Preliminary data on oxytocin modulation of neural reactivity in women to emotional stimuli of children depending on childhood emotional neglect.

Sensitivity for rewarding cues and distress signals from children is fundamental to human caregiving and modulated by the neuropeptide oxytocin. In a functional magnetic resonance imaging study, we investigated whether oxytocin regulates neural responses to reward or distress cues form children. In a placebo-controlled, within-subject design, we measured neural responses to positive, negative, and neutral cues from children in 22 healthy female subjects who received oxytocin (24 IU) versus placebo. Further, based on current literature, we hypothesized that oxytocin effects are modulated by experiences of childhood trauma. The task elicited valence-specific effects-positive images activated the ventromedial prefrontal cortex, left anterior cingulate cortex, and right putamen, and images of children in distress activated the bilateral amygdala, hippocampus, and right medial superior frontal cortex. The effects of oxytocin depended on subjective reports of childhood emotional neglect. Self-reported neglect interacted with oxytocin administration in the amygdala, hippocampus, and prefrontal areas. In individuals with higher scores of emotional neglect, oxytocin increased neural reactivity of limbic structures to positive and neutral images. Our findings need replication in larger samples and can therefore be considered preliminary but are in line with the recent literature on the modulating effect of childhood adversity on the sensitivity to oxytocin administration.

Breakdown of utilitarian moral judgement after basolateral amygdala damage.

Most of us would regard killing another person as morally wrong, but when the death of one saves multiple others, it can be morally permitted. According to a prominent computational dual-systems framework, in these life-and-death dilemmas, deontological (nonsacrificial) moral judgments stem from a model-free algorithm that emphasizes the intrinsic value of the sacrificial action, while utilitarian (sacrificial) moral judgments are derived from a model-based algorithm that emphasizes the outcome of the sacrificial action. Rodent decision-making research suggests that the model-based algorithm depends on the basolateral amygdala (BLA), but these findings have not yet been translated to human moral decision-making. Here, in five humans with selective, bilateral BLA damage, we show a breakdown of utilitarian sacrificial moral judgments, pointing at deficient model-based moral decision-making. Across an established set of moral dilemmas, healthy controls frequently sacrifice one person to save numerous others, but BLA-damaged humans withhold such sacrificial judgments even at the cost of thousands of lives. Our translational research confirms a neurocomputational hypothesis drawn from rodent decision-making research by indicating that the model-based algorithm which underlies outcome-based, utilitarian moral judgements in humans critically depends on the BLA.

Stable Anxiety and Depression Trajectories in Late Adolescence for Oral Contraceptive Users.

Background: The use of oral contraceptives (OCs) has been associated with increased incidences of anxiety and depression, for which adolescents seem to be particularly vulnerable. Rather than looking at singular outcomes, we examined whether OC use is associated with depressive and anxiety symptom trajectories from early adolescence into early adulthood. Materials and Methods: Data from 178 girls were drawn from the Research on Adolescent Development and Relationships (RADAR-Y) younger cohort study. We used assessments on 9 waves from age 13 until 24. Developmental trajectories of ratings on the Reynolds Adolescent Depression Scale (RADS-2) and the Screen for Child Anxiety Related Emotional Disorders (SCARED) were compared between never and ever users of OCs. Results: Never users showed increases in depressive and anxiety symptoms in late adolescence, whereas OC users showed a stable level of symptoms throughout adolescence. This effect remained after adjusting for baseline differences between groups in romantic relationships, sexual debut, educational level, smoking, drinking, and drug use. Age of OC use onset did not significantly predict symptom development. Conclusions: OC use in adolescence was related to an altered developmental trajectory of internalizing symptoms, in which OC users did not show an increase in depressive and anxiety symptoms in late adolescence, whereas never users did. The question remains whether this altered symptom trajectory can be considered a protective effect of OC use on psychopathology. Additional research is needed to improve our understanding of the long-term consequences of OC use on mental health.

Oxytocin system gene methylation is associated with empathic responses towards children.

Empathy is an essential component of sensitive caregiving behavior, which in turn is an important predictor of children's healthy social-emotional development. The oxytocin (OXT) system plays a key role in promoting sensitive parenting and empathy. In this study, we investigated how OXT system gene methylation was associated with empathic processes in nulliparous women (M age = 23.60, SD =0.44)-measuring both physiological facial muscle responses and ratings of compassion and positive affect to affective images depicting children. Linear mixed effects analyses demonstrated that lower methylation levels in the OXT and OXTR genes were related to enhanced empathic responses. The effect of OXT system gene methylation on empathic processes was partly qualified by an interaction with individual variations in women's care motivation. Our findings provide experimental evidence for an association between the methylation of OXT system genes and empathy.

