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Cited by 209Neuroendocrine regulation and behaviorAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesNeuropeptides and Animal Physiology

Modulation of Resting-State Amygdala-Frontal Functional Connectivity by Oxytocin in Generalized Social Anxiety Disorder

Open access
Dodhia, Sonam, Hosanagar, Avinash, Fitzgerald, Daniel A, Labuschagne, Izelle, Wood, Amanda G, Nathan, Pradeep J, Phan, K Luan·2014·Neuropsychopharmacology
DOI 10.1038/npp.2014.53PMC PMC4104324
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Abstract

Generalized social anxiety disorder (GSAD) is characterized by aberrant patterns of amygdala-frontal connectivity to social signals of threat and at rest. The neuropeptide oxytocin (OXT) modulates anxiety, stress, and social behaviors. Recent functional neuroimaging studies suggest that these effects are mediated through OXT's effects on amygdala reactivity and/or amygdala-frontal connectivity. The aim of the current study was to examine OXT's effects on amygdala-frontal resting-state functional connectivity (rsFC) in GSAD patients and healthy controls (HCs). In a randomized, double-blind, cross-over design, 18 GSAD and 18 HC participants received intranasal OXT (24 IU or 40.32 μg) or placebo (PBO) before resting-state functional magnetic resonance imaging. In individuals with GSAD, OXT enhanced rsFC of the left and right amygdala with rostral anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC), and in doing so, reversed (ie, 'normalized') the reduced amygdala-frontal connectivity observed relative to HCs evident on PBO. Higher social anxiety severity in GSAD subjects correlated with lower amygdala-ACC/mPFC connectivity on PBO and higher social anxiety also correlated with greater enhancement in amygdala-frontal connectivity induced by OXT. These findings show that OXT modulates a neural circuit known for social threat processing and emotion regulation, suggesting a neural mechanism by which OXT may have a role in the pathophysiology and treatment of social anxiety disorder.

AI snapshot

Written from the paper’s full text.

TL;DR

In patients with generalized social anxiety disorder (GSAD), intranasal oxytocin enhanced resting-state amygdala connectivity with rostral ACC/mPFC, reversing the reduced baseline connectivity seen relative to healthy controls. Higher social anxiety severity correlated with lower baseline amygdala–ACC/mPFC connectivity and greater oxytocin-induced enhancement.

Key findings

  • Significant drug-by-group interactions were found for left amygdala–rostral ACC (BA 32; peak [12, 46, 0], F(1,65)=11.16, p=0.001; cluster 1008 mm³) and right amygdala–rostral mPFC (BA 10; peak [10, 60, 4], F(1,65)=12.46, p=0.001; cluster 640 mm³).
  • On placebo, GSAD patients showed reduced left amygdala–ACC/mPFC connectivity versus healthy controls (t(1,33)=−2.58, p=0.015); right amygdala–mPFC/ACC reduction was trend-level (t(1,33)=1.911, p=0.065).
  • Oxytocin enhanced left amygdala–ACC/mPFC connectivity in GSAD at trend level (t(1,17)=2.06, p=0.055) and right amygdala–mPFC/ACC connectivity significantly (t(1,17)=4.889, p<0.001); effects were opposite in healthy controls (left t(1,16)=−2.63, p=0.018; right t(1,16)=−1.813, p=0.089). On oxytocin, GSAD patients had greater connectivity than controls (left t(1,33)=2.47, p=0.019; right t(1,33)=3.135, p=0.004).
  • In GSAD, baseline right amygdala–mPFC/ACC connectivity negatively correlated with LSAS-Social score (r=−0.504, p=0.033); left amygdala–ACC/mPFC correlations were trend-level (LSAS-Social r=−0.410, p=0.091; LSAS-Total r=−0.422, p=0.081). Oxytocin-induced change correlated with LSAS-Social at trend level (left r=0.429, p=0.076; right r=0.407, p=0.094).

Methods

  • Randomized, double-blind, placebo-controlled, counterbalanced within-subjects crossover: 18 GSAD and 18 healthy control right-handed males (GSAD 29.9±10.2 years; HC 29.4±9.0 years; age range 19–55); one HC was excluded for poor data quality. Participants received intranasal oxytocin (24 IU or 40.32 mg) or placebo 45 min before resting-state fMRI, separated by a 1-week washout.
  • Resting-state fMRI: eyes closed, 3 min 20 s, 3T Siemens Tim Trio. Seed-based connectivity used left and right amygdala AAL ROIs with SPM8 and CONN toolbox; preprocessing included slice-time correction, realignment, normalization, smoothing, and CompCor noise removal.
  • Analysis: whole-brain voxel-wise repeated-measures ANOVA for drug, group, and drug-by-group; a priori mPFC/ACC mask; cluster threshold p<0.005 with ≥44 voxels (352 mm³) for family-wise error α<0.05; post hoc t-tests and Pearson correlations with LSAS.

