Multimodal and multiscale evidence for network-based cortical thinning in major depressive disorder

Background: Major depressive disorder (MDD) is associated with widespread, irregular cortical thickness (CT) reductions across the brain. However, little is known regarding mechanisms that govern spatial distribution of the reductions.Methods: We combined multimodal MRI and genetic, cytoarchitectonic and chemoarchitectonic data to examine structural covariance, functional synchronization, gene co-expression, cytoarchitectonic similarity and chemoar-chitectonic covariance between regions atrophied in MDD.Results: Regions atrophied in MDD were associated with significantly higher structural covariance, functional syn-chronization, gene co-expression and chemoarchitectonic covariance. These results were robust against method-ological variations in brain parcellation and null model, reproducible in patients and controls, and independent of age at onset of MDD. Despite no significant differences in the cytoarchitectonic similarity, MDD-related CT reductions were susceptible to specific cytoarchitectonic class of association cortex. Further, we found that nodal shortest path lengths to disease epicenters derived from structural (right supramarginal gyrus) and chemoar-chitectonic covariance (right sulcus intermedius primus) networks of healthy brains were correlated with the extent to which a region was atrophied in MDD, supporting the transneuronal spread hypothesis that regions closer to the epicenters are more susceptible to MDD. Finally, we showed that structural covariance and func-tional synchronization among regions atrophied in MDD were mainly related to genes enriched in metabolic and membrane-related processes, driven by genes in excitatory neurons, and associated with specific neurotransmitter transporters and receptors. Conclusions: Altogether, our findings provide empirical evidence for and genetic and molecular insights into connectivity-constrained CT thinning in MDD.

Automated summary

Using multimodal MRI and various data, this study found that major depressive disorder (MDD) is associated with widespread and irregular cortical thinning. These reductions are related to structural covariance, functional synchronization, gene co-expression, and chemoarchitectonic covariance. The study also found that the specific cytoarchitectonic class and genes enriched in metabolic and membrane-related processes play a significant role in MDD.