Psychoneuroendocrinology

Editorial Board

2010-09-01

Abnormal response to stress and impaired NPS-induced hyperlocomotion, anxiolytic effect and corticosterone increase in mice lacking NPSR1

2010-09-01

Summary: NPSR1 is a G protein coupled receptor expressed in multiple brain regions involved in modulation of stress. Central administration of NPS, the putative endogenous ligand of NPSR1, can induce hyperlocomotion, anxiolytic effects and activation of the HPA axis. The role of NPSR1 in the brain remains unsettled. Here we used NPSR1 gene-targeted mice to define the functional role of NPSR1 under basal conditions on locomotion, anxiety- and/or depression-like behavior, corticosterone levels, acoustic startle with prepulse inhibition, learning and memory, and under NPS-induced locomotor activation, anxiolysis, and corticosterone release. Male, but not female, NPSR1-deficient mice exhibited enhanced depression-like behavior in a forced swim test, reduced acoustic startle response, and minor changes in the Morris water maze. Neither male nor female NPSR1-deficient mice showed alterations of baseline locomotion, anxiety-like behavior, or corticosterone release after exposure to a forced swim test or methamphetamine challenge in an open-field. After intracerebroventricular (ICV) administration of NPS, NPSR1-deficient mice failed to show normal NPS-induced increases in locomotion, anxiolysis, or corticosterone release compared with WT NPS-treated mice. These findings demonstrate that NPSR1 is essential in mediating NPS effects on behavior.

Natural variations in maternal and paternal care are associated with systematic changes in oxytocin following parent–infant contact

2010-09-01

Summary: Animal studies have demonstrated that the neuropeptide oxytocin (OT) plays a critical role in processes of parent–infant bonding through mechanisms of early parental care, particularly maternal grooming and contact. Yet, the involvement of OT in human parenting remains poorly understood, no data are available on the role of OT in the development of human fathering, and the links between patterns of parental care and the OT response have not been explored in humans. One hundred and twelve mothers and fathers engaged in a 15-min play-and-contact interaction with their 4–6-month-old infants and interactions were micro-coded for patterns of parental touch. Results showed that baseline levels of plasma and salivary OT in mothers and fathers were similar, OT levels in plasma and saliva were inter-related, and OT was associated with the parent-specific mode of tactile contact. Human mothers who provided high levels of affectionate contact showed an OT increase following mother–infant interaction but such increase was not observed among mothers displaying low levels of affectionate contact. Among fathers, only those exhibiting high levels of stimulatory contact showed an OT increase. These results demonstrate consistency in the neuroendocrine basis of human parental interactions with those seen in other mammals. The findings underscore the need to provide opportunities for paternal care to trigger the biological basis of fatherhood and suggest that interventions that permit social engagement may be recommended in conditions of diminished maternal–infant contact, such as prematurity or postpartum depression.

Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia

2010-09-01

Summary: Estrogen treatment may enhance the recovery of schizophrenia in women. However, adverse effects on uterine and breast tissue and other physical side effects may limit the long-term therapeutic use of estrogen. Raloxifene hydrochloride is a selective estrogen receptor modulator that acts as an estrogen antagonist in breast tissue and may have agonistic actions in the brain, potentially offering mental health benefits with few estrogenic side effects. To provide an indication of the potential therapeutic dose for raloxifene hydrochloride in postmenopausal women with schizophrenia, this study pools data from an ongoing randomized controlled trial of adjunctive 120mg/day oral raloxifene hydrochloride (n=13) versus oral placebo (n=13), with data from a previous pilot study administering 60mg/day raloxifene hydrochloride (n=9). Analysis of variance found significant interaction effects for total (p=.01) and general (p=.02) Positive and Negative Syndrome Scale (PANSS) symptomatology. Participants randomized to receive 120mg/day raloxifene hydrochloride experienced a significantly more rapid recovery of total and general psychotic symptoms compared to both 60mg/day raloxifene hydrochloride and placebo. The demonstrated benefit of adjunctive treatment with 120mg/day raloxifene hydrochloride offers support for the potential role of this selective estrogen receptor modulator in treating postmenopausal women with schizophrenia.

