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Objective: Hypothalamic-pituitary-adrenal axis (HPA) activity is decreased in obese pregnancy and associates with increased foetal size. Pulsatile release of glucocorticoid hormones regulates their action in target tissues. Glucocorticoids are essential for normal foetal growth, but little is known about glucocorticoid pulsatility in pregnancy. We aimed to investigate the ultradian rhythm of glucocorticoid secretion during obese and lean pregnancy and nonpregnancy. Design: Serum cortisol, cortisone, corticosterone and 11-dehydrocorticosterone were measured by LC-MS/MS from samples obtained at 10-minute intervals between 08.00-11.00 hours and 16.00-19.00 hours, from 8 lean (BMI 2) and 7 obese (BMI > 35 kg/m2) pregnant women between 16-24 weeks gestation and again at 30-36 weeks), and nonpregnant controls (lean n = 3, obese n = 4) during the luteal phase of their menstrual cycle. Interstitial fluid cortisol was measured by ELISA, from samples obtained using a portable microdialysis and automated collection device at 20-minute intervals over 24 hours. Results: Serum cortisol AUC, highest peak and lowest trough increased significantly with gestation in lean and obese pregnant compared with nonpregnant subjects. Pulsatility of cortisol was detected in interstitial fluid. In pregnant subjects, interstitial fluid pulse frequency was significantly lower with advancing gestation in obese, but not in lean. Conclusions: We demonstrate cortisol pulsatility in interstitial fluid. Pulse frequency is altered with increased gestation and BMI. This may be a novel mechanism to explain decreased HPA activity in obese pregnancy.

Background Cesarean birth rates continue to rise worldwide with recent (2016) reported rates of 24.5% in Western Europe, 32% in North America, and 41% in South America. The objective of this systematic review is to describe the long-term risks and benefits of cesarean delivery for mother, baby, and subsequent pregnancies. The primary maternal outcome was pelvic floor dysfunction, the primary baby outcome was asthma, and the primary subsequent pregnancy outcome was perinatal death. Methods and findings Medline, Embase, Cochrane, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were systematically searched for published studies in human subjects (last search 25 May 2017), supplemented by manual searches. Included studies were randomized controlled trials (RCTs) and large (more than 1,000 participants) prospective cohort studies with greater than or equal to one-year follow-up comparing outcomes of women delivering by cesarean delivery and by vaginal delivery. Two assessors screened 30,327 abstracts. Studies were graded for risk of bias by two assessors using the Scottish Intercollegiate Guideline Network (SIGN) Methodology Checklist and the Risk of Bias Assessment tool for Non-Randomized Studies. Results were pooled in fixed effects meta-analyses or in random effects models when significant heterogeneity was present (I2 ≥ 40%). One RCT and 79 cohort studies (all from high income countries) were included, involving 29,928,274 participants. Compared to vaginal delivery, cesarean delivery was associated with decreased risk of urinary incontinence, odds ratio (OR) 0.56 (95% CI 0.47 to 0.66; n = 58,900; 8 studies) and pelvic organ prolapse (OR 0.29, 0.17 to 0.51; n = 39,208; 2 studies). Children delivered by cesarean delivery had increased risk of asthma up to the age of 12 years (OR 1.21, 1.11 to 1.32; n = 887,960; 13 studies) and obesity up to the age of 5 years (OR 1.59, 1.33 to 1.90; n = 64,113; 6 studies). Pregnancy after cesarean delivery was associated with increased risk of miscarriage (OR 1.17, 1.03 to 1.32; n = 151,412; 4 studies) and stillbirth (OR 1.27, 1.15 to 1.40; n = 703,562; 8 studies), but not perinatal mortality (OR 1.11, 0.89 to 1.39; n = 91,429; 2 studies). Pregnancy following cesarean delivery was associated with increased risk of placenta previa (OR 1.74, 1.62 to 1.87; n = 7,101,692; 10 studies), placenta accreta (OR 2.95, 1.32 to 6.60; n = 705,108; 3 studies), and placental abruption (OR 1.38, 1.27 to 1.49; n = 5,667,160; 6 studies). This is a comprehensive review adhering to a registered protocol, and guidelines for the Meta-analysis of Observational Studies in Epidemiology were followed, but it is based on predominantly observational data, and in some meta-analyses, between-study heterogeneity is high; therefore, causation cannot be inferred and the results should be interpreted with caution. Conclusions When compared with vaginal delivery, cesarean delivery is associated with a reduced rate of urinary incontinence and pelvic organ prolapse, but this should be weighed against the association with increased risks for fertility, future pregnancy, and long-term childhood outcomes. This information could be valuable in counselling women on mode of delivery., In a systematic review and meta-analysis, Sarah Stock exmines the long-term risks and benefits associated with cesarean delivery for mother, baby, and subsequent pregnancies., Author summary Why was this study done? Cesarean delivery rates are rising worldwide, and in particular, rates of cesarean delivery without medical indication are increasing. The short-term associations of cesarean delivery are well described in the literature, but women are less informed of the long-term risks and benefits of cesarean delivery on themselves, their offspring, and their future pregnancies. This review aims to synthesize the available evidence on the long-term associations with cesarean delivery. What did the researchers do and find? We performed a systematic review looking for randomized controlled trials and large prospective cohort studies that assessed long-term outcomes following caesarean delivery compared with vaginal delivery. We found that cesarean delivery is associated with reduced urinary incontinence and pelvic organ prolapse in the mother but with increased odds of asthma and obesity in the child. Cesarean delivery is associated with future subfertility and several subsequent pregnancy risks such as placenta previa, uterine rupture, and stillbirth. What do these findings mean? These findings might help enhance discussions between clinicians and patients regarding mode of delivery, meaning that patients will be better informed of the potential long-term risks and benefits of cesarean delivery for themselves, their offspring, and any future pregnancies. The majority of included data are from observational studies that were performed in high-income countries. This means that the results should be interpreted with caution, and findings may not be generalizable to other healthcare settings.

Prenatal programming of hypothalamic-pituitary-adrenal (HPA) axis activity has long term implications for offspring health. Biological mechanisms underlying programming of the offspring HPA axis are poorly understood. We hypothesised that altered maternal metabolism including higher maternal obesity, glucose and lipids are novel programming factors for altered offspring HPA axis activity. Salivary cortisol levels were measured in 54 children aged 3-5 years under experimental conditions (before and after a delay of self-gratification test). Associations of child cortisol responses with maternal obesity in early pregnancy and with fasting glucose, triglycerides, HDL and total cholesterol measured in each pregnancy trimester were tested. Higher levels of maternal triglycerides and total cholesterol throughout pregnancy were associated with increased offspring cortisol reactivity. The associations were independent of maternal obesity and other confounders, suggesting that exposure to maternal lipids could be a biological mechanism of in utero programming of the offspring's HPA axis.

Background Global cesarean section (CS) rates range from 1% to 52%, with a previous CS being the commonest indication. Labour following a previous CS carries risk of scar rupture, with potential for offspring hypoxic brain injury, leading to high rates of repeat elective CS. However, the effect of delivery by CS on long-term outcomes in children is unclear. Increasing evidence suggests that in avoiding exposure to maternal bowel flora during labour or vaginal birth, offspring delivered by CS may be adversely affected in terms of energy uptake from the gut and immune development, increasing obesity and asthma risks, respectively. This study aimed to address the evidence gap on long-term childhood outcomes following repeat CS by comparing adverse childhood health outcomes after (1) planned repeat CS and (2) unscheduled repeat CS with those that follow vaginal birth after CS (VBAC). Methods and Findings A data-linkage cohort study was performed. All second-born, term, singleton offspring delivered between 1 January 1993 and 31 December 2007 in Scotland, UK, to women with a history of CS (n = 40,145) were followed up until 31 January 2015. Outcomes assessed included obesity at age 5 y, hospitalisation with asthma, learning disability, cerebral palsy, and death. Cox regression and binary logistic regression were used as appropriate to compare outcomes following planned repeat CS (n = 17,919) and unscheduled repeat CS (n = 8,847) with those following VBAC (n = 13,379). Risk of hospitalisation with asthma was greater following both unscheduled repeat CS (3.7% versus 3.3%, adjusted hazard ratio [HR] 1.18, 95% CI 1.05–1.33) and planned repeat CS (3.6% versus 3.3%, adjusted HR 1.24, 95% CI 1.09–1.42) compared with VBAC. Learning disability and death were more common following unscheduled repeat CS compared with VBAC (3.7% versus 2.3%, adjusted odds ratio 1.64, 95% CI 1.17–2.29, and 0.5% versus 0.4%, adjusted HR 1.50, 95% CI 1.00–2.25, respectively). Risk of obesity at age 5 y and risk of cerebral palsy were similar between planned repeat CS or unscheduled repeat CS and VBAC. Study limitations include the risk that women undergoing an unscheduled CS had intended to have a planned CS, and lack of data on indication for CS, which may confound the findings. Conclusions Birth by repeat CS, whether planned or unscheduled, was associated with an increased risk of hospitalisation with asthma but no difference in risk of obesity at age 5 y. Greater risk of death and learning disability following unscheduled repeat CS compared to VBAC may reflect complications during labour. Further research, including meta-analyses of studies of rarer outcomes (e.g., cerebral palsy), are needed to confirm whether such risks are similar between delivery groups., Editors' Summary Background Women who have had a previous cesarean section (CS) face a slightly elevated risk of negative outcomes during a subsequent vaginal birth. This is because, in rare cases, the abdominal CS scar ruptures during labor, which may cause complications and serious problems, such as oxygen deprivation to the brain of a child. As a result, pregnant women who have had a previous CS and their doctors sometimes make a decision to plan a repeat CS instead of a vaginal birth after cesarean section (VBAC). Besides vaginal birth being “more natural,” some studies have suggested that exposure to the mother’s microbiome (the bacteria and fungi that live in the vagina and gut) in the birth canal might be important for the healthy development of the infant’s own microbiome and its immune system. Consistent with this notion, some studies have reported higher levels of allergies (including eczema and asthma) and overweight or obesity in children born by CS. Why Was This Study Done? Scotland keeps detailed records of births and childhood health data, which allow researchers to study possible links between type of birth and subsequent childhood health outcomes. In this study, the researchers focused on singleton births (as opposed to twins, triplets, etc.) to mothers who have had a previous CS. In this group, where the decision about a preferred delivery mode is likely made before labor starts, they examined how childhood health outcomes compared between repeat CS and VBAC. What Did the Researchers Do and Find? The researchers studied all second births between 1 January 1993 and 31 December 2007 of singleton children to mothers in Scotland who had previously had a first child born by CS. Using available health records, they categorized these second births into scheduled repeat CS (assumed to be planned), unscheduled repeat CS, and VBAC. They then examined the childrens’ health records until 31 January 2015 and looked for correlations between type of birth and the following outcomes: obesity at age five years, hospitalization with asthma, prescription of a salbutamol inhaler (an asthma medication) at age five, hospitalization with inflammatory bowel disease, type 1 diabetes, learning disability, cerebral palsy, cancer, and death. Of 40,145 births that took place, 44.6% were scheduled repeat CS, 22.1% were unscheduled repeat CS, and 33.3% were VBAC. The only consistent difference the researchers found between repeat CS (scheduled or unscheduled) and VBAC was a slightly elevated risk for hospitalization with asthma in children born by CS. They felt that this was not clinically significant, especially as there was no difference in the rate of salbutamol inhaler prescription. The risk of obesity at age five was similar between children born by repeat CS (scheduled or unscheduled) and those born by VBAC. Learning disability and death were more common following unscheduled repeat CS, but not scheduled repeat CS, than following VBAC. What Do These Findings Mean? Overall, the right decision about a planned birth mode, vaginal or cesarean, depends on the individual case of mother and child. If mothers with a previous CS plan a vaginal birth, they should do so in a hospital that is prepared to perform a CS at short notice in case of scar rupture. The findings here suggest that there are no substantially worse outcomes associated with planned repeat cesarean births. They therefore support a process of planning birth after a previous CS that reflects a woman’s values and preferences. Whether the births analyzed in this study were initially planned to be vaginal or CS is not known. The researchers assumed an intended CS was one that was scheduled ahead of time and performed on the scheduled date. All other CSs were categorized as unplanned and likely represent a mix of emergency CS ahead of a planned CS and emergency CS after complications during a planned vaginal birth. The reasons for the observed higher risk of learning disability and death following unscheduled repeat CS are not clear because the records did not include the indication (i.e., the medical reason) for a CS, but the results are consistent with the known higher risk of an emergency CS to mothers and children. The risks and benefits of different birth modes, especially in view of exposure to the mother’s microbiome, are active areas of research. The results here disagree with some earlier studies in different settings, but these were unable to adjust for some factors that can affect child health that are taken into account here, such as whether mothers were obese, smoked, or had asthma. The findings of this study are consistent with a study by the same researchers that analyzed all singleton first births from the Scottish health records and found slightly increased asthma rates, but no increased obesity or type 1 diabetes, in young children who had been delivered by CS compared with those who had a vaginal birth. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001973. The Royal College of Obstetricians and Gynaecologists in the UK has a practice guideline and patient information leaflet on birth after cesarean section The American Congress of Obstetricians and Gynecologists has a practice bulletin for vaginal birth after previous cesarean delivery, women’s health resources related to vaginal birth after cesarean, and women’s health resources related to cesarean section in general Wikipedia has a page on delivery after previous cesarean section (note that Wikipedia is an online encyclopedia that anyone can edit) The Royal Australian and New Zealand College of Obstetricians and Gynaecologists has a statement on birth after previous cesarean section The Institute of Obstetricians and Gynaecologists of the Royal College of Physicians of Ireland has a clinical practice guideline on delivery after cesarean section

Stress diseases such as affective disorders are often characterized by a disturbed regulation of the hypothalamus-pituitary-adrenocortical (HPA) axis. This dysregulation can be explained by an impaired function of the receptors involved in the HPA-axis regulation, for example, the glucocorticoid receptors (GR). The regulation process of the HPA axis and the GR function are influenced by several genes, for instance by NR3C1 coding for the GR and also by FKBP5, a co-chaperone in the GR-complex. Binder et al. showed that common polymorphisms in FKBP5 are associated with increased FKBP5 protein expression as well as correlation between cortisol levels and peripheral blood FKBP5 mRNA expression. Regarding the effects of FKPB5 genotypes on psychosocial stress reaction, Ising and colleagues tested healthy subjects with the Trier Social Stress Test, a standardized paradigm to induce psychosocial stress. Subjects homozygous for any of the FKBP5 variants showed an incomplete normalization of the stress induced cortisol secretion. Recent studies demonstrated that FKBP5 and NR3C1 are involved in the endocrine stress reaction. Therefore, we expected changes of FKBP5 and NR3C1 mRNA expression in peripheral blood after exposure to a psychosocial stress situation. To address this, we performed a pilot study where we tested six healthy young men without history of psychiatric or severe somatic disorders and applied the trier social stress test (TSST). Before and after two consecutive TSSTs, we took blood samples with a venous catheter in order to measure ACTH and cortisol in plasma and mRNA expression of the candidate genes in peripheral blood. Blood cells were stabilized using PAXgene tubes, and gene expression was processed by qPCR. Briefly after the psychosocial stress the stress hormones ACTH and cortisol increased whereas the reaction to the second TSST was lower suggesting a habituation effect. These endocrine stress responses were followed by an alteration in FKBP5 gene expression, further underlining the importance of this gene for the neuroendocrine stress reaction. NR3C1 mRNA levels did not change after the TSST. Our preliminary data indicate an effect of psychosocial stress on the FKBP5 mRNA levels. Further research with larger samples sizes is required to replicate and extend these results., Background Corticosteroids are released in response to stress and have been shown to influence affective learning in rodents and humans. Many models of pathogenesis of affective and anxiety disorders have incorporated stress and cortisol as vulnerability factors. A well-established paradigm to investigate emotional learning and memory processes is classical fear conditioning. Method Here, we set out to investigate corticosteroid effects on fear acquisition and memory retention in healthy men (n=63). We first successfully established a within-subjects paradigm to evaluate both delay and trace fear conditioning in humans, measuring electromyogram (EMG) startle responses, skin conductance responses, and unconditioned stimulus (US) expectancy scores. In delay conditioning, the presentation of the conditioned stimulus (CS) is directly followed by the US, whereas in trace conditioning, there is a stimulus-free period between the offset of the CS and the US. This distinction is of special interest because the hippocampus, a brain area that is important for learning and memory and one of the main targets for corticosteroids, is suggested to code temporal information during the stimulus-free period in trace conditioning. Results We specifically targeted time-dependent effects of corticosteroids on fear conditioning in this within-subjects delay and trace conditioning paradigm by administering 10 mg hydrocortisone either 4 h or 1 h before fear acquisition. Twenty-four hours later, subjects came back for a fear memory retention test followed by extinction. Analyses show that hydrocortisone impaired trace acquisition specifically on EMG startle responses, regardless at which time point it was administered. However, we found an enhancement of EMG fear responses to the trace stimulus 24 h later only when corticosteroids were administered 4 h before acquisition. Conclusions This indicates that slow corticosteroid effects before acquisition lead to better retention of the fear memory for trace conditioning the next day., Rationale/statement of the problem Associations between stress levels in everyday life and controlled laboratory conditions remain a controversial topic. The aim of the present study was to compare psychological and physiological stress levels assessed in a real-life setting with laboratory stress levels. Methods Thirty-five healthy male students (age M = 24.4, SD = 2.6 years) took part in the study. The first part of the study consisted of a 2-day period within which subjects collected saliva and rated their stress levels on a visual analogue scale immediately after awakening, 30min later, at 9am, and then every 2 hours for a total of nine times a day while maintaining their regular daily activities. Salivary alpha-amylase (sAA) was assessed as a marker for autonomic nervous system activity at each time point. In the second part, subjects were invited to two laboratory sessions on two separate days, with randomized exposure to either a standardized stress test (cold pressor test (CPT), stress condition) or a rest condition (reading magazines). Again, sAA and subjective stress were assessed repeatedly during both conditions. Results During both days, sAA levels showed a distinct diurnal rhythm, with a trough in the morning and a steady increase over the course of the day (time effect, p, To evaluate the impact of stress on children's well-being, it is important to have valid and reliable stress assessment methods. Nevertheless, selection of an appropriate method for a particular research question may not be straightforward, as there is currently no consensus on a reference method to measure stress in children. This paper examined to what extent childhood stress can be estimated accurately by commonly applied stress measures. Two hundred and seventy-two girls between 5 and 11 years old participated in this study as part of the ChiBS project. Child-reported estimates of stress were collected through the Coddington Life Events Scale (CLES). Serum, saliva and hair samples were collected for cortisol analyses. The intercorrelations of cortisol in the different biological samples were investigated by Spearman rank correlations and Bland-Altman plots. Next, CLES-scores, salivary and hair cortisol concentrations were compared triangularly with the true, but unknown childhood stress using the Triads method, based on pair-wise Spearman's correlation coefficients and the calculation of validity coefficients. Serum cortisol (free and total) was positively correlated with salivary morning and AUC cortisol. Hair cortisol correlated with salivary morning and AUC cortisol, but not with serum cortisol. In relation to recent childhood stress (0–3 months ago), the highest validity coefficients were observed for salivary cortisol measurements, while for periods more distant in the past hair cortisol measurements displayed the highest validity coefficients. This paper investigated the relationship between cortisol measurements in different biological samples, showing a lack of association and disagreement between measures of single-point, short-term cortisol versus long(er)-term cortisol. In addition, this paper examined to what extent childhood stress can be accurately estimated by stressor questionnaires and biological markers in girls. Salivary cortisol was shown to most accurately indicate true childhood stress for short periods in the past (i.e. last three months), whereas hair cortisol may be preferred above salivary measurements for periods more distant and thus for chronic stress assessment., Rationale/statement of the problem Stress undermines health, perhaps via activation of the hypothalamic-pituitary andrenal (HPA) axis. There is evidence that psychological factors (i.e., sense of control, familiarity, effective coping, and social support) can buffer stress effects and HPA axis activation. There is also evidence that resilience and compassionate goal orientations (striving to help others rather than promoting the self) are associated with health and well-being, perhaps via HPA-buffering effects. We utilized a laboratory model of social evaluative threat (Trier Social Stress Test, TSST) to activate the HPA axis and study the stress-buffering effects of control, familiarity/coping, and compassionate goals, testing for interactions with resilience. Cortisol results were previously presented (41st International Society of Psychoneuroendocrinology (ISPNE) annual conference). Adrenocorticotropic hormone (ACTH) responses, which have now been analyzed, have strengthened the original findings. Methods Healthy participants (n=54) were exposed to a TSST after receiving a standard instruction or one of three intervention instructions (access to control over threat exposure, cognitive intervention to increase familiarity and effective coping, or a compassion intervention designed to shift goal orientation from self-promotion to helping others). ACTH responses were analyzed using a median split into low and high resilient participants (CD-RISC, Connor and Davidson, 2003). Results Overall, the type of instruction significantly interacted with resilience in modulating ACTH responses throughout the TSST (p=0.006). Low resilient participants receiving the coping intervention demonstrated higher ACTH baseline levels when compared to the other instruction groups. High resilient subjects given the compassion intervention showed reduced ACTH reactivity to the stressor relative to the other instructions. Conclusion The ACTH results mirror previously reported findings with cortisol responses to the TSST: Coping instructions increased anticipatory stress in low resilient participants, whereas compassionate goal instructions reduced stress reactivity to the TSST in high resilient participants. Further work assessing individual differences in resilience, and tailoring stress inoculation techniques accordingly, may facilitate development of more effective means of reducing the detrimental health effects of stress., Salivary cortisol has frequently been used as a biomarker of chronic stress. The results have differed considerably between studies, which could to some extent be explained by the various definitions of chronic stress cases, ranging from patients with a clinically diagnosed condition to working individuals scoring high on burnout questionnaires. Thus, it is not possible to generalize findings in the literature to stress-related conditions encountered in the clinic and it is difficult to apply the knowledge in diagnosis and treatment. The aim of this study was to elucidate the usefulness of basal salivary cortisol as a marker of chronic stress in a clinical population with stress-related exhaustion. We have measured salivary cortisol concentrations in two different samples of patients with a clinically diagnosed exhaustion disorder (ED). ED is defined as physical and mental exhaustion experienced for at least two weeks, caused by exposure to one or more stressors for a minimum of six months. In the first study, 162 patients (64% females) collected saliva samples at awakening and 15 minutes thereafter to assess the cortisol awakening response. This patient group was compared with 79 healthy controls (49% females). The patients repeated the saliva sampling at follow-up assessments after 3, 6, 12, and 18 months of treatment. The second study of 68 patients (79% females) included saliva samples taken at awakening, 30 minutes thereafter and at bedtime on two consecutive days to assess the diurnal profile, and follow-up assessments after 6 and 12 months. This study included 98 healthy controls (56% females). Age, sex, BMI, antidepressant use, and physical activity were considered as potential confounders. No significant differences were found between patients and controls in salivary cortisol awakening response (first study) or diurnal profiles (second study). Furthermore, follow-up measurements in patients indicated that salivary cortisol concentrations did not change significantly during treatment. Salivary cortisol levels, at least as measured in this study, apparently provide a rather poor reflection of the long-term stress exposure experienced by the patients in this study. Thus, basal salivary cortisol measurements are not recommended as a biomarker of stress-related exhaustion., Rationale Recent research on stress and decision making highlights the importance of considering the reciprocal relationship of these processes. Indeed, everyday experience suggests that economic decision situations can be stressful in and by themselves, particularly if they involve psychosocially stressful elements like competition. It is, however, at present not known whether or not physiological reactions elicited by the decision situation influence the decision that is reached. According to Salvador and Costa [Salvador, A. & Costa, R. (2009). Coping with competition: Neuroendocrine responses and cognitive variables. Neurosci Biobehav Rev, 33(2), 160–170], effects of competition (i.e., positive vs. negative outcomes) critically depend on the nature of applied coping strategies that are in turn related to specific physiological changes. Methods Our study examined the physiological and subjective changes induced by an established economic laboratory competition paradigm in a mixed-gender sample of 104 healthy participants. A mental arithmetic task was performed first under a piece-rate payment scheme and afterwards under a tournament (i.e., winner-takes-it-all) condition (i.e., forced competition). In a third round, subjects decided how to be paid (i.e., piece rate or tournament). Results Our results indicate that the laboratory paradigm indeed elicited physiological reactions that were related to the voluntary choice of competition. Participants that chose tournament were more likely to appraise the situation as challenging and showed higher sympathetic nervous system reactivity and higher testosterone increase during the game. Conclusion As these physiological changes are associated with an active coping mechanism (Salvador & Costa, 2009), we conclude that while competition is not per se treated as a harmful stressor, the reciprocal effect on the decision to compete again seems to depend on the use of an active coping strategy., Chronic stress is associated with negative health outcomes and is linked with neuroendocrine changes, suppressed immunity, and central nervous system neuropathology. While human studies have illustrated the benefits of stress reduction, mechanistic understanding of how decreasing stress affects health, and disease progression remains unclear. Furthermore, prior animal studies have focused primarily on increasing stress, and few animal models of stress reduction have been fully developed. Therefore, we have developed a “calm mouse model” with caging enhancements designed to reduce murine stress. Male BALB/c mice were divided into four groups (n=10/group): Control (Cntl), standard caging; Calm (Calm), large caging to reduce animal density, a cardboard nest box for shelter, paper nesting material to promote innate nesting behavior, and a polycarbonate tube to mimic tunneling; Control Exercise (Cntl Ex), standard caging with a running wheel, known to reduce stress; Calm Exercise (Calm Ex), Calm caging with a running wheel. Calm, Cntl Ex, and Calm Ex animals exhibited significantly less corticosterone production than Cntl (Day 49: Calm, Mdiff 20.5 ng corticosterone metabolites/0.05 g feces (CM), CI95 11.7–29.4, P, Statement of the problem Stressful life events have been shown to have great influence on the onset or recurrence of psychotic symptoms [1]. Increased stressful life events [2], perceived stress [3], and higher cortisol levels [4,5] have been described in subjects with a first psychotic episode. The main aim of our study was to explore the relationship between stress measures and cortisol levels in subjects with early psychoses. Methods We included 85 subjects, aged between 18 and 35 years, who attended the Early Psychosis Program from Reus (Tarragona, Spain). All subjects were assessed at baseline using a structured clinical interview (Schedules for Clinical Assessment in Neuropsychiatry) to obtain a clinical diagnosis. We stratified the sample into three groups: Group 1, first episode of psychosis (FEP, N = 36); Group 2, critical period (CP, defined as a psychotic disorder >1 year of duration of illness, N=35); and Group 3, ultra high risk (UHR, subjects with prodromal psychotic symptoms, N=14). Perceived stress was assessed with perceived stress scale (PSS). Stressful life events during the previous 6 months were assessed with the Holmes Rahe Social Readjustment Scale. A fasting morning blood sample (9 h) was obtained to determine total cortisol in plasma. SPSS v.17.0 was used for the statistical analyses. Spearman correlations were used to explore the association between continuous variables. Wilcoxon test was used to compare continuous variables between diagnostic groups. A p-value, Background Preterm birth is marked by stressful environment in intra- as well as extrauterine life. Furthermore, preterms are exposed to repeated painful procedures, loud noise, and restricted contact with parents in the neonatal intensive care unit. This environment can affect hormonal and physiological systems and lead to long-term negative outcomes. Despite this, little is known about how early-life stress affects preterms later on in childhood. The goals of the current study were threefold: (1) comparing cortisol profile, including cortisol awakening response (CAR), between preterm and full-term children; (2) assessing memory, behavior, and emotion of preterms; (3) evaluating if preterms are more responsive to an acute stressor. Methods Basal cortisol and α-amylase (sAA) profiles, including CAR of 30 preterm children were evaluated. Salivary samples were measured on two consecutive days at four time points: awakening, 30 min post-awakening, 1600h, and 2100h. Furthermore, we assess memory functions by using the wide range assessment of memory and learning and screen behavior/emotion by using strengths and difficulties questionnaire. The results of preterms were compared to an age- and sex-matched control group (n=31). One week after, the participants were exposed to Trier Social Stress Test for Children (TSST-C). Results We specifically targeted time-dependent effects of corticosteroids on fear conditioning in this withinsubjects delay and trace conditioning paradigm by administering 10 mg hydrocortisone either 4 h or 1 h before fear acquisition. Twenty-four hours later, subjects came back for a fear memory retention test followed by extinction. Analyses show that hydrocortisone impaired trace acquisition specifically on EMG startle responses, regardless at which time point it was administered. However, we found an enhancement of EMG fear responses to the trace stimulus 24 h later only when corticosteroids were administered 4 h before acquisition. Conclusions Our findings illustrate the long-lasting effects of preterm birth on the hypothalamic pituitary adrenal (HPA) axis, internalizing behavior, and memory. The findings are in line with the idea that early-life stress alters the set-point of the HPA axis thereby creating a more vulnerable phenotype., Rationale The activation of the neuroendocrine systems is a basic response to environmental perturbations, which threaten homeostasis. The HPA-axis is one of the primary effector systems, which functions to minimize deviations from the homeostatic state and help to return equilibrium following a disturbance. It has been well established that products of the HPA-axis can directly inhibit the hypothalamo-pituitary-gonadal (HPG)-axis. Consequently, following chronic stressors reproduction is impaired. Method Animals were exposed to predator scent stress for 15 min. Behaviors were assessed with the elevated plus-maze and acoustic startle response tests, 7 days later. Trauma-cue response, circulating corticosterone and testosterone, and localized brain expression of androgen receptor (AR) and estrogen receptors were subsequently assessed. All data were analyzed in relation to individual behavior patterns. The behavioral effects of testosterone agonist, testosterone receptor antagonist (flutamide), or vehicle-administered systemic one hour before and 7 days after PSS-exposure were evaluated in the same manner. Results Animals whose behavior was extremely disrupted (EBR) selectively displayed significant down-regulation of AR in the hippocampus compared to animals whose behavior was minimally (MBR) or partially (PBR) disrupted and to un-exposed controls. One-hour pre-exposure treatment with testosterone significantly increased prevalence rates of EBR and increased trauma-cue freezing responses, compared to vehicle controls. In contrast, immediate pre-exposure treatment with flutamide significantly reduced prevalence rates of extreme responders and reduced trauma-cue freezing responses compared to vehicle and testosterone treatments. Moreover, treatment with testosterone 7 days post exposure significantly reduced prevalence rates of extreme responders and reduced trauma-cue freezing responses compared to vehicle and testosterone treatments. Conclusions The gonadal steroid hormones are actively involved in the neurobiological response to predator scent stress and thus warrant further study as a potential therapeutic avenue for the treatment of anxiety-related disorders., Rationale/statement of the problem Considerable research has focused on the relationship of anxiety with alterations in the hypothalamic-pituitary-adrenal (HPA) acute stress response. Findings, however, differ among studies on adults and children, and among different types of anxiety. This study investigates the relationship of anxiety symptom severity with HPA reactivity to the cold pressor task (CPT) in preadolescent children. We hypothesize that children with increased symptoms of anxiety will have increased cortisol (HPA) reactivity to the CPT. Methods A social-evaluative adaptation of the CPT was used to elicit HPA acute stress reactivity among 42 children (26 female, 16 male) aged 8–12 years (mean age, 10 years) recruited from a child anxiety disorders clinic (n=20) and from the community at large (n=22). Repeated saliva samples were assayed for cortisol to determine maximum task response (TR) and area under the curve with respect to the increase from baseline (AUCi). Multi-dimensional anxiety measures included the Screen for Anxiety and Related Disorders (SCARED: parent and child report); State Trait Anxiety Inventory-Trait (STAI-T), and Children's Anxiety Sensitivity Index (CASI). Subjects were grouped according to recruitment source and high/low symptom measures (all subjects by anxiety measure median split); groups were compared via independent samples t-tests. Results Maximum cortisol TR and AUCi did not differ between children recruited from the anxiety disorders clinic and the community. Among all subjects, maximum TR was significantly greater for those with high anxiety symptoms on the STAI-T (p=0.006), SCARED-C (p=0.012), and SCARED-P (p=0.031), and approached significance on the CASI (p=0.056), compared to those with low symptoms on these measures. AUCi was greater among those with high symptoms on the SCARED-C (p=0.01) and SCARED-P (p=0.011), but not on the STAI-T (p=0.113) or CASI (p=0.072). Conclusion Results suggest that increased anxiety symptom severity is associated with greater cortisol reactivity to acute stress in preadolescent children. Moreover, findings were similar among youth recruited from the clinic and the community, thus providing additional evidence of the high prevalence of anxiety in children and the potential associated risk of alterations in physiological stress reactivity among those with more severe symptoms., Prior theory and research suggests that psychosocial stress during development may contribute to vulnerability to problems in adulthood in domains of both mental and physical health through alterations in both automatic attentional and psychobiological stress reactivity processes. We hypothesized that childhood exposure to family conflict would be related to variations in hypothalamic–pituitary–adrenal (HPA)-axis activity patterns and would moderate the relation between attentional bias to threat and biological stress reactivity to acute laboratory stress exposure. A sample of young adult female participants (n=116; mean age = 18.96 years, SD = 1.13 years) was classified based on their past exposure to family conflict during childhood and randomized in a crossover design to complete both a mild laboratory social stress task and a computerized task assessing attentional bias to threatening words. Salivary cortisol was measured continuously throughout the study. Exposure to family conflict during development was significantly positively correlated with baseline cortisol in the sample as a whole (r=0.35, p, Rationale Early life stress (ELS) poses a risk for mental disorders and aging-related physical diseases. Accelerated biological aging reflected in shorter leukocyte telomere length (LTL) may underlie these risks. Yet, studies examining associations between ELS and LTL have been scanty, elusive, and retrospective. We examined if objectively documented ELS in childhood, retrospectively, reported traumatic experiences across the lifespan and whether their combination is associated with LTL in later adulthood. Methods ELS, traumatic experiences, and LTL were present in 1,486 participants of the Helsinki Birth Cohort Study, born between 1934 and–44 in Helsinki, Finland. Of them 215 were recorded as separated temporarily from their parents in childhood. The separations took place during World War II when Finnish children were voluntarily evacuated unaccompanied by their parents to temporary foster care abroad (mean age at and length of separation 4.6 and 1.7 years, respectively). Traumatic experiences across the lifespan were self-reported at age 63.2 years (SD = 2.8) using the Traumatic Experiences Checklist, and LTL was measured at age 61.5 years (SD = 2.9) using real-time quantitative polymerase chain reaction (PCR) method. Results LTL did not differ significantly by separation status or by having experienced traumas (p>0.151). However, ELS and traumatic experiences interacted significantly in the analyses of LTL (p, Recently, the hypothalamic-pituitary-adrenal axis activated by psychological stress has been reported to be involved in irritable bowel syndrome (IBS) symptoms. In the present study, we investigated the effect of prolonged stress (for two weeks) on salivary adrenal hormones in individuals with IBS. The participants were 23 female college students (mean age = 18.8 years), including 10 individuals with IBS met Rome II criteria and 13 individuals without IBS (control group), and they were scheduled for a two-week teaching practice at kindergarten. Participants were asked to collect their saliva immediately (T1), 30 min after awakening (T2), and before sleep (T3) at date of a month before (D1), 3 days after (D2), 7 days after beginning of teaching practice (D3), and several days after the end of it (D4). They also completed perceived stress scale (PSS) (D1–D4). Comparisons between groups and between dates in PSS score were done using 2-way analysis of variance. Linear mixed model was applied to analyze the effects of the presence of IBS, time, and date on salivary adrenal hormones (cortisol, dehydroepiandrosterone [DHEA], DHEA-sulfate [DHEA-S]). There were significant effects of day in PSS (p < 0.0001), cortisol (p=0.002), and DHEA (p=0.02) and significant effects of time in cortisol (p, Altered long-term secretion of glucocorticoid hormones is believed to play a pivotal role in linking chronic stress to cardiometabolic risk. Despite experimental data supporting this link, previous epidemiological field studies have often yielded inconsistent results. Amongst other things, this is likely to be related to methodological limitations in the assessment of glucocorticoid secretion over prolonged periods of time. The measurement of glucocorticoids in hair may constitute a major advancement here, enabling the assessment of cumulative hormone levels over periods of up to six months. Here we will present first data from a large industry-funded cohort study investigating links between work-related stress, long-term glucocorticoid secretion and cardiometabolic risk factors. Hair samples were obtained from 1315 employees of the airline manufacturing industry and assayed for cortisol (F) and cortisone (E) concentrations using liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). In addition, relevant anthropometric, psychosocial and physiological biomarkers of cardiometabolic risk were assessed. Results reveal positive associations of hair F and E concentrations with measures of central obesity (body mass index, waist-to-hip ratio), resting systolic and diastolic blood pressure as well as fasting morning blood levels of glucose, glycated haemoglobin (HbA1c), C-reactive protein and high-density lipoprotein (negative). Significant positive associations with low-density lipoprotein and triglyceride levels were only seen for hair E but not for hair F. These findings are in line with current conceptions suggesting an important role of aberrant glucocorticoid secretion in the development of cardiometabolic risk. Implications of these data for hair analysis as an important future tool in epidemiological field research will be discussed., Narrative Exposure Therapy (NET) is a treatment method defined as a standardized, short-term intervention for treating posttraumatic stress disorder (PTSD). It comprises elements from exposure therapy and testimony therapy. NET has mainly been applied on victims of organized violence and whose life conditions are threatening and unsafe such as for refugees and asylum seekers. There are no published studies of NET applied on PTSD outpatients living in Norway with different trauma histories than war-traumas. To investigate both short-and long-term effect of NET on diagnosed PTSD symptoms, general psychological status and depression symptoms in adult patients recruited from outpatient clinics. Seventeen adult outpatients (7 males, 10 females; mean age 38.5) were assessed with the Clinical Administered PTSD-scale (CAPS) which corresponds to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, the Symptom Checklist-90-Revised (SCL-90-R), the Beck Depression Inventory (BDI-II), Dissociation Experiences Scale (DES), and Impact of Event Scale-Revised (IES-R) prior to, 1 month and 6 months after NET-treatment which consisted of 8 sessions a 90 min. T-tests for dependent samples showed a significant reduction on all the symptom criteria's CAPS (symptom B, C, and D both frequency and intensity) 1 month after treatment (p's < 0.005–0.05), five patients (29.5%) no longer fulfilled the PTSD criteria. On SCL-90-R there was a significant reduction on four subscales; the obsessive-compulsive, interpersonal sensitivity, psychotisism and the global severity index (p's < 0.05). The total depression score on BDI-II were significantly reduced (p, Objectives Multiple sclerosis (MS) as an inflammatory demyelinating disease of the brain and the spinal cord is associated with a high prevalence rate of major depressive disorder (MDD). Psychological stress has been linked to MS pathogenesis as well as relapse risk in established disease. Moreover, MS diagnosis itself may be a potential trigger for the development of posttraumatic stress disorder (PTSD). Both MDD as well as PTSD have been linked to altered hypothalamic-pituitary-adrenal (HPA) axis regulation and consecutively to elevated or lowered cortisol secretion. This study explores associations of PTSD and MDD with HPA activity in patients with MS. Methods In a cross-sectional sample of female MS patients, psychological comorbidities were diagnosed using the structured clinical interview (SCID). Circadian salivary cortisol profiles (AUC) and the cortisol awakening response (CAR) as markers of HPA axis activity were assessed over the course of 2 days. On the third day, low dose oral dexamethasone suppression was examined (post-Dex CAR/AUC). Results Forty-nine patients with relapsing-remitting MS were included. Eleven patients fulfilled diagnostic criteria for current MDD. A total of 14 patients were diagnosed with PTSD, 7 of whom developed PTSD related to MS-diagnosis. Patients with PTSD were not currently depressed. Importantly, patients with comorbid psychological disorders showed significantly lower coping resources such as self-efficacy, sense of coherence, and social support. While no significant differences were found in most measures of cortisol secretion between the three groups, we observed a trend for higher CAR after dexamethasone suppression in MS patients with PTSD. Conclusion The present study indicates a high frequency of MDD and PTSD in MS and associations to reduced salutogenetic resources. These comorbidities might be linked to different aspects of HPA axis dysregulation and could be associated to different biological pathways., Chronic psychological stress increases inflammation, providing a mechanism for the elevated risk of infectious, autoimmune and cardiovascular diseases in chronically stressed persons. While the HPA axis plays an important role in mediating the link between stressful events and inflammatory processes, it is becoming increasingly clear that immune cells can become resistant to cortisol, resulting in diminished regulation of inflammation. One potential mechanism of cortisol resistance results from decreased glucocorticoid receptor (GR) expression in immune cells during elevated cortisol exposure. Chronic stress results in chronic high cortisol exposure leading to decreased immune cell GR expression that in turn is associated with greater immune activation. Using flow cytometry we measured immune activation and GR expression (geometric mean fluorescence intensity [gMFI]) in 10 immune cell subsets in 25 post-menopausal females (10 caregivers [CGs] and 15 controls [CNTLs]). Mann–Whitney and Pearson correlations were employed for statistical analysis with p, Background Antenatal glucocorticoid (GC) exposure has been discussed as a potent programming factor of hypothalamus–pituitary–adrenal (HPA)-axis activity producing sustained alterations in cortisol secretion throughout life. So far, the assessment of HPA-axis activity in offspring of mothers treated with synthetic GCs has been limited to a time period shortly after birth, with prematurity being an important confound in most prior studies. Method The present study aimed to investigate HPA-axis reactivity of term-born children with antenatal GC exposure in a larger sample (N=209 children between 6 and 10 years of age), allowing to further address sex and drug specific effects. Cortisol secretion patterns in response to a standardized laboratory stressor (Trier Social Stress Test for Children) were assessed in children with antenatal GC exposure (a single course of either dexamethasone or betamethasone) and compared to different control groups. Results We observed significantly increased cortisol reactivity to acute psychosocial stress in 6–11 years old, term-born children exposed to antenatal synthetic GC treatment compared to controls (F(3.4,345.9) = 5.8, p, Rationale Problematic peer relationships in adolescence have long been linked with various psychological disorders, but there remain questions as to why adolescents with similar social experiences may suffer no psychological effects or why some respond with depression or anxiety while others become aggressive. Parenting style and level of chaos in the home environment have also been shown to have protective or detrimental effects in conjunction with social stressors. Adolescence is typified by substantial hormonal changes and maturation of both the pubertal and the stress systems. Ian Goodyer has suggested that atypical ratios of stress and pubertal hormones may be indicative of vulnerability for psychopathology. High cortisol and low DHEAS have been linked to depression, whereas the opposite has been found in those with aggression. This study is the first to examine the cortisol/DHEAS ratio as a moderator of peer stress in the development of psychopathology in adolescents. This investigation uses a biopsychosocial model to test the moderating role of parenting style, environmental chaos, and adrenal hormone ratios on the association between social stress and aggression or depression over a 1-year period. Methods Participants were 156 young adolescents (50% f; M age = 11 years, SD = 0.7), ethnically diverse, and predominantly middle to lower SES. Depressive symptoms, aggression, social stress, and environmental chaos were assessed via survey and interview reports from mothers and children. Parenting characteristics were assessed via mother survey. Saliva and urine samples were collected on multiple mornings to measure cortisol and DHEAS, respectively. Results Cross-sectional and longitudinal analyses indicate significant main effects of parenting style, chaos, and adrenal hormone ratios in predicting depressive symptoms and aggression and significant moderating effects on the relationship between social stressors and psychopathology. High cortisol/DHEAS ratio predicted depressive symptoms and enhanced the effects of peer problems; low ratio was predictive of aggression in adolescents with high levels of peer problems. Conclusion The results of this study shed light on factors that may better explain the varying responses adolescents have to social stressors, thereby identifying adolescents at risk for psychological problems., Background Alcohol Use Disorders (AUDs) are multiphasic, multifactorial, and heterogeneous disorders for which the differential risk traits have been proposed to be associated with distinct risk profiles. However, whether these profiles are distinct in terms of neuronal and hormonal mechanisms remains less understood. Behavioral evidence has demonstrated differential motivational systems mediating the response to alcohol, two of which are the psychomotor/cue for reward and the anxiety systems that are in turn exemplified by sensation seeking (SS) and anxiety sensitive (AS) individuals, respectively. Methods Two equally divided groups of healthy social drinker AS and SS males and females (n=48; ages 18–26) underwent a randomized double-blind placebo-controlled fMRI design. Salivary cortisol concentration was measured every 10 min during testing. Alcohol and placebo were administered based on standardized procedures, 30 min after which scanning occurred at the height of the blood alcohol curve. Two stressors differing in form and effect were used, a random presentation of standardized emotional faces, and a mental math test [The Montreal Imaging Stress Task (MIST)] performed under and accompanied by social pressure, 50–60% uncontrollable failure rate and negative feedback. Results Salivary cortisol secretion relative to ground (AUCg) was significantly different between groups and within subjects. Gender showed a significant main effect (F(1,39) = 0.6816, p = 0.013), with a females showing greater cortisol response than males. Further, a significant trait-by-gender-by-condition interaction effect was observed (F(1,39) = 6.414, p=0.015), where F_AS showed elevated AUCg under placebo, a response was largely blunted by alcohol. This interaction effect was also significant in terms of amygdalae and orbitofrontal cortical activation under MIST; both regions where significantly deactivated under alcohol in F_AS (parameter estimates, p, Oxidative stress (an imbalance between free radicals and the ability to neutralize them with antioxidants) occurs in several mental illnesses, including major depression (MDD). A major antioxidant in humans is glutathione peroxidase, which reduces GSSH to GSH, increasing glutathione's ability to scavenge free radicals. The brain, and the hippocampus (HC) in particular, is particularly sensitive to oxidative stress, and HC oxidative stress (particularly in the CA1 and CA3 & dentate gyrus [CA3&DG] subfields) may contribute to major depression. Nineteen medication-free subjects with MDD and 19 matched controls underwent 4T MRI scanning of the HC and had fasting morning venipuncture for peripheral oxidative stress assessment. Two of the MDD subjects did not have glutathione (GSH) and/or glutathione disulfide (GSSG) data. Because of the preliminary nature of the study, no corrections for multiple comparisons were applied. Across all subjects, the antioxidant Vitamin C was directly correlated with total HC (p, There is evidence that acute stress impacts decision making (DM) under risk. It has been concluded that stress prompts riskier decisions in men. However, in the DM tasks used thus far, the expected value (EV) of reward and risk of decision options are confounded and it is, therefore, unclear which component is being affected by acute stress. We developed a new DM paradigm, in which EV of reward and risk of decision options are independent and quantifiable. Subjects (5 men, age: 31.2 ±1.92 years) completed 220 trials in which they had to repeatedly choose between a safe and a risky option associated with different EV of reward and risk. Stress was induced using the Socially Evaluated Cold Pressor Test (SECPT). Each subject received the SECPT and the corresponding control condition in random order. Comparing the stress and control condition on a trial-by-trial basis, we found that, descriptively, gamble variance, a measure for the risk associated with decision options, was about 10% higher when subjects were stressed compared with when they received the control manipulation. EV of reward on which subjects gambled did not differ between stress and control manipulation. Our data provide a first hint that risk but not reward processing in healthy young men might be affected by acute stress., Obesity and the metabolic syndrome (MetS) predispose to multiple diseases and to accelerated cell aging as indexed by accelerated shortening of telomeres in peripheral blood mononuclear cells (PBMC's). Major depressive disorder (MDD) is often associated with MetS and is also associated with increased disease risk and PBMC telomere shortening. A potential role of leptin in telomere shortening has been suggested, but prior results have been inconsistent and no study has yet assessed this relationship in MDD. The goal of this study was to assess the relationship between serum leptin concentrations and PBMC telomere length in MDD and in controls and to assess whether this relationship is mediated by body-mass index (BMI) or the homeostatic model assessment of insulin resistance (HOMA-IR), two principal components of the MetS. Eighteen medication-free MDD subjects (11 female, 7 male, mean age 37.1 + 2.7 years) and 17 healthy controls (11 female, 6 male, mean age 37.8 + 3.0 years) had blood drawn for assay of fasting morning levels of leptin, glucose, and insulin and PBMC telomere length. The groups did not differ on BMI (24.66 + 3.72 vs. 24.77 + 4.29, respectively, n.s.). Analyses were co-varied for age and sex, with and without BMI. In the combined group, serum leptin concentrations were inversely correlated with telomere length (r= − 0.33, p0.30, and t=1.49, p>0.10, respectively), but leptin concentrations remained significantly correlated with telomere length (t= − 2.88, p=0.007). Relatively high leptin concentrations, in the presence or absence of increased BMI and insulin resistance, may be a risk factor for telomere shortening. While this was demonstrated here in individuals with MDD, a similar relationship in non-depressed individuals cannot be ruled out because of the small sample size., Background Affected autonomic heart regulation is implicated in the pathophysiology of cardiovascular diseases and is also associated with posttraumatic stress disorder (PTSD). However, although sympathetic hyperactivation has been repeatedly shown in PTSD, research has neglected the parasympathetic branch. The objective of this study is the long-term assessment of heart rate (HR) dynamics and its circadian changes as an index of autonomic imbalance in PTSD. Since tonic parasympathetic activity underlies long-range correlation of heartbeat interval fluctuations in healthy state, we included nonlinear (unifractal) analysis as an important and sensitive readout to assess functional alterations. Methods Electrocardiogram recordings over a 24-h period were conducted in 15 deployed male subjects with moderate to high levels of combat exposure (PTSD: n=7; combat controls: n=8). Analysis of HR dynamics included time domain, frequency domain and non-linear analysis based on detrended fluctuation analysis. Psychiatric symptoms were assessed using structured interviews, including the Clinician Administered PTSD Scale. Results Subjects with PTSD showed significantly higher baseline HR, higher LF/HF ratio in frequency domain analysis, blunted differences between daytime and nighttime measures, as well as higher scaling coefficient αfast during the day, indicating diminished tonic parasympathetic activity. Conclusions This study appears to be the first combining linear and non-linear methods to assess long-period autonomic and circadian differences in HR dynamics between combatants with and without PTSD. Diminished circadian differences and blunted tonic parasympathetic activity altering HR dynamics suggest central neuro-autonomic dysregulation that could represent a possible link to increased cardiovascular mortality in PTSD., Background Rumination, defined as past-centered negative thinking, has been linked to stress physiology and suggested to affect mental and physical health. Research has shown that both state and trait rumination is correlated with cortisol responses to psychosocial stress. It has not been addressed if state rumination is associated with cortisol responses to repeated stress. Methods Nineteen participants (aged 21–65, mean age = 53.5; nine males) were exposed to the Trier Social Stress Test (TSST) twice on consecutive days. Salivary cortisol was measured 1 min before and 1, 10, 30, 60 and 120 min post-TSST on both days. Participants provided self-reports of post-stress state rumination on both days. Participants further provided information about early adversity using the Childhood Trauma Questionnaire and self-rated depression and perceived chronic stress. Results Cortisol responses were successfully induced on both days of testing (F[1.5, 54.5] = 4.4, p=.032). State rumination scores on day 1 were significantly correlated with cortisol increases (r=.615, p=.005); interestingly, state rumination scores on day 1 of testing were related to cortisol increases the following day (r=.594, p=.007). No gender differences were found in rumination on either day (all p=n.s.). Childhood trauma, although reported at a very low level, was found to be strongly related to rumination on both days (rumination day 1: r=.547, p=.02; rumination day 2: r=.712, p=.009). Childhood trauma was further related to cortisol responses on the first, but not second, day of testing (day 1: r=.503, p=.047; day 2: r=.31, p=n.s). Conclusions Post-stress rumination on day 1 was correlated with hypothalamic–pituitary–adrenal (HPA) axis reactivity. Day 1 post-stress rumination was correlated with day 2 responses to the same stressor, but day 2 rumination was unrelated to the stress response on that day. This suggests that rumination has prolonged effects on stress reactivity. Other variables, such as subclinical childhood trauma, were also related to state rumination and cortisol responses. These factors are potential mediators of the relationship between state rumination and HPA axis stress reactivity., Rationale/statement of the problem Cortisol levels have been extensively studied in patients with posttraumatic stress disorder (PTSD), but their specific relationship to intrusive memory symptoms is unknown. Salivary alpha-amylase (sAA), an index of sympathetic activation, has never been studied in the context of PTSD. This study adopted the Trauma Film Paradigm to assess how changes in cortisol and sAA levels during memory encoding are related both to subsequent intrusive memories of the film and to individuals’ pre-existing characteristics. Methods Saliva samples were collected in the afternoon (considering the circadian rhythm of cortisol and sAA) from 58 healthy adult participants at baseline, during the film, and post-film. Measurements of pre-existing PTSD symptoms, dissociation and anxiety traits as well as intrusions of the traumatic film over the week following film viewing were assessed. Results Results showed that cortisol levels increased, whereas sAA levels decreased in response to the film. The vividness of intrusive memories was negatively correlated with cortisol levels during and after the film. Pre-existing PTSD symptom severity was negatively correlated with cortisol levels at the post-film stage and positively correlated with sAA in both during the film and post-film stages. Moreover, dissociative traits (especially dissociative amnesia) were negatively correlated with sAA levels at baseline and during the film, while anxiety traits were positively correlated with post-film sAA levels. Conclusions This is the first study to investigate the relationship between cortisol, sAA, intrusive trauma memories and pre-existing psychological traits. The results supported the hypothesis that insufficient cortisol release in the immediate aftermath of trauma is a risk factor for the development of intrusive symptoms. The findings also shed light on how pre-existing characteristics affect physiological reactions to traumatic stimuli., Rationale Currently, there are no effective interventions that prevent the development of posttraumatic stress disorder (PTSD) in recently traumatized individuals. The neuropeptide oxytocin is a potent regulator of two important processes disturbed in PTSD: it regulates physiological and behavioural stress and fear responses. In addition, oxytocin administration influences socio-emotional processes. Interestingly, high levels of acute distress after trauma and a lack of social support are risk factors for developing PTSD. Therefore, oxytocin administration appears to be a promising preventive treatment for PTSD, by hypothetically ameliorating dysregulated stress and fear responses as well as facilitating adaptive social functioning. Methods We have initiated a randomized controlled trial (RCT) to investigate the effectiveness of an intranasal oxytocin treatment regimen in preventing the development of PTSD in recently traumatized individuals at increased risk for PTSD. In addition, in the same population we are conducting an fMRI study, which will create deeper insights into the neural mechanisms through which oxytocin and social context may regulate fear responses to traumatic stress. Results In this presentation, the rationale behind stimulation of the oxytocin system in recently trauma-exposed individuals at risk for PTSD will be discussed, and an outline of the RCT will be presented. In addition, preliminary pilot data of the RCT will be shown., In a recent study, we unexpectedly found lower fasting plasma glucose concentrations in patients with stress-related exhaustion compared with healthy controls. To further elucidate the reliability of these findings we now investigated possible differences in glucose and glycated haemoglobin (HbA1c) levels between all patients with Exhaustion Disorder (ED) that entered the treatment program at the Institute of Stress Medicine, Gothenburg, Sweden between 2004 and 2010 and a healthy control population. We also investigated the development of plasma glucose during 18 months of multimodal treatment and related it to changes in symptoms of burnout, depression and anxiety. The study included 383 patients (71% females, age 21–66 years) and 199 healthy controls (50% females, age 25–54 years). All patients fulfilled the criteria for ED, which include physical and mental exhaustion experienced for at least two weeks, caused by exposure to one or more stressors for a minimum of six months. Cardinal features are markedly reduced mental energy, impaired memory and reduced capacity to meet demands. Blood samples were drawn in the morning after fasting since 22:00 the day before. Follow-up measurements were performed after 3, 6, 12, and 18 months of treatment in the patient group. Fasting plasma glucose was significantly lower in the patients (4.7±0.4 mmol/L) compared with healthy controls (5.0±0.5 mmol/L), both in women and men. HbA1c did not differ between patients and controls. These results remained after controlling for age, BMI, WHR, physical activity, and antidepressant use. In the patient group, plasma glucose levels increased significantly from inclusion to the follow-up measurements after 12 and 18 months. Changes in glucose during treatment were not related to improvement of symptoms of depression, anxiety or burnout. We confirm our previous finding that plasma glucose levels are lower in patients with stress-related exhaustion compared with healthy controls. The increase during treatment could indicate that lower level of glucose might be a consequence of long-term stress, which is normalised during treatments. Further studies are needed to confirm if this is the case and whether this relatively small difference in glucose levels is of clinical relevance., Rationale/statement of the problem The contagion of psychological states such as arousal, pain, and distress has been well established and is consistent with perception–action models of empathy. However, the recent demonstration of contagious physiological stress is more confounding because cortisol responses have been historically difficult to trace to specific subjective states or overt behaviors. Thus, it is currently unclear how someone could detect another's physiological stress (i.e., cortisol and sympathetic nervous system responses) through mere observation to produce resonating levels in themselves. It is also unclear if such resonating stress has any implications for subsequent prosocial behavior, as it does for typical empathic states like shared pain or distress. Methods In two separate studies, we assessed salivary cortisol and salivary alpha-amylase in both speakers and observers during a modified Trier Social Stress Test (TSST). In Study One, we coded a set of nonverbal behaviors from TSST speakers to determine the behavioral indices that may signal stress reactivity between individuals. In Study Two, to examine the influence of contagious stress on prosocial behavior, participants completed poststress measures of empathy and altruism. Results In both studies, observers and speakers showed evidence of contagious physiological stress responses. In Study One, speakers who demonstrated more gaze aversions showed the greatest cortisol reactivity. In Study Two, both speakers and observers showed evidence of increased prosocial behavior after the TSST. Conclusion These findings demonstrate that the contagion of physiological stress is a robust phenomenon, which may be mediated through the observation of behaviors like gaze aversion that indicate another's level of stress. The experience and resonance of stress also appears to have implications for prosocial behavior., Background Our insight into the neurobiological dynamics underlying the processes that may over time cumulate into syndromes like burn-out and depression is rapidly developing. A recent, though important, step has been to combine the relevant parameters of multiple domains (physiological, endocrine, social/emotional) to optimize prognostic accuracy. This is of relevance as initially subtle neurobiological disturbances associated with stress may indicate the start of a negative and potentially dangerous trend, both for physical and psychological health. Methods On the basis of the regular monitoring of key variables of allostatic processes (like heart rate variability, corticosteroid concentrations, and psychosocial status), risks scores for internalizing development can be calculated. When repeatedly collected by means of a standardized assessment protocol, it becomes possible to conduct trend analyses, which may potentially indicate development towards aversive outcomes like burn-out (in labour environments) or for example depression. Results On the basis of available data, algorithms have been developed combining diverse allostatic key variables into multi-level prognostic models (low–medium–high risk for internalizing development). On the basis of these models, a standardized assessment protocol is developed using state-of-the-art information technology to make the application as consumer friendly as possible. Conclusions Although some technical developments are necessary to optimize the potency of assessment protocols like the present one (e.g., sensor technology able to measure or estimate corticosteroid concentrations “on the spot”), the used algorithms do not only seem to provide valid prognostic information, though essential indicators for easy to apply preventive strategies as well. These could be instrumental in averting long-term negative psychological outcomes., Background The self-help book industry is one of the most lucrative in North America generating profits of $10 billion annually. The main purpose of self-help books is to increase the sense of worth of the readers as well as to provide them with adequate coping strategies, so they can better negotiate their stress. Despite the popularity of this literature, no study has investigated whether it impacts on people's stress reactivity. Consequently, the goal of this study was to compare consumers and non-consumers of self-help books with regard to their physiological stress response. Methods Thirty-one healthy men and women aged between 18 and 65 took part in this study. Of this group, 16 reported being consumers of self-help books, whereas the other 15 participants reported not being consumers nor attracted by these books. During their afternoon visit to the laboratory, all participants were exposed to the Trier Social Stress Test, a validated psychosocial stressor. Salivary samples were taken throughout the session in order to quantify their cortisol levels. Participants also filled out different questionnaires assessing self-esteem, depressive symptomatology and personality traits. Results In terms of stress reactivity, the area under the curve with respect to increase was significantly higher in consumers when compared to non-consumers. The two groups did not differ from each other in terms of depressive symptomatology and self-esteem. The consumer group scored lower on the “extraversion” personality trait compared to the non-consumer group. Conclusions Healthy consumers of self-help books are more stress reactive when facing a psychosocial stressor than non-consumers of self-help books. Although the current study design does not allow concluding about the efficacy of these books, the results nonetheless suggest that further investigation about the impact of this literature is necessary. Moreover, given the considerable amount of consumers of self-help books and their poor ability to cope with stress, there is clearly a need of increasing public awareness about effective coping strategies., Rationale/statement of the problem In adults, there is a robust, immediate effect of sleep on the diurnal cortisol profile. Shorter sleep duration and poorer sleep quality are associated with greater awakening response, flatter diurnal slope, and higher evening cortisol levels. Because of methodological limitations, this relation is less well-established in children and adolescents. Specifically, the use of single cortisol samples and sampling at unconventional times limit the generalizability of these findings. This study examines the influence of sleep duration, sleep quality, and daytime sleepiness on the diurnal cortisol profile in children and adolescents. Methods Children and adolescents aged 8–18 (N = 227, M = 12.61, SD = 2.04, 45.8% female) participated in the Healthy Heart Project at Concordia University. Children and adolescents rated their sleep quality on a 1–10 scale (1 = poor, 10 = excellent) and completed the Pediatric Daytime Sleepiness Scale. Parents completed the Child's Sleep Habits Questionnaire and reported their children's bedtime and waketime to derive sleep duration. Six saliva samples were collected over 2 days. Single sample (bedtime, maximum) and aggregate measures (AUCAG, AUCI, AUCTG, diurnal slope) of the diurnal cortisol profile were derived. Results After controlling for age and day of the week, higher bedtime cortisol was associated with shorter sleep duration (r= − 0.17, p=.01), poorer sleep quality (r= − 0.19, p=01), and greater child-report daytime sleepiness (r=0.16, p=.02). Higher AUCTG was associated with poorer sleep quality (r= − 0.15, p=.02); higher AUCI was related to greater child-report daytime sleepiness (r=0.14, p=.03). Parent-report sleep problems and daytime sleepiness were not associated with any cortisol measure. Maximum sample, AUCAG, and diurnal slope were not related to any sleep measure. Conclusion Poorer sleep quality, greater daytime sleepiness, and shorter sleep duration were related to higher bedtime cortisol. Poorer sleep quality and greater daytime sleepiness were associated with higher AUCTG and AUCI, respectively. While child-report measures of sleep were associated with cortisol, parent-report measures were not. Current findings offer insight into possible pathways linking sleep and health. Future studies should further elucidate this association by examining objective measures of sleep., The maintenance of cardiovascular and cerebrovascular health is based on a complex relationship between the heart and the brain. While some responses to stress are vital for survival, mental stress has also been claimed to cause cardiovascular disease. The Japanese observation from the early 1990s of a reversible stress-induced cardiomyopathy, the takotsubo cardiomyopathy (TC), a peculiar type of left ventricular (LV) dysfunction triggered by an acute strong emotional or physical stressor, supports this notion. The syndrome, mostly affecting postmenopausal women, presents signs and symptoms of acute coronary syndrome without evidence of obstructive coronary artery disease. Though the definite pathophysiology of TC remains to be identified, a catecholamine overstimulation of the myocardium is thought to underlie the pathogenesis and forms the basis for treatment of this medical entity. Direct recordings of multiunit efferent postganglionic muscle sympathetic nerve activity (MSNA) were obtained from 12 female patients, 5 in the acute (24–48 hours) and 7 in the recovery phase (1–6 months), with apical ballooning pattern and 12 healthy matched controls. MSNA was expressed as burst frequency (BF), burst incidence (BI) and relative median burst amplitude (RMBA%). All patients were investigated with ongoing medication. MSNA was lower in patients with TC as compared to matched controls, but did not differ between the acute and recovery phase of TC. RMBA%, blood pressure and heart rate did not differ between the groups. MSNA is shown to be lower in patients with TC compared to healthy controls, suggesting that sympathetic neuronal outflow is rapidly reduced following the initial phase of TC. A distension of the ventricular myocardium, due to excessive catecholamine release over the heart in the acute phase may increase the firing rate of unmyelinated cardiac c-fibre afferents resulting in widespread sympathetic inhibition. Such a mechanism may underlie the lower MSNA reported in our patients., Background Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulfate (DHEA-S) increase during acute psychosocial stress is suggested to have a protective role against the negative consequences of cortisol. We have previously reported that, in adults, the capacity to produce DHEA and DHEA-S during acute psychosocial stress declines with age. Changes in DHEA and DHEA-S levels with ageing depend on changes in the zona reticularis area in the adrenal cortex, which is responsible for DHEA and DHEA-S production. Prolonged psychosocial stress may be a factor that negatively affects the zona reticularis area. This study aimed to investigate whether self-reported prolonged stress affect the capacity to produce DHEA and DHEA-S during acute psychosocial stress. Methods 20 men and 19 women (age 30–50 years) underwent Trier Social Stress Test (TSST). Physiological measurements were performed before, directly after the stress test and after 30 min of recovery. Perceived stress at work (during the last week) was measured by the Stress-Energy (SE) questionnaire. The participants were divided into three groups based on their scores. A general linear model (multiple regression analysis) was performed, using the magnitude of stress-induced increase of DHEA and DHEA (log) as dependent variable and age and stress level group as independent variables. Results Both the medium stress group and the high stress group had lower DHEA and DHEA-S increase during acute psychosocial stress compared to individuals reporting low stress levels at work (p=0.027 and p = 0.036, respectively). Conclusions This study indicates that prolonged stress is a factor that negatively affects the zona reticularis area in the adrenal cortex and its capacity to produce DHEA and DHEA-S during acute psychosocial stress., Background Deep brain stimulation (DBS) is an effective treatment for obsessive-compulsive disorder (OCD), but its mechanism of action is largely unknown. Since DBS may induce rapid symptomatic changes and the pathophysiology of OCD has been suggested to be related to the hypothalamic-pituitary-adrenal (HPA)-axis, we set out to study whether/how DBS affects the HPA-axis in OCD patients. Methods We studied 16 therapy-refractory OCD patients treated with DBS of the accumbal area for at least 1 year in an “on” and “off” stimulation phase, with a 1-week interval. We measured 24-h urinary excretion of cortisol, adrenalin, and noradrenalin as well as obsessive-compulsive (Y-BOCS), depressive (Ham-D), and anxiety (HAM-A) symptom scores. Results Eight patients who completed the study were included in the final analysis. The comparison between DBS on and off phase revealed a change in Y-BOCS (39%), HAM-D (78%), and HAM-A (56%) scores. Median cortisol levels increased by 53% in the off phase, from 93 to 143 nmol/24 h, and correlated strongly with Y-BOCS and HAM-D changes. There was no significant change in urinary adrenaline or noradrenaline excretion. Conclusions Our findings indicate that symptom improvement in DBS for OCD patients is associated with changes in cortisol levels., Rationale/statement of the problem Lesbian (L), gay (G), and bisexual (B) individuals frequently report heightened distress due to discrimination, yet investigations into their physiological stress responsivity are missing from the literature. Our group recently showed that disclosing one's sexual orientation corresponds with comparatively lower psychiatric symptoms and morning cortisol levels than those who remain “in the closet.” Extending from our earlier studies, the current study investigated whether sexual minorities might manifest differential cortisol levels than heterosexuals (Hs) in response to social-evaluative threat. Methods Participants included 87 healthy adults (mean age 25, 54% men) identifying as L/G/B (n=46) or as Hs (n=41). Stress was induced using the Trier Social Stress Test (TSST), and 10 salivary cortisol samples were collected throughout a 2-hour afternoon visit. Results were analyzed through ANOVA split by sex with sexual orientation as the between-subject factor and cortisol as the with-subject factor while controlling for age, self-esteem, and disclosure status. Results Results reveal that L/B women had higher cortisol levels than Hs women 40 min after stress exposure. As a group, G/B men had significantly lower cortisol levels in contrast to Hs men. The covarying effects of age, self-esteem, and disclosure status intermittingly contributed to time and group effects for both sexes. Conclusions Our findings demonstrate that relative to Hs controls (1) L/B women displayed higher cortisol levels late after TSST exposure, whereas (2) G/B men displayed lower overall cortisol levels throughout testing. We previously reported that G/B men in our sample manifested lower depressive symptoms and allostatic load based on 20 biomarkers compared to Hs men. It is possible that G/B men who are able to successfully overcome stigma may be resistant to chronic stress and stress reactivity. Yet, the opposite might be true for L/B women who displayed heightened distress during recovery that may indicate ruminative processes. These results suggest that it is important to include intrasex variations such as sexual orientation as well as unique developmental challenges such as disclosure processes in future psychoneuroendocrine studies., Background A few weeks ago and for the first time in 20 years, US health officials have lowered the threshold for lead (Pb) poisoning from 10 to 5 g/dL in blood, but only in young children. However, elders are also a high-risk population when considering adverse effects of lead exposure. The association between low-level lead exposure and cognitive variability is well documented in elderly people, e.g. in the domain of attention and memory. Toxicokinetic studies have also demonstrated that the skeleton is the site of storage for around 95% of lead in the adult human body, resulting in a release of lead in blood in elderly people with bone demineralization. One potential mechanism explaining adverse health effects of lead exposure stands in its endocrine disrupting function, and a recent study has found significant associations in children between low-lead levels and cortisol reactivity to the cold pressure task. We hypothesized that this association between lead exposure and hypothalamo–pituitary–adrenal functioning could be observed in elders from the general population. Methods Pb levels were determined from blood samples of 78 elderly individuals (mean age = 58.37, SE = 4.01) without previous occupational Pb exposure. Diurnal cortisol was measured using salivary cortisol samples collected at home over two working days at awakening, 30 min after waking, 14: 00 h, 16: 00 h and before bedtime (∼10 pm) periods. Salivary cortisol reactivity was assessed in response to the Trier Social Stress Test (TSST). Results All participants showed blood Pb levels below the threshold limit recommended by the CDC with a mean Pb of 2.6 g/dL, SE = 1.4. No association was found between lead exposure and diurnal cortisol activity (n=75, r= − 0.02, p=0.98). However, the more exposed to lead, the lower the cortisol response following TSST was found in participants (n=74, r= − 0.26, p, Kudielka, Hellhammer and Wüst (2009) identified studies about how a wide sample of variables affect the measure of the concentration of cortisol; in the first place are the age and gender of participants, in women, the phase of the menstrual cycle, consume of oral contraception, and if they were pregnant or nursing, among others. Indeed, the variations of immediate physical conditions—like a sleep hours after the take of the saliva sample, strong physical activity, or if they consumed coffee, nicotine, dietary or any kind of drugs prior to the research. Finally, due to the influence of more distal variables, such as intense emotional experiences of the mother during the pregnancy and hereditary factors in general (see Bartels, de Geus, Kirshbaum, Sluyter & Boomsma, 2003) and the type of procedures, like the hour of the take of the saliva sample, because of the variation of the circadian rhythm of the cortisol. Problem If we recognize the influence of these variables, from a methodological view, it is important to control these variables in the context of a research where we use the measure of salivary cortisol. Methods The overall average and the circadian cycle of cortisol in 3,414 salivary samples taken in 12 studies in Mexico, that were discussed this hormone differences based on age, gender and consumption or not cigars variables were analysed. Results It was observed a decrease in the concentration of cortisol as the participants were advancing in age; also identified a circadian normal pattern but with higher levels in the studied sample. Finally, no significant differences were found between the concentrations of cortisol between women and men, as well as between smokers and non-smokers. Conclusion It discusses the conceptual, methodological implications and practices resulting from the findings, both for the development of future research for his study in relation to the phenomena of health and disease. Take into account the age as a factor that affects the salivary cortisol measurements., Rationale Hypothalamus–pituitary–adrenal (HPA) axis reactivity, which has been considered a potential endophenotype for psychiatric disorders, is commonly investigated by repeated-measures designs utilizing frequent sampling of salivary cortisol in temporal proximity to psychosocial stressors. To remove sources of cortisol variance, which are not related to HPA axis reactivity, researchers often utilize classification criteria to identify individuals who show no cortisol response (non-responders), for example, baseline-to-peak distances of 2.5 nmol/l. However, such classification criteria have not been systematically evaluated with regard to their classification performance. Methods As a first step, we fitted an autoregressive latent trajectory model to cortisol data, which was obtained from longitudinally sampled saliva of 504 participants, of which 309 were exposed to the Trier