Conceptual endophenotypes: A strategy to advance the impact of psychoneuroendocrinology in precision medicine.

Psychobiological research has generated a tremendous amount of findings on the psychological, neuroendocrine, molecular and environmental processes that are directly relevant for mental and physical health, but have overwhelmed our capacity to meaningfully absorb, integrate, and utilize this knowledge base. Here, we reflect about suitable strategies to improve the translational success of psychoneuroendocrinological research in the era of precision medicine. Following a strategy advocated by the National Research Council and the tradition of endophenotype-based research, we advance here a new approach, termed "conceptual endophenotypes". We define the contextual and formal criteria of conceptual endophenotypes, outline criteria for filtering and selecting information, and describe how conceptual endophenotypes can be validated and implemented at the bedside. As proof-of-concept, we describe some of our findings from research that has adopted this approach in the context of stress-related disorders. We argue that conceptual endophenotypes engineer a bridge between the bench and the bedside. This approach readily lends itself to being continuously developed and implemented. Recent methodological advances, including digital phenotyping, machine learning, grassroots collaboration, and a learning healthcare system, may accelerate the development and implementation of this conceptual endophenotype approach.

The role of early adversity and recent life stress in depression severity in an outpatient sample.

Pre-, peri-, and postnatal stress have frequently been reported to be associated with negative health outcomes during adult life. However, it is unclear, if these factors independently predict mental health in adulthood. We estimated potential associations between reports of pre-, peri-, and postnatal stress and depression severity in outpatients (N = 473) diagnosed with depression, anxiety or somatoform disorders by their family physician. We retrospectively assessed pre-, peri-, and postnatal stress and measured depression severity as well as recent life stress using questionnaires. First, we estimated if depression severity was predicted by pre-, peri- and/or postnatal stress using multiple regression models. Second, we compared pre- and postnatal stress levels between patient subgroups of different degrees of depression severity, performing multilevel linear modeling. Third, we analyzed if an association between postnatal stress and current depression severity was mediated by recent life stress. We found no associations of pre-, or perinatal stress with depression severity (all p > 0.05). Higher postnatal stress was associated with higher depression severity (p < 0.001). Patients with moderately severe and severe depression reported higher levels of postnatal stress as compared to patients with none to minimal, or mild depression (all p < 0.05). Mediation analysis revealed a significant indirect effect via recent life stress of the association between postnatal stress and depression severity (p < 0.001). In patients diagnosed for depression, anxiety, and/or somatoform disorders, postnatal but neither pre- nor perinatal stress predicted depression severity in adult life. This association was mediated by recent life stress.

Maternal adversities during pregnancy and cord blood oxytocin receptor (OXTR) DNA methylation.

The aim of this study was to investigate whether maternal adversities and cortisol levels during pregnancy predict cord blood DNA methylation of the oxytocin receptor (OXTR). We collected cord blood of 39 babies born to mothers participating in a cross-sectional study (N = 100) conducted in Basel, Switzerland (2007-10). Mothers completed the Inventory of Life Events (second trimester: T2), the Edinburgh Postnatal Depression Scale (EPDS, third trimester: T3), the Trier Inventory of Chronic Stress (TICS-K, 1-3 weeks postpartum) and provided saliva samples (T2, T3) for maternal cortisol profiles, as computed by the area under the curve with respect to ground (AUCg) or increase (AUCi) for the cortisol awakening response (CAR) and for diurnal cortisol profiles (DAY). OXTR DNA methylation was quantified using Sequenom EpiTYPER. The number of stressful life events (P = 0.032), EPDS score (P = 0.007) and cortisol AUCgs at T2 (CAR: P = 0.020; DAY: P = 0.024) were negatively associated with OXTR DNA methylation. Our findings suggest that distinct prenatal adversities predict decreased DNA methylation in a gene that is relevant for childbirth, maternal behavior and wellbeing of mother and offspring. If a reduced OXTR methylation increases OXTR expression, our findings could suggest an epigenetic adaptation to an adverse early environment.

Assessment of the cortisol awakening response: Expert consensus guidelines.

