Adverse childhood experiences and late-life diurnal HPA axis activity: Associations of different childhood adversity types and interaction with timing in a sample of older East Prussian World War II refugees.

Adverse childhood experiences (ACEs) have been associated with unfavorable health outcomes throughout the life up to old age. Mechanisms through which ACEs impact later life health are still not entirely clear. There is growing evidence for the idea that alterations in the hypothalamic pituitary adrenal (HPA) axis might cause the effects of ACEs on later health consequences. Only few studies have investigated associations between ACEs and diurnal HPA axis functioning in older adults. Therefore, we investigated the impact of type and timing of ACEs linked to flight of war on diurnal HPA axis activity in a sample of East Prussian World War II refugees aged 74-91 years. We calculated a dichotomous variable according to the (minimum) age at trauma: early ACE (eACE; 0-5 years) and late ACE (lACE; 6-17 years). Multiple linear regression analysis using different ACEs linked to flight of war (war-related trauma, individual experience of violence, neglect) as well as age at trauma and the interactions of ACEs and age at trauma as predictors and three cortisol outcomes (AUCG (area under the curve with respect to the ground), decline (morning to night) and CAR (cortisol awakening response)) was performed. For AUCG, we found a negative association of individual experience of violence only in lACE participants. For decline, a positive association with neglect was observed for the whole study sample. The overall model for CAR was not statistically significant. Our findings support the hypothesis that type as well as timing of ACEs might influence diurnal HPA axis functioning into old age. These findings may contribute to a better understanding of the lifelong influence of ACEs.

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.

Sex-specific interaction between cortisol and striato-limbic responses to psychosocial stress.

Although women and men differ in psychological and endocrine stress responses as well as in the prevalence rates of stress-related disorders, knowledge on sex differences regarding stress regulation in the brain is scarce. Therefore, we performed an in-depth analysis of data from 67 healthy participants (31 women, taking oral contraceptives), who were exposed to the ScanSTRESS paradigm in a functional magnetic resonance imaging study. Changes in cortisol, affect, heart rate and neural activation in response to psychosocial stress were examined in women and men as well as potential sex-specific interactions between stress response domains. Stress exposure led to significant cortisol increases, with men exhibiting higher levels than women. Depending on sex, cortisol elevations were differently associated with stress-related responses in striato-limbic structures: higher increases were associated with activations in men but with deactivations in women. Regarding affect or heart rate responses, no sex differences emerged. Although women and men differ in their overall stress reactivity, our findings do not support the idea of distinct neural networks as the base of this difference. Instead, we found differential stress reactions for women and men in identical structures. We propose considering quantitative predictors such as sex-specific cortisol increases when exploring neural response differences of women and men.

Investigating individual stress reactivity: High hair cortisol predicts lower acute stress responses.

Identifying individual differences in stress reactivity is of particular interest in the context of stress-related disorders and resilience. Previous studies already identified several factors mediating the individual stress response of the hypothalamus-pituitary-adrenal axis (HPA). However, the impact of long-term HPA axis activity on acute stress reactivity remains inconclusive. To investigate associations between long-term HPA axis variation and individual acute stress reactivity, we tested 40 healthy volunteers for affective, endocrine, physiological, and neural reactions to a modified, compact version of the established in-MR stress paradigm ScanSTRESS (ScanSTRESS-C). Hair cortisol concentrations (HCC) served as an integrative marker of long-term HPA axis activity. First, the ScanSTRESS-C version proved to be valid in evoking a subjective, endocrine, physiological, and neural stress response with enhanced self-reported negative affect and cortisol levels, increased heart rate as well as increased activation in the anterior insula and the dorso-anterior cingulate cortex (dACC). Second and interestingly, results indicated a lower neuroendocrine stress response in individuals with higher HCC: HCC was negatively correlated with the area under the curve (respect to increase; AUCi) of saliva cortisol and with a stress-related increase in dACC activity. The present study explicitly targeted the relationship between HCC and acute stress reactivity on multiple response levels, i.e. subjective, endocrine and neural stress responses. The lower stress reactivity in individuals with higher HCC levels indicates the need for further research evaluating the role of long-term HPA axis alterations in the context of vulnerability or immunization against acute stress and following stress-related impairments.

