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Cited by 82Neuroendocrine regulation and behaviorAutism Spectrum Disorder ResearchGenetics and Neurodevelopmental Disorders

Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain

Open access
Freeman, Sara M., Palumbo, Michelle C., Lawrence, Rebecca H., Smith, Aaron L., Goodman, Mark M., Bales, Karen L.·2018·Translational Psychiatry
DOI 10.1038/s41398-018-0315-3PMC PMC6279786
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Abstract

The prosocial hormone oxytocin (OXT) has become a new target for research on the etiology and treatment of autism spectrum disorder (ASD), a condition characterized by deficits in social function. However, it remains unknown whether there are alterations in OXT receptor (OXTR) levels in the ASD brain. This study quantified the density of OXTR and of the structurally related vasopressin 1a receptor (AVPR1a) in postmortem brain tissue from individuals with ASD and typically developing individuals. We analyzed two regions known to contain OXTR across all primates studied to date: the nucleus basalis of Meynert (NBM), which mediates visual attention, and the superior colliculus, which controls gaze direction. In the NBM specimens, we also analyzed the neighboring ventral pallidum (VP) and the external segment of the globus pallidus. In the superior colliculus specimens, we also analyzed the adjacent periaqueductal gray. We detected dense OXTR binding in the human NBM and VP and moderate to low OXTR binding in the human globus pallidus, superior colliculus, and periaqueductal gray. AVPR1a binding was negligible across all five regions in all specimens. Compared to controls, ASD specimens exhibited significantly higher OXTR binding in the NBM and significantly lower OXTR binding in the VP, an area in the mesolimbic reward pathway. There was no effect of ASD on OXTR binding in the globus pallidus, superior colliculus, or periaqueductal gray. We also found a significant negative correlation between age and OXTR binding in the VP across all specimens. Further analysis revealed a peak in OXTR binding in the VP in early childhood of typically developing individuals, which was absent in ASD. This pattern suggests a possible early life critical period, which is lacking in ASD, where this important reward area becomes maximally sensitive to OXT binding. These results provide unique neurobiological insight into human social development and the social symptoms of ASD.

AI snapshot

Written from the paper’s full text.

TL;DR

This study used pharmacologically optimized receptor autoradiography to quantify oxytocin receptor (OXTR) and vasopressin 1a receptor (AVPR1a) binding in postmortem human basal forebrain and midbrain tissue from ASD and typically developing individuals. It reports region-specific OXTR differences in ASD—higher in the nucleus basalis of Meynert and lower in the ventral pallidum—plus an age-related decline in ventral pallidum OXTR binding that appears driven by typically developing specimens.

Key findings

  • Dense OXTR binding was detected in the human nucleus basalis of Meynert (NBM) and ventral pallidum (VP), with moderate-to-low binding in the globus pallidus (GP), superior colliculus (SC), and periaqueductal gray (PAG); AVPR1a binding was negligible across all five regions.
  • ASD specimens showed significantly higher OXTR binding in the NBM (F1,33 = 10.71, p < 0.01) and significantly lower OXTR binding in the VP (F2,26 = 7.92, p < 0.01), with no significant ASD effect in GP, SC, or PAG.
  • In the VP, OXTR binding negatively correlated with age across all specimens (r = −0.4985, p < 0.01); this was driven by typically developing specimens (r = −0.6299, p < 0.01) and not ASD specimens (r = −0.0902, p = 0.73).
  • A peak in VP OXTR binding was observed in typically developing individuals around ages 2–5 years, which was absent, or possibly dampened and shifted later, in ASD; no significant sex differences or postmortem interval effects were found in any region.

