Cumulative adversity and smaller gray matter volume in medial prefrontal, anterior cingulate, and insula regions
Open accessAbstract
Background Cumulative adversity and stress are associated with risk of psychiatric disorders. While basic science studies show repeated and chronic stress effects on prefrontal and limbic neurons, human studies examining cumulative stress and effects on brain morphology are rare. Thus, we assessed whether cumulative adversity is associated with differences in gray matter volume, particularly in regions regulating emotion, self-control, and top-down processing in a community sample.Methods One hundred three healthy community participants, aged 18 to 48 and 68% male, completed interview assessment of cumulative adversity and a structural magnetic resonance imaging protocol. Whole-brain voxel-based-morphometry analysis was performed adjusting for age, gender, and total intracranial volume.Results Cumulative adversity was associated with smaller volume in medial prefrontal cortex (PFC), insular cortex, and subgenual anterior cingulate regions (familywise error corrected, p < .001). Recent stressful life events were associated with smaller volume in two clusters: the medial PFC and the right insula. Life trauma was associated with smaller volume in the medial PFC, anterior cingulate, and subgenual regions. The interaction of greater subjective chronic stress and greater cumulative life events was associated with smaller volume in the orbitofrontal cortex, insula, and anterior and subgenual cingulate regions.Conclusions Current results demonstrate that increasing cumulative exposure to adverse life events is associated with smaller gray matter volume in key prefrontal and limbic regions involved in stress, emotion and reward regulation, and impulse control. These differences found in community participants may serve to mediate vulnerability to depression, addiction, and other stress-related psychopathology.
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Despite limitations of retrospective measures, studies relying on retrospective reports of cumulative life stress have shown that lifetime stressor exposure negatively affects health-related processes and outcomes, including autonomic nervous system activity, systemic inflammatory activity, brain structure and function, rates of alcohol use, and physical and mental health status.
“Despite the limitations of retrospective measures of historical life stress exposure, studies relying on retrospective reports of cumulative life stress have been illuminating in showing that lifetime stressor exposure negatively affects health-related processes and outcomes, including autonomic nervous system activity (Lampert et al., 2016), systemic inflammatory activity (O’Donovan et al., 2012a”
From More than a feeling: A unified view of stress measurement for population science (2018) · cites this paper as Ansell et al., 2012
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredHigher cumulative adversity has been associated with reduced gray matter in several areas within the prefrontal cortex, including the mPFC, anterior cingulate, and insula.
“Higher cumulative adversity has been associated with reduced gray matter in the several areas within the prefrontal cortex, including the mPFC, anterior cingulate, and insula (Ansell et al., 2012).”
From More than a feeling: A unified view of stress measurement for population science (2018) · cites this paper as Ansell et al., 2012
The Abstract Results report that cumulative adversity was associated with smaller gray matter volume in the medial prefrontal cortex, insular cortex, and subgenual anterior cingulate. The claim’s association and named regions are supported, but the paper does not place all three regions within the prefrontal cortex; it describes them as prefrontal and limbic regions. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn humans, chronic stress exposure is associated with reduced gray matter volume in dlPFC and mPFC and spine loss from the orbital PFC.
“In humans, chronic stress exposure is associated with reduced gray matter volume in dlPFC,26 and mPFC27 and spine loss from the orbital PFC.28”
From Chronic Stress Weakens Connectivity in the Prefrontal Cortex: Architectural and Molecular Changes. (2021) · cites this paper as [27]
Citation 27 is attached to the mPFC gray-matter-volume finding, not the dlPFC or orbital-PFC spine-loss claims. The Discussion reports smaller medial prefrontal volume with greater cumulative adversity, but also states that chronic stress alone was not independently associated with structural changes; the association involving chronic stress was an interaction with cumulative adverse events. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe loss of PFC gray matter with chronic stress has also been documented in humans.
“The loss of PFC gray matter with chronic stress has also been documented in humans.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [79]
The Discussion (page not specified in our copy) reports smaller prefrontal gray matter volume in humans with greater cumulative adversity, and smaller orbitofrontal volume when adversity was accompanied by greater chronic stress. It also says chronic stress alone was not independently associated with structural changes. The study documents associations, not a measured loss of PFC gray matter over time caused by chronic stress. (LLM, conf=0.86)
Experimental — accuracy not yet measuredStructural imaging has shown that lower PFC gray matter volume correlates with exposure to adverse events.
“Structural imaging has shown that lower PFC gray matter volume correlates with exposure to adverse events79.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [79]
A community sample of individuals signed written informed consent for research approved by the Yale Institutional Review Board and was carefully assessed for high and low stress using a structured cumulative stress and adversity interview.
“A community sample of individuals signed written informed consent for research approved by the Yale Institutional Review Board and was carefully assessed for high and low stress using a structured cumulative stress and adversity interview that assessed recent and past life events (Cumulative Adversity Interview (CAI), (Ansell et al., 2012; Seo et al., 2014; Turner and Lloyd, 1995)).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Ansell et al., 2012
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Self-citationChronic Stress Weakens Connectivity in the Prefrontal Cortex: Architectural and Molecular Changes.
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Cumulative adversity sensitizes neural response to acute stress: association with health symptoms
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Self-citationAssociation of allostatic load with brain structure and cognitive ability in later life
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- Authors
- Ansell, E. B., Rando, K., Tuit, K., Guarnaccia, J., & Sinha, R.
- Affiliations
- Yale University (US)
- Corresponding author
- Sinha, Rajita
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 72
- Issue
- 1
- Pages
- 57-64
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3391585
- OpenAlex
- W2001565222
- Cited by
- 354
- References
- 76
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 26 · 2023: 29 · 2022: 25 · 2021: 28 · 2020: 29 · 2019: 21 · 2018: 50 · 2017: 20 · 2016: 23 · 2015: 20 · 2014: 28 · 2013: 19 · 2012: 7
- FWCI
- 9.82
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01-AA013892, P50-DA016556, UL1-DE019586, PL1-DA024859, K08-DA029641)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- cumulative adversity, gray matter volume, medial prefrontal cortex, anterior cingulate cortex, insula, chronic stress, life events, orbitofrontal cortex, brain structure, depression vulnerability, impulse control, emotion regulation
- MeSH terms
- Adolescent, Adult, Brain, Brain Mapping, Cerebral Cortex, Cognition, Emotions, Female, Humans, Internal-External Control, Interview, Psychological, Magnetic Resonance Imaging, Male, Middle Aged, Organ Size, Stress, Psychological, Prefrontal Cortex, Young Adult
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