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Cited by 702Memory and Neural MechanismsAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesNeural and Behavioral Psychology Studies

Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies

Open access
Fullana, M A, Harrison, B J, Soriano-Mas, C, Vervliet, B, Cardoner, N, Àvila-Parcet, A, Radua, J·2016·Molecular Psychiatry
DOI 10.1038/mp.2015.88
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Abstract

Classical Pavlovian fear conditioning remains the most widely employed experimental model of fear and anxiety, and continues to inform contemporary pathophysiological accounts of clinical anxiety disorders. Despite its widespread application in human and animal studies, the neurobiological basis of fear conditioning remains only partially understood. Here we provide a comprehensive meta-analysis of human fear-conditioning studies carried out with functional magnetic resonance imaging (fMRI), yielding a pooled sample of 677 participants from 27 independent studies. As a distinguishing feature of this meta-analysis, original statistical brain maps were obtained from the authors of 13 of these studies. Our primary analyses demonstrate that human fear conditioning is associated with a consistent and robust pattern of neural activation across a hypothesized genuine network of brain regions resembling existing anatomical descriptions of the ‘central autonomic–interoceptive network’. This finding is discussed with a particular emphasis on the neural substrates of conscious fear processing. Our associated meta-analysis of functional deactivations—a scarcely addressed dynamic in fMRI fear-conditioning studies—also suggests the existence of a coordinated brain response potentially underlying the ‘safety signal’ (that is, non-threat) processing. We attempt to provide an integrated summary on these findings with the view that they may inform ongoing studies of fear-conditioning processes both in healthy and clinical populations, as investigated with neuroimaging and other experimental approaches.

AI snapshot

Written from the paper’s full text.

TL;DR

This updated AES-SDM meta-analysis of 27 independent human fMRI fear-conditioning studies (677 healthy adults) found a robust activation pattern consistent with a central autonomic-interoceptive network, plus a distributed deactivation pattern possibly reflecting safety-signal processing. It also reports no robust amygdala involvement and identifies several task/demographic moderators of conditioning-related brain activity.

Key findings

  • Across 27 data sets and 677 participants (54% males; mean age 25.37 years), differential fear conditioning (CS+ > CS−) consistently activated bilateral anterior insular cortex/frontal operculum, ventral striatum and major thalamic nuclei, medial wall cortex including dACC/SMA/pre-SMA, SII/parietal operculum, dorsolateral prefrontal cortex, lateral premotor cortex, precuneus, lateral cerebellum, and subcortical regions including septal-hypothalamic zone, midbrain/dorsal pons, and pontomedullary junction.
  • Deactivations (CS+ < CS−) were mapped in lateral/midline primary somatosensory cortex and dorsal posterior insula, dorsal anterior prefrontal cortex, vmPFC, PCC/retrosplenial cortex/hippocampus/temporal cortex, lateral OFC, inferior parietal cortex, posterior cerebellum, dorsal caudate, and dorsal-posterior precuneus.
  • The meta-analysis did not characterize robust amygdala involvement; early-versus-late analysis showed early-phase greater activation of medial thalamus, left SII, and left AIC, while late phase showed greater subgenual ACC/vmPFC/medial OFC and right anterior hippocampus activation and greater right precuneus deactivation.
  • Studies without potential US confounding showed greater activation of rostral dACC/dmPFC, bilateral ventral AIC, ventral striatum, and right SII; higher reinforcement rate was associated with reduced activation of rostral dACC/dmPFC, right SII, and a small right AIC cluster. Meta-regressions also linked younger age, pre-conditioning phase, number of CS trials, CS-US delay, electric shock US, and cognitive task use to regional activation/deactivation differences.

