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1.  [No title available] 
PMCID: PMC3912460  PMID: 24485491
2.  [No title available] 
PMCID: PMC3912462  PMID: 24485470
3.  [No title available] 
PMCID: PMC3918518  PMID: 24485484
4.  [No title available] 
PMCID: PMC3919461  PMID: 24485492
5.  [No title available] 
PMCID: PMC3935801  PMID: 24485489
6.  [No title available] 
PMCID: PMC3967845  PMID: 24485493
7.  [No title available] 
PMCID: PMC4039194  PMID: 24485481
8.  Evidence for Alterations in Stimulatory G proteins and Oxytocin Levels in Children with Autism 
Psychoneuroendocrinology  2013;40:159-169.
The neurotransmitter oxytocin plays an important role in social affiliation. Low oxytocin levels and defects in the oxytocin receptor have been reported in childhood autism. However, little is known about oxytocin’s post-receptor signaling pathways in autism. Oxytocin signals via stimulatory and inhibitory G proteins. c-fos mRNA expression has been used as a marker of OT signaling as well as of G protein signaling. Herein, we hypothesized that oxytocin and its signaling pathways would be altered in children with autism. We measured plasma oxytocin levels by ELISA, G-protein and c-fos mRNA by PCR, and G proteins by immunoblot in cultured peripheral blood mononuclear cells (PBMCs) in children with autism and in age-matched controls. Males with autism displayed elevated oxytocin levels compared to controls (p<0.05). Children with autism displayed significantly higher mRNA for stimulatory G proteins compared to controls (p<0.05). Oxytocin levels correlated strongly positively with c-fos mRNA levels, but only in control participants (p<0.01). Oxytocin, G-protein, and c-fos mRNA levels correlated inversely with measures of social and emotional behaviors, but only in control participants. These data suggest that children with autism may exhibit a dysregulation in oxytocin and/or its signaling pathways.
PMCID: PMC4259400  PMID: 24485488
9.  Is very high C-Reactive Protein in Young Adults Associated with Indicators of Chronic Disease Risk? 
Psychoneuroendocrinology  2013;40:76-85.
Cases with very high C-reactive protein (CRP > 10 mg/l) are often dropped from analytic samples in research on risk for chronic physical and mental illness, but this convention could inadvertently result in excluding those most at risk. We tested whether young adults with very high CRP scored high on indicators of chronic disease risk. We also tested intergenerational pathways to and sex-differentiated correlates of very high CRP.
Data came from Waves I (ages 11–19) and IV (ages 24–34) of the National Longitudinal Study of Adolescent Health (N=13,257). At Wave I, participants’ parents reported their own education and health behaviors/health. At Wave IV, young adults reported their socioeconomic status, psychological characteristics, reproductive/health behaviors and health; trained fieldworkers assessed BMI, waist circumference, blood-pressure, and medication use, and collected bloodspots from which high-sensitivity CRP (hs-CRP) was assayed.
Logistic regressions revealed that many common indicators of chronic disease risk—including parental health/health behaviors reported 14 years earlier—were associated with very high CRP in young adults. Several of these associations attenuated with the inclusion of BMI. More than 75% of young adults with very high CRP were female. Sex differences in associations of some covariates and very high CRP were observed.
Especially among females, the exclusion of very high CRP cases could result in an underestimation of “true” associations of CRP with both, chronic disease risk indicators and morbidity/mortality. Very high CRP could represent an extension of the lower CRP range when it comes to chronic disease risk.
PMCID: PMC4307946  PMID: 24485478
C-reactive protein; inflammation; sex differences; cardiovascular disease risk; socioeconomic status; health disparities; intergenerational pathways; Add Health
10.  Maternal postnatal depression predicts altered offspring biological stress reactivity in adulthood 
Psychoneuroendocrinology  2015;52:251-260.
•Postnatally depressed (PND) mothers’ offspring showed increased cortisol stress reactivity.•This response at age 22-years was relative to control offspring.•There was also evidence of stable alterations in cortisol secretion in the PND group.•Offspring or subsequent maternal depression did not explain group differences.•Early maternal depression can predict offspring biological sensitivity to stress.
