Integrative Approaches Utilizing Oxytocin to Enhance Prosocial Behavior: From Animal and Human Social Behavior to Autistic Social Dysfunction
Open accessAbstract
The prevalence of autism spectrum disorder (ASD) is as high as 1 in 100 individuals and is a heavy burden to society. Thus, identifying causes and treatments is imperative. Here, we briefly review the topics covered in our 2012 Society for Neuroscience Mini-Symposium entitled “Integrative Approaches Using Oxytocin to Enhance Prosocial Behavior: From Animal and Human Social Behavior to ASD's Social Dysfunction.” This work is not meant to be a comprehensive review of oxytocin and prosocial behavior. Instead, we wish to share the newest findings on the effects of oxytocin on social behavior, the brain, and the social dysfunction of ASD at the molecular, genetic, systemic, and behavior levels, in varied subjects ranging from animal models to humans suffering from autism for the purpose of promoting further study for developing the clinical use of oxytocin in treating ASD.
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Written from the paper’s full text.
TL;DR
This mini-review integrates animal, human nonclinical, genetic, neuroimaging, and clinical evidence on oxytocin’s role in prosocial behavior and autistic social dysfunction. It argues that oxytocin is a promising but not yet clinically established treatment for ASD social deficits, with mechanisms and long-term safety still unresolved.
Key findings
- ASD prevalence is reported as at least 1 in 100 people, and there is no established pharmacological treatment for social dysfunction, the core feature of ASD.
- In prairie voles, systemic oxytocin pretreatment before a flooded-cage stressor increased sedentary social contact after return to the home cage, elevated plasma oxytocin 95 min after injection, and produced functional coupling between the paraventricular nucleus and cardioregulatory brainstem areas; an oxytocin antagonist decoupled this activity.
- In a double-blind, placebo-controlled fMRI study of 91 men aged 18–22 years (mean 20.2; oxytocin n=27, vasopressin n=27, placebo n=36), intranasal oxytocin increased caudate nucleus response to reciprocated cooperation, positively correlated with plasma oxytocin, enhanced left amygdala activation, decreased amygdala–brainstem functional connectivity, and increased amygdala connectivity with ventral anterior insula and inferior lateral temporal cortex.
- In ASD clinical studies cited, intravenous oxytocin reduced repetitive behavior in 15 medication-free adults with ASD, intranasal oxytocin improved “Reading the Mind in the Eyes” performance in male youths with ASD, and intranasal oxytocin enhanced trust, preference, and eye-gaze time with a socially cooperative partner; OXTR variants rs53576 and rs2254298 have been linked to socioemotional functioning and ASD susceptibility, though with inconsistencies.
Methods
- Design: narrative mini-review and summary of the authors’ 2012 Society for Neuroscience Mini-Symposium, explicitly not a comprehensive review of oxytocin and prosocial behavior.
- Data/sample: synthesizes findings from animal models, healthy human pharmacological challenge studies, molecular genetics, imaging genetics, and clinical ASD studies; no new primary data are collected.
- Main analysis: qualitative cross-level integration of molecular, genetic, systemic, neural, behavioral, and clinical evidence, ranging from animal models to humans with autism.
Limitations
- Stated in the paper: little is known about the mechanistic effects of oxytocin on social brain circuits; the neural mechanisms by which oxytocin improves autistic behavior are unknown; further large-scale studies or long-term trials are needed; OXTR associations show inconsistencies, null effects, and heterogeneity; future studies must examine potential social side effects and “contraindications” of oxytocin treatment.
- Evident from the text: as a mini-review/mini-symposium summary, it is not comprehensive and relies on cited studies rather than new empirical data; several cited clinical findings come from small samples, such as 15 ASD adults and 91 men, limiting generalizability.
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Cites
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Claims the paper makes
0 of 115 cited sources checked · 0 supported · 0 flagged
- Findingown data
Relative to both AVP and placebo, OT increased the caudate nucleus response to reciprocated cooperation.
“Relative to both AVP and placebo, OT increased the caudate nucleus response to reciprocated cooperation, which may augment the reward of reciprocated cooperation and/or facilitate learning that another person can be trusted.”
Quote in the paperSubstantial claim - Findingown data
The caudate nucleus response to reciprocated cooperation was positively correlated with plasma OT levels.
“Moreover, the caudate nucleus response to reciprocated cooperation was positively correlated with plasma OT levels.”
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OT pretreatment did not change overall neural activation as measured by Fos expression in the paraventricular nucleus of the hypothalamus (PVN).
“OT pretreatment did not change overall neural activation as measured by Fos expression in the paraventricular nucleus of the hypothalamus (PVN), a brain region critically involved in coordinating neuroendocrine and autonomic responses to stress.”
Quote in the paperSubstantial claim - Findingown data
OT enhanced left amygdala activation in response to reciprocated cooperation.
“OT also enhanced left amygdala activation in response to reciprocated cooperation.”
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OT pretreatment unexpectedly resulted in a trend toward heightened glucocorticoid levels.
“OT pretreatment unexpectedly resulted in a trend toward heightened glucocorticoid levels, but this may in fact be adaptive during an environmental threat that necessitates mobilization (J.R. Yee, S.W. Porges, and C.S. Carter, unpublished observations).”
