Multilevel brain heart interaction correlates with suicidal ideation in first episode drug naive major depressive disorder

Emerging evidence highlights the critical role of brain-heart interaction (BHI) in regulating affective states. However, BHI alterations and their molecular underpinnings in first-episode drug-naïve (FeDn) major depressive disorder (MDD) patients with suicidal ideation (SI) remain unclear. We collected synchronized electroencephalogram (EEG) and electrocardiogram (ECG) data from 81 MDD patients with SI (MDD-SI), 55 without SI (MDD-NSI), and 82 healthy controls (HCs). An integrative framework was developed to link a multilevel EEG-ECG derived BHI index with regional gene expression. Our study reveals that MDD-SI patients exhibit a significantly lower BHI index relative to individuals with MDD-NSI and HCs, after Bonferroni correction. Alterations were localized to the ventral insula, subgenual anterior cingulate cortex, middle frontal gyrus, dorsal posterior cingulate cortex, precuneus, and rostrodorsal angular gyrus (rAG). Notably, the BHI index in the rAG was negatively correlated with depression severity (r = -0.173, corrected p = 0.039) and SI severity (r = -0.163, corrected p = 0.045). Spatial transcriptomic analysis revealed that SI-related gene expression was enriched in pathways involving metabolic regulation, synaptic function, and signal transduction. These findings demonstrate reduced BHI in MDD-SI, identify region-specific alterations, and uncover associated molecular signatures, providing insight into the clinical detection and neurobiological mechanisms of suicidal ideation in MDD. Integrative EEG-ECG-derived brain-heart interaction profiling illuminates region-specific neurophysiological and molecular signatures underlying suicidal ideation in first-episode drug-naïve major depressive disorder.