Post-COVID Fatigue Is Associated With Reduced Cortical Thickness After Hospitalization, 2025, Hartung et al.

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Post-COVID Fatigue Is Associated With Reduced Cortical Thickness After Hospitalization

Spoiler: Authors

Tim J Hartung; Florentin Steigerwald; Amy Romanello; Cathrin Kodde; Matthias Endres; Sandra Frank; Peter Heuschmann; Philipp Koehler; Stephan Krohn; Daniel Pape; Jens Schaller; Sophia Stöcklein; Istvan Vadasz; Janne Vehreschild; Martin Witzenrath; Thomas Zoller; Carsten Finke

OBJECTIVE
Neuropsychiatric symptoms are among the most prevalent sequelae of COVID-19, particularly among hospitalized patients. Recent research has identified volumetric brain changes associated with COVID-19. However, it currently remains poorly understood how brain changes relate to post-COVID fatigue and cognitive deficits. We, therefore, aimed to assess structural brain changes after hospitalization for COVID-19 and their associations with cognitive performance and fatigue.

METHODS
We analyzed data from n = 57 patients previously hospitalized for COVID-19 (63% male, mean age 52 years) from the prospective, multicentric high-resolution platform of the German National Pandemic Cohort Network (NAPKON-HAP) and n = 57 matched healthy control participants (HC). We assessed cortical thickness and subcortical volumes in high-resolution T1-weighted MRI and their associations with cognitive performance (Montreal Cognitive Assessment) and fatigue (Fatigue Severity Scale).

RESULTS
Patients exhibited statistically significant reductions of cortical thickness in parahippocampal gyri and the temporal lobe (all p[FDR-corrected] < 0.05) as well as reduced hippocampal volumes compared to HC (left, Cohens d [95% CI] = 0.50 [0.12–0.8]; right d = 0.43 [0.05–0.80]). Higher acute COVID-19 severity was associated with reduced cortical thickness, particularly in the olfactory system. Furthermore, reduced cortical thickness of the temporal poles and the anterior and posterior cingulate gyrus was associated with more severe post-acute fatigue.

INTERPRETATION
Our results identify long-lasting macrostructural brain changes after moderate to severe COVID-19 that correlate with acute disease severity and long-term fatigue. Early identification and targeted interventions for patients at risk of persistent brain changes are needed.

TRIAL REGISTRATION
NAPKON-HAP is registered at clinicaltrials.gov (NCT04747366)

Web | DOI | PDF | Annals of Clinical and Translational Neurology | Open Access

 

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37% female.

MRI and neuropsychological testing were performed at 3 months after discharge. Data collection took place from November 2020 to November 2022.

Importantly, post-acute fatigue severity was associated with reductions in cortical thickness, which was most pronounced in the anterior and posterior cingulate gyrus and sulcus. To our knowledge, this association has not yet been shown in the context of SARS- CoV-2 infection. The anterior cingulate cortex is involved in the perception of effort, and structural as well as functional changes in this region are associated with exercise-induced fatigue.

In our primary analyses, we observed no significant associations between cognitive performance and cortical thickness or subcortical deep gray matter volumes. However, in sensitivity analyses adjusting for site and somatic comorbidities, a trend towards a thinner parahippocampal cortex being associated with lower MoCA scores became statistically significant.

As is tradition —

Early identification of patients at risk for long-term brain changes could allow for the implementation of targeted intervention and rehabilitation programs.

It is likely that fatigue will persist for several months to years in many patients and will require targeted clinical management strategies. To this end, pharmacological and non-pharmacological interventions should be explored [30].

[30] is Fighting Post-COVID and ME/CFS – development of curative therapies (2023)