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Cited by 286Child Abuse and TraumaStress Responses and CortisolTryptophan and brain disorders

Hidden wounds? inflammatory links between childhood trauma and psychopathology

Open access
Danese, Andrea, Baldwin, Jessie R.·2017·Annual Review of Psychology
DOI 10.1146/annurev-psych-010416-044208
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Abstract

Childhood trauma is a key risk factor for psychopathology. However, little is known about how exposure to childhood trauma is translated into biological risk for psychopathology. Observational human studies and experimental animal models suggest that childhood exposure to stress can trigger an enduring systemic inflammatory response not unlike the bodily response to physical injury. In turn, these “hidden wounds” of childhood trauma can affect brain development, key behavioral domains (e.g., cognition, positive valence systems, negative valence systems), reactivity to subsequent stressors, and, ultimately, risk for psychopathology. Further research is needed to better characterize the inflammatory links between childhood trauma and psychopathology. Detecting and healing these hidden wounds may help prevent and treat psychopathology emerging after childhood trauma.

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Crossref · 10.1146/annurev-psych-010416-044208

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  • Findingcitation

    In the Dunedin cohort, cumulative childhood maltreatment exposure was associated with significant and graded elevation in inflammation levels at the age-32 follow-up.

    “We found that cumulative exposure to childhood maltreatment was associated with significant and graded elevation in inflammation levels at the age-32 follow-up (Danese et al. 2007).”
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  • Findingcitation

    The Dunedin association between childhood maltreatment and elevated inflammation at age 32 was not specific to one inflammation measure but held across all available biomarkers, including CRP, fibrinogen, and white blood cell count.

    “The association was not sensitive to the particular measure of inflammation used but rather generalized to all inflammation biomarkers available, including CRP, fibrinogen, and white blood cell count, and was independent of key potential confounders, such as low birth weight, disadvantaged socioeconomic conditions of the family, and low IQ.”
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  • Findingcitation

    The Dunedin association between childhood maltreatment and elevated inflammation at age 32 was independent of key confounders such as low birth weight, family socioeconomic disadvantage, and low IQ.

    “The association was not sensitive to the particular measure of inflammation used but rather generalized to all inflammation biomarkers available, including CRP, fibrinogen, and white blood cell count, and was independent of key potential confounders, such as low birth weight, disadvantaged socioeconomic conditions of the family, and low IQ.”
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  • Findingcitation

    In the E-Risk cohort, 12-year-old maltreated children who developed depression by age 12 had elevated inflammation levels (CRP measured in dried blood spots) compared with controls.

    “We found that inflammation levels (derived by measuring CRP in dried blood spots) were elevated in maltreated children who developed depression by age 12 compared to controls (Danese et al. 2011).”
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  • Findingcitation

    The Dunedin association between childhood maltreatment and elevated inflammation at age 32 was not explained by obvious mediators such as adult stressors, poor adult health, unhealthy behaviors, or acute infections at the time of assessment.

    “Furthermore, the association was not explained by obvious mediators, such as adult stressors, poor adult health, and unhealthy behaviors, or acute infections at the time of inflammation assessment.”
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    Interpretationreasoning

    The inflammatory effects of childhood trauma can influence brain development, behavioral domains, stress reactivity, and psychopathology risk.

    “In turn, these “hidden wounds” of childhood trauma can affect brain development, key behavioral domains (e.g., cognition, positive valence systems, negative valence systems), reactivity to subsequent stressors, and, ultimately, risk for psychopathology.”
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    Premisecitation

    People with a history of childhood maltreatment have elevated lifetime risk of major depression, earlier onset, and greater comorbidity.

    “For example, individuals with a history of childhood maltreatment have high lifetime risk of major depression, as well as an earlier age of onset and greater comorbidity (Brown & Harris 1978, Kessler et al. 1997).”
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    Interpretationreasoning

    Childhood psychological trauma may alter innate immune development and produce a chronically activated, hyperreactive inflammatory response from childhood into adulthood.

    “In particular, we discuss how childhood psychological trauma could affect the development of the innate immune system and thus induce a chronically activated and hyperreactive inflammatory response starting in childhood and persisting into adult life.”
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    Premisecitation

    Childhood maltreatment predicts both high incidence and poor longitudinal course of several psychiatric disorders.

