From Fear to Anxious Misery: Developing a Defense Circuit Dimensional Classifier

描述（由申请人提供）：病理性焦虑通常“被概念化为一种夸大的恐惧状态，其中恐惧回路的过度兴奋……表现为过度警惕和对恐惧刺激的行为反应增加”（例如，Rosen 等人，1998）——本质上是正常恐惧/防御回路功能的放大。然而，我们之前的研究表明，焦虑症患者的恐惧反应在内部和外部存在显着差异。 诊断，通过恐惧想象挑战期间探测惊吓反射的强度来测量（Cuthbert et al., 2003; Lang, McTeague & Cuthbert, 2005, 2007; Lang & McTeague, 2009）。因此，特定恐惧症患者在恐惧意象过程中表现出强烈的探测惊吓增强，而患有更复杂疾病（例如恐慌症、广泛性焦虑症）的患者则典型地表现出反射反应迟钝。重要的是，在 DSM 诊断中也发现了类似的差异：总体而言，恐惧增强随着症状逐渐严重、共病而降低，尽管在挑战过程中恐惧评级较高（通常要高得多），但负面情绪测量得分较高（McTeague、Lang 等，2009、2010、2011）。 考虑到对动物和人类的研究证实恐惧回路激活（杏仁核介导）会增强惊吓反射，我们的研究提出了一个新的假设，即高度痛苦的焦虑症患者的防御回路受到损害/失调。因此，我们检查了大量患者在我们健康中心附属恐惧和焦虑症诊所 (FADC) 接受治疗时对恐惧意象挑战的反应。功能性 MRI (fMRI) 用于评估恐惧意象挑战期间的恐惧/防御回路功能，检验正常防御回路功能的改变介导恐惧反应性维度的假设，该维度范围从探针惊吓强度的高反应性到低反应性。第二个广泛的目标是检验这样的假设：回路失调和反射迟钝的增加与表明负面情感维度的自我报告的增加可靠相关，并且与治疗结果的成功成反比。因此，总体研究计划是针对跨越焦虑/情绪谱系障碍的病理学维度开发生物分类器。该方法与 RFA-MH-12-100 中实施的 NIMH 研究领域标准倡议（例如，Insel & Cuthbert 2009 所描述的）一致。 公共健康相关性：焦虑症诊断 (DSM-IV) 主要基于临床医生对行为的观察以及对患者在访谈中报告的症状的评估，而没有来自定量生物学测试的支持，而定量生物学测试是评估大多数疾病的治疗的关键。拟议的研究计划是开发定量的生物标记（反射反应和脑回路功能），定义精神病理学的基本维度“负面情感”，它跨越焦虑谱系障碍，可以与发展遗传研究更密切地联系，提供改善的预后，并有助于更好的有针对性的治疗开发。

DESCRIPTION (provided by applicant): Pathological anxiety is commonly "conceptualized as an exaggerated fear state in which hyper- excitability of fear circuits...is expressed as hypervigilance and increased behavioral responsivity to fearful stimuli" (e.g., Rosen et al., 1998)-essentially an amplification of normal fear/defense circuit function. However, our previous research has shown that anxiety patients differ substantially in fear reactivity, within and across diagnoses, as measured by the magnitude of the probe startle reflex during fear imagery challenge (Cuthbert et al., 2003; Lang, McTeague & Cuthbert, 2005, 2007; Lang & McTeague, 2009). Thus, specific phobics show robust probe startle potentiation during fear imagery, while patients with more complex disorders (e.g, panic disorder, generalized anxiety disorder) characteristically show blunted reflex responses. Importantly, similar differences are also found within DSM diagnoses: Overall, fear potentiation decreases as the symptom picture is progressively more severe, comorbid, with higher scores on measures of negative affectivity-despite ratings of high, often much higher, fear during challenge (McTeague, Lang, et al., 2009, 2010, 2011). Considering that research both with animals and humans confirms that fear-circuit activation (amygdala mediated) potentiates the startle reflex, our research invites the novel hypothesis that the defense circuit is compromised/dysregulated in highly distressed anxiety patients. Thus, we examine reactivity to a fear imagery challenge in a broad sample of patients as they present for treatment at our health-center affiliated Fear and Anxiety Disorders Clinic (FADC). Functional MRI (fMRI) is used to asses fear/defense circuit function during fear imagery challenge, testing the hypothesis that alterations in normal defense circuit function mediates a dimension of fear reactivity that ranges from hyper-reactivity to hypo-reactivity in probe startle magnitude. A second broad aim is to test the hypothesis that increased circuit dysregulation and reflex blunting are reliably related to increased self-reports indexing a dimension of negative affectivity, as well as inversely related to treatment outcome success. The general research plan is therefore to develop biological classifiers for a dimension of pathology that cuts across anxiety/mood spectrum disorders. The approach is consistent with the NIMH Research Domain Criteria initiative (e.g, as described by Insel & Cuthbert 2009) implemented in RFA- MH-12-100. PUBLIC HEALTH RELEVANCE: Anxiety disorder diagnoses (DSM-IV) are founded primarily on clinicians' observations of behavior and their assessment of the patient's report of symptoms at interview-with no support from quantitative, biological tests that are keys to the evaluation an treatment of most illnesses. The proposed research plan is to develop quantitative, biological markers (in reflex response and brain circuit function) defining a fundamental dimension of psychopathology, "negative affectivity", that cuts across anxiety spectrum disorders, that can relate more closely to developing genetic research, provide for improved prognosis, and contribute to better targeted treatment development.