Fatigue and fatigability in Parkinson's disease: a neurophysiological perspective

Fatigue is one of the most frequent and disabling non-motor symptoms in Parkinson's disease (PD). Its multidimensional nature and overlap with related symptoms contribute to diagnostic and therapeutic challenges. A distinction has been proposed between fatigue, defined as the subjective perception of lack of energy and fatigability, defined as an objective decline in performance during sustained activity. However, their underlying pathophysiological mechanisms are still unclear. We conducted a narrative review of studies investigating PD-related fatigue and fatigability with neurophysiological techniques. To highlight convergent evidence, improve understanding of the mechanisms underlying fatigue and fatigability and discuss their potential clinical implications, we integrated neurophysiological findings with neuroimaging data and emerging measures from wearable sensors. Evidence suggests that fatigue in PD is closely related to attentional and salience network dysfunction, alterations in sensory attenuation, and disrupted connectivity involving prefrontal, limbic, and basal ganglia circuits. In contrast, fatigability appears more closely related to motor network dysfunction, abnormal corticospinal excitability modulation, and dopaminergic mechanisms. Neurophysiological approaches provide valuable tools for elucidating the mechanisms of fatigue and fatigability, dissociable yet interacting constructs in PD, underpinned by distinct but overlapping neural substrates. To support clinical reasoning and inform future individualized interventions we also propose a new conceptual framework integrating the currently available neurophysiological evidence. Future research is needed to further refine the conceptual and physiological boundaries between fatigue and fatigability and ultimately improve patients' quality of life.