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（Insel & Cuthbert，2009）一致，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以杏仁核为中心的恐惧/防御回路，正如基础实验室神经科学所定义的那样，它介导了一系列强制性的生存反射，包括增强的惊吓反应，并且通常被认为在焦虑症中过度活跃。然而，我们先前的研究表明，焦虑症患者在恐惧记忆想象过程中的反射反应差异很大（Cuthbert等人，2003; Lang等人，2005，2007; Lang & McTeague，2009）。虽然大多数恐惧症患者在恐惧想象过程中表现出明显的探测惊吓幅度增加，但更广泛性焦虑症患者的高比例未能表现出显着的增强作用。奇怪的是，恐惧增强随着障碍更严重、共病、具有更大的负面影响而逐渐减少-尽管在图像期间口头报告了高的、通常高得多的恐惧（McTeague等人，2009年，2010年）。因此，我们假设恐惧回路调节/失调的一个频谱范围，诊断横切维度，并在这里使用社交焦虑障碍作为模型系统来阐明这一现象，研究健康对照和三种社交焦虑亚型：局限性、广泛性和广泛性社交焦虑伴抑郁症，直接用功能性磁共振成像（fMRI）评估回路功能，因为它与心理生理学实验室中的反射反应有关。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接是否在对叙事想象挑战的反应中存在差异; 2）直接评估反射反应和恐惧/防御回路激活模式与以高共病率、慢性化和高负性情感为特征的临床症状图片之间的关系; 3）通过使用fMRI和心理生理学评估食欲以及防御反应，更广泛地评估社交焦虑亚型之间情绪反应的潜在差异，以及4）评估在初始评估期间测量的反射和恐惧/防御回路生物标志物在预测问卷中的预后价值-基于治疗后临床状态的结局指标。

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.