Novel MRS methods for measuring brain energetics and neurotransmitter cycling

描述（由申请人提供）：了解神经元代谢对于脑功能研究至关重要，并且输注13 C标记底物的磁共振波谱（MRS）已被公认为能够测量正常和患病状态下谷氨酸神经递质循环和细胞特异性神经能量学的唯一非侵入性体内技术。使用代谢模型，在体内13 C MRS研究已经成功地比较了神经元和神经胶质细胞的能量代谢，阐明了神经能量学和神经递质循环之间的联系，并确定了多种神经和精神疾病的脑代谢改变。 然而，由于1H和13 C核之间的J-偶联引起的低灵敏度和复杂的重叠光谱，在体内人体研究在技术上具有挑战性。尽管使用解耦（一种众所周知的用于简化光谱的NMR方法）对于体内研究的成功是至关重要的，但是相关的比吸收率（SAR）限制目前将人类研究限制在枕骨脑（大脑的远端）。 高度热敏感的眼睛）和磁场强度d 4 T。 如在我们的初步数据中所描述的，我们已经开发了一种新的MRS脉冲序列家族，其同时产生同相和反相磁化，其总和导致单个峰值，从而避免了对高功率去耦的需要。这为显着扩展当前体内人类13 C MRS脑研究提供了一个重要的新机会。这项为期两年的技术开发R21项目的目标是开发优化的这些新的1H-13 C MRS方法，用于体内测量神经元和神经胶质TCA通量和谷氨酸/谷氨酰胺循环速率。重点是超高场（e7 T）间接检测方法，最大限度地提高灵敏度，以便能够在可接受的扫描时间内询问整个人脑中的小组织区域（约1 cc）。将在体外、体模中并使用大鼠动物模型对所得脉冲序列进行评价，成功完成研究计划，生成证明向人体研究过渡所需的关键初步数据。

DESCRIPTION (provided by applicant): Understanding neuronal metabolism is critical for studies of brain function, and magnetic resonance spectroscopy (MRS) of infused 13C-labeled substrates is well established as the only noninvasive in-vivo technique capable of measuring glutamate neurotransmitter cycling and cell-specific neuroenergetics in both normal and diseased states. Using metabolic modeling, in vivo 13C MRS studies have successfully compared neuronal and glial energy metabolism, elucidated the linkage between neuroenergetics and neurotransmitter cycling, and identified altered brain metabolism in multiple neurological and psychiatric diseases. In vivo human studies, however, are technically challenging due to low sensitivity and complex overlapping spectra arising from J-coupling between 1H and 13C nuclei. Although the use of decoupling, a well-known NMR method to simplify spectra, has been critical to the success of in vivo studies, associated Specific Absorption Rate (SAR) limits currently restrict human studies to the occipital brain (distal to the highly heat-sensitive eyes) and to field strengths d 4T. As described in our preliminary data, we have developed a novel family of MRS pulse sequences that simultaneously generate both in-phase and anti-phase magnetization the sum of which result in a single peak, obviating the need for high-power decoupling. This presents a major new opportunity to significantly extend current in vivo human 13C MRS brain studies. The goal of this two-year technical development R21 project is to develop optimized these new 1H-13C MRS methods for the in vivo measurement of neuronal and glial TCA fluxes and glutamate/glutamine cycling rates. The focus is on ultra-high field (e7 T) indirect detection methods that maximize sensitivity in order t enable interrogating small tissue regions (~1 cc) throughout the human brain within acceptable scan times. The resulting pulse sequence(s) will be evaluated in vitro, in phantoms, and using a rat animal model, with the successful completion of the research plan producing the critical preliminary data needed to justify transitioning to human studies.