Methods

  • Literature search in PubMed, Web of Knowledge, and Scopus for English-language peer-reviewed fMRI studies of cued fear conditioning in healthy adults (age >18 years) published January 1998–November 2013; inclusion focused on delay differential cue-conditioning with independent validation of fear-response generation and direct CS+ vs CS− comparisons.
  • Final sample: 27 independent data sets, 677 subjects; original statistical parametric maps were obtained from 13 studies, and peak regional coordinates were extracted from the remaining 14.
  • Main analysis used anisotropic effect-size signed differential mapping (AES-SDM) version 4.13 for voxel-wise random-effects meta-analysis, with default thresholds (voxel-level P<0.005 uncorrected, minimum 10 contiguous voxels), meta-regressions at P<0.0005, and supplementary analyses of US confounding, early vs late conditioning, jackknife sensitivity, heterogeneity (I²), and publication bias (Egger’s method).

Limitations

  • Stated by the authors: included studies used various statistical thresholds; the methods control false positives well but make false negatives harder to avoid; meta-regression analyses were hampered by low variability in some variables; default AES-SDM thresholds were based on uncorrected P-values; and contingency awareness could not be assessed because such data were rarely presented among individual studies.
  • Evident from the text: the meta-analysis is restricted to delay differential cue-conditioning in healthy adults, excluding trace, single-cue, masked-CS, ambiguous-US, changing-contingency, and some dual-task designs, so findings may not generalize to other fear-learning paradigms or clinical populations.
  • Evident from the text: only 13 of 27 studies contributed original SPMs, and the absence of robust amygdala findings may be partly explained by technical constraints of fMRI and other reasons noted by the authors.

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

Integrity signals

Registry

Crossref · 10.1038/mp.2015.88

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 45 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    Concurrent use of cognitive tasks reduced activation of the bilateral mid-AIC.

    “Finally, the concurrent use of cognitive tasks reduced the activation of the bilateral mid-AIC.”
    Quote in the paperSubstantial claim
  • Findingnone given

    Inclusion of this number of SPMs allowed, for the first time, estimation of task-specific optimal parameters for processing the peak information of the remaining studies.

    “Furthermore, inclusion of this number of SPMs allowed, for the first time, the estimation of the task-specific optimal parameters for processing the peak information of the remaining studies.”
    Quote in the paperSubstantial claim
  • Findingown data

    Smaller subcortical regions including the septal-hypothalamic zone and midbrain/dorsal pons (periaqueductal grey, parabrachial nucleus, reticular formation, raphe nuclei, and locus coeruleus) showed relevant involvement during differential fear conditioning.

    “We also note the relevant involvement of smaller subcortical regions including the septal-hypothalamic zone and midbrain/dorsal pons, which contains the periaqueductal grey, parabrachial nucleus, reticular formation, raphe nuclei (pontine and midbrain) and locus coeruleus.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The early conditioning phase was associated with greater relative activation of the medial thalamus, left SII, and left AIC.

    “The 'early versus late' meta-analysis indicated that the early phase was associated with greater relative activation of the medial thalamus, left SII and left AIC (Supplementary Figure S3 and Supplementary Table S4).”
    Quote in the paperSubstantial claim
  • Findingown data

    A higher CS-US reinforcement rate reduced strength of activation of the rostral dACC/dmPFC, right parietal operculum (SII), and a small cluster of right AIC.

    “A higher CS-US reinforcement rate reduced strength of activation of the rostral dACC/dmPFC (Figure 4d), right parietal operculum (SII) and a small cluster of right AIC.”
    Quote in the paperSubstantial claim
  • May combine two claims. 22
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingown data

    A longer delay between the CS and US was associated with greater activation of the subgenual ACC and vmPFC, and less activation of the right parietal operculum/SII, pre-supplementary motor area, and right premotor cortex.

    “A longer delay between the CS and US was associated with greater activation of the subgenual ACC and vmPFC, and less activation of the right parietal operculum/SII, pre-supplementary motor area and the right premotor cortex (Figure 4e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The final sample consisted of 27 independent data sets reporting a CS+ > CS- contrast, including 677 subjects (54% males), with a mean age of 25.37 years.

    “The final sample (Supplementary Figure S1) consisted of 27 independent data sets reporting a CS+ 4CScontrast (of which 19 also presented a CS+ o CScontrast) including a total of 677 subjects (54% males), with a mean age of 25.37 years (range: 20-36; s.d.= 4.19; see Table 1).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Seven large bilateral regional clusters showed consistently significant functional activations during differential fear conditioning (CS+ > CS-), including AIC/frontal operculum, ventral striatum/thalamic nuclei, medial wall cortex/dACC/precuneus, SII/parietal operculum, dorsolateral prefrontal cortex, lateral premotor cortex, ventral-posterior precuneus, and lateral cerebellum.

