Transdiagnostic Brain-Behavior Profiling to Enhance Cognitive Behavioral Therapy Response

严重抑郁障碍(MDD)和广泛性社交焦虑障碍(GSAD)是普遍存在的主要公众 健康问题。这些障碍的特征是情绪失调，无法或效率低下 调节反映在常见和特定障碍症状中的消极和积极情绪(例如，注意 偏向负面刺激、过度/不适当的负面想法、过度唤醒、快感缺乏、情绪化 钝化)。这种失调被认为是自上而下的“情绪调节”失衡的结果。 (ER)额叶节点在自下而上的皮层下‘情绪产生’(EG)节点的抑制控制中起中心作用。 额缘情绪调节与情绪突显(闪光)网络。因此，成功的治疗 有望使耀斑网络中的神经功能障碍“正常化”，这可能是 用fMRI和更远端的脑功能单位测量-事件相关电位(ERPs)来自 脑电、肌电(EMG)的惊吓增强、神经认知功能和 通过自我报告在日常生活中使用调节策略。拟议研究的首要目标是 了解CBT如何、何时和在哪里起作用，以及为谁量身定做治疗以改善临床结果。 如果没有准确地确定变化的“目标”和“预测因素”，CBT的反应将继续是 不可预测的变化，几乎没有取得有意义的临床改善的人，这使他们面临复发和 复发。我们的建议建立在我们实验室和其他机构发布的数据以及初步数据的基础上，这些数据表明 通过fMRI、ERPs、EMG和行为学检测，Flres功能对CBT后的变化很敏感。 重要的是，基线功能磁共振成像和脑行为测量的非功能磁共振成像单元都能更好地预测CBT反应 而不是基线临床措施。这些知识可以导致旨在利用资本的更精确的干预措施 和/或解释为什么CBT不起作用 一些病人。功能性磁共振成像(机械性)和非功能性磁共振成像(实用性)预测指标的双重发展 旨在推进精准医学的同时增加临床应用 门诊环境中的“生物标记物”。为了实现这个目标，我们建议使用经过充分验证的范例来 在MDD和GSAD的负面刺激、奖励过程和恐惧系统的背景下测试ER和EG，以 描述共同的和特定于疾病的改变机制和CBT结果的预测因素。我们将招收 200名患者：100名MDD(未合并GSAD)、100名GSAD(未合并MDD)，并将他们随机分为 12周的人工CBT或12周的“安慰剂”心理治疗(支持性治疗)(1：1比例)。多重 所有患者在治疗前(第0周)、治疗期间(中期/第6周)和治疗后收集闪光功能单位。 治疗(12周)以确定CBT的剂量效应，并与40名健康对照组进行比较。CBT前 基于二元(响应者/非响应者状态)和连续(变化程度)结果的预测者将 在中途(第6周)、治疗后即刻(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.