Probing Systems-Level Function of Fronto-Temporal

格兰特=P50MH58911-06-0006 在该中心最初的资助期，该项目的目的是利用恐惧回路的功能磁共振探头，以补充基础科学项目中的工作的方式，识别和描述两种主要的与恐惧相关的疾病的系统级病理生理学。未经治疗的创伤后应激障碍和惊恐障碍患者和正常对照组受试者在指示恐惧(预期性焦虑)范式和情绪/焦虑工作范式期间接受了扫描，代表了对恐惧回路的非言语和言语、翻译和面向疾病的探测。在恐惧、创伤和安全相关的刺激和背景下，杏仁核、海马体和前额叶腹内侧皮质的不同活动模式和时间进程被识别出来，用于特定的诊断、临床特征和皮质醇图谱。这种识别生物亚型和标记的工作最有意义，因为它可以为治疗机制、发展、选择或反应预测提供信息。因此，关键的下一步是在这些研究的基础上建立和扩展，使我们能够进一步将临床前与临床观察联系起来，并为焦虑症治疗做出贡献。患有创伤后应激障碍和恐慌症的患者将被随机分为5-羟色胺再摄取(SRI)药物或认知行为治疗(CBT)，并在治疗前和治疗12周后立即使用两种功能磁共振成像范式、结构MRI成像、皮质醇和自主神经测量、神经行为测量和临床评级量表进行研究。创伤暴露/创伤后应激障碍阴性受试者和正常对照组受试者将用相同的范式和间隔时间研究广泛性焦虑症(GAD)，后者提供不同的焦虑症状特征，将用这些范式研究一次。因此，定向分析将允许进一步定位和表征额叶和边缘的功能和结构，特别是与这一范围扩大的焦虑症、症状、治疗和结果衡量标准相关的功能和结构。根据其他最新的科学进展，还将对所有受试者进行5-羟色胺转运体(5-HTT)、脑源性神经营养因子(BDNF)、MAO A和B和儿茶酚-0-甲基转移酶(COMT)基因分型。这将为研究这些基因的状态与异常应激和恐惧反应之间的关系，以及识别可能代表临床相关内表型的恐惧回路活动模式提供初步基础。

GRANT=P50MH58911-06-0006 In the initial funding period for this Center, the aim of this project was to identify and characterize systems-level pathophysiology of two major, fear-related disorders using fMRI probes of fear circuitry in a manner complementary to the work in the basic science Projects. Untreated patients with PTSD and panic disorder, and normal control subjects, have been scanned during an instructed fear (anticipatory anxiety) paradigm and an emotional/anxiety work paradigm, representing non-verbal and verbal, translated and disease-oriented probes of fear circuitry. Distinct patterns and time courses of activity in amygdala, hippocampus and ventromedial prefrontal cortex were identified in association with fear, trauma and safety-related stimuli and contexts, for specific diagnosis, clinical features and cortisol profiles. Such work identifying biological sub-types and markers is most relevant when it can inform treatment mechanisms, development, selection, or response prediction. Therefore, a critical next step is to build upon and extend these studies in a manner that will enable us to further relate preclinical to clinical observations, and to make contributions to anxiety disorder therapeutics. Patients with PTSD and panic disorder will be randomized to either serotonin reuptake (SRI) medication or cognitive behavioral therapy (CBT), and studied immediately before and after 12 weeks of treatment using the two fMRI paradigms, structural MRI imaging, cortisol and autonomic measures, neurobehavioral measures, and clinical rating scales. Trauma ?exposed/PTSD negative subjects and normal control subjects will be studied with identical paradigms and intervals with generalized anxiety disorder(GAD), which provides a different anxiety symptom profile, will be studied once with these paradigms. Directed analyses will thus allow the further localization and characterization of frontal and limbic function and structure, specifically related to this broadening range of anxiety disorders, symptoms, treatments and outcome measures. In light of other recent scientific developments, serotonin transporter (5-HTT), brain derived neurotrophic factor (BDNF), MAO A and B, and catechol-0-methyl transferase (COMT) genotyping will be carried out on all subjects as well. This will provide an initial foundation for examining the relationships between the status of these genes and abnormal stress and fear responses, as well as identifying the patterns of fear circuitry activity that may represent clinically relevant endophenotypes.