Cited by 114Neuroendocrine regulation and behaviorAutism Spectrum Disorder ResearchAction Observation and Synchronization

Intranasal oxytocin enhances connectivity in the neural circuitry supporting social motivation and social perception in children with autism

Open access
Gordon, Ilanit, Jack, Allison, Pretzsch, Charlotte M., Vander Wyk, Brent, Leckman, James F., Feldman, Ruth, Pelphrey, Kevin A.·2016·Scientific Reports

Abstract

Oxytocin (OT) has become a focus in investigations of autism spectrum disorder (ASD). The social deficits that characterize ASD may relate to reduced connectivity between brain sites on the mesolimbic reward pathway (nucleus accumbens; amygdala) that receive OT projections and contribute to social motivation, and cortical sites involved in social perception. Using functional magnetic resonance imaging and a randomized, double blind, placebo-controlled crossover design, we show that OT administration in ASD increases activity in brain regions important for perceiving social-emotional information. Further, OT enhances connectivity between nodes of the brain’s reward and socioemotional processing systems, and does so preferentially for social (versus nonsocial) stimuli. This effect is observed both while viewing coherent versus scrambled biological motion, and while listening to happy versus angry voices. Our findings suggest a mechanism by which intranasal OT may bolster social motivation—one that could, in future, be harnessed to augment behavioral treatments for ASD.

AI snapshot

Written from the paper’s full text.

TL;DR

In a randomized, double-blind, placebo-controlled crossover fMRI study, intranasal oxytocin altered brain activity and effective connectivity in children with autism spectrum disorder during social perception tasks. Oxytocin increased connectivity within mesocorticolimbic reward circuitry and between mesolimbic seeds and social-perception regions, preferentially for social or rewarding stimuli.

Key findings

  • Oxytocin increased right posterior superior temporal sulcus response to coherent biological motion versus scrambled motion; under placebo, this response was not strongly differentiated.
  • Oxytocin increased right brainstem and right amygdala activation to angry versus happy voices; no clusters showed happy > angry for oxytocin > placebo.
  • During biological motion, oxytocin increased psychophysiological interaction connectivity between right nucleus accumbens and right ventrolateral/ventromedial prefrontal cortex; no clusters emerged for the left nucleus accumbens seed.
  • During affective voices, oxytocin increased happy > angry connectivity with left and right nucleus accumbens and left and right amygdala seeds across regions including precuneus, cuneus, supramarginal gyrus/Heschl’s gyrus, and fusiform gyrus; no significant findings emerged for angry > happy. Higher SRS scores were associated with greater happy > angry connectivity in several regions, while ADI-R associations were mixed.

Methods

  • Twenty-one children with ASD (8–16.5 years, 18 boys) were enrolled in a randomized, double-blind, placebo-controlled crossover design; final analyzed samples were 14 children (11 boys) for Biological Motion and 16 children (13 boys) for Affective Voices after motion-related exclusions.
  • Participants received age-adjusted intranasal oxytocin (24 IU for 16–19 years, 18 IU for 12–15 years, 12 IU for 7–11 years) or placebo before fMRI; scans included a Biological Motion task (coherent vs scrambled motion) and an Affective Voices task (happy vs angry voices).
  • Analyses used whole-brain main effects and psychophysiological interaction (PPI) analyses with nucleus accumbens and amygdala seeds; group-level models included age, full-scale IQ, and sex as covariates, with exploratory SRS and ADI-R regressors.

Limitations

  • The paper states that some participants were on preexisting medication regimens, that the sample was small with relatively few girls, and that future work should address dose effects and compare children with ASD to typically developing children.
  • The text makes evident that there was no typically developing comparison group, the study assessed a single oxytocin challenge rather than lasting therapeutic benefit, and motion artifact excluded several datasets.
  • The symptom-severity findings were exploratory, and the unexpected amygdala–primary visual connectivity finding was interpreted post hoc and requires further validation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/srep35054

Cites

77 of 77 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 13 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Oxytocin administration is associated with greater psychophysiological interaction between right nucleus accumbens and a region of ventral prefrontal cortex, peaking in right ventrolateral prefrontal cortex and extending into right ventromedial prefrontal cortex, during coherent versus scrambled biological motion.

