A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans

May combine two claims.

In the current study, the sexually differentiated effect of intranasal oxytocin on left ventral caudate activation to reciprocated cooperation was specific to rs53576 GG homozygotes and was absent in AA/AG carriers.

“Here, we show that these sex differences in OT effects are specific to individuals with the rs53576 GG genotype, and are not found for other genotypes (rs53576 AA/AG).”

May combine two claims.

For both the frequency of choosing C and the likelihood of choosing C after a CC outcome, there were no main effects of drug, sex, or genotype and no interactions, for either human or computer partners.

“For both frequency of choice C and the probability of C choices after a CC outcome, there were no main effects of drug, sex or genotype and no interaction effects for either human (Figure 2a) or computer partners (Figure 2b).”

May combine two claims.

For CC outcomes with human partners, the left ventral caudate response showed no main effects of drug, sex, or genotype.

“For CC outcomes with human partners, there were no main effects of drug, sex or genotype”

May combine two claims.

In post-hoc tests, OT reduced the left ventral caudate response to CC outcomes with human partners in females (t87=-3.08, p=0.003) but not in males (t82=0.41, p=0.69).

“Post-hoc comparisons revealed that OT decreased the left ventral caudate nucleus response to CC outcomes with human partners in females (t87=−3.08, p=0.003), but not males (t82=0.41, p=0.69).”

May combine two claims. The quote only partly states this claim.

Among males, OT treatment had no effect on the left ventral caudate response to CC outcomes with computer partners in either GG homozygotes (t34=0.92, p=0.36) or AA/AG genotypes (t45=-0.42, p=0.68).

“Among males, OT treatment had no effect in those with either the GG genotype (t34=0.92, p=0.36) or the AA/AG genotypes (t45=−0.42, p=0.68).”

May combine two claims.

Among individuals with the GG genotype, OT made the male left ventral caudate response to CC outcomes with human partners similar to the female placebo response, and vice versa.

“such that among individuals with the GG genotype OT rendered the male left ventral caudate nucleus response similar to the female left ventral caudate nucleus response in the placebo condition and vice versa”

May combine two claims.

Within each of these regions, OT reduced the response to CC outcomes in female GG homozygotes but had no significant effect in male GG homozygotes.

“Within each of these regions, OT attenuated the response to CC outcomes in female GG homozygotes but had no significant effect on male GG homozygotes.”

May combine two claims.

In most of these regions, OT significantly decreased activity relative to placebo in women and tended to increase activity relative to placebo in men among GG homozygotes.

“In most of these regions, similar to the caudate nucleus, OT significantly decreases activity relative to placebo in women and tends to increase activity relative to placebo in men among GG homozygotes.”

May combine two claims.

For CC outcomes with human partners, there were no drug-by-genotype or sex-by-genotype interactions on the left ventral caudate response.

“There were no drug × genotype or sex × genotype interactions.”

Classified as probably not a substantial claim.

The rs53576 SNP has been proposed as a strong candidate for influencing oxytocinergic function.

“A single-nucleotide polymorphism (SNP) of an adenine (A) or guanine (G) substitution within the third intron (rs53576) has been suggested as a particularly promising candidate to modulate oxytocinergic function (Tost et al., 2010, Wu et al., 2005), although the molecular functionality of this SNP is still unknown.”

• cites Tost et al., 2010Not checked yet

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• cites Wu et al., 2005Not checked yet

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

In non-human animals, oxytocin supports the formation and upkeep of social bonds.

“In non-human animals, the neuropeptide oxytocin (OT) promotes the development and maintenance of social bonds (Lim & Young, 2006).”

• cites Lim & Young, 2006Not checked yet

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

Oxytocin treatment heightens ventral striatum activity when viewing romantic partners' faces.

“enhances the ventral striatum response to viewing faces of romantic partners (Scheele et al., 2013)”

• cites Scheele et al., 2013Not checked yet

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

Intranasal oxytocin increases paternal responsiveness during play with children.

