Peter A. Bos

Acute effects of steroid hormones and neuropeptides on human social–emotional behavior: A review of single administration studies

Steroids and peptides mediate a diverse array of animal social behaviors. Human research is restricted by technical-ethical limitations, and models of the neuroendocrine regulation of social-emotional behavior are therefore mainly limited to non-human species, often under the assumption that human social-emotional behavior is emancipated from hormonal control. Development of acute hormone administration procedures in human research, together with the advent of novel non-invasive neuroimaging techniques, have opened up opportunities to systematically study the neuroendocrinology of human social-emotional behavior. Here, we review all placebo-controlled single hormone administration studies addressing human social-emotional behavior, involving the steroids testosterone and estradiol, and the peptides oxytocin and vasopressin. These studies demonstrate substantial hormonal control over human social-emotional behavior and give insights into the underlying neural mechanisms. Finally, we propose a theoretical model that synthesizes detailed knowledge of the neuroendocrinology of social-emotional behavior in animals with the recently gained data from humans described in our review.

Testosterone administration impairs cognitive empathy in women depending on second-to-fourth digit ratio

During social interactions we automatically infer motives, intentions, and feelings from bodily cues of others, especially from the eye region of their faces. This cognitive empathic ability is one of the most important components of social intelligence, and is essential for effective social interaction. Females on average outperform males in this cognitive empathy, and the male sex hormone testosterone is thought to be involved. Testosterone may not only down-regulate social intelligence organizationally, by affecting fetal brain development, but also activationally, by its current effects on the brain. Here, we show that administration of testosterone in 16 young women led to a significant impairment in their cognitive empathy, and that this effect is powerfully predicted by a proxy of fetal testosterone: the right-hand second digit-to-fourth digit ratio. Our data thus not only demonstrate down-regulatory effects of current testosterone on cognitive empathy, but also suggest these are preprogrammed by the very same hormone prenatally. These findings have importance for our understanding of the psychobiology of human social intelligence.

Testosterone, cortisol, and serotonin as key regulators of social aggression: A review and theoretical perspective

In human and non-human animals the steroid hormones cortisol and testosterone are involved in social aggression and recent studies suggest that these steroids might jointly regulate this behavior. It has been hypothesized that the imbalance between cortisol and testosterone levels is predictive for aggressive psychopathology, with high testosterone to cortisol ratio predisposing to a socially aggressive behavioral style. In this review, we focus on the effects of cortisol and testosterone on human social aggression, as well as on how they might modulate the aggression circuitry of the human brain. Recently, serotonin is hypothesized to differentiate between impulsive and instrumental aggression, and we will briefly review evidence on this hypothesis. The aim of this article is to provide a theoretical framework for the role of steroids and serotonin in impulsive social aggression in humans.

Testosterone decreases trust in socially naïve humans

Trust plays an important role in the formation and maintenance of human social relationships. But trusting others is associated with a cost, given the prevalence of cheaters and deceivers in human society. Recent research has shown that the peptide hormone oxytocin increases trust in humans. However, oxytocin also makes individuals susceptible to betrayal, because under influence of oxytocin, subjects perseverate in giving trust to others they know are untrustworthy. Testosterone, a steroid hormone associated with competition and dominance, is often viewed as an inhibitor of sociality, and may have antagonistic properties with oxytocin. The following experiment tests this possibility in a placebo-controlled, within-subjects design involving the administration of testosterone to 24 female subjects. We show that compared with the placebo, testosterone significantly decreases interpersonal trust, and, as further analyses established, this effect is determined by those who give trust easily. We suggest that testosterone adaptively increases social vigilance in these trusting individuals to better prepare them for competition over status and valued resources. In conclusion, our data provide unique insights into the hormonal regulation of human sociality by showing that testosterone downregulates interpersonal trust in an adaptive manner.

Effects of exogenous testosterone on the ventral striatal BOLD response during reward anticipation in healthy women.

