Disentangling perceptual awareness from nonconscious processing in rhesus monkeys (Macaca mulatta).

Scholars have long debated whether animals, which display impressive intelligent behaviors, are consciously aware or not. Yet, because many complex human behaviors and high-level functions can be performed without conscious awareness, it was long considered impossible to untangle whether animals are aware or just conditionally or nonconsciously behaving. Here, we developed an empirical approach to address this question. We harnessed a well-established cross-over double dissociation between nonconscious and conscious processing, in which people perform in completely opposite ways when they are aware of stimuli versus when they are not. To date, no one has explored if similar performance dissociations exist in a nonhuman species. In a series of seven experiments, we first established these signatures in humans using both known and newly developed nonverbal double-dissociation tasks and then identified similar signatures in rhesus monkeys (Macaca mulatta). These results provide robust evidence for two distinct modes of processing in nonhuman primates. This empirical approach makes it feasible to disentangle conscious visual awareness from nonconscious processing in nonhuman species; hence, it can be used to strip away ambiguity when exploring the processes governing intelligent behavior across the animal kingdom. Taken together, these results strongly support the existence of both nonconscious processing as well as functional human-like visual awareness in nonhuman animals.

Increasing Central Serotonin with 5-hydroxytryptophan Disrupts the Inhibition of Social Gaze in Nonhuman Primates.

To competently navigate the world, individuals must flexibly balance distinct aspects of social gaze, orienting toward others and inhibiting orienting responses, depending on the context. These behaviors are often disrupted amongst patient populations treated with serotonergic drugs. However, those in the field lack a clear understanding of how the serotonergic system mediates social orienting and inhibiting behaviors. Here, we tested how increasing central concentrations of serotonin with the direct precursor 5-hydroxytryptophan (5-HTP) would modulate the ability of rhesus macaques (both sexes) to use eye movements to flexibly orient to, or inhibit orienting to, faces. Systemic administrations of 5-HTP effectively increased central serotonin levels and impaired flexible orientation and inhibition. Critically, 5-HTP selectively impaired the ability of monkeys to inhibit orienting to face images, whereas it similarly impaired orienting to face and control images. 5-HTP also caused monkeys to perseverate on their gaze responses, making them worse at flexibly switching between orienting and inhibiting behaviors. Furthermore, the effects of 5-HTP on performance correlated with a constriction of the pupil, an increased time to initiate trials, and an increased reaction time, suggesting that the disruptive effects of 5-HTP on social gaze behaviors are likely driven by a downregulation of arousal and motivational states. Together, these findings provide causal evidence for a modulatory relationship between 5-HTP and social gaze behaviors in nonhuman primates and offer translational insights for the role of the serotonergic system in social gaze.SIGNIFICANCE STATEMENT Behavioral changes arising from pharmacological agents that target serotonergic functions are complex and difficult to predict. Here, we examined the causal impacts of administering the direct precursor of serotonin, 5-HTP, on orienting and inhibiting social gaze in nonhuman primates. 5-HTP increased central concentrations of serotonin and selectively impaired the ability of monkeys to inhibit orienting to faces while similarly impairing the ability of monkeys to orient to face and control images. These behavioral gaze impairments were systematically associated with a downregulation of arousal and motivational states, indexed by pupil constriction, increased time to initiate trials, and increased reaction time. These findings provide a causal link between 5-HTP and social gaze behaviors in nonhuman primates and provide translational insights about serotonergic interventions.

Self-other distinction modulates the social softness illusion.

The social softness illusion (i.e., the tendency to perceive another person's skin as softer than our own) is thought to promote the sharing of social-emotional experiences because of the rewarding properties of receiving and giving social affective touch. Here we investigated whether the ability to distinguish someone else's body from our own modulates the social softness illusion. In particular, we tested whether the spatial perspective taken by the participants and seeing or not the touched arms could alter this illusion. Pairs of female participants were assigned the roles of either the giver (i.e., delivering the touches) or the receiver (i.e., being touched). We manipulated the location of the touch (palm or forearm), the spatial perspective of the receiver's body with respect to the giver's body (egocentric or allocentric perspective), and the vision of the touched body part (the giver could either see both her own and the receiver's body part, or she was blindfolded). Consistently with previous findings, the skin of another person was perceived as softer than the own one. Additionally, the illusion was present for both the forearm and the palm, and it was stronger in allocentric compared to the egocentric perspective (i.e., when the self-other distinction was clearer). These findings show that the mechanisms underpinning the ability to represent another person's body as distinct from our own modulates the social softness illusion, and thus support the role of the social softness illusion in fostering social relationships.

