Sex differences in associations of arginine vasopressin and oxytocin with resting-state functional brain connectivity.

Oxytocin (OT) and arginine vasopressin (AVP) exert robust and sexually dimorphic influences on cognition and emotion. How these hormones regulate relevant functional brain systems is not well understood. OT and AVP serum concentrations were assayed in 60 healthy individuals (36 women). Brain functional networks assessed with resting-state functional magnetic resonance imaging (rs-fMRI) were constructed with graph theory-based approaches that characterize brain networks as connected nodes. Sex differences were demonstrated in rs-fMRI. Men showed higher nodal degree (connectedness) and efficiency (information propagation capacity) in left inferior frontal gyrus (IFG) and bilateral superior temporal gyrus (STG) and higher nodal degree in left rolandic operculum. Women showed higher nodal betweenness (being part of paths between nodes) in right putamen and left inferior parietal gyrus (IPG). Higher hormone levels were associated with less intrinsic connectivity. In men, higher AVP was associated with lower nodal degree and efficiency in left IFG (pars orbitalis) and left STG and less efficiency in left IFG (pars triangularis). In women, higher AVP was associated with lower betweenness in left IPG, and higher OT was associated with lower nodal degree in left IFG (pars orbitalis). Hormones differentially correlate with brain networks that are important for emotion processing and cognition in men and women. AVP in men and OT in women may regulate orbital frontal cortex connectivity, which is important in emotion processing. Hormone associations with STG and pars triangularis in men and parietal cortex in women may account for well-established sex differences in verbal and visuospatial abilities, respectively. © 2016 Wiley Periodicals, Inc.

Interaction of oxytocin level and past depression may predict postpartum depressive symptom severity.

We examined plasma oxytocin concentration and postpartum depression (PPD) symptom severity in women who were not depressed during pregnancy and whether this differed by major depressive disorder (MDD) history. We assessed psychiatric history and plasma oxytocin in 66 healthy pregnant women in the third trimester (M = 35 ± 3 weeks) and depressive symptoms at 6 weeks postpartum (M = 5.9 ± 0.8 weeks). Linear regression analysis was used to examine oxytocin and PPD symptom severity and moderation of oxytocin and PPD by past MDD. Women with (n = 13) and without (n = 53) past MDD differed in third trimester depressive symptom severity, but not oxytocin level, demographic factors, or birth outcomes. Controlling for third trimester depressive symptoms, oxytocin level was unrelated to PPD symptom severity [B(SE) = -.019 (.084); ß = -.025; t = -.227; p = .821]. However, oxytocin level interacted with past MDD to predict PPD symptom severity [B(SE) = 7.489 (2.429); ß = .328; t = 3.084; p = .003]. Higher oxytocin predicted greater PPD symptom severity in women with past MDD (p = .019), but not in women without (p = .216). Replication in a larger sample and methodologic challenges are discussed.

In search of an adult attachment stress provocation to measure effect on the oxytocin system: a pilot validation study.

BACKGROUND: Oxytocin is a promising biomarker for psychiatric conditions arising from early relational trauma, childhood maltreatment, and attachment dysregulation, including posttraumatic stress and dissociative disorders. OBJECTIVE: This exploratory pilot study examined plasma oxytocin as a biomarker for alterations in the attachment system. DESIGN: We used a single group, repeated-measures design with 15 women. The protocol used a film clip previously validated as a provocation to the hypothalamic-pituitary-adrenal axis. RESULTS: The repeated-measures ANOVA showed differences in oxytocin across the three time points. Correlations with oxytocin indicated that measures of dissociation and somatization correlated most strongly with higher levels of oxytocin measured during exposure to the film's bonding scene and posttraumatic stress disorder correlated most strongly with lower levels at the film's abandonment scene. Post hoc analyses revealed differences in oxytocin response related to psychopathology. CONCLUSION: Replication studies should characterize participants on a range of psychiatric conditions associated with attachment dysregulation.

Peripheral oxytocin administration buffers autonomic but not behavioral responses to environmental stressors in isolated prairie voles.