    “OT administration was associated with a greater PPI between right NAcc and a region of ventral PFC. This cluster had a peak in right ventrolateral PFC (vlPFC) and extended into right ventromedial PFC (vmPFC).”
    • Also stated in: § Discussion · plain
      “In the visual domain, inhalation of OT (relative to PLC) increased connectivity within the mesocorticolimbic pathway during the perception of coherent biological motion, specifically between NAcc and frontal regions (i.e., vm/vlPFC) known to be involved in representing reward value, social meaning, and social intentions4748.”
    Quote in the paperSubstantial claim
  • Findingown data

    Oxytocin administration induces connectivity increases with all seeds of interest (left and right nucleus accumbens and left and right amygdala) for happy versus angry voices.

    “OT administration induced connectivity increases with all seeds of interest (left and right NAcc and left and right AMYG) for HAP > ANG (see Fig. 3A).”
    Quote in the paperSubstantial claim
  • Findingown data

    Oxytocin enhances connectivity between nodes of the brain's reward and socioemotional processing systems.

    “Further, OT enhances connectivity between nodes of the brain’s reward and socioemotional processing systems, and does so preferentially for social (versus nonsocial) stimuli.”
    • Also stated in: § Discussion · plain
      “Across visual and auditory modalities, OT increased effective connectivity both within the mesocorticolimbic reward pathway and also between mesolimbic sites and cortical regions that contribute to social perception.”
    Quote in the paperSubstantial claim
  • Findingown data

    Intranasal oxytocin administration in individuals with autism spectrum disorder increases activity in brain regions important for perceiving social-emotional information.

    “we show that OT administration in ASD increases activity in brain regions important for perceiving social-emotional information.”
    • Also stated in: § Discussion · plain
      “OT administration to children and adolescents with ASD was associated with increased activity in brain regions important for social-emotional perception.”
    Quote in the paperSubstantial claim
  • Findingown data

    Oxytocin-induced connectivity increases are specific to socially rewarding (happy) versus socially aversive (angry) stimuli.

    “These effects were specific to exposure to social versus nonsocial information (Biological Motion), and to socially rewarding versus socially aversive stimuli (Affective Voices).”
    Quote in the paperSubstantial claim
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 14
  • May combine two claims.

    Findingown data

    Higher Autism Diagnostic Interview-Revised social subscale score (greater impairment) is associated with greater happy versus angry psychophysiological interaction values between left amygdala and right frontal pole, and between either left or right nucleus accumbens and ventromedial prefrontal cortex.

    “Consistent with the SRS findings, a higher ADI-R social subscale score (indicating greater impairment) was associated with greater HAP > ANG PPI values between left AMYG and right frontal pole as well as between either left or right NAcc and vmPFC.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Findingown data

    During happy voice perception, oxytocin induces increases in connectivity with precuneus from both mesolimbic sites, with nucleus accumbens interacting with more anterior precuneus and amygdala with more posterior precuneus.

    “During happy voice perception, OT also induced increases in connectivity with PCu from both mesolimbic sites, with NAcc interacting with more anterior regions of PCu and AMYG interacting with more posterior PCu regions.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Passive paradigms were employed to assess oxytocin's effects on social perception in the absence of potentially confounding task demands.

    “We employed passive paradigms in order to assess OT’s effects on social perception in the absence of potentially confounding task demands (e.g., refs 29, 30, 31, 32).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] Kaiser, M. D. et al. Neural signatures of autism. Proc Natl Acad Sci USA 107, 21223–21228, doi: 10.1073/pnas.1010412107 (2010). source

      Not checked in the free run.

    • cites [30] Belin, P., Fillion-Bilodeau, S. & Gosselin, F. The Montreal Affective Voices: a validated set of nonverbal affect bursts for research on auditory affective processing. Behavior research methods 40, 531–539 (2008). source

      Not checked in the free run.