Giving birth to a new brain: Hormone exposures of pregnancy influence human memory

Laura M. Glynn — 2010-09-01

Summary: Mammalian pregnancy produces alterations in maternal physiology that are necessary for maintaining gestation, fetal development and parturition. These changes also may prepare the maternal brain for the unique demands of motherhood. Parous rodents exhibit long-term changes in neurological structure and function and human work suggests that other landmark events in the reproductive cycle, such as menarche and menopause, influence cognition. However, the influence of pregnancy on the human brain remains to be elucidated. This study indicates that verbal recall memory (but not recognition or working memory) diminishes during human pregnancy and that these decrements persist after parturition. Further, prenatal glucocorticoids and estrogen are associated with these alterations. To meet the challenges of motherhood, the female brain may be remodeled, a process that appears to be initiated prenatally. However, it is not often that adaptation is achieved without an associated cost. For the human, in the case of the new maternal brain, diminished memory performance may reflect such a cost.

Child care setting affects salivary cortisol and antibody secretion in young children

2010-09-01

Summary: Elevated afternoon levels of cortisol have been found repeatedly in children during child care. However, it is unclear whether these elevations have any consequences. Because physiologic stress systems and the immune system are functionally linked, we examined the relationship between salivary cortisol concentration and antibody secretion across the day at home and in child care, and their relationships with parent-reported illnesses. Salivary antibody provides a critical line of defense against pathogens entering via the mouth, but little is known about its diurnal rhythm in young children or the effect of different environmental contexts. Saliva samples were taken at approximately 10:30 a.m., 3:30 p.m. and 8:00 p.m. on two child care and two home days in a sample of 65 3–5-year-old children attending very high quality, full time child care centers. Results indicated that (1) a rising cortisol profile at child care, driven by higher afternoon levels, predicted lower antibody levels on the subsequent weekend, (2) higher cortisol on weekend days was related to greater parent-reported illness, and (3) a declining daily pattern in sIgA was evident on weekend and child care days for older preschoolers, but only on weekend days for younger preschoolers. The results suggest that elevated cortisol in children during child care may be related to both lowered antibody levels and greater illness frequency.

Behavioral adjustment in a community sample of boys: Links with basal and stress-induced salivary cortisol concentrations

2010-09-01

Summary: Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been observed in association with internalizing symptoms and is thought to be involved in the pathogenesis of depression and some anxiety disorders. This study examined basal and stress-induced cortisol concentrations in relation to internalizing and externalizing symptoms in a racially mixed community sample of 102 8–11-year-old boys. Afternoon basal cortisol concentrations were positively correlated with measures of internalizing behavior problems, social problems, and emotionality. Greater change in cortisol across a home-visit challenge task was also significantly associated with internalizing behaviors and social problems, as well as attention and thought problems. The implications of these findings and how they may relate to the pathogenesis of emotional and behavioral problems are discussed.

Parathyroid hormone-related protein has an anorexigenic activity via activation of hypothalamic urocortins 2 and 3

2010-09-01

Summary: Cancer cachexia is reported to be a major cause of cancer-related death. Since the pathogenesis is not entirely understood, only few effective therapies have been established. Since myriad tumors produce parathyroid hormone-related protein (PTHrP), plasma concentrations of PTHrP are increased in cancer cachexia. We measured the food intake, gastric emptying, conditioned taste aversion (CTA), and gene expression of hypothalamic neuropeptides in mice after administering PTHrP intraperitoneally. We administered PTHrP intravenously in rats and examined the gastroduodenal motility and vagal nerve activities. We also examined whether chronic administration of PTHrP influenced the food intake and body weight. Peripherally administered PTHrP induced negative energy balance by decreasing the food intake and gastric emptying; however, it did not induce CTA. The mechanism involved the activation of hypothalamic urocortins 2 and 3 through vagal afferent pathways and the suppression of gastroduodenal motor activity. The continuous infusion of PTHrP reduced the food intake and body weight gain with a concomitant decrease in the fat and skeletal muscle. Our findings suggest that PTHrP influences the food intake and body weight; therefore, PTHrP can be considered as a therapeutic target for cancer cachexia.

Effect of service dogs on salivary cortisol secretion in autistic children

2010-09-01

Summary: Children with Autism Syndrome Disorders (ASDs) exhibit social, communicative, and behavioral deficits. We know that human interaction with dogs, which is thought to serve as a social catalyst, results in a decrease of cortisol levels in healthy adults. Introducing service dogs to children with ASD is an attractive idea that has received growing attention in recent decades. However, no study has measured the physiological impact of service dogs on these children. Therefore, the goal of our study was to assess the effects of service dogs on the basal salivary cortisol secretion of children with ASD. We measured the salivary cortisol levels of 42 children with ASD in three experimental conditions; prior to and during the introduction of a service dog to their family, and after a short period during which the dog was removed from their family. We compared average cortisol levels and Cortisol Awakening Response (CAR) before and during the introduction of the dog to the family and after its withdrawal. We found that the introduction of service dogs translated into a statistically significant diminished CAR. Before the introduction of service dogs, we measured a 58% increase in morning cortisol after awakening, which diminished to 10% when service dogs were present. The increase in morning cortisol jumped back to 48% once the dogs were removed from the families (p<0.05). However, service dogs did not have an effect on the children's average diurnal cortisol levels. These results show that the CAR of children with ASD is sensitive to the presence of service dogs, which lends support to the potential behavioral benefits of service dogs for children with autism.

