Suicide Brain Research Articles

Brain Structural and Functional Damage Network Localization of Suicide

BackgroundExtensive neuroimaging research on brain structural and functional correlates of suicide has produced inconsistent results. Despite increasing recognition that damage in multiple different brain locations that causes the same symptom can map to a common brain network, there is still a paucity of research investigating network localization of suicide. MethodsTo clarify this issue, we initially identified brain structural and functional damage locations in relation to suicide from 63 published studies with 2135 suicidal and 2606 nonsuicidal individuals. By applying novel functional connectivity network mapping to large-scale discovery and validation resting-state functional magnetic resonance imaging datasets, we mapped these affected brain locations to 3 suicide brain damage networks corresponding to different imaging modalities. ResultsThe suicide gray matter volume damage network comprised widely distributed brain areas primarily involving the dorsal default mode, basal ganglia, and anterior salience networks. The suicide task-induced activation damage network was similar to but less extensive than the gray matter volume damage network, predominantly implicating the same canonical networks. The suicide resting-state activity damage network manifested as a localized set of brain regions encompassing the orbitofrontal cortex and middle cingulate cortex. ConclusionsOur findings not only may help reconcile prior heterogeneous neuroimaging results, but also may provide insights into the neurobiological mechanisms of suicide from a network perspective, which may ultimately inform more targeted and effective strategies to prevent suicide.

Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons

Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of ‘normal’ postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on ‘normal’ noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.

Integrative Analyses of scRNA-seq, Bulk mRNA-seq, and DNA Methylation Profiling in Depressed Suicide Brain Tissues.

Suicidal behaviors have become a serious public health concern globally due to the economic and human cost of suicidal behavior to individuals, families, communities, and society. However, the underlying etiology and biological mechanism of suicidal behavior remains poorly understood. We collected different single omic data, including single-cell RNA sequencing (scRNA-seq), bulk mRNA-seq, DNA methylation microarrays from the cortex of Major Depressive Disorder (MDD) in suicide subjects' studies, as well as fluoxetine-treated rats brains. We matched subject IDs that overlapped between the transcriptome dataset and the methylation dataset. The differential expression genes and differentially methylated regions were calculated with a 2-group comparison analysis. Cross-omics analysis was performed to calculate the correlation between the methylated and transcript levels of differentially methylated CpG sites and mapped transcripts. Additionally, we performed a deconvolution analysis for bulk mRNA-seq and DNA methylation profiling with scRNA-seq as the reference profiles. Difference in cell type proportions among 7 cell types. Meanwhile, our analysis of single-cell sequence from the antidepressant-treated rats found that drug-specific differential expression genes were enriched into biological pathways, including ion channels and glutamatergic receptors. This study identified some important dysregulated genes influenced by DNA methylation in 2 brain regions of depression and suicide patients. Interestingly, we found that oligodendrocyte precursor cells (OPCs) have the most contributors for cell-type proportions related to differential expression genes and methylated sites in suicidal behavior.

Neuroimaging alterations of the suicidal brain and its relevance to practice: an updated review of MRI studies.

Suicide is a leading cause of death in the United States. Historically, scientific inquiry has focused on psychological theory. However, more recent studies have started to shed light on complex biosignatures using MRI techniques, including task-based and resting-state functional MRI, brain morphometry, and diffusion tensor imaging. Here, we review recent research across these modalities, with a focus on participants with depression and Suicidal Thoughts and Behavior (STB). A PubMed search identified 149 articles specific to our population of study, and this was further refined to rule out more diffuse pathologies such as psychotic disorders and organic brain injury and illness. This left 69 articles which are reviewed in the current study. The collated articles reviewed point to a complex impairment showing atypical functional activation in areas associated with perception of reward, social/affective stimuli, top-down control, and reward-based learning. This is broadly supported by the atypical morphometric and diffusion-weighted alterations and, most significantly, in the network-based resting-state functional connectivity data that extrapolates network functions from well validated psychological paradigms using functional MRI analysis. We see an emerging picture of cognitive dysfunction evident in task-based and resting state fMRI and network neuroscience studies, likely preceded by structural changes best demonstrated in morphometric and diffusion-weighted studies. We propose a clinically-oriented chronology of the diathesis-stress model of suicide and link other areas of research that may be useful to the practicing clinician, while helping to advance the translational study of the neurobiology of suicide.

