Direction-specific excitation-inhibition imbalances and their neurobiological substrates in recurrent major depressive disorder

Background: Major depressive disorder (MDD) is characterized by disrupted information flow among brain regions. While effective connectivity (EC) captures these causal interactions, the underlying structural and molecular basis remain unclear. This study aims to investigate direction-specific EC alterations in MDD and their associations with laminar structural covariance (SC) and transcriptional and neurotransmitter profiles. Methods: Resting-state fMRI and structural MRI data were analyzed from the REST-meta-MDD consortium (Discovery, N=1627) and an independent cohort (Validation, N=226). We calculated the unsigned and signed EC using Liang Information Flow and laminar SC based on cortical depth, and compared them between MDD patients and healthy controls. The EC alterations were further associated with molecular profiles integrating gene expression (AHBA) and neurotransmitter receptors (PET/SPECT). Then, Chain mediation analyses were performed to map the hierarchical pathways from molecular basis to EC. Finally, we evaluated the clinical potential of EC in its therapeutic responses to medication and neuromodulation in a longitudinal dataset (N = 16 for medication, N = 11 for neuromodulation). Results: Our analysis revealed no significant changes in the EC of first-episode MDD but observed a hyper-driven cerebellar-cerebral EC pattern in recurrent MDD (RMDD), characterized by a direction-specific excitation-inhibition imbalance featuring enhanced inhibitory cerebellar output alongside a concurrent increase in both inhibitory input and excitatory output within sensorimotor/cognitive regions. These alterations were physically constrained by specific laminar SC patterns, particularly involving the middle cortical lamina. Moreover, the input EC changes in RMDD patients were primarily enriched in biological processes related to the modulation of chemical synaptic transmission, whereas output EC changes were linked to synapse structure regulation. These EC alterations were closely associated with serotonergic, GABAergic, and glutamatergic neurotransmitter systems. Importantly, we identified oligodendrocyte precursor cells (OPCs) as a key cellular mediator bridging microscale molecular features to macroscale connectional alterations in RMDD. These findings were reproducible in the validation dataset. Clinically, medication treatment primarily evoked a pattern of decreased input coupled with increased output, whereas neuromodulation elicited a reciprocal shift characterized by enhanced input and attenuated output. Conclusions: These findings underscore a direction-specific gene-neurotransmitter-cell type-laminar SC-EC pathological model in RMDD. By integrating multi-scale biological mechanisms with clinical phenotypes, this study highlights the potential of directional EC as a biomarker for stratifying refractory depression and guiding precision therapeutics.