PROTON MRS STUDIES IN GENERALIZED ANXIETY DISORDER

描述(由申请者提供)：本K23奖项申请请求支持职业发展和研究计划，以研究神经生物学和广泛性焦虑症的治疗[GAD]。尽管广泛性AD是常见的、慢性的和致残的，但人们对它的研究很少，其病因学状态也不确定。在过去的三年里，申请人对广泛性焦虑症患者进行了研究，并焦急地饲养了非人类灵长类动物，使用MRS作为一种非侵入性的神经化学成像技术。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]存在解剖学上的特异性异常，N-乙酰天冬氨酸[NAA]是神经元密度或活性的假定标记物，患者的障碍在右侧DLPFC最严重。在与焦虑调节有关的区域，谷氨酸/谷氨酰胺/GABA[GIX]共振也出现异常。因此，研究计划旨在：(1)使用新的高场3T磁共振系统来测试GAD患者右侧DLPFC中NAA增加的假设，并更广泛地描述与健康成年人相比，非药物GAD患者的基线MRS特征；(2)测试GAD患者和健康对照组之间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，允许可靠和有效地评估这些以前难以分离的递质；(3)确定认知行为疗法[CBT]或帕罗西汀治疗GAD患者是否能使急性治疗阶段或持续治疗后的基线MRS组差异正常化；以及(4)检验长期(急性治疗后6个月)NAA水平与对照值不匹配的假设，即使在持续缓解的患者中也是如此，这表明特征水平异常。申请者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。已经确定了一个在作为培训和研究目标核心的实质性和方法学问题方面具有专门知识的杰出小组。在导师、这组导师和正式的教学计划的配合下，申请者计划获得必要的技能，以欣赏情绪和焦虑神经科学的进步，并将它们应用于日益复杂的GAD病理生理学和治疗研究。一个具体的长期目标是候选人在MRS中发展足够的专业知识，以维持对GAD问题和相关条件的有效和创造性的应用。

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.