Review Article | Published:

Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective

Nature Reviews Neuroscience volume 14, pages 488501 (2013) | Download Citation

Abstract

Uncertainty about a possible future threat disrupts our ability to avoid it or to mitigate its negative impact and thus results in anxiety. Here, we focus the broad literature on the neurobiology of anxiety through the lens of uncertainty. We identify five processes that are essential for adaptive anticipatory responses to future threat uncertainty and propose that alterations in the neural instantiation of these processes result in maladaptive responses to uncertainty in pathological anxiety. This framework has the potential to advance the classification, diagnosis and treatment of clinical anxiety.

Key points

  • Anxiety can be thought of as a future-oriented emotional state that is characterized by anticipatory cognitive, behavioural and affective changes in response to uncertainty about potential threat. Although it often serves an adaptive role, extreme anxiety that is disproportionate to the actual presence or likelihood of threat can cause distress and suffering for individuals with clinical anxiety disorders.

  • We propose a new model, called the 'uncertainty and anticipation model of anxiety' (UAMA), which emphasizes five processes explaining why uncertainty about future threat is so disruptive in anxiety. These five processes are inflated estimates of threat cost and probability, increased threat attention and hypervigilance, deficient safety learning, behavioural and cognitive avoidance and heightened reactivity to threat uncertainty. The neural circuitry for each of the five UAMA processes promotes an adaptive role in responding to and reducing uncertainty about threat.

  • However, alterations in that neural circuitry result in maladaptive responses to uncertainty in pathological anxiety.

  • The key brain regions implicated in maladaptive responses to uncertainty in anxiety include the amygdala, bed nucleus of the stria terminalis, ventromedial prefrontal cortex, orbitofrontal cortex, dorsomedial and dorsolateral prefrontal cortex and anterior insula.

  • The anterior mid-cingulate cortex, which is heavily interconnected with each of these brain regions, shows consistent functional and structural abnormalities in clinical anxiety. We propose a central role for this region in contributing to an array of maladaptive responses to uncertainty.

  • In focusing the experimental and theoretical literatures through the common lens of uncertainty, this perspective provides a unifying theme that binds together many diverse features of clinical anxiety and thus provides a conceptual framework for advancing future research on the neurobiology of anxiety disorders.

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References

  1. 1.

    Stumbling on Happiness (Random House, 2006).

  2. 2.

    & From normal fear to pathological anxiety. Psychol. Rev. 105, 325–350 (1998).

  3. 3.

    in Anxiety and the Anxiety Disorders (eds Tuma, A. & Maser, J.) 463–478 (Lawrence Erlbaum Associates, 1985).

  4. 4.

    , , & Phasic versus sustained fear in rats and humans: role of the extended amygdala in fear versus anxiety. Neuropsychopharmacology 35, 105–135 (2010). This comprehensive review of rodent and human startle research proposes distinct neurobiological circuits for 'fearful' and 'anxious' responses, highlighting the medial CeA and lateral CeA–lateral BNST, respectively.

  5. 5.

    Unraveling the mysteries of anxiety and its disorders from the perspective of emotion theory. Am. Psychol. 55, 1247–1263 (2000).

  6. 6.

    & The Neuropsychology of Anxiety: an Enquiry into the Functions of the Septo-Hippocampal System (Oxford Univ. Press, 2000).

  7. 7.

    Startle reactivity and anxiety disorders: aversive conditioning, context, and neurobiology. Biol. Psychiatry 52, 958–975 (2002).

  8. 8.

    , & The strong situation: a potential impediment to studying the psychobiology and pharmacology of anxiety disorders. Biol. Psychol. 72, 265–270 (2006).

  9. 9.

    & Ethoexperimental approaches to the biology of emotion. Annu. Rev. Psychol. 39, 43–68 (1988).

  10. 10.

    Neural organization of the defensive behavior system responsible for fear. Psychon. Bull. Rev. 1, 429–438 (1994).

  11. 11.

    Helplessness: on Depression, Development, and Death (W.H. Freeman and Company, 1975).

  12. 12.

    Neuroanatomy and neurotransmitter regulation of defensive behaviors and related emotions in mammals. Braz. J. Med. Biol. Res. 27, 811–829 (1994).

  13. 13.

    , & Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur. J. Pharmacol. 463, 199–216 (2003).

  14. 14.

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Press, 2000).

  15. 15.

    & Unpredictable and uncontrollable events: a new perspective on experimental neurosis. J. Abnorm. Psychol. 87, 256–271 (1978).

  16. 16.

    & Controllability and predictability in acquired motivation. Annu. Rev. Psychol. 36, 495–529 (1985).

  17. 17.

    Signaled shock-free periods and preference for signaled shock. J. Exp. Psychol. Anim. Behav. Process. 6, 65–80 (1980).

  18. 18.

    , & in Aversive Conditioning and Learning (eds Brush, F. R. & Black, A. H.) 347–400 (Academic Press, 1971).

  19. 19.

    & Knowing how much you don't know: a neural organization of uncertainty estimates. Nature Rev. Neurosci. 13, 572–586 (2012). The authors decompose uncertainty into the following four domains for adaptive decision-making and review evidence for their common and distinct neural representations: sensory, state, rule and outcome uncertainty.

