ABSTRACT Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a symptom-based diagnosis characterized by severe debilitating fatigue, cognitive dysfunction, and widespread pain. Most cases of ME/CFS begin with a viral infection or involve multiple exposures to pathogens over time. Soon after the onset of the COVID-19 pandemic, a significant portion of patients infected with SARS-CoV-2 developed chronic symptoms that overlap greatly with those of ME/CFS. Among the post-acute sequelae of COVID-19 (PASC), “brain fog” symptoms have been widely reported including in patients with mild initiating infection. Many PASC patients meet the diagnostic criteria for ME/CFS after 6 months of ongoing symptoms (referred to herein as PASCME/CFS). Given the growing number of SARS-CoV-2 infections, the disease burden on individuals with ME/CFS and PASC-ME/CFS, and the challenges associated with these conditions such as rehabilitation and workforce disruptions, elucidating the mechanisms of cognitive deficits in ME/CFS and PASC-ME/CFS is of clear

public health relevance. The current proposal will bring together two laboratories with expertise in neuroimaging and ME/CFS research to improve our understanding of the neural underpinnings of cognitive control deficits in patients with ME/CFS and PASC-ME/CFS. Through a multimodal study combining behavioral, EEG, fMRI and neuroimmune analyses, we will identify the oscillatory, connectomic and inflammatory markers of impaired cognitive control in ME/CFS and PASC-ME/CFS. Our specific aims are to: 1) define the oscillatory markers of cognitive deficits in patients, 2) define the deficits in task-induced reconfiguration in the cognitive control network in patients, 3) determine the relationships among the inflammatory, electrophysiologic, and connectomic markers of impaired cognitive control in ME/CFS and PASC-ME/CFS. Our proposal will lay the groundwork for development of novel therapies that can target the spatiotemporal neuromarkers identified in our studies to mitigate cognitive deficits in individuals with ME/CFS and PASC-ME/CFS.