Keith M. Kendrick

Oxytocin Enhances Amygdala-Dependent, Socially Reinforced Learning and Emotional Empathy in Humans

Oxytocin (OT) is becoming increasingly established as a prosocial neuropeptide in humans with therapeutic potential in treatment of social, cognitive, and mood disorders. However, the potential of OT as a general facilitator of human learning and empathy is unclear. The current double-blind experiments on healthy adult male volunteers investigated first whether treatment with intranasal OT enhanced learning performance on a feedback-guided item–category association task where either social (smiling and angry faces) or nonsocial (green and red lights) reinforcers were used, and second whether it increased either cognitive or emotional empathy measured by the Multifaceted Empathy Test. Further experiments investigated whether OT-sensitive behavioral components required a normal functional amygdala. Results in control groups showed that learning performance was improved when social rather than nonsocial reinforcement was used. Intranasal OT potentiated this social reinforcement advantage and greatly increased emotional, but not cognitive, empathy in response to both positive and negative valence stimuli. Interestingly, after OT treatment, emotional empathy responses in men were raised to levels similar to those found in untreated women. Two patients with selective bilateral damage to the amygdala (monozygotic twins with congenital Urbach–Wiethe disease) were impaired on both OT-sensitive aspects of these learning and empathy tasks, but performed normally on nonsocially reinforced learning and cognitive empathy. Overall these findings provide the first demonstration that OT can facilitate amygdala-dependent, socially reinforced learning and emotional empathy in men.

Prosocial effects of oxytocin and clinical evidence for its therapeutic potential

There has been unprecedented interest in the prosocial effects of the neuropeptide oxytocin in humans over the last decade. A range of studies has demonstrated correlations between basal oxytocin levels and the strength of social and bonding behaviors both in healthy individuals and in those suffering from psychiatric disorders. Mounting evidence suggests associations between polymorphisms in the oxytocin receptor gene and prosocial behaviors and there may also be important epigenetic effects. Many studies have now reported a plethora of prosocial effects of intranasal application of oxytocin, including the domains of trust, generosity, socially reinforced learning, and emotional empathy. The main focus of this review will be to summarize human preclinical work and particularly the rapidly growing number of clinical studies which have identified important links between oxytocin and a wide range of psychiatric disorders, and have now started to directly assess its therapeutic potential.

Oxytocin Modulates Social Distance between Males and Females

In humans, interpersonal romantic attraction and the subsequent development of monogamous pair-bonds is substantially predicted by influential impressions formed during first encounters. The prosocial neuropeptide oxytocin (OXT) has been identified as a key facilitator of both interpersonal attraction and the formation of parental attachment. However, whether OXT contributes to the maintenance of monogamous bonds after they have been formed is unclear. In this randomized placebo-controlled trial, we provide the first behavioral evidence that the intranasal administration of OXT stimulates men in a monogamous relationship, but not single ones, to keep a much greater distance (∼10–15 cm) between themselves and an attractive woman during a first encounter. This avoidance of close personal proximity occurred in the physical presence of female but not male experimenters and was independent of gaze direction and whether the female experimenter or the subject was moving. We further confirmed this unexpected finding using a photograph-based approach/avoidance task that showed again that OXT only stimulated men in a monogamous relationship to approach pictures of attractive women more slowly. Importantly, these changes cannot be attributed to OXT altering the attitude of monogamous men toward attractive women or their judgments of and arousal by pictures of them. Together, our results suggest that where OXT release is stimulated during a monogamous relationship, it may additionally promote its maintenance by making men avoid signaling romantic interest to other women through close-approach behavior during social encounters. In this way, OXT may help to promote fidelity within monogamous human relationships.

Oxytocin enhances brain reward system responses in men viewing the face of their female partner

