No abstract

Fatigue is one of the most pervasive symptoms of multiple sclerosis (MS), and has engendered hundreds of investigations on the topic. While there is a growing literature using various methods to study fatigue, a unified theory of fatigue in MS is yet to emerge. In the current review, we synthesize findings from neuroimaging, pharmacological, neuropsychological, and immunological studies of fatigue in MS, which point to a specific hypothesis of fatigue in MS: the dopamine imbalance hypothesis. The communication between the striatum and prefrontal cortex is reliant on dopamine, a modulatory neurotransmitter. Neuroimaging findings suggest that fatigue results from the disruption of communication between these regions. Supporting the dopamine imbalance hypothesis, structural and functional neuroimaging studies show abnormalities in the frontal and striatal regions that are heavily innervated by dopamine neurons. Further, dopaminergic psychostimulant medication has been shown to alleviate fatigue in individuals with traumatic brain injury, chronic fatigue syndrome, and in cancer patients, also indicating that dopamine might play an important role in fatigue perception. This paper reviews the structural and functional neuroimaging evidence as well as pharmacological studies that suggest that dopamine plays a critical role in the phenomenon of fatigue. We conclude with how specific aspects of the dopamine imbalance hypothesis can be tested in future research.

The present study investigated the neural correlates of cognitive fatigue in Multiple Sclerosis (MS), looking specifically at the relationship between self-reported fatigue and objective measures of cognitive fatigue. In Experiment 1, functional magnetic resonance imaging (fMRI) was used to examine where in the brain BOLD activity covaried with “state” fatigue, assessed during performance of a task designed to induce cognitive fatigue while in the scanner. In Experiment 2, diffusion tensor imaging (DTI) was used to examine where in the brain white matter damage correlated with increased “trait” fatigue in individuals with MS, assessed by the Fatigue Severity Scale (FSS) completed outside the scanning session. During the cognitively fatiguing task, the MS group had increased brain activity associated with fatigue in the caudate as compared with HCs. DTI findings revealed that reduced fractional anisotropy in the anterior internal capsule was associated with increased self-reported fatigue on the FSS. Results are discussed in terms of identifying a “fatigue-network” in MS.