Social Stress Test. Different sources of time-series variance were accounted for by modeling of initial cortisol levels, amplitude of the subsequently occurring secretory episodes, and continuous cortisol elimination. Assuming zero-amplitudes for individuals who show no stress response, a mixture distribution was implemented for secretory episodes, resulting in appropriate classifications of cortisol responders, or non-responders. Then, as a second step, we evaluated the classification performance of various proposed classifiers by constructing receiving operator characteristics. Results Results reveal (a) that covariance and mean structure of cortisol time-series can be sufficiently accounted for by the proposed model, allowing to infer on endocrine parameters that can barely be extracted by conventional analyses and (b) that the 2.5 nmol/l criterion is suboptimal in terms of simultaneously minimizing false-positive and false-negative classifications and inferior as opposed to other classifiers. Conclusion To maintain the low number of false positives, but to increase true-positive classifications, we suggest to lower the conventional baseline-to-peak classification threshold to 1.5 nmol/l. Furthermore, classification performance can be increased by adjusting baseline-to-peak differences for initial cortisol levels., Rationale/statement of the problem Common gene variants predisposing for altered dopamine (DA) neurotransmission are candidates for schizophrenia-susceptibility genes, although genome-wide studies so far showed a weak association of these variants with schizophrenia. It has actually become apparent that the expression of psychotic symptoms in schizophrenia is associated with the exposure of the genetically predisposed individuals to environmental risk factors during development such as early life adversity and upbringing in an unfavorable social environment. Furthermore, it has been postulated that genetic predisposition can promote not only vulnerability in response to negative environmental input, but also resilience in response to positive environmental stimulation. Methods We decided to test this hypothesis in the apomorphine-susceptible (APO-SUS) rat line, which was selected from Wistar rats on the basis of an extremely enhanced stereotypic gnawing response to administration of the dopamine agonist, apomorphine (APO-gnawing). The parental strain was used for comparison. Adult rats exposed as pups to poor maternal care and to post-weaning social-isolation rearing were examined for pre-pulse inhibition of acoustic startle (PPI), T-maze spontaneous alternation, contextual fear-conditioning and stress hormonal responses to a conditioned emotional stressor. Results Adult APO-SUS rats that had experienced poor maternal care as judged from low maternal licking and grooming (LG) scores showed dramatically enhanced stress-induced ACTH levels in the face of modest increases in circulating corticosterone (CORT) and prolactin levels. These low LG offspring also developed a basal PPI-deficit, reduced acoustic startle and impaired contextual fear-conditioning, but showed enhanced short-term memory. Additional isolation rearing abolished entirely basal PPI and impaired short-term memory in these individuals. High LG offspring, on the contrary, displayed enhanced PPI in both rearing conditions that was reduced only after CORT-challenge, while the low LG was resistant to CORT. Maternal LG history alone in Wistar rats had limited effects on the behaviour or stress response of offspring. When low maternal LG history was combined with post-weaning social isolation, basal APO-gnawing was decreased and PPI increased. High LG offspring reared in isolation displayed, however, the highest APO-gnawing and the lowest PPI levels among rats reared in social isolation. An injection of high dose CORT in the adult low LG offspring reduced PPI, whereas the high LG group was resistant to the acute effects of CORT. Conclusion If exposure to negative social environment accumulates, a schizophrenia-like phenotype, characterized by a severe deficit in sensorimotor gating and brain glucocorticoid-resistance, precipitates in the genetically predisposed individuals while the non-predisposed individuals are resilient. However, the same genetically predisposed individuals are sensitive to positive environment as well, where they improve their phenotype and outperform the controls, which do not change. This is the first animal model to find strong evidence for a differential susceptibility to stress in development depending on genetic predisposition., Telomere length (TL) is an important marker of cellular aging that can be examined from birth to death and provide information about health status and disease risk. TL shortens in early childhood with the majority of the shortening occurring by age 4. TL is associated with stress and obesity in adults. It is possible that exposure to early life stressors and excess adiposity from birth and the first year of life may impact the rate of telomere shortening. Few studies have examined TL in the first years of life, and none of them have examined stress and obesity in infants. We examined TL by qPCR using genomic DNA from dried blood spots in a sample of 109 four-year-old, low-income Latino children and their mothers. TL is expressed as T/S (the ratio of telomeric product vs. single copy gene product). This group of children and their mothers were recruited prenatally in San Francisco at which time socio-demographic and health history was assessed. In addition, child weight and length and maternal body mass index (BMI) have been assessed annually from birth with the child's weight and length measured also at birth and 6 months of age. Maternal depressive symptoms were assessed prenatally, at 4–6 weeks postpartum and annually throughout the follow-up period. Child behavior was evaluated using the child behavior checklist (CBCL) at 3 and 4 years of age for internalizing and externalizing behaviors. Student's t-tests were performed to compare TL in relationship to different childhood exposures – maternal depression, child overweight and obesity, and socio-demographic factors such as child sex, ethnicity, and socioeconomic status. Factors that were significant at p, Childhood trauma (CT) is associated with mood and anxiety disorders in adulthood, especially with posttraumatic stress disorder (PTSD). These disorders frequently co-occur, yet few PTSD comorbidity studies have focused on samples with a range of CT severity and none have included participants with adulthood-only trauma in the same study. We investigated SCID diagnoses of comorbid mood and anxiety disorders among 69 adult PTSD patients (M age = 37.94, SD=11.13; 53.6% female), with CT exposures (CTQ scores) ranging from absent to extreme. The CAPS and QIDS-SR measured PTSD and depression severity, respectively. Total CT exposure correlated with having at least one comorbid anxiety disorder diagnosis (r pb=.42, p, Rationale Life-threatening experiences, including the observations of severe trauma and/or violence, coupled with feelings of extreme fear and helplessness can result in posttraumatic stress disorder (PTSD). Unpredictability, uncontrollability, and novelty are considered key factors in eliciting and influencing the intensities of the stress responses. Personal coping strategies may affect resilience and susceptibility to stressors and, in PTSD patients, may also affect responses to stressors such as cortisol secretion. Recent interest in PTSD models focuses on the drivers of susceptibility versus resilience factors and the identification of potential targets for prevention and/or treatment of PTSD. Following a traumatic event, most individuals experience at least some symptoms of PTSD. However, many trauma survivors who develop PTSD recover over the course of months. Methods Systems and integrative biology approaches were applied to characterize the development of PTSD using an animal model of repeated social trauma/stress. Behavioral, physiological, and histopathological consequences of repeated social stress were evaluated using a modified "6 hour box-in-box resident-intruder" model. At the end of the stress episodes, mouse blood samples and organs were collected and brains were dissected into 17 different regions. Transciptomic, metabolomic, proteomic, and epigenomic changes were analyzed using microarrays. Results Pan-omic analyses of this mouse model that simulate aspects of PTSD revealed that genes involved in axonal guidance signaling, apoptosis, inflammation, corticotropin releasing hormone signaling, synaptic long-term depression, dendritic branching, and cardiac hypertrophy were upregulated in stressed mice compared to the control. Suppressed transcripts were involved in synaptic long-term potentiation, lymphocyte activation, gap junction signaling, and glucocorticoid receptor pathway. Conclusions We characterized the regulation patterns of genes, metabolites, protein, DNA methylation, and their associated networks in a mouse model of PTSD. These patterns can be used as part of a diagnostic panel for the development of PTSD and for the validation of therapeutic interventions., Background Individuals with disordered eating have the highest mortality rate of any psychiatric disorder and females make up the majority of the eating disordered population. Tobacco smokers have lower BMIs than do their non-smoking counterparts, and adolescent and adult females report using tobacco to lose or maintain body weight. Multiple biobehavioural factors contribute to this nicotine-body weight relationship, rodent studies suggest that reduced food intake following nicotine exposure may be a primary factor. Objective To examine the effects of nicotine on body weight changes in response to different food types. Methods We used an oral nicotine administration paradigm to investigate body weight changes in the presence of standard chow, high sweet and high fat foods in adolescent (N=63) and adult (N=60) female C57BL/6J mice. Mice were exposed to nicotine (200 µg/ml) or water along with one of three food types for 7 days. Results Adult mice weighed more but ate less food than did adolescents (p, Rationale/statement of the problem One in five UK women is obese at antenatal booking. Maternal obesity increases risk of offspring obesity, behavioural and metabolic disorders. Animal studies suggest male offspring are more vulnerable to these effects than females. We hypothesised that this is mediated by altered action of maternal glucocorticoids, key regulators of development and stimulators of appetite and weight gain. Methods Serum cortisol levels were measured at 16, 28 and 36 weeks gestation in n=156 class III obese (BMI > 40 kg/m2) and n=87 lean (BMI < 25 kg/m2) pregnant women. mRNA levels of 11-beta hydroxysteroid dehydrogenase type 2 (11βHSD2), which inactivates cortisol, were measured in n=36 first trimester and n=61 term placental samples. Results Cortisol levels were significantly lower throughout pregnancy in obese than lean (p4000 g) offspring (p, Rationale A recent study showed that a mineralocorticoid receptor (MR) gene variant, MR haplotype 2, was associated with higher levels of dispositional optimism, less thoughts of hopelessness, and lower risk of depression in women but not in men. Mice lacking the MR in the forebrain, MRCaMKCre mice, were generated to further investigate behavioral sex differences with and without the MR. Here, the hypothesis that sex differences would disappear after deletion of the MR was tested. Methods We used male (n=8–9) and female (n=9–14) MRCaMKCre mice and control littermates to study fear conditioning, memory performance, and extinction. The fear-conditioning paradigm assessed both context- and cue-related fear within one experimental procedure. Results At the end of the conditioning, all mice acquired the fear-motivated response. During the first minutes of the memory test, both male and female MRCaMKCre mice remembered and feared the context more than the control mice. Furthermore, female MRCaMKCre mice were not able to extinguish this memory even on the second day of memory testing. The female mutants could also not discriminate between cue (more freezing) and context periods (less freezing). In contrast, male MRCaMKCre and control mice showed extinction and were capable to discriminate, although extinction of the MRCaMKCre mice started slower. Conclusion The loss of forebrain MR does not eliminate sex differences but rather results in large differences in emotional and cognitive behaviors between female and male mice. This finding suggests a role of this receptor in the female prevalence of stress- and anxiety-regulated disorders., Rationale/statement of the problem Adverse exposures that influence growth in prenatal and early postnatal periods are thought to influence vulnerability to chronic diseases via their effects on the neuroendocrine system. In humans, assessment of the underlying mechanisms has been restricted. The aim of the present study was to investigate the effects of adverse early life exposures, specifically maternal mood, on hypothalamic–pituitary–adrenal (HPA) axis, sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) responses to an acute physiological stressor. In addition, we conducted a preliminary examination into whether effects varied by time of exposure and sex. Methods A total of 139 individuals (mean age 15.12 years) were recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Participants underwent the CO2 stress test, and indices of the PNS, SNS and HPA axis were measured. Pre-existing data on mothers’ demographic and psychosocial factors during pregnancy (18 and 32 weeks) and postnatally (8 weeks and 8 months) were extracted, as were participants’ clinical and demographic data at birth. Results Increases in both prenatal and postnatal anxiety and depression were associated with greater SNS reactivity to the stressor and slower recovery, as well as blunted HPA axis responses. Programming effects on the SNS appeared restricted to male offspring only. No consistent relationships were evident for any of the measures of pre-stress function. Conclusion We have found preliminary evidence that both pre- and postnatal maternal anxiety and depression have sustained programming effects on the SNS and HPA axis. Effects on the SNS were restricted to male offspring., Socioeconomic disadvantage during childhood has lasting effects on adult health. Children raised by less educated parents are at higher risk for later cardiovascular disease (CVD), Alzheimer's disease, and type 2 diabetes mellitus. The mechanisms through which childhood socioeconomic status (SES) affect health are unclear. Childhood SES may shape stress physiology, including neuroendocrine processes, which may negatively impact health in adulthood. Prior literature shows that less educated individuals have flatter cortisol slopes across the day compared to those higher in education. Flattened slopes have been linked to chronic stress, CVD outcomes, breast cancer mortality, and both all-cause and CVD mortality. It is unknown whether one's childhood SES, approximated by parental education level, predicts diurnal cortisol trajectories independent of one's individual education. To this end, we recruited 20 Black and 20 White women who previously participated in the National Heart, Lung, and Blood Institute (NHLBI)-supported National Growth and Health Study (NGHS) to complete a daily stress assessment, which included salivary cortisol sampling at four times per day over two consecutive days. Mixed modeling indicated that cortisol slope across the day was a function of individual education (b time×individual education= − 0.04, SE = 0.02, p=0.045). Simple slope analyses revealed that women with only a high school diploma had significantly flatter cortisol slopes (b= − 0.22, SE = 0.06, p, Rationale/statement of the problem Although tricyclic antidepressants (TCAs) are not recommended as first line therapy for depression in patients with coronary heart disease (CHD), they are still occasionally prescribed. Rationales may include resistance to other classes of antidepressants, previous response to TCAs, or treatment continuation after onset of a CHD. Despite their antidepressive effectiveness, TCAs may worsen cardiovascular prognosis because of autonomic side effects. Here, we examined potential adverse effects of TCAs on autonomic function as marked by heart rate variability (HRV) and norepinephrine (NE) levels. Methods A total of 956 outpatients with stable CHD, 44 used TCAs. All patients were prospectively followed for 7.2±2.6 years. Standard deviation of all normal RR intervals (SDNN) as a measure of HRV was calculated from 24 h-electrocardiographic recordings. NE levels were measured in plasma and 24 h-urinary samples. We also calculated hazard ratios for all-cause mortality. Results Users of TCAs had an increased risk of mortality compared to non-users (p=0.02 in an unadjusted model, p=0.01 in a model adjusted for age, sex, smoking, diabetes, congestive heart failure and depressive symptoms). When additionally adjusted for HRV and plasma NE, there was no significant association of TCA use and mortality. TCA users had an increased risk of being in the lowest tertile of HRV (p, Rationale Cognitive deficits and alterations in cortisol secretion are characteristic features of major depression disorder (MDD). The cortisol awakening response (CAR) is altered in depression and crucially depends on hippocampus function, a brain area closely related to cognitive function. Methods We examined 21 MDD patients without medication, 20 MDD patients treated with antidepressants, and 41 healthy control subjects (HC), matched for age, gender, and years of education. We applied several neuropsychological tests. Salivary cortisol levels were measured on two consecutive days at awakening, and 30 min and 60 min after awaking. Results Both patient groups did not differ in severity of depression (p=0.20). Analysis of variance (ANOVA) with CAR as dependant variable revealed a significant effect of group (p=0.01). Post-hoc tests confirmed that medicated patients exhibited a smaller CAR compared to unmedicated patients (p=0.04) and HC (p=0.01), whereas differences between unmedicated patients and HC were not significant. ANOVA for Auditory Verbal Learning Task total score revealed a significant effect of group (p=0.03). Post hoc tests confirmed that unmedicated patients were significantly impaired in verbal memory (p=0.01) whereas medicated patients were impaired on trend-level (p=0.09) when compared to HC. Differences between both patients groups were not statistically significant. Repeated-measures ANOVA revealed a significant effect for group (p=0.04) regarding non-verbal memory as measured with the Rey figure. Post hoc tests showed that unmedicated patients were significantly impaired compared to medicated patients (p=0.02) and compared to HC (p=0.06), whereas medicated patients and HC did not differ (p=0.32). In depressed patients, but not in HC, we found a negative correlation between CAR and memory function, which was driven by the unmedicated depressed patients. Conclusion The magnitude of the CAR is strongly associated with impaired memory function in unmedicated depressed patients even though CAR was not significantly increased in these patients. In contrast, medicated patients showed a blunted CAR and unimpaired cognitive function compared to controls. These results suggest that antidepressant treatment may reduce CAR and partially restore memory function even if depressive psychopathology is still present., Background Telomeres cap and protect the ends of chromosomes from fusion. Excessively shortened telomeres are associated with telomere dysfunction and chromosomal instability (CIN), DNA damage and an increased risk of degenerative diseases of ageing. Psychological stress has been strongly associated with accelerated telomere shortening, consistent with a wealth of evidence that chronic stress impacts negatively on health, possibly contributing to initiation of cancers, cardiovascular disease and neurodegenerative disorders such as Alzheimer's disease. Risk for these disorders is increased by deficiency in micronutrients, such as folate, an essential co-factor required for accurate replication of DNA and maintenance of methylation (epigenome) patterns, providing protection against CIN. Methods The aim of this preliminary study was to test the hypothesis that chronic exposure to the stress hormone cortisol impacts deleteriously on telomere length (TL) and that this effect would be further aggravated by folate (Vitamin B9) deficiency. Human lymphocytes from 3 males and 3 females (aged 53±3 years) were cultured in vitro for 12 days in medium containing either 25 or 120 nM folic acid (FA), together with either 0, 550, 1300 or 3500 nM cortisol. TL (by QFISH flow cytometry), cell growth and viability were measured. Results Cells cultured in FA-replete medium and chronically exposed to 550 or 1300 nM cortisol displayed longer TL at day 12 than cortisol-free controls (p, Background There is increasing evidence that oxytocin promotes empathy in humans. However, research on oxytocin and emotion recognition, a fundamental component of empathy, has yielded inconsistent results. Part of the problem is that studies have focused on limited, and varying, categories of emotional stimuli. Therefore, we investigated the effect of intranasal oxytocin on the identification of seven basic emotions (happiness, sadness, fear, excitement, surprise, disgust, and anger) using social and non-social stimuli, and we explored the effect of oxytocin on conceptual understanding of emotion. Method Eighty-two participants were administered a 24IU dose of intranasal oxytocin or placebo in a double-blind experiment. Participants completed the perceiving (faces, designs) and understanding (blends, changes) emotion components of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) 120 minutes after drug administration. Results Contrary to our prediction, standardized scores for accurately detecting emotions during the faces task of the MSCEIT were lower following oxytocin administration than placebo (F(1,80) = 8.861, p, Statement of the problem Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of trophic factors, which is the most abundant neurotrophin in the brain. BDNF exerts its effects by binding to the tropomyosin-related kinase B (TrkB) receptor. It enhances the growth and maintenance of several neuronal systems, serves as a neurotransmitter modulator, and participates in mechanisms of neuronal plasticity, such as long-term potentiation and learning. We aim to quantify the basal concentration and daily fluctuation of serum BDNF, as well as its possible change in response to prolonged release methylphenidate in an open, quasi-experimental and controlled study. Methods A total of 148 (115 males, 33 females) patients, of 9.77 (256) years old, were subdivided in two group. (1) Control group (n=37; 27 males, 10 females); healthy siblings of the Attention deficit hyperactivity disorder (ADHD) patients. (2) ADHD group (n=111; 88 males, 23 females), without epilepsy and with a normal value in an abbreviated intelligence test Kaufman Brief Intelligence Test (KBIT). In all subjects, after written informed consent, we performed identical clinical, psychometric and biochemical study, before and after (only ADHD group) treatment. ADHD group were diagnosed according Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria and sub-classified in the primary ADHD subtypes by EDAH scale. Measurement: BDNF by ELISA (IBL International, ref. RB59041), in serum samples obtained at 09:00 and 20:00 h, before and after 4,63 (2,3) months of the daily morning ingestion of PRMPH. Statistic: factorial analyses using statistical package STATA 12.0. Funding: Grant of Spanish government, FIS-PI07-0603. Results Serum BDNF (ng/ml) in ADHD children Control group Pre-PRMPH Post-PRMPH Day Night Day Night Day Night 36.36±11.62 31.78±11.92 31.96±12.57 28.40±12.50 29.43±12.00 26.73±12.32 Basal measurements: Day/night comparisons: z = –2.76, p=0.006. Group comparison: z=–2.19; p=0.028. ADHD pre vs. post: χ2=2.64, p = 0.1042; day vs. night: χ2=9.8, p=0.0017. Conclusion The ADHD patients show reduced BDNF serum concentrations in relation with siblings controls, concordant with the known pathophysiological mechanisms. Our results do not support the only previous contribution that indicates an increase of BDNF in untreated ADHD children, with positive correlation with the severity of the symptoms of inattention. In addition, we report for the first time “basal” response to treatment with PRMPH, with somewhat surprising results, because as neuronal trophic factor, one might expect an increase in serum in response to methylphenidate, that ameliorates neuropsychological and organic immaturity, proven the last in studies of volumetric magnetic resonance imaging (MRI)., Statement of the problem Brain-derived neurotrophic factor (BDNF), a member of the family of neurotrophic receptors, appears to intervene in the pathogenesis and treatment response in Attention deficit hyperactivity disorder (ADHD), hypothesis based on the conceptualization of ADHD as a neurodevelopmental disorder and the importance of the BDNF for normal neural development. In addition, in experimental models, psychostimulants and antidepressants increase the brain concentration of BDNF. Genetic polymorphisms related with the activity of the BDNF seem to correlate with the incidence, clinical manifestations, endophenotypes or the treatment response in ADHD. We aim to define if the response to prolonged release methylphenidate treatment is different in the main ADHD subtypes, in an open, quasi-experimental and controlled study. Methods A total of 148 (115 males, 33 females) patients, of 9.77 (2.56) years old, were subdivided in two group. (1) Control group (n=37; 27 males, 10 females); healthy siblings of the ADHD patients. (2) ADHD group (n=111; 88 males, 23 females), without epilepsy and with a normal value in an abbreviated intelligence test (KBIT). In all subjects, after written informed consent, we performed identical clinical, psychometric and biochemical study, before and after (only ADHD group) treatment. ADHD group were diagnosed according Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria and sub-classified in the primary ADHD subtypes by EDAH scale (). Measurement: BDNF by ELISA (IBL International, ref. RB59041), in serum samples obtained at 09:00 and 20:00 h, before and after 4.63 (2.3) months of the daily morning ingestion of PRMPH. Statistic: factorial analyses using statistical package STATA 12.0. Funding: Grant of Spanish government, FIS-PI07-0603. Results In the control group serum BDNF concentration in the morning (36.36±11.62 ng/ml) was very similar to the value seen in the predominantly inattentive subgroup of ADHD children, although evening concentration was higher (31.78±11.92 ng/ml). The treatment with prolonged release methyphenidate do not modify the daily fluctuation of BDNF in the children with hyperactive/impulsive/conduct disorder children, whereas in children with predominantly inattentive disorder PRMPH induces a significant decrease (χ2=6.62, p=0.010). ADHD subtypeSerum BDNF (ng/ml) in ADHD childrenPre-MPHPost-MPHDayNightDayNightPHI/CD30.76±12.3429.09±12.8230.29±12.527.25±12.93PDA35.31±12.8526.41±11.5526.97±10.325.05±10.21 PDA: Day vs. Night, pre: χ2=11.63, p=0.0019. ADHD pre- vs. post-treatment, day: χ2=6.62, p = 0.010. All statistical values for comparisons not shown were non-significant. Our results show both similar morning concentrations and daily fluctuation of BDNF, between predominantly inattentive ADHD children and healthy sibling controls. The PRMPH treatment does not modify the reduced BDNF concentration (vs. controls) in hyperactive/conduct disorder children, nor the absence of daily fluctuation; but contrary to expectation reduces the concentration in the predominantly inattentive patients to values similar to that observed at night, disappearing the highly significant basal day/night fluctuation also noted in the control group. Conclusion Besides our data in hyperactive/conduct disorder children has been reported that the major depression is also associated with a decrease in BDNF concentration. As serum BDNF seem parallel with intra-cerebral concentration, especially in messencephalic areas, this neurotrophin could be the link between ADHD and major depression, and provide a new pathway for the development of drugs for ADHD., Ratioanle/statement of the problem The second generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However, there is an increasing awareness that the use of the drug is commonly associated with serious metabolic side-effects in patients, including hyperglycemia, glucose intolerance and insulin resistance, and places patients at risk for developing cardiometabolic disorders, such as Type 2 diabetes. These side effects have been accurately modelled in rodent paradigms. We and other groups have demonstrated previously that olanzapine causes significant glucose intolerance and insulin resistance in rats. Methods In the present study, we directly compared three distinct classes of antidiabetic drugs, which included metformin (100 and 500 mg/kg, PO), rosiglitazone (6 and 30 mg/kg, PO) and glyburide (2 and 20 mg/kg, PO), on olanzapine-induced glucose dysregulation and insulin resistance. Adult female rats (n=8–10 per group) were acutely treated with lower (7.5 mg/kg) or higher (15.0 mg/kg) doses of olanzapine, and glucose intolerance was assessed using the glucose tolerance test, while insulin resistance was measured using the HOMA-IR equation. Results Both doses of olanzapine caused pronounced glucose dysregulation and insulin resistance that were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to control levels. In contrast, glyburide failed to reverse olanzapine-induced glucose intolerance, despite significantly increasing insulin levels. Conclusion These findings indicate that oral hypoglycemic drugs which influence hepatic glucose metabolism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than those affecting primarily insulin secretion, such as glyburide. The current model may also be used to better understand the biological mechanism of glucose dysregulation caused by olanzapine and how it can be reversed., Background Recent research suggests that atypical cortisol awakening response (CAR) is an outcome of negative factors, such as post traumatic stress disorder (PTSD) (Johnson et al., 2008) and insomnia (Backhaus et al., 2004), in adults. While a positive CAR is present in the vast majority of adults, less is known about the normal development of this response in children. Without a clear sense of typical emergence in early childhood, it is uncertain if risk factors can be standardly associated with the magnitude of CAR during development. Our study aims to expand current research on CAR to children under the age of 8 years. We aim to understand how CAR manifests in young children and how methodological, familial, and child-specific factors contribute to positive CAR (responders). Methods Fifty-two children (54% female) and mothers participated, ranging in age from 1 to 8 years (M: 4.88, SD: 1.72). Mothers were asked to complete several questionnaires and were sent a “cortisol packet” with instructions to obtain child saliva samples when they awoke (T1) and 45 minutes later (T2) across 2 days. “Responders” were identified as children whose cortisol levels increased from T1 to T2. Results No difference in responder group by child age was found in this sample. It may suggest a step-like model, such that emergence of positive CAR would begin in infancy (38%: Saridjan, 2010) and that rates may start to increase only around age 10 (60%: Freitag, 2009) until they stabilize in adulthood (75%: Wust, 2000). In contrast to previous literature, methodological variables, such as daily routine and time between samples (Griefahn & Robens, 2011), were not significantly associated with responder status. However, results were consistent with Saridjan and colleagues (2010), demonstrating that lower family income was associated with greater likelihood of being a responder. Maternal psychopathology had no effect on child CAR status. Interestingly, for child-specific factors, internalizing and externalizing scores had the opposite effect such that, for every increase in externalizing score the risk of being in the responder group increased by 13.5%; however, for every increase in internalizing score, the risk of being a responder decreased by 10%. Conclusions Future research should aim to understand the effects of pure internalizing and externalizing versus comorbidity on cortisol in larger samples., Background The main complaint symptom of complex regional pain syndrome type 1 (CRPS-1) is neuropathic pain. There is significant co-morbidity between neuropathic pain and neuropsychiatric disorders, including anxiety and depression. A decrease in dehydroepiandrosterone (DHEA) or increase in the molar cortisol to DHEA ratio (molar F/D ratio) is commonly found in patients with psychiatric disorders, such as major depression and posttraumatic stress disorder. However, no information about DHEA secretion is available for patients with CRPS-1. The present study determined the molar F/D ratio within the first hour after awakening in patients with CRPS-1 undergoing combined antidepressant treatment with analgesics and non-steroidal anti-inflammatory drugs. Method To do this, cortisol and DHEA concentrations were determined from saliva samples, which were collected immediately upon awakening, 30 and 60 min after awakening and at nighttime from patients with CRPS-1 (n=26) and age-matched healthy subjects (n=25). The beck depression inventory (BDI) was used to quantify depression levels in the medicated patients. The net increase in cortisol levels within the first hour after awakening (CARi) and the area under the cortisol curve with respect to ground within the first hour after awakening (CARauc) were calculated and used as an index of cortisol secretion. The area under the DHEA curve with respect to ground within the first hour after awakening (DHEAauc) was used as an index of DHEA secretion. Results The mean BDI scores of patients were 19.0±9.0 (range, 5–41). The BDI scores were not associated with any parameters for cortisol, DHEA secretion or other disease-related parameters such as disease duration, frequency of spontaneous pain, or extension of disease spread. We did not observe a difference in indices for cortisol and DHEA secretion between patients who had a value higher than the cut-off for chronic pain (BDI score 21, n=10) or patients who had lower than cut off BDI scores (n=16). Among indices for cortisol and DHEA secretion, the molar CARauc to DHEAauc (molar F/Dauc) ratio was associated with disease duration. Patients who suffered from disease for relatively longer time (subgroup 4 month ≤ ) had a higher molar F/Dauc ratio than both controls and patients who suffered for a relatively shorter time (subgroup 4 month ≥ ). There was no difference in BDI scores between subgroups. Conclusion We used combined analgesic treatment with tricyclic antidepressants, anticonvulsants and non-steroidal anti-inflammatory drugs to relieve pain and pain-related symptoms, such as depression, in patients with CRPS-1, but these results indicate that DHEA secretion after the awakening period decreases in the combined treatment condition., Statement of the problem Long-acting injectable (LAI) antipsychotics have been developed to increase compliance in schizophrenia. Risperidone-LAI was the first LAI atypical antipsychotic, as a biweekly injection. Paliperidone Palmitate (PP) is a recently developed LAI atypical antipsychotic that is administered monthly. PP is hydrolized to paliperidone (9-hydroxyrisperidone), the primary active metabolite of risperidone. Although both risperidone and paliperidone are associated with increases in prolactin levels, there is limited information regarding whether there are differences in sexual functioning between both compounds. We aimed to study whether there are changes in prolactin levels and/or sexual function after switching from LAI-risperidone to LAI-paliperidone. Methods We have studied 12 psychopathologically stable subjects with a psychotic disorder (n=10 schizophrenia, 1 schizoaffective, 1 psychosis N.O.S.) attending to the Early Psychosis Program from Reus (HPU Institut Pere Mata, Spain) treated with long-acting risperidone for at least 6 months. All participants were switched to LAI. Clinical assessment was conducted at baseline and 3 months after the switch with measures of psychopathological status (Positive and Negative Symptom Scale [PANSS], Calgary Depression Scale) and sexual dysfuncion (Arizona Sexual Experiences Scale [ASEX]). Two fasting blood samples (baseline and 3 months post-switch) were obtained to determine prolactin levels in plasma. SPSS version 17.0 was used to perform the statistical analyses. Wilcoxon test was used to explore changes in continuous variables (e.g. prolactin levels, ASEX scores) during the period of the study. A p-value < 0.05 was considered to be significant. Results There was a significant reduction in prolactin levels from baseline to the 3-month assessment. Those subjects with higher prolactin levels seemed to show a greater reduction. In relation to sexual dysfunction, although some cases improved notably in ASEX scores, the reduction was not significant in all the samples. None of the subjects reported worsening in psychotic symptoms. Conclusions In our sample, the switch from LAI-risperidone to paliperidone reduced prolactin levels during a 3-month period. However, changes in prolactin levels were not associated with a significant improvement in sexual functioning., Statement of the problem Subjects with psychosis are at risk for metabolic syndrome, mainly secondary to antipsychotic treatment although overeating also plays a role. The hypothalamic–pituitary–adrenal axis, which is involved in visceral obesity, may also affect energy balance through affecting energy intake and the risk for stress-induced hyperphagia. The main aim of the study was to study the association between salivary cortisol, overeating, and obesity in a sample of subjects with early psychosis. Methods We evaluated 53 participants (mean age: 23.5 years, 42% females) who were attending to the Early Psychosis Program from Reus (HPU Institut Pere Mata, Tarragona, Spain). All participants met criteria for a psychotic disorder or were considered at risk mental states after administration of the Schedules of Clinical Assessment in Neuropsychiatry (SCAN) or the Comprehensive Assessment of At Risk Mental States (CAARMS). Dietary habits were assessed by a dietician who administered the Eating Disorders module of the SCAN to explore two types of overeating: (1) Grazing, defined as repeatedly eating small amounts of food between mean meals (2) Binging, defined as consuming large quantities of food in a very short period of time. As grazing and binging can coexist in the same patient, we recoded overeating in four categories: (1) no overeating, (2) only grazing, (3) only binging and (4) grazing and binging. BMI and waist circumference were registered. A fasting morning saliva sample (9 h) was obtained. Salivary cortisol levels were determined by ELISA. Statistical analyses were performed with SPSS v.17.0. Kruskal–Wallis test was used to test differences between groups in continuous variables. Chi-squared tests were used to test differences between groups in categorical data. Results Of 53 participants, 37 (69.8%) reported grazing and/or binging. Salivary cortisol was not associated with BMI or waist circumference. Of all participants, the group reporting both grazing and binging showed increased salivary cortisol levels (p = 0.004) and greater BMI (p=0.035). Conclusions In young participants with early psychosis, overeating (coexistence of grazing and binging episodes) is associated with greater BMI and increased morning salivary cortisol levels., Rationale/statement of the problem Research has attempted to link atypical hormone patterns to behavior problems in adolescents with varying success. Exploring the interactive effects of hypothalamic–pituitary–adrenal (HPA) and hypothalamic–pituitary–gonadal (HPG) hormones may help clarify findings. Given the lasting influence of early life stress on hormones and mental health, considering the effect maternal depression (MD) may lend additional clarification. Methods Longitudinal data from 346 youth (171 males) were used to examine these associations. MD was measured during infancy and preschool with the Center for Epidemiologic Studies Depression scale. Morning levels of cortisol, dehydroepiandrosterone (DHEA), and testosterone were assessed at age 15 years. Internalizing and externalizing at 15, 16, 17, and 18 years were assessed with multi-informant report on the MacArthur Health and Behaviors Questionnaire using variables measuring number of symptoms (severity) and preponderance of one symptom type over the other (directionality). A two-level hierarchical linear model examined how neuroendocrine measures, early MD, and sex independently and jointly influenced mental health trajectories. Results For severity, a two-way interaction (B = −0.095, t = −2.25, p < 0.05) revealed that adolescents with high cortisol-low DHEA had more mental health symptoms and a significant three-way interaction (B = −0.019, t = −2.05, p < 0.05) revealed that adolescents exposed to early MD with high cortisol-high DHEA also displayed more symptoms. A significant three-way interaction (B = −0.213, t = −2.01, p < 0.05) revealed that girls with high cortisol-low testosterone displayed elevated mental health symptoms and a significant four-way interaction (B = −0.080, t = −2.60, p = 0.01) revealed that girls exposed to early MD with low cortisol and high testosterone also displayed increased mental health symptoms. Directionality findings revealed altered hormone patterns predicted internalizing symptoms for girls but externalizing for boys. Conclusion Results support the benefits of examining multiple hormones in the prediction of mental health problems and suggest additional hormone risk patterns are present in individuals exposed to early life MD., Rationale/statement of the problem In the central nervous system, the serotonin (5HT) neurotransmitter system plays a key role in the regulation of mood and emotion. Alterations in the 5HT system are thought to contribute to psychopathologies. In addition, drugs targeting the 5HT system are effective in the treatment of depression and anxiety disorders. Children with anxious temperament (AT) are characterized by excessive shyness, worrying, and avoidant behavior. This temperament, when stable across development, increases the risk of later developing depression and anxiety disorders. Using a well-established, nonhuman primate model of AT, we tested whether variations in the 5HT system predict individual differences in AT. We focused on the central nucleus region of the amygdala (CeA) because we have established that metabolic activity in this region is predictive of AT. Methods Using Affymetrix GeneChip® rhesus macaque genome arrays, we assessed gene expression from CeA tissue in 24 young male rhesus monkeys phenotyped for AT. Robust regression analysis was performed with correction for multiple comparisons across all annotated transcripts that are part of the neuroactive ligand pathway (KO04080) in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results As hypothesized, variation in gene expression predicted individual differences in AT. Specifically, of the thirteen 5HT receptors assessed, only the 5HT2C receptor (5HT2C; r= − 0.57, p, Rationale Although pessimistic individuals are at increased risk for developing cardiovascular disease, the biological mechanisms underlying this effect, and the social-environmental factors that modify these effects, remain unclear. To address this issue, we examined how pessimism, defined as the generalized tendency to expect negative outcomes, interacts with life stress exposure to predict metabolic health. Methods Seventy-one pre-menopausal mothers – 35 had a child with autism and 36 did not – participated in the study. They ranged from 28 to 51 years-old (M=41.3, SD = 5.1), had body mass indices from 17.2 to 43 (M=25.58, SD = 5.76), and were free of major chronic illnesses, including diabetes and metabolic syndrome. Participants provided fasting blood samples, had their body measurements taken, completed the Life Orientation Test-Revised to assess their level of pessimism (M=6.37, SD = 2.96) and the Stress and Adversity Inventory to assess their exposure to chronic stress over the life course (M=7.76, SD = 4.35). Participants’ “metabolic risk” was indexed based on waist circumference, glucose, ratio of total cholesterol to HDL, triglyceride levels, and systolic blood pressure. Results As predicted, pessimism and cumulative life stress exposure were each independently associated with greater metabolic risk, independent of age, income and caregiver status (Pessimism: