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Cited by 105Posttraumatic Stress Disorder ResearchMemory and Neural MechanismsStress Responses and Cortisol

Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors

Open access
Briscione, Maria Anne, Jovanovic, Tanja, Norrholm, Seth Davin·2014·Frontiers in Psychiatry
DOI 10.3389/fpsyt.2014.00088PMC PMC4104832
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Abstract

Post-traumatic stress disorder (PTSD) is a heterogeneous disorder that affects individuals exposed to trauma (e.g., combat, interpersonal violence, and natural disasters). It is characterized by hyperarousal, intrusive reminders of the trauma, avoidance of trauma-related cues, and negative cognition and mood. This heterogeneity indicates the presence of multiple neurobiological mechanisms underlying the development and maintenance of PTSD. Fear conditioning is a robust, translational experimental paradigm that can be employed to elucidate these mechanisms by allowing for the study of fear-related dimensions of PTSD (e.g., fear extinction, fear inhibition, and generalization of fear) across multiple units of analysis. Fear conditioning experiments have identified varying trajectories of the dimensions described, highlighting exciting new avenues of targeted, focused study. Additionally, fear conditioning studies provide a translational platform to develop novel interventions. The current review highlights the versatility of fear conditioning paradigms, the implications for pharmacological and non-pharmacological treatments, the robustness of these paradigms to span an array of neuroscientific measures (e.g., genetic studies), and finally the need to understand the boundary conditions under which these paradigms are effective. Further understanding these paradigms will ultimately allow for optimization of fear conditioning paradigms, a necessary step towards the advancement of PTSD treatment methods.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that fear conditioning paradigms provide robust, translational intermediate phenotypes for trauma-, stressor-, and anxiety-related disorders, especially PTSD. It synthesizes human and animal work on fear extinction, inhibition, generalization, and treatment development while emphasizing the need to define boundary conditions.

Key findings

  • PTSD affects 8% of the general population and approximately 20% of Operation Iraqi Freedom/Operation Enduring Freedom veterans presented with PTSD symptoms upon return; Vietnam veterans can experience persistent symptoms for as long as 40 years.
  • Fear conditioning can index dysregulated fear dimensions including fear extinction, fear inhibition, and stimulus generalization; PTSD patients have shown increased fear responses to cues they subjectively report as safe, impaired fear inhibition, altered stimulus generalization, and reduced extinction recall when tested 24 h after extinction learning.
  • Divergent extinction trajectories are reported: “fear load” (over-expression of fear during early extinction) in traumatized civilians, “persistence of fear” with impaired within-session extinction in combat veterans, and impaired between-session extinction retention.
  • Treatment targets include DCS, propranolol, morphine, antidepressants, endocannabinoid/FAAH agents, oxytocin, losartan, and retrieval + extinction; DCS effectiveness for PTSD is described as unclear due to mixed reports, though some studies show benefit under specific conditions such as virtual reality exposure.

Methods

  • Narrative review of fear conditioning and fear-potentiated startle/skin conductance studies in humans and animal models, framed by RDoC and intermediate phenotypes.
  • Discusses acquisition, extinction, fear inhibition (including AX+/BX−), generalization, and pharmacological/non-pharmacological treatment studies.
  • No primary data collection, systematic search strategy, inclusion criteria, or meta-analysis is reported.

Limitations

  • The paper states the need to understand boundary conditions under which fear conditioning paradigms, such as retrieval + extinction, are effective; these include the psychophysiological measure, reinforcement schedule, fear-relevancy of conditioned stimuli, strength of the fear memory, and presence of on-line expectancy or fear ratings.
  • As a narrative review, it does not report a systematic search, risk-of-bias assessment, or quantitative synthesis; this is evident from the text.
  • Many cited treatment findings are mixed or from preclinical/early human studies, and DCS effectiveness for PTSD is explicitly described as unclear due to mixed reports.

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

Integrity signals

Registry

Crossref · 10.3389/fpsyt.2014.00088

Cites

95 of 95 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 96 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Alterations in fear extinction, fear inhibition, and stimulus generalization have all been reported, using fear-potentiated startle methods, in populations with trauma- and stressor-related as well as anxiety disorders.

