Social status as a latent variable in the amygdala of observers of social interactions.

Successful integration into a hierarchical social group requires knowledge of the status of each individual and of the rules that govern social interactions within the group. In species that lack morphological indicators of status, social status can be inferred by observing the signals exchanged between individuals. We simulated social interactions between macaques by juxtaposing videos of aggressive and appeasing displays, where two individuals appeared in each other's line of sight and their displays were timed to suggest the reciprocation of dominant and subordinate signals. Viewers of these videos successfully inferred the social status of the interacting characters. Dominant individuals attracted more social attention from viewers even when they were not engaged in social displays. Neurons in the viewers' amygdala signaled the status of both the attended (fixated) and the unattended individuals, suggesting that in third-party observers of social interactions, the amygdala jointly signals the status of interacting parties.

Interoceptive Signals Bias Decision Making in Rhesus Macaques.

Several influential theories have proposed that interoceptive signals, sent from the body to the brain, contribute to neural processes that coordinate complex behaviors. Using pharmacological agents that do not cross the blood-brain barrier, we altered interoceptive states and evaluated their effect on decision-making in rhesus monkeys. We used glycopyrrolate, a non-specific muscarinic (parasympathetic) antagonist, and isoproterenol, a beta-1/2 (sympathetic) agonist, to create a sympathetic-dominated physiological state indexed by increased heart rate. Rhesus monkeys were trained on two variants of an approach-avoidance conflict task, where they chose between enduring mildly aversive stimuli in exchange for a steady flow of rewards, or cancelling the aversive stimuli, forgoing the rewards. The delay to interrupt the aversive stimuli and the reward were used as a measure of the cost-benefit estimation that drove the monkeys' decisions. Both drugs altered approach-avoidance decisions, substantially reducing the delay to interrupt the aversive stimuli. To determine whether this autonomic state lowered tolerance to aversive stimuli or reduced the subjective value of the reward, we tested the effects of glycopyrrolate on a food preference task. Food preference was unaltered, suggesting that the sympathetic dominated state selectively reduces tolerance for aversive stimuli without altering reward-seeking behaviors. As these drugs have no direct effect on brain physiology, interoceptive afferents are the most likely mechanism by which decision making was biased toward avoidance.

Social Status as a Latent Variable in the Amygdala of Observers of Social Interactions.

Successful integration into a hierarchical social group requires knowledge of the status of each individual and of the rules that govern social interactions within the group. In species that lack morphological indicators of status, social status can be inferred by observing the signals exchanged between individuals. We simulated social interactions between macaques by juxtaposing videos of aggressive and appeasing displays where two individuals appeared in each other's line of sight and their displays were timed to suggest the reciprocation of dominant and subordinate signals. Viewers of these videos successfully inferred the social status of the interacting characters. Dominant individuals attracted more social attention from viewers even when they were not engaged in social displays. Neurons in the viewers' amygdala signaled the status of both the attended (fixated) and the unattended individuals suggesting that in third party observers of social interactions, the amygdala signals jointly the status of interacting parties. Highlights: Monkeys infer the social status of conspecifics from videos of simulated dyadic interactionsDuring fixations neural populations signal the social status of the attended individualsNeurons in the amygdala jointly encode the status of interacting individuals. In brief: Third party-viewers of pairwise dominant-subordinate interactions infer social status from the observed behaviors. Neurons in the amygdala are tuned to the inferred dominant/subordinate status of both individuals.

Detection of latent brain states from baseline neural activity in the amygdala.

