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

项目摘要： 我建议一个为期5年的指导研究培训计划，成为儿科睡眠领域的领导者 research.我在儿童神经病学住院医师培训，并在儿科神经重症监护双奖学金培训， 临床神经生理学我目前是俄勒冈州健康中心的儿童神经病学助理教授， 科学大学。这项建议特别关注于理解睡眠作为一种调节剂的作用， 轻度TBI（mTBI）青年的恢复，以及这种介体效应的生物学机制。我 职业规划将提供我先进的定量技能，在生物统计建模和纵向分析，使用 以及先进的成像处理技术。培训将通过正式的 课程作业、指导研究、体验式学习和科学会议。 这项建议的总体目标是建立联系睡眠-觉醒障碍的机制 (SWD)，胶质淋巴通路紊乱，和持续的脑震荡后症状的青年， mTBI。每年有数百万年轻人受到mTBI的影响。脑震荡后的症状包括头痛 疲劳、易怒、混乱、健忘和情绪问题。睡眠问题也是一个常见的投诉 在这个人群中。患有mTBI和主观睡眠问题的患者报告更长时间的脑震荡后 症状然而，尽管有这些知识，仍然存在几个问题：1）在患有急性mTBI的青年中， 睡眠障碍在脑震荡后症状的持续性中发挥中介作用的程度？2)什么 这种介体效应背后的生物学机制是什么？为了回答这些问题，我 决定研究胶质淋巴通路，这是一个血管周围空间网络，支持清除 在睡眠期间从大脑中清除间质溶质和废物。最近，存在扩大的血管周围 在脑MRI上看到的ePVS被认为是胶质淋巴通路的非侵入性标志物 功能障碍我们的初步数据和其他研究者的发现表明， mTBI患者，尤其是睡眠障碍患者。我们将利用新技术 在OHSU开发，用于测量mTBI青年队列中的ePVS。这个问题的核心假设是 建议是，由SWD导致的胶质淋巴通路功能障碍推动了 脑震荡后症状持续存在为了验证这一假设，我们将1）将社署的角色定义为 在患有mTBI的青年中持续的脑震荡后症状的介质; 2）确定以下各项的联合作用： mTBI和SWD对青年ePVS负担的影响，以及ePVS负担与持续性 脑震荡症状这项研究将有助于了解睡眠如何影响mTBI后的恢复， 这种中介作用的机制。通过这项工作产生的数据将允许设计更大的 纵向研究旨在确定SWD对mTBI后结局的长期影响。它还将 鼓励探索影响TBI动物模型恢复的新机制。

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.