Threat-anticipatory psychophysiological response is enhanced in youth with anxiety disorders and correlates with prefrontal cortex neuroanatomy

Threat-anticipatory psychophysiological response is enhanced in youth with anxiety disorders and correlates with prefrontal cortex neuroanatomy

J Psychiatry Neurosci 2021;46(2):E212-E221 | PDF | Appendix

Rany Abend, PhD; Mira A. Bajaj, BA; Anita Harrewijn, PhD; Chika Matsumoto, BS; Kalina J. Michalska, PhD; Elizabeth Necka, PhD; Esther E. Palacios-Barrios, MS; Ellen Leibenluft, MD; Lauren Y. Atlas, PhD; Daniel S. Pine, MD

Background: Threat anticipation engages neural circuitry that has evolved to promote defensive behaviours; perturbations in this circuitry could generate excessive threat-anticipation response, a key characteristic of pathological anxiety. Research into such mechanisms in youth faces ethical and practical limitations. Here, we use thermal stimulation to elicit pain-anticipatory psychophysiological response and map its correlates to brain structure among youth with anxiety and healthy youth.

Methods: Youth with anxiety (n = 25) and healthy youth (n = 25) completed an instructed threat-anticipation task in which cues predicted nonpainful or painful thermal stimulation; we indexed psychophysiological response during the anticipation and experience of pain using skin conductance response. High-resolution brain-structure imaging data collected in another visit were available for 41 participants. Analyses tested whether the 2 groups differed in their psychophysiological cue-based pain-anticipatory and pain-experience responses. Analyses then mapped psychophysiological response magnitude to brain structure.

Results: Youth with anxiety showed enhanced psychophysiological response specifically during anticipation of painful stimulation (b = 0.52, p = 0.003). Across the sample, the magnitude of psychophysiological anticipatory response correlated negatively with the thickness of the dorsolateral prefrontal cortex (pFWE < 0.05); psychophysiological response to the thermal stimulation correlated positively with the thickness of the posterior insula (pFWE < 0.05).

Limitations: Limitations included the modest sample size and the cross-sectional design.

Conclusion: These findings show that threat-anticipatory psychophysiological response differentiates youth with anxiety from healthy youth, and they link brain structure to psychophysiological response during pain anticipation and experience. A focus on threat anticipation in research on anxiety could delineate relevant neural circuitry.


Submitted June 9, 2020; Revised Aug. 27, 2020; Accepted Sept. 14, 2020.

Acknowledgments: The authors thank the participants and families, as well as the staff of the Intramural Research Program of the National Institute of Mental Health (IRP, NIMH), National Institutes of Health. This research was supported (in part) by the NIMH IRP (ZIAMH002781-15, NCT00018057).

Affiliations: From the Emotion and Development Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD (Abend, Bajaj, Harrewijn, Matsumoto, Leibenluft, Pine); the Department of Psychology, University of California Riverside, Riverside, CA (Michalaska); the 3 National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, MD (Necka, Atlas); and the 1 Department of Psychology, University of Pittsburgh, Pittsburgh, PA (Palacios-Barrios).

Competing interests: No competing interests declared.

Contributors: R. Abend, K. Michalska, E. Necka, L. Atlas and D. Pine designed the study. R. Abend, M. Bajaj, A. Harrewijn, C. Matsumoto, E. Necka and E. Palacios-Barrios acquired the data, which R. Abend, M. Bajaj, C. Matsumoto, K. Michalska, E. Necka, E. Lieberluft, L. Atlas and D. Pine analyzed. R. Abend, M. Bajaj, C. Matsumoto, K. Michalska, E. Lieberluft, L. Atlas and D. Pine wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/

DOI: 10.1503/jpn.200110

Correspondence to: R. Abend, Emotion and Development Branch, National Institute of Mental Health, National Institutes of Health, 9000 Rockville Pike, Bldg 15K, MSC-2670, Bethesda, MD; rany.abend@nih.gov