CoChat
Sign Up
Cited by 1,488Stress Responses and CortisolMemory and Neural MechanismsTryptophan and brain disorders

Phasic vs Sustained Fear in Rats and Humans: Role of the Extended Amygdala in Fear vs Anxiety

Open access
Davis, Michael, Walker, David L, Miles, Leigh, Grillon, Christian·2010·Neuropsychopharmacology
DOI 10.1038/npp.2009.109PMC PMC2795099
Open this paper in CoChat — free accountOpen PDF

Abstract

Data will be reviewed using the acoustic startle reflex in rats and humans based on our attempts to operationally define fear vs anxiety. Although the symptoms of fear and anxiety are very similar, they also differ. Fear is a generally adaptive state of apprehension that begins rapidly and dissipates quickly once the threat is removed (phasic fear). Anxiety is elicited by less specific and less predictable threats, or by those that are physically or psychologically more distant. Thus, anxiety is a more long-lasting state of apprehension (sustained fear). Rodent studies suggest that phasic fear is mediated by the amygdala, which sends outputs to the hypothalamus and brainstem to produce symptoms of fear. Sustained fear is also mediated by the amygdala, which releases corticotropin-releasing factor, a stress hormone that acts on receptors in the bed nucleus of the stria terminalis (BNST), a part of the so-called 'extended amygdala.' The amygdala and BNST send outputs to the same hypothalamic and brainstem targets to produce phasic and sustained fear, respectively. In rats, sustained fear is more sensitive to anxiolytic drugs. In humans, symptoms of clinical anxiety are better detected in sustained rather than phasic fear paradigms.

Integrity signals

Registry

Crossref · 10.1038/npp.2009.109

Cites

339 of 339 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

58 of 294 cited sources checked · 31 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    Long-term fluoxetine lowers the stress-induced rise in c-Fos within the BNSTL.

    “chronic fluoxetine decreased stress-induced c-Fos increases in the BNSTL (Bechtholt et al, 2008).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Bechtholt et al, 2008 source

      The c-Fos Expression Associated with NIH section says novelty tended to decrease c-Fos in the lateral posterolateral bed nucleus of the stria terminalis (STLP), and chronic fluoxetine reversed that change. The Discussion says fluoxetine normalized novelty-inhibited c-Fos in the STLP—the opposite of decreasing a stress-induced rise. Page numbers are unavailable in our copy. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Both shock and airpuffs evoke robust and reliable cued fear-potentiated startle.

    “Both shock and airpuffs evoke robust and reliable cued fear-potentiated startle (Grillon and Ameli, 1998a; Norrholm et al, 2006).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Grillon and Ameli, 1998a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Norrholm et al, 2006 source

      The Abstract reports that pairing a colored-light cue with an airblast produced robust fear-potentiated startle and significant discrimination between cues. Norrholm et al. supports the airpuff portion of the sentence, but our copy does not establish that the effect is reliable across repeated studies or measurements. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    A treatment may reduce context anxiety by interfering with the animal's representation of the context rather than through anxiolytic action.

    “a treatment might block context anxiety, not because it was anxiolytic, but because it interfered with a representation of context.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Blanchard et al, 1976 source

      The Results and Discussion (page unavailable) suggest that familiarity with features of a threat situation can alter rats’ defensive behavior, supporting the relevance of how animals perceive a context. The paper does not test a treatment or say that interference with a context representation can reduce context anxiety instead of acting anxiolytically. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites Fanselow, 1986 source
  • Premisecitation

    Long-lasting non-associative sensitization appears to be a bed nucleus of the stria terminalis-dependent phenomenon.

    “as long-lasting non-associative sensitization also appears to be a BNST-dependent phenomenon (eg, Gewirtz et al, 1998)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Gewirtz et al, 1998 source
  • Premisecitation

    PVT is among the brain regions most responsive to stress, as shown by c-Fos induction after diverse stressors.

    “the PVT is one of the most stress-responsive areas in the brain, based on the induction of a marker of cellar activity, c-Fos, with various stressors”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Beck and Fibiger, 1995 source

      The Discussion identifies the paraventricular nucleus of the thalamus among regions with increased c-Fos expression after conditioned stress and cites reports of its response to unconditioned stressors. It does not establish that the PVT is one of the brain’s most stress-responsive regions relative to other regions. Page numbers are unavailable in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Bhatnagar and Dallman, 1998 source
    • cites Bubser and Deutch, 1999 source
  • May combine two claims. 123
  • Classified as probably not a substantial claim. 31

  • May combine two claims.

    Premisecitation

    Both acute chlordiazepoxide and chronic fluoxetine decreased stress-induced c-Fos increases in the lateral bed nucleus of the stria terminalis, providing some of the first evidence that the potential anxiolytic effects of both compounds may be mediated by actions in the bed nucleus of the stria terminalis.

    “both acute chlordiazepoxide and chronic fluoxetine decreased stress-induced c-Fos increases in the BNSTL, providing some of the first evidence that the potential anxiolytic effects of both compounds may be mediated by actions in the BNST (Bechtholt et al, 2008).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Bechtholt et al, 2008 source

      Split into 2 atoms — 0 confirmed, 0 partially supported, 2 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    After CRF infusion, startle rises from roughly 30 min, increases across a 2-h session, and persists for hours.

    “large, dose-dependent increases in startle amplitude that began ∼30 min after CRF infusion, grew steadily over the course of a 2-h test period, and lasted for several hours thereafter.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Liang et al, 1992b source

      The Results report a dose-dependent increase beginning about 30 minutes after infusion, and the Discussion says the effect lasted at least 6 hours. However, the Discussion places its maximum at about 80–90 minutes, so the claim that startle grew steadily throughout the 2-hour test overstates the time course. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Longer trace intervals make the US less predictable and result in greater context conditioning.

    “The longer the duration of the trace interval, the less predictable the US becomes, resulting in greater context conditioning (Marlin, 1981).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Marlin, 1981 source

      The paper’s summary (INTERSTIMULUS INTERVAL (SEC), page not available) says that increasing trace intervals reduce conditioning to the CS and increase conditioning to contextual cues. It does not say that the US becomes less predictable; the discussion instead calls the CS “perfectly predictive of the US” and emphasizes its changing temporal relationship to the US. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Pretreatment with the CRF antagonist α-helical CRF blocks CRF-induced startle increases, and delayed infusions of it reverse them.

    “These increases were prevented by pretreatment with α-helical CRF (αhCRF9–41), a CRF antagonist, and were reversed by delayed αhCRF9–41 infusions”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Liang et al, 1992b source
    • cites Swerdlow et al, 1989 source

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

    Premisecitation

    Context consists of static background cues during training and need not be a spatial place.

    “context is not necessarily a spatial location but a set of static background stimuli present during training”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Otto and Poon, 2006 source
    • cites Rescorla and Wagner, 1972

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Intracisternal CRF reproduces the i.c.v. effect, intrathecal CRF does not, and PVT lesions do not prevent it.

    “The effects of intra-cerebroventricular (i.c.v.) infusions were mimicked by intracisternal (fourth ventricle) but not by intrathecal (in the space around motor neurons in the spinal cord) CRF infusions and were not disrupted by lesions of the PVT”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Liang et al, 1992a source

      Experiment 1 reports that intracisternal CRF produced an increase in startle similar to i.c.v. CRF, while intrathecal CRF produced a smaller, more rapid increase—not no effect. The lesion results concern the paraventricular nucleus of the hypothalamus (PVN), not the PVT named in the citing sentence; those PVN lesions did not alter i.c.v. CRF-enhanced startle. (LLM, conf=0.91)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In CRF1 knockout mice, context-potentiated startle assessed immediately after conditioning was completely abolished, while fear-potentiated startle to a 30-second light/tone compound conditioned stimulus paired with footshock 24 hours earlier was normal.

    “CRF1 knockout mice showed a complete abolition of context-potentiated startle assessed immediately after conditioning, but normal fear-potentiated startle to a 30-s light/tone compound CS that had been paired with footshock 24 h earlier.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Risbrough et al (2009) source

  • May combine two claims.

    Premisecitation

    CRF2 knockout mice showed normal fear-potentiated startle to a discrete conditioned stimulus but some attenuation of context-potentiated startle.

    “CRF2 knockout mice also showed normal fear-potentiated startle to the discrete CS, but also some attenuation of context-potentiated startle.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Risbrough et al (2009) source

  • May combine two claims.

    Findingcitation

    BNST infusion of the CRF1 antagonist blocked sustained fear to the 8-min clicker, whereas CeA infusion of a CRF antagonist did not affect phasic fear.

