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症的神经生物学测量的发展，定义有助于加深对焦虑素质的理解的病理学的量化维度。这项研究的重点是大脑以杏仁核为中心的恐惧/防御回路，这是基础实验室神经科学定义的，它调节一系列强制性的生存反射，包括增强的惊吓反应，通常被认为是焦虑症的过度活跃。然而，我们之前的研究表明，焦虑症患者在恐惧记忆想象中的反射反应存在很大差异(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中表现出探测惊吓程度的显著增加，但更广泛的焦虑症患者中有很高比例没有表现出显著的增强。矛盾的是，恐惧增强随着障碍的加重而逐渐减少--尽管口头报告显示，在想象过程中恐惧程度很高，通常要高得多(麦克蒂格等人，2009,2010)。因此，我们假设了恐惧-回路调节/失调的一个光谱范围的、诊断的交叉维度，并在这里使用社交焦虑障碍作为模型系统来解释这一现象，研究了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，直接使用功能磁共振成像(FMRI)评估回路功能，因为它与心理生理学实验室的反射反应有关。具体目标是：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不同的叙述性表象挑战下不同；2)直接评估反射反应性与恐惧/防御回路激活模式和以高发病率、慢性化和高负性情绪为特征的临床症状图之间的关系；3)通过使用功能磁共振成像和心理生理学评估食欲和防御反应，更广泛地评估不同社交焦虑亚型在情绪反应方面的潜在差异，以及4)评估在初始评估中测量的反射和恐惧/防御回路生物标记物在预测基于问卷的治疗后临床状况结果指标中的预后价值。

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.