Generalized Anxiety Disorder and Social Anxiety Disorder:

我们的工作在提示GAD和GSP确实与不同的病理生理学相关方面具有重要意义。在最近的工作中，我们向GSP患者，GAD患者和无病理个体提供愤怒，恐惧和中性面部表情刺激。我们的数据清楚地表明，GSP和GAD的神经回路功能障碍不同。具体来说，我们发现GSP患者在几个区域（包括杏仁核）表现出对恐惧相对于中性表达的显著激活。相比之下，与健康人和GSP患者相比，GAD患者对恐惧相对于中性面孔的激活显着减少，但这与前额叶皮层外侧区域的反应显著增加相结合。重要的是，对GAD/GSP共病患者亚组进行的次要分析表明，他们表现出与GAD相关的病理学，但与GSP无关。也就是说，这些初步的结果强烈建议的重要性，系统的检查和比较的GSP，GAD，和共病GAD/GSP更全面的疾病特异性的理解和发展的新的治疗目标。 这篇论文于2008年发表在《美国精神病学杂志》上。 在最近的其他工作中，我们研究了在一个新设计的新颖的陈述范式中，接受赞扬或批评的GSP和GAD的神经反应。向参与者提供积极、消极和中立的陈述（例如，你是美丽的/丑陋的/人类），这可能是高度相关的和关于自己或不太相关的其他人（例如，他是美丽的）。又有两个主要结果。首先，在两个人群中，GSP和GAD患者对社会刺激的皮层下反应不同，这表明他们之间存在明显的双重分离。第二，研究结果表明，自我相关和内侧前额叶皮层（MPFC），中介自我相关，在GSP中的重要作用。因此，在这项任务中，GSP患者表现出显着增加MPFC和杏仁核的神经反应，对自我的负面评论（批评）。然而，这两组人对其他陈述类别的神经反应没有显著差异：关于自我的中性或积极评论，或者关于他人的负面、中性或积极评论。 这篇论文于2008年发表在《普通精神病学档案》上。 在随后的研究中，我们考虑了GSP中对关于自我的负面评论的增加的神经反应是否反映了（a）对这些评论的同意增加，和/或（B）对他人负面看法的关注或心理化增加。 再次向参与者呈现积极、消极和中立的陈述（例如，你是美丽的/丑陋的/人类），但这一次他们总是自我相关的，相反，我们操纵评论是否来自其他人（例如，你是美丽的），或者是内部产生的（例如，I am beautiful）. 结果进一步强调了MPFC在GSP病理中的关键作用，并再次证明了心理背景对GSP神经回路过度活跃的有意义的影响。 因此，在这个修改后的评论任务中，GSP患者对来自其他人的评论（即，然而，他们并没有表现出对源自自我的评论的神经反应增加（即，I评论）。 该文件目前正在准备出版。 MPFC和上下文信息在GSP中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，我们检查了对可能涉及故意越轨的社会情境的神经反应（例如，不喜欢吃的东西，或不喜欢吃的东西，乔安娜吃东西噎着了，咳嗽起来）。 没有社交焦虑的人通常对故意的社交越轨行为表现出更强的MPFC反应，大概是因为这些行为通常涉及更严重的后果（即，用乔安娜的例子来说，吐出食物会激怒主人，但咳出食物可能不会有什么后果）。 然而，在我们的研究中，GSP患者表现出相反的模式，MPFC对无意的越轨行为的反应增加，大概是因为（1）他们更关心引起尴尬，而不是愤怒，（2）故意的故事与他们无关，因为他们极不可能故意犯下社会越轨行为。 GSP中的这种高度背景依赖性反应有助于限制现有的病症模型，因此可以指导未来治疗病症的治疗制剂。该文件目前正在准备出版。 在最近的其他工作中，我们研究了刺激强化为基础的决策使用的任务，以前已被证明招募杏仁核和vmPFC在健康的个人。关于这项任务的数据还表明，性别与发展问题与普遍性别问题之间存在脱节。因此，只有GAD患者在这项任务上表现出障碍（相对于GSP患者和健康个体，两者没有显著差异）。此外，GAD/GSP共病患者在任务上也表现出明显的损害（相对于GSP患者和健康个体）。然而，GAD/GSP共病患者与单纯GAD患者的损害无显著差异。因此，这项工作强调了确定与个体状况相关的可分离病理生理学的重要性。 这篇论文于2009年发表在《心理医学》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.