oxytocin and Autism-Spectrum-Disorder

The efficacy of oxytocin in the treatment of autism spectrum disorder (ASD) has not been fully characterized. This systematic review and meta-analysis study evaluated randomized controlled trials (RCTs) on the treatment of intranasally administered oxytocin for autism.. The study was conducted in accordance with the PRISMA statement. Two authors searched Scopus, PubMed/ Medline, Google Scholar, and Web of Science search engines and databases from inception through December 2020. Quality assessment was carried out by with the "ROB-2, Cochrane collaboration's tool". The random-effects model was used for pooled analyses. I2 and Q tests were used to investigate study heterogeneity. The visual inspection of funnel plots along with Egger's regression asymmetry test was used to assess the potential sources of publication bias.. Ten RCTs were selected for the systematic review. No study corroborated the efficacy of oxytocin for the treatment of anxiety and repetitive behavior. One out of 4 studies reported clinical improvement in severity, and 1 out of 6 studies indicated improvement in social function. Our metaanalyses findings suggest that oxytocin shows no significant efficacy in the treatment of anxiety (SMD: -0.168, SE= 0.112; 95% CI: -0.387, 0.050, p = 0.132), repetitive behavior (SMD: -0.078, SE= 0.155; 95% CI: -0.382, 0.225, p = 0.614), social function (SMD: -0.018, SE= 0.133; 95% CI: -0.279, 0.242, p = 0.891) and severity (SMD: -0.084, SE= 132; 95% CI: -0.343, 0.175, p = 0.524) of autism. No significant heterogeneity nor publication bias were observed between studies.. Our findings failed to corroborate the efficacy of oxytocin in the treatment of ASD. Nonetheless, given the several limitations of our study, the results should be interpreted cautiously and stimulate future research on this timely topic.

Topics: Adult; Anxiety Disorders; Autism Spectrum Disorder; Autistic Disorder; Humans; Oxytocin; Randomized Controlled Trials as Topic

The purpose of this article is to examine the efficacy of oxytocin in treating core symptoms of autism spectrum disorder (ASD) with children.. A systematic literature search was conducted to identify randomized controlled trials (RCTs) of oxytocin for the treatment of core symptoms in children with ASD. The search included studies published between January 1, 1999 and March 15, 2023, that were randomized, single or double-blinded, and included a placebo control group. Standard screening rules were applied to select relevant studies, resulting in the inclusion of five RCTs involving 486 children with ASD.. Ultimately, a total of five RCTs, involving 486 children with ASD, were included in the review using standard screening rules.One of the included studies demonstrated a statistically significant improvement in Social Responsiveness Scale (SRS) and Repetitive Behavior Scale-Revised (RBS) scores when children with ASD were treated with oxytocin (24 IU/2 days for 6 weeks). The improvement in core symptoms persisted at the 6-month follow-up. The meta-analysis findings suggested that oxytocin might have a moderate effect in improving the core symptom of narrow interests and repetitive stereotyped behaviors in children with ASD.. While the therapeutic value of oxytocin in treating core symptoms of ASD in children is not fully established, the results of this meta-analysis indicate a potential moderate effect. However, further studies with larger sample sizes and more robust RCTs are needed to directly demonstrate the efficacy of oxytocin. Future research should also focus on effect size and outcome evaluation accuracy while minimizing bias in RCT experiments.

Topics: Autism Spectrum Disorder; Child; Control Groups; Humans; Outcome Assessment, Health Care; Oxytocin

There are currently no approved medications for the core symptoms of autism spectrum disorder (ASD), and only limited data on the management of co-occurring mental health and behavioural symptoms. The purpose of this review is to synthesize recent trials on novel treatments in ASD, with a focus on research trends in the past 2 years.. No new pharmacologic agents received regulatory approval for use in ASD. Several large randomized controlled trials (RCTs) had negative or ambiguous results (e.g. fluoxetine, oxytocin). A cross-over RCT of an oral cannabinoid suggested possible benefits for disruptive behaviours. Two large-scale multicentre trials of bumetanide were terminated early for lack of efficacy. Multicenter trials using repetitive transcranial magnetic stimulation are underway. Recent meta-analyses indicate that specific behavioural and psychological interventions can support social communication and treat anxiety. Numerous novel treatment targets informed by biological mechanisms are under investigation.. Recent data support the use of behavioural and psychological interventions for social communication and anxiety in ASD; data are more limited regarding pharmacotherapy for core and associated symptoms. Next steps include replication of early findings, trials of new molecular targets, and the identification of novel biomarkers, including genetic predictors, of treatment response.

Topics: Autism Spectrum Disorder; Cannabinoids; Communication; Fluoxetine; Humans; Multicenter Studies as Topic; Oxytocin; Randomized Controlled Trials as Topic; Transcranial Magnetic Stimulation

This study systematically reviewed available evidence regarding associations between polymorphisms of the oxytocin receptor (OXTR) gene and socio-emotional and behavioral functioning in children and adolescents. The search yielded 69 articles, which were grouped into nine categories: depression, anxiety, and internalizing symptoms, alcohol abuse, borderline personality disorder, conduct disorder symptoms or diagnosis, autism spectrum disorder, attention deficit hyperactivity disorder, early childhood attachment and behavior, pro-social skills, and resilience. Direct and/or gene x environment interactions were identified in over half of the studies. ASD and conduct disorder (including callous unemotional traits) were the diagnoses that were most studied and for which there was the strongest evidence of direct links with OXTR polymorphisms. In most studies identifying gene x environment interactions, the candidate OXTR polymorphism was rs53576. Results suggest that OXTR polymorphisms are associated with social, emotional or behavioural functioning in children and adolescents. The mixed findings do, however, highlight the need for further research.

Topics: Adolescent; Autism Spectrum Disorder; Child; Child, Preschool; Conduct Disorder; Emotions; Humans; Oxytocin; Polymorphism, Single Nucleotide; Receptors, Oxytocin; Social Behavior

There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD.. We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses.. We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles.. Most of the studies were inadequately powered (sample sizes of 20-80 participants), with short duration (8-13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms.. Some medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317.

Topics: Adolescent; Adult; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Child; Humans; Network Meta-Analysis; Oxytocin; Risperidone

Oxytocin and vasopressin are peptide hormones secreted from the pituitary that are well known for their peripheral endocrine effects on childbirth/nursing and blood pressure/urine concentration, respectively. However, both peptides are also released in the brain, where they modulate several aspects of social behaviors. Oxytocin promotes maternal nurturing and bonding, enhances social reward, and increases the salience of social stimuli. Vasopressin modulates social communication, social investigation, territorial behavior, and aggression, predominantly in males. Both peptides facilitate social memory and pair bonding behaviors in monogamous species. Here we review the latest research delineating the neural circuitry of the brain oxytocin and vasopressin systems and summarize recent investigations into the circuit-based mechanisms modulating social behaviors. We highlight research using modern molecular genetic technologies to map, monitor activity of, or manipulate neuropeptide circuits. Species diversity in oxytocin and vasopressin effects on social behaviors are also discussed. We conclude with a discussion of the translational implications of oxytocin and vasopressin for improving social functioning in disorders with social impairments, such as autism spectrum disorder.

Topics: Animals; Autism Spectrum Disorder; Humans; Male; Oxytocin; Pair Bond; Receptors, Oxytocin; Social Behavior; Vasopressins

Oxytocin (OXT) is a hypothalamic neuropeptide that is released from the posterior pituitary gland and at specific targets in the central nervous system (CNS). The prosocial effects of OXT acting in the CNS present it as a potential therapeutic agent for the treatment of aspects of autism spectrum disorder (ASD). In this article, we systematically review the functional MRI (fMRI) literature that reports task-state and resting-state fMRI (rsfMRI) studies of the neural effects of single or multiple dose intranasal OXT (IN-OXT) administration in individuals with ASD.. We searched four databases for relevant documents (PubMed, Web of Science, Scopus, and Google Scholar) using the keywords "autism spectrum disorder", "Asperger Syndrome", "oxytocin", and "fMRI". Moreover, we made a manual search to assess the quality of our automatic search. The search was confined to English language articles published in the interval February 2013 until March 2021.. The search yielded 12 fMRI studies with OXT intervention, including 288 individuals with ASD (age 8-55 years) enrolled in randomized, double-blind, placebo-controlled, parallel designs, within-subject-crossover experimental OXT trials. Studies reporting activation task and rsfMRI were summarized with region of interest (ROI) or whole-brain voxel wise analysis. The systematic review of the 12 studies supported the proposition that IN-OXT administration alters brain activation in individuals with ASD. The effects of IN-OXT interacted with the type of the task and the overall results did not indicate restoration of normal brain activation in ASD signature regions albeit the lack of statistical evidence.. A large body of evidence consistently indicates that OXT alters activation to fMRI in brain networks of individuals with ASD, but with uncertain implications for alleviation of their social deficits.

Topics: Administration, Intranasal; Adolescent; Adult; Autism Spectrum Disorder; Autistic Disorder; Child; Humans; Magnetic Resonance Imaging; Middle Aged; Oxytocin; Randomized Controlled Trials as Topic; Young Adult

The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuropsychiatric disorders including autism spectrum disorder (ASD). Early studies using intranasal oxytocin in patients with ASD yielded encouraging results and for some time, scientists and affected families placed high hopes on the use of intranasal oxytocin for behavioral therapy in ASD. However, a recent Phase III trial obtained negative results using intranasal oxytocin for the treatment of behavioral symptoms in children with ASD. Given the frequently observed autism-like behavioral phenotypes in Prader-Willi and Schaaf-Yang syndromes, it is unclear whether oxytocin treatment represents a viable option to treat behavioral symptoms in these diseases. Here we review the latest findings on intranasal OT treatment, Prader-Willi and Schaaf-Yang syndromes, and propose novel research strategies for tailored oxytocin-based therapies for affected individuals. Finally, we propose the critical period theory, which could explain why oxytocin-based treatment seems to be most efficient in infants, but not adolescents.

Topics: Administration, Intranasal; Arthrogryposis; Autism Spectrum Disorder; Craniofacial Abnormalities; Humans; Hypopituitarism; Intellectual Disability; Oxytocin; Prader-Willi Syndrome; Research Design

Intranasal oxytocin (OT) has been suggested as a putative adjunctive treatment for patients with schizophrenia and autism spectrum disorders (ASD). Here, we examine available evidence from trials investigating the effects of repeated administrations of intranasal OT on the core symptoms of patients with schizophrenia and ASD, focusing on its therapeutic efficacy and heterogeneity of response (meta-ANOVA). Repeated administration of intranasal OT does not improve most of the core symptoms of schizophrenia and ASD, beyond a small tentative effect on schizophrenia general symptoms. However, we found significant moderator effects for dose in schizophrenia total psychopathology and positive symptoms, and percentage of included men and duration of treatment in schizophrenia general symptoms. We found evidence of heterogeneity (increased variance) in the response of schizophrenia negative symptoms to intranasal OT compared with placebo, suggesting that subgroups of responsive and non-responsive patients might coexist. For other core symptoms of schizophrenia, or any of the core symptom dimensions in ASD, the response to repeated treatment with intranasal OT did not show evidence of heterogeneity. LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc.

Topics: Administration, Intranasal; Analysis of Variance; Autism Spectrum Disorder; Humans; Male; Oxytocin; Schizophrenia

Over the past 70 years, the understanding of Autism Spectrum Disorder (ASD) improved greatly and is characterized as a heterogeneous neuropsychiatric syndrome. ASD is characterized by difficulties in social communication, restricted and repetitive behavior, interests, or activities. And it is often described as a combination of genetic predisposition and environmental factors. There are many treatments and approaches to ASD, including pharmacological therapies with antipsychotics, antidepressants, mood regulators, stimulants, and behavioral ones. However, no treatment is capable of reverting ASD. This review provides an overview of animal models of autism. We summarized genetic and environmental models and then valproic acid treatment as a useful model for ASD. As well as the main therapies and approaches used in the treatment, relating them to the neurochemical pathways altered in ASD, emphasizing the pharmacological potential of peptides and bioinspired compounds found in animal venoms as a possible future treatment for ASD.

Topics: Animals; Antipsychotic Agents; Autism Spectrum Disorder; Disease Models, Animal; Humans; Mice; Oxytocin; Peptides; Valproic Acid

Intranasal oxytocin has been shown to promote social functioning and has recently been applied as a treatment for autism spectrum disorders (ASD). The current meta-analysis aims to assess the crucial question of oxytocin's efficacy in the treatment of ASD. We performed a systematic literature search, including randomized, single- or double-blind/open-label and placebo-controlled clinical trials as well as single-arm, non-randomized and uncontrolled studies investigating exogenous oxytocin effect on ASD. A total of 28 studies (N = 726 ASD patients) met our predefined inclusion criteria. We used a multilevel meta-analytic model and found that oxytocin had beneficial effects on social functioning, but did not find strong evidence for symptoms improvement in the non-social domain. Our findings suggest that oxytocin administration can be regarded as an effective treatment for some core aspects of ASD, especially in the domain of social functioning, highlighting the promise of using oxytocin as a new-generation therapeutic to address core social impairments in ASD.

Topics: Administration, Intranasal; Autism Spectrum Disorder; Double-Blind Method; Humans; Oxytocin; Randomized Controlled Trials as Topic; Treatment Outcome

Oxytocin and vasopressin systems have been studied separately in autism spectrum disorder (ASD). Here, we provide evidence from an evolutionary and neuroscience perspective about the shared mechanisms and the common roles in regulating social behaviors. We first discuss findings on the evolutionary history of oxytocin and vasopressin ligands and receptors that highlight their common origin and clarify the evolutionary background of the crosstalk between them. Second, we conducted a comprehensive review of the increasing evidence for the role of both neuropeptides in regulating social behaviors. Third, we reviewed the growing evidence on the associations between the oxytocin/vasopressin systems and ASD, which includes oxytocin and vasopressin dysfunction in animal models of autism and in human patients, and the impact of treatments targeting the oxytocin or the vasopressin systems in children and in adults. Here, we highlight the potential of targeting the oxytocin/vasopressin systems to improve social deficits observed in ASD and the need for further investigations on how to transfer these research innovations into clinical applications.

Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Humans; Oxytocin; Social Behavior; Vasopressins

Oxytocin is a hormone that mediates interpersonal relationships through enhancing social recognition, social memory, and reducing stress. It is released centrally into the cerebrospinal fluid, as well as peripherally into the blood, where it can easily be measured. Some studies indicate that the oxytocin system with its social implications might be different in people with autism spectrum disorder. With summarizing evidence of 31 studies, this meta-analysis suggests that children with autism spectrum disorder have lower blood oxytocin levels compared to neurotypical individuals. This might not be the case for adults with autism spectrum disorder, where we could not find a difference. Our findings motivate further exploration of the oxytocin system in children with autism spectrum disorder. This could lead to therapeutic options in treating autism spectrum disorder in childhood.

Topics: Autism Spectrum Disorder; Autistic Disorder; Child; Humans; Interpersonal Relations; Oxytocin

In research on autism spectrum disorder (ASD), cognitive, speech- and anxiety-related impairments have been the focus of the majority of studies. One consistently reported ASD symptom that has rarely attracted attention is disordered appetite. The goal of this paper is to assess whether ASD-related dysregulation of food intake impacts consumption of palatable foods, including sugar.. Aberrant neural processing at the reward system level is at least partially responsible for excessive intake of palatable tastants, including sugar. Impaired oxytocin (OT) signaling likely contributes to the magnitude of this overconsumption. Since intake for reward is generally elevated in individuals with ASD, one strategy to curb sugar overconsumption might utilize presentation of alternative palatable food choices that are more nutritionally adequate than sucrose. Furthermore, OT, which is clinically tested to alleviate other ASD symptoms, might be an effective tool to curb overconsumption of sugar, as well as - likely - of other excessively ingested palatable foods, especially those that have sweet taste.

Topics: Appetite; Autism Spectrum Disorder; Eating; Humans; Oxytocin

Oxytocin (OT) subserves various physiological, behavioral, and cognitive processes. This paired with the ability to administer OT with minimal and inconsistent side effects has spurred research to explore its therapeutic potential. Findings from single-dose studies indicate that OT administration may be beneficial, at least under certain circumstances. The state of the field, however, is less clear regarding effects from chronic OT administration, which more closely resembles long-term treatment. To address this gap, this review synthesizes existing findings on the use of chronic OT administration in animal and human work. In addition to detailing the effects of chronic OT administration across different functional domains, this review highlights factors that have contributed to mixed findings. Based on this review, a basic framework of interrelated regulatory functions sensitive to chronic OT administration is offered. The paper also identifies future research directions across different contexts, populations, and outcomes, specifically calling for more systematic and standardized research on chronic OT administration in humans to supplement and expand what is currently known from preclinical work.

Topics: Animals; Anxiety; Autism Spectrum Disorder; Dementia; Humans; Inflammation; Oxytocin; Pain; Schizophrenia; Sexual Dysfunction, Physiological; Stress Disorders, Post-Traumatic; Stress, Psychological; Substance-Related Disorders

Oxytocin (OT) has been implicated in various aspects of social behaviors. During the past decades there has been a surge of interest in the therapeutic potential of OT in psychiatric disorders, especially those characterized by social deficits, which the available therapeutic agents, cannot fully target. This systematic review and meta-analysis examines available evidence for the therapeutic role of OT in five psychiatric disorders characterized with difficulties in social abilities: autism spectrum disorder, schizophrenia, post-traumatic stress disorder, mood disorders and borderline personality disorder. For each disorder, we review the sample size, gender distribution and single versus long-term effects of OT. Moreover, we examine effects of OT through the lens of the social salience hypothesis, in order to identify individual characteristics and contexts that may affect the response to OT, across the disorders. We show that OT has diverse effects depending on symptoms and context. The meta-analyses revealed a small effect size of OT efficacy in schizophrenia and repetitive behaviors in ASD. Finally, we discuss shortcomings and provide recommendations for future research.

Topics: Autism Spectrum Disorder; Borderline Personality Disorder; Humans; Oxytocin; Schizophrenia; Social Behavior

Oxytocin (Oxt) is a nine amino acid peptide important in energy regulation and is essential to stress-related disorders. Specifically, low Oxt levels are associated with obesity in human subjects and diet-induced or genetically modified animal models. The striking evidence that Oxt is linked to energy regulation is that Oxt- and oxytocin receptor (Oxtr)-deficient mice show a phenotype characterized by late onset obesity. Oxt-/- or Oxtr-/- develop weight gain without increasing food intake, suggesting that a lack of Oxt reduce metabolic rate. Oxt is differentially expressed in skeletal muscle exerting a protective effect toward the slow-twitch muscle after cold stress challenge in mice. We hypothesized that Oxt potentiates the slow-twitch muscle as it does with the uterus, triggering "the oxytonic contractions". Physiologically, this is important to augment muscle strength in fight/flight response and is consistent with the augmented energetic need at time of labor and for the protection of the offspring when Oxt secretion spikes. The normophagic obesity of Oxt-/- or Oxtr-/- mice could have been caused by decreased skeletal muscle tonicity which drove the metabolic phenotype. In this review, we summarized our findings together with the recent literature on this fascinating subjects in a "new

Topics: Animals; Autism Spectrum Disorder; Cold-Shock Response; Female; Humans; Mice; Mice, Knockout; Muscle, Skeletal; Neurons; Obesity; Oxytocin; Prader-Willi Syndrome; Proteins; Receptors, Oxytocin; Uterus

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by difficulties in social communication and the presence of restricted interests and repetitive behaviors. Although behavioral interventions are numerous, there are no Federal Drug Administration approved pharmacological treatments for the core symptoms of ASD. The neuropeptide oxytocin has been studied in animals for decades, and is involved in pair bonding and social affiliation. Given oxytocin's involvement in social communication in animals, researchers have begun exploring whether oxytocin administration in humans affects social behaviors and attachment. Particular attention has been paid to whether oxytocin has therapeutic benefits for improving social behaviors in individuals with ASD. Research on oxytocin administration in ASD has utilized both behavioral and brain-based outcomes. This chapter reviews the effects of oxytocin administration in ASD, with a focus on functional outcomes from neuroimaging investigations. Evidence of potential therapeutic benefits are reviewed, as well as limitations of extant research. A proposed model for future research into the therapeutic benefits of oxytocin includes combining pharmacological (e.g. oxytocin) and behavioral (e.g. evidence-based behavioral interventions) techniques to improve social communication skills in ASD.

Topics: Animals; Autism Spectrum Disorder; Humans; Neuroimaging; Oxytocin; Social Behavior

Discrepancies in the efficacy between single-dose and repeated administrations of oxytocin on autism spectrum disorder (ASD) indicate a time-course change in efficacy. However, the hypothesis cannot be tested without a repeatable, objective, and quantitative measurement of the core symptoms of ASD. The author's research group comprehensively examined recently examined reported single-site exploratory (n=18, crossover) and multi-site confirmatory (n=106, parallel-group), double-blind, placebo-controlled trials of six-week intranasal oxytocin (48 IU/day) in adult males with ASD. The outcomes were statistically representative values of the objectively quantified facial expression intensity during a semi-structured social interaction in the Autism Diagnostic Observation Schedule. The quantitative facial expression analyses on data from these two independent clinical trials successfully detected and verified the therapeutic effect of repeated administrations of intranasal oxytocin on autistic features in facial expressions during social interaction. Furthermore, for the first time, the recent study demonstrated a time-course change in the efficacy: deterioration during the repetitive administration phase and preservation during the post-treatment phase. Together with our recent study regarding neurochemical mechanisms of deteriorating efficacy of oxytocin, the findings are expected to promote further development of optimized objective, quantitative, and repeatable outcome measures for autistic social deficits and to establish an optimized regimen of oxytocin treatment in ASD.

Topics: Adult; Autism Spectrum Disorder; Double-Blind Method; Humans; Male; Oxytocin; Randomized Controlled Trials as Topic

Current understanding of the neuroanatomical abnormalities in autism includes gross anatomical changes in several brain areas and microstructural alterations in neuronal cells as well. There are many controversies in the interpretation of the imaging data, evaluation of volume and size of particular brain areas, and their functional translation into a broad autism phenotype. Critical questions of neuronal pathology in autism include the concept of the reversible plasticity of morphological changes, volume alterations of brain areas, and both short- and long-term consequences of adverse events present during the brain development. At the cellular level, remodeling of the actin cytoskeleton is considered as one of the critical factors associated with the autism spectrum disorders. Alterations in the composition of the neuronal cytoskeleton, in particular abnormalities in the polymerization of actin filaments and their associated proteins underlie the functional consequences in behavior resulting in symptoms and clinical correlates of autism spectrum disorder. In the present review, a special attention is devoted to the role of oxytocin in experimental models of neurodevelopmental disorders manifesting alterations in neuronal morphology.

Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Brain; Cell Shape; Cell Size; Humans; Magnetic Resonance Imaging; Neurons; Oxytocin

Early life social experiences shape neural pathways in infants to develop lifelong social skills. This review presents the first unified circuit-based model of social learning that can be applied to early life social development, drawing together unique human developmental milestones, sensitive learning periods, and behavioral and neural scaffolds. Circuit domains for social learning are identified governing Activation, Integration, Discrimination, Response and Reward (AIDRR) to sculpt and drive human social learning. This unified model can be used to identify social delays earlier in development. We propose social impairments observed in Autism Spectrum Disorder are underpinned by early mistimed sensitive periods in brain development and alterations in amygdala development to disrupt the AIDRR circuits. This model directs how interventions can target neural circuits for social development and be applied early in life. To illustrate, the role of oxytocin and its use as an intervention is explored. The AIDRR model shifts focus away from delivering broad treatments based only on diagnostic classifications, to specifying and targeting the relevant circuits, at the right time of development, to optimize social learning.

Topics: Autism Spectrum Disorder; Humans; Learning; Neural Pathways; Oxytocin; Social Behavior; Social Learning

A diverse array of data has been associated with autism spectrum disorder (ASD), reflecting the complexity of its pathophysiology as well as its heterogeneity. Two important hubs have emerged, the placenta/prenatal period and the postnatal gut, with alterations in mitochondria functioning crucial in both.. Factors acting to regulate mitochondria functioning in ASD across development are reviewed in this article.. Decreased vitamin A, and its retinoic acid metabolites, lead to a decrease in CD38 and associated changes that underpin a wide array of data on the biological underpinnings of ASD, including decreased oxytocin, with relevance both prenatally and in the gut. Decreased sirtuins, poly-ADP ribose polymerase-driven decreases in nicotinamide adenine dinucleotide (NAD+), hyperserotonemia, decreased monoamine oxidase, alterations in 14-3-3 proteins, microRNA alterations, dysregulated aryl hydrocarbon receptor activity, suboptimal mitochondria functioning, and decreases in the melatonergic pathways are intimately linked to this. Many of the above processes may be modulating, or mediated by, alterations in mitochondria functioning. Other bodies of data associated with ASD may also be incorporated within these basic processes, including how ASD risk factors such as maternal obesity and preeclampsia, as well as more general prenatal stressors, modulate the likelihood of offspring ASD.. Such a mitochondria-focussed integrated model of the pathophysiology of ASD has important preventative and treatment implications.

Topics: ADP-ribosyl Cyclase 1; Autism Spectrum Disorder; Female; Humans; Melatonin; Mitochondria; Oxytocin; Placenta; Pregnancy; Serotonin; Vitamin A; Vitamin A Deficiency

Oxytocin and the oxytocin receptor (OXTR) play an important role in a large variety of social behaviors. The oxytocinergic system interacts with environmental cues and is highly dependent on interindividual factors. Deficits in this system have been linked to mental disorders associated with social impairments, such as autism spectrum disorder (ASD). This review focuses on the modulation of social behavior by alterations in two domains of the oxytocinergic system. We discuss genetic and epigenetic regulatory mechanisms and alterations in these mechanisms that were found to have clinical implications for ASD. We propose possible explanations how these alterations affect the biological pathways underlying the aberrant social behavior and point out avenues for future research. We advocate the need for integration studies that combine multiple measures covering a broad range of social behaviors and link these to genetic and epigenetic profiles.

