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

项目摘要 精神分裂症(SZ)患者表现出严重的自我反应性缺陷(即，作为精神分裂症的代理人的经历 自己的想法和行为)，这直接导致衰弱的精神症状和扭曲现实 监测(即，定义为区分自产生的信息和来自外部的信息)。 目前的药物是不够的，高达40%的SZ仍然有症状，因此迫切需要 了解潜藏在自我调节缺陷背后的神经生物学，我们认为这种缺陷会在 SZ.在这里，我们首次测试了一种新的基于自我行为的因果认知和神经生物学模型。 目的是在深圳开发新的有效疗法。特别是，我们检查了由此产生的 自我调节的经验是由对结果做出可靠预测的基本能力驱动的 一个人自己产生的行为。这种自我预测能力对于成功的编码和记忆至关重要 在现实监控过程中找回自己的想法和行为，以实现准确的自我机构判断 (即，准确识别自生成的信息)。这种自我预测能力对说话也很重要。 监控我们不断地将我们说话时听到的东西与我们期望听到的东西进行比较。之前 研究表明，内侧前额叶皮质(MPFC)是一种潜在的神经基质，调节两者 言语监控中较低水平的自我预测，现实中较高水平的自我机构判断 健康对照组(HC)的监测。在这里，我们现在测试mPFC活动是否可以因果地调节这种自我 在现实和语音监控这两个不同的任务上影响自我代理的预测能力。我们提出了一个 纵向随机对照试验中，HC和SZ被分配到每天5次的高活性药物治疗中 频率10赫兹经颅磁刺激(TMS)以增加mPFC活性或假TMS。我们用 重复测量脑磁图成像(MEGI)以检测自我调节的神经活动 关于TMS前后的现实和言语监测任务：(I)基线，(Ii)TMS后的近端 (Iii)TMS后远端(即TMS干预后1周)。具体的 目的是用MEGI描述10赫兹TMS如何调节mPFC的近端和远端机制 在现实和言语中，Hc和SZ的活动诱导神经网络和自我调节的行为改变 监控任务，与基线和假任务相比。总体假设是高频TMS将 增加mPFC的兴奋性和增强自我预测，以提高在不同任务中的自我调节能力 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为依赖自我预测驱动的自我代理提供了统一的基础。这个 长期目标是描述关键技术改进的耐久性和通用性机制 MPFC患者TMS后的自我反应能力可概括为认知、症状和生活质量的改善。 为今后TMS治疗的发展做好准备。

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.