Off-line memory consolidation impairments in multiple sclerosis patients receiving high-dose corticosteroid treatment mirror consolidation impairments in depression

2010-09-01

Summary: Background: Sleep supports the consolidation of procedural memory, however patients with major depression show impaired motor memory performance after a night of sleep. It was hypothesized that this impairment is related to hypothalamic–pituitary–adrenal (HPA) axis dysfunction. We tested if high-dose administration of corticosteroids impairs off-line motor memory consolidation in patients with multiple sclerosis (MS).Methods: Nine patients with MS receiving high-dose corticosteroid therapy (methylprednisolone) and nine MS patients receiving alternative therapy (mitoxantrone) were assessed using a sequential finger tapping task before and after a night with polysomnography. In addition, nine patients with major depression (MD) receiving antidepressants and nine healthy controls were assessed.Results: Although the four groups did not differ in practice-dependent learning, healthy subjects and MS patients receiving mitoxantrone showed markedly overnight-improvements in tapping performance of 17% and 24% while MS patients receiving high-dose corticosteroid therapy and depressed patients showed −9% and −10% overnight decrease. MS patients with and without corticosteroid therapy did not differ in their amount of REM sleep, nor did MD patients and healthy controls. In addition, we did not find any correlation between REM sleep and memory consolidation.Conclusion: Our results show that a strong intervention into the HPA system like in MS high-dose corticosteroid therapy impairs off-line motor memory consolidation comparable to the impairments seen in depressed patients. We propose therefore that depression-related changes in plasma corticosteroid levels rather than in sleep per se underlie off-line memory consolidation impairments in MD.

The high-sweet-fat food craving among women with premenstrual dysphoric disorder: Emotional response, implicit attitude and rewards sensitivity

2010-09-01

Summary: This study aimed to: (1) evaluate food craving and high-sweet-fat food craving across the menstrual cycle; (2) compare the craving and explicit/implicit emotional response to different food; and (3) investigate the reward sensitivity among PMDD and control groups. The PMDD group without treatment history and control group were evaluated for food craving, emotional response to food, implicit attitude task to food, and responsiveness to reward both in luteal and follicular phases. A total of 59 women with PMDD and 60 controls had completed the study. The results revealed that both PMDD diagnosis and luteal phase were associated with higher body mass index. The high-sweet-fat food provoked higher craving, positive emotional, and positive implicit response more than other foods. The luteal phase contributed to higher food and high-sweet-fat food cravings. Besides, the PMDD women had higher reward sensitivity, emotional response, positive implicit attitude, and craving response to high-sweet-fat foods. Further, the rewarding sensitivity was associated with emotional response to high-sweet-fat food which was associated with high-sweet-fat food craving. These results would suggest emotional response and implicit attitude might play a role for high-sweet-fat food craving of PMDD. Further, PMDD women with higher reward sensitivity should be a target group of intervention for high-sweet-fat food craving.

Cortical activation during mental rotation in male-to-female and female-to-male transsexuals under hormonal treatment

2010-09-01

Summary: There is strong evidence of sex differences in mental rotation tasks. Transsexualism is an extreme gender identity disorder in which individuals seek cross-gender treatment to change their sex. The aim of our study was to investigate if male-to-female (MF) and female-to-male (FM) transsexuals receiving cross-sex hormonal treatment have different patterns of cortical activation during a three-dimensional (3D) mental rotation task. An fMRI study was performed using a 3-T scan in a sample of 18 MF and 19 FM under chronic cross-sex hormonal treatment. Twenty-three males and 19 females served as controls. The general pattern of cerebral activation seen while visualizing the rotated and non-rotated figures was similar for all four groups showing strong occipito-parieto-frontal brain activation. However, compared to control males, the activation of MF transsexuals during the task was lower in the superior parietal lobe. Compared to control females, MF transsexuals showed higher activation in orbital and right dorsolateral prefrontal regions and lower activation in the left prefrontal gyrus. FM transsexuals did not differ from either the MF transsexual or control groups. Regression analyses between cerebral activation and the number of months of hormonal treatment showed a significant negative correlation in parietal, occipital and temporal regions in the MF transsexuals. No significant correlations with time were seen in the FM transsexuals. In conclusion, although we did not find a specific pattern of cerebral activation in the FM transsexuals, we have identified a specific pattern of cerebral activation during a mental 3D rotation task in MF transsexuals under cross-sex hormonal treatment that differed from control males in the parietal region and from control females in the orbital prefrontal region. The hypoactivation in MF transsexuals in the parietal region could be due to the hormonal treatment or could reflect a priori cerebral differences between MF transsexual and control subjects.

