Functional MR of the Effects of D-Serine

这个项目将通过以下方式检验精神分裂症与NMDA功能低下有关的假设 通过联合使用质子磁共振波谱(MRS)获得的活体脑数据 和BOLD功能磁共振成像(FMRI)。我们建议测量质子代谢物 浓度，包括N-乙酰-天冬氨酸(NAA)和N-乙酰-天冬氨酸(NAAG) 精神分裂症患者和健康对照组的前额叶皮质区域。MRS数据将在4T上获取 具有新开发的方法的扫描仪，该方法提高了峰值和信号分量的分辨率 在质子光谱内，从而改善了NAA测量的可解释性，以及扩展了MRS 包括NAAG量化的能力。这些代谢物的量化与主要 中心拨款的假说来自我们小组的工作，报告了颞叶皮质NAA的减少 双边的。此外，NAAG还被认为与NMDA功能低下有关。目前的活体测量 这些代谢物还没有同时在精神分裂症中表现出来。此外，它已经被证明是 海马区的NMDA受体对于空间学习和药理学来说是必不可少的 阻断NMDA受体会损害空间导航。因此，作为一个探索性终点，我们建议 为了在完成空间导航任务的虚拟模拟期间在3T扫描仪上获取fMRI数据， 水迷宫，评估空间记忆成绩。我们还将在过渡期间获取fMRI数据 评估关系记忆的推理任务，以及在面部回忆挑战中，先前显示的任务 是由海马体调节的。最后，我们将与唐·戈夫博士(临床试验科)合作， 招募60名精神分裂症患者参加D-丝氨酸的安慰剂对照试验，D-丝氨酸是一种甘氨酸部位的激动剂 NMDA受体。患者将使用上述MRS/fMRI方案进行成像，以检查 D-丝氨酸对空间和关系记忆成绩、BOLD激活及NAA和NAA的影响 NAAG浓度。

This project will test the hypothesis that schizophrenia is associated with NMDA hypofunction by examining in-vivo brain data acquired through the combined use of proton magnetic resonance spectroscopy (MRS) and BOLD functional magnetic resonance imaging (fMRI). We propose to measure proton metabolite concentrations, including N-acetyl-aspartate (NAA) and N-acetyl-aspartyl-glutamate (NAAG), in temporal and prefrontal cortical regions in schizophrenic patients and healthy controls. MRS data will be acquired on a 4T scanner with newly developed methods that provide improved resolution of peaks and signal components within the proton spectrum, thus improving interpretability of NAA measurements, as well as extending MRS capabilities to include quantification of NAAG. The quantification of these metabolites is relevant for the main hypothesis of the center grant as work from our group has reported reduced NAA in temporal cortex bilaterally. Further, NAAG has been implicated in NMDA hypofunction. At present in-vivo measurements of these metabolites, have not been concurrently characterized in schizophrenia. Moreover, it has been shown that NMDA receptors in the hippocampus are essential for spatial learning and that pharmacological blockade of NMDA receptors impairs spatial navigation. Therefore, as an exploratory endpoint, we propose to acquire fMRI data on a 3Tscanner during the completion of a virtual analogue of a spatial navigation task, the water maze, to assess spatial memory performance. We will also acquire fMRI data during a transitive inference task to assess relational memory, and during a facial recall challenge, tasks previously shown to be mediated by the hippocampus. Finally, in collaboration with Dr. Don Goff (Clinical Trials Section), we will enroll 60 schizophrenic patients into a placebo-controlled trial of D-serine, an agonist at the glycine site on the NMDA receptor. Patients will be imaged with the MRS/fMRI protocols described above to examine the effects of D-serine treatment on spatial and relational memory performance, BOLD activation and NAA and NAAG concentrations.