Neurobiological Mechanisms of Fatigue in Health and after COVID-19

项目总结 疲劳是神经系统、精神病学和其他慢性疾病最常见和最令人衰弱的症状之一。 疾病；然而，对它的了解仍然很少，治疗不足。SARS-CoV-2的急性后遗症 感染(PASC)是一种新的综合征，其特征是在四周或更长时间后出现一系列症状 新冠肺炎的急性期。在这些症状中，严重疲劳是最常见的，也是最令人虚弱的。 理解和治疗疲劳的关键障碍包括疲劳的多维性和缺乏 用定量的方法来表征它。在这个马赛克K99/R00应用程序中，我建议使用一个新的`疲劳 利用神经肌肉、神经经济学和计算方法来客观地研究 健康人和PASC患者疲劳的三个特征的神经生物学机制： 疲劳感(感到多么疲倦)，努力感(如何感知以前施加的力量)，以及 努力的意愿(个人做出努力的决定)。我的中心假设是 疲劳至少由三个可分离的特征组成，它们代表着不同的心理生理方面， 具有独特的神经相关性，并受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 肯尼迪·克里格研究所的实验室和约翰·霍普金斯大学生物医学工程系，将 识别编码健康人疲劳特征的脑网络(S)(目标1)，并研究如何 PASC患者的疲劳表现(目标2)。通过这些项目，以及我导师的指导 团队(博士Vikram Chib，Karen Quigley，Laura Malone和Martin Lindquist)，我将获得补充 神经成像、心理生理学、计算和翻译神经科学方面的专业知识。在R00中 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 识别大脑网络的技能(S)编码PASC中的疲劳(目标3)。这一阶段将由我自己执行 实验室在获得一个独立的教员职位后。 疲劳和PASC目前的流行病学意义使这项建议特别及时和 这很重要，因为它将极大地促进我们对疲劳的理解，并有助于NIH的恢复 主动权。此外，拟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人员，他将区分疲劳的神经生物学机制 针对不同疾病，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.