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

Tim J Hartung¹, Florentin Steigerwald¹, Amy Romanello^{1

2}, Cathrin Kodde³, Matthias Endres^{1

4

5

6

7}, Sandra Frank⁸, Peter Heuschmann^{9

10}, Philipp Koehler^{11

12

13}, Stephan Krohn^{1

2}, Daniel Pape¹⁴, Jens Schaller¹⁵, Sophia Stöcklein^{16

17}, Istvan Vadasz^{18

19

20}, Janne Vehreschild²¹, Martin Witzenrath^{3

22}, Thomas Zoller³, Carsten Finke^{1

2}; NAPKON Study Group

Collaborators, Affiliations

Collaborators

NAPKON Study Group:
Y Ahlgrimm, C Finke, J Fricke, T Keil, L Krist, N Lisewsky, M Mittermaier, M Mueller-Plathe, C Pley, S Schmidt, A Stege, F Steinbeis, S Steinbrecher, C Wildberg, M Witzenrath, E Zessin, T Zoller, C Arendt, C Bellinghausen, S Cremer, A Groh, A Gruenewaldt, Y Khodamoradi, S Klinsing, G Rohde, M Vehreschild, T Vogl, S Frank, J C Hellmuth, M Huber, S Kaeaeb, O T Keppler, E Khatamzas, C Mandel, S Mueller, M Muenchhoff, L Reeh, C Scherer, H Stubbe, M von Bergwelt, L Weiss, B Zwissler, S Cleef, M E Figuera Basso, J Franzenburg, K Franzpoetter, A Friedrichs, A Hermes, J Heyckendorf, C Kujat, I Lehmann, C Maetzler, S Meier, D Pape, S Poick, L Reinke, A K Russ, A M Scheer, D Schunk, T Tamminga, S Bohnet, D Droemann, K F Franzen, R Hoerster, N Kaeding, M Nissen, P Parschke, J Rupp, S Caesar, H Einsele, S Frantz, A Frey, A Grau, K Haas, C Haertel, K G Haeusler, G Hein, J Herrmann, A Horn, R Jahns, P Meybohm, F A Montellano, C Morbach, J Schmidt, P Schulze, S Stoerk, J Volkmann, T Bahmer, A Hermes, M Krawczak, W Lieb, S Schreiber, T Tamminga, B Balzuweit, S Berger, J Fricke, M Hummel, A Krannich, L Krist, F Kurth, J Lienau, R Lorbeer, C Pley, J Schaller, S Schmidt, C Thibeault, M Witzenrath, T Zoller, I Bernemann, T Illig, M Kersting, N Klopp, V Kopfnagel, S Muecke, M Kraus, B Lorenz-Depiereux, G Anton, A Kuehn-Steven, S Kunze, M K Tauchert, K Appel, M Brechtel, I Broehl, K Fiedler, R Geisler, S M Hopff, K Knaub, C Lee, S Nunes de Miranda, S Raquib, G Sauer, M Scherer, J J Vehreschild, P Wagner, L Wolf, J C Hellmuth, K Guenther, F Haug, J Haug, A Horn, M Kohls, C Fiessler, P U Heuschmann, O Miljukov, C Nuernberger, J P Reese, L Schmidbauer, I Chaplinskaya, S Hanss, D Krefting, C Pape, M Rainers, A Schoneberg, N Weinert, T Bahls, W Hoffmann, M Nauck, C Schaefer, M Schattschneider, D Stahl, H Valentin, P Heuschmann, A L Hofmann, S Jiru-Hillmann, J P Reese, S Herold, P Heuschmann, R Heyder, W Hoffmann, T Illig, S Schreiber, J J Vehreschild, M Witzenrath

Affiliations

¹ Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
² Berlin School of Mind and Brain, Humboldt-Universität zu Berlin, Berlin, Germany.
³ Department of Infectious Disease, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁴ Center for Stroke Research Berlin, Berlin, Germany.
⁵ German Center for Mental Health (DZPG), Partner Site, Berlin, Germany.
⁶ German Center for Neurodegenerative Diseases (DZNE), Partner Site, Berlin, Germany.
⁷ German Centre for Cardiovascular Research (DZHK), partner Site, Berlin, Germany.
⁸ Department of Anaesthesiology, LMU University Hospital, LMU Munich, Munich, Germany.
⁹ Institute of Medical Data Science, University Hospital Würzburg, Würzburg, Germany.
¹⁰ Institute of Clinical Epidemiology and Biometry, University Würzburg, Würzburg, Germany.
¹¹ Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹² Division of Clinical Immunology, Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹³ Institute of Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁴ Department I of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany.
¹⁵ Deutsche Telekom Healthcare and Security Solutions GmbH, Berlin, Germany.
¹⁶ Department of Radiology, LMU University Hospital, LMU Munich, Munich, Germany.
¹⁷ Comprehensive Pneumology Center (CPC-M), member of the German Center for Lung Research (DZL), Munich, Germany.
¹⁸ Department of Internal Medicine, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany.
¹⁹ The Cardio-Pulmonary Institute, Giessen, Germany.
²⁰ Institute for Lung Health, Giessen, Germany.
²¹ Institute for Digital Medicine and Clinical Data Sciences, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany.
²² German Center for Lung Research (DZL), Berlin, Germany.

PMID: 41288256
DOI: 10.1002/acn3.70260

Free article

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

Tim J Hartung et al. Ann Clin Transl Neurol. 2025.

Free article

. 2025 Nov 25.

doi: 10.1002/acn3.70260. Online ahead of print.

