Thalamocortical functional connectivity alterations and peripheral immune transcriptomic dysregulation in major depressive disorder patients with suicidal ideation

Suicidal ideation (SI) in major depressive disorder (MDD) presents a serious clinical concern, yet its underlying biological mechanisms remain poorly understood. Using an exploratory, multimodal design, this study included 98 MDD patients with SI (MDD_SI), 61 without SI (MDD_nSI), and 233 healthy controls (HC), and collected functional MRI and peripheral blood transcriptomic data. Network-based statistics of resting-state functional connectivity (FC) identified brain network differences among the three groups, followed by graph-theoretical analysis of derived hub regions. Differential module connectivity (MDC) analyses of blood transcriptomic modules were performed to identify group-level differences, and exploratory correlation analyses were performed to examine associations between brain network topology and transcriptomic alterations. A functional network centered on the caudal temporal thalamus (cTtha) showed significant group differences (MDD_SI > MDD_nSI >HC; p < 0.001), with increased nodal efficiency of the left cTtha in both the MDD_SI (p = 0.043) and MDD_nSI (p < 0.001) groups compared with the HC group. Modules differentiating MDD_SI from MDD_nSI were enriched in antiviral immune responses and epigenetic regulation (darkred, MDC = 1.508, p = 0.04; yellow, MDC = 0.93, p = 0.01), while SI-specific alterations involved mitochondrial energy dysregulation and nSI-specific alterations involved vascular and translational pathways. Notably, one immune-related gene module was significantly correlated with left cTtha betweenness centrality (r = 0.274, p = 0.021), degree centrality (r = 0.262, p = 0.027), and nodal efficiency (r = 0.235, p = 0.048) in the MDD_SI group. This study indicates that MDD and SI are associated with cTtha-centered functional network alterations and peripheral transcriptomic dysregulation, and that, within MDD, SI may show a potential link between cTtha-centered brain network disruption and immune transcriptomic dysregulation. These results should be interpreted cautiously given the exploratory design, binary SI assessment, and modest effect sizes.