Dissociating Fatigue and Fatigability in Multiple Sclerosis: The Role of Cognitive Processing Speed

ABSTRACT Background Fatigue in people with multiple sclerosis (PwMS) is common and disabling, yet poorly understood. This study aimed to clarify the distinction between long‐term fatigue and task‐induced fatigability and their respective pathophysiological processes, and to examine the contribution of decreased cognitive processing speed (CPS) to the relationship between structural brain damage, fatigue, and fatigability. Methods Fatigue was induced in 34 PwMS (18–49 years) and 32 age−/sex‐matched healthy controls (HCs, 24–44 years) using an individually calibrated task based on each participant's CPS. Perceived task‐induced fatigue was assessed from pre‐ to post‐task change in self‐reported fatigue, and objective fatigability from within‐task changes in performance, vigilance, and pupil diameter. Brain volumes and lesions were quantified on structural 3 T MRI. Results PwMS showed higher long‐term fatigue and slower CPS ( p  p  > 0.05), whereas perceived task‐induced fatigue remained elevated. Both CPS and long‐term fatigue—but not fatigability—were associated with putamen atrophy and lesion burden. Reduced CPS mediated the associations between putamen atrophy and long‐term fatigue (indirect effect, 95% CI [−54.48, −0.97]). Conclusions In PwMS, the association between structural brain damage and long‐term fatigue is mediated by reduced CPS, whereas objective fatigability normalizes once cognitive load is calibrated to individual CPS. These findings support adapting cognitive load to each patient's processing capacity rather than reducing task demands uniformly to help mitigate the daily‐life impact of fatigue.