    • cites [31] Kanwisher, N., McDermott, J. & Chun, M. M. The fusiform face area: A module in human extrastriate cortex specialized for face perception. J. Neurosci. 17, 4302–4311 (1997). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The findings support the notion that, in the normal course of social interaction, oxytocin serves different functions in different contexts; when highly salient but not rewarding angry cues are present, it upregulates amygdala response, whereas when happy cues are present, oxytocin facilitates communication among sites important for social motivation.

    “Thus our findings support the notion that, in the normal course of social interaction, OT serves different functions in different contexts22; when highly salient (but not rewarding) angry cues are present, it upregulates AMYG response, whereas when happy cues are present, OT facilitates communication among sites that are important for social motivation.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Interpretationown data

    Oxytocin administration can lead to beneficial effects on neural function in a range of individuals with autism spectrum disorder, but understanding individual symptomaticity is necessary to predict variability in oxytocin's therapeutic potential.

    “We propose that OT administration can lead to beneficial effects on neural function in a range of individuals with ASD, but that understanding individual symptomaticity is necessary to predict variability in OT’s therapeutic potential.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Quality assurance review excluded datasets contaminated by excessive motion, yielding final Biological Motion and Affective Voices samples of 14 and 16 children, respectively.

    “After quality assurance review to exclude datasets contaminated by excessive motion, our final Biological Motion sample included 14 children (11 boys), and our Affective Voices sample included 16 children (13 boys).”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Study design and conductown data

    The study used a randomized, double-blind, placebo-controlled crossover design in which 21 children with autism spectrum disorder received oxytocin or placebo before an initial fMRI scan and the other agent before a second fMRI scan.

    “To test this hypothesis, we employed a randomized, double-blind, placebo-controlled crossover design in which 21 children with ASD (8–16.5y, 18 boys; see Table 1 for demographic and phenotypic characteristics) received either OT or placebo (PLC) prior to an initial fMRI scan.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oxytocin can increase processing efficiency at the neuronal level by optimizing signal-to-noise during cell firing.

    “Together with recent findings showing that OT can increase processing efficiency at the neuronal level by optimizing signal-to-noise during cell firing43”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Owen, S. F. et al. Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons. Nature 500, 458–462, doi: 10.1038/nature12330 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The final Biological Motion sample included 14 children (11 boys), and the Affective Voices sample included 16 children (13 boys).

    “Our final Biological Motion sample included 14 children (11 boys), and our Affective Voices sample included 16 children (13 boys).”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Placebo and oxytocin spray containers were prepared to look identical and were counterbalanced to be randomly assigned by the pharmacy.

    “PLC and OT spray containers were prepared to look identical and were counterbalanced to be randomly assigned by the pharmacy as well.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Researchers and participants were blinded to the content of the spray.

    “Researchers, as well as participants, were blinded to the content of the spray.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Interpretationreasoning

    By impacting mesocorticolimbic connectivity, oxytocin may create a neural background in individuals with ASD that could bolster the motivation to interact socially and allow them to be more open to learn social engagement skills during treatment.

    “By impacting mesocorticolimbic connectivity, OT may create a neural background in individuals with ASD that could bolster the motivation to interact socially and allow them to be more open to learn social engagement skills during treatment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Changes in mesocorticolimbic connectivity cause changes in social motivation in individuals with ASD.
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Due to motion artifact, complete datasets from 6 children were excluded from analyses of the Biological Motion task, and 4 complete datasets were excluded from the Affective Voices task.

    “Due to motion artifact, the complete datasets from 6 children were excluded from analyses of the Biological Motion task, and 4 complete datasets were excluded from the Affective Voices task.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Interpretationreasoning

    In ASD, oxytocin may not only enhance neural activity to preferred stimuli but also improve communication among brain regions involved in social motivation and perception.