    “Seven large bilateral regional clusters were mapped as demonstrating consistently significant functional activations during differential fear conditioning (CS+ 4CS -).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Use of a pre-conditioning phase significantly reduced conditioning-related activation of several regions, all but the ventral ACC overlapping with regions implicated in the primary meta-analysis.

    “The use of a pre-conditioning phase significantly reduced conditioning-related activation of several regions.Of these regions, all but the ventral ACC (Figure 4a) overlapped with regions implicated in the primary meta-analysis (Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The late conditioning phase was associated with greater activation of the subgenual ACC/vmPFC extending to the medial OFC and the right anterior hippocampus, as well as greater deactivation of the right precuneus.

    “By comparison, the late phase was associated with greater activation of the subgenual ACC/vmPFC extending to the medial OFC and the right anterior hippocampus, as well as greater deactivation of the right precuneus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Younger age was associated with significantly greater activation of the right AIC extending to the frontal operculum, right dorsolateral prefrontal cortex, pre-supplementary motor area, and left frontal operculum, as well as greater deactivation of the left anterior hippocampus and posterior fusiform gyrus.

    “Younger age was associated with significantly greater activation of the right AIC extending to the frontal operculum, right dorsolateral prefrontal cortex, pre-supplementary motor area and the left frontal operculum, as well as greater deactivation of the left anterior hippocampus and posterior fusiform gyrus (Supplementary Table S5).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Nine large bilateral regional clusters showed consistently significant deactivations during differential fear conditioning (CS+ < CS-), including lateral/midline primary somatosensory cortex/dorsal posterior insula, dorsal anterior prefrontal cortex, vmPFC, PCC/retrosplenial cortex/hippocampus/temporal cortex, lateral OFC, inferior parietal cortex, lateral retrosplenial cortex, posterior Cerebell,

    “Nine large bilateral regional clusters were also mapped as demonstrating consistently significant deactivations during differential fear conditioning (CS+ oCS -).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In our meta-analysis, only partial involvement of default mode network regions was observed; there was no characteristic deactivation of the extended dorsomedial PFC.

    “Second, only partial involvement of the default mode network regions was observed in our meta-analysis: there was no characteristic deactivation of the extended dorsomedial PFC, which is commonly observed in fMRI studies.41”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Uninstructed fear-conditioning studies focus on fear learning, whereas instructed studies primarily capture fear expression.

    “We concentrated on uninstructed fearconditioning studies, because (contrary to instructed studies, which primarily capture fear expression) they focus on fear learning, which has a stronger theoretical link with the hypothesized etiology and pathophysiology of clinical anxiety disorders.14”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Mineka S, Zinbarg R . A contemporary learning theory perspective on the etiology of anxiety disorders: it's not what you thought it was. Am Psychol 2006; 61: 10–26. source

      Not checked in the free run.

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

    Study design and conductnone given

    The literature search, decisions on inclusion, and data extraction were all performed independently by two of the authors.

    “The literature search, decisions on inclusion and data extraction were all performed independently by two of the authors.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Cognitive demands may have a significant impact on fear conditioning processes.

    “previous laboratorybased studies have shown that cognitive demands may have a significant impact on fear conditioning processes.7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Carter RM, Hofstotter C, Tsuchiya N, Koch C . Working memory and fear conditioning. Proc Natl Acad Sci USA 2003; 100: 1399–1404. source

      Not checked in the free run.

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

    Premisecitation

    Functional deactivations may be as equally informative for understanding the neural substrates of complex mental activities, including emotion processing, as activations.