Methods

  • Postmortem, unfixed frozen human brain tissue (n = 44; 22 typically developing, 22 ASD) was obtained from the University of Maryland Brain and Tissue Bank/NIH NeuroBioBank and matched as best as possible on age, race, and sex.
  • Competitive-binding receptor autoradiography used 125I-OVTA for OXTR and 125I-LVA for AVPR1a, with selective competitors ALS-II-69 and SR49059, followed by acetylcholinesterase counterstaining and densitometry in five regions: NBM, VP, GP, SC, and PAG.
  • A Generalized Linear Model tested diagnosis, sex, race, age, brain pH, storage time, postmortem interval, sex×diagnosis, and age×diagnosis, with backward selection and specimen ID as a random factor; ADI-R correlations were examined in an ASD subset (n = 8).

Limitations

  • Stated: conclusions about an early-life critical period are based on a very small sample size, and brain bank specimens with confirmed ASD diagnoses are limited or absent at the youngest ages because of the average age of ASD diagnosis.
  • Stated: the absence of AVPR1a binding in these regions should be confirmed with secondary analyses such as in situ hybridization for AVPR1a mRNA.
  • Evident from the text: the study is postmortem and correlational, with no direct behavioral measures except ADI-R scores in a small ASD subset (n = 8), and those correlations were not significantly non-zero; adjacent regions were included opportunistically based on consistent identifiability.

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

Integrity signals

Registry

Crossref · 10.1038/s41398-018-0315-3

Cites

83 of 83 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 80 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In each of the five ROIs, there was a significant main effect of radioligand.

    “we found significant main effects of radioligand (GP: F1,44 = 23.58, p < 0.0001; VP: F1,111 = 84.64, p < 0.0001; NBM: F1,136 = 21.42, p < 0.0001; PAG: F1,144 = 19.99, p < 0.0001; SC: F1,136 = 16.70, p < 0.0001)”
    Quote in the paperSubstantial claim
  • Findingown data

    Post hoc comparisons revealed significantly higher OXTR radioligand binding than AVPR1a radioligand binding in all five regions.

    “Post hoc comparisons between the OXTR radioligand-alone and AVPR1a radioligand-alone conditions revealed significantly higher OXTR radioligand binding in all five regions”
    Quote in the paperSubstantial claim
  • Findingown data

    Dense OXTR binding is present in the human NBM and ventral pallidum (VP).

    “We detected dense OXTR binding in the human NBM and VP”
    Quote in the paperSubstantial claim
  • Findingown data

    ASD specimens exhibit significantly higher OXTR binding in the NBM compared to controls.

    “ASD specimens exhibited significantly higher OXTR binding in the NBM”
    • Also stated in: § Effects of ASD diagnosis and age on OXTR binding · plain
      “In the NBM, ASD specimens had significantly higher OXTR binding compared to TD specimens”
    Quote in the paperSubstantial claim
  • Findingown data

    In each of the five ROIs, there was a significant main effect of competitor.

    “and of competitor (GP: F1,44 = 39.64, p < 0.0001; VP: F1,111 = 128.4, p < 0.0001; NBM: F1,136 = 50.57, p < 0.0001; PAG: F1,144 = 68.04, p < 0.0001; SC: F1,136 = 55.68, p < 0.0001)”
    Quote in the paperSubstantial claim
  • May combine two claims. 15
  • Classified as probably not a substantial claim. 22

  • May combine two claims.

    Findingown data

    There were no significant sex differences in OXTR density and no significant sex × diagnosis interactions in any of the ROIs.

    “there were no significant sex differences in OXTR density and no significant sex × diagnosis interactions in any of the ROIs.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The superior colliculus (SC) has an important role in controlling eye movements and shifting gaze direction.

    “the SC has an important role in controlling eye movements and shifting gaze direction42–44.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Gandhi, N. J. & Katnani, H. A. Motor functions of the superior colliculus. Annu. Rev. Neurosci. 34, 205–231 (2011). source

      Not checked in the free run.

    • cites [43] Ma, T. P., Graybiel, A. M. & Wurtz, R. H. Location of saccade-related neurons in the macaque superior colliculus. Exp. Brain Res. 85, 21–35 (1991). source

      Not checked in the free run.

    • cites [44] Wurtz, R. H. & Goldberg, M. E. The primate superior colliculus and the shift of visual attention. Invest. Ophthalmol. 11, 441–450 (1972).

