Acute inflammation and fronto-striatal connectivity in the transition from acute to persistent fatigue after mild COVID-19: A longitudinal fMRI study

Qiange Zhu; Tao Lu; Huijie Yuan; Ya'nan Zhu; Pang Du; Haiyang Liu; Baoqi Wang; Tonghui Liu; Bo Wang; Yi Chen; Hui Ma; Jixin Liu; Yang Wang; Ming Zhang; Xuan Niu

doi:10.1016/j.bbih.2026.101196

Acute inflammation and fronto-striatal connectivity in the transition from acute to persistent fatigue after mild COVID-19: A longitudinal fMRI study

Brain Behav Immun Health. 2026 Feb 9:53:101196. doi: 10.1016/j.bbih.2026.101196. eCollection 2026 May.

Authors

Qiange Zhu¹, Tao Lu¹, Huijie Yuan¹, Ya'nan Zhu², Pang Du^{3

4}, Haiyang Liu⁵, Baoqi Wang⁶, Tonghui Liu⁷, Bo Wang⁸, Yi Chen⁹, Hui Ma¹⁰, Jixin Liu¹¹, Yang Wang¹², Ming Zhang¹, Xuan Niu¹

Affiliations

¹ Department of Medical Imaging, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
² Medical Imaging Centre, Ankang Central Hospital, Ankang, Shaanxi Province, China.
³ Department of Medical Imaging, Xi'an QinHuang Hospital, Xi'an, Shaanxi Province, China.
⁴ Department of Medical Imaging, Xi'an DaXing Hospital, Xi'an, Shaanxi Province, China.
⁵ Department of Medical Imaging, Shangluo Central Hospital, Shangluo, Shaanxi Province, China.
⁶ Department of Medical Imaging, Yanan Traditional Chinese Medicine Hospital, Yan'an, Shaanxi Province, China.
⁷ Department of Medical Imaging, Nuclear Industry 215 Hospital of Shaanxi Province, Xianyang, Shaanxi Province, China.
⁸ Department of Medical Imaging, Hanzhong Central Hospital, Hanzhong, Shaanxi Province, China.
⁹ Department of Magnetic Resonance Imaging, Yulin Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, Yulin, Shaanxi Province, China.
¹⁰ Department of Medical Imaging, Baoji High-tech Hospital, Baoji, Shaanxi Province, China.
¹¹ School of Life Science and Technology, Xidian University, Xi'an Key Laboratory of Intelligent Sensing and Regulation of Trans-Scale Life Information, Xi'an, Shaanxi, China.
¹² Department of Radiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.

Abstract

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.

Keywords: Fronto-striatal circuit; Functional connectivity; Inflammation; Mediation analysis; Post-COVID fatigue.