Dynamic connectivity alterations in anterior cingulate cortex associated with suicide attempts in bipolar disorders with a current major depressive episode

ObjectiveConsidering that the physiological mechanism of the anterior cingulate cortex (ACC) in suicide brain remains elusive for bipolar disorder (BD) patients. The study aims to investigate the intrinsic relevance between ACC and suicide attempts (SA) through transient functional connectivity (FC). MethodsWe enrolled 50 un-medicated BD patients with at least one SA, 67 none-suicide attempt patients (NSA) and 75 healthy controls (HCs). The sliding window approach was utilized to study the dynamic FC of ACC via resting-state functional MRI data. Subsequently, we probed into the temporal properties of dynamic FC and then estimated the relationship between dynamic characteristics and clinical variables using the Pearson correlation. ResultsWe found six distinct FC states in all populations, with one of them being more associated with SA. Compared with NSA and HCs, the suicide-related functional state showed significantly reduced dwell time in SA patients, accompanied by a significantly increased FC strength between the right ACC and the regions within the subcortical (SubC) network. In addition, the number of transitions was significantly increased in SA patients relative to other groups. All these altered indicators were significantly correlated with the suicide risk. ConclusionsThe results suggested that the dysfunction of ACC was relevant to SA from a dynamic FC perspective in BD patients. It highlights the temporal properties in dynamic FC of ACC that could be used as a putative target of suicide risk assessment for BD patients.

Altered volumes of the amygdala and hippocampus in the suicidal brain of patients with first episode psychosis

Altered volumes of the amygdala and hippocampus in the suicidal brain of patients with first episode psychosis

BDNF methylation and mRNA expression in brain and blood of completed suicides in Slovenia.

BACKGROUNDSuicide is a major public health problem. Worldwide, around 800000 people die by suicide every year. Suicide is a multifactorial disorder, with numerous environmental and genetic risk factors involved. Among the candidate genes, changes in the BDNF locus at the gene, epigenetic, mRNA, and protein expression levels have been implicated in psychiatric disorders, including suicidal behavior and completed suicides. AIMTo investigate changes in BDNF methylation and expression of four alternative BDNF transcripts for association with completed suicide.METHODSThis case-control study included 42 unrelated male Caucasian subjects, where 20 were control subjects who died following acute cardiac arrest, and 22 were suicide victims who died by hanging. DNA and RNA were extracted from brain tissue (Brodmann area 9 and hippocampus) and from blood. DNA methylation and mRNA expression levels were determined by targeted bisulfite next-generation sequencing and reverse-transcription quantitative PCR. Statistical analysis was done by use of two-tailed Student’s t tests for two independent samples, and the Benjamini-Hochberg procedure was implemented for correction for multiple comparisons.RESULTSIn DNA from brain tissue, there were no significant differences in BDNF methylation between the study groups. However, data showed significantly reduced DNA methylation of the BDNF region upstream of exon I in blood samples of suicide victims compared to the controls (5.67 ± 0.57 vs 6.83 ± 0.64, Pcorr = 0.01). In Brodmann area 9 of the brain of the suicide victims but not in their hippocampus, there was higher expression of BDNF transcript I-IX (NM_170731.4) compared to the controls (0.077 ± 0.024 vs 0.05 ± 0.013, P = 0.042). In blood, expression analysis for the BDNF transcripts was not feasible due to extensive RNA degradation.CONCLUSIONDespite the limitations of the study, the obtained data further support a role for BDNF in suicidality. However, it should be noted that suicidal behavior is a multifactorial disorder with numerous environmental and genetic risk factors involved.

