Mapping brain connections to inflammatory networks in depression identifies sex-specific neuroimmune networks and neurobiological subtypes

Background: Major depressive disorder is a heterogeneous psychiatric condition, complicating clinical diagnosis and treatment. Efforts to stratify MDD have led to the utilization of systemic inflammatory and neuroimaging markers. Understanding of the relationship between these markers and how they correspond to depressive symptoms is crucial for identifying personalized metrics to rationally diagnose MDD. Methods: The CANBIND1 dataset comprising cohorts of people with MDD (n=211) and age-matched healthy controls (n=122) was used. Weighted gene co-expression network analysis (WGCNA) was applied to cluster multiplex ELISA cytokine data and identify inflammatory modules. Microstructural metrics were derived from diffusion-weighted imaging (DWI) in the same individuals. The relationships among inflammatory modules, imaging markers, and clinical features were examined using correlation analysis. Results: We demonstrate that networks of peripheral inflammatory markers relate to specific depressive symptoms. Additionally, these cytokine networks are associated with diffusion MRI metrics of tissue microstructure, especially the correlated diffusion index (CDI). Distinct patterns were observed in patients compared to age-matched controls. Notably, these associations are more pronounced in gray matter than white matter, and more in females than in males. Conclusion: Our findings reveal sex-dependent networks within systemic inflammatory markers, which are in turn linked to sex-specific disease subtypes. This work provides a neurobiological framework which may facilitate the identification of biologically meaningful subtypes of depression, ultimately improving diagnosis and treatment.