Sex differences in emotional responding have been repeatedly postulated but less consistently shown in empirical studies. Because emotional reactions are modulated by cognitive appraisal, sex differences in emotional responding might depend on differences in emotion regulation. In this study, we investigated sex differences in emotional reactivity and emotion regulation using a delayed cognitive reappraisal paradigm and measured whole-brain BOLD signal in 17 men and 16 women. During fMRI, participants were instructed to increase, decrease, or maintain their emotional reactions evoked by negative pictures in terms of cognitive reappraisal. We analyzed BOLD responses to aversive compared to neutral pictures in the initial viewing phase and the effect of cognitive reappraisal in the subsequent regulation phase. Women showed enhanced amygdala responding to aversive stimuli in the initial viewing phase, together with increased activity in small clusters within the prefrontal cortex and the temporal cortex. During cognitively decreasing emotional reactions, women recruited parts of the orbitofrontal cortex, the anterior cingulate, and the dorsolateral prefrontal cortex to a lesser extent than men, while there was no sex effect on amygdala activity. In contrast, compared to women, men showed an increased recruitment of regulatory cortical areas during cognitively increasing initial emotional reactions, which was associated with an increase in amygdala activity. Clinical implications of these findings are discussed. Hum Brain Mapp, 2010.(c) 2009 Wiley-Liss, Inc.

The neuropeptide oxytocin (OXT) has previously been found to reduce amygdala reactivity to social and emotional stimuli in healthy men. The present study aimed to investigate the effect of intranasally administered OXT on brain activity in response to social emotional stimuli of varying valence in women. In a functional magnetic-resonance imaging study, sixteen women were presented with fearful, angry, happy and neutral facial expressions after a single dose of 24IU OXT or a placebo administration in a within-subject design. Group analysis revealed that the blood-oxygen-level-dependent (BOLD) signal was enhanced in the left amygdala, the fusiform gyrus and the superior temporal gyrus in response to fearful faces and in the inferior frontal gyrus in response to angry and happy faces following OXT treatment. This effect was independent of fixation pattern to specific sections of the facial stimuli as revealed by eye tracking and independent of basal plasma levels of OXT, estradiol, and progesterone. The results are at odds with the previously reported effects found in men. Future studies should include both sexes to determine a possible sexual dimorphism in the neural effects of OXT, considering gonadal steroids and OXT receptor affinity.

The fundamental ability to form attachment is indispensable for human social relationships. Impairments in social behaviour are associated with decreased quality of life and psychopathological states. In non-human mammals, the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are key mediators of complex social behaviours, including attachment, social recognition and aggression. In particular, OXT reduces behavioural and neuroendocrine responses to social stress and seems both to enable animals to overcome their natural avoidance of proximity and to inhibit defensive behaviour, thereby facilitating approach behaviour. AVP has primarily been implicated in male-typical social behaviours, including aggression and pair-bond formation, and mediates anxiogenic effects. Initial studies in humans suggest behavioural, neural, and endocrine effects of both neuropeptides, similar to those found in animal studies. This review focuses on advances made to date in the effort to understand the role of OXT and AVP in human social behaviour. First, the literature on OXT and AVP and their involvement in social stress and anxiety, social cognition, social approach, and aggression is reviewed. Second, we discuss clinical implications for mental disorders that are associated with social deficits (e.g. autism spectrum disorder, borderline personality disorder). Finally, a model of the interactions of anxiety and stress, social approach behaviour, and the oxytocinergic system is presented, which integrates the novel approach of a psychobiological therapy in psychopathological states.

BACKGROUND: Oxytocin is known to reduce anxiety and stress in social interactions as well as to modulate approach behavior. Recent studies suggest that the amygdala might be the primary neuronal basis for these effects. METHODS: In a functional magnetic resonance imaging study using a double-blind, placebo-controlled within-subject design, we measured neural responses to fearful, angry, and happy facial expressions after intranasal application of 24 IU oxytocin compared with placebo. RESULTS: Oxytocin reduced right-sided amygdala responses to all three face categories even when the emotional content of the presented face was not evaluated explicitly. Exploratory whole brain analysis revealed modulatory effects in prefrontal and temporal areas as well as in the brainstem. CONCLUSIONS: Results suggest a modulatory role of oxytocin on amygdala responses to facial expressions irrespective of their valence. Reduction of amygdala activity to positive and negative stimuli might reflect reduced uncertainty about the predictive value of a social stimulus and thereby facilitates social approach behavior.

BACKGROUND: The ability to "read the mind" of other individuals, that is, to infer their mental state by interpreting subtle social cues, is indispensable in human social interaction. The neuropeptide oxytocin plays a central role in social approach behavior in nonhuman mammals. METHODS: In a double-blind, placebo-controlled, within-subject design, 30 healthy male volunteers were tested for their ability to infer the affective mental state of others using the Reading the Mind in the Eyes Test (RMET) after intranasal administration of 24 IU oxytocin. RESULTS: Oxytocin improved performance on the RMET compared with placebo. This effect was pronounced for difficult compared with easy items. CONCLUSIONS: Our data suggest that oxytocin improves the ability to infer the mental state of others from social cues of the eye region. Oxytocin might play a role in the pathogenesis of autism spectrum disorder, which is characterized by severe social impairment.

