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.

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.

Neural responses in the pain matrix when observing pain of others are unaffected by testosterone administration in women.

There is evidence of testosterone having deteriorating effects on cognitive and affective empathic behaviour in men and women under varying conditions. However, whether testosterone influences empathy for pain has not yet been investigated. Therefore, we tested neural responses to witnessing others in pain in a within-subject placebo-controlled testosterone administration study in healthy young women. Using functional magnetic resonance imaging, we provide affirming evidence that an empathy-inducing paradigm causes changes in the activity throughout the pain circuitry, including the bilateral insula and anterior cingulate cortex. Administration of testosterone, however, did not influence these activation patterns in the pain matrix. Testosterone has thus downregulating effects on aspects of empathic behaviour, but based on these data does not seem to influence neural responses during empathy for others' pain. This finding gives more insight into the role of testosterone in human empathy.

Generous economic investments after basolateral amygdala damage.

Contemporary economic models hold that instrumental and impulsive behaviors underlie human social decision making. The amygdala is assumed to be involved in social-economic behavior, but its role in human behavior is poorly understood. Rodent research suggests that the basolateral amygdala (BLA) subserves instrumental behaviors and regulates the central-medial amygdala, which subserves impulsive behaviors. The human amygdala, however, typically is investigated as a single unit. If these rodent data could be translated to humans, selective dysfunction of the human BLA might constrain instrumental social-economic decisions and result in more impulsive social-economic choice behavior. Here we show that humans with selective BLA damage and a functional central-medial amygdala invest nearly 100% more money in unfamiliar others in a trust game than do healthy controls. We furthermore show that this generosity is not caused by risk-taking deviations in nonsocial contexts. Moreover, these BLA-damaged subjects do not expect higher returns or perceive people as more trustworthy, implying that their generous investments are not instrumental in nature. These findings suggest that the human BLA is essential for instrumental behaviors in social-economic interactions.

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.

Cognition as the tip of the emotional iceberg: A neuro-evolutionary perspective.

We emphasize the importance of a neuroevolutionary perspective in moving beyond the cognition-emotion dichotomy. Cognitive behavior depends on cortical structures firmly rooted in the emotional brain from which they have evolved. As such, there cannot be cognition without emotion. Endocrine regulation of amygdala connectivity, a neural "switch" between impulsivity and deliberation, further underscores the phylogenetic impossibility of a cognition-emotion dichotomy.

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.

Doubling down on dual systems: A cerebellum-amygdala route towards action- and outcome-based social and affective behavior.

The amygdala and cerebellum are both evolutionary preserved brain structures containing cortical as well as subcortical properties. For decades, the amygdala has been considered the fear-center of the brain, but recent advances have shown that the amygdala acts as a critical hub between cortical and subcortical systems and shapes social and affective behaviors beyond fear. Likewise, the cerebellum is a dedicated control unit that fine-tunes motor behavior to fit contextual requirements. There is however increasing evidence that the cerebellum strongly influences subcortical as well as cortical processes beyond the motor domain. These insights broadened the view on the cerebellum's functions to also include social and affective behavior. Here we explore how the amygdala and cerebellum might interact in shaping social and affective behaviors based on their roles in threat reactivity and reinforcement learning. A novel mechanistic neural framework of cerebellum-amygdala interactions will be presented which provides testable hypotheses for future social and affective neuroscientific research in humans.

Would you? Effects of oxytocin on moral choices in forensic psychopathic patients.

Psychopaths are suggested to be more likely to favor utilitarian outcomes over non-utilitarian (i.e., deontological) choices. Here we re-test this hypothesis and investigate whether oxytocin, a hormone associated with empathy, can counter this utilitarian effect. Forensic psychopathic patients and non-psychopathic controls participated in a sacrificial moral decision-making paradigm. Psychopathic patients performed the task in a double-blind cross-over placebo-controlled oxytocin administration paradigm. We found no evidence for psychopathic patients to act more utilitarian (or sacrificial) or any effect of oxytocin administration. Psychopathic traits within the control group, particularly traits associated with lack of empathy and failure to consider consequences, were however associated with more utilitarian choices, but only when these actions were low in emotion. In contrast, psychopathy severity in psychopathic patients, particularly impulsivity-related traits, predicts deontological choices, but only in highly emotional actions. Thus, although psychopathic traits do predict utilitarianism when emotional investment is low, this is not the case in full-blown psychopathy. Instead, there is a link between impulsivity and deontological choices in psychopathic patients, but only when emotional investment is high, and self-interest is not at stake. These preliminary results are discussed to whether utilitarian outcomes align with the personal goals of psychopathic individuals.

