Novel MRS methods for measuring brain energetics and neurotransmitter cycling

描述(申请人提供)：了解神经元代谢对于研究大脑功能至关重要，注入13C标记底物的磁共振波谱(MRS)被公认为唯一能够在正常和疾病状态下测量谷氨酸神经递质循环和细胞特异性神经能量学的体内非侵入性技术。利用代谢模型，体内13C-MRS研究成功地比较了神经元和神经胶质的能量代谢，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中大脑代谢的改变。然而，活体人体研究在技术上具有挑战性，因为1H和13C原子核之间的J耦合引起的灵敏度低和复杂的重叠光谱。尽管使用去偶联(一种著名的简化光谱的核磁共振方法)对活体研究的成功至关重要，但相关的特定吸收率(SAR)限制目前将人类研究限制在枕脑(远端) 高度热敏感的眼睛)和场强d 4T。正如我们的初步数据所描述的，我们已经开发出一种新的MRS脉冲序列，它同时产生同相和反相磁化，其总和导致单个峰值，从而消除了对高功率去耦合的需要。这是一个重要的新机会，可以显著扩展当前的活体人类13C MRS脑研究。这个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-13C MRS方法，用于在体测量神经元和神经胶质的TCA通量以及谷氨酸/谷氨酰胺循环率。重点是超高场(E7T)间接检测方法，这些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的小组织区域(~1cc)。所产生的脉冲序列(S)将在体外、模体中和使用大鼠动物模型进行评估，研究计划的成功完成将产生证明过渡到人体研究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.