bioimaging centers | magnetic resonance research center | faculty | Mason Graeme Finlay Mason, Ph.D. Associate Professor Yale University, School of Medicine Department of Diagnostic Radiology Division of Bioimaging Sciences Yale Magnetic Resonance Center 300 Cedar Street New Haven, Connecticut 06520-8043, United States Phone: (203) 785-6203 Fax: (203) 785-6643 graeme.mason@yale.edu Curriculum Vitae

My research integrates of quantitative approaches to measure functional brain chemistry and the study of neuropsychiatric disorders. The primary methods used are 1H and 13C magnetic resonance spectroscopy and mathematical assessment of metabolism. Current areas of research are depression, manic-depressive disorder, alcoholism, panic disorder, premenstrual syndrome, and post-partum depression. My primary areas of interest are the effects of alcohol and nicotine dependence on the brain.

A common approach to understand a system is to perturb it and observe how it responds. Psychiatric disorders provide cases of perturbed brain function and chemistry that can be studied by MRS to provide quantitative input for the mathematical understanding of the regulation of brain metabolism.

Over a decade ago, Drs. Petroff, Hyder, and Rothman found that the concentration of the inhibitory neurotransmitter GABA was reduced in the brains of many patients with epilepsy, using measurements made with 1H MRS. Then, the investigators found that effective treatments increased the concentration of GABA in those patients.

In the department of Psychiatry, Drs. John Krystal and Gerard Sanacora were interested in the effects of electroconvulsive therapy (ECT) on patients who suffered from major depressive disorder. Because ECT is based on electrically induced seizures in the brain, there was common ground with the epilepsy studies, and they brought patients for GABA scans. The result was surprising: the depressed patients had low brain GABA concentrations before their course of ECT-induced seizures, and what we have found since is that the ECT actually increases the concentration of GABA in the brain.

Since those first studies, we have found that GABA levels depend on a wide variety of parameters, including menstrual cycle (collaboration with Dr. C. Neill Epperson), anxiety disorders (collaborations with Dr. Andrew Goddard), and the subtype of depression that a patient has (collaboration with Dr. Gerard Sanacora).

1H MRS has been useful for providing concentrations of neurochemicals in psychiatric disorders, and based on those results, we have been able to make hypotheses about reasons for the changes that we see. For further investigation, we are turning to 13C MRS. 13C MRS lets us detect a naturally occurring, non-radioactive isotope of carbon called carbon-13, or 13C. Only 1% of naturally occurring carbon is 13C, so there is normally very little signal in the brain. When we inject a 13C-labeled substance like glucose (a natural sugar) into the blood, the brain uses it and makes 13C-labeled products. With 13C MRS we can observe the appearance of these products in the brain and measure rates of metabolism and neurochemicals release by the brain. For example, we are currently using these techniques to investigate why the concentration of GABA is reduced in depressed subjects, and it appears that GABA is made more slowly in people who are depressed.

SELECTED PUBLICATIONS

Mason GF, Rothman DL, Behar KL, Shulman RG (1992) NMR determination of TCA cycle rate and a-ketoglutarate/glutamate exchange rate in rat brain. J Cereb Blood Flow Metab 12: 434-447

Mason GF, Behar KL, Rothman DL, Shulman RG (1992) NMR determination of intracerebral glucose concentration and transport kinetics in rat brain in vivo. J Cereb Blood Flow Metab 12: 448-455

Mason GF, Pan JW, Ponder SL, Twieg DB, Pohost GM, Hetherington HP (1994) Detection of brain glutamate and glutamine in spectroscopic images at 4.1T. Magn Reson Med 32: 142-145

Mason GF, Gruetter R, Rothman DL, Behar KL, Shulman RG, Novotny EJ (1995) Simultaneous determination of the rates of the TCA cycle, glucose utilization, a-ketoglutarate/glutamate exchange, and glutamine synthesis in human brain by NMR. J Cereb Blood Flow Metab 15: 12-25

Mason GF, Pohost GM, Hetherington HP (1995) Numerically optimized experimental design for measurement of grey/white matter metabolite T2 in high-resolution spectroscopic images of brain. J Magn Reson, Series B 107: 68-73

