Suicidal behavior is a leading cause of death and often commences during adolescence/young adulthood (15~29 years old). The hippocampus, which consists of multiple functionally specialized subfields, may contribute to the pathophysiology of depression and suicidal behavior. We aimed to investigate the differences of hippocampal subfield volume between major depressive disorder (MDD) patients with and without suicide attempts and healthy controls in adolescents and young adults. A total of 40 MDD suicide attempters (MDD+SA), 27 MDD patients without suicide attempt (MDD-SA), and 37 healthy controls (HC) were recruited. High-resolution T1 MRI images were analyzed with the automated hippocampal substructure module in FreeSurfer 6.0. Volume differences among the groups were analyzed by a generalized linear model controlling for intracranial cavity volume (ICV). The relationship between hippocampal subfield volumes and clinical characteristics (HAM-D and SSI scores) was assessed using two-tailed partial correlation controlling for ICV in MDD+SA and MDD-SA. We found that MDD-SA had significantly smaller bilateral hippocampal fissure volume than HC and MDD+SA. No significant correlation was observed between hippocampal subfield volume and clinical characteristics (HAM-D and SSI scores) in MDD+SA and MDD-SA. Adolescent/young adult suicide attempters with MDD suicide attempters have larger bilateral hippocampal fissures than depressed patients without suicide attempts, independently from clinical characteristics. Within the heterogeneous syndrome of major depressive disorder that holds a risk for suicidality for subgroups, hippocampal morphology may help to explain or possibly predict such risk, yet longitudinal and functional studies are needed for understanding the biological mechanisms underlying.
Major depressive disorder (MDD) is a prevalent, highly debilitating disease, with a 2%-12% lifetime suicide risk [
Studies indicate that synaptic plasticity impairment in specific areas of the CNS, particularly the hippocampus, has been linked to mood disorders that usually occur during adolescence or early adulthood, which have major cognitive and emotional symptoms [
In this study, young MDD patients with and without suicide attempts as well as healthy controls were evaluated by automated hippocampal substructure segmentation of high-resolution T1-weighted images. This study is aimed at identifying volume alteration in the hippocampus in suicidal MDD. We hypothesized that young MDD patients with suicide attempts would demonstrate abnormalities in specific hippocampal subfields, and these abnormalities would be linked with MDD and suicidal ideation severity.
Participants were between 14 and 25 years old and included patients with MDD and a history of at least one suicide attempt (MDD+SA), patients with MDD and no lifetime history of suicide attempt (MDD-SA), and healthy controls (HC) with no current or history of any major DSM-IV Axis I diagnosis and no history of suicidal behavior. All subjects were Chinese Han ethnicity and right-handed, without contraindications for magnetic resonance imaging investigation. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University. The study was performed in compliance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). All participating individuals were informed of the procedures of the study. Written informed consent was obtained from
MDD patients were recruited from consecutive referrals to the Department of Psychiatry, the First Affiliated Hospital of Chongqing Medical University. A suicide attempt was defined as a self-injurious act causing physical harm with some intent to die, committed within 6 months prior to magnetic resonance scanning. All patients were assessed by two experienced psychiatrists with the Structured Clinical Interview for DSM-IV Diagnosis (SCID) [
Healthy controls were recruited through flyers and internet advertisements from the local community. Enrolled healthy controls were screened through the Structured Clinical Interview for DSM-IV nonpatient edition (SCID-NP), to ensure that the diagnosis of depression and other psychiatric diseases was excluded. Common exclusion criteria for all subjects were any other DSM-IV Axis I disorder, history of head trauma with residual effects, neurological disorders, substance or alcohol abuse/dependence at any time, uncontrolled major medical conditions, history of psychiatric disorders or suicide among first-degree relatives, and other clinically relevant abnormalities in the medical history or laboratory examinations.
T1-weighted anatomical images were acquired with a 3.0-Tesla GE Sigma HDxt MRI system (General Electric Healthcare, Chicago, Illinois, USA) using a standard 8-channel head coil with the following parameters:
Subcortical reconstruction and segmentation were performed using the FreeSurfer software suite version 6.0 (
Statistical analyses were conducted using SPSS for Mac (version 26.0; IBM Corp., Armonk, NY). The chi-squared tests were employed to test for group differences in categorical variables, such as gender. One-way ANOVAs were employed to evaluate differences in continuous variables, such as age and years of education. For the clinical subjects (MDD-SA and MDD+SA), a
Differences in hippocampal subfield volumes among the three groups were analyzed using general linear model (GLM) analyses. In these and all analyses, intracranial volume (ICV) was used as a covariate, and the false discovery rate (FDR) correction was performed in multiple comparisons across the 24 subfields. FDR correction is a less conservative approach but appropriate for exploratory analysis. Bonferroni
The relationship between hippocampal subfield volume and clinical characteristics (HAM-D and SSI scores) was assessed using partial correlation controlling for ICV. The correlation analyses were performed in MDD+SA and MDD-SA. All statistical tests were two-tailed, and the significance level was set as 0.05.
