Decreased functional connectivity in post-COVID syndrome patients with high neuroinflammatory activity

Denise Visser; Leo Pieperhoff; Luigi Lorenzini; Sandeep S.V. Golla; Sander C.J. Verfaillie; Anouk Verveen; Elsmarieke van de Giessen; Marijke E. den Hollander; Janneke Horn; Caroline M. van Heugten; Menno D. de Jong; Cees C. van den Wijngaard; Tessa van der Maaden; Maria Prins; Patrick Schober; Robert C. Schuit; Michael Kassiou; Albert D. Windhorst; Brent Appelman; Michele van Vugt; Bart N.M. van Berckel; Hans Knoop; Alle Meije Wink; Ronald Boellaard; Frederik Barkhof; Nelleke Tolboom

doi:10.1016/j.neuroimage.2026.121951

Decreased functional connectivity in post-COVID syndrome patients with high neuroinflammatory activity

Denise Visser^*
, Leo Pieperhoff
, Luigi Lorenzini
, Sandeep S.V. Golla
, Sander C.J. Verfaillie
, Anouk Verveen
, Elsmarieke van de Giessen
, Marijke E. den Hollander
, Janneke Horn
, Caroline M. van Heugten
, Menno D. de Jong
, Cees C. van den Wijngaard
, Tessa van der Maaden
, Maria Prins
, Patrick Schober
, Robert C. Schuit
, Michael Kassiou
, Albert D. Windhorst
, Brent Appelman
, Michele van Vugt

Bart N.M. van Berckel, Hans Knoop, Alle Meije Wink, Ronald Boellaard, Frederik Barkhof, Nelleke Tolboom

^*Corresponding author for this work

Vrije Universiteit Amsterdam, Department of Radiology and Nuclear Medicine
Vrije Universiteit Amsterdam
Department of Nuclear Medicine and Radiology
Utrecht University
Amsterdam UMC
Universiteit van Amsterdam, Department of Medical Psychology
University of Amsterdam
GGz InGeest Mental Health Institute
Maastricht University
National Institute of Public Health and the Environment
National Institute for Public Health and the Environment (RIVM)
Department of Anaesthesiology
The University of Sydney
Karolinska Institutet
Karolinska Institutet
University College London

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Introduction Previous research suggests some post-COVID patients with neurocognitive complaints (NCC) show neuroinflammation. Like in inflammatory diseases, this may affect network connectivity. This study aimed to compare resting-state functional connectivity in individuals with and without i) neuroinflammation and ii) persistent post-COVID NCC. Methods Forty-five participants (mean age 49±9 years, 60% female) who had a SARS-CoV-2 infection 27±9 months earlier completed neurocognitive assessment (Checklist-Individual-Strength), 60-minute dynamic [¹⁸F]DPA-714 PET scan with arterial sampling for neuroinflammation, and 3T MRI scan for resting-state functional connectivity. Twenty resting-state networks (RSNs) were identified using independent component analysis. Group differences in within-RSN connectivity were analyzed using general linear models. Differences in subcortico-cortical between-RSN connectivity—between brainstem or thalamus and cortical RSNs—were assessed using interaction models. Results Ten participants (22%) showed neuroinflammation on [¹⁸F]DPA-714 PET, and 31 (69%) reported persistent NCC. Lower within-RSN connectivity was observed in the visual-peripheral (N_voxels =3151, P_FWE '0.05, t_mean=1.77 and t_max=3.34) and dorsal-attention networks (N_voxels =29, P_FWE '0.05, t_mean=1.59 and t_max=3.66) in those with neuroinflammation, and in the visual-peripheral (N_voxels =721, P_FWE '0.05, t_mean=1.89 and t_max=3.45) and default mode networks (N_voxels =123, P_FWE '0.05, t_mean=2.24 and t_max=4.68) in those with NCC. A significant interaction effect showed reduced functional connectivity in a large, bilateral cerebellar cluster (N_voxels =2648, P_FWE '0.05, t_mean=2.31 and t_max=3.84) with increasing global [¹⁸F]DPA-714 binding in participants with NCC. Lastly, thalamic-somatomotor and brainstem-control network connectivity (between-RSN) was altered in both individuals with persistent NCC and those with neuroinflammation, with thalamic-somatomotor changes mainly driven by NCC and brainstem-control changes by neuroinflammation. Conclusion Our results suggest that neuroinflammation in individuals with persistent NCC after SARS-CoV-2 infection is linked to altered functional connectivity in RSNs central to higher-order cognitive functions.