Hyder F, Chase JR, Behar KL, Mason GF, Siddeek M, Rothman DL, Shulman RG (1996) Increased tri-carboxylic acid cycle flux in rat brain during fore-paw stimulation detected by 1H-[13C] nuclear magnetic resonance spectroscopy. Proc Natl Acad Sci USA 93: 7612-7617

Pan JW, Mason GF, Vaughan JT, Chu WJ, Zhang Y, Hetherington HP (1997) 13C editing of glutamate in human brain using J-refocused coherence transfer spectroscopy at 4.1T. Magn Reson Med 37: 355-358

Mason GF, Chu WJ, Pohost GM, Hetherington HP (1997) A general approach to numerically optimized design of experiments: application to multi-slice tissue segmentation via T1 imaging in human brain. J Magn Reson 126: 18-29; correction for publisher's error in volume 126, number 2.

Sibson NR, Dhankhar A, Mason GF, Rothman DL, Behar KL, Shulman RG (1998) Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Proc Natl Acad Sci USA 95: 316-321

Mason GF, Chu WJ, Ponder SL, Vaughan JT, Adams D, Hetherington HP (1998) Evaluation of 31P metabolite levels in grey matter and white matter using multi-slice tissue segmentation and spectroscopic imaging of human brain. Magn Reson Med 39: 346-353

Sibson NR, Shen J, Mason GF, Rothman DL, Behar KL, Shulman RG (1998) Functional energy metabolism: in vivo 13C NMR evidence for coupling of cerebral glucose consumption and glutamatergic neuronal activity. Dev Neurosci 20: 321-330

Mason GF, Pan JW, Chu WJ, Zhang YT, Newcomer BD, Hetherington HP (1999) Measurement of the Tricarboxylic Acid Cycle Rate in Human Grey and White Matter in vivo by 13C Magnetic Resonance Spectroscopy at 4.1T. J Cereb Blood Flow Metab 19: 1179-1188

Sanacora G, Mason GF, Rothman DL, Behar KL, Petroff OAC, Berman RM, Krystal JH (1999) Preliminary evidence of reduced cortical GABA levels in depressed patients assessed using 1H-magnetic resonance spectroscopy. Archives of General Psychiatry 56: 1043-1047

Mason GF, Lai JCK (2000) Nonlinear determination of Michaelis-Menten kinetics with model evaluation through estimation of uncertainties. Metab Brain Disease 15: 133-149

Sibson NR, Mason GF, Shen J, Cline GW, Herskovits AZ, Wall JEM, Behar KL, Rothman DL, Shulman RG (2001) In vivo 13C NMR measurement of neurotransmitter glutamate cycling, anaplerosis and TCA cycle flux in rat brain during [2-13C]glucose infusion. J Neurochem 76: 975-989

Goddard AW, Mason GF, Almai A, Rothman DL, Behar KL, Petroff OAC, Charney DS, Krystal JH (2001) Reductions in cortical GABA levels in panic disorder detected with 1H-magnetic resonance spectroscopy. Arch Gen Psychiatry 58: 556-561

Mason GF, Martin DL, Martin SB, Manor D, Sibson NR, Patel A, Rothman DL, Behar KL (2001) Decrease in GABA synthesis rate in rat cortex following vigabatrin administration correlates with the decrease in GAD67 protein. Brain Research 914: 81-91

Lebon V, Petersen KF, Cline GW, Shen J, Mason GF, Dufour S, Behar KL, Shulman GI, Rothman DL (2002) Astroglial contribution to brain energy metabolism in humans revealed by 13C NMR spectroscopy: elucidation of the dominant pathway for neurotransmitter glutamate repletion and measurement of astrocytic oxidative metabolism. J Neurosci 22: 1523-1531 (cover article)

Sanacora G, Mason GF, Rothman DL, Krystal JH (2002) Increased cortical GABA concentrations following selective serotonin reuptake inhibitor therapy in depressed patients. Am J Psychiatry 159: 663-665

Mason GF, Rothman DL (2002) Graded Image Segmentation of Brain Tissue in the Presence of Inhomogeneous Radio Frequency Fields. Magn Reson Imaging 20: 431-436