Negative Valence Brain Targets and Predictors of Anxiety and Depression Treatment

描述（由申请人提供）：涉及抑郁和焦虑的内化精神病理学（IP）是最普遍，最昂贵和致残的疾病之一。IP的治疗是可用的，但个体患者的反应程度是相当异质性的。信息很少，特别是在生物学领域，这有助于解释治疗反应的个体差异。NIMH的研究领域标准（RDoC）项目可以通过鼓励超越某些分类疾病及其相关症状的创新研究来解决这个问题，这些研究涉及与脑病理生理学相关的更广泛的核心（RDoC）结构，并且在各种疾病中共享。IP在额叶边缘情感调节和情绪突出（FLARES）脑回路中具有相似的功能障碍模式，两种常用的“金标准”治疗-选择性5-羟色胺再摄取抑制剂（SSRI）和认知行为疗法（CBT）-对焦虑和抑郁障碍同样有效，并且似乎改变FLARES回路中相同区域的大脑活动。拟议项目的总体目标是描述SSRI和CBT的常见与特定FLARE脑靶点，并确定FLARE功能障碍的特定方面，这些方面可能更好地预测对两者和特定治疗方式的反应。拟议的实验整合了情绪及其与认知的互动，跨越了情绪体验的几个阶段，包括探索对急性和潜在威胁的敏感性以及与FLARES大脑网络相关的自动和意志形式的影响调节的研究。这些实验将生成关于负价系统（NVS）RDoC域的数据，用于多层分析（神经回路的fMRI和EEG，生理学的皮肤电导和惊吓反应，行为的表现和自我报告）。我们建议招募200名参加我们的情绪和焦虑障碍项目的患者，寻求治疗"焦虑、担忧、抑郁情绪“（IP，包括未另行说明的那些），并将他们随机分配到SSRI或CBT的12周疗程。将在每次治疗前后测量尺寸、跨诊断NVS结构，包括FLARES功能。具体来说，该项目将研究2个具体目标：1）SSRI和CBT治疗在哪里以及如何对NVS结构产生影响？2）哪种NVS结构可以预测SSRI和CBT治疗成功的可能性？这些发现可用于指导正确的患者进行正确的治疗，从而获得最大的成功可能性。他们还阐明了一种病理生理驱动的机制模型，即治疗在大脑中的作用位置和方式，从而加速了针对内在条件下潜在病理生理学的新治疗方法的开发。

DESCRIPTION (provided by applicant): Internalizing psychopathologies (IPs) involving depression and anxiety are among the most prevalent, costly and disabling illnesses. Treatments for IPs are available but the extent to which individual patients respond is quite heterogeneous. Little information exists, particularly in the biological domain, which helps to explain individual differences in treatment response. The NIMH's Research Domain Criteria (RDoC) project may solve this problem by encouraging innovative research beyond certain categorical disorders and their associated symptoms, towards broader, core (RDoC) constructs related to brain pathophysiology, and that are shared across disorders. IPs share similar patterns of dysfunction within the Fronto-Limbic Affect Regulation and Emotional Salience (FLARES) brain circuit, and two commonly used, 'gold standard' treatments - selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapies (CBTs) - are equally effective for both anxiety and depressive disorders, and appear to change brain activity in the same areas within the FLARES circuit. The overarching goal of the proposed project is delineate what are common versus specific FLARE brain targets for SSRI and CBT and identify specific aspects of FLARE dysfunction that might better predict response to both and to a specific modality of treatment. The proposed experiments integrate emotion and its interaction with cognition across several stages of emotional experience, encompassing studies that probe sensitivity to acute and potential threat and automatic and volitional forms of affect regulation in relation to the FLARES brain network. These experiments will generate data on the negative valence systems (NVS) RDoC domain for multiple layers of analysis (fMRI and EEG for neural circuits, skin conductance and startle response for physiology, performance and self-reports for behavior). We propose to enroll 200 patients presenting to our Mood and Anxiety Disorders Program seeking treatment for disabling 'anxiety, worry, depressed mood' (IP,s including those characterized as Not Otherwise Specified) and randomize them to a 12-week course of SSRI or CBT. Dimensional, transdiagnostic NVS constructs, including FLARES function, will be measured before and after each treatment. Specifically, the project will examine 2 Specific Aims: 1) Where and how do SSRI and CBT treatments exert their effects on NVS constructs?; and 2) Which NVS construct can predict the likelihood of success from SSRI and CBT treatment? Such findings can be used to guide the right patients to the right treatments with the highest likelihood of success. They also elucidate a pathophysiologically-driven mechanistic model of where and how treatments work in the brain and thus hasten the development of new treatments that target the underlying pathophysiology across internalizing conditions.