Abstract
In ten healthy subjects and in ten patients suffering from Multiple Sclerosis (MS), we investigated the cortical functional changes induced by a standard fatiguing repetitive tapping task. The Cortical Silent Period (CSP), an intracortical, mainly GABAB-mediated inhibitory phenomenon, was recorded by two different hand muscles, one acting as prime mover of the fatiguing index-thumb tapping task (First Dorsal Interosseous, FDI) and the other one not involved in the task but sharing largely overlapping central, spinal, and peripheral innervation (Abductor Digiti Minimi, ADM). At baseline, the CSP was shorter in patients than in controls. As fatigue developed, CSP changes involved both the “fatigued” FDI and the “unfatigued” ADM muscles, suggesting a cortical spread of central fatigue mechanisms. Chronic therapy with amantadine annulled differences in CSP duration between controls and patients, possibly through restoration of more physiological levels of intracortical inhibition in the motor cortex. These inhibitory changes correlated with the improvement of fatigue scales. The CSP may represent a suitable marker of neurophysiological mechanisms accounting for central fatigue generation either in controls or in MS patients, involving corticospinal neural pools supplying not only the fatigued muscle but also adjacent muscles sharing an overlapping cortical representation.
Highlights
Fatigue is intrinsic to Multiple Sclerosis (MS) and represents the most common symptom experienced by patients along the course of the disease [1], contributing to disability and to the worsening of their daily quality of life [2, 3]
Post hoc comparisons revealed that the Cortical Silent Period (CSP) recorded in MS patients before amantadine administration was significantly shorter compared to healthy controls, whereas no significant differences emerged after both fatiguing tasks (Figure 2)
At variance with short-interval intracortical inhibition changes, a measure of GABAA activity in the motor cortex [15], which were limited to the “fatigued” First Dorsal Interosseous (FDI) muscle and spared the “unfatigued” Abductor Digiti Minimi (ADM) muscle [51], the presence of consistent CSP changes on both muscles suggests a spread of mechanisms generating fatigue at cortical level, where the neural populations controlling the FDI and ADM muscles are largely overlapping [43, 44]
Summary
Fatigue is intrinsic to Multiple Sclerosis (MS) and represents the most common symptom experienced by patients along the course of the disease [1], contributing to disability and to the worsening of their daily quality of life [2, 3]. It may originate at multiple levels of the nervous system “beginning with ideation of an activity within the cortex and ending with the process of muscle contraction and force generation” [4]. Atrophy of cortical layers and white matter [11], reduced perfusion of grey nuclei at the subcortical level [12], diffuse axonal loss [13], and alterations of connectivity [14] may contribute to generation of central fatigue.
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