Real-time fMRI Neurofeedback as a Tool to Mitigate Auditory Hallucinations in Patients with Schizophrenia

这是一份重新提交的申请，最初是为了响应RFA-MH-16-406，由R61和 R33相位。听觉言语幻觉（AH）长期以来一直是精神分裂症（SZ）的标志， Andreasen和Flaum 1991; DSM-IV）。它们很难用现有的 治疗方案。在这里，我们提出，神经反馈旨在调节上级颞回（STG） 激活不仅会导致STG中的激活变化，还会导致默认模式网络中的变化 (DMN)（R61），以及AH（R33）的减少，大脑和临床变化将相关 （R33）。当前提案的理论框架是一个AH模型，该模型假设AH的结果来自于 包括STG、内侧前额叶皮层（MPFC）和后额叶皮层在内的区域网络异常 扣带皮层（PCC），后两个区域是DMN的核心内侧枢纽，与自我参照有关 处理.该模型得到了理论论文Northoff和Qin 2010，Alderson-Day，2016和实验论文的支持。 证据Gur 1995，Liddle 1992，Dierks 1999以及我们的初步数据（PD）。 在R61和R33中，我们将在rt-fMRI干预中研究SZ耐药AH患者 在两个臂中，任务和rt-fMRI会话结构将是相同的。的 SZ干预组将从STG接收反馈，而SZ假手术组将从 运动皮层此外，2个功能性fMRI任务将检查rt-fMRI神经反馈和 大脑反应的模拟功能磁共振成像 在R61中，我们将48名SZ患者随机分配至SZ干预组（n=24）或SZ假手术-rtfMRI组 （n=24）。STG靶向神经反馈预计会引起AH（STG）相关脑区的变化 和DMN）。R61 GO标准将是STG中的BOLD信号减小，并且 SZ干预组中，rt-fMRI反馈后MPFC-PCC之间的静息状态连接减少。 在R33中，SZ干预组（随机n=52）将接受5次rt-fMRI反馈靶向 SZ-sham组（随机n=52）接受5次sham-rt-fMRI检查。根据我们的PD，我们预测 针对STG的rt-fMRI反馈将降低AH，这反过来又与STG的降低相关 激活和在DMN连接中（即，脑改变在R61中实现，并在R33中复制）在SZ- 仅干预组。五次rt-fMRI反馈将解决大脑剂量反应的问题， 临床水平。rt-fMRI神经反馈和假rt-fMRI对AH的影响（主要结局）， 妄想、阴性症状和工作记忆（WM）（探索性结局）的评估 临床和神经心理学测量。在探索性目的中，基于现有文献Garrity 2007; Whitfield-Gabrieli 2009; Rotarska-Jagiela 2010，我们预测妄想、阴性症状和WM评分的改善， 只有针对STG的rt-fMRI后神经反馈，而不是假rt-fMRI后。

This is a resubmission application, originally in response to RFA-MH-16-406 and consists of R61 and R33 phases. Auditory verbal hallucinations (AH) have long been a hallmark of schizophrenia (SZ) and are one of its major diagnostic features Andreasen and Flaum 1991; DSM-IV). They are difficult to manage with existing treatment options. Here, we propose that neurofeedback aimed to regulate the superior temporal gyrus (STG) activation will not only lead to activation changes in the STG, but also to changes in the default mode network (DMN) (R61), as well as to reductions in AH (R33), and that the brain and clinical changes will be correlated (R33). The theoretical framework for the current proposal is an AH model that assumes that AH result from abnormalities in a network of regions including STG, and medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC), the two latter regions are core medial hubs of DMN that are related to self-referential processing. This model is supported by theoretical papers Northoff and Qin 2010, Alderson-Day,2016, and experimental evidence Gur 1995, Liddle 1992, Dierks 1999 as well as our preliminary data (PD). In both R61 and R33 we will study SZ patients with medication resistant AH in the rt-fMRI intervention arm and in the sham-rt-fMRI arm. In both arms, the task and the rt-fMRI session structure will be identical. The SZ-intervention group will receive feedback from the STG while SZ-sham group will receive feedback from the motor cortex. In addition, 2 functional fMRI tasks will examine the effect of rt-fMRI neurofeedback and of sham-rt-fMRI on brain response. In the R61, we will randomly assign 48 SZ patients to either SZ-intervention (n=24) or SZ-sham-rtfMRI (n=24). The STG targeted neurofeedback is predicted to bring changes in brain regions involved in AH (STG and DMN) in SZ-intervention group only. The R61 GO criterion will be BOLD signal reduction in the STG, and resting state connectivity reduction between MPFC-PCC, post rt-fMRI-feedback in SZ-intervention group. In the R33, SZ-intervention group (random n=52) will receive 5 sessions of rt-fMRI feedback targeting STG, while SZ-sham group (random n=52) will receive 5 sham-rt-fMRI sessions. Based on our PD, we predict that rt-fMRI feedback aimed at STG will reduce AH which will be, in turn, associated with reductions in the STG activation and in the DMN connectivity (i.e., brain changes achieved in R61 and replicated in R33) in SZ- intervention group only. Five sessions of rt-fMRI feedback will address the question of dose response at brain and clinical levels. The impact of rt-fMRI neurofeedback and of sham-rt-fMRI on AH (primary outcome), and on delusions, negative symptoms and working memory (WM) (exploratory outcome) will be assessed with clinical and neuropsychological measures. In an exploratory aim, based on the existing literature Garrity 2007; Whitfield-Gabrieli 2009; Rotarska-Jagiela 2010, we predict the improvement in delusions, negative symptoms and in WM score, only post-rt-fMRI neurofeedback targeting the STG and not post-sham-rt-fMRI.