“For instance, intranasal administration of OT increases trust (Kosfeld et al., 2005), altruism (Zak et al., 2007), and emotional empathy responses (Hurlemann et al., 2010) to unknown others, as well as paternal responsiveness during play with children (Naber et al., 2010).”

• cites Naber et al., 2010Not checked yet

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May combine two claims.

Oxytocin may increase the reward or salience of positive social interactions for male GG homozygotes while decreasing those processes for female GG homozygotes.

“Thus, OT may increase the reward or salience of positive social interactions for male GG homozygotes, while decreasing those processes for female GG homozygotes.”

• AssumptionThe authors state this as an assumption: The G allele of rs53576 is assumed to underlie a more efficient oxytocin system.

Classified as probably not a substantial claim.

Oxytocin treatment boosts the ventral tegmental area reaction to socially relevant cues.

“OT treatment augments the ventral tegmental area response to socially relevant cues (Groppe et al., 2013)”

• cites Groppe et al., 2013Not checked yet

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May combine two claims.

T-allele genotypes of SNP2 had 100% higher OXTR density than C/C littermates within the nucleus accumbens, but not in other analyzed brain regions.

“Specifically, T-allele genotypes of SNP2 (either T/T or C/T) had 100% higher OXTR density than C/C littermates within the nucleus accumbens, but not within other brain regions that were analyzed.”

• cites King et al., 2013Not checked yet

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

Pups with the T allele produced more ultrasonic calls after maternal separation than C/C littermates.

“Moreover T-allele pups emitted more ultrasonic vocalizations following maternal separation compared with C/C littermates.”

• cites King et al., 2013Not checked yet

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

Evidence is growing that intranasal oxytocin affects social-emotional processing and related brain activity differently in males and females.

“Notably, there is also accumulating evidence for sex differences in effects of intranasal OT on social-emotional functioning and associated brain function (Campbell et al., 2014, Ditzen et al., 2012, Hoge et al., 2014, Lynn et al., 2014, Preckel et al., 2014).”

• cites Campbell et al., 2014Not checked yet

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• cites Ditzen et al., 2012Not checked yet

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• cites Hoge et al., 2014Not checked yet

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

In humans, oxytocin facilitates both non-reproductive and reproductive bonds.

“Building on these findings, the past decade of research has revealed that OT also facilitates both non-reproductive and reproductive bonds in humans (Bartz et al., 2011, Feldman, 2012).”

• cites Bartz et al., 2011Not checked yet

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• cites Feldman, 2012Not checked yet

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May combine two claims.

The effects of intranasal oxytocin vary across individuals and depend on factors such as genotype and sex.

“However, OT effects are often heterogeneous across individuals.”

• Also stated in: § Introduction · plain

  “Importantly, however, the effects of OT treatment are not ubiquitous, but are dependent on individual factors such as genotype and sex (Bartz et al., 2011, De Dreu et al., 2010, Olff et al., 2013, Scheele et al., 2014).”

• cites Bartz et al., 2011Not checked yet

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• cites De Dreu et al., 2010Not checked yet

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• cites Olff et al., 2013Not checked yet

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

Intranasal oxytocin increases emotional empathy responses to unknown others.

“For instance, intranasal administration of OT increases trust (Kosfeld et al., 2005), altruism (Zak et al., 2007), and emotional empathy responses (Hurlemann et al., 2010) to unknown others, as well as paternal responsiveness during play with children (Naber et al., 2010).”

• cites Hurlemann et al., 2010Not checked yet

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

Intranasal oxytocin increases altruism toward unknown others.

“For instance, intranasal administration of OT increases trust (Kosfeld et al., 2005), altruism (Zak et al., 2007), and emotional empathy responses (Hurlemann et al., 2010) to unknown others, as well as paternal responsiveness during play with children (Naber et al., 2010).”

