Omics Approaches to Investigate the Pathogenesis of Suicide.

Suicide is the second leading cause of death in U.S. adolescents and young adults and is generally associated with a psychiatric disorder. Suicidal behavior has a complex etiology and pathogenesis. Moderate heritability suggests genetic causes. Associations between childhood and recent life adversity indicate contributions from epigenetic factors. Genomic contributions to suicide pathogenesis remain largely unknown. This article is based on a workshop held to design strategies to identify molecular drivers of suicide neurobiology that would be putative new treatment targets. The panel determined that while bulk tissue studies provide comprehensive information, single-nucleus approaches that identify cell type-specific changes are needed. While single-nuclei techniques lack information on cytoplasm, processes, spines, and synapses, spatial multiomic technologies on intact tissue detect cell alterations specific to brain tissue layers and subregions. Because suicide has genetic and environmental drivers, multiomic approaches that combine cell type-specific epigenome, transcriptome, and proteome provide a more complete picture of pathogenesis. To determine the direction of effect of suicide risk gene variants on RNA and protein expression and how these interact with epigenetic marks, single-nuclei and spatial multiomics quantitative trait loci maps should be integrated with whole-genome sequencing and genome-wide association databases. The workshop concluded with a recommendation for the formation of an international suicide biology consortium that will bring together brain banks and investigators with expertise in cutting-edge omics technologies to delineate the biology of suicide and identify novel potential treatment targets to be tested in cellular and animal models for drug and biomarker discovery to guide suicide prevention.

Specific Associations Between Type of Childhood Abuse and Elevated C-Reactive Protein in Young Adult Psychiatric Rehabilitation Participants.

BACKGROUND: Early-life adversity such as childhood emotional, physical, and sexual trauma is associated with later-life psychiatric and chronic medical conditions, including elevated inflammatory markers. Although previous research suggests a role for chronic inflammatory dysfunctions in several disease etiologies, specific associations between childhood trauma types and later-life inflammation and health status are poorly understood. METHODS: We studied patients (n = 280) admitted to a psychiatric rehabilitation center. Self-reported histories of childhood emotional, physical, and sexual trauma were collected with a standard instrument. At the time of admission, we also assessed individuals' body mass index and collected blood samples used to examine inflammatory marker C-reactive protein (CRP) levels. RESULTS: The prevalence of all 3 types of abuse was relatively high at 21% or more. Fifty percent of the sample had elevations in CRP, with clinically significant elevations in 26%. We found that compared with a history of emotional or physical abuse, a history of childhood sexual trauma was more specifically associated with elevated CRP. This result held up when using linear regressions to examine the contribution of body mass index. LIMITATION: Our sample was relatively young, with an average age of 27.2 years and minimal representation of ethnic and racial minority participants. CONCLUSION: Relative to childhood emotional and physical trauma, childhood sexual trauma may lead to elevated inflammatory responses, as confirmed in our finding of an association between CRP and sexual abuse. Future studies need to assess the causal link between childhood sexual trauma and poorer health outcomes later in life.

Integrating biobehavioral information to predict mood disorder suicide risk.

The will to live and the ability to maintain one's well-being are crucial for survival. Yet, almost a million people die by suicide globally each year (Aleman and Denys, 2014), making premature deaths due to suicide a significant public health problem (Saxena et al., 2013). The expression of suicidal behaviors is a complex phenotype with documented biological, psychological, clinical, and sociocultural risk factors (Turecki et al., 2019). From a brain disease perspective, suicide is associated with neuroanatomical, neurophysiological, and neurochemical dysregulations of brain networks involved in integrating and contextualizing cognitive and emotional regulatory behaviors. From a symptom perspective, diagnostic measures of dysregulated mood states like major depressive symptoms are associated with over sixty percent of suicide deaths worldwide (Saxena et al., 2013). This paper reviews the neurobiological and clinical phenotypic correlates for mood dysregulations and suicidal phenotypes. We further propose machine learning approaches to integrate neurobiological measures with dysregulated mood symptoms to elucidate the role of inflammatory processes as neurobiological risk factors for suicide.

Cross-ethnicity/race generalization failure of behavioral prediction from resting-state functional connectivity.

