Intranasal Oxytocin Administration Research Articles

Application of intranasal oxytocin and affectionate touch reduce subsequent cortisol concentrations in romantic couples: Results from an ecological momentary assessment study

Social interactions and particularly affectionate touch are vital for mental and physical health. Research shows that affectionate touch is associated with release of oxytocin and has calming and stress reducing effects suggesting a regulatory effect of oxytocin on the hypothalamic pituitary adrenal (HPA) axis. Here, we aimed to systematically investigate the effects of repeated intranasal oxytocin administration on salivary cortisol. Furthermore, we focused on the moderating role of couples’ affectionate touch on biopsychological stress outcomes in everyday life. 80 heterosexual romantic couples (N=160 individuals) completed ecologically momentary assessments over five days. Six times per day participants answered smartphone-based questions regarding affectionate touch and momentary stress levels providing concomitant saliva samples for cortisol assessment. Half of the sample was randomly assigned to an instructed positive appraisal task. In a randomized double-blind design, both partners self-administered oxytocin or placebo on five days twice during the early evening. Multilevel analyses showed that oxytocin administration was associated with higher cortisol in the following morning and stronger decreases during the day. Subjectively reported momentary stress was associated with increase of affectionate touch in couples. Moreover, results indicate that participants, who received affectionate touch from their partner showed significantly lower cortisol levels after oxytocin administration. These results suggest that oxytocin administration paired with affectionate touch in romantic couples can influence HPA axis regulation as indicated via diurnal cortisol levels. Thereby, the data shed light on the neuroendocrine underpinnings of the health-promoting effects of intimate social relationships.

Can repeated intranasal oxytocin administration affect reduced neural sensitivity towards expressive faces in autism? A randomized controlled trial.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication and interaction. Crucial for efficient social interaction is the ability to quickly and accurately extract information from a person's face. Frequency-tagging electroencephalography (EEG) is a novel tool to quantify face-processing sensitivity in a robust and implicit manner. In terms of intervention approaches, intranasal administration of oxytocin (OT) is increasingly considered as a potential pharmacological approach for improving socio-communicative difficulties in ASD, through enhancing social salience and/or reducing (social) stress and anxiety. In this randomized, double-blind, placebo-controlled, mechanistic pharmaco-neuroimaging clinical trial, we implemented frequency-tagging EEG to conduct an exploratory investigation into the impact of repeated OT administration (4 weeks, 12 IU, twice daily) on neural sensitivity towards happy and fearful facial expressions in children with ASD (8-12 years old; OT: n = 29; placebo: n = 32). Neural effects were assessed at baseline, post-nasal spray (24 hr after the last nasal spray) and at a follow-up session, 4 weeks after the OT administration period. At baseline, neural assessments of children with ASD were compared with those of an age- and gender-matched cohort of neurotypical (NT) children (n = 39). Children with ASD demonstrated reduced neural sensitivity towards expressive faces, as compared to NT children. Upon nasal spray administration, children with ASD displayed a significant increase in neural sensitivity at the post- and follow-up sessions, but only in the placebo group, likely reflecting an implicit learning effect. Strikingly, in the OT group, neural sensitivity remained unaffected from the baseline to the post-session, likely reflecting a dampening of an otherwise typically occurring implicit learning effect. First, we validated the robustness of the frequency-tagging EEG approach to assess reduced neural sensitivity towards expressive faces in children with ASD. Furthermore, in contrast to social salience effects observed after single-dose administrations, repeated OT administration dampened typically occurring learning effects in neural sensitivity. In line with OT's social anxiolytic account, these observations possibly reflect a predominant (social) stress regulatory effect towards emotionally evocative faces after repeated OT administration.

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.

Oxytocin administration enhances pleasantness and neural responses to gentle stroking but not moderate pressure social touch by increasing peripheral concentrations.

