Neural dysregulation in post-COVID fatigue

Abstract Following infection with SARS-CoV-2, a substantial minority of people develop lingering after-effects known as ‘long COVID’. Fatigue is a common complaint with a substantial impact on daily life, but the neural mechanisms behind post-COVID fatigue remain unclear. We recruited 37 volunteers with self-reported fatigue after a mild COVID infection and carried out a battery of behavioural and neurophysiological tests assessing the central, peripheral and autonomic nervous systems. In comparison with age- and sex-matched volunteers without fatigue (n = 52), we show underactivity in specific cortical circuits, dysregulation of autonomic function and myopathic change in skeletal muscle. Cluster analysis revealed no subgroupings, suggesting post-COVID fatigue is a single entity with individual variation, rather than a small number of distinct syndromes. Based on our analysis, we were also able to exclude dysregulation in sensory feedback circuits and descending neuromodulatory control. These abnormalities on objective tests may aid in the development of novel approaches for disease monitoring. Baker et al. report evidence for changes in the state of multiple neural systems in a group of participants suffering from persistent fatigue, several weeks after a non-severe COVID infection. This suggests neural dysregulation could either be predictive of or contribute to post-COVID fatigue. Graphical Abstract Graphical abstract