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Brain Biomarkers in Suicide Attempts: Elevated 5-HT1A Heteroreceptors & Hyperactivity in Superior Temporal Gyrus (2023 Review)

Suicide, a tragic end to around 800,000 lives each year, remains one of the most perplexing and devastating phenomena in mental health.

Despite the vast number of studies and data, accurately predicting who is at risk of suicide has remained largely elusive, with current tools heavily reliant on subjective assessments and the clinician’s experience.

A recent systematic review and meta-analysis leveraging neuroimaging techniques offers new insights, suggesting that the brain’s structure and function might hold key indicators for identifying individuals at risk.


  1. High Annual Toll: Suicide claims approximately 800,000 lives globally each year, with previous attempts being the strongest predictor of future risks.
  2. Neuroimaging Insights: A recent meta-analysis of over 5,659 publications has identified the right superior temporal gyrus as a potential neural substrate linked to suicide attempts, highlighting its functional hyperactivity in individuals who have attempted suicide.
  3. Serotonin Receptors: This brain region shows an enrichment in 5-HT1A serotonin receptors, suggesting a possible neurobiological mechanism underlying suicidal behaviors.
  4. Challenges and Limitations: Despite these findings, the heterogeneity in analytical techniques and the absence of robust power analysis limit the current applicability of neuroimaging features for predicting suicide attempts, emphasizing the need for further research and replication of results.

Source: European Neuropsychopharmacology (2023)

Major Findings: Neuroimaging Features & Suicide Attempts

Nicola Meda et al. conducted a systematic review and coordinate-based meta-analysis of neuroimaging studies related to suicide attempts to understand the neural correlates of suicidal behavior – included below are the major findings.

1. Functional Hyperactivity in the Right Superior Temporal Gyrus

The meta-analysis revealed a cluster of functional hyperactivity in the right superior temporal gyrus (rSTG), specifically associated with individuals who had attempted suicide.

This finding is significant as it pinpoints a specific brain region potentially involved in the neural pathway leading to suicide attempts.

The identified cluster is located within Brodmann Area 22, a region implicated in the processing of sounds, emotional responses to auditory stimuli, and aspects of speech and language.

This area’s hyperactivity in suicide attempters suggests a possible link between altered emotional processing or linguistic interpretation and the propensity for suicidal behavior.

2. Enrichment of 5-HT1A Heteroreceptors

Utilizing JuSpace for correlating the rSTG cluster with neurotransmitter receptor maps highlighted a significant enrichment of 5-HT1A heteroreceptors within this region.

This finding implicates the serotonergic system, particularly the role of 5-HT1A receptors, in the neurobiology of suicide attempts.

The 5-HT1A receptor is known to play a crucial role in regulating mood and impulsivity, two key dimensions implicated in suicidal behavior.

The enrichment of these receptors in the rSTG suggests that dysregulation within this serotonergic pathway may contribute to the increased risk of suicide attempts.

3. Lack of Statistically Significant Morphometric Differences

Across the studies included in the meta-analysis, no statistically significant differences in brain morphometry (size, volume, or structure) were found between individuals who had attempted suicide and those who had not.

This outcome underscores the possibility that functional abnormalities, rather than structural alterations, are more closely associated with the risk of suicidal actions.

Neuroimaging in Suicide Attempts vs. Healthy Controls (2023 Review)

By analyzing data from a vast array of studies, the research sought to identify potential neurobiological markers that could enhance the accuracy of suicide risk assessments beyond the current reliance on subjective evaluations and clinician experience.


  • Search Strategy: A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science databases, yielding 5,659 publications for potential inclusion. The search targeted studies that reported on structural or functional MRI findings related to suicide attempts.
  • Study Selection: Out of the initial pool, 102 experiments were summarized, and 23 were selected for meta-analysis based on strict inclusion criteria focusing on the use of magnetic resonance imaging (MRI) to compare individuals with and without a history of suicide attempts.
  • Data Analysis: The analysis employed a coordinate-based meta-analysis approach using the activation likelihood estimation program GingerALE. This method allowed for the identification of commonly activated brain regions across studies. Additionally, JuSpace was utilized to correlate identified brain clusters with neurotransmitter receptor maps, focusing on the enrichment of 5-HT1A heteroreceptors.


  • Neuroimaging Markers: The meta-analysis pinpointed a cluster in the right superior temporal gyrus that was functionally hyperactive in individuals who had attempted suicide, implicating this region in emotional processing related to suicidal behavior.
  • Serotonin Receptors: The right superior temporal gyrus was found to be enriched in 5-HT1A heteroreceptors, suggesting a specific neurobiological pathway that could underlie the transition from suicidal ideation to attempts.
  • No Significant Morphometric Differences: The study did not find statistically significant differences in brain morphometry between individuals who had attempted suicide and those who had not, indicating that functional, rather than structural, brain differences may be more relevant in the context of suicide risk.


