliorated. Testing this population of individuals who are lower functioning or non verbal may require modification of protocols such as the addition of augmentative alternative communication options for participants to use to indicate their assent to participate and whether or not they understand instructions for looking at the target during visual fixation or for tilting forward during tilt suppression testing. In other studies in our lab, the addit ion of a training video that visually illustrates

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110 a participant going through the entire testing procedure has been proven to be helpful in preparing non verbal or lower functioning participants for testing. For clinical purposes, it is often assumed tha t a relationship exists between process sensory input. The current study did not find a significant correlation between the vestibular processing subscale of the Sensory Profile and direct measures of vestibular dysfunction in ASD. Therefore, questions arise as to whether the vestibular subscale of the Sensory Profile is measuring behavioral characteristics or preferences of children or true sensory processing deficits I t is also interesting to note that the vestibular subscale of the Sensory Profile was negatively correlated with the movement stereotypy subscale of the RBS R. Thus, the vestibular subscale of the Sensory Profile may be measuring behaviors that are more ak in to motor stereotypies in ASD rather than symptoms of vestibular processing dysfunction per se. It remains a possibility that movement stereotypies in ASD are related to vestibular processing deficits, however, this relationship was not observed in the c urrent study. Future studies should aim to investigate the level of face validity or predictive validity for sensory processing subscale results of the Sensory Profile by comparing each of these subscales to direct observations or functional measures of ta ste, tactile, auditory and visual processing and to clarify for practitioners whether definite differences in these areas are due to behaviorally based or physiologically based sensory processing deficits. If the vestibular subscale of the Sensory Profile is truly not related to direct measures of vestibular function, future studies should aim to establish parent report measures of sensory processing that exhibit a clear relationship to physiological

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111 assessments of sensory processing. An established connec tion between parent screeners and further physiological testing would be very useful to clinicians as a pediatric sensory processing evaluation tool. The rVOR is highly modifiable and amenable to rehabilitation. Thus, improvements in pediatric assessment and treatment planning in this area could have a large impact on clinical practice and functional outcomes for these children with ASD.

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112 Table 4 1. Pearson Correlation Summary Table for Neuropsychological Assessments and rVOR Time Constant of Decay in t he Dark and with Fixation Suppression. Significant positive correlations are highlighted in yellow and significant negative correlations are highlighted in blue. Pearson Correlation Statistics for Neuropsychological Assessments and Time Constant of Deca y (TCD) Age Leiter IQ Vineland II ADOS SCQ RBS R 1 Sensory Profile 2 PANESS 3 TCD Dark TCD Supp. TCD Dark .253 .229 .087 .246 .157 .367 .354 .587 ____ TCD Supp. .407 .434 .545 .154 .196 .442 .373 .445 .267 ____ Correlation is s ignifica nt at the 0.05 level 1 RBS R Stereotyped Movement subscale only 2 Sensory Profile Vestibular Processing subscale only 3 PANESS Balance sum of error scores only

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113 Table 4 2. Pearson Correlation Summary Table for Neuropsychological Assessments. Sig nificant positive correlations are highlighted in yellow and significant negative correlations are highlighted in blue. Pearson Correlation Statistics for Neuropsychological Assessments Age Leiter IQ Vineland II ADOS SCQ RBS R 1 Sensory Profile 2 PANE SS 3 Age ____ Leiter Brief IQ .592 ____ Vineland II .587 .597 ____ ADOS .022 .009 .313 ____ SCQ .396 .202 .470 0.137 ____ RBS R 1 .077 .192 .116 .534 .565 ____ Sensory Profile 2 .009 .277 .227 .546 0.43 835 ** ____ PANESS 3 .218 .300 .124 0.275 0.174 0.305 0.354 ____ Correlation is significant at the 0.05 level ** Correlation is significant at the 0.01 level 1 RBS R Stereotyped Movement subscales only 2 Sensory Profile Vestibular Processing subscale only 3 PANESS Balance sum of error scores only

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114 Figure 4 1. Scatterplots of age (in months) and time constant of decay (in seconds) in the dark condition and fixation suppression condition.

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115 Figure 4 2. Scatterplots of Leiter R Brief IQ (composite scores) and time constant of decay (in seconds) in the dark condition and fixation suppression condition.

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116 Figure 4 3. Scatterplots of Vineland II Adaptive Behavior Scales (composite scores) and time constant of decay (in sec onds) in the dark condition and fixation suppression condition.

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117 Figure 4 4. Scatterplots of Autism Diagnostic Observation Schedule (ADOS) composite scores and time constant of decay (in seconds) in the dark condition and fixation suppression condi tion.

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118 Figure 4 5. Scatterplots of Social Communication Questionnaire (SCQ; total score) and time constant of decay (in seconds) in the dark condition and fixation suppression condition.

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119 Figure 4 6. Scatterplots of Restricted Repetitive Be havior Scale Revised Stereotypy Subscale Total Score and time constant of decay (in seconds) in the dark condition and fixation suppression condition.

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120 Figure 4 7. Scatterplots of Sensory Profile (SP) Vestibular Processing Subscale Score and time constant of decay (in seconds) in the dark condition and fixation suppression condition.

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121 Figure 4 8. Scatterplots of Physical and Neurological Exam of Soft Signs (PANESS) Balance Error Subscale Total and time constant of decay (in seconds) in the d ark condition and fixation suppression condition.

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122 CHAPTER 5 ABNORMAL QUALITY OF THE ROTATIONAL VESTIBULO OCULAR REFLEX IN AUTISM SPECTRUM DISORDERS The primary measures of the rotational vestibulo ocular reflex (rVOR) include time constant of decay, gain and symmetry. Each of these parameters provides information about the functional ability of the peripheral vestibular anatomy or the central processing of vestibular sensory information via the brain stem and cerebellum. However, abnormalities in rVOR eye movements beyond these standard rVOR measures have been noted in children with autism spectrum disorders (ASD) and may be informative for better understanding the neurobiology of rVOR function and/or oculomotor function in this population. Evidence for suc h differences in rVOR are sparse in the available literature, however, and are often presented as a simple side note or post hoc observation s (Ritvo et al., 1969; Ornitz et al., 1974; Ornitz et al., 1985) or not mentioned at all (Goldberg et al., 2000). Th erefore, further evaluation of the quality of rVOR eye movements is warranted to clarify if these abnormalities exist in this population and if so, to better characterize and define them. Number of Nystagmus Beats The first abnormality of rVOR that has b een previously noted in ASD is a reduction in the number of post rotary nystagmus beats, nystagmus that occurs after rotation has ceased. Two studies reported a decreased frequency of post rotary nystagmus beats in ASD compared to controls (Ornitz et al., 1974; 1985). Ornitz et al. (1985) suggested that this decrease in the number of beats may be due to an observed in the ASD group.

