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Background: Fatigue in multiple sclerosis (MS) has been inconsistently associated with disruption of specific brain circuitries. Temporal fluctuations of fatigue have not been considered. Objective: The aim of this study was to investigate the association of fatigue with brain diffusion abnormalities, using robust criteria for patient stratification based on longitudinal patterns of fatigue. Methods: Patient stratification: (1) sustained fatigue (SF, n = 26): latest two Modified Fatigue Impact Scale (MFIS) ⩾ 38; (2) reversible fatigue (RF, n = 25): latest MFIS < 38 and minimum one previous MFIS ⩾ 38; and (3) never fatigued (NF, n = 42): MFIS always < 38 (five assessments minimum). 3T brain magnetic resonance imaging (MRI) was used to perform voxel-wise comparison of fractional anisotropy (FA) between the groups controlling for age, sex, disease duration, physical disability, white matter lesion load (T2LV), and depression. Results: SF and, to a lesser extent, RF patients showed lower FA in multiple brain regions compared to NF patients, independent of age, sex, disease duration, and physical disability. In cingulo-postcommissural-striato-thalamic regions, the differences in FA between SF and NF (but not between RF and NF or SF) patients were independent of T2LV, and in ventromedial prefronto-precommissuro-striatal and temporo-insular areas, independent of T2LV and depression. Conclusion: Damage to ventromedial prefronto-precommissuro-striatal and temporo-insular pathways appears to be a specific substrate of SF in MS.

Fatigue in multiple sclerosis (MS) has been associated with brain damage with low replicability. Temporal fatigue fluctuations have not been considered. We assessed whether sustained fatigue (SF) associates more strongly with grey matter (GM) changes than reversible fatigue (RF). Patients were stratified into three groups according to historical fatigue levels: SF (n = 30, i.e. patients who reported fatigue at the latest ≥2 assessments), RF (n = 31, i.e. patients not fatigued at the latest assessment, but reported fatigue previously), and never fatigued (NF, n = 37). Groups were compared for brain GM volume using cross-sectional voxel-based and volumetric analyses of 3T T1-weighted MRI. Confounding effects of depression and related medications were also investigated. SF and RF patients showed similar anatomical distribution of GM atrophy. While we robustly replicated the anatomical patterns of GM atrophy described in previous work, we also found an association between hippocampal atrophy and fatigue. Depression showed confounding effects in frontal, parietal, occipital, accumbal and thalamic regions. Assessed treatments showed confounding effects in frontal, parietal and striatal areas. Our results suggest that history of clinically-relevant fatigue in currently non-fatigued patients is associated with GM atrophy, potentially explaining inconsistent findings of previous studies that stratified patients using a single fatigue assessment.

Objective: To determine the motor-behavioral and neural correlates of putative functional common variants in the sodium-channel Na V 1.8 encoding gene (SCN10A) in vivo in patients with multiple sclerosis (MS). Methods:We recruited 161 patients with relapsing-onset MS and 94 demographically comparable healthy participants. All patients with MS underwent structural MRI and clinical examinations (Expanded Disability Status Scale [EDSS] and Multiple Sclerosis Functional Composite [MSFC]). Whole-brain voxel-wise and cerebellar volumetry were performed to assess differences in regional brain volumes between genotype groups. Resting-state fMRI was acquired from 62 patients with MS to evaluate differences in cerebellar functional connectivity. All participants were genotyped for 4 potentially functional SCN10A polymorphisms.Results: Two SCN10A polymorphisms in high linkage disequilibrium (r 2 5 0.95) showed significant association with MSFC performance in patients with MS (rs6795970: p 5 6.2 3 10 24 ; rs6801957: p 5 0.0025). Patients with MS with rs6795970AA genotype performed significantly worse than rs6795970 G carriers in MSFC (p 5 1.8 3 10 24 ) and all of its subscores. This association was independent of EDSS and cerebellar atrophy. Although the genotype groups showed no difference in regional brain volumes, rs6795970AA carriers demonstrated significantly diminished cerebellar functional connectivity with the thalami and midbrain. No significant SCN10A-genotype effect was observed on MSFC performance in healthy participants.Conclusions: Our data suggest that SCN10A variation substantially influences functional status, including prominent effects on motor coordination in patients with MS. These findings were supported by the effects of this variant on a neural system important for motor coordination, namely cerebello-thalamic circuitry. Overall, our findings add to the emerging evidence that suggests that sodium channel Na V 1.8 could serve as a target for future drug-based interventions to treat cerebellar dysfunction in MS.