PROJECT SUMMARY Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) and has led to a global pandemic, infecting more than 760 million people worldwide. Although COVID-19 was initially described as a respiratory disease, there is growing evidence that SARS-CoV-2 impacts the nervous system and causes impairments that may last long after the acute phase of the disease. This spectrum of persistent symptoms is called Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) or Long COVID. Physical fatigue is one of the most common symptoms associated with PASC, yet there is a limited understanding of its behavioral and neural mechanisms. Neuroinflammation is thought to be a primary contributor to feelings of fatigue in many neurological disorders, including PASC, and brain blood-brain barrier (BBB) injury is a hallmark of neuroinflammation. Despite the potential links between PASC, BBB dysfunction, and fatigue, their relationship has yet to be studied. To this end, we will use a combination of experiments in human participants, computational modeling of behavior, and neuroimaging. The central hypothesis of this proposal is that individuals with PASC will have increased BBB permeability from COVID infection, which disrupts neural processing of effort, resulting in increased feelings of physical fatigue. Aim 1 will determine the relationship between BBB permeability and neural and behavioral representations of effort assessment in individuals with PASC suffering from fatigue. We will collect measures of BBB permeability in PASC patients, have them make assessments of effort, and scan their brains with fMRI while they make these judgments. This data will allow us to study how disruptions in effort assessment are related to COVID-19-induced changes in BBB permeability, and their influence on the neural representations of effort. In Aim 2, we will investigate how BBB permeability influences individuals with PASC's immediate response to bouts of fatiguing exertion and the underlying neural processes. We will have individuals perform bouts of fatiguing exertion and simultaneously scan their brains with fMRI. This data will allow us to study how individuals with PASC's feelings of fatigue (and associated neural activity) evolve, and how COVID-induced increases in BBB permeability mediate these changes. In Aim 3 we will evaluate how BBB permeability changes through the time course of PASC and how these changes are related to behavioral and neural representations of fatigue. Over the course of a year, we will collect measures of BBB permeability in individuals with PASC and have them assess their levels of effort exertion and perform effort-based decision-making tasks while scanned with fMRI. In sum, our proposed studies will provide an understanding of the neurobiological mechanisms of fatigue in PASC. This knowledge will eventually provide candidate mechanisms to target with pharmacological intervention and inform rehabilitative care for those individuals suffering from symptoms of fatigue in PASC.

PROJECT NARRATIVE This proposal aims to understand the neurobiological mechanisms of fatigue in individuals with Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). This knowledge will eventually provide candidate mechanisms to target with pharmacological intervention and inform rehabilitative care for those individuals suffering from symptoms of fatigue in PASC.