Algorithmic biases that favor majority populations pose a key challenge to the application of machine learning for precision medicine. Here, we assessed such bias in prediction models of behavioral phenotypes from brain functional magnetic resonance imaging. We examined the prediction bias using two independent datasets (preadolescent versus adult) of mixed ethnic/racial composition. When predictive models were trained on data dominated by white Americans (WA), out-of-sample prediction errors were generally higher for African Americans (AA) than for WA. This bias toward WA corresponds to more WA-like brain-behavior association patterns learned by the models. When models were trained on AA only, compared to training only on WA or an equal number of AA and WA participants, AA prediction accuracy improved but stayed below that for WA. Overall, the results point to the need for caution and further research regarding the application of current brain-behavior prediction models in minority populations.

Transcription Factor Motifs Associated with Anterior Insula Gene Expression Underlying Mood Disorder Phenotypes.

Mood disorders represent a major cause of morbidity and mortality worldwide but the brain-related molecular pathophysiology in mood disorders remains largely undefined. Because the anterior insula is reduced in volume in patients with mood disorders, RNA was extracted from the anterior insula postmortem anterior insula of mood disorder samples and compared with unaffected controls for RNA-sequencing identification of differentially expressed genes (DEGs) in (a) bipolar disorder (BD; n = 37) versus (vs.) controls (n = 33), and (b) major depressive disorder (MDD n = 30) vs. controls, and (c) low vs. high axis I comorbidity (a measure of cumulative psychiatric disease burden). Given the regulatory role of transcription factors (TFs) in gene expression via specific-DNA-binding domains (motifs), we used JASPAR TF binding database to identify TF-motifs. We found that DEGs in BD vs. controls, MDD vs. controls, and high vs. low axis I comorbidity were associated with TF-motifs that are known to regulate expression of toll-like receptor genes, cellular homeostatic-control genes, and genes involved in embryonic, cellular/organ, and brain development. Robust imaging-guided transcriptomics by using meta-analytic imaging results to guide independent postmortem dissection for RNA-sequencing was applied by targeting the gray matter volume reduction in the anterior insula in mood disorders, to guide independent postmortem identification of TF motifs regulating DEG. Our findings of TF-motifs that regulate the expression of immune, cellular homeostatic-control, and developmental genes provide novel information about the hierarchical relationship between gene regulatory networks, the TFs that control them, and proximate underlying neuroanatomical phenotypes in mood disorders.

Frontolimbic brain volume abnormalities in bipolar disorder with suicide attempts.

Over 2.3 million people in the United States live with bipolar disorder. Sixty percent of those with a bipolar disorder diagnosis attempt suicide at least once in their lifetime and up to 19% die by suicide. However, the neurobiology of suicide attempts in bipolar disorder remains unclear. We studied the gray matter volume (GMV) of 81 participants with a bipolar-I diagnosis (age-range: 14-34 years old) and 40 healthy participants (age-range 14.7-32 years old) to compare their neuroanatomy and histories of suicide attempt. In the bipolar group, 42 were manic with ages ranging from 14-30.6 years, and 39 were depressed with ages ranging from 14-34.3 years). Twenty three bipolar participants had a suicide attempt history, and 58 had no suicide attempt history. All participants completed behavioral/diagnostic assessments and MRI. We focused on a predefined frontolimbic circuitry in bipolar disorder versus controls to first identify diagnostic GMV correlates and to specifically identify GMV correlates for suicide attempt history. We found reduced GMV in bipolar diagnosis versus controls in the subgenual cingulate and dorsolateral prefrontal cortices. Our observed regional GMV reductions were associated with histories of suicide attempts and measures of individual variations in current suicidal ideation at the time of scanning.

Neuro-transcriptomic signatures for mood disorder morbidity and suicide mortality.

