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Structural brain changes in patients with post-COVID fatigue: a prospective observational study (Heine et al, 2023)



Post-COVID syndrome is a severe long-term complication of COVID-19. Although fatigue and cognitive complaints are the most prominent symptoms, it is unclear whether they have structural correlates in the brain. We therefore explored the clinical characteristics of post-COVID fatigue, describe associated structural imaging changes, and determine what influences fatigue severity.


We prospectively recruited 50 patients from neurological post-COVID outpatient clinics (age 18–69 years, 39f/8m) and matched non-COVID healthy controls between April 15 and December 31, 2021. Assessments included diffusion and volumetric MR imaging, neuropsychiatric, and cognitive testing. At 7.5 months (median, IQR 6.5–9.2) after the acute SARS-CoV-2 infection, moderate or severe fatigue was identified in 47/50 patients with post-COVID syndrome who were included in the analyses. As a clinical control group, we included 47 matched multiple sclerosis patients with fatigue.


Our diffusion imaging analyses revealed aberrant fractional anisotropy of the thalamus. Diffusion markers correlated with fatigue severity, such as physical fatigue, fatigue-related impairment in everyday life (Bell score) and daytime sleepiness. Moreover, we observed shape deformations and decreased volumes of the left thalamus, putamen, and pallidum. These overlapped with the more extensive subcortical changes in MS and were associated with impaired short-term memory. While fatigue severity was not related to COVID-19 disease courses (6/47 hospitalised, 2/47 with ICU treatment), post-acute sleep quality and depressiveness emerged as associated factors and were accompanied by increased levels of anxiety and daytime sleepiness.


Characteristic structural imaging changes of the thalamus and basal ganglia underlie the persistent fatigue experienced by patients with post-COVID syndrome. Evidence for pathological changes to these subcortical motor and cognitive hubs provides a key to the understanding of post-COVID fatigue and related neuropsychiatric complications.

Quote from the paper

Recently, it has been suggested that effort-reward imbalance, i.e., a biased perception towards high performance costs and low benefits, is a key factor in fatigue pathogenesis.7,32 Indeed, this perception bias was linked to alterations of basal ganglia functional connectivity and dysfunction of the cortico-striatal networks.20,32 In particular, a disruption of dopaminergic basal ganglia-circuits may be a major neural substrate of fatigue and has been referred to as the dopamine imbalance hypothesis of fatigue.32 Given our current findings on basal ganglia damage and the accumulating evidence of a neuroimmunological aetiology,33 a disruption of cortico-striatal circuits together with dopaminergic imbalance in the basal ganglia might contribute to post-COVID fatigue.

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