Psychoneuroimmunoendocrinological and Neuroanatomical Basis of Suicidal Behavior

Introduction

• Suicidal behavior is influenced by psychological, environmental, and biological factors.

• Over 720,000 deaths annually are attributed to suicide, with millions experiencing suicidal ideation.

• Only a fraction of those who attempt suicide die, highlighting the importance of understanding individual vulnerabilities.

• The review focuses on the neuroanatomical basis of suicidal behavior and potential pathways for neuromodulation therapies like Transcranial Magnetic Stimulation (TMS).

• Survivors of suicide attempts often experience profound psychological distress linked to life events such as bereavement, financial hardship, professional failures, or relationship dissolution.

• Perceived social rejection and inner emptiness are also common themes.

• Albert Camus viewed suicide as an escape from the "absurd" - the conflict between humanity’s search for meaning and an indifferent universe.

• Suicide is a behavioral phenomenon with identifiable risk factors and neurobiological mechanisms.

• Suicidal behavior is categorized into:

  • Suicide: A fatal act of self-injury with intent to die.

  • Suicide Attempt: A non-lethal self-injurious act with suicidal intent.

  • Suicidal Ideation: Contemplation or preoccupation with ending one’s own life.

• Suicidal planning, involving detailed preparation for a suicide attempt, is an intermediate stage.

• Suicide is a global public health crisis with over 720,000 deaths each year.

• In 2021, suicide was the third leading cause of death among individuals aged 15–29 and the second leading cause among those aged 25–34.

• Approximately 73% of suicides occur in low- and middle-income countries.

• In the United States, over 49,000 suicide deaths were reported in 2022, equating to one suicide every 11 min.

• In the United States, 13.2 million individuals seriously contemplated suicide, and 3.8 million formulated a suicide plan in 2022.

• For every completed suicide, approximately 20 attempts occur, translating to an estimated 16 million annual suicide attempts globally and 160 million individuals experiencing suicidal ideation.

• Self-harm, including both suicide attempts and non-suicidal self-injury, is more prevalent among females and younger individuals.

• Among suicide attempters, 1.6% die by suicide within a year, and 3.9% within five years.

• Suicide rates in low- and middle-income regions (7.3–10.1 per 100,000) are comparable to high-income countries (10.9 per 100,000).

Biological and Environmental Contributions to Suicide Risk

• Suicide results from an interplay of biological predisposition and environmental influences.

• Genetic susceptibility, epigenetic modifications, and a family history of psychiatric disorders are critical individual-level factors.

• Mental health conditions such as depression, bipolar disorder, schizophrenia-spectrum disorders, substance use disorders, epilepsy and traumatic brain injury significantly elevate suicide risk across the lifespan.

• Childhood adversity contributes to vulnerability, while adolescence is often marked by the onset of severe psychiatric disorders, including mood and personality disorders.

• In adulthood and later life, substance use and chronic medical conditions further exacerbate risk.

• Environmental factors—including financial stress, social isolation, exposure to suicidal behavior in media, and access to lethal means—exert additional influence.

• These factors vary across life stages, with social and environmental stressors peaking during adolescence and adulthood.

• Approximately 80% of individuals who attempt suicide have a preexisting psychiatric disorder.

• One in eight people globally (970 million individuals) lives with a mental health condition.

Neurobiological Mechanisms and Therapeutic Perspectives

• While many individuals endure profound distress, only a subset proceeds to suicidal actions, highlighting the importance of individual vulnerability.

• This vulnerability, influenced by genetic, epigenetic, and neurobiological mechanisms, is mediated by specific neural circuits.

• From a neuroanatomical perspective, alterations in the prefrontal cortex, limbic system, and serotonergic pathways have been implicated in suicidal behavior.

• Functional and structural abnormalities in these regions disrupt emotional regulation, impulse control, and cognitive flexibility—key factors in suicidal crises.

• These findings hold significant potential for developing predictive tools to assess high-risk individuals and inform therapeutic strategies.

• Neuromodulation techniques, such as transcranial magnetic stimulation (TMS), offer promising avenues for targeted intervention, particularly in individuals with treatment-resistant psychiatric conditions.

• By modulating neural circuits implicated in suicidality, TMS represents a potential adjunct to pharmacological and psychotherapeutic interventions.

• This review examines the neuroanatomical basis of suicidal behavior and explores emerging therapeutic approaches, particularly the role of TMS, in modulating suicide-related neural circuitry.