    “As is now broadly recognized in the neuroimaging field, functional deactivations may be as equally informative for understanding the neural substrates of complex mental activities, [8][9][10] including emotion processing.8,11,12”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] Harrison BJ, Pujol J, Contreras-Rodriguez O, Soriano-Mas C, Lopez-Sola M, Deus J et al. Task-induced deactivation from rest extends beyond the default mode brain network. PLoS One 2011; 6: e22964. source

      Not checked in the free run.

    • cites [9] Harrison BJ, Pujol J, Lopez-Sola M, Hernandez-Ribas R, Deus J, Ortiz H et al. Consistency and functional specialization in the default mode brain network. Proc Natl Acad Sci USA 2008; 105: 9781–9786. source

      Not checked in the free run.

    • cites [10] Radua J, Mataix-Cols D . Heterogeneity of coordinate-based meta-analyses of neuroimaging data: an example from studies in OCD – Authors’ reply. Br J Psychiatry 2010; 197: 77. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Robustness analyses indicated that all primary results were highly replicable, with neither substantial heterogeneity nor evidence of potential publication bias in the main results.

    “Our corresponding robustness analyses indicated that all results were highly replicable, and that there was neither substantial heterogeneity nor evidence of potential publication bias in the main results (Supplementary Material).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based).

    Interpretationreasoning

    The common pattern of activation is genuinely consistent with engagement of a large-scale brain functional network, that is, a coordinated pattern of brain activation across anatomically distributed brain regions with well-known anatomical connectivity.

    “With the goal of providing an integrated perspective, we hypothesize that this common pattern of activation is genuinely consistent with the engagement of a large-scale brain functional network, that is, a coordinated pattern of brain activation across anatomically distributed brain regions with well-known anatomical connectivity.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Mechias et al.'s meta-analytic results for uninstructed conditioning studies were less robust or more inconsistent.

    “However, meta-analytic results for the uninstructed conditioning studies were noted as less robust or more inconsistent.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Mechias ML, Etkin A, Kalisch R . A meta-analysis of instructed fear studies: implications for conscious appraisal of threat. Neuroimage 2010; 49: 1760–1768. source

      Not checked in the free run.

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

    Study design and conductnone given

    Only studies with an independent validation of successful fear-response generation and direct statistical comparisons between CS+ and CS- during conditioning were included.

    “We only included studies with an independent validation of successful fear-response generation (for example, via skin conductance recordings), and those that conducted direct statistical comparisons between a CS+ and a CSduring conditioning.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Fear conditioning has become widely regarded as a valid experimental model of clinical anxiety disorders.

    “Fear conditioning has become widely regarded as a valid experimental model of clinical anxiety disorders and thus it is hoped that further advances in the scientific study of fear-conditioning processes will yield translational benefits in the form of optimized pathophysiological models of these common mental health disorders.2”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Kindt M . A behavioural neuroscience perspective on the aetiology and treatment of anxiety disorders. Behav Res Ther 2014; 62: 24–36. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies using a delay differential cue-conditioning paradigm were focused on because other paradigms (trace or single-cue) appear to engage non-overlapping neural responses.

    “We focused on studies using a delay differential cue-conditioning paradigm given that other paradigms (for example, trace or single-cue) appear to engage non-overlapping neural responses.6,19”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Knight DC, Cheng DT, Smith CN, Stein EA, Helmstetter FJ . Neural substrates mediating human delay and trace fear conditioning. J Neurosci 2004; 24: 218–228. source

      Not checked in the free run.

    • cites [19] Cheng DT, Knight DC, Smith CN, Helmstetter FJ . Human amygdala activity during the expression of fear responses. Behav Neurosci 2006; 120: 1187–1195. source

      Not checked in the free run.

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

    Premisecitation

    Within the central autonomic-interoceptive network, the AIC and dACC are conceptualized as major cortical input-output components, with the AIC generating integrated awareness and the dACC re-representing it to facilitate homeostatic autonomic and behavioral responses.

    “Within the framework of this 'central autonomic-interoceptive network', the AIC and dACC are conceptualized as the major cortical input-output components, whereby the AIC is responsible for generating an integrated awareness of one's cognitive, affective and physical state that becomes re-represented in the dACC in order to facilitate homeostatic autonomic and behavioral responses.30,33”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30] Craig AD . How do you feel—now? The anterior insula and human awareness. Nat Rev Neurosci 2009; 10: 59–70. source

      Not checked in the free run.

