Neurobiological Mechanisms of Fatigue in Health and after COVID-19

项目摘要 疲劳是神经、精神和其他慢性疾病中最常见的和使人衰弱的症状之一。 疾病;然而，对它的了解仍然很少，治疗不足。SARS-CoV-2急性期后后遗症 感染（PASC）是一种新的综合征，其特征是在感染后四周或更长时间出现一系列症状。 COVID-19的急性期在这些症状中，严重的疲劳是最常见的和衰弱的。 理解和治疗疲劳的关键障碍包括其多方面的性质和缺乏 定量方法来表征它。在这个马赛克K99/R 00应用程序，我建议使用一种新的`疲劳 范式”，利用神经肌肉、神经经济学和计算方法来客观地调查 健康个体和PASC个体疲劳的三个特征的神经生物学机制： 疲倦的感觉（一个人感到多么疲倦），努力的感觉（一个人如何感知先前施加的力量），以及 努力的意愿（一个人参与努力行动的决定）。我的核心假设是 疲劳包括至少三个可分离的特征，它们代表不同的心理生理学方面， 具有独特的神经相关性，并受到PASC的不同影响。 为K99阶段提出的实验将在Vikram Chib博士的神经经济学中执行。 约翰霍普金斯大学肯尼迪克里格研究所和生物医学工程系的实验室将 识别健康个体编码疲劳特征的大脑网络（目标1），并研究如何 疲劳表现在PASC患者中（目的2）。通过这些项目，以及我的指导， 团队（Vikram Chib，Karen Quigley，Laura马龙和Martin Lindquist博士），我将获得补充 在神经影像学，心理生理学，计算和转化神经科学的专业知识。在R 00 阶段，我建议将我在神经肌肉生理学和运动控制方面的专业知识与我新获得的 识别PASC中编码疲劳的大脑网络的技能（目标3）。此阶段将在我自己的 实验室在确保一个独立的教师职位。 疲劳和PASC的当前流行病学意义使得这一建议特别及时， 重要的是，因为它将大大提高我们对疲劳的理解，并有助于NIH的康复 倡议此外，建议的研究和培训计划将使我能够实现我的长期职业目标 成为一名独立的研究者，将区分疲劳的神经生物学机制， 不同的疾病，并制定有针对性的临床干预措施。

PROJECT SUMMARY Fatigue is one of the most common and debilitating symptoms in neurological, psychiatric, and other chronic illnesses; however, it remains poorly understood and undertreated. Post-acute sequelae of SARS-CoV-2 infection (PASC) is a novel syndrome characterized by a range of symptoms present four or more weeks after the acute phase of COVID-19. Among these symptoms, severe fatigue is the most common and debilitating. Critical hurdles to understanding and treating fatigue include its multidimensional nature and the lack of quantitative methods to characterize it. In this MOSAIC K99/R00 application, I propose to use a novel `fatigue paradigm' that leverages neuromuscular, neuroeconomic, and computational methods to objectively investigate the neurobiological mechanisms of three features of fatigue in healthy individuals and individuals with PASC: feeling of weariness (how weary one feels), sense of effort (how one perceives a previously exerted force), and willingness to exert effort (an individual's decision to engage in effortful actions). My central hypothesis is that fatigue is comprised of at least three separable features, which represent distinct psychophysiological aspects, have unique neural correlates, and are differentially affected by PASC. The experiments proposed for the K99 Phase, which will be executed in Dr. Vikram Chib's Neuroeconomic Laboratory in the Kennedy Krieger Institute and Department of Biomedical Engineering at Johns Hopkins, will identify the brain network(s) encoding the features of fatigue in healthy individuals (Aim 1) and investigate how fatigue manifests in individuals with PASC (Aim 2). Through these projects, and the guidance of my mentoring team (Drs. Vikram Chib, Karen Quigley, Laura Malone, and Martin Lindquist), I will acquire complementary expertise in neuroimaging, psychophysiology, and computational and translational neuroscience. In the R00 Phase, I propose to merge my expertise in neuromuscular physiology and motor control with my newly acquired skills to identify the brain network(s) encoding fatigue in PASC (Aim 3). This Phase will be executed in my own laboratory upon securing an independent faculty position. The current epidemiological significance of fatigue and PASC makes this proposal especially timely and important, as it will significantly advance our understanding of fatigue and contribute to the NIH's RECOVER initiative. Further, the proposed research and training plans will allow me to accomplish my long-term career goal of becoming an independent investigator who will distinguish the neurobiological mechanisms of fatigue in different illnesses and develop targeted clinical interventions.