• Understanding these mechanisms may facilitate the development of more effective prevention and intervention strategies, ultimately reducing suicide-related mortality.

Materials and Methods

• A multi-stage literature search was conducted using electronic databases, including Google Scholar, Scopus, and PubMed, to identify scientific publications suitable for analysis.

Search Strategy

Neuronatomical Basis of Suicide

• Keywords used for the literature search included:

  • PubMed: ("Suicide"[MeSH] OR suicide[tiab] OR suicidality[tiab] OR self-harm[tiab]) AND ("Anatomy"[MeSH] OR "neuroanatomy"[MeSH] OR anatomy[tiab] OR "body structure"[tiab] OR "biological structure"[tiab])

  • Google Academic: (“suicide” OR “suicidality” OR “self-harm”) AND (“anatomy” OR “body structure” OR “biological structure”)

  • Scopus: (TITLE-ABS-KEY(“suicide” OR “suicidality” OR “self-harm”) AND TITLE-ABS-KEY(“anatomy” OR “body structure” OR “biological structure”))

TMS and Suicide Behavior

• Keywords used for the literature search included:

  • PubMed: ("Transcranial Magnetic Stimulation"[Mesh] OR "TMS" OR "rTMS") AND ("suicide"[Mesh] OR "suicidal ideation" OR "suicidal behavior" OR "suicide attempt") AND ("neuromodulation" OR "brain stimulation")

  • Google Academic: "Transcranial Magnetic Stimulation" OR "TMS" OR "rTMS" AND "suicide" OR "suicidal ideation" OR "suicide attempt" OR "suicide prevention"

  • Scopus: TITLE-ABS-KEY("Transcranial Magnetic Stimulation" OR "TMS" OR "rTMS") AND TITLE-ABS-KEY("suicide" OR "suicidal ideation" OR "suicidal behavior" OR "suicide attempt" OR "suicide prevention")

Systematic Search Process

• During the identification phase, a total of 62,148 studies were retrieved for the review on the neuroanatomical basis of suicidal behavior and 29,639 for the review on TMS and suicide behavior.

• Studies were sourced from databases including PubMed, SCOPUS, and Google Scholar along with citation searching and grey literature.

• Before screening, duplicate studies were removed, and all records were evaluated for relevance based on abstracts and keywords.

• Following duplicate removal, 62,183 and 29,695 studies were screened for eligibility in the respective reviews.

• The majority of exclusions occurred during this abstract screening phase.

• A total of 59,203 studies in the neuroanatomical basis review and 26,221 in the TMS review did not meet the inclusion criteria, primarily because they did not focus on the neuroanatomical correlates of suicidal behavior or the effects of TMS on suicide risk.

• Many of these excluded studies examined psychosocial risk factors, general suicide prevention strategies, or non-biological interventions.

• Additionally, 2878 and 3438 studies, respectively, were removed as they were duplicates not initially detected during identification.

• Studies that passed the abstract screening underwent full-text eligibility review, resulting in the assessment of 102 articles in the neuroanatomical basis review and 36 in the TMS review.

• At this stage, several studies were excluded due to methodological limitations.

• A total of 14 studies in each review were removed due to the lack of accessible full text.

• Further exclusions were applied to 11 and 9 studies, respectively, because they were conducted in non-psychiatric populations or in clinical settings that were not relevant to the scope of this review.

• Additionally, 10 studies in the neuroanatomical basis review and 5 in the TMS review were excluded because they were protocols without published results.

• After applying these exclusion criteria, the final number of studies included in the systematic review was 67 for the neuroanatomical basis of suicidal behavior and 15 for TMS and suicide behavior.

Selection Criteria

• Studies were included if they investigated the neuroanatomical and biological mechanisms underlying suicidal behavior or examined the effects of TMS on suicide risk.

• Eligible studies included human participants with a history of suicidal ideation or behavior, diagnosed with psychiatric disorders by a psychiatrist.

• Research designs considered for inclusion comprised cross-sectional, longitudinal, case-control, cohort studies, or experimental designs, and neuromodulation studies involving TMS in repetitive TMS, intermittent theta burst stimulation iTBS, deep brain stimulation among other kind of noninvasive TMS treatment.

• In the search for Suicidal Behavior Neuroanatomical Basis, articles including neuroimaging research using tomographic images, fMRI, PET, or DTI were included.

