Understanding the effect of post-concussive sleep disruption on glymphatic function in collegiate athletes

Project Summary: Up to 4000 collegiate athletes annually sustain a concussion in the United States. Sleep-wake disturbance (SWD) is one of the most common complaints following a concussion. Athletes who report post-concussive SWD also report worse somatic and cognitive impairment and a longer recovery time. Unfortunately, the current therapies aimed at improving sleep in patients with concussions are limited by poor compliance and low efficacy. Our long-term goal is to target post-concussive SWD as an independent, modifiable risk factor for poor outcomes in collegiate athletes and other at-risk populations. In this study, we aim to answer two fundamental questions. First, among student-athletes, who is at risk for developing post-concussive SWD? Second, what are the biological mechanisms linking post-concussive SWD and poor outcomes? Answering those questions will advance our field by 1) allowing early identification of at-risk subjects and 2) establishing therapeutic targets for the thousands of patients who, despite their best attempts, still struggle with poor sleep following a concussion. This proposal focuses on the glymphatic pathway as a potential biological link between post-concussive SWD and poor outcomes. The glymphatic pathway is a network of perivascular spaces that supports the clearance of cerebral interstitial molecules and wastes during sleep. In animal models, concussion and sleep restriction impair glymphatic function, worsening neurological function. However, the combined effects of concussion and post-concussive SWD on glymphatic function in humans remain unknown. We hypothesize that concussion and post-concussive SWD have a multiplicative impact on glymphatic function impairment (i.e., a 'double hit' mechanism). We use magnetic resonance imaging (MRI) to measure human perivascular spaces. The number and volume of these structures (i.e., their burden) have been proposed as a surrogate marker of glymphatic function. In addition, we recently developed other MRI modalities to assess different facets of glymphatic function. To test our hypotheses, we will track sleep in a cohort of collegiate athletes during the sports season using actigraphy and a contactless bed mat sensor. We will also obtain a polysomnogram and an MRI fourteen days post-injury in those with a concussion and controls with musculoskeletal injuries. We will use advanced neuroimaging techniques to measure various aspects of glymphatic function, including perivascular space burden, contrast clearance, water diffusion, and slow vasomotor oscillations. We propose the following aims: in collegiate athletes, 1) define the pre-morbid risk factors for developing post-concussive SWD; 2) establish the combined effects of concussion and post- concussive SWD on perivascular space burden; 3) determine the association between post-concussive SWD and non-invasive, clinically available neuroimaging markers of glymphatic dysfunction. Results from this study may help identify at-risk subjects and provide the rationale for targeting glymphatic function (pharmacologically or via other interventions) to prevent post-concussive morbidity in athletes and other populations.