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123 Slow Phase Irregularity The second abnormal feature of rVOR previously noted in ASD is an irregularity in the slow phase of nystagmus eye movements. The slow phase component of nystagmus is the most informative characteristic for identifying underlying disorders (Leigh & Zee, 2006). Ornitz et al. ( 1985) found no difference in rVOR gain between ASD and controls suggesting that ASD participants demonstrate d normal cerebellar flocculus modulation of rVOR. Nonetheless t hey did report abnormal characteristics of rVOR nystagmus eye movements, such as ab errations in slow phase velocity and increased incidences of slow phases that failed to be followed by a quick phase in the opposite direction. The authors quick phases may be a result of brainstem dysfunc tion, particularly with regard to coordination between pontine reticular formation control of quick phases and vestibular nuclei control of slow phases (Ornitz et al., 1985). Since no follow up studies have been conducted it remains unclear as to whether o r not these results are replicable and what neurobiological insights into ASD they may provide. Vertical Eye Movement Intrusions The third rVOR abnormality of vertical eye movement intrusions have not been reported by the previous studies mentioned above These aberrations in rVOR have only been noted by our lab and were observed in a preliminary study conducted in preparation for the current project. In this pilot study with three children with ASD and three typically developing children age 7 to 10 year s, we observed vertical eye movement intrusions occurring concomitantly with horizontal rVOR. These vertical intrusions occurred significantly more often in the ASD group (26.67 + 4) than the typi cally developing controls, 9.61 + 3; Mann Whitney U, p = 0.0 01. However, n o

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124 significant difference in the occurrence of horizontal eye movements between groups was noted, Mann Whitney U, p = 0.35. Furthermore, these vertical intrusions were clearly visible such that novice, blind observers (n=17) were able to corre ctly identify 4.88 ( + + 1.09) of 6 ASD videos as 1). The previously cited studies noting abnormalities in number of beats and slow phase duration were conducted using electro oculograp hy (EOG) to record eye movements. Often when using this technique, movements in the vertical channel are dis carded as noise or eye blinks. Thus vertical eye movements may have been present in previous studies but not detected Without a visual recording of the eye movements as a reference, these vertical eye movement excursions were eliminated as artifact. Therefore, it would be beneficial to measure these eye movements using videooculography (VOG) or video recordings. The primary objective of the prese nt study was to replicate and extend the earlier findings of aberrations in rVOR noted by Ritvo et al. (1969), Ornitz et al. (1974) and Ornitz et al. (1985) using videooculography techniques to better characterize differences in rVOR in the dark beyond sta ndard measures of gain and time constant of decay. Based on prior studies (Ritvo et al., 1969; Ornitz et al., 1974; 1985), it was expected that the ASD group would exhibit fewer post rotary nystagmus beats than the control group. Our preliminary study sugg ested that the ASD group would also exhibit a greater number of vertical eye movement intrusions and greater number of abnormal horizontal slow phase eye movements. The current study also aimed to provide findings

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125 useful for generating hypotheses about wha t neurobiological differences in this population may serve as the basis for such qualitative differences in rVOR. Methods Participants and Recruitment For the current study, children diagnosed with autism spectrum disorders (n = 16) and typically developin g children (n = 17) ages 6 12 were recruited from the University of Florida Center for Autism and Related Disabilities (UF CARD), public schools and pediatric therapy centers within Alachua county. ASD diagnoses included: Autism ervasive Developmental Disorder Not Otherwise Specified. Diagnoses were confirmed by assessments administered by a clinical psychologist including the Autism Diagnostic Observation Schedule (ADOS; Lord et al., 2000) and the Social Communication Questionn aire (SCQ; Rutter, Bayley & Lord, 2003). Children in the ASD group with diagnoses of Fragile X, Rett Syndrome, tuberous sclerosis, seizure disorder or fetal cytomegalovirus infection were excluded from the study. Children in the typically developing group with any current or past history of psychiatric disorders were excluded from the study. Intelligence quotients were obtained for both groups via the Leiter R Brief IQ test (Roid, Miller, & Leiter, 1997). Testing Equipment Rotary chair testing was complet ed using a computer controlled, motorized rotary platform and binocular video oculography goggle (VOG) system. The motor, control system, software and video oculography goggles were manufactured by Neuro Kinetics Inc (NKI). The seating system was created b y the authors for pediatric use and includ ed a small, padded chair, safety harness and head stabilizers with occipital head rest and temporal stabilizing arms to prevent head movements and allow en bloc rotation of head

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126 and body (Figure 2 1, Chapter 2).The I Portal TM Video Oculography Goggle (VOG) System was used to record rVOR eye movements during velocity step testing and VEST TM 6.8 Software was used to analyze oculomotor screening and rVOR testing eye movement data. Additionally, we used live screen shot video recordings to observe eye movements visually during testing. Such video documentation of the eye movements are not typically included with VOG recordings, however, due to the vertical intrusions previously noted in our pilot study, we elected to rec ord that additional information. Procedure VOG System Calibration. The VOG system calibration was conducted prio r to testing each participant. The c alibration procedure involved projecting a laser stimulus onto a black screen (60 arc with 76.5 inch radius ). The laser provided a visual target that moved to specified locations + 10 from center (e.g., first 10 to the left, then right, then up and then down). Results were averaged across two trials. This procedure takes approximately 5 to 10 minutes to compl ete. Oculomotor Screening. Following VOG calibration, oculomotor screening tests were conducted to rule out any neurological impairment related to ocu lo motor function that would confound interpret at i on of rVOR eye movements. These tests included: saccade, smooth pursuit and gaze evoked nystagmus tests. For these assessments the participant was seated in the rotary chair with their head fixed in place (see Figure 2 1) while wearing the VOG system to record their eye movements as they followed a red laser st imulus through a series of movements specific to each test (see methods section in Chapter 2 for further detail). This procedure took approximately 10 15 minutes with up to 5 scheduled breaks as needed for each participant.

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127 Velocity Step Testing General P rocedure. Velocity step tests were completed in both clock wise and counter clock wise directions in the dark. Participants were seated and secured to the pediatric rotary chair while wearing the VOG system to record eye movements. Each trial began with a ramp up time of 1.2 seconds to a peak velocity of 100/sec ond for 60 seconds followed by a rapid deceleration to zero. Per rotary eye movement recordings were taken for 60 seconds, followed by post rotary recordings for up to 60 seconds or until nystagmus ceased. For each participant th ree phases of testing occurred. For phase 1 one trial was complete d in the clock wise direction. P hase 2 was a 60 second break which was provided while the participant remain ed seated in the rota ry chair and was engaged in s pace themed games. F inally phase 3 involved a second trial which was completed in the counter clock wise direction. If one of these two trials was disrupted by excessive blinking, talking, head movement or the child requesting a break, a 60 second break w as provided and the including providing the participant with instructions, two trials of rotation and 1 to 2 scheduled breaks took approximately 10 to 15 minutes to c omplete. Data Analysis Methods for analyzing number of post rotary nystagmus beats Post rotary nystagmus beats were counted manually by a research assistant using eye movement tracings provided by NeuroKinetics, LLC VEST TM 6.8 Software. A post rotary nyst agmus beat was defined as a slow phase eye movement in the direction of rotation for that trial (i.e., clock wise or counter clock wise) followed by a quick phase reset eye movement in the opposing direction. The number of post rotary nystagmus beats for c lock wise and counter clock wise trials were compared for each participant