The cortisol awakening response (CAR), the marked increase in cortisol secretion over the first 30-45 min after morning awakening, has been related to a wide range of psychosocial, physical and mental health parameters, making it a key variable for psychoneuroendocrinological research. The CAR is typically assessed from self-collection of saliva samples within the domestic setting. While this confers ecological validity, it lacks direct researcher oversight which can be problematic as the validity of CAR measurement critically relies on participants closely following a timed sampling schedule, beginning with the moment of awakening. Researchers assessing the CAR thus need to take important steps to maximize and monitor saliva sampling accuracy as well as consider a range of other relevant methodological factors. To promote best practice of future research in this field, the International Society of Psychoneuroendocrinology initiated an expert panel charged with (i) summarizing relevant evidence and collective experience on methodological factors affecting CAR assessment and (ii) formulating clear consensus guidelines for future research. The present report summarizes the results of this undertaking. Consensus guidelines are presented on central aspects of CAR assessment, including objective control of sampling accuracy/adherence, participant instructions, covariate accounting, sampling protocols, quantification strategies as well as reporting and interpreting of CAR data. Meeting these methodological standards in future research will create more powerful research designs, thus yielding more reliable and reproducible results and helping to further advance understanding in this evolving field of research.

Frequency of Perceived Poststress Symptoms in Inpatients, Outpatients and Healthy Controls: The Role of Perceived Exhaustion and Stress.

BACKGROUND: Poststress symptoms occur as a consequence of stress, most commonly during leisure periods such as weekends and vacations. However, the prevalence and the pathological mechanisms of poststress symptoms are poorly understood. METHODS: Here, we compared the frequency of poststress symptoms in healthy controls (n = 984), outpatients (n = 420), and inpatients (n = 101). In outpatients, demographic factors, psychosocial stress, and perceived exhaustion were tested as predictors of poststress symptoms with multivariate regression analysis. Poststress symptoms and perceived exhaustion were assessed using 2 Neuropattern Questionnaires (the NPQ - Patient Questionnaire and the NPQ - Symptom List), and psychosocial stress was evaluated using the Patient Health Questionnaire (PHQ). RESULTS: Poststress symptoms appeared in 2.9% of healthy controls, 20.0% of outpatients, and 34.7% of inpatients. Predictors were educational level, psychosocial stress, and perceived exhaustion. Poststress symptoms differed primarily between exhausted (75.0%) and nonexhausted patients (25.0%). CONCLUSION: Poststress symptoms are rather common in clinical populations, and they are primarily associated with the degree of perceived exhaustion. Preliminary evidence suggests that poststress symptoms are possibly related to depletion of norepinephrine stores, which may facilitate a stratified preventive and therapeutic treatment of these subjects.

Lack of Breastfeeding: A Potential Risk Factor in the Multifactorial Genesis of Borderline Personality Disorder and Impaired Maternal Bonding.

Borderline personality disorder (BPD) is characterized by a pattern of intense but unstable interpersonal relationships. These interpersonal dysfunctions may originate from impaired bonding and attachment that is determined during early life. Remarkably, it has been reported that the quality of mother-infant relationship is influenced by the feeding mode. Thus, bottle feeding instead of breastfeeding and possible lack of maternal bonding-related behavior may increase the risk for later psychopathology and attachment problems as seen in BPD. A total of 100 BPD patients and 100 matched healthy controls underwent semistructured interviews, based on retrospective information about early risk factors and breastfeeding during infancy. The authors' analyses revealed that BPD patients were significantly less breastfed compared to healthy controls (no breastfeeding in BPD: 42.4%; no breastfeeding in controls: 18.2%; p < .001). The BPD diagnosis was significantly predicted by the variable "no breastfeeding" (p < .001; odds ratio [OR] = 3.32; confidence interval [CI] [1.74, 6.34]), even after adjustment for childhood trauma and several confounding factors (p = .001). The variable "no breastfeeding" accounts for 9.1% of the variance of the BPD diagnosis and is associated with low perceived maternal bonding (p = .006). Breastfeeding may act as an early indicator of the mother-infant relationship that seems to be relevant for bonding and attachment later in life.

Prenatal programming of emotion regulation: neonatal reactivity as a differential susceptibility factor moderating the outcome of prenatal cortisol levels.

