Oral Oxytocin Facilitates Responses to Emotional Faces in Reward and Emotional-Processing Networks in Females.

INTRODUCTION: Oxytocin (OXT) is proposed as a potential therapeutic peptide for social dysfunction due to its modulatory actions on socioemotional regulation in humans. While the majority of studies have used intranasal OXT administration, we have recently shown that oral (lingual spray), but not intranasal, administration can significantly enhance activity of the brain reward system in response to emotional faces in males; however, its effects on females are unknown. METHODS: Seventy healthy females participated in the current randomized, placebo-controlled, pharmaco-imaging clinical trial, and the results were compared with our previous data from 75 males who underwent the same protocol. Participants were randomly assigned to OXT (24 IU) or placebo (PLC) groups and completed an implicit emotional face paradigm (angry/fear/happy/neutral) where they were only required to identify face gender. RESULTS: In line with previous results in males, oral OXT significantly increased plasma OXT concentration changes and enhanced putamen responses to all emotional faces compared to PLC in females. Additionally, OXT increased left amygdala activity to happy and angry faces and enhanced putamen-superior temporal gyrus functional coupling during processing of happy faces in females which was significantly different from males. CONCLUSION: Our findings suggest that oral OXT enhances responses in both reward and emotional-processing networks in females as well as males, and additionally, in females, it strengthens coupling between reward and social cognition regions.

A randomized trial shows dose-frequency and genotype may determine the therapeutic efficacy of intranasal oxytocin.

BACKGROUND: The neuropeptide oxytocin is proposed as a promising therapy for social dysfunction by modulating amygdala-mediated social-emotional behavior. Although clinical trials report some benefits of chronic treatment, it is unclear whether efficacy may be influenced by dose frequency or genotype. METHODS: In a randomized, double-blind, placebo-controlled pharmaco-functional magnetic resonance imaging trial (150 male subjects), we investigated acute and different chronic (every day or on alternate days for 5 days) intranasal oxytocin (24 international units) effects and oxytocin receptor genotype-mediated treatment sensitivity on amygdala responses to face emotions. We also investigated similar effects on resting-state functional connectivity between the amygdala and prefrontal cortex. RESULTS: A single dose of oxytocin-reduced amygdala responses to all face emotions but for threatening (fear and anger) and happy faces, this effect was abolished after daily doses for 5 days but maintained by doses given every other day. The latter dose regime also enhanced associated anxious-arousal attenuation for fear faces. Oxytocin effects on reducing amygdala responses to face emotions only occurred in AA homozygotes of rs53576 and A carriers of rs2254298. The effects of oxytocin on resting-state functional connectivity were not influenced by either dose-frequency or receptor genotype. CONCLUSIONS: Infrequent chronic oxytocin administration may be therapeutically most efficient and its anxiolytic neural and behavioral actions are highly genotype-dependent in males.

Anxiolytic Effects of Chronic Intranasal Oxytocin on Neural Responses to Threat Are Dose-Frequency Dependent.

INTRODUCTION: Anxiety disorders are prevalent mental conditions characterized by exaggerated anxious arousal and threat reactivity. Animal and human studies suggest an anxiolytic potential of the neuropeptide oxytocin (OT), yet, while a clinical application will require chronic administration protocols, previous human studies have exclusively focused on single-dose (acute) intranasal OT effects. OBJECTIVE: To facilitate the translation of the potential anxiolytic mechanism of OT into clinical application, we determined whether the anxiolytic effects of OT are maintained with repeated (chronic) administration or are influenced by dose frequency and trait anxiety. METHODS: In a pre-registered double-blind randomized placebo-controlled pharmaco-fMRI trial the acute (single dose) as well as chronic effects of two different dose frequencies of OT (OT administered daily for 5 days or every other day) on emotional reactivity were assessed in n = 147 individuals with high versus low trait anxiety (ClinicalTrials.gov ID: NCT03085654). RESULTS: OT produced valence, dose frequency, and trait anxiety-specific effects, such that the low-frequency (intermittent) chronic dosage specifically attenuated a neural reactivity increase in amygdala-insula-prefrontal circuits observed in the high anxious placebo-treated subjects in response to threatening but not positive stimuli. CONCLUSIONS: The present trial provides the first evidence that low-dose frequency chronic intranasal OT has the potential to alleviate exaggerated neural threat reactivity in subjects with elevated anxiety levels, suggesting a treatment potential for anxiety disorders.