A total of 104 subjects were recruited (40 MDD+SA, 27 MDD-SA, and 37 HC). Table
Demographic and clinical information of the subjects.
HC ( | PC ( | SA ( | ||
---|---|---|---|---|
Age (years) | 0.084 | |||
Sex | 0.465 | |||
Male | 15 | 7 | 13 | |
Female | 22 | 20 | 27 | |
Education (years) | 0.235 | |||
HAM-D | 0.845 | |||
SSI | 0.002 | |||
Number of previous attempts | — | — |
Abbreviations: SA: suicide attempters; PC: patient controls; HC: healthy controls; HAM-D: Hamilton depression rating score; SSI: scale for suicidal ideation.
Mean hippocampal subfield volumes are shown in Figure
Hippocampal subfield volumes in HC, PC, and SA.
Hippocampal subfield volume difference between healthy controls, patient controls, and suicide attempters with MDD.
Subfields | HC ( | PC ( | SA ( | HC vs. PC | HC vs. SA | PC vs SA | |||
---|---|---|---|---|---|---|---|---|---|
Left whole | |||||||||
Left hippocampal tail | 0.426 | 0.654 | 1.000 | 1.000 | 1.000 | 1.000 | |||
Left subiculum | 0.197 | 0.822 | 1.000 | 1.000 | 1.000 | 1.000 | |||
Left CA1 | 0.395 | 0.675 | 1.000 | 1.000 | 1.000 | 1.000 | |||
Left hippocampal fissure | 7.900 | 0.001 | 0.012 | 0.002 | 1.000 | 0.001 | |||
Left presubiculum | 0.293 | 0.747 | 1.000 | 1.000 | 1.000 | 1.000 | |||
Left parasubiculum | 1.585 | 0.210 | 1.000 | 1.000 | 0.258 | 0.787 | |||
Left molecular-layer-HP | 0.422 | 0.657 | 1.000 | 1.000 | 1.000 | 1.000 | |||
Left GC-ML-DG | 0.735 | 0.482 | 1.000 | 0.763 | 1.000 | 0.963 | |||
Left CA3 | 0.718 | 0.490 | 1.000 | 0.839 | 1.000 | 1.000 | |||
Left CA4 | 0.740 | 0.480 | 1.000 | 0.751 | 1.000 | 0.974 | |||
Left fimbria | 3.319 | 0.004 | 0.032 | 0.436 | 1.000 | 0.181 | |||
Left HATA | 0.344 | 0.709 | 1.000 | 1.000 | 1.000 | 1.000 | |||
Right whole | |||||||||
Right hippocampal tail | 0.835 | 0.437 | 1.000 | 1.000 | 1.000 | 0.738 | |||
Right subiculum | 0.012 | 0.988 | 1.000 | 1.000 | 1.000 | 0.705 | |||
Right CA1 | 0.129 | 0.879 | 1.000 | 1.000 | 1.000 | 1.000 | |||
Right hippocampal fissure | 9.161 | <0.001 | <0.001 | 0.001 | 1.000 | 0.001 | |||
Right presubiculum | 0.452 | 0.638 | 1.000 | 1.000 | 1.000 | 1.000 | |||
Right parasubiculum | 1.791 | 0.172 | 1.000 | 0.287 | 0.375 | 1.000 | |||
Right molecular-layer-HP | 0.082 | 0.922 | 0.998 | 1.000 | 1.000 | 1.000 | |||
Right GC-ML-DG | 0.983 | 0.378 | 1.000 | 0.496 | 1.000 | 1.000 | |||
Right CA3 | 1.762 | 0.177 | 1.000 | 0.269 | 0.431 | 1.000 | |||
Right CA4 | 1.238 | 0.295 | 1.000 | 0.356 | 1.000 | 1.000 | |||
Right fimbria | 3.108 | 0.007 | 0.042 | 0.459 | 1.000 | 0.342 | |||
Right HATA | 0.592 | 0.555 | 1.000 | 0.974 | 1.000 | 1.000 |
aBonferroni corrected for multiple comparisons between the groups.
