The Dopamine Imbalance Hypothesis of Fatigue in Multiple Sclerosis and Other Neurological Disorders

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.

Interaction between interleukin-1β and type-1 cannabinoid receptor is involved in anxiety-like behavior in experimental autoimmune encephalomyelitis

“…Interestingly, the role of dopamine in immune function and fatigue perception in MS is also emerging and other studies are needed to explore the mechanisms of dopamine imbalance in MS [63]. Here, we found that amphetamine treatment was able to restore normal CB1R functioning at GABA terminals in the striatum of EAE mice, confirming the link between the two systems in this brain area.…”

Post-Stroke Fatigue May Be Associated with the Promoter Region of a <b><i>Monoamine Oxidase A </i></b>Gene Polymorphism

“…It is believed that extensively diverse 5-HT receptors are involved in the regulation of human emotion [23] . Alternatively, our results that PSF is positively associated with the low activity of MAO-A , but not with serotonin regulating system may partly support the dopamine imbalance hypothesis in the development of fatigue [24] . Further researches are needed to replicate our findings and to elucidate genetic contribution of PSF.…”

Fatigue in multiple sclerosis – Insights into evaluation and management

“…In fact, these molecules can act by upregulating the excitatory glutamatergic transmission [109,132,215], a phenomenon that is already documented in MS patients [32,196,210,216] or downregulating the inhibitory GABAergic transmission [215]; both of which could be the final pathway toward an aberrant synaptic transmission and irreversible neurodegenerative damage [32,210] and may contribute to fatigue perception. In addition to this neurochemical imbalance, some authors raised the hypothesis of an abnormal dopaminergic transmission behind MS fatigue based on multidisciplinary studies highlighting pathologies in fronto-striatal regions that are heavily innervated by dopaminergic neurons [49].…”