History Of Early Life Adversity Research Articles

Early life adversity is associated with differential gene expression in immune cells: A cluster-based analysis across an acute psychosocial stressor

Elucidating mechanisms by which early-life adversity (ELA) contributes to increased disease risk is important for mitigating adverse health outcomes. Prior work has found differences in immune cell gene expression related to inflammation and mitochondrial activity. Using a within-person between-group experimental design, we investigated differences in gene expression clusters across acute psychosocial stress and no-stress conditions. Participants were young adults (N = 29, aged 18 – 25 years, 62 % female, 47 % with a history of ELA). Gene expression was assessed in peripheral blood mononuclear cells collected at 8 blood draws spanning two 5-hour sessions (stress vs. no-stress) separated by a week, 4 across each session (number of observations = 221). We applied two unsupervised gene clustering methods – latent profile analysis (LPA) and weighted gene co-expression analysis (WGCNA) – to cluster genes with similar expression patterns across participants. LPA identified 11 clusters, 7 of which were significantly associated with ELA-status. WGCNA identified 5 clusters, 3 of which were significantly associated with ELA-status. LPA- and WGCNA-identified clusters were correlated, and all clusters were highly preserved across sessions and time. There was no significant effect of acute stress on cluster gene expression, but there was a significant effect of time, and significant differences by ELA-status. ELA-associated clusters related to RNA splicing/processing, inflammation, leukocyte differentiation and division, and mitochondrial activity were differentially expressed across time: ELA-exposed individuals showed decreased expression of these clusters at 90-minutes while controls showed increased expression. Our findings replicate previous work in this area and highlight additional mechanisms by which ELA may contribute to disease risk.

The effect of cognitive reappraisal and early-life maternal care on neuroendocrine stress responses

Early-life adversity (ELA) is related to profound dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, reflected in both, blunted or exaggerated cortisol stress responses in adulthood. Emotion regulation strategies such as cognitive reappraisal might contribute to this inconsistent finding. Here, we investigate an interaction of early-life maternal care (MC), where low MC represents a form of ELA, and instructed emotion regulation on cortisol responses to acute stress. Ninety-three healthy young women were assigned to a low (n = 33) or high (n = 60) MC group, based on self-reported early-life MC. In the laboratory, participants received regulation instructions, asking to cognitively reappraise (reappraisal group, n = 45) or to focus on senses (control group, n = 48) during subsequent stress exposure, induced by the Trier Social Stress Test. Salivary cortisol and subjective stress levels were measured repeatedly throughout the experiment. Multilevel model analyses confirmed a MC by emotion regulation interaction effect on cortisol trajectories, while controlling for hormonal status. Individuals with low MC in the control compared with the reappraisal group showed increased cortisol responses; individuals with high MC did not differ. These results highlight the significance of emotion regulation for HPA axis stress regulation following ELA exposure. They provide methodological and health implications, indicating emotion regulation as a promising target of treatment interventions for individuals with a history of ELA.

Epigenetic age acceleration as a biomarker for impaired cognitive abilities in adulthood following early life adversity and psychiatric disorders

BackgroundEarly life adversity and psychiatric disorders are associated with earlier declines in neurocognitive abilities during adulthood. These declines may be preceded by changes in biological aging, specifically epigenetic age acceleration, providing an opportunity to uncover genome-wide biomarkers that identify individuals most likely to benefit from early screening and prevention. MethodsFive unique epigenetic age acceleration clocks derived from peripheral blood were examined in relation to latent variables of general and speeded cognitive abilities across two independent cohorts: 1) the Female Growth and Development Study (FGDS; n = 86), a 30-year prospective cohort study of substantiated child sexual abuse and non-abused controls, and 2) the Biological Classification of Mental Disorders study (BeCOME; n = 313), an adult community cohort established based on psychiatric disorders. ResultsA faster pace of biological aging (DunedinPoAm) was associated with lower general cognitive abilities in both cohorts and slower speeded abilities in the BeCOME cohort. Acceleration in the Horvath clock was significantly associated with slower speeded abilities in the BeCOME cohort but not the FGDS. Acceleration in the Hannum clock and the GrimAge clock were not significantly associated with either cognitive ability. Accelerated PhenoAge was associated with slower speeded abilities in the FGDS but not the BeCOME cohort. ConclusionsThe present results suggest that epigenetic age acceleration has the potential to serve as a biomarker for neurocognitive decline in adults with a history of early life adversity or psychiatric disorders. Estimates of epigenetic aging may identify adults at risk of cognitive decline that could benefit from early neurocognitive screening.

