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Cited by 103Neuroendocrine regulation and behaviorFunctional Brain Connectivity StudiesOlfactory and Sensory Function Studies

Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women

Open access
Bethlehem, R A I, Lombardo, M V, Lai, M-C, Auyeung, B, Crockford, S K, Deakin, J, Soubramanian, S, Sule, A +3 more·2017·Translational Psychiatry
DOI 10.1038/tp.2017.72PMC PMC5416709

Published version of a preprint

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Abstract

Oxytocin may influence various human behaviors and the connectivity across subcortical and cortical networks. Previous oxytocin studies are male biased and often constrained by task-based inferences. Here, we investigate the impact of oxytocin on resting-state connectivity between subcortical and cortical networks in women. We collected resting-state functional magnetic resonance imaging (fMRI) data on 26 typically developing women 40 min following intranasal oxytocin administration using a double-blind placebo-controlled crossover design. Independent components analysis (ICA) was applied to examine connectivity between networks. An independent analysis of oxytocin receptor ( OXTR ) gene expression in human subcortical and cortical areas was carried out to determine plausibility of direct oxytocin effects on OXTR . In women, OXTR was highly expressed in striatal and other subcortical regions, but showed modest expression in cortical areas. Oxytocin increased connectivity between corticostriatal circuitry typically involved in reward, emotion, social communication, language and pain processing. This effect was 1.39 standard deviations above the null effect of no difference between oxytocin and placebo. This oxytocin-related effect on corticostriatal connectivity covaried with autistic traits, such that oxytocin-related increase in connectivity was stronger in individuals with higher autistic traits. In sum, oxytocin strengthened corticostriatal connectivity in women, particularly with cortical networks that are involved in social-communicative, motivational and affective processes. This effect may be important for future work on neurological and psychiatric conditions (for example, autism), particularly through highlighting how oxytocin may operate differently for subsets of individuals.

AI snapshot

Written from the paper’s full text.

TL;DR

In a double-blind placebo-controlled crossover study of 26 women, intranasal oxytocin increased resting-state functional connectivity between a corticostriatal subcortical network and a cortical network involved in social-communicative, affective, language and pain-related processes. The oxytocin-related connectivity boost was stronger in women with higher autistic traits.

Key findings

  • Oxytocin significantly increased connectivity between components IC11 and IC21: t(24)=6.99, P=3.10e−7, effect size d=1.39, 95% CI 0.96–1.86, surviving Bonferroni correction; 92% (23/25) of participants showed a non-zero oxytocin-related boost over placebo.
  • Under placebo, IC11–IC21 connectivity did not differ from zero (t(24)=−0.86, P=0.39), whereas under oxytocin it was elevated above zero (t(24)=6.22, P=1.95e−6).
  • The oxytocin-related increase in connectivity covaried with autistic traits: r=0.41, one-tailed P=0.0351, with larger effects in individuals with higher autistic traits.
  • OXTR gene expression was broadly present across subcortical regions, with enrichment in nucleus accumbens, substantia nigra and hypothalamus, but only modest expression across cortical areas.

Methods

  • Double-blind randomized placebo-controlled crossover design in 26 typically developing women (age 23.6±4.6 years, range 21–50); participants received intranasal oxytocin (24 IU, 40.32 μg) or placebo 40 min before resting-state fMRI, with sessions separated by at least 1 week.
  • Resting-state fMRI data were analyzed with group independent components analysis (ICA) constrained to 30 components, followed by dual regression; 22 of 30 components were classified as gray matter and used for between-component connectivity analyses, with paired t-tests and Bonferroni correction.
  • OXTR expression was examined descriptively in post-mortem human brain datasets (BrainSpan and GTEx), and an independent normative rsfMRI dataset of 50 females was used to compare normative connectivity with placebo connectivity.

Limitations

  • The paper states the sample size is moderate and may provide low power to detect small effects; it also notes that more subtle effects are likely underpowered and require larger studies.
  • The autistic-trait correlation is described as exploratory, and the study did not include males or clinically diagnosed autistic individuals; the authors state future work should examine males and clinical samples.
  • The paper notes ongoing debate about how well intranasal oxytocin crosses the blood–brain barrier and states that the study was not designed to determine optimal dose, timing, or central binding; it also acknowledges no formal assessment was done to rule out undiagnosed autism.

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

Integrity signals

Registry

Crossref · 10.1038/tp.2017.72

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 61 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Oxytocin increases connectivity between corticostriatal circuitry typically involved in reward, emotion, social communication, language and pain processing in women.

