Low dose intranasal oxytocin delivered with Breath Powered device dampens amygdala response to emotional stimuli: A peripheral effect-controlled within-subjects randomized dose-response fMRI trial
Open accessAbstract
UNLABELLED: It is unclear if and how exogenous oxytocin (OT) reaches the brain to improve social behavior and cognition and what is the optimal dose for OT response. To better understand the delivery routes of intranasal OT administration to the brain and the dose-response, we compared amygdala response to facial stimuli by means of functional magnetic resonance imaging (fMRI) in four treatment conditions, including two different doses of intranasal OT using a novel Breath Powered device, intravenous (IV) OT, which provided similar concentrations of blood plasma OT, and placebo. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults administering a single-dose of these four treatments. We observed a treatment effect on right amygdala activation during the processing of angry and happy face stimuli, with pairwise comparisons revealing reduced activation after the 8IU low dose intranasal treatment compared to placebo. These data suggest the dampening of amygdala activity in response to emotional stimuli occurs via direct intranasal delivery pathways rather than across the blood-brain barrier via systemically circulating OT. TRIAL REGISTRATION: This trial is registered at the U.S. National Institutes of Health clinical trial registry (www.clinicaltrials.gov; NCT01983514) and as EudraCT no. 2013-001608-12.
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TL;DR
In a randomized, double-blind, double-dummy, four-way crossover fMRI trial in 16 healthy men, 8 IU intranasal oxytocin delivered by a Breath Powered device reduced right amygdala activation to angry faces compared with placebo. Intravenous oxytocin producing comparable peripheral levels did not, suggesting nose-to-brain rather than systemic blood-brain-barrier delivery.
Key findings
- Right amygdala activation during angry faces showed a significant main effect of treatment [F(3,15.1)=4.54, p=.019]; pairwise comparison showed reduced activation after 8 IU OPN-OT versus placebo (p=.002; FDR threshold p=.008).
- Happy faces showed a main effect of treatment on right amygdala activity [F(3,15)=3.44, p=.04], but the 8 IU OPN-OT versus placebo reduction (p=.01) did not survive the FDR-corrected threshold (p=.008). Ambiguous faces showed no main effect [F(3,14.6)=3.15, p=.057].
- Left amygdala showed no main effects of treatment for angry (p=.32), ambiguous (p=.37), happy (p=.14), or shape stimuli (p=.18). Right amygdala shape stimuli showed a main effect [F(3,15)=3.56, p=.04], but no post hoc comparisons survived FDR correction.
- Plasma OT concentration increased in all active treatment conditions, with no pairwise comparisons between active conditions reaching significance; adverse events were equivalent across groups (8 IU OPN-OT, three reports; 24 IU OPN-OT, two; IV OT, three; placebo, two).
Methods
- Fifty-seven male volunteers were assessed; 18 healthy males aged 20–30 years (M=23.81, SD=3.33) were randomized, and 16 were analyzed after two withdrawals. Treatments were 8 IU OPN-OT, 24 IU OPN-OT, IV OT 1 IU, and placebo in a randomized, double-blind, double-dummy, four-period crossover Latin-square design.
- An event-related fMRI social cognition task began 40 min after treatment and lasted 21 min, presenting angry, happy, and ambiguous faces plus geometric shapes. Imaging used a 3T GE scanner; preprocessing used FSL/FEAT, amygdala contrast estimates were extracted from Harvard-Oxford masks, and linear mixed models in SPSS tested treatment effects with FDR correction and Bayes factors.
- Blood plasma OT, AVP, and cortisol were collected at baseline and 0, 10, 30, 60, and 120 min after treatment and analyzed by ELISA.
Limitations
- Stated: the sample size was relatively small; the study did not compare the Breath Powered device with a traditional nasal spray device; and generalizability is limited to healthy males, with future work needed in females and psychiatric populations.
- Stated: individual differences and context can influence OT response, although the within-subjects design in a homogenous sample minimized variation from the endogenous OT system.
- Evident from the text: only 16 participants contributed imaging data after withdrawals, the design tested a single acute dose, and resting-state MRI was acquired but not analyzed for this paper.
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Claims the paper makes
0 of 56 cited sources checked · 0 supported · 0 flagged
- Findingown data
Pairwise comparisons revealed reduced right amygdala activation after the 8IU low dose intranasal treatment compared to placebo.