Negative social experiences such as social stressors and isolation influence mental and physical illnesses, including affective disorders and heart disease. Studies focused on socially monogamous prairie voles can provide insight into neurobiological systems that underlie the consequences of negative social interactions. Female prairie voles were exposed to 28 days of social isolation or pairing with a female sibling (control). Voles were administered daily oxytocin [20 µg/50 µl, subcutaneous (sc)] or saline vehicle (50 µl, sc) for 14 days and exposed to two behavioral stressors [elevated plus maze (EPM) and resident-intruder test]. Brain tissue was collected for analysis of central peptide levels in the hypothalamic paraventricular nucleus (PVN). Isolation produced autonomic changes [increased heart rate (HR) and decreased HR variability) during both acute stressors and increased anxiety behaviors in the EPM. Oxytocin injection prevented the autonomic consequences of the acute stressors in isolated prairie voles, but did not affect the behaviors tested under the present conditions. Oxytocin had no effect on the behavioral or autonomic responsiveness in paired prairie voles. Oxytocin injection may exert a beneficial effect on autonomic responses to stressors in isolated animals through increasing the number of oxytocin-containing neurons and decreasing the number of corticotropin-releasing hormone-containing neurons in the PVN. Oxytocinergic mechanisms may serve to compensate for autonomic responses associated with chronic isolation and exposure to both social and non-social acute stressors.

Consequences of early experiences and exposure to oxytocin and vasopressin are sexually dimorphic.

In the socially monogamous prairie vole, we have observed that small changes in early handling, as well as early hormonal manipulations can have long-lasting and sexually dimorphic effects on behavior. These changes may be mediated in part by changes in parental interactions with their young, acting on systems that rely on oxytocin (OT) and arginine vasopressin (AVP). Knowledge of both endogenous and exogenous influences on systems that rely on OT and AVP may be helpful in understanding sexually dimorphic developmental disorders, such as autism, that are characterized by increased anxiety and deficits in social behavior.

Detection of salivary oxytocin levels in lactating women.

Oxytocin is a neuropeptide with widespread influence on many physiological and social functions including: labor and birth, lactation, sexual behavior, nurturing maternal behaviors, and stress reduction. However, our understanding of oxytocin's roles has been hampered by lack of noninvasive methods for assessing oxytocin levels. The goal of the present study was to assess whether oxytocin could be detected in saliva and whether changes occurred in the pattern of oxytocin release among lactating women from before, at initiation and after breast feeding. Using a prospective repeated measures design, 11 research participants each provided 18 saliva samples during three feeding cycles (before, at initiation and after breast feeding) for two 24-hr data collection periods (Days 1 and 2). Within each day, saliva was collected at late evening, early morning, and late morning. Salivary samples were concentrated fourfold by dehydration prior to analysis and oxytocin was measured in saliva using an enzyme immunoassay (EIA). Salivary oxytocin values, when reconverted to their original levels, ranged from 6.44 to 61.05 pg/ml. Oxytocin values in saliva varied significantly as a function of the breast feeding cycle, but did not show reliable differences as a function of the time of feeding. Oxytocin was highest before feeding, followed by a decrease at initiation of feeding, and an increase at 30 min after feeding. The findings suggest that oxytocin release into saliva increases in anticipation of feedings. This study also supports the potential usefulness of salivary measures of oxytocin as a noninvasive index of changes in this peptide.

Associations between oxytocin receptor gene (OXTR) methylation, plasma oxytocin, and attachment across adulthood.

