Takamitsu Watanabe1, Osamu Abe2, Hitoshi Kuwabara3, Noriaki Yahata4, Yosuke Takano5, Norichika Iwashiro5, Tatsunobu Natsubori5, Yuta Aoki5, Hidemasa Takao6, Yuki Kawakubo3, Yoko Kamio7, Nobumasa Kato8, Yasushi Miyashita9, Kiyoto Kasai5, Hidenori Yamasue10. 1. Department of Neuropsychiatry, School of Medicine, University of Tokyo, Tokyo, Japan2Department of Physiology, School of Medicine, University of Tokyo, Tokyo, Japan. 2. Department of Radiology, School of Medicine, Nihon University, Tokyo, Japan4Department of Radiology, School of Medicine, University of Tokyo, Tokyo, Japan. 3. Department of Child Neuropsychiatry, School of Medicine, University of Tokyo, Tokyo, Japan. 4. Department of Neuropsychiatry, School of Medicine, University of Tokyo, Tokyo, Japan6Global Center of Excellence Program, University of Tokyo, Tokyo, Japan. 5. Department of Neuropsychiatry, School of Medicine, University of Tokyo, Tokyo, Japan. 6. Department of Radiology, School of Medicine, University of Tokyo, Tokyo, Japan. 7. Department of Child and Adolescent Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan. 8. Department of Neuropsychiatry, School of Medicine, Showa University, Tokyo, Japan. 9. Department of Physiology, School of Medicine, University of Tokyo, Tokyo, Japan. 10. Department of Neuropsychiatry, School of Medicine, University of Tokyo, Tokyo, Japan8Department of Neuropsychiatry, School of Medicine, Showa University, Tokyo, Japan9Japan Science and Technology Agency, Tokyo, Japan.
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.
RCT Entities:
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.
Authors: Tatiana M Kazdoba; Prescott T Leach; Mu Yang; Jill L Silverman; Marjorie Solomon; Jacqueline N Crawley Journal: Curr Top Behav Neurosci Date: 2016
Authors: Brian J Mickey; Joseph Heffernan; Curtis Heisel; Marta Peciña; David T Hsu; Jon-Kar Zubieta; Tiffany M Love Journal: Psychopharmacology (Berl) Date: 2016-09-10 Impact factor: 4.530
Authors: Marina Spanos; Tara Chandrasekhar; Soo-Jeong Kim; Robert M Hamer; Bryan H King; Christopher J McDougle; Kevin B Sanders; Simon G Gregory; Alexander Kolevzon; Jeremy Veenstra-VanderWeele; Linmarie Sikich Journal: Contemp Clin Trials Date: 2020-08-08 Impact factor: 2.226