PET Imaging of OFC and Amygdala in Panic Disorder

描述（由申请人提供）：这是使用FOG-PET研究惊恐障碍（PD）患者杏仁核和眼窝前额皮质（OFC）对预期焦虑和惊恐状态的反应的第二次申请。临床前研究表明，杏仁核是获得和表达条件恐惧的关键大脑结构。已经采用了几种不同的脑成像方法来表明，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，焦虑障碍患者的杏仁核激活阈值较低。几项临床前研究也表明，前额皮质内的区域对杏仁核施加控制。神经影像学数据也在人类中表明了这一点——焦虑障碍患者的一个特征是前额皮质区域活动的改变，包括前扣带和OFC。在一项使用15O-H20的PET研究中，我们发现，在服用多巴胺之前（多巴胺在PD患者中确实会引起恐慌发作，而在对照组中不会），服用多巴胺后出现恐慌的受试者的OFC活性显著降低。这一发现提示需要进一步研究PD患者杏仁核与前额叶皮层之间的关系。多巴胺引起的过度通气引起的血管收缩使得在恐慌发作时无法对杏仁核的激活进行成像。因此，在一项试点研究中，通过将FDG PET应用于多巴胺治疗，测量代谢率而不是血流量，我们能够在恐慌发作时对杏仁核和OFC进行成像。我们的试点数据显示，PD患者在服用多巴胺期间，杏仁核激活比对照组更多，但出乎意料的是，OFC代谢率也有所增加。认知行为疗法（CBT）使患者的OFC反应正常化。我们推测CBT改变前额皮质活动，从而恢复与杏仁核的正常互动。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、安慰剂和多巴胺治疗期间进行FDG PET扫描。我们预测，在预期恐慌时，与对照组相比，患者的OFC代谢率会发生改变，而在服用多西普兰期间，恐慌患者的杏仁核激活与非恐慌受试者相比会发生改变。我们还将寻找这些脑代谢分析与自主神经、神经内分泌和主观焦虑测量的变化之间的相关性。然后，患者将接受CBT治疗，并重复PET扫描。我们预测，成功的治疗将导致OFC和多巴胺诱导的杏仁核活动正常化。我们在实验的不同阶段增加了焦虑预期和焦虑唤醒的评估，并进行了一些设计更改，以确保在适当的情况下维持预期状态。本研究旨在进一步了解惊恐发作的神经解剖学基础，并为CBT的成功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.