MRS and fMRI Studies of Neurobiological Factors in Panic Disorder

描述(申请人提供)：总结：这项研究的长期目标是更好地了解惊恐障碍易感性的神经生物学基础。大多数惊恐障碍的神经生物学模型提出了两种截然不同的易损性机制之一：1)新陈代谢控制的“警报”系统功能障碍；或2)高度敏感的恐惧系统。应用大脑能量代谢的新概念和质子磁共振波谱(1H-MRS)方法，最近研究表明，恐慌症患者在神经激活过程中积累的脑乳酸水平高于对照组。乳酸盐是一种已知的恐慌原。与代谢“警报”模型一致，这可能代表代谢异常，在发病机制中起关键作用。然而，乳酸反应的升高可能是高度敏感的恐惧系统和/或持续的恐慌症状的结果，而不是具有潜在病因学意义的代谢异常。结合1H-MRS和fMRI方法，我们的目标是测试这两种方法对惊恐障碍患者脑乳酸反应升高的预测。我们将测量3组人的恐惧系统反应和脑乳酸反应：1)有症状的、未经治疗的惊恐患者，2)经过治疗、临床症状改善的惊恐患者，以及3)对照组。将通过测量杏仁核对恐惧面孔的大胆反应来测试对恐惧系统的预测。代谢模型的预测将通过1H-MRS测量视觉刺激期间的视觉皮质乳酸反应来检验。初步数据显示，在未经治疗的患者中，这两项指标都将异常升高。在接受治疗的患者中的发现将有助于确定乳酸反应升高的潜在意义。如果接受治疗的患者的乳酸反应是正常的，它不太可能反映潜在的和持久的代谢异常。然而，如果杏仁核的反应随着临床症状的改善而正常化，而乳酸反应却没有，那么乳酸反应的升高可能与恐惧反应和持续的恐慌症状无关。这将支持潜在的代谢异常模型，该模型不会因临床改善或正常化的恐惧反应而改变。之所以需要R21机制，是因为我们的方法和概念代表了研究惊恐障碍的新途径。相关性：关于恐慌症的生理原因，有两种主要的理论。该项目将测试每种理论对恐慌症患者的恐惧反应和大脑新陈代谢的预测，以更好地了解是什么导致了恐慌症。

DESCRIPTION (provided by applicant): Summary: The long-term goal of this study is to better understand the neurobiological basis of susceptibility to panic disorder. Most neurobiological models of panic disorder propose one of two contrasting mechanisms of vulnerability: 1) dysfunction of a metabolically-governed "alarm" system; or 2) a hypersensitive fear system. Applying new concepts in brain energy metabolism and proton MR spectroscopy (1H-MRS) methods, panic patients have recently been shown to.accumulate higher levels of brain lactate during,neural activation than control subjects. Lactate is a known panicogen. Consistent with metabolic "alarm" models, this might represent a metabolic abnormality with a key role in pathogenesis. However, elevated lactate responses could be a consequence of a hypersensitive fear system and/or ongoing panic symptoms, rather than a metabolic abnormality with potential etiological significance. Combining 1H-MRS and fMRI methods, we aim to test the predictions of these two accounts of elevated brain lactate responses in panic disorder. We will measure fear system responses and brain lactate responses in 3 groups: 1) symptomatic, untreated panic patients, 2) treated, clinically improved panic patients, and 3) control subjects. The prediction of a hypersensitive fear system will be tested by measuring amygdala BOLD responses to fearful faces. The prediction of the metabolic model will be tested by measuring visual cortex lactate responses during visual stimulation with 1H-MRS. Preliminary data suggest both measures will be abnormally elevated in the untreated patients. Findings in the treated patients will help define the potential significance of the elevated lactate response. If the lactate response is normal in treated patients, it is unlikely to reflect an underlying and enduring metabolic abnormality. However, if amygdala responses normalize with clinical improvement but lactate responses do not, then elevated lactate responses may be independent of fear responses and ongoing panic symptoms. This would support the model of an underlying metabolic abnormality unaltered by clinical improvement or normalized fear responses. The R21 mechanism is requested because our methods and concepts represent a new approach to the study of panic disorder. Relevance: There are two leading theories about physical causes of panic disorder. This project will test predictions of each theory about fear responses and brain metabolism in panic patients in order to better understand what causes panic disorder.