Social touch constitutes a key component of human social relationships, although in some conditions with social dysfunction, such as autism, it can be perceived as unpleasant. We have previously shown that intranasal administration of oxytocin facilitates the pleasantness of social touch and activation of brain reward and social processing regions, although it is unclear if it influences responses to gentle stroking touch mediated by cutaneous C-touch fibers or pressure touch mediated by other types of fibers. Additionally, it is unclear whether endogenous oxytocin acts via direct entry into the brain or by increased peripheral blood concentrations. In a randomized controlled design, we compared effects of intranasal (direct entry into the brain and increased peripheral concentrations) and oral (only peripheral increases) oxytocin on behavioral and neural responses to social touch targeting C-touch (gentle-stroking) or other (medium pressure without stroking) cutaneous receptors. Although both types of touch were perceived as pleasant, intranasal and oral oxytocin equivalently enhanced pleasantness ratings and responses of reward, orbitofrontal cortex, and social processing, superior temporal sulcus, regions only to gentle-stroking not medium pressure touch. Furthermore, increased blood oxytocin concentrations predicted the pleasantness of gentle stroking touch. The specificity of neural effects of oxytocin on C-touch targeted gentle stroking touch were confirmed by time-course extraction and classification analysis. Increased peripheral concentrations of oxytocin primarily modulate its behavioral and neural responses to gentle social touch mediated by C-touch fibers. Findings have potential implications for using oxytocin therapeutically in conditions where social touch is unpleasant. Key Technological Projects of Guangdong Province grant 2018B030335001. NCT05265806.

Data-driven evolutionary game models for the spread of fairness and cooperation in heterogeneous networks.

Unique large-scale cooperation and fairness norms are essential to human society, but the emergence of prosocial behaviors is elusive. The fact that heterogeneous social networks prevail raised a hypothesis that heterogeneous networks facilitate fairness and cooperation. However, the hypothesis has not been validated experimentally, and little is known about the evolutionary psychological basis of cooperation and fairness in human networks. Fortunately, research about oxytocin, a neuropeptide, may provide novel ideas for confirming the hypothesis. Recent oxytocin-modulated network game experiments observed that intranasal administration of oxytocin to a few central individuals significantly increases global fairness and cooperation. Here, based on the experimental phenomena and data, we show a joint effect of social preference and network heterogeneity on promoting prosocial behaviors by building evolutionary game models. In the network ultimatum game and the prisoner's dilemma game with punishment, inequality aversion can lead to the spread of costly punishment for selfish and unfair behaviors. This effect is initiated by oxytocin, then amplified via influential nodes, and finally promotes global cooperation and fairness. In contrast, in the network trust game, oxytocin increases trust and altruism, but these effects are confined locally. These results uncover general oxytocin-initiated mechanisms underpinning fairness and cooperation in human networks.

Sniffing oxytocin: Nose to brain or nose to blood?

In recent years ample studies have reported that intranasal administration of the neuropeptide oxytocin can facilitate social motivation and cognition in healthy and clinical populations. However, it is still unclear how effects are mediated since intranasally administered oxytocin can both directly enter the brain (nose to brain) and increase peripheral vascular concentrations (nose to blood). The relative functional contributions of these routes are not established and have received insufficient attention in the field. The current study used vasoconstrictor pretreatment to prevent intranasal oxytocin (24 IU) from increasing peripheral concentrations and measured effects on both resting-state neural (electroencephalography) and physiological responses (electrocardiogram, electrogastrogram and skin conductance). Results demonstrated that intranasal oxytocin alone produced robust and widespread increases of delta-beta cross-frequency coupling (CFC) from 30 min post-treatment but did not influence peripheral physiological measures. As predicted, vasoconstrictor pretreatment greatly reduced the normal increase in peripheral oxytocin concentrations and, importantly, abolished the majority of intranasal oxytocin effects on delta-beta CFC. Furthermore, time-dependent positive correlations were found between increases in plasma oxytocin concentrations and corresponding increases in delta-beta CFC following oxytocin treatment alone. Our findings suggest a critical role of peripheral vasculature-mediated routes on neural effects of exogenous oxytocin administration with important translational implications for its use as an intervention in psychiatric disorders.