    “Alterations in fear extinction, fear inhibition, and stimulus generalization have all been reported, using fear-potentiated startle methods, in populations with trauma- and stressor-related as well as anxiety disorders [see Figure 1; (16, 29–31)].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [16] Lissek, 2009, Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder, Behav Res Ther source

      Not checked in the free run.

    • cites [29] Jovanovic, 2005, Fear potentiation and fear inhibition in a human fear-potentiated startle paradigm, Biol Psychiatry source

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    • cites [30] Norrholm, 2006, Conditioned fear extinction and reinstatement in a human fear-potentiated startle paradigm, Learn Mem source

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    • cites [31] Glenn, 2012, The development of fear learning and generalization in 8-13 year-olds, Dev Psychobiol source

      Not checked in the free run.

  • Findingcitation

    The high comorbidity of PTSD and depression means measures of PTSD and depression may reflect overlapping symptoms of negative affect.

    “The high comorbidity of PTSD and depression highlights this problem; specifically, measures of PTSD and depression [as indexed by the Clinician Administered PTSD Scale (CAPS) and the Beck Depression Index (BDI), respectively) may reflect overlapping symptoms of negative affect (18, 19).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Brown, 1998, Structural relationships among dimensions of the DSM-IV anxiety and mood disorders and dimensions of negative affect, positive affect, and autonomic arousal, J Abnorm Psychol source

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    • cites [19] Bauer, 2013, Psychophysiological assessment of PTSD: a potential research domain criteria construct, Psychol Assess source

      Not checked in the free run.

  • Findingcitation

    PTSD patients have shown increased fear responses to cues that they subjectively report as safe.

    “For example, PTSD patients have shown increased fear responses to cues that they subjectively report as safe (28).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Jovanovic, 2012, Impaired safety signal learning may be a biomarker of PTSD, Neuropharmacology source

      Not checked in the free run.

  • Findingnone given

    Translational studies have shown that fearful memories are initially labile and are consolidated to a more permanent state, hours to days, after the initial event.

    “Translational studies have shown that fearful memories are initially labile and are consolidated to a more permanent state, hours to days, after the initial event.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Clinically, individuals with PTSD have been shown to have alterations in stimulus generalization, fear inhibition, discrimination, and fear extinction.

    “Clinically, individuals with PTSD have been show to have alterations in stimulus generalization (16), fear inhibition (29), discrimination, and fear extinction (38).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Lissek, 2009, Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder, Behav Res Ther source

      Not checked in the free run.

    • cites [29] Jovanovic, 2005, Fear potentiation and fear inhibition in a human fear-potentiated startle paradigm, Biol Psychiatry source

      Not checked in the free run.

    • cites [38] Rothbaum, 2014, A randomized, double-blind evaluation of d-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War Veterans, Am J Psychiatry source

      Not checked in the free run.

  • May combine two claims. 22
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingcitation

    Trauma-, stressor-, and anxiety-related disorders have a significant degree of heritability and genetic contributions include complex gene × environment interactions.

    “trauma-, stressor-, and anxiety-related disorders have been shown to have a significant degree of heritability and more recently, it has become increasingly clear that genetic contributions include complex gene × environment interactions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Norrholm, 2013, Differential genetic and epigenetic regulation of catechol-O-methyltransferase is associated with impaired fear inhibition in posttraumatic stress disorder, Front Behav Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    High levels of conditioned fear remaining during late extinction are related to impaired inhibition, best predicted by responses to the CS− at the end of acquisition.

    “High levels of conditioned fear remaining during late extinction are related to impaired inhibition, as it is best predicted by responses to the CS− (i.e., safety signal) at the end of acquisition (15).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Norrholm, 2011, Fear extinction in traumatized civilians with posttraumatic stress disorder: relation to symptom severity, Biol Psychiatry source

      Not checked in the free run.

    • The authors state this as an assumption: Extinction learning is a form of fear inhibition.

  • Classified as probably not a substantial claim.