OBJECTIVE: Hypothalamic-pituitary-adrenal (HPA) activation during pregnancy is linked to dysfunctional behavioral outcomes in the offspring. According to Belsky's differential susceptibility hypothesis, individuals vary regarding their developmental plasticity. Translating the differential susceptibility hypothesis to the field of fetal programming, we hypothesize that infants' temperament, as the constitutionally based reactivity to stimulation, moderates prenatal environmental effects on postnatal emotion regulation. METHODS: Maternal HPA axis activity and stress-reactivity during pregnancy was estimated, by measuring cortisol concentrations in saliva, collected at 0, 30, 45 and 60 min after awakening and in blood, collected during a laboratory stress test (Trier Social Stress Test), respectively. Newborns reactivity to stimulation was evaluated between postnatal day 10 and 14 using the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Infant's self-quieting-activities, as an indicator of emotion regulation, were evaluated at the age of six months during the still face paradigm. RESULTS: Maternal cortisol reactivity to stress during pregnancy was associated with infant's emotion regulation at the age of six months. Whereas cortisol levels after awakening in mid and late pregnancy were not associated with emotion regulation. Furthermore, regression analyses revealed that in interaction with neonatal reactivity, both, prenatal maternal HPA activity as well as prenatal maternal HPA reactivity to stress predicted emotion regulation. CONCLUSION: The findings indicate that newborns' reactivity to stimulation is moderating the association between prenatal exposure to maternal glucocorticoids and emotion regulation in infancy. Data suggests that temperamental characteristics of the newborn are a relevant differential susceptibility factor with regard to prenatal effects on emotion regulation.

Stress-induced allodynia--evidence of increased pain sensitivity in healthy humans and patients with chronic pain after experimentally induced psychosocial stress.

BACKGROUND: Experimental stress has been shown to have analgesic as well as allodynic effect in animals. Despite the obvious negative influence of stress in clinical pain conditions, stress-induced alteration of pain sensitivity has not been tested in humans so far. Therefore, we tested changes of pain sensitivity using an experimental stressor in ten female healthy subjects and 13 female patients with fibromyalgia. METHODS: Multiple sensory aspects of pain were evaluated in all participants with the help of the quantitative sensory testing protocol before (60 min) and after (10 and 90 min) inducing psychological stress with a standardized psychosocial stress test ("Trier Social Stress Test"). RESULTS: Both healthy subjects and patients with fibromyalgia showed stress-induced enhancement of pain sensitivity in response to thermal stimuli. However, only patients showed increased sensitivity in response to pressure pain. CONCLUSIONS: Our results provide evidence for stress-induced allodynia/hyperalgesia in humans for the first time and suggest differential underlying mechanisms determining response to stressors in healthy subjects and patients suffering from chronic pain. Possible mechanisms of the interplay of stress and mediating factors (e.g. cytokines, cortisol) on pain sensitivity are mentioned. Future studies should help understand better how stress impacts on chronic pain conditions.

How to measure prenatal stress? A systematic review of psychometric instruments to assess psychosocial stress during pregnancy.

BACKGROUND: A growing body of literature documents associations of maternal psychosocial stress during pregnancy with fetal, infant and child behaviour and development. However, findings across studies are often inconsistent, which may in part be due to differences in stress definitions and assessments. METHODS: We systematically reviewed methods applied to assess maternal psychosocial stress during pregnancy in studies looking at associations with biobehavioural outcomes in the offspring. A systematic literature search was performed on Web of Science and PubMed for the time period between January 1999 and October 2009. Psychometric instruments assessing maternal psychosocial stress during pregnancy were identified and described if data on psychometric properties were available. RESULTS: We identified 115 publications that assessed psychosocial stress during pregnancy with validated methods. These publications applied overall 43 different instruments assessing constructs falling under seven categories, ordered according to their frequency of use: anxiety, depression, daily hassles, aspects of psychological symptomatology (not reduced to anxiety or depression), life events, specific socio-environmental stressors and stress related to pregnancy and parenting. If available, we provide information on validity and reliability of the instruments for samples of pregnant women. CONCLUSIONS: Within the 'prenatal stress' research, a broad range of instruments is applied to assess psychosocial stress during pregnancy. Prenatal stress research should take into consideration that the variety of methods in use might hamper the comparability of stress research results. In each category of stress constructs, one instrument with good psychometric properties in pregnant women is highlighted as the best currently available measure.

