A link between sleep-wake disturbances and enlarged perivascular spaces in youth with traumatic brain injury

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Project Summary: I propose a 5-year mentored research training program to become a leader in the field of pediatric sleep research. I am residency-trained in Child Neurology, and dual fellowship-trained in Pediatric Neurocritical Care, and Clinical Neurophysiology. I am currently Assistant Professor of Child Neurology at Oregon Health and Science University. This proposal focuses specifically on understanding the role of sleep as a mediator of recovery in youth with mild TBI (mTBI), and the biological mechanisms underlying this mediator effect. My career plan will provide me advanced quantitative skills in biostatistical modeling and longitudinal analysis, use of actigraphy in sleep research, and advanced imaging processing. The training will come through formal coursework, mentored research, experiential learning, and scientific meetings. The overall objective of this proposal is to establish the mechanisms linking sleep-wake disturbances (SWD), glymphatic pathway disturbances, and persistent post-concussive symptoms in youth with mTBI. Every year, millions of youth are affected by mTBI. Post-concussive symptoms include headaches, fatigue, irritability, confusion, forgetfulness, and mood problems. Sleep problems are also a common complaint in this population. Patients with mTBI and subjective sleep problems report more prolonged post-concussive symptoms. However, despite this knowledge, several questions remain: 1) In youth with acute mTBI, to what extent do sleep disturbances play a mediating role in the persistence of post-concussive symptoms? 2) What are the biological mechanisms underlying this mediator effect? In order to answer these questions, I have decided to study the glymphatic pathway, a network of perivascular spaces that supports the clearance of interstitial solutes and wastes from the brain during sleep. Recently, the presence of enlarged perivascular spaces (ePVS) seen on brain MRI has been proposed as a noninvasive marker of glymphatic pathway dysfunction. Our preliminary data and findings from other investigators suggest that enlarged ePVS are seen in patients with mTBI, particularly in those with sleep disturbances. We will take advantage of novel technology developed at OHSU to measure ePVS in a cohort of youth with mTBI. The central hypothesis of this proposal is that glymphatic pathway dysfunction resulting from SWD drives the development and persistence of post-concussive symptoms. To test this hypothesis we will 1) Define the role of SWD as a mediator of persistent post-concussive symptoms in youth with mTBI; 2) Determine the combined effect of mTBI and SWD on ePVS burden in youth and the relationship between ePVS burden and persistent post- concussive symptoms. This research will help understand how sleep affects recovery after mTBI, and the mechanisms underlying this mediator effect. Data generated through this work will allow the design of larger longitudinal studies aimed at defining the long-term effects of SWD on outcomes after mTBI. It will also encourage the exploration of novel mechanisms affecting recovery in animal models of TBI.