PET IMAGING OF OFC AND AMYGDALA IN PANIC DISORDER

恐慌症中 OFC 和杏仁核的 PET 成像

• 批准号: 7605353
• 负责人: MONTE Stuart BUCHSBAUM
• 金额: $ 3.34万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605353
• 关键词: Abate; Acute; Adult; Aftercare; Amygdaloid structure; Animal Model; Animals; Anterior; Anxiety; Anxiety Disorders; Area; Arousal; Autonomic nervous system; Back; Blood flow; Brain; Brain region; Breathing; Brodmann' s area; Central Lateral Nucleus; Chronic; Cognitive; Cognitive Therapy; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Condition; Cues; Data; Development; Doxapram; Emotional; Emotions; Environmental air flow; Frequencies; Fright; Functional Magnetic Resonance Imaging; Funding; Generalized Anxiety Disorder; Genetic; Grant; Hamilton Rating Scale for Depression; Hand; Heart; Heart Rate; Hour; Human; Hydrocortisone; Hyperventilation; Image; Infusion procedures; Injection of therapeutic agent; Institution; Intervention; Intervention Studies; Left; Literature; Magnetic Resonance Spectroscopy; Measures; Metabolic; Methodology; Methods; Modality; Molecular Target; N-acetylaspartate; Neuroanatomy; Neurons; Neurosciences; Numbers; Outcome Measure; Panic; Panic Attack; Panic Disorder; Pathogenesis; Patients; Phase; Physiological; Physiology; Pilot Projects; Placebo Effect; Placebos; Positron-Emission Tomography; Prefrontal Cortex; Procedures; Psychological Theory; Rate; Reporting; Research; Research Design; Research Personnel; Resources; Respiration; Rest; Rodent; Role; Saline; Salivary; Sample Size; Side; Source; Staging; Stress; Tidal Volume; Traumatic Stress Disorders; Treatment outcome; United States National Institutes of Health; Universities; Work; conditioned fear; experience; frontal lobe; human subject; hypothalamic-pituitary-adrenal axis; infancy; instrument; neural circuit; neuroimaging; nonhuman primate; novel; pre-clinical; psychologic; respiratory; response; social; urinary; volunteer

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Using a variety of neuroimaging modalities including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), a substantial number of studies have not shown that changes in activation of the amygdala are common during the acute evocation of fear in normal human subjects (Rauch et al., 2003; Anand & Shekhar, 2003) Furthermore, several imaging studies suggest that patients with anxiety disorders such as panic disorder (PD), posttraumatic stress disorder (PTSD), and social anxiety disorder (SAD) have an altered threshold for amygdala activation compared to normal volunteers. These studies were stimulated by earlier work in rodents and non-human primates thate demonstrates that the lateral and central nuclei of the amygdala are required for both the acuisition and expression of a particular type of fear, conditioned fear, although some studies suggest some division of roles for regions of the central and extended amydala (Davis, 1992). Thus, there is now strong evidence that activation of the amygdala is a phylogentically conserved phenomenon for the experience of a key emotion, fear. The work supporting amygdalar activation in the pathogenesis of pathological fear in patients with anxiety disorder has helped investigators consider the genetic origins of anxiety disorder and likely molecular targets for the development fo novel interventions. Nevertheless, it is widely recognized that activation of the amygdale does not occur in insolation during fear responses. Furthermore, there are obvious limitations in extrapolating from animal models of conditioned fear to anxiety disorders in humans. For examle, conditioned fear can be readily extinguished in experimental animals but anxiety disorders are known o be chronic conditions that do not abate even if a patient has multiple experiences in which previously avoided situations do not result in acute ffear responses. Hences, it is important to consider other areas of the neural circuitry involved in fear responses when attempting to fully understand the neuroanatomy and physiology of anxiety disorders. Recently, a few research groups found that patients with PD, SAD and PSD manifest decreased PFC activity dring the experience of acute anxiety responses. In particular, decreases in activity in the anterior cingulte and in the orbital frontal cortex (OFC) have been cited. Using fMRI, our group found that amygdalar activation in normal volunteers during the presentation of fears cues is blunted when subjects are given a task that demands PFC engagement. Using magnetic resonance spectroscopy, we found decreased concentration of a marker of neuronal viability, N-acetyl aspartate, in the anterior cingulate of adult non-human primates who had been raised under conditions of mild stress dring infancy. In collaboration with colleagues at Cornell University, as part of our Conte Neuroscience Center we recently reported, using fRI, that patients with PD have increased right amygdala and decreased OFC activity during a fear-inducing procedure. Finally, in a pilot study using 15O-PET imaging involving patients with PD and normal controls, we found a marked decrease in OFC blood flow immediately prior to panic attacks induced by the administration of doxapram. This suggests, as some speculations predicts, that reduced PFC activity occurs during the anticipatory anxiety stage immediately