PSYCHO- TRAUMATOLOGY

PSYCHO-TRAUMATOLOGY

EUROPEAN JOURNAL OF

Supplement 1, 2012

Effects of Traumatic StressMolecular and Hormonal Mechanism

Abstracts from 42nd Annual Conference New York, September 11–14, 2012

42nd ANNUAL CONFERENCE

ON EFFECTS OF

TRAUMATIC STRESS

MOLECULAR ANDHORMONAL MECHANISMS

Program chair: Tom Hildebrandt

President: Rachel Yehuda

Editor: Miranda Olff

New York

September 11�14, 2012

ISPNE ABSTRACT BOOK

CONTENTS

Symposium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Hot Topics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Poster Presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

SYMPOSIUM

Sonja Entringer, Elissa S. Epel, Jue Lin, Claudia Buss, Elizabeth H. Blackburn, Hyagriv N. Simhan, Pathik D.

Wadhwa. University of California, Irvine, CA, USA

Prenatal programming of newborn and infant telomere length

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 areaof 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 biologysystem. 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.

Keywords: teleomere biology; teleomere length; newborn; health; stress; aging

Citation: European Journal of Psychotraumatology Supplement 1, 2012, 3 - http://dx.doi.org/10.3402/ejpt.v3i0.19477

Idan Shalev1,2, Terrie E. Moffitt1,2,3,4, Avshalom Caspi1,2,3,4. 1Department of Psychology and Neuroscience, Duke

University, Durham, NC, USA; 2Institute for Genome Sciences & Policy, Duke University, Durham, NC, USA;3Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; 4Social, Genetic, and

Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, UK

Childhood trauma and telomere maintenance

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

European Journal of Psychotraumatology 2012. # 2012 Symposium. This is an Open Access article distributed under the terms of the Creative CommonsAttribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/), permitting all non-commercial use, distribution, andreproduction in any medium, provided the original work is properly cited.

Citation: European Journal of Psychotraumatology Supplement 1, 2012, 3: 19555 - http://dx.doi.org/10.3402/ejpt.v3i0.19555

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http://dx.doi.org/10.3402/ejpt.v3i0.19477

http://www.eurojnlofpsychotraumatol.net/index.php/ejpt/article/view/19555


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 thechildren 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 hadnot been exposed to domestic violence, but this change was not statistically significant (b��0.059, SE�0.045,

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

(b��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

(b��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 erosionfrom baseline to follow-up measurement compared with children who had one or no kinds of violence exposures

(b��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 assess-ments of multiple violence exposures during childhood and repeated measurements of TL during this same

developmental period.

Keywords: early life trauma; teleomere length; teleomere erosion; violence


Owen M. Wolkowitz1, Synthia H. Mellon1, Elissa S. Epel1, Victor I. Reus1, Firdaus S. Dhabhar2, Yali Su3, Jue Lin1,

Elizabeth H. Blackburn1. 1University of California, San Francisco, San Francisco, CA; 2Stanford University,

Stanford, CA; 3Kronos Science Laboratories, Phoenix, AZ

From sadness to senescence: cellular effects of psychiatric syndromes

Rationale/ statement of the problem: Major depressive disorder (MDD) and other serious mental illnesses areassociated 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.

2(page number not for citation purpose)


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 ofchildhood 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 antidepressanteffects.

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.

Keywords: teleomere length; MDD; inflammation; oxidation; aging


Eli Puterman. UCSF Department of Psychiatry, San Francisco, CA, USA

Stress and cellular aging: what’s lifestyle got to do with it?

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 bullyingvictimization 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 andprospectively. 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.

Keywords: stress; aging; teleomere length; resiliency


Rebecca M. Reynolds, James O’Reilly, Shareen Forbes, Fiona C. Denison, Jane E. Norman. Tommy’s Centre for

Maternal and Fetal Health, University of Edinburgh, Edinburgh, UK

Anxiety and depression in severely obese pregnancy: associations with gestational weight gain andbirthweight

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 (BMI22.6 (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 pB0.05). Findings remainedsignificant after adjustment for social class.Obese women had less GWG than lean women (5.3 (6.0) vs. 10.2 (3.7) kg, pB

0.05). About 23% of obese had more GWG than that prescribed in the Institute of Medicine guidelines. Offspring BWT was

similar in obese and lean (3644 (515) vs. 3557 (505), p�ns).

In lean, increased BWT was associated with higher BMI (r�0.68, p�0.002) and greater GWG (r�0.57, p�0.005). BWT was

not related to BMI or GWG in obese. Higher HADS anxiety scores were associated with less GWG in lean (r��0.38, p�0.01)

but more GWG in obese (r�0.33, p�0.04). Increased state anxiety was associated with lower BWT in early pregnancy in

both groups (p�0.03) with similar patterns in late pregnancy. BWT was not related to satisfaction with life or HADS scores.



Findings remained significant after adjustment for gender, delivery gestation, maternal smoking, social class, parity and

ethnicity.

Conclusion: Severely obese pregnant women have more symptoms of anxiety and depression and are less satisfied

with life than lean women. Increased anxiety in response to pregnancy is associated with lower BWT in all, but

altered mood has differing associations with GWG in lean and obese. Understanding mood may help interventions

to optimise GWG in severely obese women.

Keywords: anxiety; depression; pregnancy; gestational weight; birthweight; obesity


Javier Labad. Hospital Psiquiatric Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain

Early-life stress, salivary HPA axis measures and cognitive profile in subjects with early psychosis

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 ofduration 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. Salivarysamples 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 valueB0.05 (bilateral) was considered to be significant. To compare those subjects with a poorercognitive performance, for each cognitive domain we compared those subjects on the first quartile (25% of lower

T-scores) with the rest of the sample (75% of greater T-scores).

Results: In relation to cognition, subjects with perinatal stress showed significantly poorer cognitive performance in

the attention/vigilance domain (r��0.378, p�0.015), whereas childhood maltreatment was associated with

significantly lower scores in social cognition (r��0.365, p�0.017). Perinatal stress and childhood maltreatment

were not associated with differences in salivary cortisol levels. Salivary cortisol levels during the neuropsychological

assessment, calculated with the area under the curve with respect to the ground, were associated with poorer visual

learning (r��0.386, p�0.014). A blunted cortisol-awakening response was associated with significantly poorerfunctioning in working memory (p�0.022).

Conclusions: Early-life stress and HPA axis measures are associated with a poorer cognitive functioning in subjects

with early psychosis. However, cognitive domains seem to be affected differently by early-life stress and HPA axis

measures: attention/vigilance by perinatal stress; social cognition by childhood maltreatment; visual and working

memory by cortisol levels.



Keywords: early life stress; HPA-axis; saliva; cognition; early psychosis; cortisol


Claudia Buss1, Sonja Entringer1, Elysia Poggi Davis1,2, Calvin J. Hobel5, James M. Swanson1, Pathik D.

Wadhwa1,2,3,4, Curt A. Sandman2. 1Department of Pediatrics, University of California, Irvine, CA, USA;2Department of Psychiatry & Human Behavior, University of California, Irvine, CA, USA; 3Department of

Obstetrics & Gynecology, University of California, Irvine, CA, USA; 4Department of Epidemiology, University

of California, Irvine, CA, USA; 5Department of Obstetrics & Gynecology, Cedars Sinai Medical Center,

Los Angeles, CA, USA

Maternal pre-pregnancy obesity and child ADHD symptoms, executive function and corticalthickness

Rationale/ statement of the problem: Increasing evidence suggests exposure to adverse conditions in intrauterine lifemay 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�7.390.9 (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 wasacquired 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 (90.002, 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.

Keywords: obesity; pregnancy; ADHD; BMI; executive function; cortical thickness


Pearl Ghaemmaghami1, Sara M. Dainese1, Roberto La Marca1, Roland Zimmermann2, Ulrike Ehlert1. 1ClinicalPsychology and Psychotherapy, University of Zurich, Zurich, Switzerland; 2Department of Obstetrics, University

Hospital Zurich, Zurich, Switzerland

The association between the acute psychobiological stress reactivity in second-trimester pregnantwomen and amniotic fluid cortisol and cortisone

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

11b-hydroxysteroid dehydrogenase Type 2 (11b-HSD2). This enzyme inactivates cortisol (F) to cortisone (E),

thereby protecting the foetus from maternal F overexposure. Studies on pregnant rats show that placental 11b-

HSD2 is up-regulated following acute maternal stress but impaired after chronic stress. Whether a similarmechanism 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 11b-HSD2 activity. Since 11b-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

11b-HSD2 activity as well and examined the association of these parameters with the amniotic fluid markers ofstress.

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 inSalE/(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 11b-HSD2. Further investigation of the influence of chronic stress on the enzyme

activity is essential.

Keywords: Prenatal stress; psychobiological stress reactivity; salivary cortisol; salivary cortisone; cortisol/cortisone

ratio; amniotic fluid


Katri Raikkonen, James O’Reilly, Anu-Katriina Pesonen, Eero Kajantie, Pia Villa, Hannele Laivuori, Esa

Hamalainen, Jonathan R. Seckl, Rebecca M. Reynolds. Institute of Behavioral Sciences, University of Helsinki,

Helsinki, Finland

Lower maternal socioeconomic position increases placental glucocorticoid sensitivity and transfer

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, aswe 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 32.29[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 �808C. 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 expres-

sion. 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.



Keywords: socioeconomic position; morbidity; mortality; gene expression; transgenerational effects


David Spiegel1, Bong-Jim Hahm1,2. 1Department of Psychiatry & Behavioral Sciences, Stanford University School

of Medicine, Standford, CA, USA; 2Department of Psychiatry & Behavioral Sciences, Seoul National University

College of Medicine, Seoul, Korea

Sleep, diurnal cortisol, and survival among women with metastatic breast cancer

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. Thiscontrol�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.

Keywords: sleep; cortisol; survival; cancer; metastatic breast cancer; prognosis


Lisa Talbot1,2, Anne Richards1,2, Sabra S. Inslicht1,2, Aoife O’Donovan1,2, Thomas C. Neylan1,2. 1University ofCalifornia, San Francisco, CA, USA; 2San Francisco VA Medical Center, San Francisco, CA, USA

Sleep and lipids in posttraumatic stress disorder

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 ambulatorypolysomnography 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’sB.05) controlling for body fat percentage as measured

by dual-energy X-ray absorptiometry scan. Lower total sleep time was significantly associated with higher total

cholesterol, VLDL cholesterol, and triglycerides in the total sample (and these relationships were strongest in the

PTSD group). Total sleep time from sleep diary was directly correlated with total adiponectin (r�.26, p�.04) and

high-molecular-weight adiponectin (r�.27, p�.01) in the full sample, and this relationship was strongest in the

control group.Discussion: The results suggest an association of sleep to cardiovascular risk factors in PTSD. Further research is

needed to assess whether effective treatment of sleep in PTSD will favorably affect lipid metabolism.

Keywords: sleep; PTSD; lipids; cardiovascular risk; metabolism


Firdaus S. Dhabhar1,2,3, Booil Jo1, Eric Neri1, Jamie Zeitzer1, Jean M. Tillie1, Nicole M. Bricker1, Bita Nouriani1,

David Spiegel1,2. 1Department of Psychiatry & Behavioral Sciences; 2Stanford Cancer Institute; 3Institute for

Immunity, Transplantation, & Infection, Stanford University School of Medicine, Stanford, CA, USA

Lower peak numbers, blunted diurnal rhythms of immune cell distribution, and sleep disruption inmetastatic breast cancer

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 obtainedevery 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 numbersand 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 immunoprotec-

tion 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.

Keywords: immune cells; diurnal rhythm; metastatic breast cancer; immunoprotection; sleep





David Jessup. University of Bristol, Bristol, UK

Circadian profiles of cytokines and HPA axis activity in patients with rheumatoid arthritis:endocrine changes and clinical improvement following treatment with timed-release tablet ofprednisone

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 ofprednisone 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-1b, 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) (pB0.005).Following TRT prednisone, the peak value of cortisol increased from 14.1 to 19.3 mg/dl, and the trough fell from

2.9 to 2.1 mg/dl (pB0.001). 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.

Keywords: cytokines; cortisol; IL-6; chronic inflammatory disease; patients; arthritis


Ned H. Kalin, Andrew S. Fox, Jonathan A. Oler, Gloria Fawcett, Jeff Rogers. University of Wisconsin School of

Medicine and Public Health, Madison, WI, USA

CRH receptor genetic variation in a developmental primate model relevant to the risk to developanxiety and depression

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 aswell 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 metabolicactivity 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.

Keywords: CRH; primate; anxiety; temperament; SNP; mRNA


Ghanshyam N. Pandey. Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago,

IL, USA

Region-specific alterations in the corticotropin-releasing factor and glucocorticoid receptors in thepostmortem brain of suicide victims

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.

Keywords: corticotropin-releasing factor (CRF); glucocorticoid receptor; suicide; depression; CRF-R1


Alan Schatzberg1, Ned H. Kalin2, Ghanshyam N. Pandey3, Joseph K. Belanoff4. 1Department of Psychiatry &

Behavioral Science, Stanford University School of Medicine, Stanford, CA, USA; 2Department of Psychiatry,

University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 3Department of Psychiatry,

University of Illinois Chicago, IL, USA; 4Corcept Therapeutics, Menlo Park, CA, USA

Genetic variation and HPA axis activity: implications for diagnosis and treatment

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 newavenues 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.

Keywords: corticotropin-releasing hormone; glucocorticoid receptor; anxiety; suicide; GR antagonists


Yoshinobu Ishitobi, Shinya Nakayama, Kana Yamaguchi, Masayuki Kanehisa, Haruka Higuma, Yoshihiro

Maruyama, Taiga Ninomiya, Shizuko Okamoto, Yoshihiro Tanaka, Jusen Tsuru, Hiroaki Hanada, Koichi

Isogawa, Jotaro Akiyoshi. Department of Neuropsychiatry, Oita University Faculty of Medicine, Hasama-Machi,

Yufu-Shi, Oita, Japan

Association of CRHR1 and CRHR2 with major depressive disorder and panic disorder in aJapanese population

Background: Major depressive disorder (MDD) and panic disorder (PD) are common and disabling medicaldisorders 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-Ahaplotype 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.

Keywords: CRHR1; CRHR2; major depressive disorder; panic disorder; Japanese population


Joseph K. Belanoff. Corcept Therapeutics Incorporated, Menlo Park, CA, USA

Development of specific glucocorticoid receptor antagonists

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, thearchetypal 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 sameclinical utility as mifepristone in blocking cortisol while eliminating the unwanted effects of progesterone blockade.




Keywords: mifepristone; Cushing syndrome; psychotic depression; cortisol; progesterone blockade


Carsten T. Wotjak. Neuronal Plasticity, Max Planck Institute of Psychiatry, Munich, Germany

Role of the endocannabinoid system in extinction of fear memories: lessons from animal studies

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 couldbe 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 andconditional 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 endocannabinoidsignaling.

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.

Keywords: endocannabinoid; fear extinction; CB1 receptor; exposure therapy; safety learning


Matthew N. Hill. Hotchkiss Brain Institute, Departments of Cell Biology and Anatomy & Psychiatry, University of

Calgary, Calgary, AB, Canada

Bidirectional regulation of endocannabinoid signaling in the amygdala contributes to activationand adaptation of the stress response

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 contentwithin 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 mg), 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 ofchronic 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.

Keywords: Fatty acid amide hydrolase; endocannabinoid; anadamide; 2-arachidonoylglycerol; CB1 receptor


Benno Roozendaal. Donders Institute for Brain, Cognition and Behaviour and Department of Cognitive

Neuroscience, Radboud University Nijmegen, Nijmegen, The Netherlands

Critical role of the endocannabinoid system in mediating rapid glucocorticoid effects on memoryfor emotionally arousing experiences

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 thispresumably 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 (PB0.05)

whereas lower doses (0.3 or 1.0 mg/kg) were ineffective. The retrieval-impairing dose of corticosterone significantlyincreased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) (pB0.05), but not

anandamide, whereas an intra-hippocampal infusion of the cannabinoid receptor type 1 (CB1) antagonist

AM251 (0.35 ng) prevented the corticosterone-induced memory retrieval impairment. We further found that an

intra-hippocampal infusion of the CB1 receptor agonist WIN55,212-2 (10 ng) impaired memory retrieval of CFC

training (pB0.001), and that this impairment was blocked by co-administration of the b-adrenoceptor antagonist

propranolol (1.25 mg). In contrast, blockade of hippocampal CB1 transmission with AM251 failed to attenuate

memory retrieval impairment induced by concurrent infusions of norepinephrine (1�3 mg).

Conclusion: These findings indicate that glucocorticoid-induced memory retrieval impairment depends onfunctional interactions between the endocannabinoid and noradrenergic systems.

Keywords: Glucocorticoid; endocannabinoid; anadamide; 2-arachidonoylglycerol; CB1 receptor; memory





Gustav Schelling. Department of Anaesthesiology, Ludwig-Maximilians-University, Munich, Germany

Endocannabinoids in stressed humans

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 leucocytecannabinoid (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 thanpatients without traumatic memories and PTSD symptoms. Furthermore, avery 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.

Keywords: PTSD; endocannabinoid; anadamide; 2-arachidonoylglycerol; CB1 receptor; CB2 receptor


Alexander Neumeister, Sean Sobin. Department of Psychiatry, New York University School of Medicine,

New York, NY, USA

Positron emission tomography offers new perspectives for evidence-based treatment development inPTSD

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 antipsychoticmedication 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

(0.7290.12 pmol/ml) relative to healthy control subjects without trauma history (HC 2.7490.85 pmol/ml, t�2.47,

df�17, p�.024) or controls with trauma history (TC 2.6790.36, 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 (VT) 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 VT 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 endocannabinoidsignaling 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.

Keywords: PTSD; endocannabinoids; CB1 receptor; brain imaging; positron emission tomography; novel

treatments


David Diamond1, Tania L. Roth2, Monika Fleshner3, Phillip R. Zoladz4. 1VA Hospital and University of SouthFlorida, Tampa, FL, USA; 2University of Delaware, Newark, DE, USA; 3University of Colorado, Boulder, CO,

USA; 4Ohio Northern University, Ada, OH, USA

Animal model of PTSD based on clinically relevant features of trauma susceptibility andexpression

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 werethen 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 memoryimpairment, 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.

Keywords: PTSD; animal model; trauma susceptibility; gene expression; cognition; hormone levels





Israel Liberzon. Department of Psychiatry, Ann Arbor VA Medical Center, University of Michigan, Ann Arbor,

MI, USA

Contextual processing deficits in PTSD: from animal models to fMRI studies

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 andsocial 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 PTSDpatients 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: hese 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 incontextualization deficits. Together, this set of studies demonstrates the combined power of translational research

into trauma psychopathology.

Keywords: PTSD; context processing; fear responses; fMRI; hippocampus; prefrontal cortex


Roger K. Pitman1, Alain Brunet2, Vadim Bolshakov1, Karine Gamache3, Karim Nader3. 1Department of

Psychiatry, Harvard Medical School, Boston, MA, USA; 2Douglas Mental Health University Institute, McGill

University, Montreal, QC, Canada; 3Department of Psychology, McGill University, Montreal, QC, Canada

Toward reconsolidation blockade as a novel treatment for PTSD

Rationale/ statement of the problem: Animal research has challenged the permanency of memory by suggest-ing 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 followingreconsolidation 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.

Keywords: PTSD; mice; classical conditioning; reconsolidation blockade; systemic drugs


Nikolaos P. Daskalakis1, Joseph Buxbaum1, Janine D. Flory1, Guiqing Cai1, Li Shen1, Linda M. Bierer1, Hagit

Cohen3, Rachel Yehuda1,2. 1Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA;2Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA; 3Anxiety and Stress

Research Unit, Beer-Sheva Mental Health Center, Beer-Sheva, Israel

Brain and blood gene expression pathways associated with susceptibility to PTSD

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 behaviorallyand 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 expres-sion 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 circadianrhythm).

Conclusions: Glucocorticoid-related gene expression is underlying the different response pattern following trauma,

with distinct regional/structural differences between male and female rats.

Keywords: PTSD; gene expression; susceptibility; glucocorticoid regulation; neurobiology; glucocorticoid receptor


Joseph B. Rayman, Eric R. Kandel. Department of Neuroscience, Howard Hughes Medical Institute, Columbia

University College of Physicians & Surgeons, New York, NY, USA

A novel mouse genetic model for post-traumatic stress disorder

Rationale/ statement of the problem: Post-traumatic stress disorder (PTSD) arises from the interaction ofgenetic 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 forTIA-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 abnormalglucocorticoid 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�environmentinteraction 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.

Keywords: genetic model; PTSD; mice; substance use; anxiety


Heather C. Abercrombie1, Michelle M. Wirth2, Allison L. Jahn3, Roxanne M. Hoks1. 1University of Wisconsin

School of Medicine and Public Health, Madison, WI, USA; 2University of Notre Dame, South Bend, IN, USA;3VA Boston Healthcare System, Boston, MA, USA

Affective style and early life experiences moderate cortisol’s effects on emotional learning

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 theeffects 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 ofconfounding 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.

Keywords: emotional memory; learning; cortisol; early life separation; trait negative affect


Sandra Ackermann1, Francina Hartmann1, Angela Heck1, Bjorn Rasch2, Andreas Papassotiropoulos1,3,4, Dominique

J.-F. de Quervain4,5. 1Division of Molecular Neuroscience, University of Basel, Basel, Switzerland; 2Division

of Biopsychology, University of Zurich, Zurich, Switzerland; 3Life Science Training Facility, University of

Basel, Basel, Switzerland; 4Psychiatric University Clinics, University of Basel, Basel, Switzerland; 5Division of

Cognitive Neuroscience, University of Basel, Basel, Switzerland

Stress, genes and emotional memory: implications for anxiety disorders

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 recallingemotional 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.

Keywords: BclI; memory; emotion


Vanessa A. van Ast1, Sandra Cornelisse2, Martijn Meeter3, Marian Joels2, Merel Kindt1. 1Department of Clinical

Psychology, University of Amsterdam, Amsterdam, The Netherlands; 2Department of Neuroscience and

Pharmacology, RMI, UMC Utrecht, Utrecht, The Netherlands; 3Department of Cognitive Psychology, VU

University, Amsterdam, The Netherlands

Time-dependent effects of cortisol on the contextual dependency of negative and neutral memories

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 memorycontextualization 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 imagine30 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 contextualiza-

tion observed in PTSD, whereas genomic effects of cortisol may open avenues for cortisol as a protective agent against

(traumatic) fear memory generalization.

Keywords: cortisol; PTSD; memory; cognitive testing


Sarah N. Garfinkel1,2,3, S. Shaun Ho1, Xin Wang1,4, James L. Abelson1, Stephen F. Taylor1, Richard Gonzalez5,

Edward E. Smith6, Israel Liberzon1. 1Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA;2Brighton and Sussex Medical School, Brighton, UK; 3Sackler Centre for Consciousness Science, University

of Sussex, Brighton, UK; 4Department of Psychiatry, University of Toledo, Toledo, OH, USA; 5Department of

Psychiatry, University of Michigan, Ann Arbor, MI, USA; 6Department of Psychology, Columbia University,

New York, NY, USA

Cortisol facilitates memory by enhancing hippocampal activation and functional connectivity

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.

Keywords: stress; genes; glucocorticoids; anxiety disorders


Marie-France Marin, Sonia J. Lupien. Centre for Studies on Human Stress, Fernand-Seguin Research Center,

Louis-H. Lafontaine Hospital, Faculty of Medicine, University of Montreal, Montreal, QC, Canada

Modulation of emotional memories upon reactivation: the role of stress hormones

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 thatmemory 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 negativesegments. 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.

Keywords: glucocorticoids; TSST; emotional memories


Ulrike Rimmele1,2, Luciana Besedovsky2, Ines Wilhelm3, Tanja Lange3, Jan Born2. 1Psychology Department,

New York University, New York, NY, USA; 2Institute of Medical Psychology and Behavioral Neurobiology,

University of Tuebingen, Tuebingen, Germany; 3Department of Neuroendocrinology, University of Luebeck,

Luebeck, Germany

Role of cortisol, sleep, and glucocorticoid receptors in memory consolidation and retrieval

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 consoli-

dation, depending on the brain state. Study II and III indicate opposing roles of MRs and GRs in memory retrieval.

Keywords: cortisol; sleep; glucocorticoid receptors; memory consolidation; retrieval


E. Ronald de Kloet1, Nikolaos P. Daskalakis1,2. 1Division of Medical Pharmacology, Leiden/Amsterdam Center for

Drug Research & Leiden University Medical Center, Leiden, The Netherlands; 2Department of Psychiatry,

Traumatic Stress Studies Division, Mount Sinai School of Medicine, New York, NY, USA




Early life stress concept: introduction

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 influencesand 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.