β=0.49, p, Background Fatigue is the most common and distressing symptom reported by breast cancer survivors and yet the pathophysiology of cancer-related fatigue remains largely unknown. Fatigue is associated with lower parasympathetic and higher sympathetic nervous system activity in non-cancer samples, but only one study has demonstrated this same relationship in breast cancer survivors. This study evaluates the relationship between fatigue and basal autonomic nervous system activity as measured by heart rate variability (HRV) in a sample of breast cancer survivors. Methods Women who had been diagnosed with early stage breast cancer before the age of 50 were recruited from the UCLA tumor registry and completed psychological questionnaires, including measures of fatigue. A subset of these women (n=30) participated in a follow-up study in which they completed measures of fatigue, energy and mood four times per day for 5 days using electronic diaries, provided 3 days of saliva samples for cortisol assessment and underwent physiological assessment including electrocardiogram (ECG). HRV was assessed via ECG R-R wave spectral and time sequence analysis. Results Questionnaire measures of fatigue were negatively associated with indices of parasympathetic nervous system activity, B= − 3.85, p = 0.04 for RMSSD (root of the mean squared difference of successive normal to normal waves) and B= − 76.97, p = 0.04 for LF power % (low-frequency wave power percentage). Daily fatigue was also associated with lower basal HRV, B= − 15.1, p = 0.04 for RMSSD. However, fatigue indices were not associated with sympathetic nervous system activity as measured by low- to high-frequency wave ratio. Of note, fatigue was not associated with average daily cortisol output (AUC). Conclusions Lower HRV has been associated with increased chronic inflammation, which is elevated in cancer survivors reporting persistent fatigue, thus providing insight into potential system interactions underlying the mechanisms for cancer-related fatigue., Background The Social Self Preservation Theory posits that situations that threaten the ‘social self’ elicit shame which, in turn, is linked to cortisol stress response. Body esteem may be one predictor of the propensity to respond with shame to stress. Hence, the present study aimed at assessing whether body esteem is associated with cortisol stress responses, and further, whether this relationship is mediated by cognitive appraisals of challenge and threat. Methods We exposed 44 participants (21 F, 21±2 years) to the Trier Social Stress Test (TSST). Salivary cortisol was assessed at −1, +1, +10, +30, and +50 min. Body esteem (BE) as well as subscales addressing appearance, weight, and attribution of others’ judgments were assessed with the Body Esteem Scale for Adolescents and Adults (BESAA). Appraisals of challenge and threat were assessed with the Primary and Secondary Appraisal Scale (PASA). Results While the TSST successfully elicited cortisol stress responses (F=6.85, p=0.001), hierarchical regression analysis revealed that females with low BE showed higher cortisol stress responses than females with high BE, while the opposite was true for males (β = 0.44, p=0.047). The same pattern was found for the two BE subscales addressing weight and overall appearance (β = 0.42, p=0.04; β = 0.42, p=0.04), but not for the attribution subscale (p, Background Hyperprolactinemia as one of the frequent adverse effects associated with the use of antipsychotics is often neglected but can interrupt the compliance of treatment (1,2). Antipsychotic-induced hyperprolactinemia in women with schizophrenia frequently results in menstrual dysfunction (3) despite its potential to block D2 receptors. However, little (or less?) is known about the effect of olanzapine on prolactin levels in women. Methods Ms. S, military white-collar, a 35-year-old woman with psychosis, experienced amenorrhea shortly after beginning as well as during treatment with risperidone, 6 mg/day. Previously, she had been treated with haloperidol; she recalled one other occasion when her menses had ceased for 3 months. Before treatment with risperidone, however, Ms. S had been having regular monthly menstrual periods. Medical evaluation revealed an elevated serum prolactin level (100 ng/ml), a negative pregnancy test, and normal thyroid function tests. Magnetic resonance imaging showed no evidence of pituitary adenoma. Alternative treatment with olanzapine was initiated and titrated to 20 mg/day. Results After 2 months of olanzapine treatment, Ms. S's monthly menses resumed. Serum prolactin levels, although still elevated, trended downward to 86 ng/ml and 52 ng/ml after 2 and 4 months of olanzapine treatment, respectively. Although she has olanzapine-induced weight gain, her psychiatric condition remained in remission. Conclusions There are clinical trials regarding improvement of hyperprolactinemia after switching to olanzapine (4). We reviewed a case in which risperidone-induced hyperprolactinemia–amenorrhea normalized without clinical worsening after switching to olanzapine., Background Amenorrhea as one of frequent adverse effects associated with the use of atypical antipyschotics is often neglected but can interrupt the compliance of treatment. There are clinical trials regarding improvement of hyperprolactinemia after switching to olanzapine while some trials regarding the opposite and the improvement with aripiprazole. Aripiprazole is an antipsychotic with partial dopamine antagonism and agonism. Its advantageous side effect profile has been described earlier. We reviewed a case in which olanzapine induced amenorrhea normalized without clinical worsening after switching to aripiprazole. Methods Ms. C, a 36-year-old woman with psychosis, developed menstrual dysfunction and galactorrhea soon after beginning a treatment of olanzapine, 20 mg/day. She reported having monthly menses before regimen. After 3 month of treatment, menses were absent and galactorrhea began. Ms. C was not pregnant. Her prolactin level was 157.20 ng/ml, and an MRI showed no sign of pituitary adenoma. Olanzapine medication was discontinued in the patients because of galactorrhea, and raised liver enzyme activities. Aripiprazole was initiated and titrated to 15 mg/day. Results After 1 month of aripiprazole treatment, monthly menses resumed and galactorrhea resolved. The serum prolactin fell to a normal level (27.20 ng/ml). Ms. C's psychiatric condition improved and she has remission. Conclusions Aripiprazole's reduced potential to elevate prolactin may provide a treatment advantage for women with schizophrenia. Moreover, since menstrual cycles may normalize during treatment with aripiprazole, women treated with this drug may have improved fertility when compared with women receiving typical antipsychotics and olanzapine. In this case, aripiprazole treatment resulted in reduction of serum prolactin levels and resolution of galactorrhea. Further studies will be required to assess the comparative effects of aripiprazole and other antipsychotics on prolactin levels and resolution of galactorrhea., Background The impact of sleep on basal Hypothalamic–Pituitary–Adrenal (HPA)-axis functioning has been well documented. Specifically, decreased sleep quality and quantity are associated with higher basal cortisol levels, one index of HPA-axis functioning. Few studies, however, have examined the impact of sleep quality and quantity on the cortisol awakening response (CAR), or the diurnal peak in cortisol that occurs shortly after awakening. Investigating this association is important given that a higher CAR is associated with an increased risk for mental and physical health problems. Therefore, the current study aims to further examine the relationship between sleep and CAR in order to gain a better understanding of sleep's impact on HPA-axis functioning. Methods 58 undergraduate students (29 males; mean age = 18.74) were assessed over two consecutive mornings. Each morning, participants completed a daily sleep diary to assess self-reported sleep quality and total sleep time (TST) from the previous night. Saliva samples were used to obtain morning cortisol levels. Participants were asked to provide four saliva samples by spitting into salivettes. The first sample was obtained immediately after awakening. The following three samples were obtained at 30, 45, and 60 minutes after the first sample. Participants repeated this procedure on Day 2. Results Multilevel growth curve modeling was used in order to examine the impact of sleep quality and quantity on CAR. Results from the current study demonstrate that TST, or the total minutes slept during the preceding night on each day was significantly associated with both the intercept and slope of the model. More specifically, lower TST was associated with lower cortisol levels at awakening (t=5.40, p, Statement of the problem The analysis of steroid hormones in hair is increasingly used in psychoneuroendocrinological research as a valid and easily implementable method for the retrospective assessment of cumulative long-term hormone secretion. To determine steroid hormone concentrations in hair, most laboratories have so far relied on immunochemical assays which are fast and easy to perform, but have a reduced reliability and analytical specificity due to cross-reactivity with other substances. Furthermore, immunoassay can only measure a single steroid at one time. By contrast, liquid chromatography tandem mass spectrometry (LC-MS/MS) has better specificity, sensitivity and reproducibility, and can measure a wide spectrum of steroid hormones simultaneously. Here, we report data on the development of a new LC-MS/MS-based method for the identification of endogenous concentrations of seven steroid hormones (cortisol, cortisone, testosterone, progesterone, corticosterone, DHEA, androstendione) in human hair. Methods Hair samples were first washed with isopropanol. Steroid hormones were extracted from 10 mg whole hair by 1.8 ml methanol incubation at room temperature. One milliliter methanol was transferred to a new tube and evaporated to dryness. Then the extraction was resuspended with 0.25 ml water, 0.20 ml of which was injected into the machine for analysis. Results The limits of detection were 0.1 pg/mg (cortisol), 0.1 pg/mg (cortisone), 0.4 pg/mg (testosterone), 0.9 pg/mg (progesterone), 0.4 pg/mg (corticosterone), 9.0 pg/mg (DHEA), 0.1 pg/mg (androstendione). Linear ranges were 0.5–100 pg/mg (cortisol), 0.5–100 pg/mg (cortisone), 2–100 pg/mg (testosterone), 4–100 pg/mg (progesterone), 2–100 pg/mg (corticosterone), 40–1000 pg/mg (DHEA) and 0.5–100 pg/mg (androstendione). Conclusions This LC-MS/MS method provides a highly specific analytical strategy for the detection of seven endogenous hormones in human hair and is thus likely to further enhance the accuracy of future research in this field., Rationale The validity of experimentally induced panic attacks as a model to study the pathophysiology of panic disorder has been questioned. Unspecific, unpleasant and aversive effects as well as specific patterns of psycho vegetative symptoms pointing to different subtypes of panic disorder have been observed. These findings raise the question of challenge paradigms as a valuable tool to identify different vulnerabilities in patients with panic disorder. Methods We compared the two most widely studied panicogenic drugs sodium lactate and cholecystokinin tetrapeptide (CCK-4) with placebo in 25 patients with panic disorder and age- and gender-matched healthy control subjects. To measure psychophysiological changes, we repeatedly administered the Acute Panic Inventory (API) and visual analogue scales for anxiety and arousal. Cardiovascular (heart rate and blood pressure) and neuroendocrine (ACTH, Cortisol and prolactin) data were recorded simultaneously. Results In patients with panic disorder, 18 out of 26 experienced a sodium lactate- or a CCK-4 induced panic attack. Lactate or CCK-4-induced symptoms and induced panic attacks were only correlated in healthy controls, but not in patients with panic disorder. (Analysis of sodium lactate- and CCK-4-induced changes of cardiovascular and neuroendocrine parameters is in progress at the moment and results will be presented). Conclusions The mechanisms of lactate and CCK-4 induced panic attacks are distinct in panic disorder patients but not in healthy controls. Different neurobiological vulnerabilities may be uncovered by different challenges and may indicate differential response to specific therapeutic interventions as well., Rationale/statement of the problem A major control demand in successful dual-task performance is the task-specific separation of task-goal representations and of the related stimulus-response translation processes. Although these cognitive control processes of task shielding and the physiological effects of acute stress share substantial neural commonalities such as their relation to the prefrontal cortex (PFC), direct empirical evidence of how specific PFC-related cognitive control processes involved in dual-tasking are influenced by acute stress is still missing. Therefore, the present study investigated the impact of acute psychosocial stress on task shielding in dual-task performance. Methods Fifty-six healthy subjects were exposed to either an acute psychosocial stressor (the Trier Social Stress Test) or a standardised control situation prior to a dual task. The individual physiological stress response was monitored by analysing salivary α-amylase (sAA) and cortisol as markers of sympathetic nervous-system and hypothalamus–pituitary–adrenal (HPA-)axis activity, respectively. Task shielding was assessed by the amount of interference of Task 2 processing on prioritised Task 1 performance (between-task interference). Results Following successful stress induction, as indicated by increases in sAA and cortisol, stressed individuals displayed increased between-task interference relative to controls. This result was further substantiated by a correlation between treatment-related increase in cortisol, but not sAA, and between-task interference. Conclusion Acute psychosocial stress reduces task shielding, and thus allows for more between-task interference in dual-task performance. We interpret this finding as a shift in cognitive control states from a more serial resource-demanding to a more parallel resource-efficient task-processing mode. The results further suggest a potential role of the HPA-stress response for the development of the observed control adjustment., Rationale/statement of the problem Leukocyte telomere length (LTL), a marker of cellular aging, has been proposed as a pathogenic mechanism by which depression may confer increased risk of adverse cardiovascular events. Prior studies have suggested that depression and depressive symptoms are associated with shorter LTL, but these studies are limited by small sample sizes, selective enrollment of participants (e.g. psychiatric outpatients), and lack of adjustment for cardiovascular risk factors and other covariates. The present study examines the association of LTL with depression and depressive symptoms in a large, populations-based cohort. Methods Participants included 2225 apparently healthy individuals from the 1995 Nova Scotia Health Survey (NSHS95) population-based study. Depressive symptoms were assessed by the Center for Epidemiological Studies-Depression (CES-D) scale. LTL was assessed by a real-time polymerase chain reaction method. Linear regression analyses were used to examine the association between LTL and depressive symptoms, probable depressive disorder (CES-D ≥ 10 or CES-D ≥ 16), and specific depressive symptom clusters (depressed affect, somatic concerns, positive affect, and interpersonal problems). These analyses were adjusted for clinical and demographic factors thought to potentially confound the association between depression and LTL, including: age, sex, body mass index, Framingham risk score, and previous ischemic heart disease. Results In an unadjusted model, each 1-point increase on the CES-D was significantly associated with a 3.49 base pair increase in LTL (95% CI = 0.39-6.60, p = 0.03). However, this association was not significant after adjustment for age and sex (B=1.20, 95% CI = − 1.85-4.25, p = 0.44) and further adjustment for other covariates (all p's ≥ 0.37). Neither probable depressive disorder nor specific depressive symptom clusters were independently associated with LTL after adjustment for covariates. Conclusion Concurrent depressive symptoms were not independently associated with LTL in a large population-based study. These results suggest that the excess risk of cardiovascular disease risk associated with concurrent depression may not be due to accelerated cellular aging., Background Cortisol is a stress-related hormone that interacts with peripheral and neural systems. Although cortisol is important for short-term stress responses, chronically high cortisol is hypothesised to underlie the long-term effects of chronic stress, including decreased dendritic arborisation in rodent prefrontal cortex (PFC). Here we examined the relationship between variation in stress-induced cortisol levels and regional brain volume in 592 young rhesus monkeys. Methods Cortisol was quantified from blood samples taken from 592 rhesus monkeys (µ-age: 1.88 years; sex: 265 F) immediately after a human intruder presented their profile to the monkey for 30 min. T1-weighted structural MRI scans, taken within 2 weeks of testing, were transformed to an atlas-based study specific template using ANTS (http://www.picsl.upenn.edu/ANTS/). For each subject, we decomposed the final standard-space transformation into affine (linear) and deformable (nonlinear) components. We then produced a 3D map of the relative volume change from the deformable transformation, which accounts for whole-brain differences. Voxelwise robust regression analyses assessed the relationship between cortisol and brain volume, as measured using the log-jacobian determinant. Results Those subjects with higher cortisol had significant decreases in cortical volume. More specifically, there was a significant negative relationship (FDR, q, Background Cortisol is critical for survival and reflects a primary mechanism by which emotions can influence immune responses throughout the periphery. Although cortisol release is adaptive in response to stress, chronically increased cortisol is known to have negative effects on both body and brain. Here we use a large sample of rhesus monkeys to examine individual differences in stress-related cortisol, in relation to white matter (WM) structure within a distributed brain network. We correlated individual differences in stress-induced cortisol with diffusion tensor imaging (DTI) measures of WM microstructure in 330 young rhesus monkeys. Methods 330 young rhesus macaques were scanned. Diffusion-weighted imaging was performed using a GE SIGNA 3T scanner. Scanning parameters were b=1000 s/mm2, TR = 10 s, TE = 77.2 ms, FOV = 14 cm, matrix = 128×128, 2.5 mm slices. Brains were transformed to a standard space using DTI-TK normalization tool (http://www.nitrc.org/projects/dtitk), which iteratively constructs a nonlinear template from the tensor files. Fractional anisotropy maps were computed in standard space. Cortisol was measured from the blood after a No Eye Contact (NEC) challenge, where a human intruder entered the room for 30 minutes without having eye contact with the monkey. We used robust regression to examine the relationship between fractional anisotropy (FA) and cortisol levels while controlling for age and sex. Results Individual differences in cortisol were correlated with DTI-measured FA in the internal capsule (p, Rationale Chronic stress has been related to lower telomerase, an enzyme that helps preserve the integrity of DNA and slow immunological aging. However, it is unknown whether daily psychological processes reflecting healthy emotion regulation protect against stress-related immune-aging. Methods We examined basal telomerase activity in a sample of 72 healthy premenopausal women across a range of stress levels, including 35 mothers caring for a child with autism and 37 low-stress control mothers of healthy children. Participants completed a nightly diary over the course of a week, reporting their exposure to positive and negative events. Then they rated the extent to which they employed various emotion-regulation strategies in response to these events. Within-subject weekly means for all measures were calculated. In addition, composite scores for positive affect in response to positive daily events and negative affect in response to daily stressors were calculated, and weekly means obtained. Depressive symptoms were assessed using the Inventory of Depressive Symptoms. On day 4 of the study week, a fasting blood draw was performed to measure peripheral blood mononuclear cells (PBMC) telomerase activity. Results Higher telomerase activity was significantly associated with the use of more resilient emotion regulation strategies, including more positive emotional responses to positive daily events (r=0.27, p=0.02) and increased savoring of positive daily events (r=0.24, p=0.04). In general, negative emotional responses and rumination in response to daily stressors were not related to telomerase with two exceptions: lower telomerase was associated with greater emotional suppression (r= − 0.34, p, Background To test how genomic loci identified in genome-wide association studies (GWAS) influence the developmental progression of smoking behavior. Design A 38-year prospective longitudinal study of a representative birth-cohort. Setting The Dunedin Multidisciplinary Health and Development Study was conducted in Dunedin, New Zealand. Participants A total of 1037 male and female study members participated in this study. Main exposures We assessed genetic risk with a multi-locus genetic risk score (GRS). The GRS was composed of single-nucleotide polymorphisms identified in three meta-analyses of GWAS of smoking quantity phenotypes. Outcome measures Smoking initiation, conversion to daily smoking, progression to heavy smoking, nicotine dependence (Fagerstrom Test of Nicotine Dependence), and cessation difficulties were evaluated at eight assessments spanning ages 11–38 years. Results GRS was unrelated to smoking initiation. However, individuals at higher genetic risk were more likely to convert to daily smoking as teenagers, progressed more rapidly from smoking initiation to heavy smoking, persisted longer in smoking heavily, developed nicotine dependence more frequently, were more reliant on smoking to cope with stress, and were more likely to fail in their cessation attempts. Further analysis revealed that two adolescent developmental phenotypes – early conversion to daily smoking and rapid progression to heavy smoking – mediated associations between the GRS and mature phenotypes of persistent heavy smoking, nicotine dependence, and cessation failure. The GRS predicted smoking risk over and above family history. Conclusions Initiatives that disrupt the developmental progression of smoking behavior among adolescents may mitigate genetic risks for developing adult smoking problems. Future genetic research may maximize discovery potential by focusing on smoking behavior soon after smoking initiation and by studying young smokers., The cellular enzyme elomerase replenishes telomeric DNA, which can be lost during repeated mitoses or during exposure to inflammation and oxidation. However, telomerase may have other, non-canonical functions, including (in animal models) antidepressant and neurogenesis-enhancing effects. In this study, we determined the relationship between telomerase activity [(measured in peripheral blood mononuclear cells (PBMCs)] and hippocampal (HC) volume in depressed individuals (MDDs) and matched controls. Nineteen medication-free subjects with MDD and 17 matched healthy controls underwent 4T MRI scanning and fasting morning venipuncture for assessment of unstimulated PBMC telomerase activity. Due to the exploratory nature of the study, corrections for multiple comparisons were not applied. Hippocampal volume was smaller, but not significantly so, in the MDDs than the controls. As reported previously, MDD subjects had significantly higher PBMC telomerase activity than the controls (p=0.007). Within the MDD group (but not in the control group or in the combined sample), PBMC telomerase activity was positively correlated with HC volume (r=0.49, p, Prior studies of Hypothalamic-Pituatary-Adrenal (HPA) associations with hippocampal (HC) volume have yielded inconsistent results. This might be due to the use of basal cortisol rather than cortisol reactivity measures and to the use of cortisol in isolation from related steroids. Therefore, in this study, we assessed the relationship of HC volume to cortisol awakening responses (CARs) and to the ratio of cortisol/DHEA in depressed (MDD) subjects and healthy controls. We additionally assessed cortisol correlations with individual HC subfield volumes. A 4 Tesla T1 MR imaging was conducted for HC volume for 19 MDD subjects and 19 matched controls. Fasting morning serum was assayed for cortisol and DHEA. In addition, salivary samples were assayed for cortisol for 17 MDDs and 15 controls across 3 days: at Waking (Sample 1) and at +30 minutes after waking (Sample 2). The CAR is the difference between daily Sample 1 and Sample 2 salivary concentrations. The slope of the CARincrease was obtained by dividing the CAR by the actual length of time between the two sample collections. Serum cortisol was not significantly correlated with HC volume. However, in the MDD group, serum DHEA, a putative anti-glucocorticoid, was positively correlated with HC volume (p, Background We investigated whether the habitual physical activity (PA) level had an impact on the acute effects of a short bout of 12 minutes of intensive exercise on cognitive performance and testosterone (T) concentration in primary school children. We further looked for associations between the T concentration and cognitive performance. Methods 42 students of a fourth grade (9–10 years of age) were randomly assigned to an experimental group (EG, n=27) and a control group (CG, n=15). The first saliva collection took place after a normal school lesson in which the students filled out a habitual physical activity questionnaire and completed the d2-test, a test of selective attention (pre-test). While the intervention (12 min) the EG performed an intensive exercise at a heart rate (HR) of 180–190 bpm and the CG participants watched a non-arousing movie. Afterwards, saliva samples were taken and both groups again completed the d2-test (post-test). Saliva was analyzed for testosterone. The whole sample was divided in low- and high physically active subjects by a median split. A 2×2×2 mixed factor ANOVA design with repeated measures was used to test for differences. Analyses were controlled for sex and BMI. Results After the intervention participants of the experimental group showed better performances in the d2-test of concentration compared to control. We further observed a significant group (EG, CG), test (pre, post), activity level (high, low) interaction indicating a different pre- to post-test development in T concentration for high- and low-active participants in the EG and CG. Post hoc pairwise comparisons revealed that after acute exercise the T concentration decreased only in habitually low-active children. Conclusions The results indicate that the intensive exercise only interacted with the hypothalamic-pituatary-gonadal (HPG) axis in habitually low-active preadolescents, but had a beneficial effect on cognitive performance for all participants independent of their activity level., Background Recent meta-analyses have stimulated an active debate on whether the serotonin transporter gene-linked polymorphic region (5-HTTLPR) is associated with an elevated vulnerability to psychiatric diseases on exposure to environmental adversity. As a potential mechanism explaining genotype-depended differences in stress sensitivity, altered stress-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis has been investigated in several experimental studies, with most of the studies comprising small samples. Methods We evaluated the association of 5-HTTLPR genotype and cortisol reactivity to acute psychosocial stress by applying a meta-analytical technique based on 11 relevant data sets (total N=1686), which were identified through a systematic literature search up to October 2011. Results The present meta-analysis indicates a small (d=0.27), but significant association between 5-HTTLPR genotype and HPA-axis reactivity to acute psychosocial stress with homozygous carriers of the S allele displaying increased cortisol reactivity compared to individuals with the S/L and L/L genotype. The latter association was not further moderated by participants’ age, sex or the type of stressor. Formal testing revealed no evidence for a substantial selection or publication bias. Conclusions Our meta-analytical results are consistent with a wide variety of experimental studies indicating a significant association between 5-HTTLPR genotype and intermediate phenotypes related to stress sensitivity. Future studies are needed to clarify the consistency of this effect and to further explore whether altered HPA-axis stress reactivity reflects a potential biological mechanism conveying an elevated risk for the development of stress-related disorders in S allele carriers., Rationale Neonatal maternal separation (MS) leads to a long-term dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis in the offspring. Consumption of highly palatable food (HPF) strongly activates the brain reward center and modulates the HPA response to stress. In this study, we have examined the effects of HPF free access during adolescence and youth on the adverse psycho-emotional behaviors by MS experience in rats. Methods Male and female SD rat pups were separated from dam for 3 h daily during PND 2–14 (MS) or left undisturbed (NH). Half of NH and MS pups had free choices of cookie (HPF) and chow from PND 28, the rest half received chow only. All rats (n = 8–10 in each group) were subjected to behavioral tests during young adulthood (PND 54–59), and the feeding conditions continued until the end of behavioral sessions. Results Maternal separation (MS) experience suppressed ambulatory activity both in male and female rats, and HPF access restored it only in males. Caudal grooming was reduced and rostral grooming increased by MS, and HPF access restored them both in males and females. HPF access did not alter MS-induced anxiety-like behaviors during elevated plus maze test both in male and females. Immobility duration during Porsolt swim test was increased by MS experience both in males and females, and HPF access restored it only in females, not in males. Conclusion Results demonstrate that free access to HPF during adolescence and youth may partly improve MS-induced anxiety-like behaviors both in male and female offspring, and depression-like behaviors only in females., Rationale/statement of the problem The impact of psychosocial stress on a variety of negative health outcomes is well documented, with much of the current research efforts directed at possible mechanisms. For example, psychosocial stress in humans has recently been associated with DNA damage that plays a role in the etiology of negative health outcomes, and also with changes in DNA transcription to messenger Ribonucleic Acid (mRNA). We have become interested in one putative regulatory element in mRNA translation to proteins: microRNA (miRNA). In this study, we aimed to investigate the relationship between psychosocial stress and changes in gene expression changes on the miRNA level, and to further investigate whether stressful life events and personality traits moderate these relationships. Methods Using a pre-post design, 36 adults were exposed to standardized psychosocial stress in the laboratory (Trier Social Stress Test [TSST]) and completed measures on perceived and chronic stress. In addition, cortisol levels were determined from saliva samples obtained prior to stressor and at eight time points during recovery. Before and after the TSST, subjects underwent a total of three blood draws from which peripheral blood mononuclear cells (PBMCs) were extracted in order to determine miRNA gene expression levels, using the Affymetrix Genechip 2.0 microRNA array. RNA was extracted from each sample and gene expression was measured by hybridization to the miRNA microarray. In an effort to identify a miRNA expression profile for the acute stress response, we compared miRNA expression changes at baseline (before onset of the stressor) with miRNA expression at the two time points following the stressor. Results The acute psychosocial stressor produced a higher cortisol response in a subset of the study participants (high responders). We expect these individuals to exhibit significant changes in miRNA expression from baseline to post-stress. We further hypothesize that these changes will be most significant for miRNAs that regulate expression of genes associated with the cortisol stress response. Conclusion Our study aims to identify a miRNA signature of social stress and to correlate differences in miRNA expression with psychological variables such as early life stress and resilience, which may function to mitigate the stress response., Background Exposure to chronic social stress is a strong predictor of postpartum depression and anxiety. Recent studies have described a chronic social stress (CSS) rodent model for postpartum depression where the repeated exposure of lactating dams to novel male intruders attenuates both the display of maternal care and growth during lactation and increases self-grooming, a measure of anxiety. Investigation of the adult female offspring of these affected dams reveals an attenuated nursing efficiency that is associated with decreases in central oxytocin, prolactin, and vasopressin gene expression. Methods The current study continued the characterization of the (CSS) model by expanding the analyses to include milk intake, saccharin intake (a measure of anhedonia), and gene expression of the stressed dams. Results CSS decreased maternal care and saccharin intake, attenuated pup milk intake by 40%, and altered gene expression in lactating dams. Conclusions It is concluded that CSS is an ethologically and translationally relevant model for postpartum depression and anxiety, as well as associated impairments in nursing., Rational/statement of the problem The low-dose dexamethasone-suppression test (DST) has originally been introduced by Yehuda et al.. Method We here report data on the salivary cortisol responses to awakening (CAR) to the DST in healthy subjects (N=102), as well as in outpatients (N=92) and inpatients (N=99) with stress related disorders. Patient groups were matched for age and sex by propensity score matching. Stress pathology was assessed by the Patient Health Questionnaire (PHQ). Results We observed stepwise highly significant differences among these three populations with respect to both supersuppression (< 2 nmol/l) and escape (> 6 nmol/l) of cortisol levels. Amazingly, a supersuppression was most frequently observed in healthy subjects, while an escape was most prevalent in inpatients, less common in outpatients, and rare in healthy subjects. While none of the healthy subjects got a PHQ diagnosis, inpatients and outpatients showed an average of 1.8 and 1.9 diagnoses, respectively, but did not differ with respect to the type and degree of stress pathology. Thus, the DST may rather be considered an unspecific test of dysregulations of the pituitary–adrenal axis. Conclusion Many research studies observed a supersuppression of cortisol levels in hypocortisolemic subjects with stress related disorders, such as post traumatic stress disorder (PTSD), fibromyalgia, chronic pelvic pain. These subjects commonly express symptoms of fatigue, pain, and an enhanced stress sensitivity, but seem to be protected against deleterious effects of cortisol on organ functions. Such a protective effect may possibly explain our observation that hypocortisolemia and supersuppression are less common in inpatients and outpatients. However, the increasing number of escapes from healthy subjects to outpatients and inpatients was not unexpected. We discuss these findings by applying an additional analysis of endophenotypes., Rationale Rodent studies indicate that the orbital and medial prefrontal cortex have an inhibitory control on the hypothalamic–pituitary–adrenal (HPA) axis, by restraining the acute stress response and facilitating negative feedback inhibition, which can also affect its basal tone of activity. Similarly in humans, extent of damage to the medial prefrontal cortex correlates negatively with cortisol levels. However, lesions of the orbital frontal cortex (OFC) in adult monkeys resulted in no effects on HPA activity. In the present study, we assessed the effects of neonatal OFC lesions on emotional and HPA reactivity to an acute stressor. Methods Subjects received bilateral aspiration lesions of orbital frontal areas 11 and 13 (Neo-Oasp, n=5) or sham operations (Neo-C, n=6) between 7 and 14 days of age. Upon reaching adulthood (6–8 years), emotional responses were examined using the Human Intruder (HI) paradigm given at 7: 00 hr for all animals and blood samples were collected immediately before and after the stressor to assess HPA axis reactivity. Two days prior to the HI test, two blood samples were collected at the same time of day but without the stressor. Diurnal cortisol rhythm was assessed one year later with blood samples collected at Lights-On (7:00 hr), Mid-day (13:00hr), and Lights-Off (19:00hr). Results In the presence of the HI, Neo-Oasp animals exhibited less species typical defensive freezing responses as compared to controls (Group: F[1,9] = 14.43, p=0.004), yet they exhibited more hostility throughout the test (Group: F[1,9] = 5.45, p=0.044). Groups did not differ in their neuroendocrine response to the HI, showing a significant increase in cortisol after the stressor as compared to baseline (F[1,9] = 22.08, p=0.001). To control for individual variability and determine that changes in hormone levels were not due to handling or sampling technique, blood samples taken without the stressor revealed that Neo-Oasp animals exhibited lower cortisol at Lights-On compared to Neo-C animals (F[1,9] = 6.01, p=0.037). This lower basal HPA activity was also observed when the diurnal cortisol rhythm was later investigated in the same animals (Group×Time of Day F[2,18] = 3.81, p=0.042). Conclusion Results indicate that OFC damage in infancy alters emotional behaviors as well as basal but not stress reactive HPA axis function., Rationale Hormonal contraception has been the subject of numerous research studies. Despite the fact pharmaceutical companies advertise the physical side effects of the medication both positive (e.g. improved acne, reduced ovarian cancer risk) and negative (e.g. increased risk of stroke, weight gain), the knowledge of the potential psychological effects are often based on Internet searches or less than credible resources. The range of empirical support for the effects of the medications on mood has been beneficial including improved mood to negative such as mental health distress. Aside from psychological research, sexual side effects including reduced libido and reduced sexual responsiveness have also been reported. The majority of the research on hormonal contraceptives has been conducted in a clinical setting. It is unclear if the preceding findings would be found with females self-selecting to use the medication as opposed to paid study participants in a clinical setting. Methods In order to gain a greater understanding of the relationship between hormonal contraceptive usage and affect, an Internet survey with females of childbearing age (age range: 17–48, N=379) was conducted to examining psychological distress (stress, anxiety, depression, and negative mood), improved mood (life satisfaction, happiness, and positive mood), and sexuality (sexual frequency and sexual satisfaction). Results Contrary to previous findings, results from this correlational study suggest no effects of hormonal contraceptive use on psychological distress or mood. Females using hormonal contraception did, however, report higher scores for sexual satisfaction and increased sexual activity. Conclusions While this investigation was not experimental and, therefore, causation cannot be determined, females using hormonal contraception may be relieved that this research suggests that these drugs do not lead to psychologically harmful side effects and sexuality may be improved with usage. More research is needed to confirm these findings., Background Avoidant personality disorder (AvPD) is a personality disorder recognized in the Diagnostic and Statistical Manual of Mental Disorders handbook (DSM-IV TR) in a person characterized by a pervasive pattern of social inhibition, feelings of inadequacy, extreme sensitivity to negative evaluation, and avoidance of social interaction. To this day, the causes of AvPD are not clearly defined, and may be influenced by a combination of social, genetic, and psychological factors. The disorder may be related to temperamental factors that are inherited. Moreover, the disorder may be related to the dysfunction of stress response systems. A role for hypothalamic-pituitary-adrenal (HPA)-axis activity in mediating stress responses has been intensively investigated for decades. Cortisol is an essential hormone in the regulation of stress response in the HPA axis, and salivary cortisol (sC) has been used as a simple, noninvasive index of free circulating cortisol levels. Recently, salivary alpha-amylase (sAA) has emerged as a new biomarker for responses to psychosocial stress within the sympathetic adrenomedullary (SAM) systems. To evaluate the effects of physical stress on HPA and SAM systems, we assessed the secretion of sAA and sC in AvPD patients and healthy volunteers after exposure to electric stimulation stress. Methods Eleven AvPD patients with no psychiatric comorbidity (7 males and 4 females, aged 25.2±4.4) and 126 healthy volunteers with no history of psychiatric disorder (56 males and 70 females, aged 25.9±4.5) participated in this study. All subjects were exposed to electric stimulation stress with the stimulator coil on their wrists. Subjects were stimulated in incremental steps until they reached their threshold stimulus, defined as the greatest stimulus they could tolerate. The greatest stimulus lasted 40 seconds. To examine sAA and sC stress responses, we measured sAA and sC levels three times immediately before, immediately after, and 20 min after the intervention. We also determined State-Trait anxiety Inventory (STAI) scores and Profile of Mood State (POMS) scores of all subjects before the intervention. This study was approved by the Ethics Committee of Oita University. Written informed consent was obtained from all participants. Results A significant sAA response to electric stimulation was found with peak values registered immediately after interventions in AvPD patients. However, we found no significant sAA response to electric stimulation in healthy controls. Moreover, AvPD patients always showed significantly higher sAA levels than healthy controls immediately before, immediately after, 20 min after the intervention. However, there was no significant difference in sC reactions between AvPD patients and healthy controls, and we found no significant sC response to electric stimulation in each group. The age, the proportion of males to females and the mean strength of electric stimulation in each group were statistically equal. STAI-Trait and STAI-State scores of AvPD patients were both greater than those of healthy controls. And POMS scores also showed greater subscales of tension-anxiety, depression, fatigue, confusion in AvPD patients than those of healthy patients. Conclusion These preliminary results suggest that AvPD patients may be easily suffered from stronger feelings of tension-anxiety, depression, fatigue, and confusion compared to healthy people in stressful situation. Moreover, AvPD patients may react to stressors with SAM systems predominantly. The above indicates that the excessive acceleration of sympathetic nerves system may be related to the pathology of AvPD., Background Bipolar disorder (BP) is often associated with altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis by chronic stress. In comparison, psychosocial stress-induced activation of salivary alpha-amylase (sAA) functions as a marker of sympathoadrenal medullary system (SAM) activity. However, in contrast to salivary cortisol, sAA has been less extensively studied in BP patients. The present study measured sAA and salivary cortisol levels in patients with BP. Methods The authors determined Profile of Mood State (POMS) and State-Trait anxiety Inventory (STAI) scores, Heart Rate Variability (HRV), and sAA and salivary cortisol levels in 25 patients with BP and 22 