“with pairwise comparisons revealing reduced activation after the 8IU low dose intranasal treatment compared to placebo.”
Quote in the paperSubstantial claim - Findingown data
There was a treatment effect on right amygdala activation during the processing of angry and happy face stimuli.
“We observed a treatment effect on right amygdala activation during the processing of angry and happy face stimuli”
Quote in the paperSubstantial claim - Findingown data
There was no main effect of treatment for right amygdala activity during the presentation of ambiguous faces.
“There was no main effect of treatment for right amygdala activity during the presentation of ambiguous faces [F(3,14.6)= 3.15, p = .057;Figs.3C and Fig. 4].”
Quote in the paperNot a substantial claim - Findingown data
There was a main effect of treatment on right amygdala activity in response to happy faces.
“There was a main effect of treatment on right amygdala activity in response to the presentation of happy faces [F(3,15) = 3.44, p = .04;Figs.3B and Fig. 4]”
Quote in the paperNot a substantial claim - Findingown data
There was a main effect of treatment on right amygdala activation during the presentation of geometric shapes.
“There was also a main effect of treatment on right amygdala activation during the presentation of geometric shapes [F(3,15) = 3.56, p = .04;Figs.3D and Fig. 4]”
Quote in the paperNot a substantial claim
- Findingown data
There was no main effect of treatment on left amygdala activity during the presentation of angry, ambiguous, happy, or geometric shape stimuli.
“In regards to left amygdala activity, a LMM revealed no main effect of treatment during the presentation of angry faces [F(3,15.1)= 1.28, p = .32],ambiguous faces [F(3,13.6)= 1.14, p = .37],happy faces [F(3,14) = 2.14, p = .14],or geometric shapes [F(3,14.4)= 1.87, p = .18;Fig. 4].”
Quote in the paperSubstantial claim - Findingown data
The reduction of right amygdala activity after 8IU OPN-OT treatment compared to placebo for ambiguous faces did not survive the FDR corrected significance threshold.
“Exploratory posthoc analyses revealed the reduction of right amygdala activity after 8IU OPN-OT treatment compared to placebo did not survive the FDR corrected significance threshold (p = 0.01; q = .05;revised threshold value of p = .008).”
Quote in the paperNot a substantial claim - Findingown data
The frequency of adverse events was equivalent between treatment groups.
“The frequency of adverse events (e.g., brief dizziness) reported was equivalent between treatment groups (8IU OPT-OT, three reports; 24IU OPT-OT, two reports, IV OT, three reports, placebo, two reports).”
Quote in the paperNot a substantial claim - Findingown data
Plasma OT concentration was significantly increased in all active treatment conditions.
“Plasma OT concentration was significantly increased in all active treatment conditions, with none of the pairwise comparisons between active conditions reaching statistical significance (see Supplementary Material Text and Fig. S3).”
Quote in the paperSubstantial claim - Findingown data
There were no main effects of treatment for any of the emotion > shape COPE value contrasts.
“There were no main effects of treatment for any of the emotion > shape COPE value contrasts (Supplementary Table 1).”
Quote in the paperNot a substantial claim - Findingown data
None of the pairwise comparisons of plasma OT concentration between active treatment conditions reached statistical significance.
“Plasma OT concentration was significantly increased in all active treatment conditions, with none of the pairwise comparisons between active conditions reaching statistical significance (see Supplementary Material Text and Fig. S3).”
Quote in the paperNot a substantial claim - Findingown data
The reduction in right amygdala activity after 8IU OPN-OT compared to placebo for happy faces was not statistically significant after multiple comparison threshold correction.
“however, posthoc comparisons indicated the reduction after 8IU OPN-OT compared to placebo was not statistically significant after multiple comparison threshold correction (p = 0.01; q = .05;revised threshold value of p = .008).”
Quote in the paperNot a substantial claim - Findingown data
Post hoc analyses for right amygdala activation during geometric shapes revealed no significant differences after FDR corrected thresholds.
“however, post hoc analyses revealed no significant differences after FDR corrected thresholds.”
Quote in the paperNot a substantial claim - Findingown data
There was a significant main effect of treatment on right amygdala activation during the presentation of angry faces.
