Resting-state functional connectivity correlates of suicidal ideation in major depressive disorder: associations with suicidal ideation severity and childhood trauma

Introduction

Suicidal ideation (SI) is a clinically critical and heterogeneous feature of major depressive disorder (MDD), affecting up to 40% of patients and conferring substantial risk of suicide attempt [1]. Neurobiological mechanisms underlying SI remain incompletely characterized, particularly regarding resting-state functional connectivity (RSFC) alterations in fronto-limbic circuitry [2]. Early-life adversity, including childhood trauma, is a robust risk factor for suicidality and may contribute to enduring alterations in networks implicated in emotion regulation and stress responsivity [3]. Identifying SI-related RSFC features and their associations with SI severity and childhood trauma may provide mechanistic insights into a developmental pathway linking early adversity to adult suicidal thinking.

Aims

(1) To identify RSFC features distinguishing suicidal depression (SD) from non-suicidal depression (NSD) in adults with MDD using region of interest (ROI)-to-ROI and seed-to-voxel analyses; (2) To examine whether SI-related RSFC features are associated with current SI severity (Beck Scale for Suicidal Ideation; SSI) and childhood trauma burden (Childhood Trauma Questionnaire; CTQ).

Methods

Participants with moderate-to-severe MDD, defined by a Hamilton Depression Rating Scale-17 (HDRS-17) total score ≥17, were classified as SD (n=59; HDRS-17 item 3 ≥2) or NSD (n=70; HDRS-17 item 3 ≤1), with healthy controls (HC; n=120). Resting-state fMRI was acquired on a 3T scanner with a repetition time of 2000 ms over 180 volumes, and preprocessed using the CONN toolbox including motion correction, CompCor denoising, and band-pass filtering (0.01–0.09 Hz). Primary analyses compared SD and NSD using region-of-interest (ROI)-to-ROI and seed-to-voxel approaches across 24 bilateral fronto-limbic ROIs. Covariates included age, sex, education, illness duration, HDRS-17 total score, and medication load index (MLI). Multiple comparison correction was applied using false discovery rate (FDR) for ROI-to-ROI and cluster-level family-wise error (FWE) for seed-to-voxel analyses. Significant RSFC features were correlated with SSI and CTQ subscales using partial correlations (FDR-corrected).

Results

ROI-to-ROI analysis yielded no significant between-group differences after FDR correction. Seed-to-voxel analysis identified three significant clusters differentiating SD and NSD. The SD group showed higher functional connectivity between the right hippocampus and left middle frontal gyrus (SD>NSD; cluster p-FWE=0.039), and between the right posterior cingulate cortex and left lateral occipital cortex (SD>NSD; cluster p-FWE=0.009). In contrast, functional connectivity between the right subgenual anterior cingulate cortex (sgACC) and left posterior cingulate cortex (PCC) was lower in the SD group (SD<NSD; cluster p-FWE=0.017). In the combined MDD group, hippocampus (HPC)–middle frontal gyrus (MidFG) connectivity was positively associated with SSI (partial r=0.394, p-FDR<0.001) and CTQ emotional neglect (partial r=0.318, p-FDR=0.003), whereas sgACC–PCC connectivity was negatively associated with SSI (partial r=-0.311, p-FDR=0.003).

Conclusion: These findings suggest that suicidal thoughts may be associated with altered hippocampal–prefrontal and sgACC–PCC functional connectivity in MDD. The observed link with childhood emotional neglect is consistent with a potential developmental pathway, whereas sgACC–PCC connectivity may more directly reflect current suicidal ideation. Future longitudinal studies are needed to clarify the temporal nature of these alterations and their potential relevance as intervention targets.

References

1. Nock MK, Borges G, Bromet EJ, et al. Cross-national prevalence and risk factors for suicidal ideation, plans and attempts. British Journal of Psychiatry. 2008;192(2):98–105.
2. Qin K, Lei D, Pinaya WHL, et al. Functional connectivity changes in major depressive disorder with suicidal ideation. Biological Psychiatry. 2024;96(6):435–444.
3. Norman RE, Byambaa M, De R, et al. The long-term health consequences of child physical abuse, emotional abuse, and neglect: a systematic review and meta-analysis. PLOS Medicine. 2012;9(11):e1001349.