Adult cognitive ability and socioeconomic status as mediators of the effects of childhood disadvantage on salivary cortisol in aging adults.

In this longitudinal study we investigate the influence of childhood disadvantage on midlife hypothalamic-pituitary-adrenal (HPA) axis regulation. Two mechanisms by which early life stress may affect later pathophysiology are through its influence on cognitive functioning or later socioeconomic (SES) disadvantage. We predicted that individual differences in young adult cognitive ability and midlife SES would mediate the influence of childhood disadvantage on midlife cortisol. On each of three nonconsecutive days, participants provided five salivary cortisol samples corresponding to their diurnal rhythm (N=727 men; mean age 55, SD=2.6). We calculated three measures of cortisol regulation (area-under-the curve cortisol reflecting total daytime cortisol output; cortisol-awakening-response; and wake-to-bed slope), averaging scores for each measure across multiple days. Childhood disadvantage combined four dichotomous indicators used previously by Rutter (1985): father low SES; mother education less than 12th grade; major family disruption/separation before age 18; and large family size (more than 5 siblings). The two mediators were a measure of general cognitive ability assessed at age 20 and highest achieved midlife SES. Men from more disadvantaged childhoods were significantly more likely to have dysregulated cortisol at midlife, with higher daytime cortisol levels decades after their childhood experience. Effects of childhood disadvantage were both direct and indirect. Cognitive ability and adult SES, however, only partially mediated the associations between early life stress and midlife cortisol. Specific indirect effects accounted for 33.8% of the total effect of childhood disadvantage [ß=0.12 (0.05; 0.18)] on total daytime cortisol. Associations remained significant after accounting for ethnicity, smoking status, and self-reported depressive symptoms.

Salivary cortisol in ambulatory assessment--some dos, some don'ts, and some open questions.

The impact of stress on health and disease is an important research topic in psychosomatic medicine. Because research on hypothalamic-pituitary-adrenal (HPA) axis regulation under controlled laboratory studies lacks ecological validity, it needs to be complemented by a research program that includes momentary ambulatory assessment. The measurement of salivary cortisol offers the possibility to trace the free steroid hormone concentrations in ambulant settings. Therefore, in this article, we first discuss the role of salivary cortisol in ambulatory monitoring. We start with a brief description of HPA axis regulation, and we then consider cortisol assessments in other organic materials, followed by a presentation of common salivary markers of HPA axis regulation suitable for ambulatory assessment. We further provide an overview on assessment designs and sources of variability within and between subjects (intervening variables), acknowledge the issue of (non)compliance, and address statistical aspects. We further give an overview of associations with psychosocial and health-related variables relevant for ambulatory assessment. Finally, we deal with preanalytical aspects of laboratory salivary cortisol analysis. The relative simplicity of salivary cortisol assessment protocols may lead to an overoptimistic view of the robustness of this method. We thus discuss several important issues related to the collection and storage of saliva samples and present empirical data on the stability of salivary cortisol measurements over time.

Positive life events predict salivary cortisol in pregnant women.

Maternal stress during pregnancy has been repeatedly associated with problematic child development. According to the fetal programming hypothesis adverse experiences during pregnancy increase maternal cortisol, which is then assumed to exert a negative effect on fetal development. Recent studies in non-pregnant women report significant associations between positive emotionality and low cortisol levels. We tested in a sample of 60 pregnant women whether both negative and positive life events independently predicted third-trimester baseline awakening cortisol levels. While the effect of negative life events proved unrelated positive life events significantly predicted lower cortisol levels. These findings suggest that positive experiences are of relevance regarding maternal morning cortisol levels in pregnancy reflecting a resource with potentially beneficial effects for the mother and the developing fetus. It might be promising for psychological intervention programs to focus on increasing positive experiences of the expecting mother rather than exclusively trying to reduce maternal stress during pregnancy.

