Project Summary/Abstract More than one million civilians experience a coma from severe traumatic brain injury (TBI) each year, and thousands of military personnel have experienced a traumatic coma since the start of Operation Enduring Freedom in 2001. Many civilians and veterans face prolonged disorders of consciousness or devastating disability, but recovery of consciousness, communication, and functional independence are possible. This recovery depends upon the preservation of axonal connections within the brainstem’s ascending arousal network (AAN), a subcortical network whose activation of the cerebral cortex is essential for human consciousness. Yet despite the AAN’s critical role in consciousness, there are currently no clinical tools available to identify comatose patients who retain sufficient AAN connectivity to recover consciousness. This limitation leads to inaccurate prognostication and increases the likelihood that life-sustaining therapy will be withdrawn prematurely in the intensive care unit. Moreover, an AAN connectivity map is needed to develop targeted therapies that stimulate AAN neurotransmission, reactivate the cortex and restore consciousness. In this R21 application, we propose to develop an automated AAN segmentation algorithm that will enable AAN connectivity mapping in patients with acute traumatic coma. The segmentation algorithm will be based upon integration of histological immunostaining data and ex vivo 7 Tesla MRI data acquired at ultra-high resolution (100-200 µm) in ten postmortem human brain specimens. The algorithm will be validated for in vivo use in an MRI dataset of 25 healthy human subjects and will then be applied to an MRI dataset acquired in 25 patients with acute traumatic coma. Our goal is to create a quantitative AAN connectivity biomarker for an upcoming clinical trial: STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness). This work is expected to have a significant positive impact because we will disseminate the automated segmentation algorithm to the academic community to advance the study of human consciousness, and because our approach will usher in a new era of targeted stimulant therapy aimed at promoting recovery of consciousness based upon personalized AAN connectivity maps.