Some studies suggest that stress-induced effects of cortisol on memory are modulated by the valence of the stimuli to be learned and retrieved. The present study investigated the effect of acute stress-induced cortisol secretion on acquisition and retrieval of pleasant, unpleasant and neutral words. Sixty healthy men were randomly assigned to one of the three experimental groups. Participants were either exposed to a standardized laboratory stressor (the Trier Social Stress Test) before learning a wordlist, or before retrieval, or were not stressed. Free recall and recognition were tested 24 h later. Free recall was not affected by stress exposure. For recognition, there was no main effect of the stressor, but a main effect of valence and a valence by group interaction emerged: recognition for positive words was significantly impaired when subjects were stressed before retrieval. In addition, a positive correlation between the cortisol response and errors of commission was found. The results suggest that acute stress impairs memory for positive stimuli and that stress-induced cortisol secretion interferes with accuracy of memory retrieval, i.e. the ability to discriminate true memories from false ones.

The risk of adverse psychological outcomes in adult victims of childhood and adolescent sexual abuse (CSA) has been documented; however, research on possible mediating variables is still required, namely with a clinical perspective. The attachment literature suggests that secure interpersonal relationships may represent such a variable. Twenty-eight women who had experienced episodes of CSA, and 16 control women, were interviewed using Bremner's Early Trauma Inventory and the DSM-IV Global Assessment of Functioning; they also responded to Collins' Relationship Scales Questionnaire, evaluating adult attachment representations in terms of Closeness, Dependence and Anxiety. Subjects with an experience of severe abuse reported significantly more interpersonal distance in relationships (low index of Closeness) than other subjects. The index of psychopathological functioning was correlated with both the severity of abuse and attachment (low index of Closeness). Regression analysis on the sample of abused women revealed that attachment predicted psychopathology when abuse was controlled for, whereas abuse did not predict psychopathology when attachment was controlled for. Therefore, preserving a capacity for closeness with attachment figures in adulthood appears to mediate the consequences of CSA on subsequent psychopathological outcome. Copyright (c) 2009 John Wiley & Sons, Ltd.Key Practitioner Message:* The way CSA victims deal with closeness and intimacy in relationships contributes to the quality of psychological outcome in adulthood.* Treatment strategies for CSA victims should emphasize the enhancement of interpersonal experiences and the strengthening of the subject's sense of closeness to others, intimacy in relationships, and confidence in others.

Psychomotor symptoms related to an impairment of the nigrostriatal dopaminergic system are frequent in major depression (MD). Repetitive transcranial magnetic stimulation (rTMS) has been discussed as a new treatment option for MD. In neurobiological terms, an influence of high-frequency rTMS on dopaminergic neurotransmission has previously been shown by several studies in animals and humans. Therefore, an improvement of psychomotor symptoms by rTMS could be assumed. The aim of this pilot study was to investigate the effect of high-frequency rTMS on psychomotor retardation and agitation in depressive patients. We investigated the effect of left prefrontal 10 Hz rTMS on psychomotor retardation and agitation in 30 patients with MD. Patients were randomly assigned to real or sham rTMS in addition to a newly initiated standardized antidepressant medication. We found a trend in the reduction of agitation (t (28)= 1.76, p = 0.09, two-tailed), but not in the reduction of retardation. Furthermore, no general additional antidepressant effect of rTMS was observed. Although there was no statistical significant influence of high-frequency rTMS on psychomotor symptoms in depressive patients, the results showed a trend in the reduction of psychomotor agitation in MD. This effect should be systematically investigated as the primary end point in further studies with larger sample sizes.

BACKGROUND: Previous experiments in patients with phobia have shown that the administration of glucocorticoids reduces fear in phobic situations. Extensive evidence indicates that elevated glucocorticoid levels inhibit memory retrieval processes. In patients with phobia, exposure to a phobic stimulus (socio-evaluative stress test) provokes retrieval of stimulus-associated fear memory that leads to a fear response. It is therefore possible that glucocorticoids reduce phobic fear by inhibiting retrieval of the previously acquired fear memory. Whether glucocorticoids reduce subjective fear also in healthy subjects exposed to a socially fearful situation is not known. METHOD: In a double-blind, placebo-controlled study, 50 healthy subjects underwent the same socio-evaluative stress test as used in a previous study in patients with social phobia. One hour before the stress test, subjects received 25mg cortisone or placebo orally. Psychological anxiety measures were repeatedly assessed. RESULTS: Although the stress situation robustly increased fear in this population of healthy subjects, cortisone treatment did not reduce subjective fear, physical discomfort or avoidance behavior when compared to placebo-treated subjects. CONCLUSION: The present study did not find evidence indicating that glucocorticoids reduce subjective fear in healthy subjects exposed to a socially fearful situation.

Repeated interactions between infant and caregiver result in either secure or insecure relationship attachment patterns, and insecure attachment may affect individual emotion-regulation and health. Given that oxytocin enhances social approach behavior in animals and humans, we hypothesized that oxytocin might also promote the subjective experience of attachment security in humans. Within a 3-week interval, 26 healthy male students classified with an insecure attachment pattern were invited twice to an experimental session. At the beginning of each experiment, a single dose of oxytocin or placebo was administered intranasally, using a double-blind, placebo-controlled within-subject design. In both conditions, subjects completed an attachment task based on the Adult Attachment Projective Picture System (AAP). Thirty-two AAP picture system presentations depicted attachment-related events (e.g. illness, solitude, separation, and loss), and were each accompanied by four prototypical phrases representing one secure and three insecure attachment categories. In the oxytocin condition, a significant proportion of these insecure subjects (N=18; 69%) increased in their rankings of the AAP prototypical "secure attachment" phrases and decreased in overall ranking of the "insecure attachment" phrases. In particular, there was a significant decrease in the number of subjects ranking the pictures with "insecure-preoccupied" phrases from the placebo to the oxytocin condition. We find that a single dose of intranasally administered oxytocin is sufficient to induce a significant increase in the experience of attachment security in insecurely attached adults.