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128 using paired t tests. This comparison was made to test for asymmetries between trials prior to pooling the data from these two trials for each participant. No difference between tri als within subjects was found ( p = .28), therefore clock wise and counter clock wise trials were pooled and a mean number of nystagmus beats was entered for each subject. An independent samples t test was conducted to compare the mean number of post rotary nystagmus beats between groups. Development and testing of a quantitative method for analyzing temporal dynamics of slow phase irregularity and vertical intrusions Tracings of post rotary nystagmus in the horizontal plane for three TD children (see Figur e 5 2) depict the rhythmicity or regularity of these eye movements. The slower excursions followed by relatively fast reset generates the saw tooth pattern depicted in Fig. 5 2. Based on these tracings, we explored (and continue to assess) the application of several statistical models designed to uncover the temporal structure in these time series and provide estimates of periodicity or regularity. These measures can then be used to quantify differences in the temporal dynamics of eye movements between the ASD and TD groups. We hypothesized that the horizontal eye movements of children with ASD would be less regular or periodic compared to TD children. Approximate Entropy (ApEn) One potentially useful statistical model to apply to these data would be Appro ximate Entropy or ApEn. The ApEn analysis is designed to provide an index of regularity that can be derived from relatively short and noisy time series (Pincus et al., 1991). ApEn requires at least 1000 data points for analysis and its output provides an i ndex of the level of regularity of a time series that ranges from 0 to 1 with 0 indicating perfect periodicity to 1 being completely random. ApEn was explored

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129 using one trial of velocity step testing from one participant from the ASD group and one from the TD group. This provide d an exemplar of the utility of this statistical approach. Spectral Analysis. A second approach to quantifying the temporal dynamics of these eye movements would be to use spectral analysis. Unlike ApEn, which is conducted in the tim e domain, spectral analysis involves a transformation to the frequency domain. Spectral analysis assesses the temporal dynamics of a time series by deconstructing the time series into a set of constituent frequency bandwidths and depicting how much of the total variance in the time series is accounted for by each frequency bandwidth. Data from one participant from each group was used to test each of these methods and the results from these preliminary analyses are presented. Spectral analysis was explored u sing comparison of peak frequency and f95 statistics (the range of frequency bandwidths needed to capture 95% of the variance in the time series) of one trial of velocity step testing from one participant from the ASD group and one from the TD group. The presence of vertical eye movements during what should be essentially horizontal rVOR eye movements may result in interference of these horizontal eye movements and may lead to a disruption in the temporal dynamics of rVOR. For instance, what is typically a periodic series of subsequent nystagmus beats with a saw tooth pattern of slow phase eye movement in one direction followed by a quick phase reset in the opposite direction in the horizontal plane becomes an irregular (or less regular pattern) of nystagmu s beats with changes in the temporal dynamics extended by vertical eye movements occurring concomitantly. This hypothesis can be tested in

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130 future analyses by applying variants of both ApEn (cross ApEn) and spectral analysis (cross spectral). Results Numbe r of Post rotary Nystagmus Beats There was no statistically significant difference in the number of post rotary nystagmus beats between groups, p = 0.94 (Table 5 1). Although both groups had similar mean number of beats (ASD = 46.25 and TD = 45.85), the AS D showed a larger standard deviation (ASD = 18.34 and TD = 10.90; see Table 5 1 for a summary of results). Slow Phase Irregularity Figure 5 2 depicts tracings of post rotary nystagmus eye movements in the horizontal plane for three typically developing c hildren. These tracings exemplify the repetitive pattern of slow phase followed by quick phase eye movements resulting in a saw tooth pattern with roughly equal amplitude and linear acceleration slopes. Figure 5 3 depicts tracings of post rotary nystagmus eye movements in the horizontal plane for three participants with ASD. These representative samples illustrate the irregular slow phase eye movements and disrupted horizontal rVOR nystagmus beat patterns seen in the ASD group. Slow phase irregularities wer e characterized by increased duration of slow phase eye movements with altered slopes (i.e., arcing slopes with changing acceleration rather than flat lines indicating consistent acceleration). Figures 5 2 and 5 3 represent short periods (3 to 5 seconds) o f the full post rotary nystagmus sequence which may last up to approximately 20 to 30 seconds in the dark. Each image illustrates the position of the eye over time for a single participant. The x axis represents the time domain and the y axis represents th

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131 rightward movement and negative values indicate leftward movement. For trials of clock wise rotation, the post rotary nystagmus should present with slow phases to the right (i.e., up or positive direction ) and quick phases to the left (i.e., down or negative direction) and vice versa for counter clock wise trials where slow phases move to the left (i.e., down or negative direction) and quick phases to the right (i.e., up or positive direction). Vertical E ye Movement Intrusions The tracings for both horizontal and vertical recordings of post rotary rVOR are presented in Figures 5 4 for the TD group and in Figure 5 5 for the ASD group All of the examples in Figure 5 4 and 5 5 are taken from the same subject s as the examples provided in Figures 5 2 and 5 3 (i.e., horizontal eye movements only). The images in Figures 5 4 and 5 5 include four lines that run in two pairs: one pair of lines represents both eyes in the vertical plane and the other pair represents both eyes in the horizontal plane. The pair of lines representing the pair of eyes should be yoked or move in parallel as can be seen in each of these examples. When both directions of eye movement (horizontal and vertical) are plotted together in this man ner, it is clear to see that vertical eye movements accompany the horizontal rVOR anomalies (see Figure 5 4 and 5 5). Figure 5 5 illustrates the horizontal rVOR slow phase irregularities observed in the ASD group and the vertical excursions that were not observed in the TD group. Figure 5 5 also illustrates the potential influence of vertical eye movements on the periodicity, trajectory and duration of horizontal rVOR slow phase eye movements in the ASD group.

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132 Preliminary Results from Temporal Dynamics Ana lysis Approximate Entropy (ApEn). In order to assess the utility of Approximate Entropy (ApEn) to capture the regularity in the post rotary horizontal eye movements, we subjected data from one TD group participant and one ASD group participant to this mode l for comparison purposes. As can be seen in Figure 5 6, the ASD participant demonstrated a higher level of complexity or irregularity (ApEn = 0.24) compared to the TD participant whose horizontal eye movements show a high degree of regularity (ApEn = 0.07 ; Figure 5 6). Spectral Analysis. Spectral analysis was used as a second potential strategy for capturing group differences in the periodicity of horizontal eye movements. Therefore, we used the data from the same two subjects (one TD participant and one ASD participant) for spectral analysis that were used to calculate ApEn. Spectral plots for 7) and vertical (Figure 5 8) plane show that in both planes of movement, the variance in the time serie s of the ASD participant was distributed over a greater range of frequency bandwidths. In contrast, the variance in the time series associated with the TD participant was largely captured by a single frequency bandwidth indicating a much higher degree of pe riodicity in the eye movements. T here was no difference between the ASD participant and the TD participants in the peak frequency of horizontal eye movements. The ASD participant, however, demonstrated a higher peak frequency (0.07) than the TD participa nt (0.02) for eye movements in the vertical plane (Figure 5 9). The ASD participant also had a higher f95 value (2.75), the frequency that accounts for 95% of the total power spectrum, than the TD participant (0.51; Figure 5 10) indicating that the ASD par ticipant