Infrequent Intranasal Oxytocin Followed by Positive Social Interaction Improves Symptoms in Autistic Children: A Pilot Randomized Clinical Trial.

INTRODUCTION: There are currently no approved drug interventions for social behavior dysfunction in autism spectrum disorder (ASD). Previous trials investigating effects of daily intranasal oxytocin treatment have reported inconsistent results and have not combined it with positive social interaction. However, in two preclinical studies we established that treatment every other day rather than daily is more efficacious in maintaining neural and behavioral effects by reducing receptor desensitization. OBJECTIVE: We aimed to establish whether a 6-week intranasal oxytocin compared with placebo treatment, followed by a period of positive social interaction, would produce reliable symptom improvements in children with ASD. METHODS: A pilot double-blind, randomized, crossover design trial was completed including 41 children with ASD aged 3-8 years. Primary outcomes were the Autism Diagnostic Observation Schedule-2 (ADOS-2) and social responsivity scale-2 (SRS-2). Secondary measures included cognitive, autism- and caregiver-related questionnaires, and social attention assessed using eye-tracking. RESULTS: Significant improvements were found for oxytocin relative to placebo in primary outcome measures (total ADOS-2 and SRS-2 scores, ps < 0.001) and in behavioral adaptability and repetitive behavior secondary measures. Altered SRS-2 scores were associated with increased saliva oxytocin concentrations. Additionally, oxytocin significantly increased time spent viewing dynamic social compared to geometric stimuli and the eyes of angry, happy, and neutral expression faces. There were no adverse side effects of oxytocin treatment. CONCLUSIONS: Overall, results demonstrate that a 6-week intranasal oxytocin treatment administered every other day and followed by positive social interactions can improve clinical, eye tracking, and questionnaire-based assessments of symptoms in young autistic children.

Oxytocin Facilitates Self-Serving Rather Than Altruistic Tendencies in Competitive Social Interactions Via Orbitofrontal Cortex.

BACKGROUND: While the neuropeptide oxytocin can facilitate empathy and altruistic behavior, it may also promote self-serving tendencies in some contexts, and it remains unclear if it would increase altruistic or self-interest behaviors when they compete within a social situation. METHODS: The current between-subject, double-blind, placebo-controlled fMRI study investigated the effect of intranasal oxytocin on empathy for social exclusion using a modified online ball-tossing game that incorporated monetary rewards and the potential to display both altruistic and self-interest behaviors. RESULTS: Results showed that when subjects in both oxytocin and placebo groups were observing a player being excluded (victim) by other players in the game, there was activation in the mentalizing network. When subjects then played both with the victim and the players who had excluded them, they threw more balls to the victim player, indicative of an altruistic response. However, subjects in the oxytocin group threw more balls to the excluder players indicative of greater self-interest, since the latter would be perceived as more likely to reciprocate to maximize financial gain. This behavioral effect of oxytocin was associated with greater medial orbitofrontal cortex activation when playing with the excluders and negatively correlated with trait-altruism scores. CONCLUSIONS: Overall, our findings suggest that in the context of competing motivations for exhibiting altruistic or self-interest behavior, oxytocin enhanced self-interest and this was associated with greater activation in frontal reward areas.

A dimensional approach to determine common and specific neurofunctional markers for depression and social anxiety during emotional face processing.

Major depression disorder (MDD) and anxiety disorder are both prevalent and debilitating. High rates of comorbidity between MDD and social anxiety disorder (SAD) suggest common pathological pathways, including aberrant neural processing of interpersonal signals. In patient populations, the determination of common and distinct neurofunctional markers of MDD and SAD is often hampered by confounding factors, such as generally elevated anxiety levels and disorder-specific brain structural alterations. This study employed a dimensional disorder approach to map neurofunctional markers associated with levels of depression and social anxiety symptoms in a cohort of 91 healthy subjects using an emotional face processing paradigm. Examining linear associations between levels of depression and social anxiety, while controlling for trait anxiety revealed that both were associated with exaggerated dorsal striatal reactivity to fearful and sad expression faces respectively. Exploratory analysis revealed that depression scores were positively correlated with dorsal striatal functional connectivity during processing of fearful faces, whereas those of social anxiety showed a negative association during processing of sad faces. No linear relationships between levels of depression and social anxiety were observed during a facial-identity matching task or with brain structure. Together, the present findings indicate that dorsal striatal neurofunctional alterations might underlie aberrant interpersonal processing associated with both increased levels of depression and social anxiety.

Oromucosal Administration of Oxytocin: The Development of 'Oxipops'.