Corticotropin releasing factor neurons in the visual cortex mediate long-term changes in visual function induced by early adversity

Early adversity can cause malfunction of the visual system in adulthood. Adult female but not male mice undergoing early chronic mild stress (ECMS) maintain ocular dominance (OD) plasticity after the critical period. How early stressful experiences have a long-term impact on it is largely unknown. Here, we observed a wide distribution of corticotropin-releasing factor (CRF)-positive neurons, which mainly colocalized with a subpopulation of GABAergic interneurons in the mouse primary visual cortex (V1). Optogenetic activation of CRF-positive neurons transfected with AAV-ChR2 evoked inhibitory currents in nearby pyramidal cells. ECMS induced a reduction in the expression of CRF mRNA in adult mouse V1. Chemogenetic activation of V1 CRF neurons impaired OD plasticity in adult ECMS females. We further showed that local administration of the corticotropin releasing factor receptor 1 (CRFR1) antagonist via an osmotic minipump into the visual cortex mimicked OD plasticity in adult ECMS females. Whole-cell recording in layer 2/3 pyramidal neurons revealed that the CRFR1 antagonist reduced the short-term depression (STD) of evoked inhibitory postsynaptic current (IPSC) in females but not in males. Likewise, CRF agonists have the opposite effect. In summary, our findings indicate that the local CRF-CRFR1 system within V1 may mediate the long-term and sex-dependent effect of early stress experiences on visual plasticity and provide a target for the prevention of visual deficits in adults with a history of early-life adversity.

Emotion Regulation as a Pathway Connecting Early Life Adversity and Inflammation in Adulthood: a Conceptual Framework.

Chronic inflammation is implicated in a variety of diseases (e.g., cardiovascular disease and cancer). Much evidence suggests that early life adversity (ELA), such as maltreatment or neglect, can increase risk for inflammation in adulthood. ELA may program proinflammatory activity via its effects on brain areas involved in emotion regulation. Of multiple emotion regulation strategies, some are considered maladaptive (e.g., expressive suppression), while others are generally adaptive (e.g., cognitive reappraisal). We propose a conceptual framework for how emotion regulation tendencies may affect vulnerability or resilience to inflammation in adults who experienced adversity in childhood and/or adolescence. In support of this framework, we summarize evidence for the relationships between emotion dysregulation and higher inflammation (i.e., vulnerability), as well as between cognitive reappraisal and lower inflammation (i.e., resilience), in healthy adults with a history of ELA. Plausible neurobiological, physiological, psychosocial, and ELA-specific factors, as well as interventions, contributing to these associations are discussed. Strengths and limitations of the extant research, in addition to ideas for future directions, are presented.

Associations among clinical variables and anger differ by early life adversity among post-9/11 veterans.

Maladaptive anger and aggression are common in US military veterans and increase risk for impaired social relationships and functioning, justice-involvement and violence. Early life (before age 18) adversity predisposes veterans to later life psychopathology, though the link to increased later life anger is unclear. We analysed cross-sectional data of 158 post-9/11 veterans from the Translational Research Center for Traumatic Brain Injury and Stress Disorders study with and without a history of early life adversity (ns = 109 and 49, respectively). We explored the relationship among major clinical variables and current veteran anger (Dimensions of Anger Reactions) and whether the associations with these variables differed among participants with and without a history of retrospective self-reported early life adversity (Childhood Trauma Questionnaire). In the overall sample, posttraumatic stress disorder (PTSD) and depression severities had the strongest associations with current veteran anger (βs = 0.261 and 0.263; p-values = 0.0022 and 0.0103, respectively). In the subsample without early life adversity, only PTSD severity was significantly associated with anger (β = 0.577, p = 0.0004). In the early life adversity subsample, this strong association weakened and was no longer significant (β = 0.168, p = 0.1007); instead, anxiety and depression severities showed moderate associations with anger (βs = 0.243 and 0.287, p-values = 0.0274 and 0.0130, respectively). Findings suggest that clinicians should screen veterans with history of early life adversity for depression and anxiety when anger is present.

