Western University Scholarship@Western Electronic Thesis and Dissertation Repository 10-29-2019 4:15 PM The Neural Circuitry of Sensory Processing in Post-traumatic Stress Disorder Sherain Harricharan The University of Western Ontario Supervisor Lanius, Ruth A. The University of Western Ontario Graduate Program in Neuroscience A thesis submitted in partial fulfillment of the equirr ements for the degree in Doctor of Philosophy © Sherain Harricharan 2019 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Psychiatric and Mental Health Commons Recommended Citation Harricharan, Sherain, "The Neural Circuitry of Sensory Processing in Post-traumatic Stress Disorder" (2019). Electronic Thesis and Dissertation Repository. 6695. https://ir.lib.uwo.ca/etd/6695 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract Background: Traumatic experiences can have severe emotional and psychological consequences, which may affect the capacity to process both internal and external sensory information. Such aberrations may have cascading effects in individuals with post-traumatic stress disorder (PTSD), where alterations in sensory processing may hinder the capacity for higher-order executive functions, including emotion regulation. Delineating the neural circuitry of subcortical and cortical structures thought to be central to sensory processing is therefore critical to the study of PTSD and may help to develop an understanding of the neurobiological mechanisms underlying this often debilitating disorder. Methods: Various neuroimaging approaches were employed to investigate sensory processing in PTSD, its dissociative subtype, and healthy controls. First, resting-state connectivity patterns of subcortical brainstem structures linked to interoceptive and exteroceptive sensory processing, including the periaqueductal gray and the vestibular nuclei, were examined (chapters 2 and 3). In addition, given that the insula is critical for relaying exteroceptive and interoceptive sensory information to other neurocognitive networks in the brain, resting-state whole brain seed-based connectivity patterns of different insula subregions were investigated (chapter 4). Furthermore, machine learning analyses were used to assess the utility of insula subregion resting-state connectivity patterns as a diagnostic predictor for classifying PTSD, its dissociative subtype, and healthy controls. Finally, a task- based paradigm using oculomotor stimuli with simultaneous traumatic autobiographical memory recall was employed to examine cortical brain structures involved in the convergence of exteroceptive and interoceptive sensory information (chapter 5). ii Results and Discussion: As compared to controls, widespread periaqueductal gray connectivity was observed with cortical structures associated with emotional reactivity and defensive responding in PTSD and its dissociative subtype at rest. In addition, as compared to controls, decreased vestibular nuclei connectivity with cortical structures essential to exteroceptive sensory processing and multisensory integration was observed in individuals with the PTSD dissociative subtype. Moreover, PTSD showed limited cortical insula subregion resting-state connectivity with frontal lobe structures involved in the central executive network, which may be associated with impairment of higher-order executive functions, including emotion regulation, in PTSD. Finally, exposure to simultaneous exteroceptive and interoceptive sensory stimuli through oculomotor eye movements performed simultaneous to traumatic memory recall engaged the dorsal attentional network and default-mode frontoparietal networks that have been demonstrated to work in tandem to facilitate connectivity with structures in the central executive network, including the dorsolateral and dorsomedial prefrontal cortex, necessary for multisensory integration and emotion regulation. This effect was greater in individuals with PTSD and may provide a neurobiological account for how oculomotion may influence the frontoparietal cortical representation of traumatic memories. Overall, the findings of this dissertation reveal that individuals with PTSD experience aberrations in the neural circuitry necessary for processing both interoceptive and exteroceptive sensory information. We hypothesize that these observed alterations in interoceptive and exteroceptive neural processing may underlie, in part, the emotion dysregulation and maladaptive responses to chronic stress, including hypervigilance and dissociative symptoms, observed in PTSD and its dissociative subtype. iii Keywords post-traumatic stress disorder, dissociation, sensory