Original language	English
Article number	121951
Journal	NeuroImage
Volume	333
DOIs	https://doi.org/10.1016/j.neuroimage.2026.121951
Publication status	Published - Jun 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Neuroinflammation
Post-COVID
Resting-state functional connectivity
rs-fMRI
TSPO PET

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Visser, D., Pieperhoff, L., Lorenzini, L., Golla, S. S. V., Verfaillie, S. C. J., Verveen, A., van de Giessen, E., den Hollander, M. E., Horn, J., van Heugten, C. M., de Jong, M. D., van den Wijngaard, C. C., van der Maaden, T., Prins, M., Schober, P., Schuit, R. C., Kassiou, M., Windhorst, A. D., Appelman, B., ... Tolboom, N. (2026). Decreased functional connectivity in post-COVID syndrome patients with high neuroinflammatory activity. NeuroImage, 333, Article 121951. https://doi.org/10.1016/j.neuroimage.2026.121951

@article{f94e33c87bd343e48eea94ae1a34e5e3,

title = "Decreased functional connectivity in post-COVID syndrome patients with high neuroinflammatory activity",

abstract = "Introduction Previous research suggests some post-COVID patients with neurocognitive complaints (NCC) show neuroinflammation. Like in inflammatory diseases, this may affect network connectivity. This study aimed to compare resting-state functional connectivity in individuals with and without i) neuroinflammation and ii) persistent post-COVID NCC. Methods Forty-five participants (mean age 49±9 years, 60\% female) who had a SARS-CoV-2 infection 27±9 months earlier completed neurocognitive assessment (Checklist-Individual-Strength), 60-minute dynamic [18F]DPA-714 PET scan with arterial sampling for neuroinflammation, and 3T MRI scan for resting-state functional connectivity. Twenty resting-state networks (RSNs) were identified using independent component analysis. Group differences in within-RSN connectivity were analyzed using general linear models. Differences in subcortico-cortical between-RSN connectivity{\textemdash}between brainstem or thalamus and cortical RSNs{\textemdash}were assessed using interaction models. Results Ten participants (22\%) showed neuroinflammation on [18F]DPA-714 PET, and 31 (69\%) reported persistent NCC. Lower within-RSN connectivity was observed in the visual-peripheral (Nvoxels =3151, PFWE '0.05, tmean=1.77 and tmax=3.34) and dorsal-attention networks (Nvoxels =29, PFWE '0.05, tmean=1.59 and tmax=3.66) in those with neuroinflammation, and in the visual-peripheral (Nvoxels =721, PFWE '0.05, tmean=1.89 and tmax=3.45) and default mode networks (Nvoxels =123, PFWE '0.05, tmean=2.24 and tmax=4.68) in those with NCC. A significant interaction effect showed reduced functional connectivity in a large, bilateral cerebellar cluster (Nvoxels =2648, PFWE '0.05, tmean=2.31 and tmax=3.84) with increasing global [18F]DPA-714 binding in participants with NCC. Lastly, thalamic-somatomotor and brainstem-control network connectivity (between-RSN) was altered in both individuals with persistent NCC and those with neuroinflammation, with thalamic-somatomotor changes mainly driven by NCC and brainstem-control changes by neuroinflammation. Conclusion Our results suggest that neuroinflammation in individuals with persistent NCC after SARS-CoV-2 infection is linked to altered functional connectivity in RSNs central to higher-order cognitive functions.",

keywords = "Neuroinflammation, Post-COVID, Resting-state functional connectivity, rs-fMRI, TSPO PET",