The offspring of depressed parents have been found to show elevated basal levels of the stress hormone cortisol. Whether heightened cortisol stress reactivity is also present in this group has yet to be clearly demonstrated. We tested whether postnatal maternal depression predicts subsequent increases in offspring biological sensitivity to social stress, as indexed by elevated cortisol reactivity.
Participants (mean age 22.4-years) derived from a 22-year prospective longitudinal study of the offspring of mothers who had postnatal depression (PND group; n = 38) and a control group (n = 38). Salivary cortisol response to a social-evaluative threat (Trier Social Stress Test) was measured.
Hierarchical linear modelling indicated that PND group offspring showed greater cortisol reactivity to the stress test than control group participants. Group differences were not explained by offspring depressive or anxiety symptoms, experiences of negative life events, elevated basal cortisol at age 13-years, subsequent exposure to maternal depression, or other key covariates.
The findings indicate that the presence of early maternal depression can predict offspring biological sensitivity to social stress in adulthood, with potential implications for broader functioning.
PMCID: PMC4309884  PMID: 25544737
Depression; Stress sensitivity; Cortisol; Maternal depression; Longitudinal; Hypothalamic–pituitary–adrenal axis
11.  Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction 
Psychoneuroendocrinology  2013;39:10.1016/j.psyneuen.2013.09.022.
Both oxytocin (OT) and vasopressin (AVP) are known to modulate social behavior, and dysfunction in both systems has been postulated as a potential cause of certain psychiatric disorders that involve social behavioral deficits. In particular, there is growing interest in intranasal OT as a potential treatment for certain psychiatric disorders, and preliminary preclinical and clinical studies suggest efficacy in alleviating some of the associated symptoms. However, the vast majority of research participants in these studies have been male, and there is evidence for sexually differentiated effects of nonapeptides in both humans and non-human animals. To date, no study has investigated the effect of intranasal OT on brain function in human males and females within the same paradigm. Previously, in a randomized, placebocontrolled, double-blind fMRI study, we reported effects of intranasal OT and AVP on behavior and brain activity of human males as they played an interactive social game known as the Prisoner’s Dilemma Game. Here, we present findings from an identical study in human females, and compare these with our findings from males. Overall, we find that both behavioral and neural responses to intranasal OT and AVP are highly sexually differentiated. In women, AVP increased conciliatory behavior, and both OT and AVP caused women to treat computer partners more like humans. In men, AVP increased reciprocation of cooperation from both human and computer partners. However, no specific drug effects on behavior were shared between men and women. During cooperative interactions, both OT and AVP increased brain activity in men within areas rich in OT and AVP receptors and in areas playing a key role in reward, social bonding, arousal and memory (e.g., the striatum, basal forebrain, insula, amygdala and hippocampus), whereas OT and AVP either had no effect or in some cases actually decreased brain activity in these regions in women. OT treatment rendered neural responses of males more similar to responses of females in the placebo group and vice-versa, raising the prospect of an inverted u-shaped dose response to central OT levels. These findings emphasize the need to fully characterize the effects of intranasal OT and AVP in both males and females and at multiple doses before widespread clinical application will be warranted.
PMCID: PMC3842401  PMID: 24157401
oxytocin; vasopressin; fMRI; cooperation; sex differences
12.  Linking Plasma Cortisol Levels to Phenotypic Heterogeneity of Posttraumatic Stress Symptomatology 
Psychoneuroendocrinology  2013;39:10.1016/j.psyneuen.2013.10.003.
Recent confirmatory factor analytic studies of the dimensional structure of posttraumatic stress disorder (PTSD) suggest that this disorder may be best characterized by five symptom dimensions—re-experiencing, avoidance, numbing, dysphoric arousal, and anxious arousal. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation in PTSD and has been attributed to enhanced glucocorticoid responsiveness. However, little is known about how altered HPA-axis function is related to this contemporary phenotypic model of PTSD.
