Mitigation of Sociocommunicational Deficits of Autism Through Oxytocin-Induced Recovery of Medial Prefrontal Activity: A Randomized Trial
Abstract
IMPORTANCE: Sociocommunicational deficits make it difficult for individuals with autism spectrum disorders (ASD) to understand communication content with conflicting verbal and nonverbal information. Despite growing prospects for oxytocin as a therapeutic agent for ASD, no direct neurobiological evidence exists for oxytocin's beneficial effects on this core symptom of ASD. This is slowing clinical application of the neuropeptide. OBJECTIVE: To directly examine whether oxytocin has beneficial effects on the sociocommunicational deficits of ASD using both behavioral and neural measures. DESIGN, SETTING, AND PARTICIPANTS: At the University of Tokyo Hospital, we conducted a randomized, double-blind, placebo-controlled, within-subject-crossover, single-site experimental trial in which intranasal oxytocin and placebo were administered. A total of 40 highly functioning men with ASD participated and were randomized in the trial. INTERVENTIONS: Single-dose intranasal administration of oxytocin (24 IU) and placebo. MAIN OUTCOMES AND MEASURES: Using functional magnetic resonance imaging, we examined effects of oxytocin on behavioral neural responses of the participants to a social psychological task. In our previous case-control study using the same psychological task, when making decisions about social information with conflicting verbal and nonverbal contents, participants with ASD made judgments based on nonverbal contents less frequently with longer time and could not induce enough activation in the medial prefrontal cortex. Therefore, our main outcomes and measures were the frequency of the nonverbal information-based judgments (NVJs), the response time for NVJs, and brain activity of the medial prefrontal cortex during NVJs. RESULTS: Intranasal oxytocin enabled the participants to make NVJs more frequently (P = .03) with shorter response time (P = .02). During the mitigated behavior, oxytocin increased the originally diminished brain activity in the medial prefrontal cortex (P < .001). Moreover, oxytocin enhanced functional coordination in the area (P < .001), and the magnitude of these neural effects was predictive of the behavioral effects (P ≤ .01). CONCLUSIONS AND RELEVANCE: These findings provide the first neurobiological evidence for oxytocin's beneficial effects on sociocommunicational deficits of ASD and give us the initial account for neurobiological mechanisms underlying any beneficial effects of the neuropeptide. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: UMIN000002241 and UMIN000004393.
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Functional neuroimaging studies in persons with autism spectrum disorder have shown differences in regional brain activation in response to social stimuli after intranasal oxytocin, compared with placebo.
“These results have been supported by functional neuroimaging studies involving persons with autism spectrum disorder, which have shown differences in regional brain activation in response to social stimuli after the administration of intranasal oxytocin, as compared with placebo.11,15–17”
From Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder (2021) · cites this paper as [11]
Several trials have shown that a single dose of intranasal oxytocin enhanced performance on measures of social cognition or motivation, compared with placebo, in persons with autism spectrum disorder.
“Several trials have shown that a single dose of intranasal oxytocin enhanced performance on measures of social cognition10,11 or motivation,12–14 as compared with placebo, in persons with autism spectrum disorder.”
From Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder (2021) · cites this paper as [11]
Oxytocin has received substantial interest as a potential treatment for psychiatric conditions such as autism, although clinical trials show modest effects.
“Oxytocin has received substantial interest as a potential treatment for psychiatric conditions such as autism spectrum conditions (ASC; henceforth autism),3 although clinical trials show modest effects.4, 5, 6”
From Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women (2017) · cites this paper as [4]
Previous studies showing oxytocin effects on emotion recognition, empathy, or face processing in adults with ASD had an average sample size of 21.5 participants.
“Moreover, previous studies showing oxytocin effects on emotion recognition, empathy, or face processing in adults with ASD had an average sample size of 21.5 participants48,50,51,86–88.”
From Randomized clinical trial shows no substantial modulation of empathy-related neural activation by intranasal oxytocin in autism (2021) · cites this paper as [86]
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- Authors
- Watanabe, T., Abe, O., Kuwabara, H., Yahata, N., Takano, Y., Iwashiro, N., Natsubori, T., Aoki, Y., Takao, H., Kawakubo, Y., Kamio, Y., Kato, N., Miyashita, Y., Kasai, K., & Yamasue, H.
- Affiliations
- The University of Tokyo (JP)
- Nihon University (JP)
- National Center of Neurology and Psychiatry (JP)
- SHOWA Medical University (JP)
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2014-02-01
- Volume
- 71
- Issue
- 2
- Pages
- 166
- ISSN
- 2168-622X (ISSN-L)
- OpenAlex
- W1985576902
- Cited by
- 183
- References
- 50
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 12 · 2023: 11 · 2022: 15 · 2021: 16 · 2020: 19 · 2019: 11 · 2018: 19 · 2017: 19 · 2016: 15 · 2015: 21 · 2014: 12
- FWCI
- 23.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (22689034)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Social Sciences › Psychology › Social Psychology › Action Observation and Synchronization
- Keywords
- autism spectrum disorder, oxytocin, medial prefrontal cortex, intranasal administration, social decision-making, placebo-controlled crossover trial, neuropeptide therapy, reaction time (psychology), functional connectivity
- MeSH terms
- Administration, Intranasal, Adult, Child Development Disorders, Pervasive, Double-Blind Method, Humans, Magnetic Resonance Imaging, Male, Oxytocin, Social Behavior, Placebo Effect, Treatment Outcome, Prefrontal Cortex, Cross-Over Studies, Young Adult
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