A systematic review of resting state functional MRI connectivity changes and cognitive impairment in multiple sclerosis

Cognitive impairment is common in multiple sclerosis (MS) and resting state functional MRI (rs-fMRI) functional connectivity (FC) is increasingly used to study its pathophysiology. 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. Embase, Medline and PsycINFO were searched for studies assessing cognitive function and rs-fMRI FC in adults with MS. 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 MR metrics. There was no clear link to increased FC during 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. These results indicate an urgent need for greater standardisation in the field - in the choice of MRI analysis and the definition of cognitive impairment. Through this we will be closer to using rs-fMRI FC as a biomarker in clinical studies, and as a tool to understand mechanisms underpinning cognitive symptoms in MS. Key pointsO_LICognitive impairment in multiple sclerosis (MS) is increasingly being researched with advanced magnetic resonance imaging (MRI) measures, including resting state functional MRI (rs-fMRI) C_LIO_LIThe rs-fMRI functional connectivity (FC) metric is associated with cognitive impairment, and has the potential to be a biomarker of cognitive decline. C_LIO_LIA main challenge to developing a FC biomarker is the lack of consistency in the direction of FC changes associated with cognitive impairment, with cognitive deficits associated with both lower and higher FC. C_LIO_LIFC changes dont appear to be linked to clinical and methodological factors such as disease phenotype, disease duration and brain region or network studied. C_LIO_LIOverall, there is substantial heterogeneity in study methodology, suggesting an acute need to standardise the study of cognitive impairment in MS and its investigation by rs-fMRI methods. C_LI