Oxytocin under opioid antagonism leads to supralinear enhancement of social attention.

To provide new preclinical evidence toward improving the efficacy of oxytocin (OT) in treating social dysfunction, we tested the benefit of administering OT under simultaneously induced opioid antagonism during dyadic gaze interactions in monkeys. OT coadministered with a µ-opioid receptor antagonist, naloxone, invoked a supralinear enhancement of prolonged and selective social attention, producing a stronger effect than the summed effects of each administered separately. These effects were consistently observed when averaging over entire sessions, as well as specifically following events of particular social importance, including mutual eye contact and mutual reward receipt. Furthermore, attention to various facial regions was differentially modulated depending on social context. Using the Allen Institute's transcriptional atlas, we further established the colocalization of µ-opioid and κ-opioid receptor genes and OT genes at the OT-releasing sites in the human brain. These data across monkeys and humans support a regulatory relationship between the OT and opioid systems and suggest that administering OT under opioid antagonism may boost the therapeutic efficacy of OT for enhancing social cognition.

Injection of a dopamine type 2 receptor antagonist into the dorsal striatum disrupts choices driven by previous outcomes, but not perceptual inference.

Decisions are often driven by a combination of immediate perception and previous experience. In this study, we investigated how these two sources of information are integrated and the neural systems that mediate this process. Specifically, we injected a dopamine type 1 antagonist (D1A; SCH23390) or a dopamine type 2 antagonist (D2A; eticlopride) into the dorsal striatum while macaques performed a task in which their choices were driven by perceptual inference and/or reinforcement of past choices. We found that the D2A affected choices based on previous outcomes. However, there were no effects of the D2A on choices driven by perceptual inference. We found that the D1A did not affect perceptual inference or reinforcement learning. Finally, a Bayesian model applied to the results suggested that the D2A may be increasing noise in the striatal representation of value, perhaps by disrupting the striatal population that normally represents value.

Live interaction distinctively shapes social gaze dynamics in rhesus macaques.

The dynamic interaction of gaze between individuals is a hallmark of social cognition. However, very few studies have examined social gaze dynamics after mutual eye contact during real-time interactions. We used a highly quantifiable paradigm to assess social gaze dynamics between pairs of monkeys and modeled these dynamics using an exponential decay function to investigate sustained attention after mutual eye contact. When monkeys were interacting with real partners compared with static images and movies of the same monkeys, we found a significant increase in the proportion of fixations to the eyes and a smaller dispersion of fixations around the eyes, indicating enhanced focal attention to the eye region. Notably, dominance and familiarity between the interacting pairs induced separable components of gaze dynamics that were unique to live interactions. Gaze dynamics of dominant monkeys after mutual eye contact were associated with a greater number of fixations to the eyes, whereas those of familiar pairs were associated with a faster rate of decrease in this eye-directed attention. Our findings endorse the notion that certain key aspects of social cognition are only captured during interactive social contexts and dependent on the elapsed time relative to socially meaningful events.

Areas of Brain Damage Underlying Increased Reports of Behavioral Disinhibition.

Disinhibition, the inability to inhibit inappropriate behavior, is seen in frontal-temporal degeneration, Alzheimer's disease, and stroke. Behavioral disinhibition leads to social and emotional impairments, including impulsive behavior and disregard for social conventions. The authors investigated the effects of lesions on behavioral disinhibition measured by the Neuropsychiatric Inventory in 177 veterans with traumatic brain injuries. The authors performed voxel-based lesion-symptom mapping using MEDx. Damage in the frontal and temporal lobes, gyrus rectus, and insula was associated with greater behavioral disinhibition, providing further evidence of the frontal lobe's involvement in behavioral inhibition and suggesting that these regions are necessary to inhibit improper behavior.

Neural correlates of apathy revealed by lesion mapping in participants with traumatic brain injuries.

Apathy, common in neurological disorders, is defined as disinterest and loss of motivation, with a reduction in self-initiated activity. Research in diseased populations has shown that apathy is associated with variations in the volume of brain regions such as the anterior cingulate and the frontal lobes. The goal of this study was to determine the neural signatures of apathy in people with penetrating traumatic brain injuries (pTBIs), as to our knowledge, these have not been studied in this sample. We studied 176 male Vietnam War veterans with pTBIs using voxel-based lesion-symptom mapping (VLSM) and apathy scores from the UCLA Neuropsychiatric Inventory (NPI), a structured inventory of symptoms completed by a caregiver. Our results revealed that increased apathy symptoms were associated with brain damage in limbic and cortical areas of the left hemisphere including the anterior cingulate, inferior, middle, and superior frontal regions, insula, and supplementary motor area. Our results are consistent with the literature, and extend them to people with focal pTBI. Apathy is a significant symptom since it can reduce participation of the patient in family and other social interactions, and diminish affective decision-making.