Immune cell dynamics in response to an acute laboratory stressor: a within-person between-group analysis of the biological impact of early life adversity

Early life adversity (ELA) is a risk factor for early onset morbidities and mortality, a relationship that may be driven in part by immune system dysregulation. One mechanism of dysregulation that has yet to be fully examined in the context of ELA is alterations to immune cell dynamics in response to acute stress. Using a within-person between-group experimental design, we investigated stress-induced changes in immune cell populations, and how these changes may be altered in individuals with a history of ELA. Participants were young adults (N = 34, aged 18–25 years, 53% female, 47% with a history of ELA). Complete immune cell counts were measured at four time-points over a 5-hour window across two sessions (Trier Social Stress Test [TSST] vs. no-stress) separated by a week. Across all participants, total white blood cells increased over time (F(3,84)=38.97, p < .001) with a greater increase in response to the TSST compared to the no-stress condition at 240 minutes post-test (b = 0.43±.19; t(179)=2.22, p = .027). This pattern was mirrored by neutrophil counts. Lymphocyte counts were initially depressed by TSST exposure (b =−205±.67; t(184)=−3.07, p = .002) but recovered above baseline. ELA status was associated with higher stress-induced immune cell counts, a difference likely driven by increases in neutrophils (F(1,22)=4.45, p = .046). Overall, these results indicate differential immune cell dynamics in response to acute stress in individuals with a history of ELA. This points to altered immune system functioning in the context of stress, a finding that may be driving increased morbidity and mortality risk for ELA-exposed individuals.

Glia-Driven Brain Circuit Refinement Is Altered by Early-Life Adversity: Behavioral Outcomes.

Early-life adversity (ELA), often clinically referred to as “adverse childhood experiences (ACE),” is the exposure to stress-inducing events in childhood that can result in poor health outcomes. ELA negatively affects neurodevelopment in children and adolescents resulting in several behavioral deficits and increasing the risk of developing a myriad of neuropsychiatric disorders later in life. The neurobiological mechanisms by which ELA alters neurodevelopment in childhood have been the focus of numerous reviews. However, a comprehensive review of the mechanisms affecting adolescent neurodevelopment (i.e., synaptic pruning and myelination) is lacking. Synaptic pruning and myelination are glia-driven processes that are imperative for brain circuit refinement during the transition from adolescence to adulthood. Failure to optimize brain circuitry between key brain structures involved in learning and memory, such as the hippocampus and prefrontal cortex, leads to the emergence of maladaptive behaviors including increased anxiety or reduced executive function. As such, we review preclinical and clinical literature to explore the immediate and lasting effects of ELA on brain circuit development and refinement. Finally, we describe a number of therapeutic interventions best-suited to support adolescent neurodevelopment in children with a history of ELA.

Early life adversity predicts brain-gut alterations associated with increased stress and mood

Alterations in the brain-gut system have been implicated in various disease states, but little is known about how early-life adversity (ELA) impacts development and adult health as mediated by brain-gut interactions. We hypothesize that ELA disrupts components of the brain-gut system, thereby increasing susceptibility to disordered mood. In a sample of 128 healthy adult participants, a history of ELA and current stress, depression, and anxiety were assessed using validated questionnaires. Fecal metabolites were measured using liquid chromatography tandem mass spectrometry-based untargeted metabolomic profiling. Functional brain connectivity was evaluated by magnetic resonance imaging. Sparse partial least squares-discriminant analysis, controlling for sex, body mass index, age, and diet was used to predict brain-gut alterations as a function of ELA. ELA was correlated with four gut-regulated metabolites within the glutamate pathway (5-oxoproline, malate, urate, and glutamate gamma methyl ester) and alterations in functional brain connectivity within primarily sensorimotor, salience, and central executive networks. Integrated analyses revealed significant associations between these metabolites, functional brain connectivity, and scores for perceived stress, anxiety, and depression. This study reveals a novel association between a history of ELA, alterations in the brain-gut axis, and increased vulnerability to negative mood and stress. Results from the study raise the hypothesis that select gut-regulated metabolites may contribute to the adverse effects of critical period stress on neural development via pathways related to glutamatergic excitotoxicity and oxidative stress.

