Mechanistic clinical trial of individualized tDCS for hallucinations in schizophrenia

绝大多数精神分裂症患者（Sz）的经验听觉言语幻觉（AVH）作为一种症状。 他们疾病的核心特征。AVH可能与增加的攻击性，痛苦，自杀率， 在社交环境中游刃有余约30%的患者对抗精神病药物治疗无效。 患者后听觉/语言区域的生理功能障碍，如左听觉皮层和 颞顶交界处，和前语言区，如左下额叶皮层和前额叶， 被认为在AVH的产生中起主要作用。非侵入性脑刺激（NIBS）方法，如 经颅磁刺激和经颅直流电刺激（tDCS）已显示出在 治疗AVH，但由于缺乏个体化靶向和缺乏靶点， 参与生物标志物。本项目研究个性化高清tDCS（HD-tDCS），一种新颖的 一种比传统tDCS产生更集中电场的技术，用于治疗AVH。抑制 HD-tDCS用于检验关于两个靶点的假设，后（PostT）和前（AntT） 听觉/语言区域，以及它们在影响感官特征（例如响度）和评估方面的作用 AVH的特征（例如显著性）。参与者随机接受假手术、活性药物 常规、主动PosT或主动AntT刺激。个体化靶向和标准化给药是 通过对每个参与者大脑中产生的电场进行MR引导的计算建模来实现 解剖学此外，通过测量治疗前/治疗后的变化来验证功能性目标接合， PostT和AntT内和之间的静息状态功能连接（rsFC）升高。病原学生物标志物 跟踪与AVH相关的源监测、预测误差和神经生理异常的方法， 还测试了治疗前/后。该项目建立在候选人的基础听觉背景上 神经生理学，精神病和非侵入性脑刺激的临床专业知识，以及最近的 基础神经影像学和神经生理学研究金培训。申请书提出了5年的职业生涯 发展计划，将提供必要的和额外的培训，在基础科学的AVH，临床试验， 设计与实现，平移神经影像学，平移神经生理学，无创脑 激励和学术职业技能。获得的技能将使候选人过渡到一个 独立的以患者为导向的研究人员，研究个体化非侵入性脑刺激治疗 神经精神症状和紊乱的症状。在项目期间，他将直接与Sz，AVH， fMRI、rsFC、aEP、计算建模、NIBS和临床试验设计。拟议临床试验的结果 这项试验将指导未来使用个体化靶向和靶向治疗神经精神疾病的新干预措施。 参与生物标志物。此外，研究结果将有可能减轻疾病带来的负担， 持续性AVH在Sz。

The large majority of patients with schizophrenia (Sz) experience auditory verbal hallucinations (AVH) as a core feature of their disorders. AVH can be associated with increased aggression, distress, suicide rates, and difficulty navigating the social environment. They are refractory to treatment with antipsychotics in ~30% of patients. Physiological dysfunction of posterior auditory/language regions, such as left auditory cortex and temporoparietal junction, and anterior language regions, such as left inferior frontal cortex and anterior insula, is thought to play a major role in generating AVH. Noninvasive brain stimulation (NIBS) approaches such as transcranial magnetic stimulation and transcranial direct current stimulation (tDCS) have shown promise in treating AVH but have been difficult to reproduce often due to lack of individualized targeting and lack of target engagement biomarkers. This project investigates individualized high-definition tDCS (HD-tDCS), a novel technique that produces a more focal electrical field than conventional tDCS, for treatment of AVH. Inhibitory HD-tDCS is used to test hypotheses regarding two targets, posterior (PosT) and anterior (AntT) auditory/language regions, and their role in influencing the sensory features (e.g. loudness) and evaluative features (e.g. salience) of AVH, respectively. Participants are randomized to receive either sham, active conventional, active PosT, or active AntT stimulation. Individualized targeting and standardized dosing is achieved by MR-guided computational modeling of electrical fields produced in each participant’s brain anatomy. Furthermore, functional target engagement is verified by measuring pre/post treatment changes in elevated resting state functional connectivity (rsFC) within and between PosT and AntT. Etiological biomarkers that track source monitoring, prediction error, and neurophysiological abnormalities associated with AVH are also tested pre/post treatment. The project builds on the candidate’s background in basic auditory neurophysiology, clinical expertise in psychotic disorders and noninvasive brain stimulation, and more recent fellowship training in basic neuroimaging and neurophysiology. The application proposes a 5-year career development program which will provide essential and additional training in basic science of AVH, clinical trials design and implementation, translational neuroimaging, translational neurophysiology, noninvasive brain stimulation, and academic career skills. The acquired skills will allow the candidate to transition into an independent patient-oriented researcher investigating individualized noninvasive brain stimulation for treatment of neuropsychiatric symptoms and disorders. During the project he will work directly with experts in Sz, AVH, fMRI, rsFC, aEPs, computational modeling, NIBS, and clinical trial design. The results of the proposed clinical trial will guide future novel interventions for neuropsychiatric disorders using individualized targeting and target engagement biomarkers. In addition the findings will have the potential to relieve the burden of illness imposed by persistent AVH in Sz.