Targeting the Auditory Control Network with Auditory Control Enhancement (ACE) in Schizophrenia

项目总结/摘要 与精神分裂症（Sz）相关的幻听是普遍的、使人衰弱的和令人不安的。 不幸的是，他们也很难治疗-幻听持续约25%的情况下，尽管 药物治疗1和认知症状的治疗（症状与全球 功能）是适度的最好的。我们提出了一种新颖的，廉价的，非侵入性的干预措施，以解决 治疗难治性症状，Sz.幻听和认知障碍 精神分裂症不是独立的。两者都与额颞叶的系统水平功能障碍有关 听觉控制网络，包括颞顶连接（TPJ）中的听觉/言语感知区，以及 腹外侧前额叶皮层（VLPFC）的认知/行为控制系统。VLPFC传统上抑制和 重新归因于大多数人的感知错误陈述2.对于精神分裂症患者， 认知控制使这成为不可能。我们实验室的数据表明，听觉控制网络功能障碍可能 是疾病早期病因学的核心3.听觉控制增强（ACE）旨在改善 听觉控制网络的功能，从而增加对假听觉系统活动的抑制， 颞顶皮层和减少幻听ACE结合了经过时间考验的心理治疗 使用经颅直流电的有针对性的非侵入性脑刺激的行为训练计划 刺激（tDCS）。我们的试点数据证明了行为训练计划的有效性， 与听觉控制网络的tDCS治疗难治性听觉障碍的协同作用 精神分裂症的幻觉为了进一步开发ACE用于疗效试验，我们计划研究神经标记物 两个假对照实验中的目标接合。目标1将确定右vlPFC的tDCS是否 在MRI期间，左TPJ（阳极）和左TPJ（阴极）改变电场测量和血氧水平依赖性 在刺激期间的（BOLD）响应，以证明tDCS电流和BOLD的标志物随时间波动。 感应电流，这些波动在空间上与计算机模型一致。目标2将审查以下方面的可行性： 受试者保留和ACE设盲。目标3将检查ACE改变行为的程度， 使用神经振荡和脑血的靶接合的神经生理学和血液动力学标记物 流量（CBF）测量。试点数据显示了我们的目标的可行性，并提供了初步证据，ACE 用精神病症状评定量表评估对幻听的强烈和持久影响 与幻听相关的认知因素的变化与 认知控制的神经振荡测量的变化。ACE代表了一种新颖的变革性干预措施 具有持久的影响，有可能改变精神分裂症的治疗，并大大改善 对受折磨的人的结果。

Project Summary/Abstract Auditory hallucinations associated with schizophrenia (Sz) are pervasive, debilitating, and disturbing. Unfortunately, they are also difficult to treat – auditory hallucinations persist in about 25% of cases despite pharmacotherapy1 and treatment of cognitive symptoms (the symptoms most strongly related to global functioning) is modest at best. We propose a novel, inexpensive, and noninvasive intervention to address treatment-refractory symptoms, a critical need in Sz. Auditory hallucinations and impaired cognition in schizophrenia are not independent. Both are associated with system-level dysfunction of the fronto-temporal auditory control network, comprising auditory/verbal perceptual areas in temporoparietal junction (TPJ) and cognitive/behavioral control systems in ventrolateral prefrontal cortex (VLPFC). VLPFC traditionally inhibits and reattributes perceptual misrepresentations in most people2. For those with schizophrenia, impairment of auditory cognitive control makes this impossible. Data from our lab suggest that auditory control network dysfunction may be central to the early etiology of the disorder3. Auditory control enhancement (ACE) is designed to improve auditory control network function, thereby increasing inhibition of spurious auditory system activity in temporoparietal cortex and reducing auditory hallucinations. ACE combines a time-tested psychotherapeutic behavioral training program with targeted non-invasive brain stimulation using transcranial Direct Current Stimulation (tDCS). Our pilot data demonstrate the effectiveness of the behavioral training program and synergistic effects with tDCS of the auditory control network for treating treatment-refractory auditory hallucinations in schizophrenia. To further develop ACE for efficacy trials, we plan to investigate neural markers of target engagement in two sham-controlled experiments. Aim 1 will determine whether tDCS of right vlPFC (anode) and left TPJ (cathode) during MRI alters electric field measures and blood oxygenation level dependent (BOLD) response during stimulation to demonstrate that markers of tDCS current flow and BOLD fluctuate with induced current, and these fluctuations align spatially with computer models. Aim 2 will examine feasibility of subject retention and blinding for ACE. Aim 3 will examine the degree to which ACE modifies behavioral, neurophysiological, and hemodynamic markers of target engagement using neural oscillatory and cerebral blood flow (CBF) measures. Pilot data show feasibility of our aims and provide preliminary evidence that ACE has strong and lasting effects on auditory hallucinations assessed with the psychotic symptoms rating scale (PSYRATS), and that changes in cognitive factors associated with auditory hallucinations strongly correlate with changes in neural oscillatory measures of cognitive control. ACE represents a novel, transformative intervention with long-lasting effects that has the potential to change the treatment of schizophrenia and vastly improve the outcome for afflicted individuals.