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

从恐惧到焦虑痛苦：开发防御电路维度分类器

• 批准号: 8366281
• 负责人: Peter J Lang
• 金额: $ 42.34万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-12 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8366281
• 关键词: Acute; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Asses; Behavior; Behavioral; Biological; Biological Markers; Biological Testing; Brain; Characteristics; Chemosensitization; Classification; Clinic; Clinical; Comorbidity; Complex; Conceptions; DSM-IV; Development; Diagnosis; Diagnostic; Diagnostic and Statistical Manual; Dimensions; Disease; Disease susceptibility; Distress; Dysthymic Disorder; Educational workshop; Emotional; Evaluation; Fright; Functional Magnetic Resonance Imaging; Generalized Anxiety Disorder; Genetic Research; Health; Human; Imagery; Incidence; Interview; Learning; Measures; Mediating; Medicine; Memory; Mental Depression; Moods; Motor; National Institute of Mental Health; Neurobiology; Panic Disorder; Pathology; Patient Self-Report; Patients; Pattern; Physiology; Prevention; Prosencephalon; Psychopathology; Questionnaires; Reaction; Recording of previous events; Reflex action; Reporting; Research; Research Proposals; Sampling; Stimulus; Strategic Planning; Stress; Symptoms; System; Testing; Treatment outcome; Work; base; behavior observation; effective therapy; improved; indexing; novel; outcome forecast; response; success; therapy development; vector

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.

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性......表现为对恐惧刺激的高度警惕和增加的行为反应性”（例如，罗森等人，1998)-本质上是正常恐惧/防御回路功能的放大。然而，我们以前的研究表明，焦虑症患者在恐惧反应方面存在很大差异，无论是在内部还是在外部。 诊断，如通过在恐惧想象挑战期间探测惊吓反射的幅度所测量的（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过程中表现出强大的探测惊吓增强，而患有更复杂疾病（例如，惊恐障碍，广泛性焦虑障碍）的患者的特征性反射反应迟钝。重要的是，在DSM诊断中也发现了类似的差异：总体而言，恐惧增强随着症状图片逐渐变得更严重、共病而降低，在负性情感的测量上具有更高的分数-尽管在挑战期间具有高的、通常高得多的恐惧评级（McTeague，Lang等人，2009年、2010年、2011年）。 考虑到对动物和人类的研究都证实了恐惧回路激活（杏仁核介导的）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，我们在我们的健康中心附属恐惧和焦虑障碍诊所（FADC）接受治疗时，在广泛的患者样本中检查了对恐惧意象挑战的反应。功能性磁共振成像（fMRI）是用来评估恐惧/防御电路功能在恐惧意象的挑战，测试的假设，在正常的防御电路功能的改变介导的范围从高反应性到低反应性的探针惊吓幅度的恐惧反应性的一个维度。第二个广泛的目的是检验这一假设，即增加电路失调和反射钝化可靠地与增加的自我报告索引一个维度的负面情感，以及负相关的治疗结果的成功。因此，一般的研究计划是开发生物分类器的病理层面，跨越焦虑/情绪谱系障碍。该方法与RFA- MH-12-100中实施的NIMH研究领域标准倡议（例如，如Insel & Cuthbert 2009所述）一致。 公共卫生相关性：焦虑症的诊断（DSM-IV）主要是建立在临床医生对患者行为的观察和他们在访谈中对患者症状报告的评估上，而没有定量的生物学测试的支持，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志物（反射反应和脑回路功能），定义精神病理学的基本维度，“消极情感”，跨越焦虑谱系障碍，可以更密切地与发展遗传研究，提供改善的预后，并有助于更好地有针对性的治疗发展。