PET Imaging of OFC and Amygdala in Panic Disorder

描述(申请人提供)：这是第二次使用FOG-PET研究惊恐障碍(PD)患者杏仁核和眼眶额叶皮质(OFC)对预期焦虑和恐慌状态的反应。临床前研究表明，杏仁核是获得和表达条件性恐惧的关键大脑结构。几种不同的脑成像方法已经被用来表明杏仁核的激活通常发生在人类恐惧和焦虑的诱导过程中。一些研究表明，焦虑症患者杏仁核激活的阈值较低。一些临床前研究现在也表明，前额叶皮质内的区域对杏仁核施加控制。神经成像数据在人类中也表明了这一点，焦虑症患者的一个特征是前额叶皮质区域活动的改变，包括前扣带回和OFC。在一项使用15O-H20的PET研究中，我们发现，在服用多沙普兰之前，随后在多沙普兰治疗后惊慌失措的受试者显示出OFC活动显著减少。多沙普兰在帕金森病患者中可靠地导致恐慌症发作，而不是对照组。这一发现表明有必要进一步研究帕金森病患者杏仁核和前额叶皮质之间的关系。多沙普兰诱导的过度换气导致的实质性血管收缩，使得人们不可能想象在真正的恐慌发作期间杏仁核的激活。因此，在一项先导性研究中，通过将FDGPET应用于多沙普兰给药，测量代谢率而不是血流，我们能够成像惊恐发作期间的杏仁核和OFC。我们的初步数据显示，在多沙普兰治疗期间，帕金森病患者比对照组更多地表现出杏仁核激活的增加，但出人意料的是，患者也表现出OFC代谢率的增加。认知行为疗法(CBT)使患者的OFC反应正常化。我们推测，CBT改变了前额叶皮质活动，从而恢复了与杏仁核的正常相互作用。我们建议研究PD患者和匹配的正常对照受试者，他们将在静息、安慰剂和多沙普兰治疗期间接受FDG PET扫描。我们预测，在预期恐慌的同时，与对照组相比，患者的OFC代谢率将发生变化，在给药多沙普兰期间，与非恐慌的受试者相比，恐慌症患者的杏仁核激活将发生变化。我们还将寻找这些大脑代谢分析与自主神经、神经内分泌和主观焦虑指标变化之间的相关性。然后，患者将接受CBT治疗，并重复进行PET扫描。我们预测，成功的治疗将导致OFC和多沙普兰诱导的杏仁核活动正常化。我们在实验的不同阶段增加了对焦虑预期和焦虑唤醒的评估，并增加了几个设计变化，以确保在适当的时候维持预期状态。本研究旨在进一步了解惊恐发作的神经解剖学基础，并为成功的CBT建立可能的作用机制。

DESCRIPTION (provided by applicant): This is a second resubmission to study the response of the amygdala and orbitofrontal cortex (OFC) in patients with panic disorder (PD) to anticipatory anxiety and panic states using FOG-PET. Preclinical research has demonstrated that the amygdala is a crucial brain structure for the acquisition and expression of conditioned fear. Several different brain imaging methods have been employed to show that amygdala activation commonly occurs during the induction of fear and anxiety in humans. Some studies suggest that the threshold for amygdala activation is lower in anxiety disorder patients. Several preclinical studies have also now shown that areas within the prefrontal cortex exert control over the amygdala. Neuroimaging data also indicate this in humans and-that 1 feature of anxiety disorder patients is an alteration in activity of prefrontal cortical areas, including the anterior cingulate and the OFC. In a PET study using 15O-H20 we found that immediately prior to the administration of doxapram, which reliably produces panic attacks in PD patients but not controls, subjects who subsequently panicked after doxapram administration showed marked reduction in OFC activity. This finding indicates the need to further study the relationship between the amygdala and prefrontal cortex in PD patients. The substantial vasoconstriction caused by doxapram-induced hyperventilation made it impossible to image amygdala activation during the actual panic attack. Therefore, by adapting FDG PET to doxapram administration in a pilot study that measures metabolic rate instead of blood flow, we are able to image the amygdala and OFC during panic attacks. Our pilot data show that PD patients demonstrate increased amygdala activation more than controls during doxapram administration, but unexpectedly also show increased OFC metabolic rate. Cognitive behavioral therapy (CBT) normalized the patients' OFC response. We speculate that CBT modifies prefrontal cortical activity thereby restoring normal interaction with the amygdala. We propose to study PD patients and matched normal comparison subjects who will undergo FDG PET scans during resting, placebo, and doxapram administration. We predict that while anticipating panic, patients will show altered OFC metabolic rate compared to controls and that during doxapram administration panicking patients will show altered amygdala activation compared to non-panicking subjects. We will also look for correlations between these brain metabolic analyses and changes in autonomic, neuroendocrine, and subjective anxiety measures. Patients will then be treated with CBT and the PET scans repeated. We predict that successful treatment will lead to a normalization in OFC and doxapram-induced amygdala activity. We have added assessment of anxious anticipation and anxious arousal at the different stages of the experiment and several design changes to insure the maintenance when appropriate of an anticipatory state. The study aims to further understanding of the neuroanatomical substrate of panic attacks and to establish a possible mechanism of action for successful CBT.