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.

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Objectives: Fatigue in multiple sclerosis (MS) is a frequent and invalidating symptom, which can be relieved by non-invasive neuromodulation, which presents only negligible side effects. A 5-day transcranial direct-current stimulation, 15 min per day, anodically targeting the somatosensory representation of the whole body against a larger occipital cathode was efficacious against MS fatigue (fatigue relief in multiple sclerosis, Faremus treatment). The present proof-of-concept study tested the working hypothesis that Faremus S1 neuromodulation modifies the homology of the dominant and non-dominant corticospinal (CST) circuit recruitment. Methods: CST homology was assessed via the Fréchet distance between the morphologies of motor potentials (MEPs) evoked by transcranial magnetic stimulation in the homologous left- and right-hand muscles of 10 fatigued MS patients before and after Faremus. Results: In the absence of any change in MEP features either as differences between the two body sides or as an effect of the treatment, Faremus changed in physiological direction the CST’s homology. Faremus effects on homology were more evident than recruitment changes within the dominant and non-dominant sides. Conclusions: The Faremus-related CST changes extend the relevance of the balance between hemispheric homologs to the homology between body sides. With this work, we contribute to the development of new network-sensitive measures that can provide new insights into the mechanisms of neuronal functional patterning underlying relevant symptoms.