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

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.

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.

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.

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.