• Only peer-reviewed journal articles were included, and no language restrictions were applied.

• In exclusion criteria, duplicate records were removed, and non-peer-reviewed sources such as conference proceedings, single clinical case report, book chapters, opinion pieces, and editorials were excluded.

• Studies that did not focus on suicidal behavior neuroanatomy or the effects of TMS on suicide risk were omitted, as were studies analyzing psychosocial factors without biological correlates.

• Research conducted in animal models or in vitro, as well as studies with inaccessible full text, were also excluded.

• Further exclusions were applied to studies with methodological weaknesses, including small sample sizes, lack of statistical analysis, or missing critical data.

• Additionally, research conducted in non-psychiatric populations and protocols without published results were not considered for inclusion.

Results

• Suicidal behavior is associated with structural and functional alterations across multiple brain regions, particularly within the prefrontal cortex (PFC), limbic system, and Default Mode Network (DMN).

• Neuroimaging studies have consistently demonstrated grey matter reductions in the PFC, particularly in the DLPFC and OFC regions, which are crucial for cognitive control, emotional regulation, and decision-making.

• Dysregulation of serotonergic, glutamatergic, and GABAergic neurotransmission in these regions correlates with heightened impulsivity, cognitive inflexibility, and emotional dysregulation, key factors contributing to suicidality.

• The anterior cingulate cortex (ACC) and amygdala exhibit hyperactivity and impaired connectivity, leading to exaggerated emotional responses and poor stress regulation.

• Additionally, alterations in the posterior cingulate cortex (PCC) and precuneus, components of the DMN, contribute to excessive rumination and self-referential thinking, further exacerbating suicidal ideation.

• These neurobiological findings provide a framework for understanding the pathophysiology of suicidality, guiding the development of targeted neuromodulation interventions.

• Most of the articles corresponded to Major Depressive Disorder (Unipolar): 65.7 % (44 articles), Bipolar Disorder: 4.5 % (3 articles) , Schizophrenia: 3.0 % (2 articles), Post-Traumatic Stress Disorder (PTSD): 1.5 % (1 articles), Neurocognitive Disorders: 4.5 % (3 articles) , Borderline Personality Disorder: 1.5 % (1 articles), others: 19.4 % (13 articles)

• Among emerging treatments, TMS has gained attention for its potential to modulate dysfunctional neural circuits implicated in suicide risk.

• High-frequency repetitive TMS applied to the left DLPFC has been shown to enhance cortical excitability and improve cognitive control, leading to significant reductions in suicidal ideation in treatment-resistant depression (TRD) patients.

• Intermittent theta-burst stimulation (iTBS), targeting the DLPFC, ventromedial prefrontal cortex (vmPFC), and frontal pole, provides rapid neuromodulatory effects and has demonstrated efficacy in adolescents and high-risk populations.

• Furthermore, bilateral stimulation of the DLPFC has been proposed to enhance interhemispheric connectivity and cognitive flexibility, offering an alternative for patients who do not respond to unilateral stimulation.

• Novel approaches, such as individual-targeted TMS (IT-TMS) directed at the subgenual ACC and high-dose TMS protocols delivering 54,000 pulses in 3 days, suggest further refinements in suicide-focused neuromodulation.

• Collectively, these findings underscore TMS as a promising intervention that directly targets prefrontal-limbic dysfunctions associated with suicidality, warranting further investigation into personalized stimulation protocols and long-term therapeutic outcomes.

Prefrontal Cortex (PFC)

• The prefrontal cortex (PFC) plays a crucial role in the neurobiological mechanisms underlying suicidal behavior.

• Structural neuroimaging studies consistently demonstrate a reduction in grey matter volume and cortical thickness within the PFC in individuals with a history of suicide attempts.

• Key subregions, including the left ventrolateral, orbitofrontal, and dorsolateral areas, are essential for executive processes, decision-making, and emotional regulation.

• Dysregulation of serotonergic neurotransmission in the PFC has been documented in suicide victims, with evidence of altered serotonin receptor function and elevated expression of tumor necrosis factor-alpha (TNF-α), highlighting a significant interaction between inflammatory processes and neurotransmitter systems in this region’s dysfunction.

• Postmortem findings indicate reduced serotonergic innervation and diminished serotonin transporter (SERT) binding in the PFC, which correlate with deficits in emotional control and decision-making, both of which are critical in preventing suicidal behavior.

