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Cited by 131Neuroendocrine regulation and behaviorAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesFace Recognition and Perception

Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder

Open access
Gorka, Stephanie M, Fitzgerald, Daniel A, Labuschagne, Izelle, Hosanagar, Avinash, Wood, Amanda G, Nathan, Pradeep J, Phan, K Luan·2015·Neuropsychopharmacology
DOI 10.1038/npp.2014.168PMC PMC4443941
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Abstract

The neuropeptide oxytocin (OXT) is thought to attenuate anxiety by dampening amygdala reactivity to threat in individuals with generalized social anxiety disorder (GSAD). Because the brain is organized into networks of interconnected areas, it is likely that OXT impacts functional coupling between the amygdala and other socio-emotional areas of the brain. Therefore, the aim of the current study was to examine the effects of OXT on amygdala functional connectivity during the processing of fearful faces in GSAD subjects and healthy controls (HCs). In a randomized, double-blind, placebo (PBO)-controlled, within-subjects design, 18 HCs and 17 GSAD subjects performed a functional magnetic resonance imaging task designed to probe amygdala response to fearful faces following acute intranasal administration of PBO or OXT. Functional connectivity between the amygdala and the rest of the brain was compared between OXT and PBO sessions using generalized psychophysiological interaction analyses. Results indicated that within individuals with GSAD, but not HCs, OXT enhanced functional connectivity between the amygdala and the bilateral insula and middle cingulate/dorsal anterior cingulate gyrus during the processing of fearful faces. These findings suggest that OXT may have broad pro-social implications such as enhancing the integration and modulation of social responses.

AI snapshot

Written from the paper’s full text.

TL;DR

In a randomized, double-blind, placebo-controlled within-subjects fMRI study, intranasal oxytocin enhanced left amygdala functional connectivity with bilateral insula and middle cingulate/dorsal anterior cingulate gyrus during fearful-face processing in generalized social anxiety disorder (GSAD) but not healthy controls. On placebo GSAD showed reduced connectivity relative to controls; oxytocin reversed this pattern.

Key findings

  • GSAD subjects had significantly less left amygdala functional connectivity than healthy controls on placebo to bilateral insula and mid/dACC; on oxytocin this group difference was no longer evident, and GSAD subjects showed enhanced connectivity relative to controls.
  • Significant group × drug interactions for left amygdala connectivity: right insula MNI (44, 6, −2), Z = 4.16, k = 627, p < 0.05 corrected; left insula MNI (−46, 12, −8), Z = 3.84, k = 129, p < 0.05 corrected; mid/dACC MNI (−12, 0, 42), Z = 3.70, k = 336, p < 0.05 corrected.
  • A group × drug interaction on left amygdala reactivity to fearful faces was confirmed: peak MNI (−24, −2, −22), Z = 2.77, k = 81, p < 0.05 small-volume corrected, such that oxytocin attenuated/normalized hyperactive amygdala reactivity in GSAD.
  • Greater left amygdala reactivity was associated with greater oxytocin-induced change in left amygdala–right insula connectivity (r = 0.46, p = 0.01); within GSAD, greater state anxiety on placebo correlated with less left amygdala–mid/dACC connectivity on placebo (r = −0.56, p = 0.02), and greater LSAS performance scores correlated with greater oxytocin-induced change in left amygdala–left insula connectivity (r = 0.55, p = 0.03).

Methods

  • Randomized, double-blind, placebo-controlled, within-subjects design: 36 right-handed male volunteers enrolled (18 HC, 18 GSAD); after exclusions for poor scan quality, 17 HC and 16 GSAD were analyzed (Table 1). Participants received intranasal oxytocin (24 IU/40.32 mg) or placebo in two fMRI sessions separated by at least 7 days.
  • During fMRI, participants completed an emotional face matching task with fearful, angry, and happy faces and a shape control task; analyses focused on fearful faces versus shapes.
  • Functional connectivity was examined using generalized psychophysiological interaction (gPPI) analyses with left and right amygdala seeds, followed by second-level 2 (group) × 2 (drug) ANOVAs; a priori region-of-interest analyses used an anterior/middle cingulate and bilateral insula mask with cluster-based correction.