“LMM revealed a significant main effect of treatment on right amygdala activation during the presentation of angry faces [F(3,15.1)= 4.54, p = .019;Figs.3A and Fig. 4].”
Quote in the paperSubstantial claim - Findingown data
In healthy volunteers, 8IU OPN-OT treatment reduces amygdala activation in response to emotional faces compared to placebo.
“In this double-blind, placebo controlled crossover trial in healthy volunteers, we show that 8IU OPN-OT treatment reduces amygdala activation in response to emotional faces compared to placebo.”
- Also stated in: § 4. Discussion · plain
“Specifically, we show that low dose intranasal OT delivered with a Breath Powered device dampens amygdala activity.”
Quote in the paperSubstantial claim - Also stated in: § 4. Discussion · plain
- Findingown data
There was a main effect for the happy faces > angry faces contrast on left amygdala activity.
“There was a main effect for the happy faces > angry faces contrast on left amygdala activity [F(3,14.7)= 4.79, p = .02]”
Quote in the paperNot a substantial claim - Findingown data
No post hoc comparisons for the right amygdala happy faces > angry faces contrast survived FDR corrected thresholds.
“but no posthoc comparisons survived FDR corrected thresholds.”
Quote in the paperNot a substantial claim - Findingown data
Right amygdala activation was significantly reduced in the 8IU OPN-OT treatment condition compared to placebo during angry face processing.
“Follow-up pairwise comparisons (q = .05,revised threshold value of p = .008)indicated that right amygdala activation was significantly reduced in the 8IU OPN-OT treatment condition in comparison to placebo (p = .002).”
Quote in the paperSubstantial claim - Findingcitation
There was no significant relationship between anger ratings and amygdala activity.
“There was no significant relationship between anger ratings and amygdala activity, which indicates that a larger neural network that goes beyond the amyg-dala likely underlies the effect of OT on social cognition (Bethlehem et al., 2013).”
Quote in the paperSubstantial claim - Findingown data
The main effect of treatment on right amygdala activity during the presentation of happy faces was statistically significant.
“These effects may not be specific to negatively valenced social stimuli as the main effect of treatment on right amygdala activity during the presentation of happy faces was also statistically significant, with subsequent posthoc comparisons revealing a reduction of activity after 8IU OPN-OT treatment compared to placebo (however this difference fell short of significance after multiple comparison”
Quote in the paperSubstantial claim - Interpretationown data
The dampening of amygdala activity in response to emotional stimuli occurs via direct intranasal delivery pathways rather than across the blood-brain barrier via systemically circulating OT.
“These data suggest the dampening of amygdala activity in response to emotional stimuli occurs via direct intranasal delivery pathways rather than across the blood-brain barrier via systemically circulating OT.”
Quote in the paperSubstantial claim - Premisecitation
The most common dose with conventional pump-actuated nasal sprays (24IU) has largely been selected due to precedence rather than experimental evidence.
“The most common dose with conventional pump-actuated nasal sprays (24IU) has largely been selected due to precedence, rather than experimental evidence (Quintana et al., 2015a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Quintana et al., 2015a
Not checked in the free run.
- Premisecitation
The amygdala is an important target of OT administration.
“Converging evidence from this field suggests the amygdalaa key brain region for emotion regulation (LeDoux, 2003), processing (Seeley et al., 2007), detection (Ousdal et al., 2008), and vigilance for social cues across sensory modalities (Whalen, 2007) is an important target of OT administration.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
In a previous randomized crossover trial, only the lower 8IU intranasal OT dose attenuated the perception of anger in facial emotion stimuli compared with placebo.
“In comparison with placebo, only the lower 8IU dose was found to attenuate the perception of anger in facial emotion stimuli.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Quintana et al., 2015b
Not checked in the free run.
- Premisecitation
Three potential routes of intranasal OT delivery to the brain have been identified: two direct nose-to-brain pathways and an indirect pathway across the BBB via systemically circulating OT.
“Three potential routes have been identified (Guastella et al., 2013;Quintana et al., 2015a): two direct nose-to-brain pathways and an indirect pathway across the BBB via systematically circulating OT.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Guastella et al., 2013 source
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- cites Quintana et al., 2015a
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- Premisecitation
The IV-OT dosage and infusion rate was chosen to generate peripheral OT concentrations equivalent to OPN-OT, as determined by a pilot pharmacokinetic study and confirmed by the subsequent experimental study.
