People with multiple sclerosis have reduced TMS-evoked motor cortical output compared with healthy individuals during fatiguing submaximal contractions.

People with multiple sclerosis (PwMS) typically experience greater levels of exercise-induced fatigue compared with healthy individuals. Therefore, this study examined performance fatigability in PwMS when executing a prolonged submaximal contraction. Nine PwMS (38 ± 7 yr, 6 females) and nine healthy controls (35 ± 6 yr, 4 females) performed an elbow flexion at 15% maximal voluntary contraction (MVC) for 26 min. MVCs were performed every 2 min during, and following, the contraction to determine if maximal force was impaired by the low-intensity contraction. Single-pulse transcranial magnetic stimulation (TMS) was delivered to the primary motor cortex with a circular coil during each MVC and during the submaximal contraction. Superimposed and resting twitches were calculated from elbow flexion torque, whereas motor-evoked potentials were calculated from biceps brachii electromyography. Ratings of perceived exertion (RPE) were obtained before each MVC. During the fatiguing contraction protocol, the MS group exhibited a reduced MVC torque compared with the healthy control group ( = 0.044), which aligned with group differences in biceps brachii EMG activity ( = 0.022) and superimposed twitch amplitude ( = 0.016). Fatigue-related decrements in MVC torque ( = 0.044) and biceps brachii EMG activity ( = 0.043) demonstrated in the MS group persisted throughout recovery. However, MS did not affect the RPE during the fatigue task. These findings suggest that PwMS may have greater levels of performance fatigability due to decreased voluntary drive from the motor cortex, which is not associated with greater ratings of perceived exertion. By combining TMS and motor nerve stimulation during a low-intensity exercise task, we were able to uncover the contribution that different levels of the CNS have during fatiguing exercise in PwMS. Our findings are novel and revealed that PwMS experienced decreased voluntary drive from the motor cortex during a low-intensity sustained fatiguing task that was associated with heightened levels of performance fatigability.