Effects of multiple-dose intranasal oxytocin administration on social responsiveness in children with autism: a randomized, placebo-controlled trial

BackgroundIntranasal administration of oxytocin is increasingly explored as a new approach to facilitate social development and reduce disability associated with a diagnosis of autism spectrum disorder (ASD). The efficacy of multiple-dose oxytocin administration in children with ASD is, however, not well established.MethodsA double-blind, randomized, placebo-controlled trial with parallel design explored the effects of a 4-week intranasal oxytocin administration (12 IU, twice daily) on parent-rated social responsiveness (Social Responsiveness Scale: SRS-2) in pre-pubertal school-aged children (aged 8–12 years, 61 boys, 16 girls). Secondary outcomes included a questionnaire-based assessment of repetitive behaviors, anxiety, and attachment. Effects of oxytocin were assessed immediately after the administration period and at a follow-up, 4 weeks after the last administration. The double-blind phase was followed by a 4-week single-blind phase during which all participants received intranasal oxytocin.ResultsIn the double-blind phase, both the oxytocin and placebo group displayed significant pre-to-post-improvements in social responsiveness and secondary questionnaires, but improvements were not specific to the intranasal oxytocin. Notably, in the single-blind phase, participants who were first allocated to intranasal placebo and later changed to intranasal oxytocin displayed a significant improvement in social responsiveness, over and above the placebo-induced improvements noted in the first phase. Participants receiving oxytocin in the first phase also showed a significant further improvement upon receiving a second course of oxytocin, but only at the 4-week follow-up. Further, exploratory moderator analyses indicated that children who received psychosocial trainings (3 or more sessions per month) along with oxytocin administration displayed a more pronounced improvement in social responsiveness.LimitationsFuture studies using larger cohorts and more explicitly controlled concurrent psychosocial trainings are warranted to further explore the preliminary moderator effects, also including understudied populations within the autism spectrum, such as children with co-occurring intellectual disabilities.ConclusionsFour weeks of oxytocin administration did not induce treatment-specific improvements in social responsiveness in school-aged children with ASD. Future studies are warranted to further explore the clinical efficacy of oxytocin administration paired with targeted psychosocial trainings that stimulate socio-communicative behaviors.Trial registration The trial was registered with the European Clinical Trial Registry (EudraCT 2018-000769-35) on June 7th, 2018 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-000769-35/BE).

Effects of chronically exogenous oxytocin on ovary and uterus: A comparison of intraperitoneal and intranasal administration

Oxytocin (OT) has been studied as a therapeutic neuropeptide in various diseases, but its effect on the ovary and uterus is not fully known. This study investigates the effects of intranasal and intraperitoneal OT administration on ovaries and uterus in rats. Four experimental groups were created using 7-week-old Sprague Dawley-type female rats: Control (Ctrl), oxytocin-intraperitoneal (0.1 µg/day) (OT-IP), oxytocin-intranasal (0.05 µg/day) (OT-IN1), and oxytocin-intranasal (0.1 µg/day) (OT-IN2). The blood, the ovarian, and the uterus were collected at the end of the 28th day of OT administration. Afterward, histological and biochemical analyses were performed. We observed that the Graaf follicles were higher in both OT-IN2 and OT-IP groups compared to the Ctrl group. Moreover, the corpus luteum was increased only in the OT-IN2 group. Ki-67, CD31, VEGF, and TGF-ß immunostaining showed no significant change in the ovary. In contrast, Ki-67, VEGF, and OTR expressions demonstrated significant alterations in the uterus. Furthermore, TGF-ß immunohistochemistry and the histopathologic score did not reveal the statistical change in the uterus. Serum hormone levels showed that the anti-Müllerian hormone increased in all OT groups vs. the Ctrl. OT-IP showed an increment of follicle-stimulating hormone and estradiol decrement. There was a decrease in serum E2 levels, although the Graaf follicle number increased in OT-IP groups compared to the Ctrl group. However, luteinizing hormone, gonadotropin-releasing hormone, progesterone, testosterone, OT levels, and oxidative stress index did not reveal any statistical difference. Accordingly, the intranasal route may have beneficial effects compared to the intraperitoneal route regarding exogenous OT administration-related studies. In conclusion, we reported that exogenous OT increases the follicle reserve and may cause histological changes in the reproductive system of female rats.