We compared morning plasma cortisol levels of drug-free civilian adults with PTSD (N=29) to trauma-exposed (TC; N=12) and non trauma-exposed healthy controls (HC; N=23). We then examined the relation between cortisol levels and a contemporary 5-factor ‘dysphoric arousal’ model of PTSD symptoms among individuals with PTSD.
After adjustment for white race/ethnicity, education, lifetime alcohol use disorder, and current smoking status, the PTSD (Cohen’s d=1.1) and TC (Cohen’s d=1.3) groups had significantly lower cortisol levels than the HC group; cortisol levels did not differ between the TC and PTSD groups. Except for age (r=−.46), none of the other demographic, trauma-related, or clinical variables, including lifetime mood/anxiety disorder and severity of current depressive and anxiety symptoms, were associated with cortisol levels. In a stepwise linear regression analysis, age (β= −.44) and severity of emotional numbing symptoms (β= −.35) were independently associated with cortisol levels in the PTSD group; none of the other PTSD symptom clusters or depression symptoms were significant. Post-hoc analyses revealed that severity of the emotional numbing symptom of restricted range of affect (i.e., unable to have loving feelings) was independently related to cortisol levels (β= −.35).
These results suggest that trauma-exposed civilian adults with and without PTSD have significantly lower cortisol levels compared to healthy, non-trauma-exposed adults. They further suggest that low cortisol levels among adults with PTSD may be specifically linked to emotional numbing symptomatology that is unique to the PTSD phenotype and unrelated to depressive symptoms.
PMCID: PMC3843152  PMID: 24275007
PTSD; cortisol; 5-factor PTSD model; numbing; hypothalamic-adrenal-pituitary axis
13.  Are genetic variations in OXTR, AVPR1A, and CD38 genes important to social integration? Results from two large U.S. cohorts 
Psychoneuroendocrinology  2013;39:10.1016/j.psyneuen.2013.09.024.
Some evidence suggests that genetic polymorphisms in oxytocin pathway genes influence various social behaviors, but findings thus far have been mixed. Many studies have been based in small samples and there is possibility of publication bias. Using data from 2 large U.S. prospective cohorts with over 11,000 individuals, we investigated 88 SNPs in OXTR, AVPR1A, and CD38, in relation to social integration (measured as social connectedness in both binary and continuous forms and being continuously married). After correction for multiple testing only one SNP in CD38 (rs12644506) was significantly associated with social integration and that SNP predicted when using a dichotomized indicator of social connectedness (adjusted p=0.02), but not a continuous measure of social connectedness or the continuously married outcome. A significant gender-heterogeneous effect was identified in one OXTR SNP on dichotomized social connectedness; specifically, rs4686302 T allele was nominally associated with social connectedness in men, whereas the association direction was opposite in women (adjusted gender heterogeneity p=0.02). Furthermore, the rs53576 A allele was significantly associated with social connectedness only in women, and the effect magnitude was stronger in a dominant genetic model (adjusted p=0.003). In summary, our findings suggested that common genetic variants of OXTR, CD38, and AVPR1A are not associated with social integration as measured in this study using the simplified Berkman-Syme Social Network Index, but these findings and other work hint that effects may be modified by gender or other social experiences. Further work considering genetic pathways in relation to social integration may be more fruitful if these additional factors can be more comprehensively evaluated.
PMCID: PMC3864016  PMID: 24209975
OXTR; CD38; AVPR1A; social integration; sex-specific; candidate gene
14.  Social partners prevent alcohol relapse behavior in prairie voles 
Psychoneuroendocrinology  2013;39:10.1016/j.psyneuen.2013.10.006.