• Significant reductions in grey matter volume and functional connectivity within PFC areas responsible for executive functions and emotional regulation have been reported.

• These structural and functional impairments are linked to increased impulsivity and compromised decision-making, frequently observed in suicide attempters.

• Elevated levels of pro-inflammatory cytokines, particularly TNF-α and interleukin-6 (IL-6), have been associated with PFC dysregulation in suicidal individuals.

• The presence of these inflammatory markers correlates with deficits in executive function, stress response, and decision-making capabilities, reinforcing the PFC’s involvement in the pathophysiology of suicidal behavior.

• Structural MRI studies consistently reveal reduced grey matter volume in the OFC of individuals with suicidality.

• This region is critically involved in regulating emotions and making adaptive decisions functions frequently compromised in those who experience suicidal ideation.

• Dysfunction of the OFC has been linked to increased emotional reactivity and impaired stress processing, underscoring its pivotal role in the pathophysiology of suicidal behaviors.

• Postmortem analyses further demonstrate elevated expression of proinflammatory cytokines, including interleukin-4 (IL-4), IL-13, IL-6, and IL-1β, in the OFC of suicide victims.

• These findings suggest that the OFC, a key region for executive function and emotional control, is a principal site for neuroinflammatory processes contributing to suicidal behavior.

• Individuals with a history of suicide attempts display increased cortical volume in the right lateral OFC, a region integral to decision-making, reward evaluation, and emotional regulation.

• Structural and functional abnormalities in this area may reflect disrupted neuronal circuits, contributing to heightened impulsivity and poor decision-making, both closely associated with suicidal tendencies.

• Suicidal ideators exhibit reduced grey matter volume and enhanced dynamic functional connectivity in the OFC.

• The posterior cingulate cortex (PCC) shows diminished functional connectivity, particularly in individuals with severe suicidal ideation, indicating impaired integration of cognitive and affective processes.

• Decreased connectivity between the right ACC and the OFC has been observed, correlating with deficits in emotional regulation.

• The DLPFC exhibits increased functional connectivity with the amygdala across all depressed individuals, including those with low and high suicidality as well as suicide attempters, when compared to healthy controls.

• This enhanced connectivity may represent a compensatory neural mechanism aimed at modulating emotional responses during self-referential tasks, such as self-face recognition.

• Moreover, reduced activation of the DLPFC has been observed in suicide attempters during the Tower of London task, a well-established assessment of executive planning ability.

• This diminished activation aligns with prior evidence associating the DLPFC with deficits in goal-directed behavior and decision-making.

• Such functional impairments in the DLPFC are likely to contribute to weakened executive control, increasing susceptibility to suicidal behavior.

• The calcarine fissure and dorsomedial prefrontal cortex (DMPFC) display distinct patterns of structural and functional alterations in individuals with a history of suicide attempts.

• Specifically, the calcarine fissure exhibits increased grey matter volume, potentially indicative of compensatory neuroplastic responses.

• Conversely, the DMPFC shows diminished connectivity, suggesting deficits in self-regulatory mechanisms and executive functioning.

• The left superior frontal gyrus, a region integral to self-awareness and sensory-motor integration, exhibits a reduced cortical surface area in individuals with a history of suicide attempts.

• This reduction may reflect compromised self-reflective capacities and a heightened tendency toward negative self-evaluation—both key contributors to the development and persistence of suicidal behavior.

Cingulate Cortex

• The ACC demonstrates significant structural and functional alterations in individuals with suicidal behavior, including an increased density of glial cells, which is closely linked to emotional dysregulation and impaired cognitive control.

• Functional neuroimaging studies emphasize the ACC’s critical role in processing psychological pain and mediating deficits in decision-making, both of which are central to the development of suicidality.

• Consistent findings indicate reductions in grey matter volume and disrupted functional connectivity within the ACC in suicidal individuals.

• Given its pivotal role in mediating emotional regulation and psychological pain, these abnormalities contribute to maladaptive cognitive-emotional interactions that increase the risk of suicidal behavior.

• Postmortem studies have identified microglial activation and elevated levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the ACC of depressed individuals who died by suicide.

• These observations suggest that chronic neuroinflammation within the ACC may interfere with essential processes of cognitive and emotional regulation, further exacerbating vulnerability to suicidality.

• The posterior cingulate cortex (PCC), a key node of the DMN, plays a fundamental role in self-referential thought, internally directed cognition, and the generation of negative affective states.