ELECTROPHYSIOLOGICAL CORRELATES OF SUICIDALITY

Suicidal risk assessment is still a major challenge not only in psychiatric practice. Clinical investigation of suicidality can be significantly improved by using standardized scales for assessing suicide risk. The choice of a method for assessing suicidality also has significant implications for the search of valid available biomarker of suicidal behavior, where a less complex suicidality assessment procedure yields inaccurate results. This article offers an overview and analyzes in detail clinical studies of suicidality by electrophysiological methods since 2005 to 5/2020, especially in connection with presumed pathophysiological mechanism of the "suicidal brain" and the chosen method of sucidality assessment. Electrophysiological methods such as quantitative electroencephalography indicators, event-related potential, loudness dependence of the auditory evoked potential, polysomnography and heart rate variability offer a robust battery of easily available methods for assessing impaired emotional regulation. Nowadays it is unfortunately very difficult to point out the optimal electrophysiological examination of suicidal behaviour because of conflicting conclusion of presented studies which have been probably caused by various suicidal risk assessments, not always available data on affecting medication prior to testing and small samples of suicidal participants among studies. The most consistent and hopeful results are presented by evaluation of theta power by quantitative electroencephalography, although there are also few conflicting conclusions. The authors of this paper believe that this article could be good starting point for further research of electrophysiological methods in the field of suicidality.

Aberrant White Matter Microstructure in Depressed Patients with Suicidality.

Depression is a common psychiatric disorder affecting 264 million people globally, and the worst outcome is suicide. While regional brain alterations in depressed suicidal brain have previously been reported, knowledge about white matter (WM) microstructure is limited. Automated fiber quantification (AFQ) acquired by magnetic resonance imaging was used to calculate diffusion properties of fiber tracks to explore the structural alteration of WM associated with suicidality in depressive patients. Cross-sectional. Forty-five depressive patients without suicidality (DS- group, 60.00% females), 53 depressed patients with suicidality (DS+ group, 66.04% females), and 59 healthy controls (HC group, 67.80% females). 3.0 T; single-shot echo-planar imaging sequence. The point-wise group difference of the fiber tracts was determined by diffusion properties including fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of 18 specific WM tracts. Analysis of covariance (ANCOVA) and partial correlation analysis were used. A threshold of P < 0.05 was considered statistically significant. The significantly different diffusion properties were found in callosum forceps, left inferior fronto-occipital fasciculus (IFOF), right anterior thalamic radiation (ATR), and left cingulum cingulate in DS- and DS+ groups. The correlation analysis results showed that MD of right ATR was significantly positively correlated with Hamilton Depression Rating Scale (HAMD) scores (r=0.363). In addition, AD of right ATR (r=0.372), MD of callosum forceps minor (r=0.511), RD of left IFOF (r=0.429), and RD of callosum forceps minor (r=0.515) were significantly positively correlated with suicide item scores of HAMD. Our demonstration of decreased WM tract integrity including callosum forceps, IFOF, and ATR confirms the central involvement of the frontal cortex and limbic system with suicidality in depression. 3 TECHNICAL EFFICACY STAGE: 3.

Functional alterations of the suicidal brain: a coordinate-based meta-analysis of functional imaging studies.