There is robust evidence for a protective role of interpersonal factors such as social support on alcohol relapse, but research on the mechanisms that social factors may be acting on to effectively protect individuals against relapse is lacking. Prairie voles are highly social, monogamous rodents that freely self-administer ethanol in high amounts, and are a useful model for understanding social influences on alcohol drinking. Here we investigated whether prairie voles can be used to model social influences on relapse using the alcohol deprivation effect, in which animals show a transient increase in ethanol drinking following deprivation. In Experiment I, subjects were housed alone during four weeks of 24-hour access to 10% ethanol in a two-bottle choice test. Ethanol was then removed from the cage for 72 hours. Animals remained in isolation or were then housed with a familiar same-sex social partner, and ethanol access was resumed. Animals that remained isolated showed an increase in ethanol intake relative to pre-deprivation baseline, indicative of relapse-like behavior. However, animals that were socially housed did not show an increase in ethanol intake, and this was independent of whether the social partner also had access to ethanol. Experiment II replicated the alcohol deprivation effect in a separate cohort of isolated animals. These findings demonstrate that prairie voles display an alcohol deprivation effect and suggest a ‘social buffering’ effect of relapse-like behavior in the prairie vole. This behavioral paradigm provides a novel approach for investigating the behavioral and neurobiological underpinnings of social influences on alcohol relapse.
PMCID: PMC3867132  PMID: 24275014
prairie vole; alcohol; relapse; alcohol deprivation effect; ethanol; social support
15.  How stable are diurnal cortisol activity indices in healthy individuals? Evidence from three multi-wave studies 
Psychoneuroendocrinology  2013;39:10.1016/j.psyneuen.2013.09.016.
Indices of cortisol activity, including the cortisol awakening response (CAR), diurnal slope, and cortisol output across the day (total daily output), are often studied as mechanistic indicators that could link stress with health. Yet there is a paucity of data speaking to their temporal features, particularly whether they behave in a more state- or trait-like manner across time.
To address this issue, data from 3 studies were used to assess CAR, diurnal slope and total daily output stability over different age groups and time spans: 130 healthy children and adolescents collected salivary cortisol samples 5 times/day (1, 4, 9 and 11 h after wake) over 2 days at 5 visits spaced 6 months apart (Study 1); 147 adolescent girls collected saliva 6 times/day (wake, 1, 4, 9 and 14 h after wake) for 2 days at 3 visits, each a year apart (Study 2); and 47 healthy, primarily middle age adults collected saliva 6 times/day (wake, 1, 4, 9 and 14 h after wake) for 3 days at 4 visits spaced 2–3 months apart (Study 3). Stability was estimated by multilevel model-derived intraclass correlation coefficients (ICCs).
Across studies, approximately 50% of the variance in cortisol indices was attributable to day-to-day fluctuations, suggesting state-like properties. Of the indices, total daily output emerged as the most stable over time, followed by diurnal slope and CAR, but stability estimates were generally quite modest regardless of index and sample. Over time spans of >1 year, ICCs were ≤.13.
Most of the variance in CAR, diurnal slope and total daily output reflects day-to-day fluctuation; there was little evidence for more stable trait-like influences. These findings suggest that future research should focus on short-term fluctuations in stress, cortisol and health, as opposed to lengthy disease processes.
PMCID: PMC3869640  PMID: 24119668
Cortisol; Hypothalamic pituitary adrenal (HPA) axis; Multilevel modeling; Stability; Within-person
16.  Enhanced Novelty-Induced Corticosterone Spike and Upregulated Serotonin 5-HT1A and Cannabinoid CB1 Receptors in Adolescent BTBR Mice 
Psychoneuroendocrinology  2013;39:158-169.
Hypothalamic pituitary adrenal (HPA) axis responses to change and social challenges during adolescence can influence mental health and behavior into adulthood. To examine how HPA tone in adolescence may contribute to psychopathology, we challenged male adolescent (5 wk) and adult (16 wk) BTBR T+tf/J (BTBR) and 129S1/SvImJ (129S) mice with novelty in sociability tests. In prior studies these strains had exaggerated or altered HPA stress responses and low sociability relative to C57BL/6J mice in adulthood. In adolescence these strains already exhibited similar or worse sociability deficits than adults or age-matched C57 mice. Yet BTBR adolescents were less hyperactive and buried fewer marbles than adults. Novelty-induced corticosterone (CORT) spikes in adolescent BTBR were double adult levels, and higher than 129S or C57 mice at either age. Due to their established role in HPA feedback, we hypothesized that hippocampal Gαi/o-coupled serotonin 5-HT1A and cannabioid CB1 receptor function might be upregulated in BTBR mice. Adolescent BTBR mice had higher hippocampal 5-HT1A density as measured by [3H]8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) binding than C57 mice, and adult BTBR 8-OH-DPAT-stimulated GTPγS binding was higher than in either C57 or 129S mice in this region. Further, BTBR hippocampal CB1 density measured by [3H]CP55,940 binding was 15-20% higher than in C57. CP55,940-stimulated GTPγS binding in adult BTBR dentate gyrus was 30% higher then 129S (p<0.05), but was not a product of greater neuronal or cell density defined by NeuN and DAPI staining. Hence hyperactive HPA responsiveness during adolescence may underlie 5-HT1A and CB1 receptor up-regulation and behavioral phenotype of BTBR mice.