Limitations

  • The paper states the sample size was small, likely reducing statistical power; the sample was restricted to males and may not generalize to females; and gPPI analyses are correlational, so directionality between amygdala and insula/mid/dACC cannot be inferred.
  • The paper also states that the functional relevance of oxytocin’s effects on amygdala reactivity and connectivity remains unclear, and future work is needed to link these effects to functional outcomes and to test other social stimuli and GABAergic mechanisms.
  • Evident from the text: this is a secondary analysis of existing fMRI data from a prior study, and the abstract reports 18 HCs and 17 GSAD subjects while the Methods and Table 1 report 17 HCs and 16 GSAD after exclusions.

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

Integrity signals

Registry

Crossref · 10.1038/npp.2014.168

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 55 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    There was no group by drug interaction for right amygdala reactivity to fearful faces.

    “There was no group  drug interaction for right amygdala reactivity to fearful faces.”
    Quote in the paperNot a substantial claim
  • Findingown data

    gPPI functional connectivity analyses indicated a significant group by drug interaction for left amygdala to bilateral insula connectivity.

    “gPPI functional connectivity analyses indicated a significant group  drug interaction for left amygdala to bilateral insula (right MNI(44, 6, À 2), Z ¼ 4.16, k ¼ 627, po0.05, corrected; left MNI ( À 46, 12, À 8), Z ¼ 3.84, k ¼ 129, po0.05, corrected)”
    Quote in the paperSubstantial claim
  • Findingown data

    Greater amygdala reactivity to fearful faces was associated with less amygdala-insula functional connectivity at baseline.

    “In support of these ideas, we found that greater amygdala reactivity to fearful faces (an indicator of anxious responding) was associated with less amygdala-insula functional connectivity at baseline.”
    Quote in the paperSubstantial claim
  • Findingown data

    In all three cases, GSAD subjects had significantly less functional connectivity than HC subjects on PBO.

    “In all three cases, GSAD subjects had significantly less functional connectivity than HC subjects on PBO.”
    Quote in the paperSubstantial claim
  • Findingown data

    A similar pattern of results was found with LSAS total scores, albeit at a trend level.

    “A similar pattern of results was found with LSAS total scores, albeit at a trend level (r ¼ 0.38, p ¼ 0.12).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 31
  • Classified as probably not a substantial claim. 27

  • May combine two claims.

    Findingown data

    On OXT, GSAD subjects displayed enhanced functional connectivity compared with HC subjects, reversing the pattern of reduced connectivity on PBO.

    “In fact, on OXT, GSAD (4HC) subjects displayed enhanced functional connectivity (ie, the pattern of reduced connectivity on PBO was reversed on OXT).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was a significant group by drug interaction on left amygdala reactivity to fearful faces, such that OXT attenuated or normalized the hyperactive amygdala reactivity to fearful faces in GSAD patients.

    “We first confirmed using a whole-brain, 2 (session: PBO, OXT)  2 (group: HC, GSAD) analysis of variance (ANOVA) that consistent with Labuschagne et al (2010), there was a significant group  drug interaction on left amygdala reactivity to fearful faces (peak MNI coordinates: ( À 24, À 2, À 22), Z ¼ 2.77, k ¼ 81, po0.05, small volume corrected), such that OXT attenuated (or normalized) the hypera”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Labuschagne et al, 2010 source

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    Findingown data

    There were no main effects of group or group by drug interactions on accuracy or response times when matching fearful faces or shapes.

    “There were no main effects of group or group  drug interactions on accuracy or response times when matching fearful faces or shapes (all ps40.05).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    The effects of oxytocin are specific to individuals with GSAD and differ from those observed in healthy volunteers.

    “the aforementioned effects of OXT are specific to individuals with GSAD and differ from that observed in healthy volunteers.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Many have posited that the amygdala is an important therapeutic target for the management of GSAD.

    “Heightened amygdala reactivity has been strongly linked to these social threat-related impairments and many have posited that the amygdala is an important therapeutic target for the management of GSAD (Labuschagne et al, 2010;Phan et al, 2006).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Labuschagne et al, 2010 source

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    • cites Phan et al, 2006 source

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

    Premisecitation

    Generalized social anxiety disorder (GSAD) is highly prevalent and characterized by extreme fear and avoidance of social situations.

    “Generalized social anxiety disorder (GSAD), also known as generalized social phobia, is highly prevalent and characterized by extreme fear and avoidance of social situations (American Psychiatric Association, 1994).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites American Psychiatric Association, 1994

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    Premisecitation

    GSAD patients exhibit attentional biases for threatening social information and exaggerated affective responses to aversive social cues.