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- Findingown data
Functional coupling with the PVN was seen in brainstem nuclei that exert both sympathetic (rostral ventrolateral medulla) and parasympathetic (dorsal vagal complex and nucleus ambiguous) influences on the heart.
“Interestingly, functional coupling with the PVN was seen in brainstem nuclei that exert both sympathetic (rostral ventrolateral medulla) and parasympathetic (dorsal vagal complex and nucleus ambiguous) influences on the heart.”
Quote in the paperSubstantial claim - Findingown data
Systemic pretreatment of OT before a brief flooded cage stressor resulted in a greater amount of time spent in sedentary social contact after being returned to the home cage.
“Systemic pretreatment of OT before a brief flooded cage stressor (which may mimic the threat of a flooded burrow in nature) resulted in a greater amount of time spent in sedentary social contact after being returned to the home cage.”
Quote in the paperSubstantial claim - Findingcitation
Voles pretreated with OT displayed elevated concentrations of plasma OT 95 min following the original injection.
“Voles pretreated with OT displayed elevated concentrations of plasma OT 95 min following the original injection, suggesting positive feedback potentiation of OT release in the context of environmental stress similar to that seen in the context of parturition (Russell et al., 2003).”
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- Premisecitation
Inhibition of the OT system by antagonist administration in marmosets and rats or OT receptor knockout in mice resulted in decreased huddling behavior.
“inhibition of the OT system by antagonist administration in marmosets (Smith et al., 2010) and rats (van Leengoed et al., 1987) or OT receptor knockout in mice (Pobbe et al., 2012) resulted in decreased huddling behavior.”
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- cites van Leengoed et al., 1987
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- cites Pobbe et al., 2012
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- Premisecitation
OT signaling in areas such as the paraventricular nucleus of the hypothalamus and central amygdala plays a critical role in modulating responses to stressful, fearful, and anxiety-provoking stimuli.
“Indeed, OT signaling in areas such as the paraventricular nucleus of the hypothalamus and central amygdala play a critical role in modulating responses to stressful, fearful, and anxietyprovoking stimuli (Neumann et al., 2000a(Neumann et al., ,b, 2002;;Huber et al., 2005;Viviani et al., 2011).”
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- cites Huber et al., 2005
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- cites Viviani et al., 2011
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- Premisecitation
Oxytocin (OT) plays an important role in social interactions that goes far beyond its previously documented effects in female reproduction.
“In the past decade, research from various fields has revealed that oxytocin (OT) plays an important role in social interactions that goes far beyond the previously documented effects in female reproduction (Carter, 2007;Donaldson and Young, 2008).”
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- cites Donaldson and Young, 2008
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- Premisecitation
OT function appears to be essential to group cohesion in prairie voles and in a variety of other species.
“OT function appears to be essential to group cohesion in prairie voles (Carter et al., 1992;Cho et al., 1999) and in a variety of other species.”
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- cites Cho et al., 1999
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- Premisecitation
Prairie voles share with humans the tendency toward forming selective preferences for familiar conspecifics.
“Prairie voles, in particular, have been useful in revealing OT's role in human sociality largely because they share with humans the tendency toward forming selective preferences for familiar conspecifics (Williams et al., 1992).”
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- Interpretationown data
OT treatment in the context of stress may shift functional neural connectivity in a manner that promotes social cohesion when there is a natural impulse to disperse.
“Recent research with prairie voles by one of the authors (J.Y.) and his coresearchers suggests that OT treatment in the context of stress may shift functional neural connectivity in a manner that promotes social cohesion when there is a natural impulse to disperse.”
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Animal models have identified basic behavioral processes such as social recognition, parental bonding, and social antagonism that are mediated or modulated by OT.
“research using animal models, including rats, sheep, and mice (Winslow et al., 2000;Choleris et al., 2007;Leng et al., 2008;Nowak et al., 2011;Gabor et al., 2012), has been a catalyst by identifying basic behavioral processes, such as social recognition, parental bonding, and social antagonism, mediated or modulated by OT that become dysregulated in human mental illness.”
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- cites Choleris et al., 2007
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- Premisecitation
Pioneering clinical studies support the notion that OT is useful for ASD therapy.
“Although pioneering clinical studies support this notion (Hollander et al., 2007;Andari et al., 2010;Guastella et al., 2010), much remains to be learned about the mechanisms by which OT modulates social behavior before it is ready for clinical use.”
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- cites Andari et al., 2010
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- cites Guastella et al., 2010
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- Premisecitation
In the context of stress, activation of the OT system may promote approach toward, affiliation with, and maintenance of proximity between familiar individuals.
“In the context of stress, activation of the OT system may promote approach toward, affiliation with, and maintenance of proximity between familiar individuals (Engelmann et al., 1996;Carter and Altemus, 1997;Young, 2002).”
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- cites Carter and Altemus, 1997
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- Premisecitation
OT increases amygdala functional connectivity with the medial prefrontal cortex at rest.
“On the other hand, OT increases amygdala functional connectivity with a key mentalizing region, the medial prefrontal cortex, at rest (Sripada et al., 2012).”
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- Premisecitation
OT decreases functional connectivity between the amygdala and brainstem effector sites of the autonomic nervous system during emotional face viewing in men.
“OT also decreases functional connectivity between the amygdala and brainstem effector sites of the autonomic nervous system during emotional face viewing in men (Kirsch et al., 2005).”