• cites Zak et al., 2007Not checked yet

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May combine two claims.

In a prior study using a subset of the current sample, intranasal oxytocin increased left ventral caudate activation to reciprocated cooperation in men but showed a non-significant trend to decrease it in women.

“Within the left ventral caudate nucleus, intranasal OT treatment increased activation to reciprocated cooperation in men, but tended to decrease activation in women.”

• Also stated in: § Introduction · boosted

  “we demonstrated sexually differentiated effects of OT treatment on the left ventral caudate nucleus response to reciprocated cooperation with human partners in the context of the iterated Prisoner’s Dilemma game (Rilling et al., 2014) such that OT augmented the male left ventral caudate nucleus response but there was a non-significant trend for OT to attenuate the female left ventral caudate n”

• cites Rilling et al., 2014Not checked yet

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

Intranasal oxytocin increases trust toward unknown others.

“For instance, intranasal administration of OT increases trust (Kosfeld et al., 2005), altruism (Zak et al., 2007), and emotional empathy responses (Hurlemann et al., 2010) to unknown others, as well as paternal responsiveness during play with children (Naber et al., 2010).”

• cites Kosfeld et al., 2005Not checked yet

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May combine two claims.

OT effects were similar for human and computer partners among female GG homozygotes, suggesting that OT effects in this subgroup are not limited to social cooperation and could extend to non-social cognition.

“Unexpectedly, effects of OT were similar when playing with human and computer partners among female GG homozygotes, suggesting that OT effects are not limited to social cooperation but could extend to non-social cognition in this sub-group.”

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

Principal components were calculated to adjust for population stratification, and the first two were entered as covariates.

“Genome wide genotypes from the Illumina PsychChip were used to calculate Principal Components using Principal Compinents Analysis (PCA) to account for population stratification.”

• Also stated in: § Principal component analysis (PCA) · plain

  “The first two PCA eigenvectors (PCA1 and PCA2), which discriminated individuals with European background from those with African and Asian background, were then included in the model as covariates to capture variance due to population structure.”

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

Men given intranasal oxytocin rate unfamiliar faces more negatively, while women rate them more positively.

“Another study (Hoge et al., 2014) found that intranasal OT was associated with more negative ratings of unfamiliar faces in men but more positive ratings in women.”

• cites Hoge et al., 2014Not checked yet

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

Previous studies show that intranasal OT increases trust, a form of social risk taking, but does not increase risk-taking in an analogous nonsocial task.

“These findings seem contradictory with previous studies showing that intranasal OT increases trust, a form of social risk taking, but does not increase risk-taking in an analogous nonsocial task (Baumgartner et al., 2008, Kosfeld et al., 2005).”

• cites Baumgartner et al., 2008Not checked yet

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• cites Kosfeld et al., 2005Not checked yet

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

Neither experimenters nor subjects knew which treatment was given.

“Both experimenters and subjects were blind to the treatment subjects received.”

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

The inverted-U shaped interpretation of OT effects is very tentative because baseline and post-drug OT levels in CSF were not measured.

“However, this inverted-U shaped interpretation of OT effects is very tentative given that we did not measure baseline and post-drug levels of OT in CSF.”

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

Under an inverted-U shaped curve, raising brain OT levels in men would increase the ventral caudate response toward the maximum, while raising OT levels in women might move them past the maximum and decrease brain activity.

“Assuming an inverted-U shaped curve, raising brain OT levels in men would augment the ventral caudate response, moving them closer to the maximum level activity. On the other hand, raising OT levels in women might displace them to the right of the maximum, decreasing brain activity.”

• AssumptionThe authors state this as an assumption: The dose-response relationship between brain oxytocin levels and neural activity follows an inverted-U shape.

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

Men given intranasal OT report less negative affect after social stress, while women given intranasal OT report more anger in the same situation.