PMCID: PMC3893037  PMID: 24126181
129S1/SvImJ; adolescent; BTBR; C57BL; cannabinoid; GTPγS autoradiography; hippocampus; HPA feedback; novelty stress; serotonin; social behavior
17.  Inhibition of 17α-hydroxylase/C17,20 lyase reduces gating deficits consequent to dopaminergic activation 
Psychoneuroendocrinology  2013;39:204-213.
Cogent evidence points to the involvement of neurosteroids in the regulation of dopamine (DA) neurotransmission and signaling, yet the neurobiological bases of this link remain poorly understood. We previously showed that inhibition of 5α-reductase (5αR), a key neurosteroidogenic enzyme, attenuates the sensorimotor gating deficits induced by DA receptor activation, as measured by the prepulse inhibition (PPI) of the acoustic startle reflex. To extend these findings, the present study was aimed at the assessment of the role of other key neurosteroidogenic enzymes in PPI, such as 17α-hydroxylase/C17,20 lyase (CYP17A1), 3α- and 3β-hydroxysteroid dehydrogenase (HSD), in Sprague-Dawley rats. The PPI deficits induced by the DAergic non-selective agonist apomorphine (APO, 0.25 mg/kg, SC) were dose-dependently attenuated by the selective CYP17A1 inhibitor abiraterone (ABI, 10-50 mg/kg, IP) in a fashion akin to that of the 5αR inhibitor finasteride (FIN, 100 mg/kg, IP). These systemic effects were reproduced by intracerebroventricular injection of ABI (1 μg/1 μl), suggesting the involvement of brain CYP17A1 in PPI regulation. Conversely, the PPI disruption induced by APO was not significantly affected by the 3α- and 3β-HSD inhibitors indomethacin and trilostane. Given that CYP17A1 catalyzes androgen synthesis, we also tested the impact on PPI of the androgen receptor (AR) antagonist flutamide (10 mg/kg, IP). However, this agent failed to reverse APO-induced PPI deficits; furthermore, AR endogenous ligands testosterone and dihydrotestosterone failed to disrupt PPI. Collectively, these data highlight CYP17A1 as a novel target for antipsychotic-like action, and suggest that the DAergic regulation of PPI is modulated by androgenic neurosteroids, through AR-unrelated mechanisms.
PMCID: PMC3940882  PMID: 24140269
17α-hydroxylase/C17,20 lyase; dopamine; prepulse inhibition of the startle; neurosteroidogenesis; androgen receptors
18.  Scn8a voltage-gated sodium channel mutation alters seizure and anxiety responses to acute stress 
Psychoneuroendocrinology  2013;39:225-236.
Stress is known to trigger seizures in patients with epilepsy, highlighting the physiological stress response as a possible therapeutic target for epilepsy treatment. Nevertheless, little is currently known about how a genetic predisposition to epilepsy interacts with the stress response to influence seizure outcome. To address this question, we examined the effect of acute stress on seizure outcome in mice with mutations in the voltage-gated sodium channel (VGSC) gene Scn8a. Scn8a mutants display spontaneous spike-wave discharges (SWDs) characteristic of absence epilepsy. We saw that the baseline frequency of SWDs in Scn8a mutants correlates closely with the diurnal activity of the hypothalamic-pituitary-adrenal (HPA) axis, with a peak in seizure activity occurring at around the same time as the peak in corticosterone (1700h–1900h). A 20-minute acute restraint stress administered in the morning increases the frequency of spontaneous SWDs immediately following the stressor. Seizure frequency then returns to baseline levels within three hours after stressor exposure, but the subsequent evening peak in seizure frequency is delayed and broadened, changes that persist into the next evening and are accompanied by long-lasting changes in HPA axis activity. Scn8a mutants also show increased anxiety-like behavior in mildly stressful situations. A 20-minute acute restraint stress can also increase the severity and duration of chemically induced seizures in Scn8a mutants, changes that differ from wild-type littermates. Overall, our data show that a voltage-gated sodium channel mutation can alter the behavioral response to stress and can interact with the stress response to alter seizure outcome.