Topics: Autism Spectrum Disorder; Epigenesis, Genetic; Gene Expression Regulation; Humans; Mental Disorders; Oxytocin; Receptors, Oxytocin; Social Behavior

Deficits in decoding and understanding facially expressed emotions occur commonly in persons with autism spectrum disorder (ASD), which contribute to the impairment of social communication that serves as one of its core diagnostic criteria. Research suggests that abnormalities of visual scanning of the face, activation of key nodes within the "social brain" by facially expressed emotions, functional connectivity within and between nodes of the "social brain", and transduction of specific neurotransmitter/neuromodulatory signals contribute to the pathogenesis of these deficits in at least some persons with ASD. Importantly, the etiologies of these deficits are heterogeneous and include genetic, immunologic, and inflammatory mechanisms, as well as in utero exposures to drugs and toxins. The manifestation and severity of these deficits can also be influenced by developmental age, IQ and genetic background. Consistent with the goals of the Special Issue, the current Review is intended to familiarize the readership with several of the leading neurobiological mechanisms proposed to underlie these deficits in decoding facially expressed emotions and stimulate interest in translational preclinical and clinical investigations, whose ultimate purpose is to attenuate their severity and, thereby, improve functional outcomes of persons with ASD.

Topics: Animals; Attention; Autism Spectrum Disorder; Brain; Facial Expression; Humans; Oxytocin; Serotonin

A combination of altered social and feeding behaviors is common in children with autism spectrum disorder (ASD); however, the underlying mechanisms are unknown. Nevertheless, it has been established that several specific neuropeptides are critically involved in the regulation of both feeding and social behavior, such as α-melanocyte-stimulating hormone (α-MSH) and oxytocin, respectively. Moreover, recent data implicated gut microbiota in regulation of host feeding and emotion and revealed its dysbiosis in ASD, suggesting a mechanistic role of altered microbiota-brain axis in ASD. In this review, we discuss how gut microbiota dysbiosis may alter hunger and satiety peptide hormones as well as brain peptidergic pathways involved in the regulation of host feeding and social behaviors and hence may contribute to the ASD pathophysiology. In particular, we show that interactions between α-MSH and oxytocin systems in the brain can provide clues for better understanding of the mechanisms underlying altered feeding and social behaviors in ASD and that the origin of such alterations can be linked to gut microbiota.

Topics: alpha-MSH; Autism Spectrum Disorder; Brain; Dysbiosis; Feeding Behavior; Gastrointestinal Microbiome; Humans; Hunger; Neuropeptides; Oxytocin; Signal Transduction

The effects of oxytocin on social cognition and behavior have recently attracted considerable attention. In particular, oxytocin has been proposed as a novel therapeutic for psychiatric disorders with social deficits such as autism spectrum disorders. This review provides a brief overview of behavioral and neural responses to oxytocin manipulations in humans and animal models. Although the differences in findings between human and animal studies should be interpreted carefully, shared behavioral phenotypes have been recognized, such as social bonding, social responses, and recognition and usage of social cues. Previous literature suggests that the neural effects of oxytocin in humans and animals overlap in the prefrontal, limbic, and paralimbic cortices. Oxytocin-induced alterations in these regions may indicate a fundamental basis for how oxytocin modulates social behaviors and facilitate the discovery of new pharmaceutical targets for treating social deficits.

Topics: Animals; Attention; Autism Spectrum Disorder; Behavior, Animal; Cerebral Cortex; Disease Models, Animal; Humans; Oxytocin; Prefrontal Cortex; Social Behavior

Recent studies have suggested oxytocin as a possible drug to treat social deficits caused by autism spectrum disorder (ASD), but the safety of intranasal oxytocin in autistic patients has not been established. The aim of this review was to characterize the side-effect profile of long-term intranasal oxytocin in treatment of ASD compared to placebo. All randomized controlled trials of intranasal oxytocin in the treatment of ASD published before 1 January 2017 that reported safety data were identified from databases, including PubMed, Embase, Cochrane Library, and International Pharmaceutical Abstract. Relevant data from the selected studies were then extracted for meta-analysis to estimate the pooled risk ratio for the most common adverse events. Descriptive analysis of severe adverse events was also conducted. Of the 223 participants in the five included studies, 123 were given oxytocin and 100 were given placebos. Nasal discomfort (14.3%), tiredness (7.2%), irritability (9.0%), diarrhea (4.5%), and skin irritation (4.5%) were the most common adverse events. None of these common adverse events was statistically associated with treatment allocation according to meta-analysis using pooled data (all P-values > 0.1). Five severe adverse events were reported, namely aggression (one in placebo, two in oxytocin) and seizures (one in placebo, one in oxytocin). Results from this systematic review support intranasal oxytocin as well tolerated and safe for use in the ASD population. Larger clinical trials should be conducted to establish the efficacy of intranasal oxytocin as a treatment of ASD.

Topics: Administration, Intranasal; Autism Spectrum Disorder; Drug-Related Side Effects and Adverse Reactions; Humans; Oxytocin

Although the neurohypophyseal hormones vasopressin (VP) and oxytocin (OT) are mostly known for their role respectively in antidiuresis, and in labour, lactation and maternal behavior, both might exert widespread influences either on emotion and cognition in healthy subjects, showing some gender-related differences. They interact with each other facilitating shifts between positive socially- oriented and defensive states. In fact, VP amplifies the reactivity to stressors showing also beneficial effects on attention, verbal learning as well as memory, whereas OT reduces the amplitude of the stress response, improves emotion processing, and can play a negative effect on memory and verbal learning in healthy individuals. Several data indicate the possible involvement of these neuropeptides in the pathophysiology of psychiatric conditions involving social interactions, such as autism, as well as in schizophrenia and depression. The aim of this paper is to review the literature relating to the role played by neurohypophyseal hormones in neuropsychiatric disorders.. We analyzed the best of published literature dealing with the relationships between neurohypophyseal hormones and neuropsychiatric conditions like autism (AD), major depressive disorder (MDD), bipolar disorder (BD) and schozophrenia, identifying keywords and MeSH terms in Pubmed and then searching them. The last search was performed on December 2017.. Several studies indicate a role played by OT and VP in AD, schizophrenia, MDD and BD. Even if conflicting data have been reported, several mechanisms may be involved in these behavioral diseases, such as differences in aminoacid sequence and peptide biological activity, neurotransmission and genetic disorders involving OT and VP receptors.. The involvment of VP and OT in neurpopsychiatric disorders can support a possible beneficial therapy with OT or with VP antagonists. The target may be obtained using effective drug delivery methods as well as the association with other drugs.

Topics: Affect; Animals; Autism Spectrum Disorder; Bipolar Disorder; Depressive Disorder, Major; Humans; Mental Disorders; Oxytocin; Pituitary Gland, Posterior; Schizophrenia; Schizophrenic Psychology; Signal Transduction; Vasopressins

Nonapeptides and their respective receptors have been conserved throughout evolution and display astonishing similarities among the animal kingdom. They can be found in worms, birds, fish, amphibians, reptiles and mammals, including rodents, non-human primates and humans. In particular, the neuropeptide oxytocin (OT) has attracted the attention of scientists due to its profound effects on social behavior. However, although both the neuropeptide and its receptor are identical in rodents and primates, the effects of OT vary greatly in the two species. Here, we provide a brief overview about OT's role in the evolution of mammals and provide reasons for the manifold effects of OT within the brain with a particular focus on the discrepancy of OT's effects in rodents and primates. In addition, we suggest new approaches towards improvement of translatability of scientific studies and highlight the most recent advances in animal models for autism spectrum disorder, a disease, in which the normal function of the OT system seems to be impaired.

Topics: Animals; Autism Spectrum Disorder; Brain; Disease Models, Animal; Humans; Mice; Neuropeptides; Oxytocin

Accurate interpretation and appropriate expression of emotions are key aspects of social-cognition. Several mental disorders are characterised by transdiagnostic difficulties in these areas and, recently, there has been increasing interest in exploring the effects of oxytocin on social-emotional functioning. This review consists of 33 studies. Fifteen of the studies included people with autism spectrum disorder, schizophrenia, borderline personality disorder, frontotemporal dementia, anorexia nervosa, bulimia nervosa, post-traumatic stress disorder, depression, and opioid and alcohol dependence. We conducted ten meta-analyses examining the effects of intranasal oxytocin on expression of emotions, emotional theory of mind, sensitivity to recognise basic emotions, and recognition of basic emotions. A single dose of intranasal oxytocin significantly improved the recognition of basic emotions, particularly fear, and increased the expression of positive emotions among the healthy individuals. Oxytocin did not significantly influence theory of mind or the expression of negative emotions among the healthy individuals. Finally, intranasal oxytocin did not significantly influence interpretation or expression of emotions among the clinical populations.

Topics: Administration, Intranasal; Autism Spectrum Disorder; Emotions; Facial Expression; Humans; Oxytocin

Autism spectrum disorder shows deficits in social communication and interaction including nonverbal communicative behaviors (e.g., eye contact, gestures, voice prosody, and facial expressions) and restricted and repetitive behaviors as its core symptoms. These core symptoms are emerged as an atypical behavioral development in toddlers with the disorder. Atypical neural development is considered to be a neural underpinning of such behaviorally atypical development. A number of studies using voxel-based morphometry have already been conducted to compare regional brain volumes between individuals with autism spectrum disorder and those with typical development. Furthermore, more than ten papers employing meta-analyses of the comparisons using voxel based morphometry between individuals with autism spectrum disorder and those with typical development have already been published. The current review paper adds some brief discussions about potential factors contributing to the inconsistency observed in the previous findings such as difficulty in controlling the confounding effects of different developmental phases among study participants.

Topics: Autism Spectrum Disorder; Autistic Disorder; Brain; Facial Expression; Humans; Image Processing, Computer-Assisted; Oxytocin

The nonapeptides oxytocin (OXT) and arginine vasopressin (AVP) are two key mediators in regulating various aspects of mammalian social behaviours. There are several lines of evidence that genetic variants of the OXT/AVP system exist in autism spectrum disorder (ASD) and that this system is dysfunctional at least in some ASD entities. These findings have stimulated the interest to perform studies testing the potential therapeutic application of OXT/AVP in ASD. In this respect animal models are critical for investigating the pathophysiology and for compound screening leading to new therapeutic approaches. Based on findings in animal models that show alterations of the OXT/AVP system, it has been hypothesised that single- or multiple-dose administration or the stimulation of endogenous release can improve several social deficits. Here we comprehensively review the role of the OXT/AVP system in social recognition, social interaction and maternal behaviour in the light of different ASD animal models and patient studies. We further discuss implications for OXT/AVP-related pharmacological interventions to alleviate social deficits in ASD in the future.

Topics: Animals; Arginine Vasopressin; Autism Spectrum Disorder; Disease Models, Animal; Humans; Interpersonal Relations; Oxytocin; Social Behavior

In this article, we conduct a comprehensive review of existing evidence for the safety and therapeutic potential of intranasal oxytocin in pediatric populations. Unique considerations for dosing and delivery of oxytocin to the nasal passageway in pediatric populations and methods to promote adherence are reviewed. Intranasal oxytocin has been administered to 261 children in three open-label studies and eight randomized controlled trials. To date, the only published results in pediatric populations have focused on autism spectrum disorder (ASD) and Prader-Willi syndrome (PWS). Results regarding efficacy for improving social impairment in ASD are equivocal, partially due to mixed methodological designs, dosing regimens, and outcome measures. At present, there is no randomized controlled evidence that oxytocin provides benefit to individuals with PWS. There is no clear evidence of a link between oxytocin administration and any specific adverse event. Adverse events have been assessed using medical interviews, open reports, checklists, and physiological assessments. Adverse events reports have been largely classified as mild (n = 93), with few moderate (n = 9) or severe (n = 3) events reported. There were 35 additional adverse events reported, without severity ratings. Severe events, hyperactivity and irritability, occurred at first administration in both placebo and oxytocin groups, and subsided subsequent to discontinuation. We note that adverse event monitoring is inconsistent and often lacking, and reporting of its relationship to the study drug is poor. Only one study reported adherence data to suggest high adherence. Recommendations are then provided for the delivery of nasal sprays to the nasal passageway, monitoring, and reporting of efficacy, safety, and adherence for oxytocin nasal spray trials in pediatric populations.

Topics: Administration, Intranasal; Autism Spectrum Disorder; Autistic Disorder; Child; Humans; Medication Adherence; Nasal Sprays; Oxytocin; Prader-Willi Syndrome; Randomized Controlled Trials as Topic

Topics: Autism Spectrum Disorder; Databases, Bibliographic; Humans; Oxytocics; Oxytocin; Randomized Controlled Trials as Topic

Autism spectrum disorder is a behavioral disorder characterized by impairments in social interaction and communication together with the presence of stereotyped behaviors and restricted interests. Although highly genetic, its etiology is complex which correlates with the extensive heterogeneity found in its clinical manifestation, adding to the challenge of understanding its pathophysiology and develop targeted pharmacotherapies. The neuropeptide oxytocin is part of a highly conserved system involved in the regulation of social behavior, and both animal and human research have shown that variation in the oxytocin system accounts for interindividual differences in the expression of social behaviors in mammals. In autism, recent studies in human patients and animal models are starting to reveal that alterations in the oxytocin system are more common than previously anticipated. Genetic variation in the key players involved in the system (i.e., oxytocin receptor, oxytocin, and CD38) has been found associated with autism in humans, and animal models of the disorder converge in an altered oxytocin system and/or dysfunction in oxytocin related biological processes. Furthermore, oxytocin administration exerts a behavioral and neurobiological response, and thus, the oxytocin system has become a promising potential therapeutical target for autism. Animal models represent a valuable tool to aid in the research into the potential therapeutic use of oxytocin. In this review, I aim to discuss the main findings related to oxytocin research in autism with a focus on findings in animal models. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 202-213, 2017.

Topics: Animals; Autism Spectrum Disorder; Disease Models, Animal; Humans; Oxytocin; Social Behavior

Extensive research efforts in the last decade have been expended into understanding whether intranasal oxytocin may be an effective therapeutic in treating social communication impairments in individuals with autism spectrum disorder (ASD). After much hyped early findings, subsequent clinical trials of longer-term administration have yielded more conservative and mixed evidence. However, it is still unclear at this stage whether these more disappointing findings reflect a true null effect or are mitigated by methodological differences masking true effects. In this review, we comprehensively evaluate the rationale for oxytocin as a therapeutic, evaluating evidence from randomized controlled trials, case reports, and open-label studies of oxytocin administration in individuals with ASD. The evidence to date, including reviews of preregistered trials, suggests a number of critical considerations for the design and interpretation of research in this area. These include considering the choice of ASD outcome measures, dosing and nasal spray device issues, and participant selection. Despite these limitations in the field to date, there remains significant potential for oxytocin to ameliorate aspects of the persistent and debilitating social impairments in individuals with ASD. Given the considerable media hype around new treatments for ASD, as well as the needs of eager families, there is an urgent need for researchers to prioritise considering such factors when conducting well-designed and controlled studies to further advance this field. Autism Res 2017, 10: 25-41. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Topics: Administration, Intranasal; Autism Spectrum Disorder; Humans; Oxytocics; Oxytocin; Research; Research Design; Treatment Outcome

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorders characterized by impaired social interactions, communication deficits, and repetitive behavior. Although the mechanisms underlying its etiology and manifestations are poorly understood, several lines of evidence from rodent and human studies suggest involvement of the evolutionarily highly-conserved oxytocin (OXT) and arginine-vasopressin (AVP), as these neuropeptides modulate various aspects of mammalian social behavior. As far as we know, there is no comprehensive review of the roles of the OXT and AVP systems in the development of ASD from the genetic aspect. In this review, we summarize the current knowledge regarding associations between ASD and single-nucleotide variants of the human OXT-AVP pathway genes OXT, AVP, AVP receptor 1a (AVPR1a), OXT receptor (OXTR), the oxytocinase/vasopressinase (LNPEP), and ADP-ribosyl cyclase (CD38).

Topics: Arginine Vasopressin; Autism Spectrum Disorder; Humans; Oxytocin; Signal Transduction

Oxytocin is a potential therapeutic for the core symptoms of autism spectrum disorder (ASD), which is currently untreatable with pharmacotherapy. Previous clinical trials of a single dose of oxytocin have consistently reported significantly positive effects on various experimental measures associated with the core symptoms of ASD. These studies used various experimental measures as surrogate endpoints of the trials. However, to date, randomized clinical trials of continual administration of oxytocin have failed to reveal significant positive effects on clinically meaningful endpoints, such as how those with ASD interact during interpersonal interactions. This article reviews both the negative and positive effects of oxytocin on the core symptoms of ASD and their surrogate markers. Some unresolved and critical issues on the development of oxytocin as a new therapeutic have been extracted: optimization of dose, duration of oxytocin treatment, and the development of objective and reliable measurements of clinically meaningful endpoints for the core symptoms of ASD. Furthermore, optimization to the intranasal delivery system and careful consideration of how individuals respond differently to treatments should be addressed in future studies.

Topics: Administration, Intranasal; Autism Spectrum Disorder; Humans; Interpersonal Relations; Oxytocin; Social Behavior; Treatment Outcome

The motivation to engage in social behaviors is influenced by past experience and internal state, but also depends on the behavior of other animals. Across species, the oxytocin (Oxt) and vasopressin (Avp) systems have consistently been linked to the modulation of motivated social behaviors. However, how they interact with other systems, such as the mesolimbic dopamine system, remains understudied. Further, while the neurobiological mechanisms that regulate prosocial/cooperative behaviors have been extensively examined, far less is understood about competitive behaviors, particularly in females. In this chapter, we highlight the specific contributions of Oxt and Avp to several cooperative and competitive behaviors and discuss their relevance to the concept of social motivation across species, including humans. Further, we discuss the implications for neuropsychiatric diseases and suggest future areas of investigation.

Topics: Aggression; Animals; Autism Spectrum Disorder; Behavior, Animal; Brain; Competitive Behavior; Cooperative Behavior; Dopamine; Female; Humans; Mental Disorders; Motivation; Oxytocin; Pair Bond; Personality Disorders; Schizophrenia; Schizophrenic Psychology; Social Behavior; Stress Disorders, Post-Traumatic; Vasopressins

Despite the sometimes heated debate about the validity of human oxytocin studies, experimental oxytocin research with intranasal administration is a growing field with promising preliminary findings. The effects of intranasally administered oxytocin compared to placebo on brain neural activity have been supported in animal studies and in human studies of neural resting state. In several studies, oxytocin sniffs have been shown to lead to down-regulation of amygdala activation in response to infant attachment vocalisations. Meta-analytic evidence shows that oxytocin enhances the salience of (emotional) stimuli, lowers stress and arousal, and elevates empathic concern and tender care, in particular for offspring and in-group members. Less firm evidence points at the amnestic effects of oxytocin. We also note that the average effect sizes of oxytocin experiments are small to modest, and that most studies include a small number of subjects and thus are seriously underpowered, which implies a high risk for publication bias and nonreplicability. Nevertheless, we argue that the power of within-subjects experiments with oxytocin has been underestimated. Much more work is needed, however, to create a firm knowledge base of the neural and behavioural effects of oxytocin. Human oxytocin research is still taking place in the context of discovery, in which bold conjectures are being generated. In the context of justification, these conjectures should subsequently be subjected to stringent attempts at refutations before we jump to theoretical or clinical conclusions. For this context of justification, we propose a multisite multiple replications project on the social stimuli salience enhancing effect of oxytocin. Clinical application of oxytocin is premature. Meta-analytically, the use of oxytocin in clinical groups tends to show only effectiveness in changing symptomatology in individuals with autism spectrum disorders but, even then, it is not yet a validated therapy and its use is premature because safety and long-term side-effects have not been sufficiently studied, in particular in children.

Topics: Administration, Intranasal; Animals; Autism Spectrum Disorder; Brain; Humans; Oxytocin; Parent-Child Relations; Parenting; Social Behavior

The neuropeptide oxytocin (OT) is an evolutionary highly conserved molecule that plays a part in the regulation of complex social cognition and behaviours. From a pathophysiological point of view, several studies have evidenced dysfunctions of the oxytocinergic system in autism spectrum disorders (ASD): a lowering of plasma OT and genetic or epigenetic anomalies of the OT receptor. Therefore, some authors have hypothesized that an abnormality in the OT neurotransmission may account for several features of autism and that a treatment restoring a normal OT pathway functioning could improve social abilities. OT administration has thus been used in clinical trials, especially in groups of subjects suffering from autism. Some studies found that OT decreased repetitive behaviours, enhanced emotional understanding of speech intonation, improved performance of the Reading the Mind in the Eyes Test and reinforced cooperation. Nevertheless, the findings of the OT administration studies on clinical samples show great diversity. The context, the personality and childhood experiences of the subject could be moderators influencing the effect of exogenous OT. Besides, three mechanisms could play a part in the action of OT on ASD social symptoms: anxiety reduction (with a lowering in the hypothalamic-pituitary-adrenal axis responsiveness and in the amygdale reactivity to social stimuli), increased affiliative motivation (involving the dopaminergic pathway and several regions of the social brain) and enhanced perceptual selectivity and social stimuli salience. To conclude, OT could be a promising molecule used as a treatment to promote social behaviours, helping individuals with ASD to develop new relationships. OT could be administered during a cognitive-behavioural therapy to reinforce the efficacy of such procedures. More studies are needed, on larger samples, to investigate the safety and efficacy of OT administration and to specify optimal dosages and characteristics of patients who may benefit from this treatment.

Topics: Autism Spectrum Disorder; Autistic Disorder; Child; Child, Preschool; Humans; Oxytocin

Oxytocin is widely used by obstetricians to induce or facilitate labor. The long lasting consequences of oxytocin administration remain however unknown. Here, we discuss recent evidence suggesting a link between oxytocin labor induction and developmental social impairments such as autism spectrum disorders (ASD). Because these associations are methodologically questionable, we provide a review of animal studies investigating the long term effects of neonatal injection of oxytocin to shed light on the biological mechanisms that mediate the contribution of early oxytocin supplementation on the development of social impairments. In contrast to this potential negative impact on development, oxytocin has been shown to ameliorate social skills of ASD patients. However, results of chronic oxytocin administration from animal experiments are contradictory. We also review recent studies looking at chronic oxytocin effects in animal and in humans. Obstetric and psychiatric uses of exogenous oxytocin both impact on oxytocinergic neurotransmission but the effects may be sharply dissimilar.

Topics: Administration, Intranasal; Animals; Animals, Newborn; Autism Spectrum Disorder; Brain; Female; Humans; Infant; Male; Oxytocin; Receptors, Oxytocin; Social Behavior Disorders

Administration of oxytocin has been proposed as a treatment for the core symptoms of autism spectrum disorder (ASD), including social-communicative deficit. Previous clinical trials have investigated the efficacy and safety of oxytocin intranasal single-dose and long-term administration for individuals with ASD. All studies suggest that singledose and long-term administration are well tolerated, and no severe adverse events have been reported. However, the efficacy of long-term oxytocin administration is controversial. Some studies have reported significant improvement of the core symptoms of ASD by long-term oxytocin administration, while other studies showed no such improvement. To elucidate the factors influencing the efficacy of oxytocin administration, it is necessary to examine the effects of administration schedules (e.g., dosage amount, frequency per day) and participant characteristics (e.g., age, sex, intellectual ability). In addition to doubts about the efficacy of particular methods of administration, questions remain about the mechanism of action of intranasal oxytocin on the central nervous system. Examination of changes in the neural underpinnings of social behavior and simultaneous oxytocin levels in blood or cerebrospinal fluid could prove important in elucidating the pharmacokinetics of intranasal oxytocin administration, which could be essential for establishing optimal oxytocin treatments for individuals with ASD.

Topics: Administration, Intranasal; Animals; Autism Spectrum Disorder; Humans; Oxytocin; Psychotropic Drugs; Randomized Controlled Trials as Topic

Neurodevelopmental disorders are increasing in prevalence worldwide. Previous work suggests that exposure to the environmental air pollutant and greenhouse gas - nitrous oxide (N. While a number of recent systematic reviews have addressed the role of general anesthesia in the surgical setting and neurodevelopmental outcomes, a narrative mini-review was conducted to first define and characterize the relevant variables (i.e., N. The results of the present mini-review indicate that exposure to N. The current evidence and subsequent hypotheses suggest that a renewed interest be taken in the toxicological assessment of environmental N

Topics: Air Pollution; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Dopamine; Environmental Exposure; Estrogens; Female; Humans; Male; Neurodevelopmental Disorders; Nitrous Oxide; Oxytocin; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, kappa

The recent involvement of oxytocin in social behavior of animals and humans has motivated the study of its effects on the social behavior of individuals with autism spectrum disorders (ASD).. To review the current state of oxytocin studies concerning its therapeutic potential in treating social deficits of the ASD population, and to establish likely future directions to be taken by the studies in this field.. Some studies have linked oxytocin to the pathophysiology of autistic disorders. Most studies that have administered oxytocin (mainly with intranasal administration of 24 IU) to ASD subjects have shown significant improvements in their social performance with acceptable safety parameters. However, there is controversial data as the outcome measures are widely dispersed, the samples are reduced and heterogeneous, and the treatment durations are different. The limitations related to the lack of understanding of the oxytocin's action mechanisms and the symptomatic heterogeneity of ASD are hampering progress towards the establishment of oxytocin as a treatment of ASD patients. Recent studies suggest the investigation of the combination of the oxytocin treatment with social skills training, and the enhancement of endogenous secretion of oxytocin.. The effects of oxytocin are promising regarding the treatment of social deficits in ASD individuals. Future studies should aim to facilitate understanding of the oxytocin's ways of action and to establish the optimal treatment regime.. La oxitocina en el tratamiento de los deficits sociales asociados a los trastornos del espectro autista.. Introduccion. La implicacion de la oxitocina en la conducta social de animales y humanos ha llevado a estudiar los efectos de su administracion en el comportamiento y cognicion social de pacientes con trastornos del espectro autista (TEA). Objetivos. Revisar la investigacion sobre el potencial terapeutico de la oxitocina en el tratamiento de los deficits sociales de la poblacion con TEA y discutir las probables direcciones futuras de los estudios en este campo. Desarrollo. Diversos trabajos han relacionado la oxitocina con la fisiopatologia de los TEA. La mayoria de los estudios que han administrado oxitocina, generalmente por via intranasal (24 UI), ha observado mejoras significativas en el rendimiento social, sin detectar efectos secundarios destacables. No obstante, existen datos contradictorios debido a la heterogeneidad de las variables analizadas por los diferentes estudios, al uso de muestras heterogeneas y pequeñas o a la diferente duracion de los tratamientos. Las limitaciones relacionadas con la falta de comprension de los mecanismos de accion de la oxitocina y la diversidad sintomatologica de los TEA dificultan el establecimiento de este peptido como tratamiento de los pacientes autistas. Estudios recientes destacan la conveniencia de explorar el efecto de la combinacion del tratamiento de oxitocina con programas conductuales de intervencion en habilidades sociales, asi como la potenciacion de la secrecion endogena de oxitocina. Conclusiones. Los efectos de la administracion de oxitocina resultan prometedores en relacion con el tratamiento de los deficits sociales en individuos con TEA. Estudios futuros deberian facilitar la comprension de las vias de accion de la oxitocina y el establecimiento de pautas optimas de tratamiento.

