Disruptions of the mother-infant relationship and stress-related behaviours: altered corticosterone secretion does not explain everything.
Faturi Claudia B,Tiba Paula A,Kawakami Suzi E,Catallani Bruna,Kerstens Marieke,Suchecki Deborah
Neuroscience and biobehavioral reviews
The hypothalamic-pituitary-adrenal (HPA) axis is the main neuroendocrine system of response to stress, and an imbalance of this system's activity is believed to be at the core of numerous psychiatric pathologies. During the neonatal period, the glucocorticoid response to stress is maintained at low levels by specific maternal behaviours, which is essential for proper brain development. Effective evaluation of the impact of increased secretion of corticosterone during an essentially anabolic developmental period on adulthood behaviour involved separation of the neonate from its mother for periods ranging from 3 to 24h. It has been shown that disinhibition of the stress response is achieved by such procedures. The pioneering studies by Seymour Levine set the stage for a prolific and promising field of study that may help neuroscientists unveil the neurobiological underpinnings of stress-related disorders. Based on a series of studies, we propose that maternal separation and maternal deprivation change stress-related behaviours, but that corticosterone seem to be only partially involved in these changes in adulthood. It appears that extra-hypothalamic corticotrophin-releasing factor and neurotransmitter systems may be the primary mediators of these behavioural outcomes.
Inflammation as a psychophysiological biomarker in chronic psychosocial stress.
Hänsel Alexander,Hong Suzi,Cámara Rafael J A,von Känel Roland
Neuroscience and biobehavioral reviews
The measurement of inflammation by biomarkers not only documents clinically relevant infections but also offers an important tool to pin point potentially harmful effects of chronic psychosocial stressors. This article focuses firstly on basic biology of inflammation and lists main biomarkers currently used in psycho-physiologic research. In the second part, the effects of the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system as pathways modulating stress-related inflammation are discussed. Furthermore, current evidence of how chronic psychosocial stressors are related to alterations in inflammatory activity is presented. In summary, job stress, low socioeconomic status, childhood adversities as well as life events, caregiver stress, and loneliness were all shown to exert effects on immunologic activity.
Contextualizing the neurobiology of conduct disorder in an emotion dysregulation framework.
Cappadocia M Catherine,Desrocher Mary,Pepler Debra,Schroeder Jessica H
Clinical psychology review
Conduct disorder (CD) represents the most common childhood psychiatric disorder found in community and mental health clinics. This paper provides a comprehensive review of the neurobiology of CD; specifically, neurological and neurochemical correlates. Converging evidence suggests that neurological profiles of individuals with CD, compared to peers, are characterized by reduced P300 brain wave amplitude, deactivation of the anterior cingulated cortex and reduced activation in the left amygdala in response to negative stimuli, and reduced right temporal lobe volume. The neurochemical profiles of individuals with CD are characterized by reduced serotonin and cortisol levels (i.e., decreased HPA axis function), as well as attenuated autonomic nervous system functioning. Popular theoretical frameworks cited within the CD literature are limited in their ability to explain and consolidate the neurological and neurochemical findings. We believe that emotion dysregulation theory, though not often used within CD research, may provide the most comprehensive and inclusive framework for understanding neurobiological aspects of this disorder. Limitations within the literature, future directions for research, and implications of the findings will be discussed.
The link between aberrant hypothalamic-pituitary-adrenal axis activity during development and the emergence of aggression-Animal studies.
Walker Sophie E,Papilloud Aurélie,Huzard Damien,Sandi Carmen
Neuroscience and biobehavioral reviews
Aggressive behavior is not uniform, including proactive and reactive forms of aggression. Aberrant functioning of the hypothalamic-pituitary-adrenal (HPA) axis is frequently associated with abnormal aggression. Here, we review the rodent literature in order to assess whether developmental abnormalities in the HPA axis can be causally linked with the emergence of abnormal aggression. We examine studies that involve genetic models and life challenges (e.g., early life stress, drug exposure) that course with developmental alterations in the HPA axis. Although the lack of systematic studies hinders development of an integrated model, existing evidence supports a U-shaped function regarding differences in HPA axis functioning during development and the emergence of aggressive phenotypes. Thus, developmentally low or high HPA axis reactivity are typically found to be aligned with the emergence of aggressive phenotypes; however, existing information is insufficient to causally link divergent HPA axis aberration with specific types of aggression. Progress in this field is needed to support interventions in children aimed at ameliorating social dysfunctions associated with aberrations in HPA axis function.
Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse.
Rinne Thomas,de Kloet E Ronald,Wouters Luuk,Goekoop Jaap G,DeRijk Roel H,van den Brink Wim
BACKGROUND:High coincidence of childhood abuse, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) has been reported in patients with borderline personality disorder (BPD). Animals exposed to early trauma show increased stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity due to an enhanced corticotropin-releasing hormone (CRH) drive and glucocorticoid feedback resistance. In humans, PTSD and MDD are associated with decreased and increased resistance to glucocorticoid feedback, respectively, which might reflect persistent changes in neuroendocrine sequelae following childhood abuse. METHODS:We investigated the relationship between childhood abuse and HPA axis function using a combined dexamethasone/CRH (DEX/CRH) test in 39 BPD patients with (n = 24) and without (n = 15) sustained childhood abuse and comorbid PTSD (n = 12) or MDD (n = 11) and 11 healthy control subjects. RESULTS:Chronically abused BPD patients had a significantly enhanced corticotropin (ACTH) and cortisol response to the DEX/CRH challenge compared with nonabused subjects. Comorbid PTSD significantly attenuated the ACTH response. CONCLUSIONS:Hyperresponsiveness of the HPA axis in chronically abused BPD subjects might be due to the enhanced central drive to pituitary ACTH release. Sustained childhood abuse rather than BPD, MDD, or PTSD pathology accounts for this effect. Possibly due to an enhanced efficacy of HPA suppression by dexamethasone, PTSD attenuates the ACTH response to DEX/CRH.
Causal effects of the early caregiving environment on development of stress response systems in children.
McLaughlin Katie A,Sheridan Margaret A,Tibu Florin,Fox Nathan A,Zeanah Charles H,Nelson Charles A
Proceedings of the National Academy of Sciences of the United States of America
Disruptions in stress response system functioning are thought to be a central mechanism by which exposure to adverse early-life environments influences human development. Although early-life adversity results in hyperreactivity of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis in rodents, evidence from human studies is inconsistent. We present results from the Bucharest Early Intervention Project examining whether randomized placement into a family caregiving environment alters development of the autonomic nervous system and HPA axis in children exposed to early-life deprivation associated with institutional rearing. Electrocardiogram, impedance cardiograph, and neuroendocrine data were collected during laboratory-based challenge tasks from children (mean age = 12.9 y) raised in deprived institutional settings in Romania randomized to a high-quality foster care intervention (n = 48) or to remain in care as usual (n = 43) and a sample of typically developing Romanian children (n = 47). Children who remained in institutional care exhibited significantly blunted SNS and HPA axis responses to psychosocial stress compared with children randomized to foster care, whose stress responses approximated those of typically developing children. Intervention effects were evident for cortisol and parasympathetic nervous system reactivity only among children placed in foster care before age 24 and 18 months, respectively, providing experimental evidence of a sensitive period in humans during which the environment is particularly likely to alter stress response system development. We provide evidence for a causal link between the early caregiving environment and stress response system reactivity in humans with effects that differ markedly from those observed in rodent models.
Hypothalamic-pituitary-adrenal axis functioning in borderline personality disorder: A meta-analysis.
Drews Elisa,Fertuck Eric A,Koenig Julian,Kaess Michael,Arntz Arnoud
Neuroscience and biobehavioral reviews
Borderline Personality Disorder (BPD) has been associated with altered hypothalamic-pituitary-adrenal (HPA) axis functioning. However, evidence is inconsistent. Therefore, the present series of meta-analyses aimed to quantify HPA axis functioning in BPD patients based on singular and continuous cortisol assessments and measures of reactivity to pharmacological and psychosocial stress. Case-control studies comparing adult BPD patients and healthy and clinical controls were considered for inclusion. The search resulted in 804 publications, of which 37 studies (k = 81; BPD n = 803, controls n = 1092) were included. Analyses were based on random effect models using standardized mean differences. BPD patients displayed elevated continuous cortisol output and blunted cortisol following psychosocial challenges. Singular cortisol assessments and cortisol after pharmacological challenges were not significantly different. Meta-analyses were limited by inconsistent reporting in individual studies and small samples for some comparisons. Due to the debilitating nature of stress-related symptoms in BPD, more research on elevated continuous cortisol output and blunted cortisol responses to psychosocial stress is warranted.
