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

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)7949-7964
Number of pages16
JournalJournal of Neuroscience
Issue number41
Publication statusPublished - 2020 Oct 7

Bibliographical note

Funding Information:
This work was supported by the California National Primate Center; National Institutes of Health DA040717, MH107444, and MH121409; University of California, Davis; and University of Maryland, College Park. Raw data are available at the National Institute of Mental Health’s Data Archive. Key statistical maps are publicly available at We thank the following for assistance and critical feedback: A. Antonacci, M. Barstead, D. Bradford, J. Curtin, L. Friedman, J. Furcolo, C. Gorgolewski, C. Grubb, D. Holley, R. Hum, C. Kaplan, C. Lejuez, D. Limon, B. Nacewicz, S. Padmala, L. Pessoa, M. Roesch, S. Rose, J. Swayambunathan, and A. Vogel; members of the Affective and Translational Neuroscience laboratory; the staff of the Maryland Neuroimaging Center; the Office of the Registrar (University of Maryland); and two anonymous reviewers. The authors declare no competing financial interests.

Publisher Copyright:
Copyright © 2020 the authors.

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)


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