STRUCTURAL ABNORMALITIES AND TREATMENT- RELATED PLASTICITY IN CLASSICAL TRIGEMINAL NEURALGIA by Danielle D. DeSouza A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Danielle D. DeSouza 2015 Structural Abnormalities and Treatment-Related Plasticity in Classical Trigeminal Neuralgia Danielle D. DeSouza Doctor of Philosophy Institute of Medical Science University of Toronto 2015 Abstract Classical trigeminal neuralgia (TN) is a unique neuropathic pain disorder characterized by highly intense electric shock-like attacks of unilateral facial pain. While TN is commonly associated with neurovascular compression of the trigeminal nerve at the root entry zone (REZ) its pathophysiology is not well understood. In conjunction with trigeminal nerve abnormalities, central gray matter and white matter (GM, WM) structure may be affected and/or contribute to the maintenance of TN. Surgical treatment for TN may produce analgesia by effectively normalizing these structural abnormalities. The main aim of this thesis is to determine if there are structural neural abnormalities in patients with TN and whether effective neurosurgical treatment can reverse these abnormalities. The specific aims were to determine: 1) if patients with TN have brain GM abnormalities; 2) if patients with TN have trigeminal nerve and/or brain WM ii abnormalities based on multiple DTI-derived metrics; 3) if effective neurosurgical treatment for TN is associated with a reversal of the trigeminal REZ and cortical and subcortical GM abnormalities that we report in studies 1 and 2 of this thesis. In groups of TN patients with right- sided pain and healthy age- and sex-matched controls, magnetic resonance imaging revealed that patients had: 1) increased GM in the sensory thalamus, amygdala, periaqueductal gray, basal ganglia, contralateral primary somatosensory cortex, and frontal pole and less GM in the pregenual anterior cingulate cortex, insula, and orbitofrontal cortex; 2) abnormalities in the trigeminal REZ and cerebral WM tracts including the corpus callosum, cingulum, corona radiata, and superior longitudinal fasciculus; and 3) a reversal ventral anterior insula and trigeminal REZ abnormalities following effective treatment, with the degree of REZ normalization correlating with pain relief. Taken together, this thesis demonstrates for the first time both trigeminal nerve and brain abnormalities in patients with TN, and the impact of effective treatment on these abnormalities. iii Acknowledgements I cannot begin to express how thankful I am for all of the support and encouragement I have received over the past five years. I would first like to thank my primary PhD advisor, Karen Davis. Karen has truly shown me what it means to be a mentor. Her knowledge and work ethic are inspiring and her focus and dedication to her trainees is second to none. Without Karen’s unwavering support and faith in my abilities, this process would not have been possible. I know I will seek Karen’s continued mentorship well beyond the PhD process. I am also extremely grateful for the opportunity to be co-supervised by Mojgan (Moji) Hodaie. Having Moji’s kindness and clinical expertise to guide these projects was a constant reminder of why our research is so important. Being able to attend pain clinics, view surgical procedures, and work directly with patients was priceless. I will no doubt bring this perspective with me to future projects I partake in. I would also like to thank my committee members David Mikulis and Jonathan Dostrovsky for their support and always insightful feedback throughout this process. David’s enthusiasm was contagious. I greatly appreciate his unique perspective and the way he challenged me to think about the data in new ways. I am incredibly honoured to have had Jonathan as a committee member. Having his wealth of knowledge to draw upon was an invaluable experience. I also thank Jonathan for providing the opportunity for me to participate in events such as the annual Brain Bee competition and the International Brain Research Organization’s School of Neuroscience. I thoroughly enjoyed these events and made lasting friendships in the process. iv Thank you to Adrian Crawley for all of your support over the years. I appreciate the countless conversations we have had about statistical methods and technical issues. Your feedback was greatly appreciated at my final committee meeting. I also extend my thanks to others who provided technical support for these projects including Geoff Pope, Paul Dufort, and the MRI technicians. Thank you, Kiki Vona, Tessa Burkholder, and Udi Blankstein for all of your administrative help and data collection. In addition to my research mentors, I express my sincere thanks to my teaching mentors who