Topics: Adolescent; Adult; Animals; Autism Spectrum Disorder; Disease Models, Animal; Dose-Response Relationship, Drug; Emotions; Female; Gene Knockdown Techniques; Humans; Male; Oxytocin; Receptors, Oxytocin; Sex Characteristics; Social Behavior Disorders

Early supports to enhance social development in children with autism are widely promoted. While oxytocin has a crucial role in mammalian social development, its potential role as a medication to enhance social development in humans remains unclear. We investigated the efficacy, tolerability, and safety of intranasal oxytocin in young children with autism using a double-blind, randomized, placebo-controlled, clinical trial, following a placebo lead-in phase. A total of 87 children (aged between 3 and 12 years) with autism received 16 International Units (IU) of oxytocin (n = 45) or placebo (n = 42) nasal spray, morning and night (32 IU per day) for twelve weeks, following a 3-week placebo lead-in phase. Overall, there was no effect of oxytocin treatment over time on the caregiver-rated Social Responsiveness Scale (SRS-2) (p = 0.686). However, a significant interaction with age (p = 0.028) showed that for younger children, aged 3-5 years, there was some indication of a treatment effect. Younger children who received oxytocin showed improvement on caregiver-rated social responsiveness ( SRS-2). There was no other evidence of benefit in the sample as a whole, or in the younger age group, on the clinician-rated Clinical Global Improvement Scale (CGI-S), or any secondary measure. Importantly, placebo effects in the lead-in phase were evident and there was support for washout of the placebo response in the randomised phase. Oxytocin was well tolerated, with more adverse side effects reported in the placebo group. This study suggests the need for further clinical trials to test the benefits of oxytocin treatment in younger populations with autism.Trial registration www.anzctr.org.au (ACTRN12617000441314).

Topics: Administration, Intranasal; Autism Spectrum Disorder; Autistic Disorder; Child; Child, Preschool; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Humans; Nasal Sprays; Oxytocin; Social Interaction; Treatment Outcome

Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. LAY SUMMARY: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.

Topics: Adolescent; Autism Spectrum Disorder; Autistic Disorder; Child; DNA Methylation; Epigenesis, Genetic; Humans; Oxytocin

Intranasal 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.. A 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.. In 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.. Future 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.. Four 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 ).

Topics: Administration, Intranasal; Autism Spectrum Disorder; Autistic Disorder; Child; Double-Blind Method; Female; Humans; Male; Oxytocin; Single-Blind Method

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.

Topics: Administration, Intranasal; Autism Spectrum Disorder; Autistic Disorder; Child; Double-Blind Method; Humans; Nasal Sprays; Oxytocin

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12

Topics: Administration, Intranasal; Animals; Autism Spectrum Disorder; Autistic Disorder; Biological Availability; Double-Blind Method; Female; Humans; Male; Nasal Sprays; Oxytocin; Rabbits; Treatment Outcome

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.. 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.. 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.. 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.. 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.

Topics: Autism Spectrum Disorder; Autistic Disorder; Child; Double-Blind Method; Humans; Oxytocin; Pilot Projects; Social Interaction

The neuropeptide oxytocin (OXT) modulates social cognition by increasing attention to social cues and may have therapeutic potential for impaired social attention in conditions such as autism spectrum disorder. Intranasal administration of OXT is widely used to examine the drug's functional effects in both adults and children and is assumed to enter the brain directly via this route. However, OXT can also influence brain function through increased blood concentrations, and we have recently shown that orally (lingual) administered OXT also modulates neural responses to emotional faces and may be better tolerated for therapeutic use. Here, we examine whether 24 IU OXT administered orally can facilitate social attention.. In a randomized, placebo-controlled pharmacologic study, we used a validated emotional antisaccade eye-tracking paradigm to explore the effects of oral OXT on bottom-up and top-down attention processing in 80 healthy male participants.. Our findings showed that in terms of top-down attention, oral OXT increased errors for both social (angry, fearful, happy, sad, and neutral emotion faces) and nonsocial stimuli (oval shapes) in the antisaccade condition but increased response latencies only in the social condition. It also significantly reduced post-task state anxiety, but this reduction was not correlated with task performance. A comparison with our previous intranasal OXT study using the same task revealed that both routes have a similar effect on increasing antisaccade errors and response latencies and on reducing state anxiety.. Overall, our findings suggest that oral administration of OXT produces similar effects on top-down social attention control and anxiety to intranasal administration and may therefore have therapeutic utility.

Topics: Administration, Intranasal; Administration, Oral; Adult; Attention; Autism Spectrum Disorder; Child; Double-Blind Method; Facial Expression; Humans; Male; Oxytocin

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).

Topics: Adult; Amygdala; Anti-Anxiety Agents; Autism Spectrum Disorder; Autistic Disorder; Humans; Male; Nasal Sprays; Neuropeptides; Oxytocin

The respective roles of the neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) in modulating social cognition and for therapeutic intervention in autism spectrum disorder have not been fully established. In particular, while numerous studies have demonstrated effects of oxytocin in promoting social attention the role of AVP has not been examined. The present study employed a randomized, double-blind, placebo (PLC)-controlled between-subject design to explore the social- and emotion-specific effects of AVP on both bottom-up and top-down attention processing with a validated emotional anti-saccade eye-tracking paradigm in 80 healthy male subjects (PLC = 40, AVP = 40). Our findings showed that AVP increased the error rate for social (angry, fearful, happy, neutral and sad faces) but not non-social (oval shapes) stimuli during the anti-saccade condition and reduced error rates in the pro-saccade condition. Comparison of these findings with a previous study (sample size: PLC = 33, OXT = 33) using intranasal oxytocin revealed similar effects of the two peptides on anti-saccade errors, although with some difference in effects of specific face emotions, but a significantly greater effect of AVP on pro-saccades. Both peptides also produced a post-task anxiolytic effect by reducing state anxiety. Together these findings suggested that both AVP and OXT decrease goal-directed top-down attention control to social salient stimuli but that AVP more potently increased bottom-up social attentional processing.

Topics: Administration, Intranasal; Arginine Vasopressin; Attention; Autism Spectrum Disorder; Humans; Male; Oxytocin

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS.. Eighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period.. There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U = 50, p = 0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events.. The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results.. Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084.

Topics: Adolescent; Autism Spectrum Disorder; Child; Child, Preschool; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 22; Humans; Oxytocin

Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder.. We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ.. Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups.. This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).

Topics: Administration, Intranasal; Adolescent; Autism Spectrum Disorder; Child; Child, Preschool; Double-Blind Method; Female; Humans; Least-Squares Analysis; Male; Oxytocin; Social Behavior; Social Skills; Treatment Failure

Prader-Willi syndrome (PWS) is characterized by hypothalamic dysfunction, hyperphagia and a typical behavioural phenotype, with characteristics of autism spectrum disorder (ASD) like stubbornness, temper tantrums and compulsivity. It has been suggested that the oxytocin system in patients with PWS is dysfunctional. In ASD, intranasal oxytocin treatment has favourable effects on behaviour.. To evaluate the effects of 3 months of twice daily intranasal oxytocin (dose range 16-40 IU/day), compared to placebo, on behaviour and hyperphagia in children with PWS.. Randomized, double-blind, placebo-controlled, crossover study in the Dutch PWS Reference Center.. Twenty-six children with PWS aged 3-11 years.. (Change in) behaviour and hyperphagia measured by Oxytocin Questionnaire and Dykens hyperphagia questionnaire.. In the total group, no significant effects of oxytocin on social behaviour or hyperphagia were found. However, in boys, the Oxytocin Questionnaire scores improved significantly during oxytocin treatment, compared to a deterioration during placebo (4.5 (-0.8 to 15.3) vs. -4.0 (-11.3 to 0.8), P = .025). The Dykens hyperphagia questionnaire scores remained similar during oxytocin treatment, while there was a deterioration during placebo (0.0 (-0.8 to 4.3) vs. -3.5 (-6.0 to 0.0), P = .046). Patients with a deletion had significant improvements in both questionnaire scores during oxytocin treatment, but deteriorations during placebo. Oxytocin treatment was well tolerated, and there were no serious adverse events.. Intranasal oxytocin treatment has positive effects on social and eating behaviour in 3-11 years aged boys with PWS and in children with a deletion without safety concerns. Intranasal oxytocin in children with PWS might be considered, but individual effects should be carefully evaluated and treatment discontinued if no effects are found.

Topics: Autism Spectrum Disorder; Child; Child, Preschool; Cross-Over Studies; Humans; Hyperphagia; Male; Oxytocin; Prader-Willi Syndrome

Intranasal administration of the neuropeptide oxytocin (OT) is increasingly explored as a potential treatment for targeting the core symptoms of autism spectrum disorder (ASD). Previously, interactions of exogenously administered OT with its endogenous production have been demonstrated following single-dose administrations. However, the impact of repeated, long-term OT use on endogenous salivary OT levels is unknown. In this double-blind, randomized, placebo-controlled study with between-subject design, 34 adult men with ASD were either assigned to a four-week treatment of once-daily intranasal OT administrations (24 IU) or placebo. Salivary OT samples were obtained before and after the treatment period as well as at two follow-up sessions, four weeks and one year after cessation of the treatment. Receiving OT intranasally but not placebo reliably increased endogenous salivary levels of OT immediately post-treatment and at the follow-up session four weeks post treatment, indicating an interaction between exogenously administered OT and its endogenous production. Notably, increases in salivary OT at the four-week follow-up session were most pronounced in individuals with larger behavioral improvements in ASD social symptoms. These results suggest that OT's positive effects on social behaviors may lead to a self-perpetuating elevation of OT levels through a feed-forward triggering of its own release. Together, the current investigation provides initial evidence that repeated intranasal administration of OT can induce long-lasting changes in endogenous salivary OT levels, presumably through a positive spiral of OT release.

Topics: Administration, Intranasal; Adult; Autism Spectrum Disorder; Autistic Disorder; Double-Blind Method; Follow-Up Studies; Humans; Male; Oxytocin

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.

Topics: Adult; Attention; Autism Spectrum Disorder; Empathy; Eye-Tracking Technology; Fixation, Ocular; Humans; Male; Oxytocin; Social Perception; Visual Perception; Young Adult

Autism spectrum disorder (ASD) is a rapidly growing neurodevelopmental disorder. Both probiotics and oxytocin were reported to have therapeutic potential; however, the combination therapy has not yet been studied. We conducted a randomized, double-blinded, placebo-controlled, 2-stage pilot trial in 35 individuals with ASD aged 3-20 years (median = 10.30 years). Subjects were randomly assigned to receive daily

Topics: Adolescent; Autism Spectrum Disorder; Biomarkers; Child; Child, Preschool; Clostridiales; Combined Modality Therapy; Double-Blind Method; Feces; Female; Gastrointestinal Microbiome; Humans; Inflammation Mediators; Lactobacillus plantarum; Male; Oxytocin; Pilot Projects; Probiotics; Social Cognition; Treatment Outcome; Young Adult

Topics: Administration, Intranasal; Animals; Autism Spectrum Disorder; Double-Blind Method; Humans; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Oxytocin

Intranasal administration of the neuropeptide oxytocin (IN-OT) is increasingly explored as a potential treatment for targeting the core symptoms of autism spectrum disorder (ASD). To date, however, the impact of multiple-dose IN-OT treatment on human neural circuitry is largely unknown, and also the possibility that long-term IN-OT use may induce long-lasting neural adaptations remains unexplored. Using a double-blind, randomized, placebo-controlled, between-subject design (including 38 adult men with ASD), this treatment-mechanism study showed that 4 weeks of daily oxytocin administration (24 IU/day) significantly altered intrinsic (resting-state fMRI) functional connectivity of the amygdala to core regions of the "social brain" (particularly orbitofrontal cortex and superior temporal sulcus) up to 4 weeks and 1 year post treatment. The neural adaptations in functional coupling of the amygdala to the orbitofrontal cortex were associated with reduced feelings of avoidance toward others and-at the trend level-reduced repetitive behaviors. These observations contribute to a deeper mechanistic understanding of the neural substrates that underlie behavioral effects of multiple-dose IN-OT treatment, and provide initial insights into the long-lasting neural consequences of chronic IN-OT use on amygdala circuitry. Future studies are however warranted to further elucidate the long-term impact of IN-OT treatment on human neural circuitry and its behavioral consequences.

Topics: Administration, Intranasal; Adolescent; Adult; Amygdala; Autism Spectrum Disorder; Autistic Disorder; Double-Blind Method; Humans; Magnetic Resonance Imaging; Male; Oxytocics; Oxytocin; Young Adult

Faces and voices are prominent cues for person-identity recognition. Face recognition behavior and associated brain responses can be enhanced by intranasal administration of oxytocin. It is unknown whether oxytocin can also augment voice-identity recognition mechanisms. To find it out is particularly relevant for individuals who have difficulties recognizing voice identity such as individuals diagnosed with autism spectrum disorder (ASD). We conducted a combined behavioral and functional magnetic resonance imaging (fMRI) study to investigate voice-identity recognition following intranasal administration of oxytocin or placebo in a group of adults diagnosed with ASD (full-scale intelligence quotient > 85) and pairwise-matched typically developing (TD) controls. A single dose of 24 IU oxytocin was administered in a randomized, double-blind, placebo-controlled and cross-over design. In the control group, but not in the ASD group, administration of oxytocin compared to placebo increased responses to recognition of voice identity in contrast to speech in the right posterior superior temporal sulcus/gyrus (pSTS/G) - a region implicated in the perceptual analysis of voice-identity information. In the ASD group, the right pSTS/G responses were positively correlated with voice-identity recognition accuracy in the oxytocin condition, but not in the placebo condition. Oxytocin did not improve voice-identity recognition performance at the group level. The ASD compared to the control group had lower right pSTS/G responses to voice-identity recognition. Since ASD is known to have atypical pSTS/G, the results indicate that the potential of intranasal oxytocin to enhance mechanisms for voice-identity recognition might be variable and dependent on the functional integrity of this brain region.

Topics: Administration, Intranasal; Adult; Autism Spectrum Disorder; Brain; Cross-Over Studies; Double-Blind Method; Humans; Identity Recognition; Magnetic Resonance Imaging; Oxytocin

Intranasal administration of the neuropeptide oxytocin (IN-OT) is increasingly considered as a potential treatment for targeting the core symptoms of autism spectrum disorder (ASD), but the effects of continual use on neural substrates are fairly unexplored and long-term effects are unknown. In this double-blind, randomized, placebo-controlled study, we investigated the effects of single-dose and multiple-dose IN-OT treatment (4 weeks of daily (24 IU) administrations) on brain activity related to processing emotional states. Thirty-eight adult men with ASD (aged between 18 and 35 years) underwent functional magnetic resonance imaging of the posterior superior temporal gyrus (pSTS) and amygdala regions while processing emotional states from point-light biological motion. In line with prior research, a single dose of IN-OT induced a reliable increase in pSTS brain activity during the processing of point-light biological motion, but no consistent long-term changes in pSTS activity were induced after the multiple-dose treatment. In terms of bilateral amygdala, the multiple-dose treatment induced a consistent attenuation in brain activity, which outlasted the period of actual administrations until four weeks and one year post-treatment. Critically, participants with stronger attenuations in amygdala-activity showed greater behavioral improvements, particularly in terms of self-reported feelings of avoidant attachment and social functioning. Together, these observations provide initial insights into the long-lasting neural consequences of chronic IN-OT use on amygdala functioning and provide first indications that the acute versus chronic effects of IN-OT administration may be qualitatively different. Larger studies are however warranted to further elucidate the long-term impact of IN-OT treatment on human neural substrates and its behavioral consequences.

Topics: Administration, Intranasal; Adolescent; Adult; Amygdala; Autism Spectrum Disorder; Autistic Disorder; Double-Blind Method; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Oxytocin; Young Adult

Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18-48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P < .001) but placebo also reduced the score (8.3 to 7.2; P < .001), no between-group difference was found (effect size -0.08; 95% CI, -0.46 to 0.31; P = .69); however, plasma oxytocin was only elevated from baseline to endpoint in the oxytocin-group compared with the placebo-group (effect size -1.12; -1.53 to -0.70; P < .0001). Among the secondary endpoints, oxytocin reduced ADOS repetitive behavior (2.0 to 1.5; P < .0001) compared with placebo (2.0 to 1.8; P = .43) (effect size 0.44; 0.05 to 0.83; P = .026). In addition, the duration of gaze fixation on socially relevant regions, another secondary endpoint, was increased by oxytocin (41.2 to 52.3; P = .03) compared with placebo (45.7 to 40.4; P = .25) (effect size 0.55; 0.10 to 1.0; P = .018). No significant effects were observed for the other secondary endpoints. No significant difference in the prevalence of adverse events was observed between groups, although one participant experienced temporary gynecomastia during oxytocin administration. Based on the present findings, we cannot recommend continuous intranasal oxytocin treatment alone at the current dose and duration for treatment of the core social symptoms of high-functioning ASD in adult men, although this large-scale trial suggests oxytocin's possibility to treat ASD repetitive behavior.

Topics: Administration, Intranasal; Adolescent; Adult; Autism Spectrum Disorder; Double-Blind Method; Gynecomastia; Humans; Japan; Male; Middle Aged; Oxytocin; Young Adult

Topics: Administration, Intranasal; Adolescent; Adult; Autism Spectrum Disorder; Double-Blind Method; Feedback, Psychological; Humans; Magnetic Resonance Imaging; Male; Nucleus Accumbens; Oxytocin; Reinforcement, Social; Social Learning; Young Adult

Previously, oxytocin, a neuropeptide implicated in human social cognition and behavior, was shown to improve people's ability to dynamically track another's emotional state ("empathic accuracy") specifically for less socially proficient individuals-i.e., healthy adults who score higher on the Autism Spectrum Quotient (AQ); conversely, oxytocin had no effect on empathic accuracy for more socially proficient individuals, who performed well following oxytocin and placebo. Here, we aimed to replicate this finding and investigate the effects of oxytocin on empathic accuracy in women. To date, women have been seriously underrepresented in human oxytocin research, and it is not known whether the effects observed in male-only samples apply to women.. In this randomized, double-blind, placebo-controlled, crossover trial, we administered 24 IU intranasal oxytocin (and, on a separate occasion, a matching placebo) to 31 men and 40 women and then measured empathic accuracy. AQ was assessed at baseline (prior to drug administration).. Replicating a 2010 study by Bartz et al., oxytocin selectively improved empathic accuracy for men who scored higher on the AQ, whereas oxytocin did not benefit their lower AQ counterparts. Conversely, we found no effect of oxytocin on empathic accuracy for women (regardless of their AQ score).. In addition to speaking to reliability, this research is important given interest in using oxytocin to augment social functioning in some psychiatric disorders marked by social cognitive impairments. More generally, this research adds to our understanding of the biological systems that support human sociality and provides further evidence for the role of oxytocin therein.

Topics: Autism Spectrum Disorder; Cross-Over Studies; Double-Blind Method; Empathy; Female; Humans; Male; Oxytocin; Social Perception

Discrepancies in efficacy between single-dose and repeated administration of oxytocin for autism spectrum disorder have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone. However, repeatable, objective, and quantitative measurement of autism spectrum disorder's core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. We tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of autism spectrum disorder. We examined videos recorded during semi-structured social interaction administered as the primary outcome in single-site exploratory (n = 18, crossover within-subjects design) and multisite confirmatory (n = 106, parallel-group design), double-blind, placebo-controlled 6-week trials of repeated intranasal administrations of oxytocin (48 IU/day) in adult males with autism spectrum disorder. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule: the maximum probability (i.e. mode) and the natural logarithm of mode on the probability density function of neutral facial expression and the natural logarithm of mode on the probability density function of happy expression. Our recent study revealed that increases in these indices characterize autistic facial expression, compared with neurotypical individuals. The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory (effect-size, -0.57; 95% CI, -1.27 to 0.13; P = 0.023) and confirmatory trials (-0.41; -0.62 to -0.20; P < 0.001). A significant interaction between time-course (at baseline, 2, 4, 6, and 8 weeks) and the efficacy of oxytocin on the natural logarithm of mode on the probability density function of neutral facial expression was found in confirmatory trial (P < 0.001). Post hoc analyses revealed maximum efficacy at 2 weeks (P < 0.001, Cohen's d = -0.78; 95% CI, -1.21 to -0.35) and deterioration of efficacy at 4 weeks (P = 0.042, Cohen's d = -0.46; 95% CI, -0.90 to -0.01) and 6 weeks (P = 0.10, Cohen's d = -0.35; 95% CI, -0.77 to 0.08), while efficacy was preserved at 2 weeks post-treatment (i.e. 8 weeks) (P < 0.001, Cohen's d = -1.24; 95% CI, -1.71 to

Topics: Administration, Intranasal; Adolescent; Adult; Autism Spectrum Disorder; Cross-Over Studies; Double-Blind Method; Facial Expression; Humans; Interpersonal Relations; Male; Middle Aged; Oxytocin; Time Factors; Young Adult

Several studies have suggested that the neuropeptide oxytocin may enhance aspects of social communication in autism. Little is known, however, about its effects on nonsocial manifestations, such as restricted interests and repetitive behaviors. In the empathizing-systemizing theory of autism, social deficits are described along the continuum of empathizing ability, whereas nonsocial aspects are characterized in terms of an increased preference for patterned or rule-based systems, called systemizing. We therefore developed an automated eye-tracking task to test whether children and adolescents with autism spectrum disorder (ASD) compared to matched controls display a visual preference for more highly organized and structured (systemized) real-life images. Then, as part of a randomized, double-blind, placebo-controlled crossover study, we examined the effect of intranasal oxytocin on systemizing preferences in 16 male children with ASD, compared with 16 matched controls. Participants viewed 14 slides, each containing four related pictures (e.g., of people, animals, scenes, or objects) that differed primarily on the degree of systemizing. Visual systemizing preference was defined in terms of the fixation time and count for each image. Unlike control subjects who showed no gaze preference, individuals with ASD preferred to fixate on more highly systemized pictures. Intranasal oxytocin eliminated this preference in ASD participants, who now showed a similar response to control subjects on placebo. In contrast, control participants increased their visual preference for more systemized images after receiving oxytocin versus placebo. These results suggest that, in addition to its effects on social communication, oxytocin may play a role in some of the nonsocial manifestations of autism.

Topics: Administration, Intranasal; Adolescent; Autism Spectrum Disorder; Child; Choice Behavior; Cross-Over Studies; Double-Blind Method; Fixation, Ocular; Humans; Male; Oxytocin; Pattern Recognition, Visual

Autism spectrum disorders (ASDs) are neurodevelopmental conditions with impairments in social communication and interaction. Empathy is the ability to understand and share another person's inner life, and it is an essential process in social cognition, which is deficient in ASD. The mismatch field (MMF) has been used as a neurophysiological marker for the automatic detection of changes in auditory stimuli. In the present study, we focused on long-term changes in MMF evoked by an empathic voice and changes in the empathy quotient (EQ) in ASD during an 8-week clinical trial using oxytocin (OT). Ten males with ASD without intellectual disability participated in this pilot study. The results demonstrated a significant positive correlation between the change in the MMF amplitude in the auditory cortex (i.e., right banks of the superior sulcus) and the change in the EQ score during the 8-week clinical trial, whereas no significant change was observed in the MMF amplitude or EQ score after the administration period of OT. Although we cannot conclude that the observed relationships were caused by OT's effect or by natural changes, our results suggest that MMF evoked by social voice can be a state-dependent marker of empathic abilities in male adults with ASD.

Topics: Acoustic Stimulation; Adult; Autism Spectrum Disorder; Empathy; Humans; Longitudinal Studies; Male; Occipital Lobe; Oxytocin; Pilot Projects; Social Behavior; Voice

Reduced attentional preference for faces and symptoms of social anxiety are common in autism spectrum disorders (ASDs). The neuropeptide oxytocin triggers anxiolytic functions and enhances eye gaze, facial emotion recognition and neural correlates of face processing in ASD. Here we investigated whether a single dose of oxytocin increases attention to faces in ASD. As a secondary question, we explored the influence of social anxiety on these effects. We tested for oxytocin's effects on attention to neutral faces as compared to houses in a sample of 29 autistic individuals and 30 control participants using a dot-probe paradigm with two different presentation times (100 or 500 ms). A single dose of 24 IU oxytocin was administered in a randomized, double-blind placebo-controlled, cross-over design. Under placebo, ASD individuals paid less attention to faces presented for 500 ms than did controls. Oxytocin administration increased the allocation of attention toward faces in ASD to a level observed in controls. Secondary analyses revealed that these oxytocin effects primarily occurred in ASD individuals with high levels of social anxiety who were characterized by attentional avoidance of faces under placebo. Our results confirm a positive influence of intranasal oxytocin on social attention processes in ASD. Further, they suggest that oxytocin may in particular restore the attentional preference for facial information in ASD individuals with high social anxiety. We conclude that oxytocin's anxiolytic properties may partially account for its positive effects on socio-cognitive functioning in ASD, such as enhanced eye gaze and facial emotion recognition.

