Mechanistic clinical trial of individualized tDCS for hallucinations in schizophrenia

绝大多数精神分裂症(Sz)患者都会出现幻听(AVH) 他们精神障碍的核心特征。AVH可能与更多的攻击性、痛苦、自杀率和 很难适应社会环境。约30%的人对抗精神病药物治疗无效 病人。后部听觉/语言区域的生理性功能障碍，如左听皮层和 颞顶交界区和前部语言区，如左下额叶皮质和前脑岛， 被认为在AVH的产生中起着重要作用。非侵入性脑刺激(NIB)方法，如 经颅磁刺激和经颅直流电刺激(Tdcs)在 治疗动静脉曲张，但由于缺乏个体化靶点和缺乏靶点，常常难以复制 参与生物标记物。本课题研究的是一种新型的个性化高清tdcs(HD-tdcs) 产生比传统tdcs更集中的电场的技术，用于治疗AVH。抑制性 HD-tDCS用于检验关于后方(Post)和前方(AntT)这两个目标的假设 听觉/语言区域及其在影响感觉特征(如响度)和评价性特征中的作用 AVH的特征(例如，显著程度)。参与者被随机分成两组，分别接受虚假的、积极的 常规的、主动的后刺激或主动的ANT刺激。个性化的靶向和标准化的剂量是 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，通过测量治疗前后的变化来验证功能靶点的参与 POST和AntT内部和之间的静息状态功能连接性(RsFC)升高。病原学生物标志物 与AVH相关的跟踪源监测、预测误差和神经生理异常是 也测试了治疗前和治疗后。该项目基于候选人在基础听觉方面的背景 神经生理学，精神障碍和非侵入性脑刺激方面的临床专业知识，以及最近 基础神经影像和神经生理学方面的团契培训。这份申请书建议的职业生涯为5年。 开发计划，将提供AVH基础科学、临床试验方面的基本和额外培训 设计和实施，翻译神经成像，翻译神经生理学，非侵入性脑 激励和学术职业技能。所获得的技能将使应聘者能够过渡到 独立的以患者为中心的研究人员研究个体化无创脑刺激治疗 神经精神症状和障碍。在项目期间，他将直接与深圳、AVH、 FMRI、rsFC、AEP、计算建模、NIBS和临床试验设计。建议的临床试验结果 试验将指导未来使用个性化靶向和靶向对神经精神障碍进行新的干预 参与生物标记物。此外，这些发现将有可能减轻强加的疾病负担。 在深圳被持久的AVH。

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.