The amygdala responds to a large variety of socially and emotionally salient environmental and interoceptive stimuli. The context in which these stimuli occur determines their social and emotional significance. In canonical neurophysiological studies, the fast-paced succession of stimuli and events induce phasic changes in neural activity. During inter-trial intervals neural activity is expected to return to a stable and relatively featureless baseline. Context, such as the presence of a social partner, or the similarity of trials in a blocked design, induces brain states that can transcend the fast-paced succession of stimuli and can be recovered from the baseline firing rate of neurons. Indeed, the baseline firing rates of neurons in the amygdala change between blocks of trials of gentle grooming touch, delivered by a trusted social partner, and non-social airflow stimuli, delivered by a computer-controlled air valve. In this experimental paradigm, the presence of the groomer alone was sufficient to induce small but significant changes in baseline firing rates. Here, we examine local field potentials (LFP) recorded during these baseline periods to determine whether context was encoded by network dynamics that emerge in the local field potentials from the activity of large ensembles of neurons. We found that machine learning techniques can reliably decode social vs. non-social context from spectrograms of baseline local field potentials. Notably, decoding accuracy improved significantly with access to broad-band information. No significant differences were detected between the nuclei of the amygdala that receive direct or indirect inputs from areas of the prefrontal cortex known to coordinate flexible, context-dependent behaviors. The lack of nuclear specificity suggests that context-related synaptic inputs arise from a shared source, possibly interoceptive inputs that signal the sympathetic- vs. parasympathetic-dominated states characterizing non-social and social blocks, respectively.

Brainwide mesoscale functional networks revealed by focal infrared neural stimulation of the amygdala.

The primate amygdala serves to evaluate emotional content of sensory inputs and modulate emotional and social behaviors; it modulates cognitive, multisensory and autonomic circuits predominantly via the basal (BA), lateral (LA), and central (CeA) nuclei, respectively. Based on recent electrophysiological evidence suggesting mesoscale (millimeters-scale) nature of intra-amygdala functional organization, we have investigated the connectivity of these nuclei using Infrared Neural Stimulation of single mesoscale sites coupled with mapping in ultrahigh field 7T functional Magnetic Resonance Imaging (INS-fMRI). Stimulation of multiple sites within amygdala of single individuals evoked 'mesoscale functional connectivity maps', allowing comparison of BA, LA and CeA connected brainwide networks. This revealed a mesoscale nature of connected sites, complementary spatial patterns of functional connectivity, and topographic relationships of nucleus-specific connections. Our data reveal a functional architecture of systematically organized brainwide networks mediating sensory, cognitive, and autonomic influences from the amygdala.

Dolichocolon (redundant colon) in a rhesus macaque (Macaca mulatta).

Dolichocolon (redundant colon) is an underdiagnosed cause of severe constipation in humans. The clinical presentation reported here in a rhesus macaque closely resembles that of intestinal adenocarcinoma, the most common neoplasia in macaques. Dolichocolon should be considered in differential diagnosis of macaques with anorexia, weight loss, and constipation.

A framework and resource for global collaboration in non-human primate neuroscience.

As science and technology evolve, there is an increasing need for promotion of international scientific exchange. Collaborations, while offering substantial opportunities for scientists and benefit to society, also present challenges for those working with animal models, such as non-human primates (NHPs). Diversity in regulation of animal research is sometimes mistaken for the absence of common international welfare standards. Here, the ethical and regulatory protocols for 13 countries that have guidelines in place for biomedical research involving NHPs were assessed with a focus on neuroscience. Review of the variability and similarity in trans-national NHP welfare regulations extended to countries in Asia, Europe and North America. A tabulated resource was established to advance solution-oriented discussions and scientific collaborations across borders. Our aim is to better inform the public and other stakeholders. Through cooperative efforts to identify and analyze information with reference to evidence-based discussion, the proposed key ingredients may help to shape and support a more informed, open framework. This framework and resource can be expanded further for biomedical research in other countries.

A context-dependent switch from sensing to feeling in the primate amygdala.

The skin transmits affective signals that integrate into our social vocabulary. As the socio-affective aspects of touch are likely processed in the amygdala, we compare neural responses to social grooming and gentle airflow recorded from the amygdala and the primary somatosensory cortex of non-human primates. Neurons in the somatosensory cortex respond to both types of tactile stimuli. In the amygdala, however, neurons do not respond to individual grooming sweeps even though grooming elicits autonomic states indicative of positive affect. Instead, many show changes in baseline firing rates that persist throughout the grooming bout. Such baseline fluctuations are attributed to social context because the presence of the groomer alone can account for the observed changes in baseline activity. It appears, therefore, that during grooming, the amygdala stops responding to external inputs on a short timescale but remains responsive to social context (or the associated affective states) on longer time scales.

Social engagement revealed by gaze following in third-party observers of simulated social conflict.