    “Childhood maltreatment predicts both high incidence and poor longitudinal course of several psychiatric disorders.”
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    • cites Brown & Harris 1978

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    • cites Kessler et al. 1997

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    Premisecitation

    Psychological trauma can trigger biological responses similar to physical trauma, including innate immune activation.

    “Psychological trauma can trigger similar biological responses as physical trauma (Molina 2005), including the activation of the innate immune system.”
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    Premisecitation

    Among bipolar patients, childhood maltreatment predicts worse course and clinical features including greater symptom severity, more comorbidity, earlier onset, rapid cycling, more episodes, and higher suicide attempt risk.

    “A history of childhood maltreatment is also highly prevalent in patients with bipolar disorder and, among bipolar patients, predicts unfavorable course of illness and clinical features such as greater severity of manic, depressive, and psychotic symptoms; higher risk of comorbid anxiety disorders and of substance or alcohol use disorders; earlier age of onset; higher risk of rapid cycling; greater”
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    Premisecitation

    Childhood maltreatment is thought to relate to a more complex PTSD presentation with emotional dysregulation, poor self-concept, and disturbed relationships.

    “and is thought to be related to more complex presentation among patients with PTSD, with symptoms including emotional dysregulation, poor self-concept, and disturbed relationships (complex PTSD) (Maercker et al. 2013).”
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    Correlated risk factors are alternative explanations for the childhood trauma-psychopathology link and must be ruled out before causal inference.

    “These correlated risk factors represent alternative explanations for the link between childhood trauma and later psychopathology and need to be ruled out before inference of causal effects can be drawn (Duncan et al. 2004).”
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    Premisecitation

    Animals exposed to early-life stress show attenuated sucrose preference and attenuated behavioral responses to cocaine or amphetamine.

    “Consistent with these findings in humans, animals experimentally exposed to early-life stress showed attenuated sucrose preference and attenuated behavioral responses (self-administration) to powerful artificial reinforcers, such as intravenous cocaine or intra-accumbens amphetamine (Matthews & Robbins 2003, Phillips et al. 1994, Pryce et al. 2004).”
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    Premisecitation

    People with a history of childhood maltreatment may be less sensitive to reward, with blunted subjective responses to reward cues and blunted basal ganglia activation during reward anticipation.

    “Human studies showed that individuals with a history of childhood maltreatment may be less sensitive to reward, as indicated by blunted subjective responses to reward-predicting cues and blunted activation in the basal ganglia during reward anticipation (Dillon et al. 2009, Guyer et al. 2006, Mehta et al. 2010).”
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    Premisecitation

    People with a history of childhood maltreatment have lower IQ and poorer declarative memory and executive function than those without.

    “Individuals with a history of childhood maltreatment have lower IQ and poorer declarative memory and executive function than individuals with no history of childhood maltreatment (Pechtel & Pizzagalli 2011).”
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    Compared with nonmaltreated individuals, those with maltreatment history have biased perceptual representations of emotions and overidentify threat signals such as angry faces.

    “Compared to nonmaltreated individuals, those with a history of maltreatment have biased perceptual representations of emotions and tend to overidentify threat signals, such as angry faces (Leppänen & Nelson 2009, Pollak & Kistler 2002).”
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    Adults reporting childhood maltreatment show high CSF CRH, greater ACTH and cortisol response to acute psychosocial stress, and greater ACTH and cortisol response to dexamethasone/CRH challenge.

    “Studies of adults reporting a history of maltreatment found consistent results, including evidence of high corticotrophin-releasing hormone (CRH) levels in the cerebrospinal fluid (Carpenter et al. 2004), greater adrenocorticotropic hormone (ACTH) and cortisol response to a laboratory-based acute psychosocial stress test (Heim et al. 2000), and greater ACTH and cortisol response to a”
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    Interpretationreasoning

    The two-way interaction between the HPA axis and inflammation suggests a need for more complex explanatory models for childhood trauma effects on brain and behavior.

    “The two-way interaction between the HPA axis and inflammation suggests the need for more complex explanatory models for the effects of childhood trauma on the brain and behavior.”
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    Interpretationcitation

    Inflammation could trigger HPA axis activation and glucocorticoid resistance, potentially being the original trigger for neuroendocrine abnormalities.

    “On the other hand, inflammation could trigger HPA axis activation (Besedovsky et al. 1986) and induce glucocorticoid resistance (Barnes & Adcock 2009), thereby potentially acting as the original trigger for neuroendocrine abnormalities.”
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    Interpretationcitation

    Maltreated individuals have elevated baseline cortisol and heightened cortisol reactivity to new stressors.