Interactive effects of early and recent exposure to stressful contexts on cortisol reactivity in middle childhood.
Jaffee Sara R,McFarquhar Tara,Stevens Suzanne,Ouellet-Morin Isabelle,Melhuish Edward,Belsky Jay
Journal of child psychology and psychiatry, and allied disciplines
BACKGROUND:Given mixed findings as to whether stressful experiences and relationships are associated with increases or decreases in children's cortisol reactivity, we tested whether a child's developmental history of risk exposure explained variation in cortisol reactivity to an experimentally induced task. We also tested whether the relationship between cortisol reactivity and children's internalizing and externalizing problems varied as a function of their developmental history of stressful experiences and relationships. METHOD:Participants included 400 children (M = 9.99 years, SD = 0.74 years) from the Children's Experiences and Development Study. Early risk exposure was measured by children's experiences of harsh, nonresponsive parenting at 3 years. Recent risk exposure was measured by children's exposure to traumatic events in the past year. Children's cortisol reactivity was measured in response to a social provocation task and parents and teachers described children's internalizing and externalizing problems. RESULTS:The effect of recent exposure to traumatic events was partially dependent upon a child's early experiences of harsh, nonresponsive parenting: the more traumatic events children had recently experienced, the greater their cortisol reactivity if they had experienced lower (but not higher) levels of harsh, nonresponsive parenting at age 3. The lowest levels of cortisol reactivity were observed among children who had experienced the most traumatic events in the past year and higher (vs. lower) levels of harsh, nonresponsive parenting in early childhood. Among youth who experienced harsh, nonresponsive parent-child relationships in early childhood and later traumatic events, lower levels of cortisol reactivity were associated with higher levels of internalizing and externalizing problems. CONCLUSIONS:Hypothalamic-pituitary-adrenal (HPA) axis reactivity to psychological stressors and the relationship between HPA axis reactivity and children's internalizing and externalizing problems vary as a function of a child's developmental history of exposure to stressful relationships and experiences.
Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease.
Kuhlman Kate Ryan,Chiang Jessica J,Horn Sarah,Bower Julienne E
Neuroscience and biobehavioral reviews
Childhood adversity has been repeatedly and robustly linked to physical and mental illness across the lifespan. Yet, the biological pathways through which this occurs remain unclear. Functioning of the inflammatory arm of the immune system and the hypothalamic-pituitary-adrenal (HPA)-axis are both hypothesized pathways through which childhood adversity leads to disease. This review provides a novel developmental framework for examining the role of adversity type and timing in inflammatory and HPA-axis functioning. In particular, we identify elements of childhood adversity that are salient to the developing organism: physical threat, disrupted caregiving, and unpredictable environmental conditions. We propose that existing, well-characterized animal models may be useful in differentiating the effects of these adversity elements and review both the animal and human literature that supports these ideas. To support these hypotheses, we also provide a detailed description of the development and structure of both the HPA-axis and the inflammatory arm of the immune system, as well as recent methodological advances in their measurement. Recommendations for future basic, developmental, translational, and clinical research are discussed.
Telomere length and cortisol reactivity in children of depressed mothers.
Gotlib I H,LeMoult J,Colich N L,Foland-Ross L C,Hallmayer J,Joormann J,Lin J,Wolkowitz O M
A growing body of research demonstrates that individuals diagnosed with major depressive disorder (MDD) are characterized by shortened telomere length, which has been posited to underlie the association between depression and increased instances of medical illness. The temporal nature of the relation between MDD and shortened telomere length, however, is not clear. Importantly, both MDD and telomere length have been associated independently with high levels of stress, implicating dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and anomalous levels of cortisol secretion in this relation. Despite these associations, no study has assessed telomere length or its relation with HPA-axis activity in individuals at risk for depression, before the onset of disorder. In the present study, we assessed cortisol levels in response to a laboratory stressor and telomere length in 97 healthy young daughters of mothers either with recurrent episodes of depression (i.e., daughters at familial risk for depression) or with no history of psychopathology. We found that daughters of depressed mothers had shorter telomeres than did daughters of never-depressed mothers and, further, that shorter telomeres were associated with greater cortisol reactivity to stress. This study is the first to demonstrate that children at familial risk of developing MDD are characterized by accelerated biological aging, operationalized as shortened telomere length, before they had experienced an onset of depression; this may predispose them to develop not only MDD but also other age-related medical illnesses. It is critical, therefore, that we attempt to identify and distinguish genetic and environmental mechanisms that contribute to telomere shortening.
