This K23 award application requests support for a career development and research plan to study the neurobiology and treatment of generalized anxiety disorder [GAD]. Although GAD is common, chronic, and disabling, it is vastly under studied, and its nosological status has been uncertain. During the past 3 years the applicant has conducted research with patients with GAD, and anxiously-reared nonhuman primates, using MRS as a non-invasive technique for neurochemical imaging. In both the preclinical and clinical samples, this preliminary research suggested anatomically-specific abnormalities in N-acetyl aspartate [NAA], a putative marker of neuronal density or viability, with disturbances in patients greatest in the right DLPFC. There were also abnormalities in glutamate/glutamine/GABA [GIx] resonance in regions implicated in anxiety regulation. Accordingly, the research plan aims to: (1) Use a new high field 3T MR system to test the hypothesis that patients with GAD have increased NAA in the right DLPFC, and, more broadly, to characterize baseline MRS characteristics in medication-free GAD patients compared to healthy adults; (2) Test the hypothesis of regionally-specific differences between patients with GAD and healthy controls in GABA and ultimately glutamate/glutamine levels, utilizing novel proton MRS editing methods that allow reliable and valid assessment of these transmitters that previously have been difficult to separate; (3) Determine whether treatment of GAD patients with cognitive behavioral therapy [CBT] or paroxetine normalizes baseline MRS group differences following an acute treatment phase or after continuation therapy; and (4) Test the hypothesis that, in the long-term (6 mo after acute treatment), NAA levels do not match control values even among patients with sustained remission, suggesting a trait-level abnormality. The applicant and primary mentor have identified several domains requiring formal instruction and rigorous training: (1) advanced proton MRS/MRI methods; (2) biostatistics and clinical research methodology; (3) neurobiology and neuropsychology of anxiety; (4) therapeutics of anxiety disorders. A distinguished group has been identified with expertise in the substantive and methodological issues at the core of the training and research goals. In concert with the mentor, this group of preceptors, and a formal didactic program, the applicant plans to acquire the skills needed to appreciate advances in the neuroscience of mood and anxiety and apply them in increasingly sophisticated studies of the pathophysiology and treatment of GAD. A specific long-term goal is for the candidate to develop sufficient expertise in MRS to sustain valid and creative application to problems of GAD and related conditions.
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