Increased peripheral NF-κB pathway activity in women with childhood abuse-related posttraumatic stress disorder.

In addition to neuroendocrine changes PTSD pathophysiology may also involve dysfunction of the innate immune inflammatory system. PTSD patients have been found to exhibit increased concentrations of circulating inflammatory markers such as C-reactive protein and interleukin-6, suggesting dysfunction of the innate immune inflammatory system. However, few studies have investigated molecular signaling pathways known to critically regulate inflammation. Additionally, the relationship between inflammatory function and immune cell glucocorticoid sensitivity has not been extensively explored in PTSD. Nuclear factor-κB (NF-κB) pathway activity was examined in peripheral blood mononuclear cells obtained from 12 women with childhood abuse-related PTSD and 24 healthy controls (ages 19-48) using DNA-binding ELISA. Glucocorticoid sensitivity of monocytes in whole blood was measured as the concentration of dexamethasone needed to suppress in vitro lipopolysaccharide-induced tumor necrosis factor-alpha production by 50% (DEX IC(50)). Women with PTSD displayed increased NF-κB pathway activity compared to controls (t [34]=2.45, p=0.02) that was positively correlated with PTSD severity (determined by PTSD symptom severity scale) (r(s)=0.39, p=0.02). Increased NF-κB pathway activity was associated with increased whole blood monocyte DEX IC(50) (i.e. decreased sensitivity of monocytes to glucocorticoids) across all participants (r=0.66, p<0.001). These findings suggest that enhanced inflammatory system activity in participants with childhood abuse-related PTSD is observable at the level of NF-κB, and that in general decreased immune cell glucocorticoid sensitivity may contribute to increased NF-κB pathway activity. Enhanced inflammation may contribute to co-morbid somatic disease risk in persons with childhood abuse-related PTSD.

Neuropattern: a new translational tool to detect and treat stress pathology. II. The Teltow study.

The present study was designed to test the clinical utility of Neuropattern (NP), a newly developed translational diagnostic tool. NP consists of biological and psychological measures that facilitate the identification of functional changes (called "neuropatterns") in patients with stress-related health problems. In this prospective, randomized control trial, we expected NP to improve therapeutic efficacy, as compared with the usual treatment. NP was applied to 101 in-patients suffering from various mental disorders (mainly depression, anxiety disorders, and adjustment disorders), and scoring high on the Symptom Checklist-90-R (SCL-90-R) somatization scale. The patients (73% females, mean ± standard deviation age 46 ± 9.03 years) were randomly assigned to two groups: in the experimental group (n = 51), physicians received results from NP diagnostics, while in the control group (n = 50), this information was not available until discharge from the hospital. Improvements of symptoms in consequence of treatment were monitored by two self-rating scales, the SCL-90-R and Short Form-12 health survey, and a physician's clinical global rating (Beeinträchtigungs-Schwere Score). There was a significantly greater improvement in the experimental group in the self-rating assessments on symptom severity (p = 0.03) and quality of life (p = 0.05), but not in the observer rating of emotional, physical, and social-communicative functioning (p = 0.13). Treatment efficacy in patients can be improved by providing the attendant physician and the patient with diagnostic information and treatment recommendations by NP. The role of concrete mediators of treatment efficacy awaits further research.

Stress exposure in intrauterine life is associated with shorter telomere length in young adulthood.

Leukocyte telomere length (LTL) is a predictor of age-related disease onset and mortality. The association in adults of psychosocial stress or stress biomarkers with LTL suggests telomere biology may represent a possible underlying mechanism linking stress and health outcomes. It is, however, unknown whether stress exposure in intrauterine life can produce variations in LTL, thereby potentially setting up a long-term trajectory for disease susceptibility. We, therefore, as a first step, tested the hypothesis that stress exposure during intrauterine life is associated with shorter telomeres in adult life after accounting for the effects of other factors on LTL. LTL was assessed in 94 healthy young adults. Forty-five subjects were offspring of mothers who had experienced a severe stressor in the index pregnancy (prenatal stress group; PSG), and 49 subjects were offspring of mothers who had a healthy, uneventful index pregnancy (comparison group; CG). Prenatal stress exposure was a significant predictor of subsequent adult telomere length in the offspring (178-bp difference between prenatal stress and CG; d = 0.41 SD units; P < 0.05). The effect was substantially unchanged after adjusting for potential confounders (subject characteristics, birth weight percentile, and early-life and concurrent stress level), and was more pronounced in women (295-bp difference; d = 0.68 SD units; P < 0.01). To the best of our knowledge, this study provides the first evidence in humans of an association between prenatal stress exposure and subsequent shorter telomere length. This observation may help shed light on an important biological pathway underlying the developmental origins of adult health and disease risk.

