HARM-A: A neurobiological predictor of comorbidity and stress reactivity in anxiety disorders

项目总结 焦虑症的共病很常见，而且与不良预后密切相关，较低的 病情缓解，残疾增加，复发率更高。然而，尽管它与临床相关，临床医生们并不确定 如何治疗合并焦虑的患者，部分原因是尚不清楚合并焦虑的患者是否有 不同的病理生理学，或者它们是否应该简单地被概念化为其部分的总和(即， 多个独立的临床实体)。共病个体的特征是有多个独立的疾病 过程阻碍了对协同作用、病理生理过程的理解，这些过程可能唯一地表征 高度并存的病人。目前的项目关注的是一种神经图谱，它对应于 共病跨越焦虑症，并在异常的大脑连接中被传递。这一神经特征是 包括更多的警觉(杏仁核增强)和更少的动机注意力(减弱的后期积极 潜伏期，LPP；详细刺激处理的脑电测量)，并被称为 伤害-A(高度警觉，减少动机注意力)。控制警报和警报的不同效果 有动机的注意，初步数据表明，较高的伤害-A与(A)更大的内在化有关 精神病理学；(B)过去共病的比率较高(控制目前的共病)和(C)增加 12-24个月后出现焦虑症(控制基线焦虑症)。那些危害-A更高的人也显示出 参与威胁检测和评估的关键节点(杏仁核-前扣带回)之间的连接异常 大脑皮质)，以及压力和负面情绪之间更强的联系。因此，危害-A可能是 在合并焦虑的情况下，结果更差，可能是通过增加产生负面情绪的风险来实现的 紧跟着紧张的事件。目前的项目通过检查负面情绪来扩展这项初步工作 对180名个体进行处理，招募以确保当前和过去内化症状的维度。 参与者将在24小时内接受3次多层次评估(fMRI、EEG、临床访谈、自我报告) 月；在每次评估中，参与者还将完成为期10天的体验抽样评估 有压力的事件和消极的情绪。该项目将测试Harm-A的双向模型，在该模型中，Harm-A 预测未来共病负荷增加，潜伏期、跨诊断性、内在化方面得分更高 精神病理学，这将反过来预测危害-A的增加(即，相互强化的“螺旋”)。它还将 评估支持更高危害-A的神经回路，并将使用经验采样数据来测试 危害-A预测压力暴露和随后的负面影响之间存在更强的联系。发现了那个 危害-A与更糟糕的内化精神病相互关联，描绘了它的 神经回路和阐明其在应激源和负面情绪之间的联系中的作用将提供一个 对共病焦虑的更大疾病负担的机械解释，并为更多 对焦虑症相关疾病的病因学理解，并用于开发有针对性的治疗方法。

PROJECT SUMMARY Comorbidity in the anxiety disorders is common and strongly associated with poor outcomes, lower rates of remission, increased disability and higher rates of relapse. Yet despite its clinical relevance, clinicians are unsure how to treat comorbid anxiety patients, in part because it is unknown whether comorbid cases are marked by distinct pathophysiology, or whether they should simply be conceptualized as the 'sum of their parts' (i.e., multiple, separate clinical entities). Characterizing comorbid individuals as having multiple, independent, disease processes occludes understanding of synergistic, pathophysiological processes that may uniquely characterize highly comorbid patients. The current project focuses on a neural profile that corresponds to increased comorbidity load across the anxiety disorders and is routed in aberrant brain connectivity. This neural profile is comprised of increased alarm (heightened amygdala) and reduced motivated attention (attenuated late positive potential, LPP; an EEG measure of elaborated stimulus processing) to negative images, and is referred to as HARM-A (Heightened Alarm, Reduced Motivated Attention). Controlling for separate effects of alarm and motivated attention, preliminary data suggest that higher HARM-A is associated with (a) greater internalizing psychopathology; (b) higher rates of past comorbidity (controlling for current comorbidity) and (c) increased dysphoria 12-24 months later (controlling for baseline dysphoria). Those with higher HARM-A also showed aberrant connectivity between key nodes involved in threat detection and appraisal (amygdala-anterior cingulate cortex), as well as a stronger link between stress and negative affect. Therefore, HARM-A might underlie the worse outcome in comorbid anxiety cases, and may do so by increasing risk for negative affect generation following stressful events. The current project extends this preliminary work by examining negative emotion processing in 180 individuals, recruited to insure dimensionality on current and past internalizing symptoms. Participants will undergo 3 multi-level assessments (fMRI, EEG, clinical interview, self-report measures) over 24 months; at each assessment, participants will also complete 10 days of experience sampling assessments of stressful events and negative affect. The project will test a bidirectional model of HARM-A, in which HARM-A predicts increased future comorbidity load and higher scores on latent, transdiagnostic, internalizing psychopathology, which will in turn predict increased HARM-A (i.e., a mutually reinforcing “spiral”). It will also assess the neurocircuitry that supports higher HARM-A and will use experience sampling data to test whether HARM-A predicts stronger linkage between stress exposure and subsequent negative affect. Finding that HARM-A is prospectively and reciprocally associated with worse internalizing psychopathology, delineating its neurocircuitry and elucidating its role in the linkage between stressors and negative affect would deliver a mechanistic explanation for greater disease burden in comorbid anxiety and provide a path forward for more etiologically tractable understanding of anxiety-related disorders, and for the development of targeted treatments.