Brain connectivity and transcriptomic similarity inform abnormal morphometric similarity patterns in first-episode, treatment-naïve major depressive disorder

Abstract

Background

Major depressive disorder (MDD) is associated with disrupted brain structural integration. Morphometric similarity offers a means to capture the coordinated patterns of various structural features. However, it remains unknown whether MDD-related changes can be detected in cortical morphometric similarity through the Morphometric Inverse Divergence (MIND) network. Additionally, the role of brain connectivity in shaping these alterations, and their links to neuroreceptors and gene expression, have yet to be investigated.

Methods

Using the T1-weighted MRI data from 71 patients with first-episode, treatment-naïve MDD and 69 healthy controls, we constructed the MIND network for all participants. We then performed between-group comparisons to investigate abnormalities in the network and spatial relationships between the observed patterns of MIND disruption and the patterns of neuroreceptors were estimated. Network-based spreading was utilized to explore the abnormalities constrained by brain connectivity based on structural, functional, and transcriptional connectome architecture and to further identify potential epicenters of MDD. In addition, partial least squares regression was conducted to examine the associations of gene expression profiles with MIND changes in MDD.

Results

Patients with MDD showed significantly increased MIND in regions associated with sensation and cognition compared with healthy controls, with this altered pattern being influenced by a combination of transcriptional and structural connectivity, and potential epicenters of MDD were identified in the frontal, parietal, and paracentral cortices. Furthermore, the cortical map of case-control differences in MIND was spatially correlated with the cannabinoid CB₁ receptor and the brain-wide expression of a weighted combination of genes. These genes were enriched for neurobiologically relevant pathways and preferentially expressed in different cell classes and cortical layers.

Conclusion

These results highlight the abnormal pattern of morphometric similarity observed in MDD, shedding light on the complex interplay between disrupted macroscale coordinated morphology and microscale molecular organization in MDD.