Structural brain changes in patients with post-COVID fatigue: a prospective observational study

Abstract

BACKGROUND: 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.  METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Deutsche Forschungsgemeinschaft (DFG) and German Ministry  of Education and Research (BMBF).