    Findingnone given

    Fear conditioning experiments have identified varying trajectories of the fear-related dimensions described.

    “Fear conditioning experiments have identified varying trajectories of the dimensions described, highlighting exciting new avenues of targeted, focused study.”
    Quote in the paperSubstantial claim

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

    Findingcitation

    Morphine has been studied as a possible intervention for fear memory consolidation, but it is unclear whether its analgesic properties reduce the potency of the CS+ or act through a separate mechanism.

    “Morphine has also been studied as a possible intervention of fear memory consolidation; however, it is not clear whether morphine's analgesic properties act to reduce the potency of the CS+ or are acting through a separate mechanism (61, 62).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [61] Parsons, 2013, Implications of memory modulation for post-traumatic stress and fear disorders, Nat Neurosci source

      Not checked in the free run.

    • cites [62] Holbrook, 2010, Morphine use after combat injury in Iraq and post-traumatic stress disorder, N Engl J Med source

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  • May combine two claims.

    Findingcitation

    D-cycloserine (DCS), an NMDA receptor partial agonist, facilitated extinction learning in rats; this finding was replicated in rodents but not replicated using skin conductance and expectancy ratings in humans.

    “Walker et al. (64) found that d-cycloserine (DCS), an NMDA receptor partial agonist, facilitated extinction learning in rats; a finding that was later replicated by several other groups employing multiple types of fear learning paradigms in rodents [e.g., Ref. (65)] but not replicated using skin conductance and expectancy ratings in humans (66).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [64] Walker, 2002, Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats, J Neurosci source

      Not checked in the free run.

    • cites [65] Richardson, 2004, Facilitation of fear extinction by D-cycloserine: theoretical and clinical implications, Learn Mem source

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    • cites [66] Guastella, 2007, A randomized controlled trial of the effect of D-cycloserine on extinction and fear conditioning in humans, Behav Res Ther source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Both auditory and visual groups discriminated between the CS+ and CS−, but the auditory group exhibited discrimination on blocks 1, 2, and 3 of fear acquisition, while the visual CS+ group exhibited discrimination on blocks 2 and 3.

    “Both groups also discriminated between the CS+ and CS−; however, the auditory group exhibited discrimination on blocks 1, 2, and 3 of fear acquisition, while the visual CS+ group exhibited discrimination on blocks 2 and 3 of fear acquisition.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Norrholm, 2011, Versatility of fear-potentiated startle paradigms for assessing human conditioned fear extinction and return of fear, Front Behav Neurosci source

      Not checked in the free run.

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

    Findingcitation

    Several candidate gene studies have identified genetic differences and specific gene pathways involved in PTSD.

    “Specifically, several candidate gene studies have identified genetic differences and specific gene pathways involved in PTSD [for a review, see (53)].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Skelton, 2012, PTSD and gene variants: new pathways and new thinking, Neuropharmacology source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Twenty-four hours later, an extinction test showed that spontaneous recovery occurred in both groups and US-expectancy ratings increased in both groups regardless of modality.

    “Twenty-four hours later an extinction test was performed. This test showed that spontaneous recovery occurred in both groups and US-expectancy ratings increased in both groups regardless of modality as well (58).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Norrholm, 2011, Versatility of fear-potentiated startle paradigms for assessing human conditioned fear extinction and return of fear, Front Behav Neurosci source

      Not checked in the free run.

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

    Findingnone given

    Several recent translational studies have explored both pharmacological and non-pharmacological means of enhancing extinction of fear and preventing its re-emergence.

    “Several recent translational studies have explored both pharmacological as well as non-pharmacological means of enhancing extinction of fear and preventing its re-emergence.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    DCS administration before or after exposure therapy was effective in alleviating symptoms of acrophobia, panic disorder, social anxiety disorder, and obsessive-compulsive disorder.

    “Shortly thereafter, several groups reported that DCS administration before or after exposure therapy, a form of treatment based on the principles of fear extinction learning, was effective in alleviating the symptoms of acrophobia (67), panic disorder (68), social anxiety disorder (69, 70), and obsessive–compulsive disorder (71–73).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [67] Ressler, 2004, Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear, Arch Gen Psychiatry source

      Not checked in the free run.