• Functional neuroimaging consistently shows that the PCC exhibits strong activation and connectivity during resting states, contrasting with its relative deactivation during tasks demanding external focus.

• These distinct functional properties highlight the PCC’s involvement in cognitive processes such as rumination, brooding, and suicidal ideation.

• The dorsal ACC displays altered connectivity with both the dorsal and ventral regions of the posterior cingulate cortex (PCC) in individuals with suicidal ideation, underscoring its role in the disrupted neural circuits of the DMN.

• Alterations in the OFC and cingulate cortex (CC) have been widely reported in individuals with suicidal ideation.

• Specifically, suicidal ideators exhibit reduced grey matter volume and heightened dynamic functional connectivity in these regions.

Parietal Cortex

• Functional connectivity between the amygdala and the inferior parietal lobule (IPL) is significantly elevated in all depressed groups compared to healthy controls, indicating enhanced integration of emotional and self-referential processes in individuals with depression and suicidal behaviors.

• Given the IPL’s role in attention modulation and self-awareness, this increased connectivity underscores its involvement in the disrupted neural circuits linked to suicidality.

• The left IPL shows a decreased cortical surface area in suicide attempters relative to clinical controls.

• As a critical node within the executive control network, the IPL is essential for regulating attention and processing self-concept.

• Its reduced surface area may reflect deficits in cognitive control and self-referential processing, both of which are fundamental for effective decision-making and maintaining emotional stability.

• Both the angular gyrus and postcentral gyrus exhibit notable structural and functional abnormalities in individuals with suicidal behavior.

• The angular gyrus displays reduced regional homogeneity in suicide attempters, reflecting impairments in attentional control and integrative processing.

• Similarly, the postcentral gyrus shows decreased structural connectivity, indicating deficits in sensory integration and motor planning, which may contribute to maladaptive cognitive and behavioral responses in those experiencing suicidal ideation.

Temporal and Insula Cortex

• The superior and middle temporal gyri exhibit significant structural and functional alterations in individuals with suicidal ideation and behaviors.

• Specifically, decreased grey matter volume and reduced regional homogeneity have been observed in these regions.

• These abnormalities are indicative of impairments in the processing of social and auditory information, both essential for generating adaptive emotional responses.

• The insular cortex, a critical component of the salience network, displays significant structural and functional disruptions in individuals with suicidal behavior.

• This region is central to amplifying neural responses to harmful stimuli and is deeply involved in processing both physical and psychological pain.

• Functional imaging studies have associated heightened insular activity with increased pain sensitivity, which may contribute to the intensification of suicidal ideation and behaviors.

• Given its pivotal role in emotional regulation and interoceptive awareness, the insular cortex is a key target for understanding and addressing the neural mechanisms underlying suicidality.

Occipital Cortex

• The lingual gyrus shows reduced grey matter volume in individuals with suicidal ideation, indicating disruptions in neural regions involved in visual and associative processing.

• Similarly, the precuneus, a key region in self-referential thought, displays decreased functional connectivity, with reductions correlating negatively with the severity of suicidal ideation.

• These findings suggest impairments in self-awareness and introspection in those experiencing suicidal ideation.

• In adolescents with high levels of suicidal ideation and those who have attempted suicide, increased amygdala connectivity with the precuneus and cuneus has been observed.

• This heightened connectivity suggests that self-referential stimuli, such as self-face recognition, are perceived as more salient and require increased cognitive effort in these groups.

• The precuneus and cuneus, regions crucial for integrating self-referential and emotional information, exhibit greater engagement, implying elevated neural resource demands during self-relevant tasks.

• The visual and motor cortices exhibit significant abnormalities in individuals with suicidal ideation and behaviors.

• Functional connectivity disruptions in the bilateral visual cortices have been associated with alterations in the salience and s, while reduced connectivity in the motor cortices indicates deficits in sensorimotor integration.

• These findings suggest that the neural disruptions observed in suicidal individuals extend beyond emotional regulation, involving broader sensory and motor networks critical for adaptive functioning.

Amygdala

• The amygdala, a central structure in emotional regulation and fear modulation, exhibits reduced serotonergic signaling in individuals who have died by suicide.

• Postmortem analyses indicate lower serotonin receptor density and impaired serotonergic neurotransmission in this region, which may contribute to increased emotional reactivity and dysregulated fear responses frequently observed in suicidality.

