BME PhD Dissertation Defense: Morgan Cambareri

Title: "The Role of the Subcortex in Sustaining Complex Dynamics Associated with Conscious Awareness - Insights from Healthy Controls and Patients with Disorders of Consciousness"

Advisory Committee: Brian Edlow, MD – HMS, MGH Neurology (Primary Advisor) David Boas, PhD – BME (Research Co-Advisor) Anna Devor, PhD – BME (Chair) Laura Lewis, PhD – BME

Abstract: Disorders of consciousness (DOC) are brain states where consciousness is impaired or altered in an individual following a severe brain injury. Despite substantial progress in detecting recovery of consciousness in patients with DOC, prognostication remains challenging, particularly for patients who experience a traumatic brain injury (TBI) due to the heterogeneous multifocal disruption of brain networks. Furthermore, while there are many new therapies being tested for patients with traumatic DOC, there is a lack of available therapies that reliably promote recovery of consciousness. Identification of prognostic biomarkers and therapeutic targets can help families make more informed decisions about continuation of life-sustaining therapy, can facilitate personalized selection of consciousness-promoting therapies, and can generate new mechanistic insights into the neurobiological basis for loss and recovery of consciousness. To this end, the research in this dissertation aims to investigate the subcortical relationships to complex cortical signatures relevant for consciousness; namely cortical resting state networks and a cortical complexity measure generated by transcranial magnetic stimulation paired with electroencephalography (TMS-EEG). First we investigated the subcortical correlates of canonical cortical resting state networks to identify subcortical network hubs. A key biomarker that scales with behavioral measures and recovery is resting state functional MRI (rs-fMRI) network integrity, in particular the default mode and the executive control networks. While damage to the subcortex is implicated in the pathogenesis of DOC, the subcortical correlates of these rs-fMRI networks have not been well studied. In our second project we investigated the subcortical connectivity to TMS evoked complexity across the cortex utilizing rs-fMRI, and diffusion MRI (dMRI). TMS-EEG shows a strong association with conscious awareness in a broad spectrum of experimental and clinical conditions, including arousal from sleep, awakening from anesthesia, and recovery from severe brain injury. Emerging evidence from animal models suggests that PCI is modulated by thalamocortical connectivity, but there is no consensus as to the anatomical basis for the generation of this complexity measure within the cortex in humans. In this study we leveraged healthy control subjects to identify if stimulation site connectivity to nuclei associated with arousal and awareness would be predictive of complexity values. In our final project we investigated TMS-EEG evoked complexity in a small subset of DoC Patients to gain insights into the applicability of the healthy control derived predictive model to severely brain injured patients.