Non-invasive biomarkers of fetal brain development reflecting prenatal stress: An integrative multi-scale multi-species perspective on data collection and analysis.
Frasch Martin G,Lobmaier Silvia M,Stampalija Tamara,Desplats Paula,Pallarés María Eugenia,Pastor Verónica,Brocco Marcela A,Wu Hau-Tieng,Schulkin Jay,Herry Christophe L,Seely Andrew J E,Metz Gerlinde A S,Louzoun Yoram,Antonelli Marta C
Neuroscience and biobehavioral reviews
Prenatal stress (PS) impacts early postnatal behavioural and cognitive development. This process of 'fetal programming' is mediated by the effects of the prenatal experience on the developing hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). We derive a multi-scale multi-species approach to devising preclinical and clinical studies to identify early non-invasively available pre- and postnatal biomarkers of PS. The multiple scales include brain epigenome, metabolome, microbiome and the ANS activity gauged via an array of advanced non-invasively obtainable properties of fetal heart rate fluctuations. The proposed framework has the potential to reveal mechanistic links between maternal stress during pregnancy and changes across these physiological scales. Such biomarkers may hence be useful as early and non-invasive predictors of neurodevelopmental trajectories influenced by the PS as well as follow-up indicators of success of therapeutic interventions to correct such altered neurodevelopmental trajectories. PS studies must be conducted on multiple scales derived from concerted observations in multiple animal models and human cohorts performed in an interactive and iterative manner and deploying machine learning for data synthesis, identification and validation of the best non-invasive detection and follow-up biomarkers, a prerequisite for designing effective therapeutic interventions.
Longitudinal patterns of cortisol regulation differ in maltreated and nonmaltreated children.
Doom Jenalee R,Cicchetti Dante,Rogosch Fred A
Journal of the American Academy of Child and Adolescent Psychiatry
OBJECTIVE:Child maltreatment is associated with dysregulation of stress-mediating systems and an increased risk of mental and physical health problems. Specifically, disruptions in hypothalamic-pituitary-adrenal (HPA) axis regulation have been reported in maltreated children. The current study investigates whether increased cortisol variability is responsible for inconsistent patterns in the literature. METHOD:This study modeled cortisol activity over 20 weeks in 187 maltreated and 154 nonmaltreated children (mean = 8.4 years, SD = 1.8 years) in order to capture week-to-week cortisol patterns. Maltreatment was assessed through coding of Department of Human Services records. Children attended an after-school program 1 day per week for 20 weeks, where saliva was collected at the same time each day and subsequently assayed for cortisol. RESULTS:Multiple-group growth curves indicated that maltreated and non-maltreated children differ in longitudinal cortisol patterns. Maltreated children showed higher variance in the initial cortisol levels and slope over time compared to nonmaltreated children, indicating greater between-person variability in the maltreated group. Maltreated children with higher cortisol at the first assessment showed cortisol suppression over time, indicating potential HPA blunting after chronic high cortisol levels. The severity, timing, and number of subtypes of maltreatment predicted individuals' cortisol variability, and both maltreatment status and greater cortisol variability predicted more behavior problems. CONCLUSION:Interventions for maltreated children may benefit from pre- and post-intervention HPA assessments to determine a component of treatment efficacy. As maltreatment dimensions predicted differential cortisol regulation, assessment of maltreatment experiences is necessary to understand alterations in behavior and HPA regulation post-intervention.
Preadolescent Adversity Programs a Disrupted Maternal Stress Reactivity in Humans and Mice.