prior to a panic attack, thus increasing amygdala activity. Previously, we have shown that in this exact same period prior to panic, patients with PD manifest increased anxiety, increased cortisol level and decreased pCO2 an indication of acute hyperventilation. On the other hand, studies in patients with generalized anxiety disorder (GAD), OCD, and PD also suggest greater activation in regions of the prefrontal cortex than in normal comparison subjects. Hence, there is ambiguity in the literature at present about the way in which the PFC and aygdala interact in PD patients at rest, during anticipatory anxiety, and during panic. Also, in our most recent pilot study using the methods we propose to use in the present study, we found tht following placebo adminitration, when subjects were in an anticipatory anxiety state, patients with PD showed increased aygdalar and increased OFC metabolic rate compared to comparison subjects. During doxapram-induced panic attacks and subtracting out the placebo responses the patients showed further greater increases in amygdalar and OFC metabolic rate compared to controls. Thus, our pilot data show patient control differences in the amygdala that are consistent with our hypotheses, but findings in the PFC that are not. Interestingly, during the placebo infusion we noted an increased left/right ratio in Brodmann area 11 in patients, consistent with psychological theory implicating an anxious anticipatory rather than arousal state. During doxapram infusion, enhanced amygdalar metabolic rate increases in patients are most prominent on the left side, suggesting continuation of anticipatory anxiety into that phase. hence, in the revised application we now include efforts to use instruments sensitive to anxious anticipation and arousal in an attempt to disaggregate these psychological states and better explain the findings. Treatment with cognitive behavioral therapy (CBT) normalized the prefrontal findings in the patients, but had no effect on the amygdala findings. Finally, in exploratory analyses of our pilot data, we uncovered differential relationships between the dorsa___d ventral amygdala and the OFC in patients compared to controls that parallel recent preclinical findings. Taken together, these observations indicate that patients with PD have abnormal patters of regional brain activation compared to controls, some of which may be amenable to improvement with sychoscial intervention, but that studies with expanded sample sizes and rigorous methodology are needed to clarify some of the inconsistencies in the existing literature. We therefore, propose to study this critical aspect of the neurocircuitry of fear by employing a study design that will permit us to image and quantify activity in the OFC and other key brain regions during three conditions of emotional arousal: 1) at rest, experiencing "ordinary" levels of anxiety; 2) during anticipatory anxiety; and 3) during panic anxiety, in untreated patients with PD, and then to repeat this after treatment with CBT. We will use panic anxiety, in untreated patients with PD, and then to repeat this after treatment with CBT. We will use doxapram as the "panicogenic" agent in this study because of its high rate of panic induction in PD patients and relatively low rate in normal volunteers and because previous work has shown that panic to doxapram is affedted by "cognitive set." We will employ 18flurodeoxyglucose (FDG) PET imaging instead of 15O-Hs) PET imaging in this study because we wish to measure the metabolic acitvity fo specific brain regions before and during panic attacks. HYPOTHESIS; 1. Prior to treatment, following a saline (placebo) injection but anticipating that they will receive the panicogen doxapram, patients with PD will show altered metabolic activity in the orbital frontal cortex (OFC) as measured by FDG-PET compared to normal comparison subjects and to a separate group of PD patients undergoing FDG-PET scans during a resting condition. 2. There will be significant statistical associations between OFC acitvity, increased anxiety, increased salivary cortisol level, increased heart rate, and increased minute ventilation (the product of respiratory frequency and the tidal volume of breathing) following saline administration (i.e. in the anticipatory state) in PD patients. 3. Prior to treatment, an injection of doxapram will prduce panic attacks in approximately 70% of patients with PD but only 20% of normal comparison subjects. Panicking subjects will show alterred OFC and amygdala metabolic activity compared to non-panicking subjects and to a separate group of PD ptients undergoing FDG-PET scans djuring a resting condition. 4. Prior to treatment, patients with PD will show increased 24-hour urinary cortisol levels, increased variability fo respiration, and decreased heart period variability compared to controls. These will be correlated with OFC metabolic activity during the FDG-PET scans, sggesting coordinated abnormalities between the autonomic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, and prefrontal cortical activity in PD patients. 5. Baseline OFC acitvity, anxiety level,cortisol and physiological measures both to saline and doxapram will be correlated with treatment response, and post treatment outcomes measures (PDSS, HAM-A, HAM-D, ASI etc.).

