Anxiety Associated With Blunted Ventromedial Prefrontal Cortex Response

Woman suffering an anxiety attack alone in the night
In a crossover randomized clinical trial, women with generalized anxiety disorder and age-matched control participants underwent fMRI during randomized intravenous bolus infusions of isoproterenol and saline in an effort to ascertain if abnormal physiological, perceptual, or neural responses during peripheral β-adrenergic stimulation indicate interoceptive dysfunction.

Study data published in JAMA Psychiatry suggest that the autonomic hyperarousal experienced by patients’ clinical anxiety may be linked to dysfunctions in the central nervous system.

This crossover randomized clinical trial was conducted between 2017 and 2019 at the Laureate Institute for Brain Research in Tulsa, Oklahoma. Briefly, women with generalized anxiety disorder (GAD) and age-matched control participants underwent functional magnetic resonance imaging (fMRI) during randomized intravenous bolus infusions of isoproterenol and saline. Isoproterenol is a rapidly acting peripheral β-adrenergic agonist that induces autonomic arousal without crossing the blood-brain barrier to directly affect brain activity.

The primary outcome was blood oxygen level-dependent responses across the whole brain during isoproterenol administration in patients with GAD compared to healthy comparators. Cardiac and respiratory responses, interoceptive awareness, and anxiety symptoms were also captured.

A total of 58 women were enrolled: 29 with GAD and 29 control participants. Mean age was comparable between the patient and control groups (26.9 ± 6.8 vs 24.4 ± 5.0 years; P =.11).

Following the 0.5-μg dose of isoproterenol, the GAD group exhibited higher elevations in heart rate (P = .002), higher intensity ratings of cardiorespiratory sensations (P =.01), and higher levels of self-reported anxiety (P =.005). Compared with the control group, the GAD group also experienced significant hypoactivation of the ventromedial prefrontal cortex (vmPFC) throughout the peak response and early recovery periods (both P <.001).

Inverse correlations were observed between vmPFC hypoactivation and heart rate (P =.001) and self-reported intensity of both heartbeat (P =.002) and breathing (P =.01) sensations. The vmPFC is associated with cardiovascular regulation the processing of fear; an underactive vmPFC may reflect poorer ability to mitigate bodily arousal. Further, these correlations were observed only at the 0.5-μg dose of isoproterenol and not at a higher-intensity dosage, suggesting that patients with GAD are hypersensitive to low levels of stimulation.

“Autonomic hyperarousal may be linked to regulatory dysfunctions in the vmPFC, which could serve as a treatment target to help patients with anxiety more appropriately appraise and regulate sympathetic arousal signals emanating from the autonomic nervous system,” investigators wrote. Study limitations include the small cohort size and the inclusion of patients taking anti-anxiety medications, which may have influenced fMRI results. Further research is necessary to better explore the correlation between GAD and vmPFC activity. 

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Teed AR, Feinstein JS, Puhl M, et al. Association of generalized anxiety disorder with autonomic hypersensitivity and blunted ventromedial prefrontal cortex activity during peripheral adrenergic stimulation: a randomized clinical trial. JAMA Psychiatry. Published online February 2, 2022. doi:10.1001/jamapsychiatry.2021.4225