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. 2023 Apr:58:101874.
doi: 10.1016/j.eclinm.2023.101874. Epub 2023 Feb 27.

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

Josephine Heine  1 , Katia Schwichtenberg  1 , Tim J Hartung  1 , Sophia Rekers  1   2 , Claudia Chien  3   4 , Fabian Boesl  1 , Rebekka Rust  3 , Christian Hohenfeld  5   6 , Julia Bungenberg  5   6 , Ana S Costa  5   6 , Carmen Scheibenbogen  7 , Judith Bellmann-Strobl  3 , Friedemann Paul  3   4 , Christiana Franke  1 , Kathrin Reetz  5   6 , Carsten Finke  1   8
Affiliations

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

Josephine Heine et al. EClinicalMedicine. 2023 Apr.

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).

Keywords: Basal ganglia; COVID-19; Fatigue; Neuroimaging; Post-COVID syndrome; Thalamus.

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Conflict of interest statement

Dr. Chien reports personal fees from Bayer, grants from Novartis, outside the submitted work. Dr. Bellmann-Strobl reports personal fees from Bayer Healthcare, personal fees from sanofi-aventis/Genzyme, personal fees from Roche, outside the submitted work. Dr. Paul reports personal fees and non-financial support from SanofiGenzyme, personal fees, non-financial support and other from BiogenIdec, personal fees and non-financial support from MedImmune, personal fees and non-financial support from Shire, personal fees and non-financial support from Alexion, grants, personal fees and non-financial support from Bayer, grants and personal fees from Novartis, grants and personal fees from Teva, grants and personal fees from Merck Serono, personal fees from Actelion, personal fees from Chugai, personal fees from Roche, personal fees from Celgene, grants from Sanofi-Aventis/Genzyme, grants from Alexion, grants from German Research Council (DFG Exc 257), grants from Werth Stiftung of the City of Cologne, grants from German Ministry of Education and Research (BMBF Competence Network Multiple Sclerosis), grants from Arthur Arnstein Stiftung Berlin, grants from EU FP7 Framework Program (combims.eu), grants from Guthy Jackson Charitable Foundation, grants from National Multiple Sclerosis Society of the USA, outside the submitted work. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
High prevalence of concurrent sleep problems, depressive and anxiety symptoms in post-COVID patients with fatigue. (BAI: Beck Anxiety Inventory, BDI-II: Beck Depression Inventory II, ESS: Epworth Sleepiness Scale, FSMC: Fatigue Scale for Motor and Cognitive Function, PSQI: Pittsburgh Sleep Quality Index).
Fig. 2
Fig. 2
Structural thalamic changes in patients with post-COVID fatigue. Patients with moderate or severe fatigue after COVID-19 showed significantly higher thalamic fractional anisotropy (FA) and surface deformations (boxplots with whiskers extending to 1.5∗IQR).
Fig. 3
Fig. 3
Structural changes in the putamen (A) and pallidum (B) in patients with post-COVID fatigue. Marked surface deformations, volume loss, and aberrant diffusion parameters show involvement of the basal ganglia in long-term fatigue after COVID-19 (boxplots with whiskers extending to 1.5∗IQR).
Fig. 4
Fig. 4
Correlation plots of clinical parameters, neuropsychiatric scales, and cognitive tests in patients with post-COVID fatigue. A. Long-term fatigue was unrelated to the severity of the acute COVID-19 disease. B. Instead, post-COVID fatigue was associated with higher depressiveness, anxiety, and an increased susceptibility to errors on a test of higher attention. Post-COVID disease duration is defined as the time between the onset of COVID-19 and study assessment. (BAI: Beck Anxiety Inventory, BDI-II: Beck Depression Inventory II, CFS-ME: chronic fatigue syndrome/myalgic encephalomyelitis – consensus criteria symptom count, ESS: Epworth Sleepiness Scale, FSMC: Fatigue Scale for Motor and Cognitive Function, mRS: modified Rankin Scale, PSQI: Pittsburgh Sleep Quality Index, RAVLT: Rey Auditory Verbal Learning Test, RT: response time ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001).
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References

    1. Paterson R.W., Brown R.L., Benjamin L., et al. The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain. 2020;143:3104–3120. - PMC - PubMed
    1. Douaud G., Lee S., Alfaro-Almagro F., et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature. 2022;604:697–707. - PMC - PubMed
    1. World Health Organization . 2021. A clinical case definition of post COVID-19 condition by a Delphi consensus, 6 October 2021. No. WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.
    1. Taquet M., Geddes J.R., Husain M., Luciano S., Harrison P.J. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021;8:416–427. - PMC - PubMed
    1. NICE guideline [NG188]. COVID-19 rapid guideline: managing the long-term effects of COVID-19. 2020.