• Although the amygdala itself does not show significant differences in activation across groups, a positive correlation between fusiform gyrus activation and amygdala activity during emotional face processing highlights its critical role in modulating responses to social and emotional stimuli.

• This finding suggests interconnected dysfunction in emotional face processing among suicide attempters.

• Additionally, the amygdala demonstrates altered functional connectivity patterns, characterized by heightened connectivity with the bilateral caudate nucleus and the precuneus, reflecting hyperactivity within emotional networks in individuals with suicidal ideation.

• These abnormalities further underscore the amygdala’s role in the exaggerated emotional reactivity seen in suicidal individuals.

• Adolescents with high levels of suicidal ideation display increased functional connectivity between the right amygdala and the rostral ACC compared to those with lower levels of ideation and healthy controls.

• This enhanced connectivity is indicative of implicit emotional evaluation processes that differentiate high-suicidal-ideation groups from individuals who have attempted suicide.

• The lateralized function of the amygdala in processing emotional and self-referential information is particularly pronounced, with right amygdala connectivity playing a pivotal role in implicit emotional regulation.

• Moreover, as a key component of the prefrontal-limbic network, the amygdala shows increased right-side volumes and disrupted functional connectivity in individuals with suicidality.

• These structural and functional changes are linked to heightened emotional reactivity and impaired fear modulation, which contribute to exaggerated stress responses and emotional dysregulation, hallmarks of suicidal behavior.

• Increased functional connectivity between the left amygdala and the rostral DLPFC has been observed in depressed adolescents who have recently attempted suicide, in contrast to those with high or low levels of suicidal ideation and healthy controls.

• This heightened connectivity is specifically associated with explicit emotional evaluation, particularly during tasks involving self-face processing.

• These findings indicate that left amygdala connectivity with the rostral ACC may represent a potential biomarker for explicit emotion dysregulation in adolescents at elevated risk of suicide attempts.

Hippocampus

• Alterations in serotonergic projections from the median raphe nucleus to the hippocampus have been identified in individuals who died by suicide, potentially impairing the regulation of stress responses and memory processing.

• Given the hippocampus’s pivotal role in modulating stress-related behaviors, such disruptions may heighten susceptibility to suicidality by reducing the ability to adapt to stressful stimuli.

• Structural and functional abnormalities are also evident in both the thalamus and hippocampus of suicide attempters.

• The thalamus shows reduced grey matter volume and impaired connectivity, while the hippocampus demonstrates decreased volume compared to controls.

• These findings indicate widespread dysfunction in regions critical for sensory relay and memory consolidation, further contributing to the neurobiological underpinnings of suicidality.

Corpus Callosum

• Disruptions in white matter integrity, particularly within the corpus callosum and anterior thalamic radiation, point to significant connectivity impairments in individuals with suicidal ideation.

• Reduced fractional anisotropy in these regions indicates microstructural abnormalities affecting interhemispheric communication and thalamo-cortical pathways.

• These alterations suggest a broader neural network dysfunction, potentially underlying the cognitive and emotional disturbances characteristic of suicidal states.

Basal Ganglia

• A reduced volume of the right pallidum has been specifically linked to a history of suicide attempts in individuals with depression.

• Given the pallidum’s critical role in reward response, social behavior, and the regulation of positive affect, structural alterations in this region may exacerbate impulsivity and affective dysregulation, key characteristics in those at elevated risk for suicide.

• Similarly, volumetric increases in the striatum, including the caudate nucleus and putamen, have been observed in individuals who have engaged in violent suicide attempts.

• These changes are associated with impaired reward processing and heightened impulsivity, traits commonly noted in high-lethality suicidal behavior.

• The striatum’s involvement in motor control and cognitive functions further underscores its role in the neurobiological mechanisms of suicidality.

• The thalamus, a central hub for integrating subcortical and cortical signals, shows significantly reduced bilateral volumes in suicide attempters compared to both clinical and healthy controls.

• As the thalamus plays a key role in emotional regulation, planning, and decision-making, volumetric reductions in this region likely contribute to deficits in emotional and cognitive processes associated with suicidal behavior.

• In addition, both the thalamus and hippocampus exhibit notable structural and functional impairments in suicide attempters.

• Reduced grey matter volume and connectivity in the thalamus, combined with decreased hippocampal volume, reflect widespread disruptions in regions essential for memory consolidation and sensory relay.

• Furthermore, alterations in serotonergic projections from the median raphe nucleus to the hippocampus have been observed in individuals who have died by suicide.

