Deep graph learning of multimodal brain networks defines treatment-predictive signatures in major depression

Major depressive disorder (MDD) presents a substantial health burden with low treatment response rates. Predicting antidepressant efficacy is challenging due to MDD's complex and varied neuropathology. Identifying biomarkers for antidepressant treatment requires thorough analysis of clinical trial data. Multimodal neuroimaging, combined with advanced data-driven methods, can enhance our understanding of the neurobiological processes influencing treatment outcomes. To address this, we analyzed resting-state fMRI and EEG connectivity data from 130 patients treated with sertraline and 135 patients with placebo from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study. A deep learning framework was developed using graph neural networks to integrate data-augmented connectivity and cross-modality correlation, aiming to predict individual symptom changes by revealing multimodal brain network signatures. The results showed that our model demonstrated promising prediction accuracy, with an R² value of 0.24 for sertraline and 0.20 for placebo. It also exhibited potential in transferring predictions using only EEG. Key brain regions identified for predicting sertraline response included the inferior temporal gyrus (fMRI) and posterior cingulate cortex (EEG), while for placebo response, the precuneus (fMRI) and supplementary motor area (EEG) were critical. Additionally, both modalities identified the superior temporal gyrus and posterior cingulate cortex as significant for sertraline response, while the anterior cingulate cortex and postcentral gyrus were common predictors in the placebo arm. Additionally, variations in the frontoparietal control, ventral attention, dorsal attention, and limbic networks were notably associated with MDD treatment. By integrating fMRI and EEG, our study established novel multimodal brain network signatures to predict individual responses to sertraline and placebo in MDD, providing interpretable neural circuit patterns that may guide future targeted interventions. Trial Registration: Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) ClinicalTrials.gov Identifier: NCT#01407094.