Advancing innovative brain imaging to detect altered glutamate modulation and network dynamics in schizophrenia

项目总结/摘要(30行为限) 精神分裂症(SZ)是最令人衰弱的终生精神疾病之一，具有巨大的社会代价。 目前的治疗在恢复现实生活功能方面的影响有限。深圳素质中的生物学研究 提供了人类大脑形态、功能和体内生化缺陷的证据 谷氨酸(Glu)传递(内侧颞叶是主要累及区域)出现为 一个重要的病理生理学假说。谷氨酸能功能低下，与N-甲基-D-天冬氨酸减少相关 D-天冬氨酸受体功能，可能会降低海马体功能，进而驱动学习和记忆 其他人和我们已经记录的深圳的赤字。鉴于改变的功能可能与改变的 海马体的生物化学，在这个建议中，我们建立了一个多层次集成的概念框架 在特定结构域机制的背景下，谷氨酸的网络功能和体内生物化学方面的缺陷， 特别是联想学习和记忆。这些努力与NIMH的R-Doc倡议一致，是 在促进多模式脑成像科学为临床相关服务方面至关重要 问题。特别是，我们试图建立深圳学习障碍的神经生物学基础，以及他们的 对疾病进展的影响。 我们介绍了(以令人信服的初步数据)体内H功能性MRS(FMRS)的应用，a 一种非常新颖的方法，实时定量测定海马区谷氨酸的调节，而受试者 参与一项联想学习和记忆任务，我们已经建立了一个强大而具体的额面- 与SZ特别相关的海马区挑战。关于海马区生化动力学的研究 功能是一项具有重大临床意义的创新，特别是当它将与- 参与者获取功能磁共振数据，以表征大脑网络动力学和有效连接。 使用横断面研究设计，我们将评估谷氨酸功能障碍的程度和进展 早期和慢性病SZ患者的网络动力学改变。除了在体内获得？H FMR和fMRI数据，我们还将获得海马区基础(非任务活动)Glu水平和 背外侧PFC(DlPFC)与活体H MRS我们的目标是揭示大脑网络和 SZ患者额叶-海马区谷氨酸功能障碍表现为dlPFC谷氨酸缺乏和 额叶-海马区网络功能障碍对额叶需求相关海马区谷氨酸调节的影响 深圳的记忆形成。此外，海马区谷氨酸调制，额叶-海马区基础(非任务 Active)Glu水平和受损的网络动态将对疾病慢性化证据高度敏感 进行性谷氨酸功能障碍与病程相关。如果得到证实，这些新方法有可能 直接检测谷氨酸激动剂改善SZ患者海马区Glu低调节的疗效 作为下一步。

PROJECT SUMMARY/ABSTRACT (30 lines limit) Schizophrenia (SZ) is one of the most debilitating, life-long mental illnesses with profound societal costs. Current treatment has a limited impact in restoring real-life functions. Biological research in the SZ diathesis has provided evidence of deficits in human brain morphology, function and in vivo biochemistry with altered glutamate (Glu) transmission (with the medial temporal lobe being the primary implicated area) emerging as one leading pathophysiologic hypothesis. Glutamatergic hypo-function, associated with diminished N-methyl- D-aspartate receptor function, may reduce hippocampal functionality, in turn driving learning and memory deficits in SZ that others and we have documented. Given that altered functionality may be related to altered biochemistry of the hippocampus, in this proposal we establish a conceptual framework integrating multi-level deficits in network function and the in vivo biochemistry of Glu in the context of a specific domain mechanism, specifically associative learning and memory. These efforts, consistent with NIMH's R-DoC initiative, are critically important in advancing the science of multimodal brain imaging in the service of clinically relevant questions. In particular, we seek to establish the neurobiological bases of learning deficits in SZ, and their impact on illness progression. We introduce (with compelling preliminary data) the application of in vivo ¹H functional MRS (fMRS), a highly novel method for quantitating the modulation of Glu in real-time in the hippocampus, while subjects engage in an associative learning and memory task that we have established as a robust and specific frontal- hippocampal challenge, of particular relevance to SZ. This focus on biochemical dynamics in hippocampal function is an innovation of substantial clinical relevance, particularly as it will be coupled with within- participants acquisition of fMRI data to characterize brain network dynamics and effective connectivity. Using a cross-sectional study design, we will assess the extent and progression of Glu dysfunction and altered network dynamics in early-course and chronically ill SZ patients. In addition to acquiring in vivo ¹H fMRS and fMRI data, we will also acquire basal (non-task active) Glu levels in the hippocampus and dorsolateral PFC (dlPFC) with in vivo ¹H MRS. Our goal is to uncover the mechanisms of brain network and Glu dysfunction in the frontal-hippocampal circuit of SZ patients by demonstrating dlPFC Glu deficits and frontal-hippocampal network dysfunctions impacting hippocampal Glu modulation related to frontal-demanding memory formation in SZ. Additionally, the hippocampal Glu modulation, frontal-hippocampal basal (non-task active) Glu levels and impaired network dynamics will be highly sensitive to illness chronicity evidence by progressive Glu dysfunction with illness duration. If confirmed, these novel methods have the potential of testing directly the efficacy of Glu agonists in ameliorating hypo-modulation of hippocampal Glu in SZ patients as the next step.