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133 required a much larger range of frequency bandwidths to account for 95% of the total variance in the time series. Discussion The present study sought to characterize key features of the eye movements associated with post rotary nystagmus in TD an d ASD participants. One aim was to establish the presence of aberrant vertical excursions in the eye movements of the ASD children. We also sought to establish the utility of two time series analyses to determine if they could capture salient features of t hese eye movements including their regularity or periodicity. No difference was found between ASD and TD participants in the number of post rotary nystagmus beats. There does appear to be a difference between groups, however, in the temporal dynamics of po st rotary nystagmus. Specifically, the TD participants exhibited a regular or periodic pattern in their horizontal eye movements whereas the ASD group exhibited considerably more irregular horizont al rVOR. This may be a result of the influence of vertical eye movements on horizontal rVOR. The difference in the regularity of the horizontal eye movements between ASD and TD children was captured nicely by both ApEn and spectral analyses. Number of Post rotary Nystagmus Beats There is conflicting evidence of de creased nystagmus beats in ASD in the literature. Ornitz et al. (1985) found a significant decrease in the number of beats in the ASD compared to the TD group when tested in the dark. However, an earlier study by Ornitz et al. (1974) with varied lighting a nd visual conditions during rVOR testing found no difference in the number of nystagmus beats between the ASD and TD groups in the dark condition. They did find a significant difference in the number of beats between

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134 groups in the presence of different vis ual fixation stimuli. It is difficult to discern the factor or factors that may account for the inconsistencies in results. Factors such as IQ or other participant demographic characteristics may account for some of the variability and the current study di d not have enough power to investigate such differences. Slow Phase Irregularity Although Ornitz et al. (1985) found no difference in rVOR gain between ASD and controls, suggesting that individuals with ASD demonstrate normal cerebellar flocculus modulati on of rVOR, they did report abnormal characteristics of rVOR nystagmus slow phase eye movements. The current study identified a potentially increased number of slow phase eye movement irregularities in ASD similar to that which Ornitz et al. (1985) describ ed previously but were unable to quantify. Such irregularities included intermittent slow phases with greater amplitude than expected, slow phases that do not promptly result in a quick phase reset eye movement or slow phases with changes in velocity. C ha nges in eye velocity during slow phase are of great interest. In Participant ASD 3, the irregular slow phase is noteworthy in that it exhibits a negative exponential curve. Such decreasing changes in slow phase velocity during spontaneous nystagmus are i ndicative of a dysfunctional neural integrator (Leigh & Zee, 2006) the brainstem neural network that mathematically integrates velocity signals into position signals for gaze stabilization (Arnold & Robinson, 1997) I n this case, however, the deca ying slo w phase velocity appeared to be intermittent (i.e., not evident in surrounding nystagmus beats) in this participant and therefore, may be caused by some other factor. It would be worth investigating whether such exponentially decreasing velocity profiles o ccur in other ASD participants within the study

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135 In light of the representative samples of rVOR tracings presented for comparison and preliminary ApEn and f95 spectral analyse s, it is clear that in this small sample of participants, there is less regulari ty or periodicity in the horizontal rVOR in the participants with ASD. It is not yet clear however, whether this disorganization of the rVOR is due to vertical eye movement intrusions or abnormalities in slow phase eye movements or both. Variants of ApEn ( cross ApEn) and spectral analysis (coherence spectra) may allow us in future studies to assess horizontal vertical coupling of eye movements objectively and quantitatively. If irregular slow phase eye movements do exist in the ASD group it would be interes ting to know whether there are also similar smooth pursuit oculomotor control differences in this population. Vertical Eye Movement Intrusions Typically developing participants exhibited substantially less overall movement in the vertical plane than ASD p articipants. What vertical movement did exist in the TD participants occurred in phase with horizontal nystagmus beats and did not seem to disru pt them. By comparison, the ASD representative examples provided here exhibited greater amplitude of eye movemen ts in the vertical direction and such eye movements occurred concomitantly with the irregularities of the horizontal slow phase eye movements observed in the se ASD participants Therefore, it may be that vertical intrusions in ASD are responsible for influ enc ing or disrupt ing the regular pattern of horizontal rVOR from occurring, whereas this does not appear to occur in the TD participants On e hypothesis for cross coupling of vertical and horizontal eye movements during horizontal rVOR is that there may b e cross talk or abnormal connectivity between the vertical and horizontal oculomotor neural integrators such as the interstitial nucleus

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136 of Cajal (for vertical eye movements), nucleus prepositus hypoglossi paramedian tracts and medial vestibular nucleus ( for horizontal eye movements; Kheradmand & Zee, 2011) Although these sites have not been reported to show morphological differences in ASD, there have been reports of general patterns of abnormal cortical cellular growth pathology such as long range neuro nal under connectivity and short range neuronal over connectivity (Courchesne et al., 2005). This hypothesis would be consistent with short range over connectivity within the brainstem oculomotor neural integrators. Alternatively, more evidence would sugg est that t he increased number of vertical eye movement intrusions noted in the ASD participants may be indicative of cerebellar damage in this population. Patients with diffuse cerebellar lesions can exhibit cross coupling of vertical and horizontal slow p hase eye movements during what should be purely horizontal rVOR (Walker & Zee, 1999; Kim et al., 2005; Moon et al., 2009) such as that observed in the ASD group in the current study. Specifically, cross coupling such as this in response to low frequency st imulation, as was provided in the current study, can specifically be indicative of dysfunction of the velocity storage mechanism of the cerebellum located in the nodulus/uvula, vermian lobules IX and X (Kherandmand & Zee, 2011) Lesions in the nodulus an d uvula (i.e., velocity storage mechanism of the cerebellum) can result in increased time constant of decay (Waespe et al., 1985). Such increases in time constant of decay have been observed in ASD previously when tested in the dark (see Chapter 3; Ornitz et al., 1985). Goldberg et al. (2000) showed a slight increase in time constant of decay in the ASD group, although not statistically significant in their sample, when tested in the dark without tilt suppression stimuli provided.

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137 The most consistently rep orted neuroanatomical abnormalities in ASD are found in the cerebellum and the inferior olivary nucleus of the brainstem (Bauman &Kemper, 2005). Deficits in oculomotor and gross motor adaptation have been attributed to abnormal cerebellar learning in ASD ( Mosconi et al., 2013). Vermian lobules VI and VII have been shown to differ in size (hyperplasic or hypoplasic) resulting in a bimodal distribution of the ASD population (Courchesne et al., 1994). Many post mortem studies have reported decreased size of th e cerebellum and number of Purkinje cells in the cerebellum of individuals with ASD (Ritvo et al., 1986; Bailey et al., 1998; Kemper & Bauman, 2002; Purcell et al., 2001; Lee et al., 2002; Palmen et al., 2004). Decreased Purkinje cells may cause notable ab errations in the VOR including hypo or hyper metric nystagmus, as demonstrated by Hg toxicity in the cerebella of guinea pigs ( Young, Chuu, Liu, Lin Shiau, 2002 ). However, in ASD, intelligence or level of function has been shown to affect the presence or absence of some cerebellar functional or structural difference (Goldberg et al. 2000; Holttum et al. 1992; Piven et al. 1992). Age related morphological changes in the inferior olivary nucleus of the brainstem in individuals with ASD have also been co nsistently reported (Bailey et al. 1998; Palmen, van Engeland, Hof, Schmitz, 2004 ; Bauman & Kemper, 2005). Motor learning in the cerebellum has been proposed to occur at the synapses between Purkinje cells and the climbing fibers that extend from the infe rior olive into the cerebellum ( Leigh & Zee, 2006 ). Since t he inferior olive plays an important role in oculomotor control and vestibular processing future studies of rVOR adaptation in ASD may help to be tter understand the functional e ffects of such deve lopmental changes in these nuclei of the brainstem.