Altered brain activities in suicidal subjects have been reported in a number of neuroimaging studies. However, the activity aberrances were inconsistent in previous investigations. Thus, we aimed to address activity abnormalities in suicidal individuals. Databases were searched to perform a meta-analysis of whole-brain functional MRI studies of suicidal individuals through January 14, 2020. Meta-analyses were conducted using Seed-based d Mapping software. Based on a meta-analysis of 17 studies comprising 381 suicidal individuals and 642 controls, we mainly found that increased activity in the bilateral superior temporal gyrus, left middle temporal gyrus, and bilateral middle occipital gyrus, along with decreased activity in the right putamen and left insula, were detected in suicidal individuals compared with nonsuicidalsubjects. To reduce methodological heterogeneity between the included studies, subanalyses of behavioral domains were conducted, and the right superior temporal gyrus was found to increase in all subanalyses of domains. In subanalyses of suicidal attempters and ideators, suicide attempters displayed hyperactivation in the bilateral superior temporal gyrus and left middle temporal gyrus and blunted responses in the left insula relative to controls. Suicidal ideators demonstrated elevated activation in the right middle occipital gyrus and reduced activity in the right putamen relative to controls. The bilateral superior temporal gyrus was the most robust finding, replicable in all data sets in the jackknife sensitive analysis. Moreover, increased activity in the right superior temporal gyrus, left middle temporal gyrus, and right middle occipital gyrus was found to be involved with higher suicide ideation scores. This study revealed several brain regions associated with suicidality. These findings may contribute to our understanding of the pathophysiology of suicide and have important implications for suicide prevention and interventions.

Brain Gene Expression- DNA Methylation Correlation in Suicide Completers

Gene expression alterations have been implicated in suicide pathology. However, the study of the regulatory effect of DNA methylation in gene expression in the suicidal brain has been restricted to candidate genes. The objective of this study was to identify genes whose expression levels are correlated with DNA methylation in the prefrontal cortex of suicides.

Altered cortical morphology in major depression disorder patients with suicidality.

Major depressive disorder (MDD) is associated with high risk of suicide, but the biological underpinnings of suicidality in MDD patients are far from conclusive. Previous neuroimaging studies using voxel-based morphometry (VBM) demonstrated that depressed individuals with suicidal thoughts or behaviors exhibit specific cortical structure alterations. To complement VBM findings, surface-based morphometry (SBM) can provide more details into gray matter structure, including the cortical complexity, cortical thickness and sulcal depth for brain images. This study aims to use SBM to investigate cortical morphology alterations to obtain evidence for neuroanatomical alterations in depressed patients with suicidality. Here, 3D T1-weighted MR images of brain from 39 healthy controls, 40 depressed patients without suicidality (patient controls), and 39 with suicidality (suicidal groups) were analyzed based on SBM to estimate the fractal dimension, gyrification index, sulcal depth, and cortical thickness using the Computational Anatomy Toolbox. Correlation analyses were performed between clinical data and cortical surface measurements from patients. Surface-based morphometry showed decreased sulcal depth in the parietal, frontal, limbic, occipital and temporal regions and decreased fractal dimension in the frontal regions in depressed patients with suicidality compared to both healthy and patient controls. Additionally, in patients with depression, the sulcal depth of the left caudal anterior cingulate cortex was negatively correlated with Hamilton Depression Rating Scale scores. Depressed patients with suicidality had abnormal cortical morphology in some brain regions within the default mode network, frontolimbic circuitry and temporal regions. These structural deficits may be associated with the dysfunction of emotional processing and impulsivity control. This study provides insights into the underlying neurobiology of the suicidal brain.

Brain Gene Expression-DNA Methylation Correlation in Suicide Completers: Preliminary Results.

Gene expression alterations have been implicated in suicide pathology. However, the study of the regulatory effect of DNA methylation on gene expression in the suicidal brain has been restricted to candidate genes. The objective of the study was to identify genes whose expression levels are correlated with DNA methylation in the prefrontal cortex of suicides. Postmortem prefrontal cortex samples from 21 suicides and six non-suicides were collected. Transcriptomic and DNA methylation profiles were evaluated with microarrays; cis correlations between gene expression and CpG methylation were screened. We then analyzed the presence of transcription factor (TF) binding sites (TFBS) at CpG sites correlated with gene expression. Gene expression of TFs involved in neurodevelopmental binding to predicted TFBS was determined in the BrainSpan database. We identified 22 CpG sites whose methylation levels correlated with gene expression in the prefrontal cortex of suicides. Genes annotated to identified CpG sites were involved in neurodevelopment (BBS4, NKX6-2, AXL, CTNND1, and MBP) and polyamine metabolism (polyamine oxidase [PAOX]). Such correlations were not detected in the nonsuicide group. Nine TFs (USF1, TBP, SF1, NRF1, RFX1, SP3, PKNOX1, MAZ, and POU3F2) showed differential expression in pre- and post-natal developmental periods, according to BrainSpan database. The integration of different omic technologies provided novel candidates for the investigation of genes whose expression is altered in the suicidal brain and their potential regulatory mechanisms.