Morrison Kathleen E,Epperson C Neill,Sammel Mary D,Ewing Grace,Podcasy Jessica S,Hantsoo Liisa,Kim Deborah R,Bale Tracy L
BACKGROUND:Adverse childhood experiences (ACEs) are one of the greatest predictors of affective disorders for women. Periods of dynamic hormonal flux, including pregnancy, exacerbate the risk for affective disturbance and promote hypothalamic-pituitary-adrenal (HPA) axis dysregulation, a key feature of affective disorders. Little is understood as to how stress experienced in late childhood, defined as preadolescence, alters the programming unique to this period of brain maturation and its interaction with the hormonal changes of pregnancy and postpartum. METHODS:Preadolescent female mice were exposed to chronic stress and examined for changes in their HPA axis during pregnancy and postpartum, including assessment of maternal-specific stress responsiveness and transcriptomics of the paraventricular nucleus of the hypothalamus. Translationally, pregnant women with low or high ACEs were examined for their maternal stress responsiveness. RESULTS:As predicted, preadolescent stress in mice resulted in a significant blunting of the corticosterone response during pregnancy. Transcriptomic analysis of the paraventricular nucleus revealed widespread changes in expression of immediate early genes and their targets, supporting the likely involvement of an upstream epigenetic mechanism. Critically, in our human studies, the high ACE women showed a significant blunting of the HPA response. CONCLUSIONS:This unique mouse model recapitulates a clinical outcome of a hyporesponsive HPA stress axis, an important feature of affective disorders, during a dynamic hormonal period, and suggests involvement of transcriptional regulation in the hypothalamus. These studies identify a novel mouse model of female ACEs that can be used to examine how additional life adversity may provoke disease risk or resilience.
Pubertal recalibration of cortisol reactivity following early life stress: a cross-sectional analysis.
DePasquale Carrie E,Donzella Bonny,Gunnar Megan R
Journal of child psychology and psychiatry, and allied disciplines
BACKGROUND:Children adopted from orphanages or other such institutions tend to display blunted reactivity to stressors - even years after arriving in their generally supportive and highly resourced postadoption homes. Puberty, a proposed sensitive period for environmental influences on stress-mediating systems, may provide an opportunity for postinstitutionalized children to recalibrate stress response systems in accordance with their now more supportive living situations. METHODS:This cross-sectional study examined the hypothalamic-pituitary-adrenocortical (HPA)-axis reactivity of 280 children ages 7 through 14 years; 122 children were adopted from institutions in 14 countries between the ages of 6 months and 5 years, after spending an average of 95% of their lives in institutional care, and 158 children of similarly high socioeconomic status in their biological families served as the nonadopted comparison group. All of the children were assessed by nurses for Tanner stage and, on a different day, completed the Trier Social Stress Test for Children. RESULTS:Using a linear mixed-effects model and seven measures of salivary cortisol, results indicated that early-pubertal postinstitutionalized children showed blunted HPA axis reactivity compared to nonadopted children, but mid/late-pubertal postinstitutionalized children displayed higher reactivity similar to the nonadopted comparison children. CONCLUSIONS:This is the first evidence of possible pubertal recalibration of HPA axis reactivity to a psychosocial stressor in postinstitutionalized children, which provides a promising avenue for future research regarding the protective factors of the postadoption environment and subsequent physiological, behavioral, and psychopathological outcomes.
Pubertal stress recalibration reverses the effects of early life stress in postinstitutionalized children.
Gunnar Megan R,DePasquale Carrie E,Reid Brie M,Donzella Bonny,Miller Bradley S.
Proceedings of the National Academy of Sciences of the United States of America
Nonhuman animal models reveal that the hypothalamic-pituitary-adrenocortical (HPA) axis calibrates to the harshness of the environment during a sensitive period in infancy. Humans exposed to depriving institutional care in infancy show reduced HPA axis responsivity, even years after they are placed in supportive, well-resourced families. This study examined whether puberty opens a window of opportunity to recalibrate the HPA axis toward more typical reactivity when children shift from harsh deprived conditions in infancy into supportive conditions in childhood and adolescence. Participants ( = 129 postinstitutionalized, 68.2% female; = 170 comparison, 52.4% female) completed 3 annual sessions beginning at ages 7 to 15 ( = 11.28, SD = 2.31). Each session assessed pubertal stage via nurse examination and cortisol reactivity to the Trier social stress test for children. The linear mixed-effects model controlling for sex and between-individual differences in pubertal stage showed a significant group by pubertal stage interaction: within-individual increases in pubertal stage were associated with increases in cortisol stress reactivity for postinstitutionalized youth but not nonadopted comparison youth. This study indicates that pubertal development reopens a window of opportunity for the HPA axis to recalibrate based on significant improvements in the supportiveness of the environment relative to that in infancy. The peripubertal period may be an important time in development where the caregiving environment has a substantial impact on the HPA axis and, perhaps, other stress-mediating systems. Future research is needed to examine the mechanisms of recalibration and whether HPA recalibration impacts physical and psychological health.