    “We also found that local infusion into the BNST of this CRF1 antagonist blocked sustained fear to the 8-min clicker, in contrast to the lack of effect of the local infusion of a CRF antagonist into the CeA on phasic fear”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Lee and Davis, 1997 source

      The section on intra-CeA infusion reports that the CRH antagonist did not block light-cued fear-potentiated startle, supporting the phasic-fear comparison. The intra-BNST results instead report attenuation of startle enhanced by infused CRH; they do not report sustained fear to an 8-minute clicker. Page numbers are unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    CRF-enhanced startle depends on BNSTL, not CeA: BNSTL lesions or local CRF antagonist blocked it, while CeA manipulations did not.

    “We also found that the BNSTL, but not the CeA, was involved in CRF-enhanced startle. For instance, excitotoxic BNSTL lesions, or local infusions of a CRF antagonist into the BNSTL, completely blocked CRF-enhanced startle, although similar lesions of the CeA, or infusions into the CeA, did not”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Lee and Davis, 1997 source

      The chemical-lesion Results report that BNST lesions completely blocked CRH-enhanced startle, whereas CeA lesions did not. The intra-BNST infusion Results report a dose-dependent attenuation by the CRH antagonist—not complete blockade—and the intra-CeA infusion Results report no blockade. The paper identifies the targeted region as BNST, without establishing the more specific BNSTL designation in these passages (page numbers unavailable). (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Oral GSK876008, a selective CRF-R1 antagonist, at doses that dose-dependently block CRF-enhanced startle, disrupted light-enhanced startle non-monotonically but did not affect fear-potentiated startle in the same rats.

    “using oral administration of the selective CRF-R1 antagonist GSK876008 (Di Fabio et al, 2008), at doses that dose dependently (linear) disrupt CRF-enhanced startle, we also observed a non-monotonic disruption of light-enhanced startle but no disruption of fear-potentiated startle in the same animals at the same doses”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Di Fabio et al, 2008 source
    • cites Walker et al, 2009 source

  • May combine two claims.

    Premisecitation

    Excitotoxic lesions of the bed nucleus of the stria terminalis, but not the central amygdala, blocked CRF-enhanced startle.

    “excitotoxic lesions of the BNST, but not the CeA, blocked CRF-enhanced startle”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Lee and Davis (1997) source

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

    Study design and conductnone given

    The account cannot easily explain why neurotoxic lesions of the central amygdala block context conditioning in some studies but not others, assuming the later lesions fully destroyed cells in the lateral central amygdala.

    “our account cannot easily explain why neurotoxic lesions of the CeA block context conditioning in some studies (Goosens and Maren, 2001) but not in others (Koo et al, 2004), assuming the later lesions fully destroyed cells in the CeAL.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Goosens and Maren, 2001 source

      The Results report that rats with neurotoxic central-amygdala lesions froze significantly less to the context than controls, supporting an impairment in context conditioning. The paper describes the effect as a deficit or attenuation, not a complete block. The comparison with other studies and the assumption about their lesion extent are not attributed to Goosens and Maren. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Koo et al, 2004 source

      The Conditioned freezing results report that rats with neurotoxic CeA lesions did not differ significantly from controls in context freezing, supporting the finding attributed to Koo et al. The Histology section says the lesions included most of the lateral CeA, not that they fully destroyed its cells; the Discussion also notes spared neurons. The citing authors’ stated assumption of complete destruction is therefore not established by this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • The authors state this as an assumption: The neurotoxic lesions in the later studies completely destroyed cells in the lateral central amygdala.

  • May combine two claims.

    Interpretationreasoning

    Electrolytic lesions of the central amygdala blocked context conditioning, which depends on the bed nucleus of the stria terminalis and CRF, because such lesions would have prevented context-induced release of CRF to the bed nucleus of the stria terminalis from the lateral central amygdala.

    “this could explain why electrolytic lesions of the CeA blocked context conditioning (Koo et al, 2004), which depends on the BNST (Sullivan et al, 2004) and CRF, because electrolytic lesions of the CeA would have prevented the context-induced release of CRF to the BNST from the CeAL (Figure 7).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Koo et al, 2004 source
    • cites Sullivan et al, 2004 source

  • May combine two claims.

    Premisecitation

    Chronic corticosterone administration upregulates CRF mRNA levels in lateral central amygdala and lateral bed nucleus of the stria terminalis neurons and interacts synergistically with CRF to increase startle amplitude.

    “previous studies have shown that chronic corticosterone administration upregulates the CRF mRNA level in CeAL and BNSTL neurons (Liu et al, 2004; Makino et al, 1994a, b; Shepard et al, 2000; Swanson and Simmons, 1989; Watts and Sanchez-Watts, 1995) and interacts synergistically with CRF to increase startle amplitude (Lee et al, 1994).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Liu et al, 2004 source

      The Introduction describes BDNF and contextual fear learning; the Discussion mentions a glucocorticoid receptor agonist in relation to spatial-memory retrieval. Neither passage addresses whether chronic corticosterone upregulates CRF mRNA in CeAL or BNSTL neurons (searched: chronic corticosterone, CRF mRNA, CeAL, BNSTL). The startle-amplitude clause is attributed to Lee et al. (1994), not to this paper. Page numbers are unavailable in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites Makino et al, 1994a, b source

      The Abstract reports that sustained corticosterone treatment elevated CRH mRNA in the central nucleus of the amygdala, supporting the core finding. The Methods specify measurements in the central amygdala and hypothalamic PVN, not the lateral central-amygdala subdivision or lateral bed nucleus of the stria terminalis. The startle-amplitude finding is attached to Lee et al. (1994), not to this source. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites Shepard et al, 2000 source

  • May combine two claims.

    Premisecitation

    Chronic inhibition of GABA synthesis in the bed nucleus of the stria terminalis produces anxiogenic effects that are reversible by local muscimol infusion into the bed nucleus of the stria terminalis.

    “Anxiogenic effects were also found after chronic inhibition of GABA synthesis in the BNST, and these effects were reversible by local infusion of muscimol into the BNST (Sajdyk et al, 2008).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Sajdyk et al, 2008 source

  • May combine two claims.

    Premisecitation

    Inhibition of GABA synthesis in the bed nucleus of the stria terminalis produced an anxiogenic effect in the plus-maze and social interaction test, reversed by local infusion of muscimol in the bed nucleus of the stria terminalis.

    “Inhibition of GABA synthesis in the BNST produced an anxiogenic effect in the plus-maze and social interaction test, another measure of sustained fear in which rats exposed to novel places under high illumination tend not to interact with each other; this effect was reversed by local infusion of muscimol in the BNST (Sajdyk et al, 2008).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Sajdyk et al, 2008 source

      The Elevated Plus-Maze, Social Interaction, and Discussion sections report anxiety-like effects after GABA-synthesis inhibition in the BNST; the Social Interaction results report reversal by local muscimol. However, the Social Interaction methods say testing occurred under low light in familiar conditions, not in novel places under high illumination. The paper describes the test as measuring anxiety-like behavior, not specifically sustained fear. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    CRF-enhanced startle was much lower in progesterone-injected rats than in vehicle-injected rats, and this effect seemed to be because of its major metabolite, allopregnanolone.

    “CRF-enhanced startle was much lower in progesterone-injected rats than in vehicle-injected rats and this effect seemed to be because of its major metabolite, allopregnanolone (Toufexis et al, 2004).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Toufexis et al, 2004 source

  • May combine two claims.

    Premisecitation

    In panic disorder, startle is larger in a threatening context but not at baseline when no stressor is present.

    “startle is exaggerated in panic disorder when tested in a threatening context (Grillon et al, 1994a), but not at baseline without obvious stressors (Amrhein et al, 2005; Ludewig et al, 2002; McTeague et al, 2009).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Grillon et al, 1994a source
    • cites Amrhein et al, 2005 source
    • cites Ludewig et al, 2002 source

  • May combine two claims.

    Premisecitation

    Risk for mood and anxiety disorders has been linked to factors such as parental anxiety history, early life stress, and female sex.

    “Various vulnerability factors have been associated with risk for mood and anxiety disorders, including a parental history of anxiety disorders (Merikangas et al, 1999), early life stress (Nemeroff, 2004), and being female (Kessler et al, 1994).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Merikangas et al, 1999 source
    • cites Nemeroff, 2004

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Kessler et al, 1994 source

  • May combine two claims.

    Premisecitation

    PTSD symptom severity correlates with self-reported danger and skin conductance responses under distal threat, and with eyeblink startle under intermediate threat, but not with any measure under proximal threat.

    “Symptom severity was strongly associated with both self-reported danger and the skin conductance response to startle stimuli under distal threat. Symptom severity was also associated with eyeblink startle magnitude under intermediate threat. None of the self-reported or physiological measures were associated with symptom severity under proximal threat.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Pole et al, 2009 source

      The Discussion reports greater skin conductance responses under low threat and greater eyeblink responses under medium threat; it also says subjective fear under low threat predicted symptom severity. But the Abstract Results and Discussion report that skin conductance under high threat predicted symptom severity, contrary to the claim that no measure was associated under proximal threat. The paper uses low, medium, and high threat rather than the citing sentence’s distal, intermediate, and proximal labels. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Light-enhanced startle is a paradigm in which acoustic startle amplitude is measured in dark then bright light, and exposure to bright light for 5-20 min significantly increases startle amplitude compared with remaining in dark.

