i Altered Hippocampal Structure In Trigeminal Neuralgia by Alborz Noorani A thesis submitted in conformity with the requirements for the degree of Master of Science Institute of Medical Science University of Toronto © Copyright by Alborz Noorani 2020 Altered Hippocampal Structure In Trigeminal Neuralgia Alborz Noorani Master of Science Institute of Medical Science University of Toronto 2020 Abstract The hippocampus has long been studied for its crucial role in learning and memory. Recent findings suggest that the hippocampus also plays a role in shaping pain experience. This thesis aims to investigate hippocampal alterations in chronic neuropathic pain, using trigeminal neuralgia (TN) as a model. TN is a facial neuropathic pain syndrome that is highly debilitating but is amenable to surgical intervention. In this thesis, structural magnetic resonance images (MRI) were used to measure grey matter volume in the hippocampus. Study 1 which includes 21 TN patients, demonstrated that the hippocampus is smaller in TN subjects and hippocampal subfields are selectively affected. Study 2 which includes 61 TN patients with MRI before and after surgery, shown that the hippocampal subfield abnormalities normalized after pain resolution following surgical interventions. This body of work highlights that the hippocampus can be dynamically altered in chronic pain conditions. ii Acknowledgements My journey towards my master’s thesis was impossible without the support and encouragement I have received from my supervisor, Dr. Mojgan (Moji) Hodaie. Moji’s kindness and clinical expertise have been the light that guided me ever since I joined the Hodaie Lab. She has always been there whether it was reviewing my slides at 5:45 am or asking how I feel at 11:30 pm when life gave me hard times. Having the opportunity to join her on her trip to Cambodia as well as observing her efforts at Baha’i Institute for Higher Education (BIHE) are priceless experiences that I will forever carry with me. It has truly been my fortunate to have her as my mentor and supervisor and I will forever be thankful for everything she has done for me. I would also like to thank my parents and brother. They have been with me every step of the way, even though we are physically apart. The courage and perseverance that my brother, Sama, has showed to pursue education have been my inspiration in this challenging journey. I would like to thank my aunt and uncle, Mitra Niroumand and Soheil Homayouni, who helped me to settle in Canada and supported me like their own child over the past six years in every situation. I would like to thank my graduate committee members Drs. Barry Sessle, Karen Davis and Massieh Moayedi, for their invaluable feedback and support at all stages of my degree. I appreciate your insight and expertise. I would also like to thank the current and past members of the Hodaie Lab with whom I have shared many joyful and unforgettable moments: Peter Hung, Jia Zhang, Dr. Adnan iii Waheed, Dr. Matthew Walker, Kaylee Sohng, Dr. Cathy Li, Sarasa Tohyama, Dr. Timur Latypov, Shaun Hanycz, Dr. Aisha Halawani, Powell Chu, and Erika Wharton-Shukster. Peter Hung, Jia Zhang, and Lizbeth Ayoub: thank you for always being there to hear my stories, help me make the right decisions, and most importantly, for your true friendship. I am thankful to receive support from the Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarships-Master’s, Ontario Graduate Scholarship, University of Toronto Centre for the Study of Pain Scientist Award, James F. Crother’s Family Fellowship in peripheral nerve damage, Unilever/Lipton graduate fellowships, and Institute of Medical Science Entrance Award. iv Statement of Contribution Alborz Noorani (author) – all aspects of the work including data collection, experimental design, data analysis, methodological development, data interpretation, and thesis preparation. Dr. Mojgan Hodaie (supervisor) – mentorship, assistance with experimental design, assistance with data interpretation, preparing manuscripts and thesis. Dr. Barry Sessle (committee member) – mentorship and assistance with thesis preparation. Dr. Karen Davis (committee member) – mentorship and assistance with thesis preparation. Dr. Massieh Moayedi (committee member) – mentorship, assistance with data interpretation in the Study II, and assistance with thesis preparation. Peter Shih-Ping Hung – assistance with experimental design, and assistance with data interpretation. Dr. Michael Vaculik (co-first author in Study I) – assistance with experimental design, data interpretation, and drafting the study I manuscript. Jia Yan Zhang – assistance with data collection. v Table of Contents ACKNOWLEDGEMENTS III STATEMENT OF CONTRIBUTION V TABLE OF CONTENTS VI LIST