    “Oxytocin increased connectivity between corticostriatal circuitry typically involved in reward, emotion, social communication, language and pain processing.”
    • Also stated in: § Discussion · plain
      “We discovered a specific corticostriatal network implicated in social-communicative, motivational and affective processes that is heavily affected by oxytocin.”
    Quote in the paperSubstantial claim
  • Findingown data

    The oxytocin-related effect on corticostriatal connectivity covaries with autistic traits, with stronger increases in individuals with higher autistic traits.

    “This oxytocin-related effect on corticostriatal connectivity covaried with autistic traits, such that oxytocin-related increase in connectivity was stronger in individuals with higher autistic traits.”
    • Also stated in: § Oxytocin-related between-component connectivity differences · hedged
      “oxytocin's effect on between-component connectivity appeared to increase with increased degree of autistic traits: r=0.41, one-tailed P=0.0351”
    Quote in the paperSubstantial claim
  • Findingown data

    The oxytocin-related increase in corticostriatal connectivity has an effect size d=1.39 (95% CI 0.96-1.86).

    “This effect was 1.39 standard deviations above the null effect of no difference between oxytocin and placebo.”
    • Also stated in: § Oxytocin-related between-component connectivity differences · plain
      “t(24)=6.99, P=3.10e−7, effect size d=1.39, 95% CI (0.96–1.86)”
    Quote in the paperSubstantial claim
  • Findingown data

    NeuroSynth decoding revealed that most terms with highest correlation with IC11 were predominantly pain-related, motor-related or language/speech-related.

    “NeuroSynth decoding revealed that most of the terms with the highest correlation with IC11 were predominantly terms referring to pain-related, motor-related or language/speech-related processes”
    Quote in the paperNot a substantial claim
  • Findingown data

    Oxytocin enhances intrinsic corticostriatal functional connectivity in women.

    “In conclusion, we have discovered that oxytocin enhances corticostriatal connectivity in women.”
    Quote in the paperSubstantial claim
  • May combine two claims. 25
  • Classified as probably not a substantial claim. 32

  • May combine two claims.

    Findingown data

    In women, OXTR is highly expressed in striatal and other subcortical regions, but shows modest expression in cortical areas.

    “In women, OXTR was highly expressed in striatal and other subcortical regions, but showed modest expression in cortical areas.”
    • Also stated in: § OXTR gene expression in the female human brain · plain
      “Expression profiles of OXTR in women derived from the GTEx data set reveal broad expression across subcortical regions, but with notable enrichments particularly in nucleus accumbens, substantia nigra and the hypothalamus”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    OXTR expression profiles in women from GTEx reveal broad expression across subcortical regions, with notable enrichments in nucleus accumbens, substantia nigra and hypothalamus.

    “Expression profiles of OXTR in women derived from the GTEx data set reveal broad expression across subcortical regions, but with notable enrichments particularly in nucleus accumbens, substantia nigra and the hypothalamus”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All examined regions showed OXTR expression significantly above 0 and significantly stronger than in skin.

    “All regions showed OXTR expression that was significantly above 0 and critically was also significantly stronger than expression in a tissue we would expect to show little expression (that is, skin)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The independent normative data set consisted of 50 females who were slightly older but did not statistically differ in age from the oxytocin sample (mean age 31.6±12.2, Wilcoxon rank-sum W=764.5, P=0.117).

    “This independent data set consisted of 50 females whom were slightly older but did not statistically differ in age (mean age 31.6±12.2, Wilcoxon rank-sum test: W=764.5, P=0.117)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cortical regions from BrainSpan exhibit significant OXTR expression above 0 and compared to skin, but at much more modest levels than some subcortical regions.

    “Cortical regions from the BrainSpan data set also exhibit significant OXTR expression (above 0 and when compared to skin; Supplementary Table S2), albeit at much more modest levels than some subcortical regions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Spatial component maps of normative and oxytocin/placebo data sets show very large correlations (nIC4-IC11, r=0.80; nIC21-IC21, r=0.69), and no other components showed correlations near this strength (all r<0.2).

    “we find very large correlations between the spatial component maps of the normative and oxytocin/placebo data sets (nIC4-IC11, r=0.80; nIC21-IC21, r=0.69, Figure 2h). No other components showed anywhere near such strong correlations (all r<0.2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Previous oxytocin studies are male biased and often constrained by task-based inferences.

    “Previous oxytocin studies are male biased and often constrained by task-based inferences.”
    • Also stated in: § Introduction · plain
      “Although there are a number of existing neuroimaging oxytocin-administration studies,9 most have relied on task-based fMRI paradigms and largely focus on males.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Bethlehem RAI, van Honk J, Auyeung B, Baron-Cohen S . Oxytocin, brain physiology, and functional connectivity: a review of intranasal oxytocin fMRI studies. Psychoneuroendocrinology 2013; 38: 962–974. source

      Not checked in the free run.