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The TD and ASD specimens were matched as best as possible on age, race, and sex.

    “The TD specimens (n = 22) and ASD specimens (n = 22) were selected with recommendations and approval from the staff of the NeuroBioBank to match as best as possible on age, race, and sex.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    It is currently unknown whether differences in OXTR distributions in the brain exist between patients with ASD and non-clinical populations.

    “it is currently unknown whether differences in OXTR distributions in the brain exist between patients with ASD and non-clinical populations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    OXTR binding in primate brains is limited to a small number of subcortical areas and putatively absent in the cortex.

    “Because OXTR binding in primate brains is limited to a small number of subcortical areas and putatively absent in the cortex35,39”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Loup, F., Tribollet, E., Dubois-Dauphin, M. & Dreifuss, J. J. Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain. Autoradiogr. Study Brain Res. 555, 220–232 (1991). source

      Not checked in the free run.

    • cites [39] Freeman, S. M. & Young, L. J. Comparative perspectives on oxytocin and vasopressin receptor research in rodents and primates: translational implications. J. Neuroendocrinol. 28, https://doi.org/10.1111/jne.12382 (2016). source

      Not checked in the free run.

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

    Premisecitation

    There is no consensus on the best methodology to measure OXT in biological fluids.

    “there is as yet no consensus on the best methodology to measure OXT22,23”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Leng G., Sabatier N. Measuring oxytocin and vasopressin: bioassays, immunoassays and random numbers. J. Neuroendocrinol. 28, https://doi.org/10.1111/jne.12413 (2016). source

      Not checked in the free run.

    • cites [23] Lefevre, A. et al. A comparison of methods to measure central and peripheral oxytocin concentrations in human and non-human primates. Sci. Rep. 7, 17222 (2017). source

      Not checked in the free run.

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

    Premisecitation

    Extensive research has established that oxytocin modulates social behavior across species, including humans.

    “Extensive research has established the potent ability of the hypothalamic neuropeptide oxytocin (OXT) to modulate social behavior across species, including humans1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Johnson, Z. V. & Young, L. J. Oxytocin and vasopressin neural networks: Implications for social behavioral diversity and translational neuroscience. Neurosci. Biobehav. Rev. 76, 87–98 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    This study is the first to determine whether OXTR binding densities are altered in the ASD brain and the first report that OXTR binding is altered in specific subregions of the ASD brain.

    “To our knowledge, this study is the first to determine whether OXTR binding densities are altered in the ASD brain, with a focus on multiple behaviorally and clinically relevant subcortical regions of the human brain.”
    • Also stated in: § Discussion · hedged
      “To our knowledge, this is the first report that OXTR binding is altered in specific subregions of the ASD brain.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    ASD is characterized by restricted interests/behaviors and deficits in social communication.

    “ASD is a heterogeneous condition characterized by restricted interests/behaviors and deficits in social communication”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Baio, J. et al. Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill. Summ. 67, 1–23 (2018). source

      Not checked in the free run.

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

    Premisecitation

    OXTR polymorphisms are linked to other measures of social behavior, such as empathy, prosocial temperament, and pair-bonding behavior, in non-ASD populations.

    “Results from studies in non-ASD populations have also linked OXTR polymorphisms to other measures of social behavior, such as empathy13, prosocial temperament14, and pair-bonding behavior15.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Rodrigues, S. M., Saslow, L. R., Garcia, N., John, O. P. & Keltner, D. Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans. Proc. Natl Acad. Sci. USA 106, 21437–21441 (2009). source

      Not checked in the free run.

    • cites [14] Tost, H. et al. A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic–limbic structure and function. Proc. Natl Acad. Sci. USA 107, 13936–13941 (2010). source

      Not checked in the free run.

    • cites [15] Walum, H. et al. Variation in the oxytocin receptor gene is associated with pair-bonding and social behavior. Biol. Psychiatry 71, 419–426 (2012). source

      Not checked in the free run.

