BRAIN PATHOPHYSIOLOGY IN ANXIETY DISORDERS

描述（由申请人提供）：惊恐障碍（PD）的特征是反复发作的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病因的基础。PD患者的恐慌反应可能是由皮层下和古皮层恐惧回路的过度活跃和额叶皮质处理的活动不足介导的，而额叶皮质处理本来可以调节焦虑。5-羟色胺能（5-HT）疗法的疗效、对5-HT化合物在PD和3个再临床焦虑模型中的反应性，以及在5-HT1A基因敲除小鼠中的工作，都表明5-HT系统在调节病理性焦虑中的作用。候选人已经制定了一个培训和研究计划，旨在阐明PD恐慌反应中涉及的神经回路，并确定可能涉及的神经化学缺陷，如果不是病因的话。利用先前在恐惧神经科学和PD心理生理学方面的训练，他计划：1)利用定量正电子发射断层扫描（PET）和[11C]-WAY 100635表征PD、焦虑障碍对照组和健康志愿者组的区域5-HT1A结合电位；2)使用[150]-H20 PET测量这些相同组对流感原反应的区域脑血流量（rCBF）的变化。广泛性社交恐惧症作为焦虑障碍的对照组，其现象学重叠，提示病理神经基质的共性。通过rCBF定义关键的神经回路被认为是研究事业的第一步，旨在利用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方法领域的专家指导和培训的5年计划。通过这样的工作，他试图为PD的病理生理学的理解做出贡献，以便为这种破坏性的和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.