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Cited by 158Memory and Neural MechanismsAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesNeural and Behavioral Psychology Studies

The translational neural circuitry of anxiety

Open access
Robinson, Oliver J, Pike, Alexandra C, Cornwell, Brian, Grillon, Christian·2019·Journal of Neurology, Neurosurgery & Psychiatry
DOI 10.1136/jnnp-2019-321400
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Abstract

Anxiety is an adaptive response that promotes harm avoidance, but at the same time excessive anxiety constitutes the most common psychiatric complaint. Moreover, current treatments for anxiety—both psychological and pharmacological—hover at around 50% recovery rates. Improving treatment outcomes is nevertheless difficult, in part because contemporary interventions were developed without an understanding of the underlying neurobiological mechanisms that they modulate. Recent advances in experimental models of anxiety in humans, such as threat of unpredictable shock, have, however, enabled us to start translating the wealth of mechanistic animal work on defensive behaviour into humans. In this article, we discuss the distinction between fear and anxiety, before reviewing translational research on the neural circuitry of anxiety in animal models and how it relates to human neuroimaging studies across both healthy and clinical populations. We highlight the roles of subcortical regions (and their subunits) such as the bed nucleus of the stria terminalis, the amgydala, and the hippocampus, as well as their connectivity to cortical regions such as dorsal medial and lateral prefrontal/cingulate cortex and insula in maintaining anxiety responding. We discuss how this circuitry might be modulated by current treatments before finally highlighting areas for future research that might ultimately improve treatment outcomes for this common and debilitating transdiagnostic symptom.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that fear and anxiety are dissociable though partly overlapping processes, with sustained anxiety maintained by a translational "anxiety network" centred on the bed nucleus of the stria terminalis (BNST), hippocampus, dorsal medial/lateral prefrontal and cingulate cortex, and insula. It reviews animal and human evidence, considers how current treatments modulate this circuitry, and identifies priorities for improving the roughly 50% recovery rates of existing interventions.

Key findings

  • Fear and anxiety can be differentiated by threat certainty: fear involves imminent, unambiguous threat mobilising active avoidance, whereas anxiety is a sustained apprehension of diffuse, uncertain future threat with passive avoidance; the paper notes a double dissociation between phasic (fear) and sustained (anxiety) threats, with the central nucleus of the amygdala (CeA) and BNST mediating fear- and anxiety-potentiated startle respectively.
  • The BNST is small but heterogeneous, with up to 18 functionally distinct subregions; some BNST lesions up-regulate anxiety while optogenetic stimulation of discrete subregions can down-regulate it, and distinct efferent connections control different features of anxiety.
  • Human unpredictable-threat paradigms (threat of shock, 7.5% CO₂ inhalation, darkness, vigilant threat monitoring, context conditioning, long-duration CS, approach-avoidance conflict) implicate the BNST, anterior insula, dmPFC/dACC, hippocampus and dlPFC; exaggerated anxiety-potentiated (but not fear-potentiated) startle is seen in panic disorder and PTSD, while GAD shows increased startle overall.
  • Treatment evidence: chronic citalopram selectively reduces anxiety-potentiated but not fear-potentiated startle, while acute citalopram increases it (consistent with transiently increased anxiety on SSRI initiation); alprazolam reduces hypervigilant responding under unpredictable shock via increased ventrolateral prefrontal-to-sensory feedback; a meta-analysis found the most robust therapy predictors were post-therapy decreases in anterior cingulate/paracingulate, inferior frontal gyrus and insula activity.

Methods

  • Design: broad narrative review intended as an introduction for those new to the field, synthesising animal (largely rodent) and human experimental psychopathology and neuroimaging work.
  • Data: no primary sample; the paper draws on cited animal lesion, optogenetic, electrophysiological and pharmacological studies, and human fMRI, MEG, startle and experimental anxiety-induction studies in healthy and clinical populations.
  • Analysis: qualitative synthesis organised around fear versus anxiety, subcortical and cortical circuitry, treatment modulation, and future perspectives; includes a table of BNST subregion functions and a simplified circuitry diagram.