Keywords: early life stress; behavioral adaptation; resilience; cognitive disorder; maternal care; signaling pathways


Esther Nederhof, Interdisciplinary Center for Pathology of Emotion, University Center for Psychiatry, University

Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Mismatch or cumulative stress: two causal mechanisms of psychiatric disease

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 adversityand 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.

Keywords: cumulative stress; mismatch hypothesis; early programming; early adversity


Karen J. Parker, Stanford University, School of Medicine, Stanford, CA, USA

Early life stress inoculation in monkeys: a pathway to resilience

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 thattemporarily 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.

Keywords: stress inoculation; monkeys; childhood stress; resilience


Rosemary C. Bagot. Mount Sinai School of Medicine, New York, NY, USA

Natural variations in maternal care determine sensitivity to glucocorticoid regulation ofhippocampal synaptic plasticity and function in adult rats

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 maternalcare. 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 orLow 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 a-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 exhibitbasally 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.

Keywords: maternal care; glucocorticoid regulation synaptic plasticity


Christian H. Vinkers1,2, Willemijn van Gastel1, Jurjen J. Luykx1, Chris Schubart1, Marian Joels3, Rene S. Kahn1,

Marco P.M. Boks1. 1Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical

Center Utrecht, Utrecht, The Netherlands; 2Division of Pharmacology, Utrecht Institute for Pharmaceutical




Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Utrecht, The Netherlands;3Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical

Center Utrecht, Utrecht, The Netherlands

The effect of cumulative stress exposure on depressive symptoms is modified by a mineralocorticoidreceptor haplotype

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 StressorChecklist) 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.

Keywords: HPA axis; mineralocorticoid; depressive; gene environment interaction; cumulative stress exposure


Laura D. Kubzansky, Department of Society, Human Development, and Health, Harvard School of Public Health,

Boston, MA, USA

A heartfelt response: oxytocin effects on response to social stress in men and women

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 onwhether 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 subjects2 (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 ageor 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.

Keywords: oxytocin; social bonding; stress regulation; gender; health


Bekh Bradley. Department of Psychiatry, Atlanta VAMC/Emory University, Decatur, GA, USA

Peripheral oxytocin, social support and psychological functioning in a highly traumatized sample

Background: Oxytocin is associated with both social cognition/perception and affiliation and with stress responseregulation. 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 urbanenvironment. Our data show a significant, positive relationship between plasma oxytocin levels and social support

from family members (pB0.05). However, we also found a significant, positive relationship between plasma

oxytocin and symptoms of depression (p�0.04) and PTSD (p�0.02) and that the relationship of peripheral

oxytocin and was strongest among those adults with a history of childhood maltreatment (pB0.05).

Implications: We found that, in a highly traumatized sample, peripheral oxytocin was positively associated

with both perceived social support and with levels of depression and PTSD. One way of understanding this data

is the idea that oxytocin is associated with salience of social cues. In some circumstances (e.g., relationships with

trusted family members), oxytocin may positively influence social perceptions/behaviors. In other circumstance(e.g., threatening interpersonal contexts), it may be a marker for trauma-related symptoms such a depression

and PTSD. Many of our study participants live in unsafe neighborhoods and have been exposed to repeated

interpersonal trauma. Interpersonal trauma, particularly in childhood, may increase the likelihood social cues

are perceived as threatening. Thus, these data point to the need for complex models in understanding rela-

tionship of trauma response and oxytocin and in efforts to use oxytocin in the treatment of trauma exposed

individuals.

Keywords: oxytocin; social support; stress response; trauma; PTSD; depression


Mark A. Ellenbogen, Christopher Cardoso, Mark Anthony Orlando, Christopher A. Brown. Centre for Research

in Human Development, Department of Psychology, Concordia University, Montreal, QC, Canada




Intranasal oxytocin improves recall of autobiographical memories: a dose-response study

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 intranasaloxytocin (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 [pr2�.23, b��0.824, t(15)��2.426, p�.026], and individuals

with higher depressive symptoms exhibited this effect in greater magnitude [pr2�.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.

Keywords: intranasal oxytocin; dose-response; 24 IU; 48 IU; depression; autobiographical memory


Christopher Cardoso1, Mark A. Ellenbogen1, Mark Anthony Orlando1, Simon L. Bacon2,3,4, Ridha Joober5.1Centre for Research in Human Development, Department of Psychology, Concordia University, Montreal, QC,

Canada; 2Department of Exercise Science, Concordia University, Montreal, QC, Canada; 3Research Center,

Hopital du Sacre-Cœur de Montreal*A University of Montreal affiliated hospital, Montreal, QC, Canada;4Research Center, Montreal Heart Institute*A University of Montreal affiliated hospital, Montreal, QC, Canada;5Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada

Intranasal oxytocin attenuates the cortisol response to physical stress: a dose�response study

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 eachsession.

Results: Salivary cortisol concentrations changed over time, peaking after 60 minutes of exercise [Quadratic:

F(1,16)�7.349, p�0.015, partial h2�0.32]. The 24 IU dose of oxytocin attenuated cortisol levels relative

to placebo [F(1,16)�4.496, p�0.05, partial h2�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 h2�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 cortisolis 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.

Keywords: intranasal oxytocin; cortisol; stress; exercise; 24 IU; 48 IU; dose-response





Jennifer A. Bartz, Department of Psychology, Faculty of Science, McGill University, Montreal, QC, Canada

Oxytocin, attachment and the shift from self to other

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 andthe 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 asses-sed 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 humansand help explain both the beneficial and potentially harmful effects of OT.

Keywords: oxytocin; attachment; anxiety; avoidance; agency; communion


Jason R. Yee, Neural Medicine, Research Triangle Institute International, Boston, MA, USA

The role of oxytocin at the interface of stress and social behavior

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 physiologyand 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 involvedin 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.

Keywords: oxytocin; stress response; social behavior; animal study





Tania L. Roth, Jennifer Blaze. Department of Psychology, University of Delaware, Newark, DE, USA

Epigenetic brain modifications associated with early-life adversity

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.

Keywords: brain development; childhood maltreatment; gene expression; DNA methylation; BDNF


Andrea Danese, Rosamund Dove. Institute of Psychiatry, King’s College London, London, UK

Leptin deficiency in maltreated children

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. Further-

more, 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.

Keywords: childhood maltreatment; childhood trauma; stress; leptin; obesity; inflammation


Nora Moog, Claudia Buss, Sonja Entringer, Curt A. Sandman, Pathik D. Wadhwa. UC Irvine Development,

Health and Disease Research Program, University of California, Irvine, CA, USA; Department of Psychiatry &

Human Behavior, University of California, Irvine, CA, USA




Exposure to childhood trauma among pregnant women is associated with increased placental CRHproduction 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 outcomeof 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 pro-

duction 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 x2(1)�4.68, p�.030,b�.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.

Keywords: childhood trauma; placental CRH; pregnancy; maternal life course history


Allison E. Gaffey, Amy K. Nuttall, Michelle M. Wirth, Kristin Valentino, Jessica D. Payne. Department of

Psychology, University of Notre Dame, Notre Dame, Indiana, IN, USA

Child abuse moderates cortisol s relationship to memory

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 mayinfluence 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, b��0.557, SE�0.212, pB0.01. When

controlling BDI, cortisol negatively correlated with memory in the abuse group and positively correlated with

memory in the no abuse group.



Conclusions: These findings are particularly compelling as the abuse group result contrasts with previous human

memory and rodent research. However, basal vs. stress-induced cortisol may differentially affect memory.

Furthermore, child abuse is likely a more profound early stressor compared to maternal neglect in rodents.

In conclusion, early experience shapes how GCs affect cognitive functioning. This study is an essential step toward

determining physiological and long-term effects of child abuse.

Keywords: glucocorticoids; memory; early life stress; salivary cortisol; HPA axis


Natalie Slopen1,2,3, Laura D. Kubzansky2, Katie A. McLaughlin1,4,5, Karestan C. Koenen6. 1Center on the

Developing Child, Harvard University, Cambridge, MA, USA; 2Harvard School of Public Health, Boston, MA,

USA; 3Harvard Graduate School of Education, Cambridge, MA, USA; 4Division of General Pediatrics, Children’s

Hospital Boston, Boston, MA, USA; 5Harvard Medical School, Boston, MA, USA; 6Mailman School of Public

Health, Columbia University, New York, NY, USA

Childhood adversity and inflammatory processes in youth: a prospective study

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 sustainedover 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 eventsoccurring 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.

Keywords: children; adolescents; youth; inflammation; C-reactive protein; interleukin-6; stressful life events;

prospective cohort


Katja Wingenfeld. Department of Psychiatry, Charite Universitatsmedizin Berlin, Campus Benjamin Franklin,

Berlin, Germany

Hypothalamic-pituitary-adrenal axis and memory in PTSD

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 declarativememory 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.

Keywords: HPA-axis; PTSD; declarative memory; cortisol; autobiographical memory


Aoife O’Donovan1, Beth E. Cohen2, Dan Bertenthal2, Mary Margaretten1, Karen Seal1, Thomas C. Neylan3.1University of California, San Francisco, CA, USA; 2San Francisco Veterans Affairs Medical Center, CA, USA;3Northern California Institute on Research and Education, San Francisco, CA, USA

Association of posttraumatic stress disorder with increased prevalence of autoimmune disorders inIraq and Afghanistan veterans

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 developingautoimmune 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 (98.7). PTSD was diagnosed in206,623 (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 disordersoverall, 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.

Keywords: autoimmune disorders; inflammation; post-traumatic stress disorder; psychiatric disorders; traumatic

stress; veterans


Janine D. Flory1, Linda M. Bierer1, Frank Desarnaud1, Iouri Makotkine1, Ashik Siddique1, Charles Marmar2,

Rachel Yehuda1. 1J. J. Peters Veterans Affairs Medical Center; Mount Sinai School of Medicine, New York, NY,

USA; 2Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA

Evidence for epigenetic alterations in PTSD

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, theadverse 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 prolongedexposure (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; 95.8945.6 pm/l vs. 73.9941.5 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 levelsincreased 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:

71.4920.3 pm/l, non-responders: 71.0916.0 pm/l), responders had higher plasma NPY (84.0924.2 pm/l)

relative to non-responders (61.0915.4 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 endogenousmechanisms 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.

Keywords: Glucocorticoid receptor; neuropeptide Y; PTSD, methlylation; prolonged exposure


Julia A. Golier, Kimberly Caramanica, James Schmeidler, Philip D. Harvey, Rachel Yehuda. J.J. Peters Veterans’Administration Medical Center and Mount Sinai School of Medicine, New York, NY, USA

A randomized, double-blind, placebo-controlled, crossover trial of mifepristone in Gulf Warveterans with chronic multisymptom illness

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 nothave 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.

Keywords: mifepristone; Gulf War veterans; chronic multisymptom illness; therapy


Divya Mehta. Max Planck Institute of Psychiatry, Munich, Germany

Evidence for distinct biological perturbations in PTSD with severe child abuse: implications forPTSD biomarkers

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 inventorywere 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.

Keywords: PTSD; child abuse; trauma; gene expression; methylation


Tobias Moeller-Bertram, Irina Strigo, Alan Simmons, Piyush Patel, Dewleen G. Baker. Department of

Anesthesiology/Psychiatry, University of California, San Diego, CA, USA

Evidence for acute central sensitization to prolonged experimental pain in subjects with 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 and11 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 drawnand 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 evaluativebrain 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.

Keywords: PTSD; pain; capsaicin; sensitization; fMRI


Alexander C. McFarlane. Centre for Traumatic Stress Studies, University of Adelaide, Adelaide, SA, Australia

The longitudinal course of posttraumatic sensitization disorder

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 stressresponse 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.

Keywords: PTSD; longitudinal course; vulnerability; allostatic load; treatment


Charles Marmar. New York University, New York, NY, USA

Longitudinal studies of trauma in police officers

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.

Keywords: stress; resilience; PTSD; cortisol; startle; MHPG; FKBP-5


Mirjam van Zuiden1,2,3, Elbert Geuze3,4, Eric Vermetten3,4, Annemieke Kavelaars2, Cobi Heijnen2. 1Departmentof Psychiatry (Anxiety Disorders), Academic Medical Center, Amsterdam, The Netherlands; 2Laboratory of

Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The

Netherlands; 3Research Centre for Military Mental Health, Dutch Ministry of Defence, Utrecht, The Netherlands;4Department of Psychiatry, Rudolf Magnus Institute, University Medical Center Utrecht, Utrecht, The Netherlands

Altered functioning of the glucocorticoid receptor pathway is a vulnerability factor for developmentof PTSD symptomatology in response to military deployment to Afghanistan

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.

Keywords: PTSD; glucocorticoid receptor; FKBP5; dexamethasone; biomarker; vulnerability; military


Victoria Risbrough, Dewleen G. Baker, Caroline Nievergelt, Brett Litz, William Nash, J. Perez, Mark Geyer.

University of California San Diego, National Center for PTSD, Boston VA, USA

Prospective assessment of psychophysiological risk factors for PTSD

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.

Keywords: PTSD; psychophysiological risk; prospective study; pre-pulse inhibition; startle; fear conditioning


Susann Steudte1, Clemens Kirschbaum1, Wei Gao1, Sabine Schonfeld2, Jurgen Hoyer2, Tobias Stalder1. 1Institute

of Biological Psychology, Technical University of Dresden, Dresden, Germany; 2Institute of Clinical Psychology

and Psychotherapy, Technical University of Dresden, Dresden, Germany

Glucocorticoids in hair as biomarkers of traumatization in healthy individuals and PTSD patients

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 theassessment 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 controlsexhibited lower hair F and E levels compared to those of non-traumatized controls (pB0.05, for both).

Furthermore, negative correlations between hair F levels and symptoms of intrusion (r��0.34, p�0.02) and the

number of different traumatic events (r��0.36, p�0.01) were found in traumatized individuals. The current

results suggest that trauma exposure may be a critical factor influencing long-term endocrine alterations, which can

be observed even in otherwise healthy and non-psychopathological individuals.

Keywords: posttraumatic stress disorder; traumatization; cortisol; cortisone; hair





HOT TOPICS

Claudia Buss1, Jens C. Pruessner2, Helen Mayberg3, Tanja Mletzko3, Charles Nemeroff4, Christine Heim5.1University of California Irvine, Irvine, CA, USA; 2McGill University, Montreal, QC, Canada; 3Emory University,

Atlanta, GA, USA; 4University of Miami, Miami, FL, USA; 5Charite University Medicine, Berlin, Germany

Larger amygdala volumes after childhood trauma associated with depression and cortisol responseto psychosocial stress in adulthood

Background: Childhood trauma is a major risk factor for the development of affective disorders later in life. Wesought to determine whether this risk is linked to neurostructural changes in limbic brain regions after childhood

trauma.

Methods: We recruited 49 medically healthy adult women (28.297.1 years of age) from the Atlanta area to include

women with/without childhood trauma and with/without major depression (MDD). Childhood trauma exposure

was quantified using the Childhood Trauma Questionnaire (CTQ). Lifetime and current diagnoses of MDD and

posttraumatic stress disorder (PTSD) were assessed using the Structured Clinical Interview for DSM-IV (SCID).

Current depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAM-D). Magnetic

resonance images were acquired, preprocessed, and registered into stereotactic space. Volume analyses of the leftand right amygdala were performed using the interactive software package DISPLAY developed at the Brain

Imaging Center of the Montreal Neurological Institute, and a standardized segmentation protocol was applied to

outline the anatomical boundaries of the amygdala. Total plasma cortisol responses to the Trier Social Stress Test

(TSST) were measured.

Results: When stratifying groups by childhood trauma exposure and MDD, women with both childhood

trauma and MDD had largest right amygdala volumes compared to all other groups (interaction effect: F�6.172,

p�0.017). Correlational analyses revealed that higher CTQ scores were associated with larger left (r�0.31,

pB0.05) and right (r�0.31, pB0.05) amygdala volumes. These correlations remained significant when controllingfor age, race, and lifetime diagnoses of MDD and PTSD. Higher CTQ scores were associated with current

depression scores (r�0.30, pB0.05), which in turn were positively associated with the size of the right amygdala

volume (r�0.32, pB0.05). Finally, the size of the left amygdala was associated with increased cortisol response to

the TSST (15 min post TSST: r�0.44, pB0.05, 30 min post TSST: r�0.436, pB0.05). A similar trend was

observed for the right amygdala.

Conclusions: These findings add to the growing understanding of the neurobiological basis that may underlie the

association between early adverse experience, stress vulnerability, and increased risk for affective disorders.

Keywords: early life stress; amygdala; depression


Hui Li1, Ning Jia2, Qian Su1, Zhongliang Zhu3,4, Xiang Liu1, Monesh Kumar Sungkur1, Samjida Majeed Padari1,

Yanyan Zhang1, Li Yang1, Guokui Tang4. 1Division of Neonatology, First Affiliated Hospital of Medical School,

Xi’an Jiaotong University, Xi’an, Shaanxi, China; 2Department of Human Anatomy and Embryology, Medical

School of Xi’an Jiaotong University, Xi’an, Shaanxi, China; 3Department of Pharmacology, Medical Schoolof Xi’an Jiaotong University, Xi’an, Shaanxi, China; 4Life Science College of Northwest University, Xi’an,

Shaanxi, China

Effects of prenatal psychosocial stress on pregnancy outcomes and physical and neurobehavioraldevelopment in infancy with gender-difference

Statement of the problem: Previous animal experiments suggest that prenatal stress affects pregnancy outcomes and

impairs cognitive functions of offspring. Our goal was to investigate how prenatal exposure to stressful life events

influence pregnancy outcome and infant’s physical and neurobehavioral development.

Methods: A clinical trial was performed. One thousand eight hundred and fifty-six pregnant women were willingly

assessed using the Life Events Scale for Pregnant Women (LESPW) before delivery. Those whose score were more

than or equal to 375 on LESPW were assigned to higher levels of psychological stress during pregnancy. One hundredand forty-two cases were selected from 1856 pregnant women controlling for variables such as gestational age,

maternal age, obstetric complications, socioeconomic status, and trait anxiety. The prenatal stress (PNS) group and

European Journal of Psychotraumatology 2012. # 2012 Hot Topics. This is an Open Access article distributed under the terms of the Creative CommonsAttribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/), permitting all non-commercial use, distribution, andreproduction in any medium, provided the original work is properly cited.


38





the control (CON) group were composed of 71 full-term infants each (1:1 pair matched). Infants’ birth

weight (BW) and head circumference (HC) from both groups were assessed at birth and the neonatal neurobehavioral

development was evaluated at 72 hours using the neonatal behavioral neurological assessment (NBNA).Results: Three hundred and twenty-seven cases from 1856 scored more than 375 on LESPW, incidence of stress was

17.62%. The proportion of undesirable pregnancy outcomes from 327 cases were 147 cases (44.95%), with

threatened abortion 38 (11.62%), premature delivery 31 (9.48%), pregnancy complications 73 (22.32%), stillbirth 5

(1.53%), and low birth weight infants 120 (36.7%). The pregnancy outcomes of the non-stressed 1529 cases were

undesirable in 579 cases (37.87%), with threatened abortion 123 (8.04%), premature delivery without cause 208

(13.6%), pregnancy complications 240 (15.70%), stillbirth 8 (0.52%), and low birth weight infants 159 (10.4%). BW,

HC and the score of NBNA of full-term infants in the PNS were lower than those of the CON (PB0.05). The score

of NBNA of boys was significantly lower with no change in BW and HC in the PNS, and BW and HC of the girlswere lower compared to boys in the PNS (PB0.05). There were no significant differences in BW, HC, and NBNA

between the boys and girls in the CON.

Conclusion: Pregnant women with stress were at increased risk of adverse pregnancy outcome, low birth weight

infants in high levels of maternal psychosocial stress were significantly higher than that of premature birth. This

shows us that PNS can induce fetal intrauterine growth retardation, and influence newborn’s physical and

neurobehavioral development, especially in newborn girls.

Keywords: prenatal psychosocial stress; infant; birth weight; head circumference; NBNA


Isabelle Ouellet-Morin, Chloe Wong, Andrea Danese, Carmine M. Pariante, Andrew S. Papadopoulos, JonathanMill, Louise Arseneault. Institute of Psychiatry, King’s College London, London, UK

Increased SERT DNA methylation is associated with bullying victimization and blunted cortisolresponse to stress in childhood: a longitudinal study of discordant MZ twins

Childhood adverse experiences are known to induce persistent changes in the hypothalamic�pituitary�adrenal

(HPA) axis reactivity to stress. However, the mechanisms by which these experiences shape neuroendocrine

response to stress remain unclear.

We tested whether bullying victimization influenced SERT DNA methylation using a discordant monozygotic

(MZ) twin design. A sub-sample of 28 MZ twin pairs discordant for bullying victimization, with data on cortisoland DNA methylation, was identified in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally

representative 1994�1995 cohort of families with twins.

Bullied twins had higher SERT DNA methylation at age 10 compared to their nonbullied MZ co-twins. This group

difference cannot be attributed to the children’s genetic makeup or their shared familial environments because of

the study design. Bullied twins also showed increasing methylation levels between age 5, prior to bullying

victimization, and age 10 whereas no such increase was detected in nonbullied twins across time. Moreover,

children with higher SERT methylation levels had lower cortisol responses to stress.

Our study extends findings drawn from animal models, supports the hypothesis that early-life stress modifies DNAmethylation at a specific CpG site in the SERT promoter and HPA functioning, and suggests that these two

systems may be functionally associated.

Keywords: SERT; DNA methylation; cortisol; HPA axis; bullying; childhood victimization


Nathalie Michels, Els Clays, Marc de Buyzere, Inge Huybrechts, Barbara Vanaelst, Stefaan de Henauw, Isabelle

Sioen. Department of Public Health, Ghent University, Ghent, Belgium

Stress biomarkers in children: heart rate variability versus salivary cortisol

Rationale/ statement of the problem: Stress is a complex phenomenon coordinated by several neural systems and

has consequently been measured by several biomarkers. Salivary cortisol is the classical used stress biomarker

representing the hypothalamic-pituitary-adrenal system. Heart rate variability (HRV), defined as the distance

variability between consecutive R peaks, is increasingly used as marker of the autonomic nervous system and as a





result also as a stress marker (defined as sympathetic over parasympathetic dominance). Associations between

children’s salivary cortisol and HRV will be examined.

Methods: In 190 children (5�10 year) of the Belgian ChiBS study salivary cortisol and HRV were sampled. Salivarycortisol samples were collected when waking up, 30 minutes and 60 minutes after wake-up and in the evening on

two weekdays. HRV measurements in supine position were undertaken with Polar chest belts during 5 minutes.

Apart from HRV time-domain analysis, also frequency-domain analysis was performed in the low-frequency (LF)

and high-frequency (HF) bands. Multilevel growth curve modelling with adjustments for age, sex, physical activity

and wake-up time was used to analyse the HRV associations with overall cortisol, cortisol awakening response

(CAR) and cortisol diurnal decline.

Results: Higher overall cortisol levels were negatively associated with mean RR, root mean square of successive

differences (RMSSD), percentage of RR intervals differing more than 5 0ms (pNN50) and HF. A steeper diurnaldecline was positively associated with normalised LF and the LF/HF ratio and negatively with HF. The CAR was

positively associated with normalised LF and the LF/HF ratio and negatively with normalised HF.

Conclusion: Higher salivary cortisol levels were associated with lower parasympathetic activity. A larger CAR and

steeper diurnal decline were associated with a sympathetic over parasympathetic dominance. Consequently, the two

main neural stress systems (represented by cortisol and HRV) show good agreement in reflecting children’s stress

status, although not all parameters were significantly related. Measuring both pathways stays recommended as the

pathways might be stimulated differently depending on the stressor.

Keywords: heart rate variability; cortisol; children; stress


Margaret H. Bublitz, Laura R. Stroud. Department of Psychiatry and Human Behavior, Brown Medical School

and The Miriam Hospital, Providence, RI, USA

Maternal history of child sexual abuse moderates the association between daily stress and diurnalcortisol in pregnancy

Introduction: Maternal hypothalamic�pituitary�adrenal (HPA)-axis functioning is a key mechanism linking stress

in pregnancy to adverse neonatal outcomes. Past research has failed to consider whether a woman’s history of child

maltreatment impacts her stress biology in pregnancy. In this study we assessed whether association between daily

stress and diurnal cortisol was moderated by maternal history of child sexual abuse (CSA).Methods: Participants were 30 pregnant women (Mage�26, SD�5) who completed a larger study of effects of

maternal mood on fetal and infant development. At baseline, women completed a modified version of the Adverse

Childhood Experiences Scale. Women were categorized into those who had a history of CSA, non-sexual

child abuse (CA), or no child abuse (NA). Women reported the severity of daily stress for 3 days at 20 (SD�2), 28

(SD�1), and 35 (SD�1) weeks gestation by completing a modified version of the Pregnancy Experiences Scale.