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- Interpretationown data
OT may function as an antistress hormone by changing physiology and neural connectivity in a manner that facilitates social cohesion in the face of environmental threats that may otherwise promote dispersal.
“In conclusion, this new research suggests that OT may function as an antistress hormone by changing physiology and neural connectivity in a manner that facilitates social cohesion in the face of environmental threats that may otherwise promote dispersal.”
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In nonhuman experimental animals, OT interacts with DA in the ventral striatum to promote social bonding.
“In nonhuman experimental animals, OT interacts with DA in the ventral striatum to promote social bonding (Young et al., 2005;Skuse and Gallagher, 2009).”
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- cites Skuse and Gallagher, 2009
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Pharmacological challenge studies in healthy humans demonstrated beneficial effects of intranasal single-dose (24-48 IU) OT on behavioral responses in various social-economic and social-cognitive tasks.
“pharmacological challenge studies in healthy humans, which demonstrated beneficial effects of intranasal single-dose (24 -48 IU) administration of OT on behavioral responses in various social-economic and social-cognitive tasks.”
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- Premisecitation
The social salience hypothesis has gained considerable support from studies showing increased eye contact and improved mind reading from facial gestures following administration of OT.
“whereas the social salience hypothesis has gained considerable support from studies showing increased eye contact (Guastella et al., 2008b) and improved”
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- cites Domes et al., 2007a
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OT is beginning to emerge as a target for adjunctive therapy of social-behavioral dysfunction in several mental disorders including ASD, borderline personality disorder, schizophrenia, and social phobia.
“it is also beginning to emerge as a target for adjunctive therapy of social-behavioral dysfunction in several mental disorders (Striepens et al., 2011), including ASD (Hollander et al., 2003(Hollander et al., , 2007;;Andari et al., 2010;Guastella et al., 2010), borderline personality disorder (Bartz et al., 2011b;Simeon et al., 2011), schizophrenia (Feifel et al., 2010;Goldman et al., 2011;Peders”
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- cites Hollander et al., 2003
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- Premisecitation
OT also seems to increase amygdala activation to threatening scenes in women.
“OT also seems to increase amygdala activation to threatening scenes in women (Lischke et al., 2012).”
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- Interpretationnone given
Genetic variation influencing the number, organization, or functioning of OT receptors would be expected to influence the efficacy of the OT signal in the brain.
“Genetic variation influencing the number, organization, or functioning of OT receptors would be expected to influence the efficacy of the OT signal in the brain.”
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Evidence for similar mechanisms in humans is limited to correlations between ventral striatum activity and plasma OT levels.
“However, evidence for similar mechanisms in humans is limited to correlations between ventral striatum activity and plasma OT levels (Strathearn et al., 2009;Atzil et al., 2011).”
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- Premisecitation
Intranasal OT has been shown to normalize heightened amygdala and medial prefrontal cortex activity associated with social anxiety disorder.
“Intranasal OT has also been shown to normalize heightened amygdala and medial prefrontal cortex activity associated with social anxiety disorder (Labuschagne et al., 2010(Labuschagne et al., , 2011)).”
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- Premisenone given
Pharmaco-functional-MRI studies involving intranasal OT administration are helping to elucidate the neural mechanisms of OT's effects on human social cognition.
“Pharmaco-functional-MRI (fMRI) studies involving intranasal OT administration are helping to elucidate the neural mechanisms of OT's effects on human social cognition.”
Quote in the paperSubstantial claim - Premisecitation
OT dampens men's amygdala response to the feedback that a social partner is not trustworthy.
“Finally, OT's effect on brain activity has been studied during social interaction, where it has been shown to dampen men's amygdala response to the feedback that a social partner is not trustworthy (Baumgartner et al., 2008).”
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- Interpretationreasoning
The molecular genetic approach provides a means of studying OT system function in individuals for whom OT administration could be problematic.
“Second, it provides a means of studying OT system function in individuals (e.g., in infants and children, pregnant women, or lactating mothers) for whom OT administration could be problematic.”
Quote in the paperSubstantial claim - Premisecitation
Two intronic single-nucleotide polymorphisms (SNPs), rs53576 and rs2254298, linked to susceptibility for ASD have in several subsequent studies also been associated with socioemotional functioning in healthy individuals.
“Two intronic single-nucleotide polymorphisms (SNPs), rs53576 and rs2254298, linked to susceptibility for ASD have in several subsequent studies also been associated with socioemotional functioning in healthy individuals.”
Quote in the paperSubstantial claim - Premisecitation
A few null or contrasting effects have been reported in studies examining these and other SNPs.
“However, a few null or contrasting effects have also been reported in studies examining these and other SNPs (Gillath et al., 2008;Apicella et al., 2010;Tansey et al., 2010).”
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Human social behavior and social stress processing are shaped by a key regulatory circuitry including the amygdala, anterior cingulate cortex (ACC), and hypothalamus.
“At the neural systems level, both human social behavior and social stress processing are shaped by a key regulatory circuitry including the amygdala, anterior cingulate cortex (ACC) and hypothalamus (Lederbogen et al., 2011;Meyer-Lindenberg et al., 2011).”
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- Premisecitation
The first study on allelic variation in rs53576 in healthy Caucasian adults demonstrated an association between OXTR genotype and morphometric alterations of the hypothalamus and amygdala.
