Fatigue-related brain dysfunctional connectivity during acute phase correlates with post-traumatic stress symptoms in individuals with COVID-19 at the 3-month follow-up.

Post-traumatic stress symptoms (PTSS) have emerged as a prominent psychological consequence of the coronavirus disease 2019 (COVID-19) pandemic. Although early-stage fatigue is a known risk factor for developing PTSS, neural mechanisms linking fatigue and PTSS after COVID-19 infection remain unclear. In this study, we investigate whether dysfunctional fatigue-related brain functional connectivity during the acute phase is associated with PTSS in individuals with COVID-19 at 3-month follow-up. This prospective, longitudinal study enrolled 153 individuals with COVID-19 during the acute phase (<28 days post-infection, baseline), of whom 106 completed follow-up assessments at 3 months post-infection. All participants underwent T1-weighted three-dimensional brain volume and resting-state functional magnetic resonance imaging (MRI) scans at baseline and neuropsychiatric assessments at both baseline and follow-up. Complete MRI and neuropsychiatric assessment data of 34 healthy controls (HCs) were also included at baseline. Brain functional networks of all the participants were analyzed. At baseline, individuals with COVID-19 exhibited lower normalized characteristic path length and higher nodal efficiency in the right inferior frontal gyrus (IFG.R) (P < 0.05), compared to HCs. These abnormal brain topological metrics were associated with fatigue and PTSS scores (P < 0.05). Mediation analysis revealed that acute-phase physical fatigue fully mediated the relationship between baseline normalized characteristic path length and chronic hyperarousal symptom. Our results confirm that disrupted global normalized characteristic path length occurs in individuals with COVID-19 during the acute phase, and crucially, demonstrate that fatigue-related functional connectivity dysfunction is associated with the severity of PTSS in the chronic phase.