Acute inflammation and fronto-striatal connectivity in the transition [to] persistent fatigue after mild [C19]: [longitudinal fMRI], 2026, Zhu et al

[forestglip]

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

Spoiler: Authors

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

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.

Web | DOI | PMC | PDF | Brain, Behavior, & Immunity - Health | Open Access

 

[Utsikt]

The protocol says they are planning on doing repeat measurements at 12 and 24 months as well.

The discussion spends a lot of time talking about effort, reward, motivation, etc.

In our study, individuals with persistent post-COVID fatigue exhibited significantly reduced functional connectivity between the left superior frontal gyrus and striatal regions (including the caudate and putamen) during the chronic phase. Such reduced connectivity may reflect impaired prefrontal regulatory capacity, which disrupts the dynamic modulation of effort cost, reward valuation, and cognitive resource allocation (Shenhav et al., 2016; Yee et al., 2021).

Specifically, the caudate and putamen, acting as the primary input nuclei, are pivotal for sustaining goal-directed drive and strictly regulating energy expenditure during cognitively or physically demanding activities (Grahn et al., 2008, 2009). When this circuit is compromised, individuals are more likely to experience diminished reward sensitivity, reduced motivation, and difficulty sustaining cognitive effort, ultimately contributing to persistent subjective fatigue.

Notably, fronto-striatal dysfunction has also been widely reported in depressive disorders, highlighting the transdiagnostic nature of this circuitry and suggesting a partially shared neural substrate related to impaired reward processing (Nusslock and Alloy, 2017; Segarra et al., 2016).

While fatigue and mood symptoms often co-occur and are difficult to disentangle behaviorally, the present findings underscore that disruption within this circuit is a central pathophysiological feature of the post-COVID syndrome, potentially manifesting as both profound fatigue and affective dysregulation.