PROTON MRS STUDIES IN GENERALIZED ANXIETY DISORDER

描述（由申请人提供）：此K23奖申请要求支持职业发展和研究计划，以研究广泛性焦虑症[GAD]的神经生物学和治疗。虽然广泛性焦虑症是常见的、慢性的和致残的，但它的研究还很不充分，其疾病分类地位也不确定。在过去3年中，申请人使用MRS作为神经化学成像的非侵入性技术，对GAD患者和焦虑饲养的非人灵长类动物进行了研究。在临床前和临床样本中，这项初步研究表明N-乙酰天冬氨酸[NAA]存在解剖学特异性异常，这是神经元密度或活力的假定标志物，患者右侧DLPFC的干扰最大。在与焦虑调节有关的区域中，谷氨酸/谷氨酰胺/GABA [GIx]共振也存在异常。因此，本研究计划的目的是：（1）使用一种新的高场3 T MR系统来检验GAD患者右侧DLPFC中NAA增加的假设，并且更广泛地描述与健康成人相比，未用药的GAD患者的基线MRS特征;（2）检验GAD患者和健康对照之间GABA和最终谷氨酸/谷氨酰胺水平的区域特异性差异的假设，利用新的质子MRS编辑方法，其允许可靠和有效地评估这些以前难以分离的递质;（3）确定用认知行为疗法[CBT]或帕罗西汀治疗GAD患者是否在急性治疗期后或在继续治疗后使基线MRS组差异正常化;（4）检验以下假设：在长期（急性治疗后6个月），即使在持续缓解的患者中，NAA水平也与对照值不匹配，表明性状水平异常。申请人和主要导师已经确定了几个需要正式指导和严格培训的领域：（1）先进的质子MRS/MRI方法;（2）生物统计学和临床研究方法;（3）焦虑的神经生物学和神经心理学;（4）焦虑症的治疗。已经确定了一个杰出的小组，该小组在培训和研究目标的核心实质性和方法问题方面具有专门知识。与导师，这组导师，和一个正式的教学计划，申请人计划获得所需的技能，欣赏情绪和焦虑的神经科学的进步，并将其应用于日益复杂的研究GAD的病理生理学和治疗。一个具体的长期目标是候选人在MRS方面发展足够的专门知识，以维持对性别与发展问题和相关条件的有效和创造性应用。

DESCRIPTION (provided by applicant): 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.