PMCID: PMC3989103  PMID: 24138934
Scn8a; Stress; Epilepsy; Anxiety; Absence; Seizures
19.  The orexigenic hormone acyl-ghrelin increases adult hippocampal neurogenesis and enhances pattern separation 
Psychoneuroendocrinology  2015;51:431-439.
•Peripheral injections of acyl-ghrelin increase adult hippocampal neurogenesis.•Peripheral injections of acyl-ghrelin enhance pattern separation dependent memory.•Systemic administration of physiological levels of acyl-ghrelin has long-lasting memory benefits.
An important link exists between intact metabolic processes and normal cognitive functioning; however, the underlying mechanisms remain unknown. There is accumulating evidence that the gut hormone ghrelin, an orexigenic peptide that is elevated during calorie restriction (CR) and known primarily for stimulating growth hormone release, has important extra-hypothalamic functions, such as enhancing synaptic plasticity and hippocampal neurogenesis. The present study was designed to evaluate the long-term effects of elevating acyl-ghrelin levels, albeit within the physiological range, on the number of new adult born neurons in the dentate gyrus (DG) and performance on the Spontaneous Location Recognition (SLR) task, previously shown to be DG-dependent and sensitive to manipulations of plasticity mechanisms and cell proliferation. The results revealed that peripheral treatment of rats with acyl-ghrelin enhanced both adult hippocampal neurogenesis and performance on SLR when measured 8–10 days after the end of acyl-ghrelin treatment. Our data show that systemic administration of physiological levels of acyl-ghrelin can produce long-lasting improvements in spatial memory that persist following the end of treatment. As ghrelin is potentially involved in regulating the relationship between metabolic and cognitive dysfunction in ageing and neurodegenerative disease, elucidating the underlying mechanisms holds promise for identifying novel therapeutic targets and modifiable lifestyle factors that may have beneficial effects on the brain.
PMCID: PMC4275579  PMID: 25462915
Adult hippocampal neurogenesis; Ghrelin; Pattern separation
20.  Blunted glucocorticoid and mineralocorticoid sensitivity to stress in people with diabetes 
Psychoneuroendocrinology  2015;51:209-218.
•Impaired stress responsivity in type 2 diabetes is associated with a lack of mineralocorticoid and glucocorticoid sensitivity.•Corticosteroid sensitivity in type 2 diabetes correlates to HbA1c.•Type 2 diabetes participants showed blunted response to stress in inflammatory cytokines.
Psychological stress may contribute to type 2 diabetes but mechanisms are still poorly understood. In this study, we examined whether stress responsiveness is associated with glucocorticoid and mineralocorticoid sensitivity in a controlled experimental comparison of people with type 2 diabetes and non-diabetic participants. Thirty-seven diabetes patients and 37 healthy controls underwent psychophysiological stress testing. Glucocorticoid (GR) and mineralocorticoid sensitivity (MR) sensitivity were measured by dexamethasone- and prednisolone-inhibition of lipopolysaccharide (LPS)-induced interleukin (IL) 6 levels, respectively. Blood pressure (BP) and heart rate were monitored continuously, and we periodically assessed salivary cortisol, plasma IL-6 and monocyte chemotactic protein (MCP-1). Following stress, both glucocorticoid and mineralocorticoid sensitivity decreased among healthy controls, but did not change in people with diabetes. There was a main effect of group on dexamethasone (F(1,74) = 6.852, p = 0.013) and prednisolone (F(1,74) = 7.295, p = 0.010) sensitivity following stress at 45 min after tasks. People with diabetes showed blunted stress responsivity in systolic BP, diastolic BP, heart rate, IL-6, MCP-1, and impaired post-stress recovery in heart rate. People with Diabetes had higher cortisol levels as measured by the total amount excreted over the day and increased glucocorticoid sensitivity at baseline. Our study suggests that impaired stress responsivity in type-2 diabetes is in part due to a lack of stress-induced changes in mineralocorticoid and glucocorticoid sensitivity.
