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The Neural Substrates of Tics Vs. Obsessive-Compulsive Behaviours in Tourette Syndrome

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The Neural Substrates of Tics vs. Obsessive-Compulsive Behaviours in Tourette Syndrome by Tracy Prema Bhikram A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Tracy Bhikram 2020 The Neural Substrates of Tics vs. Obsessive-Compulsive Behaviours in Tourette Syndrome Tracy Bhikram Doctor of Philosophy Institute of Medical Science University of Toronto 2020 Abstract Tourette Syndrome (TS) is a chronic neuropsychiatric disorder characterized by the presence of tics and is often comorbid with obsessive-compulsive symptoms (OCS). Tics and OCS share many phenomenological similarities as they are both characterized by repetitive behaviours that are often preceded by sensory phenomena; however, it not known how tics and OCS in TS differ neurobiologically from one another. Accordingly, 40 TS patients with varying severities of tics and OCS, as well as 20 healthy controls, completed an fMRI scan comprised of three functional tasks to probe different aspects of TS+OCD symptomatology. Firstly, to elucidate the neural correlates responsible for the development and modulation of urges, participants completed an emotional blink suppression paradigm. During the emotional inhibition of blinks, tic severity was found to be associated with activity in the superior frontal gyrus, whereas there were no significant associations with OCS severity. Secondly, participants completed an OCS provocation paradigm with stimuli from the checking, washing and symmetry symptom dimensions to determine the neurobiology of OCS in TS. In the patient group, negative associations between OCS severity and activity in the supramarginal gyrus, inferior frontal gyrus, sensorimotor cortex and precuneus were common among all the provocation conditions. ii Conversely, tic severity was only associated with activity in the anterior cingulate cortex for the symmetry condition. Finally, resting state functional connectivity analyses were conducted with seeds placed in the supplementary motor area (SMA), orbitofrontal cortex, insula, caudate and putamen. Within the patient group, tic severity was associated with greater connectivity between the putamen and the sensorimotor cortex; OCD severity was associated with less connectivity between the SMA and thalamus and between the caudate and precuneus. In general, the studies revealed that patients with greater symptom severities exhibited less activity in regions responsible for cortical control over cognitive and motor processing, and the activation of areas that may be more directly responsible for the occurrence of tics and OCS. The results suggest that tics and OCS are characterized by partially overlapping neural substrates that may explain why they are highly comorbid and phenomenologically similar, but also why they are still considered distinct symptom domains. iii Acknowledgments To begin, I would like to express my gratitude to my supervisor, Dr. Paul Sandor, for your steadfast support and guidance. Your mentorship has fundamentally shaped my training and this body of work. You constantly found time to prioritize my work despite your busy schedule and more than that, you always go above and beyond the duties of a graduate supervisor. Your enthusiasm and encouragement were instrumental in helping me to feel more confident about my work so that my passion for research never dwindled. I greatly admire your intelligence, compassion and work ethic, and I hope to emulate those qualities even in some small measure. I feel very lucky to have done my doctoral studies under your tutelage. To the members of my advisory committee, Dr. Adrian Crawley and Dr. Paul Arnold, thank you for your invaluable guidance and scientific insights that have pushed me to become a better researcher. I am very appreciative for the time and energy you have devoted to my research project. Dr. Crawley, I cannot express how helpful and enjoyable all of our meetings have been; I always left them feeling more optimistic about the way forward. Dr. Arnold, I am enormously grateful for your support and guidance which never wavered even when moving across the country. The dedication from the both of you to see this project through with me is something that I will be eternally grateful for. I owe a tremendous debt to Dr. Elia Abi-Jaoude who provided extensive guidance and support throughout my time as a PhD student. From brainstorming project ideas with me in the early days to inviting me to assist in reviewing journal manuscripts, you helped prepare me for this moment. And while I fondly think of you as a mentor, you never made me feel like anything less than a colleague. You always set aside time for me when I needed your help even though you were juggling a million other things, and for that I am beyond thankful. I would also like to thank all of the current and past members of the Tourette Syndrome Neurodevelopmental Clinic for your support and friendship. You all helped more than you know, and your interdisciplinary experience was extremely valuable. I am also very grateful for the help many of the team members provided in the early stages of this project, testing my paradigms and even volunteering to be my pilot participants. iv I would be remiss to overlook the generous financial support I received during my graduate studies. I would like to acknowledge the Government of Ontario, The Peterborough K.M. Hunter Foundation, Unilever/Lipton, the University Health Network and the University of Toronto/School of Graduate Studies for their significant contributions in supporting the work of graduate students such as myself. I would also like to thank the research participants who volunteered to take part in this research project, many of whom who did it simply to advance our understanding of Tourette Syndrome. Your time and effort are invaluable contributions to the TS research field. Finally, I would like to thank my family. Mom and Dad, I will never be able to express how thankful I am for your unwavering love, support and encouragement. And to my sister, even though I am the big sister, you constantly inspire me to be better and work harder; your work ethic and intelligence is something to be admired, and is only rivaled by your kind heart and fun nature. You have all been instrumental in getting me to this point, serving as my cheerleaders, DJs, obstacle removers, frustration-listeners and ‘work managers’, and for that, I will be forever grateful. v Contributions Tracy Bhikram (Author) – All aspects of the work presented in this thesis, including the planning, execution, analysis and writing, was performed in whole or in part by the author. The following contributors are acknowledged: Dr. Paul Sandor (Supervisor) – mentorship; guidance and assistance in planning, execution and analysis of experiments as well as in the interpretation of results and thesis preparation. Dr. Adrian Crawley (Thesis Committee Member) – mentorship; guidance and assistance in planning; analysis of experiments, including the interpretation of results; thesis preparation. Dr. Paul Arnold (Thesis Committee Member) – mentorship; guidance and assistance in planning; analysis of experiments, including the interpretation of results; thesis preparation Dr. Elia Abi-Jaoude – mentorship; guidance and assistance in planning, execution and analysis of experiments as well in the interpretation of results and thesis preparation. vi Table of Contents Abstract ...................................................................................................................... ii Acknowledgments ....................................................................................................... iv Contributions ............................................................................................................. vi Table of Contents ...................................................................................................... vii List of Tables ............................................................................................................. xi List of Figures .......................................................................................................... xiii Index of Abbreviations ................................................................................................xv Chapter 1 : Introduction ......................................................................................... 1 1.1 Thesis Overview and Outline ................................................................................................ 2 Chapter 2 : Literature Review................................................................................ 4 2.1 Tourette Syndrome ........................................................................................................ 5 2.1.1 Epidemiology, Clinical Course and Quality of Life ................................................. 6 2.1.2 Sensory Phenomena and Premonitory Urges ............................................................ 8 2.1.3 Comorbid disorders ................................................................................................. 11 2.1.4 Emotional Dysregulation ........................................................................................ 14 2.1.5 Treatments............................................................................................................... 16 2.1.6 Etiology ..................................................................................................................
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