Closed-loop microstimulations of the orbitofrontal cortex during real-life gaze interaction enhance dynamic social attention.

Neurons from multiple prefrontal areas encode several key variables of social gaze interaction. To explore the causal roles of the primate prefrontal cortex in real-life gaze interaction, we applied weak closed-loop microstimulations that were precisely triggered by specific social gaze events. Microstimulations of the orbitofrontal cortex, but not the dorsomedial prefrontal cortex or the anterior cingulate cortex, enhanced momentary dynamic social attention in the spatial dimension by decreasing the distance of fixations relative to a partner's eyes and in the temporal dimension by reducing the inter-looking interval and the latency to reciprocate the other's directed gaze. By contrast, on a longer timescale, microstimulations of the dorsomedial prefrontal cortex modulated inter-individual gaze dynamics relative to one's own gaze positions. These findings demonstrate that multiple regions in the primate prefrontal cortex may serve as functionally accessible nodes in controlling different aspects of dynamic social attention and suggest their potential for a therapeutic brain interface.

Autonomic and hedonic response to affective touch in autism spectrum disorder.

Interpersonal touch plays a crucial role in shaping relationships and encouraging social connections. Failure in processing tactile input or abnormal tactile sensitivity may hamper social behaviors and have severe consequences in individuals' relational lives. Autism Spectrum Disorder (ASD) is characterized by both sensory disruptions and social impairments, making affective touch an ideal meeting point for understanding these features in ASD individuals. By integrating behavioral and physiological measures, we investigated the effects of affective touch on adult individuals with ASD from both an implicit and explicit perspective. Specifically, at an implicit level, we investigated whether and how receiving an affective touch influenced participants' skin conductance tonic and phasic components. At the explicit level, we delved into the affective and unpleasant features of affective touch. Overall, we observed lower skin conductance level in ASD compared to TD subjects. Interestingly, the typically developing (TD) group showed an increased autonomic response for affective touch compared to a control touch, while ASD subjects' autonomic response did not differ between the two conditions. Furthermore, ASD participants provided higher ratings for both the affective and unpleasant components of the touch, compared to TD subjects. Our results reveal a noteworthy discrepancy in ASD population between the subjective experience, characterized by amplified hedonic but also unpleasant responses, and the physiological response, marked by a lack of autonomic activation related to affective touch. This insightful dissociation seems crucial for a deeper understanding of the distinctive challenges characterizing people with ASD and may have implications for diagnosis and therapeutic approaches.

Cooperation and competition have same benefits but different costs.

Cooperation and competition shape everyday human interactions and impact individuals' chances of success in different domains. Using a virtual Stroop test, classically employed to assess general cognitive interference, we examined the impact of social context (cooperation and competition) and other's ability (higher and lower performers) on performance, perceived stress, and autonomic activity. In Experiment 1, we found that both cooperation with a lower performer and competition with a higher performer led to similar enhancement in performance. However, only competition with a more skilled opponent induced an increase in perceived stress and physiological activity. Experiment 2 further demonstrated that these effects persisted even with prolonged exposure to these contexts. In summary, cooperation can be just as effective as competition in improving individuals' performance. However, cooperation does not carry the same level of stress and physiological burden as the competitive context, representing a healthier and more optimal way to boost individual performance.

An unbiased method to partition diverse neuronal responses into functional ensembles reveals interpretable population dynamics during innate social behavior.

In neuroscience, understanding how single-neuron firing contributes to distributed neural ensembles is crucial. Traditional methods of analysis have been limited to descriptions of whole population activity, or, when analyzing individual neurons, criteria for response categorization varied significantly across experiments. Current methods lack scalability for large datasets, fail to capture temporal changes and rely on parametric assumptions. There's a need for a robust, scalable, and non-parametric functional clustering approach to capture interpretable dynamics. To address this challenge, we developed a model-based, statistical framework for unsupervised clustering of multiple time series datasets that exhibit nonlinear dynamics into an a-priori-unknown number of parameterized ensembles called Functional Encoding Units (FEUs). FEU outperforms existing techniques in accuracy and benchmark scores. Here, we apply this FEU formalism to single-unit recordings collected during social behaviors in rodents and primates and demonstrate its hypothesis-generating and testing capacities. This novel pipeline serves as an analytic bridge, translating neural ensemble codes across model systems.

