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.

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.

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.

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.

Unzipping empathy in psychopathy: Empathy and facial affect processing in psychopaths.

Psychopathy is a neurodevelopmental disorder that has a highly deleterious effect upon both individuals and society at large. Psychopaths grossly neglect and disrespect the interests of others. Their antisocial behavior is thought to originate from a lack of empathy. However, empathy is multidimensional in nature, as evidenced by the considerable heterogeneity in extant theorizing on the subject. Here, we present the "Zipper model of empathy" that reconsiders how both its affective and cognitive components converge in mature empathic behavior. Furthermore, the Zipper model of empathy is expedient for explaining the empathy deficits in psychopathy, insofar as it brings together current theories on the dysfunctional affective components of empathy, violence inhibition, and automatic versus goal-directed attention. According to the literature, the neurobiological underpinnings of these theories are amygdala-centered; however, this article traces this specifically to the basolateral and central amygdala subregions. When viewed together, the cognitive and affective components of empathy are zipped together in a natural fashion in healthy empathic behavior, whereas psychopaths leave the zipper substantially unzipped in pursuit of their purely self-centered goals.

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.

Sniffing submissiveness? Oxytocin administration in severe psychopathy.

Psychopathy is a personality disorder associated with criminal behavior and violent recidivism, and therefore a burden to society. Social dominance is one of the characteristics of psychopathy that might contribute to these problems. Nevertheless, only few studies have objectively measured the relationship between socially dominant behavior and psychopathy. Therefore, the current study assessed performance of 21 forensic PCL-R confirmed psychopathic patients and 24 normal controls on a gaze aversion task, in which slower gaze aversion from masked angry faces compared to masked happy faces is a measure of reactive dominance. Moreover, the current study assessed the potential beneficial effects of the neuropeptide oxytocin. The results showed that psychopaths were not more dominant on the gaze aversion task compared to normal controls. However, the severity of psychopathy was positively correlated with reactive dominance. Crucially, a single nasal spray administration of oxytocin abolished the connection between psychopathy and reactive dominance. This implies that socially dominant psychopaths might benefit from oxytocin administration.

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.

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.

The Human Basolateral Amygdala Is Indispensable for Social Experiential Learning.

Trust and betrayal are central to our social world, and adaptive responses to generous and selfish behavior are crucial to our economic and social well-being [1]. We learn about others' trustworthiness through trial and error during repeated interactions [2]. By reinforcing and suppressing behavior during positive and negative interactions with conspecifics, rodent research has established a crucial role for the basolateral amygdala (BLA) in social experiential learning [3, 4]. The human BLA has undergone a reorganization with massive expansion relative to other amygdala nuclei [5], and there is no translational research on its role in experiential learning. The human amygdala is traditionally researched as a single structure [6], neglecting the sub-nuclei's structural und functional differences [7], which might explain inconsistent findings in research on social interactions [8, 9]. Here, we study whether the human BLA is necessary for social and non-social experiential learning by testing a group of five humans with selective bilateral damage to the BLA. We compared their learning behavior in a repeated trust game, and a non-social control task, to healthy, matched controls. Crucially, BLA-damaged subjects, unlike control subjects, completely failed to adapt their investments when interacting with a trustworthy and an untrustworthy partner. In the non-social task, BLA-damaged subjects learned from positive outcomes but differed from the controls by not learning from negative outcomes. Our data extend findings in rodent research by showing that the human BLA is essential for social experiential learning and provide confirmatory evidence of divergent mechanisms for differentially valenced outcomes in non-social learning.

The role of the basolateral amygdala in dreaming.

