03 Apr 24. Featured Paper

Link to paper on Plos One

Authors

Agniete Kampaite, Rebecka Gustafsson, Elizabeth N. York, Peter Foley, Niall J. J. MacDougall, Mark E. Bastin, Siddharthan Chandran, Adam D. Waldman,  Rozanna Meijboom

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.

Conclusion

Overall, the results presented were highly variable; half of those reviewed found no significant associations between brain connectivity measures and depression or fatigue. Studies reporting positive findings showed that a) brain connectivity and macrostructural changes in the cortico-thalamic-basal ganglial network were associated with fatigue in pwRRMS, b) cortico-limbic networks were associated with depression in pwRRMS, and c) structural connectivity in the cingulum and functional connectivity in the cerebellum, thalamus, frontal lobe, supramarginal gyrus, ventral tegmental area, superior ventral striatum, DMN, attention networks, and pre/post-central gyri was affected in both fatigue and depression in pwRRMS. This may suggest that structural damage of WM and GM (e.g., neuroaxonal loss and/or demyelination) within these regions is responsible for depression and fatigue in pwRRMS, albeit not consistent findings across the literature. These mixed findings are most likely due to heterogeneous methodology across the studies. Only a small number of studies investigated brain connectivity in depression, or in both depression and fatigue combined. Moreover, the complex relationship and overlap between these two phenomena complicates interpretation of findings. Further adequately powered studies using optimised structural, microstructural, and functional imaging measures in well-characterised RRMS cohorts with validated indices of fatigue and depression are required to determine jointly affected brain areas in depression and fatigue, and further elucidate disease mechanisms underlying these symptoms. Moreover, studies employing additional imaging modalities such as positron emission tomography (PET) could be reviewed to further investigate the relationship between brain changes and fatigue/depression in pwRRMS.

Keywords:

• Multiple Sclerosis
• Fatigue
• depression
• functional magnetic resonance imaging
• diffusion MRI
• positron emission tomography