Topics: Adult; Attention; Autism Spectrum Disorder; Choice Behavior; Double-Blind Method; Facial Expression; Facial Recognition; Female; Humans; Male; Middle Aged; Oxytocin; Phobia, Social; Reaction Time

The neuropeptide oxytocin has shown promise as a treatment for symptoms of autism spectrum disorders (ASD). However, clinical research progress has been hampered by a poor understanding of oxytocin's dose-response and sub-optimal intranasal delivery methods. We examined two doses of oxytocin delivered using a novel Breath Powered intranasal delivery device designed to improve direct nose-to-brain activity in a double-blind, crossover, randomized, placebo-controlled trial. In a randomized sequence of single-dose sessions, 17 male adults with ASD received 8 international units (IU) oxytocin, 24IU oxytocin or placebo followed by four social-cognitive tasks. We observed an omnibus main effect of treatment on the primary outcome measure of overt emotion salience as measured by emotional ratings of faces (η

Topics: Administration, Intranasal; Adolescent; Adult; Autism Spectrum Disorder; Cognition; Cross-Over Studies; Emotions; Facial Expression; Humans; Male; Outcome Assessment, Health Care; Oxytocics; Oxytocin; Social Behavior; Young Adult

Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

Topics: Administration, Inhalation; Autism Spectrum Disorder; Child; Female; Humans; Male; Oxytocics; Oxytocin; Social Skills

Interventions for autism are limited. The synthetic hormone oxytocin may provide a potential treatment to improve core social and behavioral difficulties in autism, but its efficacy has yet to be evaluated in young children who potentially may benefit to a greater extent. We investigated the efficacy, tolerability and safety of oxytocin treatment in young children with autism using a double-blind, randomized, placebo-controlled, crossover, clinical trial. Thirty-one children with autism received 12 International Units (IU) of oxytocin and placebo nasal spray morning and night (24 IU per day) for 5 weeks, with a 4-week washout period between each treatment. Compared with placebo, oxytocin led to significant improvements on the primary outcome of caregiver-rated social responsiveness. Overall, nasal spray was well tolerated, and the most common reported adverse events were thirst, urination and constipation. This study is the first clinical trial to support the potential of oxytocin as an early intervention for young children with autism to help improve social interaction deficits.

Topics: Administration, Intranasal; Autism Spectrum Disorder; Autistic Disorder; Child; Child, Preschool; Cross-Over Studies; Double-Blind Method; Female; Humans; Interpersonal Relations; Male; Nasal Sprays; Oxytocin; Social Behavior; Treatment Outcome

The study investigated whether baseline plasma oxytocin (OXT) concentrations might moderate the effects of nasally administered OXT on social orienting.. Thirty-one males with Autism spectrum disorder (ASD) and thirty healthy males participated in a double-blind placebo-controlled crossover trial. After administration of the compound, participants were viewing pictures from the International Affective Picture System that represented a systematic variation of pleasant, unpleasant and neutral scenes with and without humans. The outcome measures were a cardiac evoked response (ECR) and a cortical evoked long latency parietal positivity (LPP).. Males with ASD had significantly higher plasma baseline levels than the controls. In the absence of general treatment effects, higher baseline concentrations were found to be associated with larger treatment effects, particularly in the group of males with ASD. Higher post-treatment plasma OXT concentrations were found to be associated with smaller treatment effects and larger orienting responses in the placebo situation in the group of controls.. We interpret our findings as suggesting that it is the central availability of OXT determining how much of the nasally administered OXT will become centrally absorbed and how much of it will become released into the bloodstream.

Topics: Administration, Intranasal; Adolescent; Adult; Autism Spectrum Disorder; Central Nervous System Agents; Cross-Over Studies; Double-Blind Method; Emotions; Empathy; Evoked Potentials; Humans; Male; Orientation; Oxytocin; Parietal Lobe; Social Behavior; Young Adult

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.

Topics: Administration, Intranasal; Adolescent; Adult; Autism Spectrum Disorder; Autistic Disorder; Double-Blind Method; Female; Genotype; Humans; Male; Oxytocics; Oxytocin; Polymorphism, Single Nucleotide; Receptors, Oxytocin; Sex Factors; Treatment Outcome; Young Adult

Oxytocin (OT) has become a focus in investigations of autism spectrum disorder (ASD). The social deficits that characterize ASD may relate to reduced connectivity between brain sites on the mesolimbic reward pathway (nucleus accumbens; amygdala) that receive OT projections and contribute to social motivation, and cortical sites involved in social perception. Using functional magnetic resonance imaging and a randomized, double blind, placebo-controlled crossover design, we show that OT administration in ASD increases activity in brain regions important for perceiving social-emotional information. Further, OT enhances connectivity between nodes of the brain's reward and socioemotional processing systems, and does so preferentially for social (versus nonsocial) stimuli. This effect is observed both while viewing coherent versus scrambled biological motion, and while listening to happy versus angry voices. Our findings suggest a mechanism by which intranasal OT may bolster social motivation-one that could, in future, be harnessed to augment behavioral treatments for ASD.

Topics: Administration, Intranasal; Adolescent; Autism Spectrum Disorder; Brain; Brain Mapping; Child; Cross-Over Studies; Double-Blind Method; Female; Humans; Magnetic Resonance Imaging; Male; Motivation; Oxytocin; Social Perception

There is increasing interest in oxytocin as a therapeutic to treat social deficits in autism spectrum disorders (ASD). The aim of this study was to investigate the efficacy of a course of oxytocin nasal spray to improve social behavior in youth with ASD.. In a double-blind, placebo-controlled trial across two Australian university sites between February 2009 and January 2012, 50 male participants aged between 12 and 18 years, with Autistic or Asperger's Disorder, were randomized to receive either oxytocin (n = 26) or placebo (n = 24) nasal sprays (either 18 or 24 International Units), administered twice-daily for 8 weeks. Participants were assessed at baseline, after 4- and 8-weeks of treatment, and at 3-month follow-up. Primary outcomes were change in total scores on the caregiver-completed Social Responsiveness Scale and clinician-ratings on the Clinical Global Impressions-Improvement scale. Secondary assessments included caregiver reports of repetitive and other developmental behaviors and social cognition.. Australian New Zealand Clinical Trials Registry www.anzctr.org.au ACTRN12609000513213.. Participants who received oxytocin showed no benefit following treatment on primary or secondary outcomes. However, caregivers who believed their children received oxytocin reported greater improvements compared to caregivers who believed their child received placebo. Nasal sprays were well tolerated and there was no evidence of increased side effects resulting from oxytocin administration.. This is the first evaluation of the efficacy for a course of oxytocin treatment for youth with ASD. Although results did not suggest clinical efficacy, further research is needed to explore alternative delivery methods, earlier age of intervention, and the influence of caregiver expectation on treatment response.

Topics: Administration, Intranasal; Adolescent; Autism Spectrum Disorder; Child; Female; Humans; Male; Neuropeptides; Oxytocin; Social Behavior; Treatment Outcome

Autism spectrum disorder is a prevalent neurodevelopmental disorder with no established pharmacological treatment for its core symptoms. Although previous literature has shown that single-dose administration of oxytocin temporally mitigates autistic social behaviours in experimental settings, it remains in dispute whether such potentially beneficial responses in laboratories can result in clinically positive effects in daily life situations, which are measurable only in long-term observations of individuals with the developmental disorder undergoing continual oxytocin administration. Here, to address this issue, we performed an exploratory, randomized, double-blind, placebo-controlled, crossover trial including 20 high-functional adult males with autism spectrum disorder. Data obtained from 18 participants who completed the trial showed that 6-week intranasal administration of oxytocin significantly reduced autism core symptoms specific to social reciprocity, which was clinically evaluated by Autism Diagnostic Observation Scale (P = 0.034, PFDR < 0.05, Cohen's d = 0.78). Critically, the improvement of this clinical score was accompanied by oxytocin-induced enhancement of task-independent resting-state functional connectivity between anterior cingulate cortex and dorso-medial prefrontal cortex (rho = -0.60, P = 0.011), which was measured by functional magnetic resonance imaging. Moreover, using the same social-judgement task as used in our previous single-dose oxytocin trial, we confirmed that the current continual administration also significantly mitigated behavioural and neural responses during the task, both of which were originally impaired in autistic individuals (judgement tendency: P = 0.019, d = 0.62; eye-gaze effect: P = 0.03, d = 0.56; anterior cingulate activity: P = 0.00069, d = 0.97; dorso-medial prefrontal activity: P = 0.0014, d = 0.92; all, PFDR < 0.05). Furthermore, despite its longer administration, these effect sizes of the 6-week intervention were not larger than those seen in our previous single-dose intervention. These findings not only provide the evidence for clinically beneficial effects of continual oxytocin administration on the core social symptoms of autism spectrum disorder with suggesting its underlying biological mechanisms, but also highlight the necessity to seek optimal regimens of continual oxytocin treatment in future studies.

Topics: Administration, Intranasal; Adult; Autism Spectrum Disorder; Autistic Disorder; Brain; Cross-Over Studies; Double-Blind Method; Functional Neuroimaging; Gyrus Cinguli; Humans; Magnetic Resonance Imaging; Male; Neural Pathways; Oxytocics; Oxytocin; Prefrontal Cortex; Social Behavior; Treatment Outcome; Young Adult

The study investigated the effects of nasally administered oxytocin on neurophysiological orienting to empathy-evoking pictures in normally intelligent male adults with and without an autism spectrum disorder (ASD). It further investigated whether these effects might be moderated by the individual's approach and avoidance tendencies.. All subjects participated in a randomised double-blind placebo controlled crossover trial where either oxytocin (OXT) or placebo was administered preceding the viewing of affective pictures.The pictures, selected from the International Affective Picture System (IAPS), represented a systematic variation of pleasant, unpleasant and neutral scenes with and without humans. Both cardiac (ECR) and cortical (LPP) evoked orienting responses were measured and both were enhanced for the pictures with humans, in particular for the unpleasant ones.. No significant group differences were found, nor were there any treatment effects. Moderator analysis, however, demonstrated that OXT did enhance orienting to affective pictures with humansin male adults with ASD who are easily distressed when seeing others in stressful situations and in healthy males who are highly sensitive to anticipated punishment and criticism or have a low drive for goal achievement.. Individual differences in stress-related avoidance tendencies should be taken into account when considering OXT as a treatment of social deficiencies in autism.

Topics: Adolescent; Adult; Analysis of Variance; Autism Spectrum Disorder; Brain Mapping; Double-Blind Method; Electrocardiography; Electroencephalography; Evoked Potentials; Humans; Intelligence Tests; Interpersonal Relations; Male; Orientation; Oxytocin; Personality; Photic Stimulation; Psychiatric Status Rating Scales; Social Behavior; Young Adult

Pleasant touch facilitates social interactions, affiliative behavior and emotional bonding, contributing to positive infant and child development. Oxytocin is presumed to play an important role in mediating these effects of pleasant touch on brain, body and behavior. However, little is known about the role the oxytocin system plays in pleasant touch during infancy. This study examined the hypothesis that genetic variability in the oxytocin system is linked to individual differences in infants' cuddliness operationalized as parent-reported behaviors indexing an infant's motivation to seek out and enjoy caregiver touch. Our results (N = 82) show that a polymorphism in CD38 (rs3796863), previously linked with increased release of oxytocin in adults, was associated with higher reported rates of cuddliness. In contrast, infants with CD38 genotype previously linked to autism spectrum disorder (ASD) and reduced release of oxytocin in adults, was associated with lower rates of cuddliness. These findings support the hypothesis that, from early in human ontogeny, genetic variation in the oxytocin system is systematically linked to individual differences in the reported motivation to seek out, and the enjoyment of receiving, pleasant caregiver touch. This provides novel insights into the neurohormonal processes involved in pleasant touch.

Topics: Autism Spectrum Disorder; Emotions; Humans; Individuality; Infant; Oxytocin; Polymorphism, Genetic

Epidemiological studies have documented that exposure to fine particulate matter (PM

Topics: Air Pollutants; Animals; Autism Spectrum Disorder; Brain; Gliosis; Humans; Male; Oxytocin; Particulate Matter; Rats

Whether there is a relationship between oxytocin (OXT) use in labor and the risk of autism (ASD), and the nature of such relationship, is unclear. By integrating genetic and clinical data in a sample of 176 ASD participants, we tested the hypothesis that OXT is a marker for abnormal prenatal development which leads to impairments in the process of labor. OXT-exposed ASD had more obstetric complications (P = 0.031), earlier onset of symptoms (P = 0.027), poorer cognitive development (P = 0.011), higher mutation burden across neurodevelopment genes (P = 0.020; OR = 5.33) and lower transmission of polygenic risk for ASD (P = 0.0319), than non-exposed ASD. OXT seems to constitute a risk indicator rather than a risk factor for ASD, which is relevant for diagnostic and genetic counselling.

Topics: Autism Spectrum Disorder; Autistic Disorder; Cognition; Cognitive Dysfunction; Female; Humans; Oxytocin; Pregnancy

The classical motor center cerebellum is one of the most consistent structures of abnormality in autism spectrum disorders (ASD), and neuropeptide oxytocin is increasingly explored as a potential pharmacotherapy for ASD. However, whether oxytocin targets the cerebellum for therapeutic effects remains unclear. Here, we report a localization of oxytocin receptor (OXTR) in Purkinje cells (PCs) of cerebellar lobule Crus I, which is functionally connected with ASD-implicated circuits. OXTR activation neither affects firing activities, intrinsic excitability, and synaptic transmission of normal PCs nor improves abnormal intrinsic excitability and synaptic transmission of PCs in maternal immune activation (MIA) mouse model of autism. Furthermore, blockage of OXTR in Crus I in wild-type mice does not induce autistic-like social, stereotypic, cognitive, and anxiety-like behaviors. These results suggest that oxytocin signaling in Crus I PCs seems to be uninvolved in ASD pathophysiology, and contribute to understanding of targets and mechanisms of oxytocin in ASD treatment.

Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Mice; Oxytocin; Purkinje Cells; Receptors, Oxytocin

Children with attention-deficit/hyperactivity disorder (ADHD) might have similar problems as in autism spectrum disorder (ASD) and show impairment in social behaviour. Also, there is a relationship between social relationship skills and ToM (theory of mind) skills of children with ADHD. Besides, ASD is associated with prenatal exposure to high levels of androgens, and oxytocin plays a role in the modulation of emotions, coping with stress, and social behaviour like ASD. In this study, the relationship between autistic traits and serum oxytocin, testosterone, and androstenedione levels in prepubertal male drug naive children with ADHD has been investigated.. Eighty-three prepubertal children, who were diagnosed with ADHD between the ages of 6-10 years old, are included in the study. For the study, intelligence levels were evaluated by using WISC-4, and autistic traits were measured by using both social responsiveness scale and theory of mind tests. In addition, serum oxytocin, testosterone, and androstenedione levels were measured by using ELISA.. It has been found that serum testosterone levels of patients with lower autistic traits are significantly lower than those with moderate and severe autistic traits, while the serum oxytocin levels are significantly higher. Also, patients with severe autistic traits have had significantly higher serum androstenedione levels than those with lower and moderate autistic traits.. This study suggests that patients who have higher autistic traits have elevated testosterone and androstenedione levels and lower serum oxytocin levels. Further studies are needed to clarify this relationship.

Topics: Androstenedione; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Autistic Disorder; Child; Female; Humans; Male; Oxytocin; Pregnancy; Testosterone

A neurodevelopmental disease, autism spectrum disorder (ASD) occurs in males three times more commonly than girls. Higher prenatal testosterone exposure may result in autistic-like behaviour in boys, according to earlier research. It is unclear how fetal testosterone affects the development of autism. In this study, we tested the hypothesis that prenatal testosterone exposure in an animal model may result in autistic behaviours by modifying serotonin, dopamine, IGF-1 and oxytocin levels.. Group 1 (control, n = 6) and Group 2 (testosterone undecanoate, n = 6) of female rats were randomly assigned. For 2-3 days during the oestrus cycle, female rats were housed with a reproductive male (three females/one male). On the 10th day of gestation, rats in Group 1 received 1 ml/kg% 0.9 NaCl saline, whereas rats in Group 2 received 250 mg/kg testosterone undecanoate. Until weaning on postnatal day 21 (P21), the mothers were permitted to care for their pups. On P21, 40 littermates-10 male and female for control and 10 male and female from mothers that exposed to testosterone-were arbitrarily split up and housed. On P50, these mature rats were tested for their behaviour. The rats were then sacrificed. The brain tissue was subjected to histological examinations as well as biochemical tests for homovanillic acid (HVA), 5-Hydroxyindoleacetic acid (5-HIAA), oxytocin and insulin-like growth factor-1 (IGF-1).. The groups differed significantly in the behavioural examinations (three-chamber social test, passive avoidance learning analysis, open field test), with the testosterone-exposed groups exhibiting autistic symptoms to a higher extent. When compared with the control groups, testosterone exposure caused significant histological changes in the hippocampus CA1 and CA3 areas, including gliosis and cell death of neurons. In the testosterone-exposed groups, HVA, 5-HIAA and IGF-1 tissue expressions in the brain elevated, whereas oxytocin levels reduced. These findings point to a potential connection between neurodevelopmental disorders like ASD and exposure to testosterone during gestation.. Overall, we revealed that prenatal testosterone exposure led to autistic traits by elevating serotonin, dopamine and IGF-1 levels while lowering oxytocin levels.

Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Disease Models, Animal; Dopamine; Female; Humans; Hydroxyindoleacetic Acid; Insulin-Like Growth Factor I; Male; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Serotonin; Testosterone

Autism spectrum disorder (ASD) affects 1-2% of all children and poses a great social and economic challenge for the globe. As a highly heterogeneous neurodevelopmental disorder, the development of its treatment is extremely challenging. Multiple pathways have been linked to the pathogenesis of ASD, including signaling involved in synaptic function, oxytocinergic activities, immune homeostasis, chromatin modifications, and mitochondrial functions. Here, we identify secretagogin (SCGN), a regulator of synaptic transmission, as a new risk gene for ASD. Two heterozygous loss-of-function mutations in SCGN are presented in ASD probands. Deletion of Scgn in zebrafish or mice leads to autism-like behaviors and impairs brain development. Mechanistically, Scgn deficiency disrupts the oxytocin signaling and abnormally activates inflammation in both animal models. Both ASD probands carrying Scgn mutations also show reduced oxytocin levels. Importantly, we demonstrate that the administration of oxytocin and anti-inflammatory drugs can attenuate ASD-associated defects caused by SCGN deficiency. Altogether, we identify a convergence between a potential autism genetic risk factor SCGN, and the pathological deregulation in oxytocinergic signaling and immune responses, providing potential treatment for ASD patients suffering from SCGN deficiency. Our study also indicates that it is critical to identify and stratify ASD patient populations based on their disease mechanisms, which could greatly enhance therapeutic success.

Topics: Animals; Autism Spectrum Disorder; Humans; Mice; Oxytocin; Risk Factors; Secretagogins; Zebrafish

Joint attention (JA) is an important milestone in human infant development and is predictive of the onset of language later in life. Clinically, it has been reported that children at risk for or with a diagnosis of autism spectrum disorder (ASD) perform more poorly on measures of JA compared to neurotypical controls. JA is not unique to humans but has also been reported in great apes and to a lesser extent in more distantly related monkeys. Further, individual differences in JA among chimpanzees are associated with polymorphisms in the vasopressin and oxytocin genes, AVPR1A and OXTR. Here, we tested whether individual variation in DNA methylation of OXTR and AVPR1A were associated with performance on JA tasks in chimpanzees. We found that individual differences in JA performance was associated with AVPR1A methylation, but not OXTR methylation in the chimpanzees. The collective results provide further evidence of the role of AVPR1A in JA abilities in chimpanzees. The results further suggest that methylation values for AVPR1A may be useful biomarkers for identifying individuals at risk for ASD or related neurodevelopmental disorders associated with impairments in JA abilities.

Topics: Animals; Attention; Autism Spectrum Disorder; Child; Humans; Individuality; Methylation; Oxytocin; Pan troglodytes; Receptors, Vasopressin; Social Behavior; Vasopressins

The number of children diagnosed with autism spectrum disorder (ASD) has increased substantially over the past two decades. Current research suggests that both genetic and environmental risk factors are involved in the etiology of ASD. The goal of this paper is to examine how one specific environmental factor, early social experience, may be correlated with DNA methylation (DNAm) changes in genes associated with ASD. We present an innovative model which proposes that polygenic risk and changes in DNAm due to social experience may both contribute to the symptoms of ASD. Previous research on genetic and environmental factors implicated in the etiology of ASD will be reviewed, with an emphasis on the oxytocin receptor gene, which may be epigenetically altered by early social experience, and which plays a crucial role in social and cognitive development. Identifying an environmental risk factor for ASD (e.g., social experience) that could be modified via early intervention and which results in epigenetic (DNAm) changes, could transform our understanding of this condition, facilitate earlier identification of ASD, and guide early intervention efforts.

Topics: Autism Spectrum Disorder; Child; DNA Methylation; Epigenesis, Genetic; Epigenome; Humans; Oxytocin

Oxytocin is a neuropeptide hormone that plays a key role in social behavior, stress regulation, and mental health. Synthetic oxytocin administration is a common obstetrical practice, and importantly, previous research has suggested that intrapartum exposure may increase the risk of neurodevelopmental disorders, such as autism spectrum disorder.. This study aimed to examine the association between synthetic oxytocin exposure during labor and autism spectrum disorder diagnosis in the child.. This population-based retrospective cohort study compared 2 cohorts of children: (1) all children born in British Columbia, Canada between April 1, 2000 and December 31, 2014 (n=414,336 births), and (2) all children delivered at Soroka University Medical Center in Be'er-Sheva, Israel between January 1, 2011 and December 31, 2019 (n=82,892 births). Nine different exposure groups were examined. Cox proportional hazards models were used to estimate crude and adjusted hazard ratios of autism spectrum disorder in both cohorts on the basis of induction and/or augmentation exposure status. To further control for confounding by indication, we conducted sensitivity analyses among a cohort of healthy, uncomplicated deliveries and among a group that was induced only for postdates. In addition, we stratified our analyses by infant sex to assess for potential sex differences.. In the British Columbia cohort, 170,013 of 414,336 deliveries (41.0%) were not induced or augmented, 107,543 (26.0%) were exposed to oxytocin, and 136,780 (33.0%) were induced or augmented but not exposed to oxytocin. In the Israel cohort, 51,790 of 82,892 deliveries (62.5%) were not induced or augmented, 28,852 (34.8%) were exposed to oxytocin, and 2250 (2.7%) were induced or augmented but not exposed to oxytocin. On adjusting for covariates in the main analysis, significant associations were observed in the Israel cohort, including adjusted hazard ratios of 1.51 (95% confidence interval, 1.20-1.90) for oxytocin-augmented births and 2.18 (95% confidence interval, 1.32-3.57) for those induced by means other than oxytocin and not augmented. However, oxytocin induction was not significantly associated with autism spectrum disorder in the Israel cohort. In the Canadian cohort, there were no statistically significant adjusted hazard ratios. Further, no significant sex differences were observed in the fully adjusted models.. This study supports that induction of labor through oxytocin administration does not increase the risk of autism spectrum disorder in the child. Our international comparison of 2 countries with differences in clinical practice regarding oxytocin administration for induction and/or augmentation suggests that previous studies reporting a significant association were likely confounded by the underlying indication for the induction.

Topics: Autism Spectrum Disorder; Canada; Child; Female; Humans; Infant; Labor, Induced; Male; Oxytocin; Pregnancy; Retrospective Studies

Alterations in the brain's oxytocinergic system have been suggested to play an important role in the pathophysiology of autism spectrum disorder (ASD), but insights from pediatric populations are sparse. Here, salivary oxytocin was examined in the morning (AM) and afternoon (PM) in school-aged children with (n = 80) and without (n = 40) ASD (boys/girls 4/1), and also characterizations of DNA methylation (DNAm) of the oxytocin receptor gene (OXTR) were obtained. Further, cortisol levels were assessed to examine links between the oxytocinergic system and hypothalamic-pituitary-adrenal (HPA) axis signaling. Children with ASD displayed altered (diminished) oxytocin levels in the morning, but not in the afternoon, after a mildly stress-inducing social interaction session. Notably, in the control group, higher oxytocin levels at AM were associated with lower stress-induced cortisol at PM, likely reflective of a protective stress-regulatory mechanism for buffering HPA stress activity. In children with ASD, on the other hand, a significant rise in oxytocin levels from the morning to the afternoon was associated with a higher stress-induced cortisol release in the afternoon, likely reflective of a more reactive stress regulatory release of oxytocin for reactively coping with heightened HPA activity. Regarding epigenetic modifications, no overall pattern of OXTR hypo- or hypermethylation was evident in ASD. In control children, a notable association between OXTR methylation and levels of cortisol at PM was evident, likely indicative of a compensatory downregulation of OXTR methylation (higher oxytocin receptor expression) in children with heightened HPA axis activity. Together, these observations bear important insights into altered oxytocinergic signaling in ASD, which may aid in establishing relevant biomarkers for diagnostic and/or treatment evaluation purposes targeting the oxytocinergic system in ASD.