    • cites [68] Otto, 2010, Efficacy of CBT for benzodiazepine discontinuation in patients with panic disorder: further evaluation, Behav Res Ther source

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    • cites [69] Hofmann, 2006, Augmentation of exposure therapy with D-cycloserine for social anxiety disorder, Arch Gen Psychiatry source

      Not checked in the free run.

    • cites [70] Hofmann, 2013, d-Cycloserine as an augmentation strategy with cognitive-behavioral therapy for social anxiety disorder, Am J Psychiatry source

      Not checked in the free run.

    • Rests on an assumption: Exposure therapy is a form of treatment based on the principles of fear extinction learning.

  • May combine two claims.

    Findingcitation

    Ten minutes after initial assessment, both groups extinguished fear, but the auditory group displayed a steeper slope of extinction, due in part to an initial increase in fear during extinction, than the visual group.

    “Ten minutes after this initial assessment, these groups were shown to also extinguish fear; however, the auditory group displayed a steeper slope of extinction, due in part to an initial increase in fear during extinction, than the visual group.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Norrholm, 2011, Versatility of fear-potentiated startle paradigms for assessing human conditioned fear extinction and return of fear, Front Behav Neurosci source

      Not checked in the free run.

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

    Findingcitation

    GWAS data have been used to identify novel gene pathways involved in the mechanisms underlying complex disorders such as PTSD.

    “More recently, GWAS data, which is obtained when expression levels of the whole genome are analyzed in the context of PTSD, have been used to identify novel gene pathways involved in the mechanisms underlying complex disorders such as PTSD [see Ref. (54) for a review].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Almli, 2014, Genetic approaches to understanding post-traumatic stress disorder, Int J Neuropsychopharmacol source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    When DCS was administered prior to virtual reality exposure therapy, subjects showed earlier, enhanced symptom reduction and greater PTSD remission rates.

    “Specifically, when DCS was administered prior to virtual reality exposure therapy subjects showed earlier, enhanced symptom reduction and greater PTSD remission rates (78).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Difede, 2014, D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial, Neuropsychopharmacology source

      Not checked in the free run.

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

    Findingcitation

    DCS plus exposure therapy was not as effective as placebo plus exposure in a population of combat veterans with PTSD.

    “Initial reports by Litz et al. (75) suggested that DCS + exposure therapy was not as effective as placebo + exposure in a population of combat veterans with PTSD (75)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Litz, 2012, A randomized placebo-controlled trial of D-cycloserine and exposure therapy for posttraumatic stress disorder, J Psychiatr Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fear-potentiated startle is observed across species and is ideal for studying translational models of fear-related phenotypes.

    “Fear-potentiated startle is observed across species and is ideal for studying translational models of fear-related phenotypes (27).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Lissek, 2008, Generalization of conditioned fear-potentiated startle in humans: experimental validation and clinical relevance, Behav Res Ther source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Fear extinction is an important translational tool due to its relevance to limbic neural circuitry underlying fear psychopathology and its role as an experimental homolog to exposure therapy, the most effective treatment for fear and anxiety.

    “Fear extinction, as a translational tool, is an important area of study due to its relevance to the limbic neural circuitry believed to underlie fear psychopathology and also due to its role as an experimental homolog to exposure therapy, which is currently recognized as the most effective treatment for fear and anxiety.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Fear conditioning is a robust, translational experimental paradigm that can be employed to elucidate mechanisms of PTSD by allowing study of fear-related dimensions across multiple units of analysis.

    “Fear conditioning is a robust, translational experimental paradigm that can be employed to elucidate these mechanisms by allowing for the study of fear-related dimensions of PTSD (e.g., fear extinction, fear inhibition, and generalization of fear) across multiple units of analysis.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    PTSD is a heterogeneous disorder that affects individuals exposed to trauma.