    “Exposure to bright light for 5–20 min led to a significant increase in acoustic startle amplitude going from the dark to the light (light-enhanced startle) compared with startle amplitude when the rats remained in the dark.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Airpuffs do not generate sustained contextual anxiety when administered unpredictably, suggesting unpredictability per se does not elicit anxiety.

    “However, airpuffs do not generate sustained contextual anxiety when administered unpredictably (Figure 2, right panel), suggesting that unpredictability per se does not elicit anxiety (Staub et al, 1971), but see (Herry et al, 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Staub et al, 1971 source

  • May combine two claims.

    Findingreasoning

    After pairing a context with shock in rats, rats show a fear reaction in that context but not in a novel one, ruling out sensitization to shock.

    “Thus, after pairing a context with a shock in rats, the rats will show a fear reaction in that context but not in a novel one, ruling out sensitization to shock.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The procedure produced fear-potentiated startle throughout the clicker, with little or no potentiation before or after, indicating sustained fear across the 8-min clicker period.

    “Figure 6 shows that this procedure produced fear-potentiated startle throughout the duration of the clicker compared with little or no potentiation before or after the clicker, so that fear was sustained across the 8-min period when the clicker was on.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In the VR study, subjects' first choice was overwhelmingly the no shock context, and when forced to choose between predictable and unpredictable contexts, 80% avoided the unpredictable context.

    “Their first choice was overwhelmingly the no shock context. However, when they were forced to choose between the predictable and unpredictable contexts, most subjects (80%) avoided the unpredictable context (Grillon et al, 2006a).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grillon et al, 2006a source

  • May combine two claims.

    Findingcitation

    In an experiment with a 6-s light paired or unpaired with shock, baseline startle amplitude in the absence of the cue was greater in the unpaired group than in the paired group and lowest in the no-shock group.

    “Although fear-potentiated startle to the cue was retained at the 1-week test, baseline startle amplitude in the absence of the cue was greater in the unpaired group compared with that in the paired group and lowest in the group that received no shocks (Figure 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grillon and Davis, 1997

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation

    There was no pre- to post-conditioning increase in baseline startle in the absence of the clicker, indicating that the startle baseline was not influenced by contextual fear.

    “there was no pre- to post-conditioning increase in baseline startle (ie, in the absence of the clicker), indicating that the startle baseline, against which startle to the clicker was measured, was not influenced by contextual fear”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In a verbal threat experiment with predictable or unpredictable shocks, subjects showed large startle potentiation during the threat cue in the predictable condition and a linear increase in startle reactivity during the inter-trial interval from no shock to predictable to unpredictable shock.

    “Replicating the pattern of responses seen in conditioning studies, subjects showed a large startle potentiation during the threat cue in the predictable condition. They also showed a linear increase in startle reactivity during the inter-trial interval that reflected the progressive increase in reactivity (ie, anxiety) from the no shock to the predictable shock to the unpredictable shock condition”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grillon et al, 2004 source

  • May combine two claims.

    Findingown data

    Oral CRF-R1 antagonist dose-dependently blocked fear-potentiated startle to an 8-min CS, but not to 3.7-s CSs, and sometimes enhanced the latter.

    “oral administration of the CRF-R1 antagonist dose dependently blocked fear-potentiated startle to an 8-min CS presentation, but did not disrupt fear-potentiated startle to 3.7-s CS presentations, and even enhanced it in some animals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BLA infusions blocked both startle components; CeA infusions blocked neither.

    “Infusions into the BLA blocked both components and, in this study, infusions into the CeA blocked neither.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BNST infusions reduced late fear-potentiated startle (min 5-8) but enhanced early startle (min 1-5).

    “BNST infusions decreased the late component of fear-potentiated startle (ie, minutes 5–8 of the CS) but actually increased the early component (ie, minutes 1–5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In rats trained with the sustained fear paradigm, the CRF1 antagonist did not affect phasic startle to a 3.7-s clicker, confirming that sensitivity to CRF-R1 blockade depends on response duration during testing, not training type.

    “The CRF1 antagonist also had no effect on phasic startle increases (ie, to a 3.7-s clicker CS presentation) in rats trained using the sustained fear conditioning paradigm, confirming that it is the duration of the fear response during testing that confers sensitivity to CRF-R1 blockade, and not the nature of the training.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Caudal BLA infusions were most effective, matching the caudal BLA projection to BNST.

    “Infusion into the caudal BLA was the most effective (Figure 8), consistent with caudal BLA projections to the BNST”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Dong et al, 2001 source
    • cites McDonald, 1991 source
    • cites Weller and Smith, 1982 source

  • May combine two claims.

    Findingown data

    NBQX infused into CeA did not block light-enhanced startle, whereas BNST infusions did.

    “light-enhanced startle was not blocked by local infusion of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist NBQX into the CeA, but was blocked by local infusions into the BNST.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Fear-potentiated startle to the explicit conditioned stimulus was not disrupted by any dose of a CRF1 antagonist, but pre- to post-conditioning startle increases were disrupted at doses between 3 and 30 mg/kg.

    “although fear-potentiated startle to the explicit CS was not disrupted by any dose of a CRF1 antagonist, the pre- to post-conditioning startle increases were disrupted at doses of between 3 and 30 mg/kg.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    i.c.v. CRF did not occlude fear-potentiated startle to a 3.7-s visual CS, even though it greatly raised baseline startle.

    “fear-potentiated startle to a 3.7-s visual CS in other rats was not occluded by i.c.v. CRF infusions, although these infusions caused a much bigger increase in ‘baseline’ startle”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The disruptive effect on pre- to post-conditioning startle increases was not observed at 60 mg/kg, producing a non-monotonic dose-response curve.

    “However, this effect was not observed at doses of 60 mg/kg (Figure 13)—a non-monotonic dose–response curve similar to that previously observed with light-enhanced startle”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Lactating females showed significantly less CRF-enhanced startle compared with cycling females, although both groups showed a significant increase in startle amplitude after CRF infusions.

    “although both groups showed a significant increase in startle amplitude after CRF infusions, lactating females showed significantly less CRF-enhanced startle compared with cycling females (Walker et al, 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Walker et al, 2003 source

  • May combine two claims.

    Findingown data

    In castrated males, the mean level of light-enhanced startle was comparable with that observed in females, and this effect could be reversed with testosterone.

    “In castrated males, the mean level of light-enhanced startle was comparable with that observed in females and this effect could be reversed with testosterone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the authors' original study, diazepam did not block the acquisition of fear-potentiated startle in rats, only its expression.

    “in our original study we found that in rats, diazepam did not block the acquisition of fear-potentiated startle, only its expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Light-enhanced startle was statistically significant in both female groups but statistically absent in intact male rats.

    “Light-enhanced startle was statistically significant in both female groups but statistically absent in intact male rats.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Anxiety is linked to potential or distal predator presence, while fear is evoked by clear and imminent threat.

    “The state of anxiety has been linked to the potential (pre-encounter) or distal (post-encounter) presence of a predator, whereas fear is evoked by the clear and imminent threat (circa strike).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Fear and anxiety are distinct states that differ in key dimensions, with fear being phasic and anxiety sustained.

  • Classified as probably not a substantial claim.

    Premisecitation

    Sustained fear is measured using a more diffuse cue arranged so the subject does not know when the aversive event will occur, eliciting a longer-lasting state that decays more slowly.

    “In contrast, sustained fear is measured using a more diffuse cue, or cues, arranged so that the subject does not know when during the aversive event will occur. This elicits a state of fear that can last for a much longer period of time and often decays more slowly after the fearful signal is removed (de Jongh et al, 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites de Jongh et al, 2003 source
    • The authors state this as an assumption: Fear and anxiety are distinct states that differ in key dimensions, with fear being phasic and anxiety sustained.

  • May combine two claims.

    Premisecitation

    Verbal threat procedures can be used in repeated designs because learning is minimized, and a recent study showed no reduction of fear-potentiated startle when repeated four times in a single day or once per day for 4 days.

    “Finally, as learning is minimized during verbal threat, such procedures can be used in repeated designs. A recent study showed no reduction of fear-potentiated startle when a verbal threat procedure was repeated either four times in a single day or once per day for 4 days (Klumpers et al, 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Klumpers et al, 2008

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Fear-potentiated startle is closely time-locked to the CS and is generally maximal at the time after CS onset when shock occurred in training.