  • Heterogeneity & Methodological Variability: There was significant heterogeneity among the studies included in the review, stemming from differences in analytical techniques, populations studied, and the absence of robust power analysis. This variability could affect the generalizability and applicability of the findings.
  • Survival Bias: The analysis was inherently limited to individuals who survived suicide attempts, potentially excluding neurobiological markers present in individuals who died by suicide on their first attempt.
  • Need for Replication & Further Research: The findings, particularly the identification of the right superior temporal gyrus as a region of interest, need to be replicated in diverse populations and with consistent methodological approaches to confirm their validity and clinical utility.

rSTG & 5-HT1A: Functions & Effects of Dysfunction

Right Superior Temporal Gyrus (rSTG)

Basic Functions

  • Emotional Processing & Social Cognition: The rSTG plays a critical role in processing emotional content and social cues, including the tone of voice and facial expressions. It is integral to how individuals perceive and interpret social and emotional information from their environment.
  • Auditory Processing: This region is also involved in processing complex sounds, contributing to language comprehension and the interpretation of non-verbal auditory cues, which are crucial for effective communication and social interaction.

Abnormal Activation

  • Misinterpretation of Social & Emotional Cues: Hyperactivity in the rSTG could lead to heightened sensitivity or misinterpretation of emotional and social signals, potentially contributing to feelings of isolation, misunderstanding, or conflict in social relationships. This misinterpretation could exacerbate depressive symptoms or feelings of hopelessness, factors often associated with suicidal ideation and attempts.
  • Overwhelm & Stress: Excessive activation in areas involved in processing complex auditory and emotional information might also contribute to a sense of being overwhelmed, increasing stress and anxiety levels, further impacting an individual’s mental health and exacerbating risk factors for suicide.

5-HT1A Heteroreceptors

Basic Functions

  • Mood Regulation & Anxiety: 5-HT1A receptors, including both auto- and heteroreceptors, are implicated in regulating mood and anxiety levels. Heteroreceptors are located in various brain regions, including the cortex and hippocampus, and modulate the release of neurotransmitters, affecting emotional regulation and stress responses.
  • Neurogenesis: These receptors also play a role in neurogenesis and synaptic plasticity, influencing brain development and the ability to adapt to new information or environments.


  • Impaired Emotional Regulation: Dysregulation of 5-HT1A heteroreceptor function can lead to altered serotonin signaling, impacting mood regulation and stress response systems. This dysregulation can contribute to the development or exacerbation of mood disorders, anxiety, and other psychiatric conditions that increase suicide risk.
  • Neurodevelopmental & Plasticity Issues: Abnormalities in 5-HT1A receptor function could also impair neurogenesis and brain plasticity, potentially leading to altered brain development and function. These changes could affect cognitive and emotional processing, further contributing to psychiatric symptoms and the propensity for suicidal behavior.

Potential Applications & Implications of the Findings (Neuroimaging in Suicide Attempts)

The findings from the systematic review and meta-analysis on neuroimaging features associated with suicide attempts have significant potential implications for the field of psychiatry and mental health care.

Enhancing Suicide Risk Assessment

  • Objective Biomarkers: The identification of functional hyperactivity in the right superior temporal gyrus (rSTG) offers a potential objective biomarker for assessing suicide risk, supplementing traditional methods reliant on self-reported symptoms and clinical judgment.
  • Precision Psychiatry: Integrating neuroimaging data into clinical practice could pave the way for precision psychiatry, where treatment and monitoring are tailored based on the specific neurobiological profiles of individuals at risk of suicide.

Informing Therapeutic Interventions

  • Targeted Therapies: Knowledge about the enrichment of 5-HT1A heteroreceptors in the rSTG could inform the development of targeted pharmacological interventions that modulate this serotonergic pathway, potentially reducing suicide risk.
  • Psychotherapeutic Strategies: Understanding the functional abnormalities in the brain regions involved in emotional processing and decision-making may guide the development of psychotherapeutic strategies aimed at enhancing emotion regulation and coping mechanisms in at-risk individuals.

Advancing Suicide Prevention Programs

  • Early Detection: Neuroimaging markers could be incorporated into screening programs, enabling the early detection of individuals at heightened risk for suicide, particularly in high-risk populations such as those with a history of mental illness or previous suicide attempts.
  • Preventive Measures: By identifying individuals at risk before they attempt suicide, healthcare providers can implement preventive measures, including closer monitoring, personalized intervention strategies, and targeted support services.