    “These human studies highlight that maltreated individuals have elevated baseline cortisol levels and heightened cortisol reactivity in the context of new stressors.”
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    Premisecitation

    High cortisol levels are associated with hippocampal and prefrontal cortex shrinkage and amygdala hypertrophy and hypermetabolism.

    “In particular, high levels of cortisol have been associated with shrinkage of the hippocampus and the prefrontal cortex and with hypertrophy and hypermetabolism of the amygdala.”
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    Premisecitation

    PTSD patients have moderate to large elevation in several proinflammatory cytokines; this is not explained by comorbid depression and relates to illness duration.

    “Metaanalytical studies show that PTSD patients have a moderate to large elevation in levels of several proinflammatory cytokines, that these associations are not explained by comorbid depression, and that inflammation is related to illness duration (Passos et al. 2015).”
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    Premisecitation

    High inflammation predicts incident depression, poor treatment response, and recurrent course.

    “Notably, high inflammation predicts not only the risk of incident depression but also of poor response to treatment (Strawbridge et al. 2015) and an unfavorable course of illness characterized by recurrent episodes (Ford & Erlinger 2004).”
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    Interpretationreasoning

    Bipolar disorder is increasingly seen as a multisystem inflammatory disease in which inflammation contributes to onset and progression.

    “On the basis of these findings, bipolar disorder is increasingly seen as a multisystem inflammatory disease (Leboyer et al. 2012) in which inflammation contributes to the onset of illness as well as its progression (Berk et al. 2011).”
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    Case-control studies focused on single diagnoses are unsuitable for evaluating direction of effects or comprehensively assessing confounders.

    “Furthermore, this design is unsuitable for the evaluation of the direction of effects or for the comprehensive assessment of potential confounding factors.”
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    Premisecitation

    Pharmacological experiments manipulating inflammatory state reproduce sickness behavior in animal models, with decreased motor activity, social withdrawal, reduced food and water intake, increased slow-wave sleep, and altered cognition.

    “These experiments reproduced sickness behavior in animal models, with symptoms including decreased motor activity (fatigue), social withdrawal, reduced food and water intake, increased slow-wave sleep, and altered cognition (Dantzer et al. 2008).”
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    Sickness behavior after LPS is buffered by IL-10 and exacerbated in IL-10-deficient mice.

    “Furthermore, consistent with the role of inflammation in these phenomena, the expression of sickness behavior after LPS stimulation was buffered by administration of the anti-inflammatory cytokine IL-10 and exacerbated in IL-10-deficient mice (Dantzer et al. 2008).”
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    Sickness behavior is an organized, evolved behavioral strategy that facilitates fever's role in combating infections.

    “This sickness behavior was recognized as an organized, evolved behavioral strategy to facilitate the role of fever in combating viral and bacterial infections.”
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    The brain has an active immune system contributing to pathogen surveillance and tissue remodeling.

    “The brain has an active immune system that contributes both to surveillance against pathogens and to tissue remodeling.”
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    Premisecitation

    Peripheral LPS, typhoid vaccine, and IFN-α reduce ventral striatum responses to reward.

    “With regard to positive valence systems, peripheral administration of LPS (and also of typhoid vaccine and IFN-α) reduces ventral striatum responses to reward (Capuron et al. 2012, Eisenberger et al. 2010).”
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    Microglia are myeloid-origin macrophage-like cells that populate the brain parenchyma early in embryonic development and then renew themselves locally.

    “Microglia are macrophage-like cells of myeloid hematopoietic origin that colonize the brain parenchyma during early embryonic development and self-renew locally thereafter (Hanisch & Kettenmann 2007).”
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    In rodents, peripheral LPS administration causes brain proinflammatory cytokine expression, microglial activation, and reduced adult neurogenesis.

    “For example, peripheral administration of LPS in rodents induces the expression of proinflammatory cytokines in the brain (Breder et al. 1994), the activation of microglia (Monje et al. 2003), and the inhibition of adult neurogenesis (Monje et al. 2003).”
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    Adult neurogenesis is inhibited by inflammatory mediators during systemic immune activation and can be enhanced by autoreactive T cells.