Isolated theory of mind deficits and risk for frontotemporal dementia: a longitudinal pilot study.

OBJECTIVE: Recent data suggest that theory of mind (ToM) deficits represent an early symptom of the behavioural variant of frontotemporal dementia (bvFTD). However, longitudinal data on the natural history of subjects presenting with isolated ToM deficits are lacking. The aim of the study was to verify if isolated ToM deficits represent an at-risk state for prefrontal dysfunction and bvFTD. METHODS: A population of healthy subjects (n=4150, age range: 50-60 years) completed a clinical and neuropsychological evaluation including the Reading the Mind in the Eyes Test (RMET), a widely used ToM task. From this group, we recruited a low-RMET group (n=83) including subjects with RMET scores lower than 2 SDs but an otherwise normal neuropsychological evaluation and a control group. All subjects underwent evaluation at baseline and after 2 years. RESULTS: Subjects in the low-RMET group showed decline in prefrontal functions at follow-up. Moreover, at follow-up 12 subjects in the low-RMET group presented with findings suggestive of bvFTD. Neuropsychological performance was stable in the control group. CONCLUSIONS: Our data suggest that isolated ToM deficits could represent an at-risk situation for the development of future prefrontal dysfunction and bvFTD. ToM evaluation should be included in neuropsychological protocols aimed to evaluate the early phases of dementia.

Hedonic and autonomic responses in promoting affective touch.

Interpersonal touch is intrinsically reciprocal since it entails a person promoting and another receiving the touch. While several studies have investigated the beneficial effects of receiving affective touch, the affective experience of caressing another individual remains largely unknown. Here, we investigated the hedonic and autonomic responses (skin conductance and heart rate) in the person promoting affective touch. We also examined whether interpersonal relationship, gender, and eye contact modulate these responses. As expected, caressing the partner was perceived as more pleasant than caressing a stranger, especially if the affective touch occurred together with mutual eye contact. Promoting affective touch to the partner also resulted in a decrease of both autonomic responses and anxiety levels, suggesting the occurrence of a calming effect. Additionally, these effects were more pronounced in females compared to males, indicating that hedonic and autonomic aspects of affective touch are modulated by both social relationship and gender. These findings show for the first time that caressing a beloved one is not only pleasant but also reduces autonomic responses and anxiety in the person promoting the touch. This might suggest that affective touch has an instrumental role for romantic partners in promoting and reinforcing their affective bonding.

Closed-loop microstimulations of the orbitofrontal cortex during real-life gaze interaction enhance dynamic social attention.

The prefrontal cortex is extensively involved in social exchange. During dyadic gaze interaction, multiple prefrontal areas exhibit neuronal encoding of social gaze events and context-specific mutual eye contact, supported by a widespread neural mechanism of social gaze monitoring. To explore causal manipulation of real-life gaze interaction, we applied weak closed-loop microstimulations that were precisely triggered by specific social gaze events to three prefrontal areas in monkeys. Microstimulations of orbitofrontal cortex (OFC), but not dorsomedial prefrontal or anterior cingulate cortex, enhanced momentary dynamic social attention in the spatial dimension by decreasing distance of one's gaze fixations relative to partner monkey's eyes. In the temporal dimension, microstimulations of OFC reduced the inter-looking interval for attending to another agent and the latency to reciprocate other's directed gaze. These findings demonstrate that primate OFC serves as a functionally accessible node in controlling dynamic social attention and suggest its potential for a therapeutic brain interface.

Beyond alpha-band: The neural correlate of creative thinking.

The compound nature of creativity entails the interplay of multiple cognitive processes, making it difficult to attribute creativity to a single neural signature. Divergent thinking paradigms, widely adopted to investigate creative production, have highlighted the key role of specific mental operations subserving creativity, such as inhibition of external stimuli, loose semantic associations, and mental imagery. Neurophysiological studies have typically shown a high alpha rhythm synchronization when individuals are engaged in creative ideation. Also, oculomotor activity and pupil diameter have been proposed as useful indicators of mental operations involved in such a thinking process. The goal of this study was to investigate whether beyond alpha-band activity other higher frequency bands, such as beta and gamma, may subserve divergent and convergent thinking and whether those could be associated with a different gaze bias and pupil response during ideas generation. Implementing a within-subjects design we collected behavioral measures, neural activity, gaze patterns, and pupil dilation while participants performed a revised version of the Alternative Uses Task, in which divergent thinking is contrasted to convergent thinking. As expected, participants took longer to generate creative ideas as compared to common ones. Interestingly, during divergent thinking participants displayed alpha synchronization along with beta and gamma desynchronization, more pronounced leftward gaze shift, and greater pupil dilation. During convergent thinking, an opposite pattern was observed: desynchronization in alpha and an increase in beta and gamma rhythm, along with a reduction of leftward gaze shift and greater pupil constriction. The present study uncovered specific neural dynamics and physiological patterns during idea generation, providing novel insight into the complex physiological signature of creative production.