    “Post-traumatic stress disorder is a heterogeneous disorder in which symptoms span four primary symptom clusters according to the recent Diagnostic and Statistical Manual of Mental Disorders, 5th edition [DSM-5; (9)].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] 2013

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  • May combine two claims.

    Interpretationreasoning

    The dysregulated fear learning commonly observed in anxious and traumatized populations can be modeled by fear-conditioning paradigms, which can provide a translational framework.

    “The dysregulated fear learning commonly observed in anxious and traumatized populations can be modeled by fear-conditioning paradigms, which can provide a translational framework.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Using the RDoC approach, fear-conditioning studies can identify intermediate phenotypes, which represent specific components of a disorder and allow for a more direct examination of brain-behavior relationships.

    “Using the RDoC approach, fear-conditioning studies can identify intermediate phenotypes, which represent specific components of a disorder and allow for a more direct examination of brain–behavior relationships.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    The presence of divergent extinction trajectories represents a new avenue of study and may be analogous to heterogeneous responses to trauma in PTSD.

    “The presence of divergent extinction trajectories as described above represents an exciting new avenue of study and has recently been introduced in the rodent literature (43), which may be analogous to heterogeneous responses to trauma in PTSD (44).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Galatzer-Levy, 2013, Heterogeneity in threat extinction learning: substantive and methodological considerations for identifying individual difference in response to stress, Front Behav Neurosci source

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    • cites [44] Galatzer-Levy, 2013, Early PTSD symptom trajectories: persistence, recovery, and response to treatment: results from the Jerusalem Trauma Outreach and Prevention Study (J-TOPS), PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PTSD symptom clusters provide useful diagnostic criteria and could be used to discern the most effective treatment, but they represent broad categories of behavior and do not easily reflect common underlying mechanisms.

    “While PTSD symptom clusters provide a useful set of diagnostic criteria and could be used to discern the most effective treatment [for a comprehensive review, see Ref. (10)], they represent broad categories of behavior and do not easily reflect common underlying mechanisms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Norrholm, 2010, Tailoring therapeutic strategies for treating posttraumatic stress disorder symptom clusters, Neuropsychiatr Dis Treat source

      Not checked in the free run.

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

    Premisecitation

    PTSD has long been associated with intrinsic, environmental, and genetic factors.

    “Further, PTSD has long been associated with intrinsic [e.g., age and gender (48, 49)], environmental (e.g., exposure to trauma, rearing environment, degree of social support), and genetic factors (50–52).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [48] Bokszczanin, 2007, PTSD symptoms in children adolescents 28 months after a flood: age gender differences, J Trauma Stress source

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    • cites [49] Iwadare, 2014, Posttraumatic symptoms in elementary and junior high school children after the 2011 Japan earthquake and tsunami: symptom severity and recovery vary by age and sex, J Pediatr source

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    • cites [50] True, 1993, A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms, Arch Gen Psychiatry source

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    • cites [51] Binder, 2008, Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults, JAMA source

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    • cites [52] Yehuda, 2008, Maternal, not paternal, PTSD is related to increased risk for PTSD in offspring of Holocaust survivors, J Psychiatr Res source

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  • May combine two claims.

    Premisecitation

    Fear-potentiated startle can be used in several mammalian species; however, in animal models the CSs are typically auditory, whereas visual CSs are used in human studies.

    “Fear-potentiated startle can be used in several mammalian species (57); however, in animal models the CSs are typically auditory, whereas visual CSs are used in human studies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Myers, 2009, Measurement of fear inhibition in rats, monkeys, and humans with or without posttraumatic stress disorder, using the AX+, BX– paradigm

      Not checked in the free run.

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

    Premisenone given

    Treatment approaches aimed at reducing fear-related symptoms of PTSD have focused on disruption of fear memory consolidation/reconsolidation, facilitation of extinction learning, and prevention of the return of fear.

    “Not surprisingly, treatment approaches aimed at reducing the fear-related symptoms of PTSD (e.g., re-experiencing and intrusive memories) have focused on the disruption of fear memory consolidation/reconsolidation, facilitation of extinction learning, and the prevention of the return of fear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The use of intermediate phenotypes enhances the ability to identify complex gene interactions and allows for these gene pathways to be more readily studied.