    “This process can be significantly inhibited by inflammatory mediators in the context of systemic immune activation (Ekdahl et al. 2003, Monje et al. 2003) and can be potentiated by autoreactive T cells (Ziv et al. 2006).”
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    Premisecitation

    Early-life immune stimulation with LPS in rodents is associated with elevated CRH, stronger ACTH and corticosterone responses to restraint stress, reduced negative feedback sensitivity to glucocorticoids, and lower glucocorticoid receptor density across the adult brain.

    “Research in rodents has shown that early-life immune stimulation with LPS was associated with elevated levels of CRH, greater ACTH and corticosterone responses to restraint stress, decreased negative feedback sensitivity to glucocorticoids, and a reduction in glucocorticoid receptor density across the brain in adult animals (Shanks et al. 1995(Shanks et al. , 2000)).”
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    Primed microglia, compared with naive microglia in rodents, produce more proinflammatory cytokines, cause greater neurotoxicity, and show exaggerated fever and sickness behavior after subsequent inflammatory stimulation.

    “Compared to rodents with naïve microglia, rodents with primed microglia show heightened production of proinflammatory cytokines in the brain, increased neurotoxicity, and exaggerated fever and sickness behavior in response to subsequent inflammatory stimulation (Perry & Holmes 2014).”
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    Typhoid vaccine reduces sACC-amygdala connectivity and increases sACC activity during emotional face processing.

    “With regard to negative valence systems, peripheral administration of LPS potentiates amygdala activity in response to socially threatening stimuli (fear faces) (Inagaki et al. 2012), and typhoid vaccine reduces the connectivity of the sACC to the amygdala and increases the activity within the sACC during emotional face processing (Harrison et al. 2009).”
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    Depressed individuals with a history of childhood maltreatment show both elevated unstimulated inflammation and greater inflammatory responses to acute psychosocial stress compared with controls.

    “Finally, depressed individuals with a history of childhood maltreatment show both elevated unstimulated inflammation levels (Danese et al. 2008) and greater inflammatory responses to acute psychosocial stress (Pace et al. 2006) compared to controls.”
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    Premisecitation

    Individuals with a history of childhood maltreatment show both elevated unstimulated inflammation and greater proinflammatory responses to subsequent stressors.

    “Individuals with a history of childhood maltreatment show not only elevated levels of unstimulated inflammation but also greater proinflammatory responses in the context of subsequent stressors.”
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    Premisecitation

    Early-life stress is linked to markers of neuroinflammation in animal models, with initial findings suggesting significant and potentially sexually dimorphic effects.

    “In addition to elevation in peripheral inflammatory biomarkers, early-life stress has also been linked to markers of neuroinflammation.”
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    In rodents, maternal separation leads to an inflammation-mediated rise in core temperature and an increase in plasma proinflammatory cytokines.

    “In rodents, maternal separation led to an inflammation-mediated increase in core temperature (Hennessy et al. 2010b) and to an increase in proinflammatory cytokines in the plasma (Wieck et al. 2013).”
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    In nonhuman primates, maternal separation causes an immediate and prolonged increase in macrophage activity, and peer-rearing causes long-term upregulation of proinflammatory gene transcription in monocytes.

    “In nonhuman primates, maternal separation led to an immediate and prolonged increase in macrophage activity (Coe et al. 1988) and peer-rearing induced long-term upregulation in proinflammatory gene transcription in monocytes (Cole et al. 2012).”
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    Premisecitation

    Childhood trauma is indirectly linked to dysregulated innate immunity through primary neuroendocrine abnormalities, including chronic HPA axis activation that induces epigenetic changes in the glucocorticoid receptor and resistance to cortisol's anti-inflammatory effects.

    “First, the more traditional view is that childhood trauma is indirectly linked to dysregulated innate immunity because of primary neuroendocrine abnormalities.”
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    Rodents exposed to maternal separation show a greater rise in core temperature upon a second separation, greater cytokine expression after subsequent viral infection, and greater cortical microglial activation after later chronic food-restriction stress.

    “In particular, rodents exposed to maternal separation showed a greater increase in core temperature upon a second separation (Hennessy et al. 2010b), greater cytokine expression in response to subsequent viral infection (Avitsur et al. 2006), and greater cortical microglial activation following subsequent exposure to chronic food-restriction stress (Brenhouse & Thompson 2015).”
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    Maternal separation is associated with greater hippocampal expression of proinflammatory cytokine receptors, greater number and motility of cortical microglial processes, and greater microglial activation.