    “For example, laboratory studies have shown that GSAD patients exhibit attentional biases for threatening social information (Foa et al, 2000;Mogg et al, 2004), and exaggerated affective responses to aversive social cues (Hermann et al, 2002;Roelofs et al, 2009).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Foa et al, 2000 source

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    • cites Mogg et al, 2004 source

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    • cites Hermann et al, 2002 source

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    Premisecitation

    Broadly, results suggest that OXT enhances connectivity between social-emotional areas of the brain and reduces connectivity between regions implicated in fear responding.

    “Broadly, results suggest that OXT enhances connectivity between social-emotional areas of the brain, and reduces connectivity between regions implicated in fear responding.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Neuropeptides such as OXT lack spatial specificity and have receptors located throughout the brain.

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

    Premisecitation

    OXT administration increases pro-social behaviors like trust, empathy, and willingness to take social risks.

    “More recently, studies in humans have demonstrated that OXT administration increases pro-social behaviors like trust, empathy, and willingness to take social risks (Kosfeld et al, 2005), whereas dampening psychophysiological responses to stressors (Ditzen et al, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kosfeld et al, 2005 source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Brain regions are organized into networks of interconnected areas.

    “However, brain regions are organized into networks of interconnected areas (Van Den Heuvel and Hulshoff Pol, 2010), and neuropeptides, such as OXT, lack spatial specificity and have receptors located throughout the brain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Van Den Heuvel and Hulshoff Pol, 2010 source

      Not checked in the free run.

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

    Premisecitation

    OXT agonists have been shown to be effective in animal models of anxiety.

    “For years, OXT agonists have been shown to be effective in animal models of anxiety (Windle et al, 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Windle et al, 1997 source

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  • May combine two claims.

    Premisecitation

    Current pharmacological treatments for GSAD are not universally effective and there is a critical need to identify novel, effective pharmacological interventions.

    “Importantly, however, current pharmacological treatments for GSAD are not universally effective and there is a critical need to identify novel, effective pharmacological interventions (Taylor et al, 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Taylor et al, 2012 source

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

    Premisecitation

    During an interpersonal cooperation task, OXT increased functional connectivity between the amygdala and the anterior insula.

    “For example, during an interpersonal cooperation task, Rilling et al (2012) found that OXT increased functional connectivity between the amygdala and the anterior insula.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rilling et al, 2012 source

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

    Premisecitation

    Amygdala hyperactivity to threat has been shown to be modulated by pharmacological treatments including selective serotonin reuptake inhibitors and benzodiazepines.

    “Indeed, amygdala hyperactivity to threat has been shown to be modulated by pharmacological treatments including selective serotonin reuptake inhibitors (Harmer et al, 2006) and benzodiazepines (Paulus et al, 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Harmer et al, 2006 source

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    • cites Paulus et al, 2005 source

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  • May combine two claims.

    Interpretationown data

    OXT has a specific effect on fear-related amygdala reactivity and may impact GSAD patients by modulating neural responses to social signals of threat.

    “These results suggest that OXT has a specific effect on fear-related amygdala reactivity and may have an impact on GSAD patients by modulating neural responses to social signals of threat.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    OXT can inhibit neurons in the centromedial amygdala through excitatory effects on GABAergic projections from the lateral and capsular central nucleus, disrupting integration of information and inhibiting amygdala output to fear-responding areas.

    “Although the mechanisms of these effects are unclear, it has been shown that OXT can inhibit neurons in the centromedial amygdala through its excitatory effects on g-aminobutyric acid (GABA) inhibitory (GABAergic) projections that originate from the lateral and capsular part of the central nucleus of the amygdala, which disrupts integration of information and inhibits amygdala output to areas of”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Huber et al, 2005 source

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    Premisecitation

    OXT promotes GABAergic inhibition in the amygdala, making the amygdala a good candidate target for OXT's effects.

    “The amygdala is a good candidate target for OXT's effects given that, like other anxiolytic pharmacotherapies, OXT promotes GABAergic inhibition in the amygdala (Huber et al, 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Huber et al, 2005 source

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    Premisecitation

    In healthy volunteers, intranasal OXT administration dampens amygdala reactivity to threatening facial expressions and naturalistic social interactions.

    “Consistent with this evidence, functional magnetic imaging (fMRI) studies with healthy volunteers have shown that intranasal OXT administration dampens amygdala reactivity to threatening facial expressions (Domes et al, 2007;Kirsch et al, 2005), and naturalistic social interactions (Baumgartner et al, 2008).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Domes et al, 2007 source

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    • cites Kirsch et al, 2005 source

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    • cites Baumgartner et al, 2008 source

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  • May combine two claims.