Corrigendum to 'Would you? "Effects of oxytocin on moral choices in forensic psychopathic patients" [Compr. Psychoneuroendocrinology (2024) 100245].

[This corrects the article DOI: 10.1016/j.cpnec.2024.100245.].

Coalescence of dominance motivation and responses to facial anger in resting-state and event-related electrophysiology.

People vary in their proneness to dominate as a function of their motivation to fulfill their need for reward and social status. Recent research suggests that in humans dominant individuals respond vigilantly to angry faces, whereas non-dominant individuals rapidly signal submission. Dominance motivation has been suggested to reside in asymmetrical patterns of cortical and subcortical processing. The ratio between δ and ß band oscillations has been proposed as a proxy for this asymmetry, which we here aimed to map onto individual patterns of the event-related potentials (N170) as well as behavioral responses to facial anger in the context of dominance motivation. Results show that dominance motivation indeed predicts increased δ in the δ/ß asymmetry; a pattern that further translates into behavioral vigilance as well as attenuation of the event-related response to angry faces. The present data are interpreted to suggest that dominance motivation is related to increased subcortical and decreased cortical processing, and that this translates into increased vigilance in dominance challenges. This motivational state is further characterized by less detailed processing of facial information as reflected in the attenuation of N170 amplitude.

Testosterone decreases trust in socially naive 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.

Drift-diffusion modeling reveals that masked faces are preconceived as unfriendly.

During the COVID-19 pandemic, the use of face masks has become a daily routine. Studies have shown that face masks increase the ambiguity of facial expressions which not only affects (the development of) emotion recognition, but also interferes with social interaction and judgement. To disambiguate facial expressions, we rely on perceptual (stimulus-driven) as well as preconceptual (top-down) processes. However, it is unknown which of these two mechanisms accounts for the misinterpretation of masked expressions. To investigate this, we asked participants (N = 136) to decide whether ambiguous (morphed) facial expressions, with or without a mask, were perceived as friendly or unfriendly. To test for the independent effects of perceptual and preconceptual biases we fitted a drift-diffusion model (DDM) to the behavioral data of each participant. Results show that face masks induce a clear loss of information leading to a slight perceptual bias towards friendly choices, but also a clear preconceptual bias towards unfriendly choices for masked faces. These results suggest that, although face masks can increase the perceptual friendliness of faces, people have the prior preconception to interpret masked faces as unfriendly.

Social preferences trump emotions in human responses to unfair offers.

People commonly reject unfair offers even if this leaves them worse off. Some explain this as a rational response based on social preferences. Others argue that emotions override self-interest in the determination of rejection behavior. We conducted an experiment in which we measured responders' biophysical reactions (EEG and EMG) to fair and unfair offers. We measured biophysical trait anger using resting-state EEG (frontal alpha-asymmetry), state anger using facial expressions, offer expectancy processing using event-related EEG (medial-frontal negativity; MFN) and self-reported emotions. We systematically varied whether rejections led proposers to lose their share (Ultimatum Game; UG) or not (Impunity Game; IG). Results favor preference-based accounts: Impunity minimizes rejection despite increasing subjectively reported anger. Unfair offers evoke frowning responses, but frowning does not predict rejection. Prosocial responders reject unfair UG offers more often after unmet fairness expectations. These results suggest that responders do not reject unfairness out of anger. Rather, people seem motivated to reject unfair offers when they violate their behavioral code but only when rejection has payoff consequences for the proposer, allowing them to reciprocate and restore equity. Thus, social preferences trump emotions when responding to unfair offers.

Testosterone affects gaze aversion from angry faces outside of conscious awareness.

Throughout vertebrate phylogeny, testosterone has motivated animals to obtain and maintain social dominance-a fact suggesting that unconscious primordial brain mechanisms are involved in social dominance. In humans, however, the prevailing view is that the neocortex is in control of primordial drives, and testosterone is thought to promote social dominance via conscious feelings of superiority, indefatigability, strength, and anger. Here we show that testosterone administration in humans prolongs dominant staring into the eyes of threatening faces that are viewed outside of awareness, without affecting consciously experienced feelings. These findings reveal that testosterone motivates social dominance in humans in much the same ways that it does in other vertebrates: involuntarily, automatically, and unconsciously.