Neurodevelopmental origins of substance use disorders: Evidence from animal models of early-life adversity and addiction.

Addiction is a chronic relapsing disorder with devastating personal, societal, and economic consequences. In humans, early-life adversity (ELA) such as trauma, neglect, and resource scarcity are linked with increased risk of later-life addiction, but the brain mechanisms underlying this link are still poorly understood. Here, we focus on data from rodent models of ELA and addiction, in which causal effects of ELA on later-life responses to drugs and the neurodevelopmental mechanisms by which ELA increases vulnerability to addiction can be determined. We first summarize evidence for a link between ELA and addiction in humans, then describe how ELA is commonly modeled in rodents. Since addiction is a heterogeneous disease with many individually varying behavioral aspects that may be impacted by ELA, we next discuss common rodent assays of addiction-like behaviors. We then summarize the specific addiction-relevant behavioral phenotypes caused by ELA in male and female rodents and discuss some of the underlying changes in brain reward and stress circuits that are likely responsible. By better understanding the behavioral and neural mechanisms by which ELA promotes addiction vulnerability, we hope to facilitate development of new approaches for preventing or treating addiction in those with a history of ELA.

Non-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience.

Mitochondria and early-life adversity

Early-life adversity (ELA), which includes maltreatment, neglect, or severe trauma in childhood, increases the life-long risk for negative health outcomes. Mitochondria play a key role in the stress response and may be an important mechanism by which stress is transduced into biological risk for disease. By responding to cues from stress-signaling pathways, mitochondria interact dynamically with physiological stress responses coordinated by the central nervous, endocrine, and immune systems. Preclinical evidence suggests that alterations in mitochondrial function and structure are linked to both early stress and systemic biological dysfunction. Early clinical studies support that increased mitochondrial DNA content and altered cellular energy demands may be present in individuals with a history of ELA. Further research should investigate mitochondria as a potential therapeutic target following ELA.

Early Life Adversity as a Moderator of Symptom Change following Selective Serotonin Reuptake Inhibitors and Cognitive Behavioral Therapy

Early Life Adversity (ELA) is consistently linked to chronic, treatment-resistant depression and anxiety. Selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy (CBT) represent the two first-line treatments for internalizing disorders. However, little is known about the efficacy of these therapies for individuals with ELA, particularly within heterogeneous cohorts of patients with high levels of comorbidity. Treatment seeking adults with depression and/or anxiety were randomized to twelve weeks of SSRI (n = 46) or CBT (n = 50), and internalizing disorder symptoms were assessed pre- and post-treatment. Individuals with and without ELA were included. Both SSRI and CBT resulted in reductions in internalizing symptoms, as expected. A significant ELA by treatment type interaction for depression, but not anxiety, also emerged. Individuals with a positive history of ELA had a greater reduction in depression symptoms following SSRIs compared with CBT. In contrast, individuals with a negative history of ELA had a greater reduction in depression symptoms following CBT compared with SSRIs. Findings suggest that SSRIs may be particularly effective for individuals with ELA and CBT may be particularly effective for individuals without ELA in reducing depression, but not anxiety, symptoms. Clinical implications and future directions are discussed.

Region-specific effects of maternal separation on oxidative stress accumulation in parvalbumin neurons of male and female rats

Early life adversity in humans is linked to cognitive deficits and increased risk of mental illnesses, including depression, bipolar disorder, and schizophrenia, with evidence for different vulnerabilities in men versus women. Modeling early life adversity in rodents shows similar neuropsychological deficits that may partially be driven by sex-dependent dysfunction in parvalbumin (PV) interneurons in the prefrontal cortex (PFC), hippocampus (HPC), and basolateral amygdala (BLA). Research demonstrates that PV interneurons are particularly susceptible to oxidative stress; therefore, accumulation of oxidative damage may drive PV dysfunction following early life adversity. The goal of this study was to quantify oxidative stress accumulation in PV neurons in rats exposed to maternal separation (MS). Pups were separated from their dam and littermates for 4 h per day from postnatal day (P)2 to 20. Serial sections from the PFC, HPC, and BLA of juvenile (P20) rats of both sexes were immunohistochemically stained with antibodies against PV and 8-oxo-dG, a marker for oxidative DNA damage. PV cell counts, colocalization with 8-oxo-dG, and intensity of each signal were measured in each region to determine the effects of MS and establish whether MS-induced oxidative damage varies between sexes. A significant increase in colocalization of PV and 8-oxo-dG was found in the PFC and HPC, indicating increased oxidative stress in that cell population following MS. Region-specific sex differences were also revealed in the PFC, BLA, and HPC. These data identify oxidative stress during juvenility as a potential mechanism mediating PV dysfunction in individuals with a history of early life adversity.

