Causal Role of Medial Prefrontal Neural Activity in Self-Agency in Schizophrenia

项目摘要 精神分裂症患者（SZ）表现出严重的自我行为缺陷（即，作为代理人的经历 一个人自己的思想和行为），这直接有助于削弱精神病症状和扭曲现实 监视（即，定义为区分自生成信息和外部导出信息）。 目前的药物治疗不足，高达40%的SZ仍有症状，因此迫切需要 了解自我代理缺陷的神经生物学基础，我们认为这会导致精神病患者的精神病经历， SZ.在这里，我们第一次测试了一个新的因果认知和神经生物学模型的基础自我代理 目的是在深圳开发新的有效治疗方法。特别是，我们检查是否产生 自我代理的经验是由对结果做出可靠预测的基本能力驱动的 一个人自己的自发行为。这种自我预测能力对于成功的编码和记忆至关重要 在现实监控期间检索自己的思想和行动，以实现准确的自我判断 (i.e.,自我生成信息的准确识别）。这种自我预测能力对说话也很关键 监控是指我们不断地将我们说话时听到的与我们期望听到的进行比较。之前 研究表明，内侧前额叶皮层（mPFC）是一种潜在的神经基质， 在言语监测期间的较低水平的自我预测，以及在现实中的较高水平的自我判断 健康对照组（HC）。在这里，我们现在测试mPFC活动是否可以因果调节这种自我调节， 预测能力，影响现实和言语监测两个不同的任务上的自我代理。我们提出了一个 纵向随机对照试验，HC和SZ被分配到5个每日活动高- 频率10 Hz经颅磁刺激（TMS）以增加mPFC活性或假TMS。我们使用 脑磁图成像（MEGI）的重复测量，以分析自我行为背后的神经活动 在以下时间点从TMS前后的现实和言语监测任务：（i）基线，（ii）TMS后近端 (i.e.,就在TMS干预之后），和（iii）远端TMS后（即，TMS干预后1周）。具体 目的是描述MEGI，近端和远端机制的积极10 Hz TMS如何调节mPFC HC和SZ中的活动，以诱导现实和言语中自我能动性的神经网络和行为变化 监测任务，与基线和假手术相比。总的假设是，高频TMS将 增加mPFC兴奋性和增强自我预测，以提高不同言语任务的自我能动性， 现实监控如果成功，该项目将建立mPFC作为TMS治疗的新生物靶点， SZ，并将表明，mPFC提供了一个单一的基础，自我机构的依赖自我预测驱动。的 长期目标是描述改善关键性疾病的持久性和普遍性机制， 经颅磁刺激后的自我能动能力可以概括为认知、症状和生活质量的改善 为将来TMS治疗的发展。

Project Summary Patients with schizophrenia (SZ) show severe deficits in self-agency (i.e., the experience of being the agent of one's own thoughts and actions), that directly contribute to debilitating psychotic symptoms and distort reality monitoring (i.e., defined as distinguishing self-generated information from externally-derived information). Current medications are inadequate with up to 40% of SZ remaining symptomatic, thus compelling the need to understand the neurobiology underlying self-agency deficits which we believe drives psychotic experiences in SZ. Here, we test for the first time a novel causal cognitive and neurobiological model underlying self-agency with the aim of developing new effective treatments in SZ. In particular, we examine whether the resulting experience of self-agency is driven by the fundamental ability to make reliable predictions about the outcomes of one's own self-generated actions. This self-prediction ability is critical for the successful encoding and memory retrieval of one's own thoughts and actions during reality monitoring to enable accurate self-agency judgments (i.e., accurate identification of self-generated information). This self-prediction ability is also critical for speech monitoring where we continually compare what we hear while we speak with what we expect to hear. Prior studies have shown that the medial prefrontal cortex (mPFC) is a potential neural substrate that mediates both lower-level self-predictions during speech monitoring, and higher-level self-agency judgments during reality monitoring in healthy controls (HC). Here, we now test whether mPFC activity can causally modulate this self- prediction ability to impact self-agency on two different tasks of reality and speech monitoring. We propose a longitudinal randomized controlled trial in which HC and SZ are assigned to 5 daily sessions of either active high- frequency 10Hz transcranial magnetic stimulation (TMS) to increase mPFC activity or to sham TMS. We use repeated measures of magnetoencephalography imaging (MEGI) to assay neural activity underlying self-agency on reality and speech monitoring tasks from pre-to-post TMS at time-points: (i) baseline, (ii) proximal post-TMS (i.e., right after TMS intervention), and (iii) distal post-TMS (i.e., 1 week after TMS intervention). The specific aims are to delineate with MEGI, proximal and distal mechanisms of how active 10Hz TMS modulates mPFC activity in HC and SZ to induce neural network and behavioral changes in self-agency in reality and speech monitoring tasks, compared to baseline and sham. The overall hypothesis is that high frequency TMS will increase mPFC excitability and enhance self-predictions to improve self-agency on distinct tasks of speech and reality monitoring. If successful, this project will establish mPFC as a new biological target for TMS therapies in SZ, and will show that mPFC provides a unitary basis for self-agency driven by reliance on self-predictions. The long-term objective is to delineate mechanisms of durability and generalizability of how improvements in critical self-agency abilities after TMS of mPFC, can generalize to improvements in cognition, symptoms and life quality in SZ for future TMS treatment development.