The neuropeptide oxytocin (OT) has been implicated in a wide range of affiliative processes. OT exerts its functions via OT receptors, which are encoded by the oxytocin receptor gene (OXTR). Epigenetic modification of OXTR through the process of DNA methylation has been associated with individual differences in behavioral phenotypes. Specifically, lower levels of OXTR methylation have been linked to better social and affective functioning. However, research on epigenetic mechanisms of OXTR is scarce in non-clinical populations, and even less is known about epigenetic variability across adulthood. The present study assessed methylation levels at OXTR CpG site -934 and plasma OT levels in 22 young (20-31 years, M = 23.6) and 34 older (63-80 years, M = 71.4) participants. Lower levels of OXTR methylation and higher plasma OT levels were associated with less self-reported attachment anxiety in young but not older participants, with largely independent contributions of OXTR methylation and plasma OT levels. In contrast, in the overall sample, lower levels of OXTR methylation were associated with higher self-reported attachment avoidance. Age analysis suggested that these results were largely driven by young adults. Plasma OT levels were unrelated to attachment avoidance. Taken together, these findings support the emerging notion in the literature that epigenetic properties of OXTR, in addition to endogenous OT levels, are related to adult attachment. Further, the age effects observed in the associations between OXTR methylation, plasma OT, and adult attachment emphasize the importance of adopting a developmental perspective when studying properties of the OT system and their relation to affiliative processes. Findings contribute to growing evidence suggesting that epigenetic modification of genes regulating OT pathways and endogenous OT levels are associated with the way people form and maintain intimate social relationships.

An exploratory study of neurohormonal responses of healthy men to massage.

OBJECTIVE: This research examined the relationship between plasma oxytocin (OT), arginine vasopressin (AVP), cortisol, and anxiety before, during, and after a massage in healthy adult men. DESIGN: A randomized, controlled, crossover, repeated-measures, prospective experimental design with subjects acting as their own controls was used. SETTING: The research was conducted at a Midwestern University. SUBJECTS: Fourteen (14) healthy men between the ages of 19 and 45 years of age were randomly assigned to the order of two conditions: a 20-minute massage (experimental condition) or a 20-minute reading period (control condition). METHODS: Blood samples were collected at time intervals during each data collection session. Plasma OT, AVP, and cortisol levels were evaluated by enzyme immunoassay (EIA). The Spielberger State Anxiety Inventory (SAI) and autonomic measures were recorded pre- and postcondition. RESULTS: Both experimental (massage) and control (reading) conditions elicited a significant increase in plasma OT levels (p < 0.05) and a decrease in SAI score (p < 0.05) from pre- to postintervention. A significant positive correlation was detected between plasma AVP and plasma cortisol (r = 0.63, n = 24, p = 0.001) in the massage group, whereas a significant positive correlation between plasma AVP and the SAI (r = 0.47, n = 25, p = 0.016) was observed in the reading group. No significant differences were observed for the autonomic measures between conditions. CONCLUSIONS: The finding that plasma OT levels increased in both the massage and reading groups, suggests that tactile stimulus is not necessary for OT release. The results suggest that another unknown factor associated with reduction of anxiety may be involved.

The Role of Endogenous Oxytocin in Anxiolysis: Structural and Functional Correlates.

BACKGROUND: Oxytocin is anxiolytic, and administration of synthetic oxytocin in humans reduces amygdala reactivity to negative stimuli. However, it is unknown whether endogenous oxytocin levels-which are heritable and stable across time-attenuate anxiety via similar mechanisms. METHODS: In this study, we used plasma assays and structural and functional neuroimaging to examine potential anxiolytic effects of endogenous oxytocin in 73 participants. RESULTS: We found that higher endogenous oxytocin levels are associated with reduced central amygdala volume and blood oxygen level-dependent activity in response to aversive stimuli. In contrast to previous reports, we found that oxytocin was not related to patterns of functional connectivity between the amygdala and other brain regions. CONCLUSIONS: Together, our results underscore the importance of considering individual differences in participants' endogenous oxytocin with respect to anxiety-related neural activity and neuromorphology.

The Effects of Equine Assisted Therapy on Plasma Cortisol and Oxytocin Concentrations and Heart Rate Variability in Horses and Measures of Symptoms of Post-Traumatic Stress Disorder in Veterans.

