Background: Fatigue and depression are frequent and often co-occurring symptoms in multiple sclerosis (MS). Resting-state functional magnetic resonance imaging (rs-fMRI) represents a promising tool for disentangling differential associations between depression and fatigue and brain network function and connectivity. In this study we tested for associations between symptoms of fatigue and depression and DMN connectivity in patients with MS. Materials and methods: Seventy-four MS patients were included on average 14 months after diagnosis. They underwent MRI scanning of the brain including rs-fMRI, and symptoms of fatigue and depression were assessed with Fatigue Severity Scale (FSS) and Beck Depression Inventory II (BDI). A principal component analysis (PCA) on FSS and BDI scores was performed, and the component scores were analysed using linear regression models to test for associations with default mode network (DMN) connectivity. Results: We observed higher DMN connectivity with higher scores on the primary principal component reflecting common symptom burden for fatigue and depression (Cohen's f2=0.075, t=2.17, p=0.03). The secondary principal component reflecting a pattern of low fatigue scores with high scores of depression was associated with lower DMN connectivity (Cohen's f2=0.067, t=-2.1, p=0.04). Using continuous mean scores of FSS we also observed higher DMN connectivity with higher symptom burden (t=3.1, p=0.003), but no significant associations between continuous sum scores of BDI and DMN connectivity (t=0.8, p=0.4). Conclusion: Multivariate decomposition of FSS and BDI data supported both overlapping and unique manifestation of fatigue and depression in MS patients. Rs-fMRI analyses showed that symptoms of fatigue and depression was reflected in altered DMN connectivity, and that higher DMN activity was seen in MS patients with fatigue even with low depression scores.

Symptoms of fatigue and depression is reflected in altered default mode network connectivity in multiple sclerosis