PROJECT SUMMARY/ABSTRACT – Autonomic Biomarker Core While many symptoms and signs of autonomic nervous system (ANS) disorder are found in patients with persistent post-concussive symptoms (PPCS), ANS function in concussion has been extraordinarily understudied, particularly in adolescents. Despite the limited number of studies, there is clear evidence of ANS dysfunction sub-acutely and chronically following concussion. In a recent systematic review, 33/36 studies identified ANS anomalies in concussed athletes and non-athletes. The most consistent findings are lower parasympathetic activity during rest and activities that normally enhance parasympathetic response, such as deep breathing, as well as activities that normally enhance sympathetic response, such as orthostatic challenge. There are, however, major limitations in existing studies including very few studies of adolescents, small to modest sample sizes (~20 patients), and limited sets of ANS measures or autonomic challenges used in any one study. Because of these methodological limitations, prior studies do not provide clear guidance as to the best set of measures and testing conditions to assess ANS function in adolescents with PPCS. We will develop a comprehensive, scalable assessment of ANS function in adolescents. Among the many innovative features of this panel are: 1) both cardiovascular and pupillary measures of sympathetic and parasympathetic function, and 2) a standardized set of brief physiological challenges to assess both sympathetic and parasympathetic activity. We use rest, recovery, and deep breathing protocols to maximize sensitivity for detecting parasympathetic dysfunction. We use an orthostatic challenge and a psychological stressor to maximize sensitivity for detecting sympathetic dysfunction. Heart rate variability as well as heart rate, respiratory rate, and blood pressure will be recorded concurrently during these activities. We use pupillometry as a complementary non-cardiac assessment of autonomic dysfunction. We will also 3) develop norms by age and gender for all of the measures in the panel that can be incorporated into clinical decision-making. The broad range of ANS measures and testing conditions used here will identify the measures and testing conditions that best predict the persistence of concussive symptoms. This panel of measures will be used to characterize one or more ANS endophenotypes linked to clusters of PPCS symptoms. The panel of ANS measures developed here will help elucidate the pathobiologies underlying PPCS by examining the link between ANS and central nervous system markers and blood-based markers of axonal injury and neuroinflammation.