Humans and non-human primates can allocate visual attention to areas of high interest in their visual field based on the behaviors of their social partners. Allocation of attention is particularly important for third-party observers of social interactions. By following the gaze of interacting individuals, the observer can obtain information about the mental states, emotions, and intentions of others. We presented three adult monkeys (Macaca mulatta) with videos of simulated social interactions and quantified their eye movements to determine which observed behaviors were most conducive to gaze following. Social interactions were simulated by juxtaposing two videos depicting a threatening and an appeasing individual facing each other, with the timing of the facial and bodily displays adjusted to mimic an exchange of social signals. Socially meaningful facial displays combined with full body movements significantly enhanced the probability of gaze following and joint attention. Despite the synthetic nature of these interactions, the facial and bodily displays of the submissive individual elicited significantly more joint-attention than gaze-following saccades, suggesting a preferential allocation of attention to the recipients of threatening displays. Temporal alignment of gaze following and joint attention to the frames of each video showed numerous clusters of significant increases in the frequency of these saccades. These clusters suggest that some videos contained signals that can induce a quasi-automatic redirection of the observer's attention. However, these saccades occurred only on a fraction of the viewings, and we have documented large inter-individual variations. All viewers produced sequences of joint attention saccades (check-backs) shifting their attention between the two monkeys as though monitoring the simulated emitting-receiving cycle of social signals. These sequences reflect the viewer's interest in monitoring the ongoing exchange of agonistic and affiliative displays. It appears that in macaque monkeys, the scanpaths of third-party observers of simulated social interactions are informed by social-cognitive processes suggestive of mentalizing.

Large-scale intramuscular electrode system for chronic electromyography and functional electrical stimulation.

To understand how the central nervous system (CNS) enacts movements, it seems important to monitor the activities of the many muscles involved. Likewise, to restore complex movements to paralyzed limbs with electrical stimulation requires access to most limb muscles. Intramuscular electrodes are needed to obtain isolated recordings or stimulation of individual muscles. As such, we developed and tested the stability of large arrays of implanted intramuscular electrodes. We implanted 58 electrodes in 29 upper limb muscles in each of three macaques. Electrode connectors were protected within a skull-mounted chamber. During surgery, wires were tunneled subcutaneously to target muscles, where gold anchors were crimped onto the leads. The anchors were then deployed with an insertion device. In two monkeys, the chamber was fixed to the skull with a titanium baseplate rather than acrylic cement. In multiple sessions up to 15 wk after surgery, electromyographic (EMG) signals were recorded while monkeys made the same reaching movement. EMG signals were stable, with an average (SD) coefficient of variation across sessions of 0.24 ± 0.15. In addition, at 4, 8, and 16 wk after surgery, forces to incrementing stimulus pulses were measured for each electrode. The threshold current needed to evoke a response at 16 wk was not different from that at 4 wk. Likewise, peak force evoked by 16 mA of current at 16 wk was not different from 4 wk. The stability of this system implies it could be effectively used to monitor and stimulate large numbers of muscles needed to understand the control of natural and evoked movements.NEW AND NOTEWORTHY A new method was developed to enable long-lasting recording and stimulation of large numbers of muscles with intramuscular electrodes. Electromyographic signals and evoked force responses in 29 upper limb muscles remained stable over several months when tested in nonhuman primates. This system could be used effectively to monitor and stimulate numerous muscles needed to more fully understand the control of natural and evoked movements.

Restoration of complex movement in the paralyzed upper limb.

Objective.Functional electrical stimulation (FES) involves artificial activation of skeletal muscles to reinstate motor function in paralyzed individuals. While FES applied to the upper limb has improved the ability of tetraplegics to perform activities of daily living, there are key shortcomings impeding its widespread use. One major limitation is that the range of motor behaviors that can be generated is restricted to a small set of simple, preprogrammed movements. This limitation stems from the substantial difficulty in determining the patterns of stimulation across many muscles required to produce more complex movements. Therefore, the objective of this study was to use machine learning to flexibly identify patterns of muscle stimulation needed to evoke a wide array of multi-joint arm movements.Approach. Arm kinematics and electromyographic (EMG) activity from 29 muscles were recorded while a 'trainer' monkey made an extensive range of arm movements. Those data were used to train an artificial neural network that predicted patterns of muscle activity associated with a new set of movements. Those patterns were converted into trains of stimulus pulses that were delivered to upper limb muscles in two other temporarily paralyzed monkeys.Main results. Machine-learning based prediction of EMG was good for within-subject predictions but appreciably poorer for across-subject predictions. Evoked responses matched the desired movements with good fidelity only in some cases. Means to mitigate errors associated with FES-evoked movements are discussed.Significance. Because the range of movements that can be produced with our approach is virtually unlimited, this system could greatly expand the repertoire of movements available to individuals with high level paralysis.

