MULTIPLE QUANTUM CHEMICAL SHIFT IMAGING OF GABA IN BRAIN

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.