    “The use of these intermediate phenotypes not only enhances the ability to identify complex gene interactions but also allows for these gene pathways to be more readily studied.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The versatility of fear-potentiated startle allows its use in patients with visual impairment with equivalent results and lends itself to cross-over longitudinal studies in which practice effects can be minimized.

    “The advantage of this versatility is that it can be used in patients with visual impairment with equivalent results and also lends itself to the use of “cross-over” longitudinal studies in which practice effects can be minimized.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The boundary conditions under which retrieval + extinction is effective include the type of psychophysiological measure employed, the schedule of reinforcement used during acquisition, the fear-relevancy of the conditioned stimuli presented, the strength of the fear memory following acquisition, and the presence or absence of on-line measures of expectancy or fear ratings.

    “These conditions include, but are not limited to, the type of psychophysiological measure employed, the schedule of reinforcement used during acquisition, the fear-relevancy of the conditioned stimuli presented, the strength of the fear memory following acquisition, and the presence or absence of on-line measures of expectancy or fear ratings [see Ref. (37, 91–93)].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [37] Warren, 2013, Human fear extinction and return of fear using reconsolidation update mechanisms: the contribution of on-line expectancy ratings, Neurobiol Learn Mem source

      Not checked in the free run.

    • cites [91] Golkar, 2012, Are fear memories erasable?-reconsolidation of learned fear with fear-relevant and fear-irrelevant stimuli, Front Behav Neurosci source

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    • cites [92] Oyarzun, 2012, Updating fearful memories with extinction training during reconsolidation: a human study using auditory aversive stimuli, PLoS One source

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    • cites [93] Kindt, 2013, Reconsolidation in a human fear conditioning study: a test of extinction as updating mechanism, Biol Psychol source

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

    Premisecitation

    PTSD is known to affect women more commonly than men.

    “For example, PTSD is known to affect women more commonly than men (1, 94), and fear-conditioning paradigms are useful for characterizing the sex differences underlying different neuronal, endocrine, and behavioral responses to trauma and other stressors.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Kessler, 1995, Posttraumatic stress disorder in the National Comorbidity Survey, Arch Gen Psychiatry source

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    • cites [94] Breslau, 1997, Sex differences in posttraumatic stress disorder, Arch Gen Psychiatry source

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

    Premisecitation

    Inhibition of FAAH could represent a risk variant for stressor-related psychiatric disorders.

    “This work was furthered by Gunduz-Cinar et al. (84, 85) who showed that inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes the endogenous cannabinoid anandamide, enhances extinction learning in rodents and could represent a risk variant for stressor-related psychiatric disorders (84, 85).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [84] Gunduz-Cinar, 2013, Amygdala FAAH and anandamide: mediating protection and recovery from stress, Trends Pharmacol Sci source

      Not checked in the free run.

    • cites [85] Gunduz-Cinar, 2013, Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity, Mol Psychiatry source

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

    Interpretationreasoning

    Further characterization of fear conditioning-related intermediate phenotypes will enhance the utility of fear-conditioning studies.

    “While the present review summarized the current progress of interfacing fear conditioning-related intermediate phenotypes and genetic (54), behavioral (47), symptomatic (15, 45), and clinical studies (78), further characterization of these intermediate phenotypes will enhance the utility of fear-conditioning studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    By identifying these intermediate phenotypes, we can create specific testable measures, which can then be used to examine the effectiveness of treatment interventions.

    “By identifying these intermediate phenotypes, we can create specific testable measures, which can then be used to examine the effectiveness of treatment interventions.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Potential breakthroughs will increase the utility of fear-conditioning studies as a translational platform for studying the intermediate phenotypes underlying dysregulated fear learning.

    “Ultimately, potential breakthroughs will increase the utility of fear-conditioning studies as a translational platform for studying the intermediate phenotypes underlying dysregulated fear learning, a central tenant of trauma-, stressor-, and anxiety-related disorders.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Dysregulated fear learning is a central tenant of trauma-, stressor-, and anxiety-related disorders.
    • Rests on an assumption: PTSD has high comorbidity with other disorders including depression and substance abuse.