Limitations

  • Stated: animal models rely on overt behaviour and physiological measures rather than cognitions or subjective experience, and many processes (e.g. those targeted by CBT) cannot be studied in animals; many cortical regions are likely not direct functional homologues across species; animal models of treatment have often failed to translate to humans.
  • Stated: fMRI signal is "several steps away" from underlying neural activity, and higher-resolution techniques, PET ligands or direct electrical recording may be needed to corroborate translational patterns; clinical high-resolution BNST imaging is still in its infancy.
  • Stated: cross-sectional observational treatment studies cannot distinguish whether neural change is due to the intervention or reflects generic symptom change; the paper also notes that many patterns of activity are not unique to anxiety and may reflect more fundamental processes such as salience processing, and that the dlPFC–anxiety relationship is described as speculative.

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

Integrity signals

Registry

Crossref · 10.1136/jnnp-2019-321400

Cites

60 of 60 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Interpretationcitation

    The true neurobiological picture is likely to be more nuanced than the model in which anxiety and fear are putatively separate processes.

    “Although the true neurobiological picture is likely to be more nuanced than this, 10 11 this distinction is also reflected in the Research Domain Criteria (RDoC) matrix”
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  • Premisecitation

    Many animal models of anxiety, such as the elevated-plus maze, have few analogues in humans.

    “many animal models of anxiety, such as the elevated-plus maze, have few analogues in humans 22”
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  • Premisecitation

    Response rates to first-line pharmacological and psychological treatments for anxiety are less than 50%.

    “response rates to first-line pharmacological and psychological treatments are less than 50% 2”
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      “current treatments for anxiety-both psychological and pharmacological-hover at around 50% recovery rates.”
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  • Premisecitation

    Anxiety is not a unitary phenomenon.

    “clinicians have long recognised that anxiety is not a unitary phenomenon.8”
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    The amygdala's direct role in maintaining sustained anxiety symptoms has been more difficult to establish than its role in fear conditioning.

    “While the amygdala is important for fear conditioning, its direct role in maintaining sustained anxiety symptoms has been more difficult to establish.”
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    Premisecitation

    Fear and anxiety share many subjective and physiological symptoms but can be differentiated based on behavioural profiles determined by certainty, which can be subdivided into contingency, temporal precision and spatial precision of the threat.

    “While fear and anxiety share many subjective and physiological symptoms, they can be differentiated based on behavioural profiles determined by certainty, 6 7 which can be further subdivided into the contingency, temporal precision and spatial precision of the threat”
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    Interpretationnone given

    Understanding the neurobiology of anxiety and the features that differentiate adaptive from pathological anxiety is key to identifying pathological mechanisms and treatment targets.

    “we argue that understanding this neurobiology, as well as the features that differentiate adaptive from pathological anxiety, is key to identifying pathological mechanisms and treatment targets.”
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    Interpretationcitation

    Anxiety disorders share common enduring behavioural, cognitive and physiological characteristics, potentially arising from impairments in transdiagnostic features such as RDoC negative valence systems.

    “All share common enduring behavioural, cognitive and physiological characteristics, potentially arising from impairments in transdiagnostic features, as seen in the RDoC 12 domain of negative valence systems 13 which highlights exaggerated or problematic responses to 'potential threat (anxiety)'.”
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    • The authors state this as an assumption: Similar phenomenological presentations of 'anxiety' reflect true underlying neurobiological similarities.

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    Premisecitation

    Fear conditioning is a useful model of fear but is insensitive to drugs that are anxiolytic in humans and is thus a poor model of anxiety disorders such as GAD.

    “while fear conditioning is a useful model of fear, it is insensitive to drugs that are anxiolytic in humans [16][17][18][19] and is thus a poor model of anxiety disorders such as GAD.20 21”
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    Premisecitation

    Excessive anxiety symptoms can be found in GAD and panic disorder, and panic disorder including apprehension of subsequent attacks is considered better modelled by anxiety.

    “Excessive anxiety symptoms can be found in GAD and panic disorder (PD) (though panic attacks themselves may be better characterised by models of acute fear, PD (including apprehension of subsequent attacks) is considered to be better modelled by anxiety).8”
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    Premisecitation

    There is a body of research indicating that fear and anxiety are tractable and are associated with distinct pathologies.

