Increased functional connectivity between brainstem substructures and cortex in treatment resistant depression

Previous functional magnetic resonance imaging (fMRI) studies showed an abnormal brainstem-to-cortex functional connectivity (FC) in major depressive disorder. However, only few studies analyzed brainstem substructures in treatment-resistant depression (TRD). In this study, we analyzed resting-state seed-based FC between midbrain, pons, medulla oblongata and cortical/subcortical brain regions in patients with TRD (n = 24) and age- and sex-matched healthy controls (n = 24). FC was analyzed in each group and compared between groups. Correlation analyses assessed the relationship between FC strength and depressive symptom severity in regions showing significant group differences in seed-based connectivity. Our findings reveal an increased FC in the midbrain and pons to the precentral gyrus, postcentral gyrus, and temporal gyrus in patients with TRD compared to healthy controls. Interestingly, in TRD patients, FC between midbrain and cortex was negatively correlated with BDI-II scores, indicating a relationship between altered connectivity and self-reported depression severity. It is essential to note that our naturalistic, cross-sectional approach precludes causal conclusions regarding the relationship between FC and pathophysiology of TRD. The small sample size necessitates confirmation in a larger cohort. Midbrain/pons-to-cortex FC was increased in patients with TRD compared to healthy controls. Future studies should explore the relationship between abnormal brainstem-to-cortex FC and depressive symptomatology in more detail.