The role of the hypothalamic neuropeptide oxytocin in influencing the brain and behavior has been the subject of widespread research over the last few decades due, most notably, to its reported involvement in promoting social cognition and motivation, reducing anxiety, and relieving pain. It is also increasingly being considered as an important therapeutic intervention in a variety of disorders with social dysfunction as a symptom. While, in recent years, studies in humans have administered oxytocin primarily via an intranasal route, since it may partly enter the brain directly this way via the olfactory and trigeminal nerves, there is increasing evidence that many of its functional effects can be peripherally mediated via increasing its concentration in the blood. This has opened up an oromucosal administration route as an alternative, which is beneficial since the oral consumption of peptides is problematic due to their rapid breakdown in the acidic environment of the gastrointestinal system. In this review we will discuss both the methodologies we have developed for administering oxytocin via lingual application and medicated lollipops, 'oxipops', in terms of increasing blood concentrations and the bioavailability of the peptide, and also their validation in terms of functional effects on the brain and behavior. While areas under the curve are significantly greater in terms of plasma oxytocin concentrations following intranasally relative to oromucosally administered oxytocin, with the estimated absolute bioavailability of the latter being around 4.4% compared with 11.1% for intranasal administration, the time to peak concentrations (around 30 min) and functional effects on the brain and behavior are broadly similar. We will also discuss potential therapeutic advantages of the oromucosal administration of oxytocin in different clinical contexts and its wider application for other peptides which are increasingly being developed for therapeutic use.

Oral Oxytocin Blurs Sex Differences in Amygdala Responses to Emotional Scenes.

BACKGROUND: Sex differences are shaped both by innate biological differences and the social environment and are frequently observed in human emotional neural responses. Oral administration of oxytocin (OXT), as an alternative and noninvasive intake method, has been shown to produce sex-dependent effects on emotional face processing. However, it is unclear whether oral OXT produces similar sex-dependent effects on processing continuous emotional scenes. METHODS: The current randomized, double-blind, placebo-controlled neuropsychopharmacological functional magnetic resonance imaging experiment was conducted in 147 healthy participants (OXT = 74, men/women = 37/37; placebo = 73, men/women = 36/37) to examine the oral OXT effect on plasma OXT concentrations and neural response to emotional scenes in both sexes. RESULTS: At the neuroendocrine level, women showed lower endogenous OXT concentrations than men, but oral OXT increased OXT concentrations equally in both sexes. Regarding neural activity, emotional scenes evoked opposite valence-independent effects on right amygdala activation (women > men) and its functional connectivity with the insula (men > women) in men and women in the placebo group. This sex difference was either attenuated (amygdala response) or even completely eliminated (amygdala-insula functional connectivity) in the OXT group. Multivariate pattern analysis confirmed these findings by developing an accurate sex-predictive neural pattern that included the amygdala and the insula under the placebo but not the OXT condition. CONCLUSIONS: The results of the current study suggest a pronounced sex difference in neural responses to emotional scenes that was eliminated by oral OXT, with OXT having opposite modulatory effects in men and women. This may reflect oral OXT enhancing emotional regulation to continuous emotional stimuli in both sexes by facilitating appropriate changes in sex-specific amygdala-insula circuitry.

Brain development of a school-aged boy with autism spectrum condition talented in arithmetic: a case report.

Whereas autism spectrum condition is known for its social and communicative challenges, some autistic children demonstrate unusual islets of abilities including those related to mathematics, the neurobiological underpinnings of which are increasingly becoming the focus of research. Here we describe an 8-year-old autistic boy with intellectual and language challenges, yet exceptional arithmetic ability. He can perform verbal-based multiplication of three- and even four-digit numbers within 20 seconds. To gain insights into the neural basis of his talent, we investigated the gray matter in the child's brain in comparison to typical development, applying voxel-based morphometry to magnetic resonance imaging data. The case exhibited reduced gray matter volume in regions associated with arithmetic, which may suggest an accelerated development of brain regions with arithmetic compared to typically developing individuals: potentially a key factor contributing to his exceptional talent. Taken together, this case report describes an example of the neurodiversity of autism. Our research provides valuable insights into the potential neural basis of exceptional arithmetic abilities in individuals with the autism spectrum and its potential contribution to depicting the diversity and complexity of autism.

A clustering approach identifies an Autism Spectrum Disorder subtype more responsive to chronic oxytocin treatment.

