Altered homotopic functional connectivity in primary angle-closure glaucoma correlates with cell-type–specific neurotransmitter and gene expression transcriptional signatures: a functional MRI study

Background Altered homotopic functional connectivity in primary angle-closure glaucoma (PACG) and their underlying molecular mechanisms remain poorly understood. In our study, we investigated voxel-mirrored homotopic connectivity (VMHC) alterations in patients with PACG and the molecular mechanisms of VMHC. Methods In this study, we investigated alterations in VMHC among 47 patients with PACG and 45 matched healthy controls. We then integrated these spatial patterns with cortical transcriptomic data from the Allen Human Brain Atlas using partial least squares (PLS) regression to identify gene expression profiles associated with VMHC alterations. Results In this study, we identified widespread reductions in interhemispheric functional connectivity in patients with PACG using VMHC analysis. Multivariate spatial correlation with gene expression data revealed that VMHC alterations were significantly associated with a distinct transcriptional signature captured by the first PLS component. Functional enrichment of these genes indicated downregulation of pathways related to synaptic and metabolic maintenance, and upregulation of immune, stress, and chromatin regulatory processes. Cell-type analysis showed that astrocytes and endothelial cells were selectively enriched with VMHC-related genes, reflecting glial and vascular involvement. Moreover, spatial alignment with neurotransmitter receptor maps highlighted significant associations with serotonergic, dopaminergic, GABAergic, cholinergic, and opioidergic pathways, suggesting a neuromodulatory basis for VMHC disruption. Conclusion Together, these findings suggest that interhemispheric dysconnectivity in PACG is not only a reflection of functional brain changes but is also grounded in molecular and cellular mechanisms. This integrative approach advances our understanding of PACG as a brain-wide neurodegenerative condition and offers new perspectives for targeting glial, vascular, and neuromodulatory pathways in future therapeutic interventions.