Suicidal behaviors are strongly linked with mood disorders, but the specific neurobiological and functional gene-expression correlates for this linkage remain elusive. We performed neuroimaging-guided RNA-sequencing in two studies to test the hypothesis that imaging-localized gray matter volume (GMV) loss in mood disorders, harbors gene-expression changes associated with disease morbidity and related suicide mortality in an independent postmortem cohort. To do so, first, we conducted study 1 using an anatomical likelihood estimation (ALE) MRI meta-analysis including a total of 47 voxel-based morphometry (VBM) publications (i.e. 26 control versus (vs) major depressive disorder (MDD) studies, and 21 control vs bipolar disorder (BD) studies) in 2387 (living) participants. Study 1 meta-analysis identified a selective anterior insula cortex (AIC) GMV loss in mood disorders. We then used this results to guide study 2 postmortem tissue dissection and RNA-Sequencing of 100 independent donor brain samples with a life-time history of MDD (N = 30), BD (N = 37) and control (N = 33). In study 2, exploratory factor-analysis identified a higher-order factor representing number of Axis-1 diagnoses (e.g. substance use disorders/psychosis/anxiety, etc.), referred to here as morbidity and suicide-completion referred to as mortality. Comparisons of case-vs-control, and factor-analysis defined higher-order-factor contrast variables revealed that the imaging-identified AIC GMV loss sub-region harbors differential gene-expression changes in high morbidity-&-mortality versus low morbidity-&-mortality cohorts in immune, inflammasome, and neurodevelopmental pathways. Weighted gene co-expression network analysis further identified co-activated gene modules for psychiatric morbidity and mortality outcomes. These results provide evidence that AIC anatomical signature for mood disorders are possible correlates for gene-expression abnormalities in mood morbidity and suicide mortality.

Convergent neurobiological predictors of mood and anxiety symptoms and treatment response.

Introduction: Mood and anxiety disorders are leading contributors to the global burden of diseases. Comorbid mood and anxiety disorders have a lifetime prevalence of ~20% globally and increases the risk for suicide, a leading cause of death. Areas covered: In this review, authors highlight recent advances in the understanding of multilevel-neurobiological mechanisms for normal/pathological human affective-functioning. The authors then address the complex interplay between environmental-adversity and molecular-genetic mediators of brain correlates of affective-symptoms. The molecular focus is strategically limited to GTF2i, BDNF, and FKBP5 genes that are, respectively, involved in transcriptional-, neurodevelopmental- and neuroendocrine-pathway mediation of affective-functions. The importance of these genes is illustrated with studies of copy-number-variants, genome-wide association (GWAS), and candidate gene-sequence variant associations with disease etiology. Authors concluded by highlighting the predictive values of integrative neurobiological processing of gene-environment interactions for affective disorder symptom management. Expert opinion: Given the transcriptional, neurodevelopmental and neuroimmune relevance of GTF2i, BDNF, and FKBP5 genes, respectively, authors reviewed the putative roles of these genes in neurobiological mediation of adaptive affective-responses. Authors discussed the importance of studying gene-dosage effects in understanding affective disorder risk biology, and how such targeted neurogenetic studies could guide precision identification of novel pharmacotherapeutic targets and aid in prediction of treatment response.

BDNF Val66Met polymorphism tunes frontolimbic circuitry during affective contextual learning.

Adaptive learning impairments are common in cognitive and behavioral disorders, but the neurogenetic mechanisms supporting human affective learning are poorly understood. We designed a higher-order contextual learning task in which healthy participants genotyped for the Val66Met polymorphism of the brain derived neurotropic factor gene (BDNF) were required to choose the member of a picture pair most congruent with the emotion in a previously-viewed facial expression video in order to produce an advantageous monetary outcome. Functional magnetic resonance imaging (fMRI) identified frontolimbic blood oxygenation level dependent (BOLD) reactivity that was associated with BDNF Val66Met genotype during all three phases of the learning task: aversive and reward-predictive learning, contextually-challenging decision-making, and choice-related monetary loss-avoidance and gain outcomes. Relative to Val homozygotes, Met carriers showed attenuated ventromedial prefrontal response to predictive affective cues, dorsolateral prefrontal signaling that depended on decision difficulty, and enhanced ventromedial prefrontal reactivity that was specific to loss-avoidance. These findings indicate that the BDNF Val66Met polymorphism is associated with functional tuning of behaviorally-relevant frontolimbic circuitry, particularly involving the ventromedial prefrontal cortex, during higher-order learning.

Convergent BOLD and Beta-Band Activity in Superior Temporal Sulcus and Frontolimbic Circuitry Underpins Human Emotion Cognition.