Over the last decade, a number of clinical trials have reported effects of chronic treatment with intranasal oxytocin on autistic symptoms but with inconsistent findings. Autism is a heterogeneous disorder and one factor which may influence treatment outcome is whether a subtype of individuals is more sensitive to oxytocin. In a recent cross-over trial on 41 young autistic children we reported that 44% showed a reliable improvement in clinical symptoms (Autism Diagnostic Observation Schedule, ADOS-2) after a placebo-controlled, 6-week intranasal oxytocin intervention where treatment was given every other day followed by a period of positive social interaction. In the current re-assessment of the data, we used an unsupervised data-driven cluster analysis approach to identify autism subtypes using 23 different demographic, social subtype, endocrine, eye-tracking and clinical symptom measures taken before treatment and this revealed an optimum of two different subtypes. We then assessed the proportion of identified responders to oxytocin and found that while 61.5% of one subtype included responders only 13.3% of the other did so. During the placebo phase there was no difference between the two subtypes for the small proportion of responders (19.2% vs 6.7%). This oxytocin-sensitive subtype also showed overall significant post-treatment clinical and eye-tracking measure changes. The oxytocin-sensitive subtype was primarily characterized at baseline by lower initial clinical severity (ADOS-2) and greater interest in the eye-region of emotional faces. These features alone were nearly as efficient in identifying the two subtypes as all 23 baseline measures and this easy-to-conduct approach may help rapidly and objectively screen for oxytocin responders. Future clinical trials using oxytocin interventions may therefore achieve greater success by focusing on children with this specific autism subtype and help develop individualized oxytocin intervention.

Expending effort may share neural responses with reward and evokes high subjective satisfaction.

Throughout our daily lives, the levels of effort we invest in various tasks are influenced by reward processing. The subjective expectation after expending effort is a primary factor affecting reward processing. However, recent studies indicate that individual differences in reward anticipation influence this subjective valuation. To better understand the relationship between effort expenditure and the subjective valuation of rewards, in this study, we perform an experiment in which we manipulate effort, control reward expectation implicitly, and measure the subjective valuation of rewards using event-related potentials (ERPs) and physical effort through behavioral measures (number of keystrokes). In the reward-task paradigm, 30 subjects performed effort and control trials, with the reward probability comparable across the effort and control conditions. We also examined the ERPs associated with the valuation of subjective rewards, including reward positivity (RewP) and set reward expectation controlled as the baseline. The results showed that the ERP amplitudes, the number of keystrokes, and explicit satisfaction ratings were all significantly greater in the effort condition than in the control condition. The participants maintained high levels of effort throughout the sessions associated with the experiment. The results of this study suggest that when reward expectations are controlled, effort expenditure evokes neural responses similar to reward feedback being given, which is linked with increased subjective satisfaction.

Trust toward humans and trust toward artificial intelligence are not associated: Initial insights from self-report and neurostructural brain imaging.

The present study examines whether self-reported trust in humans and self-reported trust in [(different) products with built-in] artificial intelligence (AI) are associated with one another and with brain structure. We sampled 90 healthy participants who provided self-reported trust in humans and AI and underwent brain structural magnetic resonance imaging assessment. We found that trust in humans, as measured by the trust facet of the personality inventory NEO-PI-R, and trust in AI products, as measured by items assessing attitudes toward AI and by a composite score based on items assessing trust toward products with in-built AI, were not significantly correlated. We also used a concomitant dimensional neuroimaging approach employing a data-driven source-based morphometry (SBM) analysis of gray-matter-density to investigate neurostructural associations with each trust domain. We found that trust in humans was negatively (and significantly) correlated with an SBM component encompassing striato-thalamic and prefrontal regions. We did not observe significant brain structural association with trust in AI. The present findings provide evidence that trust in humans and trust in AI seem to be dissociable constructs. While the personal disposition to trust in humans might be "hardwired" to the brain's neurostructural architecture (at least from an individual differences perspective), a corresponding significant link for the disposition to trust AI was not observed. These findings represent an initial step toward elucidating how different forms of trust might be processed on the behavioral and brain level.

A brain structural connectivity biomarker for autism spectrum disorder diagnosis in early childhood.