PMCID: PMC4275581  PMID: 25462894
HPA axis; Corticosteroid sensitivity; Acute stress; Cytokines; Auto-immune diseases; Cardiovascular
21.  Oxytocin administration enhances controlled social cognition in patients with schizophrenia 
Psychoneuroendocrinology  2014;47:116-125.
Individuals with schizophrenia have functionally significant deficits in automatic and controlled social cognition, but no currently available pharmacologic treatments reduce these deficits. The neuropeptide oxytocin has multiple prosocial effects when administered intranasally in humans and there is growing interest in its therapeutic potential in schizophrenia.
We administered 40 IU of oxytocin and saline placebo intranasally to 29 male subjects with schizophrenia and 31 age-matched, healthy controls in a randomized, double-blind, placebo-controlled, cross-over study. Social cognition was assessed with The Awareness of Social Inference Test (TASIT) and the Reading the Mind in the Eyes Test (RMET). We examined the effects of oxytocin administration on automatic social cognition (the ability to rapidly interpret and understand emotional cues from the voice, face, and body); controlled social cognition (the ability to comprehend indirectly expressed emotions, thoughts, and intentions through complex deliberations over longer time periods); and a control task (the ability to comprehend truthful dialog and perform general task procedures) in individuals with and without schizophrenia using mixed factorial analysis of variance models.
Patients with schizophrenia showed significant impairments in automatic and controlled social cognition compared to healthy controls, and administration of oxytocin significantly improved their controlled, but not automatic, social cognition, F(1, 58) = 8.75; p = 0.004. Conversely, oxytocin administration had limited effects on social cognition in healthy participants. Patients and controls performed equally well and there were no effects of oxytocin administration on the control task.
Intact social cognitive abilities are associated with better functional outcomes in individuals with schizophrenia. Our data highlight the potentially complex effects of oxytocin on some but not all aspects of social cognition, and support the exploration of intranasal oxytocin as a potential adjunct treatment to improve controlled social cognition in schizophrenia. Published by Elsevier Ltd.
PMCID: PMC4280262  PMID: 25001961
Oxytocin; Schizophrenia; Social cognition
22.  The relationship between heart rate variability and inflammatory markers in cardiovascular diseases 
Psychoneuroendocrinology  2008;33(10):1305-1312.
Recent evidence implicates a cholinergic anti-inflammatory pathway. Because vagus nerve activity mediates some heart rate variability (HRV), this qualitative review examines the literature concerning circulating cytokines and HRV in cardiovascular function in humans. This qualitative review examines the literature concerning circulating cytokines and HRV in cardiovascular function in humans.
Thirteen studies on HRV, inflammation, and cardiovascular function were located by electronic library search and descriptively reviewed.
The relationship between HRV and inflammation was studied in healthy controls, patients with acute or stable coronary heart disease (CHD), patients with metabolic syndrome or impaired glucose tolerance and patients with kidney failure. Investigations focused mainly on lnterleukin-6 (IL-6) and C-reactive peptide (CRP). The majority of reviewed studies reported that parasympathetic nervous system tone as inferred from heart rate variability is inversely related to inflammatory markers (r values between −0.2 and −0.4). The relationships with inflammatory markers were similar whether derived from ECG signals as short as 5–30 min or from 24-h ECG readings for HRV analyses. While inflammatory markers appear to be related to HRV, it is a mistake to assume that the traditional “vagal measures” of HRV (such as high frequency heart rate variability) are the driving factors. Indeed, low frequency heart rate variability, a complex measure reflecting both parasympathetic and sympathetic activity, is the more commonly associated measure linked to inflammatory markers.
