Association of Generalized Anxiety Disorder With Autonomic Hypersensitivity and Blunted Ventromedial Prefrontal Cortex Activity During Peripheral Adrenergic Stimulation: A Randomized Clinical Trial
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IMPORTANCE: β-Adrenergic stimulation elicits heart palpitations and dyspnea, key features of acute anxiety and sympathetic arousal, yet no neuroimaging studies have examined how the pharmacologic modulation of interoceptive signals is associated with fear-related neurocircuitry in individuals with generalized anxiety disorder (GAD). OBJECTIVE: To examine the neural circuitry underlying autonomic arousal induced via isoproterenol, a rapidly acting, peripheral β-adrenergic agonist akin to adrenaline. DESIGN, SETTING, AND PARTICIPANTS: This crossover randomized clinical trial of 58 women with artifact-free data was conducted from January 1, 2017, to November 31, 2019, at the Laureate Institute for Brain Research in Tulsa, Oklahoma. EXPOSURES: Functional magnetic resonance imaging was used to assess neural responses during randomized intravenous bolus infusions of isoproterenol (0.5 and 2.0 μg) and saline, each administered twice in a double-blind fashion. MAIN OUTCOMES AND MEASURES: Blood oxygen level-dependent responses across the whole brain during isoproterenol administration in patients with GAD vs healthy comparators. Cardiac and respiratory responses, as well as interoceptive awareness and anxiety, were also measured during the infusion protocol. RESULTS: Of the 58 female study participants, 29 had GAD (mean [SD] age, 26.9 [6.8] years) and 29 were matched healthy comparators (mean [SD] age, 24.4 [5.0] years). During the 0.5-μg dose of isoproterenol, the GAD group exhibited higher heart rate responses (b = 5.34; 95% CI, 2.06-8.61; P = .002), higher intensity ratings of cardiorespiratory sensations (b = 8.38; 95% CI, 2.05-14.71; P = .01), higher levels of self-reported anxiety (b = 1.04; 95% CI, 0.33-1.76; P = .005), and significant hypoactivation in the ventromedial prefrontal cortex (vmPFC) that was evident throughout peak response (Cohen d = 1.55; P < .001) and early recovery (Cohen d = 1.52; P < .001) periods. Correlational analysis of physiological and subjective indexes and percentage of signal change extracted during the 0.5-μg dose revealed that vmPFC hypoactivation was inversely correlated with heart rate (r56 = -0.51, adjusted P = .001) and retrospective intensity of both heartbeat (r56 = -0.50, adjusted P = .002) and breathing (r56 = -0.44, adjusted P = .01) sensations. Ventromedial prefrontal cortex hypoactivation correlated inversely with continuous dial ratings at a trend level (r56 = -0.38, adjusted P = .051), whereas anxiety (r56 = -0.28, adjusted P = .27) and chronotropic dose 25 (r56 = -0.14, adjusted P = .72) showed no such association. CONCLUSIONS AND RELEVANCE: In this crossover randomized clinical trial, women with GAD exhibited autonomic hypersensitivity during low levels of adrenergic stimulation characterized by elevated heart rate, heightened interoceptive awareness, increased anxiety, and a blunted neural response localized to the vmPFC. These findings support the notion that autonomic hyperarousal may be associated with regulatory dysfunctions in the vmPFC, which could serve as a treatment target to help patients with GAD more appropriately appraise and regulate signals of sympathetic arousal. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02615119.
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The study using peripheral adrenergic stimulation revealed reduced activity for generalized anxiety disorder participants in the ventromedial prefrontal cortex extending to the rostral anterior cingulate cortex and in the left angular gyrus extending into the precuneus, only for the 0.5 μg dose of isoproterenol hydrochloride.
“The study which used peripheral adrenergic stimulation revealed reduced activity for GAD participants in the ventromedial prefrontal cortex extending to the rostral ACC as well as in the left angular gyrus extending into the precuneus, though only for the 0.5 μg dose of isoproterenol hydrochloride [46].”
From Neural correlates of altered interoception in depressive and anxiety disorders: a systematic review and meta-analysis (2026) · cites this paper as [46]
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- Authors
- Teed, A. R., Feinstein, J. S., Puhl, M., Lapidus, R. C., Upshaw, V., Kuplicki, R. T., Bodurka, J., Ajijola, O. A., Kaye, W. H., Thompson, W. K., Paulus, M. P., & Khalsa, S. S.
- Affiliations
- Laureate Institute for Brain Research (US)
- University of California, Los Angeles (US)
- University of California San Diego (US)
- Corresponding author
- Khalsa, Sahib S.
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2022-04-01
- Volume
- 79
- Issue
- 4
- Pages
- 323
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC8811711
- OpenAlex
- W4210493812
- Cited by
- 79
- References
- 76
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 21 · 2023: 14 · 2022: 10
- FWCI
- 15.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- JAMA Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Laureate Institute for Brain Research, University of Tulsa
- National Institute of Mental Health (K23MH112949)
- National Institute of General Medical Sciences (P20GM121312)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Health Sciences › Medicine › Psychiatry and Mental health › Psychosomatic Disorders and Their Treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Keywords
- generalized anxiety disorder, isoproterenol, beta-adrenergic stimulation, ventromedial prefrontal cortex, interoceptive awareness, heart rate response, dyspnea, women, sympathetic activation, autonomic arousal
- MeSH terms
- Adult, Anxiety Disorders, Female, Humans, Isoproterenol, Magnetic Resonance Imaging, Retrospective Studies, Prefrontal Cortex, Adrenergic Agents, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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