Background: Autism spectrum disorder (ASD) is associated with altered brain development, but it is unclear which specific structural changes may serve as potential diagnostic markers, particularly in young children at the age when symptoms become fully established. Furthermore, such brain markers need to meet the requirements of precision medicine and be accurate in aiding diagnosis at an individual rather than only a group level. Objective: This study aimed to identify and model brain-wide differences in structural connectivity using diffusion tensor imaging (DTI) in young ASD and typically developing (TD) children. Methods: A discovery cohort including 93 ASD and 26 TD children and two independent validation cohorts including 12 ASD and 9 TD children from three different cities in China were included. Brain-wide (294 regions) structural connectivity was measured using DTI (fractional anisotropy, FA) together with symptom severity and cognitive development. A connection matrix was constructed for each child for comparisons between ASD and TD groups. Pattern classification was performed on the discovery dataset and the resulting model was tested on the two independent validation datasets. Results: Thirty-three structural connections showed increased FA in ASD compared to TD children and associated with both autistic symptom severity and impaired general cognitive development. The majority (29/33) involved the frontal lobe and comprised five different networks with functional relevance to default mode, motor control, social recognition, language and reward. Overall, classification achieved very high accuracy of 96.77% in the discovery dataset, and 91.67% and 88.89% in the two independent validation datasets. Conclusions: Identified structural connectivity differences primarily involving the frontal cortex can very accurately distinguish novel individual ASD from TD children and may therefore represent a robust early brain biomarker which can address the requirements of precision medicine.

Oxytocin Reduces the Attractiveness of Silver-Tongued Men for Women During Mid-Cycle.

In humans, the neuropeptide oxytocin promotes both attraction toward and bonds with romantic partners, although no studies have investigated whether this extends to the perceived attractiveness of flirtatious language. In a within-subject, randomized double-blind placebo-controlled behavior and functional magnetic resonance imaging (fMRI) paradigm (https://clinicaltrials.gov/show/NCT03144115), 75 women rated the attractiveness of either a male face alone or paired with a verbal compliment which varied in terms of topic (women or landscapes) and figurativeness (novel or conventional metaphors or literal expressions). Subjects were tested in fertile and luteal phases of their cycle and on both occasions received either 24 IU intranasal oxytocin or placebo. Results showed that, whereas under placebo women in the fertile phase rated the facial attractiveness of men producing novel metaphorical compliments higher than in their luteal phase, following oxytocin treatment they did not. Correspondingly, under oxytocin the faces of individuals producing novel metaphorical compliments evoked greater responses in brain regions involved in processing language (middle frontal gyrus) and cognitive and emotional conflict (posterior middle cingulate and dorsal anterior cingulate) but reduced functional connectivity between the dorsal anterior cingulate and right orbitofrontal and medial frontal gyri. Thus, sex hormones and oxytocin may have opposite effects in regulating mate selection in women during their fertile phase. Novel metaphorical compliments convey a greater sexual than bonding intention and thus while sex hormones at mid-cycle may promote attraction to individuals communicating sexual rather than bonding intent, oxytocin may bias attraction away from such individuals through increasing cognitive and emotional conflict responses toward them.

The temporal dedifferentiation of global brain signal fluctuations during human brain ageing.

The variation of brain functions as healthy ageing has been discussed widely using resting-state brain imaging. Previous conclusions may be misinterpreted without considering the effects of global signal (GS) on local brain activities. Up to now, the variation of GS with ageing has not been estimated. To fill this gap, we defined the GS as the mean signal of all voxels in the gray matter and systematically investigated correlations between age and indices of GS fluctuations. What's more, these tests were replicated with data after hemodynamic response function (HRF) de-convolution and data without noise regression as well as head motion data to verify effects of non-neural information on age. The results indicated that GS fluctuations varied as ageing in three ways. First, GS fluctuations were reduced with age. Second, the GS power transferred from lower frequencies to higher frequencies with age. Third, the GS power was more evenly distributed across frequencies in ageing brain. These trends were partly influenced by HRF and physiological noise, indicating that the age effects of GS fluctuations are associated with a variety of physiological activities. These results may indicate the temporal dedifferentiation hypothesis of brain ageing from the global perspective.

Intranasal oxytocin may help maintain romantic bonds by decreasing jealousy evoked by either imagined or real partner infidelity.