    “There is a body of research indicating that fear and anxiety are tractable and are associated with distinct pathologies.6 7 9”
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    Interpretationcitation

    The story is almost certainly the same with regard to the role of the amygdala in fear, which is gradually being broken down into component microcircuits.

    “Of note, the story is almost certainly the same with regards to the role of the amygdala in fear, which is gradually being broken down into component microcircuits.45 46”
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    Premisecitation

    Some BNST lesions can up-regulate anxiety, while optogenetic stimulation of discrete BNST subregions can down-regulate anxiety.

    “Some BNST lesions can up-regulate anxiety, 37 while optogenetic stimulation of discrete BNST subregions can down-regulate anxiety.38 39”
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    According to Davis' group, anxiety is maintained by activation of corticotrophin receptors in the BNST.

    “According to Davis' group, anxiety is thus maintained by activation of corticotrophin receptors in the BNST.7”
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    Premisecitation

    The medial prefrontal cortex is implicated in attention and affective information processing and hence also involved in responses to threat.

    “the medial prefrontal cortex (mPFC) is implicated in attention and affective information processing 47 and hence also involved in responses to threat.”
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    Electrophysiological recordings in rodents show that prelimbic neurons maintain persistent firing that correlates with freezing throughout the duration of sustained threat and that prelimbic firing persists during trace fear conditioning.

    “Electrophysiological recordings in rodents show that PL neurons maintain persistent firing that correlate with freezing throughout the duration of sustained threat 51 52 and that PL firing persists during trace fear conditioning, 53”
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    Premisecitation

    Theta oscillations have been linked to anxiety in rodents and humans and display synchronised activity between the ventral hippocampus and prelimbic cortex in anxiogenic contexts.

    “This can be observed in theta oscillations, which have been linked to anxiety in rodents and humans 58 and display synchronised activity between the ventral hippocampus and PL in anxiogenic contexts.54”
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    Interpretationreasoning

    These results suggest prelimbic involvement in both defensive behaviours and the neural representation of threat (the unconditioned stimulus).

    “These results suggest PL involvement in both defensive behaviours and the neural representation of threat (ie, US).”
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    Premisecitation

    The BNST is small but heterogeneous, with up to 18 functionally distinct subregions.

    “the BNST is small but heterogeneous, with up to 18 functionally distinct subregions.36”
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    Premisecitation

    Davis and collaborators established a double dissociation between the central nucleus of the amygdala and the BNST: CeA lesions abolish fear-potentiated startle but not anxiety-potentiated startle, while BNST lesions suppress anxiety-potentiated startle but not fear-potentiated startle.

    “A series of studies by Davis and collaborators established a double dissociation between the CeA and BNST; lesions of the CeA abolish fear-potentiated startle, but not anxiety-potentiated startle, while lesions of the BNST suppress anxiety-potentiated startle, but not fear-potentiated startle.6 7”
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    Premisecitation

    The BNST is part of the extended amygdala and is well-situated to regulate defensive responses such as anxiety via GABAergic projections to various limbic, hindbrain and cortical structures.

    “The BNST is a part of the 'extended amygdala', 33 which is well-situated to regulate defensive responses such as anxiety via its GABA (gamma-aminobutyric acid)-ergic projections to various limbic, hindbrain and cortical structures.6 7 32”
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    Premisecitation

    The basolateral amygdala integrates sensory information from the environment and, via its projections, excites the central nucleus of the amygdala.

    “The BLA integrates sensory information from the environment and, via its projections, excites the CeA.”
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    Premisecitation

    The rodent mPFC subregions infralimbic and prelimbic cortex are densely interconnected with the amygdala and play opposing roles in defensive behaviours, with IL inhibiting the amygdala and defensive behaviours and PL exciting the amygdala.

    “The rodent mPFC is composed of several subregions including the infralimbic (IL) and prelimbic (PL) cortex, which are densely interconnected with the amygdala 48 and play opposing roles in defensive behaviours, 49 with the IL inhibiting the amygdala (and defensive behaviours) and the PL exciting the amygdala.”
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    Premisereasoning

    GAD is associated with increased startle overall during a threatening experimental environment, not the same pattern as PD and PTSD.

