Probing the White Matter in Schizophrenia Using Novel MRS Techniques

描述(由申请人提供)：这是一位早期研究人员提出的Brains 2011 R01提案，重点关注精神分裂症中的脑白质异常。大量文献强调了这种情况下白质的异常，并提出这些可能是导致疾病的一些核心特征出现的“连接异常”(即异常连接)综合征的基础。到目前为止，大多数研究都集中在“白质完整性降低”和髓鞘丢失作为病理生理机制的可能性上。然而，在体内几乎没有直接证据表明精神分裂症患者的髓鞘丢失。最近发展起来的MRI/MRS技术为量化白质中轴突和髓鞘相关的异常提供了机会。PI是K23职业发展奖获得者，他的研究重点是精神疾病的质子磁共振波谱(MRS)研究。在目前的提案中，他和他的同事将在4特斯拉下实施2项这样的技术(扩散张量光谱或DTS，以及磁化转移比(MTR))，并从精神分裂症患者和健康对照组右侧前额叶皮质9cc的纯白质体素收集数据。具体地说，我们将使用DTS来收集水扩散数据(类似于扩散张量成像或DTI研究)，以复制过去对该主题的研究，然后测量仅反映轴突变化的细胞内代谢物(N-乙酰天冬氨酸或NAA)的扩散特性。在同一项研究中，我们还将使用MTR检查髓鞘含量。最后，我们将通过将DTS和MTR异常与CNTRICS倡议推荐的前额相关执行功能指标Stroop任务的表现联系起来，来检验DTS和MTR异常的意义。因此，我们将解剖轴突和髓鞘相关的白质异常，以提供对精神分裂症信号传导完整性的机械性见解。我们假设髓鞘水平的降低只是画面的一部分，轴突的变化增加了一个新的维度，在检查精神分裂症的信号传导异常时需要考虑到这一点。 与公共卫生相关：精神分裂症是一种常见、慢性和严重的精神疾病，其病因尚不清楚，然而，有重要证据表明，在这种情况下，白质--大脑中包含连接不同大脑区域的电缆的部分--异常。在这项提案中，我们将使用两种新的核磁共振技术来探测健康人和精神分裂症患者的轴突(连接脑细胞的电缆)和髓鞘(绝缘这些电缆的脂肪物质)的异常。这项研究项目旨在提供有关精神分裂症患者脑白质异常的新信息，这些信息可能会改变我们对他们在精神障碍中的贡献的看法，并最终开发新的治疗方法。

DESCRIPTION (provided by applicant): This is a BRAINS 2011 R01 proposal from an early stage investigator focusing on white matter abnormalities in schizophrenia. A large literature highlights the abnormalities in white matter in this condition, and suggests that these may underlie a "dysconnection" (i.e. abnormal connection) syndrome leading to the emergence of some core features of the illness. Most research to date has focused on "reduced white matter integrity" and the possibility of myelin loss as a pathophysiological mechanism. There is little direct evidence for myelin loss in schizophrenia in vivo, however. Recently developed MRI/MRS techniques provide an opportunity quantify axon- and myelin-related abnormalities in the white matter. The PI is a K23 Career Development Award holder whose research has focused proton magnetic resonance spectroscopy (MRS) studies in psychiatric disorders. In the current proposal, he and his colleagues will implement 2 such techniques (diffusion tensor spectroscopy or DTS, and magnetization transfer ratio or MTR) at 4 Tesla and collect data from a 9cc pure white matter voxel in the right prefrontal cortex in patients with schizophrenia and healthy controls. Specifically we will use DTS to collect water diffusion data (which is analogous to diffusion tensor imaging or DTI studies) to replicate past studies on the topic, then measure the diffusion properties of an intracellular metabolite (N-acetylaspartate or NAA) which reflects axonal changes only. We will also examine myelin content using MTR in the same study. Finally, we will examine the significance of DTS and MTR abnormalities by correlating them with performance on a prefrontal-dependent measure of executive function recommended by the CNTRICS initiative, the Stroop task. Thus, we will dissect the axonal and myelin-related white matter abnormalities in a way that provides mechanistic insights into the integrity of signal conduction in schizophrenia. We hypothesize that a reduction of myelin levels is only part of the picture and that axonal changes add a new dimension which needs to be considered when examining signal conduction abnormalities in schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a common, chronic, and severe psychiatric condition whose causes are poorly understood, however, significant evidence points to abnormalities in the white matter, the part of the brain that contains the cables connecting different brain regions, in this condition. In this proposal, we will use two novel MRI techniques to probe abnormalities in axons (the cables connecting brain cells) and myelin (the fatty substance insulating those cables) in healthy people as well as those with schizophrenia. This research project is designed to provide new information on white matter abnormalities in individuals with schizophrenia which can change our thinking about their contributions to the disorder and ultimately the development of new treatments.