author = "Denise Visser and Leo Pieperhoff and Luigi Lorenzini and Golla, \{Sandeep S.V.\} and Verfaillie, \{Sander C.J.\} and Anouk Verveen and \{van de Giessen\}, Elsmarieke and \{den Hollander\}, \{Marijke E.\} and Janneke Horn and \{van Heugten\}, \{Caroline M.\} and \{de Jong\}, \{Menno D.\} and \{van den Wijngaard\}, \{Cees C.\} and \{van der Maaden\}, Tessa and Maria Prins and Patrick Schober and Schuit, \{Robert C.\} and Michael Kassiou and Windhorst, \{Albert D.\} and Brent Appelman and \{van Vugt\}, Michele and \{van Berckel\}, \{Bart N.M.\} and Hans Knoop and Wink, \{Alle Meije\} and Ronald Boellaard and Frederik Barkhof and Nelleke Tolboom",

note = "Publisher Copyright: Copyright {\textcopyright} 2026. Published by Elsevier Inc.",

year = "2026",

month = jun,

doi = "10.1016/j.neuroimage.2026.121951",

language = "English",

volume = "333",

journal = "NeuroImage",

issn = "1053-8119",

publisher = "Academic Press Inc.",

}

Visser, D, Pieperhoff, L, Lorenzini, L, Golla, SSV , Verfaillie, SCJ, Verveen, A, van de Giessen, E, den Hollander, ME, Horn, J, van Heugten, CM, de Jong, MD, van den Wijngaard, CC, van der Maaden, T, Prins, M, Schober, P , Schuit, RC, Kassiou, M, Windhorst, AD , Appelman, B, van Vugt, M, van Berckel, BNM, Knoop, H , Wink, AM , Boellaard, R , Barkhof, F & Tolboom, N 2026, 'Decreased functional connectivity in post-COVID syndrome patients with high neuroinflammatory activity', NeuroImage, vol. 333, 121951. https://doi.org/10.1016/j.neuroimage.2026.121951

TY - JOUR

T1 - Decreased functional connectivity in post-COVID syndrome patients with high neuroinflammatory activity

AU - Visser, Denise

AU - Pieperhoff, Leo

AU - Lorenzini, Luigi

AU - Golla, Sandeep S.V.

AU - Verfaillie, Sander C.J.

AU - Verveen, Anouk

AU - van de Giessen, Elsmarieke

AU - den Hollander, Marijke E.

AU - Horn, Janneke

AU - van Heugten, Caroline M.

AU - de Jong, Menno D.

AU - van den Wijngaard, Cees C.

AU - van der Maaden, Tessa

AU - Prins, Maria

AU - Schober, Patrick

AU - Schuit, Robert C.

AU - Kassiou, Michael

AU - Windhorst, Albert D.

AU - Appelman, Brent

AU - van Vugt, Michele

AU - van Berckel, Bart N.M.