“The IV-OT dosage and infusion rate was chosen as it generates peripheral OT concentrations that are equivalent to OPN-OT, as determined by a pilot pharmacokinetic study and confirmed by the subsequent experimental study”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Quintana et al., 2015b
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- Premisecitation
Circulating OT does not easily cross the blood-brain barrier due to its relatively large molecular weight.
“First, circulating OT does not easily cross the blood-brain barrier (BBB) due to its relatively large molecular weight (McEwen, 2004).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites McEwen, 2004 source
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- Premisecitation
There is a high density of OT receptors in the amygdala.
“There is a high density of OT receptors in the amygdala (Insel and Shapiro, 1992; but see Freeman et al., 2014).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Insel and Shapiro, 1992
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- cites Freeman et al., 2014 source
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- Interpretationown data
A larger neural network that goes beyond the amygdala likely underlies the effect of OT on social cognition.
“There was no significant relationship between anger ratings and amygdala activity, which indicates that a larger neural network that goes beyond the amyg-dala likely underlies the effect of OT on social cognition (Bethlehem et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bethlehem et al., 2013 source
Not checked in the free run.
- Interpretationreasoning
OT's dampening effect on amygdala activity, regardless of emotional valence, may underlie reported improvements in social behavior and cognition after IN OT via these two levels of action.
“OT's dampening effect on amygdala activity, regardless of emotional valence, may underlie reported improvements in social behavior (Yatawara et al., 2015) and cognition (Davis et al., 2013; Guastella et al., 2010) after IN OT via these two levels of action.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
OT receptors in the amygdala operate by inhibiting amygdala activity via the increase of GABAergic interneuron activity.
“These receptors have been shown to operate by inhibiting amygdala activity via the increase of GABAergic interneuron activity (Knobloch et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Knobloch et al., 2012 source
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- Interpretationown data
The dose-response data reported here suggest that a low dose of OT delivered using a Breath Powered device is sufficient to dampen amygdala activity.
“The dose-response data reported here suggest that a low dose of OT delivered using a Breath Powered device is sufficient to dampen amygdala activity.”
Quote in the paperSubstantial claim - Study design and conductcitation
By adopting this experimental design, any individual differences due to variation in the endogenous OT system are minimized.
“By adopting this experimental design, any individual differences due to variation in the endogenous OT system (Gouin et al., 2010) are minimized.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gouin et al., 2010 source
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- Study design and conductcitation
A strength of this study was the use of a within-subjects design in a homogenous sample to examine amygdala activity.
“Individual differences and context can influence the response to OT administration (Bartz et al., 2011), thus a strength of this study was the use of a within-subjects design in a homogenous sample to examine amygdala activity.”
Quote in the paperSubstantial claim - Interpretationnone given
The generalizability of these results is limited to healthy males.
“Since the generalizability of these results are limited to healthy males, future work is needed to investigate neural responses after intranasal OT administration in healthy females as well as psychiatric populations characterized by social impairments (e.g., ASD).”
Quote in the paperNot a substantial claim - Interpretationown data
Even if OT does travel across the BBB in small amounts, this quantity is not large enough to dampen amygdala activity compared to placebo.
“While there is conflicting evidence on whether peripheral OT can cross the BBB (Modi et al., 2014), our study suggests that even if OT does travel across this barrier in small amounts, this quantity is not large enough to dampen amygdala activity compared to placebo.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Modi et al., 2014 source
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- Study design and conductreasoning
The sample size was relatively small.
“Although the study recruited a similar number of participants consistent with prior OT fMRI research, the sample size was still relatively small necessitating the need for future studies to adopt larger sample sizes, which would provide more robust outcomes as small samples sizes may inflate the issue of spurious findings in oxytocin research (Lane et al., 2016;Leng and Ludwig, 2016).”
Quote in the paperNot a substantial claim - Premisecitation
The nasal cavity can only accommodate about 100 l of liquid per nostril.
