Fronto-limbic and Thalamocortical Network Alterations after COVID-19 Recovery: a Multimodal MRI Study

Background: Persistent neurological and cognitive symptoms following SARS-CoV-2 infection point to long-term alterations in brain structure and function. The thalamus, orbitofrontal cortex, and limbic networks are particularly susceptible to inflammatory and neurovascular stressors. However, the relationship between cortical, white-matter, and thalamocortical alterations in post-COVID syndrome remains unclear. Methods: 76 COVID-19 recovered participants (CRPs) and 51 healthy controls (HCs) underwent multimodal MRI comprising T1-weighted structural, diffusion, and resting-state functional acquisitions. Grey-matter morphology was assessed using voxel-based morphometry (VBM), white-matter microstructure using tract-based spatial statistics (TBSS), and thalamocortical functional connectivity (TC-FC) using seed-based analyses from major thalamic nuclei. Results were evaluated both across the groups (HC vs. CRP) and after stratifying CRPs by hospitalisation status (HC vs. Non-hospitalized patients (NHPs) vs. Hospitalized patients (HPs)). Results: No group-level grey-matter differences were observed between HCs and CRPs; however, HPs showed localized volume loss in the orbitofrontal and frontal-pole cortices (pFWE < 0.05). TBSS revealed widespread microstructural abnormalities, including reduced fractional anisotropy and mean diffusivity across association and commissural tracts (pcorr < 0.05), with regional increases in mode of anisotropy indicating selective loss of crossing fibres (pcorr < 0.05). Resting-state analyses revealed increased TC-FC from the mediodorsal thalamic nucleus to anterior cingulate, parietal, and occipital cortices (pcorr < 0.05), while differences in pulvinar and ventrolateral nuclei were not significant (pcorr > 0.05). Conclusions: Our findings indicate that COVID-19 recovery is associated with enduring alterations in fronto-limbic and thalamo-cortical circuits, most prominently in individuals with severe infection. Convergent structural and functional changes involving the orbitofrontal cortex and mediodorsal thalamus suggest network-specific reorganisation that may underpin persistent cognitive and affective symptoms of post-COVID syndrome.