    • cites [10] Beery AK, Zucker I . Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 2011; 35: 565–572. source

      Not checked in the free run.

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

    Premisecitation

    Oxytocin has received substantial interest as a potential treatment for psychiatric conditions such as autism, although clinical trials show modest effects.

    “Oxytocin has received substantial interest as a potential treatment for psychiatric conditions such as autism spectrum conditions (ASC; henceforth autism),3 although clinical trials show modest effects.4, 5, 6”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [3] Meyer-Lindenberg A . Impact of prosocial neuropeptides on human brain function. Prog Brain Res 2008; 170: 463–470. source

      Not checked in the free run.

    • cites [4] Watanabe T, Abe O, Kuwabara H, Yahata N, Takano Y, Iwashiro N et al. Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of medial prefrontal activity. JAMA Psychiatry 2013; 71: 166–175. source

      Not checked in the free run.

    • cites [5] Watanabe T, Kuroda M, Kuwabara H, Aoki Y, Iwashiro N, Tatsunobu N et al. Clinical and neural effects of six-week administration of oxytocin on core symptoms of autism. Brain 2015; 138: 3400–3412. source

      Not checked in the free run.

    • cites [6] Yatawara CJ, Einfeld SL, Hickie IB, Davenport TA, Guastella AJ . The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol Psychiatry 2015; 21: 1225–1231. source

      Not checked in the free run.

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

    Premisecitation

    Oxytocin is not necessarily a pro-social hormone; its effects are highly context- and person-dependent.

    “Oxytocin is not necessarily a ‘pro-social' hormone, as effects are highly context- and person-dependent.1, 2”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Bethlehem RAI, Baron-Cohen S, van Honk J, Auyeung B, Bos PA . The oxytocin paradox. Front Behav Neurosci 2014; 8: 48. source

      Not checked in the free run.

    • cites [2] Bartz JA, Zaki J, Bolger N, Ochsner KN . Social effects of oxytocin in humans: context and person matter. Trends Cogn Sci 2011; 15: 301–309.

      Not checked in the free run.

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

    Interpretationcitation

    Given marked heterogeneity in autism, benefits of oxytocin may vary substantially between individuals.

    “Given the marked heterogeneity in autism,7 it is possible that the benefits of oxytocin may vary substantially between individuals.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Lai M-C, Lombardo MV, Chakrabarti B, Baron-Cohen S . Subgrouping the autism “spectrum”: reflections on DSM-5. PLoS Biol 2013; 11: e1001544. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The widespread effects of oxytocin on complex human social behavior may be due to distributed influence at a neural circuit level.

    “We have theorized that the widespread effects of oxytocin on complex human social behavior may be due to distributed influence at a neural circuit level.9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Bethlehem RAI, van Honk J, Auyeung B, Baron-Cohen S . Oxytocin, brain physiology, and functional connectivity: a review of intranasal oxytocin fMRI studies. Psychoneuroendocrinology 2013; 38: 962–974. source

      Not checked in the free run.

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

    Premisecitation

    There is a strong male bias in autism diagnoses, and females may be strongly underrepresented, which may have increased the male-biased understanding of autism.

    “although there is a strong male bias in autism diagnoses,17 there is reason to believe that females are strongly underrepresented that may have increased the male-biased understanding of autism.18”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Baron-Cohen S, Lombardo MV, Auyeung B, Ashwin E, Chakrabarti B, Knickmeyer R . Why are autism spectrum conditions more prevalent in males? PLoS Biol 2011; 9: e1001081. source

      Not checked in the free run.

    • cites [18] Lai MC, Lombardo MV, Auyeung B, Chakrabarti B, Baron-Cohen S . Sex/gender differences and autism: setting the scene for future research. J Am Acad Child Adolesc Psychiatry 2015; 54: 11–24. source

      Not checked in the free run.

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

    Premisecitation

    These regions, particularly striatum, midbrain and amygdala, are typically considered highly involved in reward and emotion-related processes.

    “These regions, particularly the striatum, midbrain and amygdala, are typically considered highly involved in reward and emotion-related processes.40, 41, 42”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [40] Haber SN, Knutson B . The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 2010; 35: 4–26. source

      Not checked in the free run.

    • cites [41] Kober H, Barrett LF, Joseph J, Bliss-Moreau E, Lindquist K, Wager TD . Functional grouping and cortical–subcortical interactions in emotion: A meta-analysis of neuroimaging studies. Neuroimage 2008; 42: 998–1031. source

      Not checked in the free run.