Limitations

  • Stated: resting-state only, so task-related emotion processing/regulation effects remain unknown; only males were studied, so findings may not generalize to women; the neurochemical mechanism by which intranasal oxytocin affects resting-state amygdala connectivity cannot be identified.
  • Stated: small sample and short scan duration (3 min 20 s) increase Type II error risk; the placebo condition may not represent a true baseline; resting-state scans typically followed emotional face-processing scans, which could affect resting-state measures; acute pharmaco-fMRI limits mechanistic, clinical-outcome, and test-retest interpretation.
  • Evident: one healthy control was excluded for poor data quality; all participants were male, non-smokers, and not on medication, limiting generalizability; several key effects are reported only at trend level (p=0.055–0.094).

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

Integrity signals

Registry

Crossref · 10.1038/npp.2014.53

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 28 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    On OXT alone, GSAD patients exhibited greater right amygdala-mPFC/ACC resting-state connectivity relative to HCs (p=0.004).

    “GSAD patients exhibited greater right amygdala-mPFC/ACC connectivity relative to HCs on OXT alone t(1,33) ¼ 3.135, p ¼ 0.004”
    Quote in the paperSubstantial claim
  • Findingown data

    In GSAD patients, higher social anxiety severity (LSAS-Social) correlated with lower left amygdala-ACC/mPFC connectivity at baseline (on PBO) at trend level (r=-0.410, p=0.091).

    “At baseline (on PBO), there were trend-level negative correlations between the left amygdala- ACC/mPFC connectivity and LSAS-Social score (r ¼ À 0.410, p ¼ 0.091) as well as LSAS-Total scores (r ¼ À 0.422, p ¼ 0.081) in GSAD patients”
    Quote in the paperNot a substantial claim
  • Findingown data

    In GSAD patients, OXT compared with PBO enhanced resting-state functional connectivity of the right amygdala with rostral mPFC/ACC significantly (p<0.001).

    “OXT enhanced right amygdala-mPFC/ACC connectivity significantly in GSAD patients, t(1,17) ¼ 4.889, po0.001”
    • Also stated in: § Abstract · plain
      “In individuals with GSAD, OXT enhanced rsFC of the left and right amygdala with rostral anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC)”
    Quote in the paperSubstantial claim
  • Findingown data

    In HCs, OXT compared with PBO reduced right amygdala-mPFC/ACC resting-state connectivity at trend level (p=0.089).

    “an effect opposite in HCs, t(1,16) ¼ À 1.813, p ¼ 0.089”
    Quote in the paperNot a substantial claim
  • Findingown data

    There was a significant drug-by-group interaction in resting-state functional connectivity between the left amygdala and rostral ACC/mPFC (F(1,65)=11.16, p=0.001).

    “A significant drug-by-group interaction in rsFC was observed between the left amygdala and the rostral ACC (Brodmann Area (BA) 32) (MNI peak [12, 46, 0], F(1,65) ¼ 11.16, p ¼ 0.001)”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 16
  • May combine two claims. 12
  • The quote only partly states this claim. 1

  • Classified as probably not a substantial claim.

    Premisecitation

    OXT's effects on anxiety and social behavior are mediated through OXT's effects on amygdala reactivity and/or amygdala-frontal connectivity.

    “Recent functional neuroimaging studies suggest that these effects are mediated through OXT's effects on amygdala reactivity and/or amygdala-frontal connectivity.”
    • Also stated in: § INTRODUCTION · boosted
      “In keeping with this hypothesis, imaging studies in healthy human subjects have shown that OXT attenuates amygdala response to faces showing anger (Domes et al, 2007) and to fear conditioned socially relevant faces (Petrovic et al, 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Domes et al, 2007 source

      Not checked in the free run.

    • cites Petrovic et al, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxytocin (OXT) modulates anxiety, stress, and social behaviors.

    “The neuropeptide oxytocin (OXT) modulates anxiety, stress, and social behaviors.”
    • Also stated in: § INTRODUCTION · boosted
      “In humans, OXT has been demonstrated to have a role in social memory, emotion perception, and empathy (Bartz et al, 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bartz et al, 2011

      Not checked in the free run.

    • cites Carter et al, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The rACC/mPFC may have a role in regulating the processing of emotions, and this role may be compromised in GSAD patients.

    “This suggests that the rACC/mPFC may have a role in regulating the processing of emotions, and that this role may be compromised in GSAD patients (Klumpp et al, 2013b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Klumpp et al, 2013b

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Reduced left amygdala-rACC connectivity in GSAD patients at rest may indicate an abnormal threat-emotion processing circuit and may be a marker of the pathophysiology of GSAD at rest and during threat perception.

