MMDD: A Multimodal Multitask Dynamic Disentanglement Framework for Robust Major Depressive Disorder Diagnosis Across Neuroimaging Sites

Background/Objectives: Major Depressive Disorder (MDD) is a severe psychiatric disorder, and effective, efficient automated diagnostic approaches are urgently needed. Traditional methods for assessing MDD face three key challenges: reliance on predefined features, inadequate handling of multi-site data heterogeneity, and suboptimal feature fusion. To address these issues, this study proposes the Multimodal Multitask Dynamic Disentanglement (MMDD) Framework. Methods: The MMDD Framework has three core innovations. First, it adopts a dual-pathway feature extraction architecture combining a 3D ResNet for modeling gray matter volume (GMV) data and an LSTM–Transformer for processing time series data. Second, it includes a Bidirectional Cross-Attention Fusion (BCAF) mechanism for dynamic feature alignment and complementary integration. Third, it uses a Gradient Reversal Layer-based Multitask Learning (GRL-MTL) strategy for enhancing the model’s domain generalization capability. Results: MMDD achieved 77.76% classification accuracy on the REST-meta-MDD dataset. Ablation studies confirmed that both the BCAF mechanism and GRL-MTL strategy played critical roles: the former optimized multimodal fusion, while the latter effectively mitigated site-related heterogeneity. Through interpretability analysis, we identified distinct neurobiological patterns: time series were primarily localized to subcortical hubs and the cerebellum, whereas GMV mainly involved higher-order cognitive and emotion-regulation cortices. Notably, the middle cingulate gyrus showed consistent abnormalities across both imaging modalities. Conclusions: This study makes two major contributions. First, we develop a robust and generalizable computational framework for objective MDD diagnosis by effectively leveraging multimodal data. Second, we provide data-driven insights into MDD’s distinct neuropathological processes, thereby advancing our understanding of the disorder.