    Premisereasoning

    Prior studies have exclusively included healthy control subjects, and no study has examined OXT-induced, task-dependent changes in functional connectivity in a patient group characterized by increased fear and anxiety such as GSAD.

    “Of note, prior studies have exclusively included healthy control (HC) subjects and no study to our knowledge has examined OXT-induced, task-dependent changes in functional connectivity in a patient group characterized by increased fear and anxiety such as GSAD.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    OXT reduced functional coupling between the amygdala and the brainstem.

    “Meanwhile, Kirsch et al (2005) found that OXT reduced functional coupling between the amygdala and the brainstem.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kirsch et al, 2005 source

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    Study design and conductnone given

    Sessions were separated by a minimum of 7 days to allow for proper wash-out.

    “Sessions were separated by a minimum of 7 days to allow for proper wash-out.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    GSAD diagnoses were confirmed using the Clinical International Diagnostic Interview-Version 2.1 and Liebowitz Social Anxiety Scale probes, with GSAD patients required to have a total LSAS score greater than 70 and a social situations subscale score greater than 30.

    “GSAD diagnoses were confirmed using the Clinical International Diagnostic Interview-Version 2.1 (WHO, 1997), and probes taken from the Liebowitz Social Anxiety Scale (LSAS; Liebowitz, 1987).To ensure that GSAD patients were classified as the 'generalized' subtype, they were required to have a total LSAS score greater than 70, and a 'social situations' subscale score greater than 30.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites WHO, 1997

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    • cites Liebowitz, 1987 source

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

    Study design and conductcitation

    The fMRI scan began 45 min after inhalation of OXT or PBO, consistent with prior OXT administration studies and the expected timing of OXT's physiological effects.

    “The fMRI scan began 45 min post inhalation of OXT or PBO, and lasted for 30 min.This time frame is consistent with prior OXT administration studies and coincides with the expected timing of OXT's physiological effects (eg, Domes et al, 2007;Kirsch et al, 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Domes et al, 2007 source

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    • cites Kirsch et al, 2005 source

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

    Study design and conductcitation

    The EFMT task has been used in previous pharmaco-fMRI studies to probe drug effects on amygdala activation and amygdala functional connectivity.

    “The EFMT task has previously been described in detail elsewhere (Labuschagne et al, 2010), and has been used in previous pharmaco-fMRI studies to probe drug effects on amygdala activation (Kirsch et al, 2005;Paulus et al, 2005;Phan et al, 2008;Labuschagne et al, 2010) and amygdala functional connectivity (Gorka et al, 2013).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Labuschagne et al, 2010 source

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    • cites Kirsch et al, 2005 source

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    • cites Gorka et al, 2013 source

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    Premisecitation

    Higher levels of social inhibition are associated with reduced connectivity between the left amygdala and the insula, dACC, and hippocampus.

    “Moreover, higher levels of social inhibition, defined as the tendency to withdrawal from people or avoid social situations, is associated with reduced connectivity between the left amygdala and the insula, dACC, and hippocampus (Blackford et al, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Blackford et al, 2014 source

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  • May combine two claims.

    Interpretationown data

    OXT attenuates amygdala reactivity while simultaneously enhancing functional connectivity between the amygdala and the insula and mid/dACC.

    “This suggests that OXT attenuates amygdala reactivity while simultaneously enhancing functional connectivity between the amygdala and the insula and mid/dACC-regions heavily implicated in processing socioemotional stimuli.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Neuropeptides such as OXT lack spatial specificity and have receptors located throughout the brain.

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

    Study design and conductown data

    The study was a within-subjects, randomized, double-blind, placebo-controlled OXT administration study.

    “The study was a within-subjects, randomized, double-blind, PBO-controlled, OXT administration study.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Acute oxytocin reduces amygdala reactivity while enhancing connectivity to ACC and insula to infant laughter in nulliparous women.

    “acute OXT has been shown to reduce amygdala reactivity while enhancing connectivity to ACC and insula to infant laughter in nulliparous women”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Reim et al, 2012

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  • May combine two claims.

    Interpretationreasoning

    On placebo, individuals with GSAD may exhibit strong inverse connections between the amygdala and insula and mid/dACC, whereas on oxytocin they exhibit strong positive connections.