Preliminary data on increased reactivity towards children in distress after testosterone administration in women: A matter of protection?

Emotional reactivity to others' distress is a vital prerequisite for a caring response. Testosterone, in contrast, is mostly associated with protection of personal dominance and decreased responsiveness to others' needs. However, experimental work also indicates that rising testosterone levels in response to infant distress can potentially facilitate protection. We assessed the impact of testosterone administration on participants' emotional reactivity to infants in distress, measuring their facial responses on the corrugator supercilii forehead muscle ('frowning') and the zygomaticus major ('smiling') as an index of emotional responses towards children. Moreover, we probed whether the effect of testosterone is moderated by participants' self-reported nurturance and protective tendencies. Our preliminary results showed that testosterone not only increased emotional reactivity to empathy eliciting images of children, but that this increase was strongest in participants with strong protective tendencies. Our administration study is the first to link testosterone to infant protection.

Moral reasoning, moral decision-making, and empathy in Korsakoff's syndrome.

Korsakoff's syndrome (KS) is a neuropsychiatric disorder, caused by a vitamin B1 deficiency. Although it is known that patients with KS display diminished theory of mind functioning and frequently exhibit marked antisocial interactions little attention has so far focused on the integrity of moral decision-making abilities, moral reasoning, and empathy. In an experimental cross-sectional design, 20 patients diagnosed with KS, and twenty age-, education-, and gender-equivalent healthy participants performed tests assessing moral decision-making, moral reasoning maturity, empathy, and executive functioning. Participants were administered the Moral Behaviour Inventory (MBI) for everyday moral dilemmas, and ten cartoons of abstract moral dilemmas. Responses were scored according to the Kohlberg stages of moral reasoning. Empathy and executive functioning were assessed with the Interpersonal Reactivity Index (IRI) and the Frontal Assessment Battery (FAB). In contrast to frontal traumatic brain injury patients, KS patients did not display a utilitarian bias, suggesting preserved moral decision-making abilities. Of interest, KS patients had significantly lower levels of moral reasoning maturity on everyday moral dilemmas, and abstract moral dilemmas. In patients, empathy was moderately related to the level of moral maturity on both tasks, while executive functioning was not. In conclusion, KS patients have preserved moral decision-making abilities, but their moral reasoning abilities are poorer in everyday and abstract situations. Lower moral reasoning abilities and lower levels of empathy together may be responsible for adverse social functioning in KS.

Methylation of oxytocin related genes and early life trauma together shape the N170 response to human faces.

Childhood trauma fundamentally shapes social cognition and basic processing of social cues, which frequently cascade into adverse behavioral outcomes. Recent studies indicate that epigenetic changes in oxytocin functioning might contribute to these long-term effects, although a deeper understanding of the underlying mechanisms is still lacking. The electroencephalographic N170 response to faces might capture a neural response at the core of these interactive effects of oxytocin gene methylation and childhood adversity, given that this response is considered to reflect fundamental face processing, to be susceptible to oxytocin administration and also to be a biomarker of various psychiatric disorders. We assessed the N170 response to neutral faces in relation to participant's (81, women) recalled childhood trauma, methylation of their oxytocin structural (OXTg) and oxytocin receptor (OXTRg) genes, and endogenous levels of cortisol and testosterone. Additionally, we investigated the interactive effect of OXTg methylation and CTQ across three face sets of varying maturity. Methylation of OXTg relates to a weakened N170 response towards adults, children and infants. Moreover, methylation of both OXTRg and OXTg shaped the directionality of adversity effects, predicting a weakened N170 response in those with high methylation and hyper-vigilance with participants with low methylation. Our results are the first to relate OXT(R)g methylation to the N170 response. They shed light on biological processes linking childhood adversity and epigenetic marks to altered behavior and potentially psychopathologies.

The Basolateral Amygdala Is Essential for Rapid Escape: A Human and Rodent Study.