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

    Interpretationreasoning

    These results provide unique neurobiological insight into human social development and the social symptoms of ASD.

    “These results provide unique neurobiological insight into human social development and the social symptoms of ASD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: OXTR binding density measured in postmortem human brain tissue reflects the density of OXTR receptors in the living human brain.
    • Rests on an assumption: The ASD and TD postmortem specimens are representative of the respective populations.

  • Classified as probably not a substantial claim.

    Premisenone given

    It remains unknown whether there are alterations in OXTR levels in the ASD brain.

    “However, it remains unknown whether there are alterations in OXT receptor (OXTR) levels in the ASD brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Polymorphisms in the human OXTR gene are significantly associated with an ASD diagnosis and/or predict the severity of ASD.

    “many of these genetic studies have found that polymorphisms in the human OXT receptor (OXTR) gene are significantly associated with an ASD diagnosis and/or predict the severity of ASD4–12.”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [4] Wu, S. et al. Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. BPS 58, 74–77 (2005).

      Not checked in the free run.

    • cites [5] Parker, K. J. et al. Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder. Proc. Natl Acad. Sci. USA 111, 12258–12263 (2014). source

      Not checked in the free run.

    • cites [6] Jacob, S. et al. Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism. Neurosci. Lett. 417, 6–9 (2007). source

      Not checked in the free run.

    • cites [7] Lerer, E. et al. Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition. Mol. Psychiatry 13, 980–988 (2008). source

      Not checked in the free run.

    • cites [8] Yrigollen, C. M. et al. Genes controlling affiliative behavior as candidate genes for autism. Biol. Psychiatry 63, 911–916 (2008). source

      Not checked in the free run.

    • cites [9] Campbell, D. B. et al. Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder. J. Neurodev. Disord. 3, 101–112 (2011). source

      Not checked in the free run.

    • cites [10] Liu, X. et al. Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population. J. Hum. Genet. 55, 137–141 (2010). source

      Not checked in the free run.

    • cites [11] Wermter, A.-K. et al. Evidence for the involvement of genetic variation in the oxytocin receptor gene (OXTR) in the etiology of autistic disorders on high-functioning level. Am. J. Med. Genet. B 153B, 629–639 (2010). source

      Not checked in the free run.

    • cites [12] Ocakoğlu, F. T., Köse, S., Özbaran, B. & Onay, H. The oxytocin receptor gene polymorphism -rs237902- is associated with the severity of autism spectrum disorder: a pilot study. Asian J. Psychiatr. 31, 142–149 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The pattern of a peak in OXTR binding in the VP in early childhood in typically developing individuals and its absence in ASD suggests a possible early life critical period, which is lacking in ASD, where this reward area becomes maximally sensitive to OXT binding.

    “This pattern suggests a possible early life critical period, which is lacking in ASD, where this important reward area becomes maximally sensitive to OXT binding.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: OXTR binding density measured in postmortem human brain tissue reflects the density of OXTR receptors in the living human brain.

  • May combine two claims.

    Premisecitation

    Patients with ASD have altered gaze patterns and reduced attention to social imagery.

    “Patients with ASD have been shown to have altered gaze patterns and reduced attention to social imagery45–47.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [45] Jones, W., Carr, K. & Klin, A. Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2-year-old toddlers with autism spectrum disorder. Arch. Gen. Psychiatry 65, 946–954 (2008). source

      Not checked in the free run.

    • cites [46] Chawarska, K., Volkmar, F. & Klin, A. Limited attentional bias for faces in toddlers with autism spectrum disorders. Arch. Gen. Psychiatry 67, 178–185 (2010). source

      Not checked in the free run.

    • cites [47] Rice, K., Moriuchi, J. M., Jones, W. & Klin, A. Parsing heterogeneity in autism spectrum disorders: visual scanning of dynamic social scenes in school-aged children. J. Am. Acad. Child Adolesc. Psychiatry 51, 238–248 (2012). source

      Not checked in the free run.

