Generalized Anxiety Disorder and Social Anxiety Disorder:

我们的工作很重要，表明GAD和GSP确实与不同的病理生理有关。在最近的工作中，我们向GSP患者、GAD患者和没有病理改变的人提供愤怒、恐惧和中性的面部表情刺激。我们的数据清楚地表明，GSP和GAD的神经回路功能障碍是不同的。具体地说，我们发现GSP患者在几个区域，包括杏仁核，相对于中性表达，对恐惧的激活显著增加。相比之下，与健康人和GSP患者相比，GAD患者表现出相对于中性面孔的恐惧激活显著减少，但这与前额叶皮质外侧区域的异常反应显著增加有关。重要的是，对GAD/GSP并存的亚组患者进行的二次分析表明，他们表现出与GAD相关的病理，而不是GSP。也就是说，这些初步结果强烈表明，系统地检查和比较GSP、GAD和共病的GAD/GSP对于更全面地了解和开发新的治疗靶点具有重要意义。这篇论文发表在2008年的《美国精神病学杂志》上。 在最近的另一项工作中，我们在一种新设计的陈述范式中考察了GSP和GAD中对赞扬或批评的神经反应。参与者得到了正面、负面和中性的陈述(例如，你很漂亮/丑陋/人类)，这些陈述可能是高度相关的，也可能是关于自己的，也可能是与他人无关的(例如，他很漂亮)。再次出现了两个主要结果。首先，在患有GSP和GAD的个体之间再次出现明显的双重分离，这表明这两个群体对社会刺激的皮质下反应不同。其次，研究结果表明，自我相关和内侧前额叶皮质(MPFC)在GSP中起重要作用。因此，在这项任务中，GSP患者在MPFC和杏仁核对自我的负面评论(批评)的神经反应显著增加。然而，这两组人在对任何其他陈述类别的神经反应上没有显著差异：对自己的中性或正面评价，或对他人的负面、中性或正面评价。这篇论文发表在2008年的《普通精神病学档案》上。 在随后的工作中，我们考虑了GSP中对自我的负面评论增加的神经反应是否反映了(A)对这些评论的更多认同，和/或(B)对他人负面看法的更多关注或心理化。参与者再次被呈现出正面、负面和中性的陈述(例如，你很漂亮/丑陋/人类)，但这一次它们总是与自己相关，相反，我们操纵了评论是来自其他人(例如，你很漂亮)，还是内部产生的(例如，我很漂亮)。这一结果进一步强调了MPFC在GSP病理中的关键作用，并再次证明了心理环境对GSP神经环路过度活动的有意义的影响。因此，在这个修改的评论任务中，GSP患者在MPFC中对来自他人的评论(即你的评论)表现出显著的激活，然而，他们没有表现出对源自自我的评论(即我的评论)的神经反应增加。这篇论文目前正在准备出版。 GSP中MPFC和上下文信息的重要性在最近的其他工作中得到了进一步的证明，在这些工作中，我们研究了神经对社交情景的反应，这些社交情景可能涉及故意违规(例如，Joanna不喜欢她的食物并将其吐出)，也可能涉及无意(尴尬)违规(例如，Joanna窒息她的食物并将其呕吐)。没有社交焦虑的人通常会对故意的社交违规行为表现出更强的MPFC反应，这可能是因为这些行为通常会产生更严重的后果(比如，以乔安娜为例，吐出食物会激怒主人，但咳嗽掉食物可能不会产生后果)。然而，在我们的研究中，GSP患者表现出相反的模式，MPFC对无意违规的反应增加，想必是因为(1)他们更关心造成尴尬，而不是愤怒，(2)故意故事与他们无关，因为他们极不可能故意犯下社会违规行为。GSP中的这种高度上下文依赖的反应有助于限制现有的障碍模型，从而可能指导未来治疗该障碍的治疗配方。这篇论文目前正在准备出版。 在最近的其他工作中，我们检查了基于刺激强化的决策制定，使用了一个先前已被证明在健康个体中招募杏仁核和vmPFC的任务。关于这项任务的数据还表明，GAD和GSP之间存在分离。因此，只有GAD患者在这项任务上表现出损害(相对于GSP患者和没有显著差异的健康人)。此外，GAD/GSP并存的患者也表现出明显的任务障碍(相对于GSP患者和健康人)。然而，GAD/GSP并存的患者和单纯GAD的患者在功能损害方面无显著差异。因此，这项工作强调了确定与个体情况相关的可分离病理生理学的重要性。这篇论文发表在2009年的《心理医学》杂志上。

Our work has been important in suggesting that GAD and GSP are indeed associated with different pathophysiologies. In recent work, we presented patients with GSP, patients with GAD, and no pathology individuals with angry, fearful, and neutral facial expression stimuli. Our data clearly suggested that the neural circuitry dysfunction in GSP and GAD differ. Specifically, we found that patients with GSP showed significantly increased activation to fearful relative to neutral expressions in several regions, including the amygdala. In contrast, patients with GAD showed significantly reduced activation to fearful relative to neutral faces compared to healthy individuals and patients with GSP but this was coupled with anomalously and significantly increased responses in a lateral region of prefrontal cortex. Importantly, a secondary analysis conducted with the subgroup of patients with comorbid GAD/GSP indicated that they presented with the pathologies associated with the GAD, but not the GSP. That is, these preliminary results strongly suggest the importance of a systematic examination and comparison of GSP, GAD, and comorbid GAD/GSP for a fuller disorder-specific understanding and development of new treatment targets. This paper was published in The American Journal of Psychiatry in 2008. In other recent work, we examined the neural responses to receipt of praise or criticism in GSP and GAD within a newly design novel statement paradigm. Participants were presented with positive, negative, and neutral statements (e.g., You are beautiful/ ugly/ human) that could be either about highly relevant and about themselves or less relevant about somebody else (e.g., He is beautiful). There were again two major results. First, there again was a clear double dissociation between the individuals with GSP and GAD with suggestions of a divergent subcortical response to social stimuli in the two populations. Second, the results indicated an important role for self-relevance and medial prefrontal