Multimodal neuroimaging of frontolimbic structure and function associated with suicide attempts in adolescents and young adults with bipolar disorder
Open accessAbstract
OBJECTIVE: Bipolar disorder is associated with high risk for suicidal behavior that often develops in adolescence and young adulthood. Elucidation of involved neural systems is critical for prevention. This study of adolescents and young adults with bipolar disorder with and without a history of suicide attempts combines structural, diffusion tensor, and functional MR imaging methods to investigate implicated abnormalities in the morphology and structural and functional connectivity within frontolimbic systems. METHOD: The study had 26 participants with bipolar disorder who had a prior suicide attempt (the attempter group) and 42 participants with bipolar disorder without a suicide attempt (the nonattempter group). Regional gray matter volume, white matter integrity, and functional connectivity during processing of emotional stimuli were compared between groups, and differences were explored for relationships between imaging modalities and associations with suicide-related symptoms and behaviors. RESULTS: Compared with the nonattempter group, the attempter group showed significant reductions in gray matter volume in the orbitofrontal cortex, hippocampus, and cerebellum; white matter integrity in the uncinate fasciculus, ventral frontal, and right cerebellum regions; and amygdala functional connectivity to the left ventral and right rostral prefrontal cortex. In exploratory analyses, among attempters, there was a significant negative correlation between right rostral prefrontal connectivity and suicidal ideation and between left ventral prefrontal connectivity and attempt lethality. CONCLUSIONS: Adolescent and young adult suicide attempters with bipolar disorder demonstrate less gray matter volume and decreased structural and functional connectivity in a ventral frontolimbic neural system subserving emotion regulation. Among attempters, reductions in amygdala-prefrontal functional connectivity may be associated with severity of suicidal ideation and attempt lethality.
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Reduced gray matter volume in the orbitofrontal cortex, anterior cingulate cortex, hippocampus, and amygdala has been linked to suicidal ideation and attempts.
“Reduced gray matter volume in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), hippocampus, and amygdala has been linked to suicidal ideation and attempts (12, 13).”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [12]
The Results (Group Differences Within Imaging Modalities; page unavailable) report lower gray matter volume in the orbitofrontal cortex and hippocampus of adolescent and young adult bipolar-disorder suicide attempters. They do not report a corresponding anterior cingulate finding; the Discussion explicitly says amygdala volume did not differ between groups. The association with suicidal ideation concerned functional connectivity, not gray matter volume. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSuicidal youth often exhibit subtle but significant structural MRI alterations in regions responsible for emotional regulation and executive functioning.
“Structural MRI studies suggest that suicidal youth often exhibit subtle but significant alterations in regions responsible for emotional regulation and executive functioning.”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [12]
The Results (page unavailable) report significant structural MRI differences in the orbitofrontal cortex and hippocampus among adolescent and young-adult suicide attempters with bipolar disorder, compared with non-attempters. The Discussion links the affected frontolimbic system to emotion regulation. The claim extends these findings to suicidal youth generally and to regions responsible for executive functioning, neither of which this study establishes. (LLM, conf=0.85)
Experimental — accuracy not yet measuredReduced serotonergic tone, compounded by diminished BDNF-TrkB signaling, compromises plasticity in the frontolimbic circuits whose alterations are the most reproducible neuroimaging finding in suicidal youth.
“Reduced serotonergic tone, compounded by diminished BDNF–TrkB signaling, then compromises plasticity in the frontolimbic circuits whose alterations are the most reproducible neuroimaging finding in suicidal youth (11–13, 28).”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [12]
The Conclusions and Discussion report frontolimbic structural and functional alterations in adolescent and young-adult suicide attempters with bipolar disorder. The Introduction says imaging evidence in youth is scant, so the paper does not establish that these are the most reproducible findings across suicidal youth. It also does not show that reduced serotonergic tone and BDNF–TrkB signaling compromise frontolimbic plasticity. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCompared with nonsuicidal controls, youths with a history of suicidal behavior had decreased gray matter volumes in the hippocampus and cerebellum and decreased amygdala-prefrontal functional connectivity when viewing emotional faces.
“compared with nonsuicidal controls, youths with a history of suicidal behavior had decreased gray matter volumes in the hippocampus and cerebellum and decreased functional connectivity between the amygdala and the left ventral and right rostral PFC when viewing emotional faces (Johnston et al. 2017)”
From Adolescent Suicide as a Failure of Acute Stress-Response Systems. (2019) · cites this paper as Johnston et al. 2017
Structural MRI evidence indicates reduced ventral prefrontal and orbitofrontal cortex volume in youth reporting STB.
“Structural MRI research suggests reduced volume in the ventral prefrontal and orbitofrontal cortices among youth reporting STB”
From Neural correlates associated with suicide and nonsuicidal self-injury in youth (2021) · cites this paper as [53]
Among adolescents with MDD and BD, suicide attempters show reduced VPFC and OFC gray matter volume relative to non-attempters.
“Among adolescents with MDD and BD (53, 54), suicide attempters show reduced VPFC and OFC GMV relative to MDD and BD non-attempters, respectively.”
From Neural correlates associated with suicide and nonsuicidal self-injury in youth (2021) · cites this paper as [53]
PFC findings are complicated by inconsistent laterality effects.
“Studies on PFC differences, however, are complicated by inconsistent laterality effects (left (54, 55) versus right (53)).”
From Neural correlates associated with suicide and nonsuicidal self-injury in youth (2021) · cites this paper as [53]
BD suicide attempters have reduced hippocampal and bilateral cerebellum gray matter volume compared to BD non-attempters.
“Outside of the PFC, BD suicide attempters have reduced hippocampal (53, 54) and bilateral cerebellum (53) GMV compared to BD non-attempters.”