The processing of social information in the human brain is widely distributed neuroanatomically and finely orchestrated over time. However, a detailed account of the spatiotemporal organization of these key neural underpinnings of human social cognition remains to be elucidated. Here, we applied functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) in the same participants to investigate spatial and temporal neural patterns evoked by viewing videos of facial muscle configurations. We show that observing the emergence of expressions elicits sustained blood oxygenation level-dependent responses in the superior temporal sulcus (STS), a region implicated in processing meaningful biological motion. We also found corresponding event-related changes in sustained MEG beta-band (14-30 Hz) oscillatory activity in the STS, consistent with the possible role of beta-band activity in visual perception. Dynamically evolving fearful and happy expressions elicited early (0-400 ms) transient beta-band activity in sensorimotor cortex that persisted beyond 400 ms, at which time it became accompanied by a frontolimbic spread (400-1000 ms). In addition, individual differences in sustained STS beta-band activity correlated with speed of emotion recognition, substantiating the behavioral relevance of these signals. This STS beta-band activity showed valence-specific coupling with the time courses of facial movements as they emerged into full-blown fearful and happy expressions (negative and positive coupling, respectively). These data offer new insights into the perceptual relevance and orchestrated function of the STS and interconnected pathways in social-emotion cognition.

The Williams syndrome chromosome 7q11.23 hemideletion confers hypersocial, anxious personality coupled with altered insula structure and function.

Although it is widely accepted that genes can influence complex behavioral traits such as human temperament, the underlying neurogenetic mechanisms remain unclear. Williams syndrome (WS), a rare disorder caused by a hemizygous deletion on chromosome 7q11.23, including genes important for neuronal migration and maturation (LIMK1 and CLIP2), is typified by a remarkable hypersocial but anxious personality and offers a unique opportunity to investigate this open issue. Based on the documented role of the insula in mediating emotional response tendencies and personality, we used multimodal imaging to characterize this region in WS and found convergent anomalies: an overall decrease in dorsal anterior insula (AI) gray-matter volume along with locally increased volume in the right ventral AI; compromised white-matter integrity of the uncinate fasciculus connecting the insula with the amygdala and orbitofrontal cortex; altered regional cerebral blood flow in a pattern reminiscent of the observed gray-matter alterations (i.e., widespread reductions in dorsal AI accompanied by locally increased regional cerebral blood flow in the right ventral AI); and disturbed neurofunctional interactions between the AI and limbic regions. Moreover, these genetically determined alterations of AI structure and function predicted the degree to which the atypical WS personality profile was expressed in participants with the syndrome. The AI's rich anatomical connectivity, its transmodal properties, and its involvement in the behaviors affected in WS make the observed genetically determined insular circuitry perturbations and their association with WS personality a striking demonstration of the means by which neural systems can serve as the interface between genetic variability and alterations in complex behavioral traits.

Bridging the gene-behavior divide through neuroimaging deletion syndromes: Velocardiofacial (22q11.2 Deletion) and Williams (7q11.23 Deletion) syndromes.

Investigating the relationship between genes and the neural substrates of complex human behavior promises to provide essential insight into the pathophysiology of mental disorders. One approach to this inquiry is through neuroimaging of individuals with microdeletion syndromes that manifest in specific neuropsychiatric phenotypes. Both Velocardiofacial syndrome (VCFS) and Williams syndrome (WS) involve haploinsufficiency of a relatively small set of identified genes on the one hand and association with distinct, clinically relevant behavioral and cognitive profiles on the other hand. In VCFS, there is a deletion in chromosomal region 22q11.2 and a resultant predilection toward psychosis, poor arithmetic proficiency, and low performance intelligence quotients. In WS, there is a deletion in chromosomal region 7q11.23 and a resultant predilection toward hypersociability, non-social anxiety, impaired visuospatial construction, and often intellectual impairment. Structural and functional neuroimaging studies have begun not only to map these well-defined genetic alterations to systems-level brain abnormalities, but also to identify relationships between neural phenotypes and particular genes within the critical deletion regions. Though neuroimaging of both VCFS and WS presents specific, formidable methodological challenges, including comparison subject selection and accounting for neuroanatomical and vascular anomalies in patients, and many questions remain, the literature to date on these syndromes, reviewed herein, constitutes a fruitful "bottom-up" approach to defining gene-brain relationships.

Inferior frontal gyrus activity triggers anterior insula response to emotional facial expressions.

The observation of movies of facial expressions of others has been shown to recruit similar areas involved in experiencing one's own emotions: the inferior frontal gyrus (IFG), the anterior insula and adjacent frontal operculum (IFO). The causal link between activity in these 2 regions, associated with motor and emotional simulation, respectively, has remained unknown. Here using psychophysiological interaction and Granger Causality Modeling, we show that activity in the IFO is causally triggered by activity in the IFG, and that this effective connectivity is specific to the IFG. These findings shed new light on the intricate relationship between motor and affective components of emotional empathy.