cortex (MPFC), mediating self-relevance, in GSP. Thus, on this task patients with GSP showed significantly increased neural responses in MPFC and amygdala to negative comments about the self (criticism). However, the groups did not differ significantly in their neural responses to any of the other statement categories: neutral or positive comments about the self, or negative, neutral, or positive comments about others. This paper was published in the Archives of General Psychiatry in 2008. In subsequent work, we considered whether the increased neural responses in GSP to negative comments about the self reflects (a) increased agreement with those comments, and/or (b) increased concern or mentalizing about others negative perceptions. Participants were presented again with positive, negative, and neutral statements (e.g., You are beautiful/ ugly/ human) but this time they were always self relevant, and instead we manipulated whether the comments came from somebody else (e.g., You are beautiful), or was internally generated (e.g., I am beautiful). The results further underlined the critical role of MPFC in GSP pathology, and again demonstrated a meaningful effect of psychological context on neural-circuitry hyperactivity in GSP. Thus, on this modified comment task, patients with GSP showed significantly increased activation in MPFC to comments that came from somebody else (i.e., You comments), however, they did not show increased neural responses to comments that originated within the self (i.e., I comments). This paper is currently being prepared for publication. The importance of MPFC and contextual information in GSP was further demonstrated in other recent work, where we examined the neural response to social situations that could either involve an intentional transgression (e.g., Joanna does not like her food and spits it out), or an unintentional (embarrassing) transgression (e.g., Joanna chokes on her food and coughs it up). People with no social anxiety typically show increased MPFC responses to the intentional social transgressions, presumably because those acts typically involve more severe consequences (i.e., using the Joanna example, spitting out the food will anger the host, but coughing up the food will probably not have consequences). However, in our study patients with GSP showed the opposite pattern with increased MPFC responses to unintentional transgressions, presumably because (1) they care more about causing embarrassment, than anger, and (2) the intentional stories are not relevant to them because they are extremely unlikely to intentionally commit a social transgression. This highly context dependent response in GSP helps constrain existing models of the disorder and may thus guide future therapeutic formulations in the treatment of the disorder. This paper is currently being prepared for publication. In other recent work, we examined stimulus-reinforcement based decision making using a task that has previously been demonstrated to recruit the amygdala and vmPFC in healthy individuals. The data on this task also indicated a dissociation between GAD and GSP. Thus, only patients with GAD showed impairment on this task (relative to both patients with GSP and healthy individuals who did not significantly differ). Moreover, the patients with comorbid GAD/GSP also showed significant impairment on the task (relative to both patients with GSP and healthy individuals). However, the patients with comorbid GAD/GSP and those with GAD alone did not show significant differences in impairment. Thus, this work has underlined the importance of determining the separable pathophysiologies associated with the individual conditions. This paper was published in Psychological Medicine in 2009.