Aberrant voxel-mirrored homotopic connectivity in subcortical regions and associated transcriptional signatures in major depressive disorder with suicidal ideation

Background

Suicidal ideation (SI) is one of the most high-risk clinical symptoms in patients with major depressive disorder (MDD). Despite extensive research efforts, a reliable biomarker for assessing SI remains lacking, limiting early detection and intervention efforts.

Method

This study included 62 MDD patients with SI (MDD-SI), 66 MDD patients without SI (MDD-NSI), and 134 healthy controls. We aimed to investigate group differences in voxel-mirrored homotopic connectivity (VMHC) and further explore its associations with the severity of SI. We further utilized the REST-meta-MDD consortium dataset (N = 2380; 24 sites) to validate our main findings. Imaging transcriptomic and enrichment analysis was conducted to explore gene expression characteristics associated with the brain regions exhibiting VMHC differences between MDD-SI and MDD-NSI.

Results

Compared to MDD-NSI, MDD-SI exhibited increased VMHC in the bilateral thalamus and parahippocampal gyrus (PHG), with VMHC values in these regions positively correlated with HAMD-suicidality item scores. These differences and associations were further validated in the REST-meta-MDD consortium dataset. Imaging transcriptomic and enrichment analyses revealed that genes associated with these regions were primarily enriched in immune- and inflammation-related terms.

Conclusion

Abnormal subcortical VMHC patterns in MDD-SI, closely associated with SI severity and validated across two independent datasets, may be associated with genes enriched for immune and inflammatory processes. These findings provide novel insights into the neurobiology of MDD-SI and underscore VMHC alterations as a reliable biomarker for early detection and intervention.