    “Furthermore, maternal separation is associated with greater hippocampal expression of receptors for proinflammatory cytokines (Viviani et al. 2014), greater number and motility of cortical microglial processes (Takatsuru et al. 2015), and greater microglia activation (Brenhouse & Thompson 2015).”
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    In animal studies, early-life stress is associated with both higher unstimulated inflammation and greater proinflammatory responses to later stressors.

    “Similar to the results of human studies, early-life stress in animal studies is associated not only with high unstimulated inflammation levels but also with greater proinflammatory responses in the context of subsequent stressors.”
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    Adolescents from harsh families show declining glucocorticoid sensitivity over time and increasing ex vivo cytokine response to LPS stimulation.

    “Furthermore, a longitudinal study showed that adolescents from harsh families had declining glucocorticoid sensitivity over time and increasing ex vivo cytokine response to LPS stimulation (Miller & Chen 2010).”
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    Psychological stress increases susceptibility to infection, and traumatic experiences in children are associated with recrudescence of latent viral infections.

    “Psychological stress in general is known to increase susceptibility to infection (Cohen et al. 1991), and traumatic experiences in children have been associated with recrudescence for latent viral infections (Shirtcliff et al. 2009).”
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    Reports of childhood trauma are related to allele-specific DNA demethylation in glucocorticoid response elements of FKBP5, which is associated with lower sensitivity of peripheral blood immune cells to glucocorticoid inhibition of LPS-induced IL-6 production in vitro.

    “For example, human studies showed that reports of childhood trauma were related to allele-specific DNA demethylation in functional glucocorticoid response elements of the FKBP5 gene, which, in turn, was associated with lower sensitivity of peripheral blood immune cells to the inhibitory effect of glucocorticoids on LPS-induced production of IL-6 in vitro (Klengel et al. 2013).”
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    Maternal separation in rodent pups is associated with blunted hippocampal expression of proinflammatory mediators such as LPS binding protein and with reduced microglial cell numbers in midbrain areas.

    “Maternal separation is associated with blunted expression of proinflammatory mediators (such as LPS binding protein) in the hippocampus (Wei et al. 2012) and with reduced microglial cell numbers in midbrain areas (Chocyk et al. 2011) in rodent pups at a time when innate immunity is crucial for brain development.”
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    Premisecitation

    Childhood trauma is associated with an elevated risk of smoking, which can increase circulating inflammatory biomarkers.

    “For example, childhood trauma is associated with an elevated risk of smoking (Anda et al. 1999), which, in turn, can increase circulating inflammatory biomarkers (Shiels et al. 2014).”
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    Interpretationcitation

    Altered early-life gut microbiota could affect immune system development and directly influence brain development via inflammatory signaling through the vagus nerve or metabolic changes.

    “In turn, altered composition of the gut microbiota in early life could affect immune system development and could directly influence brain development by way of inflammatory signal transmission through the vagus nerve or through metabolic changes (Cryan & Dinan 2012).”
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    Experimentally induced sleep deprivation increases proinflammatory cytokine expression in humans, and sleep loss is associated with elevated inflammation in epidemiological studies, particularly in women.

    “In turn, experimentally induced sleep deprivation increases the expression of proinflammatory cytokines in humans (Irwin et al. 2006), and sleep loss is associated with elevated inflammation levels in epidemiological studies, particularly in women (Miller et al. 2009).”
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    Both childhood trauma and childhood innate immune activation show presumably causative associations with a wide range of adult mental health outcomes.

    “both childhood trauma and childhood innate immune activation demonstrate presumably causative associations with a wide range of adult mental health outcomes.”
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    Premisecitation

    Emerging evidence suggests both childhood trauma and childhood innate immune activation could be associated with elevated incidence of psychopathology, unfavorable course, and poor treatment response.

    “Emerging evidence suggests that both could be associated not only with an elevated incidence of psychopathology but also with an unfavorable course of illness and poor response to treatment (Agnew-Blais & Danese 2016, Nanni et al. 2012, Strawbridge et al. 2015).”
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    There is evidence of cross-sensitization between childhood stress and immune activation and of interaction between childhood trauma and inflammatory genes.

    “There is evidence of cross-sensitization between childhood stress and immune activation and of interaction between childhood trauma and inflammatory genes.”
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  • May combine two claims.

    Premisereasoning

    Evidence supports sensitization of the innate immune system after childhood trauma, including heightened inflammatory responses to subsequent stressors.