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138 Subtle dysmetria in saccade accuracy has also been observed in individuals with ASD, which may also be related to observations of cerebellar pathology ( Takarae et al., 2004 ). Such abnormal eye movements have also, however, been correlated with abnormal activity in fronto striatal circuitry in ASD (Takarae et al., 2007) areas of the brain that have been l inked to the restrict e d and repetitive behavioral symptoms of ASD (Langen et al., 2007; Lewis et al., 2007). Thus, aberrations in the oculomotor output of the rVOR may be linked to multiple neurobiological areas of interest for ASD including the cerebellar, brainstem and fronto striatal systems and could potentially serve as a model to be tter understand th e functional e ffects of differences in these brain structures in ASD. Future Studies Future studies should be aimed at investigating rVOR and oculomotor function in an effort to determine whether deficits are diffusely dispersed throughout the cerebellum or limited to one region such as the nodulus and uvula. Future studies should also aim to identify whether such deficits are present within the broad autism spectrum or within smaller subgroups such as those with above or below average IQ or presence or ab sence of language delay. High frequency, high acceleration head impulse tests can be conducted to investigate flo c culus/paraflocculus function (Walker & Zee, 1999, 2005a; Shaikh et al., 2011). If children with ASD continue to exhibit cross coupling of ver tical and horizontal movements in response to high frequency rather than low frequency stimuli only (as provided in the current study), this would provide evidence that similar cerebellar deficits may exist within the nodulus/uvula as the flocculus and par aflocculus more diffusely throughout the vestibulocerebellum rather than in one specific region alone.

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139 Furthermore, cross coupling of vertical and horizontal eye movements can also occur during horizontal optokinetic nystagmus (OKN) nystagmus induced by visual motion, and optokinetic after nystagmus (OKAN) the after response of OKN driven by optokinetic velocity storage, with nodular/uvular damage (Walker & Zee, 1999). If vertical and horizontal cross coupling is exhibited in the rVOR in ASD, it would be reasonable to expect that horizontal and vertical cross coupling would exist in OKAN as well. It has been reported that in a sample of 34 children with ASD, 28 exhibited atypical OKN oculomotor response to a hand held rotary drum with stripes (Scharre & C reedon, 1992), however, a thorough analysis of these eye movements has not been conducted and OKAN has not assessed in this population to date. Further investigation of OKN/OKAN in ASD could help to clarify whether deficits in the nodulus and uvula do exis t and to better characterize the oculomotor functions affected. Further exploration of the observation made by Ornitz et al. (1985) describing slow phase eye movements that fail to be followed by a quick phase eye movement should also be explored. One pos sible explanation is increased horizontal saccade latency in ASD reported in Chapter 2 of the current studies For each nystagmus beat a slow phase eye movement should be followed by a quick phase eye movement that resets the eye to center and prepares the eye for the next oncoming visual scene. The quick phase of each nystagmus beat is saccade like meaning that it should have the same movement profile as a saccade and depends on the same circuitry as saccade eye movements. In the current study, the ASD gro up demonstrated significantly greater horizontal saccade latency ( M = 260ms, SD = 60) than the TD group ( M = 210ms, SD = 40) Typical reactive saccade latency is approximately 200ms and saccades typically

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140 last anywhere from 20 to 200ms (Leigh & Zee, 2006). If the latency between the slow phase and the initiation of its quick phase outlasts the typical saccade duration (20 200ms), it is reasonable to suspect that this may result in the quick phase being surpassed by the initiation of the next nystagmus beat (i.e., initiation of the next slow phase) Presumably, this would result in a failure to reset the eye to center and may cause the initial nystagmus beat to have what appears to be an abnormally long excursion, as described by Ornitz et al., (1985). It wou ld be beneficial to evaluate how many of these longer slow phases with failed quick phases occur in the ASD group and whether there is any correlation between horizontal saccade latency and the number of failed quick phase errors in ASD. Lastly, to thoro ughly explore the possibility of nodular/uvular deficits in at least a sub group of the ASD population, tilt suppression tests should be conducted with lower functioning individuals with ASD. Tilt suppression is a phenomenon where pitching or tilting the h ead forward immediately following continuous rotation results in reduced post rotary nystagmus time constant of decay. The nodulus and uvula are important for tilt suppression of rVOR (Hain et al., 1988). In high functioning individuals with ASD, tilt supp ression has been shown to be normal (Goldberg et al., 2000). However, it has been estimated that individuals with lower than average IQ comprise approximately 68% of the ASD population (Yeargin Allsopp et al., 2003). Since the Goldberg et al. (2000) study included only those individuals with high functioning (i.e ., average to above average IQ) it is not clear whether a large percentage of the ASD population may indeed exhibit differences in tilt suppression. Although the current study included both children with above average, average as well as those with below average IQ, there is

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141 not enough power in the current study to evaluate whether there are differences between functional subgroups within the ASD group. Thus, it would be beneficial to test both rVOR in the dark as well as during tilt suppression in low functioning individuals with ASD to evaluate whether there are consistencies in nodulus/uvular related rVOR deficits such as increased time constant in the dark and decreased tilt suppression in at this subpopulation of the autism spectrum. Summary The current study provided descriptive evidence of cross coupling between vertical and horizontal eye movements resulting in measurable changes in the temporal dynamics of rVOR in ASD. Specifically, this abno rmal coupling of vertical eye movements to horizontal rVOR may be indicative of deficient cerebellar modulation of rVOR in ASD. It is unclear at this point whether these deficits are limited to nodular/uvular function or are representative of more diffuse cerebellar deficits in ASD. It is also difficult to rule out with the current evidence whether such differences are specific to ASD as a whole or to subgroups within the spectrum. These results warrant further study of rVOR indicators of cerebellar sensory motor processing differences in ASD.

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142 Table 5 1 Summary of Post Rotary Nystagmus Number of Beats for Velocity Step Test Group N Mean SD SE Mean p value Autism Spectrum Disorders 16 46.25 18.34 4.59 Typically Developing 17 45.85 10.90 2.64 0.94

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143 Figure 5 three ASD and three TD participants. Seventeen novice observers, with no prior knowledge of rVOR or nystagmus ages 19 to 23 years were provided a brief training ses sion including a written definition of normal rVOR a sample video of normal nystagmus obtained from a subject not included in the study, and a rubric for distinguishing normal from abnormal nystagmus. Observers were blind to group assignment and were prov ided with two videos from each of the three ASD and three TD participants in random order. Each video included 20 seconds of per rotary nystagmus followed by 20 seconds of post rotary nystagmus. Observers then

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144 Figure 5 2 Example of Post Rotary Nystagmus Slow Phase Regularity in the TD Group. A) Participant TD 1: counter clock wise velocity step post rotary nystagmus; B) Participant TD 2: clock wise velocity step test post rotary nystagmus ; C) Parti cipant TD 3: counter clock wise velocity step test post rotary nystagmus Note the regular saw tooth pattern across all participants. Participant TD 3 Participant TD 2 Participant TD 1

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145 Figure 5 3 Example of Post Rotary Nystagmus Slow Phase Irregularity in the ASD Group. A) Participant ASD 1: clock wise velocity step post rotary nystagmus with notable change in eye position and amplitude of nystagmus beats beginning at 63. 4 seconds; B) Participant ASD 2: clock wise velocity step test post rotary nystagmus with a notable interruption in horizont al nystagmus beginning at 62 seconds; C) Participant ASD 3: counter clock wise velocity step post rotary nystagmus with a notable change in slow phase velocity beginning at 65 .5 seconds a nd lasting for approximately 4 seconds. Participant ASD 1 Participant ASD 2 Participant ASD 3