• These changes may impair stress response and memory processing, as the hippocampus plays a pivotal role in managing stress-related behaviors.

• Disruptions in these pathways may increase susceptibility to suicidal behavior by reducing the individual’s capacity to adapt to stressful stimuli.

• These findings highlight widespread structural and functional abnormalities in key regions involved in emotional regulation, cognitive processing, and stress adaptation, underscoring their contribution to the neurobiological basis of suicidality.

Cerebellum, Fusiform Gyrus and Brainstem

• The cerebellum and fusiform gyrus have been implicated in the neurobiology of suicidal ideation and behavior.

• In individuals who have attempted suicide, the cerebellum exhibits reduced functional connectivity, suggesting potential deficits in motor coordination and cognitive processing.

• Conversely, the fusiform gyrus shows increased nodal efficiency, which may represent compensatory activity in regions responsible for visual and emotional processing.

• Despite its increased nodal efficiency, the fusiform gyrus demonstrates significantly lower activation during emotional face processing in suicide attempters, with this reduction extending into the lingual gyri.

• As the fusiform gyrus, particularly the fusiform face area, is essential for facial recognition and emotional evaluation, diminished activation in this region indicates potential impairments in the interpretation of emotional stimuli, distinguishing suicide attempters from ideators and non-suicidal individuals.

• The dorsal raphe nucleus, a primary source of serotonergic innervation to the forebrain, plays a key role in regulating serotonergic tone.

• Postmortem studies in individuals who died by suicide reveal an increased density and number of serotonergic neurons in the dorsal raphe nucleus, despite lower overall serotonin levels.

• This paradox suggests a compensatory mechanism aimed at preserving serotonergic neurotransmission in response to diminished serotonin availability.

• Additionally, the median raphe nucleus, which projects serotonergic fibers to both subcortical and cortical regions, including the hippocampus, shows elevated expression of tryptophan hydroxylase-2, a crucial enzyme in serotonin synthesis, in suicide victims.

• This finding reflects altered serotonergic production and underscores the median raphe nucleus’s significant role in the pathophysiology of suicidality.

• Together, these structural and functional abnormalities in key serotonergic nuclei, alongside disruptions in regions involved in emotional and cognitive processing, highlight the complex neurobiological mechanisms contributing to suicidal behaviors.

(DMN)

• Connectivity alterations within the Default Mode Network (DMN) exhibit distinct patterns in individuals with suicidality, particularly involving the posterior cingulate cortex (PCC), a key hub of the network.

• Suicide attempters show increased intra-network connectivity, whereas suicide ideators demonstrate reduced coherence between DMN regions.

• These connectivity disruptions are closely associated with impaired self-referential processing and heightened impulsivity, indicating that DMN dysregulation may underlie the maladaptive cognitive and emotional patterns observed in suicidality.

• The DMN comprises interconnected regions, including the PCC and medial prefrontal cortex, which maintain functional connectivity during resting states.

• This network has been implicated in rumination and cognitive processes related to suicidal ideation.

• Individuals with major depressive disorder frequently exhibit heightened DMN connectivity during rest, a phenomenon linked to increased rumination and negative affect.

• These findings suggest that abnormal DMN connectivity may represent a neurophysiological substrate for the maladaptive cognitive processes characteristic of mood disorders and suicidality, further emphasizing its role in the pathophysiology of these conditions.

• Genes associated with depression and suicidality play a critical role in the development and expression of these conditions, often through complex interactions with environmental factors.

• Among the key genes implicated is KCNJ2, which is involved in regulating stress responses and neural excitability.

• The AGT gene, a component of the renin-angiotensin system, has demonstrated associations with depressive symptoms and suicidal behavior.

• Furthermore, PMP2, which encodes a myelin protein, and VEZF1, involved in vascular regulation, contribute to structural and functional brain changes observed in suicidal individuals.

• Together, these genetic factors highlight the intricate neurobiological pathways contributing to the pathophysiology of suicidality.

Future Directions: Non-Invasive Neuromodulation TMS Treatment and Possible Networks in Suicide Behavior

• TMS has been explored as a potential treatment for reducing suicidal ideation, particularly in patients with major depressive disorder (MDD) and treatment-resistant depression (TRD).

• The DLPFC is a common target for TMS due to its role in cognitive control and emotion regulation.