The hypothalamic-pituitary-adrenal axis in the perinatal period: Its relationship with major depressive disorder and early life adversity

Objectives: Effects of major depressive disorder and early life adversity (ELA) on the maternal HPA axis in the perinatal period were examined.Methods: Four groups of women (n = 127) were recruited, with the perinatal groups being compared during pregnancy (Preg) and at two months postpartum (PP) – [1] Depressed during pregnancy (Depressed-Preg/PP), [2] Prior history of depression but euthymic during pregnancy (History-Preg/PP), [3] Healthy pregnant women (Control-Preg/PP), and [4] Healthy non-pregnant women (Non-pregnant Control). Serial saliva samples were collected over the course of a day and waking and evening cortisol, total cortisol output and the cortisol awakening response were examined.Results: There were no HPA axis differences among the three groups during pregnancy. A history of ELA, regardless of comorbid depression, was associated with higher evening cortisol levels during pregnancy (p = 0.015). Women in the Depressed-PP group had had higher evening cortisol levels compared to the History-PP group (p < 0.017).Conclusions: Evening cortisol measures are a potential marker for both ELA and depression, with higher levels during pregnancy being associated with ELA and higher levels postpartum being associated with antenatal depression.

On the early life origins of vulnerability to opioid addiction.

The origins and neural bases of the current opioid addiction epidemic are unclear. Genetics plays a major role in addiction vulnerability, but cannot account for the recent exponential rise in opioid abuse, so environmental factors must contribute. Individuals with history of early-life adversity (ELA) are disproportionately prone to opioid addiction, yet whether ELA interacts with factors such as increased access to opioids to directly influence brain development and function and cause opioid addiction vulnerability is unknown. We simulated ELA in female rats and this led to a striking opioid addiction-like phenotype. This was characterized by resistance to extinction, increased relapse-like behavior, and, as in addicted humans, major increases in opioid economic demand. By contrast, seeking of a less salient natural reward was unaffected by ELA, whereas demand for highly palatable treats was augmented. These discoveries provide novel insights into the origins and nature of reward circuit malfunction that may set the stage for addiction.

History of early life adversity is associated with increased food addiction and sex-specific alterations in reward network connectivity in obesity.

SummaryBackgroundNeuroimaging studies have identified obesity‐related differences in the brain's resting state activity. An imbalance between homeostatic and reward aspects of ingestive behaviour may contribute to obesity and food addiction. The interactions between early life adversity (ELA), the reward network and food addiction were investigated to identify obesity and sex‐related differences, which may drive obesity and food addiction.MethodsFunctional resting state magnetic resonance imaging was acquired in 186 participants (high body mass index [BMI]: ≥25: 53 women and 54 men; normal BMI: 18.50–24.99: 49 women and 30 men). Participants completed questionnaires to assess ELA (Early Traumatic Inventory) and food addiction (Yale Food Addiction Scale). A tripartite network analysis based on graph theory was used to investigate the interaction between ELA, brain connectivity and food addiction. Interactions were determined by computing Spearman rank correlations, thresholded at q < 0.05 corrected for multiple comparisons.ResultsParticipants with high BMI demonstrate an association between ELA and food addiction, with reward regions playing a role in this interaction. Among women with high BMI, increased ELA was associated with increased centrality of reward and emotion regulation regions. Men with high BMI showed associations between ELA and food addiction with somatosensory regions playing a role in this interaction.ConclusionsThe findings suggest that ELA may alter brain networks, leading to increased vulnerability for food addiction and obesity later in life. These alterations are sex specific and involve brain regions influenced by dopaminergic or serotonergic signalling.