have substantially contributed to my PhD experience. I have been incredibly lucky to work with some of the University of Toronto’s finest in the Faculty of Medicine. Thank you to Patricia Stewart for giving me my first teaching opportunity in neuroanatomy. This opened the door to my involvement in several courses and sparked the passion for teaching that I take with me today. Thank you so much to Cindy Morshead, Debbie Hebert, Anne Agur, Barbara (Dee) Ballyk, Paulo Koberle, and Deirdre Dawson for all of the amazing opportunities. It was a pleasure to learn from you all. When I first joined the Davis lab it was exciting to be surrounded by colleagues that were not only knowledgeable, but also extremely passionate about their work. A special thanks to Massieh Moayedi and David Chen for showing me the ropes and sharing their abundant technical knowledge, which set the foundation for my PhD studies. I thank Aaron Kucyi for all of the laughs and support he has provided over the years. His calm demeanor and listening skills over a v banana break or burrito run was often just what I needed when things became stressful. I greatly value the friendship that has developed. I also thank Ruma Goswami, Marie-Andreé Coulombe, Kasey Hemington, Joshua Cheng, and Anton Rogachov from the Davis lab for creating such an incredible lab environment. It really is a joy coming to work each day surrounded by humour and hard work. I look forward to hearing about all of the success and accomplishments coming your way. It has been a pleasure getting to work with Dave Hayes and Brendan Behan from the Hodaie lab. I always enjoy our conversations and appreciate all of the feedback you have provided along the way. I have also been fortunate to develop many friendships with colleagues outside of lab, particularly from the Toronto Western Research Institute and the Centre for Addiction and Mental Health. Thank you in particular to Yuko Koshimori, Leigh Christopher, and Antigoni Ulndreaj for their support and friendship over the years. I am forever grateful to my family for their love and encouragement. I cannot thank my parents, Terrence and Lauren DeSouza, enough for their unwavering support and belief in my abilities. I appreciate everything you have done to support me and help me achieve my goals. You have been my rock and completing this degree would not have been possible without you. I finally have that fourth ‘D’! I am so thankful for my two immensely supportive sisters, Danita and Tanya DeSouza. My sisters have been my cheerleaders from the beginning and over the years have become my best friends. Their support throughout this process has meant the world to me. Their work ethic and personal academic pursuits have been inspiring. Thank you to Luna for being a pure joy in my life. vi Thank you to Nelson Gonçalves for bringing balance to my life. Palavras não podem expressar quanto o seu amor e apoio significa para mim. Obrigado pela tua paciência e compreensão durante estes períodos de estresse. Obrigado por cuidar de mim e ter certeza que eu não esqueçesse de comer quando não era a minha prioridade. Este processo tornou-se mais fácil quando você entrou na minha vida. Work in this thesis was funded by the Physician’s Services Incorporated Foundation and the Canadian Institutes of Health Research (CIHR). I also thank the following programs for personal support: CIHR Cell Signals program, Ontario Graduate Scholarships (Government of Ontario), Pain Scientist Scholarship (University of Toronto Centre for the Study of Pain), James F. Crothers Family Fellowships in Peripheral Nerve Damage Ontario Student Opportunity Trust Funds (University of Toronto and donor), and the Purdue Pharma Ontario Graduate Scholarship in Science and Technology (University of Toronto and donor). In loving memory of Lucille and Shabir Khan, Clifton and Vivian Ng-A-Kien, Gail Ferreira Ng- A-Kien, Rocky, and my Bailey boy. I miss you dearly. vii Table of Contents Acknowledgements .............................................................................................................. iv Table of Contents ................................................................................................................ viii List of Tables ........................................................................................................................ xv List of Figures ...................................................................................................................... xvi List of Abbreviations ............................................................................................................ xix Chapter 1 Introduction and General Aims .............................................................................