From Neural correlates associated with suicide and nonsuicidal self-injury in youth (2021) · cites this paper as [53]
Within the attempter group, suicidal ideation negatively correlates with amygdala-right rostral PFC connectivity, and attempt lethality negatively correlates with amygdala-left VPFC connectivity.
“Within the attempter group, suicidal ideation negatively correlates with amygdala-right rostral PFC connectivity, and attempt lethality negatively correlates with amygdala-left VPFC connectivity (53).”
From Neural correlates associated with suicide and nonsuicidal self-injury in youth (2021) · cites this paper as [53]
During a gender-judgement emotional face task, BD attempters exhibit reduced bilateral amygdala connectivity to left VPFC across happy and neutral conditions and to right rostral PFC for neutral faces versus baseline.
“During a gender-judgement emotional face task, BD attempters exhibit reduced bilateral amygdala connectivity to the left VPFC (across happy and neutral conditions) and to the right rostral PFC for neutral faces versus baseline.”
From Neural correlates associated with suicide and nonsuicidal self-injury in youth (2021) · cites this paper as [53]
Youth STB research is characterized by alterations within prefrontal and limbic systems, where a compromised regulatory system may potentiate suicidal thinking, and perturbations in top-down and bottom-up connections may lead to suicidal behaviors.
“Consistent with Schmaal and colleagues (32), youth STB research is characterized by alterations within prefrontal (53–55) and limbic (62, 75, 102, 103) systems whereby a compromised regulatory system may potentiate suicidal thinking, and perturbations in top-down and bottom-up connections may lead to suicidal behaviors.”
From Neural correlates associated with suicide and nonsuicidal self-injury in youth (2021) · cites this paper as [53]
In mood disorders, a prior suicide attempt is associated with lower fractional anisotropy in frontal-subcortical connections.
“In mood disorders, a prior suicide attempt is associated with lower FA in frontal-subcortical connections (76-79).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [78]
Suicide attempters have less OFC and rACC activity in response to positive facial expressions and greater lateral OFC activity in response to angry facial expressions.
“Suicide attempters also have less OFC and rACC activity in response to positive facial expressions (78) and greater lateral OFC activity in response to angry facial expressions (95, 97, 104).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [78]
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Reduced lateral orbitofrontal cortex volume and suicide behavior in youth with bipolar disorder
Huber, R. S., Subramaniam, P., Kondo, D. G., Shi, X., Renshaw, P. F., & Yurgelun‐Todd, D. A. (2019) · Bipolar Disorders · doi:10.1111/bdi.12729 · Cited by 46 · see citing works
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Lippard, E. T. C., Johnston, J. A. Y., Spencer, L., Quatrano, S., Fan, S., Sankar, A., Weathers, J., Pittman, B., Oquendo, M. A., & Blumberg, H. P. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.11.097 · Cited by 44 · see citing works
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Gray matter volumetric study of major depression and suicidal behavior
Rizk, M. M., Rubin-Falcone, H., Lin, X., Keilp, J. G., Miller, J. M., Milak, M. S., Sublette, M. E., Oquendo, M. A., Ogden, R. T., Abdelfadeel, N. A., et al. (2019) · Psychiatry Research: Neuroimaging · doi:10.1016/j.pscychresns.2018.11.007 · Cited by 35 · see citing works
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- Authors
- Johnston, J. A. Y., Wang, F., Liu, J., Blond, B. N., Wallace, A., Liu, J., Spencer, L., Cox Lippard, E. T., Purves, K. L., Landeros-Weisenberger, A., Hermes, E., Pittman, B., Zhang, S., King, R., Martin, A., Oquendo, M. A., & Blumberg, H. P.
- Affiliations
- Columbia University Irving Medical Center (US)
- From the Department of Psychiatry and the Child Study Center, Yale School of Medicine, New Haven, Conn.; the Division of Psychology and Language Sciences, University College London; and the Department of Psychiatry, Columbia University Medical Center, New York.
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2017-07-01
- Volume
- 174
- Issue
- 7
- Pages
- 667-675
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC5939580
- OpenAlex
- W2584711339
- Cited by
- 247
- References
- 48
- Citations by year
- 2026: 21 · 2025: 28 · 2024: 18 · 2023: 21 · 2022: 27 · 2021: 33 · 2020: 30 · 2019: 24 · 2018: 37 · 2017: 8
- FWCI
- 22.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Brain and Behavior Research Foundation
- American Foundation for Suicide Prevention
- Bristol-Myers Squibb
- Yale University
- American Academy of Child and Adolescent Psychiatry
- National Institute of Mental Health (RC1MH088366, R01MH069747, R01MH070902, T32MH014276)
- National Institute on Drug Abuse (K25DA040032, DA040032, T32DA022975)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
- Social Sciences › Psychology › Clinical Psychology › Psychopathy, Forensic Psychiatry, Sexual Offending
- Keywords
- bipolar disorder, suicide attempts, adolescents, young adults, gray matter volume, white matter integrity, uncinate fasciculus, orbitofrontal cortex, hippocampus, cerebellum, ventral prefrontal cortex, rostral prefrontal cortex, suicidal ideation, emotion regulation, suicide prevention
- MeSH terms
- Adolescent, Amygdala, Bipolar Disorder, Cerebellum, Dominance, Cerebral, Frontal Lobe, Hippocampus, Humans, Limbic System, Magnetic Resonance Imaging, Nerve Net, Statistics as Topic, Suicide, Attempted, Risk Assessment, Diffusion Magnetic Resonance Imaging, Young Adult, Suicidal Ideation, White Matter, Gray Matter
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