    “Fear-potentiated startle is closely time-locked to the CS; hence, it is generally maximal during testing at the time after the CS onset when the shock occurred in training (Davis et al, 1989).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Davis et al, 1989 source

  • May combine two claims.

    Premisecitation

    Dark-enhanced startle is blocked by diazepam and is increased in PTSD.

    “It is blocked by the benzodiazepine diazepam (Baas et al, 2002) and is increased in PTSD (Grillon et al, 1998b).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Baas et al, 2002 source
    • cites Grillon et al, 1998b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    In both rats and humans, sustained fear appears more sensitive to clinically effective anti-anxiety drugs or treatments, perhaps due to different neural substrates.

    “Moreover, in both rats and humans, sustained fear appears to be more sensitive to clinically effective anti-anxiety drugs or treatments, perhaps as a result of the different neural substrates of each.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Fear and anxiety are distinct states that differ in key dimensions, with fear being phasic and anxiety sustained.

  • May combine two claims.

    Premisecitation

    The eyeblink component of the startle reflex in humans shares many characteristics with the whole-body startle response in rodents, including increases by anticipation of aversive stimuli and during processing of negatively valenced information.

    “The eyeblink component of the startle reflex in humans shows many of the same characteristics seen in the whole-body startle response in rodents. In particular, both are increased by anticipation of aversive stimuli and during the processing of negatively valenced information (Brown et al, 1951; Lang et al, 2000).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Brown et al, 1951 source
    • cites Lang et al, 2000 source
    • Rests on an assumption: The acoustic startle reflex is mediated by a simple brainstem and spinal cord pathway that can be measured in several species, including humans.

  • Classified as probably not a substantial claim.

    Premisecitation

    Phasic fear can be measured using a short, discrete cue predictably paired with an aversive event, eliciting a state that begins and dissipates quickly.

    “In the laboratory, phasic fear can be measured using a short, discrete cue that is predictably paired with an aversive event. This elicits a state of fear highly time-locked to the fear-inducing stimulus that begins quickly and dissipates quickly once the fear stimulus is removed (Davis et al, 1989; de Jongh et al, 2003).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Davis et al, 1989 source
    • cites de Jongh et al, 2003 source
    • The authors state this as an assumption: Fear and anxiety are distinct states that differ in key dimensions, with fear being phasic and anxiety sustained.

  • May combine two claims.

    Study design and conductreasoning

    The eyeblink startle reflex has face validity for studying aversive states and anxiety disorders, as DSM-IV-R lists exaggerated startle as a PTSD criterion.

    “In addition, the eyeblink component of the startle reflex has face validity for studying aversive states and anxiety disorders. For instance, the DSM-IV-R lists exaggerated startle as a criterion for posttraumatic stress disorder (PTSD).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The acoustic startle reflex is mediated by a simple brainstem and spinal cord pathway that can be measured in several species, including humans.

  • May combine two claims.

    Interpretationreasoning

    Knowledge of future aversive events is sufficient to create a threatening context in humans, and anticipating later shocks may elicit mild anxiety akin to pre-encounter stage.

    “For example, as humans are endowed with a cognitive system that enables symbolic representation of aversive experience, the knowledge of future aversive events is sufficient to create a threatening context. Participation in an experiment in which subjects know that they will eventually receive shocks at a later time may be akin to the pre-encounter stage and may thus elicit mild anxiety.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Fear and anxiety are distinct states that differ in key dimensions, with fear being phasic and anxiety sustained.

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

    Interpretationreasoning

    Fear and anxiety evoked experimentally in humans can be framed according to the same defensive distance continuum.

    “By analogy, fear and anxiety evoked experimentally in humans may be framed according to the same defensive distance continuum.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Fear and anxiety are distinct states that differ in key dimensions, with fear being phasic and anxiety sustained.

  • May combine two claims.

    Premisecitation

    In humans, darkness is sufficiently anxiogenic to potentiate startle, and dark-enhanced startle is replicable across laboratories and observed in adolescents and adults.

    “In contrast to rodents, humans are diurnal and feel more vulnerable in the dark (Schaller et al, 2003), and darkness is sufficiently anxiogenic in humans to potentiate startle (Grillon et al, 1997b). Dark-enhanced startle is replicable across laboratories (Grillon et al, 1999), and can be observed in both adolescents (Grillon et al, 1999) and adults (Coplan et al, 1998; Grillon and Ameli, 1998b;”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Grillon et al, 1997b source
    • cites Grillon et al, 1999 source

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

    Premisecitation

    Fear-potentiated startle can be used in mice and rhesus monkeys.

    “Fear-potentiated startle can also be used in mice (Falls et al, 1997) and rhesus monkeys (Winslow et al, 2002).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Falls et al, 1997 source
    • cites Winslow et al, 2002 source

  • May combine two claims.

    Premisecitation

    Anxiety is sensitive to anxiolytic drugs, whereas fear is not.

    “Pharmacological analyses of these defensive behaviors show that anxiety is sensitive to anxiolytic drugs, whereas fear is not (Blanchard et al, 1993).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Blanchard et al, 1993 source
    • The authors state this as an assumption: Fear and anxiety are distinct states that differ in key dimensions, with fear being phasic and anxiety sustained.

  • May combine two claims.

    Interpretationown data

    Contextual anxiety is robust but depends on a sufficiently aversive US.

    “These results indicate that contextual anxiety is robust. However, it depends on a sufficiently aversive US.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Chlordiazepoxide reduces CRF-enhanced startle but not strychnine-induced startle increases.

    “The benzodiazepine anxiolytic, chlordiazepozide, reduced this effect, but in control studies it did not reduce startle increases produced by the inhibitory glycine receptor antagonist strychnine”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Swerdlow et al, 1986 source
    • cites Kehne et al, 1981 source

  • May combine two claims.

    Interpretationnone given

    Phasic and sustained fear have distinct anatomical substrates and respond differently to drugs.

    “phasic and sustained fear differ both in terms of their anatomy and their susceptibility to different pharmacological treatments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Columns of cells in the stria terminalis and ventral basal forebrain link the central and medial amygdala nuclei with the BNST; this continuum is called the extended amygdala.

    “They showed that the central (CeA) and medial (MeA) nuclei of the amygdala and the bed nucleus of the stria terminalis (BNST) were connected by columns of cells located throughout the stria terminalis, the fiber tract that connects these amygdala nuclei with the BNST, and also in a ventrally located part of the basal forebrain.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Alheid et al, 1998 source
    • cites Alheid and Heimer, 1988 source

  • May combine two claims.

    Interpretationreasoning

    CeA electrolytic lesions cut CeA output and also sever BLA-BNST connections; many reported effects of such lesions may stem from this disconnection.

    “electrolytic lesions of the CeA will not only block outputs of the CeA but also disconnect the BLA from the BNST and we believe many effects that have been found after electrolytic lesions of the CeA may result from this disconnection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CeAL is a major source of CRF in BNSTL; electrolytic CeA lesions, unlike BLA lesions, nearly eliminate BNSTL CRF immunoreactivity in the dorsal part.

    “CeAL neurons are a major source of BNSTL CRF. This was shown by Sakanaka et al (1986), who found that electrolytic CeA, but not BLA, lesions dramatically reduced BNSTL CRF immunoreactivity, nearly depleting it entirely from the dorsal BNSTL.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sakanaka et al, 1986 source

  • May combine two claims.

    Premisecitation

    CeA and BNSTL share similar connections, cell types, and neurochemistry, including high levels of several peptides.

    “the CeA and the BNSTL are highly similar anatomically in terms of inputs, outputs, cell types, and neurochemical makeup, especially with respect to the high levels of several peptides found in both structures”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Alheid et al, 1995

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationnone given

    Several procedures-light-enhanced startle in rats, dark-enhanced startle in humans, unpredictable context conditioning or verbal threat, long-duration shock-paired cues, and brain CRF infusion-generate prolonged fear states.

    “Light-enhanced startle in rats, dark-enhanced startle in humans, context conditioning or verbal threats that involve unpredictable aversive events in rats and humans, long-duration cues paired with shocks in rats, or CRF infusion into the rat brain all produce longer, sustained states of fear.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Context conditioning serves as a model of hippocampal (and amygdala)-dependent fear conditioning, whereas phasic cue conditioning depends on the amygdala but not the hippocampus.

    “Instead, context conditioning serves as a model of hippocampal (and amygdala)-dependent fear conditioning, as opposed to phasic cue conditioning, which depends on the amygdala but not the hippocampus (Kim and Fanselow, 1992; Phillips and LeDoux, 1992).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kim and Fanselow, 1992 source
    • cites Phillips and LeDoux, 1992 source

  • May combine two claims.

    Premisecitation

    CeAL sends projections to the substantia innominata, possibly CeAM, and strongly to BNSTL.