The role of the amygdala in processing social and affective touch.

The amygdala plays a central role in emotion and social behavior, yet its role in processing social and affective touch is not well established. Longitudinal studies reveal that touch-deprived infants show later in life exaggerated emotional reactivity related to structural and functional changes in the amygdala and other brain structures. The internal organization and connectivity of the amygdala is well-suited to process the sensory features of tactile stimuli and also the socio-cognitive dimensions of the received touch. The convergent processing of bottom-up and top-down pathways that carry information about touch results in the elaboration of context appropriate autonomic responses. Indeed, the positive value of affective touch in humans and social grooming in non-human primates is correlated with vagal tone and the release of oxytocin and endogenous opioids. Grooming, the non-human primate equivalent of affective touch in humans, reduces vigilance, that depends on the amygdala. During touch-induced vagal tone and low vigilance, neural activity in the amygdala is substantially different from activity corresponding to the attentive processing of tactile stimuli. Under these circumstances neurons no longer respond phasically to each touch stimulus, rather they signal a sustained functional state in which the amygdala appears decoupled from monitoring the external environment.

Marmosets confirm that context is king.

Neural responses to vocalizations are expected to depend on the sensory features of the stimulus. In this issue of Neuron, Jovanovic and colleagues show that call-responsive neurons in the prefrontal cortex of marmosets signal not only the auditory stimulus but also the social-behavioral context.

Saccade-related neural communication in the human medial temporal lobe is modulated by the social relevance of stimuli.

Humans predominantly explore their environment by moving their eyes. To optimally communicate and process visual information, neural activity needs to be coordinated with the execution of eye movements. We investigated the coordination between visual exploration and interareal neural communication by analyzing local field potentials and single neuron activity in patients with epilepsy. We demonstrated that during the free viewing of images, neural communication between the human amygdala and hippocampus is coordinated with the execution of eye movements. The strength and direction of neural communication and hippocampal saccade-related phase alignment were strongest for fixations that landed on human faces. Our results argue that the state of the human medial temporal lobe network is selectively coordinated with motor behavior. Interareal neural communication was facilitated for social stimuli as indexed by the category of the attended information.

Infrared neural stimulation with 7T fMRI: A rapid in vivo method for mapping cortical connections of primate amygdala.

We have previously shown that INS-fMRI is a rapid method for mapping mesoscale brain networks in the macaque monkey brain. Focal stimulation of single cortical sites led to the activation of connected cortical locations, resulting in a global connectivity map. Here, we have extended this method for mapping brainwide networks following stimulation of single subcortical sites. As a testbed, we focused on the basal nucleus of the amygdala in the macaque monkey. We describe methods to target basal nucleus locations with submillimeter precision, pulse train stimulation methods, and statistical tests for assessing non-random nature of activations. Using these methods, we report that stimulation of precisely targeted loci in the basal nucleus produced sparse and specific activations in the brain. Activations were observed in the insular and sensory association cortices as well as activations in the cingulate cortex, consistent with known anatomical connections. What is new here is that the activations were focal and, in some cases, exhibited shifting topography with millimeter shifts in stimulation site. The precision of the method enables networks mapped from different nearby sites in the basal nucleus to be distinguished. While further investigation is needed to improve the sensitivity of this method, our analyses do support the reproducibility and non-random nature of some of the activations. We suggest that INS-fMRI is a promising method for mapping large-scale cortical and subcortical networks at high spatial resolution.

Mesoscopic-scale functional networks in the primate amygdala.