healthy volunteers following the application of electrical stimulation stress. Patients with bipolar disorder scored eight points or more on the Hamilton Depression Scale (HAM-D) scores. Results Tension-anxiety, depression-dejection, anger-hostility, fatigue, and confusion scores in patients with bipolar disorder were significantly increased compared to healthy controls. In contrast, Vigor scores in patients with BP were significantly decreased compared with healthy controls. There was no difference in heart rate variability measures between BP patients and healthy controls. There was no difference in the threshold of applied electrical stimulation between BP patients and healthy controls. There were significant differences in sAA levels between patients with BP and healthy controls. There were significantly higher salivary sAA levels in female patients with BP versus controls. There was a trend toward higher salivary sAA levels in male patients with BP versus controls. Finally, there were no differences in salivary cortisol levels between BP patients and controls. In the present study only three time points were explored. Furthermore, the increased secretion of sAA before and after stimulation could allude to an increased responsiveness to novel and uncontrollable situations in patients with BP. Conclusions These preliminary results suggest that sAA might be a useful biological marker of BP., Background High cerebrospinal fluid (CSF) and plasma interleukin-6 (IL-6) levels have been reported in suicide attempters. Features of the suicidal temperament include such personality traits as anger and aggression, impulsivity, anxiety proneness and low socialization. High levels of neuroticism and low levels of conscientiousness assessed with structured personality inventories have previously been associated to increased levels of IL-6, in population based samples. The aim of this study was to assess whether plasma levels of IL-6 were associated to specific personality traits in suicide attempters. Methods Plasma concentration of IL-6 was measured in 58 suicide attempters with a high throughput automated biochip immunoassay system. Patients were evaluated using the Karolinska Scale of Personality (KSP). A standard multiple regression analysis was performed with IL-6 as the dependent variable and KSP factors Neuroticism, Nonconformity, Psychoticism and Extraversion as independent variables adjusted for age and gender. Results The regression model was significant (R 2=0.40, F ratio = 7.3, df = 6, p, Rationale/statement of the problem Acute and chronic stress is commonly reported by HIV-seropositive (HIV + ) individuals and may contribute to cognitive dysfunction that interferes with treatment adherence and daily functioning. Here we present data from two studies aimed at characterizing the effects of stress and stress hormones on cognition in HIV+ women. Methods Six hundred and forty-five HIV+ and 345 at risk HIV-, predominantly African-American participants of the Women's Interagency HIV Study (WIHS), completed the 10 item Perceived Stress Scale (PSS-10) and a comprehensive neurocognitive test battery including measures of verbal learning and memory, verbal fluency, psychomotor speed, executive function, fine motor skills, working memory, attention, and concentration. High stress was defined by scores in the top quartile. Salivary cortisol levels were assessed concurrently with the neurocognitive battery and PSS-10 in 25 HIV+ women as a pilot at the Chicago WIHS. Results After adjusting for relevant demographic and behavioral characteristics, HIV+ women performed worse than HIV- women on measures of verbal learning, memory and attention (p's < 0.05). High stress was negatively associated with measures of both attention and executive function (p's < 0.05). There was a significant interaction between HIV status and perceived stress on verbal memory (p=0.02). Among HIV+ women, those with high stress performed worse on verbal memory compared to women with low stress (β=−1.89, SE=0.74, p=0.01). Conversely, among HIV- women, there was no difference in verbal memory performance by stress level (β=0.73, SE=0.99, p=0.46). There were no significant interactions between stress and HIV status on executive functioning, attention, fine motor skills, or processing speed. In HIV+ women, cortisol levels were not correlated with most outcomes, though levels were marginally associated with working memory (r=−0.37, p=0.08) which was likely attributable to women with high (r=−0.55, p=0.03) not low stress. Conclusion Our findings indicate that HIV is associated with verbal memory difficulties among women and that high perceived stress may exacerbate the effect of HIV infection on poor memory performance. Longitudinal assessments are underway to determine the robustness of these associations., Rationale/statement of the problem High blood glucose levels increase individuals’ susceptibility to age-related diseases and mortality. However, the molecular mechanisms by which hyperglycemia impairs cellular function is unclear. Emerging research suggests that mitochondrial dysfunction may be a potential allostatic mechanism that mediates the deleterious effects of hyperglycemia via dynamic pathways. Mitochondria are ubiquitous organelles that are the primary producer of cellular energy and, therefore, central to health and disease. In addition, mitochondria contain their own genetic material – the mitochondrial DNA (mtDNA). Importantly, mutations in mtDNA cause human neurological diseases, and hyperglycemia can impair mitochondrial DNA and function. Here, we hypothesized that in patients with inherited mtDNA mutations, those with poor glucose homeostasis or with diabetes would present with more severe neurological symptoms than those with normal glucose balance. Methods A literature review and retrospective study of 86 patients with the mtDNA 3243A > G mutation was conducted. We assessed glucose homeostasis and neurological symptoms using the Newcastle Mitochondrial Disease Assessment Scale (NMDAS), and Chi-squared statistics were used to compare the incidence of neurological symptoms in patients with or without glucose intolerance. Results In patients with pre-existing mitochondrial disease, the incidence of neurological symptoms, including cerebellar ataxia (OR: 9.52; 95% CI: 2.03-44.52) and peripheral neuropathy (OR: 3.91; 95% CI: 1.43-10.76) were greater in those with glucose intolerance than in those with no diagnosed glucose intolerance. In addition, a dose–response relationship linked the severity of glucose intolerance and incidence of cerebellar ataxia. Conclusions These preliminary results suggest that mtDNA mutations may render brain tissue more susceptible to glucose toxicity. Given that the accumulation of mtDNA damage occurs with senescence, our findings may have implications for resilience in the elderly. In addition to metabolic stress (i.e., hyperglycemia), mitochondrial functions are modulated by mediators of stress (i.e., cortisol), suggesting that integration of psychoneuroendocrine mediators can occur within mitochondria, thus contributing to the “wear and tear” of allostatic load. In this presentation, we introduce mitochondrial allostatic load (MAL) as a biological mechanism that might contribute to explain how metabolic and psychosocial stresses synergistically influence health and disease susceptibility., Rationale Emotions have been associated with production of pro-inflammatory cytokines such as TNF-alpha and IL-6; more precisely, negative emotions with greater cytokines level whereas positive emotions with lower level of pro-inflammatory cytokines. This may have significant repercussions on individuals’ health specifically for those who are subjected to chronic inflammation as in the case of HIV positive persons. In fact, HIV virus itself produces greater TNF-alpha production, which in its turns might promote greater IL-6 levels. Thus, this work was conducted in order to verify whether along with HIV association with pro-inflammatory cytokines production, negative and positive emotions, as well as their “balance”, might be associated with cytokines level. Methods Participants to this cross-sectional study were 90 individuals with HIV diagnosis. Emotions were assessed through the Italian version of Derogatis Affects Balance Scale edited by the first two authors of this work. The biomarkers included were viral load, TNF-alpha, and IL-6. Individuals also self-reported whether they were under antiretroviral therapy. Results A Structural Equation Model was performed in order to test if negative and positive emotions and their balance (that consisted in the ratio of positive/negative emotions) along with viral load were associated with cytokines level. Results indicated that viral load (β=0.538, p, Statement of the problem Pregnant women with stress are at increased risk of adverse pregnancy outcomes. And prenatal stress (PNS) can influence newborn's mental development. Earthquake exposure is a special stressor for pregnant women. Ningqing County is one of the worst-hit areas of the Wenchuan Earthquake (8.0 magnitude) happened in Sichuan Province, China on 12 May 2008. To explore the related influencing factors of children's mental development whose mother exposed to the earthquake, we investigated the mental development of children born after the Wenchuan Earthquake in Ningqiang County. Methods A total of 86 children aged 0–3 years were recruited in this study. They were randomly selected and were screened by “the mental developmental screening test (DST)” for children aged 0–6 years compiled by Children's Hospital of Fudan University. For ease of interpretation, children were classified in four different groups based on ages: 0-year-old; 1-years-old; 2-years-old; and 3-years-old. Results Among the 86 children, there were 54 boys and 32 girls. The mean Development Quotient (DQ) score was 98.59±2.08. Twenty two (including 18 boys and 4 girls) children's DQ score was, Statement of the problem An eight-magnitude earthquake struck Wenchuan, Sichuan Province of China on 12 May 2008. Ningqing County is one of the worst-hit areas. Earthquake exposure was a special stressor for pregnant women. But little is known about what the earthquake influence on pregnant women and the degree of the influence. Only if we understand people's mentation after a natural disaster that can we help them to get over it. To assess the impact of the earthquake on the mental health, we investigated the impact of the Wenchuan Earthquake on pregnant women who lived in Ningqiang County. Methods Women who had babies within 3 years after earthquake in Ningqiang County were randomly recruited in this study. Seventy five women were screened by employing Life Events Scale for Pregnant Women (LESPW) compiled by Yan Gao et al. in 2005 and 87 women were screened by employing Post-traumatic Stress Disorder Self-rating Scale (PTSD-SS) compiled by Xianchen Liu et al. in 1998. Results Among 75 women, the mean score of LESPW was 297.08±21.95, and 30.67% women's score was equal or greater than 375. This result was significantly higher than that of Xiaomei Li's report of general pregnant women in Weifang (223.18±129.30)(p = 0.001). The mean score of PTSD-SS was 38.55±1.56, and 19.54% women's score was equal or greater than 50. Women who had baby at age of more than 30 got more scores and more detection at the scale of LESPW compared with those age less than 30 (p < 0.05, p < 0.05 respectively), and the results at PTSD-SS similarly (p < 0.01, p < 0.001, respectively). In both scales, the detection rates were not significantly different between mother's schooling years less than or equal to 9 years and more than 9 years. Conclusion The Wenchuan earthquake brings lasting adverse influences to pregnant women in Ningqiang county of China within three years., Rationale Previous work in our and other laboratories has demonstrated dysregulated immune function and cellular oxidative stress responses in subjects with Major Depressive Disorder (MDD). In the current study, we determined whether there were differences in the transcriptional regulation of these pathways in leukocytes from subjects with MDD, and healthy controls. Methods We used genome-wide transcriptional profiling (Affymetrix U133 Plus 2 oligonucleotide arrays) and promoter-based bioinformatic strategies (TELiS) to assess transcription factor (TF) activity in leukocytes from 15 unmedicated MDD patients versus 19 age-, gender-, and ethnicity-matched healthy controls, prior to initiation of antidepressant therapy, and after 8 weeks of sertraline treatment. Results Bioinformatic analysis of 39,000 differentially expressed genes indicated increased transcriptional activity of cAMP Response Element-Binding (CREB) factor, Interferon Response Factors, and the oxidative stress-responsive Nuclear Factor (erythroid-derived 2)-like 2 (NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not CREB or interferon response factor activities. Several other transcriptionally regulated pathways previously associated with depression, including the glucocorticoid receptor (GR), nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), and early growth response proteins 1-4 (EGR1-4) pathways, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized in previous research. Quantitative RT-PCR analysis confirmed the expression profiling data. Conclusions These results are consistent with the hypothesis that oxidative stress and innate antiviral responses may be involved in MDD by activating immune cell transcriptional pathways, and that successful antidepressant therapy may result in reduced oxidative stress responses at the level of gene transcription., Background Bariatric procedures such as laparoscopic adjustable gastric banding (LAGB) can markedly decrease body adiposity in severely obese adolescents, but relatively little is known about the short-term effects of such procedures on meal-related hormonal response. Methods Participants completed a fixed size breakfast meal and fasting concentrations of appetitive hormones (leptin, insulin/glucose, ghrelin, PYY) were measured. PYY, ghrelin, and visual analog scale (VAS) ratings of fullness, hunger, nausea, and desire to eat were assessed immediately before the meal and 15, 30, 60, and 90 minutes afterwards. Results A total of 10 normal-weight controls (age: 15.4±2.0 years, BMI: 21.3±1.7 kg/m2; n=5 female) and 21 severely obese (age: 16.1±1.0 years, BMI: 46.4±6.6 kg/m2; n=18 females) adolescents were studied pre-LAGB. Eleven of the obese adolescents were studied again 122.6±17.8 days post-LAGB (BMI 40.9±7.8 kg/m2, mean change in BMI: −3.5±2.5 kg/m2). In comparison to normal-weight controls, surgical candidates had significantly higher fasting insulin and leptin and lower fasting ghrelin. Fasting PYY decreased significantly post-surgery. Meal-related suppression of ghrelin, as measured by area under the curve (AUC), was significantly less in absolute value among pre-operative candidates than among normal weight controls [t(9.65) = 2.90, p = 0.017, d = 1.29], with a trend for a decrease in AUC for candidates pre- to post-LAGB [t(10) = 2.07, p = 0.065, d = 0.811]. No significant differences for AUC for PYY were found between normal-weight controls and surgical candidates, or surgical candidates pre- to post-LAGB. Normal-weight controls and surgical candidates did not differ by AUC for any VAS rating; however, post-LAGB, adolescents reported a significantly greater AUC for nausea [t(10) = − 2.58, p=0.03]. Conclusions Despite short-term decreases in body mass index post-LAGB, few changes were observed in appetitive hormones prior to or following a standardized breakfast. In addition, subjective ratings of fullness, hunger, nausea, and desire to eat did not differ between surgical candidates and normal-weight controls, but following LAGB, adolescents reported significantly more nausea. Future studies should examine longer-term effects of LAGB on appetitive hormones., Background Posttraumatic Stress Disorder (PTSD) is a complex mental disorder with functional and structural changes in the brain that may result from mitochondria-centered responses to harmful stresses. PTSD is an ongoing issue in the military. However, at present, there is no biological tool for PTSD diagnosis. Diagnosis for PTSD is established on the basis of clinical history and mental status examination, using a clinically structured interview based on a symptom checklist or patient self-report. It is often under-diagnosis. The clinical assessment would benefit substantially from a more objective means to identify PTSD patients. Here, we present evidence that there are significant differences of expression profiles of mitochondria-focused gene in the blood between PTSD and non-PTSD control US military service members. Methods Using a mitochondria-focused gene cDNA array, we examined the expression profiles of 1170 mitochondria-focused genes across samples from subjects with (n=28) or without (n=31) probable PTSD who were active duty US Army Special Operations soldiers deployed to the Iraq and/or Afghanistan war and who were evaluated for probable current PTSD using the PTSD Checklist (PCL). Using the analytical approach of unsupervised pattern recognition with algorithmic basis of clustering, 10 clusters or pathways were revealed from the mitochondria-focused gene microarray data. Results Significance tests demonstrated different expression levels in 26 genes between PTSD and non-PTSD controls. A relationship analysis found that among the 26 genes, the expression levels of five genes were significantly correlated with the total PCL score in the PTSD subjects. Conclusion The expression of mitochondria-focused gene fingerprints and dysregulated genes in the blood of PTSD patients warrants a large size study to determine their clinical utility in military population., Rationale Deployed military personnel are at risk for (mental) health problems, including post traumatic stress disorder (PTSD), major depressive disorder (MDD), and fatigue. We hypothesized that development of these conditions is associated with biological vulnerability factors. Therefore, we assessed whether the development of PTSD, depressive and/or fatigue symptoms in response to military deployment could be predicted by glucocorticoid (GC) signalling in leukocytes and the capacity of peripheral blood cells to produce cytokines. Methods We included 1,032 Dutch military personnel prior to deployment to Afghanistan. Symptom severity was assessed 6 months after return. In blood collected prior to deployment, we assessed GC signalling in leukocytes (glucocorticoid receptor [GR] number, target gene mRNA expression, and GC-sensitivity) and cytokine production upon stimulation with LPS, PHA, or IL-1β. Results We identified different vulnerability factors for development of a high level of PTSD, depressive, and fatigue symptoms. PTSD symptom development was predicted by high GC signalling in leukocytes. In contrast, depressive symptom development was associated with low GC signalling in T-cells and high T-cell cytokine production capacity. Finally, development of fatigue was associated with low GC signalling in monocytes prior to deployment and high reactivity of monocytes to IL-1β after deployment. Conclusions The identified vulnerability factors for the development of high levels of PTSD, depressive, and fatigue symptoms were condition specific. This indicates PTSD, depression, and fatigue have different underlying biological mechanisms. Moreover, the results suggest that the biological profile prior to stress/trauma exposure may not only determine if a stress-related condition will develop but also which specific stress-related condition will develop., Rationale/statement of the problem Stress provokes physiological alterations, which are thought to mediate the development, maintenance, and progression of several disorders. Social support is thereby thought to possess a buffer function, decreasing the physiologic effects of stress. In our previous work, we were able to show a buffering effect of perceived social support (PSS) on the stress response of salivary α-amylase (sAA), an index of sympathetic nervous system activity. The aim of the present longitudinal study was to examine the effects of alterations in PSS on baseline and stress levels of sAA. Methods Swiss male recruits (n=145) participated twice in a standardized psychosocial stress test (Trier Social Stress Test for Groups, TSST-G) 10 weeks apart. Saliva was collected prior to and after the stress test to measure the activity of sAA. On both examinations, a questionnaire was distributed to determine the level of PSS (Berlin Social Support Scale, BSSS). Results The TSST-G induced a significant increase in sAA activity on both occasions, while military service resulted in an overall decrease in PSS. Changes in PSS were associated with alterations in baseline and stress responses of sAA: recruits with a decrease in PSS over the 10-week period revealed an increase in baseline activity (r= − 0.248, p=0.005) and a decrease in stress reactivity of sAA (r=0.226, p=0.010) over time. Conclusion Our findings show that military service is associated with a decrease in PSS. This decrease is related to alterations of sympathetic nervous system activity, characterized by an increased tone and decreased responsiveness. This longitudinal study emphasizes the need to boost psychosocial resources during military service., Rationale In a previous study, we examined the effect of a single intervention with high-dose corticosterone, 1h after predator stress-exposure (PSS), and showed a significant reduction in the incidence post traumatic stress disorder (PTSD)-like behaviors and improved resilience. The underlying mechanism of corticosterone action remains largely unclear. The goal of this study was to explore the cytoarchitecture and molecular changes in hippocampal subareas of animals “treated” with high-dose corticosterone immediately after exposure. Methods Animals were exposed to PSS and treated 1 hour later with corticosterone (25mg/kg) or saline. The outcome measures included behavior in an elevated plus-maze and acoustic startle response 7 days after the exposure. Pre-set cut-off behavioral criteria classified exposed animals according to behavioral responses as those with “extreme behavioral response”, “minimal behavioral response”, or “intermediate response”. Dendritic arborization in Golgi-impregnated neurons in hippocampal areas was evaluated. Given the importance of integrin 1β, calcium/calmodulin-dependent protein kinase II (CAMKII), phospho-glutamate receptor 1 (pGLU-R1), and postsynaptic density-95 (PSD-95) in neuronal function and dendritic spine plasticity, the expression of these factors in the hippocampus was also examined. Results Stress exposure altered the morphology of the hippocampal dendritic cells selectively in individuals whose behavior was extremely disrupted (EBR) in response to the exposure, whereas animals whose behavior was less severely affected displayed no significant changes in hippocampi morphology. Extreme responders clearly demonstrated significantly reduced dendritic arbor and spine density along hippocampal dendrites 8 days after exposure. The results showed that EBR animals displayed significantly lower levels of integrin 1β, CAMKII and higher expression of pGLU-R1 and PSD-95 than vehicle-treated animals. In contrast, steroid-treated stressed animals displayed significantly increased dendritic arbor and spine density, with increased levels of integrin 1β, pCAMKII, and obtunded pGLU-R1 and PSD-95 levels. Conclusions The data provide initial evidence that a single dose of corticosterone administered in the acute aftermath of stress promotes recovery while promoting enhanced neuronal and synaptic plasticity and connectivity in the secondary prevention of PTSD., Rationale/statement of the problem Women are twice as likely as men to develop Posttraumatic stress disorder (PTSD). Abnormal acquisition of conditioned fear has been suggested as a mechanism for the development of PTSD. While some studies of healthy humans suggest that women are either no different or express less conditioned fear responses during conditioning relative to men, differences in the acquisition of conditioned fear between men and women diagnosed with PTSD has not been examined. Methods Thirty-one participants (18 men, 13 women) with full or subsyndromal PTSD completed a fear-conditioning task. Participants were shown computer-generated colored circles that were paired (CS + ) or unpaired (CS − ) with an aversive electrical stimulus, and skin conductance levels were assessed throughout the task. Results Repeated measures ANOVA analyses indicated a significant sex by stimulus interaction during acquisition, F(1, 232) = 5.16, p, Rationale In healthy individuals, the magnitude of the startle-eyeblink reflex to a brief, acoustic probe is modulated by the valence (goodness/badness) of a photographic picture and this modulation shows a linear, stepwise pattern. Startle amplitude is smallest during pleasant, largest during unpleasant, and intermediate during neutral pictures. Animal work shows that startle modulation is mediated by the brain's fear/defensive circuit which is centered on the amygdala—a region important in valence and emotion regulation. We previously reported (Hazlett et al., 2007) exaggerated affective startle modulation during processing of unpleasant (e.g., “suicidal”) but not neutral words in individuals with borderline personality—a disorder characterized by emotion dysregulation and suicidal behavior. Methods In light of this work, we present preliminary data from an ongoing Department of Defense DoD-sponsored study examining whether suicidal behavior confers defensive hyperreactivity measured as increased affective startle modulation during emotional pictures, irrespective of diagnosis. We examined 40 age- and gender-matched veterans with varying levels of suicidal behavior: ideators (I): n = 9; single suicide attempters (SA): n = 10; and multiple suicide attempters (MA): n = 21. Principal disorders included post traumatic stress disorder PTSD and major depression. Participants viewed a series of intermixed standardized unpleasant, neutral, and pleasant social pictures (each presented for 6 sec and a subset containing acoustic probes) and were instructed to think about the meaning of the pictures for them personally while eyeblink responses were assessed. Results Compared with the I and SA groups, the MA group showed startle hyperreactivity during unpleasant pictures (MA > I: p = 0.03; MA > SA: p = 0.06 [trend]; Fisher's LSD). In contrast, there were no group differences during pleasant or neutral pictures (Group × Picture type interaction was non-significant, p = 0.30). Conclusion These findings indicate a spectrum of hyperreactivity during unpleasant picture viewing that parallels the severity of suicidal behavior: Startle amplitude during unpleasant pictures progressively increased from Is at the minimum, to SAs, and finally MAs at the extreme. Affective startle may provide a useful non-verbal, psychophysiological biomarker for suicidal behavior. Correlations between affective startle, symptom severity, and emotion regulation will also be presented., Rationale Post-traumatic stress disorder (PTSD) is associated with exaggerated autonomic responses to sudden, loud acoustic stimuli, particularly under conditions characterized by ambiguous threat. However, it is not clear if such exaggerated responses are a stable vulnerability factor for developing PTSD or a feature of current PTSD that resolves with symptom resolution. We investigated this issue by comparing autonomic startle responses to acoustic stimuli under low, medium, and high threat conditions in Gulf War Veterans with and without current and past PTSD. Methods Our sample included three groups: no PTSD (n=151), PTSD in remission (n=51), and current PTSD (n=54) (M age = 44.3, SD = 9.6; 11.6% female). Current and past PTSD symptoms were assessed with the clinician-administered PTSD scale. All participants were exposed to an acoustic stimulus in three conditions: 1) low threat, in which participants experienced no threat of shock; 2) medium threat, in which participants wore a finger electrode but were told that they would not get shocked; and 3) high threat, in which participants wore a finger electrode and were told that they would get shocked. Independent sample t-tests were used to compare group differences in startle responding. Results Individuals with current PTSD had significantly higher heart rate responses compared with the no PTSD group in the low, t(196) = 2.52, p=0.011, and medium threat conditions, t(66.7) = 2.40, p=0.022, and compared with the PTSD in remission group in the low, t(87) =1.957, p=0.05), and medium threat conditions, t(77.81) = 2.50, p=0.02. In analyses, including only patients with current or past PTSD who had current clinician administered PTSD scale (CAPS) across the entire range from 0 to 108 (M = 41.0, SD = 25.4), we found that higher severity of current PTSD symptoms was not only associated with higher startle responses, particularly in the medium threat condition (r = 0.22, p=0.04), but also with trend level in the low (r=0.18, p=.09) and high (r=0.18, p=0.09) threat conditions. Conclusion These results suggest that exaggerated autonomic startle responses under conditions of low and medium threat vary as a function of current PTSD severity and are not a marker of PTSD vulnerability. Moreover, the data suggest that this startle paradigm with varying threat levels may be a useful index of hyperarousal of fear-related neurocircuitry in PTSD., Rationale/statement of the problem Because posttraumatic stress disorder (PTSD) and blast-mild traumatic brain injury (mTBI) commonly are comorbid in veterans of the wars in Iraq and Afghanistan, attributing persistent behavioral or other symptoms to one or the other entity remains controversial. Here, we asked if multimodal neuroimaging would reveal persistent functional or structural abnormalities in veterans who had experienced blast-mTBIs in Iraq and/or Afghanistan and, if so, could any such abnormalities be attributed to comorbid PTSD. Methods Thirty-four blast-mTBI veterans (26 with PTSD and 8 without PTSD) and 16 Iraq and/or Afghanistan-deployed veterans without blast or blunt impact mTBI or PTSD were studied. Each veteran underwent magnetic resonance diffusion tensor (DTI) and magnetization transfer/cross-relaxation imaging (MT-CRI), as well as fluorodeoxyglucose positron emission tomography (FDG-PET); structured clinical assessments of blast and combat exposure, psychiatric diagnoses, and posttraumatic stress disorder symptoms; neurologic evaluations; and self-report scales of postconcussive symptoms (PCS), combat exposure, depression, sleep quality, and alcohol use. Results Blast-mTBI veterans exhibited reduced fractional anisotropy in the genu and splenium of the corpus callosum on DTI; reduced macromolecular-bound proton fraction (a brain putative measure of myelin integrity) in white and gray matter and multiple regions of interest on MT-CRI; and parietal, somatosensory, and visual cortex hypometabolism on FDG-PET. The presence of PTSD in mTBI veterans had no effect on DTI or MT-CRI structural brain biomarkers. The only effect of PTSD on FDG-PET functional biomarkers was lower glucose metabolism in visual cortices bilaterally. Conclusions Iraq and Afghanistan combat veterans with blast-mTBI exhibit abnormalities of brain white matter structural integrity and macromolecular organization and regional cortical glucose metabolism years after blast exposure. Although comorbid PTSD was associated with lower visual cortex metabolism, it had no effect on structural biomarkers. These findings are consistent with recent neuropathologic evidence of cortical tauopathy and neuronal degeneration in a small sample of Veterans with blast-mTBI., Rationale/statement of the problem We previously reported that hippocampal volume was associated with current, but not lifetime post traumatic stress disorder (PTSD) symptom severity. In this study, we further investigated the role of current versus remitted PTSD on the volumes of other brain regions previously implicated in PTSD. Methods Magnetic resonance imaging data from a 4 Tesla scanner of 191 veterans (75 trauma unexposed, 43 trauma exposed without PTSD, 39 trauma exposed with PTSD, 34 trauma exposed recovered from PTSD) were analyzed with FreeSurfer software program (version 4.5). Results Veterans with current PTSD had smaller hippocampal, caudal anterior cingulate, insula, and corpus callosum volumes than trauma unexposed veterans (p≤0.01), trauma-exposed veterans who had recovered from PTSD (p≤0.02) and trauma-exposed veterans who never developed PTSD (p≤0.05). Conclusion The finding that current but not lifetime PTSD accounted for the volumes of multiple brain regions suggests either that smaller brain volume is a vulnerability factor that either impedes recovery from PTSD; or less likely, that recovery is accompanied by a wide-spread restoration of brain tissue., Rational Increased GR sensitivity has been associated with PTSD severity in several studies, and in a recent report, was found to predict the extent of improvement in severity of PTSD symptoms from pre- to post-treatment. These findings provided the rational for an investigation of two GR genotype polymorphisms know to affect GR sensitivity in relation to PTSD severity and treatment response. The BclI (rs41423247) single nucleotide polymorphism (SNP) is an intronic restriction fragment length polymorphism located 646 bp downstream from GR exon 2. SNP 9β (rs6198) is located on exon 9β of the GR. It is believed to increase the stability of splice variant GRβ, an inhibitor of the wild-type GRα. Carriers of the BclI minor allele have been associated with an increased sensitivity to glucocorticoids (GCs), whereas 9β carriers have been linked to relatively diminished sensitivity. We studied these polymorphisms in the context of a treatment study in which participants were evaluated prior to and following treatment. Methods For the treatment study, subjects were randomized into two treatment conditions, weekly prolonged exposure therapy and a minimal attention, in which participants received a weekly phone call to evaluate symptom severity and monitor for safety. Clinical outcome was assessed using pre- and post-treatment Clinician Administered PTSD Scale (CAPS) total scores. Pre-treatment genotype data were available for 27 of 36 receiving prolonged exposure and for 9 or 13 who received the minimal attention condition. DNA was isolated from lymphocytes using Ficoll-Paque Plus (Amersham Pharmacia Biotech) and extracted (using FlexGene DNA Kit, Qiagen); genotyping of SNPs BclI and 9β was performed using the allelic discrimination technique with custom designed probes and primers according to the published genomic sequences, with results that did not differ from Hardy–Weinberg equilibrium. Results The presence of the G allele in the BclI SNP was inversely associated with lifetime, but not current, total CAPS score for treatment completers (t=2.94, df = 29, p=0.006), indicating a less severe lifetime course of PTSD. Polymorphisms at the Snp9Beta locus were not related to lifetime PTSD severity. The same polymorphism at BclI predicted the absence of a PTSD diagnosis following treatment (χ2(1) = 7.30, p=0.007). A similar relationship for Snp9Beta was not apparent. In order to test the relative strength of BclI genotype in the prediction of PTSD outcome, a logistic regression was performed with age, ethnicity, treatment type, and pre-treatment CAPS total score as covariates. In this model, only BclI genotype was a significant predictor (B= − 2.59, p=0.022, OR = 0.074). Without BclI genotype in the model, there was a trend for pre-treatment CAPS total score to predict PTSD at post-treatment (B=0.062, p=0.080, OR = 1.05). Conclusion The BclI polymorphism is related to a less severe lifetime course of PTSD, and is a substantial predictor of positive outcome in response to short-term psychotherapy. The relation of this genotype to recovery from PTSD was even stronger than pre-treatment clinical severity or type of treatment. The result suggests that BclI genotype may be a useful biomarker in the selection of potential treatment candidates. This work should be repeated in additional, and larger samples for verification., Background Suicidal behavior is a critical problem among military veterans. Therefore, it is important to identify psychological suicide risk factors that are unique for veterans of military service. We compared clinical features of 55 veteran suicide attempters with 55 veterans without a history of suicide attempts. Methods Demographic and clinical characteristics of suicide attempters and non-attempters were assessed and recorded. Based on the Scale for Suicide Ideation (SSI) all patients were divided into two groups: patients who do not report any suicidal ideation at all (non-ideators) and people who do (ideators). Results There was no difference between the groups with regard to age (t= − 0.71, df = 108, p=0.48), gender (χ 2=1.50, df = 1, p=0.36), and race (χ 2=4.84, df = 5, p=0.44). There were more subjects with a lifetime history of bipolar disorder, substance dependence, or psychotic disorder among suicide attempters compared to non-attempters (χ 2=6.67, df = 1, p=0.01, χ 2=4.71, df = 1, p=0.04, and χ 2=9.83, df = 1, p = 0.002, respectively). There were 34% of current suicide ideators among suicide attempters and 9.3% of suicide ideators among non-attempters (χ 2=9.67, df = 1, p=0.002). There was no difference with regard to the proportion of patients with major depression or posttraumatic stress disorder between suicide attempters and non-attempters (χ 2=0.10, df = 1, p=0.83 and χ 2=0.41, df = 1, p=0.54, respectively). Conclusion A history of suicide attempt in military veterans is associated with a lifetime history of bipolar disorder, substance dependence, psychotic disorder, or current suicidal ideation but not with a lifetime history of major depression or posttraumatic stress disorder., Rationale/statement of the problem Both bio- and neurofeedback (training) protocols are hypothesized to be beneficial in the management of arousal states and psychological recuperation after aversive and potentially traumatic experiences. As military deployments in theatres like Iraq or Afghanistan imply a significant risk for potentially traumatic experiences and stress-related outcomes, the present research explored the potency of both bio- and neurofeedback protocols during the recuperation period after the deployment of Dutch soldiers in Afghanistan. Methods Within half a year after re-deployment, 38 Afghanistan veterans (Dutch 200 Logistic Battalion) participated in the present study. Of these, 14 conducted 10 sessions of alpha power–based neurofeedback, 10 randomized beta (mock) neurofeedback, and 14 participants conducted 10 sessions of biofeedback gaming. Previously to and immediately after these sessions baseline heart rate variability (HRV), the cortisol awakening response (CAR), quantitative electroencephalography (QEEG), and cognitive performance and psychological parameters (like quality of sleep and stress-related symptoms) were assessed. Results In all conditions, HRV significantly increased (F(1,24) = 18.7, p

