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.

The challenges for the upcoming decade include clarification of the definition of IPS as well as its theoretical conceptualization and a consensus on assessment. Based on the results obtained, we propose a new theoretical model, the tri-factor model of IPS.

Increased brain activity exhibited by participants with a TBI might represent increased cerebral effort which may be manifested as cognitive fatigue. Functional MRI appears to be a potentially useful tool for understanding the neural mechanisms associated with cognitive fatigue in TBI.

Recently, there has been renewed interest in the study of cognitive fatigue. It is known that fatigue is one of the most disabling symptoms in numerous neurological populations, including stroke, multiple sclerosis, Parkinson’s disease, and traumatic brain injury. Behavioral studies of cognitive fatigue are hampered by lack of correlation of self-report measures with objective performance. Neuroimaging studies provide new insight about cognitive fatigue and its neural correlates.Impairment within the cortico-striatal network, involved in effort–reward calculation, has been suggested to be critically related to fatigue. The current review surveys the recent neuroimaging literature, and suggests promising avenues for future research.

The inter-related cognitive constructs of working memory (WM) and processing speed are fundamental components to general intellectual functioning in humans. Importantly, both WM and processing speed are highly susceptible to disruption in cases of brain injury, neurologic illness, and even in normal aging. A goal of this article is to summarize and critique the functional imaging studies of speeded working memory in neurologically impaired populations. This review focuses specifically on the role of the lateral prefrontal cortex in mediating WM performance and integrates the relevant WM literature in healthy adults with the current findings in the clinical literature. One important finding emerging from a summary of this literature is the dissociable contributions made by ventrolateral and dorsolateral prefrontal cortex (VLPFC and DLPFC) in guiding performance on tasks of WM. Throughout this review, it is shown that when cerebral resources are challenged, it is DLPFC, and often right DLPFC specifically, that plays a critical role in modulating WM functioning. In addition, this article will examine the relationship between task performance and brain activation across studies to clarify the role of increased DLPFC activity in clinical samples. Finally, explanations are offered for the observed increased DLPFC activation and the potentially unique role of right DLPFC in mediating WM performance during periods of cerebral challenge.

Although it is known that processing speed deficits are one of the primary cognitive impairments in multiple sclerosis (MS), the underlying neural mechanisms responsible for impaired processing speed remain undetermined. Using BOLD functional magnetic resonance imaging, the current study compared the brain activity of 16 individuals with MS to 17 healthy controls (HCs) during performance of a processing speed task, a modified version of the Symbol Digit Modalities Task. Although there were no differences in performance accuracy, the MS group was significantly slower than HCs. Although both groups showed similar activation involving the precentral gyrus and occipital cortex, the MS showed significantly less cerebral activity than HCs in bilateral frontal and parietal regions, similar to what has been reported in aging samples during speeded tasks. In the HC group, processing speed was mediated by frontal and parietal regions, as well as the cerebellum and thalamus. In the MS group, processing speed was mediated by insula, thalamus and anterior cingulate. It therefore appears that neural networks involved in processing speed differ between MS and HCs, and our findings are similar to what has been reported in aging, where damage to both white and gray matter is linked to processing speed impairments.