AU - Knoop, Hans

AU - Wink, Alle Meije

AU - Boellaard, Ronald

AU - Barkhof, Frederik

AU - Tolboom, Nelleke

PY - 2026/6

Y1 - 2026/6

N2 - Introduction Previous research suggests some post-COVID patients with neurocognitive complaints (NCC) show neuroinflammation. Like in inflammatory diseases, this may affect network connectivity. This study aimed to compare resting-state functional connectivity in individuals with and without i) neuroinflammation and ii) persistent post-COVID NCC. Methods Forty-five participants (mean age 49±9 years, 60% female) who had a SARS-CoV-2 infection 27±9 months earlier completed neurocognitive assessment (Checklist-Individual-Strength), 60-minute dynamic [18F]DPA-714 PET scan with arterial sampling for neuroinflammation, and 3T MRI scan for resting-state functional connectivity. Twenty resting-state networks (RSNs) were identified using independent component analysis. Group differences in within-RSN connectivity were analyzed using general linear models. Differences in subcortico-cortical between-RSN connectivity—between brainstem or thalamus and cortical RSNs—were assessed using interaction models. Results Ten participants (22%) showed neuroinflammation on [18F]DPA-714 PET, and 31 (69%) reported persistent NCC. Lower within-RSN connectivity was observed in the visual-peripheral (Nvoxels =3151, PFWE '0.05, tmean=1.77 and tmax=3.34) and dorsal-attention networks (Nvoxels =29, PFWE '0.05, tmean=1.59 and tmax=3.66) in those with neuroinflammation, and in the visual-peripheral (Nvoxels =721, PFWE '0.05, tmean=1.89 and tmax=3.45) and default mode networks (Nvoxels =123, PFWE '0.05, tmean=2.24 and tmax=4.68) in those with NCC. A significant interaction effect showed reduced functional connectivity in a large, bilateral cerebellar cluster (Nvoxels =2648, PFWE '0.05, tmean=2.31 and tmax=3.84) with increasing global [18F]DPA-714 binding in participants with NCC. Lastly, thalamic-somatomotor and brainstem-control network connectivity (between-RSN) was altered in both individuals with persistent NCC and those with neuroinflammation, with thalamic-somatomotor changes mainly driven by NCC and brainstem-control changes by neuroinflammation. Conclusion Our results suggest that neuroinflammation in individuals with persistent NCC after SARS-CoV-2 infection is linked to altered functional connectivity in RSNs central to higher-order cognitive functions.

AB - Introduction Previous research suggests some post-COVID patients with neurocognitive complaints (NCC) show neuroinflammation. Like in inflammatory diseases, this may affect network connectivity. This study aimed to compare resting-state functional connectivity in individuals with and without i) neuroinflammation and ii) persistent post-COVID NCC. Methods Forty-five participants (mean age 49±9 years, 60% female) who had a SARS-CoV-2 infection 27±9 months earlier completed neurocognitive assessment (Checklist-Individual-Strength), 60-minute dynamic [18F]DPA-714 PET scan with arterial sampling for neuroinflammation, and 3T MRI scan for resting-state functional connectivity. Twenty resting-state networks (RSNs) were identified using independent component analysis. Group differences in within-RSN connectivity were analyzed using general linear models. Differences in subcortico-cortical between-RSN connectivity—between brainstem or thalamus and cortical RSNs—were assessed using interaction models. Results Ten participants (22%) showed neuroinflammation on [18F]DPA-714 PET, and 31 (69%) reported persistent NCC. Lower within-RSN connectivity was observed in the visual-peripheral (Nvoxels =3151, PFWE '0.05, tmean=1.77 and tmax=3.34) and dorsal-attention networks (Nvoxels =29, PFWE '0.05, tmean=1.59 and tmax=3.66) in those with neuroinflammation, and in the visual-peripheral (Nvoxels =721, PFWE '0.05, tmean=1.89 and tmax=3.45) and default mode networks (Nvoxels =123, PFWE '0.05, tmean=2.24 and tmax=4.68) in those with NCC. A significant interaction effect showed reduced functional connectivity in a large, bilateral cerebellar cluster (Nvoxels =2648, PFWE '0.05, tmean=2.31 and tmax=3.84) with increasing global [18F]DPA-714 binding in participants with NCC. Lastly, thalamic-somatomotor and brainstem-control network connectivity (between-RSN) was altered in both individuals with persistent NCC and those with neuroinflammation, with thalamic-somatomotor changes mainly driven by NCC and brainstem-control changes by neuroinflammation. Conclusion Our results suggest that neuroinflammation in individuals with persistent NCC after SARS-CoV-2 infection is linked to altered functional connectivity in RSNs central to higher-order cognitive functions.

KW - Neuroinflammation

KW - Post-COVID

KW - Resting-state functional connectivity

KW - rs-fMRI

KW - TSPO PET

UR - https://www.scopus.com/pages/publications/105037829515

U2 - 10.1016/j.neuroimage.2026.121951

DO - 10.1016/j.neuroimage.2026.121951

M3 - Article

C2 - 42034234

AN - SCOPUS:105037829515

SN - 1053-8119

VL - 333

JO - NeuroImage

JF - NeuroImage

M1 - 121951

ER -

Decreased functional connectivity in post-COVID syndrome patients with high neuroinflammatory activity

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Keywords

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