Default modetwork connectivity and its clinical relevance for depression in multiple sclerosis: A scoping review

Depression is one of the most disabling neuropsychiatric manifestations of multiple sclerosis (MS), yet its neural mechanisms have received limited investigation. Growing evidence suggests that large-scale brain network dysfunction, particularly the default mode network (DMN), may play a key role in MS-related depression.

This scoping review aimed to synthesize the available evidence on the relationship between DMN resting-state functional connectivity and depressive symptoms in individuals with MS.

A scoping review was conducted in accordance with PRISMA-ScR guidelines. PubMed, Scopus, Web of Science, and Embase were searched up to November 2025. Studies were included if they involved adults with MS, assessed depressive symptoms using validated measures, and examined DMN connectivity using resting-state fMRI.

Across the four included studies, consistent alterations of DMN connectivity were observed in relation to depressive symptoms in MS. These included posterior cingulate cortex hypoconnectivity, anterior cingulate cortex hyperconnectivity, and widespread hippocampal-DMN disconnection. DMN abnormalities were associated with depressive symptom severity and were only partially explained by lesion burden, brain atrophy, disability or cognitive status. Notably, aerobic exercise induced changes in DMN connectivity that paralleled reductions in depressive symptoms, suggesting that DMN dysfunction may be a modifiable target.

Converging evidence indicates that depression in MS is linked to alterations in DMN functional organization, supporting a network-based model of MS-related depression rather than a purely reactive psychiatric interpretation. Although the current evidence is limited by small sample sizes and predominantly cross-sectional designs, these findings highlight the DMN as a promising neurobiological marker and potential therapeutic target.