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 使用包括正电子发射断层扫描（PET）和功能磁共振成像（fMRI）在内的各种神经影像学手段，大量研究并未表明正常人类受试者在急性恐惧唤起过程中杏仁核激活的变化是常见的。 Rauch 等，2003；Anand & Shekhar，2003）此外，一些影像学研究表明，患有焦虑症（例如惊恐障碍 (PD)、创伤后应激障碍）的患者与正常志愿者相比，创伤后应激障碍（PTSD）和社交焦虑症（SAD）的杏仁核激活阈值发生了变化。 这些研究受到早期对啮齿动物和非人类灵长类动物的研究的启发，这些研究表明杏仁核的外侧核和中央核对于获取和表达特定类型的恐惧（条件性恐惧）是必需的，尽管一些研究表明，杏仁核的外侧核和中央核对于特定类型的恐惧（条件性恐惧）的获取和表达是必需的。中央和扩展杏仁核区域的作用（Davis，1992）。 因此，现在有强有力的证据表明，杏仁核的激活是一种在系统发育上保守的现象，可用于体验关键情绪——恐惧。 支持杏仁核激活在焦虑症患者病理性恐惧发病机制中的工作帮助研究人员考虑焦虑症的遗传起源以及开发新干预措施的可能分子靶标。 然而，人们普遍认为，在恐惧反应期间，杏仁核不会在阳光下激活。 此外，从条件性恐惧的动物模型推断人类焦虑症也存在明显的局限性。 例如，在实验动物中，条件性恐惧可以很容易地消除，但众所周知，焦虑症是一种慢性疾病，即使患者多次经历过先前避免的情况不会导致急性恐惧反应，这种慢性疾病也不会减轻。 因此，在尝试充分了解焦虑症的神经解剖学和生理学时，考虑涉及恐惧反应的神经回路的其他区域非常重要。 最近，一些研究小组发现，PD、SAD 和 PSD 患者在经历急性焦虑反应时表现出 PFC 活性降低。 特别是前扣带皮层和眶额皮质（OFC）的活动减少。 使用功能磁共振成像，我们的小组发现，当受试者接受需要前额皮质参与的任务时，正常志愿者在呈现恐惧线索时杏仁核的激活会减弱。 使用磁共振波谱，我们发现在婴儿期轻度应激条件下长大的成年非人类灵长类动物的前扣带皮层中，神经元活力标记物 N-乙酰天冬氨酸的浓度降低。 作为 Conte 神经科学中心的一部分，我们与康奈尔大学的同事合作，最近使用 fRI 报告称，PD 患者在恐惧诱发过程中右侧杏仁核增加，OFC 活动减少。 最后，在一项针对 PD 患者和正常对照者使用 15O-PET 成像的初步研究中，我们发现在服用多沙普仑诱发惊恐发作之前，OFC 血流量显着减少。 正如一些推测所预测的那样，这表明在惊恐发作之前的预期焦虑阶段，PFC 活动减少，从而增加了杏仁核活动。 之前，我们已经证明，在恐慌发生之前的同一时期，患有以下疾病的患者 PD 表现为焦虑增加、皮质醇水平升高和 pCO2 降低，这是急性过度换气的迹象。 另一方面，对广泛性焦虑症（GAD）、强迫症和帕金森病患者的研究也表明，与正常对照受试者相比，前额皮质区域的激活程度更高。 因此，目前文献中关于 PD 患者在休息、预期焦虑和恐慌期间 PFC 和 aygdala 相互作用的方式尚不明确。 此外，在我们最近使用我们建议在本研究中使用的方法进行的试点研究中，我们发现在给予安慰剂后，当受试者处于预期焦虑状态时，与对照组相比，PD 患者表现出 aygdalar 增加和 OFC 代谢率增加科目。 