    • cites [42] Lindquist KA, Wager TD, Kober H, Bliss-Moreau E, Barrett LF . The brain basis of emotion: a meta-analytic review. Behav Brain Sci 2012; 35: 121–143. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    There are notable male biases throughout neuroscience and medical research.

    “There are notable male biases throughout neuroscience and medical research and this bias may explain why studies looking at the effects of drugs tend to miss many adverse effects or show a lack of efficacy when applied to females.10, 46”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Beery AK, Zucker I . Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 2011; 35: 565–572. source

      Not checked in the free run.

    • cites [46] McCarthy MM, Arnold AP, Ball GF, Blaustein JD, De Vries GJ . Sex differences in the brain: the not so inconvenient truth. J Neurosci 2012; 32: 2241–2247. source

      Not checked in the free run.

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

    Interpretationreasoning

    The observed connectivity effects with rsfMRI may not necessarily be mediated by direct action of oxytocin on OXTR in specific cortical regions.

    “Given the lack of cortical specificity for OXTR enrichment, it remains possible that the observed connectivity effects with rsfMRI may not necessarily be mediated by direct action of oxytocin on OXTR in specific cortical regions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Given the lack of specificity within cortex, these data support examining oxytocin-related effects on intrinsic functional connectivity across all between-networks connections.

    “Given the lack of specificity within cortex, these data also support an approach for examining oxytocin-related effects on intrinsic functional connectivity that examines all between-networks connections, as all may be susceptible to plausible effects.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The oxytocin dose (24 IU) and timing (40 min before fMRI) are the most commonly used in oxytocin administration studies to date.

    “This timing and dosage are by far the most commonly used in oxytocin administration studies to date.25”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] MacDonald E, Dadds MR, Brennan JL, Williams K, Levy F, Cauchi AJ . A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research. Psychoneuroendocrinology 2011; 36: 1114–1126. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    It is the oxytocin condition that drives enhancements in connectivity between these components, and the placebo condition is a good approximation of normative functional connectivity effects within this corticostriatal circuit.

    “This further clarifies our interpretation that it is indeed the oxytocin condition that drives enhancements in connectivity between these components and that the placebo condition is a good approximation of normative functional connectivity effects within this corticostriatal circuit.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Previous neuroimaging studies in humans have largely focused on amygdala-related effects and to a lesser extent on striatal regions.

    “previous neuroimaging studies in humans have largely focused on amygdala-related effects and to a lesser extent on striatal regions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These data indicate that oxytocin could have potent direct effects on OXTR within subcortical circuitry, particularly striatum and midbrain, but may also have similar OXTR-driven effects to a lesser extent across most cortical areas where OXTR expression is modest.

    “As a whole, these data indicate that oxytocin could have potent direct effects on OXTR within subcortical circuitry, particular areas of the striatum and midbrain, but may also have similar OXTR-driven effects to a lesser extent across most cortical areas where OXTR expression is modest.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    On average intranasal oxytocin improves eye contact during naturalistic social interaction, but the largest effects occur for individuals who typically make the least amount of eye contact.

    “on average intranasal oxytocin improves eye contact during naturalistic social interaction, but the largest effects occur for individuals who typically make the least amount of eye contact.8”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Auyeung B, Lombardo MV, Heinrichs M, Chakrabarti B, Sule A, Deakin JB et al. Oxytocin increases eye contact during a real-time, naturalistic social interaction in males with and without autism. Transl Psychiatry 2015; 5: e507. source

      Not checked in the free run.

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

    Interpretationcitation

    These brain regions overlap with areas typically considered important in language, social communication, self-referential and social cognition, pain and emotion.

    “These brain regions overlap with areas typically considered important in processes such as language, social communication, self-referential and social cognition, pain and emotion.35, 36, 37, 38, 39”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [35] Hickok G, Poeppel D . The cortical organization of speech processing. Nat Rev Neurosci 2007; 8: 393–402. source

      Not checked in the free run.

    • cites [36] Friederici AD . The cortical language circuit: from auditory perception to sentence comprehension. Trends Cogn Sci 2012; 16: 262–268. source

      Not checked in the free run.

    • cites [37] Yang DY-J, Rosenblau G, Keifer C, Pelphrey KA . An integrative neural model of social perception, action observation, and theory of mind. Neurosci Biobehav Rev 2015; 51: 263–275. source

      Not checked in the free run.

    • cites [38] Amodio DM, Frith CD . Meeting of minds: the medial frontal cortex and social cognition. Nat Rev Neurosci 2006; 7: 268–277. source

      Not checked in the free run.

    • cites [39] Wager TD, Atlas LY, Lindquist MA, Roy M, Woo C-W, Kross E . An fMRI-based neurologic signature of physical pain. N Engl J Med 2013; 368: 1388–1397. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sex differences in the OXTR system are documented, suggesting findings in males may not generalize to females.