    “The reduced left amygdala-rACC connectivity we found in GSAD patients at resting state may indicate an abnormal threat-emotion processing circuit in these patients at baseline and may be a marker of the pathophysiology of GSAD at rest and during threat perception (Prater et al, 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Prater et al, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    OXT modulates a neural circuit known for social threat processing and emotion regulation, suggesting a neural mechanism by which OXT may have a role in the pathophysiology and treatment of social anxiety disorder.

    “These findings show that OXT modulates a neural circuit known for social threat processing and emotion regulation, suggesting a neural mechanism by which OXT may have a role in the pathophysiology and treatment of social anxiety”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The study used a randomized, double-blind, placebo-controlled, cross-over design.

    “In a randomized, double-blind, cross-over design, 18 GSAD and 18 HC participants received intranasal OXT (24 IU or 40.32 mg) or placebo (PBO) before resting-state functional magnetic resonance imaging.”
    • Also stated in: § Study Design and Drug Administration · plain
      “The current study was a within-subjects, randomized, double-blind, PBO-controlled, counterbalanced study.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The study was approved by the Standing Committee on Ethics in Research involving Humans of Monash University and all subjects provided written informed consent.

    “This study was approved by the Standing Committee on Ethics in Research involving Humans of Monash University and all the subjects provided written informed consent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    OXT may have a role in ameliorating abnormalities associated with emotion regulation pathways in GSAD observed at rest, suggesting a neural mechanism by which OXT may exert its effects acutely.

    “Our findings of enhanced connectivity suggest that OXT may have a role in ameliorating abnormalities associated with emotion regulation pathways in GSAD observed at rest (Prater et al, 2013), suggesting a neural mechanism by which OXT may exert its effects acutely.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Prater et al, 2013 source

      Not checked in the free run.

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

    Study design and conductnone given

    Averaged scan-to-scan head motion was incorporated as covariates in the fMRI analyses at the second level.

    “averaged scan-to-scan head motion was incorporated as covariates in the fMRI analyses at the second level.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Some evidence suggests OXT can be an effective treatment for GSAD.

    “Interestingly, some evidence has suggested that OXT can be an effective treatment for GSAD (Guastella et al, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Guastella et al, 2009 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Family-wise error correction at alpha<0.05 was achieved with a voxel threshold of p<0.005 and a cluster size of at least 44 voxels.

    “a family-wise error correction at ao0.05 is achieved with a voxel threshold of po0.005 and a cluster size of at least 44 voxels (352 mm 3 ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Head movement did not differ between groups or between sessions.

    “no between-group differences in movement were observed for either maximum total movement (GSAD vs HC on OXT: p ¼ 0.360; SAD vs HC on PBO: p ¼ 0.342) or average movement between scans (GSAD vs HC on OXT: p ¼ 0.664; GSAD vs HC on PBO: p ¼ 0.924).”
    • Also stated in: § RESULTS · plain
      “Neither group showed session differences in either maximum total (OXT vs PBO in GSAD: p ¼ 0.662; OXT vs PBO in HC: p ¼ 0.229) or average movement between scans (OXT vs PBO in GSAD: p ¼ 0.570; OXT vs PBO in HC: p ¼ 0.563).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    GSAD diagnosis was determined by the Clinical International Diagnostic Interview (CIDI) version 2.1 and the Liebowitz Social Anxiety Scale (LSAS) total score, and confirmed with a physician interview.

    “A GSAD diagnosis was determined by the Clinical International Diagnostic Interview (CIDI) version 2.1 (WHO, 1997) and the Liebowitz Social Anxiety Scale (LSAS) total score (Liebowitz, 1987), and the diagnosis was confirmed with a physician interview.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites WHO, 1997

      Not checked in the free run.

    • cites Liebowitz, 1987 source

      Not checked in the free run.

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

    Study design and conductown data

    Data from one HC participant were excluded due to poor quality of data collected.

    “Data from one HC participant were excluded due to poor quality of data collected.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All subjects met minimum movement threshold of <3 mm in any direction to be included in the analyses.

    “All subjects met minimum movement threshold of o3 mm in any direction to be included in the analyses.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Oxytocin has been shown to have differential effects on emotional responding in males and females.

    “Second, OXT has been shown to have differential effects on emotional responding in males and females (Domes et al, 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Domes et al, 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    The observations of enhanced connectivity may be pertinent in other disorders associated with amygdala-mPFC disruption and associated social dysfunction, such as depression, autism, and schizophrenia.

    “These observations of enhanced connectivity may be pertinent in other disorders associated with amygdala-mPFC disruption and associated social dysfunction like depression, autism, and schizophrenia.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The study explored oxytocin's effect only in males at rest, so further studies are needed to see whether the findings generalize to women.

    “Our study explored OXT's effect only in males at rest, thus further studies are needed to see whether our findings would generalize to women.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Interpretations about mechanisms from acute placebo-controlled pharmacological fMRI studies are limited.

