Fatigue is one of the most disabling symptoms of multiple sclerosis (MS); it influences patients’ quality of life. The etiology of fatigue is complex, and its pathogenesis is still unclear and debated. The objective of this review was to describe potential brain structural and functional dysfunctions underlying fatigue symptoms in patients with MS. To reach this purpose, a systematic review was conducted of published studies comparing functional brain activation and structural brain in MS patients with and without fatigue. Electronic databases were searched until 24 February 2021. The structural and functional outcomes were extracted from eligible studies and tabulated. Fifty studies were included: 32 reported structural brain differences between patients with and without fatigue; 14 studies described functional alterations in patients with fatigue compared to patients without it; and four studies showed structural and functional brain alterations in patients. The results revealed structural and functional abnormalities that could correlate to the symptom of fatigue in patients with MS. Several studies reported the differences between patients with fatigue and patients without fatigue in terms of conventional magnetic resonance imaging (MRI) outcomes and brain atrophy, specifically in the thalamus. Functional studies showed abnormal activation in the thalamus and in some regions of the sensorimotor network in patients with fatigue compared to patients without it. Patients with fatigue present more structural and functional alterations compared to patients without fatigue. Specifically, abnormal activation and atrophy of the thalamus and some regions of the sensorimotor network seem linked to fatigue.

Muscle fatigue induced by voluntary exercise, which requires central motor drive, causes central fatigue that impairs endurance performance of a different, non-fatigued muscle. This study investigated the impact of quadriceps fatigue induced by electrically-induced (no central motor drive) contractions on single-leg knee-extension (KE) performance of the subsequently exercising ipsilateral quadriceps. On two separate occasions, eight males completed constant-load (85% of maximal power-output) KE exercise to exhaustion. In a counterbalanced manner, subjects performed the KE exercise with no pre-existing quadriceps fatigue in the contralateral leg on one day (No-PreF), while on the other day, the same KE exercise was repeated following electrically-induced quadriceps fatigue in the contralateral leg (PreF). Quadriceps fatigue was assessed by evaluating pre- to post-exercise changes in potentiated twitch force (ΔQtw,pot; peripheral-fatigue), and voluntary muscle activation (ΔVA; central-fatigue). As reflected by the 57±11% reduction in electrically-evoked pulse force, the electrically-induced fatigue protocol caused significant knee-extensors fatigue. KE endurance time to exhaustion was shorter during PreF compared to No-PreF (4.6±1.2 vs 7.7±2.4 min; p<0.01). While ΔQtw,pot was significantly larger in No-PreF compared to PreF (-60% vs -52%, p<0.05), ΔVA was greater in PreF (-14% vs -10%, p<0.05). Taken together, electrically-induced quadriceps fatigue in the contralateral leg limits KE endurance performance and the development of peripheral fatigue in the ipsilateral leg. These findings support the hypothesis that the crossover-effect of central fatigue is mainly mediated by group III/IV muscle afferent feedback and suggest that impairments associated with central motor drive may only play a minor role in this phenomenon.

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Purpose: This study evaluated whether central motor drive during fatiguing exercise plays a role in determining performance and the development of neuromuscular fatigue during a subsequent endurance task. Methods: On separate days, 10 males completed three constant-load (80% peak power output), single-leg knee-extension trials to task failure in a randomized fashion. One trial was performed without preexisting quadriceps fatigue (CON), and two trials were performed with preexisting quadriceps fatigue induced either by voluntary (VOL; involving central motor drive) or electrically evoked (EVO; without central motor drive) quadriceps contractions (~20% maximal voluntary contraction (MVC)). Neuromuscular fatigue was assessed via pre-post changes in MVC, voluntary activation (VA), and quadriceps potentiated twitch force (Q tw,pot ). Cardiorespiratory responses and rating of perceived exertion were also collected throughout the sessions. The two prefatiguing protocols were matched for peripheral fatigue and stopped when Q tw,pot declined by ~35%. Results: Time to exhaustion was shorter in EVO (4.3 ± 1.3 min) and VOL (4.7 ± 1.5 min) compared with CON (10.8 ± 3.6 min,