在多沙普仑引起的惊恐发作期间，扣除安慰剂反应后，与对照组相比，患者的杏仁核和 OFC 代谢率进一步增加。 因此，我们的试验数据显示患者杏仁核的控制差异与我们的假设一致，但 PFC 的结果则不然。 有趣的是，在安慰剂输注期间，我们注意到患者布罗德曼 11 区的左/右比率增加，这与暗示焦虑预期状态而不是唤醒状态的心理学理论一致。 在多沙普仑输​​注期间，患者左侧杏仁核代谢率增加最为明显，表明预期焦虑会持续到该阶段。 因此，在修订后的应用程序中，我们现在努力使用对焦虑预期和唤醒敏感的工具，试图分解这些心理状态并更好地解释研究结果。 认知行为疗法（CBT）使患者的前额叶结果正常化，但对杏仁核结果没有影响。 最后，在对试验数据的探索性分析中，我们发现了患者背侧杏仁核和 OFC 与对照者之间的差异关系，这与最近的临床前研究结果相似。 总而言之，这些观察结果表明，与对照组相比，帕金森病患者的区域大脑激活模式异常，其中一些可能可以通过心理干预得到改善，但需要扩大样本量和严格的方法论来澄清一些问题。现有文献中的不一致。 因此，我们建议通过采用一种研究设计来研究恐惧神经回路的这一关键方面，该研究设计将使我们能够在三种情绪唤醒条件下对 OFC 和其他关键大脑区域的活动进行成像和量化：1）在休息时，经历“普通”程度的焦虑； 2）预期焦虑期间； 3) 在惊恐焦虑期间，在未经治疗的 PD 患者中进行测试，然后在接受 CBT 治疗后重复此操作。我们将在未经治疗的 PD 患者中使用恐慌焦虑，然后在 CBT 治疗后重复此操作。 在本研究中，我们将使用多沙普仑作为“引起恐慌”的药物，因为它在帕金森病患者中诱发恐慌的几率较高，而在正常志愿者中诱发恐慌的几率相对较低，而且之前的研究表明，多沙普仑的恐慌受到“认知设定”的影响。 在本研究中，我们将采用 18 氟脱氧葡萄糖 (FDG) PET 成像而不是 15O-Hs) PET 成像，因为我们希望测量恐慌发作之前和期间特定大脑区域的代谢活动。 假设; 1. 在治疗前，注射生理盐水（安慰剂）后，但预计将接受恐慌剂多沙普仑，通过 FDG-PET 测量，与正常对照受试者相比，PD 患者的眶额皮质 (OFC) 代谢活动会发生改变以及另一组在静息状态下接受 FDG-PET 扫描的 PD 患者。 2. 在施用盐水后（即在预期状态下），OFC 活动、焦虑增加、唾液皮质醇水平增加、心率增加和每分钟通气量增加（呼吸频率和呼吸潮气量的乘积）之间存在显着的统计关联。 ）在帕金森病患者中。 3. 在治疗前，注射多沙普仑会导致约 70% 的 PD 患者出现惊恐发作，但正常对照受试者中只有 20% 会出现惊恐发作。 与非惊慌受试者和另一组在静息状态下接受 FDG-PET 扫描的 PD 患者相比，惊慌受试者的 OFC 和杏仁核代谢活动会发生改变。 4. 在治疗前，与对照组相比，PD 患者的 24 小时尿皮质醇水平升高，呼吸变异性增加，心率变异性降低。 这些将与 FDG-PET 扫描期间的 OFC 代谢活动相关，提示 PD 患者自主神经系统、下丘脑-垂体-肾上腺 (HPA) 轴和前额皮质活动之间的协调异常。 5. 基线 OFC 活动、焦虑水平、皮质醇和盐水和多沙普仑的生理测量将与治疗反应和治疗后结果测量（PDSS、HAM-A、HAM-D、ASI 等）相关。