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

项目摘要 焦虑症中的合并症很常见，与不良结局、低发病率和高死亡率密切相关。 缓解，残疾增加和复发率较高。然而，尽管它的临床意义，临床医生不确定 如何治疗共病焦虑症患者，部分原因是尚不清楚共病病例是否以 不同的病理生理学，或者它们是否应该简单地被概念化为“它们部分的总和”（即， 多个独立的临床实体）。将共病个体表征为具有多种独立疾病 过程阻碍了对协同的病理生理过程的理解，这些过程可能是唯一的特征， 高度共病的患者。目前的项目集中在一个神经轮廓，对应于增加 焦虑症的共病负荷，并在异常的大脑连接中路由。这个神经轮廓 包括警报增加（杏仁核升高）和动机性注意力减少（晚期阳性反应减弱 电位，LPP;精心制作的刺激处理的EEG测量）到负图像，并被称为 HARM-A（警报升高，动机性注意力降低）。控制报警和 有动机的注意力，初步数据表明，较高的HARM-A与（a）更大的内化 精神病理学;（B）既往合并症发生率较高（控制当前合并症）和（c）增加 12-24个月后出现烦躁不安（对照基线烦躁不安）。那些HAM-A较高的人也表现出 在威胁检测和评估中涉及的关键节点之间的异常连接（杏仁核-前扣带回 皮质），以及压力和负面影响之间更强的联系。因此，伤害-A可能是 在共病焦虑病例中，结果更糟，并且可能通过增加产生负面情绪的风险来实现 压力事件之后。目前的项目通过研究消极情绪来扩展这一初步工作 在180个人中进行处理，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项多水平评估（fMRI，EEG，临床访谈，自我报告措施） 在每次评估中，参与者还将完成10天的经验抽样评估， 压力事件和负面影响。该项目将测试HARM-A的双向模型，其中HARM-A 预测未来合并症负荷增加，潜在、转诊断、内化 精神病理学，这反过来又会预测HARM-A的增加（即，一个相互加强的“螺旋”）。它还将 评估支持较高HARM-A的神经回路，并将使用经验采样数据来测试是否 HARM-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 HARM-A与更差的内化精神病理学具有前瞻性和非前瞻性相关性， 神经回路和阐明其在压力源和负面影响之间的联系中的作用将提供一个 机制解释更大的疾病负担在共病焦虑，并提供了一个前进的道路， 对焦虑相关疾病的病因学易处理的理解，并用于靶向治疗的开发。

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.