The specificity of fatigue-related brain activity in early Multiple Sclerosis.

People with multiple sclerosis (pwMS) frequently experience fatigue. However, little is known about its brain substrates in the early stages of the disease. This study aims at exploring functional brain activity associated to fatigue during a working memory (N-Back) task in pwMS and matched healthy controls (HC). 16 recently diagnosed pwMS and 17 HC performed a fatigue induction task in conditions of high or low cognitive load (HCL/LCL), followed by the N-Back task with 3 levels of difficulty (1 to 3-back) in a 3T MRI scanner. A questionnaire assessing trait fatigue (in everyday life) and scales assessing current state of fatigue at different time points were also administered. Following fatigue induction, subjective fatigue increased, in both groups and both fatigue conditions. However, evolution of fatigue followed the same trajectory in pwMS and HC. Overall, only task difficulty (but not fatigue induction) had an influence on N-Back performance. Regarding fMRI data, negative associations between trait fatigue score and brain activity were observed in pwMS, while the associations are positive in HC. There also exist group-specific patterns of brain activity when 2-back and 3-back difficulty levels are compared to 1-back, with interaction effects in regions belonging to the striato-thalamo-cortical (STC) network: the thalami, the cingulate cortex, the basal ganglia (right caudate) and the fronto-parietal cortex. The results indicate that specific parts of the STC circuitry are related to trait fatigue during task performance in pwMS and HC, despite similar behavioral performance and subjective fatigue level. This confirms the implication of the STC loops in fatigue pathophysiology, occurring from the early stages of the disease. The presence of negative associations in pwMS was interpreted as an alteration of automated strategies leading to a reorganized pattern of activation in pwMS, and that this cerebral reorganization could trigger fatigue.