Anxiety, comorbidity, negative affect, and fear circuit activation

描述（由申请人提供）：与NIMH的研究领域标准倡议一致（Insel & Cuthbert, 2009），主要研究目标是推进焦虑谱系障碍的神经生物学测量的发展，定义病理学的定量维度，促进对焦虑素质的理解。这项工作的重点是大脑中以杏仁核为中心的恐惧/防御回路，根据基础实验室神经科学的定义，它调节一系列强制性的生存反射，包括增强的惊吓反应，通常被认为在焦虑症中过度活跃。然而，我们之前的研究表明，焦虑患者在恐惧记忆意象中的反射反应性差异很大（Cuthbert et al., 2003; Lang et al., 2005, 2007; Lang & McTeague, 2009）。虽然大多数恐惧症患者在恐惧意象中表现出明显的探针惊吓强度增加，但很大比例的广泛性焦虑症患者没有表现出明显的增强。矛盾的是，随着疾病的严重程度、共病程度和负面影响的加重，恐惧增强会逐渐减弱——尽管在想象过程中口头报告的恐惧程度很高，通常要高得多（McTeague et al., 2009, 2010）。因此，我们假设了恐惧回路调节/失调的全谱、诊断交叉维度，并将社交焦虑障碍作为模型系统来阐明这一现象，研究健康对照者和三种社交焦虑亚型：局限性、广泛性和伴抑郁的广泛性社交焦虑，并在心理生理学实验室直接使用功能磁共振成像（fMRI）评估回路功能，因为它与反射性有关。具体目的是：1)确定不同社交焦虑亚型的恐惧/防御回路结构的激活及其功能连通性是否在对叙事意象挑战的反应中存在差异；2)直接评估反射性、恐惧/防御回路激活模式与以高合并症、慢性和高负性情绪为特征的临床症状之间的关系；3)利用功能磁共振成像（fMRI）和心理生理学更广泛地评估社交焦虑亚型之间情绪反应性的潜在差异；4)评估在初始评估中测量的反射和恐惧/防御回路生物标志物在预测治疗后临床状态的问卷结果测量中的预后价值。

DESCRIPTION (provided by applicant): Consistent with NIMH's Research Domain Criteria initiative (Insel & Cuthbert, 2009), the primary research goal is to advance the development of neurobiological measures of anxiety spectrum disorder, defining quantitative dimensions of pathology that advance understanding of the anxiety diathesis. The work's focus is the brain's amygdala-centered fear/defense circuit, as defined by basic laboratory neuroscience, which mediates a range of obligatory survival reflexes, including the potentiated startle response, and is generally held to be hyper-active in anxiety disorders. Our previous research indicates, however, that anxiety patients differ widely in their reflex reactivity during fear memory imagery (Cuthbert et al., 2003; Lang et al., 2005, 2007; Lang & McTeague, 2009). While most phobic patients show marked increases in probe startle magnitude during fear imagery, a high percentage of patients with more generalized anxiety disorders fail to show significant potentiation. Paradoxically, fear potentiation decreases progressively as the disorder is more severe, co-morbid, with greater negative affect-despite verbal reports of high, often much higher, fear during imagery (McTeague et al., 2009, 2010). Thus, we hypothesize a spectrum-wide, diagnosis cross-cutting dimension of fear-circuit regulation/dysregulation, and here use social anxiety disorder as a model system to elucidate the phenomenon, studying healthy controls and three social anxiety subtypes: circumscribed, generalized, and generalized social anxiety with depression, assessing circuit function directly with functional Magnetic Resonance Imaging (fMRI) as it relates to reflex reactivity in the psychophysiology laboratory. The specific aims are 1) to determine if activation of fear/defense circuit structures and their functional connectivity differ in response to narrative imagery challenges across social anxiety subtypes; 2) to directly assess the relationship between reflex reactivity and fear/defense circuit activatio patterns and a clinical symptom picture characterized by high co-morbidity, chronicity, and high negative affect; 3) to more broadly evaluate potential differences in emotional reactivity across social anxiety subtypes by assessing appetitive, as well as defensive reactivity using fMRI and psychophysiology, and 4) to evaluate the prognostic value of reflex and fear/defense circuit bio-markers measured during in initial assessment in predicting questionaire-based outcome measures of clinical status following treatment. PUBLIC HEALTH RELEVANCE: Currently, the diagnosis of anxiety disorder depends almost entirely on patient-interview and the clinician's assessment the patient's symptom report. The clinician has available no neurobiological measures of anxiety disorder-as when an internist orders an electro- cardiogram of the heart to help interpret a patient's report of chest pain. The proposed research explores quantitative measures of brain function and reflex reactivity that could define a dimension of anxiety disorder severity, and thus potentially enhance the clinician's understanding of the patient, improving diagnosis significantly and guiding new treatments.