BRAIN PATHOPHYSIOLOGY IN ANXIETY DISORDERS

描述（由申请人提供）：惊恐障碍（PD）的特点是反复惊恐发作和严重的进行性残疾。临床前工作和神经影像学研究表明，恐惧神经回路的病理性失调可能是其病因的基础。假设帕金森病中的恐慌反应是由皮层下和古皮层恐惧回路过度活跃以及额叶皮层处理活动不足介导的，否则额叶皮层处理会起到中度焦虑的作用。血清素能 (5-HT) 疗法的功效、PD 和 3 个临床焦虑模型中对 5-HT 化合物的反应性以及在 5-HT1A 敲除小鼠中的工作都表明 5-HT 系统在调节病理性焦虑中发挥作用。候选人制定了一项培训和研究计划，旨在阐明与帕金森病恐慌反应有关的神经回路，并确定可能涉及的神经化学物质缺乏（如果不是病因）。利用先前在恐惧神经科学和 PD 心理生理学方面的培训，他计划：1) 使用定量正电子发射断层扫描 (PET) 和 [11C]-WAY 100635 表征 PD、焦虑症对照组和健康志愿者组中的区域 5-HT1A 结合潜力； 2）在这些相同的组中使用[150]-H20 PET测量局部脑血流量（rCBF）对恐慌剂的反应变化。由于重叠的现象学表明病理神经基质的共性，广泛性社交恐惧症将作为焦虑症对照组。通过 rCBF 定义关键神经回路被认为是研究生涯的第一步，旨在使用 PET 表征病理性焦虑回路的化学介质。候选人将需要 PET rCBF 和配体方法学方面的强化指导和教学。他设计了一个由神经科学、焦虑症和 PET 方法领域的专家提供的为期 5 年的指导和培训计划。通过这些工作，他试图促进对帕金森病病理生理学的理解，以便为这种破坏性且未被充分认识的脑部疾病提出改进的治疗方法。

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.