A qualitative review of the neurophysiological underpinnings of fatigue in multiple sclerosis

Fatigue is debilitating in multiple sclerosis (MS) and may have multiple causes. Recent investigations into objectively measurable correlates of fatigue have used transcranial magnetic stimulation (TMS) to examine a range of neurophysiological measures of neural excitability that may be altered in patients with MS. This qualitative review was conducted to test the hypothesis that changes in neural excitability are a contributing factor in MS-related fatigue. A search of the English language literature led to the compilation and synthesis of original research papers in which various aspects of neural excitability and neural transmission were measured using TMS in patients with MS. The resulting papers were classified into three categories of study relevant to fatigue: abnormalities in excitability and their correlation with self-reported fatigue; effects of exercise-induced fatigue on neural excitability; and effects of fatigue medications on neural excitability. Evidence of an association between fatigue and intracortical inhibition is both limited and conflicting, and no evidence suggests associations of fatigue with corticomotor excitability or neuronal conduction. Pharmacologically-induced changes in fatigue were found to correlate with changes in intracortical excitability. No conclusions could be drawn regarding neural excitability and exercise-induced fatigue, due to variability in study populations, outcome measures, and exercise protocols across different studies. Suggestions for future studies in this area are proposed with a view to identifying potentially modifiable factors contributing to fatigue in MS.