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

    Study design and conductnone given

    Experimenters were blind to specimen diagnosis during quantification.

    “Experimenters were blind to specimen diagnosis during quantification.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    A recent meta-analysis across 516 participants reported no significant association between baseline levels of OXT in plasma and cerebrospinal fluid.

    “a recent meta-analysis across 516 participants reported no significant association between baseline levels of OXT in plasma and cerebrospinal fluid25”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Valstad, M. et al. The correlation between central and peripheral oxytocin concentrations: a systematic review and meta-analysis. Neurosci. Biobehav. Rev. 78, 117–124 (2017). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The nucleus basalis of Meynert (NBM) mediates selective and sustained visual attention.

    “The NBM mediates selective and sustained visual attention40,41”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] Muir, J. L., Page, K. J., Sirinathsinghji, D. J., Robbins, T. W. & Everitt, B. J. Excitotoxic lesions of basal forebrain cholinergic neurons: effects on learning, memory and attention. Behav. Brain. Res. 57, 123–131 (1993). source

      Not checked in the free run.

    • cites [41] Sarter, M., Gehring, W. J. & Kozak, R. More attention must be paid: the neurobiology of attentional effort. Brain. Res. Rev. 51, 145–160 (2006). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    It is unclear whether peripheral measures of OXT are accurate approximations for levels of OXT in the central nervous system.

    “it is unclear whether these peripheral measures of OXT are accurate approximations for levels of OXT in the central nervous system24.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Leng, G. & Ludwig, M. Intranasal oxytocin: myths and delusions. Biol. Psychiatry https://doi.org/10.1016/j.biopsych.2015.05.003.(2015) source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The anatomical boundaries of the five ROIs were confirmed by comparison to the most detailed and up-to-date atlas of the human brain.

    “compared to the most detailed and up-to-date atlas of the human brain52 to confirm the anatomical boundaries of our five ROI”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Ding, S.-L. et al. Comprehensive cellular-resolution atlas of the adult human brain. J. Comp. Neurol. 524, 3127–3481 (2016). source

      Not checked in the free run.

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

    Premisecitation

    IN-OXT has been shown in an increasing number of studies to change social visual attention in non-clinical populations of humans.

    “IN-OXT has also been shown in an increasing number of studies to change social visual attention in non-clinical populations of humans77–81.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [77] Hubble, K. et al. Oxytocin increases attention to the eyes and selectively enhances self-reported affective empathy for fear. Neuropsychologia 106, 350–357 (2017). source

      Not checked in the free run.

    • cites [78] Tollenaar, M. S., Chatzimanoli, M., van der Wee, N. J. A. & Putman, P. Enhanced orienting of attention in response to emotional gaze cues after oxytocin administration in healthy young men. Psychoneuroendocrinology 38, 1797–1802 (2013). source

      Not checked in the free run.

    • cites [79] Pfundmair, M., Zwarg, C., Paulus, M. & Rimpel, A. Oxytocin promotes attention to social cues regardless of group membership. Horm. Behav. 90, 136–140 (2017). source

      Not checked in the free run.

    • cites [80] Guastella, A. J., Mitchell, P. B. & Dadds, M. R. Oxytocin increases gaze to the eye region of human faces. Biol. Psychiatry 63, 3–5 (2008). source

      Not checked in the free run.

    • cites [81] Ellenbogen, M. A., Linnen, A.-M., Grumet, R., Cardoso, C. & Joober, R. The acute effects of intranasal oxytocin on automatic and effortful attentional shifting to emotional faces. Psychophysiology 49, 128–137 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [59] Lee, M. R. et al. Effect of alcohol use disorder on oxytocin peptide and receptor mRNA expression in human brain: a post-mortem case–control study. Psychoneuroendocrinology 85, 14–19 (2017). source

      Not checked in the free run.

    • cites [60] Lee, M. R. et al. Oxytocin receptor mRNA expression in dorsolateral prefrontal cortex in major psychiatric disorders: a human post-mortem study. Psychoneuroendocrinology 96, 143–147 (2018). source

      Not checked in the free run.