    “Sex differences in the OXTR system are documented,11, 12, 13 suggesting that findings in males may not generalize to females.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Dumais KM, Veenema AH . Vasopressin and oxytocin receptor systems in the brain: sex differences and sex-specific regulation of social behavior. Front Neuroendocrinol 2015; 40: 1–23. source

      Not checked in the free run.

    • cites [12] Kramer KM, Cushing BS, Carter CS, Wu J, Ottinger MA . Sex and species differences in plasma oxytocin using an enzyme immunoassay. Can J Zool 2004; 82: 1194–1200. source

      Not checked in the free run.

    • cites [13] Ebner NC, Chen H, Porges E, Lin T, Fischer H, Feifel D et al. Oxytocin’s effect on resting-state functional connectivity varies by age and sex. Psychoneuroendocrinology 2016; 69: 50–59. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The study used a double-blind randomized placebo-controlled crossover design with 26 women receiving oxytocin and placebo in counterbalanced order.

    “In a double-blind randomized placebo-controlled crossover design, 26 women (age: 23.6±4.6 years, range (21–50)) received an oxytocin nasal spray (24 IU, 40.32 μg, Syntocinon-spray; Novartis, Switzerland, pump-actuated) in one session and placebo (the same solution except for the active oxytocin) in the other session in a counterbalanced order.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The small number of existing rsfMRI oxytocin-administration studies use seed-based analyses that do not allow for hypothesis-free examination across the connectome.

    “the small number of existing rsfMRI oxytocin-administration studies5, 13, 19, 20 use seed-based analyses that do not allow for hypothesis-free examination across the connectome.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [5] Watanabe T, Kuroda M, Kuwabara H, Aoki Y, Iwashiro N, Tatsunobu N et al. Clinical and neural effects of six-week administration of oxytocin on core symptoms of autism. Brain 2015; 138: 3400–3412. source

      Not checked in the free run.

    • cites [13] Ebner NC, Chen H, Porges E, Lin T, Fischer H, Feifel D et al. Oxytocin’s effect on resting-state functional connectivity varies by age and sex. Psychoneuroendocrinology 2016; 69: 50–59. source

      Not checked in the free run.

    • cites [19] Sripada CS, Phan KL, Labuschagne I, Welsh R, Nathan PJ, Wood AG . Oxytocin enhances resting-state connectivity between amygdala and medial frontal cortex. Int J Neuropsychopharmacol 2013; 16: 255–260. source

      Not checked in the free run.

    • cites [20] Koch SBJ, van Zuiden M, Nawijn L, Frijling JL, Veltman DJ, Olff M . Intranasal oxytocin normalizes amygdala functional connectivity in posttraumatic stress disorder. Neuropsychopharmacology 2016; 41: 2041–2051. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Although oxytocin acts directly at a local level via OXTR, it can potentially affect widespread circuit-level dynamics via connections to areas densely populated with OXTR.

    “Although oxytocin acts directly at a local level via the oxytocin receptor (OXTR), it can potentially affect widespread circuit-level dynamics via connections to areas that are densely populated with OXTR.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    None of the participants had received a formal diagnosis of autism nor indicated possible undiagnosed autism, although no formal assessment was done to rule this out.

    “None of the participants had received a formal diagnosis of autism nor did they give any indication that they may have gone undiagnosed. Although we acknowledge no assessment was done to formally rule this out.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study was conducted in accordance with the Declaration of Helsinki and had ethical approval from the NHS Research Ethics Service.

    “All research was conducted in accordance with the Declaration of Helsinki and the study had received ethical approval from the NHS Research Ethics Service (NRES Committee East of England—Cambridge Central; REC reference number 14/EE/0202).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Sessions were separated by at least 1 week to ensure washout, and for non-contraceptive participants both sessions took place in early follicular phase to ensure similar hormone levels.

    “Sessions were separated by at least 1 week (to ensure full wash-out from the first administration) when participants were on hormonal contraceptive (19/26). When participants were not on hormonal contraceptive (7/26) both sessions took place in the early follicular phase of the menstrual cycle to ensure similar hormone levels between sessions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The present study highlights neural systems underlying these cognitive processes as key target for oxytocin administration.

    “The present study also highlights neural systems underlying these cognitive processes as key target for oxytocin administration.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    This male bias may explain why studies looking at effects of drugs tend to miss many adverse effects or show a lack of efficacy when applied to females.

    “There are notable male biases throughout neuroscience and medical research and this bias may explain why studies looking at the effects of drugs tend to miss many adverse effects or show a lack of efficacy when applied to females.10, 46”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Beery AK, Zucker I . Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 2011; 35: 565–572. source

      Not checked in the free run.

