Reducing neural perseveration through closed loop real time fMRI neurofeedback to alleviate depressive symptoms

摘要 抑郁症是全球残疾的主要原因，目前对抑郁症的治疗策略， 一半的患者没有明显的治疗获益。本R61/R33提案是根据 NIMH战略目标3.1：“基于基因组学、神经科学的发现开发新的干预措施 和行为科学。”我们将测试一种新的心理治疗策略的有效性，第一个实时功能磁共振成像 神经反馈疗法，使用基于云的模式分类来解码患者的注意力状态， 基于这种状态动态地调节任务刺激（在“闭环”中），而不是基于 通过跟踪局部感兴趣区域中的激活的单独的计量器传送反馈。 这个R61/R33的总体目标是测试闭环实时fMRI神经反馈， 专门针对我们假设的抑郁症的注意力机制（即，负性神经持续 降低抑郁症的严重程度。这项研究将是第一个实时fMRI对 负面注意力偏差 在R61阶段60，年龄18-65岁的MDD受试者将被随机分配接受以下治疗： 主动神经反馈（n=30）与假反馈（n=30）。我们有三个目标：1）建立神经靶点 使用活动与假手术中负性注意状态的神经持续性的前后变化的参与 神经反馈; 2）确定减少负性神经持续性所需的最低“剂量”训练 3）（探索性）建立行为目标的参与，在一个 眼注视任务比较主动与假神经反馈。 R61的Go/No-Go标准：在神经持续性中至少存在中等效应量（Cohen d ≥ 0.4） 与假NF相比，真实的降低。我们的初步研究（Mennen et al 20）发现效应量为0.83。因此 该标准具有临床意义和现实性，并将证明目标接合。 在R33阶段，80例年龄为18-65岁的MDD受试者将被随机分配至活性药物治疗组， 神经反馈（n=40）与假反馈（n=40）。我们有三个目的：1）进行一项随机对照研究， 比较实时神经反馈与假手术对抑郁症结局的影响; 2）确定 在R61期建立的神经持续性标记物与R61期神经持续性标记物减少之间的关系。 抑郁症状; 3）通过比较MADRS评分确定治疗效果的持久性 3个月随访时，接受真实的NF治疗的患者与接受假NF治疗的患者相比。 冲击该项目将建立实时功能磁共振成像神经反馈作为减少神经持续性的一种手段， 作为MDD的治疗方法。这一系列研究的结果将为反馈策略提供信息， 提高对负性注意和抑郁症神经机制的理解。我们的云平台 将易于扩展，并允许传播到数千家医院和研究机构。

ABSTRACT Current treatment strategies for major depression, the leading cause of disability worldwide, leave more than half of patients with no meaningful treatment benefit. This R61/R33 proposal was developed in keeping with NIMH Strategic Objective 3.1 to “Develop new interventions based on discoveries in genomics, neuroscience and behavioral science.” We will test the efficacy of a new psychotherapeutic strategy, the first real-time fMRI neurofeedback therapy to use cloud-based pattern classification to decode the patient’s attentional state and dynamically modulate task stimuli (in a “closed loop”) based on this state, rather than the standard approach of conveying feedback through a separate gauge that tracks activation in a localized region of interest. The overall objective of this R61/R33 is to test whether closed-loop real-time fMRI neurofeedback that specifically targets our hypothesized attentional mechanism of depression (i.e., neural perseveration of negative states) reduces depression severity. This study will be the first dose-finding test of real-time fMRI effect on negative attention bias. During the R61 Phase 60 participants with MDD ages 18-65 years will be randomly assigned to treatment with active neurofeedback (n=30) vs sham feedback (n=30). We have three aims: 1) Establish neural target engagement using pre-post change in neural perseveration of negative attentional states in active vs sham neurofeedback; 2) Determine the lowest “dose” of training necessary to reduce neural perseveration of negative states; 3) (Exploratory) Establish behavioral target engagement using perseveration on negative images in an eye gaze task comparing active vs sham neurofeedback. Go/No-Go Criteria for R61: There will be at least a medium effect size (Cohen’s d ≥ 0.4) in neural perseveration reduction comparing real to sham NF. Our pilot study (Mennen et al 20) found an effect size of 0.83. Therefore this criterion is both clinically meaningful and realistic and will demonstrate target engagement. During the R33 Phase 80 participants with MDD ages 18-65 will be randomly assigned to treatment with active neurofeedback (n=40) vs sham feedback (n=40). We have three aims: 1) To conduct a randomized controlled trial (RCT) to compare the effect of real-time neurofeedback vs. sham on depression outcome; 2) To determine the relationship between the markers of neural perseveration established in the R61 phase and the reduction in depressive symptoms; and 3) To determine the durability of the treatment effect by comparing MADRS scores at 3 months followup between those who received real as compared to sham NF. Impact. This project will establish real-time fMRI neurofeedback as a means of reducing neural perseveration of negative states as a treatment for MDD. Results from this line of research will inform feedback strategies and improve understanding of neural mechanisms underlying negative attention and MDD. Our cloud based platform would be readily scalable and allow dissemination to thousands of hospital and research facilities.