The primate amygdala performs multiple functions that may be related to the anatomical heterogeneity of its nuclei. Individual neurons with stimulus- and task-specific responses are not clustered in any of the nuclei, suggesting that single-units may be too-fine grained to shed light on the mesoscale organization of the amygdala. We have extracted from local field potentials recorded simultaneously from multiple locations within the primate (Macaca mulatta) amygdala spatially defined and statistically separable responses to visual, tactile, and auditory stimuli. A generalized eigendecomposition-based method of source separation isolated coactivity patterns, or components, that in neurophysiological terms correspond to putative subnetworks. Some component spatial patterns mapped onto the anatomical organization of the amygdala, while other components reflected integration across nuclei. These components differentiated between visual, tactile, and auditory stimuli suggesting the presence of functionally distinct parallel subnetworks.

Multidimensional processing in the amygdala.

Brain-wide circuits that coordinate affective and social behaviours intersect in the amygdala. Consequently, amygdala lesions cause a heterogeneous array of social and non-social deficits. Social behaviours are not localized to subdivisions of the amygdala even though the inputs and outputs that carry social signals are anatomically restricted to distinct subnuclear regions. This observation may be explained by the multidimensional response properties of the component neurons. Indeed, the multitudes of circuits that converge in the amygdala enlist the same subset of neurons into different ensembles that combine social and non-social elements into high-dimensional representations. These representations may enable flexible, context-dependent social decisions. As such, multidimensional processing may operate in parallel with subcircuits of genetically identical neurons that serve specialized and functionally dissociable functions. When combined, the activity of specialized circuits may grant specificity to social behaviours, whereas multidimensional processing facilitates the flexibility and nuance needed for complex social behaviour.

Multidimensional Neural Selectivity in the Primate Amygdala.

The amygdala contributes to multiple functions including attention allocation, sensory processing, decision-making, and the elaboration of emotional behaviors. The diversity of functions attributed to the amygdala is reflected in the response selectivity of its component neurons. Previous work claimed that subsets of neurons differentiate between broad categories of stimuli (e.g., objects vs faces, rewards vs punishment), while other subsets are narrowly specialized to respond to individual faces or facial features (e.g., eyes). Here we explored the extent to which the same neurons contribute to more than one neural subpopulation in a task that activated multiple functions of the amygdala. The subjects (Macaca mulatta) watched videos depicting conspecifics or inanimate objects, and learned by trial and error to choose the individuals or objects associated with the highest rewards. We found that the same neurons responded selectively to two or more of the following task events or stimulus features: (1) alerting, task-related stimuli (fixation icon, video start, and video end); (2) reward magnitude; (3) stimulus categories (social vs nonsocial); and (4) stimulus-unique features (faces, eyes). A disproportionate number of neurons showed selectivity for all of the examined stimulus features and task events. These results suggest that neurons that appear specialized and uniquely tuned to specific stimuli (e.g., face cells, eye cells) are likely to respond to multiple other types of stimuli or behavioral events, if/when these become behaviorally relevant in the context of a complex task. This multidimensional selectivity supports a flexible, context-dependent evaluation of inputs and subsequent decision making based on the activity of the same neural ensemble.

Conserved features of anterior cingulate networks support observational learning across species.

The ability to observe, interpret, and learn behaviors and emotions from conspecifics is crucial for survival, as it bypasses direct experience to avoid potential dangers and maximize rewards and benefits. The anterior cingulate cortex (ACC) and its extended neural connections are emerging as important networks for the detection, encoding, and interpretation of social signals during observational learning. Evidence from rodents and primates (including humans) suggests that the social interactions that occur while individuals are exposed to important information in their environment lead to transfer of information across individuals that promotes adaptive behaviors in the form of either social affiliation, alertness, or avoidance. In this review, we first showcase anatomical and functional connections of the ACC in primates and rodents that contribute to the perception of social signals. We then discuss species-specific cognitive and social functions of the ACC and differentiate between neural activity related to 'self' and 'other', extending into the difference between social signals received and processed by the self, versus observing social interactions among others. We next describe behavioral and neural events that contribute to social learning via observation. Finally, we discuss some of the neural mechanisms underlying observational learning within the ACC and its extended network.