Abstract
The long-term impact of COVID-19 on the brain is multifaceted, encompassing structural and functional disruptions. A cohesive theory of the underlying mechanisms of the Post-COVID Syndrome (PCS) remains unknown, primarily due to high variability in findings across independent studies. Here, we present a multimodal, cross-sectional MRI analysis of brain morphology (T1-MRI), tissue microstructure (diffusion-MRI), functional connectivity (functional-MRI), and cerebral blood flow (arterial spin labeling MRI) in COVID-recovered patients (CRPs, N=76) and healthy controls (HCs, N = 51). Although the global brain volumes did not differ between the two groups, CRPs showed focal atrophy in the right basal ganglia and limbic structures, along with cortical thinning in paralimbic regions (prefrontal cortex, insula) (p < 0.05). Diffusion MRI analysis revealed reduced fractional anisotropy and elevated radial diffusivity in the uncinate fasciculus and cingulum. No differences were observed in resting-state functional connectivity (RSFC) and cerebral blood flow between HCs and CRPs (p > 0.05). We further investigated the effect of infection severity by stratifying the CRPs into hospitalized (HP; N = 21) and non-hospitalized (NHP; N = 46) groups. The microstructural damage was linked to infection severity, more pronounced in the HPs (p < 0.05). In HPs, RSFC was diminished between components of the default mode network and the insula and caudate as compared with HCs and NHPs (p < 0.05). Results suggest COVID-19 is associated with selective structural and functional alterations in basal ganglia-limbic-cortical circuits, with stronger effects in severe cases. Overall, our findings both validate previously reported neuroimaging biomarkers and reveal new ones associated with the post-COVID syndrome, motivating future hypothesis-driven studies on behavioral correlates and therapeutic interventions.