Repetitive Transcranial Magnetic Stimulation as a Probe of Episodic Memory Neurocircuitry in Schizophrenia

项目摘要 精神分裂症是一种与独立生活和功能障碍有关的致残性疾病。 情景记忆(EM)是精神分裂症患者常见的一个重要认知领域。前楔形核 是EM电路中的关键节点，它与其他EM相关结构具有相互连接，包括 背外侧前额叶皮质(DLPFC)和前扣带回皮质(ACC)。楔前叶的变化 精神分裂症患者的连通性与EM缺陷有关。然而，确切的机制是通过 楔前叶功能障碍与EM损害的关系尚不清楚。迫切需要更好地定义 神经基础服务于这一临床现象。 重复性经颅磁刺激(RTMS)能够直接操纵局部大脑的激活 以及间接操纵目标的相关神经网络中的激活。这创造了一个机会 在大脑回路中影响不同的生理变化，澄清神经结构中断和 精神疾病方面的网络。我们的目标是证明rTMS与楔前区接触，并 阐明精神分裂症患者EM功能障碍的机制。我们的中心假设是rTMS将 调节楔前叶的功能激活和与相关EM电路的连接。我们还将 检查rTMS对EM性能的影响。我们的长期目标是为调查人员提供一条途径 认为楔前叶是治疗精神分裂症EM功能障碍的潜在靶点。 在目标1中，我们将展示针对楔前叶的rTMS对功能激活的影响。 在执行扫描仪内EM任务期间。我们假设rTMS会调节楔前叶的活动， 作为rTMS目标参与的证据。我们预计，与假刺激相比，1赫兹的rTMS 将降低激活，而20赫兹rTMS将增加楔前叶的激活。在目标2中，我们将 展示rTMS对精神分裂症患者楔前功能连通性的影响。我们 假设rTMS将改变楔前叶和相关脑区之间的静息状态功能连接 EM电路，特别是DLPFC和ACC。我们预计，与假刺激相比，功能性刺激 对1赫兹rTMS的反应，楔前叶、DLPFC和ACC之间的静态连通性将降低 并增加对20赫兹rTMS的响应。在目标3中，我们将演示rTMS对EM性能的影响 精神分裂症患者。我们假设，楔前rTMS将与EM性能的变化有关。 我们预计，与假刺激相比，1赫兹的rTMS会损害性能，而20赫兹的rTMS会 提高扫描仪内EM任务期间的性能。这项研究将提供rTMS调节的证据 精神分裂症患者楔前叶内的活动及其相关的EM回路。这将通知您 随后针对楔前叶的临床试验用于治疗精神分裂症的EM功能障碍。

Project Abstract Schizophrenia is a disabling illness associated with impairments in independent living and functioning. Episodic memory (EM) is an important cognitive domain commonly impaired in schizophrenia. The precuneus is a key node in EM circuitry that has reciprocal connections with other EM relevant structures, including the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC). Alterations in precuneus connectivity are associated with EM deficits in schizophrenia. However, the exact mechanisms by which precuneus dysfunction is related to EM impairment is unclear. There is a critical need to better define the neural underpinnings subserving this clinical phenomenon. Repetitive transcranial magnetic stimulation (rTMS) enables direct manipulation of local brain activation and indirect manipulation of activation in the target's associated neural networks. This creates an opportunity to effect disparate physiologic changes in brain circuits, clarifying the role of disrupted neural structures and networks in psychiatric illness. Our objectives are to demonstrate that rTMS engages the precuneus and to clarify the mechanisms underlying EM dysfunction in schizophrenia. Our central hypotheses are that rTMS will modulate functional activation of the precuneus and connectivity with associated EM circuitry. We will also examine the effect of rTMS on EM performance. Our long-term goal is to provide a path for investigators considering the precuneus as a potential target for the treatment of EM dysfunction in schizophrenia. In Aim 1, we will demonstrate the impact of rTMS targeting the precuneus on functional activation during performance of an in-scanner EM task. We hypothesize that rTMS will modulate precuneus activity, serving as evidence of rTMS target engagement. We expect that, compared to sham stimulation, 1 Hz rTMS will decrease activation and 20 Hz rTMS will increase activation of the precuneus. In Aim 2, we will demonstrate the effects of rTMS on precuneus functional connectivity in individuals with schizophrenia. We hypothesize that rTMS will alter resting state functional connectivity between the precuneus and associated EM circuitry, specifically the DLPFC and the ACC. We expect that, compared to sham stimulation, functional connectivity at rest between the precuneus, the DLPFC, and the ACC will decrease in response to 1 Hz rTMS and increase in response to 20 Hz rTMS. In Aim 3, we will demonstrate the effect of rTMS on EM performance in schizophrenia. We hypothesize that precuneus rTMS will be associated with changes in EM performance. We expect that compared to sham stimulation, 1 Hz rTMS will impair performance and that 20 Hz rTMS will improve performance during an in-scanner EM task. This study will provide evidence that rTMS modulates activity within the precuneus and associated EM circuitry in individuals with schizophrenia. This will inform subsequent clinical trials targeting the precuneus for the treatment of EM dysfunction in schizophrenia.