Brain connectivity changes underlying depression and fatigue in relapsing-remitting multiple sclerosis: A systematic review

Abstract

Multiple Sclerosis (MS) is an autoimmune disease affecting the central nervous system, characterised by neuroinflammation and neurodegeneration. Fatigue and depression are common, debilitating, and intertwined symptoms in people with relapsing-remitting MS (pwRRMS). An increased understanding of brain changes and mechanisms underlying fatigue and depression in RRMS could lead to more effective interventions and enhancement of quality of life. To elucidate the relationship between depression and fatigue and brain connectivity in pwRRMS we conducted a systematic review. Searched databases were PubMed, Web-of-Science and Scopus. Inclusion criteria were: studied participants with RRMS (n ≥ 20; ≥ 18 years old) and differentiated between MS subtypes; published between 2001-01-01 and 2023-01-18; used fatigue and depression assessments validated for MS; included brain structural, functional magnetic resonance imaging (fMRI) or diffusion MRI (dMRI). Sixty studies met the criteria: 18 dMRI (15 fatigue, 5 depression) and 22 fMRI (20 fatigue, 5 depression) studies. The literature was heterogeneous; half of studies reported no correlation between brain connectivity measures and fatigue or depression. Positive findings showed that abnormal cortico-limbic structural and functional connectivity was associated with depression. Fatigue was linked to connectivity measures in cortico-thalamic-basal-ganglial networks. Additionally, both depression and fatigue were related to altered cingulum structural connectivity, and functional connectivity involving thalamus, cerebellum, frontal lobe, ventral tegmental area, striatum, default mode and attention networks, and supramarginal, precentral, and postcentral gyri. Qualitative analysis suggests structural and functional connectivity changes, possibly due to axonal and/or myelin loss, in the cortico-thalamic-basal-ganglial and cortico-limbic network may underlie fatigue and depression in pwRRMS, respectively, but the overall results were inconclusive, possibly explained by heterogeneity and limited number of studies. This highlights the need for further studies including advanced MRI to detect more subtle brain changes in association with depression and fatigue. Future studies using optimised imaging protocols and validated depression and fatigue measures are required to clarify the substrates underlying these symptoms in pwRRMS.

Fig 1. Flowchart of literature search.

Performed in January 2023. Based on PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only [97]. D: Depression, DTI: Diffusion tensor imaging, F: Fatigue, (f)MRI: (functional) magnetic resonance imaging, (RR)MS: (relapsing-remitting) multiple sclerosis.

Fig 2

Sagittal (A), axial (B), and coronal (C) view of brain regions suggested to be involved in depression (magenta), fatigue (blue) or both* (yellow) in >1 study, using conventional MRI, structural and functional connectivity. Brain regions were extracted from brain atlases available in FSL [156] and superimposed on a template T1w image, available in MRIcron [157]. Results from included publications were compiled and summarised in this figure by the authors of this study, using MRIcron [157]. AG: angular gyrus (as a region of default mode network), Am: amygdala, CC: corpus callosum, Cing: cingulum, CN: caudate nucleus, DLPFC: dorsolateral prefrontal cortex, FEF: frontal eye field (as a region of dorsal attention network), FL: frontal lobe, Hpp: hippocampus, IFG: inferior frontal area, IPS: intraparietal sulcus (as a region of dorsal attention network), MPFC: medial prefrontal cortex (as a region of default mode network), MTG: middle temporal gyrus, P: putamen, PCG: precentral gyrus, PoCG: postcentral gyrus, Prc: precuneus (as a region of default mode network), SFG: superior frontal gyrus, SG: supramarginal gyrus, SMA: supplementary motor area, STG: superior temporal gyrus, Str: superior ventral striatum, VTA: ventral tegmental area. *Overlapping brain regions between symptoms, in at least 1 study for each symptom.