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University of Florida Thesis Or Dissertation Formatting THE NEURAL CIRCUITRY OF RESTRICTED REPETITIVE BEHAVIOR By BRADLEY JAMES WILKES 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 2018 © 2018 Bradley James Wilkes To my father, Wade Wilkes, for his lifelong support, love, and encouragement ACKNOWLEDGMENTS This research was supported by funding from the Dissertation Research Award from the American Psychological Assocation, the Pilot Project Award (Non-Patient Oriented Clinical/Translational Research) from the Clinical and Translational Science Institute at the University of Florida, the Robert A. and Phyllis Levitt Award, the Gerber Behavioral and Cognitive Neuroscience Psychology Research Award, and the Jacquelin Goldman Scholarship in Developmental Psychology. I would especially like to thank Drs. Mark Lewis, Marcelo Febo, David Vaillancourt, Luis Colon-Perez, Darragh Devine, Timothy Vollmer, and Michael King for their support and guidance. 4 TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................. 4 LIST OF TABLES ............................................................................................................ 7 LIST OF FIGURES .......................................................................................................... 8 LIST OF ABBREVIATIONS ........................................................................................... 10 ABSTRACT ................................................................................................................... 12 CHAPTER 1 GENERAL INTRODUCTION AND LITERATURE REVIEW ................................... 14 Background ............................................................................................................. 14 Studying Neural Circuitry with Magnetic Resonance Imaging ................................. 19 Magnetic Resonance Imaging of Repetitive Behavior in ASD and IDD .................. 25 Magnetic Resonance Imaging in Animal Models with Repetitive Behavior ............. 43 Conclusions ............................................................................................................ 60 Future Directions .................................................................................................... 67 2 VOLUMETRIC MAGNETIC RESONANCE IMAGING IN AN ANIMAL MODEL OF REPETITIVE BEHAVIOR ................................................................................. 75 Introduction ............................................................................................................. 75 Methods .................................................................................................................. 76 Results .................................................................................................................... 82 Discussion .............................................................................................................. 91 3 DIFFUSION WEIGHTED MAGNETIC RESONANCE IMAGING IN AN ANIMAL MODEL OF REPETITIVE BEHAVIOR .................................................................... 99 Introduction ............................................................................................................. 99 Methods ................................................................................................................ 100 Results .................................................................................................................. 105 Discussion ............................................................................................................ 111 4 VOLUMETRIC MAGNETIC RESONANCE IMAGING IN CHILDREN AND ADOLESCENTS WITH AUTISM SPECTRUM DISORDER .................................. 119 Introduction ........................................................................................................... 119 Methods ................................................................................................................ 120 Results .................................................................................................................. 125 Discussion ............................................................................................................ 136 5 5 DIFFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING IN CHILDREN AND ADOLESCENTS WITH AUTISM SPECTRUM DISORDER ......................... 145 Introduction ........................................................................................................... 145 Methods ................................................................................................................ 146 Results .................................................................................................................. 151 Discussion ............................................................................................................ 154 6 GENERAL DISCUSSION ..................................................................................... 162 Summary and Synthesis of Results ...................................................................... 163 Conclusions and Future Directions ....................................................................... 168 APPENDIX A REGIONS OF INTEREST FOR ATLAS BASED VOLUMETRY ........................... 173 B SUPPLEMENTARY DATA .................................................................................... 177 LIST OF REFERENCES ............................................................................................. 181 BIOGRAPHICAL SKETCH .......................................................................................... 203 6 LIST OF TABLES Table page 1-1 Summary of studies that observed a correlation between neuroimaging findings and RRB in ASD and IDD. .................................................................... 71 2-1 List of brain regions which showed a significant volume difference (FDR corrected, p < .05) in SH-B6 and SH-C58 mice .................................................. 87 2-2 List of brain regions which showed a significant volume difference (FDR corrected, p < .05) in EE-C58 and SH-C58 mice ................................................ 89 4-1 Number of participant in each group, with mean age and IQ ............................ 121 4-2 Effect of diagnosis and gender on age and IQ ................................................. 125 4-3 List of brain regions (ROIs) which showed a significant volume difference (FDR corrected, p < .05) between ASD and TD participants ............................ 132 4-4 List of brain regions (ROIs) which showed a significant volume difference (FDR corrected, p < .05) between female ASD and TD participants ................ 133 5-1 Number of participant in each group, with mean age and IQ ............................ 147 5-2 Effect of diagnosis and gender on age and IQ ................................................. 151 A-1 List of atlases and brain regions used for volumetry in animal studies ............. 173 A-2 List of atlases and brain regions used for volumetry in human studies ............. 175 B-1 List of brain regions which showed a significant volume difference (FDR corrected, p < .05) in SH-B6 and EE-C58 mice ................................................ 177 B-2 List of brain regions which showed a significant volume difference (FDR corrected, p < .05) between male and female participants ............................... 179 7 LIST OF FIGURES Figure page 1-1 Structures and connections of brain circuits implicated in RRB in the human and mouse .......................................................................................................... 17 1-2 Cortico-basal ganglia macro-circuits in the human brain .................................... 18 2-1 Mean total number of vertical repetitive motor behaviors exhibited by SH- C58, EE-C58, and SH-B6 groups ....................................................................... 82 2-2 Heat map of significant F-statistic values for one-way ANOVA of volume differences among animal groups ....................................................................... 83 2-3 Significant t-statistic values for post-hoc t-test of volume differences between SH-C58 and SH-B6 mice .................................................................................... 84 2-4 t-statistic values for post-hoc t-test of volume differences between SH-C58 and EE-C58 mice ............................................................................................... 85 2-5 Significant t-statistic values for post-hoc t-test of volume differences between EE-C58 and SH-B6 mice .................................................................................... 86 2-6 Significant t-values for the linear model relating volume and repetitive motor behavior including mice from all groups.. ........................................................... 90 2-7 t-values for the linear model relating volume and repetitive motor behavior including only SH-C58 mice................................................................................ 91 3-1 Mean total number of vertical repetitive motor behaviors exhibited by SH- C58, EE-C58, and SH-B6 groups. .................................................................... 105 3-2 Heat map of significant F-statistic values for one-way ANOVA of FA differences between animal groups .................................................................. 106
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