THE POTENTIAL USE OF INTRANASAL OXYTOCIN AS EARLY PREVENTIVE INTERVENTION FOR POST-TRAUMATIC STRESS DISORDER

IntroductionPost-traumatic stress disorder (PTSD) is defined by an exaggerated fear responses (FA) which fails to extinguish over time and cannot be inhibited in safe contexts. Studies report that traumatic experiences (TE) affect hormonal systems mediated by the hypothalamic-pituitary-adrenal (HPA) axis and the oxytocinergic system. Oxytocin (OXT) is a neurohormone produced in the hypothalamus that has social functions like the promotion of prosocial and affiliative behaviors, increased self-confidence and positive social memories. In PTSD there is a diminished inhibitory top-down control over the FA, which is characterized by amygdala hyperactivity, ventromedial prefrontal cortex (vmPFC) hypoactivity and diminished structural and functional connectivity between both areas, which results in anxiety increase and dysregulated autonomic and endocrine FA. In parallel, TE decrease the synthesis and release of OXT, resulting in the dysfunction of the negative feedback mechanism on the HPA, leading to hypercortisolemia and maximizing the response to a stressful stimulus. Previous studies report that the administration of OXT can reduce cortisol levels as well as attenuating amygdala hyperactivity and normalizing the connectivity of this structure with frontal areas, diminishing the FA. Therefore, OXT has been investigated as a potential therapeutic agent administered intranasally early after trauma as a strategy to prevent PTDS on individuals having high risk.ObjectivesThe aim of this work is to review the potential of intranasal OXT administration as early preventive intervention for PTSD.MethodsSystematic review of the literature published in Pubmed, using the terms “Oxytocin”, “Post-traumatic Stress Disorder”, “Stress”.ResultsStudies found significant associations between TE and OXT and report that TE and PTSD are strongly associated with reductions in OXT. Literature report that the acute effects of OXT administrations in individuals with TE tend to be anxiolytic only in less severe forms, by modulating the HPA axis and the autonomic nervous system. Moreover, in recent TE, OXT seems to increase the re-experience of traumas and restore the function of different networks associated with fear control in PTSD patients. FMRI studies indicate that intranasal OXT attenuates amygdala hyperactivity and enhances amygdala´s connectivity with vmPFC, resulting in increased control over the FA. Finally, studies report that a single oxytocin administration increases neuronal fear processing but repeated administration reduces PTSD symptoms up to 6 months post trauma in patients with high acute symptoms.ConclusionsRepeated administration of intranasal oxytocin early after trauma seems to diminish the acute symptoms in early stages of PTDS, being a potential pharmacological strategy to prevent PTDS in individuals at high risk by increasing the control of FA.Disclosure of InterestNone Declared

Effects of exogenous oxytocin and estradiol on resting-state functional connectivity in women and men

Possible interactions of the neuropeptide oxytocin and the sex hormone estradiol may contribute to previously observed sex-specific effects of oxytocin on resting-state functional connectivity (rsFC) of the amygdala and hippocampus. Therefore, we used a placebo-controlled, randomized, parallel-group functional magnetic resonance imaging study design and measured amygdala and hippocampus rsFC in healthy men (n = 116) and free-cycling women (n = 111), who received estradiol gel (2 mg) or placebo before the intranasal administration of oxytocin (24 IU) or placebo. Our results reveal significant interaction effects of sex and treatments on rsFC of the amygdala and hippocampus in a seed-to-voxel analysis. In men, both oxytocin and estradiol significantly decreased rsFC between the left amygdala and the right and left lingual gyrus, the right calcarine fissure, and the right superior parietal gyrus compared to placebo, while the combined treatment produced a significant increase in rsFC. In women, the single treatments significantly increased the rsFC between the right hippocampus and the left anterior cingulate gyrus, whereas the combined treatment had the opposite effect. Collectively, our study indicates that exogenous oxytocin and estradiol have different region-specific effects on rsFC in women and men and that the combined treatment may produce antagonistic effects.