Rationale/statement of the problem Substantial evidence suggests conditions in intrauterine life may play a critical role in subsequent health and disease susceptibility related outcomes (i.e., the concept of fetal or developmental programming of health and disease). The elucidation of biological mechanisms underlying these effects is an area of active investigation. We suggest that telomere biology may represent a novel mechanism underlying the effects of a disparate set of suboptimal intrauterine exposures on various health and disease risk phenotypes. From an evolutionary-developmental perspective, energy substrate availability (i.e., nutrition) and challenges that have the potential to impact the structural or functional integrity and survival of the organism (i.e., stress) likely represent the most important environmental considerations underlying natural selection and developmental plasticity. Maternal stress and nutrition in pregnancy therefore represent attractive candidate processes in the context of fetal programming of telomere biology. Our previous work has established an important role for prenatal stress and stress-related processes in adult telomere biology Methods In two longitudinal birth cohorts, stress- and nutrition-related processes were assessed during pregnancy and telomere length (TL) was subsequently measured in newborns (cord blood) and infants (buccal cells). Results (1) Among the nutrition-related factors, maternal lower folate levels (an essential methyl donor) and higher triglyceride concentrations in early pregnancy were significantly and independently associated with shorter newborn TL. (2) Among psychosocial stress-related measures, higher maternal pregnancy-specific stress was associated with shorter newborn TL. (3) Maternal estrogen (E3) levels during early pregnancy were associated with longer infant TL. Conclusion Taken together, our findings provide the first evidence in humans that maternal nutrition and stress-related processes during pregnancy may exert a programming effect on the newborn and infant telomere biology system. In utero telomere biology represents a potential molecular mechanism whereby different exposures in this critical developmental period before birth could impact subsequent health and disease susceptibility related outcomes over the life span, including aging and longevity, Rationale/statement of the problem Stress in early life is known to have a powerful direct effect on poor health in later life. This direct effect requires one or more underlying mechanisms that can maintain it across the life-course. It is therefore essential to characterize the biological mechanisms through which children may acquire such lasting vulnerability to disease, namely, the mechanisms of biological embedding. One plausible mechanism may lie in changes to DNA. New research suggests that stress exposures can accelerate the erosion of DNA segments called telomeres. In the past 2 years, six studies provided support for an association between telomere length (TL) and childhood stress. Although these studies advance understanding of the link between childhood stress and TL, almost all studies have relied on adult measures of TL and retrospective recall of stress years after the stress was experienced raising important questions about the true nature of these findings. Interpretation of findings from cross-sectional studies of TL is ambiguous in light of recent longitudinal analyses of repeated TL measurements. These recent findings indicate that the temporal process of telomere erosion is more complex than initially assumed, and that repeated measures (not just length at one time point) are needed to measure true telomere erosion in individuals who are experiencing stress. Moreover, given the elapsed time between the putative stress exposure and the measurement of TL, it has not been clear whether telomeres began eroding during stress exposure or whether erosion occurred years later, possibly promoted by the sequelae of childhood stress or other intervening variables. In our study, we used a longitudinal design to test the effects of violence exposure during childhood on telomere erosion in a cohort of young children. We tested the hypothesis that cumulative violence exposure would accelerate telomere erosion in children while they experienced stress. Method Participants were 236 children (49% females; 42% with one or more violence exposures) recruited from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative UK 1994–1995 birth cohort. Each child's mean relative telomere length was measured simultaneously in baseline and follow-up DNA buccal cells, using the quantitative PCR method for T/S ratio. Violence was assessed as exposure to maternal domestic violence, frequent bullying victimization and physical maltreatment by an adult. We interviewed mothers (or the primary caregiver) about each exposure when the children were 5, 7, and 10 years of age and compiled a cumulative record of each child's exposure to violence. Nearly 54.2% (N=128) of the children were not violence exposed, 29.2% (N=69) were exposed to 1 type of violence, and 16.5% (N=39) were exposed to 2 or more types of violence. To test the main hypothesis that violence exposure would accelerate telomere erosion between ages 5 and 10 years, we conducted ordinary least squares multiple regression analysis. The outcome variable was age-10 TL, controlling for baseline TL at age 5 years and sex, SES, and body mass index as covariates. Results We first examined the effect of each type of violence exposure on TL separately. Children exposed to domestic violence showed slightly accelerated telomere erosion from age 5 to 10, compared with children who had not been exposed to domestic violence, but this change was not statistically significant (β= −.059, SE=.045, p=0.196). Children exposed to frequent bullying victimization also showed slight but nonsignificant accelerated telomere erosion from age 5 to 10, compared with children who had not been exposed to bullying victimization (β = −0.041, SE=0.037, p=0.274). Children who were physically maltreated did show significantly accelerated telomere erosion from age 5 to 10, compared with children who had not been exposed to physical maltreatment (β= −0.085, SE= 0.037, p= 0.022). Next, we tested the main hypothesis that cumulative exposure to violence will be associated with accelerated TL erosion. Children who experienced two or more kinds of violence exposure showed significant TL erosion from baseline to follow-up measurement compared with children who had one or no kinds of violence exposures (β = −0.054, SE=0.023, p=0.020). Conclusion This finding provides the first evidence that stress-related accelerated telomere erosion in buccal cells can be observed already at young age while children are experiencing stress. Children who experienced two or more types of violence exposure between age-5 baseline and age-10 follow-up measurements showed significantly more telomere erosion, even after adjusting for confounding factors. The results of the present study add weight to the hypothesis that exposure to stress in childhood can alter biological processes in relation to telomere erosion. Methodological strengths of this study include a longitudinal design with reliable and valid prospective assessments of multiple violence exposures during childhood and repeated measurements of TL during this same developmental period., Rationale/statement of the problem Major depressive disorder (MDD) and other serious mental illnesses are associated with high rates of comorbid medical illnesses. Many of these comorbid conditions are more typically seen in the aged, raising the possibility that these psychiatric illnesses are associated with accelerated aging. An emerging biomarker of cell aging and of increased risk of medical illness is leukocyte telomere length, and several studies have now characterized leukocyte telomere length in MDD and other psychiatric illnesses. Fewer psychiatric studies have characterized the activity of telomerase, an enzyme that can elongate and preserve telomeric DNA, or have investigated the biochemical mediators of accelerated telomere shortening. Methods Seven studies examining telomere length in MDD, three studies in schizophrenia, two studies in bipolar illness, two studies in PTSD, and one study in generalized anxiety disorder were reviewed, as were one study of telomerase activity in MDD and one study in schizophrenia. Additional studies in chronically stressed individuals and in individuals with histories of childhood adversity were also reviewed. Results Shortened leukocyte telomeres have been demonstrated in MDD, bipolar illness, schizophrenia, anxiety disorders, and post-traumatic stress disorder, although in some studies, only subgroups of patients (e.g., those with longer lifetime exposure to the illness, those with poor responses to treatment, or those with preexisting histories of childhood adversity) showed shortened telomeres. Leukocyte telomere shortening is correlated with peripheral indices of increased oxidative stress and increased immune activation. Two studies (one in caregivers with high depression ratings and one in unmedicated patients with MDD) reported elevated peripheral blood mononuclear cell (PBMC) telomerase activity, perhaps representing a compensatory attempt by the body to preserve endangered telomeres. Preliminary data in MDD suggest that relatively low telomerase activity before treatment, and greater treatment-associated increases in telomerase activity, are associated with better antidepressant responses. This, plus the preliminary observation that PBMC telomerase activity is directly correlated with hippocampal volume (by MRI) in MDD, support emerging preclinical data that telomerase has intrinsic neurotrophic and antidepressant effects. Conclusion Telomere shortening in MDD and certain other psychiatric conditions may, at least partially, reflect chronic exposure to inflammation and oxidation. As such, it may be a bellwether of increased medical risk, or it may play a more direct causal role in accelerated aging. The interplay of telomere integrity and telomerase activity may be an important determinant of psychiatric and medical outcome. Overall, the data are consistent with the view that MDD and certain other psychiatric illnesses have systemic manifestations beyond the brain and call into question the dichotomy of “mental” vs. “physical” illnesses., Rationale/statement of the problem Chronic stressors across the life course predict accelerated pathogenesis of diseases of aging and early mortality. Telomere length, the DNA-based biomarker indicating cellular aging, is a mechanism of disease development, and shortens in a dose response fashion by duration and severity of life stressor exposures. Telomere length provides an important window in understanding a life span model of the accumulation of stress on aging. Self-reported perceived chronic stress and exposure to stressful life experiences during childhood and adulthood are related to short telomeres. While the expectation that the accumulation of life stress leads to cellular senescence, most studies indicate cross-sectional associations between life stressors and telomere length. Findings suggesting longitudinal associations between life stressors and telomere shortening are best represented in studies associating self-reported early childhood traumatic experiences with short telomeres in adulthood. Adults reporting moderate-to-severe childhood maltreatment and stressful experiences, such as divorce and parental separation, are more likely to have significantly shorter telomeres than those reporting no childhood maltreatment. To date, only one study has prospectively demonstrated associations between traumatic experiences and telomere shortening. Five-year-old children exposed to two or more traumatic stressors, including maternal domestic violence, frequent bullying victimization and physical maltreatment by an adult, have shorter telomeres at age 10 compared with children exposed to less or no violent stressors. No studies, however, indicate prospective effects of adulthood stressors on telomere shortening over time. Perhaps, as we suggest elsewhere, chronic stressor effects on biological pathways are rarely main effects, but rather an intricate interplay between life adversity and resiliency factors. Our work, and that of others, is increasing our understanding of how psychological stress resilience, social connections, and lifestyle may moderate relationships between life stressors and health. Here, we present evidence from two studies that support our proposed model that behavioral and psychosocial resiliency can buffer the effects of stress on telomere length, both cross-sectionally and prospectively. Cross-sectionally, we tested whether multisystem resiliency – defined as a composite of healthy emotion regulation, strong social connections, and being physically active – mitigates previously demonstrated associations between concurrent depression diagnosis and telomere length. We found support for this model, which will be presented. In a second study we examined how a lifestyle composite might buffer stress-induced telomere shortening prospectively. Methods Two hundred sixty-one non-smoking women between the ages of 50 and 65 were recruited for a prospective study on telomere length change over the course of the year. Leukocyte telomere length (LTL) was assayed at baseline and 12-month follow-up. Perceived stress, typical dietary practices, sleep quality, and exercise levels were self-reported at baseline, 4 months, 8 months, and 12 month follow-up. Seventeen questions about life events that may have occurred in the previous year were asked at follow-up, including events such as divorce, death of a family member, and job loss. Health events were not included as they may confound effects of stressors on telomere biology. Women with histories of cancer, who were premenopausal, or did not have complete self-report data were excluded from these analyses, leaving a final sample of 196 women. Results Results indicated that perceived stress at baseline, perceived stress accumulated over the year, or accumulation of stressors over the year were unrelated to 12-month LTL, covarying baseline telomere length, age, BMI, and income level. However, findings do suggest significant interactions between markers of stress and a healthy lifestyle over the year composed of healthy dietary practices, sleep quality, and exercising. For those at one standard deviation below mean healthy lifestyle, baseline perceived stress (b=−8.51, SE=4.05, p=.04) and accumulation of life stressors over the year (b=−34.51, SE=15.21, p=.02), were significantly associated with shorter LTL at follow-up, covarying baseline telomere length, age, BMI, and income level. On the contrary, at one standard deviation above the mean of healthy lifestyle, stress markers were unrelated to telomere shortening over the year. Conclusion In summary, healthy lifestyle factors and psychosocial resiliency may interrupt a cascade of harmful effects that accelerate cellular aging, diminishing the impact that chronic psychological or objective life stress has on health. From conception to death, we are exposed to stressors. And while stressors may shape the manifestation of resiliency factors, leading to an interrelated cluster, our work suggests that psychosocial resources and lifestyle factors can add up to multisystem resiliency, providing increasing cellular buffering from life stress. Without attending to such interactions, stress effects are often masked and missed., Rationale/statement of the problem Obesity is associated with increased symptoms of anxiety and depression. We hypothesised that severe obesity in pregnancy would be associated with adverse psychological health, with effects on gestational weight gain (GWG) and baby birthweight (BWT). We aimed to study mood and birth outcomes among participants in a longitudinal study of severe obesity in pregnancy. Methods In this study, 140 severely obese (body mass index [BMI] (mean (SD)) 44.1 (4.1) kg/m2) and 96 lean (BMI 22.6 (1.6) kg/m2) pregnant women were recruited. Ethical approval and written, informed consent were obtained. Obese women were advised about healthy eating and weight maintenance. Serial weights were recorded and GWG calculated between 16 and 36 weeks’ gestation. Women were asked to complete validated questionnaires to assess mood, including ‘satisfaction with life’, Hospital Anxiety and Depression Scale (HADS) and Spielberger State and Trait Anxiety in early (12–20 weeks’ gestation) and late pregnancy (28–32 weeks’ gestation). Term BWT (>37 weeks’ gestation) was recorded (n=234). Results Obese women were significantly less satisfied with life than lean women and had higher HADS depression and anxiety scores, and state and trait anxiety scores at both time points (all p, Rationale/statement of the problem Although heritability is an important factor related to the onset of psychotic disorders, environmental factors also play a role. Early-life stress, which includes both prenatal stressful exposures and childhood maltreatment, has been suggested to have an impact on the developing brain. Cognitive alterations in schizophrenia and psychotic disorders have been described in several neuropsychological domains: attention, memory (verbal, visual and working memory), processing speed, reasoning and social cognition. Recent studies suggest that the hypothalamic–pituitary–adrenal (HPA) axis modulates cognitive functioning in patients with psychosis but that this association does not seem to be related to increased exposure to stressful events. We aimed to study whether early-life stress and the HPA axis are associated with a poorer cognitive performance in subjects with a psychotic disorder. Methods We studied 46 subjects with an early psychosis (aged 18–35 years), who were attending the Early Psychosis Program from Reus (HPU Institut Pere Mata, Spain). These subjects included three clinical populations: (1) first episode of psychosis (FEP, N=17); (2) critical period (CP, defined as a psychotic disorder >1 year of duration of illness, N=17); and (3) ultra high risk (UHR, subjects with prodromal psychotic symptoms, N=12). All subjects were assessed using a structured clinical interview (Schedules for Clinical Assessment in Neuropsychiatry and Comprehensive Assessment of at Risk Mental States) to obtain a clinical diagnosis. Obstetric history and perinatal stress were assessed retrospectively by parental recall, usually from the mother. Childhood maltreatment was assessed with the Childhood Trauma Questionnaire. The MATRICS Consensus Cognitive Battery was administered to explore neuropsychological functioning in seven domains: attention/vigilance, speed of processing, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. This cognitive battery gives T-scores corrected for age, sex and education level. Salivary samples at different times were obtained to determine cortisol levels. Three samples were obtained the same day of the neuropsychological assessment (before, during and after the battery). The area under the curve during these three assessments was calculated. Participants were also asked to collect salivary samples on a different day at home, on waking, 30’ post-waking, 60’ post-waking, 10.00 h, 23.00 h and at 10.00 h post-administration of 0.25 mg of dexamethasone the prior evening. The cortisol awakening response was calculated. Statistical analyses were performed with SPSS v.19.0. Spearman correlation was used to explore the association between CTQ scores, cortisol measures and cognitive domains. Wilcoxon test was used to compare ordinal and continuous data between groups. A p value, Rationale/statement of the problem Increasing evidence suggests exposure to adverse conditions in intrauterine life may increase the risk of developing attention-deficit/hyperactivity disorder (ADHD) in childhood. High maternal pre-pregnancy body mass index (BMI) has been shown to predict child ADHD symptoms; however, the neurocognitive processes underlying this relationship are not known. The aim of the present study was to test the hypothesis that this association is mediated by alterations in child executive function and cortical development. Methods A population-based cohort of 174 children (mean age=7.3±0.9 (SD) years, 55% girls) was evaluated for ADHD symptoms, using the Child Behavior Checklist, and for neurocognitive function, using the Go/No-go Task. This cohort had been followed prospectively from early gestation and birth through infancy and childhood with serial measures of maternal and child prenatal and postnatal factors. In 108 children, a structural MRI scan was acquired and the association between maternal obesity and child cortical thickness was investigated using Freesurfer software. Results Maternal pre-pregnancy BMI was a significant predictor of child ADHD symptoms (F (1,158)=4.80, p=0.03) and of child performance on the Go/No-go Task (F (1,157)=8.37, p=0.004) after controlling for key potential confounding variables. A test of the mediation model revealed that the association between higher maternal pre-pregnancy BMI and child ADHD symptoms was mediated by impaired executive function (inefficient/less attentive processing; Sobel test: t=2.39 (±0.002, SEM); p=0.02). Interestingly, after controlling for key potential confounding variables pre-pregnancy obesity was furthermore associated with region-specific thinner cortices, including regions previously reported to be thinner in children with ADHD, like the prefrontal cortex. Conclusion To the best of our knowledge, this is the first study to report the neurocognitive underpinnings of maternal pre-pregnancy BMI-related effects on child ADHD risk. These results add further evidence to the growing awareness that neurodevelopmental disorders such as ADHD may have their foundations very early in life., Rationale/statement of the problem Scientific evidence indicating that excessive stress during human pregnancy can have long-lasting effects on mother and child is increasing. But the underlying biological mechanisms remain elusive. Recent findings suggest a key role of the hypothalamic–pituitary–adrenal axis and the placental enzyme 11β-hydroxysteroid dehydrogenase Type 2 (11β-HSD2). This enzyme inactivates cortisol (F) to cortisone (E), thereby protecting the foetus from maternal F overexposure. Studies on pregnant rats show that placental 11β-HSD2 is up-regulated following acute maternal stress but impaired after chronic stress. Whether a similar mechanism exists in humans is unclear. Therefore, we investigated the acute stress response of salivary F (SalF) in second-trimester pregnant women undergoing amniocentesis and compared this response with amniotic fluid F, E, and the E/(E+F) ratio as an index of placental 11β-HSD2 activity. Since 11β-HSD2 is also present in the adult salivary glands, we determined salivary E (SalE) and the SalE/(SalE+SalF) ratio, as a marker for salivary 11β-HSD2 activity as well and examined the association of these parameters with the amniotic fluid markers of stress. Methods Repeated saliva samples and an aliquot of amniotic fluid were collected from 34 healthy pregnant women (mean age=37.5, SD=3.9 years) undergoing amniocentesis for karyotyping. Changes in stress perception and state anxiety were monitored using questionnaires. Participants were re-invited for a control condition after receiving the inconspicuous test results of the amniocentesis. Results Compared to the control condition, the pregnant participants showed significant increases in psychological distress during the amniocentesis. SalF and SalE increased correspondingly while SalE/(SalE+SalF) decreased. SalF correlated positively with amniotic fluid E (r=.38, p=.048), and a stronger decrease in SalE/(SalE+SalF) was associated with increased amniotic fluid E/(E+F) (r=.44, p=.02). Conclusions The present results further our understanding of the maternal–foetal stress response considerably and suggest that during acute stress, maternal F is converted to E within the foeto-placental unit. This is most probably due to the activity of placental 11β-HSD2. Further investigation of the influence of chronic stress on the enzyme activity is essential., Rationale/statement of the problem Lower socioeconomic position is associated with increased risk of morbidity and premature mortality from physical and mental disorders and confers similar “transgenerational” consequences on the offspring. The effects on the offspring appear initiated prenatally as lower socioeconomic position also increases risk of prematurity and small/large body size at birth. The biological mechanisms remain, however, elusive. We hypothesized that fetoplacental stress (glucocorticoid) hormone exposure might mediate the link, as we have found in first and second generation exposures to glucocorticoids in rodent pregnancy. We therefore examined associations between socioeconomic position and placental expression of placental genes involved in glucocorticoid exposure and transfer between the mother and fetus. Methods Biopsies of placental tissue were obtained from 62 healthy (mothers age 32.2±[SD] years), singleton, term pregnancies (37–42 gestational weeks) a maximum of 90 min after (vaginal or caesarian) delivery, snap frozen in liquid nitrogen, and stored at −80°C. Placental mRNAs encoding glucocorticoid receptor (GR) and 11-beta hydroxysteroid dehydrogenase 1 (HSD1) and 2 (HSD2), which regenerate and inactivate glucocorticoids respectively, were determined by real-time PCR. Level of education and occupational status of the mother, indices of socioeconomic position, were obtained from hospital birth records. Results Placental GR and HSD1 mRNAs increased with decreasing maternal education (unadjusted p values for linear trend=0.04 and 0.02, respectively; p values adjusted for maternal age at delivery, fetal birth weight, and length of gestation=0.08 and 0.02, respectively). Mothers with secondary education (n=23) had 52.9% (95% CI=6.2 to 99.6, p=0.03, adjusted p=0.04) higher placental GR mRNA and 81.9% (95% CI=6.9 to 156.9, p=0.03, adjusted p=0.03) higher HSD1 mRNA compared with mothers with tertiary education (n=39). The associations were similar with occupational status. Level of education and occupational status of the mothers were not associated with placental HSD2 mRNA (unadjusted/adjusted p-values>0.58). Conclusions Lower socioeconomic position is associated with higher placental GR and HSD1 gene expression. This combination will both regenerate active glucocorticoids in placenta (with potential impact locally in placental cells and by spill-over on the fetus) and increase placental sensitivity to glucocorticoids. By analogy with preclinical mechanistic studies, this may have immediate offspring and transgenerational effects on cardiometabolic and neuropsychiatric risk but adds placental glucocorticoid sensitivity and regeneration as novel processes involved., Rationale In previous research, we found that flattened diurnal cortisol predicted early mortality with breast cancer, independent of other known risk factors, and this has since been confirmed among patients with lung cancer. In that study, loss of diurnal variation in cortisol was associated with self-reported awakenings during the night, implying an interaction with sleep disruption. This suggested that objective measures of sleep would clarify the relationship between disruption of circadian cortisol rhythms and sleep disturbance. Methods Here we recruited 101 women with metastatic breast cancer and 16 age- and socioeconomic status-matched controls. We measured sleep using full electroencephalographic (EEG), electro-oculographic, and electromyographic recordings in the clinical research center, where we were also able to draw blood samples throughout the night using a long IV line through a hole in the wall. Sleep measures were confirmed with two nights of home EEG recordings and 2 weeks of actigraphy. Results Among 63 for whom complete cortisol and sleep data are now available, we observed a phase shift in the relationship between the peak of cortisol and wake time such that patients woke earlier than their cortisol peak. Controls woke on average 1 h 20 min before the cortisol peak, whereas patients woke 1 h 54 min before. This control–patient difference was not statistically significant. However, among all subjects, there was a significant .38 correlation between diurnal cortisol slope and time from waking to the cortisol peak, such that those who woke earlier in relation to the cortisol peak had flatter cortisol slopes. Among the patients alone, the correlation was .43. This suggests that flattening of diurnal cortisol is associated with early morning waking. In the sample of 101, we found a relationship between misalignment of preferred and actual bedtimes and disease-free interval (DFI), the time from initial breast cancer diagnosis to date of metastasis. Shorter DFI is a strong predictor of reduced survival time. Going to bed earlier or later than preferred bedtime was associated with shorter DFIs, compared with aligned bedtime (HR=3.25, 95%CI=1.17–8.98, p=.023, and HR=3.55, 95%CI=1.33–9.45, p=.011, respectively). Mean DFI was 92.1 months (preferred), 39.8 months (earlier than preferred), and 54.1 months (later than preferred; Log Rank p=.002). Conclusions Thus waking ahead of the normal morning cortisol peak was related to flatter diurnal cortisol, and misalignment of preferred and actual sleep times was also associated with poor prognosis., Background Sleep disturbances are among the most common symptoms of posttraumatic stress disorder (PTSD). There is growing evidence that sleep fragmentation and short sleep duration are risk factors for hyperlipidemia, diabetes, obesity, and other risk factors for vascular disease. No work has examined the association of sleep with lipid metabolism in PTSD. Methods A cross-sectional 2×2 design (PTSD/control × male/female) included medication-free, nonobese, medically healthy subjects. The sample was comprised of 42 individuals with current chronic PTSD (52% female; M age=30.81, SD=6.55) and 45 age-and gender-matched controls without PTSD (51% female; M age=30.04, SD=8.07), ranging in age from 20 to 50 years. Sleep was monitored by diary for 1 week, and ambulatory polysomnography was performed over three nights on a research inpatient unit. Morning fasting lipids and adiponectin were measured after the second night of sleep. Results PTSD subjects had significantly elevated total cholesterol, very-low-density lipoprotein (VLDL) cholesterol, and triglycerides relative to controls (all p's, Rationale The peak number of protective immune cells measured in the blood at the zenith of their diurnal rhythm is a measure of their overall capacity for immunoprotection. Rhythmic diurnal changes in blood immune cell numbers reflect a redistribution of cells from the blood to other body compartments, and back into the blood. This redistribution may be critical for leukocyte maintenance and for the surveillance and effector functions of the immune system. Methods We investigated diurnal changes in absolute numbers of NK cells in patients with metastatic breast cancer (MBC) (n=48) and controls (n=19). Sleep quality was measured by home actigraphy. Leukocyte differentials were combined with flow cytometry to calculate NK cell numbers in whole blood samples obtained every 4h, starting 12 h (T1) after the midpoint of sleep on day 1 and ending 12 h (T7) after the midpoint of sleep on day 2. Results In agreement with the literature, control subjects showed peak blood NK cell numbers at T1, with a decrease to their diurnal trough at around the sleep midpoint (T4), followed by a return to diurnal peak numbers 12 h later. Compared to controls, patients with MBC showed significantly lower peak NK cell numbers (p=0.039), suggesting an overall decrease in NK-cell-mediated immunoprotection for patients. Interestingly, among patients, higher peak NK cell numbers were associated with a longer disease-free interval (p=0.036) and higher Karnofsky Performance Rating (p=0.083, trend), collectively indicating an association between higher peak NK cell numbers and better health and functional status. Compared to controls, patients with MBC also showed a smaller peak to trough decrease (p=0.006) that suggests reduced diurnal NK cell redistribution among different immune compartments which could also decrease immunoprotection. We further investigated the relationship between sleep disruption and damped NK cell rhythms in MBC patients. Higher average wake time after sleep onset was associated with a smaller peak to trough decrease (R=−0.38, p=0.006). The average number of awakenings was also associated with a smaller peak to trough decrease (R=−0.36, p=0.014). In contrast, average sleep efficiency was associated with a larger peak to trough decrease (R=−0.40, p=0.005), indicating a positive association between better sleep and a healthier diurnal NK cell rhythm. Conclusion These results suggest that patients with MBC have reduced NK-cell-mediated immunoprotection compared to controls and that among patients, higher NK cell numbers are related to longer disease-free interval and better Karnofsky status. Patients with MBC also show decreased diurnal NK cell redistribution compared to controls, and among patients, reduced diurnal NK cell redistribution is associated with increased sleep disruption., Background Joint stiffness in rheumatoid arthritis (RA) is worse in the morning and has been associated with increased secretion of the pro-inflammatory cytokine IL-6 and with decreased secretion of cortisol, suggesting that clinical symptoms may be related to hormonal and immune circadian variations. We measured 24-h blood profiles of IL-6 and cortisol in patients with RA to determine any changes in IL-6 and cortisol following a 2-week course of prednisone administered orally in a specially designed timed-release tablet (TRT). Methods Nine patients with active RA were clinically assessed and had 24-h blood sampling before and after a 2-week course of TRT prednisone (5 mg per day). Patients took the TRT orally at 2200 h, and the prednisone was released at 0200 h. Changes in circadian variation in cortisol and IL-6 and clinical measures were compared using random coefficient regression modelling and Wilcoxon matched-pairs signed-rank test. Results IL-1ra, IL-1β, IL-4 and TNF showed no circadian variation prior to TRT prednisone. Significant alterations in circadian profiles and concentrations of IL-6 and cortisol were observed following TRT prednisone. The peak value of IL-6 fell from 42.5 to 21.3 pg/ml and occurred earlier (0134 h compared to 0827 h) (p < 0.005). Following TRT prednisone, the peak value of cortisol increased from 14.1 to 19.3 µg/dl, and the trough fell from 2.9 to 2.1 µg/dl (p < 0.001). There was a close correlation between reduction of IL-6 and improvement in morning joint stiffness following TRT. Conclusions These experiments cast new light on circadian patterns of cytokines and hormones in a chronic inflammatory disease. We propose that these changes in IL-6 and cortisol, prior to the onset of morning joint stiffness, are functionally important in mediating the improvement in joint stiffness following prednisone in patients with RA., Background Using a well-established non-human primate model of anxious temperament (AT) we characterized alterations in the neural circuit that underlie the dispositional risk to develop anxiety and depression. Genetic variation encoding the CRHR1 and CRHR2 receptors was determined to examine the extent to which putative functional variants in the expression of these receptors may contribute to the expression of the risk phenotype as well as its underlying neural substrate. In a subset of monkeys, we sampled tissue from the central nucleus of the amygdala (Ce) to quantitate mRNA expression patterns. Methods In a large cohort of young rhesus monkeys (n>300), all part of a multigenerational family pedigree, we characterized AT with threat-related behavioral and cortisol measures and its underlying neural circuit with FDG-PET. In all animals, all exons from these genes were sequenced and SNPs with potential functional significance were tested for their relation to AT and brain metabolism in regions underlying AT. Rhesus Affymetrix microarrays were used to determine Ce gene expression patterns. Results Regarding CRHR1, we found that SNPs affecting exon 6 of CRHR1 influence both AT and metabolic activity in the anterior hippocampus and Ce. Data will also be presented regarding variation in CRHR2 in relation to AT, cortisol, and underlying brain function. Gene expression data from the Ce demonstrated alterations in diverse systems, including neuroplasticity. Conclusions These data suggest that genetic variation in CRHR1 and CRHR2 affects the risk for anxiety and affective disorders by influencing the function of the neural circuit underlying AT, and that differences in gene expression or the protein sequence involving CRHR1 exon 6 may be important. Exon 6 is of particular interest because its expression in primates is very different than that in non-primate species. In addition, Ce mRNA data implicate neuroplasticity systems in the development and maintenance of AT. These data suggest novel treatment approaches for early life interventions with the potential to decrease the risk of children with AT to develop anxiety and depressive disorders., Rationale Abnormalities of hypothalamic–pituitary–adrenal (HPA) axis in depression and suicide are among the most consistent findings in biological psychiatry. However, the specific molecular mechanism associated with HPA axis abnormality in the brain of depressed or suicidal subjects is not clear. It is believed that abnormal HPA axis is caused by increased levels of corticotropin-releasing factor (CRF) and decreased levels of glucocorticoid receptor (GR) in the brain of depressed or suicide subjects. To study their role in teenage suicide, we determined the protein and gene expression of CRF, CRF receptors, and GR in the prefrontal cortex (PFC), hippocampus, and amygdala of teenage suicide victims and teenage normal control subjects. Methods The postmortem brain samples were obtained from the Maryland Brain Collection at the Maryland Psychiatric Research Center, Baltimore, MD, USA. Samples were obtained from 24 teenage suicide victims and 24 normal teenage control subjects. Psychological autopsy was performed and the subjects were diagnosed according to the DSM-IV (SCID). Protein expression was determined using Western blot and gene expression (mRNA) was determined using real-time RT-polymerase chain reaction (qPCR) technique. Results We observed that the protein and gene expression of the CRF was significantly increased in the PFC (Brodmann area 9) and in amygdala, but not in the hippocampus, of teenage suicide victims compared with normal control subjects. The protein and gene expression of CRF-R1 was significantly decreased in the PFC and amygdala, but not in the hippocampus, of suicide victims. We also observed a significant decrease in the protein and mRNA expression of GR in the PFC and amygdala, but not in the hippocampus, of teenage suicide victims compared with control subjects. Conclusion These results thus indicate that suicidal behavior is associated with increased CRF and decreased GR in certain specific areas of the brain of suicide victims compared with controls., Background Hypothalamic-pituitary-adrenal (HPA) axis activity remains a major focus for the study of the pathophysiology of anxiety and depressive disorders. Recent developments in genetics allow for potential new avenues for assessing risk and for developing new treatments. We will address recent studies on genetics of HPA axis dysregulation in a preclinical model of anxiety/depression, the brains of suicide victims, and severely ill delusional and nondelusional depressives. Last, the development of new glucocorticoid receptor (GR) antagonists that may prove useful as therapeutics in major psychiatric disorders is reviewed. Methods Ned Kalin will first present data on a stress model of anxiety/depression in rhesus monkeys. Over 400 monkeys were characterized on behavior and positron emission tomography imaging in response to an intruder and were genotyped for alleles for both corticotropin-releasing hormone receptors (CRH-R1 and CRH-R2). Shyam Pandey will report on gene expression for CRH-R1, CRH-R2, GR, and the mineralocorticoid receptor (MR) in multiple brain regions of adolescents who committed suicide and in matched controls who did not. In a sample of 122 subjects, Alan Schatzberg will present data on genetic variation differences in GR and CRH-R1 between severely depressed patients (delusional and nondelusional) and healthy controls as well as on the relationship of CRH and GR alleles to mean cortisol activity collected hourly from 6 PM to 1 AM as well as from 1 AM to 9 AM. Finally, Joseph Belanoff of Corcept Therapeutics will discuss the application of medicinal stereochemistry in the development of GR antagonists with greater GR specificity and organ selectivity than those currently available. Results Associations between allelic variations in HPA axis genes and behavior were observed for CRH-R1 and CRH-R2 alleles in the rhesus monkey. Decreased message expression for GR and CRH-R1 was observed in key brain regions in suicide victims. Allelic variation for CRH_R1 and GR was associated with risk for severe depression and psychosis, and GR alleles were associated with elevated cortisol levels. A number of nonsteroidal GR antagonists have been synthesized and are active in various animal models. Conclusions HPA axis remains a potential source of diagnostic tests and innovative treatment., Background Major depressive disorder (MDD) and panic disorder (PD) are common and disabling medical disorders with stress and genetic components. Dysregulation of the stress response of the hypothalamic–pituitary–adrenal axis, including the corticotrophin-releasing hormone (CRH) signaling via primary receptors (CRHR1 and CRHR2), is considered to play a major role for onset and recurrence in MDD and PD. Methods To confirm the association of CRHR1 and CRHR2 with MDD and PD, we investigated 12 single nucleotide polymorphisms (SNPs) in MDD patients (n=173), PD patients (n=180) and healthy controls (n=285). Results The SNP rs110402 and rs242924 in the CRHR1 gene and the rs3779250 in the CRHR2 gene were associated with MDD. The SNP rs242924 in the CRHR1 gene was also associated with PD. The T-A-T-G-G haplotype consisting of rs7209436 and rs173365 in CRHR1 was positively associated with MDD. The T-A haplotype consisting of rs7209436 and rs110402 in CRHR1 was positively associated with MDD. The C-C haplotype consisting of rs4722999 and rs37790 in CRHR1 was associated with PD. Conclusion These results provide support for an association of CRHR1 and CRHR2 with MDD and PD., Background/Methods Mifepristone, a potent glucocorticoid receptor (GR) and progesterone receptor (PR) antagonist, has recently become the first medication approved for the treatment of Cushing's syndrome, the archetypal illness of cortisol excess. Mifepristone is also being studied for the treatment of psychotic depression in a Phase 3 study and in numerous academic studies on diseases in which GR antagonism is thought to be potentially useful. In all cases, mifepristone utility is generated by its ability to block GR and its antagonism of PR is either irrelevant or troublesome. A selective GR antagonist may confer the same benefits of mifepristone while removing an important liability. Results Data are provided from animal and human studies of mifepristone and animal studies of novel, selective GR antagonists in metabolic and psychiatric diseases. Conclusions Pre-clinical studies indicate that selective GR antagonists may potentially have the same clinical utility as mifepristone in blocking cortisol while eliminating the unwanted effects of progesterone blockade., Rationale Generalized avoidance belongs to the core symptoms of a variety of anxiety disorders such as panic disorder or posttraumatic stress disorder. However, therapy for avoidance behavior still bears many obstacles. Even though exposure-based approaches are the method of choice, they suffer from inferior patient compliance. This can be ascribed to patients’ inability to stand the high emotional load experienced during the therapeutic sessions. The situation could be much improved if (1) learning about the safety of a feared situation could be enforced, while (2) the negative effect inherent to the exposure is decreased. This would allow for the number/duration of the exposure sessions to be restricted to a minimum, and at the same time, the emotional load of the therapeutic sessions could be dampened, with direct consequences on compliance rates. So far, however, most of the treatments with anxiolytic capabilities (e.g., benzodiazepines) lead to state-dependency or amnesia, with the consequence that safety learning is attenuated, if not completely blocked. Methods The role of the endocannabinoid system in fear relief and safety learning was investigated in numerous animal studies employing pharmacological and genetic approaches. Behavioral experiments involved classical fear conditioning and inhibitory avoidance learning, followed by extinction training and safety learning. Mice were treated with the CB1 receptor antagonist/inverse agonist SR141716 (3 mg/kg) or the endocannabinoid uptake/degradation inhibitor AM404 (3 mg/kg). Parts of the experiments were performed with conventional and conditional mice lacking expression of CB1 receptors either in the entire brain or in distinct neuronal populations. Results Our studies revealed the following key findings: (1) Endocannabinoids play an essential role in acute fear relief, once the averseness of the test situation exceeded a certain threshold. (2) These effects are mediated via CB1 on glutamatergic nerve terminals. (3) The capacity of the endocannabinoid system is limited in highly aversive situations but can be reestablished by blocking of endocannabinoid uptake/degradation. (4) At the same time, signaling via CB1 on dopamine D1 receptor positive neurons contributes not only to acute fear relief but also to safety learning in an inhibitory avoidance task. (5) The efficiency of safety learning in this task can be improved and the risk of relapse of avoidance behavior can be reduced by pharmacological enhancement of endocannabinoid signaling. Conclusion Drugs promoting endocannabinoid signaling via CB1 receptors may represent a new class of compounds that combine the advantages of “happy pills” (in terms of fear and stress relief) with those of “smart drugs” (i.e., facilitated safety learning), thus increasing compliance rates and success of exposure-based therapies in anxiety disorders., Rationale Endocannabinoids have been shown to be important for the regulation of multiple aspects of the stress response, although the neural circuits underlying this phenomenon are not well characterized. The amygdala is rich in cannabinoid receptors and endocannabinoid content and is well seated to integrate the role of endocannabinoid signaling to the regulation of the stress response. This series of studies sought to determine the roles of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the amygdala with respect to both activation and adaptation of the stress response. Methods For the first two experiments, male Sprague-Dawley rats were employed. For acute activation of the stress response, a 30 min exposure to restraint stress was employed, while 9 days of 30 min restraint was employed to examine adaptation of the stress response. In the third study, C57Bl/6 mice (both wild type and those deficient in the AEA degrading enzyme fatty acid amide hydrolase, FAAH) were employed. Results Exposure to acute restraint stress increased the hydrolytic activity of FAAH and decreased AEA content within the amygdala. Local administration of a FAAH inhibitor (10 ng) into the basolateral amygdala (BLA) reduced stress-induced corticosterone secretion, indicating that a FAAH-mediated loss of AEA signaling in the BLA contributes to activation of the stress response. Following 9 days of repeated restraint, the corticosterone response to stress habituated, and this adaptive response was reversed by local administration of AM251 (1 µg), a CB1 receptor antagonist, into the BLA. Consistent with this, repeated restraint stress caused an increase in 2-AG content within the amygdala, indicating that a recruitment of amygdalar 2-AG signaling is required for stress adaptation. Chronic stress exposure caused an increase in FAAH activity and a reduction in AEA content within the amygdala. FAAH deficient mice did not exhibit this reduction in AEA content and were similarly protected against the ability of chronic stress to cause dendritic expansion and spine growth within the BLA, as well as heightened indices of anxiety. Conclusion These findings indicate that AEA and 2-AG signaling at the CB1 receptor within the amygdala both serve to inhibit activation of the stress response. AEA appears to serve more of a tonic, gatekeeper role, the loss of which promotes activation of the stress response. Prevention of this loss of AEA signaling, through a blockade of FAAH activity, is capable of dampening the effects of acute and chronic stress. On the other hand, 2-AG signaling is recruited by repeated restraint stress to promote habituation and adaptation of the stress response. As such, a ying-yang model exists within the amygdala with the two endocannabinoid ligands serving different roles to regulate the stress response., Rationale There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the neurobiological mechanism underlying this presumably nongenomically mediated glucocorticoid action remains to be elucidated. Here, we show that the hippocampal endocannabinoid system, a rapidly activated retrograde messenger system, is involved in mediating glucocorticoid effects on retrieval of contextual fear memory. Methods For all three experiments, male Sprague-Dawley rats were trained on a hippocampus-dependent contextual fear-conditioning (CFC) task and retention was tested 24 h later. All drugs were administered 60 min before retention testing. Results Systemic injections of corticosterone (3.0 mg/kg) impaired memory retrieval of CFC training (P < 0.05) whereas lower doses (0.3 or 1.0 mg/kg) were ineffective. The retrieval-impairing dose of corticosterone significantly increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) (p, Rationale The endocannabinoid system has been shown to be an important regulator of the stress response and adaptation to stressful situations and environments in animals. Little is known, however, about the role of this system in acutely and chronically stressed humans. Methods We developed an HPLC-MS-MS-based method to measure plasma concentrations of the ECs anandamide (ANA), 2-arachidonoylglycerol (2-AG), the N-acyl-ethanolamides palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamine (SEA), and N-oleoyldopamine (OLDA), determined leucocyte cannabinoid (CB) receptor mRNA and genotyped the CB receptor genes (CB1/CB2) for known single nucleotide polymorphisms in critically ill patients. Results We used these methods in a number of studies in healthy volunteers, critically ill patients, and individuals with PTSD to delineate the relationship between peripheral EC signaling and the intensity of acute and chronic traumatic stress. In a first series of experiments, we exposed healthy volunteers (n=21) to acute kinetic stress during a parabolic flight experiment. Stress-tolerant participants (n=14) showed a significant increase in plasma EC concentrations and unchanged plasma cortisol concentrations whereas highly stressed individuals (n=7) showed an absent EC response, a reduced expression of leukocyte CB1 mRNA, and a massive activation of the hypothalamic-pituitary-adrenal axis. Physical stress in trained and physically fit individuals (n=12) induced by hard exercise during mountaineering or cycling also resulted in elevated EC concentrations, which returned to baseline after termination of the stressful activity. In contrast, chronically stressed individuals with traumatic memories from war and torture experiences with (n=10) and without PTSD (n=18) showed persistent elevations of plasma EC concentrations when compared to non-traumatized controls (n=20). EC plasma levels correlated with scores on the clinician-administered PTSD scale. Analogous findings came from an earlier study in patients with heart disease awaiting cardiac surgery (n=90). In this study, patients with traumatic memories and evidence of PTSD from previous life-threatening experiences associated with cardiac disease (n=57) and evidence of PTSD (n=8) had significantly higher EC plasma concentrations than patients without traumatic memories and PTSD symptoms. Furthermore, a very recent study in patients after cardiac surgery (n=95) found an association between a single nucleotide polymorphisms of the gene encoding the CB2 receptor and the intensity of post-traumatic stress symptoms after surgery. Conclusion These findings point to a possible involvement of the EC system in acutely and chronically stressed humans with traumatic memories and PTSD. Additional studies of EC signaling in PTSD patients before and after therapeutic interventions could lead to novel biomarkers and to further progress in the understanding of PTSD and the multiple biological and behavioral sequelae of this complex disorder., Background Combat-related posttraumatic stress disorder (PTSD) is increasingly recognized as a primary challenge to the fitness of American military personnel and represents a significant military and national public health concern (Hoge et al. 2004; Thomas et al. 2010). A few available drugs (e.g., selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors) provide some benefit in the management of PTSD symptoms and have been approved by the Food and Drug Administration for the treatment of PTSD, but most meta-analytic reviews (Stein et al., 2006) have concluded that the benefits are minimal and there may be relatively less benefit for combat veterans (Friedman et al., 2007). Popular augmentation strategies using second-generation antipsychotic medication were also recently shown to be ineffective in the treatment PTSD (Krystal et al., 2011). Deficits in CB1 receptor–mediated eCB signaling may play a key role in the etiology of PTSD and may mediate important components of the PTSD phenotype. Therefore, we propose to enhance eCB signaling as a novel, evidence-based treatment for PTSD with the potential to prevent both the behavioral (anxiety, impaired extinction) and molecular adaptations to trauma (increased CB1 receptor expression; Suarez et al., 2009) associated with PTSD. Methods Using radioligands and positron emission tomography (PET) imaging on a high-resolution PET scanner, we tested novel models of the etiology of PTSD involving these systems and their associated receptors. Results Four main lines of translational evidence implicate a defect in CB1 receptor–mediated eCB signaling in the pathogenesis of PTSD. In initial experiments, we found that (a) plasma AEA levels are decreased in PTSD patients (0.72±0.12 pmol/ml) relative to healthy control subjects without trauma history (HC 2.74±0.85 pmol/ml, t=2.47, df=17, p=.024) or controls with trauma history (TC 2.67±0.36, t=2.81, df = 10, p=0.018); (b) there are statistically detectable correlations between earlier age at first trauma and lower AEA levels in PTSD (r=0.45, p=0.073) and between magnitude of the decrease with a longer duration of PTSD (r=−0.48, p=0.059); (c) there are elevated [11C]OMAR volume of distribution (V T) levels (corresponding to elevated CB1 receptor density) in the fear circuit in PTSD relative to healthy people. This upregulation develops to compensate for the existing eCB deficit in PTSD and causes impaired fear processing, increased stress sensitivity and anxiety in PTSD as supported by (d) a statistically detectable positive correlation between amygdala [11C]OMAR V T and anxiety symptoms (r=0.56, p=0.09), perceived stress (r=0.57, p=0.018), and abnormal fear processing measured during fear conditioning tests (r=0.69, p=0.003). Conclusions These first data in PTSD provide evidence for abnormal CB1 receptor–mediated endocannabinoid signaling in PTSD and also provide a basis for evidence-based treatment development for this patient population. Inhibition of fatty acid amid hydrolase, the endocannabinoid degrading enzyme, appears to be an attractive candidate for such an undertaking., Rationale/statement of the problem There is an insufficient understanding of the neurobiology of post-traumatic stress disorder (PTSD). Therefore, the development of an animal model of PTSD that takes into account clinical features of the disorder is of value toward enhancing our understanding of the mechanisms, and in the development of novel treatments, of emotional trauma. Methods Adult male rats were administered chronic psychosocial stress composed of two 1-hour periods of inescapable exposure to a cat, in conjunction with daily unstable pair housing, over a 31 day period. The rats were then given a battery of tests, including measures of behavior (anxiety testing, startle response), cognition (predator-based fear memory and new memory testing), hormone levels (basal and evoked glucocorticoids), responses to pharmacological agents (dexamethasone and yohimbine) and cardiovascular activity (blood pressure/heart rate). In addition, we measured epigenetic alterations (methylation) of the brain-derived neurotrophic factor (BDNF) gene. Results Psychosocially stressed rats exhibited a PTSD-like phenotype. The stressed rats exhibited a strong fear-conditioned memory of the two cat exposures, an increase in behavioral signs of anxiety, an exaggerated startle response, increased blood pressure, greater sensitivity to yohimbine and a hippocampus-dependent memory impairment, relative to controls. In addition, stressed rats exhibited reduced basal glucocorticoid levels, greater sensitivity to dexamethasone and hypermethylation of the BDNF gene in the hippocampus. Conclusion These findings demonstrate that intense psychosocial stress produced dramatic changes in physiology and behavior in rats which are comparable to those observed in people diagnosed with PTSD. This rat model, therefore, may enhance our understanding of the mechanisms underlying human trauma and in the development of more effective pharmacotherapy for people with PTSD., Background Context processing imbues appropriate salience to the stimuli that is encountered. This ability enables us to hide from a predator in the wild, but to enjoy a visit to the zoo, although the lion may look the same in both contexts. Failures in contextual processing can lead to inappropriate fear responses rooted in failures to use safety cues, consider internal states, anticipate events, or appraise them properly. Posttraumatic stress disorder (PTSD) is associated with exaggerated fear, unwanted recollection, and inappropriate emotional and social responses. We proposed that PTSD pathophysiology involves deficits in context processing and examined this hypothesis using PTSD animal model and fMRI studies in patients with PTSD. Methods Using validated animal model of PTSD, we examined fear conditioning, fear extinction and context-dependent extinction recall, and fear renewal in single prolonged stress (SPS)-exposed animals. We further examined the relationships between glucocorticoid receptors (GRs) upregulation in SPS, and fear renewal deficits were observed. Using 3T fMRI paradigm, we examined fear conditioning, fear extinction, extinction recall, and fear reinstatement in PTSD patients and trauma-exposed control subjects. Results In humans, we found that fear-conditioning procedures activated fear-associated brain regions, but PTSD patients had similar fMRI activation maps to trauma-exposed controls during fear conditioning and extinction. However, they exhibited decreased responses to contextual signals of safety and danger. In animal work, we found that the SPS-exposed animals exhibited normal levels of conditioning and extinction, but specific deficits in context-dependent extinction recall and fear renewal. In “dismantling” studies, only animals exposed to full SPS and that demonstrated largest upregulation of GR in hippocampus and prefrontal cortex exhibited fear renewal deficits. Conclusions These results demonstrate contextualization deficits in PTSD subjects. PTSD animal model findings mirror those observed in PTSD patients and further implicate specific molecular targets in defined brain regions in contextualization deficits. Together, this set of studies demonstrates the combined power of translational research into trauma psychopathology., Rationale/statement of the problem Animal research has challenged the permanency of memory by suggesting that reactivation (retrieval) of a specific memory may return it to a labile state from which it must be “re-consolidated” if it is to persist. Pharmacologically blocking reconsolidation offers the therapeutic possibility of weakening traumatic memories in post-traumatic stress disorder (PTSD). Methods We have been testing the above hypothesis using systemic drugs approved for human use. In rats we employ classical conditioning consisting of pairing a tone CS with a shock US on Day 1 (acquisition), presenting the tone without shock on Day 2 (reactivation) followed by drug, and then re-presenting the CS alone on Days 3 and 10 (tests). We have also used slice electrophysiology to measure the increase in cortico- and thalamo-lateral amygdala synaptic efficacy as a result of the tone-shock association, and then decrement in this efficacy following reconsolidation blockade. In PTSD subjects, we have administered oral drug along with verbal or written narration of the traumatic event (reactivation) and subsequently measured the strength of the traumatic memory via psychophysiological recording during script-driven imagery, and/or symptom report. Results In animal work, we have found that the antiglucocorticoid receptor mifepristone, the protein synthesis inhibitor rapamycin, and the alpha-2-adrenergic autoreceptor agonist clonidine all block partially reconsolidation of conditioned fear. Clonidine does so in a dose-dependent manner. Additionally, rapamycin reverses the synaptic enhancement described above, providing an underlying physiological basis for reconsolidation blockade. In humans, we have found that traumatic memory reactivation plus double-blind, placebo-controlled propranolol reduce physiologic responding during script-driven imagery, and that six weekly open-label propranolol plus memory reactivation sessions reduce PTSD symptoms to a similar degree as current cognitive behavioral treatments. A double-blind clinical trial is underway. Conclusion The above results show progress toward a clinical application of reconsolidation blockade, but much more needs to be done before efficacy is demonstrated., Background The identification of molecular post-traumatic stress disorder (PTSD) susceptibility pathways associated with different patterns of behavioral response to trauma is essential to an understanding of the neurobiology of PTSD and can pave the design for new treatments. Although several genes have been reported to be differentially expressed in PTSD, methodological constraints have limited the interpretation, for example, variation in the type or magnitude of trauma exposure, inter-individual genetic variation, and tissue specificity of response. Animal models are useful in delineating some of these issues. In this study, we used a unique animal model of PTSD with ecological and population validity. Adult rats were exposed briefly to predator scent stress, which mimics a threatening situation. Rats respond heterogeneously to this type of traumatic stress behaviorally and physiologically, similar to human response variability. In this model, two behavioral extremes can be studied – vulnerable and resistant ‘subtypes’. Methods Sprague-Dawley rats were exposed to the scent of cat urine. The outcome measures included behavior in an elevated plus-maze and the acoustic startle response 7 days after exposure. Cut-off behavioral criteria classified exposed rats according to their behavioral response as those with ‘extreme behavioral response’ and ‘minimal behavioral response’ (MBR), with unexposed rats as controls. From the tissue obtained 24 h after the behavioral tests, basal gene expression using Illumina BeadArrays was evaluated for whole blood and three brain areas: amygdala, anterior cortex and hippocampus. For data quality control and differential expression analysis, we used R and LIMMA (as included in MeV software), respectively. Pathway analysis was performed with ingenuity. Results There was only minimal overlap in gene expression across brain regions and gender demonstrating the existence of distinct tissue-specific susceptibility pathways in male and female rats. Among the differentially expressed genes, the ones regulated by the glucocorticoid receptor (e.g., FKBP5, Per-1, and NPY) were particularly over-represented (especially in blood and hippocampus), indicating that glucocorticoid regulation is involved in vulnerability and resistance to trauma. The observed gene expression profiles may also indicate the over-representation of discrete functional biological clusters and pathways (e.g., MAPK signaling and circadian rhythm). Conclusions Glucocorticoid-related gene expression is underlying the different response pattern following trauma, with distinct regional/structural differences between male and female rats., Rationale/statement of the problem Post-traumatic stress disorder (PTSD) arises from the interaction of genetic and environmental factors. Thus, a better understanding of the molecular etiology of PTSD would be greatly facilitated by the development of animal models that explore gene×environment interaction in the context of traumatic stress. To this end, we have identified a new mouse genetic model for stress vulnerability that may provide novel insight into the neurobiology of PTSD. Our studies focus on mice that are deficient for TIA-1, a prion-related RNA binding protein that regulates the expression of multiple target genes in the mammalian brain. Methods TIA-1 KO mice and wild-type littermates are generated from TIA-1 heterozygous crosses. All behavioral (fear conditioning, open field, elevated-plus maze, forced-swim test) and electrophysiological (hippocampal field recordings) experiments are conducted in accordance with standard protocols. Results Under baseline conditions, TIA-1 KO mice are indistinguishable from wild-type controls in all behavioral and neuroendocrinological measures evaluated thus far. However, several weeks after exposure to contextual fear conditioning, TIA-1 KO mice demonstrate increased anxiety and despair-like behavior, as well as abnormal glucocorticoid production. Moreover, these phenotypes are observed predominantly in female animals. Electrophysiological studies reveal aberrant synaptic plasticity in the ventral hippocampus of knockout animals in response to corticosterone treatment, consistent with a critical role for TIA-1 in normal emotional memory formation in the hippocampus during stress. Finally, molecular data suggest that TIA-1 may regulate alternative splicing of the glucocorticoid receptor, which is known to be important for both hypothalamic–pituitary–adrenal (HPA) axis function and hippocampal synaptic plasticity during stress. Conclusion TIA-1 KO mice recapitulate several key features of chronic PTSD observed in humans. Thus, our studies demonstrate that TIA-1-deficient mice represent a useful model in the study of gene×environment interaction during traumatic stress, and may contribute to our knowledge of the molecular basis of PTSD. Finally, because individuals with PTSD are also susceptible to substance abuse, we, therefore, discuss the utility of TIA-1 knockout mice in the study of PTSD and comorbid substance use disorders., Background Relatively little is known about how lasting qualities of the individual (e.g., traits and/or one's past history) moderate the effects of cortisol on emotional learning. We hypothesized that cortisol would have more pronounced effects on memory formation in individuals who show greater levels of trait negative affect (Trait NA) or who experienced early life separation (ELS). Methods In Study 1, involving 42 healthy adults (22 women), we examined how Trait NA moderated the effects of cortisol administration (IV-administered 0.1 mg/kg/30 min hydrocortisone; CORT) vs. placebo on memory formation for unpleasant and neutral photographs. In a preliminary study (Study 2), in 18 depressed adults (10 women), we examined how ELS (because of parental divorce or permanent separation) moderated the effects of CORT (15 mg orally administered hydrocortisone) vs. placebo on memory formation for positive and negative words. Results In Study 1, we found that in women with higher Trait NA, CORT facilitated memory formation. In women with lower levels of Trait NA, CORT had no effects of memory formation. Study 2 revealed that in depressed women with ELS, CORT facilitated memory formation for negative words. Specifically, CORT (vs. placebo) biased memory in a negative direction by an average of 4.2 (SD=0.73) words in women with ELS. In depressed women without ELS, CORT had no effect on memory formation. In both studies, 1 & 2, effects were less robust in men or trended in the opposite direction, which may represent true sex differences or may be because of confounding factors, such as differences in cortisol elevations for men vs. women. Conclusions In summary, our data suggest that lasting qualities of individuals, such as Trait NA or history of early separation, moderate cortisol's effects on emotional memory. Further investigation into how variation in personal traits and past experiences moderate cortisol's effects on emotional cognition is one important step in elucidating why some individuals are more sensitive than others to the detrimental (e.g., negatively biasing) effects of stress on emotional cognition and memory. These data may also inform research regarding the use of corticosteroid receptor ligands in treatment for psychopathology. Individual differences in affective style or past experiences may predict therapeutic response to corticosteroid receptor ligands., Background Enhanced memory for emotional events is a well-known phenomenon. From an evolutionary perspective, it is an adaptive mechanism, as it helps to remember threatening as well as pleasurable experiences. Stress hormones are important players in the regulation of emotional memory. Specifically, in animals and in humans, glucocorticoids enhance memory consolidation of emotionally arousing experiences but impair memory retrieval. Glucocorticoid actions are partly mediated by glucocorticoid receptors in the hippocampus, amygdala and prefrontal cortex, key brain regions for emotional memory. Here, we investigated whether the BclI polymorphism of the glucocorticoid receptor gene is associated with emotional memory in healthy young subjects. This polymorphism has been previously related to traumatic memories and posttraumatic stress disorder (PTSD) symptoms in patients who underwent heart surgery (Hauer et al., 2011). Methods To assess memory performance, we used a picture-learning task consisting of learning and recalling emotional and neutral photographs on two consecutive days in 841 healthy young subjects. Genotyping of the BclI polymorphism was done with Pyrosequencing on a PyroMark ID System. Results The BclI variant was associated with short-delay recall of emotional pictures: GG-carriers showed increased emotional memory performance as compared to CG- and CC-carriers. We did not find a genotype-dependent difference in recall performance for neutral pictures. Conclusion These findings indicate that the BclI polymorphism contributes to inter-individual differences in emotional memory in healthy young subjects and suggest a genetic link between emotional memory in healthy humans and traumatic memory in patients who underwent cardiac surgery., Background The inability to store fearful memories into their original encoding context may be an important vulnerability factor for developing anxiety disorders like posttraumatic stress disorder (PTSD). Such altered memory contextualization may develop through the effects of the well-known stress hormone cortisol on underlying memory neurocircuitry, rich in corticosteroid receptors. By binding to these receptors, cortisol induces rapid non-genomic effects followed by slower genomic effects that are thought to modulate cognitive function in various ways. Here, we tested these time-dependent effects of cortisol on the contextualization of negative versus neutral memories. Methods In a double blind, placebo-controlled design, 60 men were randomly assigned to one out of three possible groups. 1) In the rapid cortisol group, participants received 10mg hydrocortisone 30 min before completing the “associative imagination task” (AIT), 2) while the slow cortisol group received the drug 240 min before the task. 3) A third group received placebo at both times. During the AIT task, participants were instructed to vividly imagine 30 neutral and 30 negative words in unique background pictures. Approximately, 24 h later, participants completed two surprise memory tests: cued retrieval and recognition. Crucially, to assess memory contextualization, half of the negative and neutral words were tested in intact contexts, whereas the other half of the words were tested in rearranged context combinations. Results Recognition data showed that negative memories were generally less context-bound than neutral memories. Moreover, cortisol exerted time-dependent effects on contextual dependency of negative memories: Cortisol’ rapid effects impaired contextualization, whereas cortisols’ slow effects enhanced negative memory contextualization. In contrast, neutral memory contextualization remained unaltered by cortisol irrespective of the timing of the drug. Conclusions This study shows distinct time-dependent effects of cortisol on the contextualization of negative memories. These results suggest that non-genomic effects of cortisol may underlie impaired memory contextualization observed in PTSD, whereas genomic effects of cortisol may open avenues for cortisol as a protective agent against (traumatic) fear memory generalization., Background Stress and stress hormones (e.g., cortisol) modulate memory processes in both facilitative and deleterious ways, but mechanisms of memory enhancement are not yet fully understood. Specific effects of cortisol may be of particular interest, given its importance in a range of stress-related illness that is associated with cognitive changes. Methods To elucidate potential mechanisms of memory facilitation via pharmacological manipulation; healthy participants underwent functional magnetic resonance imaging after oral-administration of 100 mg of hydrocortisone (N=14) or placebo (N=12). Participants viewed compound pictures consisting of faces superimposed upon buildings. A surprise memory test was administered 24 h later. Results Cortisol at encoding enhanced subsequent memory only for face-building combinations but not for faces or buildings alone. Cortisol increased anterior hippocampal activation and a mediation analysis suggests that cortisol enhancement of conjunctive memory was at least partially mediated through this enhanced hippocampal activity. Cortisol memory enhancement was also associated with increased hippocampal interconnectivity. Conclusions These results support the hypothesis that the hippocampus may be an integral participant in cortisol's memory facilitation effects, with potential implications for psychopathologies like posttraumatic stress disorder, that involve stress-axis, hippocampal, and memory abnormalities., Background The stress hormone cortisol is known to modulate different memory processes. In general, high levels of cortisol increase memory consolidation, especially for emotional material. For a long time, memories were thought to be stable and resistant to changes after their consolidation was completed. However, recent evidence suggests that consolidated memories are subject to modulation upon their recall (reactivation). This suggests that memory reactivation opens a window of opportunity allowing the memory trace to be modulated in a lasting manner. Given that cortisol is an important modulator of memory, we were interested in investigating how it could modulate reactivated memories. Methods In the first study, 32 healthy men and women encoded a slideshow containing neutral and negative segments. Two days later, all participants recalled the slideshow (reactivation) and were randomly assigned to a stressor, the Trier Social Stress Test (TSST) or a control condition. Memory was reassessed immediately after that, as well as 5 days later. For the second study, 33 healthy men were exposed to the slideshow (as described above). Three days later, they were either administered with a placebo or metyrapone (a cortisol synthesis inhibitor). All participants had to recall the slideshow when the medication was active, and 4 days later. The third study assessed the impact of real negative news from the media. Fifty-six healthy men and women who were media consumers were either exposed to real negative news or to real neutral ones. Subsequently, they were all exposed to the TSST and their memory for the news was assessed 24h later. Results Study 1 demonstrated that emotional memory was enhanced following stress and this effect was still observed 5 days later. Study 2 results showed that memory reactivation of the emotional material was lower in the metyrapone group and this deficit was still present 4 days later. Study 3 demonstrated that women who were exposed to real negative news remembered this news more and were more stress reactive to a subsequent stressor. Conclusions Memory is an active process that can be updated upon its reactivation and cortisol can act as a modulator of this process. Results of our studies will be discussed with regards to their relevance to the clinical domain, more particularly for posttraumatic stress disorder., Background Memory functions involve three stages: encoding, consolidation, and retrieval. Modulating effects of glucocorticoids (GCs) have been consistently observed for encoding and retrieval. However, little is known on how GCs affect consolidation. Methods In Study I, after encoding emotional and neutral texts, cortisol or placebo was intravenously infused while participants were either awake (N=16) or napped (N=16). Study II and III investigate the mechanisms underlying the fact that memory retrieval is impaired at very low as well as very high cortisol levels but not at intermediate levels. Using specific receptor antagonists, we examined the role of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in memory retrieval. Using a double-blind within-subject, cross-over design, participants retrieved emotional and neutral material (learnt 3 days earlier) between 7:45 a.m. and 9:15 a.m. after administration of 400 mg of the MR blocker spironolactone vs. placebo (200 mg at 22:30 p.m. and 200mg at 4 a.m., Study II) or the GR blocker mifepristone vs. placebo (200 mg at 23:00 p.m., Study III). Results In Study I, retention of temporal order within the texts was enhanced when cortisol was infused during the wake phase but impaired when it was infused during sleep. In Study II, blockade of MRs impaired free recall of both texts and pictures, especially for emotional material. In contrast, blockade of GRs resulted in better memory retrieval. Conclusions Study I points toward fundamentally different mechanisms of cortisol on hippocampal memory consolidation, depending on the brain state. Study II and III indicate opposing roles of MRs and GRs in memory retrieval., Rationale/statement of the problem Stressful experiences during early life can remodel brain circuitry underlying behavioral adaptation with consequences for resilience and vulnerability to emotional and cognitive disorders. At least in the rodent this apparent permanent outcome of early adversity can be modulated by maternal influences and depends on the later life environmental context with the stress hormones of the hypothalamus-pituitary-adrenal axis in the driver's seat. A frequently investigated model is the animal that has experienced as pup reduced maternal care. Such a period of early neglect enhances the pup's responsivity to adverse emotional experiences, an effect that can even be detected within families and was found to advance prematurely the development of emotional and fear circuitry. Alternatively, enhanced care is capable of overridingthe lasting impact of neurotoxicity in early life. For instance, the frequently reported adverse effect of early life treatment with dexamethasone (as life-saving treatment of prematurely born infants) is strikingly attenuated by enhanced maternal care induced by daily handling. Methods Dr. Nederhof will review recent animal and human studies supporting the cumulative stress and mismatch hypotheses. Dr. Parker will present behavioral and neuroendocrine data from monkey studies supporting the idea of stress inoculation following early exposure to moderate stressors. Dr. Bagot will address the importance of later-life context when investigating the effects of early-life experience using rats exposed as pups to varying levels of maternal care and ex-vivo electrophysiology. Dr. Vinkers will demonstrate in healthy volunteers a modulation by genotype and gender of the accumulating effects of stress on psychiatric outcome, Rationale/statement of the problem The cumulative stress hypothesis states that aversive experiences early in life predispose individuals to be more vulnerable to aversive challenges later in life. Indeed, adversity has consistently been associated with psychopathology; however, it is neither a determinative nor a sufficient explanation. The mismatch hypothesis provides an alternative explanation; adverse experiences early in life trigger adaptive processes, thereby rendering an individual to be better adapted to adversity later in life. Methods A review of both the animal and human literature on the interaction between early and later adversity and its relation with psychopathology. Results In the animal literature, support for both the cumulative stress hypothesis and the mismatch hypothesis was found. The human literature is characterized by a general paucity of interaction studies. Convincing evidence for individual differences in sensitivity to early programming suggests that both hypotheses might be true but applicable to different individuals. Conclusion The cumulative stress hypothesis is proposed to apply to individuals who were not or only to a small extent programmed by their early environment, the mismatch hypothesis to individuals who experienced strong programming effects., Early exposure to severe stress in childhood increases the incidence of mood and anxiety disorders in adulthood. Far less researched, but of equal importance, is the theory that moderate early stress exposure instead of increasing vulnerability results in subsequent resilience. Variously described as inoculating, immunizing, steeling, or toughening, the notion that moderate postnatal stress exposure strengthens resistance to subsequent stressors has far-reaching implications for understanding the pathogenesis and prevention of stress-related affective disorders. Although the psychobiology of stress-inoculation-induced resilience in humans is largely unknown, new insights have emerged from seven studies of monkeys previously exposed to moderate postnatal stress compared to no-stress control-rearing conditions. Evidence from these studies indicates that early exposure to moderate stressors that temporarily stimulate anxiety and activate the hypothalamic-pituitary-adrenal (HPA) axis leads subsequently to diminished negative arousal, prosocial tendencies, enhanced cognitive control, increased curiosity, larger prefrontal cortical volumes, and attenuated HPA axis activation. In contrast to rodents, rearing differences in the development of neuroendocrine stress resistance in monkeys are more closely related to differences in prior stress exposure than to differences in maternal care. In addition, unlike in rodents, no rearing differences in glucocorticoid feedback sensitivity were observed in monkeys, suggesting that the neural basis of stress resistance in primates may differ from that in rodents. Finally, results from a pharmacological study, which further support the key role of acute early anxiety exposure in promoting the development of subsequent behavioral indications of resilience, will be presented. Findings from these non-human primate studies support the intriguing hypothesis that moderate early stress exposure may likewise provide a pathway to resilience in humans., Rationale Variations in maternal care in the rat associate with robust differences in hippocampal synaptic plasticity and learning in the offspring. In addition, differences in stress reactivity associate with variations in maternal care. However, the potential influence of stress on hippocampal function is often overlooked in studies of effects of early life experience. Previously, we found differential modulation of hippocampal function and plasticity by stress in adult offspring exposed to varying levels of maternal care. N-methyl-D-aspartate receptors (NMDAR) regulate synaptic plasticity, and NMDAR function is modulated by stress and CORT. We hypothesised that altered NMDAR function underlies the interaction of maternal and stress effects on hippocampal synaptic plasticity. Methods We used electrophysiology to examine NMDAR-dependent LTP and NMDAR synaptic function in adult offspring of mothers that varied in the frequency of pup licking/grooming (LG), i.e., High or Low LG. Results Under basal conditions, long-term potentiation (LTP) was impaired in the hippocampal dentate gyrus of Low LG offspring relative to High LG offspring. Synaptic NMDAR function was enhanced in Low LG offspring with no change in α-amino-3-hydroxy-methyl-4-isoxazole propionic acid receptor function (AMPAR). NMDAR antagonism by low concentration APV rescued the basal LTP deficit in Low LG offspring and inhibited LTP in High LG offspring. Stress-level CORT (100nM) rapidly enhanced LTP in offspring of Low LG rats and impaired LTP in offspring of High LG rats. CORT robustly increased NMDAR function in High LG offspring, eliminating the maternal effect. CORT did not affect NMDAR function in Low LG offspring. Thus, Low LG offspring exhibit basally elevated NMDAR function coupled with insensitivity to CORT modulation indicative of a chronic alteration of NMDAR. Conclusion These results suggest that low maternal care exerts a lasting effect on hippocampal plasticity through enhanced function of NMDAR in synapses. The blunted effect of CORT on synaptic NMDAR in Low LG rats could be adaptive in promoting cognitive functioning in challenging conditions, such as the improved contextual fear conditioning previously observed in these rats., Rationale/statement of the problem Stress exposure increases the risk for the development of depression. The leading hypothesis is that stress exposure only increases the risk in individuals combining a vulnerable genetic background with (repeated) stress exposure. However, it is currently unknown which (combination) of stressful life events are the most etiologically relevant to predict depressive symptoms. Preliminary evidence suggests that repeated cumulative stress may have the highest impact. Methods We aimed to determine the effects of repeated stress exposure on depressive symptoms (Beck Depression Inventory) in a cross-sectional sample of healthy subjects (n=563). Repeated stress exposure was operationalized as exposure to three stressors: early life stress (Childhood Trauma Questionnaire), later life stress (Life Stressor Checklist) and daily hassles. Because of the importance of the mineralocorticoid receptor (MR) for HPA axis responsivity, we investigated whether the MR haplotype (rs5522 and rs2070951) modified stress-induced depressive symptoms. For genetic analyses, we divided subjects into a low stress exposure group (0–1 positive stress domains) and high stress exposure group (2–3 positive three stress domains). Gender and cannabis use were included as covariates. Results Childhood trauma, later life stressors, and current daily hassles independently and cumulatively contributed to depressive symptoms (continuous and dichotomized). High cumulative stress exposure was associated with depressive symptoms (p=5.4xe−20). This effect was moderated by the MR haplotype (p=0.009) and was more pronounced in female subjects (p=3.0xe−6). Conclusion Cumulative exposure to three independent stressors contributed to the development of depressive symptoms in a healthy sample. Thus, our data implicate the existence of a multiple hit model in which independent but cumulative stress exposure leads to increased depressive symptoms. Multiple assessments across various stress domains may increase the validity and reliability of stress exposure compared to a single assessment. Importantly, the MR haplotype moderated the cumulative effects of stress on depressive symptoms, confirming and extending earlier studies, which showed that the MR haplotype 2 is associated with reduced optimism and a blunted stress response., Rationale/statement of the problem Animal research has indicated that oxytocin is involved in social bonding, stress regulation, and positive physiologic adaptations that may be linked with greater longevity and successful aging. Because of its potential role in promoting positive human social behavior, recent research has focused on whether oxytocin may lead to improved social and emotional functioning for various mental disorders. Moreover, given its apparent anti-stress effects, some investigators have posited that oxytocin may provide the basis for the observed beneficial effects of positive social relationships on health. While knowledge of the effects of oxytocin in healthy humans remains limited, the emerging research has raised some doubt as to whether effects are uniformly prosocial or stress-reducing. Moreover, gender differences in these stress-related effects have been speculated but not tested in humans. In this study, we examine whether oxytocin enhances salutary responses to social stress and compare effects between men and women. Methods Hypotheses were tested with a placebo-controlled, double-blind experiment, using a between subjects 2 (male vs. female)×2 (oxytocin vs. placebo) design. Participants (n=99) were randomized to receive either intranasal oxytocin spray or placebo (saline) nasal spray. Social stress was induced using the Trier Social Stress Test (TSST). Baseline measures of estradiol were obtained via saliva samples. Primary outcomes were cardiovascular (CV) reactivity, objective behavior during the stress task coded by observers unaware of the oxytocin condition, and self-reported affective responses. Results Analyses were conducted using two-way analysis of variance models (or ANCOVA if covariates such as age or estradiol were included). Participants given oxytocin, relative to placebo, responded to social stress with a challenge orientation characterized by a benign pattern of cardiovascular reactivity. For example, participants given oxytocin, compared to placebo participants, exhibited a trend toward greater increases in cardiac output [F(1, 68)=3.31, p=0.07, d=0.47] and ventricular contractility [indicating more sympathetic activation; F(1, 71)=2.98, p=0.09, d=0.45]. Gender differences also emerged. Men given oxytocin reported less negative affect (e.g., mean change between baseline and social stress task, men=0.26 vs. women=2.14) and had greater vagal rebound. However, women given oxytocin reported more anger (e.g., mean change men=−0.62 vs. women=0.71) and had better math performance following social stress. Conclusion Findings indicated that oxytocin stimulates an approach-oriented cardiovascular profile during social stress, suggesting mechanisms by which oxytocin might influence health. However, before considering oxytocin as therapeutic or uniformly beneficial, greater understanding of possible gender dimorphic effects is needed., Background Oxytocin is associated with both social cognition/perception and affiliation and with stress response regulation. Both stress response regulation and social factors influence response to trauma. While some social/interpersonal factors may mitigate response to trauma (e.g., social support), others can contribute to trauma-related symptoms (e.g., interpersonal avoidance). While most research on the effects of oxytocin shows a positive influence on social cognition/affiliation, other research suggests that this influence varies with context (e.g., oxytocin is associated with decreased trust/affiliation in the context of social threat). Furthermore, some studies of endogenous oxytocin levels show positive relationship between with symptoms of trauma related disorders (e.g., depression and posttraumatic stress disorder (PTSD)). Methods and results We present data from a sample (n=90) of highly traumatized adults living in an urban environment. Our data show a significant, positive relationship between plasma oxytocin levels and social support from family members (p, Rationale/statement of the problem We previously found that the intranasal administration of oxytocin positively altered self-reported personality. Changes in self-perception may represent one mechanism by which oxytocin facilitates prosocial behavior. To follow up this finding, we explored the acute effects of two doses of intranasal oxytocin (24 IU or 48 IU) on autobiographical memory. We predicted that oxytocin would decrease participants’ recall of overgeneral autobiographical memories (non-specific memories of the past) in a dose-dependent fashion. Since depressed individuals recall more overgeneral memories for past events, we hypothesized that the relation between oxytocin and autobiographical memory would be moderated by depressive symptoms. Methods Seventeen males self-administered a placebo or oxytocin on three separate occasions in a placebo-controlled, double-blind, and within-subjects experiment. Participants were administered the Autobiographical Memory Test (AMT) 110 min after drug administration. Results Participants recalled fewer overgeneral memories following the administration of 24 IU, but not 48 IU, of intranasal oxytocin relative to placebo [pr 2=.23, b=−0.824, t(15)=−2.426, p=.026], and individuals with higher depressive symptoms exhibited this effect in greater magnitude [pr 2=.20, b=−0.148, t(15)=−2.285, p=0.037]. Conclusions The findings suggest that a 24 IU dose of intranasal oxytocin alters the recall of personal past memories, which may be a mechanism by which oxytocin changes self-perceptions. This is one of the first dose-response studies on intranasal oxytocin, and our findings suggest lower doses of oxytocin may have greater beneficial effects in young adults presenting with high depressive symptoms., Rationale/statement of the problem Intranasal oxytocin attenuates cortisol levels during social stress inductions. However, no research to date has documented the dose–response relationship between intranasal oxytocin administration and cortisol, and researchers examining intranasal oxytocin have not examined the cortisol response to physical stress. We, therefore, examined the effects of 24 and 48 IU of intranasal oxytocin on the cortisol response to vigorous exercise. Methods Seventeen males participated in a randomized, placebo-controlled, double-blind, and within-subject experiment. Participants engaged in vigorous exercise for 60 minutes following the administration