Threat imminence reveals links among unfolding of anticipatory physiological response, cortical-subcortical intrinsic functional connectivity, and anxiety

Rany Abend*, Sonia G. Ruiz, Mira A. Bajaj, Anita Harrewijn, Julia O. Linke, Lauren Y. Atlas, Anderson M. Winkler, Daniel S. Pine

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

Abstract

Excessive expression of fear responses in anticipation of threat occurs in anxiety, but understanding of underlying pathophysiological mechanisms is limited. Animal research indicates that threat-anticipatory defensive responses are dynamically organized by threat imminence and rely on conserved circuitry. Insight from basic neuroscience research in animals on threat imminence could guide mechanistic research in humans mapping abnormal function in this circuitry to aberrant defensive responses in pathological anxiety. 50 pediatric anxiety patients and healthy-comparisons (33 females) completed an instructed threat-anticipation task whereby cues signaled delivery of painful (threat) or non-painful (safety) thermal stimulation. Temporal changes in skin-conductance indexed anxiety effects on anticipatory responding as function of threat imminence. Multivariate network analyses of resting-state functional connectivity data from a subsample were used to identify intrinsic-function correlates of anticipatory-response dynamics, within a specific, distributed network derived from translational research on defensive responding. By considering threat imminence, analyses revealed specific anxiety effects. Importantly, pathological anxiety was associated with excessive deployment of anticipatory physiological response as threat, but not safety, outcomes became more imminent. Magnitude of increase in threat-anticipatory physiological responses corresponded with magnitude of intrinsic connectivity within a cortical-subcortical circuit. Moreover, more severe anxiety was associated with stronger associations between anticipatory physiological responding and connectivity that ventromedial prefrontal cortex showed with hippocampus and basolateral amygdala, regions implicated in animal models of anxiety. These findings link basic and clinical research, highlighting variations in intrinsic function in conserved defensive circuitry as a potential pathophysiological mechanism in anxiety.

Original languageEnglish
Article number100428
JournalNeurobiology of Stress
Volume16
DOIs
Publication statusPublished - Jan 2022
Externally publishedYes

Bibliographical note

Funding Information:
We would like to thank Kalina J. Michalska, Elizabeth Necka, Chika Matsumoto, and Esther E. Palacios-Barrios for their assistance. We also 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).

Funding Information:
We would like to thank Kalina J. Michalska, Elizabeth Necka, Chika Matsumoto, and Esther E. Palacios-Barrios for their assistance. We also 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 ).

Publisher Copyright:
© 2022

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