Significance Sexual monogamy is potentially costly for males, and few mammalian species along with humans exhibit it. The hypothalamic peptide oxytocin (OXT) has been implicated in mediating pair bonds in various species, but as yet, we know little about neurobiological factors that might act to promote fidelity, especially in men. Here we provide evidence for a mechanism by which OXT may contribute to romantic bonds in men by enhancing their partners attractiveness and reward value compared with other women. The biological mechanisms underlying long-term partner bonds in humans are unclear. The evolutionarily conserved neuropeptide oxytocin (OXT) is associated with the formation of partner bonds in some species via interactions with brain dopamine reward systems. However, whether it plays a similar role in humans has as yet not been established. Here, we report the results of a discovery and a replication study, each involving a double-blind, placebo-controlled, within-subject, pharmaco-functional MRI experiment with 20 heterosexual pair-bonded male volunteers. In both experiments, intranasal OXT treatment (24 IU) made subjects perceive their female partners face as more attractive compared with unfamiliar women but had no effect on the attractiveness of other familiar women. This enhanced positive partner bias was paralleled by an increased response to partner stimuli compared with unfamiliar women in brain reward regions including the ventral tegmental area and the nucleus accumbens (NAcc). In the left NAcc, OXT even augmented the neural response to the partner compared with a familiar woman, indicating that this finding is partner-bond specific rather than due to familiarity. Taken together, our results suggest that OXT could contribute to romantic bonds in men by enhancing their partners attractiveness and reward value compared with other women.

Oxytocin facilitates protective responses to aversive social stimuli in males

The neuropeptide oxytocin (OXT) can enhance the impact of positive social cues but may reduce that of negative ones by inhibiting amygdala activation, although it is unclear whether the latter causes blunted emotional and mnemonic responses. In two independent double-blind placebo-controlled experiments, each involving over 70 healthy male subjects, we investigated whether OXT affects modulation of startle reactivity by aversive social stimuli as well as subsequent memory for them. Intranasal OXT potentiated acoustic startle responses to negative stimuli, without affecting behavioral valence or arousal judgments, and biased subsequent memory toward negative rather than neutral items. A functional MRI analysis of this mnemonic effect revealed that, whereas OXT inhibited amygdala responses to negative stimuli, it facilitated left insula responses for subsequently remembered items and increased functional coupling between the left amygdala, left anterior insula, and left inferior frontal gyrus. Our results therefore show that OXT can potentiate the protective and mnemonic impact of aversive social information despite reducing amygdala activity, and suggest that the insula may play a role in emotional modulation of memory.

Depression uncouples brain hate circuit

It is increasingly recognized that we need a better understanding of how mental disorders such as depression alter the brains functional connections to improve both early diagnosis and therapy. A new holistic approach has been used to investigate functional connectivity changes in the brains of patients suffering from major depression using resting-state functional magnetic resonance imaging (fMRI) data. A canonical template of connectivity in 90 different brain regions was constructed from healthy control subjects and this identified a six-community structure with each network corresponding to a different functional system. This template was compared with functional networks derived from fMRI scans of both first-episode and longer-term, drug resistant, patients suffering from severe depression. The greatest change in both groups of depressed patients was uncoupling of the so-called ‘hate circuit’ involving the superior frontal gyrus, insula and putamen. Other major changes occurred in circuits related to risk and action responses, reward and emotion, attention and memory processing. A voxel-based morphometry analysis was also carried out but this revealed no evidence in the depressed patients for altered gray or white matter densities in the regions showing altered functional connectivity. This is the first evidence for the involvement of the ‘hate circuit’ in depression and suggests a potential reappraisal of the key neural circuitry involved. We have hypothesized that this may reflect reduced cognitive control over negative feelings toward both self and others.

An Oxytocin-Induced Facilitation of Neural and Emotional Responses to Social Touch Correlates Inversely with Autism Traits

Social communication through touch and mutual grooming can convey highly salient socio-emotional signals and has been shown to involve the neuropeptide oxytocin (OXT) in several species. Less is known about the modulatory influence of OXT on the neural and emotional responses to human interpersonal touch. The present randomized placebo (PLC)-controlled within-subject pharmaco-functional magnetic resonance imaging (fMRI) study was designed to test the hypothesis that a single intranasal dose of synthetic OXT (24 IU) would facilitate both neural and emotional responses to interpersonal touch in a context- (female vs male touch) and trait- (autistic trait load) specific manner. Specifically, the experimental rationale was to manipulate the reward value of interpersonal touch independent of the intensity and type of actual cutaneous stimulation administered. Thus, 40 heterosexual males believed that they were touched by either a man or a woman, although in fact an identical pattern of touch was always given by the same female experimenter blind to condition type. Our results show that OXT increased the perceived pleasantness of female, but not male touch, and associated neural responses in insula, precuneus, orbitofrontal, and pregenual anterior cingulate cortex. Moreover, the behavioral and neural effects of OXT were negatively correlated with autistic-like traits. Taken together, this is the first study to show that the perceived hedonic value of human heterosexual interpersonal touch is facilitated by OXT in men, but that its behavioral and neural effects in this context are blunted in individuals with autistic traits.