Rodent research delineates how the basolateral amygdala (BLA) and central amygdala (CeA) control defensive behaviors, but translation of these findings to humans is needed. Here, we compare humans with natural-selective bilateral BLA lesions to rats with a chemogenetically silenced BLA. We find, across species, an essential role for the BLA in the selection of active escape over passive freezing during exposure to imminent yet escapable threat (Timm). In response to Timm, BLA-damaged humans showed increased startle potentiation and BLA-silenced rats demonstrated increased startle potentiation, freezing, and reduced escape behavior as compared to controls. Neuroimaging in humans suggested that the BLA reduces passive defensive responses by inhibiting the brainstem via the CeA. Indeed, Timm conditioning potentiated BLA projections onto an inhibitory CeA pathway, and pharmacological activation of this pathway rescued deficient Timm responses in BLA-silenced rats. Our data reveal how the BLA, via the CeA, adaptively regulates escape behavior from imminent threat and that this mechanism is evolutionary conserved across rodents and humans.

Oxytocin reduces neural activation in response to infant faces in nulliparous young women.

Infant faces have distinctive features that together are described as baby schema, a configuration that facilitates caregiving motivation and behavior, and increases the perception of cuteness. In the current functional magnetic resonance imaging (fMRI) study, we investigated the effect of a within-subjects intranasal oxytocin administration (24 IU) and caregiving motivation on neural responses to infant faces of varying baby schema in 23 healthy nulliparous women. Overall, infant faces elicited activation in several brain regions involved in reward and salience processing, including the ventral tegmental area (VTA), putamen, amygdala, anterior cingulate cortex (ACC), and insula, and this activation was related to self-reported caregiving motivation. Critically, whereas we hypothesized enhanced neural caregiving-related responses after oxytocin administration, we observed reduced activation in the VTA, putamen and amygdala after oxytocin compared to placebo. In nulliparous women, oxytocin has been shown to reduce neural responses in the same regions in response to social stimuli using other paradigms. Oxytocin might affect neural activation toward social stimuli depending on elicited arousal and personal characteristics. The current study is the first to demonstrate this effect in response to infant faces and thereby adds to specify the role of oxytocin in human social information processing.

Ethnic effects when facing children: An ERP study.

Abundant research has highlighted a disadvantage experienced by children of ethnic minority groups in, for example, educational and health care settings. In order to understand implicit attitudes that contribute to ethnic disparities, underlying neural correlates have been widely studied. However, this has been limited to the context of adults. Using a sample of nulliparous Caucasian females (N = 46), the current study is the first to examine how early attentional and facial perceptual processing stages, assessed with event-related brain potentials (ERPs), differentiate for stimuli of young ingroup (of the same ethnicity) or outgroup (of a different ethnicity) children. Additionally, we assessed how a differentiation in ERPs may relate to subsequent adult responsiveness to children by measuring both cuteness ratings and motivation to view child faces. Similar to previous findings for adult facial stimuli, we found significant differences in attentional (N200) and facial perceptual (N170) processing when adults were faced with children of different ethnicities. Furthermore, increased differentiation in attentional processing (N200) for ingroup and outgroup children was associated with reduced cuteness ratings of outgroup children. Importantly however, participants showed no overall preference for ingroup child faces, as motivation to view child faces was even greater towards outgroup child faces. In addition, increased self-reported motivation for parental care was related to enhanced cuteness appraisals of outgroup child faces. Taken together, these findings reveal how early social categorization processes may lead to biased behavior when interacting with children of ethnic minorities.

How Oral Contraceptives Impact Social-Emotional Behavior and Brain Function.

Millions of women worldwide use oral contraceptives ('the pill'; OCs), often starting at a pubertal age when their brains are in a crucial developmental stage. Research into the social-emotional effects of OCs is of utmost importance. In this review, we provide an overview of studies that have emerged over the past decade investigating how OCs, and their main ingredients estradiol (E) and progesterone (P), influence social-emotional behaviors and underlying brain functions. Based on this overview, we present a heuristic model that postulates that OCs modulate core social-emotional behaviors and brain systems. Research domains and challenges for the future, as well as implications, are discussed.

Testosterone Administration Moderates Effect of Social Environment on Trust in Women Depending on Second-to-Fourth Digit Ratio.

Animal research has established that effects of hormones on social behaviour depend on characteristics of both individual and environment. Insight from research on humans into this interdependence is limited, though. Specifically, hardly any prior testosterone experiments in humans scrutinized the interdependency of testosterone with the social environment. Nonetheless, recent testosterone administration studies in humans repeatedly show that a proxy for individuals' prenatal testosterone-to-estradiol ratio, second-to-fourth digit-ratio (2D:4D ratio), influences effects of testosterone administration on human social behaviour. Here, we systematically vary the characteristics of the social environment and show that, depending on prenatal sex hormone priming, testosterone administration in women moderates the effect of the social environment on trust. We use the economic trust game and compare one-shot games modelling trust problems in relations between strangers with repeated games modelling trust problems in ongoing relations between partners. As expected, subjects are more trustful in repeated than in one-shot games. In subjects prenatally relatively highly primed by testosterone, however, this effect disappears after testosterone administration. We argue that impairments in cognitive empathy may reduce the repeated game effect on trust after testosterone administration in subjects with relatively high prenatal testosterone exposure and propose a neurobiological explanation for this effect.