Reduction in Suicidal Ideation:

• Several studies have shown that TMS targeting the DLPFC can significantly reduce suicidal ideation.

• High-frequency repetitive TMS at 10 Hz applied to the left DLPFC was the most commonly used protocol in the reviewed studies.

• This method showed significant efficacy in reducing suicidal ideation in both outpatient and inpatient settings, particularly in patients with major depressive disorder (MDD) and treatment-resistant depression (TRD).

• A study found that bilateral repetitive TMS was more effective than sham treatment in reducing suicidal ideation in TRD patients, with 40.4% of participants experiencing resolution of suicidal thoughts.

• Another study reported that both 10 Hz rTMS and iTBS were effective in reducing suicidality, with no significant difference between the two modalities.

Mechanisms of Action:

• The exact neural mechanisms by which TMS reduces suicidal ideation are not fully understood.

• Changes in frontostriatal functional connectivity have been correlated with reductions in suicidality following TMS.

• Additionally, TMS may influence brain perfusion and cognitive control processes which are critical for emotion regulation.

Accelerated TBS (aTBS):

• Accelerated TBS, which involves multiple sessions of TMS daily, has shown promise in rapidly reducing suicidal ideation.

• In a study with suicidal therapy-resistant depressed patients, accelerated intermittent TBS (aiTBS) applied to the left DLPFC significantly decreased suicidal ideation scores, although the efficacy compared to sham treatment needs further validation.

• Another trial in adolescents with MDD and suicidal ideation is investigating the efficacy of sequential bilateral aTBS.

Safety and Tolerability

• TMS, including accelerated protocols, has been found to be safe and well-tolerated in both adults and adolescents.

• Studies have reported no significant adverse effects, making it a viable option for patients who do not respond to traditional antidepressant treatments.

Bibliographic Findings

• The left DLPFC was consistently identified as the primary target region in most of the reviewed studies.

• This area plays a crucial role in executive functioning, emotional regulation, and cognitive control, which are often impaired in patients with depression and suicidality.

• High-frequency repetitive TMS applied to the left DLPFC has been extensively validated for major depressive disorder (MDD) and treatment-resistant depression (TRD), with substantial evidence indicating significant reductions in suicidal ideation.

• In several systematic reviews and meta-analyses, targeting the left DLPFC was shown to reduce both depressive symptoms and suicidal thoughts, emphasizing its therapeutic relevance.

• Expanding beyond the DLPFC, some novel approaches have investigated stimulation of the frontal pole and ventromedial prefrontal cortex (vmPFC), which are associated with impulse control and decision-making.

• A study targeting the frontal pole with iTBS aimed to enhance the connectivity between the limbic system and the prefrontal cortex, thereby reducing impulsive suicidal behaviors, particularly in high-risk veteran populations.

• In another innovative protocol, IT-TMS was used to stimulate the subgenual ACC through the DLPFC.

• This personalized approach was intended to enhance neuromodulation precision by addressing individual variations in brain network dysfunction.

• Bilateral stimulation protocols were discussed in several reports, especially for patients with severe TRD.

• Bilateral stimulation involves targeting both hemispheres of the prefrontal cortex, potentially yielding broader modulation of neural circuits implicated in mood and suicidality.

• This approach has shown promise in patients who do not respond to unilateral stimulation, suggesting that simultaneous engagement of both prefrontal hemispheres may produce superior clinical outcomes.

• Furthermore, systematic reviews have highlighted the potential of bilateral and multiple-region targeting protocols to improve not only emotional regulation but also cognitive flexibility.

• Finally, some studies focused on the frontostriatal network, which plays a critical role in mood regulation and impulsivity.

• A secondary analysis of clinical data revealed that reductions in suicidal ideation following eight weeks of 5 Hz rTMS were correlated with decreased frontostriatal connectivity.

• The integrity of frontostriatal white matter at baseline was found to predict the response to TMS, suggesting that frontostriatal modulation may be a key mechanism underlying the anti-suicidal effects of TMS.

Stimulation Protocols

High-frequency rTMS resulted in a 47 \% reduction in suicidal ideation Abdelnaim et al., 2020.

Intermittent Theta Burst Stimulation (iTBS)

iTBS was used for adolescents with treatment-resistant depression, observing notable improvements in suicidal ideation.

Low-Frequency rTMS at 5 Hz

Over an eight-week period, this protocol reduced suicidal ideation by decreasing frontostriatal functional connectivity, underscoring the