ABSTRACT
Introduction: Cognitive impairment in multiple sclerosis (MS) is increasingly being investigated with resting-state functional MRI (rs-fMRI) functional connectivity (FC). However, results remain difficult to interpret, showing both high and low FC associated with cognitive impairment. We conducted a systematic review of rs-fMRI studies in MS to understand whether the direction of FC change relates to cognitive dysfunction, and how this may be influenced by the choice of methodology. Methods: Embase, Medline, and PsycINFO were searched for studies assessing cognitive function and rs-fMRI FC in adults with MS. Results: Fifty-seven studies were included in a narrative synthesis. Of these, 50 found an association between cognitive impairment and FC abnormalities. Worse cognition was linked to high FC in 18 studies, and to low FC in 17 studies. Nine studies found patterns of both high and low FC related to poor cognitive performance, in different regions or for different magnetic resonance (MR) metrics. There was no clear link to increased FC during the early stages of MS and reduced FC in later stages, as predicted by common models of MS pathology. Throughout, we found substantial heterogeneity in study methodology, and carefully consider how this may impact on the observed findings. Discussion: These results indicate an urgent need for greater standardization in the field-in terms of the choice of MRI analysis and the definition of cognitive impairment. This will allow us to use rs-fMRI FC as a biomarker in future clinical studies, and as a tool to understand mechanisms underpinning cognitive symptoms in MS.