To identify associations between each thalamic nucleus and fatigue and to explore whether the effect of aerobic capacity on this symptom is mediated by the thalamus in people with multiple sclerosis (pwMS).

Fatigue is a common symptom in pwMS affecting mental and physical domains. Different factors including aerobic capacity, disability and cognitive impairment contribute to fatigue perception. The thalamus, with its nuclei related to motor and cognitive aspects, is involved in fatigue pathogenesis.

In this cross-sectional analysis, 74 pwMS underwent a clinical evaluation with rating of Expanded Disability Status Scale (EDSS), modified fatigue impact scale (MFIS) and symbol digit modalities test (SDMT); a cardiopulmonary exercise testing to assess maximal oxygen uptake (VO2max) and brain MRI to quantify global and thalamic nuclei volumes. A group of 47 sex-and-age-matched healthy controls (HC) was included for MRI data comparison, while a subgroup of HC (10) also presented VO2max values.

In pwMS, fatigue was associated with atrophy of left lateral-dorsal thalamic nucleus (r-value: -0.278, p≤0.018), with a stronger association with cognitive rather than physical fatigue. Worse fatigue (higher MFIS) was associated with lower VO2max (r-value:-0.263, p=0.027), higher EDSS (r-value:0.353, p=0.003) and lower SDMT (r-value:-0.353, p=0.003). The latter two were associated to a widespread pattern of atrophy within the thalamus. Lower VO2max was only associated to atrophy of the lateral-dorsal thalamic nuclei. In HC, higher aerobic capacity was associated with greater volume of the whole thalamus, pulvinar and ventral nuclei (r-value: from 0.674 to 0.714, p≤0.012). In pwMS, there was a significant indirect effect of aerobic capacity on fatigue through the volume of the left lateral-dorsal thalamic nucleus (b =-0.305, CI [-0.678,-0.005]).

Aerobic capacity exerts a positive effect on fatigue related to MS. This effect is mediated by the left lateral-dorsal thalamic nucleus.