Dissociation of vicarious and experienced rewards by coupling frequency within the same neural pathway.

Vicarious reward, essential to social learning and decision making, is theorized to engage select brain regions similarly to experienced reward to generate a shared experience. However, it is just as important for neural systems to also differentiate vicarious from experienced rewards for social interaction. Here, we investigated the neuronal interaction between the primate anterior cingulate cortex gyrus (ACCg) and the basolateral amygdala (BLA) when social choices made by monkeys led to either vicarious or experienced reward. Coherence between ACCg spikes and BLA local field potential (LFP) selectively increased in gamma frequencies for vicarious reward, whereas it selectively increased in alpha/beta frequencies for experienced reward. These respectively enhanced couplings for vicarious and experienced rewards were uniquely observed following voluntary choices. Moreover, reward outcomes had consistently strong directional influences from ACCg to BLA. Our findings support a mechanism of vicarious reward where social agency is tagged by interareal coordination frequency within the same shared pathway.

Pain perception and physiological responses are modulated by active support from a romantic partner.

As social animals, humans are strongly affected by social bonds and interpersonal interactions. Proximity and social support from significant others may buffer the negative outcomes of a painful experience. Several studies have investigated the role of romantic partners' support in pain modulation, mostly focusing on tactile support and showing its effectiveness in reducing pain perception. Nevertheless, no study so far has investigated the role of supportive speaking on pain modulation, nor has compared the effects of a tactile and vocal support within the same couples. The present study directly compared for the first time the efficacy of mere presence (Passive Support) and different forms of active (Touch, Voice, Touch + Voice) support from a romantic partner during a painful experience in a naturalistic setting. We assessed pain modulation in 37 romantic couples via both subjective (self-reported ratings) and physiological (skin conductance) measurements. We found that all three types of active support were equally more effective than passive support in reducing the painful experience at both subjective and physiological levels; interestingly, our results suggest that supportive speaking can reduce pain perception with respect to passive support to a similar extent as tactile support does. Overall, this study highlights the relevance of an active support in reducing pain perception, with active types of support being more effective than passive support, regardless of its specific modality.

Empathic deficits in combat veterans with traumatic brain injury: a voxel-based lesion-symptom mapping study.

OBJECTIVE: To understand better which brain regions support emotional empathy. BACKGROUND: Emotional empathy, the ability to interpret and share the affective states of others, is a key component in human social interaction. Previous research has suggested that emotional empathy relies on several distinct brain regions, although further evidence from human lesion studies is needed to determine which regions are critical. METHODS: We studied 192 male Vietnam combat veterans who had sustained focal penetrating traumatic brain injuries, and 54 non-brain-injured veterans. We used voxel-based lesion-symptom mapping on computed tomographic scans to elucidate the neural bases of self-reported emotional empathy as measured by the Balanced Emotional Empathy Scale. RESULTS: Damage in several brain regions, particularly the ventrolateral prefrontal cortex, left and right posterior temporal lobes, and insula, was associated with diminished emotional empathy. CONCLUSIONS: These findings provide further insight into the neural substrates of emotional empathy, and are consistent with the notion that emotional empathy is supported by a distributed network of brain regions. Additional work may advance our understanding of the empathic deficits commonly observed in patients with neurologic and psychiatric disorders.

Widespread implementations of interactive social gaze neurons in the primate prefrontal-amygdala networks.

Social gaze interaction powerfully shapes interpersonal communication. However, compared with social perception, very little is known about the neuronal underpinnings of real-life social gaze interaction. Here, we studied a large number of neurons spanning four regions in primate prefrontal-amygdala networks and demonstrate robust single-cell foundations of interactive social gaze in the orbitofrontal, dorsomedial prefrontal, and anterior cingulate cortices, in addition to the amygdala. Many neurons in these areas exhibited high temporal heterogeneity for social discriminability, with a selectivity bias for looking at a conspecific compared with an object. Notably, a large proportion of neurons in each brain region parametrically tracked the gaze of self or other, providing substrates for social gaze monitoring. Furthermore, several neurons displayed selective encoding of mutual eye contact in an agent-specific manner. These findings provide evidence of widespread implementations of interactive social gaze neurons in the primate prefrontal-amygdala networks during social gaze interaction.