With the increase in the number of horses being used in Equine-Assisted Activities and Therapies (EAAT) programs and with the increasing concern for animal welfare, it is important to understand the impact of such interventions on the stress level and quality of life for the horses involved. The purpose of the present pilot study was to test the hypothesis that participation in EAAT would acutely alter physiological markers of stress and well-being, including plasma cortisol, plasma oxytocin, and heart rate variability (HRV), in horses and that symptoms of posttraumatic stress disorder (PTSD) would be reduced after five sessions of EAAT in veterans who had previously been diagnosed with PTSD. Nine healthy geldings, of various breeds, ages 10-23 years, conditioned and experienced as therapeutic riding horses, were selected to participate in the study. Of these, seven were selected at random to wear electrocardiogram units, and all nine were used for blood sampling to measure plasma cortisol and oxytocin. Each horse was randomly assigned to partner with a veteran for five EAAT sessions, 1 hour in duration. A standing control was conducted on a later date on which horses did not participate in EAAT. Measurement after 5 days of EAAT was conducted immediately after the end of the last session on day 5 using the Brief Symptom Inventory and the PCL-5 (a 20 item self-report measure of the Diagnostic and Statistical Manual of Mental Disorders - 5 for symptoms of PTSD). Two way repeated measure analysis of variance showed no significant day by time interactions for plasma cortisol (P = .821) or oxytocin (P = .861). There was a significant day by time interaction (P = .006) for heart rate (HR); where on day 1, HR (bpm) was significantly lower during the interaction with the veterans. There were no significant differences in HRV variables. Posttherapy measures in PTSD symptoms in veterans were significantly reduced except for interpersonal sensitivity (P = .08) and phobic anxiety (P = .17). There was an effect of EAAT on HR which was significantly reduced on day 2 during the actual EAAT session. Equine-Assisted Activities and Therapies had no effect on respiration rate and systolic or diastolic blood pressure in veterans involved in five sessions of EAAT, lasting 60 minutes in duration over the course of 5 days. Stress levels, as demonstrated by plasma cortisol concentrations and HRV, did not change in horses involved in EAAT sessions with veterans who had been previously diagnosed with PTSD. Furthermore, the horses used in this study did not demonstrate increased levels of well-being as demonstrated by the lack of change in plasma oxytocin concentrations after EAAT sessions. Symptoms of PTSD did change significantly in the veterans who participated in this study.

Peripheral oxytocin and vasopressin modulates regional brain activity differently in men and women with schizophrenia.

BACKGROUND: Oxytocin (OT) and arginine vasopressin (AVP) exert sexually dimorphic effects on cognition and emotion processing. Abnormalities in these hormones are observed in schizophrenia and may contribute to multiple established sex differences associated with the disorder. Here we examined sex-dependent hormone associations with resting brain activity and their clinical associations in schizophrenia patients. METHODS: OT and AVP serum concentrations were assayed in 35 individuals with schizophrenia (23 men) and 60 controls (24 men) from the Chicago BSNIP study site. Regional cerebral function was assessed with resting state fMRI by measuring the amplitude of low-frequency fluctuations (ALFF) which are believed to reflect intrinsic spontaneous neuronal activity. RESULTS: In female patients, lower OT levels were associated with lower ALFF in frontal and cerebellar cortices (p's < 0.05) and in female controls AVP levels were inversely associated with ALFF in the frontal cortex (p = 0.01). In male patients, lower OT levels were associated with lower ALFF in the posterior cingulate and lower AVP levels were associated with lower ALFF in frontal cortex (p's < 0.05). In male controls, lower OT levels were associated with lower ALFF in frontal cortex and higher ALFF in the thalamus (p's < 0.05). There were some inverse ALFF-behavior associations in patients. CONCLUSIONS: Alterations in peripheral hormone levels are associated with resting brain physiology in a sex-dependent manner in schizophrenia. These effects may contribute to sex differences in psychiatric symptom severity and course of illness in schizophrenia.

Oxytocin: behavioral associations and potential as a salivary biomarker.