    “The CeAL instead projects to the substantia innominata, perhaps to the CeAM, and quite prominently to the BNSTL”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bourgeais et al, 2001 source
    • cites Dong et al, 2001 source
    • cites Petrovich and Swanson, 1997 source

  • May combine two claims.

    Interpretationreasoning

    Contextual cues are constant reminders of the US but less predictive of its occurrence, leaving organisms in a sustained state of fearful apprehension.

    “In contrast to discrete cues that precisely signal the timing of US delivery, contextual cues are constant reminders of the US, but are less predictive of their occurrence; they leave the organisms in a sustained state of fearful apprehension.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    CRF's action on startle is mediated by brain CRF receptors and does not require the hypothalamic-pituitary-adrenal axis.

    “Together, these findings indicated that the effects of CRF on startle were directly mediated by CRF receptors in the brain, and did not involve activation of the CRF-regulated hypothalamic–pituitary–adrenal axis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The basolateral amygdala sends projections to both CeA and BNSTL, with the caudal BLA contributing especially to BNSTL.

    “The basolateral nucleus of the amygdala (BLA) also projects not only to the CeA but also to the BNSTL, particularly from the caudal part of the BLA (BLAc)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Dong et al, 2001 source
    • cites McDonald, 1991 source
    • cites Weller and Smith, 1982 source

  • May combine two claims.

    Premisecitation

    A cue paired with a US becomes the best predictor and overshadows the context, leading to little context conditioning; when CS and US are unpaired, the context becomes the only predictor, leading to increased context conditioning.

    “A cue paired with a US becomes the best predictor of the US. The cue overshadows the context, which then elicits little context conditioning (Rescorla and Wagner, 1972). In contrast, when the CS and US are not paired, the context becomes the only predictor of the US, although a poor one, leading to increased context conditioning (Odling-Smee, 1975a, b; Rescorla and Wagner, 1972).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Rescorla and Wagner, 1972

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Odling-Smee, 1975a source
    • cites Odling-Smee, 1975b source

  • May combine two claims.

    Interpretationreasoning

    CRF-enhanced startle is a prolonged startle increase that responds to benzodiazepines and is not conditioning-dependent.

    “Thus, CRF-enhanced startle leads to a sustained increase in startle amplitude, is sensitive to benzodiazepines, and does not involve conditioning.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CeA output goes mainly to the lateral BNST, while MeA output goes mainly to the medial BNST.

    “They also showed that the CeA projected primarily to the lateral division of the BNST (BNSTL) and that the MeA projected primarily to the medial division of the BNST (BNSTM).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Alheid et al, 1998 source
    • cites Alheid and Heimer, 1988 source

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Startle potentiation to a discrete cue that reliably predicts an aversive event or a verbal threat indexes phasic fear.

    “Fear-potentiated startle to a discrete cue predictably paired with an aversive cue or with a verbal threat is a measure of phasic fear.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The study was not designed to evaluate context conditioning and lacked context discrimination controls necessary to rule out non-associative sensitization.

    “As this study was not designed with the specific intent to evaluate context conditioning, we did not include context discrimination controls that would be necessary to rule out the possibility that these increases were because of non-associative sensitization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PVT axons appear to contact CRF neurons in CeAL, which suggests direct modulation of CRF signaling.

    “PVT fibers appear to make contact onto CRF-containing neurons in the CeAL (Li and Kirouac, 2008), suggesting that they can directly modulate CRF transmission.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Li and Kirouac, 2008 source

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

    Premisecitation

    The PVT-amygdala pathway is proposed to be a key regulator of the HPA stress response.

    “Bhatnagar and Dallman (1998) suggested that the PVT to the amygdala pathway is a key regulator of the hypothalamic-pituitary-adrenal response to stress.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bhatnagar and Dallman, 1998 source

  • May combine two claims.

    Interpretationreasoning

    Both fear effects require the BLA, but whether they use the same or different BLA neurons is unknown.

    “we believe both effects involve the BLA, although we cannot say for certain whether the same or different BLA neurons are involved.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Drugs or manipulations acting via different systems (CeA vs BNST) should summate on startle, while those acting via the same system should occlude each other.

    “the influence of startle on treatments that acted through different systems (ie, the CeA or BNST) would be additive, whereas the effects on startle of treatments that acted through the same system (ie, both CeA or both BNST) would occlude one another”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Walker and Davis, 2002b source

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

    Premisecitation

    BNSTL lesions after training impair freezing and corticosterone responses to a context CS but not to a brief auditory CS; CeA lesions impair freezing to both.

    “Sullivan et al (2004) reported that post-training electrolytic BNSTL lesions disrupt freezing, as well as corticosterone responses to a context CS, but do not affect these same responses to a brief auditory CS, whereas CeA lesions disrupt freezing to both.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sullivan et al, 2004 source

  • May combine two claims.

    Premisecitation

    In rats, CeAM is innervated by nearly all other amygdala nuclei, but CeAL receives almost no intra-amygdala input.

    “in the rat, the CeAM receives input from almost all other nuclei within the amygdala, whereas the CeAL receives virtually no amygdala input at all”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jolkkonen and Pitkanen, 1998 source

  • May combine two claims.

    Interpretationcitation

    The shift from CeAM to BNSTL control may start 4-60 s after CS onset, with full BNSTL dependence taking several minutes.

    “we suspect that the transition from CeAM to BNSTL involvement may begin between 4 and 60 s after CS onset, although it may be several minutes before the response is fully dependent on the BNSTL.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Davis et al, 1989 source
    • cites Walker and Davis, 1997a source

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

    Interpretationreasoning

    A more conservative view is that BNSTL lesions impair context freezing because context cues and their responses are always long-lasting.

    “a more conservative interpretation may be that BNSTL lesions disrupt context-elicited freezing simply because context CSs are invariably long in duration, and so also are the responses they evoke.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    CeA and BNST systems are not completely separate and likely interact, perhaps in the BLA.

    “This suggests that at some level (quite possibly the BLA and perhaps elsewhere as well), these systems do interact and are thus not totally independent from each other”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Intra-BNST cobalt chloride before testing disrupted context freezing and lowered heart rate and blood pressure.

    “Resstel et al (2008) reported that pre-test intra-BNST infusions cobalt chloride, which block neurotransmitter release but not action potential propagation, disrupted context-elicited freezing, and decreased heart rate and arterial blood pressure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Resstel et al, 2008 source

  • May combine two claims.

    Premisecitation

    The CRF-R1/2 antagonist αhCRF9-41 given i.c.v. did not affect fear-potentiated startle to a 3.7-s light, but disrupted light-enhanced startle at 5 μg and not at 25 μg.

    “de Jongh et al (2003) reported that i.c.v. infusions of the CRF-R1/2 antagonist αhCRF9–41 had no effect on fear-potentiated startle to a 3.7-s light, but significantly disrupted light-enhanced startle at an intermediate (5 μg) but not at a higher dose (25 μg).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites de Jongh et al, 2003 source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    CeA lesion effects may arise from damage to CeAL, which is thought to mediate sustained fear via BNST projections.

    “the effects of CeA lesions may have been because of destruction of the CeAL, which we believe is particularly involved in sustained fear through projections to the BNST.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    The heaviest projections from the basolateral amygdala to the central amygdala are to the medial central amygdala, which projects to the hypothalamus and brainstem to mediate phasic fear responses.

    “The heaviest projections from the BLA to the CeA are to the CeAM, which in turn projects to the hypothalamus and brainstem to mediate phasic fear responses.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Glutamate may selectively activate medial central amygdala neurons that mediate short-duration fear responses, whereas CGRP, corticosterone, and/or other peptide receptors may selectively influence lateral central amygdala neurons that mediate more sustained fear responses.

    “It is therefore possible that glutamate selectively activates CeAM neurons that mediate short-duration fear responses, whereas CGRP, corticosterone, and/or other peptide receptors selectively influence CeAL neurons that mediate more sustained fear responses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Social defeat behavior in Syrian hamsters was reduced by pre-defeat unilateral electrolytic central amygdala lesions or by pre-test unilateral intra-lateral bed nucleus of the stria terminalis infusion of the CRF antagonist D-Phe CRF12-41.

    “Jasnow et al (2004) found that social defeat behavior in Syrian hamsters was reduced by pre-defeat unilateral electrolytic CeA lesions or by pre-test unilateral intra-BNSTL infusion of the CRF antagonist, D-Phe CRF12–41.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jasnow et al (2004) source

  • May combine two claims.

    Interpretationreasoning

    The blockade of CRF-enhanced startle by basolateral amygdala infusion could explain why electrolytic lesions of the central amygdala blocked CRF-enhanced startle, because these lesions would disconnect the basolateral amygdala from the bed nucleus of the stria terminalis, though other possibilities cannot be ruled out.