A meta-study on transcription factor networks in the suicidal brain

There is evidence supporting the presence of brain gene expression differences between suicides and non-suicides. Such differences have been implicated in suicide pathophysiology. However, regulatory factors underlying these gene expression differences have not been fully understood. Therefore, the identification of differences in regulatory mechanisms, i.e., transcriptional factors between suicides and non-suicides is crucial for the understanding of suicide neurobiology. In this study, we conducted a transcription factor network meta-study with freely available data from the prefrontal cortex of suicides and non-suicides with different mental disorders, including major depression disorder, bipolar disorder and schizophrenia, as well as healthy controls. Disorder-specific characteristics of suicides and non-suicides transcription factor networks were detected, i.e., the presence of immune response genes in both suicides and non-suicides with major depression disorder networks. Also, we found the presence of ESR1, which has been implicated to give resilience to social stress, in the non-suicides network but not in the suicides with major depression network. Suicides and non-suicides with bipolar disorder shared only three genes in common: FOS, CRY1 and PER2. In addition, we found a higher number of genes involved in immune response in the non-suicides with bipolar disorder compared to the suicides with bipolar disorder network. The suicides and non-suicides with schizophrenia networks exhibited clear differences, including the presence of circadian cycle genes in the suicides with schizophrenia network and their absence in the non-suicides with schizophrenia network. The results of this study provide insight on the regulatory mechanisms underpinning transcriptional changes in the suicidal brain.

Network-based approach to identify molecular signatures in the brains of depressed suicides

BackgroundSuicide is a serious and global health problem that has a strong association with major depressive disorder (MDD). Weighted gene co-expression network analysis (WGCNA) was performed for the construction of a co-expression network to get important gene modules associated with depressed suicide. MethodsTranscriptome sequencing data from dorsolateral prefrontal cortex was used, which included 29 non-psychiatric controls (CON), 21 MDD suicides (MDD-S) and 9 MDD non-suicides (MDD-NS) of medication-free sudden death individuals. ResultsThe highest correlation in the module-traits relationship was discovered between the black module and suicide (r = -0.30, p = 0.024) as well as MDD (r = -0.34, p = 0.010).Furthermore, the expression levels of genes decreased progressively across the three groups (CON>MDD-NS>MDD-S). Therefore, the genes in the black module was selected for subsequent analyses. Protein-Protein Interaction Network found that the top 10 hub genes were somehow involved in depressed suicide including JUN, FOS, ATF3, MYC, EGR1, FOSB, DUSP1, NFKBIA, TLR2, NR4A1. Most of the GO terms were enriched in cell death and apoptosis and KEGG was mainly enriched in MAPK pathway. Cell Type–Specific Analysis found these genes were significantly enriched in endothelial and microglia (p<0.000) cell types. In addition, 92 genes in this module had at least one highly significant differentially methylated positions between MDD-S and controls. ConclusionCell death and apoptosis may participate in the interplay between depressed suicide and neuro-inflammation system.

Aberrant functional connectivity and graph properties in bipolar II disorder with suicide attempts

