Disturbed hierarchy and mediation in reward-related circuits in depression.

Backgrounds/objective: Deep brain stimulation (DBS) has proved the viability of alleviating depression symptoms by stimulating deep reward-related nuclei. This study aims to investigate the abnormal connectivity profiles among superficial, intermediate, and deep brain regions within the reward circuit in major depressive disorder (MDD) and therefore provides references for identifying potential superficial cortical targets for non-invasive neuromodulation.

Methods: Resting-state functional magnetic resonance imaging data were collected from a cohort of depression patients (N = 52) and demographically matched healthy controls (N = 60). Utilizing existing DBS targets as seeds, we conducted step-wise functional connectivity (sFC) analyses to delineate hierarchical pathways linking to cerebral cortices. Subsequently, the mediation effects of cortical regions on the interaction within reward-related circuits were further explored by constructing mediation models.

Results: In both cohorts, sFC analysis revealed two reward-related pathways from the deepest DBS targets to intermediate regions including the thalamus, insula, and anterior cingulate cortex (ACC), then to the superficial cortical cortex including medial frontal cortex, posterior default mode network (pDMN), and right dorsolateral prefrontal cortex (DLPFC). Patients exhibited reduced sFC in bilateral thalamus and medial frontal cortex in short and long steps respectively compared to healthy controls. We also discovered the disappearance of the mediation effects of superficial cortical regions on the interaction between DBS targets and intermediate regions in reward-related pathways in patients with MDD.

Conclusion: Our findings support abnormal hierarchical connectivity and mediation effects in reward-related brain regions at different depth levels in MDD, which might elucidate the underlying pathophysiological mechanisms and inspire novel targets for non-invasive interventions.