Fostering Research & Clinical Trials

  • Causal Research: These findings underscore the need for further research to explore the causal relationships between neurobiological abnormalities and suicidal behavior, potentially uncovering new pathways for intervention.
  • Clinical Trials: The role of the rSTG and 5-HT1A heteroreceptors in suicide risk can be investigated in clinical trials, testing the efficacy of interventions aimed at modulating these neurobiological targets.

Drugs Targeting 5-HT1A Heteroreceptors as Interventions?

The recent findings highlighting the role of the right superior temporal gyrus (rSTG) and its enrichment in 5-HT1A heteroreceptors in individuals who have attempted suicide bring to light the potential therapeutic implications of targeting this specific neural pathway.

SSRIs & 5-HT1A Heteroreceptors

SSRIs, a commonly prescribed class of antidepressants, increase serotonin levels in the brain by inhibiting its reuptake.

Although they primarily target serotonin transporters, their long-term use is associated with desensitization of 5-HT1A autoreceptors and potentially affects heteroreceptors, leading to enhanced serotonergic neurotransmission.

This mechanism may have implications for modulating the activity in the rSTG and addressing the hyperactivity observed in individuals at risk of suicide.

Buspirone & its Dual Role

This anxiolytic medication, known for its affinity for 5-HT1A receptors, acts as a partial agonist.

Buspirone’s action on 5-HT1A heteroreceptors could theoretically modulate serotonergic activity in key brain regions, including the rSTG, potentially normalizing the hyperactive functional patterns linked to suicidal behavior.

Potential for Neuromodulation Techniques

TMS is a non-invasive neuromodulation technique that can alter neural activity in specific brain regions.

Given the identified hyperactivity in the rSTG, targeted TMS could be explored as a method to directly modulate this region’s activity, potentially offering a novel intervention strategy for individuals with heightened suicide risk.

Correlation vs. Causation in Suicide Biomarker Research

The identification of biomarkers associated with suicide attempts, such as the functional hyperactivity in the right superior temporal gyrus (rSTG) and the enrichment of 5-HT1A heteroreceptors, represents a significant advancement in understanding the neurobiological aspects of suicidal behavior.

However, it’s crucial to distinguish between correlation and causation in interpreting these findings.

The presence of certain biomarkers in individuals who have attempted suicide does not necessarily mean these biomarkers caused the suicide attempts.

  • Response to Stress: Changes in the brain, including alterations in specific biomarkers, could be a response to the extreme psychological stress experienced before, during, and after a suicide attempt. This suggests that the observed biomarker changes might be consequences of suicidal behavior or the associated mental health conditions, rather than their cause.
  • Complex Interplay: Suicide attempts are the result of a complex interplay of environmental, psychological, and biological factors. While biomarkers can indicate a biological predisposition or response, they operate within a broader context that includes individual life experiences, environmental stressors, and psychological states. These factors can influence both the emergence of biomarkers and the risk of suicide independently.
  • Pre-existing Conditions: It’s challenging to establish a clear temporal relationship between the presence of specific biomarkers and the occurrence of suicide attempts. Without longitudinal studies tracking these biomarkers over time in individuals who later attempt suicide, it’s difficult to ascertain whether the biomarkers were present before the suicidal behavior and thus contributed to its development.
  • Individual Variability: There is significant heterogeneity among individuals who attempt suicide, including the methods used, the underlying mental health conditions, and their biological makeup. This diversity suggests that no single biomarker or set of biomarkers can universally predict or cause suicide attempts across all individuals.
  • Secondary Manifestations: Biomarkers identified in association with suicide attempts might be epiphenomena—secondary manifestations of underlying mental health disorders such as depression, anxiety, or psychosis, rather than direct causes of suicidal behavior. These conditions themselves are complex and multifactorial, with their own set of associated biomarkers.

Conclusion: Neuroimaging Biomarkers in Suicide Attempts

The systematic review and coordinate-based meta-analysis conducted on the role of neuroimaging in identifying individuals at risk of suicide attempts marks a significant advancement in our understanding of the neurobiological underpinnings of suicidal behavior.

By pinpointing functional hyperactivity in the right superior temporal gyrus and its enrichment in 5-HT1A heteroreceptors, the study offers new insights into the potential neural pathways that could predispose individuals to suicide attempts.

While the findings highlight the complexity of predicting suicidal behavior, they underscore the promise of neuroimaging as a tool for enhancing risk assessment beyond traditional subjective methods.

However, the lack of significant morphometric differences between attempters and non-attempters emphasizes the need for further research to explore the functional, rather than structural, brain abnormalities associated with suicide risk.

The study’s limitations, including the heterogeneity of included research and the necessity for replication in diverse populations, highlight the importance of cautious interpretation and application of these findings.

Overall, this research paves the way for future studies to refine our understanding of suicide risk, potentially leading to the development of more accurate predictive tools and targeted interventions.


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