Fatigue in multiple sclerosis: Does the functional or structural damage prevail?

Fatigue in multiple sclerosis (MS) is a highly invalidating symptom, lacking efficacious drugs. This topical review aims at assessing the signs in the literature of functional versus structural damage prevalence at the origin of MS fatigue by focusing on papers that assessed the two counterparts in the same patients, paying attention that the fatigue levels do not correlate with clinical severity. We summarize and discuss evidence of increased levels of fatigue occurring together with the alterations of functional connectivity at multiple levels, in the absence of any relationship with lesion load and local atrophy of the involved structures. Specifically, neuronal communication mainly altered in the corticomuscular synchronizations, between hemispheric homologs and in the resting-state networks involved in emotion (cingulate cortex) and effort-reward balance (striatum and inferior parietal lobule). Finally, given the functional prevalence in neuronal network alterations at the origin of fatigue in MS, we highlight the relevance of developing treatments aiming at compensating the neuronal electric communication dysfunctions.