Topics: Autism Spectrum Disorder; Autistic Disorder; Child; DNA Methylation; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Oxytocin; Pituitary-Adrenal System; Psychomotor Agitation; Receptors, Oxytocin

Maternal labor epidural analgesia (LEA) and oxytocin use for labor and delivery have been reported to be associated with child autism spectrum disorders (ASD). However, it remains unclear whether these 2 common medications used during labor and delivery have synergistic associations with ASD risk in children.. To assess the independent associations of LEA and oxytocin during labor and delivery with ASD, as well as outcome modification associated with the concurrent use of both interventions.. Data for this cohort study included 205 994 singleton births with vaginal deliveries in a single integrated health care system in Southern California from calendar years 2008 to 2017. Children were followed up to December 31, 2021. Data on use of LEA and oxytocin, covariates, and ASD outcome in children were obtained from electronic medical records. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) adjusting for covariates.. Labor epidural analgesia and/or oxytocin use during labor and delivery.. A child's clinical diagnosis of ASD during follow-up and at age of diagnosis.. Among the cohort, 153 880 children (74.7%) were exposed to maternal LEA and 117 808 children (57.2%) were exposed to oxytocin during labor and delivery. The population of children was approximately half boys and half girls. The median (IQR) age of the mothers was 30.8 (26.8-34.5) years for those not exposed to LEA, 30.0 (25.9-33.8) years for those exposed to LEA, 30.4 (26.5-34.1) years for those unexposed to oxytocin, and 30.0 (25.9-33.9) years for those exposed to oxytocin during labor and delivery. A total of 5146 children (2.5%) had ASD diagnosed during follow-up. Oxytocin exposure was higher among LEA-exposed (67.7%) than -unexposed (26.1%) children. The ASD risk associated with LEA was independent of oxytocin exposure (HR, 1.28; 95% CI, 1.18-1.38); however, the ASD risk associated with oxytocin was not significant after adjusting for LEA exposure (HR, 1.05; 95% CI, 0.99-1.12). A significant interaction of LEA and oxytocin on child ASD risk was found (P = .02 for interaction). Compared with no exposure, HRs were 1.20 (95% CI, 1.09-1.32) for LEA alone, 1.30 (95% CI, 1.20-1.42) for both LEA and oxytocin, and 0.90 (95% CI, 0.78-1.04) for oxytocin alone.. The findings of this cohort study suggest an association between maternal LEA and ASD risk in children, and the risk appeared to be further increased if oxytocin was also administered. Oxytocin exposure without LEA exposure was not associated with ASD risk in children. These findings must be interpreted with caution. Further studies are needed to replicate or refute the study results and examine biological plausibility.

Topics: Adult; Analgesia, Epidural; Analgesics; Autism Spectrum Disorder; Child; Cohort Studies; Female; Humans; Labor, Obstetric; Male; Oxytocin; Pregnancy

Individuals with ASD are known to have a tendency to have tactile sensory processing issues that could be associated with their impairment as regards social communication. The alterations in tactile processing in autistic subjects are usually accompanied by hypersensitivity and other unpleasant emotions induced by tactile contact. In our study, we investigated the impact of the velocity and the force of a tactile stroke received impersonally by a custom-built robotic device. A total of 21 adults with ASD and 22 adults from a control group participated in our study. The participants' responses were assessed according to subjective scales, EEG changes, and the dynamics of saliva antioxidants and oxytocin. It was found that the oxytocin level was significantly lower in subjects with ASD but increased after tactile stimulation. However, contrary to expectations, the increase in the oxytocin level in the target group negatively correlated with the subjective pleasantness of tactile stimulation and was probably associated with a stress-induced effect. The basic levels of antioxidants did not differ between the TD and ASD groups; however, these had significantly increased in individuals with ASD by the end of the study. The EEG findings, which revealed enhanced antioxidant levels, contributed to the relief of the cognitive control during the study.

Topics: Adult; Antioxidants; Autism Spectrum Disorder; Humans; Oxytocin; Robotic Surgical Procedures; Touch

This chapter provides an overview of the oxytocinergic system and its role in social behavior. We first consider the relationship between oxytocin and social behavior in neurotypical individuals, focusing on studies that have looked at effects of intranasal oxytocin treatment, as well as research investigating the genetic and epigenetic mechanisms associated with individual differences in social behavior. We then outline the proposed role of the oxytocinergic system in autism spectrum disorder and Williams syndrome, two neurodevelopmental disorders where a dysfunctional oxytocinergic system is thought to lead to difficulties in social behavior. Given the contrasting social phenotypes of these disorders, they provide an intriguing comparison through which we can better understand the role of the oxytocinergic system in social behavior. Finally, we consider how future research can best harness the potential of oxytocin, both by addressing measurement and administration issues inherent in many studies, and by developing our understanding of the oxytocinergic system so we are better able to identify the people who are likely to benefit from oxytocin treatment, and intervene at the right time.

Topics: Administration, Intranasal; Autism Spectrum Disorder; Central Nervous System; Humans; Oxytocin; Receptors, Oxytocin; Social Behavior

Administration of intranasal oxytocin has been found to improve social cognition in a number of brain conditions, including autism spectrum disorder and schizophrenia. Whether this approach is relevant in dementias is currently unknown, particularly in frontotemporal dementia, a younger-onset dementia characterized clinically by marked changes in social cognition and behavior and focal atrophy of the frontal and temporal lobes. This chapter provides an overview of the deficits in social cognition in frontotemporal dementia and reviews the emerging evidence of intranasal oxytocin administration as a potential treatment option for these deficits. Future research directions will also be discussed.

Topics: Autism Spectrum Disorder; Frontotemporal Dementia; Humans; Neuropsychological Tests; Oxytocin; Social Behavior

Topics: Autism Spectrum Disorder; Autistic Disorder; Humans; Oxytocin; Social Behavior

The neural basis of abnormal social behavior in autism spectrum disorders (ASDs) remains incompletely understood. Here we used two complementary but independent brain-wide mapping approaches, mouse resting-state fMRI and c-Fos-iDISCO+ imaging, to construct brain-wide activity and connectivity maps of the Cntnap2 knockout (KO) mouse model of ASD. At the macroscale level, we detected reduced functional coupling across social brain regions despite general patterns of hyperconnectivity across major brain structures. Oxytocin administration, which rescues social deficits in KO mice, strongly stimulated many brain areas and normalized connectivity patterns. Notably, chemogenetically triggered release of endogenous oxytocin strongly stimulated the nucleus accumbens (NAc), a forebrain nucleus implicated in social reward. Furthermore, NAc-targeted approaches to activate local oxytocin receptors sufficiently rescued their social deficits. Our findings establish circuit- and systems-level mechanisms of social deficits in Cntnap2 KO mice and reveal the NAc as a region that can be modulated by oxytocin to promote social interactions.

Topics: Animals; Autism Spectrum Disorder; Brain; Membrane Proteins; Mice; Mice, Knockout; Nerve Tissue Proteins; Oxytocin; Receptors, Oxytocin; Social Behavior

Various single nucleotide polymorphisms (SNPs) in the oxytocin receptor (OXTR) gene have been associated with behavioral traits, autism spectrum disorder (ASD) and other diseases. The non-synonymous SNP rs4686302 results in the OXTR variant A218T and has been linked to core characteristics of ASD, trait empathy and preterm birth. However, the molecular and intracellular mechanisms underlying those associations are still elusive. Here, we uncovered the molecular and intracellular consequences of this mutation that may affect the psychological or behavioral outcome of oxytocin (OXT)-treatment regimens in clinical studies, and provide a mechanistic explanation for an altered receptor function. We created two monoclonal HEK293 cell lines, stably expressing either the wild-type or A218T OXTR. We detected an increased OXTR protein stability, accompanied by a shift in Ca

Topics: Autism Spectrum Disorder; Female; HEK293 Cells; Humans; Infant, Newborn; Oxytocin; Pregnancy; Premature Birth; Receptors, Oxytocin; Structure-Activity Relationship

Several parents have recently asked me if oxytocin would be helpful for treating their children with autism spectrum disorder (ASD). What do we currently know about the use of oxytocin for the treatment of children with ASD?. Autism spectrum disorder is prevalent among children in Canada, with most affected children experiencing difficulties with social function. Behavioural and educational interventions are the first-line treatments for children with ASD. Multiple studies of oxytocin in children with ASD from the past 2 decades provide equivocal results related to social functioning, and a recent large study did not show benefit from treatment with oxytocin. Small sample sizes and differences in participant age, oxytocin formulation and dose, treatment duration, outcome measures, and analytic methods may help explain some of these disparities. The fact that ASD has a range of clinical presentations may also contribute to mixed results. The use of oxytocin has limited benefit in changing social function in children with ASD and there is no support for its current use in the treatment of this population.

Topics: Administration, Intranasal; Autism Spectrum Disorder; Canada; Child; Humans; Oxytocin; Parents

The outcomes of supplementation with L-carnosine have been investigated in clinical trials in children with autism spectrum disorder (ASD). However, reports on the effects of L-carnosine in humans have been inconsistent, and the efficacy of L-carnosine supplementation for improving ASD symptoms has yet to be investigated in animal studies. Here, we examined the effects of oral supplementation with L-carnosine on social deficits in CD157KO mice, a murine model of ASD. Social deficits in CD157KO mice were assessed using a three-chamber social approach test. Oral supplementation with L-carnosine attenuated social behavioral deficits. The number of c-Fos-positive oxytocin neurons in the supraoptic nucleus and paraventricular nucleus was increased with L-carnosine supplementation in CD157KO mice after the three-chamber social approach test. We observed an increase in the number of c-Fos-positive neurons in the basolateral amygdala, a brain region involved in social behavior. Although the expression of oxytocin and oxytocin receptors in the hypothalamus was not altered by L-carnosine supplementation, the concentration of oxytocin in cerebrospinal fluid was increased in CD157KO mice by L-carnosine supplementation. These results suggest that L-carnosine supplementation restores social recognition impairments by augmenting the level of released oxytocin. Thus, we could imply the possibility of a safe nutritional intervention for at least some types of ASD in the human population.

Topics: Animals; Autism Spectrum Disorder; Carnosine; Dietary Supplements; Mice; Oxytocin; Receptors, Oxytocin

Zebrafish are highly social teleost fish and an excellent model to study social behavior. The neuropeptide Oxytocin is associated different social behaviors as well as disorders resulting in social impairment like autism spectrum disorder. However, how Oxytocin receptor signaling affects the development and expression kinetics of social behavior is not known. In this study we investigated the role of the two oxytocin receptors, Oxtr and Oxtrl, in the development and maintenance of social preference and shoaling behavior in 2- to 8-week-old zebrafish. Using CRISPR/Cas9 mediated oxtr and oxtrl knock-out fish, we found that the development of social preference is accelerated if one of the Oxytocin receptors is knocked-out and that the knock-out fish reach significantly higher levels of social preference. Moreover, oxtr

Topics: Animals; Autism Spectrum Disorder; Oxytocin; Receptors, Oxytocin; Social Behavior; Zebrafish

Impairment of social functioning skills is a key hallmark of autism. The neuropeptide oxytocin (OXT) is a blood-based biomarker of social functioning, and a candidate for individualized treatment of ASD. The effects of OXT on the social brain are mediated by the OXT receptor (OXTR). This study assessed the clinical utility of blood OXT serum levels and the OXT receptor (OXTR) genotype as biomarkers of autism and its severity in a pediatric population in Iraq.. Blood samples were collected from patients with a clinical diagnosis of ASD (n = 60) and corresponding age and gender matched healthy controls (n = 60). All clinical samples were processed at the Department of Pathology and Forensic Medicine, Faculty of Medicine, University of Kufa in Iraq. Blood serum was assayed for OXT by sandwich ELISA. Receiver operator analysis (ROC) determined area under the curve (AUC), cutoff values, and sensitivity and specificity of OXT values for accuracy of diagnosis of ASD. Isolated genomic DNA was genotyped for the OXTR gene rs2268491(C/T) SNP using allele-specific PCR. The significance of genotype (CC, CT, and TT) and allele (C and T) distributions in different patient groups was assessed using odd ratios (OR) with 95% confidence intervals (CI) and the Chi-square test. All statistical analysis was performed used SPSS software.. Study characteristics in the ASD population revealed a high level of consanguinity (36.66%), and ASD recurrence rate (11.66%) and family history (28.33%). OXT levels in patients with ASD (157.58±28.81 pg/ml) were significantly higher (p = 0.003) compared to controls (75.03±6.38 pg/ml). Within stratified ASD severity groups-OXT levels were significantly different (P = 0.032). ROC analysis determined similar AUC values for overall ASD (0.807), and stratified mild (0.793), moderate (0.889), and severe categories (0.795). The best cutoff for diagnosis of ASD was 83.8 pg/ml OXT with a sensitivity and specificity of 80% and 72.1% respectively. OXTR gene rs2268491(C/T) genotyping found that ASD patients have significantly lower (p = 0.021) genotype CC frequency and a significantly higher (p = 0.04) occurrence of the heterozygous CT genotype relative to controls. ASD subjects produced highest OXT levels with the TT genotype. T allele distribution was higher in ASD males. ASD males had significantly lower distribution of the CC genotype (48.89%) compared to females (80%) (Chi-square test: χ2 = 4.43, df = 1, p = 0.035). Whereas distribution of the CT genotype was significantly higher in autistic males (44.45%) compared to females (13.33%) (Chi-square test: χ2 = 4.68, df = 1, p = 0.03).. Peripheral OXT levels and OXTR genetic alterations are potential biomarkers of social functioning in the ASD patient setting. The stratification of patients with ASD into severity categories shows significant differences both in OXT levels and OXTR (rs2268491, C/T) genotype and allele distributions, that can be sex dependent. OXT based therapies will require personalized medicine tactics to correctly identify patients with ASD who require neuropeptide boosting in social settings.

Topics: Autism Spectrum Disorder; Biomarkers; Case-Control Studies; Child; Female; Humans; Iraq; Male; Neuropeptides; Oxytocin; Polymorphism, Genetic; Precision Medicine; Receptors, Oxytocin; Serum

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by specific social symptoms, restricted interests, stereotyped repetitive behaviors, and delayed language development. The 3q29 microdeletion (3q29del), a recurrent copy number variant, confers a high risk for ASD and schizophrenia, and serves as an important pathological model for investigating the molecular pathogenesis of a large number of neurodevelopmental and psychiatric conditions. Recently, mouse models carrying a deletion of the chromosomal region corresponding to the human 3q29 region (Df/+ mice) were generated and demonstrated neurodevelopmental and psychiatric conditions associated behavioral abnormalities, pointing to the relevance of Df/+ mice as a model for these conditions with high construct and face validity. Currently, the molecular pathogenesis of these behavioral phenotypes in Df/+ mice remains unclear. The oxytocin (OXT) system plays a central role in social behavior across species and has a potential role in ASD. In this study, to elucidate the molecular mechanisms behind impaired social behavior in Df/+ mice, we investigated the possible involvement of OXT signaling in impaired social behavior in Df/+ mice. We demonstrated that OXT administration restored the impaired social behavior in Df/+ mice. We also demonstrated that the number of OXT-positive cells in the paraventricular nucleus (PVN) was significantly lower in Df/+ mice than in wild-type (WT) littermates. Consistent with this, the level of OXT peptide in the cerebral cortex of Df/+ mice was lower than in WT littermates. Our study may provide important insights into the molecular pathophysiological basis of neurodevelopmental and psychiatric conditions, including ASD.

Topics: Animals; Autism Spectrum Disorder; Brain; Chromosome Deletion; Chromosomes, Human, Pair 3; Developmental Disabilities; Disease Models, Animal; Intellectual Disability; Mice; Oxytocin; Social Behavior

Decreased attention to social information is considered an early emerging symptom of autism spectrum disorder (ASD), although the underlying causes remain controversial. Here we explored the impact of nonsocial object salience on reduced attention to social stimuli in male ASD compared with typically developing (TD) children. Correlations with blood concentrations of neuropeptides linked with social cognition were also investigated. Eye-tracking was performed in 102 preschool-aged boys (50 ASD, 52 TD) using a paradigm with social (faces) versus nonsocial (objects) stimuli presented in pairs in two conditions where nonsocial stimulus salience was varied. Basal oxytocin (OXT) and vasopressin concentrations were measured in blood. Compared with TD boys those with ASD viewed social stimuli less only when they were paired with low-salience nonsocial objects. Additionally, boys with ASD spent less time than TD ones viewing facial features, particularly the eyes. In TD boys, OXT concentrations and cognitive development scores were positively associated with time spent viewing the eye region, whereas for boys with ASD associations with time spent viewing faces were negative. Reduced gaze toward social stimuli in ASD relative to TD individuals may therefore be influenced by how salient the paired nonsocial objects are for the latter. On the other hand, reduced interest in the eyes of faces in boys with ASD is not influenced by how salient competing nonsocial stimuli are. Basal OXT concentrations and cognitive development scores are predictive of time spent viewing social stimuli in TD boys (eyes) and those with ASD (faces) but in the opposite direction. LAY SUMMARY: Children with autism exhibit reduced attention to social paired with nonsocial stimuli compared to typically developing children. Using eye-tracking we show this difference is due to typically developing rather than autistic boys being more influenced by how interesting competing nonsocial objects are. On the other hand, reduced time looking at the eyes in autistic relative to typically developing boys is unaffected by nonsocial object salience. Time spent viewing social stimuli is associated with cognitive development and blood levels of oxytocin.

Topics: Autism Spectrum Disorder; Autistic Disorder; Child; Child, Preschool; Eye Movements; Eye-Tracking Technology; Humans; Male; Oxytocin

Atypical responses to sensory stimuli are considered as a core aspect and early life marker of autism spectrum disorders (ASD). Although recent findings performed in mouse ASD genetic models report sensory deficits, these were explored exclusively during juvenile or adult period. Whether sensory dysfunctions might be present at the early life stage and rescued by therapeutic strategy are fairly uninvestigated. Here we found that under cool environment neonatal mice lacking the autism-associated gene Magel2 present pup calls hypo-reactivity and are retrieved with delay by their wild-type dam. This neonatal atypical sensory reactivity to cool stimuli was not associated with autonomic thermoregulatory alteration but with a deficit of the oxytocinergic system. Indeed, we show in control neonates that pharmacogenetic inactivation of hypothalamic oxytocin neurons mimicked atypical thermosensory reactivity found in Magel2 mutants. Furthermore, pharmacological intranasal administration of oxytocin to Magel2 neonates was able to rescue both the atypical thermosensory response and the maternal pup retrieval. This preclinical study establishes for the first-time early life impairments in thermosensory integration and suggest a therapeutic potential benefit of intranasal oxytocin treatment on neonatal atypical sensory reactivity for autism.

Topics: Administration, Intranasal; Age Factors; Animals; Antigens, Neoplasm; Autism Spectrum Disorder; Autistic Disorder; Central Nervous System Agents; Female; Hypesthesia; Hypothalamus; Maternal Behavior; Mice; Oxytocin; Proteins; Social Behavior

Although initially showing great potential, oxytocin treatment has encountered a translational hurdle in its promise of treating the social deficits of autism. Some debate surrounds the ability of oxytocin to successfully enter the brain, and therefore modify neuroanatomy. Moreover, given the heterogeneous nature of autism, treatment will only amerliorate symptoms in a subset of patients. Therefore, to determine whether oxytocin changes brain circuitry, and whether it does so variably, depending on genotype, we implemented a large randomized, blinded, placebo-controlled, preclinical study on chronic intranasal oxytocin treatment in three different mouse models related to autism with a focus on using neuroanatomical phenotypes to assess and subset treatment response. Intranasal oxytocin (0.6IU) was administered daily, for 28 days, starting at 5 weeks of age to the 16p11.2 deletion, Shank3 (exon 4-9) knockout, and Fmr1 knockout mouse models. Given the sensitivity of structural magnetic resonance imaging (MRI) to the neurological effects of interventions like drugs, along with many other advantages, the mice underwent in vivo longitudinal and high-resolution ex vivo imaging with MRI. The scans included three in vivo T1weighted, 90 um isotropic resolution scans and a T2-weighted, 3D fast spin echo with 40um isotropic resolution ex vivo scan to assess the changes in neuroanatomy using established automated image registration and deformation based morphometry approaches in response to oxytocin treatment. The behavior of the mice was assessed in multiple domains, including social behaviours and repetitive behaviours, among others. Treatment effect on the neuroanatomy did not reach significance, although the pattern of trending effects was promising. No significant effect of treatment was found on social behavior in any of the strains, although a significant effect of treatment was found in the Fmr1 mouse, with treatment normalizing a grooming deficit. No other treatment effect on behavior was observed that survived multiple comparisons correction. Overall, chronic treatment with oxytocin had limited effects on the three mouse models related to autism, and no promising pattern of response susceptibility emerged.

Topics: Administration, Intranasal; Animals; Autism Spectrum Disorder; Autistic Disorder; Disease Models, Animal; Fragile X Mental Retardation Protein; Humans; Mice; Microfilament Proteins; Nerve Tissue Proteins; Neuroanatomy; Oxytocin; Random Allocation; Social Behavior

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high phenotypic and genetic heterogeneity. The common variants of specific oxytocin-related genes (OTRGs), particularly OXTR, are associated with the aetiology of ASD. The contribution of rare genetic variations in OTRGs to ASD aetiology remains unclear.. We catalogued publicly available de novo mutations (DNMs) [from 6,511 patients with ASD and 3,391 controls], rare inherited variants (RIVs) [from 1,786 patients with ASD and 1,786 controls], and both de novo copy number variations (dnCNVs) and inherited CNVs (ihCNVs) [from 15,581 patients with ASD and 6,017 controls] in 963 curated OTRGs to explore their contribution to ASD pathology, respectively. Finally, a combined model was designed to prioritise the contribution of each gene to ASD aetiology by integrating DNMs and CNVs.. The rare genetic variations of OTRGs were significantly associated with ASD aetiology, in the order of dnCNVs > ihCNVs > DNMs. Furthermore, 172 OTRGs and their connected 286 ASD core genes were prioritised to positively contribute to ASD aetiology, including top-ranked MAPK3. Probands carrying rare disruptive variations in these genes were estimated to account for 10∼11% of all ASD probands.. Our findings suggest that rare disruptive variations in 172 OTRGs and their connected 286 ASD core genes are associated with ASD aetiology and may be potential biomarkers predicting the effects of oxytocin treatment.. Guangdong Key Project, National Natural Science Foundation of China, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province.

Topics: Autism Spectrum Disorder; Biomarkers; DNA Copy Number Variations; Genetic Predisposition to Disease; Humans; Oxytocin

Topics: Autism Spectrum Disorder; Humans; Oxytocin; Social Behavior

Oxytocin is a neuropeptide synthesized in the hypothalamus. In addition to its role in parturition and lactation, oxytocin mediates social behavior and pair bonding. The possibility of using oxytocin to modify behavior in neurodevelopmental disorders, such as autism spectrum disorder, is of clinical interest. Microglia are tissue-resident macrophages with roles in neurogenesis, synapse pruning, and immunological mediation of brain homeostasis. Recently, oxytocin was found to attenuate microglial secretion of proinflammatory cytokines, but the source of this oxytocin was not established. This prompted us to investigate whether microglia themselves were the source.. We examined oxytocin expression in human and murine brain tissue in both sexes using immunohistochemistry. Oxytocin mRNA expression and secretion were examined in isolated murine microglia from wild type and oxytocin-knockout mice. Also, secretion of oxytocin and cytokines was measured in cultured microglia (MG6) stimulated with lipopolysaccharide (LPS).. We identified oxytocin expression in microglia of human brain tissue, cultured microglia (MG6), and primary murine microglia. Furthermore, LPS stimulation increased oxytocin mRNA expression in primary murine microglia and MG6 cells, and oxytocin secretion as well. A positive correlation between oxytocin and IL-1β, IL-10 secretion emerged, respectively.. This may be the first demonstration of oxytocin expression in microglia. Functionally, oxytocin might regulate inflammatory cytokine release from microglia in a paracrine/autocrine manner.

Topics: Animals; Autism Spectrum Disorder; Cells, Cultured; Cytokines; Female; Humans; Lipopolysaccharides; Male; Mice; Mice, Knockout; Microglia; Oxytocin; RNA, Messenger

Topics: Animals; Autism Spectrum Disorder; Female; Humans; Male; Mammals; Oxytocin; Pars Compacta; Receptors, Oxytocin; RNA, Messenger; Substantia Nigra

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by deficits in social behaviour, increased repetitive behaviour, anxiety and gastrointestinal symptoms. The aetiology of ASD is complex and involves an interplay of genetic and environmental factors. Emerging pre-clinical and clinical studies have documented a potential role for the gut microbiome in ASD, and consequently, the microbiota represents a potential target in the development of novel therapeutics for this neurodevelopmental disorder. In this study, we investigate the efficacy of the live biotherapeutic strain, Blautia stercoris MRx0006, in attenuating some of the behavioural deficits in the autism-relevant, genetic mouse model, BTBR T+ Itpr3tf/J (BTBR). We demonstrate that daily oral administration with MRx0006 attenuates social deficits while also decreasing repetitive and anxiety-like behaviour. MRx0006 administration increases the gene expression of oxytocin and its receptor in hypothalamic cells in vitro and increases the expression of hypothalamic arginine vasopressin and oxytocin mRNA in BTBR mice. Additionally at the microbiome level, we observed that MRx0006 administration decreases the abundance of Alistipes putredinis, and modulates the faecal microbial metabolite profile. This alteration in the metabolite profile possibly underlies the observed increase in expression of oxytocin, arginine vasopressin and its receptors, and the consequent improvements in behavioural outcomes. Taken together, these findings suggest that the live biotherapeutic MRx0006 may represent a viable and efficacious treatment option for the management of physiological and behavioural deficits associated with ASD.

