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Martin P. Paulus, MD; Justin S. Feinstein, BS; Gabriel Castillo, BS; Alan N. Simmons, PhD; Murray B. Stein, MD, MPH

Arch Gen Psychiatry. 2005;62:282-288.

Background  Functional neuroimaging may elucidate the pathophysiologic features of anxiety disorders and the site of action of anxiolytic drugs. A large body of evidence suggests that the amygdala and associated limbic structures play a critical role in the expression of anxiety and may be treatment targets for anxiolytic drugs.

Objective  To determine whether lorazepam dose-dependently attenuates blood oxygenation level–dependent functional magnetic resonance imaging (BOLD fMRI) activation in the amygdala and associated limbic structures during an emotion face assessment task.

Participants and Design  Fifteen healthy volunteers participated in a double-blind, placebo-controlled, randomized dose-response study. Subjects underwent imaging 3 times (at least a week apart) and were given either a single-dose placebo or 0.25 mg or 1.0 mg of lorazepam 1 hour prior to an MRI session. During fMRI, subjects completed an emotion face assessment task, which has been shown to elicit amygdala activation.

Main Outcome Measures  The BOLD-fMRI activation in amygdala, insula, and medial prefrontal cortex during the emotion face assessment task.

Results  Lorazepam significantly attenuated the BOLD-fMRI signal in a dose-dependent manner in bilateral amygdala and insula but not in the medial prefrontal cortex. Lorazepam did not affect the BOLD-fMRI signal in the primary visual cortex.

Conclusions  The current finding provides the first neuroimaging evidence of a dose-dependent change induced by an established therapeutic agent in brain regions known to be critical for the mediation of anxiety. This investigation may help to support the use of BOLD-fMRI with pharmacological probes to investigate the neural circuits underlying anxiety and the use of fMRI as a tool in the development of new anxiolytic agents.

Author Affiliations: Laboratory of Biological Dynamics and Theoretical Medicine (Dr Paulus and Messrs Feinstein and Castillo) and Department of Psychiatry (Drs Paulus, Simmons, and Stein), University of California, San Diego; and Veterans Affairs San Diego Healthcare System (Drs Paulus and Stein).

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