    “GAD does not follow quite the same pattern-it is associated with increased startle overall during a threatening experimental environment.”
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    Premisecitation

    A key role of the amygdala may be in goal-directed cognitive processing and/or behaviour toward relevant or salient information.

    “It has therefore been argued that perhaps a key role of the amygdala is in goal-directed cognitive processing and/or behaviour toward relevant/salient information.s26”
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    Interpretationreasoning

    A possible neural model of anxiety emerges from animal studies: environmental signals from the ventral hippocampus and interoceptive signals from the anterior insula help maintain threat representation in the prelimbic cortex, which is then used to guide defensive behaviours via the BNST and amygdala and may be under the control of the dorsolateral prefrontal cortex.

    “A possible neural model of anxiety that emerges from these studies in animals is that environmental signals from the ventral hippocampus and interoceptive signals from the anterior insula help maintain threat representation in the PL, which is then used to guide defensive behaviours via the BNST and the amygdala and may be under the control of the dlPFC (see figure 1).”
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    Premisecitation

    In humans, elevated fMRI activity in dorsal regions of the prefrontal cortex (dmPFC and dACC) has been associated with both unpredictable threat processing and pathological anxiety.

    “In humans, elevated fMRI activity in dorsal regions of the PFC (dorsomedial PFC (dmPFC) and dorsal anterior cingulate (dACC)) has been associated with both unpredictable threat processing and pathological anxiety.s27”
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    Activity in the amygdala was elevated in those with social phobia relative to controls, and it was argued that this elevated response was critical for the development of excessive anxiety.

    “Activity in the amygdala was also shown to be elevated in those with social phobia relative to controls, s21,s22 and it was argued that this elevated response was critical for the development of the excessive anxiety.”
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    In young monkeys, as in children, heightened reaction to novelty and potential threat characterises an anxious temperament disposition, which is a well-established risk for the development of anxiety.

    “In young monkeys, as in children, heightened reaction to novelty and potential threat characterises an anxious temperament disposition, which is a well-established risk for the development of anxiety.s5”
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    Premisecitation

    Maternal separation stress in young monkeys activates the right dorsolateral prefrontal cortex but deactivates the left dorsolateral prefrontal cortex.

    “Maternal separation stress in young monkeys activates the right dlPFc, but deactivates the left dlPFC.s4”
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    Premisecitation

    It has been argued that specifically the rostral part of the dmPFC drives conscious threat appraisal and worry.

    “It has been argued, moreover, that it is specifically the rostral part of the dmPFC that drives conscious threat appraisal and worry.s28”
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    Premisecitation

    The hippocampus is involved in anxiety, due perhaps to its key role in contextual learning/memory and prospection or alternatively a role in avoidance.

    “As also highlighted in the animal work above, the hippocampus is involved in anxiety, due, perhaps, to its key role in contextual learning/memory s39 and prospection s40 or, alternatively, a role in avoidance.24,s41,s42”
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    Interpretationcitation

    As with the amygdala, dACC/dmPFC hyperactivity in psychiatric disorders may be due to a more generic role in anticipating emotional stimuli and hence a key role in appraising and expressing behavioural responses to the level of environmental threat.

    “as with the amygdala, this may be due to a more generic role in anticipating emotional stimuli s33 and hence a key role in appraising and expressing behavioural responses to the level of environmental threat.s34”
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    Premisecitation

    It has been argued that this circuitry represents a human functional homologue of the rodent prelimbic-amygdala/BNST circuit.

    “To this end, it has been argued that this circuitry represents a human (functional) homologue of the rodent PL-amygdala/BNST circuit highlighted above.s30,s34-s37”
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    Functional imaging studies show that connectivity between the amygdala and mPFC increases when healthy individuals are exposed to threat of unpredictable shock, and that the strength of this connectivity is greater in individuals with higher dispositional anxiety.