Temporal dynamics of cortisol-associated changes in mRNA expression of glucocorticoid responsive genes FKBP5, GILZ, SDPR, PER1, PER2 and PER3 in healthy humans.

Secretion of the stress hormone cortisol follows a circadian rhythm and is stimulated following stress exposure. Cortisol regulates the transcription of several genes, primarily through activation of the glucocorticoid receptor (GR). Previously, we showed an upregulation of PERIOD genes PER1 and PER3 after pharmacological/glucocorticoid challenge in vivo and in vitro. The current study aims to investigate the temporal association between unstimulated, diurnal cortisol secretion and the expression of selected GR-target genes (PER1, PER2, PER3, FKBP5, GILZ and SDPR) in vivo to determine the timing of the most pronounced coupling between cortisol and mRNA expression. Unstimulated plasma and saliva cortisol concentrations and gene expression levels in whole blood were measured every 15 min from early morning until 16:00 h in 18 healthy men. Time-lagged correlations of cortisol concentrations with mRNA expression levels were assessed allowing lags between -240 and + 240 min. Strong positive correlations at non-zero lags between cortisol levels and the expression of FKBP5 (plasma: r = 0.74 (CI = 0.65-0.81), p < 0.001, lag + 90 min; saliva: r = 0.71 (CI = 0.61-0.78), p < 0.001, lag + 75 min), and GILZ (plasma: r = 0.59 (CI = 0.46-0.69), p < 0.001, lag + 30 min; saliva r = 0.53 (CI = 0.41-0.63), p < 0.001, lag +15 min) were observed. Expressions of PERIOD genes and SDPR correlated only weakly with cortisol (all |r| < 0.25). Our findings demonstrate strong correlations between cortisol secretion and gene expression in humans under unstimulated conditions. The observed time-lags can guide future research aiming to characterize glucocorticoid-dependent gene expression in clinical samples with stress-related disorders.

The burden of conscientiousness? Examining brain activation and cortisol response during social evaluative stress.

Although conscientiousness has for a long time been considered generally adaptive, there are findings challenging this view, suggesting that conscientiousness might be less advantageous during uncontrollable stress. We here examined the impact of conscientiousness on brain activation during and the cortisol response following an uncontrollable social evaluative stress task in order to test this hypothesis. Brain activation and cortisol levels were measured during an fMRI stress task, where subjects (n=86) performed cognitive tasks containing preprogrammed failure under time pressure, while being monitored by a panel of experts inducing social-evaluative threat. The degree of conscientiousness was measured using the NEO-FFI. We observed a positive correlation between conscientiousness and salivary cortisol levels in response to the stressful task in male subjects only. In male subjects conscientiousness correlated positively with activation in right amygdala and left insula, and, moreover, mediated the influence of amygdala and insula activation on cortisol output. This pattern of brain activation can be interpreted as a disadvantageous response to uncontrollable stress to which highly conscientious individuals might be predisposed. This is the first study showing the effect of conscientiousness on physiology and brain activation to an uncontrollable psychosocial stressor. Our results provide neurobiological evidence for the hypothesis that conscientiousness should not just be seen as beneficial, but rather as a trait associated with either costs or benefits depending on the extent to which one is in control of the situation.

Sex-specific association between functional neuropeptide S receptor gene (NPSR1) variants and cortisol and central stress responses.