“It has been reported the nasal cavity can only accommodate about 100 l of liquid per nostril (Merkus et al., 2003) and a double-dummy design would increase the volume to an unacceptable level.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Merkus et al., 2003 source
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- Classified as probably not a substantial claim. 19
- May combine two claims. 18
- The quote only partly states this claim. 1
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThere were no significant relationships between nasal valve dimensions and right amygdala activation after any of the treatments.
“or between nasal valve dimensions and right amygdala activation after any of the treatments (Supplementary Table 3).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThere was a main effect for the happy faces > angry faces contrast for the right amygdala.
“There was a main effect for the happy faces > angry faces contrast for the right amygdala [F(3,14.7)= 4.46, p = .02]”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).
Findingown dataNo post hoc comparisons for the left amygdala happy faces > angry faces contrast survived FDR corrected thresholds.
“but no posthoc comparisons survived FDR corrected thresholds.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThere were no significant relationships between intensity of anger ratings and right amygdala activations after any of the treatments.
“Finally, there were no significant relationships between intensity of anger ratings and right amygdala activations after any of the treatments (Supplementary Table 2)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIV-OT treatment produced comparable levels of systemic OT exposure with IN-OT administration and did not modulate amygdala activity compared to placebo.
“As IV-OT treatment, which produced comparable levels of systemic OT exposure with IN-OT administration, did not modulate amygdala activity compared to placebo, this study demonstrates that nose-to-brain pathways produce neural effects, suggesting facilitated entry to, or activity in, the brain with at least this form of intranasal delivery.”
- Also stated in: § 4. Discussion · plain
“We found no evidence that 1 IU of peripherally administered OT influences amygdala activity.”
Quote in the paperSubstantial claim- Also stated in: § 4. Discussion · plain
May combine two claims.
Findingown dataPosthoc comparisons revealed a reduction of right amygdala activity after 8IU OPN-OT treatment compared to placebo for happy faces, but this difference fell short of significance after multiple comparison threshold adjustment.
“with subsequent posthoc comparisons revealing a reduction of activity after 8IU OPN-OT treatment compared to placebo (however this difference fell short of significance after multiple comparison threshold adjustment).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationDose-dependent effects of OT on social behavior in animals and humans indicate that lower doses of OT may be more efficacious.
“Dose-dependent effects of OT on social behavior in animals (Benelli et al., 1995;Popik et al., 1992) and humans (Cardoso et al., 2013;Hall et al., 2012;Quintana et al., 2015b) that indicate that lower doses of OT may be more efficacious warrants further research.”
Quote in the paperSubstantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
Study design and conductown dataParticipants were randomized to one of four treatment sequences using a four-period four-treatment Latin square method.
“Participants were randomized to one of four treatment sequences, using a four-period four-treatment Latin square method (ACDB-BDCA-CBAD-DABC in a 4:4:4:4 ratio).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataThe trial used a randomized, placebo-controlled, double-blind, double-dummy, four-period crossover design.
“Participants received 8IU OPN-OT intranasally, 24IU OPN-OT intranasally, OT delivered intravenously (1IU), and placebo in a randomized, placebo-controlled, double-blind, double-dummy, four-period crossover design.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationThere is both animal and human research to suggest systemic OT can influence social behavior and cognition.
“There is both animal (Popik et al., 1992) and human (Hollander et al., 2007(Hollander et al., , 2003) ) research to suggest systemic OT can influence social behavior and cognition”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationThe mechanisms underlying nose-to-brain OT activity are poorly understood, particularly regarding potential peripheral effects, required dosage, and the origin of observed increases in CSF OT after intranasal administration.
“However, the mechanisms underlying nose-to-brain OT activity are poorly understood (Quintana et al., 2016), particularly in respect to potential peripheral effects, required dosage (Leng and Ludwig, 2016), and the origin (i.e., endogenous vs. exogenous) of observed increases in CSF OT concentrations after intranasal administration (Neumann et al., 2013).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIntranasal administration of OT improves the accuracy of social information appraisal, the encoding of social memories, and the retrieval of social cues.
“For example, intranasal administration of OT improves the accuracy of social information appraisal, the encoding of social memories, and the retrieval of social cues (Guastella and MacLeod, 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Guastella and MacLeod, 2012 source
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PremisecitationIn the previous trial, no such effects were observed with the intravenous route despite equivalent peripheral OT concentrations, providing behavioral evidence that OT travels to the brain via nose-to-brain pathways and that a lower dose may be more optimal than the traditional dosage.
