Beyond physical performance: neurophysiological and neuroimaging insights into sensorimotor function in multiple sclerosis

Fatigue and fatigability are disabling symptoms in people with multiple sclerosis (PwMS), even when clinical disability is low. The mechanisms underlying these symptoms remain poorly understood. Recent literature distinguishes subjective fatigue from perceived fatigability, suggesting partially independent regulatory processes including interoception, psychological factors, and neuromuscular function. This study investigated how these mechanisms contribute to fatigue and fatigability in PwMS with mild disability. Twenty relapsing-remitting PwMS (EDSS 0–3.5) underwent an assessment including walking endurance (six-minute walking test), subjective fatigue (visual analogue scale), perceived physical fatigability (Pittsburgh Fatigability Scale), and physical fatigue impact (Modified Fatigue Impact Scale), interoceptive accuracy, muscle function and transcranial magnetic stimulation to quantify corticospinal excitability and inhibition. Walking endurance was strongly associated with perceived physical fatigability and physical fatigue impact, but not with subjective fatigue. Among the potential underlying mechanisms, only corticospinal excitability, indexed by the excitatory recruitment curve slope, was significantly related to physical fatigue impact and fatigability. No significant associations emerged with interoceptive accuracy, psychological measures, or muscle function. These findings support the partial independence of fatigue and fatigability, highlight cortical excitability as a key contributor to perceived physical fatigability in PwMS, and identify it as a promising target for individualized rehabilitation and neuromodulation strategies.