    • cites [61] Bethlehem, R. A. I. et al. Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women. Transl. Psychiatry 7, e1099 (2017). source

      Not checked in the free run.

    • cites [35] Loup, F., Tribollet, E., Dubois-Dauphin, M. & Dreifuss, J. J. Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain. Autoradiogr. Study Brain Res. 555, 220–232 (1991). source

      Not checked in the free run.

    • cites [39] Freeman, S. M. & Young, L. J. Comparative perspectives on oxytocin and vasopressin receptor research in rodents and primates: translational implications. J. Neuroendocrinol. 28, https://doi.org/10.1111/jne.12382 (2016). source

      Not checked in the free run.

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

    Premisecitation

    Gregory et al. reported decreased OXTR mRNA in the superior temporal gyrus of ASD specimens.

    “Gregory et al.58 reported decreased OXTR mRNA in the superior temporal gyrus of ASD specimens, but Mor et al.57 reported increased OXTR mRNA in the prefrontal cortex of ASD specimens.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Gregory, S. G. et al. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med. 7, 62 (2009). source

      Not checked in the free run.

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

    Premisecitation

    Unlike the current study, which used histological sections to preserve neuroanatomy, both prior studies worked with tissue homogenates.

    “Finally, unlike the current study, which used histological sections to preserve neuroanatomy, both of these prior studies worked with tissue homogenates.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [57] Mor, M., Nardone, S., Sams, D. S. & Elliott, E. Hypomethylation of miR-142 promoter and upregulation of microRNAs that target the oxytocin receptor gene in the autism prefrontal cortex. Mol. Autism 6, 46 (2015). source

      Not checked in the free run.

    • cites [58] Gregory, S. G. et al. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med. 7, 62 (2009). source

      Not checked in the free run.

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

    Premisecitation

    Mor et al. reported increased OXTR mRNA in the prefrontal cortex of ASD specimens.

    “Gregory et al.58 reported decreased OXTR mRNA in the superior temporal gyrus of ASD specimens, but Mor et al.57 reported increased OXTR mRNA in the prefrontal cortex of ASD specimens.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Mor, M., Nardone, S., Sams, D. S. & Elliott, E. Hypomethylation of miR-142 promoter and upregulation of microRNAs that target the oxytocin receptor gene in the autism prefrontal cortex. Mol. Autism 6, 46 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The model of OXT action in the primate brain is supported by evidence from human studies and provides a theoretical framework for the neural basis of the social symptoms of ASD.

    “This model of OXT action in the primate brain is also supported by evidence from human studies and provides a theoretical framework for the neural basis of the social symptoms of ASD.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    Relatively little is known about specific measures of the OXT system in either ASD or TD brains.

    “There has been a variety of research on gross neuroanatomical differences between people with ASD and TD individuals, but relatively little is known about specific measures of the OXT system in either ASD or TD brains.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    IN-OXT treatment can ameliorate the lack of attentional preference for faces that is characteristic of patients with ASD.

    “It is also known that IN-OXT treatment can ameliorate82 the lack of attentional preference for faces46 that is characteristic of patients with ASD.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [82] Kanat, M. et al. Restoring effects of oxytocin on the attentional preference for faces in autism. Transl. Psychiatry 7, e1097 (2017). source

      Not checked in the free run.

    • cites [46] Chawarska, K., Volkmar, F. & Klin, A. Limited attentional bias for faces in toddlers with autism spectrum disorders. Arch. Gen. Psychiatry 67, 178–185 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Our methods did not detect AVPR1a binding in any ROI, which suggests a lack of AVPR1a expression in these regions of the human brain.

    “Our methods did not detect AVPR1a binding in any ROI, which suggests a lack of AVPR1a expression in these regions of the human brain”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IN-OXT treatment increases gaze following, increases socially oriented gaze, and alters social attention in a wide variety of contexts in macaques.