Urbanicity, behavior problems and HPA axis regulation in preschoolers.
Growing up in cities is associated with increased risk for developing mental health problems. Stress exposure and altered stress regulation have been proposed as mechanisms linking urbanicity and psychopathology, with most research conducted in adult populations. Here, we focus on early childhood, and investigate urbanicity, behavior problems and the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, a central circuit of the stress system, in a sample of N = 399 preschoolers aged 45 months. Urbanicity was coded dichotomously distinguishing between residences with more or less than 100,000 inhabitants. Behavior problems were measured using the Child Behavior Checklist (CBCL) 1½ - 5. Cortisol stress reactivity was assessed using an age-appropriated game-like stress task, and cortisol in the first morning urine was measured to assess nocturnal HPA axis activity. Urbanicity was not associated with behavior problems, urinary cortisol or the cortisol stress response. Neither urinary cortisol nor salivary cortisol response after stress exposure were identified as mediators of the relationship between urbanicity and behavior problems. The findings suggest no strong association of urbanicity with behavior problems and HPA axis regulation in preschool age. To our knowledge, this is the youngest sample to date studying the relationship between urbanicity and behavior problems as well as HPA axis regulation. Future research should examine at which age associations can first be identified and which mechanisms contribute to these relationships.
Linking post-stressor interpersonal processes in adolescent girls' close friendships with acute HPA stress responses.
Calhoun Casey D,Patterson Megan W,Bendezú Jason José,Helms Sarah W,Owens Sarah A,Rudolph Karen D,Hastings Paul D,Prinstein Mitchell J
Journal of adolescence
INTRODUCTION:For adolescent girls, close friendships may facilitate stress management and mitigate risk for internalizing psychopathology. However, little is known about how friendship processes may buffer (or potentially exacerbate) acute psychobiological responses to interpersonal stressors in ways that affect risk. METHODS:In a sample of 220 girls (ages 12-17 years) with a history of internalizing symptoms, this study investigated friendship dynamics following the Trier Social Stress Test (TSST) to evaluate associations between post-stressor friendship behaviors (expressions of vulnerability by the stressed teen; support offered by their close friend) and hypothalamic-pituitary-adrenal (HPA) axis stress responses. RESULTS:Multilevel regression modeling revealed that girls who displayed more pronounced cortisol reactivity expressed greater vulnerability to, and received greater support from, their close friend. Expressed vulnerability was associated with more efficient cortisol recovery. Close friend support was not significantly associated with cortisol recovery, nor did it influence the connection between expressed vulnerability and cortisol recovery. CONCLUSIONS:Findings suggest that HPA reactivity may prompt expressions of vulnerability to girls' close friends, and in this context, promote more efficient HPA recovery. Findings highlight the role friendship dynamics may play in HPA-related risk for internalizing symptoms and point to expressed vulnerability in adolescent girls' close friendships as a potential consideration for interpersonally-centered therapeutic approaches.
HPA-axis stress reactivity in youth depression: evidence of impaired regulatory processes in depressed boys.
Lopez-Duran Nestor L,McGinnis Ellen,Kuhlman Kate,Geiss Elisa,Vargas Ivan,Mayer Stefanie
Stress (Amsterdam, Netherlands)
Given the link between youth depression and stress exposure, efforts to identify related biomarkers have involved examinations of stress regulation systems, including the hypothalamic-pituitary-adrenal (HPA) axis. Despite these vast efforts, the underlying mechanisms at play, as well as factors that may explain heterogeneity of past findings, are not well understood. In this study, we simultaneously examined separate components of the HPA-axis response (e.g. activation intensity, peak levels, recovery) to the Socially Evaluated Cold-Pressor Test in a targeted sample of 115 youth (age 9-16), recruited to overrepresent youth with elevated symptoms of depression. Among youth who displayed a cortisol response to the task, depression symptoms were associated with higher peak responses but not greater rate of activation or recovery in boys only. Among those who did not respond to the task, depression symptoms were associated with greater cortisol levels throughout the visit in boys and girls. Results suggest that depression symptoms are associated with a more prolonged activation of the axis and impaired recovery to psychosocial stressors primarily in boys. We discussed two potential mechanistic explanations of the link between depression symptoms and the duration of activation: (1) inhibitory shift (i.e. point at which the ratio of inhibitory and excitatory input into the axis shifts from greater excitatory to greater inhibitory input) or (2) inhibitory threshold (i.e. level of cortisol exposure required to activate the axis' feedback inhibition system).
