Oxytocin’s neurochemical effects in the medial prefrontal cortex underlie recovery of task-specific brain activity in autism: a randomized controlled trial
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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.
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Oxytocin changes activity in the insular cortex and ventromedial prefrontal cortex and reduces neural responses to stress-related and painful stimuli in the amygdala.
“Furthermore, it has been shown that OXT not only modulates activity in the insular cortex (Striepens et al., 2012;Wigton et al., 2015) and VMPFC (Aoki et al., 2015;Labuschagne et al., 2012) but also reduces the neural response to stress-associated signals (Maier et al., 2018) and painful stimuli in the amygdala (AMY) (Paloyelis et al., 2016).”
From Oxytocin enhances the pain‐relieving effects of social support in romantic couples (2019) · cites this paper as Aoki et al., 2015
Most randomized clinical trials have found some oxytocin effects on ASD symptoms and brain function, but not all trials have reported effects.
“While most randomized clinical trials have found some oxytocin effects on ASD symptoms33,50–52 and brain function50–52,80,81, not all trials have reported effects82.”
From Randomized clinical trial shows no substantial modulation of empathy-related neural activation by intranasal oxytocin in autism (2021) · cites this paper as [80]
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Self-citation
- Authors
- Aoki, Y., Watanabe, T., Abe, O., Kuwabara, H., Yahata, N., Takano, Y., Iwashiro, N., Natsubori, T., Takao, H., Kawakubo, Y., Kasai, K., & Yamasue, H.
- Affiliations
- The University of Tokyo (JP)
- Nihon University (JP)
- Japan Science and Technology Agency (JP)
- Corresponding author
- Yamasue, H
- Venue
- Molecular Psychiatry
- Published
- 2014-07-29
- Volume
- 20
- Issue
- 4
- Pages
- 447-453
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4378254
- OpenAlex
- W2047889404
- Cited by
- 95
- References
- 55
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 5 · 2021: 14 · 2020: 8 · 2019: 6 · 2018: 19 · 2017: 11 · 2016: 11 · 2015: 14
- FWCI
- 17.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (221S0003, 26670535, 22689034, 26250024, 25461751)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- oxytocin, autism spectrum disorder, ventromedial prefrontal cortex, N-acetylaspartate, intranasal administration, neurochemical effects, placebo response, high-functioning autism
- MeSH terms
- Administration, Intranasal, Adult, Aspartic Acid, Autistic Disorder, Double-Blind Method, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Magnetic Resonance Spectroscopy, Oxygen, Oxytocics, Oxytocin, Protons, Retrospective Studies, Time Factors, Prefrontal Cortex, Recovery of Function, Young Adult
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