    • cites [46] McCarthy MM, Arnold AP, Ball GF, Blaustein JD, De Vries GJ . Sex differences in the brain: the not so inconvenient truth. J Neurosci 2012; 32: 2241–2247. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Oxytocin exerts its effect on social salience and social cognition by modulating stress and reward processing.

    “It has been previously hypothesized that oxytocin exerts its effect on social salience and social cognition by modulating stress and reward processing.1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Bethlehem RAI, Baron-Cohen S, van Honk J, Auyeung B, Bos PA . The oxytocin paradox. Front Behav Neurosci 2014; 8: 48. source

      Not checked in the free run.

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

    Premisecitation

    Women tend to suffer more from acute and chronic pain.

    “Similar to oxytocin research, research on pain has traditionally been heavily male biased,16 whereas women tend to suffer more from acute and chronic pain.58”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Mogil JS . Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon. Nat Rev Neurosci 2012; 13: 859–866. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Some neuroimaging studies indicate potential differences in the oxytocin system between sexes.

    “This bias can be observed in much of the prior work on oxytocin in humans as well, with some neuroimaging studies indicating potential differences in the oxytocin system between sexes.13, 14, 47, 48, 49”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [13] Ebner NC, Chen H, Porges E, Lin T, Fischer H, Feifel D et al. Oxytocin’s effect on resting-state functional connectivity varies by age and sex. Psychoneuroendocrinology 2016; 69: 50–59. source

      Not checked in the free run.

    • cites [14] Domes G, Lischke A, Berger C, Grossmann A, Hauenstein K, Heinrichs M et al. Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology 2010; 35: 83–93. source

      Not checked in the free run.

    • cites [47] Riem MME, van IJzendoorn MH, Tops M, Boksem M, Rombouts SA, Bakermans-Kranenburg MJ . No laughing matter: intranasal oxytocin administration changes functional brain connectivity during exposure to infant laughter. Neuropsychopharmacology 2012; 37: 2174–2174. source

      Not checked in the free run.

    • cites [48] Rilling JK, Demarco AC, Hackett PD, Chen X, Gautam P, Stair S et al. Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology 2013; 39: 237–248. source

      Not checked in the free run.

    • cites [49] Gao S, Becker B, Luo L, Geng Y, Zhao W, Yin Y et al. Oxytocin, the peptide that bonds the sexes also divides them. Proc Natl Acad Sci USA 2016; 113: 7650–7654. source

      Not checked in the free run.

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

    Interpretationown data

    The highlighted effect places emphasis on striatal interactions with cortical areas associated with pain processing.

    “The highlighted effect places emphasis on striatal interactions with cortical areas that are associated with pain processing.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    The multi-echo fMRI approach is a strength that could help counteract issues associated with statistical power.

    “However, our multi-echo fMRI approach is a strength that could help counteract issues associated with statistical power.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Oxytocin can act as a painkiller.

    “These results are interesting in light of work showing that oxytocin can not only act as an anxiolytic,51, 52 but can also act as a painkiller.53”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Rash JA, Aguirre-Camacho A, Campbell TS . Oxytocin and pain: a systematic review and synthesis of findings. Clin J Pain 2013; 30: 453–462. source

      Not checked in the free run.

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

    Premisecitation

    Research on pain has traditionally been heavily male biased.

    “Similar to oxytocin research, research on pain has traditionally been heavily male biased,16 whereas women tend to suffer more from acute and chronic pain.58”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Zagni E, Simoni L, Colombo D . Sex and gender differences in central nervous system-related disorders. Neurosci J 2016; 2016: 1–13. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previous studies examining functional connectivity during tasks show enhanced connectivity in women but decreased connectivity in men.

    “For example, previous studies examining functional connectivity during tasks show enhanced connectivity in women but decreased connectivity in men.47, 50”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Riem MME, van IJzendoorn MH, Tops M, Boksem M, Rombouts SA, Bakermans-Kranenburg MJ . No laughing matter: intranasal oxytocin administration changes functional brain connectivity during exposure to infant laughter. Neuropsychopharmacology 2012; 37: 2174–2174. source

      Not checked in the free run.

    • cites [50] Wittfoth-Schardt D, Gründing J, Wittfoth M, Lanfermann H, Heinrichs M, Domes G et al. Oxytocin modulates neural reactivity to children’s faces as a function of social salience. Neuropsychopharmacology 2012; 37: 1799–1807. source

      Not checked in the free run.

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

    Premisecitation

    Male bias can be observed in much of prior work on oxytocin in humans.

