STRUCTURAL AND FUNCTIONAL CONNECTIVITY IN SCHIZOPHRENIA IN NEUROPSYCHIATRIC DISOR

尽管在描绘MRI灰质异常方面已经取得了相当大的进展 在精神分裂症方面，在评估白质异常，即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进展相对较小。这些长久以来被认为在精神分裂症中是不正常的区域。后来的许多研究人员都假设精神分裂症存在某种类型的连接缺陷或断开模式。我们计划在这项提案中明确调查这类异常情况。 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 精神分裂症的解剖和功能水平。因此，我们计划采用一部小说和 研究精神分裂症患者异常脑连接的综合方法，包括 分析白质纤维束的异常，以及这些通路相互连接的网络节点。作为一个驱动生物学项目(DBP)，这一综合目标将需要由该赠款中的其他子项目提供的高度先进的计算策略和健壮的软件实施。该项目将重点介绍磁共振扩散张量成像(DTI)，这是一种相对较新的磁共振成像技术，为研究和量化大脑中的白质异常提供了独特的机会。它还将包括对已知的精神分裂症异常的工作、情景和语义记忆系统的功能磁共振(FMRI)探针。我们使用功能磁共振成像将特别关注精神分裂症病理生理学中涉及的区域之间的连接，使用记忆激活任务来揭示假想的异常。一项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。这项任务是基于我们之前在正常人和接受手术治疗的已知癫痫灶患者的fMRI经验而开发的。早期使用电生理学方法的证据表明，类似的实验对额叶和颞叶病变位置的敏感性，以及大量的PET和fMRI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，使用功能磁共振成像研究工作记忆系统，该范式已被我们的团队证明在神经科患者和对照组中有力地激活了前额叶和顶叶皮质。在健康对照中，类似的结果在PET和功能磁共振文献中已被广泛报道。在目前的研究中，这项任务将为我们提供一个机会来检查额顶连接和感兴趣的基底节部位，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模仿了我们之前的模块化设计 实验将用于激活左下前额叶和左上颞叶感兴趣区(ROI)。更广泛的正电子发射计算机断层扫描和功能磁共振成像文献通常暗示这些站点用于语言和语义记忆检索。这些前沿技术将与对所涉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，以充分确定样本的特征。此外，虽然不是这个项目的重点，但我们还将采集所有受试者的血液进行基因分析。

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.