“As no such effects were observed with the intravenous route, despite equivalent peripheral OT concentrations, this provided behavioral evidence that OT travels to the brain via nose-to-brain pathways and that a lower dose may be more optimal than the traditional dosage usually administered, at least when delivered with the novel device.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Quintana et al., 2015b
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Study design and conductown dataAn independent statistician provided the randomization code, and both participants and research team were blinded to treatment using visually matching devices and IV apparatus.
“An independent statistician (Smerud Medical Research International AS, Oslo, Norway) provided the randomization code, and both the participants and research team were blinded to treatment using visually matching devices and IV apparatus during data collection.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationA pragmatic approach guided by prior fMRI OT research was taken for sample size determination.
“A pragmatic approach guided by prior fMRI OT research (Domes et al., 2007(Domes et al., , 2010;;Kirsch et al., 2005;Lischke et al., 2012) was taken for sample size determination reflecting the phase 1 status of OT administration using the Breath Powered device and the complex nature of the study design.”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataTwo participants withdrew after enrollment, and their data were not included in the analyses.
“Two participants withdrew after enrollment [1 withdrew after the first session (Placebo) and the other withdrew after completing three sessions (8IU OPN-OT, IV-OT, Placebo)].Data from these participants are not included in the analyses.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThe data are consistent with recently reported results from the same experiment suggesting that a low dose of OT delivered by a Breath Powered device modulates the perception of anger in neutral facial stimuli.
“The data are also consistent with recently reported results from the same experiment suggesting that a low dose of OT delivered by a Breath Powered device modulates the perception of anger in neutral facial stimuli (Quintana et al., 2015b).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Quintana et al., 2015b
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Interpretationown dataThe tested type of intranasal OT delivery, but not peripherally delivered OT that produces similar blood levels, replicates prior findings of reduced right amygdala activation in response to emotional stimuli after OT treatment.
“Results indicate that the tested type of intranasal OT delivery -but not peripherally delivered OT that produces similar blood levels -replicates prior findings of reduced right amygdala activation in response to emotional stimuli after OT treatment (Domes et al., 2007;Labuschagne et al., 2010;Petrovic et al., 2008).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThe data are in line with animal research that has associated a lower OT dose with stronger increases in social recognition.
“Furthermore, the data are in line with animal research that has associated a lower OT dose with stronger increases in social recognition (Benelli et al., 1995;Popik et al., 1992), which is pertinent given the crucial role of the amygdala in social cognition and behavior.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Benelli et al., 1995 source
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- cites Popik et al., 1992 source
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- Rests on an assumption: The amygdala plays a crucial role in social cognition and behavior.
Classified as probably not a substantial claim.
Study design and conductcitationPost hoc tests were adjusted for multiple comparisons using a 5% false discovery rate.
“Posthoc tests were performed to compare each treatment condition, with the adjustment of critical p values to correct for multiple comparisons using a 5% false discovery rate (FDR; Benjamini and Hochberg, 1995).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Benjamini and Hochberg, 1995 source
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PremisecitationIV-OT administration can plausibly influence central activity through the stimulation of peripheral OT receptors or via small amounts of OT crossing the BBB.
“IV-OT administration can plausibly influence central activity through the stimulation of peripheral OT receptors (Leng and Ludwig, 2016) or via small amounts of OT crossing the BBB (Neumann et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown dataThe observed reductions in right amygdala activation during the presentation of both negatively and positively valenced stimuli after intranasal OT treatment and the additional main effect of treatment on amygdala reactivity to shapes are consistent with the hypothesis that intranasal OT delivery has two levels of action: a bottom-up effect that facilitates approach-related behaviors and a top-dow
“The observed reductions in right amygdala activation during the presentation of both negatively and positively valenced stimuli after intranasal OT treatment and the additional main effect of treatment on amygdala reactivity to shapes -which did not reveal any posthoc differences between groups but were in the same direction as the other analyses -are consistent with the hypothesis that intranasal”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Quintana et al., 2015a
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- cites Kemp and Guastella, 2011 source
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- cites Bartz et al., 2011
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InterpretationreasoningThis study demonstrates that nose-to-brain pathways produce neural effects, suggesting facilitated entry to, or activity in, the brain with at least this form of intranasal delivery.