Topics: Animals; Anxiety; Arginine Vasopressin; Autism Spectrum Disorder; Autistic Disorder; Clostridiales; Disease Models, Animal; Mice; Mice, Inbred Strains; Oxytocin; RNA, Messenger

Autism is a neurodevelopmental disorder with a neurobiological basis, characterized by a qualitative disturbance in social interaction and communication, associated with restricted interests and stereotyped behaviors. The genesis of autism cannot be interpreted through a single theory, and we can't compartmentalize brain areas as the only ones responsible for it. Among the neurobiological bases we can include: deficit in the social reward system, which generates poor social initiative; dysfunctions and disorders of the amygdala and the mirror neuron system, related to compromised empathy and social cognition; abnormalities in the minicolumns related to hyper-systematization; persistent inflammatory phenomena of the central nervous system related to microglia; alterations of neuropeptides such as oxytocin, vasopressin and cortisol, which compromise socialization, and neuronal inhibition disorders, expressed in GABAergic dysfunctions in interneurons, linked to autistic behaviors, epilepsy and sensory phenomena. Understanding the neurobiological bases of autism is complex and there is no single explanation or specific biological marker. However, identifying processes related to social cognition, molecular, inflammatory, neuromodulation mechanisms and bases linked to sensory disorders are fundamental elements.. El autismo es un trastorno del neurodesarrollo de base neurobiológica, caracterizado por una alteración cualitativa en la interacción social y la comunicación, asociado a intereses restringidos y conductas estereotipadas. La génesis del autismo no puede interpretarse a través de una sola teoría, tampoco podemos compartimentalizar áreas del cerebro como únicos responsables de la misma. Entre las bases neurobiológicas podemos incluir: déficit en el sistema de recompensa social, lo cual genera pobre iniciativa social; disfunciones y trastornos de la amígdala y el sistema de neuronas espejo, relacionadas al compromiso en la empatía y la cognición social; anormalidades en las minicolumnas relacionadas con la hiper-sistematización; fenómenos inflamatorios persistentes del sistema nervioso central relacionados a la microglía; alteraciones de los neuropéptidos como oxitocina, vasopresina y cortisol, que comprometen la socialización, y trastornos en la inhibición neuronal, expresados en disfunciones gabaérgicas en las inteneuronas, vinculadas a conductas autistas, epilepsia y fenómenos sensoriales. La comprensión de las bases neurobiológicas del autismo son complejas y no existe un marcador biológico específico. Sin embargo, identificar procesos relacionados a la cognición social, mecanismos moleculares, inflamatorios, de neuromodulación y bases vinculadas a trastornos sensoriales son elementos fundamentales.

Topics: Autism Spectrum Disorder; Autistic Disorder; Brain; Humans; Oxytocin; Social Behavior

Gut microbes can modulate almost all aspects of host physiology throughout life. As a result, specific microbial interventions are attracting considerable attention as potential therapeutic strategies for treating a variety of conditions. Nonetheless, little is known about the mechanisms through which many of these microbes work. Recently, we and others have found that the commensal bacterium Limosilactobacillus reuteri (formerly Lactobacillus reuteri) reverses social deficits in several mouse models (genetic, environmental, and idiopathic) for neurodevelopmental disorders in a vagus nerve-, oxytocin-, and biopterin-dependent manner. Given that gut microbes can signal to the brain through the immune system and L. reuteri promotes wound healing via the adaptive immune response, we sought to determine whether the prosocial effect mediated by L. reuteri also depends on adaptive immunity. Here, we found that the effects of L. reuteri on social behavior and related changes in synaptic function are independent of the mature adaptive immune system. Interestingly, these findings indicate that the same microbe (L. reuteri) can affect different host phenotypes through distinct mechanisms.

Topics: Animals; Autism Spectrum Disorder; Immune System; Limosilactobacillus reuteri; Mice; Oxytocin; Social Behavior

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social behaviors and communication. In rodents and humans, prenatal exposure to antiepileptic valproic acid is associated with an increased risk for autistic-like characteristics. One potential treatment is oxytocin, a prosocial neuropeptide that can be delivered intranasally. However, the sex-specific effects of valproic acid exposure and intranasal oxytocin treatment on behavior have not been fully explored. Pregnant Long Evans rats were administered valproic acid (500 mg/kg) or saline midday on gestational day 12, and after weaning, male and female pups were assigned to control (saline-saline), valproic acid-saline, or valproic acid-oxytocin groups. Oxytocin (0.8 IU/kg) or saline was delivered intranasally 30-60 min before tests for anxiety-like behaviors (elevated plus maze), social interactions (sociability) and sociosexual behaviors (partner preference, 50 kHz vocalizations and scent marking). Prenatal exposure to valproic acid resulted in sex-specific differences in behavior. When compared to controls, valproic acid males showed enhanced anxiety-like behaviors in adolescence and fewer scent marks in adulthood, while valproic acid females showed reduced sexual (partner) preference as adults. Intranasal oxytocin was anxiolytic for valproic acid males, but moderately anxiogenic for valproic acid females, and in both sexes it surprisingly impaired social interactions in the sociability test. Furthermore, intranasal oxytocin failed to improve sociosexual deficits in valproic acid rats. These findings highlight the importance of conducting preclinical studies in both sexes, and suggest that oxytocin may be an effective treatment in animal models with heightened anxiety-like behaviors.

Topics: Administration, Intranasal; Animals; Anti-Anxiety Agents; Anticonvulsants; Autism Spectrum Disorder; Behavior, Animal; Female; Male; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Long-Evans; Sex Factors; Sexual Behavior, Animal; Social Behavior; Valproic Acid

Topics: Autism Spectrum Disorder; Humans; Oxytocin; Social Behavior

Some studies have indicated an increased risk of attention deficit hyperactivity disorder (ADHD) and a small, sex-specific association with autism spectrum disorder (ASD) among children prenatally exposed to obstetric oxytocin. Since oxytocin is widely used in the obstetric ward, these potentially deleterious effects are of concern. Thus, we aimed to examine whether obstetric oxytocin treatment for labour induction or augmentation is associated with ADHD and ASD in offspring born in a two-country design based on data from Denmark and Finland.. This population-based study used data from national registers in Denmark and Finland. Singletons born in Denmark 2000-10 (n = 577 380) and Finland 1991-2010 (n = 945 543), who survived infancy, were followed until 31 December 2015. ADHD and ASD were defined using diagnostic codes. For ADHD, we also included information on prescribed and redeemed ADHD medication in the definition. Hazards ratios (HRs) with 95% confidence intervals (CI), modelled with age as the underlying time scale, were calculated to estimate the associations.. Oxytocin was used in 31% and 46% of the included deliveries in Denmark and Finland, respectively. In crude analyses, prenatal oxytocin was associated with an approximately 20% increased risk of ADHD and ASD, but confounder adjustment attenuated the association. The adjusted HR was 1.03, 95% CI 1.01-1.05, for ADHD and 1.05, 95% CI 1.02-1.08, for ASD. The results were similar in across country and gender.. We found an association between synthetic oxytocin and ADHD or ASD which is unlikely to reflect a causal association and thus should not support the concern of clinical use. Our results help to allay concerns of obstetric use of oxytocin causing ADHD or ASD.

Topics: Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Child; Denmark; Female; Finland; Humans; Male; Oxytocin; Pregnancy

Topics: Autism Spectrum Disorder; Autistic Disorder; Epigenesis, Genetic; Humans; Oxytocin; Receptors, Oxytocin; Social Behavior

Many neurodevelopmental disorders (NDDs) share common learning and behavioural impairments, as well as features such as dysregulation of the oxytocin hormone. Here, we examined DNA methylation (DNAm) in the 1st intron of the oxytocin receptor gene, OXTR, in patients with autism spectrum (ASD), attention deficit and hyperactivity (ADHD) and obsessive compulsive (OCD) disorders. DNAm of OXTR was assessed for cohorts of ASD (blood), ADHD (saliva), OCD (saliva), which uncovered sex-specific DNAm differences compared to neurotypical, tissue-matched controls. Individuals with ASD or ADHD exhibiting extreme DNAm values had lower IQ and more social problems, respectively, than those with DNAm within normative ranges. This suggests that OXTR DNAm patterns are altered across NDDs and may be correlated with common clinical outcomes.

Topics: Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; DNA Methylation; Female; Humans; Male; Obsessive-Compulsive Disorder; Oxytocin; Receptors, Oxytocin

The underlying mechanism of oxytocin (OT) neurons in the development of social interaction remains unclear. In a recent study, Lewis et al. characterized OT neuronal subtypes and provided evidence that expression of the autism spectrum disorder (ASD) gene Fmr1 in parvocellular OT neurons is essential for peer-peer but not filial social interactions.

Topics: Autism Spectrum Disorder; Fragile X Mental Retardation Protein; Humans; Neurons; Oxytocin; Social Interaction

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZ

Topics: Administration, Intranasal; Animals; Autism Spectrum Disorder; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Humans; Mice; Mutation, Missense; Nerve Tissue Proteins; Neurons; Oxytocin; Point Mutation; Promoter Regions, Genetic; Protein Binding; Receptors, Oxytocin; Receptors, Vasopressin; Social Behavior; Transcription, Genetic; Transposases

Treatment-resistant schizophrenia (TRS) has a quite complex pathophysiology that includes not only severe positive symptoms but also other symptom domains. Much attention has been devoted to the overlapping psychological and biological profiles of schizophrenia and autistic spectrum disorder (ASD). We compared TRS patients (n = 30) with schizophrenia patients in remission (RemSZ, n = 28) and ASD patients (n = 28), focusing on general cognitive and social cognitive impairment and oxytocin system dysfunction. Our analyses revealed that there was no difference in oxytocin concentration among the three groups. The TRS patients' oxytocin blood concentrations were positively correlated with their processing speed and theory-of-mind scores, whereas the RemSZ and ASD groups had no significant relation with any measures. Rs53576, a single nucleotide polymorphism on the oxytocin receptor gene, affected social cognition abilities in the schizophrenia group. Although the overall findings are preliminary, they indicate that oxytocin system dysfunction could be involved in the serious cognitive deficits in TRS patients. Further, these results suggest that patients with TRS might have early neurodevelopmental abnormalities based on their shared biological features with ASD patients.

Topics: Autism Spectrum Disorder; Humans; Oxytocin; Polymorphism, Single Nucleotide; Receptors, Oxytocin; Schizophrenia

Cesarean section (C/S) is one way of delivering babies, and is chosen when mothers or babies are facing problems or life-threatening conditions during pregnancy. Many meta-analyses have suggested an etiological relationship between C/S delivery and autism spectrum disorders (ASDs). However, as a risk factor for ASDs, C/S delivery has not yet been well studied. Because C/S deliveries have been increasing, it is very important to investigate the causal association between C/S and ASDs. Here, using three approaches, we showed experimentally that C/S delivery induced ASD-like traits in offspring mice, and that some of these changes were ameliorated by one-time oxytocin (OXT) treatment. Treatment with OXT receptor antagonists before natural delivery also induced ASD-related behaviors. Moreover, wild-type mice born to OXT-KO dams showed similar changes. Thus, insufficient OXT exposure from dams to offspring during delivery may be a trigger for ASD-related behaviors.

Topics: Animals; Autism Spectrum Disorder; Cesarean Section; Female; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Oxytocin; Risk Factors

Topics: Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Female; Humans; Oxytocin; Pregnancy

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by communication disability with no curative treatment. Maternal separation-induced ultrasonic vocalisation (USV) was widely used to assess communication disability between pups and dams. Particularly, USV calls in many genetically modified ASD model mice were altered. Previously, we demonstrated that mice pups exposed to valproic acid in utero (VPA pups) showed decreased number of USV calls on postnatal day 11 and were rescued by subcutaneous injection of oxytocin. However, the qualitative change of USV calls by oxytocin has not been evaluated in VPA pups. In the present study, we examined the duration of oxytocin effect and analysed the altered pattern of USV calls using VPA pups. The oxytocin administration increased the total number of USV calls and the effect persisted up to 120 min in VPA pups. The pattern analysis revealed that the increase in the number of complex calls also persisted up to 120 min. These results suggested that oxytocin had a prolonged effect on USV calls, mainly on complex calls, in VPA pup, showing that oxytocin could recover their social modality to respond to maternal separation.

Topics: Animals; Autism Spectrum Disorder; Communication; Disease Models, Animal; Female; Humans; Male; Maternal Deprivation; Maternal Exposure; Mice; Oxytocin; Pregnancy; Social Interaction; Ultrasonic Waves; Valproic Acid; Vocalization, Animal

Untreated perinatal depression can have severe consequences for the mother and her children. However, both the efficacy to mothers and safety to exposed infants of pharmacological antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been questioned. We previously reported that maternal SSRI exposure increased hippocampal IL-1β levels, which may be tied to limited efficacy of SSRIs during the postpartum to the dam but is not yet known whether maternal postpartum SSRIs affect the neuroinflammatory profile of adult offspring. In addition, although controversial, perinatal SSRI exposure has been linked to increased risk of autism spectrum disorder (ASD) in children. Oxytocin (OT) is under investigation as a treatment for ASD, but OT is a large neuropeptide that has difficulty crossing the blood-brain barrier (BBB). Triozan

Topics: Adult Children; Animals; Autism Spectrum Disorder; Doublecortin Protein; Female; Fluoxetine; Hippocampus; Humans; Inflammation; Male; Neurogenesis; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Stress, Psychological

Evidence suggests that intranasal application of oxytocin facilitates empathy and modulates its underlying neural processes, which are often impaired in individuals with autism spectrum disorders (ASD). Oxytocin has therefore been considered a promising candidate for the treatment of social difficulties in ASD. However, evidence linking oxytocin treatment to social behavior and brain function in ASD is limited and heterogeneous effects might depend on variations in the oxytocin-receptor gene (OXTR). We examined 25 male ASD patients without intellectual disability in a double-blind, cross-over, placebo-controlled fMRI-protocol, in which a single dose of oxytocin or placebo was applied intranasally. Patients performed three experiments in the MRI examining empathy for other's physical pain, basic emotions, and social pain. All participants were genotyped for the rs53576 single-nucleotide polymorphism of the OXTR. Oxytocin increased bilateral amygdala responsiveness during the physical pain task for both painful and neutral stimuli. Other than that, there were no effects of oxytocin treatment. OXTR genotype did not significantly interact with oxytocin treatment. Our results contribute to the growing body of empirical literature suggesting heterogenous effects of oxytocin administration in ASD. To draw clinically relevant conclusions regarding the usefulness of oxytocin treatment, however, empirical studies need to consider methods of delivery, dose, and moderating individual factors more carefully in larger samples.

Topics: Administration, Intranasal; Adolescent; Adult; Autism Spectrum Disorder; Brain; Double-Blind Method; Empathy; Genotype; Humans; Magnetic Resonance Imaging; Male; Oxytocin; Receptors, Oxytocin; Social Behavior; Translational Research, Biomedical; Young Adult

The efficacy and reliability of using intranasal oxytocin (OT) to clinically enhance social functions remains undependable. We discuss the potential benefit of concurrent administration of OT and naloxone (NAL) to robustly modulate social behavior. We further suggest that combinatorial neuropharmacology approaches should exploit the interactions between OT and serotonin to regulate social functions.

Topics: Autism Spectrum Disorder; Humans; Neuropharmacology; Oxytocin; Reproducibility of Results; Social Behavior; Social Cognition

Intranasal oxytocin (IN OXT) has been proposed as a treatment for autism spectrum disorder (ASD); however, little is known about the effects of long-term exposure. This is the first study in a non-human primate species to examine how developmental exposure to chronic IN OXT affects juvenile's interactions with family members, social preference for parents versus strangers, anxiety-like behavior, and cerebral glucose metabolism. Titi monkeys are socially monogamous and biparental; their family bonds share important characteristics with human family bonds. Fourteen males and 15 females were treated intranasally with saline (n = 14) or 0.8 IU/kg OXT (n = 15), daily from 12 to 18 months of age. Compared to SAL-treated animals, OXT-treated animals of both sexes spent significantly more time grooming other family members (F

Topics: Administration, Intranasal; Animals; Anxiety; Autism Spectrum Disorder; Behavior, Animal; Callicebus; Female; Glucose; Male; Models, Animal; Oxytocin; Sex Factors; Social Behavior

The role of oxytocin in social cognition has attracted tremendous interest in social neuroscience and psychiatry. Some studies have reported improvement in social symptoms following oxytocin treatment in autism spectrum disorders (ASD), while others point to endogenous factors influencing its efficiency and to mixed results in terms of long-term clinical benefits. Epigenetic modification to the oxytocin receptor gene (OXTR) in ASD could be an informative biomarker of treatment efficacy. Yet, little is known about the relationship between OXTR methylation, clinical severity, and brain function in ASD. Here, we investigated the relationship between OXTR methylation, ASD diagnosis (in N = 35 ASD and N = 64 neurotypical group), measures of social responsiveness, and resting-state functional connectivity (rsFC) between areas involved in social cognition and reward processing (in a subset of ASD, N = 30). Adults with ASD showed higher OXTR methylation levels in the intron 1 area compared with neurotypical subjects. This hypermethylation was related to clinical symptoms and to a hypoconnectivity between cortico-cortical areas involved in theory of mind. Methylation at a CpG site in the exon 1 area was positively related to social responsiveness deficits in ASD and to a hyperconnectivity between striatal and cortical brain areas. Taken together, these findings provide initial evidence for OXTR hypermethylation in the intron area as a potential biomarker for adults with ASD with less severe developmental communication deficits, but with impairments in theory of mind and self-awareness. Also, OXTR methylation in the exon 1 area could be a potential biomarker of sociability sensitive to life experiences.

Topics: Adult; Autism Spectrum Disorder; Autistic Disorder; Brain; Epigenesis, Genetic; Humans; Oxytocin; Receptors, Oxytocin; Site-Specific DNA-Methyltransferase (Adenine-Specific)

Oxytocin is a hormone naturally produced in the human body that can make the womb (uterus) contract during labor. Manufactured oxytocin is frequently given to mothers in labor to strengthen the contractions or in some cases to start labor. This study compared children with a diagnosis of autism and children without autism to see whether children with autism received more oxytocin during labor. The odds of a child having an autism diagnosis were significantly higher if the delivery was a first-time Cesarean section, if the mother had a body mass index of 35 or higher, or if the reason for delivery were a range of fetal problems that made delivery necessary. It was found that boys who were exposed to oxytocin for longer periods of time during labor and received higher total doses of oxytocin had significantly higher odds of developing autism. There were no significant associations of oxytocin dosing and autism noted in female children. As this is the first study to look at any relationship between the dose of oxytocin received during labor and the odds of developing autism, further study needs to be done to determine whether there is any cause and effect relationship. Thus, at this time, there is no recommended change in clinical practice.

Topics: Autism Spectrum Disorder; Autistic Disorder; Cesarean Section; Child; Female; Humans; Labor, Obstetric; Male; Oxytocin; Pregnancy

Autism spectrum disorder (ASD) is a neurodevelopmental disorder estimated by the World Health Organization to occur in one of 160 children worldwide. No pharmaceutical treatments are available to improve the deficits in social communication that are common symptoms of ASD. Recent clinical trials have focused on the nasal application of oxytocin, a neuronal peptide known to regulate a variety of social behaviours. However, the effect of oxytocin on this deficit is inconclusive. By contrast, evidence from ASD animal model studies indicates that when animals are treated with oxytocin during early development, improvements in social deficits are observed in adulthood. Thus, it is necessary to examine the effect of therapeutic target medication prescribed in early development. Mice prenatally exposed to valproic acid (VPA) are widely used as an animal model of ASD. However, many behavioural studies have been conducted during adulthood rather than early development. To establish a screening system to identify therapeutic drugs that are effective when delivered during the early postnatal period, it is important to examine the early developmental changes in their communicative behaviours. In the present study, we examined the ultrasonic vocalisation (USV) of VPA-exposed mice pups during their early postnatal developmental days. USV rates were comparable to those of the controls until the first week of their life but declined more on postnatal day 11. We checked the expression of oxytocin system in the hypothalamus and found the down-regulation of oxytocin and CD38, and up-regulation of oxytocin receptor in the VPA pups. Acute administration of oxytocin on postnatal day 11 increased the call rate of VPA pups. Taken together, we have demonstrated there was a deficiency in the oxytocinergic signalling in the VPA pups and also shown the existence of time periods that are effective with respect to screening the therapeutic drugs.

Topics: ADP-ribosyl Cyclase 1; Animals; Autism Spectrum Disorder; Disease Models, Animal; Female; Maternal Deprivation; Mice; Mice, Inbred ICR; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, Oxytocin; Social Behavior; Valproic Acid; Vocalization, Animal

Topics: Arginine Vasopressin; Autism Spectrum Disorder; Autistic Disorder; Biomarkers; Female; Humans; Infant; Infant, Newborn; Male; Medical Records; Neuropeptides; Neurophysins; Oxytocin; Prospective Studies; Protein Precursors; Social Behavior; Vasopressins

Oxytocin (OT) is a critical molecule for social recognition and memory that mediates social and emotional behaviours. In addition, OT acts as an anxiolytic factor and is released during stress. Based on the activity of CD38 as an enzyme that produces the calcium-mobilizing second messenger cyclic ADP-ribose (cADPR), CD157, a sister protein of CD38, has been considered a candidate mediator for the production and release of OT and its social engagement and anti-anxiety functions. However, the limited expression of CD157 in the adult mouse brain undermined confidence that CD157 is an authentic and/or actionable molecular participant in OT-dependent social behaviour. Here, we show that CD157 knockout mice have low levels of circulating OT in cerebrospinal fluid, which can be corrected by the oral administration of nicotinamide riboside, a recently discovered vitamin precursor of nicotinamide adenine dinucleotide (NAD). NAD is the substrate for the CD157- and CD38-dependent production of cADPR. Nicotinamide riboside corrects social deficits and fearful and anxiety-like behaviours in CD157 knockout males. These results suggest that elevating NAD levels with nicotinamide riboside may allow animals with cADPR- and OT-forming deficits to overcome these deficits and function more normally.

Topics: ADP-ribosyl Cyclase; Animals; Antigens, CD; Anxiety; Autism Spectrum Disorder; Dietary Supplements; Disease Models, Animal; Female; GPI-Linked Proteins; Male; Mice; Mice, Mutant Strains; Niacinamide; Oxytocin; Pyridinium Compounds; Social Behavior

To describe the rationale, design, and methods of the Autism Centers of Excellence (ACE) network Study of Oxytocin in Autism to improve Reciprocal Social Behaviors (SOARS-B).. This phase 2 clinical trial was designed to evaluate the use of intranasal oxytocin treatment to improve social difficulties in individuals with autism spectrum disorder (ASD). In total, 290 participants ages 3 to 17 years with a DSM-5 diagnosis of ASD were enrolled to receive 24 weeks of treatment with either oxytocin or a matched placebo at one of seven collaborating sites. Participants were subsequently treated with open-label oxytocin for 24 additional weeks. Post-treatment assessments were done approximately 4 weeks after treatment discontinuation. Plasma oxytocin and oxytocin receptor gene (OXTR) methylation level were measured at baseline, and week 8, 24 and 36 to explore potential relationships between these biomarkers and treatment response.. This report describes the rationale, design, and methods of the SOARS-B clinical trial.. There is a tremendous unmet need for safe and effective pharmacological treatment options that target the core symptoms of ASD. Several studies support the hypothesis that intranasal oxytocin could improve social orienting and the salience of social rewards in ASD, thereby enhancing reciprocal social behaviors. However, due to conflicting results from a number of pilot studies on the prosocial effects of exogenous oxytocin, this hypothesis remains controversial and inconclusive. SOARS-B is the best powered study to date to address this hypothesis and promises to improve our understanding of the safety and efficacy of intranasal oxytocin in the treatment of social deficits in children with ASD.

Topics: Administration, Intranasal; Adolescent; Autism Spectrum Disorder; Autistic Disorder; Child; Child, Preschool; Humans; Oxytocin; Social Behavior

Parallel processing circuits are thought to dramatically expand the network capabilities of the nervous system. Magnocellular and parvocellular oxytocin neurons have been proposed to subserve two parallel streams of social information processing, which allow a single molecule to encode a diverse array of ethologically distinct behaviors. Here we provide the first comprehensive characterization of magnocellular and parvocellular oxytocin neurons in male mice, validated across anatomical, projection target, electrophysiological, and transcriptional criteria. We next use novel multiple feature selection tools in Fmr1-KO mice to provide direct evidence that normal functioning of the parvocellular but not magnocellular oxytocin pathway is required for autism-relevant social reward behavior. Finally, we demonstrate that autism risk genes are enriched in parvocellular compared with magnocellular oxytocin neurons. Taken together, these results provide the first evidence that oxytocin-pathway-specific pathogenic mechanisms account for social impairments across a broad range of autism etiologies.

Topics: Animals; Autism Spectrum Disorder; Disease Models, Animal; Fragile X Mental Retardation Protein; Gene Knock-In Techniques; Male; Mice; Mice, Knockout; Neurons; Object Attachment; Oxytocin; Social Behavior

The aim of the current study was to compare levels of oxytocin, cortisol, and testosterone in adolescents with either autism spectrum disorder (ASD), or oppositional defiant disorder (ODD)/conduct disorder (CD), and in typically developing individuals (TDI), and relate hormone levels to severity and subtype of aggression and callous-unemotional (CU) traits. Saliva concentrations of oxytocin, cortisol, and testosterone were assessed in 114 male participants (N = 49 ASD, N = 37 ODD/CD, N = 28 TDI,) aged 12-19 years (M = 15.4 years, SD = 1.9). The ASD and the ODD/CD groups had significantly lower levels of oxytocin than the TDI group, and the ODD/CD group had significantly higher levels of testosterone than the ASD group. There were no group effects on cortisol levels. Group differences remained for oxytocin after correcting for the influence of CU traits, but were not significant after controlling for aggression. Results for testosterone became non-significant after correction for either CU traits or aggression. Across groups, higher levels of CU traits were related to higher levels of cortisol and testosterone, however, proactive and reactive aggression were unrelated to all three hormonal levels. The current findings show that, regardless of cognitive ability or comorbid disorders, the diagnostic groups (ASD, ODD/CD) differ from each other by their hormonal levels, with the ASD group characterized by relative low level of oxytocin, and the ODD/CD group by a relative low level of oxytocin and high level of testosterone. These group effects were partly driven by differences in CU traits between the groups.

