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

描述(申请人提供)：病理性焦虑通常是“被概念化为一种夸张的恐惧状态，其中恐惧回路的过度兴奋……表现为对恐惧刺激的高度警惕和行为反应增加”(例如，Rosen等人，1998)--本质上是对正常恐惧/防御回路功能的放大。然而，我们之前的研究表明，焦虑症患者在恐惧反应方面有很大的不同，无论是内部还是外部 诊断是通过探头在恐惧表象挑战中惊恐反射的大小来衡量的(Cuthbert等人，2003；Lang，McTeague&Cuthbert，2005,2007；Lang&McTeague，2009)。因此，特定的恐惧症患者在恐惧想象中表现出强大的探测惊吓增强，而更复杂的障碍(如惊恐障碍、广泛性焦虑障碍)的患者典型地表现出迟钝的反射反应。重要的是，在DSM诊断中也发现了类似的差异：总体而言，恐惧增强随着症状图景的逐渐严重而减少，在消极情感测量上的得分更高--尽管在挑战中的恐惧评级很高，往往要高得多(McTeague，Lang等，2009、2010、2011)。考虑到对动物和人类的研究都证实了恐惧回路的激活(杏仁核介导)增强了惊吓反射，我们的研究提出了一个新的假设，即高度痛苦的焦虑患者的防御回路受到损害/失调。因此，我们在我们医疗中心附属的恐惧和焦虑症诊所(FADC)接受治疗的患者中，检测了他们对恐惧意象挑战的反应。功能磁共振成像(FMRI)被用来评估恐惧表象挑战时的恐惧/防御回路功能，以检验以下假设：正常防御回路功能的改变调节从高反应到低反应的恐惧反应维度。第二个广泛的目标是检验这样一个假设，即增加的电路失调和反射迟钝与增加的自我报告有关，并与负面情感的一个维度索引，以及与治疗结果的成功负相关。因此，总体研究计划是为跨越焦虑/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所述)是一致的。 公共卫生相关性：焦虑症诊断(DSM-IV)主要基于临床医生对行为的观察和他们在访谈中对患者症状报告的评估-没有定量生物测试的支持，这些测试是评估大多数疾病治疗的关键。拟议的研究计划是开发定量的生物标记物(在反射反应和大脑回路功能中)，定义精神病理学的一个基本维度，即跨越焦虑症谱系障碍的“负面情感”，它可以与发展基因研究更密切地联系起来，提供改善预后，并有助于更好的靶向治疗开发。

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.