    “while acute PBOcontrolled pharmacological fMRI studies provide insight into the effects OXT on rsFC, interpretations about mechanisms are limited and additional research is needed to determine how these connectivity patterns relate to clinical outcomes or to underlying dysfunctional processes, and to measure test-retest reliability.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The authors had previously shown that oxytocin enhances amygdala connectivity to rostral anterior cingulate cortex at rest in healthy volunteers.

    “We had previously shown that OXT enhances amygdala connectivity to rostral ACC at rest in healthy volunteers (Sripada et al, 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sripada et al, 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). The quote only partly states this claim.

    Interpretationreasoning

    The therapeutic benefit of oxytocin in autism may be due to improved amygdala-mPFC connectivity.

    “This therapeutic benefit may be due to improved amygdala-mPFC connectivity.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    The resting-state scans typically occurred after the emotional faces processing scans, which could exert effects on the resting-state condition, though this is partly mitigated by the placebo-controlled design.

    “The design also involved the resting-state scans typically occurring after the emotional faces processing scans, which could exert effects on the resting-state condition; however, this is partly mitigated by our PBO-controlled design.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Previous studies have shown that oxytocin receptors in the amygdala potentiate GABAergic inhibition.

    “Previous studies have shown that OXT receptors in the amygdala potentiate GABAergic inhibition (ie, Huber et al, 2005;Viviani et al, 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Huber et al, 2005 source

      Not checked in the free run.

    • cites Viviani et al, 2011 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The current design does not allow disambiguation of the effect of placebo, so the baseline measure may not represent a true baseline and would more accurately be interpreted as functional connectivity under placebo.

    “It should be noted the current design does not allow us to disambiguate the effect of PBO and thus the 'baseline' measure may not represent a true baseline and would more accurately be interpreted as functional connectivity under PBO.”
    Quote in the paperNot a substantial claim
24 of 24

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Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Left-amygdala interaction peak disagrees with Table 2

    Major

    The results give the left-amygdala-ACC interaction peak as [12, 46, 0] with F=11.16. Table 2 lists the corresponding ACC cluster at [−10, 42, 6] with F=11.81; the reported cluster volumes agree at 1008 mm3 and 126 eight-mm3 voxels, indicating these are the same cluster.

  • Both baseline correlations are called significant although the left is trend-level

    Minor

    The discussion describes significant negative baseline correlations for both amygdala seeds. The results report the left-sided LSAS-Social correlation as trend-level (p=0.091); only the right-sided correlation is significant.

  • Left-sided connectivity increase is called significant despite a trend-level result

    Minor

    The results explicitly describe the OXT-related increase in left amygdala-ACC/mPFC connectivity in GSAD as trend-level (p=0.055), whereas the discussion calls increases on both the left and right significant.

  • Group ages are reversed between the text and Table 1

    Minor

    The text assigns the 29.9-year mean age to GSAD and the 29.4-year mean to healthy controls, while Table 1 assigns those values to the opposite groups.

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Authors
Dodhia, S., Hosanagar, A., Fitzgerald, D. A., Labuschagne, I., Wood, A. G., Nathan, P. J., & Phan, K. L.
Affiliations
  • University of Illinois Chicago (US)
  • University of Michigan (US)
  • Monash University (AU)
  • University of Cambridge (GB)
Corresponding author
Phan, K Luan
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2014-03-05
Volume
39
Issue
9
Pages
2061-2069
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2014.53
PMC
PMC4104324
OpenAlex
W1981467710
Semantic Scholar
08ef1c1b11185cca4eace73366ef13cbe83699c3
Cited by
209
References
54
Citations by year
2026: 7 · 2025: 9 · 2024: 9 · 2023: 10 · 2022: 14 · 2021: 13 · 2020: 31 · 2019: 19 · 2018: 19 · 2017: 26 · 2016: 22 · 2015: 22 · 2014: 6
FWCI
37.59
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research Bank (Australian Catholic University) (submittedVersion)
  • Own your potential (DEAKIN) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Funders
  • Brain and Behavior Research Foundation
  • National Alliance for Research on Schizophrenia and Depression
  • Australian Rotary Health
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
generalized social anxiety disorder, oxytocin, resting-state functional connectivity, rostral anterior cingulate cortex, medial prefrontal cortex, emotion regulation, intranasal oxytocin
MeSH terms
Administration, Intranasal, Adult, Amygdala, Anxiety Disorders, Central Nervous System Agents, Double-Blind Method, Frontal Lobe, Humans, Functional Laterality, Magnetic Resonance Imaging, Male, Middle Aged, Neural Pathways, Oxytocin, Psychiatric Status Rating Scales, Rest, Social Perception, Cross-Over Studies, Young Adult

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