Mechanisms Underlying Disorders of Consciousness: Insights from Anatomical Connectivit

Disorders of consciousness (DOC) resulting from severe brain injury that disrupt arousal and awareness systems (main components of consciousness) bear one of the most complex patterns of neuropathology, often widespread and variable across patients. This makes it difficult to both unveil the mechanisms contributing to the pathological states of consciousness and develop reliable biomarkers to assist in the accurate diagnosis of patients with varying levels of residual awareness. To better address these issues, I present four studies aiming at elucidating the mechanisms underlying DOC using diffusing imaging techniques to assess anatomical connectivity in patient and healthy populations. Study 1 examines the relationship between thalamo-cortical connectivity and variations in consciousness impairment. Study 2 replicates and expands upon Study 1 in a separate, larger cohort of patients, while additionally investigating thalamo-basal ganglia connectivity. Findings that replicated included a general pattern of decreased thalamo-prefrontal and increased thalamo-occipital connectivities in patients on the lower end of the consciousness spectrum compared to the higher end. The thalamo-prefrontal system is critical for maintaining conscious behavior and consistently implicated in DOC. The paradoxical increase in thalamo-occipital connectivity presents a novel finding and could underlie the brain's compensatory mechanism counteracting the loss of activity in more severely injured higher-order fronto-parietal-temporal cortices. Moreover, to enhance diagnostic accuracy, multivariate classifications were also carried out in both studies to identify neural markers that successfully distinguished among the patients. Study 3 and 4 focus on uncovering the multifaceted roles of an underappreciate structure, the external globus pallidus (GPe), and discuss its potential influence in the context of DOC. We found GPe to contain limbic, associative, and sensorimotor territories and direct prefrontal and thalamic connections, potential routes for impacting arousal and awareness. Addressing the limitations of the most widely accepted model, The Mesocircuit Hypothesis, in explaining the mechanisms underlying DOC, I propose a new working model with incorporation of GPe to help disentangle the pallidal circuits that differentially contribute to aspects of consciousness and motor behavior. These studies provide vital insights into the mechanisms associated with loss and recovery of consciousness, and may also facilitate important clinical and ethical implications.