    “On PBO, individuals with GSAD may exhibit strong inverse connections between the amygdala and insula and mid/dACC, whereas on OXT they exhibit strong positive connections.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Reduced amygdala-insula connectivity may reflect diminished insula modulatory influences on amygdala reactivity, which could impair interoception and potentiate autonomic anxiety responses during social threat.

    “reduced connectivity may reflect diminished insula modulatory influences on amygdala reactivity, which could impair interoception and potentiate autonomic anxiety responses during social threat.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Within individuals with GSAD, oxytocin may not enhance amygdala to insula and mid/dACC connectivity per se; rather, oxytocin may change the direction of connectivity effects.

    “within individuals with GSAD, OXT may not 'enhance' amygdala to insula and mid/dACC connectivity per se.Rather, the findings could be interpreted as OXT changing the direction of connectivity effects.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    Oxytocin enhanced amygdala-insula functional connectivity and this reflected an increased ability to assess internal states to guide decision-making.

    “Rilling et al (2012) also found that OXT enhanced amygdala-insula functional connectivity and posited that this reflected an increased ability to assess internal states (eg, somatic markers) to guide decision-making.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rilling et al (2012) source

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    Premisecitation

    The amygdala, insula, and ACC are increasingly implicated in the pathophysiology of GSAD.

    “these three regions in particular-amygdala, insula, and ACC-are increasingly implicated in the pathophysiology of GSAD (Etkin and Wager, 2007;Marazziti et al, 2014;Miskovic and Schmidt, 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Etkin and Wager, 2007 source

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    • cites Marazziti et al, 2014

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    • cites Miskovic and Schmidt, 2012 source

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    Interpretationcitation

    Dysfunctional salience processing may underlie maladaptive attentional biases for social-evaluative stimuli characteristic of GSAD.

    “it is possible that dysfunctional salience processing underlies maladaptive attentional biases for socialevaluative stimuli that are characteristic of GSAD (Asmundson and Stein, 1994).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Asmundson and Stein, 1994 source

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    Interpretationreasoning

    Enhanced amygdala-insula connectivity could increase autonomic regulation.

    “Enhanced connectivity could therefore have the opposite effect and increase autonomic regulation.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Functional coupling between the insula and amygdala is necessary for the regulation of autonomic responses and the awareness of interoceptive states.

    “functional coupling between these areas is necessary for the regulation of autonomic responses and the awareness of interoceptive states (Craig, 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Craig, 2009 source

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  • Classified as probably not a substantial claim.

    Premisecitation

    The insula has direct projections to the amygdala.

    “The insula has direct projections to the amygdala”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Craig, 2009 source

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

    Premisecitation

    The mid/dACC is activated in response to numerous social contexts and, through functional interactions with other limbic areas, recruits regions necessary for affect regulation, directs attentional control, and ameliorates cognitive conflicts.

    “As for the mid/dACC, it is activated in response to numerous social contexts, and through functional interactions with other limbic areas, recruits regions necessary for affect regulation, directs attentional control, and ameliorates cognitive conflicts (Kerns et al, 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kerns et al, 2004 source

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  • May combine two claims.

    Interpretationreasoning

    Inverse connectivity between amygdala and insula/mid/dACC may reflect aberrant interactions between socio-emotional regions, leading to anxious responding and/or deficits in social processing.

    “Inverse connectivity may reflect aberrant interactions between these socio-emotional regions, leading to anxious responding and/or deficits in social processing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The sample size was small and this likely reduced statistical power.

    “although a within-subjects study, the sample size was small and this likely reduced statistical power.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Positive connectivity between amygdala and insula/mid/dACC may be an indicator of adaptive functional interactions which facilitate social recognition and affect modulation.

    “Conversely, positive connectivity may be an indicator of adaptive functional interactions which facilitate social recognition and affect modulation.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Hyperactive amygdala responding is coupled with reduced insula and mid/dACC activation on placebo and the opposite pattern on oxytocin (reduced amygdala reactivity coupled with enhanced insula and mid/dACC activation).

    “This would imply that hyperactive amygdala responding is coupled with reduced insula and mid/dACC activation on PBO and the opposite pattern on OXTreduced amygdala reactivity is coupled with enhanced insula and mid/dACC activation.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    These neural effects may have broad pro-social implications such as enhancing the integration and modulation of social responses.

    “These neural effects may have broad pro-social implications such as enhancing the integration and modulation of social responses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The relation between oxytocin and anxious responding is nuanced and oxytocin's effects may be most consistent in the context of dysfunctional physiological states.