“The first study on allelic variation in rs53576 (Tost et al., 2010) was conducted in a large sample of healthy Caucasian adults and demonstrated an association between OXTR genotype and morphometric alterations of the hypothalamus and amygdala.”
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- Premisecitation
Homozygotes of the C allele of OXTR rs2268498 demonstrated a decreased response in the inferior occipital gyrus during the recognition of fearful facial expressions.
“Here (O'Connell et al., 2012), homozygotes of the C allele demonstrated a decreased response in the inferior occipital gyrus during the recognition of fearful facial expressions, an area crucial for the processing of visual emotional stimuli that has been shown to be directly modulated by OT in a previous pharmacological challenge study (Domes et al., 2010).”
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Initial studies have linked variation in OXTR to susceptibility for mental disorders characterized by social deficits, such as ASD, schizophrenia, and severe aggressive behaviors in childhood.
“Indeed, initial studies have linked variation in OXTR to susceptibility for mental disorders characterized by social deficits, such as ASD (Wu et al., 2005;Jacob et al., 2007;Lerer et al., 2008;Yrigollen et al., 2008;Gregory et al., 2009;Tansey et al., 2010;Wermter et al., 2010;Campbell et al., 2011), schizophrenia (Montag et al., 2012), and severe aggressive behaviors in childhood (Malik et al.,”
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A common variant in CD38 (rs3796863) linked to lower plasma OT levels and risk for autism affects neural response of the fusiform gyrus during visual processing of social stimuli.
“In addition, a recent pharmaco-imaging genetics study (Sauer et al., 2012) demonstrated effects of a common variant in CD38 (rs3796863) that has been linked to lower plasma OT levels (Feldman et al., 2012) and risk for autism (Higashida et al., 2012) on neural response of the fusiform gyrus during visual processing of social stimuli.”
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These findings were not replicated in a subsequent large study in healthy Caucasians using voxel-based morphometry and automated amygdala segmentation methods.
“These findings were not replicated in a subsequent large study in healthy Caucasians using voxel-based morphometry and automated amygdala segmentation methods (Tost et al., 2011).”
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- Interpretationnone given
The molecular genetic approach demonstrates that the effects of intranasally administered OT have parallels in naturally occurring individual differences.
“First, it demonstrates that the effects of intranasally administered OT have parallels in naturally occurring individual differences.”
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All participants, regardless of whether they received OT or placebo, showed improvements in affective speech comprehension from preinfusion to postinfusion.
“They observed that all participants, regardless of whether they received OT or placebo, showed improvements in affective speech comprehension from preinfusion to postinfusion.”
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- Interpretationcitation
These findings, together with recent case reports, suggest the possibility that OT could be used to treat the currently untreatable autistic social dysfunction.
“Although these findings, together with recent case reports showing improvements in autistic symptoms (Munesue et al., 2010;Kosaka et al., 2012), suggest the possibility that OT could be used to treat the currently untreatable autistic social dysfunction (Modi and Young, 2012), further large-scale studies or long-term trials are needed to assess the potential for further clinical application.”
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Individual differences in genetically determined factors related to oxytocin, such as SNPs in OXTR and CD38 in humans and OXTR/CD38 knock-out mice, shape individual differences at the neural level, such as function and structure in the limbic and paralimbic brain regions.
“Individual differences in genetically determined factors related to oxytocin such as SNPs in oxytocin receptor genes (OXTR) and CD38 in humans and OXTR/CD38 knock-out mice(Takayanagi et al., 2005;Jin et al., 2007) shape individual differences at the neural level such as function and structure in the limbic and paralimbic brain regions.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Takayanagi et al., 2005
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- cites Jin et al., 2007
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- Interpretationreasoning
Individual differences in these brain functions and structures should generate behavioral characteristics ranging from normal to extremes, including various social behaviors such as pair bonding, parental care, mate guarding, selective partner preference, monogamy, empathy, trust, ethnocentrism, social anxiety, social withdrawal, and ASD's social dysfunctions.
“Individual differences in these brain functions and structures should generate behavioral characteristics ranging from normal to extremes, including various social behaviors such as pair bonding, parental care, mate guarding, selective partner preference, monogamy, empathy, trust, ethnocentrism, social anxiety, social withdrawal, and ASD's social dysfunctions.”
Quote in the paperSubstantial claim - Premisecitation
Male youths with ASD who received intranasal administration of OT showed significantly better performance on the Reading the Mind in the Eyes task compared with those receiving placebo.
“Guastella et al. (2010) reported that male youths with ASD who received intranasal administration of OT showed significantly better performance on the”
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- Interpretationreasoning
Several different levels of evidence from animal models, genetic and human nonclinical and clinical studies support an association of OT with a wide range of social emotional behaviors from animal affiliation and bonding to human social perception, trust, and ethnocentrism.
“As reviewed above, several different levels of evidence from animal models, genetic and human nonclinical and clinical studies support an association of OT with a wide range of social emotional behaviors from animal affiliation and bonding to human social perception, trust, and ethnocentrism.”
Quote in the paperSubstantial claim - Interpretationnone given
Although human and animal studies are in different streams, genetic factors related to oxytocin and their neural and behavioral phenotypes are homologous at each level.
