Mapping the brain's fatigue network: a transdiagnostic systematic review and meta-analysis on functional correlates of mental fatigue.

Mental fatigue is a significant psychopathological symptom that has recently gained attention, particularly in chronic fatigue syndrome/myalgic encephalomyelitis and Post-COVID-19 condition. However, fatigue is a clinically relevant symptom across a wide range of mental and neurological disorders. To identify a transdiagnostic functional network associated with fatigue, we conducted an activation likelihood estimation meta-analysis of neuroimaging studies. The primary inclusion criterion was studies involving any medical condition where patients exhibited significantly higher levels of fatigue compared to healthy controls. A systematic literature review across three major scientific databases identified 46 eligible neuroimaging studies, including a total of 2603 individuals. The meta-analysis of these studies revealed a widespread cortical-subcortical network involving frontal, limbic, basal ganglia and parietal structures. Three main clusters were highlighted: a frontal-striatal-limbic cluster, a frontal-cingulate cluster and a parietal cluster, with regions implicated in cognitive, emotional and somatosensory symptoms associated with mental fatigue. Quality analysis indicated a moderate risk of bias in the majority of the included studies. Overall, our findings provide scientific evidence for a transdiagnostic mental fatigue network in the brain, with key nodes located in the lateral frontal cortex, cingulate cortex, insula, thalamus, precuneus and caudate. These results support the theory of thalamic-striatal-cortical dysfunction, which may impair compensatory mechanisms related to mental fatigue. Additionally, abnormal activation of limbic and parietal regions may contribute to cognitive, emotional and attentional impairments linked to fatigue.