Oxytocin Facilitates the Extinction of Conditioned Fear in Humans

BACKGROUND Current neurocircuitry models of anxiety disorders posit a lack of inhibitory tone in the amygdala during acquisition of Pavlovian fear responses and deficient encoding of extinction responses in amygdala-medial prefrontal cortex circuits. Competition between these two responses often results in a return of fear, limiting control over anxiety. However, one hypothesis holds that a pharmacologic strategy aimed at reducing amygdala activity while simultaneously augmenting medial prefrontal cortex function could facilitate the extinction of conditioned fear. METHODS Key among the endogenous inhibitors of amygdala activity in response to social fear signals is the hypothalamic peptide oxytocin. To address the question whether oxytocin can strengthen Pavlovian extinction beyond its role in controlling social fear, we conducted a functional magnetic resonance imaging experiment with 62 healthy male participants in a randomized, double-blind, parallel-group, placebo-controlled design. Specifically, subjects were exposed to a Pavlovian fear conditioning paradigm before receiving an intranasal dose (24 IU) of synthetic oxytocin or placebo. RESULTS Oxytocin, when administered intranasally after Pavlovian fear conditioning, was found to increase electrodermal responses and prefrontal cortex signals to conditioned fear in the early phase of extinction and to enhance the decline of skin conductance responses in the late phase of extinction. Oxytocin also evoked an unspecific inhibition of amygdalar responses in both phases. CONCLUSIONS Collectively, our findings identify oxytocin as a differentially acting modulator of neural hubs involved in Pavlovian extinction. This specific profile of oxytocin action may open up new avenues for enhancing extinction-based therapies for anxiety disorders.

Fear processing and social networking in the absence of a functional amygdala

BACKGROUND The human amygdala plays a crucial role in processing social signals, such as face expressions, particularly fearful ones, and facilitates responses to them in face-sensitive cortical regions. This contributes to social competence and individual amygdala size correlates with that of social networks. While rare patients with focal bilateral amygdala lesion typically show impaired recognition of fearful faces, this deficit is variable, and an intriguing possibility is that other brain regions can compensate to support fear and social signal processing. METHODS To investigate the brains functional compensation of selective bilateral amygdala damage, we performed a series of behavioral, psychophysiological, and functional magnetic resonance imaging experiments in two adult female monozygotic twins (patient 1 and patient 2) with equivalent, extensive bilateral amygdala pathology as a sequela of lipoid proteinosis due to Urbach-Wiethe disease. RESULTS Patient 1, but not patient 2, showed preserved recognition of fearful faces, intact modulation of acoustic startle responses by fear-eliciting scenes, and a normal-sized social network. Functional magnetic resonance imaging revealed that patient 1 showed potentiated responses to fearful faces in her left premotor cortex face area and bilaterally in the inferior parietal lobule. CONCLUSIONS The premotor cortex face area and inferior parietal lobule are both implicated in the cortical mirror-neuron system, which mediates learning of observed actions and may thereby promote both imitation and empathy. Taken together, our findings suggest that despite the pre-eminent role of the amygdala in processing social information, the cortical mirror-neuron system may sometimes adaptively compensate for its pathology.

Musical Training Induces Functional Plasticity in Perceptual and Motor Networks: Insights from Resting-State fMRI

A number of previous studies have examined music-related plasticity in terms of multi-sensory and motor integration but little is known about the functional and effective connectivity patterns of spontaneous intrinsic activity in these systems during the resting state in musicians. Using functional connectivity and Granger causal analysis, functional and effective connectivity among the motor and multi-sensory (visual, auditory and somatosensory) cortices were evaluated using resting-state functional magnetic resonance imaging (fMRI) in musicians and non-musicians. The results revealed that functional connectivity was significantly increased in the motor and multi-sensory cortices of musicians. Moreover, the Granger causality results demonstrated a significant increase outflow-inflow degree in the auditory cortex with the strongest causal outflow pattern of effective connectivity being found in musicians. These resting state fMRI findings indicate enhanced functional integration among the lower-level perceptual and motor networks in musicians, and may reflect functional consolidation (plasticity) resulting from long-term musical training, involving both multi-sensory and motor functional integration.