Finally, women provided salivary cortisol samples at wake-up,�30 minutes after waking, and bedtime on each day

of diary collection.

Results: Twenty-three percentage of women in this pilot study reported CSA (N�7), 47% (N�14) reportedCA, and 30% (N�9) reported NA. Hierarchical linear modeling (HLM) analyses were computed to assess whether

prior day or same day stress predicted daily cortisol values (adjusting for gestational age at sampling and time of

awakening). We found that maternal history of abuse moderated the association between prior daily stress and

cortisol at awakening (p�0.07), and 30 minutes post awakening (p�0.006), but not bedtime (p�0.18). As stress

the previous day increased, morning cortisol values in women with CSA history decreased, cortisol in NA women

increased, and cortisol in CA women showed no change. Maternal history of child abuse did not moderate the

association between daily stress and maternal cortisol on the same day (p’s�0.10).

Conclusions: Results show a dynamic association between daily stressful experiences and diurnal cortisol inpregnancy and suggest that patterns of maternal cortisol following stress differ according to maternal abuse history.

These findings have important implications for understanding links between maternal CSA history and adverse

neonatal outcomes.

Keywords: child sexual abuse; pregnancy; daily stress; cortisol






Adam Walker, Robin Smith, Bret Beenders, Keith Kelley, Robert Dantzer. Symptom Research, MDACC, Houston,

TX, USA; Animal Science, UIUC, Urbana, IL, USA

NMDA receptor activation mediates lipopolysaccharide-induced depressive-like behavior

Background: Inflammation associated with cancer and induced by cancer therapy is associated with clinical signs of

sickness behavior that can culminate in the development of symptoms of depression. Intraperitoneal administra-

tion of lipopolysaccharide to mice induces depressive-like behavior. Lipopolysaccharide-induced depressive-like

behavior is mediated by activation of indoleamine 2,3-dioxygenase (IDO) that degrades tryptophan along the

kynurenine pathway and produces kynurenine metabolites such as quinolinic acid that acts as a N-Methyl-D-

aspartate (NMDA) receptor agonist. The present study was carried out to determine whether the NMDA receptorantagonist ketamine alleviates lipopolysaccharide-induced depressive-like behavior.

Methods: Mice were injected intraperitoneally with ketamine or saline immediately before administration of the

cytokine inducer lipopolysaccharide or saline via the same route. Their behavior and bodyweight were monitored

up to 28 h post-injection. Depressive-like behavior was measured by increased immobility in the forced swim test

and decreased sucrose preference for a sucrose solution. Brain, liver and plasma were collected 6 h and 28 h after

treatment to measure biomarkers of inflammation.

Results: Lipopolysaccharide induced the expression of cytokine, IDO, tryptophan 2,3-dioxygenase (TDO) and heme

oxygenase-1 at the periphery and in the brain. This effect was not altered by ketamine pretreatment. Ketamineblocked the development of depressive-like behavior but had no effect on sickness behavior measured by body

weight loss, reduced food intake and decreased motor activity.

Conclusions: These data indicate that ketamine is able to abrogate inflammation-induced depressive-like behavior

by antagonising the activating effects of kynurenine metabolites on NMDA receptors.

Keywords: lipopolysaccharide; ketamine; mouse; depression; indoleamine 2,3 dioxygenase; kynurenine


Andrea Fuchsl, Inga D. Neumann, Stefan O. Reber. Department of Behavioral and Molecular Neurobiology,

University of Regensburg, Regensburg, Germany

Increased plasma ACTH response to a prolonged heterotypic stressor following chronicsubordinate colony housing is likely mediated by a reduction in negative feedback inhibition

Background: Chronic subordinate colony housing (CSC, 19d) is an established mouse model for chronic

psychosocial stress and causes glucocorticoid (GC) resistance in splenocytes and IL-4 producing peripheral

lymph node cells. Here we tested the hypothesis that CSC further causes development of GC resistance at the level

of the pituitary gland, which is, in turn, causally involved in the increased plasma ACTH response to prolongedheterotypic stressor exposure (4h of restraint/ shaking) following CSC exposure.

Methods: Male mice were either exposed to the CSC model or single-housed for control (SHC), in order to

investigate changes at the level of the pituitary gland, measured by molecular (Western Blotting, qPCR) and

in vitro techniques.

Results: To exclude that the increased plasma ACTH secretion in response to acute heterotypic stressors is

mediated by an increased responsiveness of the pituitary to hypothalamic corticotrophin releasing hormone (CRH)

and/or arginine vasopressin (AVP) we first employed Western Blotting to reveal possible changes in pituitary CRH

receptor 1 (CRH-R1) and AVP receptor 1b (AVP-R1b) expression. However, CRH-R1 expression was significantlylower, while AVP-R1b expression was unaffected in CSC compared with single-housed control (SHC) mice, arguing

against an increased pituitary responsiveness. In order to exclude altered receptor sensitivity we are currently

investigating if the in vitro ACTH release from whole pituitaries in response to CRH, AVP and CRH�AVP are

similar between CSC and SHC mice.

Conclusions: In line with the hypothesis of a reduced negative feedback inhibition, CSC compared with SHC mice

showed a down-regulation of glucocorticoid receptor (GR), mRNA (qPCR) and protein (Western Blotting)

expression in pituitary tissue. Although a comparable corticosterone-mediated in vitro inhibition of CRH-induced

ACTH release from whole pituitaries between SHC and CSC mice argues against a CSC-induced reduction ofnegative feedback inhibition we are currently testing this under in vivo conditions employing the dexamethasone

suppression test.




Keywords: stress; CSC; HPA axis; pituitary; ACTH; corticosterone


Manuela S. Bartlang1, Inga D. Neumann2, David A. Slattery2, Nicole Uschold-Schmidt2, Dominik Kraus2,

Charlotte Helfrich-Forster1, Stefan O. Reber2. 1Department of Neurobiology and Genetics, University of

Wurzburg, Wurzburg, Germany; 2Department of Behavioural and Molecular Neuroendocrinology, University of

Regensburg, Regensburg, Germany

Time matters: pathological effects of repeated psycho social stress during the active, but notinactive, phase of male mice

Recent findings in rats employing repeated restraint stress indicated that the physiological consequences ofstressor exposure are strongly dependent on the time of day of stressor exposure. To investigate whether this is

also true for clinically more relevant chronic/repeated psychosocial stressors and whether repeated stressor

exposure during light- or dark-phase is more detrimental for an organism, we exposed male C57BL/6 mice to

social defeat (SD; 2 h) for 19 consecutive days (except day 7 and 14) either in the light-phase between Zeitgeber-

time (ZT)1 and ZT3 (SDL mice) or in the dark-phase between ZT13 and ZT15 (SDD mice) and compared them

with single-housed control mice in four different experiments. While SDL mice showed a more prolonged increase

in adrenal weight and an attenuated adrenal responsiveness to ACTH in vitro after stressor termination, SDD

mice showed reduced dark-phase home-cage activity on observation days 7, 14 and 20, flattening of the diurnalcorticosterone rhythm, lack of social preference towards an unfamiliar male conspecific and higher in vitro IFN-gsecretion from mesenteric lymph node cells on day 20/21. In addition, the colitis-aggravating effect of stressor

exposure was more pronounced in SDD than SDL mice, indicated by increased body weight loss and

inflammatory shortening of the colon following 8 days of dextran sulphate sodium treatment. In conclusion, the

present findings demonstrate that chronic/intermittent SD effects on behaviour, physiology and immunology

strongly depend on the time of day of stressor exposure. While physiological parameters were more affected by

SD during the light-phase, that is, the inactive phase of mice, behavioural and immunological parameters were

more affected by SD during the dark-phase. Our results imply that repeated daily psychosocial stressor exposurehas a more negative outcome when applied during the dark/active phase. In contrast, the minor physiological

changes seen in SDL mice might represent beneficial adaptations preventing the formation of those maladaptive

consequences.

Grant Support: This study was supported by the Deutsche Forschungsgemeinschaft (DFG FO-207/13-1).

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the

manuscript.

Keywords: psychosocial stress; social defeat; time of day; light-phase; dark-phase; behaviour; physiology;

immunology


Francesca Brambilla1, Mariarosa Serra2, Giulia Perini3, Giovanni Biggio4. 1Department of Psychiatry, Sacco

Hospital, Milano, Italy; 2CNR institute for Neurosciences, Cagliari, Italy; 3Cittadella Universitaria, Monserrato-Cagliari, Italy; 4Department of Neurosciences, Padova University, Padova, Italy

Neuroactive steroid secretion in panic disorder

Centrally secreted neurosteroids and peripherally secreted centrally active neurosteroids increase after stressful

stimuli modulating anxiety in experimental animals and possibly in humans. Their altered secretions have been

reported in panic disorders (PDs) and suggested to be a possible cause or an effect of the panic symptomatology.

We have studied in two successive experiments related to PDs the secretions of neuroactive steroids. In experiment

1, we measured the neuroactive steroids in 25 women and 13 men with PD during an interictal phase to see whether

their secretion is related to panic symptomatology and whether it changes after successful pharmacotherapy. Inexperiment 2, neuroactive steroids were examined in normal probands, 42 women and 17 men who reacted with

acute panic symptomatology to inhalation of 7% CO2, to see whether neurosteroid alterations precede as a cause

or follow as an effect of the acute panic attacks, possibly clarifying their pathogenetic mechanism in PDs.





In experiment 1, we found that compared to controls, women with PDs had significantly higher levels of

progesterone in the midluteal phase of the cycle, of pregnenolone in the premenstrual phase, of 3a,5a-

tetrahydroprogesterone in the follicular phase, and of 3a,5a-tetrahydrodeoxycorticosterone in the premenstrualphase, whereas in men with PDs, the plasma concentrations of progesterone and dehydroepiandrosterone were

greater than in controls both in a drug-free month and during paroxetine therapy, in both cases correlating

significantly with the panic scores. In experiment 2, we found a trend toward a decrease of neurosteroid con-

centrations during and after CO2 inhalation, with no correlations between panic symptomatology and neurosteroid

secretion. This would exclude that their possible alterations could be either a cause or an effect of panic attacks.

Keywords: panic disorder; neuroactive steroids; biochemical stress


Amy Lehrner, Linda M. Bierer, Heather N. Bader, Iouri Makotkine, Vincent Passarelli, Janine D. Flory, Rachel

Yehuda. J. J. Peters Veterans Affairs Medical Center; Mount Sinai School of Medicine, New York, NY, USA

Distinct influence of maternal and paternal PTSD on Holocaust offspring

Rationale: Holocaust offspring are at greater risk for the development of Posttraumatic stress disorder (PTSD)

than comparison subjects, and the increased vulnerability appears to be associated with maternal PTSD. Paternal

PTSD is associated with increased vulnerability to depression in Holocaust offspring. In prior studies, neuro-

endocrine alterations have been observed in Holocaust offspring that resemble those described in association

with PTSD and PTSD risk. Holocaust offspring were more likely to show cortisol hypersuppression on the

dexamethasone suppression test (DST) in association with parental PTSD even if offspring had not developed

lifetime PTSD. These data imply an enhanced glucocorticoid receptor responsiveness that might be associated withPTSD risk, as has been demonstrated in other populations at risk for PTSD, such as soldiers preparing to deploy

for combat. More recently, it has been of interest to consider the differential contributions of maternal vs. paternal

PTSD on offspring neuroendocrinology. Such work may identify putative epigenetic changes underlying neuro-

endocrine alterations associated with PTSD risk.

Methods: The current study examined glucocorticoid responsiveness as reflected by the 0.50 mg dexamethasone

suppression test (DST) and the lysozyme stimulation test (LST) in 81 Holocaust offspring, the majority of whom

(73%) had two Holocaust exposed parents. The offspring were subdivided based on maternal and paternal PTSD.

The LST is an in vitro test of glucocorticoid responsiveness carried out in live cultured lymphocytes exposed tovarying doses of dexamethasone (DEX) for which a lower IC50-DEX for lysozyme inhibition indicates increased GR

responsiveness.

Results: In this sample, there was a significant correlation between the cortisol response to DEX (expressed as

cortisol decline from pre- to post-DEX), and the lysozyme IC50-DEX (r��0.521, df�43, p50.0005; controlling for

age, gender, BMI and DEX levels), reflecting that the cortisol response following ingestion of an oral dose of 0.5 mg

DEX resulted in a similar response to that associated with exposing cultured lymphocytes from the same individual

to DEX in vitro. There was a main effect [F(1,42)�4.48, p�0.04] of paternal PTSD on the DST, controlling for age,

gender, BMI, DEX levels, and parental Holocaust exposure (i.e., to control for those cases in which a non-PTSDparent was also not a Holocaust survivor). This main effect demonstrated that offspring with only paternal PTSD

had evidence of diminished cortisol suppression (non-suppression) compared to the three other groups (offspring

without paternal PTSD with or without maternal PTSD, and offspring with both maternal and paternal PTSD).

With respect to the IC50-DEX, there was a similar main effect indicating that offspring with paternal PTSD

had higher IC50-DEX values (M9SD, 6.9 894.04 nM) reflecting diminished glucocorticoid sensitivity [F(1,53)�4.40, p�0.04], whereas offspring with maternal PTSD (5.4094.16 nM) had lower IC50-DEX values [F(1,53)�6.81,

p�0.01]. In a logistic regression analysis, paternal PTSD predicted offspring lifetime depression (b�1.40, p�0.032,

OR�4.07) and lifetime MDD (b�1.25, p�0.048, OR�3.50), controlling for maternal and paternal Holocaustexposure and maternal PTSD. Interestingly, maternal and paternal PTSD were associated with different self-

reported offspring impressions of the effects of their parents’ Holocaust exposure. Maternal PTSD was associated

with believing one has psychological scars as a result of being raised by survivor parents, whereas paternal PTSD

was associated with believing one has a greater sensitivity to violence and injustice because of parents’ Holocaust

experiences.

Conclusions: The data indicate that maternal and paternal PTSD may contribute uniquely to neuroendocrine

alterations and to psychiatric and psychological outcomes in Holocaust survivor offspring.




Keywords: glucocorticoid receptor; PTSD; risk; Holocaust; intergenerational transmission; maternal stress


Shireen Sindi1, Alexandra Fiocco1,3, Robert-Paul Juster1, Isabelle Ouellet-Morin1, Marie France Marin1, CatherineLord2, Jens C. Pruessner2, Sonia J. Lupien1,4. 1Centre for Studies on Human Stress, Mental Health Research

Centre Fernand Seguin, Louis H Lafontaine Hospital, Montreal, QC, Canada; 2McGill University, Montreal, QC,

Canada; 3Ryerson University, Toronto, ON, Canada; 4Universite de Montreal, Montreal, QC, Canada

Investigation of hippocampal volume and trauma symptoms in older and young adults

Background: Smaller hippocampal volume (HV) and a history of childhood trauma are important risk factors for

developing post-traumatic stress disorder (PTSD) in adulthood. However, many individuals experience traumatic

events throughout lifespan but do not develop a PTSD diagnosis. Few studies have assessed how these

vulnerabilities might correspond with adult trauma symptoms among healthy populations. The goal of this study

was to, therefore, assess how childhood trauma and HV are associated with adult trauma symptoms among youngand older adults without PTSD.

Methods: Thirty-two healthy older adults and 28 young adults completed the Trauma Symptoms Checklist and the

Childhood Trauma Questionnaire. Magnetic resonance imaging scans were performed and HV measurements were

obtained through manual segmentation using a well-validated protocol.

Results: Multiple regressions computed for each age group showed that in both young and older adults, childhood

trauma was not associated with HV. However, in young adults, HV was significantly associated with magnitude

of adult trauma symptoms such that young adults with small HV reported more adult trauma symptoms. No

significant associations between HV and adult trauma symptoms were observed in older adults.Conclusions: These novel results reveal that smaller HV is associated with adult trauma symptoms among healthy

young adults, but not older adults. It is possible that small HV supersedes childhood trauma in explaining

adulthood trauma symptoms among healthy young adults. Based on these findings, it would be interesting for

future studies to investigate how hippocampal-dependent processes might contextualize concomitant trauma

symptoms.

Keywords: adult trauma symptoms; childhood trauma symptoms; hippocampal volume; aging; young adults


Nestor L. Lopez-Duran. Department of Psychology, University of Michigan, Ann Arbor, MI, USA

Childhood depression and HPA-axis reactivity revisited: a comparison of three modelingapproaches of dense sampling data

Background: There is accumulating evidence of hypothalamic�pituitary�adrenal (HPA)-axis dysregulation indepressed children and adolescents. For example, depressed children tend to show a pattern of nonsuppression to

the Dexamethasone Suppression Test, suggesting atypical feedback sensitivity of the axis. However, evidence

linking HPA-axis stress reactivity during laboratory tasks and pediatric depression is more limited and con-

tradictory, with studies showing both blunted and hyperactive cortisol responses to stress in depressed youth.

These conflicting findings may been partially attributed to key group differences across studies, such as the age of

the sample, depression severity, or history of maltreatment. In this talk, I discuss another key source of

variability: individual differences in peak timing, as a factor that can obscure the nature of the depression-HPA-

axis relation. I then compare two common modeling approaches (GLM repeated measures and Growth CurveModeling) with a Functional Data Analysis approach in their ability to account for individual differences in peak

times.

Methods: We examined depressive symptoms as predictive of HPA-axis reactivity in two different studies. The first

study involved 65 children ages 6�7 participating in a large longitudinal study of the development of internalizing

and externalizing symptoms. These children completed two standard laboratory stress tasks. Saliva cortisol was

sampled at 5-minute intervals for 60 minutes. Internalizing symptoms were measured via the parent-completed

Child Behavior Checklist. The second study involved 60 children ages 9�16 participating in a study of

neuroendocrine functioning in depressed youth. These children also completed a standard laboratory stress task





after which saliva cortisol was measured at 10 minute intervals. Depressive symptoms were measured via the

Children’s Depression Inventory. We then compared three approaches to model cortisol stress reactivity as

predicted by internalizing (study 1) depressive symptoms (study 2): (1) a standard repeated measures (RM)approach, (2) a standard growth curve (GC) approach modeling change from the time of the stressor (using pre-

stress time as the intercept), and (3) a functional data analysis (FDA) approach using individual peak times as a

common anchor. This FDA approach involves the shifting of individual curves horizontally so that all individual

peaks are anchored on a common time point. This allows for the estimation of true peaks (intercept) and

acceleration towards this peak (slopes) while controlling for individual variability in peak times.

Results: In both of our studies, the RM and the CG models failed to find a link between internalizing/depressive

symptoms and atypical HPA-axis reactivity (p for internalizing and depressive symptoms in both studies and both

approaches �0.20). Specifically, the RM approach did not reveal an impact of depressive or internalizingsymptoms on any specific time point. The GC modeling approach did not reveal an impact of symptoms

on baseline levels (intercept) or the acceleration from baseline (slopes). However, using a functional data

analysis framework we found that youth depression was associated with higher peak levels (anchored intercept)

but not with reactivity slopes (p for internalizing and depressive symptoms impact on the intercept in both

studies B.01).

Conclusions: Our data suggest that traditional modeling approaches, such as RM and GC may not be sensitive to

one type of anomaly associated with depressive symptoms. Specifically, significant individual and group variability

in time-to-peak may confound the type of fixed-time comparisons obtained with RM and GC approaches. Incontrast, using the FDA approach, which controls for this variability, we found that depression impacts the final

post-stress peaks but not the slope towards this peak. Since peak levels are a function of initial levels (baseline),

rate of activation (slope) and time to peak (duration of activation), our results suggest that internalizing/depressive

symptoms are associated with anomalies in the duration of post-stress HPA-axis activation leading to elevated

post-stress peaks.

Keywords: HPA-axis; cortisol; depression; growth curve modeling; children; adolescents


Maria Giese, J. Beck, Serge Brand, F. Muheim, Martin Hatzinger, Edith Holsboer-Trachsler, Anne Eckert.

Psychiatric University Clinics, University of Basel, Basel, Switzerland

Diurnal pattern of serum BDNF before partial sleep deprivation in stress-related mood disorders �an association with therapy response in major depression

Background: Depression is one of the most prevalent forms of mood disorders. Compelling evidence suggests

that mood disorders are characterized by reduced neuronal plasticity, which can be brought about by exposure

to stress. Furthermore, there is good agreement in considering key proteins such as the brain-derived

neurotrophic factor (BDNF), as a central player for the effects of stress on brain function and plasticity and

psychopathological implications. Still, there is a high non-responder rate in antidepressant therapy, which

explains the need to find reliable predictors for adequate treatment. Previous studies revealed that plasma andserum BDNF levels in depressed patients were significantly lower than in healthy controls. Since the protein can

cross the blood brain-barrier serum content correspondingly correlates with cortical BDNF concentrations

suggesting BDNF levels as a promising candidate biomarker for depression and antidepressant treatment

response.

Methods: To investigate the association between serum BDNF levels and treatment outcome, blood was drawn

from 28 patients with a major depressive episode (DMS-IV, ICD-10) that participated in a double-blind placebo

controlled treatment study. All patients were treated with a stable mirtazapine monotherapy. Partial sleep

deprivation (PSD) was performed after one week. Placebo controlled additional morning treatment with thestimulant modafinil to reduce microsleep throughout the day was started during PSD and maintained over two

weeks. Serum concentrations of BDNF and cortisol were assessed by an enzyme-linked immunosorbent assay

(ELISA) from day 1 (‘‘before PSD’’) at 8 am, 2 pm, 8 pm and day 2 (‘‘after PSD’’) at 8 am, 2 pm and 8 pm.

Samples were appropriately diluted and detection of soluble BDNF or cortisol was carried out in an antibody

sandwich format in duplicates and means were calculated for the corresponding group. Moreover, sleep EEG and

microsleep episodes were recorded with a portable EEG. Depression severity using the Hamilton Depression




Rating Scale and mood, tiredness and relaxation were assessed with visual analog scales (VASs) for psychological

functioning at days 1, 2 and 3 (‘‘after recovery night’’) as well as after one and two weeks of ongoing treatment.

Results: Notably, depressive patients who showed an acute HDRS-6 improvement after PSD exhibited a prominentdiurnal pattern of serum BDNF levels during the day before PSD whereas acute non-responders did not show such

a pattern and BDNF levels were rather constantly expressed. Serum BDNF levels were significantly elevated in

acute responders compared to non-responders in the morning at 8.00 am before PSD corrected for Bonferroni (p�

0.01). Also responders after two weeks (FU2) exhibited a prominent diurnal serum BDNF pattern before and after

PSD on day one and two, while it was more pronounced after PSD. There was no diurnal pattern for non-

responders after two weeks before; however, after PSD on day two an even modest diurnal change was visible in

this group but less pronounced compared to FU2-responders. We found no association between treatment

condition placebo vs. modafinil and response for acute neither response after two weeks. When we linked dailypeak BDNF levels from day two at 2 pm with overall HDRS-6 improvement, responders were associated with

elevated BDNF levels compared to non-responders on day three after recovery night already. Even after one (FU1)

and two (FU2) weeks increased BDNF levels of day two at 2 pm were more prominent in the responder group. This

difference between responders and non-responders of peak serum BDNF levels from 2 pm after PSD was

statistically significant after two weeks. In addition, HDRS-6 improvement after two weeks of on-going treatment

was significantly correlated with elevated serum BDNF levels in all patients. Moreover, peak levels of serum BDNF

after PSD on day 2 at 2 pm were correlated with increased relaxation and improved mood in all depressive patients.

In addition, placebo treated patients during PSD exhibited a significant increase of serum cortisol levels duringPSD when compared to morning peak levels at 8 am between day one and two. There was no serum cortisol

increase in the modafinil treated group during PSD intervention.

Conclusions: Altogether, it seems that a diurnal pattern of serum BDNF during the day is necessarily associated

with acute and response after two weeks in terms of partial sleep deprivation independently from additional

treatment (modafinil vs. placebo). BDNF levels peaking in the morning and declining during the day seem to be

favourable for an antidepressant response. Therefore, BDNF expression profile in serum at baseline could be used

as possible predictor for therapy outcome.