“Although human and animal studies are in different streams, genetic factors related to oxytocin and their neural and behavioral phenotypes are homologous at each level.”
- Also stated in: § Conclusion · plain
“Although human and animal studies are in different streams, genetic factors related to oxytocin and their neural and behavioral phenotypes are homologous at each level.”
Quote in the paperNot a substantial claim - Also stated in: § Conclusion · plain
- Interpretationreasoning
Accumulated evidence further supports the involvement of OT in the pathophysiology of disorders with pronounced social deficits including social anxiety disorder, borderline personality disorder, schizophrenia, and ASD.
“Accumulated evidence further supports the involvement of OT in the pathophysiology of disorders with pronounced social deficits including social anxiety disorder, borderline personality disorder, schizophrenia, and ASD.”
Quote in the paperSubstantial claim - Premisecitation
Several pioneering studies have suggested improvements in autistic behavioral and cognitive characteristics following administration of OT.
“Furthermore, several pioneering studies have suggested improvements in autistic behavioral and cognitive characteristics following administration of OT.”
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- cites Andari et al., 2010
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- Interpretationcitation
Individual differences in genetically determined factors related to oxytocin such as SNPs in OXTR and CD38 in humans and OXTR/CD38 knock-out mice shape individual differences at the neural level such as function and structure in the limbic and paralimbic brain regions.
“Individual differences in genetically determined factors related to oxytocin such as SNPs in oxytocin receptor genes (OXTR) and CD38 in humans and OXTR/CD38 knock-out mice (Takayanagi et al., 2005;Jin et al., 2007) shape individual differences at the neural level such as function and structure in the limbic and paralimbic brain regions.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Takayanagi et al., 2005
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- cites Jin et al., 2007
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- Interpretationreasoning
Risk variants in OXTR and CD38 alter the structural and functional properties of neural regions of the extended limbic regulatory network, particularly in hypothalamus, amygdala, higher-order regulatory areas of the anterior cingulate gyrus, and relevant input areas of the circuitry involved in the visual processing of social stimuli such as the fusiform gyrus.
“Together, while some of the observed heterogeneities calls for further empirical clarification, these imaging genetics findings underscore that risk variants in OXTR and CD38 alter the structural and functional properties of neural regions of the extended limbic regulatory network, particularly in hypothalamus, amygdala, higher-order regulatory areas of the anterior cingulate gyrus, and relevant”
Quote in the paperSubstantial claim - Interpretationreasoning
It is expected that the therapeutic effects of exogenous oxytocin or its agonists can improve the behavioral and neural phenotypes associated with oxytocin-related genetic factors.
“It is expected that the therapeutic effects of exogenous oxytocin or its agonists can improve the behavioral and neural phenotypes associated with oxytocin-related genetic factors.”
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- May combine two claims. 23
- Classified as probably not a substantial claim. 6
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Findingown dataOT was associated with decreased amygdala functional connectivity with the brainstem compared with placebo, and increased amygdala functional connectivity with both the ventral anterior insula and the inferior lateral temporal cortex.
“Finally, OT was associated with decreased amygdala functional connectivity with the brainstem compared with placebo (as expected), and increased amygdala functional connectivity with both the ventral anterior insula and the inferior lateral temporal cortex.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAt least 1 in every 100 people has some form of autism spectrum disorder (ASD).
“Recent worldwide epidemiological studies have shown that at least 1 in every 100 people has some form of autism spectrum disorder (ASD) (Brugha et al., 2011;Kim et al., 2011;Autism andDevelopmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators andCDC, 2012).”
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PremisecitationHumans exposed to OT make more eye contact, feel increased in-group trust, and are better able to infer emotions from other people's facial expressions.
“Humans exposed to OT make more eye contact, feel increased in-group trust, and are better able to infer emotions from other peoples' facial expressions (Bartz et al., 2011a;Meyer-Lindenberg et al., 2011;Striepens et al., 2011;Van Ijzendoorn and Bakermans-Kranenburg, 2012).”
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PremisecitationAnimal research documents a pivotal role of OT in promoting social bonding and attachment and in controlling fear and stress responses.
“The basis of this prevailing view has progressed from animal research documenting a pivotal role of OT in promoting social bonding and attachment (Insel, 1992;Young et al., 1998;Insel and Young, 2001;Kendrick, 2004;Neumann, 2009;Insel, 2010) and controlling fear and stress responses (Neumann, 2002;Huber et al., 2005;Lukas et al., 2011;Viviani et al., 2011;Knobloch et al., 2012) to pharmacological”
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PremisecitationOT suppresses the aversive response to infant crying, represented in the amygdala, while augmenting the empathic response, represented in the insula.
“Results were interpreted to suggest that OT suppresses the aversive response to infant crying, represented in the amygdala, while augmenting the empathic response, represented in the insula.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Riem et al., 2011
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- cites Riem et al., 2012
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May combine two claims.
InterpretationreasoningThese latter results suggest that OT may enhance the amygdala's ability to elicit subjective feeling states and enhance attention to salient social stimuli.
“These latter results suggest that OT may enhance the amygdala's ability to elicit subjective feeling states and enhance attention to salient social stimuli.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataIn a double-blind, placebo-controlled study, 91 men between the ages of 18 and 22 years were randomized to receive intranasal OT, intranasal vasopressin (AVP), or intranasal placebo.