of placebo or intranasal oxytocin on three occasions. Saliva samples and mood ratings were collected at 8 intervals across each session. Results Salivary cortisol concentrations changed over time, peaking after 60 minutes of exercise [Quadratic: F(1,16)=7.349, p=0.015, partial η2=0.32]. The 24 IU dose of oxytocin attenuated cortisol levels relative to placebo [F(1,16)=4.496, p=0.05, partial η2=0.22) and the 48 IU dose, although the latter fell just short of statistical significance [F(1,16)=3.054, p=0.10, partial η2=0.16). There was no difference in the cortisol response to exercise in participants who were administered 48 IU of intranasal oxytocin relative to placebo. Intranasal oxytocin had no effect on mood. Conclusion This is the first study to demonstrate that the effect of intranasal oxytocin on salivary cortisol is dose-dependent, and that intranasal oxytocin attenuates cortisol levels in response to physical stress. Future research using exogenous oxytocin will need to consider the possibility of dose–response relations., Background Accumulating research indicates that oxytocin (OT) plays a key role in human social cognition and behavior. Inspection of the data, however, suggests that the social effects of OT often depend on contextual factors, including person characteristics. For example, some studies show that OT is helpful for avoidantly attached individuals, who are less socially engaged, whereas other studies show that OT exacerbates chronic interpersonal insecurities in anxiously attached individuals, who are preoccupied with closeness. Such variability raises questions about the mechanism by which OT influences human social behavior. Drawing upon animal research on OT and the other-directed (e.g., maternal) behavior, we propose that OT induces a similar shift in focus away from self and toward others in humans. This theory would explain some of the person-specific effects of OT since becoming more other- and less self-oriented should be helpful for avoidant individuals who are excessively focused on the self to the exclusion of others, but could be hurtful for anxious individuals who are already overly other focused and have no sense of self. Methods Thirty-one males received 24 IU intranasal OT/placebo in a randomized, double-blind, crossover trial and then completed tasks assessing the implicit cognitive accessibility and explicit self perceptions of agency (self orientation) and communion (other orientation). Individual differences in attachment were assessed at baseline. Results OT significantly decreased the cognitive accessibility of agency (self) and increased the cognitive accessibility of communion (other). Similarly, OT significantly decreased the endorsement of agency traits (arrogant) and increased the endorsement of communal traits (kind, warm, caring). Critically, this OT-induced shift from self to other differentially affected avoidant and anxiously attached participants, with avoidant individuals, who are generally low in communion, showing the largest increase in communion following OT, but anxious individuals, who are generally low in agency, showing even further reduction in agency/sense of self. Conclusions These data shed light on the variability in extant research on the social effects of oxytocin in humans and help explain both the beneficial and potentially harmful effects of OT., Background The neuropeptide oxytocin (OT) is well known for its positive effects on dampening stress responses and increasing prosocial behavior. This view of OT has led to increased interest in its application for the treatment of a wide range of disorders that include autism, anxiety, trauma, and schizophrenia. However, paradoxical findings in recent work have revealed that OT may play a more nuanced role in regulating physiology and behavior. This work is beginning to shed new light on contextual factors that may influence the direction of OT's effects. Methods In the present study, we used female prairie voles (Microtus ochrogaster) to study the mechanisms through which OT pretreatment and a familiar social context interact to influence the response to a naturalistic stressor. Prairie voles were chosen as a model to examine interactions between stress and sociality because, such as humans, they exhibit vagal cardioregulatory dominance and selective preferences for familiar social partners. Results We found that OT pretreatment prior to a stressor was associated with changes in behavior, plasma hormone concentrations, and patterns of functional coupling between brain areas known to be critically involved in stress responses and social cognition. Conclusion This talk will discuss recent work, from our lab and others, that examines the role of OT at the interface of stress and social behavior., Rationale/statement of the problem Childhood maltreatment negatively impacts brain development, often producing transgenerational continuity of abusive parenting and increased risk for a range of psychiatric disorders. The biological basis for these far-reaching effects is not currently understood, but evidence suggests traumatic events could affect behavioral trajectories through changes in gene expression that are mediated by DNA methylation. Methods To explore this, we exposed male and female infant rats to nurturing or adverse caregiving environments. We measured changes in DNA methylation and gene expression in developing and adult animals. Candidate genes were selected according to their role in brain plasticity, responsiveness to stress, and association with several psychiatric disorders. Results Exposure to adverse caregiving environments induced long-lasting changes in cortical DNA methylation and expression of the brain-derived neurotrophic factor (BDNF) gene. In addition, females exposed to adverse caregiving environments later mistreated their own offspring, and their offspring likewise displayed altered DNA methylation. We are currently investigating the impact of nurturing vs. adverse caregiving environments on epigenetic gene regulation within a larger behaviorally relevant brain network (the medial prefrontal cortex, central/basolateral amygdala, dorsal vs. ventral hippocampus). Preliminary biochemistry data indicate caregiving experiences trigger epigenetic changes that differ between brain regions, sexes, and gene locus. Conclusions These findings demonstrate the remarkable ability of early-life caregiving environments to produce distinct epigenetic modifications across behaviorally relevant brain regions. Our work as well as that of others suggests that DNA methylation serves as a biological pathway linking early-life adversity to long-term (and perhaps multigenerational) changes in neurobiology and behavior., Background Childhood maltreatment is linked to multiple metabolic and immunological abnormalities. Experimental research in animal models showed that stressful experiences in early life may also be associated with impaired leptin response to physiological stimuli, such as adiposity and inflammation. Therefore, we tested if maltreated children showed leptin deficiency. Methods We assessed leptin and C-reactive protein in dried blood spots and anthropometric measures from 170 twelve-year-old participants of the Environmental Risk (E-Risk) Study. Childhood maltreatment was prospectively assessed through repeated interviews with mothers in the first decade of study participants’ life. Results Maltreated children showed a trend towards lower leptin levels than non-maltreated children. Furthermore, maltreated Children showed reduced leptin response to increasing inflammation and adiposity levels. These findings could not be explained by key potential confounders or pre-existing abnormalities in energy homeostasis. Conclusions Childhood maltreatment is associated with leptin deficiency, which could contribute to previously reported metabolic and immune abnormalities. Exposure to childhood trauma among pregnant women is associated with increased placental CRH production over gestation., Rationale Exposure to traumatic events, particularly during sensitive periods in childhood, is known to have persisting effects on health and disease risk in adult life. A few studies that have examined the course and outcome of later pregnancies in women with early trauma history bring up the intriguing possibility of transgenerational transmission of the effect of maternal childhood trauma on her developing fetus. However, the mechanism(s) underlying this effect have yet to be clarified. In humans and other higher primates, a stress-related system that is particularly relevant for key gestational processes, fetal development, and birth outcomes is placental corticotropin-releasing hormone (pCRH). In this study, we address the hypothesis that history of early life trauma is associated with variation in the level and trajectory of pCRH production over the course of human gestation. Methods A study population of sociodemographically and ethnically diverse women with singleton pregnancies (N=333) provided information about childhood abuse and neglect (Childhood Trauma Questionnaire, or CTQ). Placental CRH levels were assessed prospectively at 1–5 time points over gestation (T1: mean=15.0 weeks, SD=.72 until T5: mean=36.5 weeks, SD=.78). Because of the expected exponential increase of pCRH production over gestation, pCRH values were log-transformed and Generalized Estimating Equation modeling was employed. Results One hundred thirty-seven women (41.1%) reported having experienced at least one type of trauma during childhood, and 75 (22.5%) reported exposure to multiple traumas. A higher childhood trauma score was significantly associated with higher pCRH levels over the entire period of gestation (Wald χ 2(1)=4.68, p =.030, β=.005). With the exception of physical and sexual abuse, this relationship was observed for all trauma subscales. The effect was dose dependent, with a higher number of different types of traumas being related to higher concentrations of pCRH. Conclusion To the best of our knowledge, this is the first report linking exposure to traumatic events in childhood with subsequent placental physiology, thus identifying a possible mechanism of transgenerational transmission. Given the importance of placental CRH in primate pregnancy, this finding also may have appreciable clinical significance., Background Early life stress restructures the nervous system. In rodents, the level of maternal care causes lifelong differences in central glucocorticoid (GC) sensitivity and memory. Furthermore, human adults with a history of child abuse have decreased hippocampal GC receptor gene expression and lower cortisol responses to stress. As GCs modulate memory, hypothalamic–pituitary–adrenal (HPA) axis functions altered by atypical care may influence memory. Methods Participants were women (N=55) reporting no-to-minimal abuse (no maltreatment group) on the Child Trauma Questionnaire and those reporting clinically significant sexual or physical abuse (abuse group). Participants completed the Beck Depression Inventory (BDI), as depression is more prevalent in child abuse survivors and is known to impact cortisol levels. Participants then completed the Emotional Picture Memory Task. During encoding, participants viewed pictures composed of negative or neutral emotionally valenced objects and backgrounds. In a surprise retrieval test, participants indicated if objects and backgrounds presented separately were the same, similar, or new to those viewed earlier. Saliva samples were collected to measure basal (unstressed) cortisol levels. Analyses focused on “gist” memory, and the percentage of responses when an object viewed previously was classified as similar or the same. Higher cortisol has been tied to better gist memory. Results Abuse history moderated cortisol's effect on gist memory, β=−0.557, SE=0.212, p, Rationale/statement of the problem Retrospective studies show that childhood adversity is associated with systemic inflammation in adulthood. Few prospective studies have examined whether childhood adversity influences inflammation in an observable manner during childhood or adolescence and whether these effects are sustained over time. Methods Using longitudinal data from the Avon Longitudinal Study of Parents and Children, we examined associations between acute adverse events at seven time points prior to age 8 and inflammation at ages 10 and 15. Inflammatory markers at age 10 included interleukin-6 (IL-6; N=4,655) and C-reactive protein (CRP; N=4,647), and CRP was measured again at age 15 (N=3,286). We further evaluated whether body mass index (BMI), depression, or cigarette smoking mediated associations between adverse events and inflammation. Results Adverse events in middle childhood (occurring between ages 6 and 8), as well as cumulative adversity between the ages of 1.5 and 8 years, were associated with higher levels of IL-6 and CRP at age 10. Adverse events occurring in early childhood (age 1.5) or middle childhood (age 8), and cumulative adversity between the ages of 1.5 through 8 years predicted increased levels of CRP at age 15, and these associations persisted after adjustment for CRP at age 10. Some, but not all, of these associations were mediated by BMI. Conclusions This study documents that exposure to adverse events prior to age 8 is associated with elevated inflammation at age 10 and in mid-adolescence. These findings provide prospective evidence for a biological mechanism by which early experiences may shape long-term health., Rationale/statement of the problem In posttraumatic stress disorder (PTSD), enhanced negative feedback of the hypothalamic–pituitary–adrenal axis is a prominent finding, which has often been interpreted in the context of enhanced glucocorticoid receptor sensitivity. Neuropsychological alterations are also an important feature in PTSD. Problems particularly with learning and memory have been found, including deficits in verbal declarative memory as well as autobiographical memory. In healthy humans, most studies suggest impairing effects of glucocorticoids on memory retrieval. Up to now, studies that investigate the effects of cortisol administration on memory in patients with PTSD are rare and yielded inconclusive results. Methods In a placebo controlled cross-over study, we compared the effect of exogenous cortisol on memory retrieval in patients with PTSD (N=44) with the effects in healthy controls (N=65). Results Opposing effects of cortisol on memory were observed when comparing patients with controls. In controls, cortisol had impairing effects on memory retrieval, whereas in patients with PTSD cortisol had enhancing effects on memory retrieval. Conclusion The present results suggest beneficial effects of acute cortisol elevations on hippocampal mediated memory processes in PTSD. Possible neurobiological mechanisms underlying these findings are discussed., Rationale Accumulating evidence links posttraumatic stress disorder (PTSD) with elevated inflammatory activity. However, the clinical significance of this association is unclear. Although inflammation could increase the risk of autoimmune disease, little is known about whether patients with PTSD are at increased risk of developing autoimmune disorders. Methods We conducted a retrospective cohort study of 673,277 Iraq and Afghanistan veterans younger than 55 years, who received VA healthcare from October 1, 2005, to March 31, 2012, with at least 1 year of follow-up. Department of Veterans Affairs administrative data were used to identify ICD-9 codes for mental health and autoimmune disorders and to obtain sociodemographic, military service, and health service utilization information. Generalized linear models were used to ascertain the association of PTSD with subsequent autoimmune diagnoses after adjusting for age, race, and number of primary care visits. Results The sample was 88% male and 49% white with a mean age of 31.3 years (±8.7). PTSD was diagnosed in 206,623 (31%) veterans, and mental health disorders other than PTSD were diagnosed in an additional 132,242 (20%) veterans. Compared to veterans with no mental health diagnoses, those diagnosed with PTSD had increased risk for subsequent diagnosis with thyroiditis (adjusted relative risk [ARR]=1.74; 95% CI 1.67, 1.82), rheumatoid arthritis (ARR=1.92; 95% CI 1.67, 2.20), inflammatory bowel disease (ARR=1.32; 95% CI, 1.20, 1.46), multiple sclerosis (ARR=2.23; 95% CI, 1.88, 2.64), systemic lupus erythematous (ARR=1.81; 95% CI, 1.48, 2.23), and any of these disorders alone or in combination (ARR=1.50; 95% CI, 1.45, 1.56). Moreover, while there was an increased risk for each of these disorders in veterans with mental health disorders other than PTSD, the risk was consistently higher in those diagnosed with PTSD. Women had significantly higher risk for autoimmune disorders overall, but the pattern of results was similar in men and women. Conclusion Veterans with PTSD appear to be at increased risk for autoimmune disorders compared to those with no or other mental health diagnoses. Future prospective longitudinal cohort studies are needed to establish causality, measure inflammatory markers in conjunction with PTSD, and evaluate whether successful treatment of PTSD reduces risk of autoimmune disorders., Rationale/statement of the problem Neuropeptide Y (NPY) is a peptide with behaviorally relevant effects on the hippocampus and is thought to function as an endogenous anxiolytic. In prior work, we reported that veterans who had recovered from combat-related post-traumatic stress disorder (PTSD) had higher levels than those who were not combat exposed. NPY levels were significantly associated with the extent of symptom improvement, suggesting that plasma NPY levels may represent a biological correlate of resilience to, and/or recovery from, the adverse effects of trauma exposure. Cytosine methylation of the glucocorticoid gene (GR methylation) has been associated with PTSD risk and/or symptom expression. GR methylation is influenced by environmental factors that can result in enduring differences in function, including neuroendocrine regulation. As the NPY gene has glucocorticoid response elements, levels of circulating NPY represent a potential indicator of alterations in GR responsivity. Methods The relationship of NPY to PTSD and GR methylation was examined in two samples. In the first sample, veterans who developed PTSD following combat exposure were compared to those who did not develop PTSD. In a second sample, veterans with combat-related PTSD were assessed prior to and following a course of prolonged exposure (PE). Results In the cross-sectional study, veterans with PTSD had higher NPY levels than those who never developed PTSD (t (62)=−1.99, p=0.05; 95.8±45.6 pm/l vs. 73.9±41.5 pm/l). NPY associated with number of GR methylated sites in the full sample (r=0.35, n=64, p=0.005), but not with average percent methylation (r=−0.05). When the associations were examined separately by PTSD group status, results showed a positive association between NPY and number of methylated sites (r=0.36) as well as percent methylation (r=0.38) in veterans with PTSD. However, NPY was only associated with the number of methylated sites (r=0.35) in the subjects who did not develop PTSD following combat exposure. In the treatment study, plasma NPY levels increased among veterans who responded to treatment (who no longer met diagnostic criteria for PTSD following PE), compared to treatment non-responders, as indicated by a significant group æ time interaction (F1,14=5.48, p=0.035). While plasma NPY was comparable in the two groups at pretreatment (responders: 71.4±20.3 pm/l, non-responders: 71.0±16.0 pm/l), responders had higher plasma NPY (84.0±24.2 pm/l) relative to non-responders (61.0±15.4 pm/l). Both pretreatment number of GR methylated sites (r=0.53, n=16, p=0.04) and average percent GR methylation (r=0.75, n=15, p=0.001) were associated with higher plasma NPY at post-treatment. Conclusion To the extent that improvement from symptomatic PTSD may involve a mobilization of endogenous mechanisms to reduce hyperarousal and other post-trauma sequellae, the results of these studies are consistent in suggesting a role for NPY. NPY was elevated in a sample of combat veterans with PTSD, and increased in association with PTSD improvement in response to trauma-focused treatment. GR methylation was associated with combat-related PTSD in a cross-sectional study, and with treatment associated improvement in PTSD. These findings suggest that epigenetic modification of the GR gene may be associated with resilience in PTSD., Background Nearly 34–65% of Gulf War veterans (GWV) continue to suffer from chronic multisymptom illness (CMI); novel pharmacological treatment approaches are needed to improve the health of these veterans. This study aims to determine whether mifepristone, a glucocorticoid receptor antagonist, can reverse the neuroendocrine alterations described in GWV and improve the physical health, mental health, and neurocognitive functioning of GWV with CMI. Methods Sixty-five GWV were enrolled into the study; 36 eligible GWV who met criteria for CMI and did not have any exclusionary medical or psychiatric conditions were randomized to receive mifepristone (200 mg/day) or matched placebo first in this crossover study. Both treatment phases lasted 6 weeks and were separated by a 4-week wash-out period. The primary clinical outcome measure was the change from treatment baseline to treatment endpoint in the physical health component score (PCS) of the veterans SF-36 health survey. Primary neurocognitive outcome measures included change in spatial working memory and verbal declarative memory as measured by the MATRICS Consensus Cognitive Battery. Additional outcome measures included change in the mental health components score (MCS) of the SF-36 and self-reported symptoms of fatigue, depression, and PTSD. Cortisol and ACTH levels and a measure of glucocorticoid sensitivity (lysozyme IC50-DEX) were also obtained to characterize the neuroendocrine response to mifepristone in GWV with CMI. Results Data collection is complete; results regarding the primary and secondary clinical, neuropsychological, and neuroendocrine outcome measures will be presented. Conclusion If this study shows that mifepristone improves physical health or cognition or reduces constituent symptoms of CMI in GWV, it would suggest that mifepristone may be of therapeutic value in this population., Rationale/statement of the problem Evidence for distinct biological perturbations in posttraumatic stress disorder (PTSD) with severe child abuse versus no child abuse: consequences for robust biomarkers for PTSD. The identification of biomarkers for PTSD has been difficult, likely due to inter-individual differences in genetic risk factors and environmental exposures. The aim of the current study was to interrogate the influences of the environment on gene expression profiles by characterizing biological differences in PTSD after severe child abuse versus PTSD after adult trauma. Methods A total of 396 trauma-exposed individuals were included in this study. The PTSD symptomatic scale (PSS), clinician-administered PTSD scales (CAPS), childhood trauma questionnaire, and trauma events inventory were used to assess current clinical PTSD and childhood and adult trauma severity. Whole blood gene expression and DNA methylation was measured on Illumina Human-HT12v3 and Human Methylation 450k arrays. Analysis was performed by using R software. Results Of 741 transcripts significantly associated with current PTSD severity, only 2% was associated with PTSD in both, individuals exposed to child abuse and adult trauma (N=32) and individuals exposed to adult trauma only (N=29), after accounting for adult trauma severity. Expression differences were also reflected in DNA methylation differences between the groups. Functional annotations revealed distinct biological pathways enriched among the expression profiles associated with PTSD in these two groups. Conclusion These data suggest that PTSD occurring after severe child abuse is biologically distinct from PTSD after adult trauma, therefore, accounting for different environmental variables is crucial for identification of biomarkers for PTSD., Statement of the Problem Pain and posttraumatic stress disorder (PTSD) are highly comorbid conditions. Patients with chronic pain have higher rates of PTSD. Likewise, patients with PTSD are often diagnosed with numerous chronic pain conditions. Despite the high pain-PTSD comorbidity, the pathophysiologic mechanisms underlying this phenomenon are incompletely understood and only recently researchers have started to investigate pain-PTSD overlap using experimental pain models. The aim of the present study was to examine the activation of the pain-processing pathway in a cohort of combat PTSD compared to combat controls in response to a prolonged painful stimulus. Methods Novel data from the experimental pain model using intramuscular capsaicin comparing a group of 10 Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans with combat-related PTSD and 11 matched OEF/OIF veterans without PTSD will be presented. Intramuscular capsaicin causes a prolonged, deep-aching muscle pain, resembling pain associated with chronic pain states. Following capsaicin injection into the left thigh muscle, subjects underwent functional magnetic resonance imaging scanning while whole brain perfusion was measured with arterial spin labeling (ASL). At every 10 min, samples of cerebrospinal fluid (CSF) were drawn and subjective pain ratings were measured throughout the scanning window (30 min). Following scanning, CSF draws and pain ratings continued and evidence for central sensitization was assessed by temporal summation of repeated pressure pain stimuli. Results Our results show evidence for an acute form of central sensitization in the PTSD group in comparison to matched combat controls. The maximum pain response and initial pain decrease were not different between the two groups, yet significantly higher pain ratings were observed in the PTSD group 15 min postinjection of capsaicin. ASL showed significant group by time interactions within pain-processing network, whereby PTSD group maintained high levels of brain perfusion in the ventral medial frontal gyurs and other interoceptive and evaluative brain circuits throughout the second half of the scan, similar to subjective pain ratings. Furthermore, significantly higher temporal summation of pain was also noted in the PTSD compared to the control group. Conclusion We found increased sensitivity to prolonged, deep experimental pain in combat-related PTSD compared to traumatized subjects who never developed PTSD following combat. We posit that this increased pain response on behavioral, spinal, and supraspinal levels is related to a form of acute central sensitization in these individuals in response to a prolonged pain stimulus. Initial neuroimaging findings point to differential activation of frontal systems as potentially underlying pain-PTSD pathways and perhaps provide initial mechanisms for the development of testable models of perturbed pain processing in PTSD., The gradual emergence of symptoms following exposure to traumatic events has presented a major conceptual challenge to psychiatry. The presumption that all people have significant acute symptoms is not supported by careful longitudinal research. One such study of 1,018 accident victims conducted over 2 years will be presented. The mechanism that leads to the progressive escalation of symptoms with the passage of time leading to delayed onset post-traumatic stress disorder (PTSD) involves the process of sensitisation and kindling. The acute stress response represents the neurobiological platform for the different trajectories of symptoms, and data on 49 participants will be presented, demonstrating how the acute hypothalamic–pituitary–adrenal axis reactivity and melatonin levels predict later symptoms. The development of traumatic memories at the time of stress exposure represents a major vulnerability through repeated environmental triggering of the increasing dysregulation of an individual's neurobiology. An increasing body of evidence demonstrates how the increased allostatic load associated with PTSD. This broader perspective has important implications for developing treatments that address the underlying dysregulation of cortical arousal and neurohormonal abnormalities, following exposure to traumatic stress., Background Results will be presented on a prospective longitudinal study of risk and resilience for post-traumatic stress disorder (PTSD) symptoms in 400 police academy recruits, assessed during academy training and followed during the first 7 years of police service. Methods Utilizing Latent Growth Mixture Modeling (LGMM) we have established three symptom trajectories, highly resilient, initially distressed with gradual improvement, and increasing distress. Results We will present findings on the relations of the following predictors ascertained during academy training to the three PTSD symptom trajectories: I.Q., family histories of anxiety, depression, alcohol and drug abuse, neuroticism, personal histories of childhood or adolescent traumatic exposure, levels of awakening cortisol, fear-potentiated acoustic startle, MHPG and cortisol responses to a critical incident video challenge, sleep quality as measured by actigraphy, and candidate polymorphisms including serotonin transporter (SLC6A4), adrenergic pathway genes, ADRB1, ADRB2, ADRA2C, brain derived neurotrophic factor gene (BDNF), genes for several critical components of the hypothalamic–pituitary–adrenal (HPA) axis such as the glucocorticoid receptor (NR3C1), CRH receptor 1 (CRHR1), and FK506 binding protein 5 (FKBP5) and Catechol-O-methyltransferase (COMT). Conclusion Mulivariate models of risk and resilience will be presented utilizing a multinomial logistic regression nested in the unconditional LGMM., Rationale PTSD is associated with changes in the glucocorticoid receptor (GR) pathway. We hypothesized that altered functioning of the GR pathway is already present before development of PTSD and thus represents a biological vulnerability factor for the development of PTSD. Therefore, we investigated the predictive value of several GR pathway components for the development of high levels of PTSD symptoms. Methods We included a cohort of 1,032 Dutch soldiers prior to deployment to Afghanistan. GR pathway components were assessed in blood collected prior to deployment. PTSD symptoms were assessed 6 months after return. Results A high GR number, high GILZ mRNA expression, and low FKBP5 mRNA expression in leukocytes prior to deployment were independently associated with development of high levels of PTSD symptoms. In addition, sensitivity of T-cells for regulation by the synthetic glucocorticoid dexamethasone was associated with development of high levels of PTSD symptoms. However, the direction of the association between dexamethasone-sensitivity and PTSD depended on the presence of co-morbid depressive symptoms. Conclusions Altered functioning of the GR pathway in leukocytes is a vulnerability factor for development of high levels of PTSD symptoms. The identification of such biological vulnerability factors for PTSD could facilitate the selection of individuals for preventive treatment within groups at risk for trauma-exposure., Rationale/statement of the problem There is an urgent need to develop biological and behavioral predictors of PTSD risk/resilience in individuals with high trauma exposure, such as active military duty. First, we will briefly review psychophysiological risk factors for PTSD. Second, we will describe preliminary data from a prospective study of active duty Marines examining psychophysiological responses before and after deployment to Iraq or Afghanistan. Third, we will discuss our cross-species work in animal models of PTSD risk/resilience to inform these study findings. Methods This study was conducted as part of a 4 h battery (clinical, psychosocial, laboratory, and psychophysiological assessments) conducted both before, and 3 and 6 months after deployment (Marine Resiliency Study) in >2,500 Marines. Here, we examined (1) effect of deployment overall on physiological reactivity measures on baseline startle, pre-pulse inhibition, and affective modulation of startle and (2) comparison of pre-deployment startle reactivity across subjects matched for combat exposure with and without PTSD symptoms, 3 months post-deployment. Results We observed small but significant increases in baseline startle and pre-pulse inhibition after deployment. Startle potentiation to aversive images was also significantly increased after deployment. Importantly, baseline startle magnitude before deployment was significantly greater in subjects that went on to develop PTSD symptoms after deployment compared to their combat-matched controls. Conclusions These results support previous reports suggesting that startle reactivity may probe trait biological processes that confer risk for PTSD symptoms. To complement these findings, we (1) are conducting a similar prospective study to determine if fear conditioning and extinction performance predicts deployment-related stress disorders and (2) have developed a homologous rodent model to aid identification of potential epigenetic mechanisms underlying psychophysiological and fear-processing risk factors., While posttraumatic stress disorder (PTSD) and traumatization have frequently been associated with altered activity of the hypothalamic-pituitary-adrenal axis, specific results on changes in cortisol secretion have been relatively inconsistent. Amongst other things, this may be because of (i) limitations of previous methods for the assessment of long-term cortisol secretion as well as (ii) differences in the composition of the control group in which traumatized and non-traumatized individuals are often not distinguished. The current study aimed to address these problems by using assessments of glucocorticoids in hair as a measure of cumulative hormone secretion over prolonged periods of time and by carefully distinguishing between traumatized and non-traumatized controls. Data were obtained from 28 PTSD patients, 27 traumatized healthy controls, and 32 non-traumatized controls. Concentrations of cortisol (F) and cortisone (E) in proximal 3 cm hair segments were determined via LC-MS/MS. In addition, the severity of PTSD symptoms, the number of different lifetime-traumatic events, chronic stress, and depressiveness were measured. Results revealed that PTSD patients and traumatized healthy controls exhibited lower hair F and E levels compared to those of non-traumatized controls (p

Aims Disrupted intermediary metabolism may contribute to the adverse pregnancy outcomes in women with very severe obesity. Our aim was to study metabolism in such pregnancies. Methods We recruited a longitudinal cohort of very severely obese (n = 190) and lean (n = 118) glucose-tolerant women for anthropometric and metabolic measurements at early, mid and late gestation and postpartum. In case–control studies of very severely obese and lean women we measured glucose and glycerol turnover during low- and high-dose hyperinsulinaemic–euglycaemic clamps (HEC) at early and late pregnancy and in non-pregnant women (each n = 6–9) and body fat distribution by MRI in late pregnancy (n = 10/group). Results Although greater glucose, insulin, NEFA and insulin resistance (HOMA-IR), and greater weight and % fat mass (FM) was observed in very severely obese vs lean participants, the degree of worsening was attenuated in the very severely obese individuals with advancing gestation, with no difference in triacylglycerol (TG) concentrations between very severely obese and lean women at term. Enhanced glycerol production was observed in early pregnancy only in very severely obese individuals, with similar intrahepatic FM in very severely obese vs lean women by late gestation. Offspring from obese mothers were heavier (p = 0.04). Conclusions/interpretation Pregnancies complicated by obesity demonstrate attenuation in weight gain and insulin resistance compared with pregnancies in lean women. Increased glycerol production is confined to obese women in early pregnancy and obese and lean individuals have similar intrahepatic FM by term. When targeting maternal metabolism to treat adverse pregnancy outcomes, therapeutic intervention may be most effective applied early in pregnancy. Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3708-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Obesity is the most common antenatal comorbidity, affecting one in five of the antenatal population in the UK. It is associated with adverse outcomes for mother and baby in both the short and long term. Increasing data suggest that maternal obesity may programme offspring later life obesity and premature mortality, with high birth weight being a marker for increased risk. The mechanism by which maternal obesity causes excessive neonatal birth weight is incompletely understood but considerable evidence implicates insulin resistance and/or hyperglycaemia. There are currently no effective interventions to mitigate the effects of obesity during pregnancy. In this thesis, we present the findings from a randomised, double blind, placebo controlled trial designed to examine the efficacy of metformin, an insulin-sensitising agent, in obese pregnant women. The aim of the trial was to determine whether giving metformin to obese pregnant women from between 12 and 16 weeks’ gestation until birth, would improve maternal and fetal outcomes. The primary outcome measure was birth weight of the baby, using this as a surrogate marker for the future life risk of the child developing obesity. Nested within this large clinical trial were a series of mechanistic sub-studies. To examine the effect of metformin on maternal insulin resistance at 36 weeks’ gestation, we used the hyperinsulinaemic euglycaemic clamp with concomitant use of stable isotope tracers. This enabled us to characterise in greater detail insulin sensitivity, endogenous glucose production and lipolysis. To determine the effect of metformin on maternal and fetal body composition we used magnetic resonance imaging and spectroscopy. This allowed us to quantify subcutaneous and intra-abdominal adipose tissue deposition and hepatic and skeletal muscle ectopic lipid deposition in the mother; and to measure subcutaneous adipose tissue deposition, hepatic lipid and hepatic volume in the fetus. To determine the effect of metformin on maternal endothelial function, we measured endothelium-dependent flow-mediated dilatation at the beginning and end of pregnancy. Change in diameter of the brachial artery in response to a flow stimulus created by arterial occlusion was measured using ultrasound imaging. We found no significant effect of metformin on birth weight. Mean birth weight was 3463 g (SD 660) in the placebo group and 3462 g (SD 548) in the metformin group (adjusted mean difference in z score –0·029, 95% CI –0·217 to 0·158; p=0·7597). Subjects taking metformin did demonstrate increased insulin sensitivity (M/I difference between means during high dose insulin of 0.02 [95% CI 0.001 to 0.03] milligrams per kilogram fat free mass per minute per pmol/L, p=0.04) but also enhanced endogenous glucose production (difference between means 0.54 [95% CI 0.08 to 1.00] milligrams per kilogram fat free mass per minute, p=0.02), compared with those taking placebo. We did not demonstrate any differences between treatment groups in maternal subcutaneous and intra-abdominal adipose tissue, or ectopic lipid deposition, or in fetal body fat distribution and liver volume. Participants in both treatment groups demonstrated a decline in endothelium-dependent flow-mediated dilatation between early and late pregnancy but there were no differences in the magnitude of that decline between the treatment groups. In conclusion, metformin, administered to obese, non-diabetic pregnant women, does not have any significant effect on birth weight of the baby. Our clamp studies demonstrated that subjects taking metformin were indeed more insulin-sensitive than those taking placebo, but the higher endogenous glucose production in this group suggests a reduced ability to suppress hepatic glucose production in response to insulin. This increased glucose flux may in part explain the lack of effect of metformin on fetal nutrition and growth. We can conclude that metformin, should not be used as an intervention in obese pregnant women to prevent excess birth weight. The global obesity epidemic is one of the greatest public health challenges we face and the cycle of disadvantage continues to be perpetuated to the next generation. The lack of any effective interventions for this high-risk group remains a significant concern and an important area for further research.

Obesity is the most common antenatal comorbidity, affecting one in five of the antenatal population in the UK. It is associated with adverse outcomes for mother and baby in both the short and long term. Increasing data suggest that maternal obesity may programme offspring later life obesity and premature mortality, with high birth weight being a marker for increased risk. The mechanism by which maternal obesity causes excessive neonatal birth weight is incompletely understood but considerable evidence implicates insulin resistance and/or hyperglycaemia. There are currently no effective interventions to mitigate the effects of obesity during pregnancy. In this thesis, we present the findings from a randomised, double blind, placebo controlled trial designed to examine the efficacy of metformin, an insulin-sensitising agent, in obese pregnant women. The aim of the trial was to determine whether giving metformin to obese pregnant women from between 12 and 16 weeks’ gestation until birth, would improve maternal and fetal outcomes. The primary outcome measure was birth weight of the baby, using this as a surrogate marker for the future life risk of the child developing obesity. Nested within this large clinical trial were a series of mechanistic sub-studies. To examine the effect of metformin on maternal insulin resistance at 36 weeks’ gestation, we used the hyperinsulinaemic euglycaemic clamp with concomitant use of stable isotope tracers. This enabled us to characterise in greater detail insulin sensitivity, endogenous glucose production and lipolysis. To determine the effect of metformin on maternal and fetal body composition we used magnetic resonance imaging and spectroscopy. This allowed us to quantify subcutaneous and intra-abdominal adipose tissue deposition and hepatic and skeletal muscle ectopic lipid deposition in the mother; and to measure subcutaneous adipose tissue deposition, hepatic lipid and hepatic volume in the fetus. To determine the effect of metformin on maternal endothelial function, we measured endothelium-dependent flow-mediated dilatation at the beginning and end of pregnancy. Change in diameter of the brachial artery in response to a flow stimulus created by arterial occlusion was measured using ultrasound imaging. We found no significant effect of metformin on birth weight. Mean birth weight was 3463 g (SD 660) in the placebo group and 3462 g (SD 548) in the metformin group (adjusted mean difference in z score –0·029, 95% CI –0·217 to 0·158; p=0·7597). Subjects taking metformin did demonstrate increased insulin sensitivity (M/I difference between means during high dose insulin of 0.02 [95% CI 0.001 to 0.03] milligrams per kilogram fat free mass per minute per pmol/L, p=0.04) but also enhanced endogenous glucose production (difference between means 0.54 [95% CI 0.08 to 1.00] milligrams per kilogram fat free mass per minute, p=0.02), compared with those taking placebo. We did not demonstrate any differences between treatment groups in maternal subcutaneous and intra-abdominal adipose tissue, or ectopic lipid deposition, or in fetal body fat distribution and liver volume. Participants in both treatment groups demonstrated a decline in endothelium-dependent flow-mediated dilatation between early and late pregnancy but there were no differences in the magnitude of that decline between the treatment groups. In conclusion, metformin, administered to obese, non-diabetic pregnant women, does not have any significant effect on birth weight of the baby. Our clamp studies demonstrated that subjects taking metformin were indeed more insulin-sensitive than those taking placebo, but the higher endogenous glucose production in this group suggests a reduced ability to suppress hepatic glucose production in response to insulin. This increased glucose flux may in part explain the lack of effect of metformin on fetal nutrition and growth. We can conclude that metformin, should not be used as an intervention in obese pregnant women to prevent excess birth weight. The global obesity epidemic is one of the greatest public health challenges we face and the cycle of disadvantage continues to be perpetuated to the next generation. The lack of any effective interventions for this high-risk group remains a significant concern and an important area for further research.