    “This work provides anatomical support for other findings in macaques, which indicate that IN-OXT treatment increases gaze following67, increases socially oriented gaze68, and alters social attention in a wide variety of contexts69–74.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [67] Putnam, P. T., Roman, J. M., Zimmerman, P. E. & Gothard, K. M. Oxytocin enhances gaze-following responses to videos of natural social behavior in adult male rhesus monkeys. Psychoneuroendocrinology 72, 47–53 (2016). source

      Not checked in the free run.

    • cites [68] Chang, S. W. C., Barter, J. W., Ebitz, R. B., Watson, K. K. & Platt, M. L. Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta). Proc. Natl Acad. Sci. USA 109, 959–964 (2012). source

      Not checked in the free run.

    • cites [69] Parr, L. A., Modi, M., Siebert, E. & Young, L. J. Intranasal oxytocin selectively attenuates rhesus monkeys’ attention to negative facial expressions. Psychoneuroendocrinology https://doi.org/10.1016/j.psyneuen.2013.02.011 (2013). source

      Not checked in the free run.

    • cites [70] Ebitz, R. B., Watson, K. K. & Platt, M. L. Oxytocin blunts social vigilance in the rhesus macaque. Proc. Natl Acad. Sci. USA 110, 11630–11635 (2013). source

      Not checked in the free run.

    • cites [71] Dal Monte, O. et al. Oxytocin under opioid antagonism leads to supralinear enhancement of social attention. Proc. Natl Acad. Sci. USA 114, 5247–5252 (2017). source

      Not checked in the free run.

    • cites [72] Parr, L. A. et al. Effects of chronic oxytocin on attention to dynamic facial expressions in infant macaques. Psychoneuroendocrinology 74, 149–157 (2016). source

      Not checked in the free run.

    • cites [73] Simpson, E. A. et al. Inhaled oxytocin increases positive social behaviors in newborn macaques. Proc. Natl Acad. Sci. USA 111, 6922–6927 (2014). source

      Not checked in the free run.

    • cites [74] Dal Monte, O., Noble, P. L., Costa, V. D. & Averbeck, B. B. Oxytocin enhances attention to the eye region in rhesus monkeys. Front. Neurosci. 8, 41 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    OXT acting at OXTR in the NBM could modulate the activity of an extensive network of brain areas and influence social behavioral processes like social visual attention, gaze direction, and social decision making.

    “Based on this connectivity of the NBM, we and others have postulated that OXT acting at OXTR in the NBM could modulate the activity of an extensive network of brain areas (which may themselves lack OXTR) and influence social behavioral processes like social visual attention, gaze direction, and social decision making38,39,64,65.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [38] Freeman, S. M. et al. Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus). Neuroscience https://doi.org/10.1016/j.neuroscience.2014.04.055 (2014). source

      Not checked in the free run.

    • cites [39] Freeman, S. M. & Young, L. J. Comparative perspectives on oxytocin and vasopressin receptor research in rodents and primates: translational implications. J. Neuroendocrinol. 28, https://doi.org/10.1111/jne.12382 (2016). source

      Not checked in the free run.

    • cites [64] Putnam, P. T., Young, L. J. & Gothard, K. M. Bridging the gap between rodents and humans: the role of non-human primates in oxytocin research. Am. J. Primatol. 80, e22756 (2018). source

      Not checked in the free run.

    • cites [65] Piva, M. & Chang, S. W. C. An integrated framework for the role of oxytocin in multistage social decision-making. Am. J. Primatol. https://doi.org/10.1002/ajp.22735 (2018). source

      Not checked in the free run.

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

    Premisecitation

    Most children with ASD begin showing symptoms in the age range of 2 to 5 years and typically receive an ASD diagnosis by age four.

    “This idea is interesting in the context of autism, because most children with ASD begin showing symptoms in this age range and typically receive an ASD diagnosis by age four53.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Christensen, D. L. et al. Prevalence and characteristics of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2012. MMWR Surveill. Summ. 65, 1–23 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    All five areas contained putative OXTR binding, which agrees with the older study and supports the idea that these tools are more selective in the human brain compared to nonhuman primate brain.