  20. 20.

    Will it hurt less if I can control it? A complex answer to a simple question. Psychol. Bull. 90, 89–101 (1981).

  21. 21.

    & in Stress and Anxiety (eds Spielberger, C. D. & Sarason, I. G.) 121–128 (Hemisphere, 1972).

  22. 22.

    The Emotional Brain: the Mysterious Underpinning of Emotional Life (Simon and Schuster, 1996).

  23. 23.

    & Fear as an intervening variable in avoidance conditioning. J. Comp. Psychol. 39, 29–50 (1946).

  24. 24.

    Cognitive Therapy and the Emotional Disorders (International Universities Press, 1976).

  25. 25.

    , & in Generalized Anxiety Disorder: Advances in Research and Practice (eds Heimberg, R. G., Turk, C. L. & Mennin, D. S.) 77–108 (Guilford, 2004).

  26. 26.

    & Emotional processing of fear: exposure to corrective information. Psychol. Bull. 99, 20–35 (1986).

  27. 27.

    , & A functional analysis of danger and safety signals in anxiety disorders. Clin. Psychol. Rev. 27, 114–126 (2007).

  28. 28.

    & An insular view of anxiety. Biol. Psychiatry 60, 383–387 (2006).

  29. 29.

    Fear, vigilance, and ambiguity: initial neuroimaging studies of the human amygdala. Curr. Dir. Psychol. Sci. 7, 177–188 (1998). An early critique of neuroimaging studies that equates amygdala activation with the experience of fear; this paper provides an alternative framework in which the amygdala modulates vigilance in response to environmental uncertainty.

  30. 30.

    , & A modern learning theory perspective on the etiology of panic disorder. Psychol. Rev. 108, 4–32 (2001).

  31. 31.

    , & Uncontrollability and unpredictability in post-traumatic stress disorder: an animal model. Psychol. Bull. 112, 218–238 (1992).

  32. 32.

    & A contemporary learning theory perspective on the etiology of anxiety disorders: it's not what you thought it was. Am. Psychol. 61, 10–26 (2006).

  33. 33.

    & Fears, phobias, and preparedness: toward an evolved module of fear and fear learning. Psychol. Rev. 108, 483–522 (2001).

  34. 34.

    Associative learning deficits increase symptoms of anxiety in humans. Biol. Psychiatry 51, 851–858 (2002).

  35. 35.

    et al. Classical fear conditioning in the anxiety disorders: a meta-analysis. Behav. Res. Ther. 43, 1391–1424 (2005).

  36. 36.

    & Anticipatory anxiety and risk perception. Cogn. Ther. Res. 11, 551–565 (1987).

  37. 37.

    Trait anxiety and pessimistic appraisal of risk and chance. Pers. Individ. Dif. 22, 465–476 (1997).

  38. 38.

    Anxiety and risky decision-making: the role of subjective probability and subjective costs of negative events. Pers. Individ. Dif. 43, 243–253 (2007).

  39. 39.

    , & The role of positive beliefs about worry in generalized anxiety disorder and its treatment. Clin. Psychol. Psychother. 6, 126–138 (1999).

  40. 40.

    & Cognitive processes in anxiety. Adv. Behav. Res. Ther. 5, 51–62 (1983).

  41. 41.

    , , & Cognitive biases in generalized social phobia. J. Abnorm. Psychol. 105, 433–439 (1996).

  42. 42.

    , & Anticipated reactions to social events: differences among individuals with generalized social phobia, obsessive compulsive disorder, and nonanxious controls. Cogn. Ther. Res. 24, 731–746 (2000).

  43. 43.

    & Cognitive bias in acute stress disorder. Behav. Res. Ther. 36, 1177–1183 (1998).

  44. 44.

    & Judgment under uncertainty: heuristics and biases. Science 185, 1124–1131 (1974).

  45. 45.

    , , & Risk as feelings. Psychol. Bull. 127, 267–286 (2001). Drawing from a broad range of psychological and behavioural economics research, the authors propose the influential 'risk-as-feelings' hypothesis that emphasizes the impact of emotions on apparently suboptimal decision-making.

  46. 46.

    , & Predicting events of varying probability: uncertainty investigated by fMRI. Neuroimage 19, 271–280 (2003).

  47. 47.

    , , , & Distributed neural representation of expected value. J. Neurosci. 25, 4806–4812 (2005).

  48. 48.

    , & Human insula activation reflects risk prediction errors as well as risk. J. Neurosci. 28, 2745–2752 (2008). Although many studies have probed neural correlates of reward prediction and reward prediction errors, this study identifies the anterior insula as a critical site for risk prediction (that is, uncertainty associated with predictions) and risk prediction errors.

  49. 49.

    & Neurons in the orbitofrontal cortex encode economic value. Nature 441, 223–226 (2006).

  50. 50.

    & Neural representations of subjective reward value. Behav. Brain Res. 213, 135–141 (2010).

  51. 51.

    , & Appetitive and aversive goal values are encoded in the medial orbitofrontal cortex at the time of decision making. J. Neurosci. 30, 10799–10808 (2010).