    “On the one hand, we have summarized the evidence for the sensitization of the innate immune system after childhood trauma, including findings of heightened inflammatory responses in the context of subsequent stressors”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Individuals with emotional symptoms may self-harm to relieve distress or with intent to end their lives.

    “For example, individuals with emotional symptoms may engage in self harm either to relieve distress or, more dramatically, with intent to end their lives (Agnew-Blais & Danese 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Agnew-Blais & Danese 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an experimental rat model, pups separated from mothers later showed more depressive-like symptoms and lower prefrontal cortex parvalbumin than unchallenged pups.

    “An experimental model in rats demonstrated that pups separated from their mothers later showed more depressive-like symptoms and lower levels of parvalbumin (a GABAergic marker) in the prefrontal cortex compared to unchallenged pups (Leussis et al. 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Leussis et al. 2012

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    None of the findings discussed can be taken in isolation as definitive evidence for the mediating role of inflammation in the association between childhood trauma and psychopathology.

    “None of the findings discussed in this review can be taken in isolation as definitive evidence for the mediating role of inflammation in the association between childhood trauma and psychopathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Physical exercise and antidepressant medications have demonstrated an ability to buffer the effects of early-life stress on brain and behavioral outcomes.

    “and have demonstrated an ability to buffer the effects of early-life stress on brain and behavioral outcomes (Harrison & Baune 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Harrison & Baune 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Not all cases of psychopathology are associated with childhood trauma, and not all individuals with a history of childhood trauma develop psychopathology.

    “With regard to causal inference, not all cases of psychopathology are associated with childhood trauma, and not all individuals with a history of childhood trauma develop psychopathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the E-Risk Longitudinal Twin Study, depressed 12-year-olds with a history of maltreatment had significant inflammation elevation compared with controls, whereas depressed children without such history did not.

    “We have observed similar stratified findings among 12-year-old members of the E-Risk Longitudinal Twin Study, in which depressed children with a history of maltreatment already had significant elevation in inflammation levels compared to controls, whereas depressed children without a history of maltreatment did not (Danese et al. 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Danese et al. 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Physical exercise and antidepressant medications have anti-inflammatory effects.

    “For example, both physical exercise and antidepressant medications have anti-inflammatory effects (Gleeson et al. 2011, Hannestad et al. 2011)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gleeson et al. 2011

      Not checked in the free run.

    • cites Hannestad et al. 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adolescents with a history of early-life stressors showed persistently elevated inflammation even after depressive symptoms remitted, whereas those without such history showed reductions as symptoms abated.

    “In addition, although adolescents with a history of early-life stressors showed persistently elevated inflammation levels even after the remission of depressive symptoms, their counterparts without a history of early-life stressors showed reductions in inflammation levels as their depressive symptoms abated (Miller & Cole 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Miller & Cole 2012

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Because it occurs early in life, childhood psychological trauma could influence immune system development, promoting chronic activation and hyperreactivity of the inflammatory response from childhood into adult life.

    “Notably, because of its occurrence early in life, childhood psychological trauma could influence immune system development, promoting chronic activation and hyperreactivity of the inflammatory response from childhood into adult life.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    These hidden wounds could affect brain and behavior over the lifetime by influencing brain development, potentiating neuroendocrine and immune responses to subsequent stressors, and biasing key domains of brain functioning.

    “In turn, these “hidden wounds” of childhood psychological trauma could affect the brain and behavior over the course of an individual’s lifetime by influencing brain development, potentiating the neuroendocrine and immune responses to subsequent stressors, and biasing key domains of brain functioning.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    An initial mild stressor can increase lymphocyte trafficking to the brain, which reduces secondary neuronal damage by microglia and produces autoreactive memory T cells that increase neuroprotection against subsequent stressors.

    “An initial mild stressor can increase lymphocyte trafficking to the brain, which in turn reduces secondary neuronal damage by the microglia and produces autoreactive memory T cells that increase neuroprotection in the face of subsequent stressors (Lewitus & Schwartz 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lewitus & Schwartz 2009

      Not checked in the free run.

63 of 63

  • The authors state this as an assumption.

    The experiences and physiology of animal models are similar enough to those of humans to allow causal generalization from animal experiments to humans.

    “generalization of causal inference from the narrow context of the experiment to the life of living humans requires demonstration (or assumption) that the experiences and physiology in animal models are similar to those of humans (i.e., external or ecological validity).”