processing, neuroimaging, brainstem, periaqueductal gray, vestibular system, insula, prefrontal cortex, frontoparietal network, multisensory integration, executive function, emotion regulation Summary for Lay Audience Post-traumatic stress disorder (PTSD) is a psychiatric disorder that is triggered by an individual experiencing or witnessing a traumatic event, which may precipitate persistent flashbacks and severe anxiety, causing individuals to be fearful and hypervigilant of their surroundings. Approximately 14-30% of traumatized individuals may present with a dissociative subtype of PTSD, which is often associated with repeated trauma or childhood trauma. These patients may present with additional symptoms, including depersonalization and derealization, where they may feel as if the world or self is “dream-like” and not real and/or describe “out-of-body” experiences. This dissertation explores potential neural alterations that may signify how traumatized individuals with PTSD and its dissociative subtype experience sensations differently, whether they are from the outside world (i.e. touch, auditory, visual sensations) or from the internal body (i.e. emotions, visceral sensations). It is hypothesized that alterations in neural pathways important for the processing of these sensations may have cascading effects on the performance of higher- order cognitive functions, including emotion regulation. Various functional magnetic resonance imaging techniques were employed to examine brain structures critical to sensory processing in individuals with PTSD, the PTSD dissociative subtype and healthy controls. iv The cumulative findings from this dissertation have been summarized into a theoretical framework that hypothesizes a neurobiological account through which sensory processing may be impacted in traumatized individuals. v Co-Authorship Statement Sherain Harricharan, Maria Densmore, Dr. Andrew Nicholson, Dr. Mischa Tursich, Dr. Jean Théberge, Dr. Margaret McKinnon, Dr. Paul Frewen, Dr. Richard Neufeld, Dr. Daniela Rabellino, Dr. Allan Schore Dr. Janine Thome, Dr. Bessel Van der Kolk, Dr. Ruth Lanius As author of this thesis and the primary author of the four experimental chapters, Sherain Harricharan was responsible for designing the experiments, data analysis, and writing the completed thesis and manuscripts for each experiment. Maria Densmore helped supervise the statistical analysis used to investigate neuroimaging data (Chapters 2-5) and assisted in data analysis for Chapter 5. Dr. Andrew Nicholson supervised the machine learning neuroimaging analysis used in Chapter 4 and was consulted about the neuroscientific inferences made from experimental findings in Chapters 3 and 4. Dr. Mischa Tursich helped design the task-based paradigm used in Chapter 5. Dr. Jean Théberge oversaw the implementation of brain imaging acquisition methods used to collect neuroimaging data in Chapters 2-5. Dr. Margaret McKinnon was consulted about the neuroscientific inferences made from the experimental findings for Chapter 5 and helped revise the experimental manuscripts for Chapter 2-5. Dr. Paul Frewen was consulted about the neuroscientific inferences made from the experimental findings for Chapter 2,4 and 5. Dr. Richard Neufeld was consulted about the statistical analysis used to study neuroimaging data in Chapters 3 and 4. Dr. Daniela Rabellino and Dr. Allan Schore were consulted about the neuroscientific inferences made from the experimental findings for Chapter 2. Dr. Janine Thome was consulted about the neuroscientific inferences made from the experimental findings for Chapter 4. Dr. Bessel Van der Kolk was consulted about the neuroscientific inferences made from the experimental vi findings for Chapter 5. Dr. Ruth Lanius supervised all stages of this thesis and assisted in experimental design and manuscript revisions for all four experimental chapters. vii Acknowledgments Foremost, I would like to thank my supervisor, Dr. Ruth Lanius. Thank you for taking a chance on me and providing me with an amazing opportunity that ignited my passion for studying post-traumatic stress disorder. I feel incredibly proud of the work done in our lab and it is because of the confidence and trust you instill in your staff and students. Next, I would like to thank Suzy Southwell and Stephanie Nevill for all the hard work they do in recruiting and assessing participants for our numerous studies. In addition, I would like to thank Maria Densmore for her guidance and mentorship to ensure neuroimaging statistical models are implemented correctly. I would also like to thank Nancy Mazza for all the administrative work she does