    “This result could explain why electrolytic lesions of the CeA blocked CRF-enhanced startle because these lesions would effectively disconnect the BLA from the BNST, although other possibilities cannot be ruled out.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    The current working hypothesis is that CRF terminals in the bed nucleus of the stria terminalis act presynaptically on basolateral amygdala terminals within the lateral bed nucleus of the stria terminalis, promoting glutamate release and excitatory drive onto lateral bed nucleus of the stria terminalis neurons.

    “Our current working hypothesis is that CRF terminals in the BNST act presynaptically on BLA terminals within BNSTL, where they promote glutamate release and, therefore, excitatory drive onto BNSTL neurons.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The lateral central amygdala, activated by the basolateral amygdala, the stress-sensitive paraventricular thalamus, and cortical inputs, projects to and releases CRF that acts presynaptically on glutamate terminals from the caudal basolateral amygdala.

    “The CeAL, activated perhaps by the BLA but also by the stress-sensitive PVT, and by cortical inputs, projects to and releases CRF that acts presynaptically on glutamate terminals from the caudal BLA”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The observed behavioral effects in those studies might have been attributable to an interruption of the basolateral amygdala-to-lateral bed nucleus of the stria terminalis pathway instead.

    “Thus, the observed behavioral effects in these studies might have been attributable to an interruption of this pathway instead.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Neither unilateral intra-central amygdala TTX infusions nor unilateral intra-lateral bed nucleus of the stria terminalis infusions of D-Phe CRF12-41 disrupted shock-induced reinstatement of extinguished cocaine-seeking behavior, but the combination of both treatments on opposite sides did.

    “Erb et al (2001) found that neither unilateral intra-CeA TTX infusions nor unilateral intra-BNSTL infusions of D-Phe CRF12–41 disrupted shock-induced reinstatement of extinguished cocaine-seeking behavior, but that the combination of both treatments, again on opposite sides of the brain, did.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Erb et al (2001) source

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

    Interpretationnone given

    Inhibitory feedback to the medial central amygdala from either the lateral central amygdala or the bed nucleus of the stria terminalis shuts down the medial central amygdala, allowing a seamless transition from phasic to sustained fear.

    “Inhibitory feedback to the CeAM from either the CeAL or the BNST shuts down the CeAM, allowing a seamless transition from phasic to sustained fear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both stress and the stress-related hormone corticosterone increase CRF mRNA levels in central amygdala neurons.

    “both stress (Albeck et al, 1997; Hatalski et al, 1998; Hsu et al, 1998; Kalin et al, 1994; Makino et al, 1999) and the stress-related hormone corticosterone increase CRF mRNA level in CeA neurons (Makino et al, 1994b; Shepard et al, 2000; Thompson et al, 2004; Watts and Sanchez-Watts, 1995).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Albeck et al, 1997 source
    • cites Hatalski et al, 1998 source
    • cites Hsu et al, 1998 source

  • May combine two claims.

    Premisecitation

    In rats undergoing chronic immobilization stress (2 hours per day for 15 days), potassium-evoked glutamate release was persistently elevated, and this increase was normalized by intra-bed nucleus of the stria terminalis infusions of the CRF-R1 antagonist NBI-27914.

    “They have found that [K+]-evoked glutamate release was persistently elevated in rats undergoing chronic immobilization stress (2 h/day for 15 days) and that this increase was normalized by intra-BNST infusions of the CRF-R1 antagonist NBI-27914.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Forray et al, 2005

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Lactation is associated with high progesterone levels, and anxiolytic effects are seen during lactation, probably because progesterone and its GABAA receptor modulating metabolites increase GABA transmission.

    “Lactation is associated with high progesterone levels, and anxiolytic effects are seen during lactation, probably because progesterone and its GABAA receptor modulating metabolites (most notably allopregnanolone) increase GABA transmission (c.f., Lambert et al, 2001; Lan and Gee, 1994) (eg, Akwa et al, 1999; Bitran et al, 1995, 1999; Brot et al, 1997).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Lambert et al, 2001 source
    • cites Lan and Gee, 1994 source
    • cites Akwa et al, 1999 source

  • May combine two claims.

    Interpretationreasoning

    The working model of phasic versus sustained fear focuses on the basolateral amygdala, central amygdala, and lateral bed nucleus of the stria terminalis, with CRF-containing projections from the lateral central amygdala to the lateral bed nucleus of the stria terminalis involved in sustained fear.

    “Figure 14 summarizes our working model of phasic vs sustained fear focusing on the BLA, CeA, and BNSTL and how CRF-containing projections from the CeAL to the BNSTL are involved in sustained fear.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The results of the Jasnow et al (2004) and Erb et al (2001) studies are consistent with the conclusions drawn, but are not definitive because only a partial implementation of the crossed-lesion design was used.

    “Although the results of both studies are consistent with the conclusions that were drawn, they are not definitive insofar as only a partial implementation of the crossed-lesion design was used.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Medial central amygdala neurons thought to mediate short-duration fear responses through direct projections to the brainstem are AMPA-responsive, whereas lateral central amygdala neurons that may mediate longer-duration fear responses indirectly via projections to the lateral bed nucleus of the stria terminalis are not.

    “One possibility is that the CeAM neurons thought to mediate short-duration fear responses through direct projections to the brainstem are AMPA-responsive, whereas the CeAL neurons that may mediate longer duration fear responses indirectly by way of projections to the BNSTL are not.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Diazepam was found in humans to disrupt acquisition of cued fear-potentiated startle conditioning when given before training, but not when given before a performance test that assessed expression of an acquired conditioned fear response.

    “diazepam was found in humans to disrupt acquisition of cued fear-potentiated startle conditioning when given before training, but not when given before a performance test that assessed the expression of an acquired conditioned fear response (Scaife, 2005; Scaife et al, 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Scaife, 2005

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Scaife et al, 2005 source

  • May combine two claims.

    Premisecitation

    Initial studies found that diazepam and alprazolam decreased fear-potentiated startle during a verbal threat procedure, but these findings were not confirmed in several studies using various benzodiazepines.

    “Initial studies found that diazepam (Bitsios et al, 1999) and alprazolam (Riba et al, 2001) decreased fear-potentiated startle during a verbal threat procedure in which short-duration threat cues predicted a shock, but these findings were not confirmed in several studies using various benzodiazepines (Baas et al, 2002; Grillon et al, 2006b; Riba et al, 1999; Scaife et al, 2005).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bitsios et al, 1999 source
    • cites Riba et al, 2001 source
    • cites Baas et al, 2002 source

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

    Premisecitation

    It has been argued that the positive effect of benzodiazepines on fear-potentiated startle did not reflect genuine reductions in fear but was artifactual, secondary to reduced baseline startle reactivity.

    “it has been argued that the positive effect of benzodiazepines on fear-potentiated startle (Bitsios et al, 1999; Riba et al, 2001) did not reflect genuine reductions in fear but was artifactual, secondary to reduced baseline startle reactivity (Grillon and Baas, 2002; Walker and Davis, 2002b).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Grillon and Baas, 2002 source
    • cites Walker and Davis, 2002b source

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

    Interpretationcitation

    The attenuating effect of benzodiazepines on startle is not surprising, given that these drugs have muscle relaxant and sedative properties.

    “The attenuating effect of benzodiazepines on startle is not surprising, given that these drugs have muscle relaxant and sedative properties (File, 1982).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites File, 1982 source

  • May combine two claims.

    Premisecitation

    Benzodiazepines can disrupt learning and memory processes, raising the possibility that they reduce fear conditioning because of amnestic effects rather than anxiolytic properties when given before training.

    “These latter processes can be disrupted by benzodiazepines (Dickinson-Anson and McGaugh, 1997; Harris and Westbrook, 2001; Jensen et al, 1979; Pain et al, 2002), raising the possibility that benzodiazepines reduce fear conditioning because of their amnestic effects, rather than their anxiolytic properties when given before training.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Dickinson-Anson and McGaugh, 1997 source
    • cites Harris and Westbrook, 2001 source
    • cites Jensen et al, 1979 source

  • May combine two claims.

    Premisenone given

    Most human studies use verbal threat to a specific cue, which examines the expression of fear responses, whereas animal studies rely on fear conditioning, a task that depends on learning and memory.

    “most human studies use verbal threat to a specific cue, which examines the expression of fear responses, whereas animal studies rely on fear conditioning, a task that depends on learning and memory.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Startle in rats may be much less sensitive to the sedative effects of benzodiazepines, allowing higher doses in rats than in humans and thus allowing anxiolytic effects in phasic fear to be measured.

    “another possibility is that startle in rats is much less sensitive to the sedative effects of benzodiazepines so that much higher doses can be used in rats than in humans, thus allowing anxiolytic effects in phasic fear to be measured.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Gonadal steroids appear to affect sustained but not phasic fear, supporting the idea that these procedures produce qualitatively different forms of fear or anxiety-like behaviors.

