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Heartbeat-evoked neural response abnormalities in generalized anxiety disorder during peripheral adrenergic stimulation

Neuropsychopharmacology (2024)Cite this article

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Abstract

Hyperarousal symptoms in generalized anxiety disorder (GAD) are often incongruent with the observed physiological state, suggesting that abnormal processing of interoceptive signals is a characteristic feature of the disorder. To examine the neural mechanisms underlying interoceptive dysfunction in GAD, we evaluated whether adrenergic modulation of cardiovascular signaling differentially affects the heartbeat-evoked potential (HEP), an electrophysiological marker of cardiac interoception, during concurrent electroencephalogram and functional magnetic resonance imaging (EEG-fMRI) scanning. Intravenous infusions of the peripheral adrenergic agonist isoproterenol (0.5 and 2.0 micrograms, μg) were administered in a randomized, double-blinded and placebo-controlled fashion to dynamically perturb the cardiovascular system while recording the associated EEG-fMRI responses. During the 0.5 μg isoproterenol infusion, the GAD group (n = 24) exhibited significantly larger changes in HEP amplitude in an opposite direction than the healthy comparison (HC) group (n = 24). In addition, the GAD group showed significantly larger absolute HEP amplitudes than the HC group during saline infusions, when cardiovascular tone did not increase. No significant group differences in HEP amplitude were identified during the 2.0 μg isoproterenol infusion. Using analyzable blood oxygenation level-dependent fMRI data from participants with concurrent EEG-fMRI data (21 GAD and 21 HC), we found that the aforementioned HEP effects were uncorrelated with fMRI signals in the insula, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, amygdala, and somatosensory cortex, brain regions implicated in cardiac signal processing in prior fMRI studies. These findings provide additional evidence of dysfunctional cardiac interoception in GAD and identify neural processes at the electrophysiological level that may be independent from blood oxygen level-dependent responses during peripheral adrenergic stimulation.

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Fig. 1: Isoproterenol-induced changes in HEP amplitude and cardiorespiratory sensation.
Fig. 2: Association between two self-reported personality traits and the average HEP amplitude (avHEP) during the peak period of the saline infusion.

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Acknowledgements

Megan Sinik, B.S., Dhvanit Raval, B.S., and Chloe Sigman, B.S., provided physiological data processing assistance. Rachel Lapidus, Ph.D., Valerie Upshaw, M.S.N., C.N.A.P., and Maria Puhl, Ph.D., provided data collection assistance. Megan Cole, R.N., Jeanne Echols, R.N., Lisa Augustine, R.N., Susan Maxey, R.N., and Lindsey Bailey, N.T., provided isoproterenol preparation assistance. We also acknowledge the key contributions of the late Jerzy Bodurka to the acquisition of the functional neuroimaging data. The results included in the present paper were presented at the American College of Neuropsychopharmacology meeting, in December 2022.

Funding

This work was supported by the National Institute of Mental Health (K23MH112949 [to SSK]), National Institute of General Medical Sciences Center (Grant No. 1P20GM121312 [to MPP and SSK]), and The William K. Warren Foundation. CV is supported, in part, by the Fédération pour la recherche sur le cerveau (FRC), the Union Nationale de Familles et Amis de Personnes Malades et Handicapées Psychiques (UNAFAM), and by the Fondation des Gueules Cassées. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Laureate Institute for Brain Research, Tulsa, OK, USA

    Charles Verdonk, Adam R. Teed, Evan J. White, Xi Ren, Jennifer L. Stewart, Martin P. Paulus & Sahib S. Khalsa

  2. VIFASOM (EA 7330 Vigilance Fatigue, Sommeil et Santé Publique), Université Paris Cité, Paris, France

    Charles Verdonk

  3. French Armed Forces Biomedical Research Institute, Brétigny-sur-Orge, France

    Charles Verdonk

  4. Oxley College of Health Sciences, University of Tulsa, Tulsa, OK, USA

    Jennifer L. Stewart, Martin P. Paulus & Sahib S. Khalsa

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Contributions

Concept and design: Khalsa. Acquisition, analysis, or interpretation of data: Verdonk, Teed, White, Ren, Stewart, Paulus, and Khalsa. Drafting of the manuscript: Verdonk and Khalsa. Critical revision of the manuscript for important intellectual content: Verdonk, Teed, White, Ren, Stewart, Paulus, and Khalsa. Statistical analysis: Verdonk and Khalsa. Obtained funding: Paulus and Khalsa. Administrative, technical, or material support: Khalsa. Supervision: Khalsa.

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Correspondence to Sahib S. Khalsa.

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MPP is an advisor to Spring Care, Inc., a behavioral health startup, and he has received royalties for an article about methamphetamine in UpToDate, both unrelated to the current work. All other authors report no biomedical financial interests or potential conflicts of interest.

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Verdonk, C., Teed, A.R., White, E.J. et al. Heartbeat-evoked neural response abnormalities in generalized anxiety disorder during peripheral adrenergic stimulation. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01806-5

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