PROJECT SUMMARY This project is a multi-site clinical trial of a transcranial magnetic stimulation-electroencephalography (TMS-EEG) device for diagnostic and prognostic use in critically ill patients with acute disorders of consciousness (DoC). Acute DoC after severe brain injury affect more than 1 million people worldwide each year. Withdrawal of life- sustaining therapy based on a perceived poor prognosis is the most common cause of death. However, recent studies suggest that 15-20% of patients who appear unresponsive in the intensive care unit are covertly conscious when assessed with advanced neurotechnologies and that the presence of covert consciousness predicts long-term recovery. Accordingly, recent clinical guidelines published by the American Academy of Neurology, American Congress of Rehabilitation Medicine, and the U.S. National Institute on Disability, Independent Living and Rehabilitation Research (2018), as well as the European Academy of Neurology (2020) and the International Federation of Clinical Neurophysiology (2020), endorsed the use of advanced neurotechnologies to detect covert consciousness in patients with DoC. Motivated by these recently published clinical guidelines and by emerging evidence that TMS-EEG outperforms other advanced neurotechnologies with respect to its sensitivity for identifying conscious patients, we propose an R01 project that will test the diagnostic and prognostic utility of TMS-EEG measures of brain complexity in the intensive care unit. We hypothesize that TMS-EEG detects high brain complexity compatible with consciousness in patients whose behavioral examination reveals a minimally conscious state, and that TMS- EEG predicts long-term recovery of function in patients whose behavioral examination suggests a coma or vegetative state. We will also perform functional magnetic resonance imaging and EEG assessments to provide mechanistic insights into the brain network connectivity properties that underly TMS-EEG measurements of brain complexity. This study leverages an interdisciplinary team of neurologists, neuroscientists, and electrophysiologists, all with experience and expertise in developing state-of-the-art diagnostic and prognostic tools for patients with DoC. Translation of TMS-EEG to the intensive care unit has the potential to save lives by preventing premature withdrawal of life-sustaining therapy in patients who have the potential for long-term recovery.

PROJECT NARRATIVE This R01 project is a multi-site clinical trial of transcranial magnetic stimulation-electroencephalography (TMS- EEG), whose goal is to determine whether TMS-EEG measurements of brain complexity detect and predict recovery of consciousness in critically ill patients with acute severe brain injuries. The clinical motivation for this trial is that TMS-EEG measurements of brain complexity have the potential to improve the accuracy of diagnosis and prognosis in the intensive care unit, thereby informing decisions about life-sustaining therapy for patients with severe brain injuries. We will also use functional MRI and EEG in this project to provide mechanistic insights into the brain network connectivity properties that underly TMS-EEG measurements of brain complexity.