Women With GAD Have Autonomic Hypersensitivity After Low-Level Adrenergic Stimulation

The control room of an fMRI machine. You can see various images of a brain on the computer monitor in the foreground and the fMRI machine in the room beyond the glass. No people.
This study assessed neural responses with functional magnetic resonance imaging after intravenous infusions of 0.5 and 2.0 μg isoproterenol or saline.

Low levels of adrenergic stimulation were associated with autonomic hypersensitivity among women with generalized anxiety disorder (GAD), according to results of a crossover, randomized clinical trial, published in JAMA Psychiatry.

Patients (n=29) with GAD and matched controls (n=29) were recruited between 2017 and 2019 at the Laureate Institute for Brain Research in the United States. This study assessed neural responses with functional magnetic resonance imaging (fMRI) after intravenous infusions of 0.5 and 2.0 μg isoproterenol or saline. In addition, participants were monitored for cardiac and respiratory responses, interoceptive awareness, and anxiety.

The GAD and control cohorts were aged mean 26.9 (standard deviation [SD], 6.8) and 24.4 (SD, 5.0) years and BMI was 25.64 (SD, 4.59) and 24.04 (SD, 3.12) kg/m2, respectively. The patient and control cohorts differed significantly at baseline for the 7-Item GAD scale (GAD-7; t[38.76], -18.01; P <.001), Overall Anxiety Severity and Impairment Scale (OASIS; t[50.16], -19.06; P <.001), Anxiety Sensitivity Index 3 (ASI-3; t[32.82], -7.17; P <.001), and 9-Item Patient Health Questionnaire (PHQ-9; t[30.75], -11.13; P <.001).

During the trial, the GAD cohort had increased retrospective intensity of heartbeat (t[278.81], 5.04; P <.001) and breathing (t[276], 3.70; P <.001) sensations, and anxiety (t[281.32], 2.84; P =.005) after receiving 0.5-μg isoproterenol and anxiety after receiving 2-μg isoproterenol (t[281.11], 3.36; P =.001).

The GAD cohort had decreased blood oxygen level-dependent signal changes from the bilateral ventromedial prefrontal cortex (vmPFC) to the rostral anterior cingulate cortex (x, -6.9; y, 44.6; z, 0.1) and from the left angular gyrus to the precuneus (x, -37; y, -65.3; z, 36.2).

During the 0.5-μg isoproterenol dose, vmPFC hypoactivation was inversely correlated with heart rate (r, -0.51; P =.001) and retrospective intensity of heartbeat (r, -0.5; P =.002) and breathing (r, -0.44; P =.01) sensations.

This study was limited by the small size, the fact that patients were allowed to continue using their psychotropic medications, and the lack of participants who were men.

“In this crossover randomized clinical trial, women with GAD showed autonomic hypersensitivity during low levels of adrenergic stimulation characterized by an elevated heart rate, heightened interoceptive awareness, increased anxiety, and a blunted neural response localized to the vmPFC. 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,” the study authors concluded.

Disclosure: An author declared affiliations with industry. Please refer to the original article for a full list of 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. 2022;e214225. doi:10.1001/jamapsychiatry.2021.4225