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.