Authors

Collaborators

NAPKON Study Group:
Y Ahlgrimm, C Finke, J Fricke, T Keil, L Krist, N Lisewsky, M Mittermaier, M Mueller-Plathe, C Pley, S Schmidt, A Stege, F Steinbeis, S Steinbrecher, C Wildberg, M Witzenrath, E Zessin, T Zoller, C Arendt, C Bellinghausen, S Cremer, A Groh, A Gruenewaldt, Y Khodamoradi, S Klinsing, G Rohde, M Vehreschild, T Vogl, S Frank, J C Hellmuth, M Huber, S Kaeaeb, O T Keppler, E Khatamzas, C Mandel, S Mueller, M Muenchhoff, L Reeh, C Scherer, H Stubbe, M von Bergwelt, L Weiss, B Zwissler, S Cleef, M E Figuera Basso, J Franzenburg, K Franzpoetter, A Friedrichs, A Hermes, J Heyckendorf, C Kujat, I Lehmann, C Maetzler, S Meier, D Pape, S Poick, L Reinke, A K Russ, A M Scheer, D Schunk, T Tamminga, S Bohnet, D Droemann, K F Franzen, R Hoerster, N Kaeding, M Nissen, P Parschke, J Rupp, S Caesar, H Einsele, S Frantz, A Frey, A Grau, K Haas, C Haertel, K G Haeusler, G Hein, J Herrmann, A Horn, R Jahns, P Meybohm, F A Montellano, C Morbach, J Schmidt, P Schulze, S Stoerk, J Volkmann, T Bahmer, A Hermes, M Krawczak, W Lieb, S Schreiber, T Tamminga, B Balzuweit, S Berger, J Fricke, M Hummel, A Krannich, L Krist, F Kurth, J Lienau, R Lorbeer, C Pley, J Schaller, S Schmidt, C Thibeault, M Witzenrath, T Zoller, I Bernemann, T Illig, M Kersting, N Klopp, V Kopfnagel, S Muecke, M Kraus, B Lorenz-Depiereux, G Anton, A Kuehn-Steven, S Kunze, M K Tauchert, K Appel, M Brechtel, I Broehl, K Fiedler, R Geisler, S M Hopff, K Knaub, C Lee, S Nunes de Miranda, S Raquib, G Sauer, M Scherer, J J Vehreschild, P Wagner, L Wolf, J C Hellmuth, K Guenther, F Haug, J Haug, A Horn, M Kohls, C Fiessler, P U Heuschmann, O Miljukov, C Nuernberger, J P Reese, L Schmidbauer, I Chaplinskaya, S Hanss, D Krefting, C Pape, M Rainers, A Schoneberg, N Weinert, T Bahls, W Hoffmann, M Nauck, C Schaefer, M Schattschneider, D Stahl, H Valentin, P Heuschmann, A L Hofmann, S Jiru-Hillmann, J P Reese, S Herold, P Heuschmann, R Heyder, W Hoffmann, T Illig, S Schreiber, J J Vehreschild, M Witzenrath

Affiliations

¹ Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
² Berlin School of Mind and Brain, Humboldt-Universität zu Berlin, Berlin, Germany.
³ Department of Infectious Disease, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁴ Center for Stroke Research Berlin, Berlin, Germany.
⁵ German Center for Mental Health (DZPG), Partner Site, Berlin, Germany.
⁶ German Center for Neurodegenerative Diseases (DZNE), Partner Site, Berlin, Germany.
⁷ German Centre for Cardiovascular Research (DZHK), partner Site, Berlin, Germany.
⁸ Department of Anaesthesiology, LMU University Hospital, LMU Munich, Munich, Germany.
⁹ Institute of Medical Data Science, University Hospital Würzburg, Würzburg, Germany.
¹⁰ Institute of Clinical Epidemiology and Biometry, University Würzburg, Würzburg, Germany.
¹¹ Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹² Division of Clinical Immunology, Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹³ Institute of Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁴ Department I of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany.
¹⁵ Deutsche Telekom Healthcare and Security Solutions GmbH, Berlin, Germany.
¹⁶ Department of Radiology, LMU University Hospital, LMU Munich, Munich, Germany.
¹⁷ Comprehensive Pneumology Center (CPC-M), member of the German Center for Lung Research (DZL), Munich, Germany.
¹⁸ Department of Internal Medicine, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany.
¹⁹ The Cardio-Pulmonary Institute, Giessen, Germany.
²⁰ Institute for Lung Health, Giessen, Germany.
²¹ Institute for Digital Medicine and Clinical Data Sciences, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany.
²² German Center for Lung Research (DZL), Berlin, Germany.

PMID: 41288256
DOI: 10.1002/acn3.70260

Abstract

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, Cohen's 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).

Keywords: COVID‐19; cognitive dysfunction; fatigue; magnetic resonance imaging; post‐acute COVID‐19 syndrome.

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References

1. T. J. Hartung, T. Bahmer, I. Chaplinskaya‐Sobol, et al., “Predictors of Non‐Recovery From Fatigue and Cognitive Deficits After COVID‐19: A Prospective, Longitudinal, Population‐Based Study,” eClinicalMedicine 69 (2024): 102456.
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1. R. A. Evans, H. McAuley, E. M. Harrison, et al., “Physical, Cognitive, and Mental Health Impacts of COVID‐19 After Hospitalisation (PHOSP‐COVID): A UK Multicentre, Prospective Cohort Study,” Lancet Respiratory Medicine 9, no. 11 (2021): 1275–1287.
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Post-COVID Fatigue Is Associated With Reduced Cortical Thickness After Hospitalization

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

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