  52. 52.

    & Neural computations associated with goal-directed choice. Curr. Opin. Neurobiol. 20, 262–270 (2010).

  53. 53.

    , , & Does the orbitofrontal cortex signal value? Ann. NY Acad. Sci. 1239, 87–99 (2011).

  54. 54.

    Cross-species studies of orbitofrontal cortex and value-based decision-making. Nature Neurosci. 15, 13–19 (2012).

  55. 55.

    , & A neural substrate of prediction and reward. Science 275, 1593–1599 (1997).

  56. 56.

    & Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature 459, 837–841 (2009).

  57. 57.

    et al. Temporal difference models describe higher-order learning in humans. Nature 429, 664–667 (2004).

  58. 58.

    , , , & From fear to safety and back: reversal of fear in the human brain. J. Neurosci. 28, 11517–11525 (2008). Using a fear-reversal paradigm, the authors show that the vmPFC dynamically tracks cues predicting safety, shifting its responses following a reversal of cue–outcome contingencies.

  59. 59.

    , , , & Differential roles of human striatum and amygdala in associative learning. Nature Neurosci. 14, 1250–1252 (2011).

  60. 60.

    & Emotion and decision-making: affect-driven belief systems in anxiety and depression. Trends Cogn. Sci. 16, 476–483 (2012).

  61. 61.

    , , , & Threat-related attentional bias in anxious and nonanxious individuals: a meta-analytic study. Psychol. Bull. 133, 1–24 (2007).

  62. 62.

    & Anxiety Dsorders and Phobias: a Cognitive Perspective (Basic Books, 1985).

  63. 63.

    , & Interpretation of homophones related to threat in anxiety states. J. Abnorm. Psychol. 98, 31–34 (1989).

  64. 64.

    & Interpretive cues and ambiguity in generalized anxiety disorder. Behav. Res. Ther. 42, 881–892 (2004).

  65. 65.

    & Social phobia and interpretation of social events. Behav. Res. Ther. 38, 273–283 (2000).

  66. 66.

    & Interpreting neutral faces as threatening is a default mode for socially anxious individuals. J. Abnorm. Psychol. 117, 680–685 (2008).

  67. 67.

    , & Interpretation of ambiguous interoceptive stimuli in panic disorder and nonclinical panic. Cogn. Ther. Res. 25, 235–246 (2001).

  68. 68.

    et al. Sentence completion test in combat veterans with and without PTSD: preliminary findings. Psychiatry Res. 113, 303–307 (2002).

  69. 69.

    et al. Cerebral glucose metabolism associated with a fear network in panic disorder. Neuroreport 16, 927–931 (2005).

  70. 70.

    et al. Higher brain blood flow at amygdala and lower frontal cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with normals. Psychiatry 63, 65–74 (2000).

  71. 71.

    et al. Alterations in cerebral perfusion in posttraumatic stress disorder patients without re-exposure to accident-related stimuli. Clin. Neurophysiol. 117, 637–642 (2006).

  72. 72.

    et al. Neural correlates of declarative memory for emotionally valenced words in women with posttraumatic stress disorder related to early childhood sexual abuse. Biol. Psychiatry 53, 879–889 (2003).

  73. 73.

    et al. Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Arch. Gen. Psychiatry 66, 1099–1107 (2009).

  74. 74.

    et al. Common changes in cerebral blood flow in patients with social phobia treated with citalopram or cognitive-behavioral therapy. Arch. Gen. Psychiatry 59, 425–433 (2002).

  75. 75.

    , , , & Trait-like brain activity during adolescence predicts anxious temperament in primates. PLoS ONE 3, e2570 (2008).

  76. 76.

    et al. Amygdalar and hippocampal substrates of anxious temperament differ in their heritability. Nature 466, 864–868 (2010).

  77. 77.

    & Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476–1488 (2007). This meta-analysis identifies a common pattern of amygdala and insula hyperactivity across different anxiety disorders, as well as disorder-specific patterns of hyper- and hypoactivation.

  78. 78.

    et al. Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of treatment response. Am. J. Psychiatry 166, 302–310 (2009).

  79. 79.

    , , , & Failure of anterior cingulate activation and connectivity with the amygdala during implicit regulation of emotional processing in generalized anxiety disorder. Am. J. Psychiatry 167, 545–554 (2010).

  80. 80.

    et al. Neural correlates of speech anticipatory anxiety in generalized social phobia. Neuroreport 15, 2701–2705 (2004).

  81. 81.

    et al. Amygdala and ventrolateral prefrontal cortex function during anticipated peer evaluation in pediatric social anxiety. Arch. Gen. Psychiatry 65, 1303–1312 (2008).

  82. 82.

    Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).

  83. 83.

    & Amygdala circuitry in attentional and representational processes. Trends Cogn. Sci. 3, 65–73 (1999). This review emphasizes the importance of the amygdala in appetitive as well as aversive conditioning and highlights distinct subregions involved in the representation of value versus attentional processes.

  84. 84.

    & Different roles for amygdala central nucleus and substantia innominata in the surprise-induced enhancement of learning. J. Neurosci. 26, 3791–3797 (2006).

  85. 85.

