Brain anatomical correlates of fatigue in multiple sclerosis

Abstract

Fatigue is one of the most debilitating symptoms in patients with multiple sclerosis (MS). Despite its clinical significance, the aetiology and pathophysiology of MS-related fatigue are not well understood. Current evidence and understanding of the neuroanatomical underpinnings of MS-related fatigue are reviewed in this article. The aims of this paper are to (1) review the findings of previous structural neuroimaging studies on MS-related fatigue and summarize consistent findings regarding brain circuitry associated with fatigue in MS, (2) contextualize these findings with the neurochemistry of the relevant circuits and (3) discuss future perspectives with regard to impact on fatigue management of MS patients and methodological challenges towards improved understanding of fatigue pathogenesis. The detailed understanding of the neuroanatomical underpinnings of fatigue might contribute to the identification of novel treatment targets and factors determining treatment resistance to drugs used in current clinical practice.

A novel classification of fatigue in multiple sclerosis based on longitudinal assessments

“…Medication was defined as a dichotomous variable, based on treatment with at least one of the above-mentioned medications. Since depression is a significant confounder of fatigue, 2 we ran a third GLM analysis adjusting also for CES-D (in addition to age, sex, disease duration, EDSS, and medication).…”

“…1 The neural basis of fatigue has been investigated in several magnetic resonance imaging (MRI) studies. 2 These studies showed associations between fatigue and structural brain abnormalities that characterize MS, such as white matter lesions 3–6 and brain atrophy. 4,7–9 However, among the plethora of neuroimaging studies investigating the relationship between those structural brain abnormalities and fatigue, only some showed significant associations, while others failed to replicate those findings.…”

Fatigue, depression, and pain in multiple sclerosis: How neuroinflammation translates into dysfunctional reward processing and anhedonic symptoms

“…11,12,14 Interestingly, MS patients show impaired reward responsiveness, especially when suffering from fatigue. 15 Moreover, neuroimaging studies have shown overlapping structural and functional alterations of mesocorticolimbic pathways in MS patients Fatigue, depression, and pain in multiple sclerosis: How neuroinflammation translates into dysfunctional reward processing and anhedonic symptoms suffering from fatigue, 1,16 depression, 2,4 and pain. 17 Furthermore, all three symptoms have been linked to dysfunction of monoaminergic neurotransmission in central nervous system (CNS) inflammation.…”

“…Moreover, we will discuss the potential therapeutic implications and limitations of such a framework. 11,18,19,21,22 Neuroimaging findings Fatigue, depression, and pain are associated with several structural and functional changes of the brain in MS 1,2,4,16,17 and beyond. 1,23,24 Such changes have been most consistently observed in the prefrontal cortex, the basal ganglia, and the limbic system.…”

“…1,23,24 Such changes have been most consistently observed in the prefrontal cortex, the basal ganglia, and the limbic system. 1,2,4,16,17,23,24 Structural neuroimaging findings In MS patients suffering from fatigue and depression, a higher lesion load and more severe cortical atrophy, particularly in the prefrontal cortex, have been observed. [25][26][27] Similarly, prefrontal gray matter alterations have been frequently reported in chronic pain patients (for a review, see Kang et al 24 ) but have thus far not been assessed in MS.…”