    “Overall, therefore, gonadal steroids appear to affect sustained but not phasic fear, providing further support for the idea that these different procedures produce qualitatively different forms of fear or anxiety-like behaviors.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The reduction in startle baseline by diazepam in humans and rodents might be caused by an anxiolytic effect on contextual anxiety rather than simply reflecting a nonspecific side effect.

    “it is possible that rather than simply reflecting a nonspecific side effect, the reduction in startle baseline by diazepam in humans (Baas et al, 2002) and rodents (Guscott et al, 2000) might be caused by an anxiolytic effect on contextual anxiety.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Baas et al, 2002 source
    • cites Guscott et al, 2000 source

  • May combine two claims.

    Premisecitation

    The effect of diazepam on conditioned fear did not appear to be due to a disruption of memory consolidation because diazepam blocked conditioned fear when given before but not after training.

    “This effect did not appear to be due to a disruption of memory consolidation because diazepam blocked conditioned fear when given before but not after training (Scaife et al, 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Scaife et al, 2005 source

  • May combine two claims.

    Premisecitation

    In several cases, lesions of the central amygdala did not block the anxiolytic effects of benzodiazepines, although central amygdala lesions tended to have anxiolytic effects on their own.

    “in several cases, lesions of the CeA did not block these anxiolytic effects of benzodiazepines, although the CeA lesions tended to have anxiolytic effects on their own (Kopchia et al, 1992; Yadin et al, 1991; Treit et al, 1993b).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kopchia et al, 1992 source
    • cites Yadin et al, 1991 source
    • cites Treit et al, 1993b source

  • May combine two claims.

    Premisecitation

    Baas et al (2002) reported that neither diazepam nor oxazepam reduced fear-potentiated startle, although these drugs reduced baseline startle.

    “Baas et al (2002) conducted four separate within- and between-subject studies and reported that neither diazepam nor oxazepam reduced fear-potentiated startle, although these drugs reduced baseline startle.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Baas et al, 2002 source

  • May combine two claims.

    Interpretationcitation

    This result agrees with the clinical view that specific phobias respond poorly to citalopram compared with other anxiety disorders, and with rodent work suggesting serotonin is not essential for phasic fear-potentiated startle.

    “This is in line with the clinical observation that specific phobias respond less well to treatments such as citalopram than other pathological anxiety states (Baldwin et al, 2005) and with preclinical evidence in rodents showing that the serotonergic system may not be critical for the expression of phasic fear-potentiated startle (Davis et al, 1988).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Baldwin et al, 2005 source
    • cites Davis et al, 1988 source

  • May combine two claims.

    Premisecitation

    Taking part in a study where aversive stimuli will later be delivered resembles the pre-encounter stage of the defensive distance model and can produce mild, measurable anxiety.

    “participating in an experiment involving the future delivery of aversive stimuli can be considered analogous to the pre-encounter stage of the defensive distance model and can evoke mild and measurable anxiety (Bocker et al, 2004; Grillon et al, 1998c).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bocker et al, 2004 source
    • cites Grillon et al, 1998c source

  • May combine two claims.

    Premisecitation

    Hierarchical models support a broad negative affectivity factor common to most anxiety disorders and depression, plus a distinct fear factor that separates anxiety disorders.

    “Hierarchical models confirm the presence of a unique broad negative affectivity factor that cuts across most anxiety disorders (including depression), and of a separate and a unique fear factor that discriminates among anxiety disorders (Brown et al, 1998).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Brown et al, 1998 source

  • May combine two claims.

    Premisecitation

    Acute citalopram raises both fear to predictable shock and anxiety to unpredictable shock.

    “although acute citalopram increased both fear and anxiety to predictable and unpredictable shock, respectively (Grillon et al, 2007)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grillon et al, 2007 source

  • May combine two claims.

    Premisecitation

    This broad vulnerability factor is stronger in GAD, panic disorder, and PTSD, weaker in circumscribed fear disorders like simple phobia, and intermediate in social phobia.

    “the broad vulnerability factor loads more heavily in GAD, panic disorder, and PTSD and less on disorders with circumscribed fear such as simple phobias, with social phobia being intermediate (Chantarujikapong et al, 2001; Craske and Waters, 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Chantarujikapong et al, 2001 source
    • cites Craske and Waters, 2005 source

  • May combine two claims.

    Premisecitation

    Anxiety disorders vary in how specific the threat is, from diffuse threats in GAD to circumscribed threats in specific phobias; diffuse threats produce chronic sustained anxiety, while circumscribed ones produce strong fear.

    “Anxiety disorders also differ from each other in the primary object or specificity of threat, ranging from diffuse (eg, in generalized anxiety disorder (GAD)) to circumscribed (eg, in specific phobias), the former leading to symptoms of chronic sustained anxiety and the latter prompting strong fear (Cuthbert et al, 2003; Lang et al, 2000).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cuthbert et al, 2003 source
    • cites Lang et al, 2000 source

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

    Interpretationcitation

    This distinction may aid in separating fear-related from anxiety-related disorders by their core features and in finding vulnerability markers in high-risk people.

    “It can be noted that it may help distinguish among fear- and anxiety-related anxiety disorders (Watson, 2005; Kruger et al, 1988) based on core underlying features and help discover vulnerability markers in individuals at high risk for these conditions.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Watson, 2005 source
    • cites Kruger et al, 1988

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Interpretationreasoning

    Using phasic and sustained fear as operational definitions of fear and anxiety carries implications for several areas of clinical research.

    “The distinction between phasic and sustained fear as operational definitions of fear and anxiety has implications in several areas of clinical research.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In rats, giving citalopram acutely before training was reported to strengthen fear conditioning to a 20-second tone paired with footshock, while chronic dosing did the reverse.

    “Acute administration of citalopram in rats before training was reported to increase fear conditioning to a 20-s tone paired with footshock, whereas chronic administration had the opposite effect (Burghardt et al, 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Burghardt et al, 2004 source

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

    Interpretationreasoning

    The fear-versus-anxiety distinction from the potentiated startle model may be a useful tool for classifying anxiety states.

    “The distinction between fear and anxiety states based on our model of potentiated startle may therefore provide a valuable tool when classifying anxiety states.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Buspirone, which acts on serotonin and dopamine D2 receptors, has been reported repeatedly to lower fear-potentiated startle after acute dosing and also to lower light-enhanced startle.

    “Buspirone is a mixed serotonergic agonist and dopamine D2 antagonist that has repeatedly been found to reduce the expression of fear-potentiated startle after acute administration (Kehne et al, 1988; Mansbach and Geyer, 1988), as well as light-enhanced startle (Walker and Davis, 1997a).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kehne et al, 1988 source
    • cites Mansbach and Geyer, 1988 source
    • cites Walker and Davis, 1997a source

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

    Premisenone given

    Simple phobia, marked by fear of specific objects or situations, is the classic fear disorder.

    “Simple phobia, which is associated with fear to circumscribed objects or situations, is the archetype of a fear-related disorder.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Worry is viewed by some as a cognitive avoidance strategy that lowers anticipatory anxiety.

    “First, worry is essentially a cognitive avoidance strategy, which, some suggest, serves to reduce anticipatory anxiety (Borkovec and Inz, 1990).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Borkovec and Inz, 1990 source

  • May combine two claims.

    Interpretationreasoning

    That neuroticism had no effect under proximal threat agrees with evidence that anxious or at-risk individuals do not show greater fear of imminent danger.

    “The finding that neuroticism had no effect during proximal threat is consistent with results indicating that individuals with or at-risk for an anxiety disorder had no increase in fearfulness to imminent danger.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Phenotypic studies separate panic disorder from PTSD, but startle studies indicate both share a susceptibility to stronger sustained fear in aversive contexts.

    “For example, although panic disorder and PTSD are distinguishable based on phenotypic studies (Kruger et al, 1988, Vollebergh et al, 2001), startle studies suggest that these two disorders share a common susceptibility to enhanced sustained fear to aversive contexts.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kruger et al, 1988

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Vollebergh et al, 2001 source

  • May combine two claims.

    Premisecitation

    Men and women have similar fear-potentiated startle to a threat cue, but women show greater sustained anxiety to unpredictable shocks.

    “Men and women do not differ in their fear-potentiated startle to a threat cue, but women show enhanced sustained anxiety to unpredictable shocks (Grillon, 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grillon, 2008 source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    In two studies, unmedicated patients with panic disorder, PTSD, or GAD were compared with healthy controls.

    “The patients were not medicated and were compared with healthy controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Fear responses to a nonspecific stressor are similar in anxious patients and controls, but sustained contextual fear to unpredictable aversive stimuli separates PTSD or panic disorder from controls and from GAD.

