STRUCTURAL AND FUNCTIONAL CONNECTIVITY IN SCHIZOPHRENIA

精神分裂症的结构和功能连接

• 批准号: 6988900
• 负责人: ANDREW J SAYKIN
• 金额: $ 27.14万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-17 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988900
• 关键词: bioimaging /biomedical imaging; brain imaging /visualization /scanning; brain mapping; brain morphology; central neural pathway /tract; cooperative study; functional magnetic resonance imaging; human subject; intercellular connection; magnetic resonance imaging; patient oriented research; positron emission tomography; schizophrenia; synapses; white matter

Although considerable progress has been made in delineating MRI gray matter abnormalities in schizophrenia, relatively little progress has been made in evaluating white matter abnormalities, or the white matter fiber tract connections between gray matter regions, particularly those that connect the frontal and temporal lobes. These tracts that have long been thought to be abnormal in schizophrenia. Many subsequent investigators have hypothesized some type of connectivity deficit or disconnection model of schizophrenia. We plan to explicitly investigate such anomalies in this proposal. The overarching aim of this three-year proposal is to investigate abnormalities of connectivity at an anatomic and functional level in schizophrenia. Accordingly, we plan to employ a novel and integrative approach to investigating abnormal brain connectivity in schizophrenia, including an analysis of white matter fiber tract abnormalities, as well as the network nodes that these pathways interconnect. As a Driving Biological Project (DBP), this integrative aim will require the highly advanced computational strategies and robust software implementation provided by other subprojects in this grant. This project will emphasize MR Diffusion Tensor Imaging (DTI), a relatively new MR imaging technique that affords a unique opportunity to investigate and quantify white matter abnormalities in the brain. It will also include functional MRI (fMRI) probes of working, episodic, and semantic memory systems known to be abnormal in schizophrenia. Our use of fMRI will focus specifically on connectivity among regions implicated in the pathophysiology of schizophrenia using memory activation tasks to bring out the hypothesized abnormalities. An event related verbal episodic encoding and recognition memory task will target prefrontal and medial temporal sites. This task was developed based on our prior fMRI experience in normals and in patients with known seizure foci undergoing surgical treatment. Earlier evidence using electrophysiological methods suggested sensitivity of similar experiments to frontal vs. temporal lobe lesion location and numerous PET and fMRI studies have implicated these regions in schizophrenia. We will investigate the working memory system with fMRI using the n-back paradigm which has been shown by our group to robustly activate the prefrontal and parietal cortex in neurological patients and controls. Similar results in healthy controls have been widely reported in the PET and fMRI literature. In the present study, this task will afford us an opportunity to examine fronto-parietal connectivity and basal ganglia sites of interest that are also often activated. Finally, an event-related semantic memory task patterned after our earlier blocked design experiments will be used to activate left inferior prefrontal and left superior temporal regions of interest (ROIs). The broader PET and fMRI literature typically implicates these sites for language and semantic memory retrieval. These leading edge technologies will be integrated with volumetric and shape analyses of implicated gray matter structures as well as clinical and neurocognitive assessments to fully characterize the sample. In addition, although not the focus of this project, we will also collect blood from all subjects for genetic analysis.

尽管在描述 MRI 灰质异常方面已经取得了相当大的进展 对于精神分裂症，在评估白质异常或灰质区域之间的白质纤维束连接，特别是连接额叶和颞叶的白质纤维束连接方面取得的进展相对较小。这些束长期以来一直被认为是精神分裂症患者的异常。许多后续研究人员假设了精神分裂症的某种类型的连接缺陷或断开连接模型。我们计划在本提案中明确调查此类异常情况。 这项为期三年的提案的总体目标是调查以下位置的连接异常情况： 精神分裂症的解剖和功能水平。因此，我们计划采用一种新颖且 研究精神分裂症异常大脑连接的综合方法，包括 分析白质纤维束异常以及这些通路互连的网络节点。作为一个驱动生物项目（DBP），这一综合目标将需要本次拨款中其他子项目提供的高度先进的计算策略和强大的软件实现。该项目将重点强调 MR 扩散张量成像 (DTI)，这是一种相对较新的 MR 成像技术，为研究和量化大脑白质异常提供了独特的机会。它还将包括功能性 MRI (fMRI) 探针，用于检测精神分裂症中已知异常的工作记忆、情景记忆和语义记忆系统。我们对功能磁共振成像的使用将特别关注与精神分裂症病理生理学有关的区域之间的连接，使用记忆激活任务来找出假设的异常。与事件相关的言语情景编码和识别记忆任务将针对前额叶和内侧颞叶部位。这项任务是根据我们之前对正常人和接受手术治疗的已知癫痫灶患者进行功能磁共振成像的经验而开发的。早期使用电生理学方法的证据表明，类似实验对额叶与颞叶病变位置的敏感性，并且大量 PET 和功能磁共振成像研究表明这些区域与精神分裂症有关。我们将使用 n-back 范式通过 fMRI 研究工作记忆系统，我们的小组已证明该范式可以强有力地激活神经系统患者和对照组的前额叶和顶叶皮层。 PET 和 fMRI 文献中广泛报道了健康对照的类似结果。在本研究中，这项任务将为我们提供一个机会来检查额顶叶连接性和基底神经节的感兴趣部位，这些部位也经常被激活。 最后，一个与事件相关的语义记忆任务以我们早期的块设计为模式 实验将用于激活左下前额叶和左上颞叶感兴趣区域（ROI）。更广泛的 PET 和功能磁共振成像文献通常暗示这些位点用于语言和语义记忆检索。这些前沿技术将与相关灰质结构的体积和形状分析以及临床和神经认知评估相结合，以充分表征样本。此外，虽然不是这个项目的重点，我们也会采集所有受试者的血液进行基因分析。