    “Together, these findings suggest that the relation between OXT and anxious responding is nuanced and that OXT's effects may be most consistent in the context of dysfunctional physiological states.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    gPPI analyses are correlational and therefore directionality between amygdala and the insula and mid/dACC cannot be inferred.

    “gPPI analyses are correlational and therefore directionality between amygdala and the insula and mid/dACC cannot be inferred.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The sample was restricted to males and may not generalize to females.

    “our sample was restricted to males, given the role of sex hormones on OXT neural effect's (Domes et al, 2010), and may not generalize to females.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Domes et al, 2010 source

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46 of 46

  • The paper relies on this without support.

    Neuropeptides such as OXT lack spatial specificity and have receptors located throughout the brain.

    “neuropeptides, such as OXT, lack spatial specificity and have receptors located throughout the brain.”
1 of 1

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    “normalized the abnormal neural responses to negative social stimuli in patients with social anxiety disorder (32, 33).”

    From Placebo treatment facilitates social trust and approach behavior (2018) · cites this paper as [33]

  • Recent neuroimaging studies have reported oxytocin-induced increases in neural activation in regions, including the amygdala, which are associated with processing of salience and arousal.

    “These studies have reported oxytocin-induced increases in neural activation in regions, including the amygdala, which are associated with processing of salience and arousal (Frijling et al., 2016;Gorka et al., 2015;Koch et al., 2016).”

    From Meta-analytic review of the effects of a single dose of intranasal oxytocin on threat processing in humans (2018) · cites this paper as Gorka et al., 2015

  • OXT moderates ACC activity.

    “OXT has been found to moderate ACC activity (Gorka et al, 2015;Scheele et al, 2014a)”

    From Oxytocin Facilitates Pavlovian Fear Learning in Males (2016) · cites this paper as Gorka et al, 2015

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.

  • Figure 2 assigns the amygdala-reactivity correlation to the opposite insula

    Minor

    The results associate placebo amygdala reactivity with changes in left amygdala-right insula connectivity, whereas the Figure 2 caption labels the corresponding correlation as left amygdala-left insula connectivity.

  • Abstract sample sizes conflict with the reported exclusions

    Minor

    The methods state that 18 people were enrolled in each group and that one control and two GSAD participants were excluded, leaving 17 controls and 16 GSAD participants, as Table 1 reports. The abstract instead says 18 controls and 17 GSAD participants performed the study.

  • Figure 2 assigns the LSAS correlation to the opposite insula

    Minor

    The results associate LSAS performance scores with changes in left amygdala-left insula connectivity, whereas the Figure 2 caption assigns that correlation to left amygdala-right insula connectivity.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Walter B, Blecker C, Kirsch P, Sammer G, Schienle A, Stark R et al (2003). Marina: An easy to use tool for the creation of masks for interest analyses. Neuroimage 19: S47.

Cited by

Sorted by citations

Related

Authors
Gorka, S. M., Fitzgerald, D. A., Labuschagne, I., Hosanagar, A., Wood, A. G., Nathan, P. J., & Phan, K. L.
Affiliations
  • University of Illinois Chicago (US)
  • United States Department of Veterans Affairs (US)
  • Monash University (AU)
  • University of Michigan (US)
  • Murdoch Children's Research Institute (AU)
  • University of Cambridge (GB)
Corresponding author
Phan, K Luan
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2014-07-07
Volume
40
Issue
2
Pages
278-286
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2014.168
PMC
PMC4443941
OpenAlex
W2143428277
Semantic Scholar
343adbf61cf90f13289572bb124bf2fda624e89d
Cited by
131
References
46
Citations by year
2026: 7 · 2025: 6 · 2024: 9 · 2023: 6 · 2022: 6 · 2021: 11 · 2020: 10 · 2019: 11 · 2018: 19 · 2017: 21 · 2016: 10 · 2015: 13 · 2014: 1
FWCI
22.25
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (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
  • UCB Pharma
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 › Cognitive Neuroscience › Face Recognition and Perception
Keywords
oxytocin, generalized social anxiety disorder, amygdala, functional connectivity, fearful faces, insula, anterior cingulate cortex, threat processing, social anxiety, intranasal administration, psychophysiological interaction
MeSH terms
Facial Recognition, Adult, Amygdala, Anxiety Disorders, Brain Mapping, Double-Blind Method, Face, Facial Expression, Humans, Magnetic Resonance Imaging, Male, Neural Pathways, Neuropsychological Tests, Oxytocin, Photic Stimulation, Social Perception, Anti-Anxiety Agents

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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