    “these results show that in ASD, OT may not only serve to enhance neural activity to “preferred” stimuli, but also improve communication among brain regions involved in social motivation and perception.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Owen, S. F. et al. Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons. Nature 500, 458–462, doi: 10.1038/nature12330 (2013). source

      Not checked in the free run.

    • cites [37] Gordon, I. et al. Oxytocin enhances brain function in children with autism. Proceedings of the National Academy of Sciences of the United States of America 110, 20953–20958, doi: 10.1073/pnas.1312857110 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    One participant could not complete both visits and was excluded.

    “One participant could not complete both visits and was excluded.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Participants were excluded if they had movement in any dimension ≥4 mm and/or ≥25% of volumes identified as outliers according to DVARS, such that only participants with acceptable motion under both oxytocin and placebo visits were included.

    “we elected to exclude participants where for either visit, the participant had one or more of the following: movement in any dimension ≥4 mm, and/or ≥25% of volumes identified as outliers according to the DVARS metric72 such that only participants who displayed acceptable amounts of motion under both the OT and PLC visits were included in analysis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Power, J. D., Barnes, K. A., Snyder, A. Z., Schlaggar, B. L. & Petersen, S. E. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. NeuroImage 59, 2142–2154, doi: 10.1016/j.neuroimage.2011.10.018 (2012). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The current results illustrate a discrete aspect of oxytocin's effect captured by measures of connectivity.

    “the current results illustrate a discrete aspect of OT’s effect captured by measures of connectivity”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Gordon, I. et al. Oxytocin enhances brain function in children with autism. Proceedings of the National Academy of Sciences of the United States of America 110, 20953–20958, doi: 10.1073/pnas.1312857110 (2013). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The study used a randomized, double-blind, placebo-controlled crossover design.

    “We used a randomized, double blind, placebo-controlled crossover design.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    For the vocal affect perception paradigm, fewer motion outlier volumes were detected for oxytocin than placebo scans (3.6 versus 5.5% of all time points identified as outliers), although there were no significant differences across treatment conditions as characterized by RMS movement metrics.

    “For the vocal affect perception paradigm, fewer motion outlier volumes were detected for OT than PLC scans (3.6 versus 5.5% of all time points identified as outliers, respectively), although there were no significant differences across treatment conditions as characterized by RMS movement metrics.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Age, full scale IQ, and sex were included as covariates in the group-level analysis.

    “Age (de-meaned), full scale IQ (de-meaned), and sex (dummy coded, female = 1) were included as covariates.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim.

    Study design and conductcitation

    ASD diagnosis was confirmed using the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview - Revised (ADI-R).

    “with ASD diagnosis confirmed using the Autism Diagnostic Observation Schedule70 and the Autism Diagnostic Interview – Revised (ADI-R)35.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Lord, C. et al. The Autism Diagnostic Observation Schedule-Generic: A standard measure of social and communication deficits associated with the spectrum of autism. J. Autism Dev. Disord. 30, 205–223 (2000). source

      Not checked in the free run.

    • cites [35] Lord, C., Rutter, M. & Le Couteur, A. Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of autism and developmental disorders 24, 659–685 (1994). source

      Not checked in the free run.

21 of 21
  • The paper relies on this without support.

    There is a lack of sensitive, objective measures designed to illuminate mechanisms of change in oxytocin treatment for autism spectrum disorder.

    “Our understanding of the potential for OT to treat ASD is hampered by a lack of sensitive, objective measures that are designed to illuminate mechanisms of change.”
  • The paper relies on this without support.

    There have been few studies of oxytocin's effects on brain activity in children, creating a translational gap between the push for clinical use of oxytocin and limited understanding of developmental and contextual factors shaping its effects on neural function and behavior.

    “Despite cautionary calls16 regarding the use of OT to treat ASD prior to understanding its developmental effects, there have been few studies of OT’s effects on brain activity in children, creating a translational gap between the push for clinical use of OT and our limited understanding of the developmental and contextual factors that shape its effects on neural function and resulting behavior.”
  • The paper relies on this without support.