A common anterior insula representation of disgust observation, experience and imagination shows divergent functional connectivity pathways.

Similar brain regions are involved when we imagine, observe and execute an action. Is the same true for emotions? Here, the same subjects were scanned while they (a) experience, (b) view someone else experiencing and (c) imagine experiencing gustatory emotions (through script-driven imagery). Capitalizing on the fact that disgust is repeatedly inducible within the scanner environment, we scanned the same participants while they (a) view actors taste the content of a cup and look disgusted (b) tasted unpleasant bitter liquids to induce disgust, and (c) read and imagine scenarios involving disgust and their neutral counterparts. To reduce habituation, we inter-mixed trials of positive emotions in all three scanning experiments. We found voxels in the anterior Insula and adjacent frontal operculum to be involved in all three modalities of disgust, suggesting that simulation in the context of social perception and mental imagery of disgust share a common neural substrates. Using effective connectivity, this shared region however was found to be embedded in distinct functional circuits during the three modalities, suggesting why observing, imagining and experiencing an emotion feels so different.

Investigating the molecular basis of major depressive disorder etiology: a functional convergent genetic approach.

Genes play a major role in behavioral adaptation to challenging environmental stimuli, but the complexity of their contribution remains unclear. There is growing evidence linking disease phenotypes with genes on the one hand, and the genesis of stress-related disorders like major depression, as a result of exposure to stressful environmental pathogens on the other. Here we illustrate the convergent role of monoaminergic genes in regulating the underlying biological mechanisms of stress and the emotions. By reviewing data that support a role of monoaminergic and other related genes in environmental adaptation, we conclude by advocating the use of convergent approaches in examining the genetic modulation of disease phenotypes.

Catechol-o-methyltransferase polymorphism and susceptibility to major depressive disorder modulates psychological stress response.

OBJECTIVES: The stress response is related to both physiological and psychological factors and is strongly marked by a neuroendocrine component. Genetic factors are believed to underlie individual differences in the degree of stress resilience and thereby contribute in determining susceptibility to stress-related pathologies like major depressive disorder (MDD). Little, however, is known about the genetic influence on the endocrine and behavioural stress response in relation to MDD. METHODS: Here, we sought to examine the effects of the catechol-o-methyltransferase polymorphism on psychological stress in three groups of individuals with different degrees of susceptibility to MDD (i.e. healthy controls, healthy high risk probands to MDD and those suffering from MDD). This genotype is involved in the metabolism of catecholamines (dopamine, norepinephrine and epinephrine). RESULTS: Allelic variations of this polymorphism were found to influence the degree of subjective stress experience and plasma epinephrine stress response. Interactions between catechol-o-methyltransferase polymorphism and diagnostic group in measures of plasma epinephrine, cortisol and subjective responses to psychological stress were also found, with the influence of the different alleles on these measures differing between healthy controls relative to MDD patients and high risk probands. CONCLUSION: These observations support a possible role for catechol-o-methyltransferase polymorphism in the endocrine and subjective response to psychological stress and thus may qualify as a possible candidate gene involved in the pathogenesis of MDD.

Empathy for positive and negative emotions in the gustatory cortex.

Anterior insula and adjacent frontal operculum (hereafter referred to as IFO) are active during exposure to tastants/odorants (particularly disgusting ones), and during the viewing of disgusted facial expressions. Together with lesion data, the IFO has thus been proposed to be crucial in processing disgust-related stimuli. Here, we examined IFO involvement in the processing of other people's gustatory emotions more generally by exposing participants to food-related disgusted, pleased and neutral facial expressions during functional magnetic resonance imaging (fMRI). We then exposed participants to pleasant, unpleasant and neutral tastants for the purpose of mapping their gustatory IFO. Finally, we associated participants' self reported empathy (measured using the Interpersonal Reactivity Index, IRI) with their IFO activation during the witnessing of others' gustatory emotions. We show that participants' empathy scores were predictive of their gustatory IFO activation while witnessing both the pleased and disgusted facial expression of others. While the IFO has been implicated in the processing of negative emotions of others and empathy for negative experiences like pain, our finding extends this concept to empathy for intense positive feelings, and provides empirical support for the view that the IFO contributes to empathy by mapping the bodily feelings of others onto the internal bodily states of the observer, in agreement with the putative interoceptive function of the IFO.