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146 Figure 5 4. Verti cal and Horizontal Eye Movements during Post Rotary Nystagmus in the TD Group. A) Participant TD 1: counter clock wise velocity step post rotary nystagmus; B) Participant TD 2: clock wise velocity step test post rotary nystagmus; C) Participant TD 3: count er clock wise velocity step test post rotary nystagmus. Note that there is minimal movement in the vertical plane for all three subjects. Participant TD 1 Participant TD 2 Participant TD 3

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147 F igure 5 5 Vertical and Horizontal Eye Movements during Post Rotary Nystagmus in the ASD Group. A) Partici pant ASD 1: clock wise velocity step post rotary nystagmus; B) Participant ASD 2: clock wise velocity step test post rotary nystagmus; C) Participant ASD 3: counter clock wise velocity step test post rotary nystagmus. Note that there are large movements in the vertical plane that are coupled with horizontal slow phase irregularities. Participant ASD 1 Participant ASD 2 Participant ASD 3

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148 Figure 5 6. Approximate entropy (ApEn) of horizontal rVOR during velocity step testing in the dark presented for one ASD participant and one typically developing contro l. value for the ASD participant indicates increased complexity in the ASD Horizontal rVOR Approximate Entropy (ApEn)

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149 Figure 5 7. Spectral plot comparison of horizontal eye movements during a single trial of velocity step testing in the dark for one ASD and one TD participant. Note that the ASD participant exhibits a greater amount of noise across a wider range o f frequencies indicating that the ASD data is less periodic. ASD Participant TD Participant

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150 Figure 5 8 Spectral plot comparison of vertical eye movements during a single trial of velocity step testing in the dark for one ASD and one TD participant. Note that the ASD participant exhibits a greater amount of noise across a wider range of frequencies. ASD Participant TD Participant ASD Participant TD Participant

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151 Figure 5 9 Peak f requency of horizontal and vertical rVOR measured in one ASD and one TD participant during velocity step testing in the dark. Note that there i s no difference in the peak frequency between the TD and ASD for eye movements in the horizontal plane; however, there is a large difference for eye mov ements in the horizontal plane. The ASD participant exhibits a peak vertical frequency that is much high er than the horizontal frequency and H orizontal Vertical Peak Frequency

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152 Figure 5 10 Comparison of the f95 or the frequency that accounts for 95% of the total power spectrum for one ASD and one TD participant during velocity step testing in the dark. f95 Horizontal rVOR

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153 CHAPTER 6 CONCLUSIONS Objective The overall objective of the current studies was to provide a comprehensive, detailed and systematic evaluation of horizontal rotational vestibulo ocular reflex (r VOR ) in children with autism spe ctrum disorders ( ASD ) The studies described in Chapters 2, 3, 4 and 5 were developed to achieve the following specific aims: (1) to identify alterations in horizontal rVOR in ASD; (2) to determine differences in fixation suppression of rVOR in ASD compar ed to typically developing children; and (3) to identify correlations between rVOR and functional measures in ASD. Summary of Results Fixation Suppression and Smooth Pursuit Deficits in ASD: Chapters 2 and 3 In the current studies, children ages 6 12 di agnosed with ASD demonstrated increased time constant of decay of post rotary nystagmus during velocity step tests in the dark and with fixation suppression (Chapter 2). Increased time constants during velocity step tests in the dark have previously been r eported in ASD Ornitz et al. (1985) and are consistent with the current findings. The significantly increased time constant of decay of post rotary nystagmus during velocity step tests with fixation suppression stimuli in ASD was surprising (Chapter 2). T he cerebellum is important for visual suppression of rVOR p articularly the flocculus/paraflocculus (Zee et al., 1981; Belton and McCrea, 2000, 2002; Rambold et al., 2002). This finding of decreased visual suppression of rVOR in ASD is inconsistent with pr evious reports of significantly decreased post rotary nystagmus duration following velocity step tests in the dark when various fixation suppression stimuli were presented

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154 after rotation stopped. Additionally, there was no difference in time constant of de cay in the light condition, which is inconsistent with a very early study that reported significantly decreased duration of post rotary nystagmus following velocity step testing in a well lit room (Ritvo et al., 1969). Reasons for the differences between t hese two studies may include differences in participant demographics and method s In the Ritvo et al. (1969) study 26 children ages 3 to 7 years were characterized as having infantile In the Ornitz et al. (1974) study included 21 children ages 3 to 5 years with infantile selective in recruiting only children with high functioning ASD whose diagnoses were confirmed using validated diagnostic assessment tools. Only a small proportion of our sample was non verbal or had limited verbal abilities (n = 3 out of 16). Another possible explanation for the difference between studies may result from d ifferences in testing protocols. The current study conducted velocity step tests with a ramp up time of 1.2 seconds to a peak velocity of 100/second for 60 seconds of rotation using a motorized rotary chair. Visual fixation suppression stimuli in the curr ent study were provided both during and after rotation. Both previous studies conducted the standard Barany procedure including 10 revolutions within 20 seconds with a rotary chair operated by hand. Ornitz et al. (1974) conducted this rotation protocol in the dark and only provided visual stimuli after rotation had stopped. Thus, although the previous studies may have reached a constant peak velocity reaching nearly 180/second, it is unclear as to the duration of time that the constant velocity was provide d since the rotation was

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155 conducted by hand. Thus, there may have been differences between studies both in participants as well as in the amount and duration of vestibular stimulation. Even though the ASD group followed the same pattern of decreased gain a nd time constants in fixation suppression conditions compared to dark conditions, their gain was consistently higher than controls. Per rotary nystagmus gain during velocity step tests as well as gain during SHA tests were higher in ASD in the dark as well as with fixation suppression (Chapter 2 and 3 respectively). Taken together, the findings from Chapter 2 indicate that differences in rVOR time constant of decay in ASD are of central rather than peripheral origin. Increased time constants in the dark su ggest cerebellar nodulus/uvula deficits in the ASD group. However, increased per rotary gain suggests deficits in cerebellar flocculus modulation of rVOR The lack of fixation suppression on the post rotary time constant of decay of rVOR further supports t he idea of cerebellar modulation deficits in ASD. Although not statistically significant, trends were noted towards smooth pursuit differences in ASD (Chapter 2). Smooth pursuit deficits may explain lack of fixation suppression in ASD and cannot be rule d out at this time. Additionally, smooth pursuit deficits in ASD support the idea of vestibulo cerebellar deficits both in the flocculus/paraflocculus (Zee et al., 1981; Belton et al., 2000, 2002; Rambold et al., 2002) as well as the nodulus/uvula (Heinen and Keller 1996; Walker et al., 2008b). During SHA tests in the dark (Chapter 3), there was no difference in phase between groups at each frequency. The ASD group followed the same trend as controls of improved efficiency of gain at higher frequencies of rotation. However, the ASD group did show significantly increased gain compared to controls in the dark. An increase in