The brain neuropeptide S (NPS) system has recently generated substantial interest and may be of major relevance for central stress regulation. The NPS receptor (NPSR1) is highly expressed in the limbic system, exogenous NPS exerts pronounced anxiolytic and fear-attenuating effects in rodents and extensive close crosstalk between the NPS system and the hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated. In humans, associations between NPSR1 variants and anxiety and panic disorder, as well as amygdala responsiveness to fear- relevant faces and prefrontal cortex activity in a fear conditioning paradigm have been reported. Moreover, a NPSR1 sequence variant was found to be associated with cortisol stress responses in males. Here, we performed a haplotype-based analysis covering three functional NPSR1 single nucleotide polymorphisms in the promoter (rs2530547), in exon 3 (rs324981) and exon 6 (rs727162) in 277 healthy subjects who were exposed to the Trier Social Stress Test (TSST). A significant sex-specific association with salivary cortisol responses to acute psychosocial stress was detected for the common TTC haplotype 2 (frequency of about 20%). In an additional study using an imaging genetics approach, 65 healthy subjects were exposed to a stress paradigm for scanner environments ("ScanSTRESS"). We found a significant and, again, sex-specific interaction between rs324981 (whose minor T-allele is harbored by haplotype 2) and the neural stress response in a cluster close to the parahippocampal gyrus (whole brain corrected). Moreover, as in the TSST sample, NPSR1 variation was associated with salivary cortisol responses (on a trend level) in a sex-specific way. In summary, our preliminary findings in two independent cohorts exposed to different stress paradigms suggest that the NPS system significantly influences acute stress responses and that sequence variation in NPSR1 may contribute to sex differences in stress regulation.

Cortisol, but not intranasal insulin, affects the central processing of visual food cues.

Stress glucocorticoids and insulin are important endocrine regulators of energy homeostasis, but little is known about their central interaction on the reward-related processing of food cues. According to a balanced group design, healthy food deprived men received either 40IU intranasal insulin (n=13), 30mg oral cortisol (n=12), both (n=15), or placebo (n=14). Acoustic startle responsiveness was assessed during presentation of food and non-food pictures. Cortisol enhanced startle responsiveness during visual presentation of "high glycemic" food pictures, but not during presentation of neutral and pleasant non-food pictures. Insulin had no effect. Based on the "frustrative nonreward" model these results suggest that the reward value of high glycemic food items is specifically increased by cortisol.

Neuroimaging evidence for a role of neural social stress processing in ethnic minority-associated environmental risk.

IMPORTANCE: Relative risk for the brain disorder schizophrenia is more than doubled in ethnic minorities, an effect that is evident across countries and linked to socially relevant cues such as skin color, making ethnic minority status a well-established social environmental risk factor. Pathoepidemiological models propose a role for chronic social stress and perceived discrimination for mental health risk in ethnic minorities, but the neurobiology is unexplored. OBJECTIVE: To study neural social stress processing, using functional magnetic resonance imaging, and associations with perceived discrimination in ethnic minority individuals. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional design in a university setting using 3 validated paradigms to challenge neural social stress processing and, to probe for specificity, emotional and cognitive brain functions. Healthy participants included those with German lineage (n = 40) and those of ethnic minority (n = 40) from different ethnic backgrounds matched for sociodemographic, psychological, and task performance characteristics. Control comparisons examined stress processing with matched ethnic background of investigators (23 Turkish vs 23 German participants) and basic emotional and cognitive tasks (24 Turkish vs 24 German participants). MAIN OUTCOMES AND MEASURES: Blood oxygenation level-dependent response, functional connectivity, and psychological and physiological measures. RESULTS: There were significant increases in heart rate (P < .001), subjective emotional response (self-related emotions, P < .001; subjective anxiety, P = .006), and salivary cortisol level (P = .004) during functional magnetic resonance imaging stress induction. Ethnic minority individuals had significantly higher perceived chronic stress levels (P = .02) as well as increased activation (family-wise error-corrected [FWE] P = .005, region of interest corrected) and increased functional connectivity (PFWE = .01, region of interest corrected) of perigenual anterior cingulate cortex (ACC). The effects were specific to stress and not explained by a social distance effect. Ethnic minority individuals had significant correlations between perceived group discrimination and activation in perigenual ACC (PFWE = .001, region of interest corrected) and ventral striatum (PFWE = .02, whole brain corrected) and mediation of the relationship between perceived discrimination and perigenual ACC-dorsal ACC connectivity by chronic stress (P < .05). CONCLUSIONS AND RELEVANCE: Epidemiologists proposed a causal role of social-evaluative stress, but the neural processes that could mediate this susceptibility effect were unknown. Our data demonstrate the potential of investigating associations from epidemiology with neuroimaging, suggest brain effects of social marginalization, and highlight a neural system in which environmental and genetic risk factors for mental illness may converge.