Keywords: major depression; therapy response; sleep deprivation; BDNF; cortisol; diurnal pattern


Alexander Lischke1,2,3, Matthias Gamer4, Christoph Berger2, Annette Grossmann5, Karlheinz Hauenstein5,

Markus Heinrich6, Sabine C. Herpertz7, Gregor Domes6. 1Department of General Psychiatry, University of

Heidelberg, Heidelberg, Germany; 2Department of Psychiatry and Psychotherapy, University of Rostock, Rostock,

Germany; 3Department of Psychology, University of Greifswald, Greifswald, Germany; 4Department of SystemsNeuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 5Department of Radiology,

University of Rostock, Rostock, Germany; 6Department of Psychology, University of Freiburg, Freiburg im

Breisgau, Germany; 7Department of General Psychiatry, University of Heidelberg, Heidelberg, Germany

Oxytocin increases amygdala-dependent threat-processing in females

Background: Over the last decade, the neuropeptide oxytocin has attracted considerable attention for its crucial role

in social behavior. Motivated by animal studies showing that oxytocin attenuates stress and anxiety in rodents,

numerous studies have been conducted to investigate whether oxytocin has similar effects on stress and anxiety in

humans. Most of these studies have revealed that oxytocin also attenuates stress and anxiety in humans, presumably

by decreasing amygdala activity during the processing of threatening stimuli. However, these studies have almost

exclusively been conducted in males, leaving open whether the observed effects can be generalized to females.Methods: To investigate how oxytocin affects amygdala-dependent threat-processing in females, we used functional

magnetic resonance imaging (fMRI) to measure females’ amygdala reactivity to threatening and nonthreatening

faces (study one: n�16) and scenes (study two: n�14) after intranasal application of oxytocin or placebo. We also

recorded females’ eye movements during stimulus processing to investigate whether oxytocin-induced changes in

amygdala activity are accompanied by corresponding changes in gaze behavior.

Results: There were no differences in females’ gaze behavior during stimulus processing after oxytocin as compared

to placebo administration. However, after oxytocin administration females showed more amygdala activity to

threatening faces (study one) and scenes (study two) than after placebo administration.




Conclusions: Taken together, the present findings suggest that oxytocin enhances amygdala-dependent threat-

processing in females, which is in sharp contrast with previous findings showing that oxytocin attenuates

amygdala-dependent threat-processing in males. Although these findings point to a possible sexual dimorphism in

oxytocin-mediated threat-processing, future studies are warranted to further address this issue, preferably by

directly comparing oxytocin effects on threat-processing between males and females.

Keywords: oxytocin; amygdala; threat; fear; female; functional magnetic resonance imaging; eye tracking


Claudia Lange1,3, Felix Bermpohl1, Marcus Ising2, Manfred Uhr2, Mazda Adli1. 1Charite�Universitatsmedizin

Berlin, Department for Psychiatry and Psychotherapy, Charite Campus Mitte Berlin, Berlin, Germany;2Max-Planck-Institute for Psychiatry, Munich, Germany; 3Psychiatric Hospital of the University of Basel, Basel,

Switzerland

The influence of psychosocial stress on HPA system regulation and cognitive performance inpatients recovered from depression

Rationale/ statement of the problem: Despite numerous studies on the influence of psychosocial stress on

hypothalamic-pituitary-adrenal axis (HPA) system responsivity, heterogeneous results have been found with

regard to depression in remission. In addition, knowledge concerning cognitive functioning in the remitted state is

also narrow showing thus far inconsistent results. The present study investigated the effect of psychosocial stress on

the cortisol response and cognitive performance in patients recovered from depression in comparison to healthy

controls.Methods: Eighty patients who have recovered from depression for at least 6 months (average: 31 months) and 80

healthy matched controls were investigated on the effects of psychosocial stress (TSST) on the performance in an

affective go/nogo task. Cortisol responses, behavioral inhibition, reaction time performance and emotional-

cognitive functioning were analyzed. We hypothesized that stress vulnerability of cognitive performance is

positively correlated to HPA system responsiveness (measured by salivary cortisol) in both healthy subjects and

remitted patients but larger in remitted patients compared to healthy controls.

Results: Thus far, preliminary analyses reveal no abnormal stress-associated HPA system response in patients

recovered from depression in comparison to healthy controls. However, remitted patients showed impairedattentional set shifting in the go/nogo task. This impairment was positively correlated with the duration of illness.

Conclusion: Our study is the first to investigate affective go/nogo task performance and effects of a stress challenge

test in patients recovered from depression. Our data demonstrate that attentional set shifting deficits are not only

present during acute episodes but also in remission. These deficits seem to be correlated with the duration of illness.

Nonetheless, restored stress-associated HPA system function suggests recovery of the HPA system reactivity to

psychosocial stress in patients remitted from depression. This in turn suggests that the observed cognitive

impairment is not mediated by abnormal HPA responses.

Cognitive impairment in the area of executive functioning may be considered a specific trait marker that persistsafter clinical and neuroendocrinological remission.

Keywords: cortisol; TSST; remitted depression; executive functioning; affective go/nogo task; cognitive impairment


Sinai Cave, Tatja Hirvikoski, Anna-Lena Nordstrom, Peter Nordstrom, Marie Asberg, Jussi Jokinen. Department

of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Stockholm, Sweden

Hypothalamic�pituitary�thyroid (HPT) axis and exposure to interpersonal violence in childhoodamong women with borderline personality disorder

Background: A relationship between exposure to sexual violence and thyroid hormone alterations have been

observed among women with premenstrual dysphoric disorder (PMDD), as well as women with posttraumatic stress

disorder (PTSD). Women with Borderline Personality Disorder (BPD) report a high estimate of childhood trauma.





The aim of the present study was to assess relationships between thyroid hormone measures and exposure to

violence in childhood in females with BPD.

Methods: Ninety-two clinically euthyroid women with BPD diagnosis and at least two prior serious suicideattempts in their history were assessed with the Karolinska Interpersonal Violence Scales (KIVS). The KIVS is a

new structured interview, containing four subscales with concrete examples of exposure to violence and expressed

violent behavior in childhood (between 6 and 14 years of age) and during adult life (15 years or older). In addition

to serum cortisol, baseline thyroid functioning was evaluated by measuring plasma thyroid stimulating hormone

(TSH), free and bound Triiodothyronine (T3) and Thyroxine (T4) levels, as well as the FT3/FT4 (free T3/ free T4)

ratio, by immunoassays.

Results: The FT3/FT4 ratio showed a significant negative correlation with exposure to violence as a child.

Conclusions: Altered thyroid activity, especially FT3/FT4 levels, was associated with exposure to violence inchildhood in suicide attempters. Severe childhood trauma-related stress may promote lasting altered thyroid levels

and/or contribute to the development of psychopathology associated with BPD traits, coming to the notice of

psychiatric care.

Keywords: thyroid hormones; borderline personality disorder; interpersonal violence; traumatic stress


Stefan Roepke, Katja Wingenfeld, Linn K. Kuehl, Kim Hinkelmann, Christian Otte. Department of Psychiatry,

Charite�Universitatsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

Mineralocorticoid receptor function and visuo-spatial memory in patients with borderlinepersonality disorder

Background: Cortisol is closely associated with memory function via mineralocorticoid and glucocorticoid

receptors (MR/GR) in the brain. While GR are expressed throughout the brain, MR is predominantly expressed in

the hippocampus. Patients with borderline personality disorder (BPD) often show impaired memory function as

well as alterations in cortisol secretion. We have previously shown that hydrocortisone, an unspecific GR/MR

agonist, enhances memory function in BPD. To disentangle GR and MR effects on memory processes in BPD, we

tested hippocampus-dependent visuospatial memory performance after MR stimulation with fludrocortisone inthe current study.

Methods: In a placebo-controlled, within-subject crossover study, patients with BPD received placebo or 0.4 mg of

fludrocortisone orally before memory testing. We used the Rey-Osterrieth Complex Figure Test to measure

visuoconstruction, immediate visuospatial memory, and delayed visuospatial memory.

Results: After fludrocortisone intake, BPD patients (n�17) showed significantly impaired visuospatial memory

function compared to the placebo condition (effect of treatment, p�0.01).

Conclusions: In contrast to the mixed GR/MR agonist hydrocortisone, the MR agonist fludrocortisone impairs

hippocampus-dependent visuospatial memory function in patients with BPD. This impairing effect might bemediated by MR-induced negative feedback inhibition of cortisol leading to decreased GR signaling.

Keywords: borderline personality disorder; mineralocorticoid receptor; fludrocortisone; visuospatial memory


Kate Ryan Kuhlman, Nestor L. Lopez-Duran. University of Michigan, Ann Arbor, MI, USA

Understanding the role of early life trauma in the neuroendocrine dysregulation of youth depression

Background: To date there are inconsistent empirical findings regarding the nature of hypothalamic�pituitary�adrenal (HPA)-axis dysregulation in depressed youth. Some of these inconsistencies may be explained in part byexposure to different types of trauma. The purpose of this study is to clarify the interplay between trauma exposure

and neuroendocrine reactivity in depressed youth. We hypothesized that exposure to specific subtypes of trauma

will moderate the effect of depression on dysregulation of the stress response system.

Methods: Participants were 51 depressed and non-depressed youth (22 males; mean age�12.9, SD�2.8).

Participants completed a semi-structured clinical interview, an Early Trauma Inventory (ETI), and a 90-minute





stress task which included saliva samples upon arrival, after a 30 minute baseline, 25, 35, 45, 55, and 65 minutes

following the SE-Current Procedural Terminology (CPT).

Results: There were no differences between depressed and non-depressed participants in reported exposure totrauma of any type. However, depressed participants had higher cortisol levels during the regulation phase,

45 [F(15,35)�2.65, pB0.05], 55 [F(15,35)�2.64, pB0.05], and 65 [F(15,35)�3.11, pB0.01] minutes after the

stressor. We also found that there was a main effect of depression symptoms [F(11,35)�296.18, pB0.05] on

cortisol reactivity (AUCi). In addition, we found that there was a significant interaction of depression and trauma

history [F(2,30)�523.29, pB0.05], in that exposure to abuse, but not general trauma, increased AUCi in the

depressed sample only.

Conclusions: Depressed youth with a history of abuse are more likely to have a specific dysregulation of the HPA-

axis related to an inability to ‘‘shut down’’ the stress response as evidenced by later peak times. This suggests thatabuse may have an impact specifically on HPA regulatory capacity. We did not find this effect for general trauma

highlighting the potential differential role of various types of trauma on HPA functioning.

Keywords: abuse; acute stress; adolescent; depression; salivary cortisol; trauma





POSTERS

Nina Hohne, Hildegard Pfister, Tanja Bruckl, Petra Zimmermann, Manfred Uhr, Florian Holsboer, Marcus Ising.

Max Planck Institute of Psychiatry, Munich, Germany

Effect of psychosocial stress on FKBP5 and NR3C1 gene expression in healthy young men

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 theHPA 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, weexpected 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 analteration 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.

Keywords: HPA axis; FKBP5; NR3C1; gene expression; stress hormones; TSST


Sandra Cornelisse1, Vanessa A. van Ast2, Marian Joels1, Merel Kindt2. 1Department of Neuroscience andPharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The

Netherlands; 2Department of Clinical Psychology, University of Amsterdam, Amsterdam, The Netherlands

A delay and trace fear conditioning paradigm in humans: time-dependent effects of corticosteroids?

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, andunconditioned 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

European Journal of Psychotraumatology 2012. # 2012 Posters. This is an Open Access article distributed under the terms of the Creative CommonsAttribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/), permitting all non-commercial use, distribution, andreproduction in any medium, provided the original work is properly cited.


50





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 tracestimulus 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.

Keywords: fear conditioning; EMG; hydrocortisone; startle response; cortisol


Nadine Skoluda1, Johanna Marie Doerr1, Urs Markus Nater1, Myriam V. Thoma2, Ulrike Ehlert3. 1University of

Marburg, Marburg, Germany; 2Brandeis University, Boston, MA, USA; 3University of Zurich, Zurich, Switzerland

Psychological stress levels and autonomic activity in everyday life are related to stress responses inthe laboratory

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 laboratorysessions 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, pB0.001). Self-reported stress levels significantly fluctuated over

the course of the 2 days (time effect, p�0.022). In the laboratory part, the CPT resulted in significant increases in

sAA and in self-reported stress levels (time effect, p�0.004; interaction effect, p�0.001). Regression analyses

revealed that overall sAA levels in everyday life predicted sAA levels in both laboratory conditions (pB0.01). Thesame held true for subjective stress levels (pB0.001). It was also found that overall subjective stress levels in

everyday life predicted the psychological laboratory stress response (p�0.024). Furthermore, a trend was found for

the sAA awakening response predicting overall sAA in the stress condition (p�0.067).

Conclusions: Stress levels in everyday life were shown to predict psychological as well as physiological stress levels in

the laboratory. Furthermore, subjects with high stress levels in everyday life experienced a more pronounced

psychological stress response to a laboratory stressor.

Keywords: cold pressor test; alpha-amylase; stress response; daily stress; autonomic activity


Barbara Vanaelst, Inge Huybrechts, Karin Bammann, Nathalie Michels, Tineke de Vriendt, Krishna Vyncke,

Isabelle Sioen, Licia Iacoviello, Kathrin Gunther, Denes Molnar, Lauren Lissner, Noellie Rivet, Jean-Sebastien

Raul, Stefaan de Henauw. Department of Public Health, Ghent University, Ghent, Belgium

Intercorrelations between serum-, salivary- and hair-cortisol and child-reported estimates of stressin elementary school girls

To evaluate the impact of stress on children’s well-being, it is important to have valid and reliable stress assess-

ment 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 stressmeasures.





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 differentbiological 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.

Keywords: cortisol; child; stress; questionnaire; biomatrices


Stefanie Eva Mayer, James L. Abelson, Thane Erickson, Hedieh Briggs, Jennifer Crocker, Israel Liberzon.

Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

Brief cognitive interventions interact with resilience to modulate ACTH response to the TrierSocial Stress Test

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 socialevaluative 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 tohelping 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 instructionsreduced 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.

Keywords: HPA-axis; ACTH; TSST; resilience; cognitive intervention






Ingibjorg H. Jonsdottir, Kristina Glise, Gunnar Ahlborg, Anna Sjors. The Institute of Stress Medicine,

Gothenburg, Sweden

Salivary cortisol is not a valid marker of stress-related exhaustion

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 theusefulness 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 studyof 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.

Keywords: burnout; exhaustion; HPA-axis; longitudinal; salivary cortisol


Magdalena Buckert1, Christiane Schwieren2, Brigitte M. Kudielka3, Christian J. Fiebach1. 1Department of

Psychology, Goethe University Frankfurt, Frankfurt a. M., Germany; 2Department of Economics, University of

Heidelberg, Heidelberg, Germany; 3Department of Psychology, University of Regensburg, Regensburg, Germany

Stress and the choice of competition in an economic tournament game

Rationale: Recent research on stress and decision making highlights the importance of considering the reciprocalrelationship 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 economiclaboratory 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.

Keywords: competition; decision making; stress; heart rate; testosterone; economic tournament


Blake Gurfein, Andrew Stamm, Peter Bacchetti, Mary Dallman, Nachiket Nadkarni, Jeffrey Milush, Chadi

Touma, Rupert Palme, Jan Pieter Konsman, Michael Acree, Mary Premenko-Lanier, Nicolas Darcel, Frederick

Hecht, Douglas Nixon. University of California San Francisco, San Francisco, CA, USA

The calm mouse: an animal model of stress reduction

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 ofstress 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, PB0.0001; Cntl Ex,Mdiff 22.5 ng CM, CI95 13.4�31.5, PB0.0001; Calm Ex, Mdiff 21.8 CM, CI95 11.7�32.0, P�0.0003). Calm animals

gained greater body mass than Cntl, although they had similar weekly energy intake. We also observed changes

in body composition, spleen mass, and spleen composition. In particular, we found that Calm mice had a

significantly greater proportion and absolute number of splenic CD19� B lymphocytes when compared with Cntl

(proportion: Mdiff 6.7% of splenocytes, PB0.0001; absolute number: Mdiff 9.04�106 cells, CI95 8.3�106�9.8�106, PB0.0001).

Our data indicate that both Calm and exercise caging generated reductions in physiologic stress measures in

mice and that Calm animals exhibited increases in splenocyte subpopulations that may underlie changesin functional immunity. Collectively, the Calm model represents a promising approach to studying the biological

effects of stress reduction in the context of health and in conjunction with disease models.

Keywords: neuroendocrine; stress reduction; animal model; immunology; glucocorticoid


Laura Ortega1, Rosa Monseny1, Itziar Montalvo1, Nuria Manzanares1, Joan Franch1, Brian R. Walker2, Alfonso

Gutierrez-Zotes1, Rebecca M. Reynolds2, Javier Labad1. 1Hospital PsiquiAtric Universitari Institut Pere Mata

de Reus, IISPV, Universitat Rovira i Virgili, Tarragona, Spain; 2Endocrinology Unit, University/BHF Centre for

Cardiovascular Science, University of Edinburgh, Edinburgh, UK

Stressful life events, perceived stress and morning plasma cortisol in subjects with early psychosis

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 relationshipbetween 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 fastingmorning 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-valueB0.05 was

considered significant.

Results: In all subjects, stressful life events were positively associated with perceived stress (r�0.244, p�0.033) but

not with plasma cortisol levels. In the stratified analysis by diagnoses, no significant differences in stressful life

events were found between all three groups. Subjects at risk for psychosis (UHR) reported greater scores in PSS

(30.6911.7) than other groups (FEP: 27.090.1; CP: 20.9), this result being statistically significant (p�0.003).Those subjects from the critical period group showed increased plasma cortisol (20.794.8) when compared to

UHR (18.996.4) and FEP (18.1294.5) groups.

Conclusion: UHR subjects report greater levels of perceived stress when compared to those subjects with

a psychotic disorder. Stressful life events and perceived stress are associated but not with plasma cortisol

levels.

Keywords: stress; perceived stress; psychosis; cortisol levels


Andrea Amaro Quesada, Rosana M. Tristao, Fernanda B. Vianna, Lucas B.D. Barbosa, Igor C. Carneiro, Caroline

N. Minchillo, Riccardo Pratesi, Oliver T. Wolf. Department of Cognitive Psychology, Faculty of Psychology,

Ruhr-University Bochum, Bochum, Germany; International Graduate School of Neuroscience (IGSN), Ruhr-

Universitat Bochum, Bochum, Germany; School of Medicine, University of Brasilia, Brasilia, Brazil

Hyperresponse to acute stress and poorer memory in former preterm children

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 a-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 within-

subjects delay and trace conditioning paradigm by administering 10 mg hydrocortisone either 4 h or 1 h before fearacquisition. 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.

Keywords: preterm birth; cortisol; CAR; a-amylase; memory; behavior; childhood






Nitsan Kozlovsky1, Joseph Zohar2, Zeev Kaplan1, Hagit Cohen1. 1Beer-Sheva Mental Health Center, Ben-Gurion

University of the Negev, Beer-Sheva, Israel; 2The Chaim Sheba Medical Center, Tel-Aviv University, Tel-Aviv, Israel

Beyond the HPA-axis: the role of the gonadal steroid hormone receptors in modulating stressrelated responses in an animal model of PTSD

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 thatproducts 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 comparedto 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.

Keywords: PTSD; animal models; gonadal steroid hormones; stress response; HPA Axis


Marcia J. Slattery, Adam J. Grieve, Elliott M. Paletz, Ned H. Kalin. Department of Psychiatry, University of

Wisconsin School of Medicine and Public Health, Madison, WI, USA

Anxiety symptom severity differentiates HPA acute stress reactivity in children

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.

Keywords: anxiety; children; stress; cortisol; cold pressor task


Charissa Andreotti, Paige Garrard, Sneha Venkatraman, Linda Luecken, Bruce Compas. Department of

Psychology, Vanderbilt University, Nashville, TN, USA

Effects of chronic family stress during development on attentional bias and psychobiological stressreactivity in women

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 stressexposure.

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, pB0.001) and total cortisol area under the curve (r�0.26, p�0.005).

A linear regression analysis indicated a negative main effect of conflict exposure, b(3, 45)��0.36, p�0.022,and a significant interaction of the effects of conflict exposure and attentional bias to conflict stimuli on cortisol,

b(3, 45)��0.30, p�0.42. Specifically, attentional bias to conflict stimuli was positively related to cortisol

reactivity to an acute stressor, but only for individuals exposed to lower levels of family conflict during

development.

Results suggest that exposure to chronic stress early in development shapes later perception and interpretation of

environmental cues as stressful and has an enduring impact on biological reactivity to acute stress. These findings

expand on earlier work by Luecken and colleagues presenting a combined cognitive-affective model to link

characteristics of the family environment during development to alterations in psychological and physiologicalstress reactivity processes in adulthood, which may ultimately underlie illness vulnerability.

Keywords: chronic stress; cortisol; attentional bias; family conflict; attention


Katri Savolainen1, Johan G. Eriksson2,3,4,5,6, Laura Kananen7,8, Eero Kajantie2,9, Iiris Hovatta7,8,10, Marius Lahti1,

Jari Lahti1, Anu-Katriina Pesonen1, Kati Heinonen1, Katri Raikkonen1. 1Institute of Behavioural Sciences,

University of Helsinki, Helsinki, Finland; 2Diabetes Prevention Unit, Department of Chronic Disease Prevention,

National Institution for Health and Welfare, Helsinki, Finland; 3Folkhalsan Research Centre, Helsinki, Finland;4Unit of General Practice, Helsinki University of Central Hospital, Helsinki, Finland; 5Vasa Central Hospital,Vaasa, Finland; 6Department of General Practice and Primary Health Care, University of Helsinki,

Helsinki, Finland; 7Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of

Helsinki, Helsinki, Finland; 8Department of Medical Genetics, Haartman Institute, Faculty of Medicine,

University of Helsinki, Helsinki, Finland; 9Hospital for Children and Adolescents, Helsinki University of Central

Hospital, Helsinki, Finland; 10Department of Mental Health and Substance Abuse Services, National Institute for

Health and Welfare, Helsinki, Finland





Combination of early life stress and traumatic experiences across the lifespan are associated withshorter leukocyte telomere length in later adulthood: the Helsinki Birth Cohort Study

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, studiesexamining 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 (pB0.008). Those participants who

were separated and had experienced an emotional trauma across the lifespan displayed shorter LTL than those

who were not separated regardless of their traumatic experiences. In contrast, those participants who were separated

but who had not experienced an emotional trauma did not differ in LTL from the non-separated.

Conclusion: ELS and traumatic experiences may, in combination, contribute to accelerated cellular aging and shedlight into the underlying mechanisms linking ELS and early traumatic experiences with mental disorders and

aging-related diseases.

Keywords: telomere length; early life stress; trauma; cellular aging; aging-related disorders


Nagisa Sugaya, Shuhei Izawa, Keisuke Saito, Kentaro Shirotsuki, Shinobu Nomura, Hironori Shimada, Kazutaka

Ikeda. Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Advanced Research Center for Human

Sciences, Waseda University, Saitama, Japan

Enhanced increase in cortisol/DHEA ratio under prolonged stress in individuals with irritablebowel syndrome

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 teachingpractice (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 (pB0.0001), cortisol (p�0.002), and DHEA (p�0.02) and significant

effects of time in cortisol (pB0.0001), DHEA (pB 0.0001), DHEA-S (pB0.0001), and DHEA-S:DHEA ratio (pB

0.0001). A significant interaction between group and time was found in cortisol:DHEA ratio (F�6.9, p�0.001).

Cortisol:DHEA ratio at T2 was higher than ratio at T1 and T3, and ratio at T1 was higher than ratio at T3 in bothgroups. Cortisol:DHEA ratio at T2 in IBS group was higher than that in control group.

Cortisol:DHEA ratio in participants of the present study responded to prolonged stress, and individuals with IBS

showed higher cortisol:DHEA ratio at 30 min after awakening than individuals without IBS during experiment

period. These results of this study using prolonged stressor differs from that of our previous study using acute stressor

that individuals with IBS showed lower DHEA-S level and DHEA-S:DHEA ratio throughout the experiment.




Keywords: Irritable bowel syndrome; cortisol; DHEA; DHEA-S; stress


Tobias Stalder, Clemens Kirschbaum, Robert Miller, Joachim Fischer. Department of Psychology, Technical

University of Dresden, Dresden, Germany; Institute of Public Health, Mannheim Medical Faculty, Heidelberg

University, Heidelberg, Germany

Glucocorticoids in hair in relation to cardiometabolic risk markers

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 periodsof 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 ofglucose, 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.

Keywords: hair; cardiometabolic syndrome; glucocorticoid; stress; cortisol; cortisone


Anne Marita Milde, Tove Saga Nordling, Dag Øystein Nordanger. University of Bergen, Department of Biological

and Medical Psychology, Bergen, Norway; Resource Centre on Traumatic Stress, Violence and Suicide

prevention, Western region, Norway; Health Bergen, Psychiatric Youth Unit, Bergen, Norway; UNI Health,RKBU, Norway

The effect of Narrative Exposure Therapy on posttraumatic stress disorder: an outpatientintervention study

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 adultpatients 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’sB0.005�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’sB0.05). The total depression

score on BDI-II were significantly reduced (pB0.05), also intrusion on IES-R and its total score (pB0.05).6 months after treatment 7 of 14 patients (50%) (3 drop-outs) did not have PTSD according to CAPS, DES overall

score was significant reduced (pB0.05), as well as all scales on IES-R (p’sB0.01�0.05) and CAPS (p’sB0.01�0.05)

except criterion B (re-experience symptoms). However, there was no longer a significant reduction on BDI-II total

score or the SCL-90-R in total.

