title: Oxytocin improves behavioural and neural deficits in inferring others' social emotions in autism.
abstract: Recent studies have suggested oxytocin's therapeutic effects on deficits in social communication and interaction in autism spectrum disorder through improvement of emotion recognition with direct emotional cues, such as facial expression and voice prosody. Although difficulty in understanding of others' social emotions and beliefs under conditions without direct emotional cues also plays an important role in autism spectrum disorder, no study has examined the potential effect of oxytocin on this difficulty. Here, we sequentially conducted both a case-control study and a clinical trial to investigate the potential effects of oxytocin on this difficulty at behavioural and neural levels measured using functional magnetic resonance imaging during a psychological task. This task was modified from the Sally-Anne Task, a well-known first-order false belief task. The task was optimized for investigation of the abilities to infer another person's social emotions and beliefs distinctively so as to test the hypothesis that oxytocin improves deficit in inferring others' social emotions rather than beliefs, under conditions without direct emotional cues. In the case-control study, 17 males with autism spectrum disorder showed significant behavioural deficits in inferring others' social emotions (P = 0.018) but not in inferring others' beliefs (P = 0.064) compared with 17 typically developing demographically-matched male participants. They also showed significantly less activity in the right anterior insula and posterior superior temporal sulcus during inferring others' social emotions, and in the dorsomedial prefrontal cortex during inferring others' beliefs compared with the typically developing participants (P < 0.001 and cluster size > 10 voxels). Then, to investigate potential effects of oxytocin on these behavioural and neural deficits, we conducted a double-blind placebo-controlled crossover within-subject trial for single-dose intranasal administration of 24 IU oxytocin in an independent group of 20 males with autism spectrum disorder. Behaviourally, oxytocin significantly increased the correct rate in inferring others' social emotions (P = 0.043, one-tail). At the neural level, the peptide significantly enhanced the originally-diminished brain activity in the right anterior insula during inferring others' social emotions (P = 0.004), but not in the dorsomedial prefrontal cortex during inferring others' beliefs (P = 0.858). The present findings suggest that oxytocin enhances the ability to understand others' social emotions that have also required second-order false belief rather than first-order false beliefs under conditions without direct emotional cues in autism spectrum disorder at both the behaviour and neural levels.
authors.affiliation: 1 Department of Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: 1 Department of Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Yahata
authors.affiliation: 2 Department of Physiology, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: 1 Department of Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Takano
authors.affiliation: 3 Department of Child Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kawakubo
authors.affiliation: 3 Department of Child Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kuwabara
authors.affiliation: 1 Department of Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Norichika
authors.initials: N
authors.lastname: Iwashiro
authors.affiliation: 1 Department of Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tatsunobu
authors.initials: T
authors.lastname: Natsubori
authors.affiliation: 1 Department of Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Inoue
authors.affiliation: 1 Department of Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Motomu
authors.initials: M
authors.lastname: Suga
authors.affiliation: 4 Department of Radiology, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Takao
authors.affiliation: 4 Department of Radiology, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: 4 Department of Radiology, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Gonoi
authors.affiliation: 4 Department of Radiology, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kunimatsu
authors.affiliation: 1 Department of Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Kasai
authors.affiliation: 1 Department of Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan 5 Japan Science and Technology Agency, CREST, 5 Sambancho, Chiyoda-ku, Tokyo 102-0075, Japan yamasue-tky@umin.ac.jp.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yamasue
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D002659:Child Development Disorders, Pervasive / Q000188:drug therapy / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004644:Emotions / Q000502:physiology; D004645:Empathy / Q000187:drug effects / Q000502:physiology; D005149:Facial Expression; D059907:Functional Neuroimaging; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010121:Oxytocin / Q000008:administration & dosage / Q000494:pharmacology*; D010919:Placebos; D012938:Social Perception; D056345:Theory of Mind / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D010919:Placebos; D010121:Oxytocin
keywords: empathy; mentalizing; neuropeptide; perspective taking; theory of mind