  • The paper relies on this without support.

    Animal models of early-life stress, such as maternal separation, adequately model childhood trauma in humans.

    “Experimental animal models have been used to strengthen causal inference for the link between childhood trauma and immune system abnormalities and to investigate more invasive measures of immune functioning.”

  • The paper relies on this without support.

    Peripheral inflammation biomarkers such as CRP, fibrinogen, and white blood cell count reflect innate immune activity relevant to brain function.

    “The association was not sensitive to the particular measure of inflammation used but rather generalized to all inflammation biomarkers available, including CRP, fibrinogen, and white blood cell count, and was independent of key potential confounders, such as low birth weight, disadvantaged socioeconomic conditions of the family, and low IQ.”

  • The paper relies on this without support.

    The association between childhood trauma and elevated inflammation is not entirely due to unmeasured confounding.

    “The association was not sensitive to the particular measure of inflammation used but rather generalized to all inflammation biomarkers available, including CRP, fibrinogen, and white blood cell count, and was independent of key potential confounders, such as low birth weight, disadvantaged socioeconomic conditions of the family, and low IQ.”

  • The paper relies on this without support.

    Findings from animal models of neuroinflammation and early-life stress generalize to humans.

    “However, this type of investigation is possible in experimental animal models, and initial findings suggest earlylife stress has significant and potentially sexually dimorphic effects (Ganguly & Brenhouse 2015).”

  • The paper relies on this without support.

    Chronic stress and physical injury can induce inflammation.

    “In turn, chronic stress and physical injury can induce inflammation.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Stress-associated glucocorticoid resistance, together with autonomic stimulation, can promote activation of inflammatory pathways, which ultimately leads to structural damage in the brain and functional changes in connected neural networks implicated in the further regulation of stress and emotion.

    “As summarized in a recent review, stress-associated glucocorticoid resistance, together with autonomic stimulation, can promote activation of inflammatory pathways, which ultimately leads to structural damage in the brain and functional changes in connected neural networks implicated in the further regulation of stress and emotion (Danese & Baldwin 2017).”

    From Child Sexual Abuse as a Unique Risk Factor for the Development of Psychopathology: The Compounded Convergence of Mechanisms (2021) · cites this paper as Danese & Baldwin 2017

    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 measured

  • Stress-related hormones mediate the stress response to induce changes in heart rate, blood pressure, metabolism, and immune function.

    “These stress-related hormones mediate the stress response (92) to induce changes in heart rate, blood pressure, metabolism (93), and immune function (94).”

    From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [94]

Cites

Flagged first, then by citations

Research works printed but not linked: 6

  1. Bowlby J, 1951, Bull. World Health Organ., 3, 355
  2. Brenhouse HC, 2015, Maternal separation increases IBA-1 expression: a microglia activation marker in the prefrontal cortex of adolescent males following a second hit of stress
  3. Briquet P, 1859, Traite clinique et thérapeutique de l'hystérie
  4. Freud S, 1962, The Standard Edition of the Complete Psychological Works of Sigmund Freud, Vol. IV: The Interpretation of Dreams (First Part)
  5. Miller MA, 2009, Sleep, 32, 857
  6. Tottenham N, 2009, Front. Hum. Neurosci., 3, 68

Cited by

Sorted by citations

Related

Authors
Danese, A., & Baldwin, J. R.
Affiliations
King's College London (GB)
Corresponding author
Danese, Andrea
ORCID
Venue
Annual Review of Psychology
Publisher
Annual Reviews
Published
2017-01-03
Volume
68
Issue
1
Pages
517-544
ISSN
  • 0066-4308 (ISSN-L)
  • 1545-2085
DOI
10.1146/annurev-psych-010416-044208
OpenAlex
W2271144139
Cited by
286
References
196
Citations by year
2026: 23 · 2025: 36 · 2024: 33 · 2023: 33 · 2022: 35 · 2021: 37 · 2020: 31 · 2019: 18 · 2018: 30 · 2017: 9 · 2016: 1
FWCI
2.87
Type
journal article
Language
en
Open access
Locations
  • Annual Review of Psychology (publishedVersion)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
childhood trauma, psychopathology, systemic inflammation, biological risk factors, stress exposure, brain development, stress reactivity
MeSH terms
Adult, Animals, Mental Disorders, Brain, Child, Child Abuse, Humans, Immunity, Inflammation, Stress, Psychological

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