The Effect of Intranasal Oxytocin on Sexual Function in Men and Women: A Systematic Review

Background: Intranasal oxytocin can be used as a promising moiety for the treatment of sexual disorders. Objective: This study was carried out to systematically review the effect of intranasal oxytocin on sexual function in men and women Methods: We systematically searched databases (e.g., Cochrane Central Register of Controlled Trials Library, MEDLINE, Web of Science, Scopus, ProQuest, Google Scholar and Persian databases). All types of published clinical trials comparing different doses of intranasal oxytocin sprays with placebo sprays were included in the study. The primary outcome was sexual function and secondary outcomes were endocrine and cardiovascular measures and also side effects Results: A total of six studies were ultimately eligible for inclusion in the study. Though intranasal oxytocin improves various parameters of sexual function in men and women, according to the sexual response cycle, these changes are not statistically meaningful compared to the control group. Only one study revealed a meaningful impact on orgasm parameters and after orgasm, especially in men. In all studies, intranasal oxytocin administration has significantly and transiently increased plasma concentrations of oxytocin with no meaningful effect on other endocrine hormones. A study showed that the heartbeat is increased transiently during the arousal and orgasm stages, and such increase is meaningfully higher in men than in women. Conclusion: Intranasal oxytocin administration fails to meaningfully affect the classical parameters of sexual response, but it improves the orgasmic and post-orgasmic dimensions, especially in men. To evaluate the effects of intranasal oxytocin administrations, we need more long-term clinical trials.

May application of oxytocin be relevant in the therapy of perinatal mental disorders?

The perinatal period is a time, when mental diseases occur more frequently, than in other stages of life. Treatment of postpartum depression, psychosis, anxiety is a very hard task. Many psychotropic drugs display a toxic potential during the perinatal period. Hence, it seems that, searching for an alternative pharmacotherapy is relevant. Oxytocin is a substance, that may be successfully used in gynecological treatment. However, its potential is definitely greater. Studies from recent years indicated, that oxytocin is involved in complex pathomechanism of affective disorders. Latest outcomes indicate, that intranasal administration of oxytocin is effective in the treatment of anxiety- and depressive behaviors. The aim of the study is based on the question: Is oxytocin relevant for mental disorders in perinatal period therapy? This question was posed in order to gain psychiatric knowledge about perinatal period’s mental problems and indicates putative novel therapeutic solutions. The research team has performed a review of the studies, searching well-known online scientific databases, including PubMed, ScienceDirect, Scopus and MedLine. Our findings shed light on oxytocin’s significance in a potential new therapy of perinatal mental disorders. Further studies should be focused on intranasal oxytocin administration and its effectivity in the treatment of mentioned diseases, adverse effects, pharmacovigilance, pharmacokinetics and pharmacodynamics. Still, scarce data from clinical studies do not allow the implementation of oxytocin in treatment of perinatal affective disturbances, despite of rationale psychobiological and pharmacological prerequisites. Hence, it is necessary to investigate the relation: oxytocin intervention — perinatal affective disorders.

Effects of intranasal oxytocin on neural reward processing in children and adolescents with reactive attachment disorder: A randomized controlled trial

