MULTIPLE QUANTUM CHEMICAL SHIFT IMAGING OF GABA IN BRAIN

γ-氨基丁酸(GABA)是人脑皮质的主要抑制性神经递质。在我们的实验室中，我们开发了单体素1H磁共振波谱(MRS)编辑方法，用于测量人脑中的GABA浓度。利用GABA-MRS的研究为GABA增强的抗癫痫药物和改变GABA代谢的疾病的机制提供了重要的见解，包括成人和青少年癫痫，以及最近的酒精中毒和抑郁症。这些发现支持了GABA代谢在神经和精神疾病的发病机制和治疗中的重要作用。开发用于绘制区域GABA浓度和合成速率的GABA光谱成像(SI)将极大地增强MRS研究提供的信息。然而，仍然存在重大挑战，包括1)消除与强烈肌酸共振的重叠，2)将GABA共振与共同编辑的大分子的共振分离，3)开发反向检测方法，允许测量具有1H MRS灵敏度的13C同位素的GABA合成，4)实现尽可能高的灵敏度和分辨率。最近，我们通过使用一种新的多量子(MQ)过滤方法获得了人类大脑中第一个GABA SI，该方法在不牺牲相对于J编辑方法的敏感性的情况下完全抑制重叠的肌酸。在这项建议中，我们将扩展这些结果，通过体内多量子2D MRS方法的发展，明确地将GABA从污染的大分子共振中分离出来。逆单量子2D方法将被开发用于从注入的[1-13C]葡萄糖中映射[2-13C]GABA的周转率。与布鲁克海文国家实验室的H.P.Hetherington博士合作，这些方法将与4T下的高分辨率、高场SI相结合。这些方法将在适当的幻影、动物模型和2.IT和4T的人类志愿者中进行测试和验证。这项建议的总体目标是将GABA浓度和合成率的SI发展为一种强有力的方法，用于临床研究GABA代谢在正常大脑功能和疾病中的作用。

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in human cortex. In our laboratory we have developed single-voxel 1H magnetic resonance spectroscopy (MRS) editing methods for measuring GABA concentration in the human brain. Studies using GABA MRS have provided important insight into the mechanism of GABA-enhancing antiepileptic drugs and altered-GABA metabolism in disease including adult and juvenile epilepsy and recently alcoholism and depression. These findings support an important role of GABA metabolism in the pathogenesis and treatment of neurological and psychiatric disorders. The development GABA spectroscopic imaging (SI) for mapping regional GABA concentrations and synthesis rates will greatly enhance the information available from MRS studies. However significant challenges remain including 1) elimination of overlap with the intense creatine resonance, 2) separation of the GABA resonance from the resonance of co-edited macromolecules 3) the development of inverse detection methods which allow measurement of GABA synthesis from infused 13C isotope with 1H MRS sensitivity, 4) achievement of the highest possible sensitivity and resolution. Recently we have obtained the first GABA SI in human brain by the use of a novel multiple quantum (MQ) filtering method which provides complete suppression of overlapping creatine without sacrificing sensitivity relative to J editing methods. In this proposal we will extend these results to obtain unequivocal separation of GABA from contaminating macromolecule resonances through the development of in vivo multiple quantum 2D MRS methods. Inverse single quantum 2D methods will be developed for mapping of the turnover rate of [2-13C] GABA from infused [1- 13C]glucose. In collaboration with Dr. H.P. Hetherington at Brookhaven National Laboratories these methods will be combined with high resolution, high field SI at 4T. These methods will be tested and validated in appropriate phantoms, animal models, and human volunteers at 2.IT and 4T. The overall goal of this proposal is to develop SI of GABA concentration and synthesis rate into a robust method for clinical research into the role of GABA metabolism in normal brain function and in disease.