The results indicate that even in a relatively small sample, NET has value of transference and can also be a useful

treatment for outpatients living in a nonthreatening environment. Further investigations are needed to assess more

extended effects, in particular on depression.

Keywords: Narrative Exposure Therapy; treatment effect; PTSD; outpatients; depression


Kristin J. Ziegler1, Jan-Felix Kersten2, Schulamith Kruger3, Karl-Heinz Schulz1, Christoph Heesen3, Stefan M.

Gold3. 1Department of Medical Psychology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg,

Germany; 2Institute for Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf (UKE),

Hamburg, Germany; 3Institute for Neuroimmunology and Clinical Multiple Sclerosis Research (inims), University

Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany

Salivary cortisol profiles in multiple sclerosis patients with comorbid depression and posttraumaticstress disorder

Objectives: Multiple sclerosis (MS) as an inflammatory demyelinating disease of the brain and the spinal cordis 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 awakeningresponse (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 withPTSD.

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.

Keywords: multiple sclerosis; salivary cortisol; depression; PTSD; coping resources


Jeffrey Milush1, Vanessa York1, Aric Prather2, Douglas Nixon1, Hecht Frederick3, Elissa S. Epel4. 1Division ofExperimental Medicine, UCSF, San Francisco, USA; 2Center for Health and Community, UCSF, San Francisco,

USA; 3Osher Center for Integrative Medicine, UCSF, San Francisco, USA; 4Department of Psychiatry, UCSF, San

Francisco, USA





Effect of chronic stress and in vivo cortisol measures on immune cell glucocorticoid receptorexpression and cellular immune activation

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 importantrole 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 employedfor statistical analysis with pB0.05 considered significant.

No statistically significant difference in daily cortisol exposure was observed between CGs and CNTLs; however,

CGs did exhibit greater T cell immune activation (p�0.029). Contrary to our hypothesis, T cell immune activation

was not associated with decreased GR expression. In fact, CGs had equal or a trend toward greater GR expression

compared to CNTLs. CGs did demonstrate a statistically significant negative correlation between total daily in

vivo cortisol levels and GR expression in CD4� and CD8� T cells (�0.74 (pB0.02) and �0.81 (pB0.02),

respectively). Combining groups, we observed a positive trend in GR expression and perceived stress in two

monocyte subsets (CD14br and CD14dimCD16�). A statistically significant negative correlation between GRexpression in the pro-inflammatory CD14brCD16� and CD14dimCD16� monocyte subsets and their relative

frequency was also observed (�0.47 (p�0.02) and �0.52 (p�0.01), respectively).

Elevated inflammation during chronic stress may not result simply from down-regulation of GR in immune cells.

Cortisol and GR expression may influence the frequencies of pro-inflammatory monocyte subsets (CD14brCD16�

and CD14dimCD16�) that may be important in regulating chronic inflammation.

Keywords: chronic stress; glucocorticoid receptor; inflammation; cortisol; immune activation; flow cytometry;

HPA axis


Nina Alexander, Franziska Rosenlocher, Tobias Stalder, Julia Linke, Wolfgang Distler, Joachim Morgner, Clemens

Kirschbaum. Department of Biopsychology, Technische Universitat Dresden, Dresden, Germany

Impact of antenatal synthetic glucocorticoid exposure on endocrine stress reactivity in term bornchildren

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 priorstudies.

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, pB0.001).This finding appeared to be independent of the specific synthetic GC used and was found to be more pronounced

in females.

Conclusions: The present study provides first evidence for long-lasting effects of antenatal synthetic GC exposure

on HPA-axis reactivity in term-born children. These findings may bear important implications regarding the

vulnerability for stress-related physical and psychiatric disorders, for which dysregulation of the HPA-axis has been

discussed as a potential causal factor.




Keywords: synthetic glucocorticoids; antenatal; HPA-axis; stress reactivity; children; trier social stress test


Mary Eileen Saczawa, Julia. A. Graber, Jeanne Brooks-Gunn. University of Florida, Gainesville, FL, USA;

Teacher’s College at Columbia University, New York, NY, USA

The relationship between social stressors and psychopathology: a short-term longitudinal study ofmoderating factors

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 boththe 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 wereassessed 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.

Keywords: cortisol; DHEAS; ratio; family; depression; aggression; peer


Malak Abu Shakra, Jens C. Pruessner, Alain Dagher, Marco Leyton, Robert Pihl. Department of Psychology,

McGill University, Montreal, QC, Canada

Why gender matters: differential effects of stress and alcohol on cortisol secretion and neural stresscircuitry activation among sensation seeking and anxiety-sensitive males and females

Background: Alcohol Use Disorders (AUDs) are multiphasic, multifactorial, and heterogeneous disorders forwhich 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 withinsubjects. 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, pB0.05

respectively: �2.103; �2.229).

Conclusions: These findings provide evidence for the notion that distinct risk personality profiles are associated

with differential vulnerability for AUDs. They further support the self-medication theory, whereby AS individualsdrink to dampen stress, rendering the former a negative reinforcer targeting and inhibiting their neural and

hormonal stress circuitry.

Keywords: alcohol; sensation seeking; anxiety sensitivity; fMRI; cortisol; stress response; amygdale; orbitofrontal

cortex


Owen M. Wolkowitz, Synthia H. Mellon, Yali Su, Victor I. Reus, Scott Mackin, Heather M. Burke, Rebecca

Rosser, John Coetzee, Elissa S. Epel, Steven P. Hamilton, Craig J. Nelson, Laura Mahan, Michelle Coy, Michael

W. Weiner, Susanne Mueller. Department of Psychiatry, University of California School of Medicine, SanFrancisco, CA, USA

Peripheral indices of oxidative stress are correlated with hippocampal volume in major depressionand in controls

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 HCand 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 (pB0.03) and CA3&DG (pB0.04)

subfield volumes. Glutathione peroxidase was directly correlated with total HC (pB0.006) and CA1 (pB0.009) and

CA3&DG (pB0.002) subfield volumes. Levels of the antioxidant and GSH were directly correlated withCA2 (pB0.02)

and CA3&DG (pB0.03) subfield volumes. In the controls, a similar pattern was observed at or near the significance

threshold. In the MDD group alone, glutathione peroxidase activity was directly correlated with total HC volume (pB

0.05) and tended to be directly correlated with CA3&DG subfield volume (pB0.07). The antioxidant ratio of GSH/GSSG

(an index of antioxidant reserves) was directly correlated with CA2 (pB0.02) and CA3&DG (pB0.03) subfield volumes.

These exploratory data are consistent with the hypothesis that oxidative stress is related to diminished hippocampal

volume, with the CA3&DG subfield perhaps being the most sensitive. The relationship of peripheraloxidative stress

to local oxidative stress in the HC is unknown, but studies in humans have suggested some degree of direct

correlation between blood and cerebrospinal fluid (CSF) oxidative markers, and peripheral oxidative stress

measures are increased in several neurodegenerative diseases.

Keywords: oxidative stress; depression; hippocampus; glutathione peroxidase


Hannah Bruehl, Peter N.C. Mohr, Alex Hatri, Hauke R. Heekeren. Affective Neuroscience & Psychology of

Emotion, Department of Educational Science and Psychology, Freie Universitaet Berlin, Berlin, Germany





Acute stress prompts riskier decisions in young men

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 acutestress.

We developed a new DM paradigm, in which EV of reward and risk of decision options are independent and

quantifiable. Subjects (5 men, age: 31.291.92 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 stressedcompared 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.

Keywords: stress; cortisol; decision making under risk; reward


Owen M. Wolkowitz, Jodie Bryk, Synthia H. Mellon, Elissa S. Epel, Elizabeth H. Blackburn, Jue Lin, Robert H.Lustig, Peter J. Havel, Victor I. Reus, Heather M. Burke, Rebecca Rosser, John Coetzee, Laura Mahan, Michelle

Coy, Steven P. Hamilton, Craig J. Nelson. University of California San Francisco, San Francisco CA, USA;

University of California Davis, Davis, CA, USA; University of Pittsburgh Medical Center, Pittsburgh, PA,

USA

Serum leptin concentrations and telomere length in MDD and in controls

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 telomereshortening. 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, pB0.02),

with and without co-varying for BMI. This relationship remained significant in the MDD group alone (r��0.54,

pB0.04) but missed significance in the controls (r��0.23, ns). Hierarchical linear regression, entering BMI and

HOMA-IR prior to leptin (with telomere length the dependent variable) showed that BMI and HOMA-IR were not

significantly correlated with telomere length (t�1.04, p�0.30, 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.

Keywords: leptin; telomeres; depression; body-mass index; insulin resistance; metabolic syndrome; obesity






Agorastos Agorastos, Oliver Stiedl, Judith A. Boel, Pia S. Heppner, Torben Hager, Tobias Moeller-Bertram, Uzair

Haji, Arame Motazedi, Dewleen G. Baker. Veterans Affairs Center of Excellence for Stress and Mental Health, VA

San Diego, CA, USA; University Department of Psychiatry and Psychotherapy, Hamburg, Germany; Behavioral

Neuroscience Group, VU University, Amsterdam, The Netherlands; Department of Psychiatry, UCSD, La Jolla,

CA, USA

Diminished vagal activity and blunted circadian heart rate dynamics in posttraumatic stressdisorder assessed through 24-h linear and unifractal analysis

Background: Affected autonomic heart regulation is implicated in the pathophysiology of cardiovascular diseasesand 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 dynamicsincluded 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 afast

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.

Keywords: autonomic nervous system; detrended fluctuation analysis; heart rate variability; parasympathetic

nervous system; posttraumatic stress disorder; sympathetic nervous system


Danielle Gianferante, Myriam V. Thoma, Juliette Saltz, Brian Dahlben, Holly Beaulac, Nicolas Rohleder. BrandeisUniversity, Waltham, MA, USA

Post-stress rumination after initial psychosocial stress predicts cortisol responses to repeated stressexposure

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, butnot 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.

Keywords: rumination; stress; cortisol; HPA axis


Chia-Ying Chou1, Roberto La Marca2, Andrew Steptoe3, Chris R. Brewin. 1Clinical Educational & Health

Psychology, University College London, London, UK; 2Epidemiology and Public Health, University College

London, London, UK; 3Clinical Psychology and Psychotherapy, University of Zurich, Zurich, Switzerland

Salivary cortisol and alpha-amylase during traumatic memory encoding*relationships withintrusions and pre-existing characteristics

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 filmviewing 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 memoriesand 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.

Keywords: PTSD; cortisol; alpha-amylase; trauma; dissociation; memory


Jessie Frijling1, Mirjam van Zuiden1, Saskia Koch1, Laura Nawijn1, Dick Veltman1,2, Miranda Olff1,3. 1Departmentof Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2VU University

Medical Center, Amsterdam, The Netherlands; 3Arq Psychotrauma Expert Group, Diemen, The Netherlands

Boosting the oxytocin system in acute trauma victims at risk for PTSD: the rationale and designof a randomized controlled trial

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 andfear 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.

Keywords: PTSD; traumatic stress; oxytocin; RCT; fMRI; social support


Anna Sjors1, Per-Anders Jansson2, Jan W. Eriksson2, Ingibjorg H. Jonsdottir2. 1The Institute of Stress Medicine,

Gothenburg, Sweden; 2The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of

Gothenburg, Sweden

Lower fasting plasma glucose levels in patients with stress-related exhaustion

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�54years). 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 (4.790.4 mmol/L) compared with healthy controls

(5.090.5 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.

Keywords: blood sugar; burnout; exhaustion disorder; fatigue; stress


Tony W. Buchanan1, Christina N. White1, Mary Kralemann1, Stephanie D. Preston2. 1Department of Psychology,

Saint Louis University, St. Louis, MO, USA; 2Department of Psychology, University of Michigan, Ann Arbor, MI,USA

The contagion of physiological stress: causes and consequences

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 hasany 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. InStudy 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.

Keywords: physiological stress; salivary cortisol; salivary alpha-amylase; prosocial behavior; Trier Social Stress

Test (TSST)


Victor L. Kallen, Jan-Willem Mark, Luc Bischoff, Ben van Ommen, Nico van Meeteren. TNO, Netherlands

Organisation for Applied Scientific Research, The Netherlands

Predicting internalizing outcomes based on psychophysiological dynamics

Background: Our insight into the neurobiological dynamics underlying the processes that may over time cumu-

late into syndromes like burn-out and depression is rapidly developing. A recent, though important, step hasbeen 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 environ-ments) 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 foreasy to apply preventive strategies as well. These could be instrumental in averting long-term negative psychological

outcomes.

Keywords: depression; burn-out; prognostic modelling; allostasis; health


Marie-France Marin, Catherine Raymond, Julie-Katia Morin-Major, Anne Hand, Robert-Paul Juster, Shireen

Sindi, Sonia J. Lupien. Centre for Studies on Human Stress, Fernand-Seguin Research Center, Louis-H.

Lafontaine Hospital, University of Montreal, Montreal, QC, Canada





Tell me what you read and I will tell you if you are stressed: stress reactivity in consumers ofself-help books

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 toprovide 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 toquantify 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 depres-

sive 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 theefficacy 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.

Keywords: stress; cortisol; self-help books; auto-therapy


Jinshia Ly, Sivan Rotenberg, Jennifer J. McGrath. Department of Psychology, Concordia University, Montreal,

QC, Canada

Subjective sleep is associated with the diurnal cortisol profile in children and adolescents

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 a1�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 daytimesleepiness 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.

Keywords: sleep duration; sleep quality; diurnal cortisol profile; children and adolescents; parent-report


Yrsa Bergmann Sverrisdottir. Department of Clinical Neurophysiology, Institute of Neuroscience and Physiology,

Gothenburg, Sweden

Sympathetic nerve activity in takotsubo cardiomyopathy

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 affectingpostmenopausal 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.

Keywords: sympathetic nerve activity; takotsubo cardiomyopathy; emotional stress; women; postmenopaus; blood

pressure


Anna-Karin Lennartsson, Ingibjorg H. Jonsdottir. Institute of Stress Medicine, Gothenburg, Sweden

Lower DHEA and DHEA-S response during acute psychosocial stress is related to higherperceived stress at work

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 thezona 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 duringacute 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.

Keywords: acute stress; DHEA and DHEA-S response; prolonged stress


Pelle de Koning. Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam,

The Netherlands

Symptom improvement in deep brain stimulation for obsessive-compulsive disorder is related tocortisol changes

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.

Keywords: deep brain stimulation; nucleus accumbens; hypothalamic-pituitary-adrenal axis; cortisol;

catecholamines; obsessive-compulsive disorder


Robert-Paul Juster1,2, Nathan G. Smith3, Philip J. Johnson4, Jean-Philippe Lefebvre-Louis5, Marie-France

Marin1,6, Shireen Sindi1,2, Jens C. Pruessner2, Sonia J. Lupien1,7. 1Centre for Studies on Human Stress,

Fernand-Seguin Research Centre of Louis-H. Lafontaine Hospital, Montreal, QC, Canada; 2Department of

Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; 3Department of Educational andCounseling Psychology, McGill University, Montreal, QC, Canada; 4Department of Psychology, McGill

University, Montreal, QC, Canada; 5Department of Social Work, University of Montreal, Montreal, QC, Canada;6Department of Neuroscience, University of Montreal, Montreal, QC, Canada; 7Department of Psychiatry,

University of Montreal, Montreal, QC, Canada

The effects of sexual orientation on stress-reactive cortisol: are sexual minority women ruminativeand men resilient?

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 levelslate 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.

Keywords: sexual minority stress; cortisol; Trier Social Stress Test; stress reactivity; disclosure; rumination; resiliency


Pierrich Plusquellec, Alexandra Fiocco, Sonia J. Lupien. Centre for Studies on Human Stress, Fernand Seguin

Research Centre of Louis-H. Lafontaine; Department of Psychiatry, University of Montreal, Montreal, QC, Canada;

School of Psychoeducation, University of Montreal, Montreal, QC, Canada; Department of Psychology, RyersonUniversity, Toronto, ON, Canada

Low lead levels associated with blunted cortisol reactivity in a sample of elders from the generalpopulation

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 meanPb 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, pB0.03), even when controlling for age, and levels of education (n�73,

b��0.24, p�0.05).

Conclusions: Lead levels, even at a very low level of exposure, are associated with a blunted cortisol response

to the TSST. These findings support the relationship between environmental contaminants and stress, and support

the idea that regulation should be applied to the aging population. The next step will be to determine whether

the association between lead exposure and cognitive variability could be explained by impairment of the stresssystem.




Keywords: lead exposure; cortisol reactivity; diurnal cortisol activity; elders; general population; regulation


Claudia Vega-Michel, Everardo Camacho. Laboratorio de Psiconeuroinmunologıa, ITESO, Mexico

Sociodemographic variables, life style and cortisol levels in a sample of Mexicans

Kudielka, Hellhammer and Wust (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 pregnancyand 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.

Keywords: cortisol; sociodemographic variables; life habits; health; disease


Robert Miller, Tobias Stalder, Franziska Plessow. Department of Psychology, Technische Universitat Dresden,

Dresden, Germany

Evaluation of classification criteria for the detection of cortisol pulses in repeated-measuresdesigns

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 frequentsampling 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 thesubsequently 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.

Keywords: autoregressive latent trajectory model; cortisol; longitudinally; Trier Social Stress Test; time-series

variance


Nikolaos P. Daskalakis1,2 E. Ronald de Kloet1. 1Division of Medical Pharmacology, Leiden/Amsterdam Center for

Drug Research Leiden University Medical Center, Leiden, The Netherland; 2Current address: Department of

Psychiatry - Traumatic Stress Studies Division, Mount Sinai School of Medicine, New York, NY, USA

Animal model of differential susceptibility to stress in development: implications for schizophrenia

Rationale/ statement of the problem: Common gene variants predisposing for altered dopamine (DA) neuro-

transmission are candidates for schizophrenia-susceptibility genes, although genome-wide studies so far showed aweak 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 ratsexposed 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, characterizedby a severe deficit in sensorimotor gating and brain glucocorticoid-resistance, precipitates in the genetically pre-

disposed 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.

Keywords: animal model; schizophrenia; maternal behavior; cortisol; offspring






Janet M. Wojcicki, Melvin B. Heyman, Jue Lin, Elizabeth H. Blackburn, Elissa S. Epel. University of California

San Francisco, San Francisco, CA, USA

Early life obesity, maternal depression, and telomere length in Latino children

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 tocompare 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 pB0.10 were subsequently entered into a multivariate regression model to evaluate independent predictors for

shortened TL.

In bivariate analysis, being obese at 6 months of age (weight/length]95th percentile) and being obese at both 6

and 12 months of age were associated with shorter TL at age 4 (1.6290.36 versus 1.8490.34, p�0.02 and 1.449

0.30 versus 1.8290.34, p�0.02, respectively). Exposure to maternal depressive symptoms at age 3 was also

associated with shorter TL (1.6690.25 versus 1.8190.33, p�0.07). Children of Mexican descent tended to havelonger telomeres than those of Central American ancestry (1.8590.31 versus 1.7390.38, pB0.07). Exposure to

maternal depressive symptoms at other timepoints in early childhood and internalizing or externalizing behavior

was not associated with shorter TL. In linear multiple regression analysis, female sex (Coeff�0.18, 95%CI: 0.04�0.31) as and maternal TL (Coeff�0.18, 95% CI: 0.04�0.31) predicted longer TL, whereas being obese at 6 and 12

months (Coeff��0.49, 95% CI: �0.79 to 0.19) predicted shorter TL.

In this population of low-income Latino children, obesity in the first year of life was associated with shorter telomere

length at age 4, independent of sex mother’s TL and mother’s depression. Thus, obesity early in life may shape TL,

whereas obesity in the toddler and preschool years may be less associated with obesity at age 4.

Keywords: childhood; obesity; stress; maternal depression; Latino


Julia Morgan, Solara Calderon, Molly Lebow, Dan Iosifescu, Dennis Charney, Adriana Feder. Department of

Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

Childhood trauma and comorbid mood and anxiety disorders in adult patients with post-traumaticstress disorder

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 samestudy. 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 (rpb�.42, pB.001) and logistic regression indicated that

CT exposure predicted comorbid anxiety disorder diagnosis after controlling for demographics, mood disorder, and

PTSD severity. Significant correlations were also identified between particular CT subtypes and the presence of a

comorbid anxiety disorder. Total CT exposure did not predict current or past mood disorder diagnosis or

depression severity. These findings support a relationship between CT and the presence of additional anxiety




disorders in adult patients with PTSD, and highlight the need for thorough diagnostic assessment and special

treatment planning to address the full spectrum of psychopathology in adult PTSD patients with significant

histories of CT.

Keywords: childhood trauma; PTSD; mood disorders; anxiety disorders


Rasha Hammamieh, Seid Muhie, Ruoting Yang, Marti Jett. Integrative and Systems Biology, US Army Center for

Environmental Health Research, Fort Detrick, MD, USA

Systems biology of post-traumatic stress disorder: characterization of pathways and networksinvolved in the development of PTSD

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 stressresponses. 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 ofthe 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 theirassociated 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.

Keywords: genetics; DNA methylation; animal model; trauma; PTSD


Alicia R. Revitsky, Laura Cousino Klein. The Pennsylvania State University, University Park, PA, USA

Nicotine exposure results in food consumption differences between adolescent and adult femalemice

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 dotheir 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 mg/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 (pB0.05). Mice exposed to high fat foodweighed the most, but ate the least (pB0.05). While there were no main effects of nicotine on body weight in either





age group, nicotine-exposed adults consumed less food than did water-exposed adults (pB0.05), this effect was not

seen in adolescents. Among the nicotine-exposed mice, adolescents consumed more food than did adults (pB0.05).

Conclusions: These findings suggest, in females, the appetite suppression qualities of nicotine differ basedon age, with nicotine exposure actually increasing food consumption in adolescents. Nicotine’s effects on food

intake do not result in body weight changes in either age group.

Keywords: nicotine exposure; food consumption; adolescent; adult; female; mice


James O’Reilly, Nor Mohd-Shukri, Jonathan R. Seckl, Jane E. Norman, Rebecca M. Reynolds. Centre for

Cardiovascular Science, University of Edinburgh, Edinburgh, UK

Altered glucocorticoid action in obese pregnancy is modulated by diet and is associated withgestational weight gain but has similar influences on birthweight in males and females

Rationale/ statement of the problem: One in five UK women is obese at antenatal booking. Maternal obesityincreases 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 (BMIB25 kg/m2) pregnant women. mRNA levels of 11-beta hydroxysteroid dehydrogenase

type 2 (11bHSD2), 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 (pB0.05) Obese reportedsimilar appetite and total calorie intake to lean but had significantly less gestational weight gain (10.193.7 kg vs.

5.595.6 kg, pB0.01); this inversely correlated with cortisol levels (r��0.27, pB0.01). Cortisol levels correlated

positively with reported pregnancy intake of protein, fat, saturated fatty acids and sugars in lean (all pB0.05).

Placental expression of 11bHSD2 increased in association with increasing obesity in early pregnancy (r�0.21,

pB0.01) and was highest in term placenta in obese women with macrosomic (�4000 g) offspring (pB0.05). There

were no gender-specific effects of maternal overnutrition on birthweight, placental gene expression or maternal

glucocorticoid levels.

Conclusions: Lower circulating cortisol levels in obese pregnancy, together with the more effective placental barrierto maternal glucocorticoids may be a mechanism contributing to higher birthweight in offspring of obese women.

In lean women, dietary composition may regulate cortisol levels during pregnancy.

Keywords: maternal obesity; cortisol levels; birthweight; gestational weight gain


Judith P. ter Horst, Maaike H. van der Mark, E. Ronald de Kloet, Melly S. Oitzl. Department of Medical

Pharmacology, Leiden University Medical Center, Leiden, The Netherlands

Sex differences in fear conditioning: a role of the forebrain mineralocorticoid receptor

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 depressionin 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 controlmice. 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.

Keywords: fear conditioning; sex differences; mineralocorticoid receptor


Kavita Vedhara, Chris Metcalfe, Heather Brant, Anna Crown, Kate Northstone, Karen Dawe, Stafford Lightman,

George Davey-Smith. University of Nottingham, Nottingham, UK; University of Bristol, Bristol, UK

Maternal mood and neuroendocrine programming: effects of time of exposure and sex

Rationale/ statement of the problem: Adverse exposures that influence growth in prenatal and early postnatalperiods 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 havesustained programming effects on the SNS and HPA axis. Effects on the SNS were restricted to male offspring.