“For instance, men treated with intranasal OT report less negative affect following social stress, whereas women treated with intranasal OT treatment report enhanced anger in the same situation (Kubzansky et al., 2012).”

• cites Kubzansky et al., 2012Not checked yet

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May combine two claims.

Marsh and colleagues (2012) found OT administration effects only in GG homozygotes and not in A allele carriers, suggesting greater responsiveness to OT among GG individuals.

“In addition, Marsh and colleagues (2012) demonstrated effects of OT administration that were only evident among GG homozygotes but not A allele carriers, suggesting heightened responsiveness to OT treatment among individuals with the GG genotype.”

• cites Marsh et al., 2012Not checked yet

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May combine two claims.

OT treatment might increase the reward or salience of positive social interactions for male GG homozygotes but decrease those processes for female GG homozygotes.

“That is, OT treatment might increase the reward or salience of positive social interactions for male GG homozygotes, but decrease those processes for female GG homozygotes.”

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

Genotyping for rs53576 employed a TaqMan allelic discrimination assay, with quality control that included positive and negative controls, duplicate samples, and Hardy-Weinberg equilibrium checks.

“rs53576 genotyping was performed by a TaqMan allelic discrimination assay, on an ViiA™7 Instrument (Applied Biosystems, Foster City, California), using a commercial TaqMan assay reagent kit (Applied Biosystems), as described in Bradley et al. (2008).”

• Also stated in: § Genotyping · plain

  “Quality control (QC) included the analysis of positive and negative controls, duplicate samples, as well as the evaluation of Hardy Weinberg Equilibrium using an exact test (https://www.pharmgat.org/pharmgat.org/Tools/exacthwelongform).”

Classified as probably not a substantial claim.

Subjects were assigned randomly to intranasal oxytocin or placebo.

“104 men and 100 women from the Emory University community between the ages of 18 and 22 (mean age for men=19.97 years; mean age for women=20.21 years) were randomized to receive intranasal OT (50 men and 50 women) or intranasal placebo (54 men and 50 women).”

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

Sexually differentiated effects of OT are not unprecedented.

“Although these sex differences in OT effects on the neural response to social cooperation may seem surprising; sexually differentiated effects of OT are not without precedent.”

• cites Kubzansky et al., 2012Not checked yet

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• cites Ditzen et al., 2012Not checked yet

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

After social stress, men given intranasal oxytocin report less negative mood, but women report more anger.

“Finally, men treated with intranasal OT report less negative affect following social stress, whereas women treated with intranasal OT treatment report enhanced anger in the same situation (Kubzansky et al., 2012).”

• cites Kubzansky et al., 2012Not checked yet

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May combine two claims.

The region-of-interest analysis targeted the left ventral caudate nucleus according to pre-specified hypotheses, and restricting the number of ROIs reduced power loss from multiple comparisons.

“We performed a region of interest analysis based on a priori hypotheses, supplemented with a whole brain analysis.”

• Also stated in: § Neuroimaging procedures · plain

  “we wanted to limit the number of ROIs to mitigate loss of power due to multiple comparisons (Poldrack, 2007).”

• cites Poldrack, 2007Not checked yet

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

OXTR rs53576 genotype frequencies were in Hardy-Weinberg equilibrium for the full sample and for each subgroup.

“In addition, genotypes for OXTR rs53576 did not deviate from the Hardy-Weinberg equilibrium (all p>0.19) for the sample as a whole or for each sub-group (Table 1).”

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

During couple conflict, intranasal oxytocin raises autonomic nervous system activity in men but lowers it in women.

“while intranasal OT administration during couple conflict augments activity of the autonomic nervous system (ANS) in men, it attenuates ANS activity in women (Ditzen et al., 2012).”

• cites Ditzen et al., 2012Not checked yet

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

OT administration increases autonomic nervous system activity and emotional responses to couple conflict in males but decreases these physiological and subjective responses in females.