ObjectiveThe physiological mechanism of suicide attempt (SA) in bipolar II disorder (BD-II) remains only partially understood. The study seeks to identify the dysfunction pattern in suicide brain for BD-II patients. MethodsGraph theory was utilized to explore topological properties at whole-brain, module and region levels based on resting-state functional MRI (rs-fMRI) data, which acquired from 38 un-medicated BD-II patients with at least one SA, 60 none SA (NSA) patients and 69 healthy controls (HCs). Finally, the correlation relationship between graph metrics and clinical variables were estimated. ResultsCompared with NSA patients and HCs, the functional connectivity strength between limbic/sub-cortical (LIMB/SubC) and frontoparietal network (FPN) were significantly weakened. Nodal strength in left head of caudate nucleus (HCN), raphe nucleus (RN), right nucleus accumbens (NAcc), right subgenual anterior cingulate cortex (sgACC) and nodal efficiency in right sgACC, right HCN for SA patients were significantly reduced relative to NSA and HCs. In particular, nodal strength in RN and nodal efficiency in right sgACC showed a significant negative correlation with Nurses’ Global Assessment of Suicide Risk (NGASR) scores. LimitationsThis is a single-mode cross-sectional study, the results were not verified by multi-center data. ConclusionsThe abnormal disrupted FC between LIMB/SubC and FPN is associated with SA in BD-II patients, which increased the susceptibility of suicide. Especially, the dysfunction in RN and right sgACC predict a higher suicide risk in BD-II patients.The results can help us to understand the suicide mechanism and early judgment of suicidal behaviors for BD-II patients.

Membrane-Associated α-Tubulin Is Less Acetylated in Postmortem Prefrontal Cortex from Depressed Subjects Relative to Controls: Cytoskeletal Dynamics, HDAC6, and Depression.

Cytoskeletal proteins and post-translational modifications play a role in mood disorders. Post-translational modifications of tubulin also alter microtubule dynamics. Furthermore, tubulin interacts closely with Gαs, the G-protein responsible for activation of adenylyl cyclase. Postmortem tissue derived from depressed suicide brain showed increased Gαs in lipid-raft domains compared with normal subjects. Gαs, when ensconced in lipid rafts, couples less effectively with adenylyl cyclase to produce cAMP, and this is reversed by antidepressant treatment. A recent in vitro study demonstrated that tubulin anchors Gαs to lipid rafts and that increased tubulin acetylation (due to HDAC6 inhibition) and antidepressant treatment decreased the proportion of Gαs complexed with tubulin. This suggested that deacetylated-tubulin might be more prevalent in depression. This study examined tubulin acetylation in whole-tissue homogenate, plasma membrane, and lipid-raft membrane domains in tissue from normal control subjects, depressed suicides, and depressed nonsuicides (human males/females). While tissue homogenate showed no changes in tubulin acetylation between control, depressed suicides, and depressed nonsuicides, plasma membrane-associated tubulin showed significant decreases in acetylation from depressed suicides and depressed nonsuicides compared with controls. No change was seen in expression of the enzymes responsible for tubulin acetylation or deacetylation. These data suggest that, during depression, membrane-localized tubulin maintains a lower acetylation state, permitting increased sequestration of Gαs in lipid-raft domains, where it is less likely to couple to adenylyl cyclase for cAMP production. Thus, membrane tubulin may play a role in mood disorders, which could be exploited for diagnosis and treatment.SIGNIFICANCE STATEMENT There is little understanding about the molecular mechanisms involved in the development of depression and, in severe cases, suicide. Evidence for the role of microtubule modifications in progression of depressive disorders is emerging. These postmortem data provide strong evidence for membrane tubulin modification leading to reduced efficacy of the G protein, Gαs, in depression. This study reveals a direct link between decreased tubulin acetylation in human depression and the increased localization of Gαs in lipid-raft domains responsible for attenuated cAMP signaling. The evidence presented here suggest a novel diagnostic and therapeutic locus for depression.