    & A model for Pavlovian learning: variations in the effectiveness of conditioned but not of unconditioned stimuli. Psychol. Rev. 87, 532–552 (1980).

  86. 86.

    Emotion and cognition and the amygdala: from “what is it?” to “what's to be done?” Neuropsychologia 48, 3416–3429 (2010).

  87. 87.

    & Pathways for emotion: interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey. Neuroscience 115, 1261–1279 (2002).

  88. 88.

    & The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35, 4–26 (2010).

  89. 89.

    & Generalized anxiety disorder (GAD) as an unsuccessful search for safety. Clin. Psychol. Rev. 14, 743–753 (1994).

  90. 90.

    et al. Increased anxiety during anticipation of unpredictable but not predictable aversive stimuli as a psychophysiologic marker of panic disorder. Am. J. Psychiatry 165, 898–904 (2008).

  91. 91.

    et al. Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder. Behav. Res. Ther. 47, 111–118 (2009).

  92. 92.

    et al. Increased anxiety during anticipation of unpredictable aversive stimuli in posttraumatic stress disorder but not in generalized anxiety disorder. Biol. Psychiatry 66, 47–53 (2009). In a rare study directly comparing patients with different anxiety disorders with healthy controls, the authors showed that there is increased startle responding under unpredictable (but not predictable) threat conditions in PTSD but not GAD.

  93. 93.

    et al. Impaired fear inhibition is a biomarker of PTSD but not depression. Depress. Anxiety 27, 244–251 (2010).

  94. 94.

    , & Aversive Pavlovian conditioning in childhood anxiety disorders: impaired response inhibition and resistance to extinction. J. Abnorm. Psychol. 118, 311–321 (2009).

  95. 95.

    & AX+, BX- discrimination learning in the fear-potentiated startle paradigm: possible relevance to inhibitory fear learning in extinction. Learn. Mem. 11, 464–475 (2004).

  96. 96.

    & Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74 (2002).

  97. 97.

    , & Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. Neuropsychopharmacology 36, 529–538 (2011). By selectively inactivating different structures during fear conditioning and extinction, the authors demonstrated a double dissociation between prelimbic and infralimbic cortices with regard to their involvement in fear expression and extinction memory, respectively.

  98. 98.

    , , & Extinction learning in humans: role of the amygdala and vmPFC. Neuron 43, 897–905 (2004).

  99. 99.

    et al. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol. Psychiatry 62, 446–454 (2007).

  100. 100.

    et al. Neural activity associated with monitoring the oscillating threat value of a tarantula. Proc. Natl Acad. Sci. USA 107, 20582–20586 (2010). Subjects were exposed to a live tarantula during fMRI scanning using a paradigm that allowed for the dissociation of brain regions responsive to absolute threat proximity versus approach and/or withdrawal of threat.

  101. 101.

    , & Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research — past, present, and future. Biol. Psychiatry 60, 376–382 (2006).

  102. 102.

    et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol. Psychiatry 66, 1075–1082 (2009).

  103. 103.

    et al. Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch. Gen. Psychiatry 61, 168–176 (2004).

  104. 104.

    , , , & Corticolimbic blood flow during nontraumatic emotional processing in posttraumatic stress disorder. Arch. Gen. Psychiatry 63, 184–192 (2006).

  105. 105.

    , , , & Ventromedial prefrontal cortex reactivity is altered in generalized anxiety disorder during fear generalization. Depress. Anxiety 30, 242–250 (2013).

  106. 106.

    et al. A functional magnetic resonance imaging predictor of treatment response to venlafaxine in generalized anxiety disorder. Biol. Psychiatry 63, 858–863 (2008).

  107. 107.

    Limbic-cortical dysregulation: a proposed model of depression. J. Neuropsychiatry Clin. Neurosci. 9, 471–481 (1997).

  108. 108.

    Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology 36, 183–206 (2011).

  109. 109.

    et al. Reduced structural connectivity of a major frontolimbic pathway in generalized anxiety disorder. Arch. Gen. Psychiatry 69, 16–24 (2012).

  110. 110.

    et al. Preliminary evidence of white matter abnormality in the uncinate fasciculus in generalized social anxiety disorder. Biol. Psychiatry 66, 691–694 (2009).

  111. 111.

    & The structural integrity of an amygdala-prefrontal pathway predicts trait anxiety. J. Neurosci. 29, 11614–11618 (2009).

  112. 112.

    & Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders. Mol. Psychiatry 17, 132–141 (2012). This review challenges the predominant model of the inhibition of amygdala by the vmPFC and suggests a more complex framework in which activation of distinct vmPFC subregions can be associated with either positive or negative affect.

  113. 113.

    et al. Focal brain damage protects against post-traumatic stress disorder in combat veterans. Nature Neurosci. 11, 232–237 (2008).

  114. 114.

    et al. Enhanced amygdala and medial prefrontal activation during nonconscious processing of fear in posttraumatic stress disorder: an fMRI study. Hum. Brain. Mapp. 29, 517–523 (2008).

  115. 115.

    , , , & Alterations in the neural circuitry for emotion and attention associated with posttraumatic stress symptomatology. Psychiatry Res. 172, 7–15 (2009).

