Abstract Objective Neuroimaging studies have demonstrated aberrant structure and function of the “cognitive-affective cerebellum” in Major Depressive Disorder (MDD), although the specific role of the cerebello-cerebral circuitry in this population remains largely uninvestigated. The objective of this study was to delineate the role of cerebellar functional networks in depression. Methods A total of 308 unmedicated participants completed resting-state functional magnetic resonance imaging scans, of which 247 (148 MDD; 99 Healthy Controls, HC) were suitable for this study. Seed-based resting-state functional connectivity (RsFc) analysis was performed using three cerebellar regions of interest (ROIs): ROI 1 corresponded to default mode network (DMN) / inattentive processing; ROI 2 corresponded to attentional networks including frontoparietal, dorsal attention, and ventral attention; ROI 3 corresponded to motor processing. These ROIs were delineated based on prior functional gradient analyses of the cerebellum. A general linear model was used to perform within-group and between-group comparisons. Results In comparison to HC, participants with MDD displayed increased RsFc within the cerebello-cerebral DMN (ROI 1 ) and significantly elevated RsFc between the cerebellar ROI 1 and bilateral angular gyrus at a voxel threshold ( p &lt; 0.001, two-tailed) and at a cluster level ( p &lt; 0.05, FDR-corrected). Group differences were non-significant for ROI 2 and ROI 3 . Conclusions These results contribute to the development of a systems neuroscience approach to the diagnosis and treatment of MDD. Specifically, our findings confirm previously reported associations between MDD, DMN, and cerebellum, and highlight the promising role of these functional and anatomical locations for the development of novel imaging-based biomarkers and targets for neuromodulation therapies.

Cerebello-cerebral Functional Connectivity Networks in Major Depressive Disorder: A CAN-BIND-1 Study Report