OBJECTIVE: Lack of appropriate top-down governance by frontal cortical regions over a hypersensitive amygdala-centered fear neurocircuitry has been hypothesized to be central in the pathophysiology of panic disorder. The aim of this study was to examine regional cerebral blood flow changes in response to anxiety/panic provocation in subjects with panic disorder and healthy comparison subjects. METHOD: Quantitative water method positron emission tomography was used to obtain brain images of five untreated subjects with panic disorder and five healthy comparison subjects before and during anxiogenic challenge with intravenous doxapram, an acute respiratory stimulant. RESULTS: Baseline perfusion of the orbitofrontal cortex predicted panic attacks: lower perfusion was associated with heightened anxiety in response to doxapram challenge. CONCLUSIONS: The orbitofrontal cortex may be important in the regulation of responding to fear and is a potential area of aberrant functioning in panic disorder.