  116. 116.

    et al. Orbitofrontal cortex lesions alter anxiety-related activity in the primate bed nucleus of stria terminalis. J. Neurosci. 30, 7023–7027 (2010).

  117. 117.

    , , , & Safety behaviours preserve threat beliefs: protection from extinction of human fear conditioning by an avoidance response. Behav. Res. Ther. 47, 716–720 (2009).

  118. 118.

    , , , & An experimental investigation of the role of safety-seeking behaviours in the maintenance of panic disorder with agoraphobia. Behav. Res. Ther. 37, 559–574 (1999).

  119. 119.

    , & Traumatic avoidance learning: the outcomes of several extinction procedures with dogs. J. Abnorm. Social Psychol. 48, 291–302 (1953).

  120. 120.

    , & Impairment of avoidance performance by intrastriatal administration of 6-hydroxydopamine. Pharmacol. Biochem. Behav. 2, 97–103 (1974).

  121. 121.

    , & A neurochemical and behavioral investigation of the involvement of nucleus accumbens dopamine in instrumental avoidance. Neuroscience 52, 919–925 (1993).

  122. 122.

    , & Different lateral amygdala outputs mediate reactions and actions elicited by a fear-arousing stimulus. Nature Neurosci. 3, 74–79 (2000).

  123. 123.

    & Active avoidance learning requires prefrontal suppression of amygdala-mediated defensive reactions. J. Neurosci. 33, 3815–3823 (2013).

  124. 124.

    , , & Avoiding negative outcomes: tracking the mechanisms of avoidance learning in humans during fear conditioning. Front. Behav. Neurosci. 3 (2009).

  125. 125.

    & Neural systems underlying approach and avoidance in anxiety disorders. Dialogues Clin. Neurosci. 12, 517–531 (2010).

  126. 126.

    et al. The integration of negative affect, pain and cognitive control in the cingulate cortex. Nature Rev. Neurosci. 12, 154–167 (2011). On the basis of a comprehensive survey of diverse literatures, as well as a meta-analysis of studies involving pain, negative affect and cognitive control, the authors propose a central and overarching role for the aMCC in executing 'adaptive control' in the face of uncertainty.

  127. 127.

    , , , & Effects of cognitive-behavioral therapy on brain activation in specific phobia. Neuroimage 29, 125–135 (2006).

  128. 128.

    , , & Exposure therapy triggers lasting reorganization of neural fear processing. Proc. Natl Acad. Sci. USA 109, 9203–9218 (2012).

  129. 129.

    , , , & Effects of predictability of shock timing and intensity on aversive responses. Int. J. Psychophysiol. 80, 112–118 (2011).

  130. 130.

    & Alcohol stress response dampening: selective reduction of anxiety in the face of uncertain threat. J. Psychopharmacol. 26, 232–244 (2012).

  131. 131.

    , , , & Anxious responses to predictable and unpredictable aversive events. Behav. Neurosci. 118, 916–924 (2004).

  132. 132.

    , & Neural correlates of unconditioned response diminution during Pavlovian conditioning. Neuroimage 40, 811–817 (2008).

  133. 133.

    et al. Uncertainty during anticipation modulates neural responses to aversion in human insula and amygdala. Cereb. Cortex 20, 929–940 (2010).

  134. 134.

    & Uncertainty is associated with biased expectancies and heightened responses to aversion. Emotion 11, 413–424 (2011).

  135. 135.

    et al. Processing of temporal unpredictability in human and animal amygdala. J. Neurosci. 27, 5958–5966 (2007). This translational study showed that mice and humans exposed to a temporally unpredictable, neutral tone demonstrated a common pattern of amygdala activation and increased anxious behaviour.

  136. 136.

    , & Overlapping and distinct brain regions associated with the anxiolytic effects of chlordiazepoxide and chronic fluoxetine. Neuropsychopharmacology 33, 2117–2130 (2008).

  137. 137.

    et al. The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by fear-potentiated startle. Biol. Psychiatry 60, 760–766 (2006).

  138. 138.

    et al. Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology 161, 233–247 (2002).

  139. 139.

    , & Waiting for spiders: brain activation during anticipatory anxiety in spider phobics. Neuroimage 37, 1427–1436 (2007).

  140. 140.

    , , , & Phasic and sustained fear in humans elicits distinct patterns of brain activity. Neuroimage 55, 389–400 (2011).

  141. 141.

    et al. Interactions between transient and sustained neural signals support the generation and regulation of anxious emotion. Cereb. Cortex 23, 49–60 (2012).

  142. 142.

    , & Dissecting the anticipation of aversion reveals dissociable neural networks. Cereb. Cortex 4 Jul 2012 (doi:10.1093/cercor/bhs175).

  143. 143.

    , & Human bed nucleus of the stria terminalis indexes hypervigilant threat monitoring. Biol. Psychiatry 68, 416–424 (2010). When presented with false physiological feedback that they believed to be yoked to the delivery of an electric shock, individuals with high levels of trait anxiety showed increased BNST activation as threat became more proximal.

  144. 144.

    & The intolerance of uncertainty scale: psychometric properties of the English version. Behav. Res. Ther. 40, 931–945 (2002).

