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

Studies of lesion location have been unsuccessful in identifying mappings between single brain regions and post-stroke depression (PSD). Based on studies implicating the reward system in major depressive disorder without stroke, we investigated structural correlates within this system and their associations with PSD. The study enrolled 16 healthy controls, 12 stroke patients with PSD and 34 stroke patients free of PSD. Participants underwent 3T structural and diffusion MRI. Graph theoretical measures were used to examine global topology and whole-brain connectome analyses were employed to assess differences in the interregional connectivity matrix between groups. Structural correlates specific to the reward system were examined from grey matter volumes and by reconstructing its main white matter pathways, namely the medial forebrain bundle and cingulum connections, using deterministic tractography. Fractional anisotropy (FA) was derived as a measure of microstructural organization, and extracellular free-water (FW) as a possible proxy of neuroinflammation. Subnetworks of decreased FA-weighted and increased FW-weighted connectivity were observed in patients with PSD relative to healthy controls. These networks subsumed the majority of regions constituting the reward system. Within the reward system, FA and FW of major connection pathways and grey matter volume were collectively predictive of PSD, explaining 37.8% of the variance in depression severity. PSD is associated with grey matter volume loss, reduced FA and increased extracellular FW in the reward system, similar to features observed in major depression without stroke. Structural characterization of the reward system is a promising biomarker of vulnerability to depression after stroke.