Mapping the neural and molecular basis underlying fatigue in Parkinson’s disease

Fatigue is a common and debilitating non-motor symptom in patients with Parkinson's disease (PD). By integrating the activation likelihood estimation (ALE) meta-analysis and activation network mapping (ANM) technique, the brain network underlying fatigue (referred to as "fatigue-related network") in PD was identified, comprising widespread brain regions primarily involving the somatomotor and frontoparietal networks. This network was interpreted through transcriptomic patterns, chemoarchitectures, and behavioral relevance. Fatigue-related genes were predominantly enriched in synaptic and actin filament-related biological processes and showed primary expression in neurons and oligodendrocytes. The fatigue-related network closely corresponded to the spatial distribution of acetylcholine, glutamate, and norepinephrine systems and was primarily linked to motor function. This study defines a distinct brain network substrate underlying fatigue in PD, advancing our understanding of the neurobiological mechanisms and facilitating the development of effective therapies for affected patients.