    • cites [33] Medford N, Critchley HD . Conjoint activity of anterior insular and anterior cingulate cortex: awareness and response. Brain Struct Funct 2010; 214: 535–549. source

      Not checked in the free run.

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

    Premisecitation

    The vmPFC and PCC are recognized as a characteristic functional signature of the human default mode network, a large-scale brain system that exhibits consistent functional decreases in activity in fMRI studies when goal-directed task performance is compared with low task demand such as passive resting states.

    “vmPFC and PCC, in particular, has become recognized as a characteristic functional signature of the human 'default mode network'-a large-scale brain system that exhibits consistent functional decreases in activity in fMRI studies when conditions of goal-directed task performance are compared with conditions of low task demand, such as passive resting states.8,9”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Harrison BJ, Pujol J, Contreras-Rodriguez O, Soriano-Mas C, Lopez-Sola M, Deus J et al. Task-induced deactivation from rest extends beyond the default mode brain network. PLoS One 2011; 6: e22964. source

      Not checked in the free run.

    • cites [9] Harrison BJ, Pujol J, Lopez-Sola M, Hernandez-Ribas R, Deus J, Ortiz H et al. Consistency and functional specialization in the default mode brain network. Proc Natl Acad Sci USA 2008; 105: 9781–9786. source

      Not checked in the free run.

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

    Study design and conductcitation

    The default AES-SDM statistical thresholds were based on uncorrected P-values, which may be seen as a limitation.

    “Despite providing an optimal balance between sensitivity and false positive rate, 13 the default AES-SDM statistical thresholds were based on uncorrected P-values, which may be seen as a limitation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Radua J, Mataix-Cols D, Phillips ML, El-Hage W, Kronhaus DM, Cardoner N et al. A new meta-analytic method for neuroimaging studies that combines reported peak coordinates and statistical parametric maps. Eur Psychiatry 2012; 27: 605–611. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Processing of the CS- is not a passive condition; it places specific demands on learning, attentional and cognitive evaluative processes.

    “First, processing of CSis not a passive condition; it places specific demands on learning, attentional and cognitive evaluative processes.40”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] van Well S, Visser RM, Scholte HS, Kindt M . Neural substrates of individual differences in human fear learning: evidence from concurrent fMRI, fear-potentiated startle, and US-expectancy data. Cogn Affect Behav Neurosci 2012; 12: 499–512. source

      Not checked in the free run.

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

    Premisecitation

    Both the PCC/retrosplenial cortex and hippocampus are well-known components of an extended episodic memory network, and it has been proposed that coengagement of these areas may specifically encode episodic memory traces of the CS/US association.

    “Both regions are well-known components of an extended episodic memory network and it has been proposed recently that the coengagement of these areas may specifically encode episodic memory traces of the CS/US association.46”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Holt DJ, Coombs G, Zeidan MA, Goff DC, Milad MR . Failure of neural responses to safety cues in schizophrenia. Arch Gen Psychiatry 2012; 69: 893–903. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Human fMRI fear-conditioning studies primarily evoke a central autonomic-interoceptive network response that, in addition to representing autonomic responses to threat, also likely represents broader threat appraisal and response processes across cognitive, motivational, and psychomotor domains.

    “Therefore, it seems reasonable to suggest human fMRI fear-conditioning studies primarily evoke a central autonomicinteroceptive network response that, in addition to representing autonomic responses to threat, also likely represent broader threat appraisal and response processes that cut across cognitive, motivational and psychomotor domains.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A certain component of the rostral dACC/dmPFC response during fear conditioning is specifically cognitively modulated and dissociable from autonomic arousal changes.

    “From these studies, there is evidence that a certain component of the rostral dACC/dmPFC response during fear conditioning is specifically cognitively modulated and dissociable from autonomic arousal changes.35”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Kalisch R, Gerlicher AM . Making a mountain out of a molehill: on the role of the rostral dorsal anterior cingulate and dorsomedial prefrontal cortex in conscious threat appraisal, catastrophizing, and worrying. Neurosci Biobehav Rev 2014; 42: 1–8. source

      Not checked in the free run.