“As IV-OT treatment, which produced comparable levels of systemic OT exposure with IN-OT administration, did not modulate amygdala activity compared to placebo, this study demonstrates that nose-to-brain pathways produce neural effects, suggesting facilitated entry to, or activity in, the brain with at least this form of intranasal delivery.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationOutputs to the amygdala via the olfactory bulbs or transport through brain extracellular fluid from olfactory bulb and brainstem delivery sites after intranasal delivery may facilitate reductions in amygdala activity via a local GABAergic circuit.
“Outputs to the amygdala via the olfactory bulbs (Sosulski et al., 2012) or transport through brain extracellular fluid (Neumann et al., 2013) from olfactory bulb and brainstem delivery sites after intranasal delivery may facilitate these reduc-tions in amygdala activity via a local GABAergic circuit.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationThe olfactory bulbs and brainstem are the two first central destinations for intranasal OT delivery.
“The olfactory bulbs and brainstem are the two first central destinations for intranasal OT delivery (Quintana et al., 2015a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Quintana et al., 2015a
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOther studies have reported similar results after administration of 24 IU, but dosages are difficult to compare between experiments as these studies used traditional nasal spray devices to administer OT.
“Of note, other studies have reported similar results after administration of 24 IU (Domes et al., 2007;Kanat et al., 2015;Labuschagne et al., 2010), however, the dosages are difficult to compare between experiments as these studies used traditional nasal spray devices to administer OT.”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Interpretationown dataThis result provides additional evidence to suggest a lower intranasal OT dose may better facilitate the modulation of social cognition and behavior and that peripheral actions of OT do not appear to have any significant neural corollaries.
“This result provides additional evidence to suggest a lower intranasal OT dose may better facilitate the modulation of social cognition and behavior and that peripheral actions of OT do not appear to have any significant neural corollaries.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.
InterpretationcitationCross reactivity with AVP receptors may offset the activation of OT receptors and heighten reactivity of the hypothalamic-pituitary-adrenal axis, which may explain why an effect was found with the 8IU dose but not the 24IU dose.
“First, cross reactivity with AVP receptors may offset the activation of OT receptors (Neumann and Landgraf, 2012) and heighten reactivity of the hypothalamic-pituitary-adrenal axis (Legros, 2001).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Neumann and Landgraf, 2012
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- cites Legros, 2001 source
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May combine two claims.
PremisecitationIndividual differences and context can influence the response to OT administration.
“Individual differences and context can influence the response to OT administration (Bartz et al., 2011), thus a strength of this study was the use of a within-subjects design in a homogenous sample to examine amygdala activity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bartz et al., 2011
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSmall sample sizes may inflate the issue of spurious findings in oxytocin research.
“which would provide more robust outcomes as small samples sizes may inflate the issue of spurious findings in oxytocin research (Lane et al., 2016;Leng and Ludwig, 2016).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningThe present study design did not include a comparison between the Breath Powered device and a traditional nasal spray device.
“The present study design also did not include a comparison between the Breath Powered device and a traditional nasal spray device.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Research has not yet evaluated amygdala activity after intravenous delivery with an intranasal OT comparator.
“however, research has not yet evaluated amygdala activity after intravenous delivery with an intranasal OT comparator.”
The paper relies on this without support.
These findings are the first to report direct comparison of intranasal delivery to systemic delivery of OT.
“These findings are the first to report direct comparison of intranasal delivery to systemic delivery of OT.”
The paper relies on this without support.
This study presents the first data to evaluate neural activity after different intranasal OT doses, in addition to an IV OT administration arm to control for peripheral effects.
“We present the first data to evaluate neural activity after different intranasal OT doses, in addition to an IV OT administration arm to control for peripheral effects.”
The paper relies on this without support.
The amygdala plays a crucial role in social cognition and behavior.
“which is pertinent given the crucial role of the amygdala in social cognition and behavior.”
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?
The insula and amygdala seem to be key target regions in the brain, with oxytocin modulating amygdala responsiveness to emotional faces or social stimuli in general.
“In this context, the insula17 as well as the amygdala seem to be key target regions in the brain, with oxytocin modulating amygdala responsiveness to emotional faces18–22 or social stimuli in general23.”