Correlational evidence in humans shows that levels of the androgen hormone testosterone are positively related to reinforcement sensitivity and competitive drive. Structurally similar anabolic-androgenic steroids (AAS) are moreover widely abused, and animal studies show that rodents self-administer testosterone. These observations suggest that testosterone exerts activational effects on mesolimbic dopaminergic pathways involved in incentive processing and reinforcement regulation. However, there are no data on humans supporting this hypothesis. We used functional magnetic resonance imaging (fMRI) to investigate the effects of testosterone administration on neural activity in terminal regions of the mesolimbic pathway. In a placebo-controlled double-blind crossover design, 12 healthy women received a single sublingual administration of .5 mg of testosterone. During MRI scanning, participants performed a monetary incentive delay task, which is known to elicit robust activation of the ventral striatum during reward anticipation. Results show a positive main effect of testosterone on the differential response in the ventral striatum to cues signaling potential reward versus nonreward. Notably, this effect interacted with levels self-reported intrinsic appetitive motivation: individuals with low intrinsic appetitive motivation exhibited larger testosterone-induced increases but had smaller differential responses after placebo. Thus, the present study lends support to the hypothesis that testosterone affects activity in terminal regions of the mesolimbic dopamine system but suggests that such effects may be specific to individuals with low intrinsic appetitive motivation. By showing a potential mechanism underlying central reinforcement of androgen use, the present findings may moreover have implications for our understanding of the pathophysiology of AAS dependency.

Comprehensive in vitro toxicity testing of a panel of representative oxide nanomaterials: First steps towards an intelligent testing strategy

Nanomaterials (NMs) display many unique and useful physico-chemical properties. However, reliable approaches are needed for risk assessment of NMs. The present study was performed in the FP7-MARINA project, with the objective to identify and evaluate in vitro test methods for toxicity assessment in order to facilitate the development of an intelligent testing strategy (ITS). Six representative oxide NMs provided by the EC-JRC Nanomaterials Repository were tested in nine laboratories. The in vitro toxicity of NMs was evaluated in 12 cellular models representing 6 different target organs/systems (immune system, respiratory system, gastrointestinal system, reproductive organs, kidney and embryonic tissues). The toxicity assessment was conducted using 10 different assays for cytotoxicity, embryotoxicity, epithelial integrity, cytokine secretion and oxidative stress. Thorough physico-chemical characterization was performed for all tested NMs. Commercially relevant NMs with different physico-chemical properties were selected: two TiO2 NMs with different surface chemistry – hydrophilic (NM-103) and hydrophobic (NM-104), two forms of ZnO – uncoated (NM-110) and coated with triethoxycapryl silane (NM-111) and two SiO2 NMs produced by two different manufacturing techniques – precipitated (NM-200) and pyrogenic (NM-203). Cell specific toxicity effects of all NMs were observed; macrophages were the most sensitive cell type after short-term exposures (24-72h) (ZnO>SiO2>TiO2). Longer term exposure (7 to 21 days) significantly affected the cell barrier integrity in the presence of ZnO, but not TiO2 and SiO2, while the embryonic stem cell test (EST) classified the TiO2 NMs as potentially ‘weak-embryotoxic’ and ZnO and SiO2 NMs as ‘non-embryotoxic’. A hazard ranking could be established for the representative NMs tested (ZnO NM-110 > ZnO NM-111 > SiO2 NM-203 > SiO2 NM-200 > TiO2 NM-104 > TiO2 NM-103). This ranking was different in the case of embryonic tissues, for which TiO2 displayed higher toxicity compared with ZnO and SiO2. Importantly, the in vitro methodology applied could identify cell- and NM-specific responses, with a low variability observed between different test assays. Overall, this testing approach, based on a battery of cellular systems and test assays, complemented by an exhaustive physico-chemical characterization of NMs, could be deployed for the development of an ITS suitable for risk assessment of NMs. This study also provides a rich source of data for modeling of NM effects.

New evidence on testosterone and cooperation

arising from C. Eisenegger, M. Naef, R. Snozzi, M. Heinrichs & E. Fehr 463, 356–359 (2010)10.1038/nature08711; Eisenegger et al. replyIn February 2010, Eisenegger et al. reported increased fair bargaining behaviour after administration of testosterone in an ultimatum game. However, unfair offers in the ultimatum game typically are rejected; thus, not only the motives for social cooperation but also the threat of financial punishment may have accounted for these effects. Here, using the public goods game (PGG), we unambiguously show increased social cooperation after testosterone administration, but only among subjects with low levels of prenatal testosterone (measured by the right hand’s second-to-fourth-digit ratio (2D:4D)). This finding establishes positive effects of testosterone on social cooperation, with prenatal hormonal priming providing for important individual variability.

