Probing Systems-Level Function of Fronto-Temporal

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GRANT=P50MH58911-06-0006 In the initial funding period for this Center, the aim of this project was to identify and characterize systems-level pathophysiology of two major, fear-related disorders using fMRI probes of fear circuitry in a manner complementary to the work in the basic science Projects. Untreated patients with PTSD and panic disorder, and normal control subjects, have been scanned during an instructed fear (anticipatory anxiety) paradigm and an emotional/anxiety work paradigm, representing non-verbal and verbal, translated and disease-oriented probes of fear circuitry. Distinct patterns and time courses of activity in amygdala, hippocampus and ventromedial prefrontal cortex were identified in association with fear, trauma and safety-related stimuli and contexts, for specific diagnosis, clinical features and cortisol profiles. Such work identifying biological sub-types and markers is most relevant when it can inform treatment mechanisms, development, selection, or response prediction. Therefore, a critical next step is to build upon and extend these studies in a manner that will enable us to further relate preclinical to clinical observations, and to make contributions to anxiety disorder therapeutics. Patients with PTSD and panic disorder will be randomized to either serotonin reuptake (SRI) medication or cognitive behavioral therapy (CBT), and studied immediately before and after 12 weeks of treatment using the two fMRI paradigms, structural MRI imaging, cortisol and autonomic measures, neurobehavioral measures, and clinical rating scales. Trauma ?exposed/PTSD negative subjects and normal control subjects will be studied with identical paradigms and intervals with generalized anxiety disorder(GAD), which provides a different anxiety symptom profile, will be studied once with these paradigms. Directed analyses will thus allow the further localization and characterization of frontal and limbic function and structure, specifically related to this broadening range of anxiety disorders, symptoms, treatments and outcome measures. In light of other recent scientific developments, serotonin transporter (5-HTT), brain derived neurotrophic factor (BDNF), MAO A and B, and catechol-0-methyl transferase (COMT) genotyping will be carried out on all subjects as well. This will provide an initial foundation for examining the relationships between the status of these genes and abnormal stress and fear responses, as well as identifying the patterns of fear circuitry activity that may represent clinically relevant endophenotypes.