Reactive attachment disorder (RAD) is associated with socially and emotionally withdrawn/inhibited behaviors and reduced neural responses to rewards. Children and adolescents with RAD show aberrant attachment behaviors, and existing psychotherapies are difficult to maintain; therefore, pharmacological interventions to aid and boost treatment responses are needed. Oxytocin (OT) administration is known to promote reward functioning. We investigated whether single-use intranasal OT administration improved neural responses during reward processing in patients with RAD compared with healthy controls. Twenty-four male children and adolescents with RAD (10–18 years old) and 27 age- and sex-matched typically developing individuals (10–17 years old) were included in this randomized, double-blind, placebo-controlled, cross-over, functional magnetic resonance imaging study. Following a single intranasal OT (24 IU) or placebo administration, neural responses were investigated using a monetary reward task. In the RAD group, OT significantly increased subjective motivation scores, significantly enhanced activation in the right middle frontal gyrus, and reduced activation in the right precentral gyrus during the monetary reward task. Additional analyses revealed increased activation in the bilateral caudate at a more lenient threshold. Under placebo conditions, the severity of internalizing problems in patients with RAD was negatively correlated with ventral striatal activity. Moreover, the effect of OT on ventral striatum activity was positively associated with the severity of internalizing problems in patients with RAD. Intranasal OT administration enhanced activity in the reward pathway in male children and adolescents with RAD, suggesting that exogenous OT promotes reward processing and reward-related motivational behavior in these individuals. Further investigation is needed to fully understand the neural mechanisms of intranasal OT and identify novel targets for pediatric cases with RAD.Clinical trial registration: UMIN-CTR; UMIN000013215. URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000015419

Behavior and heart rate variability after intranasal administration of oxytocin in Holstein steers.

Oxytocin (OXT) is a neuropeptide that regulates memory, emotion, stress response, and behavior in the brain. In our previous study with cattle, we demonstrated the anti-stress effect of intracerebroventricularly administered OXT on the central nervous system. However, it is important to investigate the effects of this peptide after intranasal administration, as it offers convenience and non-invasiveness for practical use. Therefore, this study investigated the effects of intranasal OXT on the behavior and autonomic nervous system of Holstein steers. The experiment followed a within-subjects design, including a total of six steers. Each steer received intranasal administration of either 1 mL of saline (SAL), 100 µg OXT (OXT100), or 200 µg OXT (OXT200). However, due to some issues, the sample size for the OXT200 group was reduced to five. After these treatments, we conducted electrocardiography recordings to analyze heart rate variability (HRV) and also made behavioral observations for 90 min. OXT200 tended to increase the time spent ruminating while lying down (Steel's multiple comparison test; P=0.053). In contrast, OXT treatment did not affect HRV indices. In conclusion, the current OXT dosage did not significantly affects behavior or the autonomic nervous system. However, the observed tendency to increase rumination may suggest a central effect of OXT.

Dissecting social decision-making: A spotlight on oxytocinergic transmission.

Social decision-making requires the ability to balance both the interests of the self and the interests of others to survive in social environments. Empathy is essential to the regulation of this type of interaction, and it often sustains relevant prosocial behaviors such as altruism and helping behavior. In the last decade, our capacity to assess affective and empathy-like behaviors in rodents has expanded our understanding of the neurobiological substrates that underly social decision-making processes such as prosocial behaviors. Within this context, oxytocinergic transmission is profoundly implicated in modulating some of the major components of social decision-making. Thus, this review will present evidence of the association between oxytocin and empathy-like and prosocial behaviors in nonhuman animals. Then, we will dissect the involvement of oxytocinergic transmission-across different brain regions and pathways-in some of the key elements of social decision-making such as emotional discrimination, social recognition, emotional contagion, social dominance, and social memory. Evidence of the modulatory role of oxytocin on social decision-making has raised considerable interest in its clinical relevance, therefore we will also discuss the controversial findings on intranasal oxytocin administration.

Pilot Randomised, Double‐Blind, Placebo‐Controlled Crossover Trial Evaluating the Feasibility of an Intranasal Oxytocin in Improving Social Cognition in Individuals Living with Alzheimer’s Disease