Oxytocin (OT) is a neuropeptide that is produced primarily in the hypothalamus and is best known for its role in mammalian birth and lactation. Recent evidence also implicates OT in social behaviors, including parental behavior, the formation of social bonds, and the management of stressful experiences. OT is reactive to stressors, and plays a role in the regulation of both the central and autonomic nervous system, including effects on immune and cardiovascular function. Knowledge of patterns of OT release would be of value in many fields of science and medicine. However, measurements of OT concentration in blood are infrequently performed, and previous attempts to measure OT in saliva have been unsuccessful. Using a sensitive enzyme immunoassay (EIA) and concentrated samples we were able to detect reproducible changes in salivary OT as a function of lactation and massage. These results indicate that measurements of biologically relevant changes in salivary OT are possible. These results confirm the biological relevance of changes in salivary OT with stressors and support saliva as a noninvasive source to monitor central neuroendocrine function.

Neonatal oxytocin treatment modulates oxytocin receptor, atrial natriuretic peptide, nitric oxide synthase and estrogen receptor mRNAs expression in rat heart.

Oxytocin (OT) has been implicated in reproductive functions, induction of maternal behavior as well as endocrine and neuroendocrine regulation of the cardiovascular system. Here we demonstrate that neonatal manipulation of OT can modulate the mRNAs expression for OT receptor (OTR), atrial natriuretic peptide (ANP), endothelial nitric oxide synthase (eNOS) and estrogen receptor alpha (ERalpha) in the heart. On the first day of postnatal life, female and male rats were randomly assigned to receive one of the following treatments: (a) 50microl i.p. injection of 7microg OT; (b) 0.7microg of OT antagonist (OTA); or (c) isotonic saline (SAL). Hearts were collected either on postnatal day 1 or day 21 (D1 or D21) and the mRNAs expression of OTR, ANP, inducible NOS (iNOS), eNOS, ERalpha and estrogen receptor beta (ERbeta) were compared by age, treatment, and sex utilizing real time PCR. OT treatment significantly increased heart OTR, ANP and eNOS mRNAs expression on D1 in both males and females, ERalpha increased only in females. While there were significant changes in the relative expression of all types of mRNA between D1 and D21, there were no significant treatment effects observed in D21 animals. OTA treatment significantly decreased basal ANP and eNOS mRNAs expression on D1 in both sexes. The results indicate that during the early postnatal period OT can have an immediate effect on the expression OTR, ANP, eNOS, and ERalpha mRNAs and that these effects are mitigated by D21. Also with the exception of ERalpha mRNA, the effects are the same in both sexes.

Oxytocin selectively increases ERalpha mRNA in the neonatal hypothalamus and hippocampus of female prairie voles.

During neonatal development exogenous oxytocin increases ERalpha immunoreactivity in the hypothalamus of female prairie voles. The purpose of this study was to determine if the increase in ERalpha is associated with an increase in ERalpha mRNA expression and to determine if the effect is specific to ER subtype or if oxytocin also influences ERbeta mRNA expression. On the day of birth female prairie vole pups were treated with oxytocin, an oxytocin antagonist, or saline. Brains were collected and RT-PCR was used to determine the effect of treatment on ER mRNA production in the hypothalamus, hippocampus, and cortex. Within 2h of treatment oxytocin significantly increased ERalpha mRNA expression in the hypothalamus and hippocampus, but not the cortex, while inhibiting the effects of endogenous oxytocin reduced the expression of ERalpha mRNA in the hippocampus. Neonatal treatment did not affect the expression of ERbetamRNA. The results demonstrate that the effects of oxytocin treatment are region and ER subtype specific and that during the neonatal period oxytocin can affect the expression of ERalpha by altering message production. The regional specific changes in ERalpha mRNA expression in females are consistent with studies examining the behavioral and physiological effects of neonatal manipulation of oxytocin in females.

Modulation of corticotropin-releasing hormone type 2 receptor and urocortin 1 and urocortin 2 mRNA expression in the cardiovascular system of prairie voles following acute or chronic stress.

