Evaluation of MS related central fatigue using MR neuroimaging methods: Scoping review

Fatigue is a common and debilitating symptom in multiple sclerosis (MS). Over the past decade, a growing body of research has focussed on the pathophysiological mechanisms underlying central (cognitive and physical) fatigue in MS. The precise mechanisms causing fatigue in MS patients are complex and poorly understood, and may differ between patients. Advanced quantitative magnetic resonance imaging (MRI) techniques allow for objective assessment of disease pathology and have been used to characterise the pathophysiology of central fatigue in MS.

To systematically review the existing literature of MRI-based studies assessing the pathophysiological mechanisms of MS-related central fatigue.

A systematic literature search of four major databases (PubMed, Medline, Embase, Scopus and Google Scholar) was conducted to identify MRI-based studies of MS-related fatigue published in the past 20 years. Studies using the following MRI-based methods were included: structural (lesion load/atrophy), T1 relaxation time/magnetisation transfer ratio (MTR), diffusion tensor imaging (DTI), functional MRI (fMRI) and magnetic resonance spectroscopy (MRS).

A total of 92 studies were identified as meeting the search criteria and included for review. Structurally, regional gray/white matter atrophy, cortical thinning, decreased T1 relaxation times and reduced fractional anisotropy were associated with central fatigue in MS. Functionally, hyperactivity and reduced functional connectivity in several regional areas of frontal, parietal, occipital, temporal and cerebellum were suggested as causes of central fatigue. Biochemically, a reduction in N-acetyl aspartate/creatine and increased (glutamine+glutamate)/creatine ratios were correlated with fatigue severity in MS.

Several advanced quantitative MRI methods have been employed in the study of central fatigue in MS. Central fatigue in MS is associated with macro/microstructural and functional changes within specific brain regions (frontal, parietal, temporal and deep gray matter) and specific pathways/networks (cortico-cortical and cortico-subcortical). Alternations in the cortico-striatal-thalamocortical (CSTC) loop are correlated with the development of fatigue in MS patients.