Keywords: maternal mood; HPA; SNS; foetal programming hypothesis


Pardis Esmaeili, Eli Puterman, Aric Prather, Sheila Loharuka, Elissa S. Epel, David Rehkopf, Zoe Evans, A. Janet

Tomiyama, Barbara Laraia. Psychiatry, UCSF, San Francisco, CA, USA; School of Medicine, Stanford University,

Stanford, CA, USA; Psychology, Rutgers University, Piscataway, NJ, USA; School of Public Health, UCB, Berkeley,

CA, USA

The lingering effect of childhood socioeconomic status: parental education predicts diurnal cortisoltrajectory in adulthood

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 individualeducation. 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 (btime�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, pB0.001) than those with more than a high

school diploma (b��0.26, SE�0.02, pB0.001). Cortisol slopes were also a function of parental education

(btime*parental education��0.04, SE�0.02, p�0.038). Simple slopes analyses revealed that women with parents who

received only high school educations had significantly flatter cortisol slopes (b��0.20, SE�0.06, pB0.001)

compared to those with parents who received more than a high school diploma (b��0.24, SE�0.02, pB0.001).

Importantly, the effect of parental education was independent of individual education. These findings provide

preliminary evidence that parental education, a marker of childhood SES, can influence neuroendocrine activitybeyond childhood, having lasting effects into adulthood with important implications for health.

Keywords: cortisol; diurnal slope; HPA-axis; childhood SES; parent education


Linn Kristina Kuehl1, Frank Zimmermann-Viehoff2, Heidi Danker-Hopfe1, Mary A. Whooley2,3, Christian Otte1.1Department of Psychiatry and Psychotherapy, Campus Benjamin Franklin, Charite University Medicine Berlin,

Berlin, Germany; 2VA Medical Center, San Francisco, CA, USA; 3Department of Medicine and of Epidemiology

and Biostatistics, University of California, San Francisco, CA, USA

Tricyclic antidepressants, autonomic function and mortality in patients with coronary heartdisease: data from the heart and soul study

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

7.292.6 years. Standard deviation of all normal RR intervals (SDNN) as a measure of HRV was calculated from24 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 (pB0.01) and in the highest tertile

of urinary NE (pB0.01) and plasma NE (pB0.01). Adjustment for age, sex, smoking, diabetes, congestive heart

failure and depressive symptoms did not significantly change the results.Conclusion: Use of TCAs was associated with increased mortality in patients with CHD. Unfavourable changes in

autonomic function as marked by low HRV and high NE levels might be a potential mechanism.

Keywords: depression; coronary heart disease; tricyclic antidepressants; heart rate variability; norepinephrine


Kim Hinkelmann, Christoph Muhtz, Lucia Dettenborn-Betz, Agorastos Agorastos, Katja Wingenfeld, Carsten

Spitzer, Klaus Wiedemann, Christian Otte. Department of Psychiatry, Charite Medical Center, Campus Benjamin

Franklin, Berlin, Germany; Department of Psychosomatics, University Hospital of Hamburg UKE, Hamburg,Germany; Department of Psychiatry, University Hospital of Hamburg UKE, Asklepios Fachklinik Tiefenbrunn,

Germany





Cortisol awakening response is associated with hippocampus-dependent cognitive impairment inmajor depression

Rationale: Cognitive deficits and alterations in cortisol secretion are characteristic features of major depres-

sion disorder (MDD). The cortisol awakening response (CAR) is altered in depression and crucially depends onhippocampus 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 negativecorrelation 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.

Keywords: cortisol awakening response; depression; memory


Caroline Bull1,2, Helen Christensen3, Michael Fenech1. 1CSIRO Food and Nutritional Sciences, Adelaide,

Australia; 2Department of Microbiology & Immunology, School of Molecular & Biomedical Sciences, University

of Adelaide, Australia; 3Black Dog Institute, University of New South Wales, Sydney, NSW, Australia

Cortisol is associated with longer telomeres in human lymphocytes cultured in folate-replete anddeficient conditions

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 de-

generative 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 5393 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 nMcortisol. 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 (pB0.03). In FA-deficient cultures TL increased with increasing cortisol,

however, this effect was not significant in this sample size. TL was longer in lymphocytes cultured in low FA

conditions, compared with those in FA-replete medium (pB0.0001). The strongest cell growth was recorded in

FA-replete cultures, with cortisol having no effect. Cell viability (%) was higher in cells exposed to cortisol, and this




effect was strongest in FA-deficient cultures, with 16% of variance being attributable to treatment (p�0.0002), and

72% to time (pB0.0001).

Conclusions: The results of this study do not support the hypothesis that cortisol, folate deficiency or their interactioncan explain telomere shortening associated with psychological stress. Further analyses are being performed to deter-

mine if cortisol causes changes in CIN or epigenome status and the extent to which these effects correlate with TL.

Keywords: telomere; cortisol; folate; DNA damage; methylation; lymphocytes


Christopher Cardoso, Mark A. Ellenbogen, Anne-Marie Linnen, Ridha Joober. Centre for Research in HumanDevelopment, Concordia University, Montreal, QC, Canada; Douglas Mental Health University Institute, McGill

University, Montreal, QC, Canada

The effect of intranasal oxytocin on perceiving and understanding emotion on the Mayer-Salovey-Caruso Emotional Intelligence Test

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, pB.01, h2�.10).

Accuracy ratings worsened following oxytocin because participants rated all emotions with greater intensity,

particularly facial expressions of surprise and disgust. Oxytocin did not influence performance on tasks related tounderstanding emotions or tasks using non-social stimuli.

Conclusions: Oxytocin appears to influence the recognition of facial expressions of emotion by increasing

the perceived intensity of the emotion, while having no effect on more complex processing (i.e., understand-

ing emotion). The present findings further support the view that oxytocin influences social information proces-

sing by increasing the salience of emotional stimuli, which may have positive or negative effects depending on

context.

Keywords: MSCEIT; intranasal oxytocin; surprise; disgust; emotion recognition; faces


Marıa-del-Carmen Augustin-Morales, Marıa-Josee Ruiz-Ramos, Isabel Cubero-Millan, Laura Moreno-Garcıa,

Fuensanta Justicia-Martınez, Ana Naranjo-Goomez, Eduardo Narbona-Loopez, Antonio Molina-Carballo. UGC

Pediatrıa. Hospital Clınico San Cecilio, SAS, Universidad de Granada, Granada, Spain

Methylphenidate does not restore the reduced serum BDNF levels in ADHD children

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 thetropomyosin-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

36.36911.62 31.78911.92 31.96912.57 28.40912.50 29.43912.00 26.73912.32

Basal measurements: Day/night comparisons: z��2.76, p�0.006. Group comparison: z��2.19; p�0.028.

ADHD pre vs. post: x2�2.64, p�0.1042; day vs. night: x2�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 previouscontribution that indicates an increase of BDNF in untreated ADHD children, with positive correlation with theseverity of the symptoms of inattention. In addition, we report for the first time ‘‘basal’’ response to treatment withPRMPH, with somewhat surprising results, because as neuronal trophic factor, one might expect an increase inserum in response to methylphenidate, that ameliorates neuropsychological and organic immaturity, proven the lastin studies of volumetric magnetic resonance imaging (MRI).

Keywords: methylphenidate; reduced serum; BDNF levels; ADHD; children


Antonio Molina-Carballo, Isabel Cubero-Millan, Mara-Jose Ruiz-Ramos, Irene Machado-Casas, Francisco

Contreras-Chova, Francisco Moreno-Madrid, Jose Uberos, Antonio Munoz-Hoyos. UGC Pediatrıa. Hospital

Clınico San Cecilio, SAS, Universidad de Granada, Granada, Spain

Different basal concentration and different response of BDNF to prolonged releasemethylphenidate between ADHD subtypes

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 hyperactivitydisorder (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; 88males, 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 (36.36911.62 ng/ml) was very similar to

the value seen in the predominantly inattentive subgroup of ADHD children, although evening concentration was

higher (31.78911.92 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 (x2�6.62, p�0.010).

Serum BDNF (ng/ml) in ADHD children

Pre-MPH Post-MPH

ADHD subtype Day Night Day Night

PHI/CD 30.76912.34 29.09912.82 30.29912.5 27.25912.93

PDA 35.31912.85 26.41911.55 26.97910.3 25.05910.21

PDA: Day vs. Night, pre: x2�11.63, p�0.0019. ADHD pre- vs. post-treatment, day: x2�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.

Keywords: basal concentration; response of BDNF; prolonged release; methylphenidate; ADHD subtypes


Heidi Noel Boyda, Ric M. Procyshyn, Lurdes Tse, Erin Hawkes, C. Helen Jin, Catherine C.Y. Pang, William G.

Honer, Alasdair M. Barr. Departments on Pharmacology and Psychiatry, Faculty of Medicine, University ofBritish Columbia, Vancouver, BC, Canada

‘‘Differential effects of three classes of antidiabetic drugs on olanzapine-induced glucosedysregulation and insulin resistance in female rats’’

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 dysregula-

tion 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.

Keywords: olanzapine; metformin; rosiglitazone; glyburide; glucose intolerance; insulin resistance


Ellen Gabrielle Waxler, Cecilia Martinez-Torteya, Alex Busuito, Amanda Broderick, James L. Abelson, Maria

Muzik. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

Early cortisol awakening response as a biological risk marker in young children

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 CARwould 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), werenot 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.

Keywords: preschoolers; cortisol awakening response; stress; risk factors; internalizing problems; externalizing

problems


Jai Y. Park1, Ryun S. Ahn2. 1Department of Anesthesiology and Pain Medicine, The Armed Forces Capital

Hospital, Seoul, Korea; 2Department of Integrative Medicine, CHA Medical University, Seoul, Korea

The hypothalamus�pituitary�adrenal axis in patients with CRPS type 1: molar cortisol to DHEAratio increases with disease duration

Background: The main complaint symptom of complex regional pain syndrome type 1 (CRPS-1) is neuro-

pathic 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 awakeningin 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 groundwithin the first hour after awakening (DHEAauc) was used as an index of DHEA secretion.

Results: The mean BDI scores of patients were 19.099.0 (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 month5) had a higher molar F/Dauc ratio than both controls and patients whosuffered 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.

Keywords: CRPS-1; BDI scores; CAR; molar cortisol to DHEA ratio; disease duration; medication condition


Itziar Montalvo, Laura Ortega, Xavi Lopez, Montse Sole, Rosa Monseny, Joan Franch, Javier Labad. Hospital

Universitari Psiquiatric Institut Pere Mata, Reus, Spain, Institut d’Investigacio Pere Virgili, Reus, Spain, Universitat

Rovira i Virgili, Tarragona, Spain

Changes in prolactin levels and sexual functioning after switching from long-acting injectablerisperidone to paliperidone palmitate in young psychotic patients: a case series

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 andpaliperidone 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 (ArizonaSexual 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-valueB0.05 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 a3-month period. However, changes in prolactin levels were not associated with a significant improvement in sexual

functioning.

Keywords: prolactin levels; sexual functioning; risperidone; paliperidone palmitate; a case series; psychosis


Rosa Monseny, Laura Ortega, Itziar Montalvo, Joan Franch, Brian Walker, Rebecca Reynolds, Javier Labad.

Hospital Psiquiatric Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain

Overeating is associated with increased salivary cortisol and greater BMI in subjects with earlypsychosis

Statement of the problem: Subjects with psychosis are at risk for metabolic syndrome, mainly secondary toantipsychotic 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.

Keywords: prolactin levels; sexual functioning; a case series; psychosis patients; risperidone


Paula Lynn Ruttle, Elizabeth A. Shirtcliff, Jeffrey M. Armstrong, Marjorie H. Klein, Marilyn J. Essex. Department

of Psychiatry, School of Medicine and Public Health, University of Wisconsin�Madison, Madison, WI, USA;

Department of Psychology, University of New Orleans, New Orleans, LA, USA

Clarifying divergent hormone-behavior associations: the influence of neuroendocrine measures andearly maternal depression on adolescent mental health trajectories

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, pB0.05) 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, pB0.05) 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, pB0.05) 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.Conclusions: 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.

Keywords: cortisol; testosterone; DHEA; early maternal depression; mental health; adolescence


Patrick H. Roseboom, Steve A. Nanda, Jonathan A. Oler, Andrew S. Fox, Alexander J. Shackman, Steve E.

Shelton, Ned H. Kalin. Department of Psychiatry, University of Wisconsin, Madison, WI, USA

Serotonin 2c receptor gene expression in the rhesus amygdala predicts anxious temperament

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 contributeto 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 withcorrection 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, pB0.01) was identified in the

microarray analysis as significantly negatively correlated with AT. Quantitative real-time polymerase chain reaction

analysis using the same CeA RNA samples confirmed this association (r��0.65, pB0.001). Underscoring the

anatomical specificity of this effect, the significant relationship between 5HT2C receptor mRNA levels and AT was

not observed in the motor cortex, a brain region not associated with AT (r�0.10, p�0.64).Conclusions: Previous work by others has shown robust levels of 5HT2C receptor mRNA and radioligand binding

in the monkey CeA. In addition, rodent models have indicated a role for the 5HT2C receptor in anxiety-like

responding. Our findings suggest that higher levels of 5HT2C receptor gene expression are associated with lower

levels of AT. Increased expression of the gene encoding for this receptor may facilitate 5HT signaling in the

amygdala thereby promoting adaptive responses and resilience to potentially anxiety provoking situations.

Keywords: serotonin; 2c receptor; gene expression; rhesus amygdale; anxiety; temperament






Laura Kurtzman, Aoife O’Donovan, Katrina Koslov, Justine Arenander, Elissa S. Epel, George Slavich. University

of California, San Francisco, USA; University of California, Los Angeles, CA, USA

Sweating the big stuff: dispositional pessimism exacerbates the deleterious effects of life stress onmetabolic health

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 greatermetabolic risk, independent of age, income and caregiver status (Pessimism: b�0.49, pB0.001; Stress: b�0.33,

p�0.003). Moreover, when adjusting for age, income and caregiver status, pessimism interacted with cumulative

stress exposure to predict greater metabolic risk (F�7.29, p�0.01). Decomposing this interaction effect revealed that

pessimistic individuals experiencing high levels of cumulative life stress had the poorest metabolic health.

Conclusions: These results suggest that pessimistic individuals living under high levels of stress may have the

greatest risk for cardiovascular disease and highlight pessimistic beliefs as a possible treatment target for reducing

stress-related disease burden.

Keywords: pessimism; life stress; metabolic health; cardiovascular disease


Alexandra Dupont, Julienne E. Bower, Patricia A. Ganz. University of California Los Angeles, Los Angeles, CA,

USA

Lower heart rate variability is associated with cancer-related fatigue in breast cancer survivors

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 parasympa-

thetic 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 cancersurvivors.

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 nervoussystem 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.




Keywords: heart rate variability; autonomic nervous system; fatigue; breast cancer


Sarah B. Lupis, Myriam V. Thoma, Nicolas Rohleder, Jutta Wolf. Institution of Psychology, Brandeis University,

Waltham, MA, USA

Gender-dependent effects of body esteem and appraisal on cortisol stress responses

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, 2192 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 (b�0.44, p�0.047). The same pattern was found for the two BE subscales

addressing weight and overall appearance (b�0.42, p�0.04; b�0.42, p�0.04), but not for the attribution subscale

(pB0.24). Body esteem was also associated with challenge appraisals in a gender-dependent manner: males withhigh BE reported feeling less challenged, while females with high BE reported feeling more challenged (b��0.63,

p�0.005). Neither threat nor challenge scores were themselves linked to cortisol responses.

Conclusions: Despite the strong social-evaluative component of our stress test, these findings suggest that how one

feels about one’s weight and overall physical appearance matters more than what one thinks others may think in

this regard. Interestingly, those feelings and beliefs may be associated with gender differences in stress appraisal,

such that for females, high BE may be stress protective, while for men, low BE may lead to disengagement from

a stressful situation.

Keywords: cortisol; stress; body esteem; threat; challenge; appraisal


Alpay Ates, Osman Metin Ipcioglu, Alpaslan Cosar, Tutuncu Recep, Gunay Huseyin, Algul Ayhan, Ebrinc Servet.

GATA Haydarpasa Military Training Hospital, Psychiatry and Biochemistry Services, Istanbul, Turkey

Hyperprolactinemia and amenorrhea associated with risperidone normalized after switching toolanzapine: a case report

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.

Keywords: olanzapine; risperidone; hyperprolactinemia; amenorrhea; treatment; psychosis


Alpay Ates, Osman Metin Ipcioglu, Recep Tutuncu, Alpaslan Cosar, Huseyin Gunay, Cengiz Basoglu. GATAHaydarpasa Military Training Hospital, Psychiatry and Biochemistry Services, Istanbul, Turkey

Amenorrhea associated with olanzapine normalized after switching to aripiprazole: a case report

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. After3 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, womentreated 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.

Keywords: aripiprazole; olanzapine; amenorrhea; treatment; psychosis


Andrew Garton, Ivan Vargas, Paige Galecki, Nestor L. Lopez-Duran. University of Michigan, Ann Arbor, MI,USA

Understanding the impact of sleep duration on cortisol awakening response during earlyadulthood

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 sleepand 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 onCAR. 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, pB0.0001), but a steeper post-awakening cortisol

slope (t��2.55, p�0.01). After accounting for TST, however, sleep quality did not significantly predict any

parameters in the model.

Conclusions: Contrary to prior research that has reported no or a small association between sleep duration and

CAR, our study shows that participants with shorter sleep duration have lower cortisol levels at awakening and a

faster rate of cortisol increase following awakening. Thus, these findings suggest that the amount a person sleepsmay directly impact their diurnal cortisol pattern the subsequent morning.

Keywords: HPA axis; cortisol; sleep; college students


Wei Gao1,2, Tobias Stalder1, Susann Steudte1, Clemens Kirschbaum1, Paul Foley1, Manfred Rauh3, Huihua

Deng2. 1Department of Psychology, Technical University of Dresden, Dresden, Germany; 2Key Laboratory of

Child Development and Learning Science (Southeast University), Ministry of Education, Research Center of

Learning Science, Southeast University, Nanjing, China; 3Kinder- und Jugendklinik, Universitatsklinikum

Erlangen, Erlangen, Germany

Determination of steroid hormones in human hair as a retrospective biomarker withHPLC-MS/MS

Statement of the problem: The analysis of steroid hormones in hair is increasingly used in psychoneuroendocri-

nological 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.

Keywords: human hair; steroid hormones; high performance liquid chromatography; mass spectrometry


Katharina Gaudlitz, Jens Plag, Sarah Schumacher. Department of Psychiatry and Psychotherapy, Charite,

Universitatsmedizin Berlin, Berlin, Germany





Distinct panicogenic activity of sodium lactate and cholecystokinin tetrapeptide in patients withpanic disorder

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 ofpsycho 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.

Keywords: panic disorder; CCK-4; lactate; acute panic inventory; panicogenic activity


Franziska Plessow, Susann Schade, Clemens Kirschbaum, Rico Fischer. Department of Psychology, Technische

Universitat Dresden, Dresden, Germany

Acute psychosocial stress determines cognitive control states in dual-task performance

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 ofhow 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 a-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.

Keywords: psychosocial stress; cognitive control; dual task performance; HPA axis; physiological stress






Jonathan A. Shaffer, Elissa S. Epel, Min Suk Kang, Siqin Ye, Joseph E. Schwartz, Karina W. Davidson, Susan

Kirkland, Lawrence S. Honig, Daichi Shimbo. Columbia University, New York, NY, USA; University of

California-San Francisco, San Francisco, CA, USA; Dalhousie University, Halifax, NS, Canada

Depressive symptoms are not associated with leukocyte telomere length: findings from the NovaScotia Health Survey (NSHS95) population-based study

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, butthese 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.

Keywords: depression; depressive symptoms; telomere; cardiovascular disease; cellular aging


Andrew S. Fox, Jonathan A. Oler, Alexander J. Shackman, Andrew L. Alexander, Richard J. Davidson, Ned H.

Kalin. Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, USA

Cortisol predicts decreased cerebral cortical volume in 592 young non-human primates

Background: Cortisol is a stress-related hormone that interacts with peripheral and neural systems. Althoughcortisol 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 (m-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 transformationinto 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, qB0.05, two-tailed) between the log-jacobian and cortisol in

cytoarchitectonic areas 47o, 46/9, 46 and 8 within the PFC, as well as motor area 4 and parietal area PGa (MIP).



http://www.picsl.upenn.edu/ANTS/


Conclusions: These results provide novel evidence that higher cortisol is associated with less PFC volume in young

primates, and builds on previous work examining the relationship between stress and cortical thickness in older

adult humans. These data, collected in very young animals, demonstrate that PFC volume and cortisol are negatively

associated early in life. These findings are particularly interesting because the PFC regions identified here undergo

substantial development throughout late childhood and early adulthood. Moreover, because changes in PFC are

thought to underlie the emergence of adult-like cognitive and emotional functioning, our findings may have great

relevance to the later development of affective psychopathology.

Keywords: cortisol; prefrontal cortex; primate; imaging; anxiety


Do P.M. Tromp, Andrew S. Fox, Jonathan A. Oler, Nagesh Adluru, Richard J. Davidson, Andrew L. Alexander,

Ned H. Kalin. Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, USA

Cortisol predicts increased internal capsule integrity in a large sample of non-human primates

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) structurewithin 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 themonkey. 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 (pB0.001,

two-tailed test, uncorrected), among other regions. The internal capsule is widely connected to distributed brain

regions. Therefore, we used deterministic tractography to specifically identify the regions that were connected to

the internal capsule region that predicted plasma cortisol levels. Results demonstrated connectivity with the dorsal

putamen, anterior cingulate, hypothalamus, and brainstem structures.

Conclusions: Our data suggest that naturally occurring increased levels of cortisol are associated with structuraldifferences in key WM regions that coordinate long-range connectivity. Because these connections are important

for adaptive and maladaptive stress responses, these findings are highly relevant to understanding the development

of stress-related psychopathology.

Keywords: cortisol; diffusion tensor imaging; DTI; primate; anxiety


Justine Arenander, Kirstin Aschbacher, Laura Kurtzman, Jue Lin, Aric Prather, Eli Puterman, Katrina

Koslov, Josh Cheon, Owen M. Wolkowitz, Elizabeth H. Blackburn, Elissa S. Epel. University of California, SanFrancisco, CA, USA

Cell aging and resilience: associations between daily emotion regulation and increased telomeraseactivity

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.



http://www.nitrc.org/projects/dtitk

http://www.nitrc.org/projects/dtitk



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 DepressiveSymptoms. 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, pB0.01) and higher levels of depressive symptoms (r��0.24,

p�0.05). There were no overall differences in telomerase activity between caregivers versus controls.Conclusion: These are the first findings to link daily emotion-regulation processes to telomerase activity. Daily

emotion regulation strategies characterized by greater engagement with the positive and lower emotional

suppression are associated with increases in telomerase, which may contribute to resilient immune cell aging.

Emotion regulation, particularly in relation to the use of strategies that maintains a positive outlook in the face of

stressful life exposures, may protect against cell aging.

Keywords: emotion regulation; cell aging; telomerase; telomeres; coping; positive psychology; chronic stress;

psychoneuroimmunology; resilience


Daniel Belsky. Duke University, Durham, NC, USA

Polygenic risk accelerates the developmental progression to persistent heavy smoking and nicotinedependence: evidence from a 4-decade longitudinal study

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 ofsingle-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 de-

pendence (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 adolescentdevelopmental 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.

Keywords: smoking behavior; genetic risk; longitudinal study; adolescent development






Owen M. Wolkowitz, Synthia H. Mellon, Elizabeth H. Blackburn, Jue Lin, Elissa S. Epel, Victor I. Reus, Heather

M. Burke, Rebecca Rosser, John Coetzee, Laura Mahan, Michelle Coy, Scott Mackin, Steven P. Hamilton, J. Craig

Nelson, Michael W. Weiner, Susanne Mueller. Department of Psychiatry, University of California School of

Medicine, San Francisco, CA, USA

PBMC telomerase activity correlates with hippocampal volume in major depression

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 relationshipbetween 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 positivelycorrelated with HC volume (r�0.49, pB0.04).

The relationship between telomerase activity in PBMCs and telomerase activity in the HC is unknown.

Nonetheless, these results are consistent with emerging preclinical data that telomerase may have neurotrophic and

antidepressant effects, may facilitate the neurotrophic effects of brain derived neruotrophic factor (BDNF) and

may reverse certain signs of aging, and with clinical data that telomerase may be associated with favorable

antidepressant responses. Our finding of significant telomerase/HC correlations only in the MDD subjects raises

the possibility that telomerase may play a compensatory or reparative role in this disease.

Keywords: telomerase; depression; hippocampal volume; antidepressant effects


Owen M. Wolkowitz, Jin Rowen, Sara Mason, Synthia H. Mellon, Victor I. Reus, Elissa S. Epel, Heather M. Burke,

Rebecca Rosser, John Coetzee, Laura Mahan, Michelle Coy, J. Craig Nelson, Steven P. Hamilton, Sally Mendoza,

Michael W. Weiner, Susanne Mueller. Department of Psychiatry, University of California School of Medicine, San

Francisco, CA, USA

Cortisol awakening response and cortisol/DHEA ratio associations with hippocampal volume inMDD

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 tothe 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 samplecollections.