Testosterone reduces functional connectivity during the 'Reading the Mind in the Eyes' Test.

Women on average outperform men in cognitive-empathic abilities, such as the capacity to infer motives from the bodily cues of others, which is vital for effective social interaction. The steroid hormone testosterone is thought to play a role in this sexual dimorphism. Strikingly, a previous study shows that a single administration of testosterone in women impairs performance on the 'Reading the Mind in Eyes' Test (RMET), a task in which emotions have to be inferred from the eye-region of a face. This effect was mediated by the 2D:4D ratio, the ratio between the length of the index and ring finger, a proxy for fetal testosterone. Research in typical individuals, in individuals with autism spectrum conditions (ASC), and in individuals with brain lesions has established that performance on the RMET depends on the left inferior frontal gyrus (IFG). Using functional magnetic resonance imaging (fMRI), we found that a single administration of testosterone in 16 young women significantly altered connectivity of the left IFG with the anterior cingulate cortex (ACC) and the supplementary motor area (SMA) during RMET performance, independent of 2D:4D ratio. This IFG-ACC-SMA network underlies the integration and selection of sensory information, and for action preparation during cognitive empathic behavior. Our findings thus reveal a neural mechanism by which testosterone can impair emotion-recognition ability, and may link to the symptomatology of ASC, in which the same neural network is implicated.

Dissociated neural effects of cortisol depending on threat escapability.

Evolution has provided us with a highly flexible neuroendocrine threat system which, depending on threat imminence, switches between active escape and passive freezing. Cortisol, the "stress-hormone", is thought to play an important role in both fear behaviors, but the exact mechanisms are not understood. Using pharmacological functional magnetic resonance imaging we investigated how cortisol modulates the brain's fear systems when humans are under virtual-predator attack. We show dissociated neural effects of cortisol depending on whether escape from threat is possible. During inescapable threat cortisol reduces fear-related midbrain activity, whereas in anticipation of active escape cortisol boosts activity in the frontal salience network (insula and anterior cingulate cortex), which is involved in autonomic control, visceral perception and motivated action. Our findings suggest that cortisol adjusts the human neural threat system from passive fear to active escape, which illuminates the hormone's crucial role in the adaptive flexibility of fear behaviors.

Oxytocin reduces neural activity in the pain circuitry when seeing pain in others.

Our empathetic abilities allow us to feel the pain of others. This phenomenon of vicarious feeling arises because the neural circuitry of feeling pain and seeing pain in others is shared. The neuropeptide oxytocin (OXT) is considered a robust facilitator of empathy, as intranasal OXT studies have repeatedly been shown to improve cognitive empathy (e.g. mind reading and emotion recognition). However, OXT has not yet been shown to increase neural empathic responses to pain in others, a core aspect of affective empathy. Effects of OXT on empathy for pain are difficult to predict, because OXT evidently has pain-reducing properties. Accordingly, OXT might paradoxically decrease empathy for pain. Here, using functional neuroimaging we show robust activation in the neural circuitry of pain (insula and sensorimotor regions) when subjects observe pain in others. Crucially, this empathy-related activation in the neural circuitry of pain is strongly reduced after intranasal OXT, specifically in the left insula. OXT on the basis of our neuroimaging data thus remarkably decreases empathy for pain, but further research including behavioral measures is necessary to draw definite conclusions.

Improved memory for reward cues following acute buprenorphine administration in humans.

In rodents, there is abundant evidence for the involvement of the opioid system in the processing of reward cues, but this system has remained understudied in humans. In humans, the happy facial expression is a pivotal reward cue. Happy facial expressions activate the brain's reward system and are disregarded by subjects scoring high on depressive mood who are low in reward drive. We investigated whether a single 0.2mg administration of the mixed mu-opioid agonist/kappa-antagonist, buprenorphine, would influence short-term memory for happy, angry or fearful expressions relative to neutral faces. Healthy human subjects (n38) participated in a randomized placebo-controlled within-subject design, and performed an emotional face relocation task after administration of buprenorphine and placebo. We show that, compared to placebo, buprenorphine administration results in a significant improvement of memory for happy faces. Our data demonstrate that acute manipulation of the opioid system by buprenorphine increases short-term memory for social reward cues.