    Oxytocin-induced changes in the neural underpinnings of social motivation translate into improved response to behavioral interventions in children with ASD.

    “These findings lead us to believe that intranasal OT, via its effects on the neural underpinnings of social motivation, could improve response to behavioral interventions that provide a rich array of social learning opportunities.”
  • The paper relies on this without support.

    Changes in mesocorticolimbic connectivity cause changes in social motivation in individuals with ASD.

    “By impacting mesocorticolimbic connectivity, OT may create a neural background in individuals with ASD that could bolster the motivation to interact socially and allow them to be more open to learn social engagement skills during treatment.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Acute IN-OT enhanced functional connectivity between PFC and NAc while viewing biological motion.

    “In a separate study, acute IN-OT enhanced functional connectivity between PFC and NAc while viewing biological motion [49].”
  • Intranasal OXT leads to increased activation in brain regions involved in perceiving and thinking about social-emotional information and enhances effective connectivity between nodes of the brain's reward and socioemotional processing systems.

    “At the neural networks level, it has been shown that intranasal OXT leads to increased activation in the brain regions known to be involved in perceiving and thinking about social-emotional information and enhances effective connectivity between nodes of the brain’s reward and socioemotional processing systems [87, 88].”
  • Exogenous oxytocin has behavioural effects in humans, particularly in social deficit-related psychiatric disorders such as autism and schizophrenia.

    “Exogenous oxytocin in humans also appears to have behavioural effects, particularly in such social deficit-related psychiatric disorders as autism and schizophrenia9–13.”

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Consistentr(14) = 0.28reported p = .3 · recomputed p = .294

    “r(14) = 0.28, p = .300”

1 of 1

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • ADI-R connectivity finding is attributed to the wrong seed-region pair

    Major

    The Discussion says greater historical symptom severity was associated with increased connectivity between right NAcc and frontal pole. The Results instead assign the frontal-pole finding to left AMYG and the right-NAcc finding to vmPFC.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Brothers, L. The social brain: a project for integrating primate behavior and neurophysiology in a new domain. Concepts in Neuroscience 1, 27–51 (1990).
  2. Love, T. M. Oxytocin, motivation and the role of dopamine. Pharmacol Biochem Behav 119, 49–60, doi: 10.1016/j.pbb.2013.06.011 (2014). · DOI · Paper page

Cited by

Sorted by citations

Authors
Gordon, I., Jack, A., Pretzsch, C. M., Vander Wyk, B., Leckman, J. F., Feldman, R., & Pelphrey, K. A.
Affiliations
  • Bar-Ilan University (IL)
  • George Washington University (US)
  • Yale University (US)
Corresponding author
  • Gordon, Ilanit
  • Jack, Allison
Venue
Scientific Reports
Published
2016-11-15
Volume
6
Issue
1
Pages
35054-35054
ISSN
2045-2322 (ISSN-L)
OpenAlex
W2557098163
Cited by
114
References
77
Citations by year
2026: 5 · 2025: 10 · 2024: 5 · 2023: 13 · 2022: 17 · 2021: 18 · 2020: 11 · 2019: 14 · 2018: 9 · 2017: 12
FWCI
18.34
Type
journal article
Language
en
Open access
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion)
Funders
  • National Science Foundation
  • Yale University
  • Lee Foundation
  • National Institutes of Health (MH018268-31, UL1TR001863)
  • National Institute of Mental Health (T32MH018268)
  • National Center for Advancing Translational Sciences
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Social Sciences › Psychology › Social Psychology › Action Observation and Synchronization
Keywords
intranasal oxytocin, autism spectrum disorder, social motivation, social perception, mesolimbic reward pathway, nucleus accumbens, amygdala, brain connectivity, social-emotional processing, biological motion, voice emotion perception, children
MeSH terms
Autism Spectrum Disorder, Administration, Intranasal, Adolescent, Brain, Brain Mapping, Child, Double-Blind Method, Female, Humans, Magnetic Resonance Imaging, Male, Motivation, Oxytocin, Social Perception, Cross-Over Studies

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