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 (pB0.04). In the combined sample and in

the MDD group separately, the serum ratio of cortisol/DHEA was inversely correlated with HC volume (pB0.002

and p�0.009, respectively).

The average CAR slope across all three days of collection was not significantly correlated with HC volume.

However, consistent with reports that CAR reactivity is greatest on the first day of collection, CAR slopes on Day

1 were negatively correlated with total HC volume (pB0.02) and with CA1 subfield volume (pB0.05). Correlation




coefficients were similar in the separate MDD and control groups but were not statistically significant, given the

smaller sample sizes.

This exploratory study (small sample with no correction for multiple comparisons) suggests that stimulated(e.g., CAR) cortisol levels and consideration of cortisol in relation to DHEA, are more likely to reveal significant

correlations with HC volume. HC volume may be especially sensitive to stimulated peak levels of cortisol and to

cortisol actions when unmitigated by DHEA actions.

Keywords: cortisol; depression; hippocampus; DHEA; cortisol awakening response


Henning Budde, Mirko Wegner, Claudia Windisch. Department of Sport Science, School of Science and

Engineering, Reykjavik University, Reykjavik, Iceland

Influence of physical activity and acute exercise on cognitive performance and saliva testosteronein preadolescent school children

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) of180�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 theT 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.

Keywords: testosterone; acute exercise; children; school; cognition; physical activity


Matthis Wankerl, Robert Miller, Tobias Stalder, Clemens Kirschbaum, Nina Alexander. Biopsychology,Technische Universitat, Dresden, Germany

The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cortisol stressreactivity: a meta-analysis

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 investi-

gated 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 identifiedthrough 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.

Keywords: 5-HTTLPR; hypothalamus-pituitary-adrenal axis; stress; cortisol; saliva; meta-analysis


Jin-Young Kim, Eunyoung Park, Joo Young Lee, Jong-Ho Lee, Jeong Won Jahng. Dental Research Institute,

Department of Oral and Maxillofacial Surgery, Seoul National University School of Dentistry, Seoul, Korea

Free access to highly palatable food during adolescence and youth ameliorates depression-likebehaviors of female, but not male, rats that experienced neonatal maternal separation

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.

Keywords: neonatal maternal separation; palatable food; adolescence; psycho-emotional behaviors


Anett Mueller, Magdalena Jurkiewicz, Jamie Ferri, Stephanie Izzi, C. Johns, Xiao Wu, A.A. Stone, Turhan Canli.

Stony Brook University, Stony Brook, NY, USA

MicroRNA profiling of the human stress response

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 theAffymetrix 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.

Keywords: stress; gene expression; microRNA


Christorpher Murgatroyd, Lindsay Carini, Benjamin Nephew. Department of Biomedical Sciences, Tufts University

Cummings School of Veterinary Medicine, Grafton, MA, USA; School of Healthcare Science, Manchester

Metropolitan University, Manchester, UK

Effects of chronic social stress on maternal behavior, anhedonia, milk intake, pup growth, and geneexpression

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 toinclude 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.

Keywords: postpartum depression; anxiety; maternal behavior; stress; anhedonia


Sandra Waeldin1, Dominic Vogt1, Torsten Hero1, Michael Linden2, Dirk H. Hellhammer1. 1Department of Clinical

and Physiological Psychology, University of Trier, Trier, Germany; 2Research group Psychosomatic Rehabilitation,

Charite University, & Department of Behavioral Medicine and Psychosomatics, Rehabilitation Center Seehof,

Berlin, Germany

Cortisol levels differ after the low dose dexamethasone-suppression test in outpatients andinpatients with stress related disorders as compared to healthy subjects

Rationale/ 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 bothsupersuppression (B2 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 protectedagainst 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.

Keywords: cortisol response; stress; dexamethasone suppression; stress-related disorders; inpatient; outpatient


Jessica Raper1,3, Mark Wilson2,3, Mar Sanchez2,3, Jocelyne Bachevalier1,3. 1Department of Psychology;2Department of Psychiatry and Behavioral Sciences; 3Yerkes National Primate Research Center, Emory University,Atlanta, GA, USA

Neonatal orbital frontal damage alters basal cortisol and emotional reactivity, but not stressreactive cortisol response, in adult rhesus monkeys

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 ascompared 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.

Keywords: stress; cortisol response; orbital frontal cortex; HPA activity; emotional reactivity






Dixie Meyer. Saint Louis University, St. Louis, MO, USA

Investigating the effects of hormonal contraceptive use on mood and sexuality

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 includ-ing 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.

Keywords: hormonal contraception; psychological distress; sexuality; mood


Yoshihiro Maruyama, Aimi Kawano, Shizuko Okamoto, Tomoko Ando, Yoshinobu Ishitobi, Yoshihiro Tanaka,

Masayuki Kanehisa, Haruka Higuma, Taiga Ninomiya, Aya Inoue, Jusen Tsuru, Jotaro Akiyoshi. Department of

Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan

The comparative study of salivary alpha-amylase and salivary cortisol reaction to electricstimulation in avoidant personality disorder

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 avoidanceof 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 investi-

gated 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 SAMsystems, 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 25.294.4) and 126

healthy volunteers with no history of psychiatric disorder (56 males and 70 females, aged 25.994.5) 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.

Keywords: cortisol; personality disorders; avoidant personality disorder; stress; salivary markers


Jotaro Akiyoshi, Yoshihiro Tanaka, Yoshinobu Ishitobi, Yoshihiro Maruyama, Aimi Kawano, Tomoko Ando,

Shizuko Okamoto, Masayuki Kanehisa, Haruka Higuma, Taiga Ninomiya, Jusen Tsuru, Hiroaki Hanada.

Department of Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan

Salivary alpha-amylase and cortisol responsiveness following electrical physical stress in bipolardisorder patients

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 andsalivary 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 vari-ability 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.

Keywords: salivary markers; bipolar disorder; cortisol response; stress; biological markers






Jussi Jokinen, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

Interleukin-6 reflects trait impulsivity in suicide attempters

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 (R2�0.40, F ratio�7.3, df�6, pB0.0001), and the results suggested

that high scores on Extraversion were associated with high levels of IL-6 (t ratio�4.14, pB0.0001). IL-6 levels

showed a significant positive correlation with trait impulsivity (r�0.39, p�0.003).

Conclusions: In suicide attempters, IL-6 may be related to trait impulsivity, a key feature of the suicidaltemperament. This study motivates further studies on cytokine activity and their involvement in behavioural

development. The study adds further support on biological involvement in suicidal behaviour.

Keywords: cytokines; neuroinflammation; suicide; depression; personality; impulsivity


Leah H. Rubin1, Kathleen M. Weber2, Mardge Cohen3, Eileen Martin1, Victor Valcour4, Ruth M. Greenblatt5, Joel

Milam6, Kathryn Anastos7, Mary Young8, Elizabeth T. Golub9, Pauline M. Maki10. 1Department of Psychiatry,

University of Illinois at Chicago, Chicago, IL, USA; 2The Core Center, Bureau of Health Services of Cook County,

Chicago, IL, USA; 3Departments of Medicine Stroger Hospital and Rush University, Chicago IL, USA;4Department of Medicine, University of California, San Francisco, CA, USA; 5Departments of Clinical Medicine

and Epidemiology, University of California, San Francisco, CA, USA; 6Institute for Health Promotion & Disease

Prevention Research, University of Southern California, Los Angeles, CA, USA; 7Departments of Medicine and

Epidemiology & Population Health, Albert Einstein College of Medicine, New York, NY, USA; 8Georgetown

University School of Medicine, Washington, DC, USA; 9Department of Epidemiology, Johns Hopkins School of

Public Health, Baltimore, MD, USA; 10Department of Psychology, University of Illinois at Chicago, Chicago, IL,

USA

The effects of stress and stress hormones on cognition in HIV-seropositive women

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 theneurocognitive 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’sB0.05). High stress was negatively

associated with measures of both attention and executive function (p’sB0.05). 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 (b��1.89, SE�0.74, p�0.01).

Conversely, among HIV- women, there was no difference in verbal memory performance by stress level (b�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.

Keywords: HIV; stress; stress hormones; cognition


Dhom Martin Picard, Nichola Lax, Thiloka Ratnaike, Robert-Paul Juster, Douglass M. Turnbull. Department of

Kinesiology, McGill University, Canada; Mitochondrial Research Group, Institute for Brain Ageing and Vitality,

Newcastle University, Newcastle, UK; Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital ofPhiladelphia and University of Pennsylvania, Philadelphia, PA, USA

Mitochondrial allostatic load? The combined effect of glucose intolerance and mitochondrial DNAmutations on the incidence of neurological symptoms

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, mutationsin 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, includingcerebellar 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 thispresentation, 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.

Keywords: mitochondria; hyperglycemia; allostatic load; mitochondrial DNA; primary effects


Andrea Norcini Pala, Patrizia Steca, Simona Varani, Leonardo Calza, Vincenzo Colangeli, Pierluigi Viale.

Department of Psychology, Milano Bicocca University, Milano, Italy

Emotions may influence the production of pro-inflammatory cytokines in HIV positive individuals

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 ofpro-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 andpositive 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 (b�0.538, pB0.001), negative emotions (b�0.366, pB0.05) andpositive/negative emotions (b��0.420, pB0.05) ratio were significantly associated with greater TNF-alpha

production. No significant associations were observed with IL-6.

Conclusion: Taken together, these results may indicate that together with virus effect in producing greater

inflammation, emotions may also contribute to it. Negative emotions could then promote greater inflammation

whereas, when individuals experience more positive emotions than negative, inflammation might be reduced.

Keywords: HIV; cytokines; emotions; inflammation


Hui Li1, Qian Su1, Dongge Cai1, Ning Jia2, Yan Qin3, Li Yang1, Jinni Zhang1, Qinghong Li4, Yuanyuan Zhang1,Samjida Majeed Padari1, Monesh Kumar Sungkur1, Zhongliang Zhu5,6. 1Division of Neonatology, First Affiliated

Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi, China; 2Department of Human Anatomy

and Embryology, Medical School of Xi’an Jiaotong University, Xi’an, Shaanxi, China; 3Division of Obstetrics,

Hospital, Hanzhong, Shaanxi, China; 4Division of Neonatology, Child and Maternity Health Hospital of Shaanxi

Province, Shaanxi, China; 5Department of Pharmacology, Medical School of Xi’an Jiaotong University, Xi’an,

Shaanxi, China; 6Life Science College of Northwest University, Xi’an, Shaanxi, China

A study on mental development of children born after earthquake in Ningqiang County of China

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 forpregnant 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

98.5992.08. Twenty two (including 18 boys and 4 girls) children’s DQ score was B85, and they shared the

percentage of 25.6. The mean Mental Development Index (MI) score was 97.3591.64. Seventeen children’s MI

score was less than 85, and they shared the percentage of 19.8. The incidence of DQB85 was significantly higher

than the national urban average (14.9%) (p�0.006). The incidence of DQB85 was 33.3% among boys, which was

higher than 12.5% among girls (p�0.032). There was no significant difference in the incidence of MIB85

compared with the national urban average (6.0%) (p�0.35). DQ and MI scores, the rate of DQB85 and MIB85,

were not significantly different between mother’s schooling years 59 years and more than 9 years. There was nosignificant difference among all groups by age in terms of DQ and MI scores.

Conclusions: Earthquake possibly contributes to the retardation of children born after Wenchuan Earthquake in

Ningqiang County of China.

Keywords: children; earthquake; development quotient; mental development index






Dongge Cai1, Qian Su1, Ning Jia2, Yan Qin3, Li Yang1, Zhongliang Zhu4,5, Rui Chen6, Qing Gao7, Hui Li1.1Division of Neonatology, First Affiliated Hospital of Medical School, Xi’an Jiaotong University, Xi’an, Shaanxi,

China; 2Department of Human Anatomy and Embryology, Medical School of Xi’an Jiaotong University, Xi’an,

Shaanxi, China; 3Division of Obstetrics, Hospital, Hanzhong, Shaanxi, China; 4Department of Pharmacology,

Medical School of Xi’an Jiaotong University, Xi’an, Shaanxi, China; 5Life Science College of Northwest

University, Xi’an, Shaanxi, China; 6Division of Obstetrics and Gynaecology, First Affiliated Hospital of Medical

College, Xi’an, Shaanxi, China; 7Division of Obstetrics and Gynaecology, Second Affiliated Hospital of MedicalSchool, Xi’an Jiaotong University, Xi’an, Shaanxi, China

Effects of earthquake on pregnant women in Ningqiang County of China within three years

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 inthis 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 297.08921.95, 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 (223.189129.30)(p�0.001). The mean score of PTSD-SS was 38.5591.56, 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 (pB0.05, pB0.05 respectively),and the results at PTSD-SS similarly (pB0.01, pB0.001, 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.

Keywords: pregnant woman; earthquake; LESPW; PTSD-SS


Synthia H. Mellon1, Marcus D. Schonemann1, Owen M. Wolkowitz2, Elissa S. Epel2, Steven P. Hamilton2, Victor I.

Reus2, Heather M. Burke2, Rebecca Rosser2, Phuong Hoang1, Laura Mahan2, Michelle Coy2, Steven W. Cole3.1Departments of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA,

USA; 2Department of Psychiatry, University of California, San Francisco, CA, USA; 3Department of Medicine,

Hematology-Oncology, University of California, Los Angeles, CA, USA

Alterations in leukocyte transcription factor activities are associated with major depressive disorderand antidepressant treatment

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.

Keywords: depression; antidepressant treatment; leukocytes; immune function; stress responses


Robyn Sysko, Michael J. Devlin, Janet Schebendach, Ellen Zimmerli, Marian Tanofsky-Kraff, Judith Korner,

Jack A. Yanovski, Jeffrey Zitsman, B. Timothy Walsh. Division of Clinical Therapeutics, New York State Psychiatric

Institute, New York, NY, USA; Department of Psychiatry, College of Physicians and Surgeons of Columbia

University, New York, NY, USA

Hormonal responses among normal-weight adolescents and obese teenagers undergoinglaparoscopic adjustable gastric banding

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: 15.492.0 years, BMI: 21.391.7 kg/m2; n�5 female) and 21

severely obese (age: 16.191.0 years, BMI: 46.496.6 kg/m2; n�18 females) adolescents were studied pre-LAGB.

Eleven of the obese adolescents were studied again 122.6917.8 days post-LAGB (BMI 40.997.8 kg/m2, mean

change in BMI:�3.592.5 kg/m2). In comparison to normal-weight controls, surgical candidates had significantlyhigher 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 appetitivehormones 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.

Keywords: laparoscopic adjustable gastric banding; adolescent; eating behavior; appetitive hormones


Lei Zhang, Xianzhang Hu, David M. Benedek, Carol S. Fullerton, Robert D. Forsten1, James A. Naifeh, XiaoxiaLi, He Li, K. Nikki Benevides, Robert L. Ursano. Center for the Study of Traumatic Stress, Department of

Psychiatry, USUHS. Bethesda, MD USA; 1The active duty U.S. Army Special Operations Unit, DOD. Fort Bragg,

NC, USA





Dysregulated mitochondria-focused genes in US military service members with PTSD

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 forPTSD 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 wereevaluated 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

Keywords: PTSD; array; mitochondria; biomarker; PTSD Checklist; military


Mirjam van Zuiden1,2,3, Elbert Geuze3,4, Eric Vermetten3,4, Annemieke Kavelaars2, Cobi Heijnen2. 1Department of

Psychiatry (Anxiety Disorders), Academic Medical Center, Amsterdam, Utrecht, The Netherlands; 2Laboratory

of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht,

The Netherlands; 3Research Centre for Military Mental Health, Dutch Ministry of Defence, Utrecht, Utrecht, TheNetherlands; 4Department of Psychiatry, Rudolf Magnus Institute, University Medical Center Utrecht, Utrecht,

The Netherlands

Biological vulnerability factors for the development of PTSD, depressive, and fatigue symptoms inresponse to military deployment are condition specific

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-1b.

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 todeployment and high reactivity of monocytes to IL-1b 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.




Keywords: PTSD; fatigue; depression; glucocorticoid; cytokine; biomarker; vulnerability; military


Roberto La Marca1, M. Bosch1,2, S. Trulec-Sefidan1,2, H. Annen2, T. Wyss3, Ulrike Mader3, L. Roos3, U. Ehlert1.1Clinical Psychology and Psychotherapy, University of Zurich, Zurich, Switzerland; 2Military Academy, ETH

Zurich, Zurich, Switzerland; 3Swiss Federal Institute of Sports Magglingen SFISM, Magglingen, Switzerland

A decrease in perceived social support during military service is associated with a concomitantincrease in baseline and decrease in stress reactivity levels of salivary a-amylase

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 a-amylase (sAA), an index of sympatheticnervous 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 stressresponses 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 responsive-

ness. This longitudinal study emphasizes the need to boost psychosocial resources during military service.

Keywords: perceived stress; Trier Social Stress Test; amylase; stress reactivity; military service


Nitsan Kozlovsky1, Joseph Zohar2, Kaplan Zeev1, Hagit Cohen1. 1Beer-Sheva Mental Health Center, Ben-Gurion

University of the Negev, Beersheva, Israel; 2The Chaim Sheba Medical Center, Tel-Aviv University, Tel-Aviv, Israel

High dose corticosterone immediately after stress exposure prevents hippocampal cytoarchitectureand neuronal plasticity damage in an animal model of PTSD

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 of 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. Theoutcome 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

1b, 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 whosebehavior 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 1b, CAMKII and

higher expression of pGLU-R1 and PSD-95 than vehicle-treated animals. In contrast, steroid-treated stressedanimals displayed significantly increased dendritic arbor and spine density, with increased levels of integrin 1b,

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.

Keywords: PTSD; stress; corticosterone; neuronal plasticity; hippocampus


Sabra S. Inslicht1,2, Thomas J. Metzler1,2, Mohammed Milad3,4, Suzanne Pineles5, Scott Orr3,4, Charles Marmar6,Thomas C. Neylan1,2. 1University of California, San Francisco, San Francisco, CA, USA; 2San Francisco VA

Medical Center, San Francisco, CA, USA; 3Massachusetts General Hospital, Charlestown, MA, USA; 4Harvard

Medical School, Charlestown, MA, USA; 5Veterans Affairs Boston Healthcare System, Boston, MA, USA;6New York University Langone Medical Center, New York, NY, USA

Sex differences in fear conditioning in posttraumatic stress disorder

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 fearbetween 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, pB0.05. Women had greater differential conditioned skin conductance responses (CS� trials

compared to CS� trials) than did men, suggesting greater acquisition of conditioned fear in women with PTSD.Conclusion: In contrast to studies of healthy individuals, we found enhanced acquisition of conditioned fear in

women with PTSD. Greater fear conditioning in women may either be a pre-existing vulnerability trait or an

acquired phenomenon that emerges in a sex-dependent manner after the development of PTSD. Characterization

the underlying mechanisms of these differences is needed to clarify sex-related differences in the pathophysiology of

PTSD.

Keywords: sex differences; learning; conditioning; fear; posttraumatic stress disorder; galvanic skin response


Erin A. Hazlett1,2, Nicholas Fernandez1, Scott Sasso1, Antonia S. New1,2, Marianne Goodman1,2. 1Mental Illness

Research, Education, and Clinical Center (MIRECC VISN 3), James J. Peters VA Medical Center, New York, NY,

USA; 2Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

A non-verbal, quantitative measure of emotion dysregulation in veterans: is affective startle apotential biomarker for suicide?

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 unpleasantpictures (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.

Keywords: emotion; emotion dysregulation; fear/defensive brain circuitry; affective startle eyeblink modulation;

suicide ideation; suicidal behavior


Adam Luxenberg, Aoife O’Donovan, Sabra S. Inslicht, Thomas J. Metzler, Jennifer Hlavin, Michael W. Weiner,

Thomas C. Neylan. University of California, San Francisco, CA, USA; San Francisco VA Medical Center,

San Francisco, CA, USA; Northern California Institute on Research and Education, San Franscisco, CA, USA

Exaggerated autonomic responding to acoustic stimuli in Gulf War Veterans with current versusremitted post-traumatic stress disorder

Rationale: Post-traumatic stress disorder (PTSD) is associated with exaggerated autonomic responses to sudden, loudacoustic 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) lowthreat, 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 clinicianadministered 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.

Keywords: veterans; Gulf War; PTSD; autonomic response


Elaine R. Peskind, Donna J. Cross, Vasily Yarnykh, Kathleen Pagulayan, David Hoff, Kim Hart, Nathalie Martin,

Todd Richards, Murray A. Raskind, Satoshi Minoshima, Eric C. Petrie. VA Puget Sound Health Care System,

Seattle, WA, USA; University of Washington, Seattle, WA, USA

Neuroimaging biomarkers in veterans with blast-mild traumatic brain injury with or withoutcomorbid 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, attributingpersistent 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 andcombat 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 glucosemetabolism 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.

Keywords: mild traumatic brain injury; neuroimaging; biomarkers; PTSD; magnetic resonance imaging;

FDG-PET


Linda L. Chao1,2,3,4, Michael W. Weiner1,2,3, Thomas C. Neylan1,4. 1Department of Psychiatry, University of

California, San Francisco, CA, USA; 2Department of Radiology and Biomedical Imaging, University of

California, San Francisco, CA, USA; 3Center for Imaging of Neurodegenerative Diseases, San Francisco Veterans

Affairs Medical Center, San Francisco, CA, USA; 4Mental Health Service, San Francisco Veterans Affairs Medical

Center, San Francisco, CA, USA

Regional cerebral volumes in veterans with current versus remitted posttraumatic stress disorder:a study at 4 Tesla

Rationale/ statement of the problem: We previously reported that hippocampal volume was associated withcurrent, 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, 43trauma 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 (p50.01), trauma-exposed veterans who had recovered from

PTSD (p50.02) and trauma-exposed veterans who never developed PTSD (p50.05).

Conclusions: 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.

Keywords: veterans; PTSD; brain volume


Matthew W. Elmes, Linda M. Bierer, Rachel Yehuda. J. J. Peters Veterans Affairs Medical Center; Mount Sinai

School of Medicine, New York, NY, USA

Glucocorticoid receptor polymorphisms predict response to treatment in PTSD

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 nucleotidepolymorphism (SNP) is an intronic restriction fragment length polymorphism located 646 bp downstream from

GR exon 2. SNP 9b (rs6198) is located on exon 9b of the GR. It is believed to increase the stability of splice variant

GRb, an inhibitor of the wild-type GRa. Carriers of the BclI minor allele have been associated with an increased

sensitivity to glucocorticoids (GCs), whereas 9b 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 symptomseverity 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 9b 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, totalCAPS 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 (x2(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.




Keywords: glucocorticoid receptor; PTSD; genetics; BclI polymorphism; predictors of treatment; prolonged

exposure therapy


Leo Sher, Kristin Holmes, Janine D. Flory, Linda M. Bierer, Rachel Yehuda. James J. Peters Veterans’

Administration Medical Center and Mount Sinai School of Medicine, New York, NY, USA

Clinical features of military veterans with or without a history of suicide attempt

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 andrecorded. 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

(x2�1.50, df�1, p�0.36), and race (x2�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 (x2�6.67, df�1, p�0.01, x2�4.71, df�1, p�0.04, and x2�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 (x2�9.67, df�1, p�0.002). There was no difference with regard to the proportion of patients withmajor depression or posttraumatic stress disorder between suicide attempters and non-attempters (x2�0.10, df�1, p�0.83 and x2�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.

Keywords: suicide; veterans; substance dependence; psychosis; bipolar disorder


Victor L. Kallen1, Nelleke van Wouwe1,2, Marian Dekker3,4, Ad Denissen3, Geert van Boxtel4, Eric Vermetten5.1TNO Netherlands Organisation for Applied Scientific Research; 2Vanderbilt University, Nashville, TN, USA;3Philips Research; 4Tilburg University, The Netherlands; 5Dutch Ministry of Defense, Department Military

Mental Health, Utrecht, The Netherlands

Using bio- and neurofeedback to enhance psychological recuperation in Afghanistan veterans

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, pB.05), though no differences were foundbetween conditions (F(3,25)�0.90, n.s.). No significant results were found in CAR or in any EEG component or

derivative. However, stress-related symptoms appeared to decrease significantly, though only in the bio- and

neurofeedback alpha conditions (F(3,43)�2.85, pB.05). Working memory was significantly increased in the

neurofeedback alpha condition only (F(3,37)�2.78, pB.05).