Heart rate variability is inversely correlated with inflammatory markers in healthy individuals as well as in those with cardiovascular diseases.
PMCID: PMC4266571  PMID: 18819754
Autonomic nervous; system; Vagal nerve; Heart rate variability; Coronary heart disease; Inflammation
23.  Prenatal Stress, Partner Support, and Infant Cortisol Reactivity in Low-Income Mexican American Families 
Psychoneuroendocrinology  2013;38(12):10.1016/j.psyneuen.2013.09.006.
Maternal exposure to significant prenatal stress can negatively affect infant neurobiological development and increase the risk for developmental and health disturbances. These effects may be pronounced in low SES and ethnic minority families. We explored prenatal partner support as a buffer of the impact of prenatal stress on cortisol reactivity of infants born to low-income Mexican American women. Women (N=220; age 18–42; 84% Spanish-speaking; 89% foreign born; modal family income $10,000–$15,000) reported on economic stress and satisfaction with spousal/partner support during the prenatal period (26–38 weeks gestation), and infant salivary cortisol reactivity to mildly challenging mother-infant interaction tasks was assessed at women’s homes at six weeks postpartum. Multilevel models estimated the interactive effect of prenatal stress and partner support on cortisol reactivity, controlling for covariates and potential confounds. Infants born to mothers who reported high prenatal stress and low partner support exhibited higher cortisol reactivity relative to those whose mothers reported high support or low stress. The effects did not appear to operate through birth outcomes. For low-income Mexican American women, partner support may buffer the impact of prenatal stress on infant cortisol reactivity, potentially promoting more adaptive infant health and development.
PMCID: PMC3844006  PMID: 24090585
prenatal stress; infant cortisol; partner support
24.  Medroxyprogesterone acetate is associated with increased sleep spindles during non-rapid eye movement sleep in women referred for polysomnography 
Psychoneuroendocrinology  2013;38(12):10.1016/j.psyneuen.2013.08.012.
Sleep spindles are characteristic electroencephalographic waveforms that may play functionally significant roles in sleep-dependent memory consolidation, cortical development, and neuropsychiatric disorders. Circumstantial evidence has connected endogenous progesterone and its metabolites to the production of sleep spindles, however, the effects of exogenous progestins on sleep spindles have not been described in women. We examined differences in sleep spindle frequency and morphology in a clinical sample of women (n=21) referred for polysomnography taking depot medroxyprogesterone acetate (MPA), relative to a matched comparison group. Consistent with our hypotheses, women taking MPA demonstrated significantly higher sleep spindle density and maximal amplitude relative to comparison patients. Our results suggest that progestins potentiate the generation of sleep spindles, which may have significant implications for research that examines the role of these waveforms in learning, development, and mental illness.
PMCID: PMC3844048  PMID: 24054762
medroxyprogesterone; sleep spindles; progestin; progesterone
25.  Diurnal profiles of salivary cortisol and alpha-amylase change across the adult lifespan: Evidence from repeated daily life assessments 
Psychoneuroendocrinology  2013;38(12):10.1016/j.psyneuen.2013.09.008.
Salivary cortisol and alpha-amylase are known to have distinctive diurnal profiles. However, little is known about systematic changes in these biomarkers across the adult lifespan. In a study of 185 participants (aged 20–81 years), time-stamped salivary cortisol and alpha-amylase were collected 7 times/day over 10 days. Samples were taken upon waking, 30 minutes later, and then approximately every 3 hours until 9pm. Multilevel models showed that older age was associated with increased daily cortisol secretion as indicated by greater area under the curve, attenuated wake-evening slopes, and more pronounced cortisol awakening responses. Further, older age was related to greater daily alpha-amylase output and attenuated wake-evening slopes. No age differences were observed regarding the alpha-amylase awakening response. Our findings may contribute to a better understanding of age-related differences in functioning of stress-related systems.
PMCID: PMC3844069  PMID: 24099860
ageing; cortisol; lifespan; salivary alpha-amylase

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