Neuroimaging studies have repeatedly shown amygdala activity during sleep (REM and NREM). Consequently, various theorists propose central roles for the amygdala in dreaming - particularly in the generation of dream affects, which seem to play a major role in dream plots. However, a causal role for the amygdala in dream phenomena has never been demonstrated. The traditional first step in determining this role is to observe the functional effects of isolated lesions to the brain structure in question. However, circumscribed bilateral amygdala lesions are extremely rare. Furthermore, the treatment of the amygdala as a unitary structure is problematic, as the basolateral and centromedial amygdala (BLA and CMA) may serve very different functions. We analysed 23 dream reports collected from eight adult patients with bilateral calcification of the BLA as a result of a very rare genetic condition called Urbach-Wiethe Disease (UWD). We compared these dream reports to 52 reports collected from 17 matched controls. Given that the BLA has been implicated in various affective processes in waking life, we predicted that the emotional content of the patients' dreams would differ from that of controls. Due to the exploratory nature of this research, a range of different dream characteristics were analysed. A principal components analysis run on all data returned three key factors, namely pleasantness, length and danger. The UWD patients' dream reports were significantly more pleasant and significantly shorter and less complex than control reports. No differences were found in levels of threat or danger. The results support some current hypotheses concerning the amygdala's role in dreaming, and call others into question. Future research should examine whether these UWD patients show generally impaired emotional episodic memory due to BLA damage, which could explain some of the current findings.

Parental touch reduces social vigilance in children.

The sense of touch develops in utero and enables parent-child communication from the earliest moments of life. Research shows that parental touch (e.g., licking and grooming in rats, skin-to-skin care in humans) has organizing effects on the offspring's stress system. Little is known, however, about the psychological effects of parental touch. Building on findings from ethology and psychology, we propose that parental touch-even as subtle as a touch on the shoulder-tells children that their environment is safe for exploration, thus reducing their social vigilance. We tested this hypothesis in late childhood (ages 8-10) and early adolescence (ages 11-14) in 138 parent-child dyads. Parents were randomly assigned to touch or not touch their child briefly and gently on the shoulder, right below the deltoid. Parental touch lowered children's implicit attention to social threat. While parental touch lowered trust among socially non-anxious children, it raised trust among those who needed it the most: socially anxious children. The effects were observed only in late childhood, suggesting that parental touch loses its safety-signaling meaning upon the transition to adolescence. Our findings underscore the power of parental touch in childhood, especially for children who suffer from social anxiety.

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.

Effects of testosterone administration on threat and escape anticipation in the orbitofrontal cortex.

Recent evidence suggests that the steroid hormone testosterone can decrease the functional coupling between orbitofrontal cortex (OFC) and amygdala. Theoretically this decoupling has been linked to a testosterone-driven increase of goal-directed behaviour in case of threat, but this has never been studied directly. Therefore, we placed twenty-two women in dynamically changing situations of escapable and inescapable threat after a within-subject placebo controlled testosterone administration. Using functional magnetic resonance imaging (fMRI) we provide evidence that testosterone activates the left lateral OFC (LOFC) in preparation of active goal-directed escape and decouples this OFC area from a subcortical threat system including the central-medial amygdala, hypothalamus and periaqueductal gray. This LOFC decoupling was specific to threatening situations, a point that was further emphasized by an absence of such decoupling in a second experiment focused on resting-state connectivity. These results not only confirm that testosterone administration decouples the LOFC from the subcortical threat system, but also show that this is specifically the case in response to acute threat, and ultimately leads to an increase in LOFC activity when the participant prepares a goal-directed action to escape. Together these results for the first time provide a detailed understanding of functional brain alterations induced by testosterone under threat conditions, and corroborate and extend the view that testosterone prepares the brain for goal-directed action in case of threat.

Proximity alert! Distance related cuneus activation in military veterans with anger and aggression problems.

