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Original Investigation |

Mitigation of Sociocommunicational Deficits of Autism Through Oxytocin-Induced Recovery of Medial Prefrontal Activity:  A Randomized Trial

Takamitsu Watanabe, MD1,2; Osamu Abe, MD, PhD3,4; Hitoshi Kuwabara, MD, PhD5; Noriaki Yahata, PhD1,6; Yosuke Takano, MD, PhD1; Norichika Iwashiro, MD1; Tatsunobu Natsubori, MD1; Yuta Aoki, MD1; Hidemasa Takao, MD, PhD4; Yuki Kawakubo, PhD5; Yoko Kamio, MD, PhD7; Nobumasa Kato, MD, PhD8; Yasushi Miyashita, PhD2; Kiyoto Kasai, MD, PhD1; Hidenori Yamasue, MD, PhD1,8,9
[+] Author Affiliations
1Department of Neuropsychiatry, School of Medicine, University of Tokyo, Tokyo, Japan
2Department of Physiology, School of Medicine, University of Tokyo, Tokyo, Japan
3Department of Radiology, School of Medicine, Nihon University, Tokyo, Japan
4Department of Radiology, School of Medicine, University of Tokyo, Tokyo, Japan
5Department of Child Neuropsychiatry, School of Medicine, University of Tokyo, Tokyo, Japan
6Global Center of Excellence Program, University of Tokyo, Tokyo, Japan
7Department of Child and Adolescent Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan
8Department of Neuropsychiatry, School of Medicine, Showa University, Tokyo, Japan
9Japan Science and Technology Agency, Tokyo, Japan
JAMA Psychiatry. 2014;71(2):166-175. doi:10.1001/jamapsychiatry.2013.3181.
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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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Figure 1.
Task Design and Effects on Behavior

A, Participants were instructed to make friend or foe judgments for each movie in a series of short movies in which a professional actor spoke an emotionally positive or negative word (verbal information) while exhibiting emotionally positive or negative facial and vocal expressions (nonverbal information). B, Responses to incongruent stimuli were classified as nonverbal information–based judgments (NVJs) or verbal information–based judgments (VJs). NV−V+ indicates stimuli with negative nonverbal information and positive verbal information; NV+V−, stimuli with positive nonverbal information and negative verbal information. C, Intranasal administration of oxytocin significantly increased the number of NVJs, which was lower in untreated individuals with autism spectrum disorders compared with typically developing individuals in our previous study.8 Error bars indicate standard error of the mean. D, This oxytocin-induced increase in the number of NVJs was observed regardless of the order of drug administration. E, Intranasal oxytocin significantly decreased response times for the NVJs, which were longer in untreated individuals with autism spectrum disorders than in typically developing individuals (eFigure 2 in Supplement). F, This oxytocin-induced shortening of response times for NVJs was observed regardless of the order of drug administration. G, The oxytocin-induced increase in the number of NVJs significantly correlated with oxytocin-induced shortening of response times to incongruent stimuli, which suggests a common neural effect of oxytocin.aP < .05.bP > .05.

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Figure 2.
Enrollment and Randomization of Participants

Among the 40 individuals with autism spectrum disorders enrolled in this trial, 7 were excluded from the analysis because of technical problems in recording behavioral data (2 participants), current use of psychotropic medications (2 participants), or frequent unnatural responses to the congruent stimuli (3 participants). As their unnatural responses, 1 of the 3 excluded participants judged actors with positive nonverbal and positive verbal information as foe in 19 of 20 stimuli in the oxytocin session and 11 of 20 stimuli in the placebo session, 1 participant judged actors with positive nonverbal and positive verbal information as foe in 20 of 20 stimuli in both the oxytocin and placebo sessions, and the other judged actors with negative nonverbal and negative verbal information as friend in 11 of 20 stimuli in both the oxytocin and placebo sessions. In the remaining 33 participants, the number of atypical responses ranged from 0 to 4. We observed essentially the same statistical conclusions when the 2 medicated participants were not excluded (eAppendix 2 in Supplement).

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Figure 3.
Effects on Brain Activity

A, Oxytocin significantly increased nonverbal information–based judgment (NVJ)–specific activity (NVJ > verbal information–based judgment [VJ]) only in the anterior cingulate cortex (ACC) and dorsal medial prefrontal cortex (dmPFC), whose activity was lower in untreated individuals with autism spectrum disorders (ASD) than in typically developing (TD) individuals in our previous study.8 Even in the oxytocin session alone, activity in the ACC and dmPFC was significantly greater during NVJs than VJs, which had previously been observed only in TD individuals and not in individuals with ASD.8 To show the interaction of brain activity (type of drug × type of response × type of incongruent stimuli), we previously calculated the interaction between the latter 2 factors as the difference between NVJ and VJ. AI indicates anterior insula; IFG: inferior prefrontal gyrus; Lt, left; Rt, right; STP: superior temporal pole; and error bars, standard error of the mean. B, A voxelwise whole-brain search found significant activations in the medial prefrontal cortex (Table; eFigure 6 in Supplement), an area related to various introspective and social cognitions. Its location partially overlapped with our predefined ACC and dmPFC regions of interest (circles), which supports the regional specificity of oxytocin’s neural effects. P < .001, uncorrected for presentation purposes. C, The NVJ-specific activity in the ACC and dmPFC showed significant positive correlations with the number of NVJs only after oxytocin administration. In our previous case-control study,8 these correlations were also observed in TD individuals but not in ASD individuals. Oxytocin-induced increases in NVJ-specific brain activity in the ACC and dmPFC were significantly correlated with oxytocin-induced increases in the number of NVJs (D) and oxytocin-induced shortening of response times for NVJs (E).aP < .05, Bonferroni corrected.bP < .001.cP < .05.dP < .01.eP < .01 in a test of the differences between 2 Pearson correlation coefficients.

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Figure 4.
Effects of Oxytocin on Functional Connectivity

A, Intranasal oxytocin significantly enhanced nonverbal information–based judgment (NVJ)–specific functional connectivity (psychophysiological interaction) from the dorsal medial prefrontal cortex (dmPFC) to the anterior cingulate cortex (ACC), whereas it did not enhance the opposite connectivity. Significance is shown for greater functional connectivity during NVJs than verbal information–based judgments (VJs) in the oxytocin session alone. Error bars indicate standard error of the mean. B, Our predefined ACC region of interest partially overlapped with the region that showed increased connectivity from the dmPFC in a voxelwise whole-brain connectivity analysis with the dmPFC seed (eTable 5 in Supplement). This result reveals the spatial specificity of oxytocin-induced enhancements of functional connectivity from the dmPFC. P < .001, uncorrected for presentation purposes. C, The NVJ-specific connectivity from the dmPFC to the ACC significantly correlated with the number of NVJs only after oxytocin administration, which suggests that this connectivity is associated with NVJs. Oxytocin-induced enhancement of functional connectivity from the dmPFC to the ACC significantly correlated with oxytocin-induced increases in the number of NVJs (D) and shortening of response times for NVJs (E).aP < .001.bP > .05.cP < .01 in 1-sample t test.dP < .05.

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