The purpose of this study was to compare the effects of an acute stressor (restraint) versus a chronic stressor (social isolation) on the expression of mRNAs for corticotropin-releasing hormone receptor type 2 (CRH-R2) and urocortin 1 (Ucn 1) and urocortin 2 (Ucn 2) in the cardiovascular system of socially monogamous prairie voles of both sexes. Acute restraint for 1 h was followed by a marked increase in plasma corticosterone, and when the animals were re-paired for 1 day, the increment of corticosterone was normalized. However, following chronic social isolation for 4 weeks, plasma corticosterone did not differ significantly from the levels measured in animals living in pairs. Restraint or isolation significantly decreased CRH-R2 mRNA in ventricle, atria, and aorta; however, when these animals were re-paired for 1 day, the modulation of CRH-R2 mRNA was normalized in restraint but not in isolated animals. Restraint stress increased the Ucn 1 mRNA expression in the heart of female and male prairie voles, and when the animals were re-paired, the modulation of Ucn 1 mRNA expression was normalized. However, chronic isolation showed no effect on cardiac Ucn 1 mRNA expression. Although acute restraint stress produced no effect on the cardiac Ucn 2 mRNA expression, chronic isolation was followed by an increased heart Ucn 2 mRNA expression in both sexes. When the isolated animals were re-paired for 1 day, the cardiac Ucn 2 mRNA expression remained upregulated. The results of the present study reveal that acute restraint as well as social isolation can have significant consequences for the modulation of gene expression for the CRH-R2 and the urocortin peptides in cardiovascular tissue in female and male prairie voles.

Sex and diagnosis specific associations between DNA methylation of the oxytocin receptor gene with emotion processing and temporal-limbic and prefrontal brain volumes in psychotic disorders.

BACKGROUND: The oxytocin (OT) system, including receptor epigenetic mechanisms, has been shown to influence emotion processing, especially in females. Whether OT receptor (OXTR) epigenetic alterations occur across psychotic disorders in relation to illness-related disturbances in social cognition and brain anatomy is unknown. METHODS: Participants with affective and nonaffective psychotic disorders (92 women, 75 men) and healthy controls (38 women, 37 men) from the Chicago site of the BSNIP study completed the Penn Emotion Recognition Test (ER-40), a facial emotion recognition task. We measured cytosine methylation at site -934 upstream of the OXTR start codon in DNA from whole blood, and for the first time their relationship with plasma OT levels assessed by enzyme-immunoassay. Volumes of brain regions supporting social cognition were measured from MRI scans using FreeSurfer. RESULTS: Patients with prototypic schizophrenia features showed higher levels of DNA methylation than those with prototypic bipolar features. Methylation was higher in women than men, and was associated with poorer emotion recognition only in female patients and controls. Greater methylation was associated with smaller volumes in temporal-limbic and prefrontal regions associated previously with social cognition, but only in healthy women and females with schizophrenia. CONCLUSION: DNA methylation of the OXTR site -934 was higher in schizophrenia spectrum than bipolar patients. Among patients, it was linked to behavioral deficits in social cognition and neuroanatomic structures known to support emotion processing only in schizophrenia spectrum individuals.

Physiological and behavioral responses to interleukin-1beta and LPS in vagotomized mice.

It is well established that peripheral administration of interleukin-1 (IL-1) and lipopolysaccharide (LPS) can activate the hypothalamo-pituitary-adrenocortical (HPA) axis, alter brain catecholamine and indoleamine metabolism, and affect behavior. However, the mechanisms of these effects are not fully understood. Stimulation of afferents of the vagus nerve has been implicated in the induction of Fos in the brain, changes in body temperature, brain norepinephrine, and some behavioral responses. In the present study, the IL-1beta- and LPS-induced changes in certain behaviors, HPA axis activation, and catecholamine and indoleamine metabolism were studied in mice following subdiaphragmatic vagotomy. IL-1beta and LPS induced the expected decreases in sweetened milk, food intake, and locomotor activity, and the responses to IL-1beta, but not LPS, were slightly attenuated in vagotomized mice. Subdiaphragmatic vagotomy also attenuated the IL-1beta- and LPS-induced increases in plasma ACTH and corticosterone, but the attenuations of the responses to IL-1beta were only marginally significant. There were also slight reductions in the responses in catecholamine and serotonin metabolism, and the increases in brain tryptophan in several brain regions. These results indicate that the vagus nerve is not the major pathway by which abdominal IL-1beta and LPS effect behavioral, HPA and brain catecholamine and indoleamine responses in the mouse. These results resemble those we observed in subdiaphragmatically vagotomized rats, but in that species the subdiaphragmatic vagotomy markedly attenuated the ACTH and corticosterone responses, and prevented the hypothalamic noradrenergic activation, as well as the fever. Overall the results indicate that the various responses to peripheral IL-1 and LPS involve multiple mechanisms including vagal afferents, and that there are species differences in the relative importance of the various mechanisms.

