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Research Articles, Behavioral/Cognitive

Anxiety and the Neurobiology of Temporally Uncertain Threat Anticipation

Juyoen Hur, Jason F. Smith, Kathryn A. DeYoung, Allegra S. Anderson, Jinyi Kuang, Hyung Cho Kim, Rachael M. Tillman, Manuel Kuhn, Andrew S. Fox and Alexander J. Shackman
Journal of Neuroscience 7 October 2020, 40 (41) 7949-7964; DOI: https://doi.org/10.1523/JNEUROSCI.0704-20.2020
Juyoen Hur
1Department of Psychology, Yonsei University, Seoul, 03722, Republic of Korea
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Jason F. Smith
2Departments of Psychology
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Kathryn A. DeYoung
2Departments of Psychology
3Family Science
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Allegra S. Anderson
6Department of Psychological Sciences, Vanderbilt University, Nashville, Tennessee 37240
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Jinyi Kuang
7Department of Psychology, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Hyung Cho Kim
2Departments of Psychology
4Neuroscience and Cognitive Science Program
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Rachael M. Tillman
2Departments of Psychology
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Manuel Kuhn
8Center for Depression, Anxiety and Stress Research, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478
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Andrew S. Fox
9Department of Psychology
10California National Primate Research Center, University of California, Davis, California 95616
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Alexander J. Shackman
2Departments of Psychology
4Neuroscience and Cognitive Science Program
5Maryland Neuroimaging Center, University of Maryland, College Park, Maryland 20742
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Abstract

When extreme, anxiety—a state of distress and arousal prototypically evoked by uncertain danger—can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for fMRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically colocalized in frontocortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with frontocortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala—the two major subdivisions of the extended amygdala—play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to temporally uncertain and certain threat anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety.

SIGNIFICANCE STATEMENT Anxiety—an emotion prototypically associated with the anticipation of uncertain harm—has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended amygdala occupies center stage in neuropsychiatric models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about the neurobiology of anxiety and fear.

  • affective neuroscience
  • anxiety and fear
  • bed nucleus of the stria terminalis
  • emotion
  • extended amygdala
  • Research Domain Criteria (RDoC)
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The Journal of Neuroscience: 40 (41)
Journal of Neuroscience
Vol. 40, Issue 41
7 Oct 2020
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Anxiety and the Neurobiology of Temporally Uncertain Threat Anticipation
Juyoen Hur, Jason F. Smith, Kathryn A. DeYoung, Allegra S. Anderson, Jinyi Kuang, Hyung Cho Kim, Rachael M. Tillman, Manuel Kuhn, Andrew S. Fox, Alexander J. Shackman
Journal of Neuroscience 7 October 2020, 40 (41) 7949-7964; DOI: 10.1523/JNEUROSCI.0704-20.2020

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Anxiety and the Neurobiology of Temporally Uncertain Threat Anticipation
Juyoen Hur, Jason F. Smith, Kathryn A. DeYoung, Allegra S. Anderson, Jinyi Kuang, Hyung Cho Kim, Rachael M. Tillman, Manuel Kuhn, Andrew S. Fox, Alexander J. Shackman
Journal of Neuroscience 7 October 2020, 40 (41) 7949-7964; DOI: 10.1523/JNEUROSCI.0704-20.2020
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Keywords

  • affective neuroscience
  • anxiety and fear
  • bed nucleus of the stria terminalis
  • emotion
  • extended amygdala
  • Research Domain Criteria (RDoC)

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