“In addition, OT administration increases ANS activity and emotional responses to couple conflict in males whereas decreases these physiological and subjective responses in females (Ditzen et al., 2012).”

• cites Ditzen et al., 2012Not checked yet

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May combine two claims.

The results support the hypothesis that the rs53576 G allele is linked to more efficient oxytocinergic function, possibly through upregulated receptor expression, and thus to stronger effects of OT treatment.

“These results support the hypothesis that rs53576 G allele is associated with more efficient oxytocinergic function, perhaps due to upregulated receptor expression, and therefore leads to enhanced effects of OT treatment (Marsh et al., 2012, Moons et al., 2014).”

• cites Marsh et al., 2012Not checked yet

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• cites Moons et al., 2014Not checked yet

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

OT has opposing effects on intergroup cooperation in the Public Goods Game among individuals with intuitive versus reflective cognitive styles.

“Further, it has been recently reported that OT has opposing effects on intergroup cooperation in the Public Goods Game among individuals with intuitive vs. reflective cognitive styles (Ma et al., 2015).”

• cites Ma et al., 2015Not checked yet

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

Decision-making in the iterated PD game may be more cognitively based and cortically mediated, with top-down cognitive processes overriding emotional influences in this sample of highly educated, high-functioning undergraduates.

“Although intranasal OT modulated activity within the striatum, it may be that decision-making in our iterated PD game is more cognitively-based and cortically-mediated. That is, top-down cognitive processes may be overriding emotional influences in this sample of highly educated and high-functioning undergraduate students.”

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

Intranasal OT increases cooperation in the PD game among men high rather than low in attachment avoidance.

“For example, intranasal OT increases cooperation in the PD game among men who are high rather than low in attachment avoidance (De Dreu, 2012).”

• cites De Dreu, 2012Not checked yet

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

Intranasal OT has been discussed as a promising candidate to improve social functioning in various psychiatric disorders, including autism spectrum disorder, depression, and schizophrenia.

“Indeed, intranasal administration of OT has been discussed as a promising candidate to improve social functioning in a variety of psychiatric disorders, including autism spectrum disorder, depression and schizophrenia (Macdonald & Feifel, 2013, Zink & Meyer-Lindenberg, 2012).”

• cites Macdonald & Feifel, 2013Not checked yet

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• cites Zink & Meyer-Lindenberg, 2012Not checked yet

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

The modulation of intranasal OT effects by sex and OXTR gene polymorphism might have important implications for the potential clinical application of OT treatment.

“The modulation of intranasal OT effects by sex and OXTR gene polymorphism might have important implications for the potential clinical application of OT treatment.”

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

The effects of intranasal OT on cooperative behavior depend on the participant's attachment style or cognitive style.

“Several studies show that the effects of intranasal OT on cooperative behavior depend on the participant’s attachment style (Bartz et al., 2010, De Dreu, 2012) or cognitive style (Ma et al., 2015).”

• cites Bartz et al., 2010Not checked yet

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• cites De Dreu, 2012Not checked yet

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• cites Ma et al., 2015Not checked yet

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May combine two claims.

The study did not characterize participants' attachment or cognitive style, so it could not evaluate the potential influence of attachment style on cooperation-related neural and behavioral responsiveness to OT.

“We did not characterize the attachment or cognitive style of the participants in our study, so we are unable to evaluate the potential influence of attachment style on cooperation-related neural and behavioral responsiveness to OT.”

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

An accumulating body of literature has reported individual differences in responses to OT treatment and urged caution against uniform application of OT for potential clinical treatment.

“However, an accumulating body of literature has reported individual differences in responses to OT treatment and therefore urged caution against uniform application of OT for potential clinical treatment (Bartz et al., 2011, Olff et al., 2013, Rilling et al., 2014).”

• cites Bartz et al., 2011Not checked yet

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• cites Olff et al., 2013Not checked yet

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• cites Rilling et al., 2014Not checked yet

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