Neurobiological Mechanisms of Fatigue in Health and after COVID-19

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.