    “Specifically, functional imaging studies show that connectivity between the amygdala and the mPFC increases when healthy individuals are exposed to threat of unpredictable shock, and that the strength of this connectivity is greater in individuals with higher dispositional anxiety.s35-s37”
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    Theta activity from the anterior hippocampus (or ventral in rodents) correlates with anxiety level in humans, while theta from the posterior hippocampus correlates with spatial memory performance in a simulated human version of the rodent Morris water maze task.

    “Consistent with functional differentiation along the longitudinal axis of the rodent hippocampus, s43 theta activity (2-8 Hz) from anterior hippocampus (or ventral in rodents) correlates with anxiety level in humans 58 ; and at the same time theta from posterior hippocampus correlates with spatial memory performance in a simulated human version of the rodent Morris water maze task.s44”
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    Interpretationcitation

    In pathological anxiety, pathophysiology is not associated with chronic activation of the anterior insula but rather with heightened response during anxiety induction, possibly reflecting a feeling of lack of control as well as autonomic and emotional distress during threat.

    “In this instance, pathophysiology is not associated with chronic activation of the anterior insula but rather with heightened response during anxiety induction, possibly reflecting a feeling of lack of control s62 as well as autonomic and emotional distress during threat.s23”
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    Approach-avoidance conflict tasks implicate the hippocampus, and this conflict has been shown to be exacerbated, leading to increased avoidance, in humans during induced anxiety and in pathological anxiety.

    “Critically, such tasks implicate the hippocampus 24,s41,s42 and this conflict has been shown to be exacerbated, leading to increased avoidance, in humans during induced anxiety, s55 and in pathological anxiety.s56”
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    Interpretationcitation

    Threat of shock modulates memory performance, improving contextual learning under threatening conditions, which may be one mechanism by which the hippocampus maintains traumatic memories in disorders with elevated anxiety such as PTSD.

    “Finally, threat of shock also modulates memory performance, improving contextual learning under threatening conditions, s48,s49 which may be one mechanism by which the hippocampus maintains traumatic memories in disorders which feature elevated anxiety such as PTSD.s50”
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    Interpretationreasoning

    Connectivity between the hippocampus, BNST, amygdala and medial prefrontal/cingulate cortex may contribute to a putative 'anxiety network' that may also be regulated by dlPFC.

    “Specifically, connectivity between the hippocampus, BNST amygdala and medial prefrontal/cingulate cortex may contribute to a putative 'anxiety network' that may also be (down)regulated by dlPFC.”
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    Premisecitation

    Both the anxiolytic effects of chronic SSRI administration and the anxiogenic effects of acute SSRI administration have been replicated in rodents.

    “Both the anxiolytic effects of chronic SSRI administration and the anxiogenic effects of acute SSRI administration have been replicated in rodents”
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    Interpretationreasoning

    When the dlPFC is activated to keep task goals in mind, dlPFC engagement suppresses emotional interference and alleviates anxiety.

    “When the dlPFC is activated to keep task goals in mind, dlPFC engagement also suppresses emotional interference and alleviates anxiety.”
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    Premisecitation

    The dlPFC is involved in anxiety regulation and dispositional anxiety in humans.

    “the dlPFC is involved in anxiety regulation and dispositional anxiety in humans”
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    Premisecitation

    The current view is that the effects of chronic and acute SSRI administration involve the BNST and result from interactions between serotonin and corticotropin-releasing factors (CRFs).

    “the current view is that these effects involve the BNST 7 and result from interactions between serotonin and corticotropin-releasing factors (CRFs).”
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    Interpretationcitation

    The BNST is a promising biomarker of disease and treatment targeting.

    “making this structure a promising biomarker of disease and treatment targeting.”
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    Premisecitation

    The reduction of hypervigilant responding by alprazolam is driven by increased feedback signalling from ventrolateral prefrontal to sensory cortices.

    “that this is driven by increased feedback signalling from ventrolateral prefrontal to sensory cortices.”
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    Interpretationnone given

    Neural dysfunction can take two forms: chronic activation (inappropriate activation in the absence of anxiety induction challenge) or exaggerated activation in response to an unpredictable threat.

    “Neural dysfunction can take two forms, chronic activation (inappropriate activation in the absence of anxiety induction challenge, for example, heightened amygdala-dmPFC connectivity) or exaggerated activation in response to an unpredictable threat (i.e.insula).”
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    Premisecitation

    rTMS of the dlPFC is approved by the Food and Drug Administration as a second-line treatment for depression.