    “This bias can be observed in much of the prior work on oxytocin in humans as well, with some neuroimaging studies indicating potential differences in the oxytocin system between sexes.13, 14, 47, 48, 49”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [13] Ebner NC, Chen H, Porges E, Lin T, Fischer H, Feifel D et al. Oxytocin’s effect on resting-state functional connectivity varies by age and sex. Psychoneuroendocrinology 2016; 69: 50–59. source

      Not checked in the free run.

    • cites [14] Domes G, Lischke A, Berger C, Grossmann A, Hauenstein K, Heinrichs M et al. Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology 2010; 35: 83–93. source

      Not checked in the free run.

    • cites [47] Riem MME, van IJzendoorn MH, Tops M, Boksem M, Rombouts SA, Bakermans-Kranenburg MJ . No laughing matter: intranasal oxytocin administration changes functional brain connectivity during exposure to infant laughter. Neuropsychopharmacology 2012; 37: 2174–2174. source

      Not checked in the free run.

    • cites [48] Rilling JK, Demarco AC, Hackett PD, Chen X, Gautam P, Stair S et al. Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology 2013; 39: 237–248. source

      Not checked in the free run.

    • cites [49] Gao S, Becker B, Luo L, Geng Y, Zhao W, Yin Y et al. Oxytocin, the peptide that bonds the sexes also divides them. Proc Natl Acad Sci USA 2016; 113: 7650–7654. source

      Not checked in the free run.

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

    Interpretationnone given

    This is the first work on between-component connectivity in a female rsfMRI oxytocin administration study.

    “To our knowledge, this is the first work on the topic of between-component connectivity in a female rsfMRI oxytocin administration study”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Multi-echo EPI acquisition and the ME-ICA denoising technique greatly enhance temporal signal-to-noise ratio and allow for enhanced ability to reduce false positives.

    “Multi-echo EPI acquisition and the ME-ICA denoising technique employed here is known to greatly enhance temporal signal-to-noise ratio and allow for enhanced ability to reduce false positives.31”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Kundu P, Brenowitz ND, Voon V, Worbe Y, Vértes PE, Inati SJ et al. Integrated strategy for improving functional connectivity mapping using multiecho fMRI. Proc Natl Acad Sci USA 2013; 110: 16187–16192. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The results may be particularly important for understanding how oxytocin changes neurodynamics relevant for many neuropsychiatric conditions with deficits in those domains and neural circuits.

    “These corticostriatal networks have roles in social-communicative, motivational and affective processes, and the results may be particularly important for understanding how oxytocin changes neurodynamics that may be relevant for many neuropsychiatric conditions with deficits in those domains and neural circuits.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The sample size is moderate and potentially provides low power to detect small effects.

    “First, the sample size is moderate and potentially provides low power to detect small effects.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Oxytocin can act as an anxiolytic.

    “These results are interesting in light of work showing that oxytocin can not only act as an anxiolytic,51, 52 but can also act as a painkiller.53”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [51] MacDonald K, Feifel D . Oxytocin’s role in anxiety: a critical appraisal. Brain Res 2014; 1580: 22–56. source

      Not checked in the free run.

    • cites [52] Churchland PPS, Winkielman P . Modulating social behavior with oxytocin: how does it work? What does it mean? Horm Behav 2012; 61: 392–399. source

      Not checked in the free run.

45 of 45

  • The paper relies on this without support.

    This is the first study to investigate how oxytocin affects intrinsic functional organization of the human brain at the level of between-network interactions.

    “To our knowledge, this is the first study to investigate how oxytocin affects intrinsic functional organization of the human brain at the level of between-network interactions.”

  • The paper relies on this without support.

    There is a lack of prior literature on oxytocin's network level effects on brain connectivity in women.

    “Given the lack of prior literature on oxytocin's network level effects on brain connectivity in women we chose to use a robust data-driven (hypothesis-free) approach to assess potential connectivity differences.”

  • The authors state this as an assumption.

    If normative connectivity looks similar to placebo, then oxytocin is the primary reason for the induced change in connectivity and not a placebo-related change.

    “Our logic here is that if normative connectivity looks similar to patterns we see during placebo, then we can reasonably infer that oxytocin is the primary reason for the induced change in connectivity and not due to some placebo-related change and no effect of oxytocin.”
3 of 3

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?

  • Administration of synthetic oxytocin enhances activity in brain areas linked to wellbeing, reward, and social activity.

    “These studies have shown that administration of synthetic oxytocin enhances the activity in brain areas linked to wellbeing, reward, and social activity (Andari et al., 2016; Bethlehem et al., 2017).”