Topics: Adolescent; Aggression; Attention Deficit and Disruptive Behavior Disorders; Autism Spectrum Disorder; Child; Conduct Disorder; Humans; Hydrocortisone; Male; Netherlands; Oxytocin; Saliva; Testosterone; Young Adult

The nonapeptide hormone oxytocin (OT) has pivotal brain roles in social recognition and interaction and is thus a promising therapeutic drug for social deficits. Because of its peptide structure, however, OT is rapidly eliminated from the bloodstream, which decreases its potential therapeutic effects in the brain. We found that newly synthesized OT analogues in which the Pro

Topics: ADP-ribosyl Cyclase 1; Animals; Autism Spectrum Disorder; Behavior, Animal; Calcium; Disease Models, Animal; Female; HEK293 Cells; Humans; Male; Membrane Glycoproteins; Mice; Mice, Inbred ICR; Mice, Knockout; Oxytocin; Receptors, Oxytocin; Social Behavior

Autism-affected individuals are characterized by lower plasma oxytocin and its ectoenzyme regulator CD38. Oxytocin, a hypothalamic hormone secreted upon the release of CD38, plays a role in social behavior and bonding. All-trans retinoic acid is a potent inducer of CD38 and can be used as a novel therapeutic strategy in autism. We investigated the role of beta-carotene in rescuing autistic-like behavior in BALB/c and BTBR mice. Beta-carotene derivatives are preferred as they are neither toxic nor teratogenic. Beta-carotene at 0.1-5.0 mg/kg was administered orally to BALB/c and BTBR newborn mice on days 1-7. They were tested at age 2-3 months for five behavioral tests for "autism"; in addition, brain CD38, oxytocin, oxytocin receptor, Brain Derived Neurotrophic Factor (BDNF) and retinoic acid receptor gene expression, serum oxytocin levels, and neurological score were evaluated. Beta-carotene administered at birth significantly increased T-maze alternations and led to longer time spent with an unfamiliar mouse in the "three-chamber test" and less time spent in the empty chamber. Furthermore, enhanced activity in the open field test; increased time spent in the reciprocal social interaction test; decreased grooming and bedding behaviors; and enhanced brain CD38, oxytocin, oxytocin receptor, BDNF, retinoic acid gene expression, and serum oxytocin levels. No changes in neurological score were observed. Beta-carotene oral supplementation to BALB/c and BTBR mice at birth significantly reduced restricted and stereotyped behaviors and interests, increased social interactions and communication, CD38, and oxytocin, probably by enhancing brain neuroplasticity without toxicity. Thus, beta-carotene administered after birth to newborns of families predisposed to "autism" has the potential to prevent/ameliorate" autistic like behavior". These results support further clinical studies.

Topics: ADP-ribosyl Cyclase 1; Animals; Animals, Newborn; Autism Spectrum Disorder; Autistic Disorder; Behavior, Animal; beta Carotene; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Female; Interpersonal Relations; Male; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Oxytocin; Receptors, Retinoic Acid; Social Behavior

Currently, there are no established pharmaceutical strategies that effectively treat social deficits in autism spectrum disorder (ASD). Oxytocin, a neurohormone that plays a role in multiple types of social behaviors, has been proposed as a possible therapeutic against social impairment and other symptoms in ASD. However, from the standpoint of pharmacotherapy, oxytocin has several liabilities as a standard clinical treatment, including rapid metabolism, low brain penetrance, and activity at the vasopressin (antidiuretic hormone) receptors. The present studies describe findings from a preclinical screening program to evaluate oxytocin receptor (OXTR) agonists and oxytocin metabolites for potential clinical use as more optimal treatments. We first investigated two synthetic oxytocin analogs, TC-OT-39 and carbetocin, using in vitro cell-based assays for pharmacological characterization and behavioral tests in the BALB/cByJ mouse model of ASD-like social deficits. Although both TC-OT-39 and carbetocin selectively activate the OXTR, neither synthetic agonist had prosocial efficacy in the BALB/cByJ model. We next evaluated two oxytocin metabolites: OT(4-9) and OT(5-9). While OT(5-9) failed to affect social deficits, the metabolite OT(4-9) led to significant social preference in the BALB/cByJ model, in a dose-dependent manner. The increased sociability was observed at both 24 h and 12 days following the end of a subchronic regimen with OT(4-9) (2.0 mg/kg). Overall, these results suggest that the prosocial effects of oxytocin could be mediated by downstream activity of oxytocin metabolites, raising the possibility of new pathways to target for drug discovery relevant to ASD.

Topics: Animals; Autism Spectrum Disorder; Compulsive Behavior; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Male; Mice, Inbred BALB C; Oxytocin; Psychotropic Drugs; Receptors, Oxytocin; Social Behavior

There were few reports of oxytocin (OXT) concentrations of autism spectrum disorder (ASD) patients with severe intellectual disabilities. We measured serum OXT concentrations in 79 hospitalized patients with severe intellectual disabilities (16-60 years old, 50 males and 29 females, 54 ASD patients) and investigated the associations between serum OXT concentration, symptom scores, sex differences, and autism spectrum disorder. There were no significant effects of diagnosis, severity of intellectual disabilities, and total score of the Japanese version of the Aberrant Behavior Checklist (ABC-J), the Childhood Autism Rating Scale-Tokyo Version (CARS-TV), and the Japanese version of the Repetitive Behavior Scale-Revised (RBS-R). However, there were sex differences in the correlations between OXT concentrations and subscale scores in the ASD group. The male ASD group (n = 39) showed negative correlations between RBS-R Self-injurious and Sameness subscale scores and serum OXT concentrations. In the female ASD group(n = 15), CARS-TV Nonverbal communication subscale scores and RBS-R Compulsive subscale scores were seen to positively correlate with serum OXT concentrations. These findings suggest that OXT functions differ in males and females with severe intellectual disabilities and that OXT partly affects autism and related to some of the repetitive behaviors and nonverbal communication, in ASD patients with severe intellectual disabilities.

Topics: Adolescent; Adult; Autism Spectrum Disorder; Biomarkers; Female; Humans; Intellectual Disability; Male; Middle Aged; Oxytocin; Severity of Illness Index; Sex Characteristics; Young Adult

Autism spectrum disorder (ASD) is characterized by early onset of behavioral and cognitive alterations. Low plasma levels of oxytocin (OT) have also been found in ASD patients; recently, a critical role for the enzyme CD38 in the regulation of OT release was demonstrated. CD38 is important in regulating several Ca

Topics: ADP-ribosyl Cyclase 1; Amines; Animals; Anxiety; Autism Spectrum Disorder; Behavior, Animal; Brain Stem; Calcium; Fear; Gene Expression Regulation; Genotype; Magnetic Resonance Imaging; Male; Maze Learning; Megalencephaly; Membrane Glycoproteins; Memory; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuronal Plasticity; Oxytocin; Polymorphism, Single Nucleotide; Prefrontal Cortex; Reflex, Startle; Risk Factors; Social Behavior

Oxytocin (OT) plays a pivotal role in interpersonal bonding, affiliation, and trust, and its intranasal administration is increasingly considered as a potential treatment for autism spectrum disorder.. We explored whether variations in endogenous salivary OT concentration are related to interindividual differences in core autism symptoms and expressions of attachment in 38 male adults with autism spectrum disorder. Further, resting-state functional magnetic resonance imaging was adopted to specifically explore whether interindividual differences are reflected in the intrinsic network organization of key regions of the central oxytocinergic system.. Positive correlations were identified between peripheral OT and expressions of secure attachment (the State Adult Attachment Measure and the Inventory of Peer Attachment), but no significant relationships were identified with scales assessing core autism symptom domains (the Social Responsiveness Scale and the Repetitive Behavior Scale). At the neural level, higher levels of endogenous OT were associated with lower degrees of interregional functional coupling between the amygdala and hippocampal regions. Interestingly, a single dose of exogenously administered OT induced a further reduction in amygdala-hippocampal connectivity, indicating that a higher availability of OT can alter the degree of amygdala-hippocampal connectivity.. The identified associations between the oxytocinergic system, expressions of secure attachment, and amygdala-hippocampal pathways are anticipated to be of relevance for understanding the role of OT in modulating appropriate neural and physiological responses to stress and restoring homeostasis.

Topics: Administration, Intranasal; Adult; Amygdala; Autism Spectrum Disorder; Brain Mapping; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Neural Pathways; Oxytocin; Young Adult

Compelling evidence for the far-reaching role of oxytocin (OT) in social cognition and affiliative behaviors set the basis for examining the association between genetic variation in the OT receptor (OXTR) gene and risk for autism spectrum disorder (ASD). In the current study, gene-environment interaction between OXTR and prenatal exposure to either OT or OXTR antagonist (OXTRA) in predicting early social communication development was examined. One hundred and fifty-three children (age: M = 4.32, SD = 1.07) were assigned to four groups based on prenatal history: children whose mothers prenatally received OXTRA and Nifedipine to delay preterm labor (n = 27); children whose mothers received Nifedipine only to delay preterm labor (n = 35); children whose mothers received OT for labor augmentation (n = 56), and a no intervention group (n = 35). Participants completed a developmental assessment of intelligence quotient (IQ), adaptive behavior, and social communication abilities. DNA was extracted via buccal swab. A genetic risk score was calculated based on four OXTR single nucleotide polymorphisms (rs53576, rs237887, rs1042778, and rs2254298) previously reported to be associated with ASD symptomatology. OXTRrisk-allele dosage was associated with more severe autism diagnostics observation schedule (ADOS) scores only in the OXTRA group. In contrast, in the Nifedipine, OT, and no intervention groups, OXTRrisk-allele dosage was not associated with children's ADOS scores. These findings highlight the importance of both genetic and environmental pathways of OT in signaling early social development and raise the need for further research in this field. Autism Res 2019, 12: 1087-1100. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In the current study, we examined if the association between prenatal exposure to an oxytocin receptor antagonist (OXTRA) and autism spectrum disorder (ASD) related impairments are dependent on an individual's genetic background for the oxytocin receptor gene (OXTR). Children who carried a greater number of risk alleles for the OXTR gene and whose mothers received OXTRA to delay preterm labor showed more ASD-related impairments. The results highlight the importance of both genetic and environmental pathways of oxytocin in shaping early social development.

Topics: Adult; Autism Spectrum Disorder; Child; Child, Preschool; Communication Disorders; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Male; Nifedipine; Obstetric Labor, Premature; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, Oxytocin; Risk Assessment; Social Change; Social Communication Disorder; Tocolytic Agents

Research suggests that children with autism spectrum disorder (ASD) may have reduced empathy, as measured by an impaired contagious yawn response, compared to typically developing (TD) children. Other research has failed to replicate this finding, instead attributing this phenomenon to group differences in attention paid to yawn stimuli. A third possibility is that only a subgroup of children with ASD exhibits the impaired contagious yawn response, and that it can be identified biologically. Here we quantified blood concentrations of the "social" neuropeptide oxytocin (OXT) and evaluated yawning behavior and attention rates during a laboratory task in children with ASD (N = 34) and TD children (N = 30) aged 6-12 years. No group difference in contagious yawning behavior was found. However, a blood OXT concentration × group (ASD vs. TD) interaction positively predicted contagious yawning behavior (F

Topics: Autism Spectrum Disorder; Child; Empathy; Female; Humans; Male; Oxytocin; Photic Stimulation; Social Behavior; Yawning

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by changes in social interactions, impaired language and communication, fear responses and presence of repetitive behaviours. Although the genetic bases of ASD are well documented, the recent increase in clinical cases of idiopathic ASD indicates that several environmental risk factors could play a role in ASD aetiology. Among these, maternal exposure to psychosocial stressors during pregnancy has been hypothesized to affect the risk for ASD in offspring. Here, we tested the hypothesis that preconceptional stressful experiences might also represent crucial elements in the aetiology of ASD. We previously showed that social isolation stress during adolescence results in a marked decrease in the brain and plasma concentrations of progesterone and in the quality of maternal care that these female rats later provide to their young. Here we report that male offspring of socially isolated parents showed decreased agonistic behaviour and social transmission of flavour preference, impairment in reversal learning, increased seizure susceptibility, reduced plasma oxytocin levels, and increased plasma and brain levels of BDNF, all features resembling an ASD-like phenotype. These alterations came with no change in spatial learning, aggression, anxiety and testosterone plasma levels, and were sex-dependent. Altogether, the results suggest that preconceptional stressful experiences should be considered as crucial elements for the aetiology of ASD, and indicate that male offspring of socially isolated parents may be a useful animal model to further study the neurobiological bases of ASD, avoiding the adaptations that may occur in other genetic or pharmacologic experimental models of these disorders.

Topics: Animals; Autism Spectrum Disorder; Behavior, Animal; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Female; Hippocampus; Isoniazid; Male; Maternal Exposure; Oxytocin; Paternal Exposure; Phenotype; Prefrontal Cortex; Pregnancy; Rats; Seizures; Social Behavior; Social Isolation; Stress, Psychological; Testosterone

Oxytocin (OT), a neuropeptide involved in affiliation has been shown to enhance social skills in patients with autism spectrum disorders (ASD). Nevertheless, OT improvements seem ephemeral. Animal research has demonstrated OT action on serotonin (5-HT), an interaction that we also found in the healthy human brain. Whether such synaptic interplay also occurs in ASD patients is unknown. To address this issue, we mapped the effects of intranasal OT on 5-HT in 18 patients with ASD and 24 healthy controls (HC) in a double blind, placebo controlled, within subject PET-scan experiment. Each participant underwent two scans: baseline and spray (OT or placebo). Using the radiotracer [18 F]MPPF, marking the 5-HT 1A receptor (5-HT1AR), we measured MPPF-Binding Potential (BP) as an index of OT-induced serotonin functional modulation. At baseline ASD patients did not differ from controls for 5-HT1AR concentration and distribution. However, while OT significantly increased MPPF BP in several brain regions of HC, no changes were observed in the ASD group. Serotonin serum concentration analysis corroborated these results. Our findings suggest a disturbed OT-serotonin interaction in autism. This may limit the potential benefits of OT in these patients and open the ways to investigate combined OT-serotonin treatments.

Topics: Administration, Intranasal; Adult; Autism Spectrum Disorder; Brain; Double-Blind Method; Humans; Male; Oxytocin; Positron-Emission Tomography; Receptor, Serotonin, 5-HT1A; Serotonin; Synaptic Transmission; Young Adult

Autism spectrum disorder (ASD) is characterized by social impairments and repetitive behaviors, and affects 1 in 68 US children. Despite ASD's societal impact, its disease mechanisms remain poorly understood. Recent preclinical ASD biomarker discovery research has implicated the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP), and their receptors, OXTR and AVPR1A, in animal models. Efforts to translate these findings to individuals with ASD have typically involved evaluating single neuropeptide measures as biomarkers of ASD and/or behavioral functioning. Given that ASD is a heterogeneous disorder, and unidimensional ASD biomarker studies have been challenging to reproduce, here we employed a multidimensional neuropeptide biomarker analysis to more powerfully interrogate disease status and symptom severity in a well characterized child cohort comprised of ASD patients and neurotypical controls. These blood-based neuropeptide measures, considered as a whole, correctly predicted disease status for 57 out of 68 (i.e., 84%) participants. Further analysis revealed that a composite measure of OXTR and AVPR1A gene expression was the key driver of group classification, and that children with ASD had lower neuropeptide receptor mRNA levels compared to controls. Lower neuropeptide receptor mRNA levels also predicted greater symptom severity for core ASD features (i.e., social impairments and stereotyped behaviors), but were unrelated to intellectual impairment, an associated feature of ASD. Findings from this research highlight the value of assessing multiple related biological measures, and their relative contributions, in the same study, and suggest that low blood neuropeptide receptor availability may be a promising biomarker of disease presence and symptom severity in ASD.

Topics: Arginine Vasopressin; Autism Spectrum Disorder; Autistic Disorder; Biomarkers; Child; Female; Humans; Male; Neuropeptides; Oxytocin; Receptors, Neuropeptide; Receptors, Oxytocin; Receptors, Vasopressin; Social Behavior; Stereotyped Behavior

Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the bloodstream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application. The aim of this study is to evaluate the disposition, nasal absorption, and therapeutic potential of OXT after nasal administration. The pharmacokinetics of OXT after intravenous bolus injection to rats followed a two-compartment model, with a rapid initial half-life of 3 min. The nasal bioavailability of OXT was approximately 2%. The brain concentration of OXT after nasal application was much higher than that after intravenous application, despite much lower concentrations in the plasma. More than 95% of OXT in the brain was directly transported from the nasal cavity. The in vivo stress-relief effect by OXT was observed only after intranasal administration. These results indicate that pharmacologically active OXT was effectively delivered to the brain after intranasal administration. In conclusion, the nasal cavity is a promising route for the efficient delivery of OXT to the brain.

Topics: Administration, Intranasal; Animals; Autism Spectrum Disorder; Behavior, Animal; Biological Availability; Brain; Disease Models, Animal; Humans; Injections, Intravenous; Male; Mice; Oxytocin; Rats; Rats, Wistar; Stress, Psychological; Treatment Outcome

Evidence supports the notion that autistic symptoms and behaviors should be regarded as dimensional traits. The present study aimed to investigate the role of vasopressin (AVP), brain-derived neurotrophic factor (BDNF) and oxytocin (OXT) as potential biochemical correlates of subclinical autistic traits in a cohort of healthy young adults. One hundred and fifty-three subjects (80 males, 73 females) were recruited. Participants completed the Autism Spectrum Quotient (AQ), a widely used measure for the identification of autistic traits in the general population. Additionally, blood samples were obtained from all participants at the same time of the day to control for circadian variation. We conducted a multiple regression analysis using the AQ score as the dependent variable and age, sex, AVP, BDNF and OXT levels as the independent variables. The model explained approximately the 22% of the variance of the AQ score. Among the parameters included in the analysis, only BDNF levels were independent predictors of AQ score.

Topics: Adult; Autism Spectrum Disorder; Autistic Disorder; Biomarkers; Brain-Derived Neurotrophic Factor; Female; Humans; Male; Oxytocin; Regression Analysis; Vasopressins; Young Adult

Intranasal oxytocin (OT) has been shown to improve social communication functioning of individuals with autism spectrum disorder (ASD) and, thus, has received considerable interest as a potential ASD therapeutic agent. Although preclinical research indicates that OT modulates the functional output of the mesocorticolimbic dopamine system that processes rewards, no clinical brain imaging study to date has examined the effects of OT on this system using a reward processing paradigm. To address this, we used an incentive delay task to examine the effects of a single dose of intranasal OT, versus placebo (PLC), on neural responses to social and nonsocial rewards in children with ASD.. In this placebo-controlled double-blind study, 28 children and adolescents with ASD (age: M = 13.43 years, SD = 2.36) completed two fMRI scans, one after intranasal OT administration and one after PLC administration. During both scanning sessions, participants completed social and nonsocial incentive delay tasks. Task-based neural activation and connectivity were examined to assess the impact of OT relative to PLC on mesocorticolimbic brain responses to social and nonsocial reward anticipation and outcomes.. Central analyses compared the OT and PLC conditions. During nonsocial reward anticipation, there was greater activation in the right nucleus accumbens (NAcc), left anterior cingulate cortex (ACC), bilateral orbital frontal cortex (OFC), left superior frontal cortex, and right frontal pole (FP) during the OT condition relative to PLC. Alternatively, during social reward anticipation and outcomes, there were no significant increases in brain activation during the OT condition relative to PLC. A Treatment Group × Reward Condition interaction revealed relatively greater activation in the right NAcc, right caudate nucleus, left ACC, and right OFC during nonsocial relative to social reward anticipation during the OT condition relative to PLC. Additionally, these analyses revealed greater activation during nonsocial reward outcomes during the OT condition relative to PLC in the right OFC and left FP. Finally, functional connectivity analyses generally revealed changes in frontostriatal connections during the OT condition relative to PLC in response to nonsocial, but not social, rewards.. The effects of intranasal OT administration on mesocorticolimbic brain systems that process rewards in ASD were observable primarily during the processing of nonsocial incentive salience stimuli. These findings have implications for understanding the effects of OT on neural systems that process rewards, as well as for experimental trials of novel ASD treatments developed to ameliorate social communication impairments in ASD.

Topics: Administration, Intranasal; Adolescent; Autism Spectrum Disorder; Brain; Child; Double-Blind Method; Facial Recognition; Female; Humans; Male; Neural Pathways; Oxytocin; Psychomotor Performance; Reaction Time; Reward; Saliva; Social Perception

The neuropeptide and hormone oxytocin is known to have a significant impact on social cognition and behaviour in humans. There is growing concern regarding the influence of exogenous oxytocin (OT) administration in early life on later social and emotional development, including autism spectrum disorder (ASD). No study has examined offspring development in relation to the dose of exogenous oxytocin administered during labour.. Between 1989 and 1992, 2,900 mothers were recruited prior to the 18th week of pregnancy, delivering 2,868 live offspring. The Child Behaviour Checklist was used to measure offspring behavioural difficulties at ages 5, 8, 10, 14 and 17 years. Autism spectrum disorder was formally diagnosed by consensus of a team of specialists. At 20 years, offspring completed a measure of autistic-like traits, the Autism Spectrum Quotient (AQ). Oxytocin exposure prior to birth was analysed using categorical and continuous approaches (maternal oxytocin dose) with univariate and multivariate statistical techniques.. Categorical analyses of oxytocin exposure prior to birth demonstrated no group differences in any measures of child behaviour. A small in magnitude dose-response association was observed for clinically significant total behaviour symptoms (adjusted odds ratio 1.03; 95% CI: 1.01-1.06, p < .01). Exogenous oxytocin administration prior to birth was not associated with ASD (OR: 0.64; 95% CI: 0.15-2.12, p = .46) or high levels of autistic-like traits (p = .93), as assessed by the AQ.. This study is the first to investigate longitudinal mental health outcomes associated with the use of oxytocin-based medications during labour. The results do not provide evidence to support the theory that exogenous OT has a clinically significant negative impact on the long-term mental health of children.

Topics: Adolescent; Autism Spectrum Disorder; Child; Child Behavior Disorders; Child Development; Child, Preschool; Female; Humans; Labor, Induced; Longitudinal Studies; Male; Oxytocin; Pregnancy; Prenatal Exposure Delayed Effects; Retrospective Studies; Young Adult

Perinatal administration of serotonin (5HT) agonist 5-methoxytryptamine (5MT) induces developmental hyperserotonemia (DHS; elevated blood serotonin) and produces behavioral and neurochemical changes in rats relevant to Autism Spectrum Disorder (ASD), such as oxytocin dysregulation. Disruption of the oxytocin system may underlie many of the social deficits present in ASD individuals, thus we investigated the mechanism(s) underlying DHS-induced oxytocin dysregulation. The most parsimonious mechanism of 5HT action would be alteration of 5HT receptors on oxytocin cells; 5HT is known to influence cell survival as well as influence oxytocin release via 5HT

Topics: 5-Methoxytryptamine; Animals; Autism Spectrum Disorder; Autistic Disorder; Disease Models, Animal; Female; Hypothalamus; Male; Oxytocin; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Serotonin; Sex Characteristics; Sex Factors; Sexual Behavior

Disturbance of neurotransmitters and neuromodulators is thought to underlie the pathophysiology of autism spectrum disorder (ASD). Studies of 15q dup mouse models of ASD with human 15q11-13 duplication have revealed that restoring serotonin (5-HT) levels can partially reverse ASD-related symptoms in adults. However, it remains unclear how serotonin contributes to the behavioral symptoms of ASD. In contrast, oxytocin (OXT) has been found to involve social and affiliative behaviors. In this study, we examined whether serotonin-OXT interaction during the early postnatal period plays a critical role in the restoration of social abnormality in 15q dup mice. OXT or the 5-HT

Topics: Animals; Animals, Newborn; Autism Spectrum Disorder; Autistic Disorder; Brain; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Oxytocin; Serotonin; Social Behavior

Topics: Autism Spectrum Disorder; Autistic Disorder; Humans; Oxytocin; Receptors, Oxytocin; Social Behavior

Oxytocin appears beneficial for autism spectrum disorder (ASD), and more than 20 single-nucleotide polymorphisms (SNPs) in oxytocin receptor (OXTR) are relevant to ASD. However, neither biological functions of OXTR SNPs in ASD nor critical OXTR SNPs that determine oxytocin's effects on ASD remains known. Here, using a machine-learning algorithm that was designed to evaluate collective effects of multiple SNPs and automatically identify most informative SNPs, we examined relationships between 27 representative OXTR SNPs and six types of behavioral/neural response to oxytocin in ASD individuals. The oxytocin effects were extracted from our previous placebo-controlled within-participant clinical trial administering single-dose intranasal oxytocin to 38 high-functioning adult Japanese ASD males. Consequently, we identified six different SNP sets that could accurately predict the six different oxytocin efficacies, and confirmed the robustness of these SNP selections against variations of the datasets and analysis parameters. Moreover, major alleles of several prominent OXTR SNPs-including rs53576 and rs2254298-were found to have dissociable effects on the oxytocin efficacies. These findings suggest biological functions of the OXTR SNP variants on autistic oxytocin responses, and implied that clinical oxytocin efficacy may be genetically predicted before its actual administration, which would contribute to establishment of future precision medicines for ASD.

Topics: Adolescent; Adult; Algorithms; Alleles; Autism Spectrum Disorder; Genetic Variation; Genotype; Humans; Machine Learning; Male; Oxytocin; Polymorphism, Single Nucleotide; Receptors, Oxytocin; Social Behavior; Young Adult

A recent study has linked individual differences in face recognition to rs237887, a single-nucleotide polymorphism (SNP) of the oxytocin receptor gene ( OXTR; Skuse et al., 2014). In that study, participants were assessed using the Warrington Recognition Memory Test for Faces, but performance on Warrington's test has been shown not to rely purely on face recognition processes. We administered the widely used Cambridge Face Memory Test-a purer test of face recognition-to 370 participants. Performance was not significantly associated with rs237887, with 16 other SNPs of OXTR that we genotyped, or with a further 75 imputed SNPs. We also administered three other tests of face processing (the Mooney Face Test, the Glasgow Face Matching Test, and the Composite Face Test), but performance was never significantly associated with rs237887 or with any of the other genotyped or imputed SNPs, after corrections for multiple testing. In addition, we found no associations between OXTR and Autism-Spectrum Quotient scores.