    “rTMS of the dlPFC is approved by the Food and Drug Administration as a secondline treatment for depression”
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    Premisecitation

    Deep brain stimulation of the BNST reduces anxiety in a rodent model and in humans.

    “Deep brain stimulation of the BNST reduces anxiety in a rodent model and in humans.s94”
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    Premisecitation

    The BNST is a small but functionally complex structure comprised of at least 18 subregions involved, among other functions, in opposing anxiolytic and anxiogenic circuits.

    “It is a small but functionally complex structure comprised of at least 18 subregions 36 involved, among other functions, in opposing anxiolytic and anxiogenic circuits.”
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    CRF1 antagonists have failed in human models and in clinical trials.

    “these have failed in human models s92 and in clinical trials.s93”
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    Interpretationnone given

    Fear-related defensive responses are mediated by the CeA; anxiety-related defensive responses are mediated by the BNST.

    “Fear-related and anxietyrelated defensive responses are mediated by the CeA and BNST, respectively.”
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    Premisecitation

    Following extinction, activity is reduced in the amygdala, insula and anterior cingulate, but increased in the dlPFC.

    “activity was reduced in the amygdala, insula and anterior cingulate, but increased in the dlPFC s89 following extinction.”
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    Interpretationnone given

    Structures implicated in anxiety but not fear include the BNST, hippocampus, dmPFC, insula and dlPFC.

    “Structures implicated in anxiety but not fear include the BNST, hippocampus, dmPFC, insula and dlPFC.”
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    Extinction is thought to be the mechanism by which exposure therapy works.

    “extinction is thought to be the mechanism by which exposure therapy works”
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  • Classified as probably not a substantial claim.

    Premisecitation

    Medial prefrontal and amygdala activity predict treatment response to CBT in anxiety.

    “Medial prefrontal and amygdala activity have been argued to predict treatment response to CBT in anxiety”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites s85

      Not checked in the free run.

51 of 51

  • The authors state this as an assumption.

    Similar phenomenological presentations of 'anxiety' reflect true underlying neurobiological similarities.

    “based on the assumption that similar phenomenological presentations of 'anxiety' reflect true underlying neurobiological similarities”

  • The paper relies on this without support.

    Contemporary interventions for anxiety were developed without an understanding of the underlying neurobiological mechanisms that they modulate.

    “contemporary interventions were developed without an understanding of the underlying neurobiological mechanisms that they modulate.”

  • The paper relies on this without support.

    Little is known about anxiety, especially its many human-specific cognitive-affective features.

    “little is known about anxiety, especially its many human-specific cognitive-affective features.”

  • The paper relies on this without support.

    Despite symptom heterogeneity, there are no clear objective markers that can differentiate between disorders which feature anxiety, and there is strong symptom overlap.

    “we do not at present have clear objective markers that can differentiate between disorders which feature anxiety, and there is, moreover, strong symptom overlap.”

  • The paper relies on this without support.

    Many of the regions, especially the PFC, are not clear translational homologues across species.

    “many of the regions (especially the PFC) are not clear translational homologues across species”

  • The paper relies on this without support.

    Human work highlights that many patterns of activity are not unique to anxiety and may instead reflect more fundamental cognitive processes, such as salience processing.

    “human work highlights that many of these patterns of activity are not unique to anxiety and may instead reflect more fundamental cognitive processes, such as salience processing”

  • The paper relies on this without support.

    Current categorical disease classifications for anxiety disorders have heterogeneity within diagnostic categories and overlapping symptoms across disorders.

    “One key problem with the current categorical disease classifications for anxiety disorders is that of heterogeneity within diagnostic categories and overlapping symptoms across disorders.”

  • The paper relies on this without support.

    The RDoC matrix highlights several constructs (acute threat, potential threat (anxiety) and sustained threat) that map onto the distinction between anxiety and fear.

    “the RDoC matrix highlighting several constructs (acute threat, potential threat (anxiety) and sustained threat) that map onto the distinction made in this article between anxiety and fear.”