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

    Study design and conductnone given

    The results of our meta-regression analyses were hampered by low variability in some of the variables studied.

    “In addition, the results of our meta-regression analyses were hampered by the low variability in some of the variables studied.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The current analysis included 13 original SPMs to more effectively estimate the contrasts of interest.

    “and the inclusion of 13 original SPMs to more effectively estimate the contrasts of interest.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    The different studies included in the meta-analysis employed various statistical thresholds, and although the methods provide excellent control for false positives, it is more difficult to avoid false negatives.

    “Our study nevertheless has some limitations inherent to most meta-analyses; the different studies included employed various statistical thresholds, and although our methods provide excellent control for false positives it is more difficult to avoid false negatives.13”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Radua J, Mataix-Cols D, Phillips ML, El-Hage W, Kronhaus DM, Cardoner N et al. A new meta-analytic method for neuroimaging studies that combines reported peak coordinates and statistical parametric maps. Eur Psychiatry 2012; 27: 605–611. source

      Not checked in the free run.

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

    Premisecitation

    Previous fMRI studies of fear conditioning have argued that vmPFC deactivation likely represents processing of the CS- as a non-threat or safety signal, with particular emphasis on fear-response inhibition.

    “Previous fMRI studies of fear conditioning have argued that vmPFC deactivation is indeed likely to represent processing of the CSas a non-threat or 'safety' signal, with particular emphasis on fear-response inhibition.42,43”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Milad MR, Wright CI, Orr SP, Pitman RK, Quirk GJ, Rauch SL . Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol Psychiatry 2007; 62: 446–454. source

      Not checked in the free run.

    • cites [43] Schiller D, Levy I, Niv Y, LeDoux JE, Phelps EA . From fear to safety and back: reversal of fear in the human brain. J Neurosci 2008; 28: 11517–11525. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The current analysis used novel meta-analytic methods that combine the positive features of typical coordinate approaches with those from standard meta-analytic methods.

    “Strengths of the current analysis include the following: the use of novel meta-analytic methods that combine the positive features of typical coordinate approaches with those from standard metaanalytic methods;”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Co-deactivation of the lateral OFC is consistently implicated as part of the extended neural circuitry of reward-associative learning, with evidence for specialized contributions between medial and lateral vmPFC/OFC regions.

    “Co-deactivation of the lateral OFC is also interesting in this context, having been consistently implicated as part of the extended neural circuitry of reward-associative learning, albeit with evidence existing for specialized contributions between medial and lateral vmPFC/OFC regions.45”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Grabenhorst F, Rolls ET . Value, pleasure and choice in the ventral prefrontal cortex. Trends Cogn Sci 2011; 15: 56–67. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Brain responses in the rostral dACC/dmPFC, right SII, and ventral AIC likely represent the common influence of uncertainty or unpredictability, because studies without potential confounding had generally lower reinforcement rates.

    “As those studies without potential confounding had generally lower reinforcement rates, these brain responses likely represent the common influence of uncertainty or unpredictability, that is, where lower reinforcement rates increase uncertainty or unpredictability.”
    Quote in the paperSubstantial claim
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  • The paper relies on this without support.

    The relationships between fear/anxiety and central interoceptive representations remain largely unexplored in the neuroscientific study of patients with clinical anxiety disorders.

    “It is notable that these relationships remain largely unexplored in the neuroscientific study of patients with clinical anxiety disorders, thus potentially representing a novel research avenue.”

  • The paper relies on this without support.

    Technical constraints of fMRI and other reasons do not fully account for the absence of amygdala involvement in the meta-analysis.

    “Although the absence of amygdala involvement may be partly explained by technical constraints of fMRI and other reasons, 4,17 it seems reasonable to also conclude that human fMRI fear-conditioning experiments generally do not evoke consistent responses within the classical amygdala defense/threat detection circuitry.”
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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?

  • There is still a consensus that the amygdala, hippocampus, vmPFC, and ACC are central to fear learning and, especially, fear extinction.