AbstractBackgroundIndividuals living with Alzheimer’s disease (AD) demonstrate global deficits in social cognition. These deficits have been associated with impaired interpersonal relationships amongst caregivers, in turn contributing to a greater sense of caregiver ‘burden’. In other areas of neuropsychiatric disease (i.e., autism spectrum disorder), intranasal oxytocin (INOT) administration has shown replicable improvements in social cognitive function, particularly in Theory of Mind. Recently, randomised controlled trials (RCTs) in frontotemporal dementia have reported that repeated INOT administration may be regarded as safe and well tolerated at higher doses ‐ resulting in changes to apathy and improvements in empathic concern, as rated by a caregiver. To date, no studies have investigated the feasibility of an INOT treatment in individuals living with AD. Here, we conducted a pilot feasibility trial to determine the feasibility of recruitment, the acceptability of enrolment and the adherence to an INOT treatment in order to inform the subsequent design of a future RCT. Secondly, we sought to determine the effect size estimates on key potential social cognitive function outcome measures related to both the participant and their caregiver.MethodFour individuals living with AD were enrolled in a single‐centre, randomised, double‐blind, placebo‐controlled crossover trial involving a one‐week treatment period with both INOT (72 IU) and placebo.ResultAll participants reported no treatment‐causative or serious adverse events, following repeated INOT administration. While acceptability of enrolment was excellent (100%), as well as INOT treatment adherence (placebo, 95%; INOT, 98%), our feasibility of recruitment was not acceptable (i.e., only 7% of fifty‐eight individuals with dementia screened met inclusion criteria). However, positive/large effects were associated with expected secondary outcomes around self‐reported health and wellbeing, caregiver ‘burden’, intimacy and interpersonal bonding, following repeated INOT administration.ConclusionThese data provide the first evidence demonstrating the safety and tolerability of INOT administration in individuals living with AD. Despite limitations in sample size, moderate‐to‐large effect size improvements were identified in participant health outcomes as well as core social cognitive functions and burden as reported by a caregiver. This suggests potential broad‐ranging beneficial effects of INOT which should be assessed in future RCTs from multiple perspectives.

ODP576 A pilot randomized clinical trial of intranasal oxytocin to promote weight loss in children, adolescents, and adults with hypothalamic obesity

Abstract Many individuals with brain tumors affecting the hypothalamus and pituitary gain weight excessively after tumor treatment. There is currently no FDA-approved treatment for this condition, which is called hypothalamic obesity. In animals and in some preliminary studies in humans, the hypothalamic hormone oxytocin impacts metabolism, and may be deficient in individuals with hypothalamic obesity. Therefore, we performed a randomized, double-blind, placebo-controlled, cross-over trial to test the effects of 8 weeks of intranasal administration of oxytocin as compared to placebo on body weight in children, adolescents, and young adults (ages 10-<35y) with excess weight gain related to hypothalamic/pituitary brain tumors (N=13). We did not detect an effect of oxytocin on body weight or other metabolic measures. Overall oxytocin appeared well-tolerated, with most side effects being mild and not different from placebo. Our pilot study yielded several other lessons. First, affected individuals have many other medical problems. Also, individuals with hypothalamic obesity also differ from each other with respect to factors that impact body weight (e. g., appetite and eating behavior) and thus future larger studies could test different individualized dosing strategies, combination therapies, and a wider scope of outcomes to examine further the potential value of oxytocin treatment in this disorder. Keywords: Craniopharyngioma, Hypothalamic Dysfunction, Hypothalamus, Obesity, Weight Loss. Presentation: No date and time listed

Oro-mucosal administration of oxytocin using medicated lollipops alters social attention, similar to intranasal and lingual routes: Implications for therapeutic use.

A key functional effect of intranasal administration of the neuropeptide oxytocin is on top-down control of social attention. However, an oro-mucosal administration route may be better tolerated for chronic therapeutic use and evidence suggests that some functional effects of oxytocin can be mediated via peripheral routes. The current study investigated if oxytocin administered orally using medicated lollipops can both increase blood oxytocin concentrations and influence social attention and state anxiety. In a randomized, double-blind, clinical trial adult male participants received oral oxytocin (24IU) or placebo 30-min before completing a well-established anti-saccade paradigm which can assess treatment effects on both top-down and bottom-up attention. Oxytocin administration modulated top-down social attentional processing by increasing anti-saccade error rates on both social and non-social stimuli although it only increased response latencies for social cues. Anti-saccade errors were also positively associated with the proportionate increase in plasma oxytocin concentrations. A comparison analysis showed that oral oxytocin administration increased blood concentrations to a similar degree as given by lingual spray, although less than when given intranasally. Importantly, attentional and anxiolytic effects of oxytocin in the anti-saccade task were similar across intranasal, lingual, and oral administration routes. These findings demonstrate that oral administration of oxytocin, similar to via intranasal and lingual routes, can modulate top-down social attention and state anxiety and support its potential for therapeutic use. They also provide further evidence that functional effects of exogenously administered oxytocin can be mediated indirectly either by crossing the blood brain barrier or producing receptor mediated vagal stimulation, as opposed to via direct entry into the brain.

