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Background Increasing evidence supported the possible neuro-invasion potential of SARS-CoV-2. However, no studies were conducted to explore the existence of the micro-structural changes in the central nervous system after infection. We aimed to identify the existence of potential brain micro-structural changes related to SARS-CoV-2. Methods In this prospective study, diffusion tensor imaging (DTI) and 3D high-resolution T1WI sequences were acquired in 60 recovered COVID-19 patients (56.67% male; age: 44.10 ± 16.00) and 39 age- and sex-matched non-COVID-19 controls (56.41% male; age: 45.88 ± 13.90). Registered fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were quantified for DTI, and an index score system was introduced. Regional volumes derived from Voxel-based Morphometry (VBM) and DTI metrics were compared using analysis of covariance (ANCOVA). Two sample t-test and Spearman correlation were conducted to assess the relationships among imaging indices, index scores and clinical information. Findings In this follow-up stage, neurological symptoms were presented in 55% COVID-19 patients. COVID-19 patients had statistically significantly higher bilateral gray matter volumes (GMV) in olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl's gyrus and right cingulate gyrus and a general decline of MD, AD, RD accompanied with an increase of FA in white matter, especially AD in the right CR, EC and SFF, and MD in SFF compared with non-COVID-19 volunteers (corrected p value <0.05). Global GMV, GMVs in left Rolandic operculum, right cingulate, bilateral hippocampi, left Heschl's gyrus, and Global MD of WM were found to correlate with memory loss ( p value <0.05). GMVs in the right cingulate gyrus and left hippocampus were related to smell loss ( p value <0.05). MD-GM score, global GMV, and GMV in right cingulate gyrus were correlated with LDH level ( p value <0.05). Interpretation Study findings revealed possible disruption to micro-structural and functional brain integrity in the recovery stages of COVID-19, suggesting the long-term consequences of SARS-CoV-2. Funding Shanghai Natural Science Foundation, Youth Program of National Natural Science Foundation of China, Shanghai Sailing Program, Shanghai Science and Technology Development, Shanghai Municipal Science and Technology Major Project and ZJ Lab.

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The human orbitofrontal cortex, ventromedial prefrontal cortex (vmPFC), and anterior cingulate cortex are involved in reward processing and thereby in emotion but are also implicated in episodic memory. To understand these regions better, the effective connectivity between 360 cortical regions and 24 subcortical regions was measured in 172 humans from the Human Connectome Project and complemented with functional connectivity and diffusion tractography. The orbitofrontal cortex has effective connectivity from gustatory, olfactory, and temporal visual, auditory, and pole cortical areas. The orbitofrontal cortex has connectivity to the pregenual anterior and posterior cingulate cortex and hippocampal system and provides for rewards to be used in memory and navigation to goals. The orbitofrontal and pregenual anterior cortex have connectivity to the supracallosal anterior cingulate cortex, which projects to midcingulate and other premotor cortical areas and provides for action-outcome learning including limb withdrawal or flight or fight to aversive and nonreward stimuli. The lateral orbitofrontal cortex has outputs to language systems in the inferior frontal gyrus. The medial orbitofrontal cortex connects to the nucleus basalis of Meynert and the pregenual cingulate to the septum, and damage to these cortical regions may contribute to memory impairments by disrupting cholinergic influences on the neocortex and hippocampus.