    “there is still a consensus that the Am, Hip, vmPFC, and ACC are central to fear learning [review in Ref. (193, 194)] and, especially, fear extinction [reviews in Ref. (187, 188, 195)].”

    From The Stress Acceleration Hypothesis of Nightmares (2017) · cites this paper as [193]

    The citation is attached to the fear-learning portion of the sentence, not the separately cited extinction portion. The Primary meta-analytic results and Functional activations discussion implicate the ACC, vmPFC and hippocampus in fear conditioning, but the latter explicitly says the meta-analysis did not find robust amygdala involvement. The paper therefore does not support presenting all four regions as consistently central to fear learning. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Recent meta-analyses of fMRI threat learning studies fail to find BOLD changes in the amygdala.

    “The challenges of using BOLD imaging to study the human amygdala is reflected in recent meta-analyses of fMRI threat learning studies, which fail to find BOLD changes in the amygdala [78]”

    From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [78]

  • Meta-analyses and individual studies reliably show activation in the insula cortex, striatum, and dACC during threat learning.

    “In contrast to difficulties in detecting BOLD changes in the amygdala during threat learning, meta-analyses and individual studies reliably show activation in a number of other brain regions, including the insula cortex, which is linked to physiological arousal responses [79], the striatum, and the dACC (e.g., [76, 78, 80]).”

    From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [78]

  • During the Acquisition phase, subjects showed CS+ versus CS- BOLD signal in regions typically identified in threat conditioning studies.

    “During the Acquisition phase, subjects showed CS + versus CS -BOLDsignal in regions typically identified in threat conditioning studies, similar to the results of a recent meta-analysis (Fullana et al., 2016) (Figure 4; Table 1).”

    From Active avoidance: Neural mechanisms and attenuation of pavlovian conditioned responding (2017) · cites this paper as Fullana et al., 2016

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.

  • Male percentage differs between results and table

    Minor

    The Results section reports 54% males in the 677-subject sample, while Table 1 reports 53% for the same total.

  • Reported age range excludes an age in Table 1

    Minor

    The reported upper end of the mean-age range is 36 years, but Table 1 includes a study with a mean age of 36.5 years.

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References 74 · Cited by 702

Research works printed but not linked: 2

  1. Öhman A . Human fear conditioning and the amygdala. In: Whalen PJ, Phelps EA (eds) The Human Amygdala. Guilford Press: New York, 2009.
  2. Harrison BJ, Fullana MA, Soriano-Mas C, Via E, Pujol J, Martinez-Zalacain I et al A neural mediator of human anxiety sensitivity (in press).

Authors
Fullana, M. A., Harrison, B. J., Soriano-Mas, C., Vervliet, B., Cardoner, N., Àvila-Parcet, A., & Radua, J.
Affiliations
  • Universitat Autònoma de Barcelona (ES)
  • The University of Melbourne (AU)
  • KU Leuven (BE)
Corresponding author
Harrison, B J
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2015-06-30
Volume
21
Issue
4
Pages
500-508
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2015.88
OpenAlex
W1519591349
Semantic Scholar
1c2db1b7d291b2185ba4b7150c4b5f31cf90c06f
Cited by
702
References
74
Citations by year
2026: 49 · 2025: 64 · 2024: 138 · 2023: 77 · 2022: 78 · 2021: 68 · 2020: 57 · 2019: 54 · 2018: 44 · 2017: 39 · 2016: 28 · 2015: 6
FWCI
3.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Lirias (submittedVersion, other-oa)
  • Research Portal (King's College London) (submittedVersion)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion)
Funders
  • National Health and Medical Research Council (1025619)
  • Instituto de Salud Carlos III (PI13/01958, CP14/00041, PI12/00273, CP10/00604)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
Keywords
fear conditioning, anxiety disorders, brain activation patterns
MeSH terms
Adult, Anxiety, Anxiety Disorders, Brain, Brain Mapping, Conditioning, Classical, Fear, Female, Gyrus Cinguli, Humans, Magnetic Resonance Imaging, Male

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