Changes in social functioning and circulating oxytocin and vasopressin following the migration to a new country.

Prior studies have reported associations between plasma oxytocin and vasopressin and markers of social functioning. However, because most human studies have used cross-sectional designs, it is unclear whether plasma oxytocin and vasopressin influences social functioning or whether social functioning modulates the production and peripheral release of these peptides. In order to address this question, we followed individuals who experienced major changes in social functioning subsequent to the migration to a new country. In this study, 59 new international students were recruited shortly after arrival in the host country and reassessed 2 and 5 months later. At each assessment participants provided information on their current social functioning and blood samples for oxytocin and vasopressin analysis. Results indicated that changes in social functioning were not related to changes in plasma oxytocin. Instead, baseline oxytocin predicted changes in social relationship satisfaction, social support, and loneliness over time. In contrast, plasma vasopressin changed as a function of social integration. Baseline vasopressin was not related to changes in social functioning over time. These results emphasize the different roles of plasma oxytocin and vasopressin in responses to changes in social functioning in humans.

Effects of sex, menstrual cycle phase, and endogenous hormones on cognition in schizophrenia.

BACKGROUND: In women with schizophrenia, cognition has been shown to be enhanced following administration of hormone therapy or oxytocin. We examined how natural hormonal changes across the menstrual cycle influence cognition in women with schizophrenia. We hypothesized that female patients would perform worse on "female-dominant" tasks (verbal memory/fluency) and better on "male-dominant" tasks (visuospatial) during the early follicular phase (low estradiol and progesterone) compared to midluteal phase (high estradiol and progesterone) in relation to estradiol but not progesterone. METHODS: Fifty-four women (23 with schizophrenia) completed cognitive assessments and provided blood for sex steroid assays and oxytocin at early follicular (days 2-4) and midluteal (days 20-22) phases. Men were included to verify the expected pattern of sex differences on cognitive tests. RESULTS: Expected sex differences were observed on "female-dominant" and "male-dominant" tasks (p<0.001), but the magnitude of those differences did not differ between patients and controls (p=0.44). Cognitive performance did not change across the menstrual cycle on "female-dominant" or "male-dominant" tasks in either group. Estradiol and progesterone levels were unrelated to cognitive performance. Oxytocin levels did not change across the menstrual cycle but were positively related to performance on "female-dominant" tasks in female patients only (p<0.05). CONCLUSIONS: Sex differences in cognitive function are preserved in schizophrenia. Oxytocin levels do not change across the cycle, but relate to enhanced performance on female dominant tests in women. Physiological levels of oxytocin may thus have a more powerful benefit in some cognitive domains than estrogens in schizophrenia.

Plasma oxytocin explains individual differences in neural substrates of social perception.

The neuropeptide oxytocin plays a critical role in social cognition and behavior. A number of studies using intranasal administration have demonstrated that oxytocin improves social perception. However, little is known about the relationship between individual differences in endogenous levels of oxytocin and social cognition. In the current study, we assessed the relationship between endogenous oxytocin and brain activity during an animacy perception paradigm. Thirty-seven male participants underwent scanning and provided a blood sample for oxytocin analysis. In line with previous research, perception of animacy was associated with activations in superior temporal sulcus, inferior frontal gyrus, and medial prefrontal cortex (mPFC). Notably, participants' levels of plasma oxytocin robustly predicted activation in areas critical for social cognitive processes, such that higher oxytocin levels were related to increased activity in dorsal mPFC, ventral mPFC, dorsolateral PFC, superior temporal gyrus, and temporoparietal junction (TPJ), suggesting differential processing of social stimuli. Together these results show that stable variations in endogenous oxytocin levels explain individual differences in social perception.