Perceived and physiological arousal during a stress task: Can they differentiate between anxiety and depression?

Gwendolyn C. Dieleman, Jan van der Ende, Frank C. Verhulst, Anja C. Huizink — 2010-09-01

Summary: Background: Anxiety and depression might be two different valid constructs that often co-occur, or they could be different manifestations of the same underlying vulnerability. A theoretical framework to address this question is the tripartite model, by Clark and Watson, which hypothesizes that physiological hyperarousal (PH) is specific for anxiety. Knowledge about the relationship between PH, psychophysiological measures, perceived arousal, and anxiety would increase our understanding of the validity of the PH construct in this model. Our objective was to assess whether (a) hypothalamic–pituitary–adrenocortical (HPA) axis functioning, and (b) perceived arousal before, during and after stress can differentiate anxious from depressive children.Methods: In a general population sample of 225 children aged 8–12 years, self-reported anxiety and depressive symptoms were assessed using the Multidimensional Anxiety Scale for Children (MASC) and the Children's Depression Inventory (CDI). Perceived arousal was assessed using a self-report questionnaire before, during and after a stress task. Basal and reactive HPA-axis functioning were used as indices for psychophysiological arousal.Results: Our data showed that the relation between perceived arousal and anxiety problems is stronger than the relation with depressive problems. Reactive HPA-axis functioning is reduced in children with depressive problems.Conclusions: Some evidence was found in support of the tripartite model. Our findings indicate that perceived arousal to a challenge might be a useful tool to assess the PH component of the tripartite model. Reactive HPA-axis functioning might be able to differentiate between anxiety and depressive problems in children in a general population sample, but effect sizes are small and replication is needed.

Maternal and umbilical cord androgen concentrations do not predict digit ratio (2D:4D) in girls: A prospective cohort study

2010-09-01

Summary: Digit ratio (2D:4D) is widely used as a marker of prenatal androgen exposure. However, there are no published prospective studies where prenatal androgen exposure has been measured and correlated with digit ratio in adult life. We aimed to establish the prospective relationship between prenatal androgen exposure in the second and third trimesters of pregnancy (as measured by maternal circulating androgen concentrations and umbilical cord androgen concentrations) and digit ratio in adolescent girls. Androgen concentrations (testosterone, free androgen index, androstenedione, DHEAS) and sex hormone binding globulin (SHBG) were measured in stored plasma samples from pregnant mothers at 18 (n=118) and 34/36 (n=114) weeks of gestation and in cord blood (n=82) from the Western Australian Pregnancy (Raine) Cohort Study (www.rainestudy.org.au). Digit ratio was measured in 244 female offspring from this cohort at age 14–16 years. Only one borderline statistically significant correlation between maternal circulating androstenedione levels at 18 weeks of gestation and left hand digit ratio was seen. No other statistically significant relationship between maternal androgen concentrations or umbilical cord androgen concentrations and digit ratio in adolescence were observed. These findings suggest that variation in 2D:4D in girls is not established as a result of testosterone concentrations in the second and third trimesters. We conclude that prenatal androgen exposure as measured by maternal circulating androgen concentrations at 18 and 34/36 weeks of gestation or in the umbilical cord at birth may not predict digit ratio in girls.