Testosterone administration modulates neural responses to crying infants in young females

Parental responsiveness to infant vocalizations is an essential mechanism to ensure parental care, and its importance is reflected in a specific neural substrate, the thalamocingulate circuit, which evolved through mammalian evolution subserving this responsiveness. Recent studies using functional Magnetic Resonance Imaging (fMRI) provide compelling evidence for a comparable mechanism in humans by showing thalamocingulate responses to infant crying. Furthermore, possibly acting on this common neural substrate, steroid hormones such as estradiol and testosterone, seem to mediate parental behavior both in humans and other animals. Estradiol unmistakably increases parental care, while data for testosterone are less unequivocal. In humans and several other animals, testosterone levels decrease both in mothers and fathers during parenthood. However, exogenous testosterone in mice seems to increase parenting, and infant crying leads to heightened testosterone levels in human males. Not only is the way in which testosterone is implicated in parental responsiveness unresolved, but the underlying mechanisms are fully unknown. Accordingly, using fMRI, we measured neural responses of 16 young women who were listening to crying infants in a double blind, placebo-controlled, counterbalanced, testosterone administration experiment. Crucially, heightened activation in the testosterone condition compared to placebo was shown in the thalamocingulate region, insula, and the cerebellum in response to crying. Our results by controlled hormonal manipulation confirm a role of the thalamocingulate circuit in infant cry perception. Furthermore, the data also suggest that exogenous testosterone, by itself or by way of its metabolite estradiol, in our group of young women acted on this thalamocinculate circuit to, provisionally, upregulate parental care.

The oxytocin paradox

In 2005, Kosfeld et al. published their now seminal paper showing that intranasal oxytocin (OXT) administration increased interpersonal trust (Kosfeld et al., 2005). This finding spawned broad interest into the effects of OXT on social and emotional behavior in humans (Bos et al., 2012), and its implications for translational medicine (Meyer-Lindenberg et al., 2011; Striepens et al., 2011). Over the years OXT has gained the reputation of facilitating empathy and affiliation, based on early findings reporting beneficial effects of OXT on trust (Kosfeld et al., 2005), social support (Heinrichs et al., 2003), and processing social information (Hollander et al., 2007; Savaskan et al., 2008; Unkelbach et al., 2008; Hurlemann et al., 2010). This view is supported by studies showing that OXT improves cognitive empathic abilities such as mindreading (Domes et al., 2007; Bartz et al., 2010; Guastella et al., 2010) and recognizing positive emotional expressions (Marsh et al., 2010). As a result of these positive effects on social behavior, there has been considerable speculation about OXTs therapeutic potential in people with social and emotional disabilities. This prosocial view of OXT has been challenged by findings showing that the effects of OXT are strongly context-dependent (Bartz et al., 2011; Bos et al., 2012). For example, OXT has also been shown to increase envy and gloating (Shamay-Tsoory et al., 2009), defensiveness toward out-group members (De Dreu et al., 2010, 2011) and increased in-group conformity (Stallen et al., 2012). Although this ethnocentrism might be considered prosocial within ones own group, defensiveness toward an out-group is not, and extreme ethnocentrism often leads to nationalism or even racism. This paradox gives rise to two questions. First, how can the beneficial effects of OXT on empathy, trust and affiliation be compatible with its seemingly contradictory anti-social effects? Second, what implication does this have for the therapeutic potential of OXT in social and emotional neurodevelopmental conditions? With regard to the first question, we provide a brief overview of the literature aiming to understand the mechanism(s) underlying OXTs efficacy. There are two main perspectives on how OXT affects social behavior (via anxiety reduction or increasing social salience), which try to reconcile its pro- and anti-social roles, but there have been no attempts to date to integrate these into a single viewpoint. A potential third factor, reward sensitivity might aid this integration. We propose a model that unites these perspectives, providing new avenues of research into OXTs efficacy in social and emotional neurodevelopmental conditions.

The neural mechanisms by which testosterone acts on interpersonal trust.

Recently, we demonstrated that the steroid-hormone testosterone reduces interpersonal trust in humans. The neural mechanism which underlies this effect is however unknown. It has been proposed that testosterone increases social vigilance via neuropeptide systems in the amygdala, augmenting communication between the amygdala and the brain stem. However, testosterone also affects connectivity between the orbitofrontal cortex (OFC) and the amygdala, which could subsequently lead to increased vigilance by reduced top-down control over the amygdala. Here, in a placebo-controlled testosterone administration study with 16 young women, we use functional magnetic resonance imaging to get more insights into neural mechanisms whereby testosterone acts on trust. Several cortical systems, among others the OFC, are involved in the evaluation of facial trustworthiness. Testosterone administration decreased functional connectivity between amygdala and the OFC during judgments of unfamiliar faces, and also increased amygdala responses specifically to the faces that were rated as untrustworthy. Finally, connectivity between the amygdala and the brain stem was not affected by testosterone administration. Although speculative, a neurobiological explanation for these findings is that in uncertain social situations, testosterone induces sustained decoupling between OFC and amygdala by a prefrontal-dopaminergic mechanism, subsequently resulting in more vigilant responses of the amygdala to signals of untrustworthiness.