Problems involving anger and aggression are common after military deployment, and may involve abnormal responses to threat. This study therefore investigated effects on neural activation related to threat and escapability among veterans with deployment experience. Twenty-seven male veterans with anger and aggression problems (Anger group) and 30 Control veterans performed a virtual predator-task during fMRI measurement. In this task, threat and proximity were manipulated. The distance of cues determined their possibility for escape. Cues signaled impending attack by zooming in towards the participant. If Threat cues, but not Safe cues, reached the participants without being halted by a button press, an aversive noise (105dB scream) was presented. In both the Threat and the Safe condition, closer proximity of the virtual predator resulted in stronger activation in the cuneus in the Anger versus Control group. The results suggest that anger and aggression problems are related to a generalized sensitivity to proximity rather than preparatory processes related to task-contingent aversive stimuli. Anger and aggression problems in natural, dynamically changing environments may be related to an overall heightened vigilance, which is non-adaptively driven by proximity.

The Basolateral Amygdalae and Frontotemporal Network Functions for Threat Perception.

Although the amygdalae play a central role in threat perception and reactions, the direct contributions of the amygdalae to specific aspects of threat perception, from ambiguity resolution to reflexive or deliberate action, remain ill understood in humans. Animal studies show that a detailed understanding requires a focus on the different subnuclei, which is not yet achieved in human research. Given the limits of human imaging methods, the crucial contribution needs to come from individuals with exclusive and selective amygdalae lesions. The current study investigated the role of the basolateral amygdalae and their connection with associated frontal and temporal networks in the automatic perception of threat. Functional activation and connectivity of five individuals with Urbach-Wiethe disease with focal basolateral amygdalae damage and 12 matched controls were measured with functional MRI while they attended to the facial expression of a threatening face-body compound stimuli. Basolateral amygdalae damage was associated with decreased activation in the temporal pole but increased activity in the ventral and dorsal medial prefrontal and medial orbitofrontal cortex. This dissociation between the prefrontal and temporal networks was also present in the connectivity maps. Our results contribute to a dynamic, multirole, subnuclei-based perspective on the involvement of the amygdalae in fear perception. Damage to the basolateral amygdalae decreases activity in the temporal network while increasing activity in the frontal network, thereby potentially triggering a switch from resolving ambiguity to dysfunctional threat signaling and regulation, resulting in hypersensitivity to threat.

Testosterone abolishes implicit subordination in social anxiety.

Neuro-evolutionary theories describe social anxiety as habitual subordinate tendencies acquired through a recursive cycle of social defeat and submissive reactions. If so, the steroid hormone testosterone might be of therapeutic value, as testosterone is a main force behind implicit dominance drive in many species including humans. We combined these two theories to investigate whether the tendency to submit to the dominance of others is an implicit mechanism in social anxiety (Study-1), and whether this can be relieved through testosterone administration (Study-2). Using interactive eye-tracking we demonstrate that socially anxious humans more rapidly avert gaze from subliminal angry eye contact (Study-1). We replicate this effect of implicit subordination in social anxiety in an independent sample, which is subsequently completely abolished after a single placebo-controlled sublingual testosterone administration (Study-2). These findings provide crucial evidence for hormonal and behavioral treatment strategies that specifically target mechanisms of dominance and subordination in social anxiety.

The role of the basolateral amygdala in the perception of faces in natural contexts.

The amygdala is a complex structure that plays its role in perception and threat-related behaviour by activity of its specific nuclei and their separate networks. In the present functional magnetic resonance imaging study, we investigated the role of the basolateral amygdala in face and context processing. Five individuals with focal basolateral amygdala damage and 12 matched controls viewed fearful or neutral faces in a threatening or neutral context. We tested the hypothesis that basolateral amygdala damage modifies the relation between face and threatening context, triggering threat-related activation in the dorsal stream. The findings supported this hypothesis. First, activation was increased in the right precentral gyrus for threatening versus neutral scenes in the basolateral amygdala damage group compared with the control group. Second, activity in the bilateral middle frontal gyrus, and left anterior inferior parietal lobule was enhanced for neutral faces presented in a threatening versus neutral scene in the group with basolateral amygdala damage compared with controls. These findings provide the first evidence for the neural consequences of basolateral amygdala damage during the processing of complex emotional situations.