Acute inflammation and fronto-striatal connectivity in the transition from acute to persistent fatigue after mild
Qiange Zhu1, Tao Lu1, Huijie Yuan1
1Department of Medical Imaging, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
Background:
Persistent fatigue is one of the most common and disabling sequelae of COVID-19, yet its neurobiological mechanisms remain poorly understood. Emerging evidence implicates systemic inflammation and fronto-striatal dysfunction in fatigue across diverse clinical conditions. However, the links between early inflammatory responses, brain connectivity, and the acute-to-chronic trajectory of post-COVID fatigue are unclear.
Methods:
In a multi-center longitudinal cohort of 193 young-to-middle-aged adults with mild COVID-19, we assessed acute-phase C-reactive protein (CRP), fatigue severity (FAS) at <1 month (acute, FAS-1) and 3 months (chronic, FAS-2) post-infection, and resting-state fMRI at 3 months. Functional connectivity (FC) differences between participants with persistent (n = 48) and non-persistent fatigue (n = 145) were examined, and mediation analyses were performed to evaluate pathways linking CRP, FC alterations, and fatigue progression.
Results:
Acute-phase CRP levels were elevated in the persistent fatigue group and positively correlated with fatigue severity at both time points. Compared with the non-persistent group, individuals with persistent fatigue showed reduced functional connectivity (FC) between the left superior frontal gyrus (SFG L) and striatal regions (caudate L and putamen L). This SFG L-striatal FC was negatively correlated with fatigue severity. Crucially, a chain mediation model suggested that the association between CRP on chronic fatigue was statistically mediated through two sequential pathways: (1) via acute fatigue alone, and (2) via acute fatigue followed by reduced SFG L-striatal FC.
Conclusion:
In this cohort of mild COVID-19 survivors, this study identifies acute inflammation (elevated CRP) as a significant predictor of post-COVID fatigue and suggests that reduced fronto-striatal connectivity may mediate the transition from acute to chronic fatigue. These findings highlight the fronto-striatal circuit as a potential imaging biomarker and point to the acute phase as a critical window for anti-inflammatory or neuromodulatory interventions. Further longitudinal and interventional studies are needed to validate these mechanisms and therapeutic strategies.