Altered Cortical Morphology in Major Depression Disorder Patients with Suicidality

Background: Most cerebral gray matter studies investigating suicidality in depression have used voxel-based morphometry analyses. This study aims to investigate cortical morphology alterations to provide more detailed insight into gray matter structure and to obtain evidence for neuroanatomical alterations in the suicidal brain. Method: We performed a surface-based morphometry analysis to estimate the complexity of cortical folding (fractal dimension, FD), sulcal depth (SD) and cortical thickness (CT) in 39 healthy controls (HC), 40 depressed patients without suicidality (PC) and 39 with suicidality (SU) using the Computational Anatomy Toolbox (CAT12). Then, we performed correlation analyses between clinical data and the cortical surface measurements in patients. Findings: We found compared to both the HC and PC groups, the SU group showed significantly decreased SD in the frontal, limbic, parietal, temporal, and occipital regions and decreased FD in the frontal regions. In both the PC and SU groups, a significant negative correlation was found between the SD of the left caudal anterior cingulate cortex and Hamilton Depression Rating Scale (HAMD) scores. Interpretation: Abnormal cortical morphology in the default mode network, frontolimbic circuitry and temporal regions are implicated in MDD patients with suicidality. These structural deficits may represent a neurobiological endophenotype related to suicidality in MDD patients, which may be related to reported deficits in emotional processing and impulsivity control. Funding Statement: This study was supported by National Natural Science Foundation (Nos.81971595, 81771812, 81761128023, 81621003 and 81801681), PCSIRT (No.IRT16R52), Science and Technology Department of Sichuan (2018SZ0391) and Innovation Spark Project of Sichuan University (2019SCUH0003). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: This study was approved by the Ethics Committee of West China Hospital, Sichuan University, and all subjects provided written informed consent.

Sex differences in brain gene expression among suicide completers

BackgroundSuicide rates vary substantially by sex. Suicides committed by males significantly outnumber female suicides. Disparities in community and social factors provide a partial explanation for this phenomenon. Thus, the evaluation of sex differences at a biological level might contribute to the elucidation of the factors involved in this imbalance. The aim of the present study was to evaluate sex-specific gene expression patterns in the suicidal brain. Methodspostmortem samples from the dorsolateral prefrontal cortex (DLPFC) of 75 Latino individuals were analyzed. We considered the following groups: i) male suicides (n = 38), ii) female suicides (n = 10), iii) male controls (n = 20), and iv) female controls (n = 7). Gene expression profiles were evaluated by microarrays. Differentially expressed genes among the groups were identified with a linear model. Similarities and differences in the gene sets between the sexes were identified. ResultsDifferentially expressed genes were identified between suicides and controls of each sex: 1,729 genes in females and 1,997 genes in males. Female-exclusive suicide genes were related to cell proliferation and immune response. Meanwhile, male-exclusive suicide genes were associated to DNA binding and ribonucleic protein complex. Sex-independent suicide genes showed enrichment in mitochondrial and vesicular functions. LimitationsRelatively small sample size. Our diagnosis approach was limited to information found on coroner's records. The analysis was limited to a single brain area (DLPFC) and we used microarrays. ConclusionPreviously unexplored sex differences in the brain gene expression of suicide completers were identified, providing valuable foundation for the evaluation of sex-specific factors in suicide.

Exploratory analysis of genetic variants influencing molecular traits in cerebral cortex of suicide completers.

Genetic factors have been implicated in suicidal behavior. It has been suggested that one of the roles of genetic factors in suicide could be represented by the effect of genetic variants on gene expression regulation. Alteration in the expression of genes participating in multiple biological systems in the suicidal brain has been demonstrated, so it is imperative to identify genetic variants that could influence gene expression or its regulatory mechanisms. In this study, we integrated DNA methylation, gene expression, and genotype data from the prefrontal cortex of suicides to identify genetic variants that could be factors in the regulation of gene expression, generally called quantitative trait locus (xQTLs). We identify 6,224 methylation quantitative trait loci and 2,239 expression quantitative trait loci (eQTLs) in the prefrontal cortex of suicide completers. The xQTLs identified influence the expression of genes involved in neurodevelopment and cell organization. Two of the eQTLs identified (rs8065311 and rs1019238) were previously associated with cannabis dependence, highlighting a candidate genetic variant for the increased suicide risk in subjects with substance use disorders. Our findings suggest that genetic variants may regulate gene expression in the prefrontal cortex of suicides through the modulation of promoter and enhancer activity, and to a lesser extent, binding transcription factors.