State associations with the cortisol awakening response in healthy females

Tobias Stalder, Phil Evans, Frank Hucklebridge, Angela Clow — 2010-09-01

Summary: The current study examined intra-individual relationships between the cortisol awakening response (CAR) and state sleep-related and psychosocial variables in a pooled design study. 12 healthy female participants (age range: 22–41 years.) were examined on 12 study days each, occurring at three-day intervals. Quantitative diaries capturing state sleep-related and psychosocial variables were filled out on the evening before each study day as well as 45min post-awakening on the study day. On each study day, salivary free cortisol was determined at 0, 15, 30, and 45min post-awakening. Relationships between cortisol measures and psychosocial variables were analysed using dummy-variable linear regression models. State variability in the CAR (area under increase curve; AUCI) was found to be inversely related to simultaneous variability in awakening time (β=−.29, p<.005) and positively related to variability in adverse psychosocial states of stress (β=.22, p<.01) and tension (β=.32, p<.001) measured 45min post-awakening. In addition, levels of the CAR were also found to decrease linearly over the study period across participants (β=−.19, p<.01) and this time trend could not be explained through a relationship between the CAR and any of the examined variables. The results are discussed within the context of previous evidence and potential implications for cross-sectional research are highlighted.

Use of a resting control day in measuring the cortisol response to mental stress: Diurnal patterns, time of day, and gender effects

William R. Lovallo, Noha H. Farag, Andrea S. Vincent — 2010-09-01

Summary: In laboratory studies of individual differences in stress reactivity, cortisol responses are typically measured by comparing a prestress baseline with values obtained at the end of the stressor. In the present study, we measured cortisol in this manner on a stress day, but we also took samples on a second day when the volunteers rested in the lab at the same time of day and for the same duration. We compared stress responses as the difference from pre- to poststress and also poststress vs. rest day control. The latter method allowed a greater appreciation of how stress perturbed the underlying diurnal baseline. Although the effect of stress was statistically significant when measured as the change from pre- to poststress, the magnitude of the effect was 54% larger when measured against the time-of-day control from the rest day. In particular the diurnal control method provided a wider range of stress values that potentially provide a greater range of response values in carrying out analyses of individual differences.

Fetal androgen exposure and pragmatic language ability of girls in middle childhood: Implications for the extreme male-brain theory of autism

2010-09-01

Summary: Prenatal exposure to testosterone has been shown to affect fetal brain maturation as well as postnatal cognition and behavior in animal studies. Although there are well-established sex-differences in the use of social communication (or ‘pragmatic language’) in humans, there has been limited investigation of the association between fetal testosterone exposure and postnatal pragmatic language ability. In this prospective study, pragmatic language skills, assessed using a pragmatic language score (PLS), were measured in 78 girls aged 10 years and correlated with testosterone levels in umbilical cord blood. A measure of the biologically active, ‘free’ fraction of testosterone, the free androgen index (FAI), was positively correlated with the PLS (R=.3). Regression analyses showed that the FAI was a significant, positive predictor of pragmatic language difficulties in girls after controlling for maternal and infant-health variables (B=0.02, 95% confidence interval=0.01–0.04, p=0.02). This is the first prospective study to identify an association between early life testosterone exposure and pragmatic language difficulties in girls. These novel findings are discussed with reference to the ‘extreme male-brain’ theory of autism.

Estrogenic regulation of limbic cannabinoid receptor binding

2010-09-01

Summary: Sex differences have been identified in many of the behavioral and physiological effects of cannabinoids. While estrogen has been linked to some of these variations, the effects of estrogen on cannabinoid receptor binding have not been characterized within regions of the brain specifically implicated in stress responsivity and emotional behavior. To examine sex differences, and the role of estradiol, in regulation of the cannabinoid receptor, we compared the binding site density of the cannabinoid receptor within the amygdala, hippocampus and hypothalamus in males, cycling females, ovariectomized (OVX) females and estradiol-treated OVX females (OVX+E). Our data reveal that males and OVX females have higher amounts of hypothalamic and lower amounts of amygdalar cannabinoid receptor binding relative to both cycling females and OVX+E females. Within the hippocampus, ovariectomy resulted in an upregulation of cannabinoid receptor binding. These data provide a putative biochemical mechanism mediating the observed behavioral and physiological sex differences in the effects of cannabinoids, particularly with respect to stress and emotional behavior.

Cortisol reduces recall of explicit contextual pain memory in healthy young men

2010-09-01

Summary: Remembering painful incidents has important adaptive value but may also contribute to clinical symptoms of posttraumatic stress disorder and chronic pain states. Because glucocorticoids are known to impair memory retrieval processes, we investigated whether cortisol affects recall of previously experienced pain in healthy young men. In a double-blind, placebo-controlled crossover study, 20 male participants were presented pictures, half of them combined with a heat-pain stimulus. The next day, the same pictures were shown in the absence of pain. Cortisol (20mg) administered 1h before retention testing reduced recall of explicit contextual pain memory, whereas it did not affect pain threshold or pain tolerance.