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.).

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 使用各种神经影像模式，包括正电子发射断层扫描（PET）和功能磁共振成像（fMRI），大量的研究并未表明杏仁核激活的变化在正常人类受试者中急性唤起恐惧期间很常见与正常志愿者相比，疾病（PD），创伤后应激障碍（PTSD）和社交焦虑症（SAD）的杏仁核激活阈值有所改变。 这些研究是通过啮齿动物和非人类灵长类动物的早期工作刺激的，这表明杏仁核的侧向和中央核是特定类型的恐惧的提取和表达所必需的。 因此，现在有强有力的证据表明，杏仁核的激活是一种基于关键情感的经验，恐惧的天哪现象。 支持焦虑症患者病理恐惧的发病机理中支持杏仁核激活的工作有助于研究人员考虑焦虑症的遗传起源，并可能针对新的干预措施开发的分子靶标。 然而，人们广泛认识到，在恐惧反应期间，杏仁核的激活不会发生。 此外，从有条件恐惧的动物模型推断到人类的焦虑症中存在明显的局限性。 对于审查，可以在实验动物中很容易消灭条件的恐惧，但焦虑症是慢性病，即使患者有多种经验，在这种情况下，以前避免的情况不会导致急性FFEAR反应。 一方面，重要的是要考虑恐惧反应涉及的其他领域，试图充分理解焦虑症的神经解剖学和生理学。 最近，一些研究小组发现，患有PD，SAD和PSD的患者降低了PFC活性，从而散发出急性焦虑反应的经历。 特别是，已经引用了前扣c和轨道额皮层（OFC）的活性下降。 使用fMRI，我们的小组发现，在提示提示期间，当受试者的任务需要PFC参与时，正常志愿者的杏仁核激活会贬低。 使用磁共振光谱，我们发现在轻度压力疲劳的条件下，在成年非人类灵长类动物的前扣带回中，神经元活力，N-乙酰天冬氨酸的标记浓度降低。 作为我们最近使用FRI的CONTE神经科学中心的一部分，与康奈尔大学的同事合作，PD患者在引起恐惧的过程中增加了右Amygdala和OFC活动的降低。 最后，在一项使用涉及PD和正常对照的患者的15型PET成像的试点研究中，我们发现在doxapram施用恐慌发作之前，OFC血流明显降低。 正如一些猜测所预测的那样，这表明PFC活性减少在恐慌发作前的预期焦虑阶段发生，从而增加了杏仁核活性。 以前，我们已经表明，在恐慌之前的同一时期，患者 PD表现出增加的焦虑，皮质醇水平升高并降低PCO2急性高换气的指示。 另一方面，对普遍焦虑症（GAD），OCD和PD患者的研究也表明，前额叶皮层区域的激活比正常比较受试者更大。 因此，目前文献中存在歧义性，即PFC和Aygdala在休息，预期焦虑期和恐慌期间的PD患者中相互作用的方式。 同样，在我们最新的试点研究中，使用我们建议在本研究中使用的方法，我们发现安慰剂管理后，当受试者处于预期焦虑状态时，与比较受试者相比，PD患者的质量增加和OFC代谢率增加。 与对照组相比，在多克萨普拉姆引起的恐慌发作并减去安慰剂反应中，患者的杏仁核和OFC代谢率进一步增加。 因此，我们的试点数据显示，杏仁核中患者的控制差异与我们的假设一致，但是PFC中的发现却不是一致的。 有趣的是，在安慰剂输注期间，我们注意到，在Brodmann地区11的左/右比例中，患者的左/右比例增加了，这与心理理论一致，这意味着焦虑的预期性而不是唤醒状态。 在Doxapram输注过程中，左侧最突出的患者杏仁核代谢率提高，这表明预期焦虑持续到该阶段。 因此，在修订后的应用中，我们现在包括使用对焦虑期望和唤醒敏感的工具的努力，以试图分解这些心理状态并更好地解释发现。 认知行为疗法（CBT）的治疗使患者的前额叶发现标准化，但对杏仁核的发现没有影响。 最后，在对我们的试验数据的探索性分析中，我们发现了与最近的临床前发现相比，患者的dorsa___________________________________________________________________________________________。 综上所述，这些观察结果表明，与对照组相比，PD患者具有区域大脑激活的异常模式，其中一些可能可以通过Sychoscial Issistion进行改进，但是需要进行扩展的样本量和严格的方法学以阐明现有文学中的某些不一致。 因此，我们建议通过采用一种研究设计来研究恐惧神经记录的这一关键方面，该设计将使我们能够在情绪唤醒的三个条件下形象和量化OFC和其他关键大脑区域的活动：1）在休息时，经历“普通”的焦虑水平； 2）在预期焦虑症中； 3）在恐慌期间，未经治疗的PD患者，然后在用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，然后在用CBT治疗后重复此焦虑。 在本研究中，我们将使用doxapram作为“惊恐”药物，因为它在PD患者中的惊恐率很高，而正常志愿者的率相对较低，并且由于以前的工作表明对Doxapram的恐慌受到“认知集”的影响。 在这项研究中，我们将使用18荧光脱氧葡萄糖（FDG）PET成像，而不是15o-hs）宠物成像，因为我们希望在恐慌发作前和期间测量特定的特定大脑区域的代谢积极性。 假设; 1。在治疗之前，在注射盐水（安慰剂）后，但预计他们将接受Panicogen doxapram，PD患者与正常比较受试者相比，通过FDG-PET测量的轨道额叶皮层（OFC）中的代谢活性会改变，与正常的PD患者相比，PD患者在静止状态下进行了PD患者。 2。在盐水给药后，OFC积极性，增加焦虑症，增加的皮质醇水平增加，心率增加，心率增加，呼吸频率和呼吸的潮汐量增加（即预期状态），PD患者在PD患者中。 3。在治疗之前，大约70％患有PD的患者，但只有20％的正常比较受试者，注射Doxapram会引起惊恐发作。 与非固定受试者相比，恐慌的受试者将显示出改变的OFC和杏仁核代谢活性，并且与正在进行FDG-PET扫描的单独的PD Ptients相比，将改变静止状态。 4.治疗之前，与对照组相比，PD患者将显示24小时尿皮质醇水平增加，呼吸可变性增加以及心脏周期变异性降低。 这些将与FDG-PET扫描期间OFC代谢活性，自主神经系统之间的配位异常，下丘脑 - 垂体 - 肾上腺肾上腺（HPA）轴以及PD患者的前额叶皮质活性相关。 5。盐水和盐水的基线焦虑水平，皮质醇和生理措施都将与治疗反应以及治疗后的治疗结果（PDSS，HAM-A，HAM-D，ASI，ASI等）相关。