Effects of single- and multiple-dose oxytocin treatment on amygdala low-frequency BOLD fluctuations and BOLD spectral dynamics in autism

Prior neuroimaging clinical trials investigating the neural effects of intranasal administration of the neuropeptide oxytocin demonstrated a key role of the amygdala in oxytocin’s neuromodulatory effects. These studies mostly demonstrated the acute effects of single-dose administrations, examining task-dependent effects of oxytocin on brain activity elicited during explicit experimental tasks or stimuli presentations. The increased consideration of oxytocin as a potential ameliorating treatment in autism spectrum disorder (ASD) requires a better understanding of how multiple-dose oxytocin administration affects intrinsic, task-free, amygdala function. In this double-blind, randomized, placebo-controlled trial with between-subject design, 38 adult men with ASD underwent resting-state fMRI scanning before and after oxytocin or placebo treatment. Effects were assessed either after a single-dose administration, consisting of 24 international units, or after multiple-dose treatment, consisting of 4 weeks of once-daily nasal spray administrations. Compared to placebo, oxytocin induced a decrease in intrinsic resting-state BOLD signal amplitudes of the bilateral amygdala (fractional amplitudes of low-frequency fluctuations) and modulated cross-frequency interactions between adjacent BOLD frequency components. The right amygdala showed a pattern of reduced cross-frequency harmonicity, while the left amygdala showed a relative increase in harmonic cross-frequency interactions after oxytocin treatment. Notably, the direction and magnitude of BOLD spectral changes induced after a single-dose were qualitatively similar to treatment effects induced after multiple-dose treatment. Furthermore, the identified spectral changes in amygdalar BOLD amplitude and cross-frequency harmonicity were associated with improved feelings of tension, reflecting oxytocin’s anxiolytic, stress-reducing neuromodulatory role. The observed effects of oxytocin on amygdalar BOLD spectral characteristics and associated behaviors contribute to a deeper mechanistic understanding of the intrinsic, task-free neuromodulatory dynamics that underlie single- and multiple-dose oxytocin treatment in ASD. European Clinical Trial Registry (Eudract 2014-000586-45).

Frequency-Tagging EEG of Superimposed Social and Non-Social Visual Stimulation Streams Provides No Support for Social Salience Enhancement after Intranasal Oxytocin Administration.

The social salience hypothesis proposes that the neuropeptide oxytocin (OT) can impact human social behavior by modulating the salience of social cues. Here, frequency-tagging EEG was used to quantify the neural responses to social versus non-social stimuli while administering a single dose of OT (24 IU) versus placebo treatment. Specifically, two streams of faces and houses were superimposed on one another, with each stream of stimuli tagged with a particular presentation rate (i.e., 6 and 7.5 Hz or vice versa). These distinctive frequency tags allowed unambiguously disentangling and objectively quantifying the respective neural responses elicited by the different streams of stimuli. This study involved a double-blind, placebo-controlled, cross-over trial with 31 healthy adult men. Based on four trials of 60 s, we detected robust frequency-tagged neural responses in each individual, with entrainment to faces being more pronounced in lateral occipito-temporal regions and entrainment to houses being focused in medial occipital regions. However, contrary to our expectation, a single dose of OT did not modulate these stimulus-driven neural responses, not in terms of enhanced social processing nor in terms of generally enhanced information salience. Bayesian analyses formally confirmed these null findings. Possibly, the baseline ceiling level performance of these neurotypical adult participants as well as the personal irrelevance of the applied stimulation streams might have hindered the observation of any OT effect.