Neuroimaging studies of mechanism, modulation, and plasticity of cognitive impairment in first-episode schizophrenia

摘要 认知障碍是精神分裂症的核心、难治性症状，具有强烈的 对功能结局的影响。尤其是工作记忆的缺陷，这是 更高层次的认知，已经在精神分裂症中得到了很好的证明。然而，机制 人们对这些赤字背后的原因知之甚少。功能磁共振连通方法的最新进展 提供在网络层面更好地了解工作记忆功能障碍的机会。 了解认知障碍，特别是早期阶段的认知障碍，可以加速新的 个性化治疗。事实上，功能连接磁共振越来越多地被用来精确地选择 经颅磁刺激(TMS)的靶点。在拟议的一系列神经成像研究中， 分析，我们的目标是(1)确定工作记忆损伤背后的电路级机制 在首发精神分裂症患者中，(2)调节和测量目标网络中的活动 (3)确定TMS的反应性是否可以预测纵向结果。 这些目标与NIMH的战略研究目标直接一致，因为(1)它们定义了 复杂行为的机制和(2)包括为期一年的跟踪评估，以及 因此，在疾病的早期阶段绘制其进展图。为了实现这些目标，我们设计了成像和 脑刺激实验，将使我们能够研究休息任务动态之间的工作记忆- 相关的大脑网络。目标1将结合功能连通性和图论来描述 任务相关网络的分离-整合动力学，如前顶控制网络和 默认模式网络；并确定首发患者与健康人的不同程度 这些网络措施中的控制。它还将把这些差异与行为表现联系起来。目标2 将利用TMS来调节作为首发患者认知障碍基础的网络中的活动 患有精神分裂症。重要的是，我们将使用组合来为每个患者个性化目标区域 休息和基于任务的连接。然后我们将比较TMS前后的行为和 连通性测量并确定TMS引起的连通性变化程度如何预测 行为上的改善。最后，目标3将确定TMS诱导的可塑性的程度 与患者在一年内纵向测量的功能结果有关。PI的主线 培训目标是(1)获得TMS理论和实践方面的专业知识，(2)开发 在精神分裂症的临床和认知方面的专业知识，以及(3)扩展他在连接方面的技能 方法通过图论方法，并将这些技术应用于fMRI数据。

ABSTRACT Cognitive impairment is a core, treatment-resistant symptom of schizophrenia that has strong influence on functional outcome. In particular, deficits in working memory, an important component of higher order cognition, have been well documented in schizophrenia. Nevertheless, mechanisms underlying these deficits are poorly understood. Recent advances in functional MRI connectivity methods provide an opportunity to better understand working memory dysfunction at the network level. Understanding cognitive impairment especially in its early phase could accelerate the development of new personalized treatments. Indeed, functional connectivity MRI is increasingly utilized to precisely select targets for Transcranial Magnetic Stimulation (TMS). In the proposed series of neuroimaging studies and analyses, our goals are to (1) identify circuit-level mechanisms that underlie working memory impairment in first-episode patients with schizophrenia, (2) modulate and measure activity in target networks that are disrupted in these patients, and (3) determine if TMS responsiveness predicts longitudinal outcomes. These goals are directly in line with NIMH’s strategic research objectives in that (1) they define the mechanism of a complex behavior and (2) they include a follow-up assessment over a 1-year period, and thus chart progression of an illness in its early phase. To achieve these goals, we designed imaging and brain stimulation experiments that will allow us to study rest-task dynamics between working memory- related brain networks. Aim 1 will combine functional connectivity and graph theory to characterize the segregation-integration dynamics of task-related networks such as frontoparietal control network and default mode network; and determine the degree to which first-episode patients differ from healthy controls in these network measures. It will also link these differences to behavioral performance. Aim 2 will utilize TMS to modulate activity in networks that underlie disrupted cognition in first-episode patients with schizophrenia. Importantly, we will individualize the target region for each patient using a combination of resting and task-based connectivity. We will then compare pre- and post-TMS behavioral and connectivity measures and determine how the degree of TMS-induced change in connectivity predicts improvement in behavior. Finally, Aim 3 will determine the degree to which TMS-induced plasticity is associated with functional outcome measured longitudinally over one year in patients. The PI’s main training goals are (1) to acquire expertise on theoretical and practical aspects of TMS, (2) to develop expertise on clinical and cognitive aspects of schizophrenia, and (3) extend his skills in connectivity methods via graph theoretical approaches and apply these techniques on fMRI data.