Chronic psychological stress during adolescence induces sex-dependent adulthood inflammation, increased adiposity, and abnormal behaviors that are ameliorated by selective inhibition of soluble tumor necrosis factor with XPro1595

Physical and psychosocial maltreatment experienced before the age of 18, termed early life adversity (ELA), affects an estimated 39% of the world’s population, and has long-term detrimental health and psychological outcomes. While adult phenotypes vary following ELA, inflammation and altered stress responsivity are pervasive. Cytokines, most notably tumor necrosis factor (TNF), are elevated in adults with a history of ELA. While soluble TNF (solTNF) drives chronic inflammatory disease, transmembrane TNF facilitates innate immunity. Here, we test whether solTNF mediates the behavioral and molecular outcomes of adolescent psychological stress by administering a brain permeable, selective inhibitor of solTNF, XPro1595. Male and female C57BL/6 mice were exposed to an aggressive rat through a perforated translucent ball (‘predatory stress’) or transported to an empty room for 30 min for 30 days starting on postnatal day 34. Mice were given XPro1595 or vehicle treatment across the last 15 days. Social interaction, sucrose preference, and plasma inflammation were measured at 2 and 4 weeks, and open field behavior, adiposity, and neuroinflammation were measured at 4 weeks. Chronic adolescent stress resulted in increased peripheral inflammation and dysregulated neuroinflammation in adulthood in a sex-specific manner. Abnormal social and open field behavior, fat pad weight, and fecal boli deposition were noted after 30 days; solTNF antagonism ameliorated the effects of stress. Together, these data support our hypothesis, and suggest that targeting solTNF with XPro1595 may improve quality of life for individuals with a history of adolescent stress.

Early life adversity blunts responses to pioglitazone in depressed, overweight adults

PurposeEarly life adversity is associated with both metabolic impairment and depression in adulthood, as well as with poorer responses to antidepressant medications. It is not yet known whether individual differences in sensitivity to antidiabetic medications could also be related to early life adversity. We examined whether a history of early life adversity affected the observed changes in metabolic function and depressive symptoms in a randomized trial of pioglitazone for augmentation of standard treatments for depression. PurposeEarly life adversity is associated with both metabolic impairment and depression in adulthood, as well as with poorer responses to antidepressant medications. It is not yet known whether individual differences in sensitivity to antidiabetic medications could also be related to early life adversity. We examined whether a history of early life adversity affected the observed changes in metabolic function and depressive symptoms in a randomized trial of pioglitazone for augmentation of standard treatments for depression. FindingsWe found that early life adversity significantly impaired the metabolic response to pioglitazone. Effects on depressive symptoms did not reach significance, but nonetheless suggested that pioglitazone could mitigate the depressant effects of childhood adversity, only among those insulin resistant at baseline. ConclusionsWe conclude that a history of early life adversity may impair the body’s ability to respond to insulin sensitizing pharmacotherapy, and furthermore that its contribution to resistant depression may function in part via the generation of an insulin resistant phenotype.

Blunted endocrine response to a combined physical-cognitive stressor in adults with early life adversity.

The negative health effects of early life adversity (ELA) continue long into adulthood. Changes in the physiological response to psychosocial stressors have been proposed to mediate this effect. However, many previous studies have come to contradicting conclusions as to whether ELA induces a long-term increase or decrease in stress reactivity. Therefore, we tested the association of ELA exposure and adult stress reactivity in a sample of early life adoptees and controls. Two previously validated stressful elements (bilateral feet CPT and the Paced Auditory Serial Addition Task (PASAT)) were combined in an extended Cold Pressor Test (CPT). This test was performed on 22 participants who had experienced severe ELA (separation from biological parents, institutionalization, and adoption in early childhood), and in 22 age-matched control participants. A prior history of ELA was associated with blunted reactivity of the hypothalamic-pituitary-adrenal (HPA) axis (Cohen´s d = 0.680). Cardiovascular reactivity remained unchanged, and affective reactivity (self-report ratings) were increased in participants exposed to ELA compared to the control group (range Cohen´s d: 0.642-0.879). Our results suggest that the activity of the HPA axis reactivity was inhibited in ELA participants. Importantly, cardiovascular stress responsiveness was not affected by ELA. This separation of the HPA axis and cardiovascular stress responses may best be explained by ELA selectively enhancing central feedback-sensitivity to glucocorticoids, but preserving cardiovascular/ autonomic stress reactivity.