Large-scale Gradient Dysfunction of the Functional Connectome in Major Depression

Abstract Major depressive disorder (MDD) is associated with coexisting disturbances in low-level sensory processing and high-order cognitive functions. However, the neurobiological mechanism underlying these phenotype deficits remains poorly understood. Here, we collect large-sample, multisite resting-state functional magnetic resonance imaging data (1,150 patients with MDD and 1,084 healthy controls) and postmortem gene expression data. We show downgraded and contracted connectome gradients that are mainly involved in primary sensory and transmodal regions in patients with MDD relative to healthy controls, leveraging an association with gene expression enriched in transsynaptic signaling and calcium ion binding. Machine learning approaches based on support vector regression suggest that the alterations of connectome gradients in patients significantly predict depressive symptoms. These results shed light on gradient dysfunction of the large-scale functional connectomes in MDD and consolidate the spectrum deficits of sensory and cognitive processing in this disorder.