Neuroimaging markers of cognitive fatigue in individuals with post-acute sequelae of SARS-CoV-2 infection

•Persistent cognitive fatigue is common in individuals with Post-Acute Sequelae of SARS-CoV-2 Infection.•We explored brain activation in PASC patients during a fatiguing cognitive task.•PASC patients showed differences in brain activation in fatigue-related and additional regions.•PASC patients also had increased frontal task-related activation compared to controls.•Findings suggest PASC patients may exert more mental effort during demanding tasks. Persistent cognitive fatigue (CF) is the most reported symptom in Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), but little is known about its underlying neural basis. This pilot study examined fMRI brain activation patterns during a fatiguing task in those with and without PASC. We hypothesized that individuals with PASC would show changes in CF-related brain activation within fatigue network. Participants were 10 adults with PASC and persistent CF and 10 age- and gender-matched healthy controls. The 2-back working memory task was used during fMRI to induce CF. Patients with PASC reported greater CF, as measured using a Visual Analogue Scale of Fatigue (VAS-F), throughout the task. The relationship of brain activation in the fatigue network to increased CF during the fatiguing task did not differ between groups. There were, however, more areas inside and outside the fatigue network that were activated in the PASC group as reported CF increased. The relationship between brain activation and scores on the 2-back did differ between groups, with the PASC group showing more frontal activation. Findings suggest that individuals with PASC and CF may need to exert greater mental effort during demanding cognitive tasks, reflected in recruitment of a broader network of brain regions.