Topics: Adolescent; Adult; Autism Spectrum Disorder; Face; Female; Genotype; Humans; Male; Memory; Oxytocin; Polymorphism, Single Nucleotide; Receptors, Oxytocin; Recognition, Psychology; Social Behavior; Young Adult

Exogenous oxytocin administration is widely reported to improve social cognition in human and nonhuman primate adults. Risk factors of impaired social cognition, however, emerge in infancy. Early interventions-when plasticity is greatest-are critical to reverse negative outcomes.. We tested the hypothesis that oxytocin may exert similar positive effects on infant social cognition, as in adults. To test this idea, we assessed the effectiveness of acute, aerosolized oxytocin on two foundational social cognitive skills: working memory (i.e., ability to briefly hold and process information) and social gaze (i.e., tracking the direction of others' gaze) in 1-month-old nursery-reared macaque monkeys (Macaca mulatta). We did not predict sex differences, but we included sex as a factor in our analyses to test whether our effects would be generalizable across both males and females.. In a double-blind, placebo-controlled design, we found that females were more socially skilled at baseline compared to males, and that oxytocin improved working memory and gaze following, but only in males.. These sex differences, while unexpected, may be due to interactions with gonadal steroids and may be relevant to sexually dimorphic disorders of social cognition, such as male-biased autism spectrum disorder, for which oxytocin has been proposed as a potential treatment. In sum, we report the first evidence that oxytocin may influence primate infant cognitive abilities. Moreover, these behavioral effects appear sexually dimorphic, highlighting the importance of considering sex differences. Oxytocin effects observed in one sex may not be generalizable to the other sex.

Topics: Administration, Intranasal; Animals; Animals, Newborn; Autism Spectrum Disorder; Double-Blind Method; Female; Fixation, Ocular; Macaca mulatta; Male; Memory; Memory, Short-Term; Nurseries, Infant; Oxytocics; Oxytocin; Sex Characteristics; Sex Factors; Social Behavior; Social Perception

Several common alleles in the oxytocin receptor gene (OXTR) are associated with altered brain function in reward circuitry in neurotypical adults and may increase risk for autism spectrum disorders (ASD). Yet, it is currently unknown how variation in the OXTR relates to brain functioning in individuals with ASD, and, critically, whether neural endophenotypes vary as a function of aggregate genetic risk. Here, for we believe the first time, we use a multi-locus approach to examine how genetic variation across several OXTR single-nucleotide polymorphisms (SNPs) affect functional connectivity of the brain's reward network. Using data from 41 children with ASD and 41 neurotypical children, we examined functional connectivity of the nucleus accumbens (NAcc) - a hub of the reward network - focusing on how connectivity varies with OXTR risk-allele dosage. Youth with ASD showed reduced NAcc connectivity with other areas in the reward circuit as a function of increased OXTR risk-allele dosage, as well as a positive association between risk-allele dosage and symptom severity, whereas neurotypical youth showed increased NAcc connectivity with frontal brain regions involved in mentalizing. In addition, we found that increased NAcc-frontal cortex connectivity in typically developing youth was related to better scores on a standardized measure of social functioning. Our results indicate that cumulative genetic variation on the OXTR impacts reward system connectivity in both youth with ASD and neurotypical controls. By showing differential genetic effects on neuroendophenotypes, these pathways elucidate mechanisms of vulnerability versus resilience in carriers of disease-associated risk alleles.

Topics: Adolescent; Alleles; Autism Spectrum Disorder; Autistic Disorder; Brain; Case-Control Studies; Child; Female; Frontal Lobe; Gene Dosage; Gene Frequency; Genetic Variation; Humans; Male; Neuroimaging; Nucleus Accumbens; Oxytocin; Polymorphism, Single Nucleotide; Receptors, Oxytocin; Reward; Social Behavior

To date, no curative psychopharmacologic treatment exists for the core symptoms of autism spectrum disorder (ASD) as well as for schizophrenia. Bumatenide is a specific antagonist of the first isoform of the Na-K-Cl cotransporter (NKCC1). It is usually used as a diuretic but may also promote a decrease in intraneuronal chloride ion concentration leading to hyperpolarization in neuronal membrane and subsequent decrease in neuronal hyperexcitability. This physiologic effect has been considered to be behind the relative efficacy of bumetanide in improving symptoms of ASD and, to a lesser extent, schizophrenia. However, insulin growth factor-1 (IGF-1) shows the same physiologic effect. In addition, it may improve brain network dysconnectivity which is known to be an important neurobiological feature in ASD and schizophrenia. IGF-1 has started to prove its efficacy in improving symptoms of children with Rett syndrome, a genetic disorder that shares several clinical similarities with ASD. IGF-1 may also improve oxytocin secretion through the enhancement of the transient potential receptor V2 channel function. Accordingly, IGF-1 should be studied as a potential treatment of ASD and other mental disorders characterized with brain dysconnectivity such as schizophrenia.

Topics: Animals; Autism Spectrum Disorder; Brain; Bumetanide; Child; Child, Preschool; Chlorides; Endocannabinoids; Humans; Insulin-Like Growth Factor I; Models, Theoretical; Myelin Sheath; Neurons; Oligodendroglia; Oxytocin; Psychotic Disorders; Rett Syndrome; Schizophrenia; Solute Carrier Family 12, Member 2

Oxytocin (OT) and the serotonergic system putatively play important roles in autism spectrum disorder (ASD) etiology and symptoms, but no direct neurobiological evidence exists for long-term OT administration effects on the brain's serotonergic system. This pilot study examined 10 male participants with ASD who were administered OT intranasally for 8-10 weeks in an open-label, single-arm, nonrandomized, and uncontrolled manner. Positron emission tomography (PET) with a radiotracer (

Topics: Adult; Autism Spectrum Disorder; Brain; Female; Humans; Male; Oxytocin; Pilot Projects; Serotonin; Serotonin Plasma Membrane Transport Proteins; Young Adult

The core symptoms of autism spectrum disorder (ASD) comprise impairments of social communication and social interactions as well as restricted and repetitive patterns of interests and activities. No definitive treatments for these core symptoms currently exist. Oxytocin, a highly conserved peptide, has been suggested to moderate inter-individual relationships based on the results of many vertebrate studies. Recently, oxytocin has received a great deal of attention as a promising candidate for the treatment of ASD. Here, we review studies on the role of oxytocin in ASD. Numerous randomized controlled trials (RCTs) have shown single- dose oxytocin administration to have significantly favorable effects compared with placebo for both neuro-typical individuals and individuals with ASD. Furthermore, extended administra- tion of oxytocin was associated with effects that significantly exceeded those of a placebo in three of five published RCTs for ASD. Moreover, approximately 20 RCTs investigating whether oxytocin is favorable for ASD participants are in progress, according to clinical trial registries certified by the World Health Organization. The results of these RCTs may elucidate the issues regarding favorable and adverse effects, appropriate doses and treatment durations, participant selection, and specifically how to assess the changes in impairments of social com- munication and social interactions. In addition, it is necessary to consider which version of the Diagnostic and Statistical Manual of Mental Disorders (DSM) is used for the diagnosis of ASD in each RCT because the range of individuals diagnosed with ASD has become gradually nar- rower with each DSM revision, i. e., the Fourth Edition, the Fourth Edition Text Revision, and the Fifth Edition.

Topics: Autism Spectrum Disorder; Humans; Oxytocin; Practice Guidelines as Topic; Randomized Controlled Trials as Topic

Social deficits are a hallmark feature of autism spectrum disorder (ASD) and related developmental syndromes. Although there is no standard treatment for social dysfunction, clinical studies have identified oxytocin as a potential therapeutic with prosocial efficacy. We have previously reported that peripheral oxytocin treatment can increase sociability and ameliorate repetitive stereotypy in adolescent mice from the C58/J model of ASD-like behavior. In the present study, we determined that prosocial oxytocin effects were not limited to the adolescent period, since C58/J mice, tested in adulthood, demonstrated significant social preference up to 2 weeks following subchronic oxytocin treatment. Oxytocin was also evaluated in adult mice with underexpression of the N-methyl-d-aspartate receptor NR1 subunit (encoded by Grin1), a genetic model of autism- and schizophrenia-like behavior. Subchronic oxytocin had striking prosocial efficacy in male Grin1 knockdown mice; in contrast, chronic regimens with clozapine (66 mg/kg/day) or risperidone (2 mg/kg/day) failed to reverse deficits in sociability. Neither the subchronic oxytocin regimen, nor chronic treatment with clozapine or risperidone, reversed impaired prepulse inhibition in the Grin1 knockdown mice. Overall, these studies demonstrate oxytocin can enhance sociability in mouse models with divergent genotypes and behavioral profiles, adding to the evidence that this neurohormone could have therapeutic prosocial efficacy across a spectrum of developmental disorders.

Topics: Animals; Autism Spectrum Disorder; Behavior, Animal; Choice Behavior; Disease Models, Animal; Female; Gene Knockdown Techniques; Hyperkinesis; Male; Mice; Nerve Tissue Proteins; Oxytocin; Prepulse Inhibition; Receptors, N-Methyl-D-Aspartate; Social Behavior

The neuropeptide oxytocin (OT) is one of the major targets of research in neuroscience, with respect to social functioning. Oxytocin promotes social skills and improves the quality of face processing in individuals with social dysfunctions such as autism spectrum disorder (ASD). Although one of OT's key functions is to promote social behavior during dynamic social interactions, the neural correlates of this function remain unknown. Here, we combined acute intranasal OT (IN-OT) administration (24 IU) and fMRI with an interactive ball game and a face-matching task in individuals with ASD (N = 20). We found that IN-OT selectively enhanced the brain activity of early visual areas in response to faces as compared to non-social stimuli. OT inhalation modulated the BOLD activity of amygdala and hippocampus in a context-dependent manner. Interestingly, IN-OT intake enhanced the activity of mid-orbitofrontal cortex in response to a fair partner, and insula region in response to an unfair partner. These OT-induced neural responses were accompanied by behavioral improvements in terms of allocating appropriate feelings of trust toward different partners' profiles. Our findings suggest that OT impacts the brain activity of key areas implicated in attention and emotion regulation in an adaptive manner, based on the value of social cues.

Topics: Administration, Intranasal; Amygdala; Autism Spectrum Disorder; Cues; Emotions; Female; Humans; Interpersonal Relations; Magnetic Resonance Imaging; Male; Oxytocin; Social Behavior

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired communication, difficulty in companionship, repetitive behaviors and restricted interests. Recent studies have shown amelioration of ASD symptoms by intranasal administration of oxytocin and demonstrated the association of polymorphisms in the oxytocin receptor (Oxtr) gene with ASD patients. Deficient pruning of synapses by microglial cells in the brain has been proposed as potential mechanism of ASD. Other researchers have shown specific activation of microglial cells in brain regions related to sociality in patients with ASD. Although the roles of Oxtr and microglia in ASD are in the spotlight, the relationship between them remains to be elucidated. In this study, we found abnormal activation of microglial cells and a reduction of postsynaptic density protein PSD95 expression in the Oxtr-deficient brain. Moreover, pharmacological inhibition of microglia during development can alter the expression of PSD95 and ameliorate abnormal mother-infant communication in Oxtr-deficient mice. Our results suggest that microglial abnormality is a potential mechanism of the development of Oxt/Oxtr mediated ASD-like phenotypes.

Topics: Animals; Autism Spectrum Disorder; Brain; Female; Male; Maternal-Fetal Exchange; Maternal-Fetal Relations; Mice, Knockout; Microglia; Minocycline; Oxytocin; Pregnancy; Receptors, Oxytocin

This longitudinal study investigated whether variation in the oxytocin receptor gene (OXTR) and early parent-child interactions predicted later empathic behavior in 84 toddlers at high or low familial risk for autism spectrum disorder. Two well-studied OXTR single-nucleotide polymorphisms, rs53576 and rs2254298, were examined. Parent-child interaction was measured at 15 and 18 months of age during free play sessions. Empathy was measured at 24 and 30 months using a response to parental distress paradigm. While there was no direct association between parent-child interaction quality or OXTR and empathy, rs53576 moderated the relation between interaction quality and empathy. Results suggest that the interplay between OXTR and early parent-child interactions predicts individual differences in empathy in children at varying risk for atypical social development. Findings are consonant with a differential susceptibility model in which an OXTR variant may increase the social salience of interaction processes for specific allele carriers. These results increase our understanding of predictors of empathy development in young children with a wide range of social outcomes. (PsycINFO Database Record

Topics: Age Factors; Autism Spectrum Disorder; Child; Child, Preschool; Empathy; Female; Genetic Association Studies; Genotype; Humans; Longitudinal Studies; Male; Oxytocin; Parent-Child Relations; Polymorphism, Single Nucleotide; Receptors, Oxytocin; Regression Analysis; Saliva

Maternal obesity during pregnancy has been associated with increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), in offspring. Here, we report that maternal high-fat diet (MHFD) induces a shift in microbial ecology that negatively impacts offspring social behavior. Social deficits and gut microbiota dysbiosis in MHFD offspring are prevented by co-housing with offspring of mothers on a regular diet (MRD) and transferable to germ-free mice. In addition, social interaction induces synaptic potentiation (LTP) in the ventral tegmental area (VTA) of MRD, but not MHFD offspring. Moreover, MHFD offspring had fewer oxytocin immunoreactive neurons in the hypothalamus. Using metagenomics and precision microbiota reconstitution, we identified a single commensal strain that corrects oxytocin levels, LTP, and social deficits in MHFD offspring. Our findings causally link maternal diet, gut microbial imbalance, VTA plasticity, and behavior and suggest that probiotic treatment may relieve specific behavioral abnormalities associated with neurodevelopmental disorders. VIDEO ABSTRACT.

Topics: Animals; Autism Spectrum Disorder; Diet, High-Fat; Dysbiosis; Female; Gastrointestinal Microbiome; Germ-Free Life; Housing, Animal; Limosilactobacillus reuteri; Male; Mice; Mice, Inbred C57BL; Obesity; Oxytocin; Pregnancy; Social Behavior; Ventral Tegmental Area

Autism spectrum disorder (ASD) is defined by impairments of social interaction and the presence of obsessive behaviors. The "twin" nonapeptides oxytocin (OXT) and arginine-vasopressin (AVP) are known to play regulatory roles in social behaviors. However, the plasma levels and behavioral relevance of OXT and AVP in children with ASD have seldom been investigated. It is also unknown whether their mothers have abnormal plasma peptide levels. Here, using well-established methods of neuropeptide measurement and a relatively large sample size, we determined the plasma levels of the two neuropeptides in 85 normal children, 84 children with ASD, and 31 mothers from each group of children. As expected, children with ASD had lower plasma OXT levels than gender-matched controls (P = 0.028). No such difference was found for plasma AVP concentrations. Correlation analysis showed that ASD children with higher plasma OXT concentrations tended to have less impairment of verbal communication (Rho = -0.22, P = 0.076), while those with higher plasma AVP levels tended to have lower levels of repetitive use of objects (Rho = -0.231, P = 0.079). Unlike the findings in children, maternal plasma OXT levels showed no group difference. However, plasma AVP levels in the mothers of ASD children tended to be lower than in the mothers of normal children (P = 0.072). In conclusion, our results suggest that the OXT system is dysregulated in children with ASD, and that OXT and AVP levels in plasma seem to be associated with specific autistic symptoms. The plasma levels of OXT or AVP in mothers and their ASD children did not seem to change in the same direction.

Topics: Analysis of Variance; Arginine Vasopressin; Autism Spectrum Disorder; Child; Child, Preschool; China; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Mothers; Oxytocin; Severity of Illness Index; Sex Factors; Statistics as Topic

The neuropeptide oxytocin (OT) has received increased experimental attention for its putative role in both normal social functioning and several psychiatric disorders that are partially characterized by social dysfunction (e.g., autism spectrum disorders: ASD). Many human experimental studies measure circulating plasma levels of OT in order to examine the relationship between the hormone and behavior. Urinary OT (uOT) assays offer a simple, easy, and non-invasive method to measure peripheral hormone levels, but the correspondence between uOT and plasma OT (pOT) levels is unclear. Here, we conducted two within-subjects, double-blind studies exploring changes in uOT and pOT levels following administration of two drugs: MDMA, an oxytocin-releasing drug (Study 1), and intranasal oxytocin (INOT: Study 1 and 2).. In Study 1, 14 adult participants (2 females) were each administered either oral 1.5mg/kg MDMA or 40IU INOT across two different study sessions. In Study 2, 10 male participants (adolescents and young adults) diagnosed with ASD received either 40IU INOT or placebo across two different sessions. In both studies, blood and urine samples were collected before and after drug administration at each study session. For Study 1, 10 participants provided valid plasma and urine samples for the MDMA session, and 8 provided valid samples for the INOT session. For Study 2, all 10 participants provided valid samples for both INOT and placebo sessions. Pre- and post-administration levels of pOT and uOT were compared. Additionally, correlations between percent change from baseline uOT and pOT levels were examined.. Study 1: Plasma OT and uOT levels significantly increased after administration of MDMA and INOT. Furthermore, uOT levels were positively correlated with pOT levels following administration of MDMA (r=0.57, p=0.042) but not INOT (r=0.51, p=0.097). Study 2: There was a significant increase in uOT levels after administration of INOT, but not after administration of placebo. Under both conditions, INOT and placebo, significant increases in pOT levels were not observed. Additionally, change from baseline uOT and pOT levels were positively correlated (r=0.57, p=0.021). There was no significant correlation between uOT and pOT levels following placebo administration.. Our results show a measurable and significant increase in pOT and uOT levels after the administration of MDMA (Study 1) and INOT (Study 1 and Study 2). Additionally, a positive correlation between uOT and pOT levels was observed in both samples (healthy adults and ASD patients) in at least one condition. However, uOT and pOT levels were not correlated under all conditions, suggesting that uOT levels do not fully correspond to pOT levels in the time windows we measured. Future studies should further examine the relationship between levels of pOT and uOT in healthy and clinical populations on measures of social behavior because uOT may serve as an additional non-invasive method to measure peripheral OT changes.

Topics: Administration, Intranasal; Adolescent; Adult; Autism Spectrum Disorder; Double-Blind Method; Female; Humans; Male; N-Methyl-3,4-methylenedioxyamphetamine; Neuropeptides; Neurotransmitter Agents; Oxytocin; Young Adult

The neuropeptide oxytocin (OXT) has been implicated in the pathophysiology of behavioural deficits among patients with autism spectrum disorder (ASD). However, the molecular mechanisms underlying its role in ASD remain unclear. In the present study, a murine model with ASD-like phenotypes was induced by intra-medial amygdala injection of N-methyl-d-aspartate, and it was used to investigate the role of OXT in behaviour regulation. Behavioural tests were performed to verify the ASD-like phenotypes of N-methyl-d-aspartate-treated mice, and the results showed that mice with bilateral medial amygdala lesions presented significant behavioural deficits, including impaired learning and memory and increased anxiety and depression. We also observed a notably decreased level of OXT in both the plasma and the hypothalamus of medial amygdala-lesioned mice, and the extracellular signal-regulated kinase (ERK) was activated. Further studies demonstrated that the administration of OXT alleviated ASD-like symptoms and significantly inhibited phosphorylation of ERK; the inhibitory effect was similar to that of U0126, an ERK signalling inhibitor. In addition, OXT administration modulated the expression of downstream proteins of the ERK signalling pathway, such as cyclic adenosine monophosphate response element binding and c-fos. Taken together, our data indicate that OXT plays an important role in ameliorating behavioural deficits in an ASD-like mouse model, which was mediated by inhibiting the ERK signalling pathway and its downstream proteins.

Topics: Amygdala; Animals; Autism Spectrum Disorder; Behavior, Animal; Cell Count; Cyclic AMP Response Element-Binding Protein; Down-Regulation; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Hypothalamus; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; N-Methylaspartate; Nerve Tissue Proteins; Neurons; Oxytocin; Phenotype; Proto-Oncogene Proteins c-fos; Social Behavior; Up-Regulation

Attention Deficit/Hyperactivity Disorder (ADHD) and autism spectrum disorder (ASD) are highly comorbid, and both disorders share executive function deficits. Accumulating evidence suggests that ASD patients have significantly lower peripheral oxytocin (OXT) levels compared with their normal counterparts, and that the repetitive behavior seen in ASD is related to abnormalities in the OXT system. In this study, we investigated whether serum levels of OXT are altered in pediatric patients with ADHD. We measured serum OXT levels: drug naive ADHD (n=23), medicated ADHD (n=13), and age- and sex- matched, neurotypical controls (n=22). Patients were evaluated using the ADHD-RS. Serum levels of OXT in total subjects with ADHD were significantly decreased compared with those of neurotypical controls, and serum levels of OXT in drug naive ADHD patients were significantly lower than those in medicated ADHD patients. Interestingly, there was a significant negative correlation between serum OXT levels and ADHD-RS total scores, as well as ADHD-RS inattentive scores in all ADHD patients. In conclusion, this study suggests that decreased levels of OXT may play a role in the pathophysiology of patients with ADHD and its inherent inattentiveness.

Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Biomarkers; Child; Comorbidity; Executive Function; Female; Humans; Male; Oxytocin

There is considerable interest in the potential therapeutic role of the neuropeptide oxytocin in altering attentional bias towards emotional social stimuli in psychiatric disorders. However, it is still unclear whether oxytocin primarily influences attention towards positive or negative valence social stimuli. Here in a double-blind, placebo controlled, between subject design experiment in 60 healthy male subjects we have used the highly sensitive dual-target rapid serial visual presentation (RSVP) paradigm to investigate whether intranasal oxytocin (40IU) treatment alters attentional bias for emotional faces. Results show that oxytocin improved recognition accuracy of neutral and happy expression faces presented in the second target position (T2) during the period of reduced attentional capacity following prior presentation of a first neutral face target (T1), but had no effect on recognition of negative expression faces (angry, fearful, sad). Oxytocin also had no effect on recognition of non-social stimuli (digits) in this task. Recognition accuracy for neutral faces at T2 was negatively associated with autism spectrum quotient (ASQ) scores in the placebo group, and oxytocin's facilitatory effects were restricted to a sub-group of subjects with higher ASQ scores. Our results therefore indicate that oxytocin primarily enhances the allocation of attentional resources towards faces expressing neutral or positive emotion and does not influence that towards negative emotion ones or non-social stimuli. This effect of oxytocin is strongest in healthy individuals with higher autistic trait scores, thereby providing further support for its potential therapeutic use in autism spectrum disorder.

Topics: Administration, Intranasal; Adult; Attention; Autism Spectrum Disorder; Double-Blind Method; Face; Facial Expression; Humans; Male; Oxytocin; Reaction Time; Recognition, Psychology

Marijuana exerts profound effects on human social behavior, but the neural substrates underlying such effects are unknown. Here we report that social contact increases, whereas isolation decreases, the mobilization of the endogenous marijuana-like neurotransmitter, anandamide, in the mouse nucleus accumbens (NAc), a brain structure that regulates motivated behavior. Pharmacological and genetic experiments show that anandamide mobilization and consequent activation of CB1 cannabinoid receptors are necessary and sufficient to express the rewarding properties of social interactions, assessed using a socially conditioned place preference test. We further show that oxytocin, a neuropeptide that reinforces parental and social bonding, drives anandamide mobilization in the NAc. Pharmacological blockade of oxytocin receptors stops this response, whereas chemogenetic, site-selective activation of oxytocin neurons in the paraventricular nucleus of the hypothalamus stimulates it. Genetic or pharmacological interruption of anandamide degradation offsets the effects of oxytocin receptor blockade on both social place preference and cFos expression in the NAc. The results indicate that anandamide-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward. Deficits in this signaling mechanism may contribute to social impairment in autism spectrum disorders and might offer an avenue to treat these conditions.

Topics: Analysis of Variance; Animals; Arachidonic Acids; Autism Spectrum Disorder; Benzamides; Benzodiazepines; Camphanes; Carbamates; Clozapine; Cocaine; Endocannabinoids; Immunohistochemistry; Infusions, Intraventricular; Lipids; Male; Mice; Mice, Inbred C57BL; Nucleus Accumbens; Oxytocin; Piperazines; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Reward; Signal Transduction; Social Behavior

Obstructive sleep apnea (OSA) is characterized by reductions in breathing amplitude during sleep caused by an obstructed or collapsed upper airway. The neutrophil to lymphocyte ratio (NLR) has been proposed as a novel biomarker for systemic inflammatory response. The aim of the present study was to evaluate the relationship between NLR and OSA.. The study population consisted of 195 consecutive patients with clinical suspicion of OSA. Full night polysomnography was performed for all patients. Patients with an apnea hypopnea index (AHI) ≥ 5 were considered to have OSA. NLR was calculated as the ratio of neutrophil count to lymphocyte count.. While 130 patients (91 male, mean age: 49.9 ± 9.8 years) had OSA, 65 patients (42 male, mean age: 48.7 ± 10.2 years) had normal findings according to AHI scores. Cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes mellitus and smoking were more common in patients with OSA. Patients with OSA had significantly higher NLR than controls (1.87 ± 0.80 vs 1.49 ± 0.48, p=0.005). AHI score was significantly correlated with NLR (r=0.228, p=0.001). NLR and presence of hyperlipidemia were independent predictors of OSA (OR: 2.451, 2.850, p=0.001, 0.004, respectively). NLR of 1.62 or higher predicted OSA with a sensitivity of 56.2 % and specificity of 63.1 %.. NLR was higher and also correlated with AHI score in patients with OSA which has not been reported previously. NLR more than 1.62 was an independent predictor of OSA. A simple, cheap white blood cell count may also give an idea about the presence and severity of OSA (Tab. 3, Fig. 3, Ref. 30).

Topics: Adolescent; Adult; Autism Spectrum Disorder; Child; Child, Preschool; Female; Humans; Male; Oxytocin