BACKGROUND: While romantic jealousy may help to maintain relationships, following partner infidelity and an irretrievable loss of trust it can also promote break-ups. The neuropeptide oxytocin can enhance the maintenance of social bonds and reduce couple conflict, although its influence on jealousy evoked by imagined or real infidelity is unclear. AIMS: This study aimed to investigate the effects of intranasal oxytocin (24 IU) on romantic jealousy in both males and females in imagined and real contexts. METHODS: Seventy heterosexual couples participated in this double-blind, placebo-controlled, between-subject design study. Jealousy was firstly quantified in the context of subjects imagining partner infidelity and secondly in a Cyberball game where their partner interacted preferentially with an opposite-sexed rival stranger to simulate partner exclusion, or rejected a neutral stranger but not the partner. RESULTS: Oxytocin primarily decreased jealousy and arousal ratings towards imagined emotional and sexual infidelity by a partner in both sexes. During the Cyberball game, while male and female subjects in both groups subsequently threw the ball least often to the rival stranger, under oxytocin they showed reduced romantic jealousy and arousal ratings for stranger players, particularly the rival one, and reported reduced negative and increased positive feelings while playing the game. CONCLUSIONS: Together, our results suggest that oxytocin can reduce the negative emotional impact of jealousy in established romantic partners evoked by imagined or real infidelity or exclusive social interactions with others. This provides further support for oxytocin promoting maintenance of relationships.

Oxytocin facilitates socially directed attention.

Socially directed gaze following is an important component of social interaction and communication, allowing us to attend mutually with others to objects or people so that we can share their experience and also learn from them. This type of joint social attention is impaired in disorders such as autism. Previous research has demonstrated that the neuropeptide oxytocin can facilitate attention toward social cues, although to date no study in humans has investigated its influence on socially directed gaze or on associations of the latter with autistic and empathic traits. In a within-subject, randomized, placebo-controlled trial we used eye-tracking to investigate the effects of intranasal oxytocin (24 IU) on socially directed gaze toward one of two objects in 40 adult male subjects. Subjects viewed videos of an actor and actress directing their gaze toward one of two objects by either moving only their eyes, moving both their eyes and head, or moving their eyes and head and pointing with a finger. Results showed that OXT increased the proportion of time subjects viewed the object the actor or actress were looking/pointing at across all three conditions, although unexpectedly we found no associations with trait autism or empathy under either placebo or OXT treatments. These findings demonstrate that OXT can facilitate socially directed gaze following to promote mutual attention toward objects which may be potentially beneficial therapeutically in disorders with impaired social communication and interaction.

In the nose or on the tongue? Contrasting motivational effects of oral and intranasal oxytocin on arousal and reward during social processing.

Intranasal oxytocin exerts wide-ranging effects on socioemotional behavior and is proposed as a potential therapeutic intervention in psychiatric disorders. However, following intranasal administration, oxytocin could penetrate directly into the brain or influence its activity via increased peripheral concentrations crossing the blood-brain barrier or influencing vagal projections. In the current randomized, placebo-controlled, pharmaco-imaging clinical trial we investigated effects of 24IU oral (lingual) oxytocin spray, restricting it to peripherally mediated blood-borne and vagal effects, on responses to face emotions in 80 male subjects and compared them with 138 subjects treated intranasally with 24IU. Oral, but not intranasal oxytocin administration increased both arousal ratings for faces and associated brain reward responses, the latter being partially mediated by blood concentration changes. Furthermore, while oral oxytocin increased amygdala and arousal responses to face emotions, after intranasal administration they were decreased. Thus, oxytocin can produce markedly contrasting motivational effects in relation to socioemotional cues when it influences brain function via different routes. These findings have important implications for future therapeutic use since administering oxytocin orally may be both easier and have potentially stronger beneficial effects by enhancing responses to emotional cues and increasing their associated reward.

Oxytocin biases eye-gaze to dynamic and static social images and the eyes of fearful faces: associations with trait autism.

A key functional effect of intranasal oxytocin with potential therapeutic relevance for autism-spectrum disorder is its reported facilitation of attention towards social stimuli, notably the eye region of faces. In the current randomized placebo-controlled within-subject experiment on 40 healthy males, we investigated the robustness of this facilitation of attention by intranasal oxytocin (24IU) towards social cues. Eye-tracking measures of preference for dynamic and static social vs. non-social stimuli were taken in four different paradigms where autistic individuals tend to exhibit reduced interest in social stimuli. Additionally, we investigated whether oxytocin increases attention towards the eyes relative to other salient face regions in an emotional face paradigm. Results showed that the time spent viewing both dynamic and static social vs. non-social stimuli was negatively associated with trait autism and significantly increased following intranasal oxytocin. For face stimuli, oxytocin primarily increased gaze towards the eyes of fearful expression faces but not for other face emotions. Overall, our findings demonstrate that oxytocin significantly shifts gaze preference towards social vs. non-social stimuli and to the eyes of fearful faces. Importantly, oxytocin appears generally to shift attention more towards salient social stimuli of particular relevance in the context of autism providing further support for its potential therapeutic use in autism-spectrum disorder.