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156 SHA gain may be related to a lack of inhibition from the cerebellum and to hyper responsivity to vestibular stimuli in ASD (Robinson, 19 76; Thurston, Leigh, Abel & the findings of increased time constants of decay for velocity step testing in the dark. Fixation suppression SHA tests (Chapter 3) showed no d ifference in gain between groups at any frequency tested. Increased phase lag was observed in ASD only at 0.5Hz the highest rotation frequency tested. Since this difference in phase lag was observed during fixation suppression testing, the difference in A SD may possibly be related to optokinetic or smooth pursuit system deficits. However, increased phase lead may also indicate either peripheral vestibular differences or central deficits at the brainstem level in vestibular nuclei function (Shepard & Telian 1996). Further studies are warranted to discern whether these differences are due to perturbations in the peripheral or central nervous system and where they are located. Neuropsychological Correlates to rVOR in ASD: Chapter 4 It is clear that a relati onship exists between measures of rVOR and vestibulo spinal function in ASD. This relationship may indicate a global vestibular processing deficit in this population. However, since the direct observations of vestibulo spinal function provided by the PANES S balance error scores displayed a bimodal distribution, these results should be interpreted with caution as there may be subgroups within the autism spectrum based on presence or absence of a balance deficit. The relationship between balance and rVOR defi cits may also be dependent on this bimodal difference in balance. Sensory Profile vestibular processing sub scores were not correlated with either measures of vestibulo ocular or vestibulo spinal function in the children with ASD in the

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157 current study. How ever, the Sensory Profile vestibular subscale was correlated with the RBS R stereotypy subscale and may reflect stereotypic behavior in ASD rather than vestibular processing dysfunction. A lack of any significant relationship between Sensory Profile vestib ular processing subscales and direct measures of vestibular function was surprising and also warrants further study. rVOR Qualitative Differences in ASD: Chapter 5 Statistical measures of regularity (ApEn and spectral analysis) appear to be promising me thods of analysis for evaluating differences in rVOR quality in ASD. Based on preliminary approaches to the data with these methods, it appeared that there were increased slow phase irregularities in ASD that may be related to vertical eye movement intrusi ons. If cross coupling between vertical and horizontal eye movements during rVOR in response to low frequency stimuli can be demonstrated, this may indicate cerebellar deficits, possibly in the nodulus/uvula. However, increased saccade latency in ASD may a lso explain slow phase deficits in this population such as failure to execute a quick phase following slow phase eye movements, as previously noted by Ornitz et al., 1985. Further analysis of the qualitative differences in rVOR in ASD is warranted and may help provide further evidence for deficient cerebellar modulation of rVOR. Implications Autism spectrum disorders (ASD) are currently diagnosed on the basis of abnormal behavior within three core domains: (1) social skills, (2) communication skills, and (3) restricted/repetitive behaviors (American Psychiatric Association, 2000). Beyond the three main behavioral domains of ASD, deficits in sensory processing and motor coordination have been observed in young children less than 2 to 3 years of age who were later diagnosed with ASD ( Baranek, 1999; Karmel, 2010; Landa, Garrett Mayer,

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158 2006; Teitelbaum, P., Teitelbaum, O., Nye, Fryman, Maurer, 1998 ; Watson, Baranek, Crais, Reznick, 2007; Zwaigenbaum et al. 2005 ). Early identification and early intervention ha ve been shown to have a significant effect on the prognosis for young children with ASD (Dawson et al. 2001; Rogers, 1998 ). However, an early diagnosis of ASD has often been limited to children who are approximately 2 to 3 years of age (Lord, 1995; Moore, & Goodson, 2003 ; Rogers, 2000 ). Yet, it is clear that the abnormal neurobiological processes resulting in ASD occur during fetal development ( Rodier, 2002 ; Rodier, Ingram, Tisdale, Nelson, & Romano, 1996 ) and/or infancy ( Courchesne, Redcay, Morgan, Kenned y, 2005 ) long before the onset of the classic behavioral symptoms currently used to affirm a diagnosis. Thus, identification of a bio behavioral marker that occurs early in development and is related to the neurobiology of ASD would be particularly useful both for earlier identification of risk and for understanding the neuropathological processes resulting in ASD. Thus, sensory and motor abnormalities may currently provide the earliest warning signs of risk for ASD. The rVOR is a promising candidate for an early sensorimotor bio behavioral marker of risk for ASD for several reasons. First, horizontal rVOR has been previously shown to be abnormal in young children with ASD (Ornitz et.al, 1985; Ritvo, 1969). Second, the rVOR involves integration of sensory an d motor information at sites that have been shown to have morphological abnormalities in ASD such as the brainstem (Rodier, 2002; Jou et al., 2009), cerebellum ( Scott, Schumann, Goodlin Jones, Amaral, 2009 ) thalamus and parietal lobes ( Baron Cohen et al. 2009; Teitelbaum, Teitelbaum, Nye, Fryman Maurer, 1998 ).Third, the anatomy and physiology of the rVOR is one of

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159 the best studied of all the vestibular and postural reflexes which provides a solid foundation for studying this reflex and its related neurob iology in ASD. Fourth, the rVOR can be measured reliably in infants as young as 6 months of age ( Phillips, Backous, 2002 ); hence, if an rVOR marker were selective for ASD, then this reflex may provide a promising means for early identification of ASD risk. Lastly, the rVOR is highly modifiable ( Braswell, Rine, 2006; Schubert, Zee, 2010 ) therefore, it is reasonable to suspect that at least some of the deficits of rVOR in ASD could respond to vestibular rehabilitation interventions. The results of these studi es provide a comprehensive, detailed and systematic evaluation of horizontal rotational rVOR in children with ASD. Additionally, these results may aid the identification of neural substrates responsible for vestibular related sensorimotor deficits observe d in ASD. If rVOR abnormalities are selective for ASD, then rVOR tests could potentially provide a promising method for early identification of ASD. As of yet, diagnoses on the spectrum cannot be reliably confirmed until 2 3 years of age (Rogers, 2000). Ho wever, the rVOR can be measured reliably in infants as young as 6 months (Phillips & Backous, 2002). Furthermore, the vestibular system is fully developed by 9 weeks in utero; thus, aberrations in vestibular function may provide a critical time point for i nvestigation of fetal vestibular development and related neural development. Alternatively, if rVOR abnormalities are present in a sub population of ASD, then rVOR tests could potentially serve as a technique for patient treatment matching with vestibular and oculomotor related interventions for this population. Certain rVOR characteristics can be modified through experience, and therefore, may become a useful outcome measure for specific interventions. Thus, studying the nature

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160 of perturbations in the rVOR in ASD, holds promise to improve early identification of sensorimotor deficits, to inform sensorimotor intervention methods and to guide future studies of aberrant neural mechanisms underlying vestibular related sensorimotor deficits in ASD. Limitations Although the current study had sufficient power for the main comparisons of rVOR metrics, the relatively small sample size (n = 16 ASD participants and n = 17 TD participants) may not have had sufficient power to identify subtle oculomotor differences or neuropsychological assessment correlations and may have potentially lead to Type II errors or missing differences between groups. Another limitation to the current study is that SHA tests were not conducted at sufficiently low frequency cycles to calculat e time constant of decay such as 0.01 or 0.02Hz Future studies should be conducted with SHA at such frequency cycles, if possible, in order to estimate time constants for comparison in ASD. Based on velocity step tests, it is expected that children with A SD would demonstrate higher time constants of decay during SHA tests conducted in the dark and with fixation suppression. Lastly, the current study aimed to recruit high functioning children with ASD in an effort to better match the typically developing c ontrol group on age and IQ. Therefore, the results of the current study cannot be extrapolated to individuals with ASD who are lower functioning. Based on correlations discovered between IQ and functional ability measures it would be reasonable to suspect that rVOR deficits would be even greater in individuals with ASD who are lower functioning.