“In a double-blind, placebocontrolled study, 91 men between the ages of 18 and 22 years (mean, 20.2 years) were randomized to receive intranasal OT (n ϭ 27), intranasal vasopressin (AVP) (n ϭ 27) or intranasal placebo (n ϭ 36).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisereasoningCurrent perspectives emphasize OT's potency as a facilitator of sociality in human social cognition and behavior.
“Current perspectives on the neuromodulatory effects of OT in the domain of human social cognition and behavior emphasize its potency as a facilitator of sociality.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe anxiolytic action of OT has been shown as decreased endocrine and subjective responses to social stress or as reduced negative cognitive self-appraisal in individuals scoring high in trait anxiety.
“The anxiolytic action of the peptide has indeed been shown as decreased endocrine and subjective responses to social stress (Heinrichs et al., 2003) or as reduced negative cognitive self-appraisal in individuals scoring high in trait anxiety (Alvares et al., 2012), whereas the social salience hypothesis has gained considerable support from studies showing increased eye contact (Guastella et al., 2”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Heinrichs et al., 2003
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- cites Alvares et al., 2012
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe OT receptor gene (OXTR) is located on chromosome 3p25, spans 17 kb, and encodes a 389 aa polypeptide with seven transmembrane domains belonging to the class I G-protein-coupled receptor family.
“The OT receptor gene (OXTR) is located on chromosome 3p25, spans 17 kb (Inoue et al., 1994), and encodes a 389 aa polypeptide with seven transmembrane domains belonging to the class I G-protein-coupled receptor family (Gimpl and Fahrenholz, 2001).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationOT has been implicated in impeded trust and cooperation as well as in negatively biased recollections of maternal care and closeness in insecurely or anxiously attached individuals.
“In addition, OT has been implicated in impeded trust and cooperation as well as in negatively biased recollections of maternal care and closeness in insecurely or anxiously attached individuals (Bartz et al., 2010(Bartz et al., , 2011b)).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Bartz et al., 2010
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- cites Bartz et al., 2011b
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May combine two claims.
PremisecitationOT modulates amygdala activity when viewing human face stimuli in a sexually dimorphic manner, with OT generally decreasing amygdala activation to emotional faces in men but increasing it in women.
“These studies showed that OT modulates amygdala activity when viewing human face stimuli in a sexually dimorphic manner, with OT generally decreasing amygdala activation to emotional faces in men (Kirsch et al., 2005;Domes et al., 2007b;Petrovic et al., 2008) but increasing it in women (Domes et al., 2010).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Kirsch et al., 2005
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- cites Domes et al., 2007b
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- cites Domes et al., 2010 source
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PremisecitationAn allele-load-dependent decrease in hypothalamus gray matter volume was observed in rs53576 A allele carriers that predicted lower prosocial temperament specifically in males.
“Specifically, consistent with a prior report in ASD (Kurth et al., 2011), an allele-load-dependent decrease in hypothalamus gray matter volume was observed in rs53576 A allele carriers that predicted lower prosocial temperament specifically in males.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Tost et al., 2010
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- cites Kurth et al., 2011
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Premisecitationrs2268498 contributes to moral judgments and negative emotionality; rs7632287 is associated with childhood social behavior, adult pair-bonding, and ASD susceptibility; rs1042778 is associated with prosocial decision making and parental touch.
“A particularly interesting example is rs2268498 (T/C), a functional polymorphism in the promoter region of the gene that contributes to moral judgments (Walter et al., 2012) and negative emotionality (Montag et al., 2011), as well as the intronic variant rs7632287 (G/A) that has been associated with childhood social behavior and adult pair-bonding (Walum et al., 2012) as well as susceptibility to”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Walter et al., 2012
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- cites Walum et al., 2012
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- cites Israel et al., 2009
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PremisecitationInstead, a significant decrease in hypothalamus volume and altered function of dorsal anterior cingulate gyrus during emotion processing was observed, a discrepancy that may relate to differences in imaging methods and/or population stratification effects.
“Instead, a significant decrease in hypothalamus volume and altered function of dorsal anterior cingulate gyrus during emotion processing was observed, a discrepancy in findings that may relate to differences in imaging methods and/or population stratification effects.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tost et al., 2011
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PremisecitationThe A allele of rs53576 has been associated with a larger startle response, reduced emotion-reading abilities, reduced maternal sensitivity, fewer affiliative displays, reduced trust, increased hormonal and neurocardiac reactivity to social stress, and lower optimism, mastery, and self-esteem.
“The A allele of rs53576 has been associated with a larger startle response and reduced emotion-reading abilities (Rodrigues et al., 2009), reduced maternal sensitivity (Bakermans-Kranenburg and van Ijzendoorn, 2008), fewer affiliative displays (Kogan et al., 2011), reduced trust (Krueger et al., 2012), increased hormonal and neurocardiac reactivity to social stress (Norman et al., 2012), and lower”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Rodrigues et al., 2009
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- cites Bakermans-Kranenburg and van Ijzendoorn, 2008
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- cites Krueger et al., 2012 source
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PremisecitationThe first imaging genetics study in healthy Japanese adults detected an association of the rs2254298 A allele and larger amygdala volumes, consistent with a second smaller study in adolescents of mixed ethnicity.
