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

首发精神分裂症认知障碍的机制、调节和可塑性的神经影像学研究

• 批准号: 10238002
• 负责人: H Hamdi Eryilmaz
• 金额: $ 18.52万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238002
• 关键词: Adolescence; Anatomy; Area; Attention; Behavior; Behavioral; Brain; Brain imaging; Clinical; Cognition; Cognitive; Complex; Data; Development; Disease; Disease Progression; Dorsal; Environment; Exhibits; Frequencies; Functional Magnetic Resonance Imaging; Goals; Graph; Image; Impaired cognition; Impairment; Individual; Intervention; Lead; Link; Magnetic Resonance Imaging; Measures; Memory impairment; Mentorship; Methodology; Methods; National Institute of Mental Health; Neuronal Plasticity; Neurosciences Research; Onset of illness; Outcome; Outcome Measure; Patients; Performance; Phase; Recovery; Research; Research Personnel; Resistance; Rest; Schizophrenia; Selection for Treatments; Series; Short-Term Memory; Symptoms; Task Performances; Techniques; Training; Transcranial magnetic stimulation; Work; base; cognitive control; cognitive function; connectome; critical period; design; effective intervention; experience; experimental study; first episode schizophrenia; flexibility; follow up assessment; frontier; functional disability; functional outcomes; graph theory; improved; indexing; nervous system disorder; network dysfunction; neuroimaging; neuroregulation; noninvasive brain stimulation; novel; novel strategies; optimal treatments; outcome prediction; personalized medicine; predict responsiveness; response; segregation; skills; targeted treatment; theories; tool; treatment strategy

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.

摘要 认知障碍是精神分裂症的一个核心、难治性症状，具有很强的 对功能结果的影响。特别是工作记忆的缺陷，工作记忆的重要组成部分， 高阶认知，在精神分裂症中有很好的记录。然而，机制 对这些缺陷的根本原因知之甚少。功能磁共振成像连接方法的研究进展 提供了一个机会，以更好地了解工作记忆功能障碍的网络水平。 了解认知障碍，特别是在其早期阶段，可以加速新的发展， 个性化治疗。事实上，功能连接MRI越来越多地用于精确选择 经颅磁刺激（TMS）的目标。在拟议的一系列神经影像学研究中， 分析，我们的目标是（1）确定电路水平的机制，工作记忆损伤的基础 在首发精神分裂症患者中，（2）调节和测量 在这些患者中中断，和（3）确定TMS反应性是否预测纵向结果。 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，（2）包括1年内的随访评估，以及 从而在疾病的早期阶段记录疾病的进展。为了实现这些目标，我们设计了成像和 大脑刺激实验将使我们能够研究工作记忆之间的休息任务动力学， 相关的大脑网络目标1将联合收割机功能连通性和图论相结合， 任务相关网络的分离-整合动力学，如额顶叶控制网络和 默认模式网络;并确定首发患者与健康患者的差异程度 在这些网络措施的控制。它还将这些差异与行为表现联系起来。目的2 将利用经颅磁刺激来调节网络的活动，这些网络是首次发病患者认知障碍的基础。 精神分裂症重要的是，我们将使用一种组合来个性化每个患者的目标区域。 休息和基于任务的连接。然后，我们将比较TMS前后的行为和 连通性的措施，并确定如何程度的TMS引起的变化，连接预测 行为的改善。最后，目标3将确定TMS诱导的可塑性的程度， 与患者一年内纵向测量的功能结局相关。PI的主要 培训目标是（1）获得TMS理论和实践方面的专业知识，（2）开发 精神分裂症的临床和认知方面的专业知识，以及（3）扩展他的连接技能 方法通过图形理论的方法和应用这些技术的fMRI数据。