Microstructural changes in the reward system are associated with post-stroke depression

Background: Studies of lesion location have been unsuccessful in identifying simple mappings between single brain regions and post-stroke depression (PSD). This might partly reflect the involvement of multiple interconnected regions in the regulation of mood. In this study, we set out to investigate whole-brain network structure and white matter connectivity in the genesis of PSD. Based on studies implicating regions of the reward system in major depressive disorder without stroke, we investigated the overlap of whole-brain correlates of PSD with this system and performed a focused analysis of grey matter and white matter projections within the reward system and their associations with the development of PSD. Methods: The study enrolled 46 patients with first ischemic stroke, 12 were found to have PSD (D+ group) and 34 were free of PSD (D-) based on scores on the Geriatric Depression Scale. A group of 16 healthy controls were also recruited. Participants underwent research MRI with 3T structural and diffusion sequences. Graph theoretical measures derived from measures of microstructure were used to examine global topology and whole-brain connectome analyses were employed to assess differences in the interregional connectivity matrix between the three groups. Structural correlates specific to the reward system were examined by measuring grey matter volumes from regions in this circuit and by reconstructing its main white matter pathways, namely the medial forebrain bundle and connections within the cingulum bundle with deterministic tractography. For network connections and tracts, we derived measures of microstructural organization (FA), and also extracellular free-water content (FW) as a possible proxy of neuroinflammation. Results: The topology of structural networks differed across the three groups. Network modularity, weighted by extracellular FW content, increased with depression severity and connectome analysis identified networks of decreased FA-weighted and increased FW-weighted connectivity in patients with PSD relative to healthy controls. Intrinsic frontal and fronto-subcortical connections were a notable feature of these networks, which also subsumed the majority of regions defined as constituting the reward system. Within the reward system, grey matter volume of cortical and subcortical regions, as well as FA and FW of major connection pathways, were collectively predictive of PSD severity, explaining 76.8% of the variance in depression severity. Conclusions: Taken together, these findings indicate that PSD is associated with microstructural characteristics of the reward system, similar to those observed in major depressive disorder without stroke. Alterations in the reward system appear to drive differences in whole-brain network structure found in patients with PSD. Even in the absence of a simple relationship with lesion size and location, neuroimaging measures can explain much of the variance in depression scores. Structural characterization of the reward system is a promising biomarker of vulnerability to depression after stroke.