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.
Highlights
Fatigue is a common symptom in multiple sclerosis (MS), with up to 90% of individuals with MS reporting fatigue [1]
AND CONCLUSION In this review, we propose that fatigue arises due to an imbalance of dopamine, a modulatory neurotransmitter, in the CNS and the immune system
Based on the evidence cited above and building upon a previous framework on fatigue [9], we propose that fatigue depends on the base levels of dopamine in the CNS
Summary
Fatigue is a common symptom in multiple sclerosis (MS), with up to 90% of individuals with MS reporting fatigue [1]. One of the ultimate goals of this review is to investigate the evidence that supports the dopamine imbalance hypothesis by examining studies showing structural and functional abnormalities in areas enervated by dopamine and clinical trials showing alleviation of fatigue after dopamine medication. The current review examines the evidence in support of the dopamine imbalance hypothesis by focusing on central fatigue, which can be experienced as both physical and mental in nature. This hypothesis was developed based on evidence from both animal and clinical studies, which showed the effects of basal ganglia damage to be similar to the symptoms of central fatigue. The D1 and D5 receptors belong to the D1-like group, while the rest of the DRs belong to the D2-like group of receptors [10, 13] These receptors have different distribution densities in the CNS, depending on the brain region. Increased amount of dopamine release in the striatum and the PFC has been shown to be associated with cognitive flexibility [see Ref. [27] for review]
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