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Connectomics-Based Functional Network Alterations in both Depressed Patients with Suicidal Behavior and Healthy Relatives of Suicide Victims.

ABSTRACT: Understanding the neural mechanisms of suicidal behavior is crucial. While regional brain alterations have previously been reported, knowledge about brain functional connectomics is currently limited. Here, we investigated differences in global topologic network properties and local network-based functional organization in both suicide attempters and suicide relatives. Two independent samples of depressed suicide attempters (N?=?42), depressed patient controls (N?=?43), healthy controls (N?=?66) as well as one sample of healthy relatives of suicide victims (N?=?16) and relatives of depressed patients (N?=?16) were investigated with functional magnetic resonance imaging in the resting-state condition. Graph theory analyses were performed. Assortativity, clustering coefficients, global efficiency, and rich-club coefficients were calculated. A network-based statistic approach was finally used to examine functional connectivity matrices. In comparison to healthy controls, both patient groups showed significant reduction in assortativity, and decreased functional connectivity in largely central and posterior brain networks. Suicide attempters only differed from patient controls in terms of higher rich-club coefficients for the highest degree nodes. Compared to patient relatives and healthy controls, suicide relatives showed reduced assortativity, reduced clustering coefficients, increased global efficiency, and increased rich-club coefficients for the highest degree nodes. Suicide relatives also showed reduced functional connectivity in one anterior and one posterior sub-network in comparison to healthy controls, and in a largely anterior brain network in comparison to patient relatives. In conclusion, these results suggest that the vulnerability to suicidal behavior may be associated with heritable deficits in global brain functioning - characterized by weak resilience and poor segregation - and in functional organization with reduced connectivities affecting the ventral and dorsal prefrontal cortex, the anterior cingulate, thalamus, striatum, and possibly the insula, fusiform gyrus and the cerebellum.

SUBMITTER: Wagner G

PROVIDER: S-EPMC6778100 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Connectomics-Based Functional Network Alterations in both Depressed Patients with Suicidal Behavior and Healthy Relatives of Suicide Victims.

Wagner Gerd G de la Cruz Feliberto F Köhler Stefanie S Pereira Fabricio F Richard-Devantoy Stéphane S Turecki Gustavo G Bär Karl-Jürgen KJ Jollant Fabrice F

Scientific reports 20191004 1

Understanding the neural mechanisms of suicidal behavior is crucial. While regional brain alterations have previously been reported, knowledge about brain functional connectomics is currently limited. Here, we investigated differences in global topologic network properties and local network-based functional organization in both suicide attempters and suicide relatives. Two independent samples of depressed suicide attempters (N = 42), depressed patient controls (N = 43), healthy controls (N = 66) ...[more]

PMID: 31586117

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Project description:Although suicide is the second-leading cause of death in adolescents and young adults worldwide, little progress has been made in developing reliable biological markers of suicide risk and suicidal behavior. Converging evidence suggests that excitatory and inhibitory cortical processes mediated by the neurotransmitters glutamate and ?-aminobutyric acid (GABA) are dysregulated in suicidal individuals. This study utilized single- and paired-pulse transcranial magnetic stimulation (TMS) to assess excitatory and inhibitory cortical functioning in healthy control adolescents (n?=?20), depressed adolescents without any history of suicidal behavior ("Depressed", n?=?37), and depressed adolescents with lifetime history of suicidal behavior ("Depressed+SB", n?=?17). In a fixed-effects general linear model analysis, with age, sex, and depression severity as covariates, no significant group main effects emerged for resting motor threshold, intracortical facilitation, short-interval intracortical inhibition, or cortical silent period. However, group main effects were significant for long-interval intracortical inhibition (LICI) at interstimulus intervals (ISIs) of 100?ms and 150?ms, but not 200?ms. Depressed+SB adolescents demonstrated impaired LICI compared to healthy control and Depressed adolescents, while healthy control and Depressed participants did not differ in LICI. Multiple linear robust regression revealed significant positive linear relationships between lifetime suicidal behavior severity and impairment in LICI at 100-ms and 150-ms ISIs. In a post hoc receiver operating characteristic analysis, LICI significantly discriminated Depressed from Depressed+SB youth in 100-ms and 150-ms paradigms. These findings suggest that GABAB receptor-mediated inhibition is distinctly dysregulated in depressed adolescents with histories of suicidal behavior. Further research is warranted to establish the utility of cortical inhibition in the assessment of suicide risk and as a target for treatment interventions.

Project description:Suicide is one of the leading causes of death globally for all ages, and as such presents a very serious problem for clinicians worldwide. However, the underlying neurobiological pathology remains to a large extent unknown. In order to address this gap, we have carried out a genome-wide investigation of the gene expression in the amygdala, hippocampus, prefrontal cortex and thalamus in post-mortem brain samples obtained from 20 suicide completers and 7 control subjects. By KEGG enrichment analysis indicated we identified novel clusters of downregulated pathways involved in antigen neutralization and autoimmune thyroid disease (amygdala, thalamus), decreased axonal plasticity in the hippocampus. Two upregulated pathways were involved in neuronal death in the hippocampus and olfactory transduction in the thalamus and the prefrontal cortex. Autoimmune thyroid disease pathway was downregulated only in females. Metabolic pathways involved in Notch signaling amino acid metabolism and unsaturated lipid synthesis were thalamus-specific. Suicide-associated changes in the expression of several genes and pseudogenes that point to various functional mechanisms possibly implicated in the pathology of suicide. Two genes (SNORA13 and RNU4-2) involved in RNA processing were common to all brain regions analyzed. Most of the identified gene expression changes were related to region-specific dysregulated manifestation of genetic and epigenetic mechanisms underlying neurodevelopmental disorders (SNORD114-10, SUSd1), motivation, addiction and motor disorders (CHRNA6), long-term depression (RAB3B), stress response, major depression and schizophrenia (GFAP), signal transduction at the neurovascular unit (NEXN) and inhibitory neurotransmission in spatial learning, neural plasticity (CALB2; CLIC6, ENPP1). Some of the differentially expressed genes were brain specific non-coding RNAs involved in the regulation of translation (SNORA13). One, (PARM1) is a potential oncogene and prognostic biomarker for colorectal cancer with no known function in the brain. Disturbed gene expression involved in antigen neutralization, autoimmunity, neural plasticity, stress response, signal transduction at the neurovascular unit, dysregulated nuclear RNA processing and translation and epigenetic imprinting signatures is associated with suicide and point to regulatory non-coding RNAs as potential targets of new drugs development.

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Connectomics-Based Functional Network Alterations in both Depressed Patients with Suicidal Behavior and Healthy Relatives of Suicide Victims.

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Connectomics-Based Functional Network Alterations in both Depressed Patients with Suicidal Behavior and Healthy Relatives of Suicide Victims.

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