“The first imaging genetics study in a large sample of healthy Japanese adults (Inoue et al., 2010) used manual tracing methods to derive amygdala volumes, and examined the relationship of these measures to seven SNPs and one haplotype block in OXTR linked to ASD.Consistent with a second smaller study in adolescents of mixed ethnicity (Furman et al., 2011), the authors detected an association of”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Inoue et al., 2010
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- cites Furman et al., 2011
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PremisecitationThe AA genotype of rs53576 has been associated with reduced positive affect in men and a reduced tendency to seek social support during distress when such behavior is culturally normative.
“The AA genotype of rs53576 has been associated with reduced positive affect in men (Lucht et al., 2009) and a reduced tendency to seek social support during distress when such behavior is culturally normative (Kim et al., 2010).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Lucht et al., 2009
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- cites Kim et al., 2010
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PremisecitationVariation at rs2254298 has been associated with prosociality, trait empathy, attachment anxiety in females and autism-spectrum quotient in males, infant-caregiver attachment security in non-Caucasians, and parental touch during interactions with infants.
“Variation at rs2254298 has been associated with prosociality (Israel et al., 2009); trait empathy (Wu et al., 2012); attachment anxiety in females and autism-spectrum quotient in males (Chen, 2012); infant-caregiver attachment security in non-Caucasians (Chen et al., 2011a); and parental touch during interactions with infants (Feldman et al., 2012).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Israel et al., 2009
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- cites Wu et al., 2012
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- cites Feldman et al., 2012
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PremisecitationThe structural and functional anatomy of these networks is highly heritable and shaped by a multitude of genetic variants, some of them conferring risk for mental disorders.
“The structural and functional anatomy of these networks is highly heritable (Peper et al., 2007) and shaped by a multitude of genetic variants, some of them conferring risk for mental disorders (Pezawas et al., 2005;Meyer-Lindenberg et al., 2009).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Peper et al., 2007
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- cites Pezawas et al., 2005
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- cites Meyer-Lindenberg et al., 2009
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PremisecitationASD individuals exhibited stronger interactions with the most socially cooperative partner and reported enhanced feelings of trust and preference with increased gazing time into the eyes after OT administration together with elevated plasma levels of OT.
“This study revealed that ASD individuals exhibited stronger interactions with the most socially cooperative partner and that they reported enhanced feelings of trust and preference with increased gazing time into the eyes after OT administration together with elevated plasma levels of OT.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Andari et al., 2010
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PremisecitationA significant increase in brain activation was observed in risk allele carriers that was further enhanced through the intranasal application of OT.
“Here, a significant increase in brain activation was observed in risk allele carriers that was further enhanced through the intranasal application of OT.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sauer et al., 2012
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenEarly or long-term administration of oxytocin might even have an effect at the genetic level, such as epigenetic effects like methylation of OXTR.
“Furthermore, early or long-term administration of oxytocin might even have an effect at the genetic (e.g., epigenetic, such as methylation of OXTR) level.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThose who received placebo first tended to revert to baseline after a 1 week infusion interval, whereas those who received OT first retained the ability to accurately assign emotional significance to speech intonation in the speech comprehension task.
“However, although those who received placebo first tended to revert to baseline after a 1 week infusion interval, those who received OT first retained the ability to accurately assign emotional significance to speech intonation in the speech comprehension task (Hollander et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hollander et al., 2007
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PremisecitationA lower-than-normal plasma OT level in ASD subjects and an association of ASD with OXTR further support a link between OT and ASD, although some inconsistency in association between ASD and OXTR was also recognized.
“A lower-than-normal plasma OT level in ASD subjects (Modahl et al., 1998;Andari et al., 2010;Munesue et al., 2010) and an association of ASD with OXTR (Wu et al., 2005;Jacob et al., 2007;Lerer et al., 2008;Liu et al., 2010) further support a link between OT and ASD, although some inconsistency in association between ASD and OXTR was also recognized (Tansey et al., 2010;Campbell et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Modahl et al., 1998
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- cites Wu et al., 2005
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- cites Tansey et al., 2010
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PremisecitationOT can contribute to the pathophysiology of ASD and could be a candidate therapeutic agent for the symptoms of ASD.
“it was suggested that OT can contribute to the pathophysiology of ASD, a sexually dimorphic neurodevelopmental disorder with social deficits as a core feature, and that it could be a candidate thera-peutic agent for the symptoms of ASD (Yamasue et al., 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yamasue et al., 2009 source
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PremisecitationThe OT system is evolutionarily highly conserved in the mammalian brain and overlapping regions such as the amygdala, striatum, hypothalamus, and medial frontal cortex are shared neural effector sites in both humans and animals.
“as the OT system is evolutionarily highly conserved in the mammalian brain and overlapping regions such as the amygdala, striatum, hypothalamus, and medial frontal cortex were indicated as shared neural effector sites in both humans and animals (Young et al., 2001;Hammock and Young, 2006;Inoue et al., 2010;Tost et al., 2010Tost et al., , 2011;;Furman et al., 2011;Yamasue et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Young et al., 2001
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- cites Hammock and Young, 2006
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- cites Inoue et al., 2010
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Classified as probably not a substantial claim.
Study design and conductcitationIn a randomized and double-blind design, 15 medication-free adults with ASD without intellectual disability received a continuous infusion of synthetic OT or placebo over 4 h.