  145. 145.

    et al. Intolerance of uncertainty and information processing: evidence of biased recall and interpretations. Cogn. Ther. Res. 29, 57–70 (2005).

  146. 146.

    et al. Increasingly certain about uncertainty: intolerance of uncertainty across anxiety and depression. J. Anxiety Disord. 26, 468–479 (2012).

  147. 147.

    & The neural basis of financial risk taking. Neuron 47, 763–770 (2005).

  148. 148.

    , & A common role of insula in feelings, empathy and uncertainty. Trends Cogn. Sci. 13, 334–340 (2009).

  149. 149.

    et al. Differential effects of insular and ventromedial prefrontal cortex lesions on risky decision-making. Brain 131, 1311–1322 (2008).

  150. 150.

    , , , & Functional neuroanatomy of aversion and its anticipation. Neuroimage 29, 106–116 (2006). This study identifies a broad network of regions that are commonly activated in anticipation of and in response to aversive images, including the amygdala, ACC, anterior insula, dorsolateral PFC and OFC.

  151. 151.

    , & Impact of continuous versus intermittent CS–UCS pairing on human brain activation during Pavlovian fear conditioning. Behav. Neurosci. 121, 635–642 (2007).

  152. 152.

    Descartes' Error: Emotion,Reason, and the Human Brain (Penguin Books, 1994).

  153. 153.

    How do you feel — now? The anterior insula and human awareness. Nature Rev. Neurosci. 10, 59–70 (2009). Craig presents an updated theory of anterior insula function, highlighting this region's role in the integration of feeling states across time and conscious awareness.

  154. 154.

    & Prospection: experiencing the future. Science 317, 1351–1354 (2007). The authors propose that decision-making about future events results from simulation of those events and their anticipated emotional consequences and discuss common errors of prospection that result from such simulations.

  155. 155.

    et al. Dorsolateral prefrontal cortex activation during emotional anticipation and neuropsychological performance in posttraumatic stress disorder. Arch. Gen. Psychiatry 69, 360–371 (2012).

  156. 156.

    et al. Anxiety positive subjects show altered processing in the anterior insula during anticipation of negative stimuli. Hum. Brain. Mapp. 32, 1836–1846 (2011).

  157. 157.

    , , , & Anticipation of aversive visual stimuli is associated with increased insula activation in anxiety-prone subjects. Biol. Psychiatry 60, 402–409 (2006).

  158. 158.

    , , & Intolerance of uncertainty correlates with insula activation during affective ambiguity. Neurosci. Lett. 430, 92–97 (2008).

  159. 159.

    et al. Anatomical connections between brain areas activated during rectal distension in healthy volunteers: a visceral pain network. Eur. J. Pain 14, 142–148 (2010).

  160. 160.

    et al. Functional connectivity of the insula in the resting brain. Neuroimage 55, 8–23 (2011).

  161. 161.

    et al. A role for the human dorsal anterior cingulate cortex in fear expression. Biol. Psychiatry 62, 1191–1194 (2007).

  162. 162.

    & Conjoint activity of anterior insular and anterior cingulate cortex: awareness and response. Brain Struct. Funct. 214, 535–549 (2010).

  163. 163.

    , , , & The adaptive threat bias in anxiety: amygdala–dorsomedial prefrontal cortex coupling and aversive amplification. Neuroimage 60, 523–529 (2012).

  164. 164.

    & Anatomical insights into the interaction of emotion and cognition in the prefrontal cortex. Neurosci. Biobehav. Rev. 36, 479–501 (2012).

  165. 165.

    et al. Voxel-based analysis of MRI reveals anterior cingulate gray-matter volume reduction in posttraumatic stress disorder due to terrorism. Proc. Natl Acad. Sci. USA 100, 9039–9043 (2003).

  166. 166.

    et al. Altered processing of contextual information during fear extinction in PTSD: an fMRI study. CNS Neurosci. Ther. 17, 227–236 (2011).

  167. 167.

    et al. Neural networks of information processing in posttraumatic stress disorder: a functional magnetic resonance imaging study. Biol. Psychiatry 58, 111–118 (2005).

  168. 168.

    , & Insula reactivity and connectivity to anterior cingulate cortex when processing threat in generalized social anxiety disorder. Biol. Psychol. 89, 273–276 (2012).

  169. 169.

    et al. Anterior cingulate cortex volume reduction in patients with panic disorder. Psychiatry Clin. Neurosci. 62, 322–330 (2008).

  170. 170.

    et al. Damage to the right dorsal anterior cingulate cortex induces panic disorder. J. Affect. Disord. 133, 569–572 (2011).

  171. 171.

    Prospective long-term follow-up of 44 patients who received cingulotomy for treatment-refractory obsessive-compulsive disorder. Am. J. Psychiatry 159, 269–275 (2002).

  172. 172.

    , , & Meta-analytical comparison of voxel-based morphometry studies in obsessive-compulsive disorder versus other anxiety disorders. Arch. Gen. Psychiatry 67, 701–711 (2010).

  173. 173.