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

    Interpretationreasoning

    Understanding fear conditioning-related intermediate phenotypes and their divergent manifestations in a broader etiology may lead to more effective treatment and preventative strategies for PTSD and other trauma-, stressor-, and anxiety-related disorders.

    “Understanding these phenotypes (i.e., fear inhibition, high fear load, fear generalization, etc.) and the divergent manifestations of these responses in the context of a broader etiology (i.e., genetic, behavioral, symptomatic, and clinical studies) may lead to more effective treatment and preventative strategies for PTSD and other trauma-, stressor-, and anxiety-related disorders.”
    Quote in the paperNot a substantial claim
34 of 34

  • The authors state this as an assumption.

    Extinction learning is a form of fear inhibition.

    “This is based on the notion that extinction learning is a form of fear inhibition.”

  • The paper relies on this without support.

    Exposure therapy is a form of treatment based on the principles of fear extinction learning.

    “DCS administration before or after exposure therapy, a form of treatment based on the principles of fear extinction learning, was effective in alleviating the symptoms of acrophobia”

  • The paper relies on this without support.

    Dysregulated fear learning is a central tenant of trauma-, stressor-, and anxiety-related disorders.

    “Ultimately, potential breakthroughs will increase the utility of fear-conditioning studies as a translational platform for studying the intermediate phenotypes underlying dysregulated fear learning, a central tenant of trauma-, stressor-, and anxiety-related disorders.”

  • The paper relies on this without support.

    PTSD has high comorbidity with other disorders including depression and substance abuse.

    “This is especially useful due to the high comorbidity of PTSD and other disorders including depression and substance abuse.”
4 of 4

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?

  • Fear extinction is widely utilized as a translational animal model for exposure therapies used for anxiety disorders.

    “Fear extinction has been widely utilized as a translational animal model for the exposure therapies used for anxiety disorders (Briscione et al., 2014; Myers & Davis, 2006; Quirk & Mueller, 2007).”

    From Nicotine addiction and psychiatric disorders (2015) · cites this paper as Briscione et al., 2014

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.

  • OEF and OIF are assigned to the wrong operations

    Minor

    The abbreviations are reversed: Operation Iraqi Freedom corresponds to OIF, and Operation Enduring Freedom corresponds to OEF.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. 2013, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, DSM-5
  2. Myers, 2009, Measurement of fear inhibition in rats, monkeys, and humans with or without posttraumatic stress disorder, using the AX+, BX– paradigm, 61

Cited by

Sorted by citations

Related

Authors
Briscione, M. A., Jovanovic, T., & Norrholm, S. D.
Affiliations
Emory University (US)
Corresponding author
Norrholm, Seth Davin
ORCID
Norrholm, Seth Davin
Venue
Frontiers in Psychiatry
Publisher
Frontiers Media SA
Published
2014-07-21
Volume
5
Pages
88-88
ISSN
1664-0640 (ISSN-L)
DOI
10.3389/fpsyt.2014.00088
PMC
PMC4104832
OpenAlex
W1969678755
Semantic Scholar
24e29ca8baee20676f53554bf85407077d1a7deb
Cited by
105
References
94
Citations by year
2026: 4 · 2025: 7 · 2024: 6 · 2023: 11 · 2022: 5 · 2021: 12 · 2020: 7 · 2019: 8 · 2018: 8 · 2017: 8 · 2016: 10 · 2015: 15 · 2014: 3
FWCI
14.16
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Defense
  • National Alliance for Research on Schizophrenia and Depression
  • National Institute of General Medical Sciences (T32GM008605)
  • National Center for Research Resources (UL1RR025008)
  • Congressionally Directed Medical Research Programs (W81XWH-08-2-0170)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
post-traumatic stress disorder, fear conditioning, fear extinction, fear inhibition, fear generalization, hyperarousal, trauma exposure, anxiety-like behavior, translational model, PTSD treatment, genetic research, neurobiological mechanisms

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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