    From The Oxytocinergic System as a Mediator of Anti-stress and Instorative Effects Induced by Nature: The Calm and Connection Theory (2021) · cites this paper as Bethlehem et al., 2017

    The Discussion reports that oxytocin increased connectivity in a corticostriatal network associated with reward and social-communicative processes in women. It does not establish increased activity within those brain areas, and it does not identify them as areas linked to wellbeing. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Although OXTR mRNA can be measured in some portions of the human cortex, autoradiographic studies of OXTR binding have not generated complementary evidence of functional, cell-surface OXTR in these regions of the cortex in humans or in nonhuman primates.

    “Although these studies and others59–61 indicate that OXTR mRNA can be measured in some portions of the human cortex, autoradiographic studies of OXTR binding have not generated complementary evidence of functional, cell-surface OXTR in these regions of the cortex in humans35 or in nonhuman primates39.”

    From Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain (2018) · cites this paper as [61]

  • In humans, OXTR mRNA is detected in the nucleus accumbens.

    “OXTR mRNA has been detected in the nucleus accumbens (Bethlehem et al. 2017; Quintana et al. 2019)”

    From Distribution of brain oxytocin and vasopressin V1a receptors in chimpanzees (Pan troglodytes): comparison with humans and other primate species (2022) · cites this paper as Bethlehem et al. 2017

  • IN-OT enhances the coordination of corticostriatal networks involved in social emotive, motivational, and communicative processes.

    “Notably, IN-OT enhances the coordination of corticostriatal networks involved in social emotive, motivational, and communicative processes [41]”

    From Translational opportunities for circuit-based social neuroscience: advancing 21st century psychiatry (2021) · cites this paper as [41]

  • Prairie voles and other monogamous species express high levels of oxytocin receptors in the nucleus accumbens while non-monogamous species do not.

    “Prairie voles and other monogamous species, including marmosets and humans express high levels of oxytocin receptors (OXTR) in the NAc while non-monogamous species, such as laboratory mice and rhesus macaques, do not 24–26.”

    From Social experience alters oxytocinergic modulation in the nucleus accumbens of female prairie voles (2022) · cites this paper as [26]

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.

  • Not confirmedt(24) = 6.99reported p = 3.1e-7 · recomputed p < .001

    “t(24)=6.99, p=3.10e-7”

  • Not confirmedt(24) = -0.86reported p = .39 · recomputed p = .398

    “t(24)=−0.86, p = .39”

  • Not confirmedt(24) = 6.22reported p = .00000195 · recomputed p < .001

    “t(24)=6.22, p=1.95e-6”

  • Not confirmedt(64.6) = -1.507reported p = .137 · recomputed p = .137

    “t(64.6)=−1.507, p = .1370”

  • Consistentt(49) = 1.23reported p = .22 · recomputed p = .225

    “t(49)=1.23, p = .22”

5 of 5

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.

  • Reported age spread is incompatible with the age range

    Minor

    With 26 participants and a mean age of 23.6, a participant aged 50 would be 26.4 years above the mean. That single deviation alone requires a sample standard deviation of at least 5.28 years, exceeding the reported 4.6 years.

1 of 1

Cites

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3 of the 70 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Bethlehem, R. A. I., Lombardo, M. V., Lai, M.-C., Auyeung, B., Crockford, S. K., Deakin, J., Soubramanian, S., Sule, A., Kundu, P., Voon, V, & Baron-Cohen, S.
Affiliations
  • University of Cambridge (GB)
  • Centre for Addiction and Mental Health (CA)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Bethlehem, R A I
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2017-04-18
Volume
7
Issue
4
Pages
e1099-e1099
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/tp.2017.72
PMC
PMC5416709
OpenAlex
W2605494294
Semantic Scholar
8abb550a569f85444aa7fa6d513e3841ebb6447d
Cited by
96
References
70
Citations by year
2026: 1 · 2025: 9 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 10 · 2020: 28 · 2019: 14 · 2018: 12 · 2017: 4
FWCI
22.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Wellcome Trust
  • Centre for Addiction and Mental Health
  • National Institute for Health and Care Research (NF-SI-0515-10097)
  • Cambridge Trust
  • Hospital for Sick Children
  • Darwin Trust of Edinburgh
  • Medical Research Council
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
  • Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
Keywords
intranasal oxytocin, corticostriatal connectivity, resting-state functional connectivity, women, autistic traits, striatum, sex differences, autism spectrum disorder
MeSH terms
Administration, Intranasal, Adult, Affect, Cerebral Cortex, Communication, Corpus Striatum, Double-Blind Method, Female, Humans, Magnetic Resonance Imaging, Middle Aged, Motivation, Nerve Net, Social Behavior, Gene Expression, Receptors, Oxytocin, Young Adult, Connectome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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