The discriminant and receiver operating characteristic analyses revealed that the left hippocampal fissure volume of 131 mm3 (82.5% sensitivity, 63.0% specificity) and the right hippocampal fissure volume of 149 mm3 (70.0% sensitivity, 70.4% specificity) allowed optimal discrimination between SA and PC (Figure
The left and right fissure volumes as discriminators of the SA and PC groups (receiver operating characteristic).
No significant correlation was observed between hippocampal subfield volumes and clinical characteristics (HAM-D and SSI scores) in SA and MDD-SA (Table
Correlations observed between hippocampal subfield volumes in patients of major depressive disorder (SA and PC) and clinical characteristics (HAM-D and SSI scores).
Subfields | HAM-D | SSI |
---|---|---|
Left hippocampal tail | 0.085 | -0.030 |
Left subiculum | 0.135 | -0.023 |
Left CA1 | 0.065 | -0.126 |
Left hippocampal fissure | 0.009 | 0.065 |
Left presubiculum | 0.018 | -0.068 |
Left parasubiculum | -0.161 | -0.164 |
Left molecular-layer-HP | 0.055 | -0.116 |
Left GC-ML-DG | 0.089 | -0.068 |
Left CA3 | 0.075 | -0.102 |
Left CA4 | 0.105 | -0.083 |
Left fimbria | -0.005 | 0.062 |
Left HATA | 0.116 | -0.205 |
Right hippocampal tail | 0.053 | -0.062 |
Right subiculum | 0.155 | 0.112 |
Right CA1 | 0.105 | -0.004 |
Right hippocampal fissure | 0.042 | 0.093 |
Right presubiculum | 0.101 | 0.141 |
Right parasubiculum | 0.140 | -0.030 |
Right molecular-layer-HP | 0.084 | 0.019 |
Right GC-ML-DG | 0.098 | 0.008 |
Right CA3 | -0.021 | -0.061 |
Right CA4 | 0.113 | 0.031 |
Right fimbria | -0.034 | -0.040 |
Right HATA | 0.127 | -0.051 |
Abbreviations: SA: suicide attempters; PC: patient controls; HAM-D: Hamilton depression rating score; SSI: scale for suicidal ideation; CA: cornu ammonis; GC-DG: granule cell layer of dentate gyrus; HATA: hippocampus-amygdala transition area.
Suicidal behavior is an extreme act of subjects with MDD compounded by environmental stimuli with biological vulnerability resulting from impaired brain structural plasticity [
Given its role in the encoding and recall of the emotional significance of events, the hippocampus may influence emotional reactions and regulatory processes. Moreover, impairment of memory has been associated with suicide attempts, implicating the involvement of the hippocampus in this process. Although hippocampal volume reductions have been observed in adult [
In line with our results, the hippocampus volume showed no significant difference in the MDD and MDD+SA groups in postmortem morphometric studies [
Although it did not survive Bonferroni correction, we observed that bilateral fimbria volume in MDD+SA decreased compared to MDD-SA and HC. As a main output structure of the polysynaptic intrahippocampal pathway (PIP), the fimbria plays a crucial role in the encoding and consolidation process of memory formation [
Our findings are in line with previous studies [
There are several limitations that warrant discussion. The present study cannot establish causality between hippocampus subfield alternation and suicide attempt due to the cross-sectional design. Future longitudinal prospective studies are needed to follow young depressed patients to compare the alteration of the hippocampus before and after a suicide attempt and track the changes of suicidal ideation to behavior. The study did not examine the variability associated with multiple potentially relevant dimensions, such as disease duration, age of onset, and the lethality of suicide attempts, which reduces the power to interpret the findings. Additionally, of note, the present study has a wide age range covering both pubertal teenagers and young adults from 14 to 25 years old. Although age was included as a covariate, the effect of brain development would be ignored. In addition, the moderate sample size might have limited the statistical power to identify less robust effects. Thus, future studies with larger samples are warranted.
In summary, the present study provides evidence of the impact of suicidality on hippocampus subfield volume in adolescent/young adult MDD patients. Depressed suicide attempters have larger bilateral hippocampal fissures than depressed patients without suicide attempts, independently from clinical characteristics. Longitudinal studies will be helpful to understand the causal relationship between disorder progression and volumetric changes in hippocampal subfields.
Access to data is restricted.
The authors declare that they have no conflicts of interest.
Qi Zhang and Su Hong contributed equally to the article as co-first authors.