    “We found that all five areas contained putative OXTR binding, which agrees with what was reported in the older study (mentioned above35) and supports the idea that these tools are more selective in the human brain compared to that in a nonhuman primate brain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Loup, F., Tribollet, E., Dubois-Dauphin, M. & Dreifuss, J. J. Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain. Autoradiogr. Study Brain Res. 555, 220–232 (1991). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The conclusions about the early-life transient increase in OXTR binding are based on a very small sample size.

    “Thus, we recognize that our conclusions here are based on a very small sample size, but we felt this pattern was notable and its implications are highly deserving of future research.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The NBM provides cholinergic input to the entire cortex as well as the amygdala and other regions of the social brain.

    “The NBM provides cholinergic input to the entire cortex63 as well as the amygdala and other regions of the social brain (see Fig. 5 in the recent review by Putnam et al.64 for an anatomical model of NBM connectivity to social neural networks).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [63] Mesulam, M. M., Mufson, E. J., Levey, A. I. & Wainer, B. H. Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J. Comp. Neurol. 214, 170–197 (1983). source

      Not checked in the free run.

    • cites [64] Putnam, P. T., Young, L. J. & Gothard, K. M. Bridging the gap between rodents and humans: the role of non-human primates in oxytocin research. Am. J. Primatol. 80, e22756 (2018). source

      Not checked in the free run.

35 of 35

  • The paper relies on this without support.

    OXTR binding density measured in postmortem human brain tissue reflects the density of OXTR receptors in the living human brain.

    “whether OXTR binding densities are altered in the ASD brain”

  • The paper relies on this without support.

    The ASD and TD postmortem specimens are representative of the respective populations.

    “postmortem brain tissue from individuals with ASD and typically developing individuals”
2 of 2

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?

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.

  • VP diagnosis test has incompatible degrees of freedom

    Minor

    The methods define diagnosis as two groups, TD and ASD, so a main-effect test of diagnosis has one numerator degree of freedom. The reported VP statistic has two numerator degrees of freedom and therefore cannot be the stated diagnosis main-effect test.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Putnam, P., Zimmerman, P. & Gothard, K. Oxytocin Injected into the Nucleus Basalis of Meynert of Monkeys Enhanced Basic Social Behaviors and Modulated Neural Activity in the Basolateral Nuclei of the Amygdala, Conference proceedings. Gordon Research Conference: New Frontiers in Amygdala Research: From Rodent to Man. (Easton, MA, 2015).

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Related

Authors
Freeman, S. M., Palumbo, M. C., Lawrence, R. H., Smith, A. L., Goodman, M. M., & Bales, K. L.
Affiliations
  • University of California, Davis (US)
  • Emory University (US)
Corresponding author
Freeman, Sara M.
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2018-12-04
Volume
8
Issue
1
Pages
257-257
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-018-0315-3
PMC
PMC6279786
OpenAlex
W2903316410
Semantic Scholar
5acc1e5f03c3c66e64e4f7bf1d6f365587b7a2e3
Cited by
82
References
83
Citations by year
2026: 5 · 2025: 6 · 2024: 9 · 2023: 10 · 2022: 19 · 2021: 20 · 2020: 11 · 2019: 1
FWCI
10.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R21MH110014)
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
autism spectrum disorder, oxytocin receptor, vasopressin 1a receptor, nucleus basalis of Meynert, ventral pallidum, globus pallidus, superior colliculus, periaqueductal gray, age-related changes, critical period, social development (developmental psychology), postmortem brain
MeSH terms
Autism Spectrum Disorder, Adolescent, Adult, Age Factors, Autoradiography, Child, Child, Preschool, Humans, Male, Mesencephalon, Tissue Banks, Single-Blind Method, Receptors, Vasopressin, Receptors, Oxytocin, Young Adult, Basal Forebrain

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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.

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