Cortisol administration induces global down-regulation of the brain's reward circuitry.

Research in rodents and humans has shown divergent effects of the glucocorticoids corticosterone and cortisol (CRT) on reward processing. In rodents, administration of CRT increases reward drive by facilitating dopamine release in the ventral striatum. In humans, correspondingly, risky decision-making increases when CRT levels are elevated. Human stress studies contrariwise show that elevated CRT is accompanied by a decrease in reward-related brain activity. There are however no direct insights into how CRT acts on the reward system in the human brain. Accordingly, we used pharmacological functional magnetic resonance imaging (pharmaco-fMRI) to investigate the effects of CRT on the brain's reward system. In a randomized within-subject design we administered a high dose of CRT (40 mg) and placebo to twenty healthy male volunteers on separate days, and used a monetary incentive delay task to assess the effects of the hormone on the striatum and the amygdala in anticipation of potential reward. In contrast to animal studies, we show that this high dose of CRT strongly decreases activity of the striatum in both reward and non-reward conditions. Furthermore, we observed reductions in activity in the basolateral amygdala, a key regulator of the brain's reward system. Crucially, the overall down-regulation of the brain's reward circuit was verified on the subjective level as subjects reported significantly reduced reward preference after CRT. In sum, we provide here direct evidence in humans that CRT acts on brain regions involved in reward-related behavior, that is, the basolateral amygdala and the striatum. Our findings suggest that CRT in the quantity and time course presently used globally down-regulates the reward system, and thereby decreases motivational processing in general.

Cortisol administration increases hippocampal activation to infant crying in males depending on childhood neglect.

Animal studies show that exposure to parental neglect alters stress regulation and can lead to neural hyposensitivity or hypersensitivity in response to cortisol, most pronounced in the hippocampus. Cortisol, the end product of the hypothalamic-pituitary-adrenal (HPA) axis, has also been related to parenting more directly, for example, in both sexes, cortisol levels increase when listening to infants crying, possibly to activate and facilitate effective care behavior. Severe trauma is known to negatively affect the HPA-axis in humans; however, it is unknown whether normal variation in parental care in the healthy population can alter sensitivity of the hippocampus to cortisol. Here, we investigate whether variation in experienced neglect changes neural sensitivity to cortisol when humans listen to infant crying, which is an unequivocal signal relevant for care behavior. In a placebo-controlled, within-subject neuroimaging study, we administered 40 mg cortisol to 21 healthy young males without children and used a validated task for measuring neural responses to infant crying. The Dutch version of the Childhood Trauma Questionnaire was used to index participants' early exposure to abuse and neglect. The data show that cortisol markedly increased hippocampal activation toward crying infants, and this effect varied significantly with parental neglect, even in our nonclinical subject sample. Without exposure to severe trauma or neglect, reduced self-experienced quality of parental care in the normal range already substantially increased hippocampal responsivity to cortisol. Altered hippocampal sensitivity to cortisol might be a cross-species marker for the risk of developing later life psychopathology.

Testosterone administration modulates moral judgments depending on second-to-fourth digit ratio.

Moral judgment involves the interplay of emotions and social cognitions. The male sex-hormone testosterone might play a role in moral reasoning as males are more utilitarian than females in their moral decisions, and high salivary testosterone levels also are associated with utilitarian moral decisions. However, there is no direct evidence for a role of testosterone in moral reasoning. Recent testosterone administration studies show effects on cognitive empathy and social cooperation, which depend on right-hand's second-to-fourth (2D:4D) digit ratio, a proxy for prenatal sex-hormone (testosterone-versus-estradiol) priming. Here, in a placebo-controlled within-subjects design using 20 young females we show that 2D:4D predicts 44% of the variance in the effects of testosterone administration on moral judgment. Subjects who show an increase in utilitarian judgments following testosterone administration have significantly higher than average 2D:4D (relatively high prenatal estradiol priming), while subjects showing more deontological judgments following testosterone administration have near-significantly lower 2D:4D (relatively high prenatal testosterone priming). We argue that prenatally-organized differences in aromatase, i.e. conversion from testosterone to estradiol in the brain, might underlie these effects. Our findings suggest that early neurodevelopmental effects of sex steroids play a crucial role in the activational effects of hormones on moral reasoning later in life.