BRAIN PATHOPHYSIOLOGY IN ANXIETY DISORDERS

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DESCRIPTION (provided by applicant): Panic disorder (PD) is characterized by recurrent panic attacks and severe, progressive disability. Preclinical work and neuroimaging studies suggest that pathological dysregulation of fear neurocircuitry may be fundamental to the etiology. Panic responses in PD are hypothetically mediated by overactivity in subcortical and paleocortical fear circuits and underactivity in frontal cortical processing that would otherwise serve to moderate anxiety. Efficacy of serotonergic (5-HT) therapies, reactivity to 5-HT compounds in PD and in 3reclinical anxiety models, and work in the 5-HT1A knockout mouse all point to a role for the 5-HT system in modulating pathological anxiety. The Candidate has developed a program of training and research aimed at elucidating the neural circuitry involved in the panic response in PD and defining a neurochemical deficiency that may be involved, if not etiological. Utilizing prior training in both the neuroscience of fear and the psychophysiology of PD, he plans to: 1) characterize the regional 5-HT1A binding potential in PD, an anxiety disorder control group, and a healthy volunteer group using quantitative positron emission tomography (PET) and [11C]-WAY 100635; and 2) measure change in regional cerebral blood flow (rCBF) in response to a panicogen using [150]-H20 PET in these same groups. Generalized social phobia will serve as the anxiety disorder control group due to overlapping phenomenology suggestive of commonalities in the pathological neural substrates. Defining key neurocircuitry by rCBF is considered the 1st step in a research career aimed at characterizing the chemical mediators of pathological anxiety circuits using PET. The Candidate will require intensive mentoring and didactics in PET rCBF and ligand methodologies. He has designed a 5-year program of mentorship and training by experts in the fields of neuroscience, anxiety disorders, and PET methodologies. Through such work, he seeks to contribute to the understanding of the pathophysiology of PD in order to suggest improved therapeutics for this devastating and underrecognized brain disorder.