    , , , & Anxiety dissociates dorsal and ventral medial prefrontal cortex functional connectivity with the amygdala at rest. Cereb. Cortex 21, 1667–1673 (2011).

  174. 174.

    et al. A functional magnetic resonance imaging investigation of uncertainty in adolescents with anxiety disorders. Biol. Psychiatry 63, 563–568 (2008).

  175. 175.

    , , , & Connectivity-based segmentation of human amygdala nuclei using probabilistic tractography. Neuroimage 56, 1353–1361 (2011).

  176. 176.

    et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am. J. Psychiatry 167, 748–751 (2010).

  177. 177.

    Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res. Rev. 22, 229–244 (1996).

  178. 178.

    & Specificity in the projections of prefrontal and insular cortex to ventral striatopallidum and the extended amygdala. J. Neurosci. 25, 11757–11767 (2005).

  179. 179.

    et al. Functional network dysfunction in anxiety and anxiety disorders. Trends Neurosci. 35, 527–535 (2012).

  180. 180.

    & Psychopathology and the human connectome: toward a transdiagnostic model of risk for mental illness. Neuron 74, 990–1004 (2012). The authors propose a novel framework for investigating the neural basis of psychiatric disorders, suggesting that an emphasis on functional connectivity within large-scale networks will allow the identification of broad risk-related phenotypes and advance the classification and identification of these disorders.

  181. 181.

    & Considering PTSD from the perspective of brain processes: a psychological construction approach. J. Trauma. Stress 24, 3–24 (2011).

  182. 182.

    et al. Attention bias modification treatment: a meta-analysis toward the establishment of novel treatment for anxiety. Biol. Psychiatry 68, 982–990 (2010).

  183. 183.

    et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch. Gen. Psychiatry 61, 1136–1144 (2004).

  184. 184.

    , , & Facilitation of extinction of conditioned fear by D-cycloserine: implications for psychopathology. Curr. Dir. Psychol. Sci. 14, 214–219 (2005).

  185. 185.

    et al. Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch. Gen. Psychiatry 63, 298–304 (2006).

  186. 186.

    et al. D-cycloserine augmented exposure therapy for obsessive-compulsive disorder. Biol. Psychiatry 62, 835–838 (2007).

  187. 187.

    , , , & A randomized placebo-controlled trial of D-cycloserine to enhance exposure therapy for posttraumatic stress disorder. Biol. Psychiatry 71, 962–968 (2012).

  188. 188.

    et al. Augmentation of behavior therapy with D-cycloserine for obsessive-compulsive disorder. Am. J. Psychiatry 165, 335–341 (2008).

  189. 189.

    et al. Efficacy of D-cycloserine for enhancing response to cognitive-behavior therapy for panic disorder. Biol. Psychiatry 67, 365–370 (2010).

  190. 190.

    , , & D-cycloserine for the augmentation of an attentional training intervention for trait anxiety. J. Anxiety Disord. 24, 440–445 (2010).

  191. 191.

    Reading and controlling human brain activation using real-time functional magnetic resonance imaging. Trends Cogn. Sci. 11, 473–481 (2007).

  192. 192.

    , , , & Volitional control of anterior insula activity modulates the response to aversive stimuli. A real-time functional magnetic resonance imaging study. Biol. Psychiatry 68, 425–432 (2010).

  193. 193.

    Life in the future versus life in the present. Clin. Psychol. Sci. Pr. 9, 76–80 (2002).

  194. 194.

    & Expanding our conceptulization of and treatment for generalized anxiety disorder: integrating mindfulness/acceptance-based approaches with existing cognitive-behavioral models. Clin. Psychol. Sci. Pr. 9, 54–68 (2002).

  195. 195.

    , , , & Manual for the State-Trait Anxiety Inventory (Consulting Psychologists, 1983).

  196. 196.

    et al. Testing a tripartite model: I. Evaluating the convergent and discriminant validity of anxiety and depression symptom scales. J. Abnorm. Psychol. 104, 3–14 (1995).

  197. 197.

    , , , & Distinguishing dimensions of anxiety and depression. Cogn. Ther. Res. 25, 1–22 (2001).

  198. 198.

    & Behavioral inhibition, behavioral activation, and affective responses to impending reward and punishment: the BIS/BAS Scales. J. Pers. Soc. Psychol. 67, 319–333 (1994).

  199. 199.

    , & Development and validation of brief measures of positive and negative affect: the PANAS scales. J. Pers. Soc. Psychol. 54, 1063–1070 (1988).

  200. 200.

    , , & Development and validation of the Penn State Worry Questionnaire. Behav. Res. Ther. 28, 487–495 (1990).

  201. 201.

    et al. Development and validation of the Inventory of Depression and Anxiety Symptoms (IDAS). Psychol. Assess. 19, 253–268 (2007).

  202. 202.

    , , & An inventory for measuring clinical anxiety: psychometric properties. J. Consult. Clin. Psychol. 56, 893–897 (1988).

  203. 203.

    , , & Anxiety sensitivity, anxiety frequency and the prediction of fearfulness. Behav. Res. Ther. 24, 1–8 (1986).

  204. 204.

    & Structure of anxiety and the anxiety disorders: a hierarchical model. J. Abnorm. Psychol. 105, 181–193 (1996).