Interparental conflict and child HPA-axis responses to acute stress: Insights using intensive repeated measures.
Kuhlman Kate Ryan,Repetti Rena L,Reynolds Bridget M,Robles Theodore F
Journal of family psychology : JFP : journal of the Division of Family Psychology of the American Psychological Association (Division 43)
Interparental conflict is a common source of psychosocial stress in the lives of children. The purpose of this study was to examine the association between recent interparental conflict and one component of the physiological stress response system, the hypothalamic-pituitary-adrenal (HPA)-axis. Parents of 42 children (ages 8-13 years) completed daily diaries of interparental conflict for 8 weeks. At the end of the 8 weeks, youth participated in the Trier Social Stress Test for Children (TSST-C) while providing 2 pre- and 4 poststress salivary cortisol samples. Youth whose fathers reported a pattern of increasing interparental conflict over the past 8 weeks demonstrated an exaggerated HPA-axis response to acute stress. Mother-reported interparental conflict was not associated with children's HPA-axis responses without accounting for fathers' reports. When accounting for fathers' reports, the offspring of mothers reporting higher average daily interparental conflict demonstrated an attenuated HPA-axis response to the stressor. By estimating both average exposure and recent patterns of change in exposure to conflict, we address the circumstances that may prompt attenuation versus sensitization of the HPA-axis in the context of interparental conflict. We conclude that the HPA-axis is sensitive to proximal increases in interparental conflict which may be one pathway through which stress affects health across development, and that incorporating father's reports is important to understanding the role of the family environment in stress responses. This study further demonstrates the value of using intensive repeated measures and multiple reporters to characterize children's psychosocial environment. (PsycINFO Database Record
Polygenic risk score of SERPINA6/SERPINA1 associates with diurnal and stress-induced HPA axis activity in children.
Utge Siddheshwar,Räikkönen Katri,Kajantie Eero,Lipsanen Jari,Andersson Sture,Strandberg Timo,Reynolds Rebecca M,Eriksson Johan G,Lahti Jari
PURPOSE:Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood. Variation in genes SERPINA6 encoding for CBG, SERPINA2 and SERPINA1 (serpin family A member 6, 2, and 1) have been shown to influence morning plasma cortisol and CBG in adults. However, association of this genetic variation with diurnal and stress-induced salivary cortisol remain unknown. This study aims to investigate the effect of genetic variation in SERPINA6/2/1 loci on diurnal and stress-induced salivary cortisol in children. METHODS:We studied 186, 8-year-old children with genome-wide genotyping. We generated weighted polygenic risk score (PRS) based on 6 genome-wide significant SNPs (rs11621961, rs11629171, rs7161521, rs2749527, rs3762132, rs4900229) derived from the CORNET meta-analyses. Salivary cortisol was measured across one day and in response to the Trier Social Stress Test for Children (TSST-C). RESULTS:Mixed models, adjusted for covariates, showed that the PRS x sampling time interactions associated with diurnal (P < 0.001) and stress-induced (P = 0.009) salivary cortisol. In the high PRS group (dichotomized at median) the diurnal salivary cortisol pattern decreased less from awakening to bedtime than in the low PRS group (standardized estimates of sampling time -0.64 vs. -0.73, P < 0.0001 for both estimates). In response to stress, salivary cortisol increased in the high PRS group while it remained unchanged in the low PRS group (standardized estimates of sampling time 0.12, P = 0.015 vs. -0.06, P = 0.16). These results were mainly driven by minor alleles of rs7161521 (SERPINA6) and rs4900229 (SERPINA1). CONCLUSIONS:Genetic variation in SERPINA6/2/1loci may underpin higher hypothalamic-pituitary-adrenocortical axis activity in children.