The association among individual gray matter volume of frontal-limbic circuitry, fatigue susceptibility, and comorbid neuropsychiatric symptoms following COVID-19

Background: Fatigue is often accompanied by comorbid sleep disturbance and psychiatric distress following the COVID-19 infection. However, identifying individuals at risk for developing post-COVID fatigue remains challenging. This study aimed to identify the neurobiological markers underlying fatigue susceptibility and further investigate their effect on COVID-19-related neuropsychiatric symptoms. Methods: Individuals following a mild SARS-CoV-2 infection (COV+) underwent neuropsychiatric measurements (n = 335) and MRI scans (n = 271) within 1 month (baseline), and 191 (70.5 %) of the individuals were followed up 3 months after infection. Sixty-seven healthy controls (COV−) completed the same recruitment protocol. Results: Whole-brain voxel-wise analysis showed that gray matter volume (GMV) during the acute phase did not differ between the COV+ and COV− groups. GMV in the right dorsolateral prefrontal cortex (DLPFC) and left dorsal anterior cingulate cortex (dACC) were associated with fatigue severity only in the COV+ group at baseline, which were assigned to the frontal system and limbic system, respectively. Furthermore, fatigue mediated the associations between volume differences in fatigue susceptibility and COVID-related sleep, post-traumatic stress disorder, anxiety and depression. Crucially, the initial GMV in the right DLPFC can predict fatigue symptoms 3 months after infection. Conclusions: We provide novel evidence on the neuroanatomical basis of fatigue vulnerability and emphasize that acute fatigue is an important link between early GMV in the frontal-limbic regions and comorbid neuropsychiatric symptoms at baseline and 3 months after infection. Our findings highlight the role of the frontal-limbic system in predisposing individuals to develop post-COVID fatigue.