Transdiagnostic Brain-Behavior Profiling to Enhance Cognitive Behavioral Therapy Response

抑郁症（MDD）和广泛性社交焦虑症（gSAD）是常见的抑郁症和社交焦虑症的主要症状之一， 健康问题这些疾病的特征是情绪失调，不能或效率低下， 调节反映在常见和疾病特异性症状中的消极和积极影响（例如，注意力 对负面刺激的偏见，过度/不适当的负面想法，过度觉醒，快感缺乏，情绪 钝化）。这种失调被认为是由自上而下的“情绪调节” (ER)额叶神经节在大脑皮层下自下而上的“情绪产生”（EG）节点的抑制控制中起中心作用， 额叶边缘情感调节和情绪显著性（FLARES）网络。因此，成功的治疗 将有望使FLARES网络中的神经功能紊乱“正常化”， 用功能磁共振成像和更远的脑功能单位--事件相关电位（ERPs）测量， 脑电图、来自肌电图（EMG）的惊吓增强、神经认知表现，以及 通过自我报告在日常生活中使用调节策略。拟议研究的总体目标是 了解CBT如何、何时、何地起作用，以及为谁量身定制治疗以改善临床结果。 如果没有准确确定的“目标”和“预测”的变化，CBT反应将继续是 不可预测地变化，很少有患者获得有意义的临床改善，使他们处于复发的风险中， 复发我们的建议是建立在我们实验室和其他机构公布的数据以及初步数据的基础上的， FLARES功能，如fMRI，ERPs，EMG和行为所测定的，对CBT后的变化敏感。 重要的是，基线fMRI和非fMRI脑行为测量单位都能更好地预测CBT反应 比基线临床测量。这些知识可以导致更精确的干预措施，旨在资本化 在CBT之前可能存在的“优势”或改善“缺陷”和/或解释为什么CBT不起作用 一些病人。功能磁共振成像（“机械”）和非功能磁共振成像（“实用”）预测因子和指标的双重发展 治疗变化的目的是推进精准医学，同时增加临床效用， “生物标志物”在门诊设置。为了实现这一目标，我们建议采用经过验证的范例， 在MDD和gSAD中，在负面刺激、奖励过程和恐惧系统的背景下测试ER和EG， 描述常见的和疾病特异性的变化机制和CBT结果的预测因子。我们将招收 200例患者：100例MDD（无共病gSAD），100例gSAD（无共病MDD），并将其随机分配至 12周的手动CBT或12周的“安慰剂”心理治疗（支持治疗）（1：1的比例）。多 将在所有患者中收集FLARES功能的单位之前（第0周）、期间（中间/第6周）和之后 治疗（第12周），以确定CBT“剂量”的影响，并在40名健康对照进行比较。预CBT 基于二元（应答者/非应答者状态）和连续（变化程度）结局的预测因子将 在治疗中途（第6周）、治疗后立即（第12周）和6个月随访时进行检查。

Major Depressive Disorder (MDD) and generalized Social Anxiety Disorder (gSAD) are pervasive major public health problems. These disorders are characterized by emotion dysregulation, an inability or inefficiency to regulate negative and positive affect as reflected in common and disorder-specific symptoms (e.g., attentional bias to negative stimuli, excessive/inappropriate negative thoughts, hyperarousal, anhedonia, emotional blunting). Such dysregulation is believed to result from an imbalance between top-down ‘emotion regulating’ (ER) frontal nodes central in inhibitory control of bottom-up subcortical ‘emotion-generating’ (EG) nodes in a Fronto-Limbic Affect Regulation and Emotional Salience (FLARES) network. Therefore, successful treatment would be expected to ‘normalize’ neurofunctional disturbances in the FLARES network, which can be measured with fMRI and more distal units of brain function -- event-related potentials (ERPs) from electroencephalography, startle potentiation from electromyography (EMG), neurocognitive performance, and use of regulation strategies in daily life via self-report. The overarching objective of the proposed study is to understand how, when, and where CBT works and for whom to tailor treatment to improve clinical outcome. Without precisely identified “targets” and “predictors” of change, CBT response will continue to be unpredictably varied with few achieving meaningful clinical improvement placing them at risk for relapse and recurrence. Our proposal builds on published data from our lab and others and Preliminary Data which shows FLARES function, as assayed with fMRI, ERPs, EMG, and behaviors, is sensitive to change following CBT. Importantly, both baseline fMRI and non-fMRI units of brain-behavioral measures predict CBT response better than baseline clinical measures. Such knowledge can lead to more precise interventions aimed at capitalizing on ‘strengths’ or improving ‘deficits’ that may each exist before CBT and/or explain why CBT does not work for some patients. The dual development of fMRI (‘mechanistic’) and non-fMRI (‘pragmatic’) predictors and indices of therapeutic change is aimed at advancing precision medicine while increasing the clinical utility of ‘biomarkers’ in the outpatient setting. With this objective, we propose to employ well-validated paradigms to test ER and EG in the context of negative stimuli, reward processes, and fear systems in MDD and gSAD to delineate common and disorder-specific mechanisms of change and predictors of CBT outcome. We will enroll 200 patients: 100 MDD (without comorbid gSAD), 100 gSAD (without comorbid MDD) and randomize them to 12 weeks of manualized CBT or 12 weeks of ‘placebo’ psychotherapy (supportive therapy) (1:1 ratio). Multiple units of FLARES function will be collected in all patients before (Week 0), during (midway/Week 6) and after treatment (Week 12) to ascertain CBT ‘dose’ effects, and in 40 healthy controls for comparison. Pre-CBT predictors based on binary (responder/non-responder status) and continuous (extent of change) outcomes will be examined midway (Week 6), immediately after treatment (Week 12), and at 6-month follow-up.