Oxytocin enhances basolateral amygdala activation and functional connectivity while processing emotional faces: preliminary findings in autistic vs non-autistic women.

Oxytocin is hypothesized to promote social interactions by enhancing the salience of social stimuli. While previous neuroimaging studies have reported that oxytocin enhances amygdala activation to face stimuli in autistic men, effects in autistic women remain unclear. In this study, the influence of intranasal oxytocin on activation and functional connectivity of the basolateral amygdala-the brain's 'salience detector'-while processing emotional faces vs shapes was tested in 16 autistic and 21 non-autistic women by functional magnetic resonance imaging in a placebo-controlled, within-subject, cross-over design. In the placebo condition, minimal activation differences were observed between autistic and non-autistic women. However, significant drug × group interactions were observed for both basolateral amygdala activation and functional connectivity. Oxytocin increased left basolateral amygdala activation among autistic women (35-voxel cluster, Montreal Neurological Institute (MNI) coordinates of peak voxel = -22 -10 -28; mean change = +0.079%, t = 3.159, PTukey = 0.0166) but not among non-autistic women (mean change = +0.003%, t = 0.153, PTukey = 0.999). Furthermore, oxytocin increased functional connectivity of the right basolateral amygdala with brain regions associated with socio-emotional information processing in autistic women, but not in non-autistic women, attenuating group differences in the placebo condition. Taken together, these findings extend evidence of oxytocin's effects on the amygdala to specifically include autistic women and specify the subregion of the effect.

Eye tracking unconscious face-to-face confrontations: dominance motives prolong gaze to masked angry faces.

In primates, dominance/submission relationships are generally automatically and nonaggressively established in face-to-face confrontations. Researchers have argued that this process involves an explicit psychological stress-manipulation mechanism: Striding with a threatening expression, while keeping direct eye contact, outstresses rivals so that they submissively avert their gaze. In contrast, researchers have proposed a reflexive and implicit modulation of face-to-face confrontation in humans, on the basis of evidence that dominant and submissive individuals exhibit vigilant and avoidant responses, respectively, to facial anger in masked emotional Stroop tasks. However, these tasks do not provide an ecologically valid index of gaze behavior. Therefore, we directly measured gaze responses to masked angry, happy, and neutral facial expressions with a saccade-latency paradigm and found that increased dominance traits predict a more prolonged gaze to (or reluctance to avert gaze from) masked anger. Furthermore, greater non-dominance-related reward sensitivity predicts more persistent gaze to masked happiness. These results strongly suggest that implicit and reflexive mechanisms underlie dominant and submissive gaze behavior in face-to-face confrontations.

Roles of the bed nucleus of the stria terminalis and amygdala in fear reactions.

The bed nucleus of the stria terminalis (BNST) plays a critical modulatory role in driving fear responses. Part of the so-called extended amygdala, this region shares many functions and connections with the substantially more investigated amygdala proper. In this chapter, we review contributions of the BNST and amygdala to subjective, behavioral, and physiological aspects of fear. Despite the fact that both regions are together involved in each of these aspects of fear, they appear complimentary in their contributions. Specifically, the basolateral amygdala (BLA), through its connections to sensory and orbitofrontal regions, is ideally poised for fast learning and controlling fear reactions in a variety of situations. The central amygdala (CeA) relies on BLA input and is particularly important for adjusting physiological and behavioral responses under acute threat. In contrast, the BNST may profit from more extensive striatal and dorsomedial prefrontal connections to drive anticipatory responses under more ambiguous conditions that allow more time for planning. Thus current evidence suggests that the BNST is ideally suited to play a critical role responding to distant or ambiguous threats and could thereby facilitate goal-directed defensive action.

A mu-opioid feedback model of human social behavior.

Since the discovery of pain relieving and rewarding properties of opiates such as morphine or heroin, the human mu-opioid system has been a target for medical research on pain processing and addiction. Indeed, pain and pleasure act mutually inhibitory on each other and the mu-opioid system has been suggested as an underlying common neurobiological mechanism. Recently, research interest extended the role of the endogenous mu-opioid system beyond the hedonic value of pain and pleasure towards human social-emotional behavior. Here we propose a mu-opioid feedback model of social behavior. This model is based upon recent findings of opioid modulation of human social learning, bonding and empathy in relation to affiliative and protective tendencies. Fundamental to the model is that the mu-opioid system reinforces socially affiliative or protective behavior in response to positive and negative social experiences with long-term consequences for social behavior and health. The functional implications for stress, anxiety, depression and attachment behaviors are discussed.