Lack of pre-movement facilitation as neurophysiological hallmark of fatigue in patients with Parkinson's disease: A single pulse TMS study

Background: Fatigue is a debilitating symptom in Parkinson's disease (PD), significantly affecting quality of life. Despite its prevalence, the underlying neurophysiological mechanisms remain poorly understood. Recent evidence suggests that deficits in cortical motor preparation processes may contribute to PD-related fatigue. Methods: This study investigated premovement facilitation (PMF), a marker of corticospinal excitability during motor preparation, in 20 healthy subjects (HS) and 28 PD patients, subdivided into those with fatigue (PDwF, n = 14) and without fatigue (PDwoF, n = 14). Participants performed a reaction time (RT) task involving thumb abduction following a visual go signal, while transcranial magnetic stimulation (TMS) was applied over the primary motor cortex (M1) at intervals of 50, 100, and 150 ms before movement onset. Motor-evoked potentials (MEPs) were recorded from the abductor pollicis brevis (APB) and the task-irrelevant abductor digiti minimi (ADM). Results: In HS and PDwoF, MEP APB amplitude increased progressively when TMS was applied at 150, 100, and 50 ms before movement onset, reflecting intact PMF, with the greater MEP APB amplitude at the shorter interval (50 ms). However, in PDwF patients, PMF was absent on the most affected side, while it remained preserved on the less affected side. Furthermore, the absence of PMF correlated with fatigue severity (FSS scores) and rigidity subscores, highlighting a link between impaired motor preparation and clinical symptoms. Conclusion: These findings suggest that cortical dysfunction in motor preparation contributes to PD-related fatigue, particularly in the most affected hemisphere. The observed PMF deficits provide a potential neurophysiological marker for fatigue in PD, supporting future investigations into targeted therapeutic interventions to restore motor excitability and alleviate fatigue symptoms.