title: Oxytocin's neurochemical effects in the medial prefrontal cortex underlie recovery of task-specific brain activity in autism: a randomized controlled trial.
abstract: The neuropeptide oxytocin may be an effective therapeutic strategy for the currently untreatable social and communication deficits associated with autism. Our recent paper reported that oxytocin mitigated autistic behavioral deficits through the restoration of activity in the ventromedial prefrontal cortex (vmPFC), as demonstrated with functional magnetic resonance imaging (fMRI) during a socio-communication task. However, it is unknown whether oxytocin exhibited effects at the neuronal level, which was outside of the specific task examined. In the same randomized, double-blind, placebo-controlled, within-subject cross-over clinical trial in which a single dose of intranasal oxytocin (24 IU) was administered to 40 men with high-functioning autism spectrum disorder (UMIN000002241/000004393), we measured N-acetylaspartate (NAA) levels, a marker for neuronal energy demand, in the vmPFC using (1)H-magnetic resonance spectroscopy ((1)H-MRS). The differences in the NAA levels between the oxytocin and placebo sessions were associated with oxytocin-induced fMRI signal changes in the vmPFC. The oxytocin-induced increases in the fMRI signal could be predicted by the NAA differences between the oxytocin and placebo sessions (P=0.002), an effect that remained after controlling for variability in the time between the fMRI and (1)H-MRS scans (P=0.006) and the order of administration of oxytocin and placebo (P=0.001). Furthermore, path analysis showed that the NAA differences in the vmPFC triggered increases in the task-dependent fMRI signals in the vmPFC, which consequently led to improvements in the socio-communication difficulties associated with autism. The present study suggests that the beneficial effects of oxytocin are not limited to the autistic behavior elicited by our psychological task, but may generalize to other autistic behavioral problems associated with the vmPFC.
authors: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Y
authors: Y
authors: Aoki
authors: 1] Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [2] Department of Physiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: T
authors: T
authors: Watanabe
authors: 1] Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [2] Department of Radiology, Nihon University School of Medicine, Tokyo, Japan.
authors: O
authors: O
authors: Abe
authors: Department of Child Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: H
authors: H
authors: Kuwabara
authors: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: N
authors: N
authors: Yahata
authors: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Y
authors: Y
authors: Takano
authors: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: N
authors: N
authors: Iwashiro
authors: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: T
authors: T
authors: Natsubori
authors: Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: H
authors: H
authors: Takao
authors: Department of Child Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Y
authors: Y
authors: Kawakubo
authors: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: K
authors: K
authors: Kasai
authors: 1] Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [2] Japan Science and Technology Agency, CREST, Tokyo, Japan.
authors: H
authors: H
authors: Yamasue
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001321:Autistic Disorder / Q000188:drug therapy* / Q000473:pathology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010100:Oxygen / Q000097:blood; D010120:Oxytocics / Q000008:administration & dosage / Q000494:pharmacology; D010121:Oxytocin / Q000008:administration & dosage* / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D011522:Protons; D020127:Recovery of Function / Q000187:drug effects*; D012189:Retrospective Studies; D013997:Time Factors; D055815:Young Adult
chemical_list: D010120:Oxytocics; D011522:Protons; D001224:Aspartic Acid; D010121:Oxytocin; C000179:N-acetylaspartate; D010100:Oxygen