    “These results confirm that although fearful responses to a nonspecific stressor do not differ between clinically anxious patients and controls, sustained contextual fear to unpredictable aversive stimuli distinguishes individuals with PTSD or panic disorder from controls and individuals with GAD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Panic disorder involves brief, unpredictable, uncontrollable panic attacks separated by strong anticipatory anxiety about them, which raises the chance of further attacks.

    “Panic disorder is similarly characterized by brief and intermittent unpredictable and uncontrollable aversive episodes (panic attacks) interspersed with high levels of anticipation anxiety of these aversive events, which in turn increases the likelihood of panic attacks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Findings in anxious patients suggest two dimensions of startle reactivity: high phasic fear without high sustained fear (as in simple phobia), and high sustained fear without high phasic fear (as in PTSD and panic disorder).

    “Taken together, the results obtained in anxious patients point to two dimensions of startle reactivity: one corresponding to high levels of phasic fear (eg, simple phobia) in the absence of heightened sustained fear and the other of heightened sustained fear (eg, PTSD, panic disorder) without elevated phasic fear.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    That only high-risk females show greater contextual anxiety points to sex differences in sustained anxiety, matching rodent findings.

    “The fact that only high-risk females show elevated contextual anxiety suggests gender differences in sustained anxiety, which is consistent with basic findings in rodents.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Worry uses verbal rumination to divert attention from the real threat and thereby reduce anxiety.

    “Worrisome thinking relies on verbally mediated processes (rumination) to shift the focus of attention away from the actual threat in order to reduce anxiety.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    GAD also differs from PTSD and panic disorder because those two involve sudden paroxysms of arousal, while GAD involves chronic anxiety without such paroxysms.

    “GAD also differs from PTSD and panic disorder, in which the latter two conditions involve sudden attacks of increased arousal (paroxysm), whereas GAD involves chronically elevated anxiety in the face of no such paroxysm.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    GAD involves excessive worry that cannot be controlled.

    “Given that GAD is characterized by excessive and uncontrollable worry (Borkovec et al, 1991; Roemer et al, 2002)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Borkovec et al, 1991
    • cites Roemer et al, 2002

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    Worry may not equal anticipatory anxiety; instead it may be a way of coping with anxiety.

    “From this perspective, worry may not be equivalent with anticipatory anxiety, rather it is an attempt to cope with anxiety (Craske, 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Craske, 1999

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    PTSD and panic disorder share features such as stress that is unpredictable and uncontrollable, and heightened anxiety sensitivity.

    “PTSD and panic disorder share common phenomenology, including the unpredictable and uncontrollable nature of the stress and enhanced anxiety sensitivity (Asmundson and Stapleton, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Asmundson and Stapleton, 2008 source

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

    Premisecitation

    Neuroticism is broadly accepted as a risk factor for anxiety disorders.

    “Neuroticism is a widely recognized risk factor for anxiety disorders (Bienvenu and Stein, 2003; Kendler et al, 2002).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bienvenu and Stein, 2003 source
    • cites Kendler et al, 2002 source

  • May combine two claims.

    Premisecitation

    PTSD follows uncontrollable, unpredictable traumatic events and involves intrusive memories along with hyperarousal and anxiety.

    “PTSD is precipitated by uncontrollable and unpredictable traumatic events, which result in intrusive recollections of the trauma with associated hyper-arousal and anxiety (American Psychiatric Association, 1994).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites American Psychiatric Association, 1994

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Research on physiological reactivity in GAD finds little hyperarousal and some signs of reduced arousal.

    “study on physiological reactivity in GAD has found minimal evidence of hyper-arousal and some evidence of reduced arousal (Hoehn-Saric et al, 1989).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hoehn-Saric et al, 1989 source

  • May combine two claims.

    Premisecitation

    Neuroticism correlated with stronger potentiation under intermediate distal threat, but not under proximal or more distal threat.

    “Neuroticism was associated with elevated potentiation in conditions of intermediate distal threat, but not in the condition when threat was proximal or more distal.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Waters et al, 2008 source

  • May combine two claims.

    Premisecitation

    Vietnam veterans with PTSD had normal fear-potentiated startle to a shock-predicting CS, yet stronger context conditioning upon returning to the room where they had been shocked.

    “Vietnam veterans with PTSD showed normative levels of fear-potentiated startle to a CS that predicted a shock, but enhanced context conditioning when returning to an experimental room where they had previously received shocks (Grillon et al, 1998c).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grillon et al, 1998c source

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

    Premisecitation

    Neuroticism is a basic personality trait linked to a tendency to feel negative emotions.

    “neuroticism, a core personality dimension associated with a proneness to experience negative feelings (Costa and McCrae, 1992).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Costa and McCrae, 1992

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    These findings were ascribed to sex differences in the BNST and to sex hormone effects on those structures.

    “These results were attributed to sexual dimorphism in the BNST (Allen and Gorski, 1990) and to the action of sex hormones on these structures (Toufexis, 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Allen and Gorski, 1990 source
    • cites Toufexis, 2007 source
146 of 146

  • The authors state this as an assumption.

    Fear and anxiety are distinct states that differ in key dimensions, with fear being phasic and anxiety sustained.

    “The major premise of this study is that although the symptoms of fear and anxiety are very similar, they differ in terms of certain key dimensions.”
    “Although the symptoms of fear and anxiety are very similar, they also differ.”

  • The paper relies on this without support.

    The acoustic startle reflex is mediated by a simple brainstem and spinal cord pathway that can be measured in several species, including humans.

    “The review will focus on studies that use the acoustic startle reflex, a very short latency reflex that is mediated by a simple brainstem and spinal cord pathway that can be measured in several species, including humans.”

  • The paper relies on this without support.

    Rats only freeze in a state of fear.

    “because rats only freeze in a state of fear”

  • The authors state this as an assumption.

    A serial circuit from the central amygdala to the bed nucleus of the stria terminalis is critical for the behavior under study.

    “Assuming that a serial CeA-to-BNST circuit is critical for the behavior in question, one would predict that the effect of the ipsilateral CeA plus BNST treatments would equal in magnitude to that obtained by unilaterally manipulating either structure alone and less than that of contralateral CeA plus BNST treatments.”

  • The authors state this as an assumption.

    The neurotoxic lesions in the later studies completely destroyed cells in the lateral central amygdala.

    “assuming the later lesions fully destroyed cells in the CeAL.”
5 of 5

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?

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 12 is described with conflicting cue types

    Minor

    The paper describes both experiments in Figure 12 as using auditory cues, but later identifies a 3.7-s light as a result shown in that figure.

1 of 1

Cites

Flagged first, then by citations

4 of the 343 references couldn’t be matched to a known paper.

Research works printed but not linked: 6

  1. Costa PT, McCrae RR (1992). Revised NEO Personality Inventory (NEO-PI-R) and NEO Five Factor Inventory (NEO-FFI) Professional Manual. Psychological Assessment Resources: Odessa, FL.
  2. Grillon C, Ameli R (1998a). Effects of threat and safety signals on startle during anticipation of aversive shocks, sounds, or airblasts. J Psychophysiol 12: 329–337.
  3. Grillon C, Baas JMP, Pine DS, Lissek S, Lawley M, Ellis V et al (2006c). The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by fear-potentiated startle. Biol Psychiatry 60: 760–766. · DOI · Paper page
  4. Hamm AO, Globisch J, Cuthbert BN, Vaitl D (1991a). Startle modulation in simple phobics and controls. Psychophysiology 28: s28.
  5. Riba J, Rodriguez-Fornells A, Urbano G, Antonijoan R, Barbanoj MJ (1999). Fear potentiated startle of the acoustic startle response is preserved after lorazepam administration to human subjects. Psychophysiology 36 (Suppl 1): S94.
  6. Scaife JJC, Langley RRW, Bradshaw CCM, Szabadi EE (2005). Diazepam suppresses the acquisition but not the expression of ‘fear-potentiation’ of the acoustic startle response in man. J Psychopharmacol 19: 347–356. · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Davis, M., Walker, D. L., Miles, L., & Grillon, C.
Affiliations
  • Emory University (US)
  • National Institutes of Health (US)
Corresponding author
Davis, Michael
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2009-08-19
Volume
35
Issue
1
Pages
105-135
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2009.109
PMC
PMC2795099
OpenAlex
W1972489844
Cited by
1,488
References
343
Citations by year
2026: 44 · 2025: 71 · 2024: 72 · 2023: 86 · 2022: 86 · 2021: 95 · 2020: 120 · 2019: 109 · 2018: 97 · 2017: 96 · 2016: 123 · 2015: 100 · 2014: 82 · 2013: 83 · 2012: 80
FWCI
14.96
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
anxiety, extended amygdala, bed nucleus of the stria terminalis, amygdala, acoustic startle response, corticotropin-releasing factor, hypothalamus, brainstem
MeSH terms
Amygdala, Animals

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 under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

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 ›

Are you an author, or do you see a problem with this page? Request a review