Molecular signatures of aberrant dynamic structure-function coupling in major depressive disorder

Disruptions in structure-function coupling (SFC) in major depressive disorder (MDD) have been reported. Given the brain functional dynamics over time, whether/how dynamic SFC changes in MDD and its associated molecular signatures is still elusive. Here, we integrate multimodal neuroimaging, neurotransmitter density maps, transcriptome, and plasma proteome to investigate the biological correlates of abnormal dynamic SFC in MDD. Using resting-state functional and structural connectivity data of 21,030 individuals (19,107 healthy controls and 1923 MDD patients) from UK Biobank, we identified a robust reductions of dynamic SFC in cortical regions primarily localized in the somatomotor and dorsal attention networks. Spatial association analyses further showed associations between these alterations and the neurotransmitters of norepinephrine, GABA and histamine, the genes regulating neurodevelopment and energy metabolism, the cell types of oligodendrocyte and astrocyte, and the neuropeptide of MCHR1 and ADIPOR2. Moreover, we found that the immune- and inflammation-related proteins were associated with regional abnormal dynamic SFC, which showed overlap with known drug targets, suggesting potential therapeutic relevance. In summary, our research provides evidence for abnormal dynamic SFC in MDD and identifies associated multimodal molecular signatures, highlighting the importance of dynamic structure-function relationships in MDD-related brain dysfunction and contributing to a better understanding of its neurobiological basis.