Discussion: Although the number of participants in the present study is yet quite small, and no posttreatment

assessment after some weeks or months could be conducted, the present findings do support the hypothesis that

both bio- and neurofeedback may contribute to psycho(physio)logical recuperation after (professional) challenging

periods. Initial effects may be expected on self-reported psychological well-being and working memory

performance.

Keywords: biofeedback; veterans; working memory; psychophysiology; cortisol; EEG





INDEX

A

Abelson, James L. 21, 52, 84

Abercrombie, Heather C. 19

Ackermann, Sandra 20

Acree, Michael 54

Adli, Mazda 47

Adluru, Nagesh 94

Agorastos, Agorastos 65, 79

Ahlborg, Gunnar 53

Ahn, Ryun S. 84

Akiyoshi, Jotaro 12, 101, 102

Alexander, Andrew L. 93, 94

Alexander, Nina 61, 97

Algul, Ayhan 89

Anastos, Kathryn 103

Ando, Tomoko 101, 102

Andreotti, Charissa 57

Annen, H. 109

Arenander, Justine 88, 94

Armstrong, Jeffrey M. 86

Arseneault, Louise 39

Asberg, Marie 47

Aschbacher, Kirstin 94

Ates, Alpay 89, 90

Augustin-Morales, Marıa-del-Carmen 81

B

Bacchetti, Peter 54

Bachevalier, Jocelyne 100

Bacon, Simon L. 27

Bader, Heather N. 43

Bagot, Rosemary C. 24

Baker, Dewleen G. 34, 36, 65

Bammann, Karin 51

Barbosa, Lucas B.D. 55

Barr, Alasdair M. 83

Bartlang, Manuela S. 42

Bartz, Jennifer A. 28

Basoglu, Cengiz 90

Beaulac, Holly 65

Beck, J. 45

Beenders, Bret 41

Belanoff, Joseph K. 11, 12

Belsky, Daniel 95

Benedek, David M. 107

Benevides, Nikki K. 107

Berger, Christoph 46

Bermpohl, Felix 47

Bertenthal, Dan 32

Besedovsky, Luciana 22

Bierer, Linda M. 18, 32, 43, 113, 114

Biggio, Giovanni 42

Bischoff, Luc 68

Blackburn, Elizabeth H. 1, 2, 64, 75, 94, 96

Blaze, Jennifer 29

Boel, Judith A. 65

Boks, Marco P.M. 24

Bolshakov, Vadim 17

Born, Jan 22

Bosch, M. 109

Bower, Julienne E. 88

Boyda, Heidi Noel 83

Bradley, Bekh 26

Brambilla, Francesca 42

Brand, Serge 45

Brant, Heather 78

Brewin, Chris R. 66

Bricker, Nicole M. 9

Briggs, Hedie 52

Broderick, Amanda 84

Brooks-Gunn, Jeanne 62

Brown, Christopher A. 26

Bruckl, Tanja 50

Bruehl, Hannah 63

Brunet, Alain 17

Bryk, Jodie 64

Bublitz, Margaret H. 40

Buchanan, Tony W. 67

Buckert, Magdalena 53

Budde, Henning 97

Bull, Caroline 80

Burke, Heather M. 63, 64, 96, 106

Buss, Claudia 1, 6, 29, 38

Busuito, Alex 84

Buxbaum, Joseph 18

C

Cai, Dongge 105, 106

Cai, Guiqing 18

Calderon, Solara 75

Calza, Leonardo 104

Camacho, Everardo 73

Canli, Turhan 98

Caramanica, Kimberly 33

Cardoso, Christopher 26, 27, 81

Carini, Lindsay 99

Carneiro, Igor C. 55

Caspi, Avshalom 1

Cave, Sinai 47

116

Chao, Linda L. 112

Charney, Dennis 75

Chen, Rui 106

Cheon, Josh 94

Chou, Chia-Ying 66

Christensen, Helen 80

Clays, Els 39

Coetzee, John 63, 64, 96

Cohen, Beth E. 32

Cohen, Hagit 18, 56, 109

Cohen, Mardge 103

Colangeli, Vincenzo 104

Cole, Steven W. 106

Compas, Bruce 57

Contreras-Chova, Francisco 82

Cornelisse, Sandra 20, 50

Cosar, Alpaslan 89, 90

Cousino Klein, Laura 76

Coy, Michelle 63, 64, 96, 106

Craig Nelson, J. 64, 96

Crocker, Jennifer 52

Cross, Donna J. 112

Crown, Anna 78

Cubero-Millan, Isabel 81, 82

D

Dagher, Alain 62

Dahlben, Brian 65

Dainese, Sara M. 6

Dallman, Mary 54

Danese, Andrea 29, 39

Danker-Hopfe, Heidi 79

Dantzer, Robert 41

Darcel, Nicolas 54

Daskalakis, Nikolaos P. 18, 22, 74

Davey-Smith, George 78

Davidson, Karina W. 93

Davidson, Richard J. 93, 94

Davis, Elysia Poggi 6

Dawe, Karen 78

de Buyzere, Marc 39

de Henauw, Stefaan 39, 51

de Kloet, E. Ronald 22, 74, 77

de Koning, Pelle 71

de Quervain, Dominique J.-F. 20

de Vriendt, Tineke 51

Dekker, Marian 114

Deng, Huihua 91

Denison, Fiona C. 4

Denissen, Ad 114

Desarnaud, Frank 32

Dettenborn-Betz, Lucia 79

Devlin, Michael J. 107

Dhabhar, Firdaus S. 2, 9

Diamond, David 16

Distler, Wolfgang 61

Doerr, Johanna Marie 51

Domes, Gregor 46

Dove, Rosamund 29

Dupont, Alexandra 88

E

Eckert, Anne 45

Ehlert, Ulrike 6, 51, 109

Ellenbogen, Mark A. 26, 27, 81

Elmes, Matthew W. 113

Entringer, Sonja 1, 6, 29

Epel, Elissa S. 1, 2, 60, 63, 64, 75, 78, 88, 93, 94,

96, 106

Erickson, Thane 52

Eriksson, Jan W. 67

Eriksson, Johan G. 57

Esmaeili, Pardis 78

Essex, Marilyn J. 86

Evans, Zoe 78

F

Fawcett, Gloria 10

Feder, Adriana 75

Fenech, Michael 80

Fernandez, Nicholas 110

Ferri, Jamie 98

Fiebach, Christian J. 53

Fiocco, Alexandra 44, 72

Fischer, Joachim 59

Fischer, Rico 92

Fleshner, M. 16

Flory, Janine D. 18, 32, 43, 114

Foley, Paul 91

Forbes, Shareen 4

Forsten, Robert D. 107

Fox, Andrew S. 10, 87, 93, 94

Franch, Joan 54, 85, 86

Frederick, Hecht 60

Frijling, Jessie 66

Fuchsl, Andrea 41

Fullerton, Carol S. 107

G

Gaffey, Allison E. 30

Galecki, Paige 90

Gamache, Karine 17

Gamer, Matthias 46

Ganz, Patricia A. 88

Gao, Qing 106

Gao, Wei 37, 91

117

Garfinkel, Sarah N. 21

Garrard, Paige 57

Garton, Andrew 90

Gaudlitz, Katharina 91

Geuze, Elbert 36, 108

Geyer, Mark 36

Ghaemmaghami, Pearl 6

Gianferante, Danielle 65

Giese, Maria 45

Glise, Kristina 53

Gold, Stefan M. 60

Golier, Julia A. 33

Golub, Elizabeth T. 103

Gonzalez, Richard 21

Goodman, Marianne 110

Graber, Julia A. 62

Greenblatt, Ruth M. 103

Grieve, Adam J. 56

Grossmann, Annette 46

Gunay, Huseyin 89, 90

Gunther, Kathrin 51

Gurfein, Blake 54

Gutierrez-Zotes, Alfonso 54

H

Hohne, Nina 50

Hamalainen, Esa 7

Hager, Torben 65

Hahm, Bong-Jim 8

Haji, Uzair 65

Hamilton, Steven P. 63, 64, 96, 106

Hammamieh, Rasha 76

Hanada, Hiroaki 12, 102

Hand, Anne 68

Hart, Kim 112

Hartmann, Francina 20

Harvey, Philip D. 33

Hatri, Alex 63

Hatzinger, Martin 45

Hauenstein, Karlheinz 46

Havel, Peter J. 64

Hawkes, Erin 83

Hazlett, Erin A. 110

Hecht, Frederick 54

Heck, Angela 20

Heekeren, Hauke R. 63

Heesen, Christoph 60

Heijnen, Cobi 36, 108

Heim, Christine 38

Heinonen, Kati 57

Heinrich, Markus 46

Helen Jin, C. 83

Helfrich-Forster, Charlotte 42

Hellhammer, Dirk H. 99

Heppner, Pia S. 65

Hero, Torsten 99

Herpertz, Sabine C. 46

Heyman, Melvin B. 75

Higuma, Haruka 12, 101, 102

Hill, Matthew N. 13

Hinkelmann, Kim 48, 79

Hirvikoski, Tatja 47

Hlavin, Jennifer 111

Ho, S. Shaun 21

Hoang, Phuong 106

Hobel, Calvin J. 6

Hoff, David 112

Hoks, Roxanne M. 19

Holmes, Kristin 114

Holsboer-Trachsler, Edith 45

Holsboer, Florian 50

Honer, William G. 83

Honig, Lawrence S. 93

Hovatta, Iiris 57

Hoyer, Jurgen 37

Hu, Xianzhang 107

Huybrechts, Inge 39, 51

I

Iacoviello, Licia 51

Ikeda, Kazutaka 58

Inoue, Aya 101

Inslicht, Sabra S. 8, 110, 111

Iosifescu, Dan 75

Ipcioglu, Osman Metin 89, 90

Ishitobi, Yoshinobu 12, 101, 102

Ising, Marcus 47, 50

Isogawa, Koichi 12

Izawa, Shuhei 58

Izzi, Stephanie 98

J

Jahn, Allison L. 19

Jahng, Jeong 98

Jansson, Per-Anders 67

Jessop, David 10

Jett, Marti 76

Jia, Ning 38, 105, 106

Jo, Booil 9

Joels, Marian 20, 24, 50

Johns, C. 98

Johnson, Philip J. 71

Jokinen, Jussi 47, 103

Jonsdottir, Ingibjorg H. 53, 67, 70

Joober, Ridha 27, 81

118

Jurkiewicz, Magdalena 98

Juster, Robert-Paul 44, 68, 71, 104

Justicia-Martınez, Fuensanta 81

K

Kahn, Rene S. 24

Kajantie, Eero 7, 57

Kalin, Ned H. 10, 11, 56, 87, 93, 94

Kallen, Victor L. 68, 114

Kananen, Laura 57

Kandel, Eric R. 18

Kanehisa, Masayuki 12, 101, 102

Kang, Min 93

Kaplan, Zeev 56

Kavelaars, Annemieke 36, 108

Kawano, Aimi 101, 102

Kelley, Keith 41

Kersten, Jan-Felix 60

Kim, Jin-Young 98

Kindt, Merel 20, 50

Kirkland, Susan 93

Kirschbaum, Clemens 37, 59, 61, 91, 92, 97

Klein, Marjorie H. 86

Kloet, E.R. de 22

Koch, Saskia 66

Koenen, Karestan C. 31

Konsman, Jan Pieter 54

Korner, Judith 107

Koslov, Katrina 88, 94

Kozlovsky, Nitsan 56, 109

Kruger, Schulamith 60

Kralemann, Mary 67

Kraus, Dominik 42

Kubzansky, Laura D. 25, 31

Kudielka, Brigitte M. 53

Kuehl, Linn K. 48, 79

Kuhlman, Kate Ryan 48

Kurtzman, Laura 88, 94

L

La Marca, Roberto 6, 66, 109

Labad, Javier 5, 54, 85, 86

Lahti, Jari 57

Lahti, Marius 57

Laivuori, Hannele 7

Lange, Claudia 47

Lange, Tanja 22

Laraia, Barbara 78

Lax, Nichola 104

Lebow, Molly 75

Lee, Jong-Ho 98

Lee, Joo 98

Lefebvre-Louis, Jean-Philippe 71

Lehrner, Amy 43

Lennartsson, Anna-Karin 70

Leyton, Marco 62

Li, He 107

Li, Hui 38, 105, 106

Li, Qinghong 105

Li, Xiaoxia 107

Liberzon, Israel 17, 21, 52

Lightman, Stafford 78

Lin, Jue 1, 2, 64, 75, 94, 96

Linden, Michael 99

Linke, Julia 61

Linnen, Anne-Marie 81

Lischke, Alexander 46

Litz, Brett 36

Liu, Xiang 38

Loharuka, Sheila 78

Lopez-Duran, Nestor L. 44, 48, 90

Lopez, Xavi 85

Lord, Catherine 44

Lissner, Lauren 51

Luecken, Linda 57

Lupien, Sonia J. 21, 44, 68, 71, 72

Lupis, Sarah B. 89

Lustig, Robert H. 64

Luxenberg, Adam 111

Luykx, Jurjen J. 24

Ly, Jinshia 69

M

Machado-Casas, Irene 82

Mackin, Scott 63, 96

Mader, U. 109

Mahan, Laura 63, 64, 96, 106

Maki, Pauline M. 103

Makotkine, Iouri 32, 43

Manzanares, Nuria 54

Margaretten, Mary 32

Marin, Marie-France 21, 44, 68, 71

Marita Milde, Anne 59

Mark, Jan-Willem 68

Marmar, Charles 32, 35, 110

Martin, Eileen 103

Martin, Nathalie 112

Martinez-Torteya, Cecilia 84

Maruyama, Yoshihiro 12, 101, 102

Mason, Sara 96

Mayberg, Helen 38

Mayer, Stefanie Eva 52

McFarlane, Alexander C. 35

McGrath, Jennifer J. 69

McLaughlin, Katie A. 31

119

Meeter, Martijn 20

Mehta, Divya 34

Mellon, Synthia H. 2, 63, 64, 96, 106

Mendoza, Sally 96

Metcalfe, Chris 78

Metzler, Thomas J. 110, 111

Meyer, Dixie 101

Michels, Nathalie 39, 51

Milad, Mohammed 110

Milam, Joel 103

Mill, Jonathan 39

Miller, Robert 59, 73, 97

Milush, Jeffrey 54, 60

Minchillo, Caroline N. 55

Minoshima, Satoshi 112

Mletzko, Tanja 38

Moeller-Bertram, Tobias 34, 65

Moffitt, Terrie E. 1

Mohd-Shukri, Nor 77

Mohr, Peter N.C. 63

Molina-Carballo, Antonio 81, 82

Molnar, Denes 51

Monseny, Rosa 54, 85, 86

Montalvo, Itziar 54, 85, 86

Moog, Nora 29

Moreno-Garcıa, Laura 81

Moreno-Madrid, Francisco 82

Morgan, Julia 75

Morgner, Joachim 61

Morin-Major, Julie-Katia 68

Motazedi, Arame 65

Mueller, Anett 98

Mueller, Susanne 63, 96

Muheim, F. 45

Muhie, Seid 76

Muhtz, Christoph 79

Munoz-Hoyos, Antonio 82

Murgatroyd, Christorpher 99

Muzik, Maria 84

N

Nader, Karim 17

Nadkarni, Nachiket 54

Naifeh, James A. 107

Nakayama, Shinya 12

Nanda, Steve A. 87

Naranjo-Gomez, Ana 81

Narbona-Lopez, Eduardo 81

Nash, William 36

Nater, Urs Markus 51

Nawijn, Laura 66

Nederhof, Esther 23

Nelson, Craig J. 63, 64

Nemeroff, Charles 38

Nephew, Benjamin 99

Neri, Eric 9

Neumann, Inga D. 41, 42

Neumeister, Alexander 15

New, Antonia S. 110

Neylan, Thomas C. 8, 32, 110, 111, 112

Nievergelt, Caroline 36

Ninomiya, Taiga 12, 101, 102

Nixon, Douglas 54, 60

Nomura, Shinobu 58

Norcini Pala, Andrea 104

Nordanger, Dag Øystein 59

Nordling, Tove Saga 59

Nordstrom, Anna-Lena 47

Nordstrom, Peter 47

Norman, Jane E. 4, 77

Northstone, Kate 78

Nouriani, Bita 9

Nuttall, Amy K. 30

O

O’Donovan, Aoife 8, 32, 88, 111

O’Reilly, James 4, 7, 77

Oitzl, Melly S. 77

Okamoto, Shizuko 12, 101, 102

Oler, Jonathan A. 10, 87, 93, 94

Olff, Miranda 66

Orlando, Mark Anthony 26, 27

Orr, Scott 110

Ortega, Laura 54, 85, 86

Otte, Christian 48, 79

Ouellet-Morin, Isabelle 39, 44

P

Padari, Samjida Majeed 38, 105

Pagulayan, Kathleen 112

Paletz, Elliott M. 56

Palme, Rupert 54

Pandey, Ghanshyam N. 11

Pang, Catherine C.Y. 83

Papadopoulos, Andrew S. 39

Papassotiropoulos, Andreas 20

Pariante, Carmine M. 39

Park, Jai Y. 84

Park, Eunyoung 98

Parker, Karen J. 23

Passarelli, Vincent 43

Patel, Piyush 34

Payne, Jessica D. 30

Perez, J. 36

Perini, Giulia 42

Peskind, Elaine R. 112

Pesonen, Anu-Katriina 7, 57

120

Petrie, Eric C. 112

Pfister, Hildegard 50

Picard, Dhom Martin 104

Pihl, Robert 62

Pineles, Suzanne 110

Pitman, Roger K. 17

Plag, Jens 91

Plessow, Franziska 73, 92

Plusquellec, Pierrich 72

Pratesi, Riccardo 55

Prather, Aric 60, 78, 94

Premenko-Lanier, Mary 54

Preston, Stephanie D. 67

Procyshyn, Ric M. 83

Pruessner, Jens C. 38, 44, 62, 71

Puterman, Eli 3, 78, 94

Q

Qin, Yan 105, 106

Quesada, Andrea Amaro 55

R

Raikkonen, Katri 7, 57

Raper, Jessica 100

Rasch, Bjorn 20

Raskind, Murray A. 112

Ratnaike, Thiloka 104

Rauh, Manfred 91

Raul, Jean-Sebastien 51

Rayman, Joseph B. 18

Raymond, Catherine 68

Reber, Stefan O. 41, 42

Recep, Tutuncu 89

Rehkopf, David 78

Reus, Victor I. 2, 63, 64, 96, 106

Revitsky, Alicia R. 76

Reynolds, Rebecca M. 4, 7, 54, 77

Reynolds, Rebecca 86

Richards, Anne 8

Richards, Todd 112

Rimmele, Ulrike 22

Risbrough, Victoria 36

Rivet, Noellie 51

Roepke, Stefan 48

Rogers, Jeff 10

Rohleder, Nicolas 65, 89

Roos, L. 109

Roozendaal, Benno 14

Roseboom, Patrick H. 87

Rosenlocher, Franziska 61

Rosser, Rebecca 63, 64, 96, 106

Rotenberg, Sivan 69

Roth, Tania L. 16, 29

Rowen, Jin 96

Rubin, Leah H. 103

Ruiz-Ramos, Marıa-Jose 81, 82

Ruttle, Paula Lynn 86

S

Saczawa, Mary Eileen 62

Saito, Keisuke 58

Saltz, Juliette 65

Sanchez, Mar 100

Sandman, Curt A. 6, 29

Sasso, Scott 110

Savolainen, Katri 57

Schade, Susann 92

Schatzberg, Alan 11

Schebendach, Janet 107

Schelling, Gustav 15

Schmeidler, James 33

Schonemann, Marcus D. 106

Schonfeld, Sabine 37

Schubart, Chris 24

Schulz, Karl-Heinz 60

Schumacher, Sarah 91

Schwartz, Joseph E. 93

Schwieren, Christiane 53

Seal, Karen 32

Seckl, Jonathan R. 7, 77

Serra, Mariarosa 42

Servet, Ebrinc 89

Shackman, Alexander J. 87, 93

Shaffer, Jonathan A. 93

Shakra, Malak Abu 62

Shalev, Idan 1

Shelton, Steve E. 87

Shen, Li 18

Sher, Leo 114

Shimada, Hironori 58

Shimbo, Daichi 93

Shirotsuki, Kentaro 58

Shirtcliff, Elizabeth A. 86

Siddique, Ashik 32

Simhan, Hyagriv N. 1

Simmons, Alan 34

Sindi, Shireen 44, 68, 71

Sioen, Isabelle 39, 51

Sjors, Anna 53, 67

Skoluda, Nadine 51

Slattery, David A. 42

Slattery, Marcia J. 56

Slavich, George 88

Slopen, Natalie 31

Smith, Edward E. 21

Smith, Nathan G. 71

Smith, Robin 41

121

Sobin, Sean 15

Sole, Montse 85

Spiegel, David 8, 9

Spitzer, Carsten 79

Stalder, Tobias 37, 59, 61, 73, 91, 97

Stamm, Andrew 54

Steca, Patrizia 104

Steptoe, Andrew 66

Steudte, Susann 37, 91

Stiedl, Oliver 65

Stone, A.A. 98

Strigo, Irina 34

Stroud, Laura R. 40

Su, Qian 38, 105, 106

Su, Yali 2, 63

Sugaya, Nagisa 58

Sungkur, Monesh Kumar 38, 105

Sverrisdottir, Yrsa Bergmann 70

Swanson, James M. 6

Sysko, Robyn 107

T

Talbot, Lisa 8

Tanaka, Yoshihiro 12, 101, 102

Tang, Guokui 38

Tanofsky-Kraff, Marian 107

Taylor, Stephen F. 21

ter Horst, Judith P. 77

Thoma, Myriam V. 51, 65, 89

Tillie, Jean M. 9

Tomiyama, A. Janet 78

Touma, Chadi 54

Tristao, Rosana M. 55

Tromp, Do P.M. 94

Trulec-Sefidan, S. 109

Tse, Lurdes 83

Tsuru, Jusen 12, 101, 102

Turnbull, Douglass M. 104

Tutuncu, Recep 90

U

Uberos, Jose 82

Uhr, Manfred 47, 50

Ursano, Robert L. 107

Uschold-Schmidt, Nicole 42

V

Valcour, Victor 103

Valentino, Kristin 30

van Ast, Vanessa A. 20, 50

van Boxtel, Geert 114

van der Mark, Maaike H. 77

van Gastel, Willemijn 24

van Meeteren, Nico 68

van Ommen, Ben 68

van Wouwe, Nelleke 114

van Zuiden, Mirjam 36, 66, 108

Vanaelst, Barbara 39, 51

Varani, Simona 104

Vargas, Ivan 90

Vedhara, Kavita 78

Vega-Michel, Claudia 73

Veltman, Dick 66

Venkatraman, Sneha 57

Vermetten, Eric 36, 108, 114

Viale, Pierluigi 104

Vianna, Fernanda B. 55

Villa, Pia 7

Vinkers, Christian H. 24

Vogt, Dominic 99

Vyncke, Krishna 51

W

Wadhwa, Pathik D. 1, 6, 29

Waeldin, Sandra 99

Walker, Adam 41

Walker, Brian R. 54

Walker, Brian 86

Walsh, B. Timothy 107

Wang, Xin 21

Wankerl, Matthis 97

Waxler, Ellen Gabrielle 84

Weber, Kathleen M. 103

Wegner, Mirko 97

Weiner, Michael W. 63, 96, 111, 112

White, Christina N. 67

Whooley, Mary A. 79

Wiedemann, Klaus 79

Wilhelm, Ines 22

Wilson, Mark 100

Windisch, Claudia 97

Wingenfeld, Katja 31, 48, 79

Wirth, Michelle M. 19, 30

Wojcicki, Janet M. 75

Wolf, Jutta 89

Wolf, Oliver T. 55

Wolkowitz, Owen M. 2, 63, 64, 94, 96, 106

Wong, Chloe 39

Wotjak, Carsten T. 13

Wu, Xiao 98

Wyss, T. 109

Y

Yamaguchi, Kana 12

Yang, Li 38, 105, 106

122

Yang, Ruoting 76

Yanovski, Jack A. 107

Yarnykh, Vasily 112

Ye, Siqin 93

Yee, Jason R. 28

Yehuda, Rachel 18, 32, 33, 43, 113, 114

York, Vanessa 60

Young, Mary 103

Z

Zeev, Kaplan 109

Zeitzer, Jamie 9

Zhang, Jinni 105

Zhang, Lei 107

Zhang, Yanyan 38

Zhang, Yuanyuan 105

Zhu, Zhongliang 38, 105, 106

Ziegler, Kristin J. 60

Zimmerli, Ellen 107

Zimmermann-Viehoff, Frank 79

Zimmermann, Petra 50

Zimmermann, Roland 6

Zitsman, Jeffrey 107

Zohar, Joseph 56, 109

Zoladz, P.R. 16

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PSYCHO- TRAUMATOLOGY

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