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161 Future Studies Future studies will be required to address questions of specificity to ASD. The first question is whether differences in rVOR suppression are speci fic to ASD or simply to developmental disabilities in general. This question can be answered by comparing groups of children with ASD to other groups with developmental disabilities of known etiology that are not related to ASD, such as children with Down syndrome or cerebral palsy. One study of individuals with Down syndrome reported that during velocity step tests of rVOR, adults with Down syndrome exhibit decreased number of per and post rotary nystagmus beats when tested in the dark and reduced fixatio n suppression of rVOR gain. However, there was no mention of significant differences between Down syndrome and controls for time constant of decay in either the dark or fixation suppression conditions. Therefore, questions remain as to the specificity of t he time constant and qualitative differences observed in ASD. One extension of the current work could compare rVOR metrics from velocity step tests in the dark and with fixation suppression between groups of children with ASD and Down syndrome. If rVOR met rics were found to be specific to ASD such as time constant of decay, this information may help to differentiate cerebellar deficits between these two groups. Optokinetic nystagmus (OKN) and optokinetic after nystagmus (OKAN) are repetitive eye movement responses to visual motion stimuli rather than vestibular stimuli as with per and post rotary nystagmus is to rVOR. Like rVOR however, both OKN and OKAN are also dependent upon normal functioning of the nodulus and uvula. Horizontal OKAN is prolonged with damage to these structures (Angelaki & Hess, 1994; Wearne et al., 1998). OKAN has not been studied in ASD; however, based on the results of the current study and possible indications that they involve damage to or deficits in

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162 nodulus/uvula function, it wo uld be reasonable to suspect that OKAN would be prolonged in ASD. OKN has been briefly described in the literature to differ from controls in one oculomotor study (Scharre & Creedon, 1992), but it remains unclear as to the exact nature of these aberrations A systematic examination of OKN and OKAN in ASD would be beneficial for better understanding cerebellar optokinetic differences and possible smooth pursuit differences in this population. Furthermore, since the current study found differences in ASD betw een full field visual stimuli in the light condition and foveal vision provided during fixation suppression, SHA rotary chair testing with OKN full visual field stimuli (Brey, McPherson & Lynch, 2008b) may also help to determine whether or not there are di fferences in visual processing of full field vs. foveal fixation for suppression of rVOR in ASD. Future studies should aim to include lower functioning individuals with ASD to determine if they exhibit the same differences in rVOR as the individuals inclu ded in the current study who are considered high functioning. Several oculomotor deficits in ASD have been linked to other measures of functional level such as presence or absence of language delay (Takarae et al., 2004; Takarae et al., 2008). Presence or absence of the current study did not record or compare history of language development, we did find a correlation with other measures of functional ability. Future studie s should assess whether or not rVOR differences are dependent upon history of language development. General Summary The results of the present studies suggest that there are vestibular processing deficits in the ASD sample tested. These deficits may be con sistent with reports of cerebellar deficits in the ASD population and warrant further study. Specifically, the

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163 ability to suppress rotationally evoked nystagmus is a good indicator of connections between midline cerebellar structures and vestibular nuclei (Brey et al., 2008b). Since children with ASD demonstrate deficits in visual suppression of nystagmus in the current study, these results indicate that the connections between these two structures should be an area of interest for further neuroanatomical s tudy Specifically, the relationship between Purkinje cell input to the vestibular nuclei is of interest for further study in this population

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164 APPENDIX GLOSSARY OF TERMS RELATED TO VESTIBULO OCULAR REFLEXES Acceleration degrees 2 / second Frequency (Hz) cycles / second. Gain the ratio of peak eye velocity (i.e., output) to peak head velocity (i.e., input) ; a measure of accuracy of the rVOR; perfect gain = 1. Latency the timing relationship between visual target onset and eye movement toward the t arget Nystagmus (specifically vestibular nystagmus) repetitive oscillating eye movements that occur in response to angular vestibular stimulation or optokinetic stimulation; includes two types of eye movements: a slow phase excursion followed by a quick/ fast phase reset of the eye to physiological center. Optokinetic Nystagmus (OKN) nystagmus that occurs in response to optokinetic stimuli; specifically in response to continuous, repetitive movement of full field (minimum of 90% of visual scene ); for exa mple, nystagmus that occurs in response to looking a moving car window at scenery passing by); primarily driven by smooth pursuit system; requires several seconds to build up response; will cease as soon as visual scene stops moving (Shepard & Schubert, 20 08). Optokinetic After Nystagmus (OKAN) the prolonged nystagmus that occurs after OKN response to full field visual scene motion; occurs only when subject is placed in the dark immediately following at least 30 seconds of exposure to full field visual m otion; primarily driven by optokinetic system (Leigh & Zee, 2006). Per rotary nystagmus repetitive eye movements that occur during continuous en bloc whole body rotation. Phase the timing relationship between head velocity and eye velocity ; eye movem ents should be 180 degrees offset from head movement (i.e., moving in the opposing direction) Pitch rotation around the pitch axis; interaural axis; y axis; results in vertical eye movements. Post rotary nystagmus repetitive eye movements that occur during continuous en bloc whole body rotation. Roll rotation around the roll axis; naso occipital axis; x axis; results in torsion eye movements. Sinusoidal Harmonic Acceleration Test (SHA) whole body en bloc rotary chair test with an oscillating si de to side motion profile; typically conducted at peak

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165 velocities of 50 60 degrees/second and at a range of frequencies from 0.01 up to 2.0 Hz; eye movement are recorded during rotation to measure gain, phase and symmetry of rVOR. Symmetry the compariso n between the rVOR response for each direction of movement clock wise or counter clock wise; asymmetrical responses can reflect unilateral deficits. Time Constant of Decay (TCD) the time it takes rVOR slow phase velocity to decrease to 37% of its peak v elocity. Velocity Step Test whole body en bloc rotation rVOR testing conducted with the participant seated on a rotary chair with a movement profile that includes a specified acceleration to a constant velocity for a set duration of time followed by rap id deceleration to stop; conducted in clock wise and counter clock wise directions with a minimum of 60 second break between trials; eye movement recordings during and after rotation measure gain, symmetry and time constant of decay of rVOR. Velocity de grees / second Yaw rotation around the yaw axis; rostral caudal; z axis; results in horizontal eye movements

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175 BIOGRAPHICAL SKETCH Tana Bleser Carson was born in Key Largo, Florida. She attended Coral Shores High School, where she graduated in 2003. After high school, she attended the University of Florida for her undergraduate studies and gradu ated with a Bachelor of Science in Neurobiological Sciences in 2007. She continued at the University of Florida for her graduate studies in the Psychology PhD Program studying Behavioral and Cognitive Neuroscience with a research focus on sensory and motor processing in autism spectrum disorders. In 2009, she began a dual enrollment in the Master of Occupational Therapy Program in the College of Health and Professions Nursing and Pharmacy also at the University of Florida She graduated the Master of Occupa tional Therapy Program in December of 2011 and obtained Occupational Therapy licensure in February of 2012. She was awarded her PhD in Psychology in the area of Behavioral and Cognitive Neurosciences at the University of Florida College of Liberal Arts and Sciences in 2013.