  205. 205.

    , & Structural relationships among dimensions of the DSM-IV anxiety and mood disorders and dimensions of negative affect, positive affect, and autonomic arousal. J. Abnorm. Psychol. 107, 179–192 (1998).

  206. 206.

    The structure of common mental disorders. Arch. Gen. Psychiatry 56, 921–926 (1999).

  207. 207.

    , , , & The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch. Gen. Psychiatry 62, 182–189 (2005).

  208. 208.

    & Is obsessive-compulsive disorder an anxiety disorder? Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 338–352 (2006).

  209. 209.

    Rethinking the mood and anxiety disorders: a quantitative hierarchical model for DSM-V. J. Abnorm. Psychol. 114, 522–536 (2005).

  210. 210.

    & A proposal for a dimensional classification system based on the shared features of the DSM-IV anxiety and mood disorders: implications for assessment and treatment. Psychol. Assess. 21, 256–271 (2009).

  211. 211.

    , & in Human Helplessness: Theory and Applications (eds Garber, J. & Seligman, M. E. P.) 131–169 (Academic Press, 1980).

  212. 212.

    , & Hopelessness depression: a theory-based subtype of depression. Psychol. Rev. 96, 358–372 (1989).

  213. 213.

    , , & in Comorbidity of Mood and Anxiety Disorders (eds Maser, J. D. & Cloninger, C. R.) 499–543 (American Psychiatric Press, 1990).

  214. 214.

    , & Neuroeconomic approaches to mental disorders. Neuron 67, 543–554 (2010).

  215. 215.

    & Risk perception by patients with anxiety disorders. J. Nerv. Ment. Dis. 182, 465–470 (1994).

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Acknowledgements

The authors wish to thank L. Abramson, R. Davidson, N. Kalin, J. Curtin and members of the Curtin laboratory for feedback on previous versions of this manuscript. This work was supported by the National Science Foundation (Graduate Research Fellowship to D.W.G.) and the US National Institute of Mental Health (R01-MH74847, K02-MH082130 to J.B.N.).

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  1. Departments of Psychiatry and Psychology, Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin–Madison, 1500 Highland Avenue, Madison, Wisconsin 53705, USA.

    • Dan W. Grupe
    •  & Jack B. Nitschke

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The authors declare no competing financial interests.

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Correspondence to Dan W. Grupe or Jack B. Nitschke.

Glossary

Anxiety

The suite of anticipatory affective, cognitive and behavioural changes in response to uncertainty about a potential future threat.

Ventromedial prefrontal cortex

(vmPFC). It encompasses the medial orbitofrontal cortex, posterior frontopolar cortex, subgenual anterior cingulate cortex (ACC) and inferior pregenual ACC, including Brodmann areas 11, 14 and 25, and portions of 10, 24 and 32.

Orbitofrontal cortex

(OFC). Medial and lateral aspects of the orbital surface of the prefrontal cortex, including Brodmann areas 11, 13 and 14, and ventral portions of 10 and 47/12.

Fear-potentiated startle

The enhanced response to a startling stimulus observed in negative arousing states, such as fear or anxiety.

Hypervigilance

A state of increased attention to a perceived threat in one's environment.

Fear conditioning

The process by which a neutral conditioned stimulus (CS+) becomes associated with an aversive, unconditioned stimulus (US) through repeated contingent presentations of the CS+ and US, resulting in fear expression following presentation of the CS+ alone.

Prediction error

The difference between predicted and actual outcomes, which results in a neural signal that leads to increasingly accurate future predictions.

Rostral cingulate cortex

Encompasses the anterior cingulate cortex and anterior mid-cingulate cortex, including Brodmann areas 24, 25, 32 and 33.

Associability

The propensity of a stimulus to form associations with other stimuli in the environment; associability increases following surprising or unpredicted outcomes.

Conditional discrimination tasks

A variant of fear-conditioning paradigms that allows for the independent investigation of safety learning and the inhibition of fear responses in the presence of learned safe cues.

Fear extinction

An active learning process in which a conditioned stimulus (CS+) is repeatedly presented in the absence of a contingent unconditioned stimulus (US), leading to a new association between the CS+ and safety that competes with the original association between the CS+ and US.

Diffusion tensor imaging

An MRI technique that assays the diffusion properties of water molecules, providing insight into the microstructural properties of white matter.

Uncinate fasciculus

The primary white matter tract connecting ventral portions of the prefrontal cortex and anterior cingulate cortex with medial temporal lobe structures, including the amygdala.

Exposure therapy

A therapeutic technique in which individuals are presented with feared objects, situations or memories in a safe setting, thus causing a reduction of fearful associations.

Cognitive behavioural therapy

A diverse collection of therapies in which there is an emphasis on the correction or restructuring of inaccurate beliefs and maladaptive behaviours.

Benzodiazepines

A widely used class of GABA receptor agonists for the treatment of anxiety disorders.

Interoception

The perception of sensory events occurring within one's body.

D-cycloserine

A partial agonist of the NMDA glutamate receptor that has been shown to enhance learning.

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DOI

https://doi.org/10.1038/nrn3524

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