  • The paper relies on this without support.

    Animal models are essential to advance mechanistic understanding of behaviours.

    “Animal models are essential to advance mechanistic understanding of behaviours”

  • The paper relies on this without support.

    Pathological anxiety is a disorder of feelings supported by conscious and unconscious experiences.

    “Pathological anxiety is, above all, a disorder of feelings supported by conscious and unconscious experiences”

  • The paper relies on this without support.

    Animal models rely on overt behaviour and physiological measures, rather than cognitions or subjective experiences.

    “animal models rely on overt behaviour and physiological measures, rather than cognitions or subjective experiences.”

  • The paper relies on this without support.

    Many processes, for example, the psychological symptoms targeted by CBT, cannot be directly studied in animal models.

    “many processes, for example, the psychological symptoms targeted by CBT cannot be directly studied in animal models”

  • The paper relies on this without support.

    Many regions, especially cortical areas, are likely not direct functional homologues across animal models.

    “many regions-especially cortical areas-are likely not direct functional homologues across animal models”

  • The paper relies on this without support.

    Many animal models of treatment have failed to translate to humans.

    “many animal models of treatment have failed to translate to humans.”

  • The paper relies on this without support.

    Ethical issues with exposing children and adolescents to aversive events such as shock are a difficulty in developmental work.

    “the most important being the ethical issues with exposing children and adolescents to aversive events such as shock.”

  • The paper relies on this without support.

    Exposure is primarily targeted at fear responding but can also be used to reduce anxiety.

    “Exposure is primarily targeted at fear responding (eg, phobias), but can also be used to reduce anxiety.”

  • The paper relies on this without support.

    The actions of neuropeptide CRF on the BNST in relation to sustained anxiety provided a strong rationale for the therapeutic development of CRF1 antagonists to treat mood and anxiety disorders.

    “the actions of neuropeptide CRF on the BNST in relation to sustained anxiety provided a strong rationale for the therapeutic development of CRF1 antagonists to treat mood and anxiety disorders.”
17 of 17

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.

  • PL is defined as both prelimbic and paralimbic cortex

    Minor

    The main text defines PL as the prelimbic cortex, whereas the figure caption defines it as the paralimbic cortex.

  • CO2 paradigm specifies both 7.5% and greater than 7.5%

    Minor

    The paradigm is described as using a 7.5% CO2 concentration, but its table description specifies a concentration greater than 7.5%.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. NiMH Research Domain Criteria (RDoC). project Negative Valence Systems: Workshop Proceedings, 2011.

Cited by

Sorted by citations

Related

Authors
Robinson, O. J., Pike, A. C., Cornwell, B., & Grillon, C.
Affiliations
  • University College London (GB)
  • Swinburne University of Technology (AU)
  • National Institute of Mental Health (US)
Corresponding author
Robinson, Oliver J
ORCID
Venue
Journal of Neurology, Neurosurgery & Psychiatry
Publisher
BMJ
Published
2019-06-29
Volume
90
Issue
12
Pages
jnnp-2019-321400
ISSN
  • 0022-3050 (ISSN-L)
  • 1468-330X
DOI
10.1136/jnnp-2019-321400
OpenAlex
W2956101215
Semantic Scholar
4399a9d113eab2c5214b740808e96099303a8494
Cited by
158
References
60
Citations by year
2026: 7 · 2025: 26 · 2024: 37 · 2023: 24 · 2022: 28 · 2021: 21 · 2020: 13 · 2019: 2
FWCI
2.03
Type
journal article
Language
en
Open access
Locations
  • Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • Swinburne figshare (Swinburne University of Technology) (submittedVersion)
Funders
  • National Institute of Mental Health (ZIAMH002798)
  • Medical Research Council (MR/K024280/1, MR/R020817/1)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
Keywords
anxiety, neural circuits, fear, translational research, bed nucleus of the stria terminalis, amygdala, hippocampus, prefrontal cortex, insula, cingulate cortex, anxiety treatment, neuroimaging
MeSH terms
Anxiety, Anxiety Disorders, Brain Mapping, Fear, Humans, Nerve Net

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

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

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

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