From Randomized clinical trial shows no substantial modulation of empathy-related neural activation by intranasal oxytocin in autism (2021) · cites this paper as [19]
Neural evidence from the same data set suggested that intranasal 8IU oxytocin (but not the other oxytocin treatments) reduced amygdala activation during the presentation of social stimuli.
“Moreover, neural evidence from the same data set also suggested that intranasal 8IU (but not the other oxytocin treatments) reduced amygdala activation during the presentation of social stimuli.41”
The present result adds to existing behavioral and neural evidence that lower oxytocin doses delivered with the Breath Powered device may be more efficacious, at least for single administration trials.
“The present result also adds to existing behavioral40 and neural41 evidence that lower oxytocin doses delivered with the Breath Powered device may be more efficacious, at least for single administration trials.”
Statistics recomputed
Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.
- ConsistentF(3, 15.1) = 4.54reported p = .019 · recomputed p = .019
“F(3,15.1)= 4.54, p = .019”
- ConsistentF(3, 15) = 3.44reported p = .04 · recomputed p = .044
“F(3,15) = 3.44, p = .04”
- ConsistentF(3, 14.6) = 3.15reported p = .057 · recomputed p = .057
“F(3,14.6)= 3.15, p = .057”
- ConsistentF(3, 15) = 3.56reported p = .04 · recomputed p = .040
“F(3,15) = 3.56, p = .04”
- ConsistentF(3, 14.7) = 4.46reported p = .02 · recomputed p = .020
“F(3,14.7)= 4.46, p = .02”
- ConsistentF(3, 15.1) = 1.28reported p = .32 · recomputed p = .317
“F(3,15.1)= 1.28, p = .32”
- ConsistentF(3, 13.6) = 1.14reported p = .37 · recomputed p = .367
“F(3,13.6)= 1.14, p = .37”
- ConsistentF(3, 14) = 2.14reported p = .14 · recomputed p = .141
“F(3,14) = 2.14, p = .14”
- ConsistentF(3, 14.4) = 1.87reported p = .18 · recomputed p = .181
“F(3,14.4)= 1.87, p = .18”
- ConsistentF(3, 14.7) = 4.79reported p = .02 · recomputed p = .016
“F(3,14.7)= 4.79, p = .02”
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.
Stated trial duration exceeds the entire task duration
MinorFive blocks of 20 trials at approximately 140 seconds per trial would take about 233 minutes, but the task and fMRI sequence is stated to last 21 minutes.
“The social cognition task consisted of five blocks of 20 trials (Fig. 2).Each trial of approximately 140 s duration”
“The social cognition task and fMRI sequence began 40 min after treatment administration, lasting 21 min (Fig. 2).”
The citation lists haven’t been fetched yet
References 70 · Cited by 102
- Authors
- Quintana, D. S., Westlye, L. T., Alnæs, D., Rustan, Ø. G., Kaufmann, T., Smerud, K. T., Mahmoud, R. A., Djupesland, P. G., & Andreassen, O. A.
- Affiliations
- Oslo University Hospital (NO)
- Smerud Medical Research (Norway) (NO)
- OptiNose (United States) (US)
- OptiNose (Norway) (NO)
- Corresponding author
- Andreassen, Ole A.
- ORCID
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 69
- Pages
- 180-188
- ISSN
- 0306-4530 (ISSN-L)
- OpenAlex
- W2341490827
- Cited by
- 102
- References
- 70
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 11 · 2023: 8 · 2022: 12 · 2021: 15 · 2020: 10 · 2019: 8 · 2018: 17 · 2017: 11 · 2016: 1
- FWCI
- 19.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Psychoneuroendocrinology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc-nd)
- Funders
- Universitetet i Oslo
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Face Recognition and Perception
- Keywords
- intranasal oxytocin, amygdala activation, emotional face processing, dose-response relationship, intravenous oxytocin, blood-brain barrier, emotional stimuli
- MeSH terms
- Facial Recognition, Administration, Intranasal, Adult, Amygdala, Blood-Brain Barrier, Brain, Cognition, Dose-Response Relationship, Drug, Double-Blind Method, Emotions, Facial Expression, Humans, Magnetic Resonance Imaging, Male, Oxytocin, Social Behavior, Cross-Over Studies, Young Adult
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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