OF ABBREVIATIONS X LIST OF FIGURES XIII LIST OF TABLES XV CHAPTER 1 LITERATURE REVIEW 1 1.1 Pain 1 1.1.1 Nociception 1 1.1.2 Chronic pain 4 1.1.2.1 Chronic neuropathic pain 6 1.1.3 Trigeminal neuralgia 8 1.1.3.1 Trigeminal system anatomy 8 1.1.3.2 Trigeminal neuralgia pain 14 1.1.3.3 Treatment strategies for TN 16 1.2 The hippocampus and pain 18 1.2.1 Hippocampal formation anatomy 19 1.2.2 Hippocampal function and connection 22 1.2.2.1 Intrinsic hippocampal circuitry 22 1.2.2.2 Extrinsic hippocampal circuitry 25 1.2.3 The role of hippocampus in chronic pain conditions 26 1.2.3.1 Nociception and the hippocampus 28 vi 1.2.3.2 Stress and anxiety, as moderators of chronic pain, induce changes in the hippocampal complex 30 1.2.4 Sex differences in the hippocampus 34 1.3 Structural brain imaging 37 1.3.1 Structural MRI 37 1.3.1.1 T1-Weighted imaging 37 1.3.1.2 Grey matter analysis 38 1.3.2 Hippocampal involvement in pain processing – evidence from neuroimaging 40 CHAPTER 2 AIMS & HYPOTHESES 42 2.1 Study I: Selective hippocampal subfield volume reductions in classic trigeminal neuralgia 42 2.1.1 Main Aim 42 2.1.2 Specific Aims 43 2.1.3 Hypotheses 43 2.2 Study II: TN pain relief reverses hippocampal abnormalities 44 2.2.1 Main Aim 44 2.2.2 Specific Aims 45 2.2.3 Hypotheses 45 CHAPTER 3 STUDY I: SELECTIVE HIPPOCAMPAL SUBFIELD VOLUME REDUCTIONS IN CLASSIC TRIGEMINAL NEURALGIA 46 3.1 Abstract 46 3.2 Introduction 47 3.3 Methods 49 3.3.1 Ethics 49 3.3.2 Participants 50 3.3.3 Imaging 50 3.3.4 Automated volumetric hippocampal segmentation 52 3.3.5 Intracranial Volume Correction 53 3.3.6 Manual volumetric hippocampal segmentation 53 3.3.7 Statistical analysis 54 3.4 Results 54 3.4.1 Subject Demographics 54 vii 3.4.2 Automated hippocampal subfield segmentation in R-TN subjects and matched controls 55 3.4.3 Sex dependent differences in hippocampal subfield volumes 59 3.4.4 Correlation of hippocampal subfields changes and pain duration 59 3.4.5 Manual hippocampal segmentation in R-TN subjects and controls 63 3.5 Discussion 64 3.5.1 Hippocampal subfield volume reductions in R-TN subjects correlate with CNS circuits involved in pain processing 65 3.5.2 Bilateral hippocampal subfield reductions in R-TN female subjects 66 3.5.3 Aberrant neurogenesis as the substrate for volume loss in hippocampal subfields 67 3.5.4 Study limitations 68 3.6 Conclusions 69 CHAPTER 4 STUDY II: PAIN RELIEF NORMALIZES HIPPOCAMPAL ABNORMALITIES IN TRIGEMINAL NEURALGIA 70 4.1 Abstract 70 4.2 Introduction 71 4.3 Methods 73 4.3.1 Participants 73 4.3.1.1 TN Patients 73 4.3.1.2 Healthy participants - Cam-CAN 74 4.3.1.3 Healthy controls validation 74 4.3.2 Automated subcortical segmentation 75 4.3.3 Surgical intervention and treatment responses 75 4.3.4 Subcortical volume correction 76 4.3.5 Volumetric percent change after surgery 77 4.3.6 Statistical Analysis 77 4.4 Results 78 4.4.1 Subject demographics 78 4.4.2 Pain relief increases hippocampal volume 80 4.4.3 Pain relief normalizes the hippocampal abnormalities 81 4.4.4 Hippocampal subfields increase significantly after pain relief 83 4.4.5 Sex dependent changes in the hippocampus 85 4.5 Discussion 86 viii 4.5.1 Anatomical segmentation reveals bilateral increase in subregions involved in pain modulation 86 4.5.2 Axial segmentation 88 4.5.3 Hippocampal increase in size may be a consequence of neurogenesis 89 4.5.4 Sex differences in response to pain relief 89 4.5.5 Study Limitations 90 CHAPTER 5 GENERAL DISCUSSION 92 5.1 Summary of findings 92 5.2 Trigeminal neuralgia as a model of evoked pain 93 5.3 Hippocampal alterations in TN 94 5.4 Hippocampal alterations may be related to altered hippocampal cellular mechanisms including neurogenesis and/or microglia regulation 96 5.5 Limitations 98 CHAPTER 6 CONCLUSION 100 CHAPTER 7 FUTURE DIRECTIONS 101 REFERENCES 103 ix List of Abbreviations ACC Anterior Cingulate Cortex ACV Anticonvulsant AHN Adult Hippocampal Neurogenesis ANOVA Analysis Of Variance BEST Bayesian Estimation Supersedes the t-test BNI Barrow Neurological Institute BNZ Benzodiazepine CA Cornu Ammoris Cam-CAN Cambridge Centre For Ageing And Neuroscience CBZ Carbamazepine CIHR Canadian Institutes Of Health Research CNS Central Nervous System DG Dentate Gyrus EC Entorhinal Cortex eTIV Estimated Total Intracranial Volume fMRI Functional Magnetic Resonance Imaging GBP Gabapentin GC DG Granule Cell Layer Of Dentate Gyrus GC-ML-DG Granule Cell And Molecular Layer Of The Dentate Gyrus GKRS Gamma Knife Radiosurgery x GM Grey Matter HATA Hippocampus–Amygdala-Transition-Area HDI Highest Density Interval HPA Hypothalamic-Pituitary-Adrenal IASP International Association For The Study Of Pain ICV Intracranial Volume IHS International Headache Society LTP Long-Term Potentiation MCC Midcingulate