“The authors examined 15 medication-free adults with ASD without intellectual disability who underwent two identical challenge days in which they received a continuous infusion of synthetic OT (pitocin) or placebo over 4 h in a randomized and double-blind design.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hollander et al., 2003
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The paper relies on this without support.
There is no established pharmacological treatment for social dysfunction, the core feature of ASD.
“However, there is no established pharmacological treatment for social dysfunction, the core feature of ASD.”
The paper relies on this without support.
Little is known about the mechanistic effects of OT on social brain circuits, which are at the core of the observed behavioral changes.
“Specifically, little is known about the mechanistic effects of OT on social brain circuits, which are at the core of the observed behavioral changes.”
The paper relies on this without support.
The neural mechanisms by which OT improves autistic behavior are unknown.
“mechanisms by which OT improves autistic behavior are also unknown.”
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?
Intranasal oxytocin administration may be effective for autism spectrum disorder.
“recent studies have proposed that intranasal oxytocin administration may be effective.2, 3”
We conducted intention-to-treat analyses including all participants, and subgroup analyses in only male participants with good adherence (>50%).
“We conducted intention-to-treat (ITT) analyses including all participants, and subgroup analyses in only male participants with good adherence (>50%) because sex-based differences in responses to oxytocin administration have been reported (Table 1, Figure 1).2, 38”
Sex-based differences in responses to oxytocin administration have been reported.
“because sex-based differences in responses to oxytocin administration have been reported (Table 1, Figure 1).2, 38”
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“In addition, OT has been implicated in impeded trust and cooperation as well as in negatively biased recollections of maternal care and closeness in insecurely or anxiously attached individuals (Bartz et al., 2010, 2011b).”
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Genomic and epigenetic evidence for oxytocin receptor deficiency in autism
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Self-citationPositive Association of the Oxytocin Receptor Gene (OXTR) with Autism in the Chinese Han Population
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Oxytocin Attenuates Amygdala Reactivity to Fear in Generalized Social Anxiety Disorder
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“Intranasal OT has also been shown to normalize heightened amygdala and medial prefrontal cortex activity associated with social anxiety disorder (Labuschagne et al., 2010, 2011).”
BackgroundIntranasal Administration of Oxytocin Increases Envy and Schadenfreude (Gloating)
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“However, recent studies contrast with the notion that OT exerts uniformly positive effects on human social cognition and behavior in showing that the peptide can also promote envy and gloating (schadenfreude) (Shamay-Tsoory et al., 2009), ethnocentrism (including prejudice, xenophobia, and racial bias) (De Dreu et al.”
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“…a decreased response in the inferior occipital gyrus during the recognition of fearful facial expressions, an area crucial for the processing of visual emotional stimuli that has been shown to be directly modulated by OT in a previous pharmacological challenge study (Domes et al., 2010).”
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“Higher-resolution imaging studies have now begun to elucidate the specific amygdala subregions responsible for these effects (Gamer et al., 2010).”
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“These studies showed that OT modulates amygdala activity when viewing human face stimuli in a sexually dimorphic manner, with OT generally decreasing amygdala activation to emotional faces in men (Kirsch et al., 2005; Domes et al., 2007b; Petrovic et al., 2008) but increasing it in women (Domes et al.”
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“In addition, OT has been implicated in impeded trust and cooperation as well as in negatively biased recollections of maternal care and closeness in insecurely or anxiously attached individuals (Bartz et al., 2010, 2011b).”
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Clinical potential of oxytocin in autism spectrum disorder: current issues and future perspectives
Benner, S., & Yamasue, H. (2017) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000341 · Cited by 19 · see citing works
Self-citationNovel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals
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Current Practice and Future Avenues in Autism Therapy
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The need for a comprehensive molecular characterization of autism spectrum disorders
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Oxytocin as a potential pharmacological tool to combat obesity
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Road From Nose to Brain for Treatment of Alzheimer: The Bumps and Humps
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Self-citation
- Authors
- Yamasue, H., Yee, J. R., Hurlemann, R., Rilling, J. K., Chen, F. S., Meyer-Lindenberg, A., & Tost, H.
- Affiliations
- Japan Science and Technology Agency (JP)
- RTI International (US)
- University of Bonn (DE)
- Emory University (US)
- University of Freiburg (DE)
- Heidelberg University (DE)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-10-10
- Volume
- 32
- Issue
- 41
- Pages
- 14109-14117a
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6622380
- OpenAlex
- W1973821096
- Semantic Scholar
- d4d1458505846a549f2fa12fc3c49e0328fb913e
- Cited by
- 149
- References
- 158
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 10 · 2022: 9 · 2021: 12 · 2020: 4 · 2019: 6 · 2018: 8 · 2017: 10 · 2016: 10 · 2015: 18 · 2014: 22 · 2013: 31
- FWCI
- 34.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Journal of Neuroscience Nursing
- Funders
- Japan Society for the Promotion of Science (22689034, 23659558)
- 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 › Human-Animal Interaction Studies
- Keywords
- oxytocin, prosocial behavior, autism spectrum disorder, social dysfunction, social behavior, animal models, oxytocin therapy, social brain, autism genetics
- MeSH terms
- Animals, Autistic Disorder, Humans, Neural Pathways, Oxytocin, Social Behavior, Social Environment
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 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
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