Magnetic Resonance Spectroscopy and Imaging Studies of Brain Functions

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

The goal of this research is to develop advanced magnetic resonance spectroscopy (MRS) and imaging techniques and to apply them and other complementary methods to study brain metabolism, neurotransmission, and enzyme activity. MRS allows in vivo measurement of the neurotransmission of glutamate and GABA, which plays important roles in many major psychiatric diseases, including depression and schizophrenia. During 2020 we completed quantification of 13C labeling of both glutamate and glutamine measured from a 12.6 cm3 voxel placed in the limbic structure of human brain at 7 Tesla. This was achieved using a new technique developed by our group that uses proton channel only. For 13C labeling of the much weaker glutamine signal we obtained an intra-subject coefficient of variation of 11% for the 13C fractional enrichment of glutamine C4. Our results demonstrated that both glutamate and glutamine 13C labeling can be measured with very high precision from a small localized region with the sensitivity of proton MRS using standard hardware for studying glutamate neurotransmission in vivo. Furthermore, we have finished our analysis of 13C MRS data acquired from the frontal lobe of human subjects. Our results demonstrated that carbonic anhydrase activity can be quantified from the frontal lobe of human brain using saturation transfer 13C MRS (Li et al, Carbonic anhydrase activity in the frontal lobe of human brain, NMR Biomed., 34:e4501 (2021). By comparing with the bicarbonate dehydrate rate constant measured from the occipital lobe, we found no significant difference in carbonic anhydrase activity between frontal and occipital lobes in heathy subjects. This observation makes it possible to use carbonic anhydrase activity in the occipital lobe as an internal control in psychiatric studies. By performing line fitting of 13C signals using a linear combination model, we further found that glutamine C5 and aspartate C4 can be fitted well, despite the much larger static magnetic field distortion in the frontal lobe. Our Cramer-Rao lower bound for glutamine C5/glutamate C5 ratio is 10.6%, similar to those observed in many proton MRS studies. Therefore, both glutamate C5, which is not overlapped by other signals, and glutamine C5, which is overlapped by aspartate C4, can be measured in the carboxylic/amide region of 13C MRS from the frontal lobe at 7 Tesla using oral administration of uniformly 13C-labeled glucose. In addition to the above, we are also making progress in developing novel techniques to increase the sensitivity of 13C-labeled signals. Membrane lipids are implicated in many neuropsychiatric disorders including major depression. Although phosphoesters can be measured by 31P MRS their quantification has been highly controversial. We acquired 31P MRS data from human subjects at both 3 and 7 Tesla. We found a large discrepancy between phosphoesters measured at 3 and 7 Tesla using standard spectral fitting techniques. Our observation matches literature reports. However, there has been no analysis of this discrepancy, hindering application of 31P MRS to characterizing membrane metabolism in neuropsychiatric disorders. We discovered that the phosphocreatine/(phosphocholine + glycerophosphocholine) ratio is approximately a constant (2.5) due to intrinsic biochemical constraints. Using this internal standard we established that phosphoesters can be accurately measured at 7 Tesla using 31P MRS, while at 3 Tesla 31P MRS with standard fitting procedures significantly underestimates phosphoesters (Li et al, Cerebral phosphoester signals measured by 31P magnetic resonance spectroscopy at 3 and 7 Tesla, PLoS One, 16:e0248632 (2021)).