DESCRIPTION (provided by applicant): Each year millions of Americans are concussed from sport-related incidents, accidents or military service. While extensive research has been done to identify biomarkers for diagnosing concussion, a specific biomarker for concussion recovery has yet to be identified. Concussion is a brain injury with physiological effects on cerebral blood flo (CBF) and autonomic nervous system (ANS) function. These effects may be why exercise exacerbates concussion symptoms. Thus, exercise intolerance is a physiological sign of concussion. Ergo, normal exercise tolerance indicates physiological recovery. Our long-term goal is to better understand the systemic physiological disturbance of concussion to develop reliable methods for the differential diagnosis of concussion and of post-concussion syndrome, to establish objective markers of recovery, and to develop novel treatments to speed recovery. The overall objective of this application is to identify the physiological mechanisms of exercise intolerance in concussion. The rationale for the proposed study is that our work could show that systematic determination of return of exercise tolerance is a specific biological marker of recovery from concussion. This would help patients and clinicians know with confidence when it is safe to return to activity. We developed the Buffalo Concussion Treadmill Test to systematically evaluate exercise tolerance in concussed athletes. We have found abnormally elevated CBF during exercise after concussion in association with altered sensitivity to the effects of CO2 that blunts ventilation. We have also detected that cardiac output (CO) is low after concussion. A fundamental question is whether exercise tolerance after concussion is limited centrally (brain) or peripherally (cardiovascular/muscle). We will examine this by pursuing the following two specific aims: (1) Identify the source (central or peripheral) of exercise intolerance in concussion and (2) Identify the mechanism of central exercise intolerance in concussion. Concussed male and female participants will have measures of CO2 sensitivity, ventilation, CBF (by arterial spin labelling in the MRI), blood lactate, and CO at res and during simulated exercise (head down tilt, HDT) in the MRI machine and during the Buffalo treadmill exercise test soon after concussion and upon recovery. We will also measure DTI to evaluate for injury to the brainstem and corpus callosum. Values will be compared to those in healthy controls. The work is expected to identify that the physiological mechanism of exercise intolerance in concussion is central from abnormal control of CBF. The work is expected to establish that return of normal physiology (and of normal exercise tolerance) is a functional biomarker of recovery from concussion. The work is significant because a physiological biomarker will impact how patients are judged clinically to be recovered from concussion, i.e., physiologically ready to ret...