Functional connectivity of anterior cingulate cortex subregions in suicidal ideation in major depression: circuit mechanisms, exploratory classification, and treatment-related changes

Suicidal ideation (SI) is a critical challenge in major depressive disorder (MDD), yet its precise neural circuitry remains elusive. Although anterior cingulate cortex (ACC) is implicated, its subregional roles remain poorly understood. This study aimed to delineate SI-specific neural circuitry by examining whole-brain functional connectivity (FC) of ACC subregions: subgenual ACC (sgACC), pregenual ACC (pgACC), and dorsal ACC (dACC). Resting-state functional magnetic resonance imaging data were analyzed from 237 MDD patients (109 with SI [MDD-SI], 128 without SI [MDD-NSI]) and 152 healthy controls (HCs) at baseline. Group assignment relied on lifetime SI (trait-like SI) from the Columbia-Suicide Severity Rating Scale, with current SI (state-like SI) measured by the suicide item of 17-item Hamilton Depression Rating Scale. Of these, 129 MDD patients underwent 8-week follow-up scanning after treatment. Cross-sectional analysis identified two SI-specific FC alterations: left pgACC-right precuneus and left dACC-left fusiform connectivity. These FCs were enhanced in MDD-SI compared to MDD-NSI, showed no differences between MDD-NSI and HCs, and correlated with trait-like SI severity. An exploratory model incorporating these FCs and clinical covariates achieved an area under the curve (AUC) of 0.723 for trait-like SI identification. Longitudinally, the baseline elevation in left pgACC-right precuneus FC normalized after treatment specifically in MDD-SI, and this reduction paralleled the decrease in state-like SI severity. Our findings clarify ACC subregion-specific SI mechanisms, provide an exploratory evaluation of trait-like SI identification and identify a potential state-like SI therapeutic circuit. Collectively, this work translates vague ACC abnormality into localizable circuits, advancing precision neuroscience for MDD-SI.