BRAIN PATHOPHYSIOLOGY IN ANXIETY DISORDERS

描述(由申请人提供)：惊恐障碍(PD)的特征是反复惊恐发作和严重的进行性残疾。临床前工作和神经成像研究表明，恐惧神经回路的病理性失调可能是病因的基础。帕金森病患者的惊恐反应假设是由皮质下和古皮质恐惧回路的过度活动以及额叶皮质处理的活动不足所介导，否则，额叶皮质处理将起到缓解焦虑的作用。5-羟色胺(5-HT)治疗的有效性，在帕金森病和3种再临床焦虑模型中对5-羟色胺化合物的反应性，以及在5-HT1a基因敲除小鼠中的工作，都表明5-羟色胺系统在调节病理性焦虑方面发挥了作用。这位候选人已经制定了一项培训和研究计划，旨在阐明帕金森氏症惊恐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帕金森病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和[11C]-Way 100635来表征焦虑症对照组和健康志愿者组帕金森病患者的局部5-HT1a结合潜力；以及2)在这些相同的组中，使用[150]-H20PET来测量局部脑血流量对致癌物的响应变化。广泛性社交恐惧症将作为焦虑症对照组，因为重叠的现象学暗示了病理神经基础中的共性。通过rCBF定义关键神经回路被认为是研究生涯的第一步，目的是利用PET表征病理性焦虑回路的化学介质。应聘者将需要在PET、rCBF和配基方法方面进行密集的指导和教学。他设计了一个为期5年的计划，由神经科学、焦虑症和PET方法学领域的专家进行指导和培训。通过这样的工作，他试图为理解帕金森病的病理生理学做出贡献，以便为这种毁灭性的和未被认识到的大脑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.