HPA axis genetic variation, pubertal status, and sex interact to predict amygdala and hippocampus responses to negative emotional faces in school-age children

Pagliaccio, David; Luby, Joan L.; Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S.; Belden, Andy C.; Botteron, Kelly N.; Harms, Michael P.; Deanna, M

doi:10.1016/j.neuroimage.2015.01.017

Cited by 45 publications

(25 citation statements)

References 72 publications

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“…Based on our data, we cannot rule out a higher genetic risk profile for affective disorders in the ELA group. However, recent research suggests that, when faced with strong environmental stressors, the genetic risk for abnormal neurobiological development associated with an increased risk for affective disorders might be overridden by the environmental stressor [58]. Being separated from the primary caretaker in infancy is clearly one of the strongest stressors in early life and, therefore, the genetic risk in these children might contribute less to the changes observed.…”

Section: Discussionmentioning

confidence: 99%

Effects of Early-Life Adversity on Hippocampal Structures and Associated HPA Axis Functions

Dahmen¹,

Puetz

Scharke

et al. 2017

Dev Neurosci

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Early-life adversity (ELA) is one of the major risk factors for serious mental and physical health risks later in life. ELA has been associated with dysfunctional neurodevelopment, especially in brain structures such as the hippocampus, and with dysfunction of the stress system, including the hypothalamic-pituitary-adrenal (HPA) axis. Children who have experienced ELA are also more likely to suffer from mental health disorders such as depression later in life. The exact interplay of aberrant neurodevelopment and HPA axis dysfunction as risks for psychopathology is not yet clear. We investigated volume differences in the bilateral hippocampus and in stress-sensitive hippocampal subfields, behavior problems, and diurnal cortisol activity in 24 children who had experienced documented ELA (including out-of-home placement) in a circumscribed duration of adversity only in their first 3 years of life in comparison to data on 25 control children raised by their biological parents. Hippocampal volumes and stress-sensitive hippocampal subfields (Cornu ammonis [CA]1, CA3, and the granule-cell layer of the dentate gyrus [GCL-DG]) were significantly smaller in children who had experienced ELA, taking psychiatric diagnoses and dimensional psychopathological symptoms into account. ELA moderated the relationship between left hippocampal volume and cortisol: in the control group, hippocampal volumes were not related to diurnal cortisol, while in ELA children, a positive linear relationship between left hippocampal volume and diurnal cortisol was present. Our findings show that ELA is associated with altered development of the hippocampus, and an altered relationship between hippocampal volume and HPA axis activity in youth in care, even after they have lived in stable and caring foster family environments for years. Altered hippocampal development after ELA could thus be associated with a risk phenotype for the development of psychiatric disorders later in life.

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Section: Discussionmentioning

confidence: 99%

Effects of Early-Life Adversity on Hippocampal Structures and Associated HPA Axis Functions

Dahmen¹,

Puetz

Scharke

et al. 2017

Dev Neurosci

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“…Sex is an important modifier of effects of stress-system genetic variation (e.g., HPA axis genetic variation) on programming(18, 68). Sex-specific effects of prenatal stress on respiratory control processes may also play a role, with males being more adversely impacted(69).…”

Section: Discussionmentioning

confidence: 99%

Prenatal and postnatal stress and asthma in children: Temporal- and sex-specific associations

Lee

Chiu

Rosa

et al. 2016

Journal of Allergy and Clinical Immunology

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BACKGROUND Temporal- and sex-specific effects of perinatal stress have not been examined for childhood asthma. OBJECTIVES We examined associations between pre- and/or postnatal stress and children's asthma (n=765) and effect modification by sex in a prospective cohort study. METHODS Maternal negative life events (NLEs) were ascertained prenatally and postpartum. NLEs scores were categorized as 0, 1-2, 3-4, or ≥5 to assess exposure-response relationships. We examined effects of pre- and postnatal stress on children's asthma by age 6 years modeling each as independent predictors; mutually adjusting for prenatal and postnatal stress; and finally considering interactions between pre- and postnatal stress. Effect modification by sex was examined in stratified analyses and by fitting interaction terms. RESULTS When considering stress in each period independently, among boys a dose-response relationship was evident for each level increase on the ordinal scale prenatally (OR=1.38, 95% CI 1.06, 1.79; p-for-trend=0.03) and postnatally (OR=1.53, 95% CI 1.16, 2.01; p-for-trend=0.001); among girls only the postnatal trend was significant (OR=1.60, 95% CI 1.14, 2.22; p-for-trend=0.005). Higher stress in both the pre- and postnatal periods was associated with increased odds of being diagnosed with asthma in girls [OR=1.37, 95% CI 0.98, 1.91 (pinteraction=0.07)] but not boys [OR=1.08, 95% CI 0.82, 1.42 (pinteraction=0.61)]. CONCLUSIONS While boys were more vulnerable to stress during the prenatal period, girls were more impacted by postnatal stress and cumulative stress across both periods in relation to asthma. Understanding sex and temporal differences in response to early life stress may provide unique insight into asthma etiology and natural history.

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“…Prior work also relates variants in these genes to decreases in volume and increases in reactivity to emotional stimuli in the amygdala and hippocampus (e.g. Pagliaccio et al, 2013; 2015), which could suggest an impact on amygdala connectivity as well. While these putative relationships have not yet been tested, they build on prior work relating cortisol to amygdala connectivity (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…had full access to all study data and takes responsibility for the integrity of the data and accuracy of the data analysis. This work comprised a portion of D.P.’s dissertation: Pagliaccio, D. (2015). The Effects of HPA Axis Genetic Variation and Early Life Stress on Cortisol Levels in Preschool Age Children and on Amygdala and Hippocampus Volumes, Reactivity, and Connectivity at School Age (Doctoral dissertation).…”

mentioning

confidence: 99%

Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation.

Pagliaccio¹,

Luby²,

Bogdan³

et al. 2015

Journal of Abnormal Psychology

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125

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Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within four hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9–14 year olds; N=120). Whole-brain regression analyses indicated that increasing genetic ‘risk’ predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic ‘risk’ and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology.

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HPA axis genetic variation, pubertal status, and sex interact to predict amygdala and hippocampus responses to negative emotional faces in school-age children

Cited by 45 publications

References 72 publications

Effects of Early-Life Adversity on Hippocampal Structures and Associated HPA Axis Functions

Effects of Early-Life Adversity on Hippocampal Structures and Associated HPA Axis Functions

Prenatal and postnatal stress and asthma in children: Temporal- and sex-specific associations

Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation.

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