Genetic and environmental effects on diurnal dehydroepiandrosterone sulfate concentrations in middle-aged men.

BACKGROUND: Dehydroepiandrosterone sulfate (DHEAS) is important for its association with immune system function and health outcomes. The characterization of the genetic and environmental contributions to daily DHEAS concentrations is thus important for understanding the genetics of health and aging. METHODS: Saliva was collected from 783 middle-aged men (389 complete pairs and 5 unpaired twins) as part of the Vietnam Era Twin Study of Aging. Samples were taken at multiple specified time points across two non-consecutive days in the home and one day at the study sites. A twin modeling approach was used to estimate genetic and environmental contributions for time-specific and average DHEAS concentrations. RESULTS: There was a consistent diurnal pattern for DHEAS concentrations in both at-home and day-of-testing (DOT) measures, which was the highest at awakening and decreased slightly throughout the day. Heritability estimates were significant for measures at 10 am, 3 pm and bedtime for the in-home days and at 10 am and 3 pm on the DOT, ranging between 0.37 and 0.46. CONCLUSIONS: The significant heritability estimates later in the day reflect time-specific genetic effects for DHEAS, compared with prior twin and family designs studies which frequently used averaged morning-only measures. Additive genetic influences on DHEAS concentrations were consistent between at-home and DOT measures.

Plasma oxytocin concentration during pregnancy is associated with development of postpartum depression.

Postpartum depression (PPD) affects up to 19% of all women after parturition. The non-apeptide oxytocin (OXT) is involved in adjustment to pregnancy, maternal behavior, and bonding. Our aim was to examine the possible association between plasma OXT during pregnancy and the development of PPD symptoms. A total of 74 healthy, pregnant women were included in this prospective study. During the third trimester of pregnancy and within 2 weeks after parturition, PPD symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). Blood samples for plasma OXT assessment were collected in the third trimester. Following the literature, participants with postpartum EPDS scores of 10 or more were regarded as being at risk for PPD development (rPPD group). In a logistic regression analysis, plasma OXT was included as a potential predictor for being at risk for PPD. Results were controlled for prepartal EPDS score, sociodemographic and birth-outcome variables. Plasma OXT concentration in mid-pregnancy significantly predicted PPD symptoms at 2 weeks postpartum. Compared with the no-risk-for-PPD group, the rPPD group was characterized by lower plasma OXT concentrations. To our knowledge, this is the first study to show an association between prepartal plasma OXT concentration and postpartal symptoms of PPD in humans. Assuming a causal relationship, enhancing OXT release during pregnancy could serve as a potential target in prepartum PPD prevention, and help to minimize adverse effects of PPD on the mother-child relationship.

Negative emotionality, depressive symptoms and cortisol diurnal rhythms: analysis of a community sample of middle-aged males.

Prior research suggests that individuals with particular personality traits, like negative emotionality, are at greater risk for adverse health outcomes. Despite bivariate associations between negative emotionality, depressive symptoms and the hypothalamic pituitary adrenal axis (HPA axis), few studies have sought to understand the biological pathways through which negative emotionality, depressive symptomatology and cortisol-one of the primary hormonal products of the HPA axis--are associated. The present study explored whether negative emotionality influenced cortisol dysregulation through current depressive symptomatology and whether negative emotionality served as a moderator of the relationship between depressive symptoms and cortisol. In the community-based Vietnam Era Twin Study of Aging, 783 male twins completed two days of cortisol saliva sampling in their natural environments. Three measures of cortisol were analyzed: waking levels, the cortisol awakening response, and the peak to bed slope. Depressive symptoms significantly mediated the associations between negative emotionality and the peak to bed slope. A 2-way interaction between depressive symptoms and negative emotionality was significant for the peak to bed slope and for waking levels of cortisol. Exploration of the interactions illustrated that depressive symptoms only affected cortisol slopes at average or high levels of negative emotionality and only affected waking levels at low levels of negative emotionality. Negative emotionality and depressive symptoms were not related to the cortisol awakening response. This is the first study to find indirect associations between negative emotionality and peak to bed cortisol slopes through depressive symptoms. These findings illustrate the complex interplay between personality characteristics, depressive symptoms and different indices of the cortisol diurnal rhythm.

