Hippocampal-DMN disconnectivity in MS is related to WM lesions and depression

The hippocampus is part of the default-mode network (DMN) and is functionally hit early in multiple sclerosis (MS). Hippocampal and DMN dysfunctions have been associated with depression, both in patients with MS and in major depressive disorders. We hypothesized that white matter lesions may contribute, through a disconnection mechanism, to hippocampal dysfunction. To test this, we assessed the relationship between hippocampal resting-state (RS) functional connectivity (FC) abnormalities with brain T2 lesion volumes and the presence and severity of depression. Structural and RS fMRI images were acquired from 69 patients with cognitively intact MS and 42 matched healthy controls (HC). Depression was quantified using the Montgomery-Asberg Depression Rating Scale. Seed-voxel hippocampal RS FC was assessed. SPM8 was used for between-group comparisons and correlation analysis between RS FC abnormalities with clinical and structural MRI variables. Compared to HC, patients with MS showed a significant atrophy of the whole brain and left hippocampus (P < 0.001), and a distributed pattern of decreased RS FC between the hippocampi and several cortical-subcortical regions, which were mostly located within the DMN. Reduced hippocampal RS FC with regions of the DMN was strongly correlated with higher T2 lesion volume, longer disease duration, and the severity of depression and disability. In patients with cognitively preserved MS, brain focal WM lesions are related to the functional integration of the hippocampus to other brain regions of the DMN, suggesting a disconnection syndrome. Such a disruption of hippocampal RS FC is likely to contribute to the occurrence of depression and to clinical disability.