Cross-sectional and 35-year longitudinal assessment of salivary cortisol and cognitive functioning: the Vietnam Era twin study of aging.

High levels of cortisol, a sign of potential hypothalamic-pituitary-adrenal (HPA) axis dysregulation, have been associated with poor cognitive outcomes in older adults. Most cortisol research has focused on hippocampal-related abilities such as episodic memory; however, the presence of glucocorticoid receptors in the human prefrontal cortex suggests that cortisol regulation is likely to be associated with prefrontally-mediated executive function abilities. We hypothesized that elevated cortisol levels would be associated with poorer frontal-executive function in addition to episodic memory. We assessed cortisol from 15 saliva samples paralleling individual diurnal rhythms across three non-consecutive days in a group of 778 middle-aged twin men ages 51-60. Cognitive domains created from 24 standard measures included: general cognitive ability, verbal and visual-spatial ability, verbal and visual-spatial memory, short-term/immediate memory, working memory, executive function, verbal fluency, abstract reasoning, and psychomotor processing speed. Adjusting for general cognitive ability at age 20, age, race, and multiple health and lifestyle indicators, higher levels of average area-under-the-curve cortisol output across three days were significantly associated with poorer performance in three domains: executive (primarily set-shifting) measures, processing speed, and visual-spatial memory. In a 35-year longitudinal component of the study, we also found that general cognitive ability at age 20 was a significant predictor of midlife cortisol levels. These results possibly support the notion that glucocorticoid exposure is associated with cognitive functions that are mediated by frontal-striatal systems, and is not specific to hippocampal-dependent memory. The results also suggest that the direction of effect is complex.

Cortisol levels in pregnancy as a psychobiological predictor for birth weight.

Antenatal maternal stress is thought to negatively affect fetal development, birth outcomes, and infant's development. Glucocorticoids are suggested to be a common link between prenatal stressors and infant's health. However, data on these mechanisms are rare and sometimes conflicting. The objective of this study was to examine the effects of maternal distress during pregnancy on fetal development and birth weight in humans prospectively. This study focuses on cortisol as one mediating the mechanism of the association between maternal distress and birth outcomes. Pregnancy-related and general distress was measured in 81 women with uncomplicated, singleton pregnancies. The rise of salivary cortisol on awakening (CAR) was assessed in weeks 13-18 and 35-37 postmenstrual age of pregnancy. Mothers completed a structured interview, the perceived stress scale, a widely used psychological instrument that provided a global measure of perceived stress, as well as the Prenatal Distress Questionnaire, a self-report questionnaire designed to assess worries and anxiety in pregnancy. Pre-, peri-, and postnatal medical risk factors as well as birth characteristics were extracted from medical records routinely kept by the attending obstetricians. Hierarchical multiple regressions indicate that maternal cortisol levels explained 19.8% of the variance in birth weight and 9% of the variance in body length at birth, even after controlling for gestational age, parity, pre-pregnancy BMI, smoking, and infant's sex. Newborns of mothers with higher cortisol levels in pregnancy had lower birth weights and were shorter at birth. An ANCOVA for repeated measures indicated that, after controlling for covariates, pregnancy-related as well as general distress in pregnancy did not influence cortisol levels after awakening (area under the curve). No significant associations between perceived stress and anthrometric measures at birth were found. In conclusion, maternal cortisol levels in pregnancy influence intrauterine growth and may be a better predictor for birth outcome than perceived stress.