Spectroscopic imaging of glutamate C4 turnover in human brain

Pan, Jullie W.; Stein, Daniel T.; Telang, Frank; Lee, J.H.; Shen, Jun; Brown, Peter B.; Cline, Gary W.; Mason, Graeme F.; Shulman, Gerald I.; Rothman, Douglas L.; Hetherington, Hoby P.

doi:10.1002/1522-2594(200011)44:5<673::aid-mrm3>3.0.co;2-l

Cited by 67 publications

(67 citation statements)

References 14 publications

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“…Gln is subsequently released by astrocytes and taken up by the neuronal terminals to be reconverted to Glu (for review see . Calculations based on these findings indicate that the energy demands of glutamatergic neurons account for 80-90% of total cortical glucose usage in rats (Sibson et al 1998) and humans (Pan et al 2000).…”

Section: The Neural Origin Of Bold Responsementioning

confidence: 95%

The neural basis of the blood–oxygen–level–dependent functional magnetic resonance imaging signal

Logothetis

2002

Phil. Trans. R. Soc. Lond. B

830

516

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Magnetic resonance imaging (MRI) has rapidly become an important tool in clinical medicine and biological research. Its functional variant (functional magnetic resonance imaging; fMRI) is currently the most widely used method for brain mapping and studying the neural basis of human cognition. While the method is widespread, there is insufficient knowledge of the physiological basis of the fMRI signal to interpret the data confidently with respect to neural activity. This paper reviews the basic principles of MRI and fMRI, and subsequently discusses in some detail the relationship between the blood-oxygenlevel-dependent (BOLD) fMRI signal and the neural activity elicited during sensory stimulation. To examine this relationship, we conducted the first simultaneous intracortical recordings of neural signals and BOLD responses. Depending on the temporal characteristics of the stimulus, a moderate to strong correlation was found between the neural activity measured with microelectrodes and the BOLD signal averaged over a small area around the microelectrode tips. However, the BOLD signal had significantly higher variability than the neural activity, indicating that human fMRI combined with traditional statistical methods underestimates the reliability of the neuronal activity. To understand the relative contribution of several types of neuronal signals to the haemodynamic response, we compared local field potentials (LFPs), single-and multi-unit activity (MUA) with high spatio-temporal fMRI responses recorded simultaneously in monkey visual cortex. At recording sites characterized by transient responses, only the LFP signal was significantly correlated with the haemodynamic response. Furthermore, the LFPs had the largest magnitude signal and linear systems analysis showed that the LFPs were better than the MUAs at predicting the fMRI responses. These findings, together with an analysis of the neural signals, indicate that the BOLD signal primarily measures the input and processing of neuronal information within a region and not the output signal transmitted to other brain regions.

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Section: The Neural Origin Of Bold Responsementioning

confidence: 95%

The neural basis of the blood–oxygen–level–dependent functional magnetic resonance imaging signal

Logothetis

2002

Phil. Trans. R. Soc. Lond. B

830

516

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“…This result is in excellent agreement with that obtained by Hawkins et al (1983), who found a significant regional correlation between glucose influx and glucose utilization. Pan et al (2000) measured gray and white matter neuronal glucose oxidation in a similar volume of the visual cortex as in the present study using magnetic resonance spectroscopy. Three of the four subjects used in this study were also measured in the study of Pan et al (2000), and their rates of CMR Glc have been used to calculate the maximum rate of glucose transport, V max (Table 1).…”

Section: Glucose Transport Kineticsmentioning

confidence: 97%

“…The detection of glucose by NMR spectroscopy in human studies has been limited to relatively large volumes of 27 to 36 mL containing a mixture of gray and white matter and cerebrospinal fluid. It has been well established that there is a large difference in the cerebral metabolic rate of glucose (CMR Glc ) between gray and white matter (Mason et al, 1999;Pan et al, 2000;Phelps et al, 1979;Reivich et al, 1979). This suggests that the glucose transport kinetics and/or the absolute glucose concentrations between gray and white matter may substantially differ.…”

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confidence: 99%

Differentiation of Glucose Transport in Human Brain Gray and White Matter

Graaf

Pan

Telang

et al. 2001

J Cereb Blood Flow Metab

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Summary:Localized 1 H nuclear magnetic resonance spectroscopy has been applied to determine human brain gray matter and white matter glucose transport kinetics by measuring the steady-state glucose concentration under normoglycemia and two levels of hyperglycemia. Nuclear magnetic resonance spectroscopic measurements were simultaneously performed on three 12-mL volumes, containing predominantly gray or white matter. The exact volume compositions were determined from quantitative T 1 relaxation magnetic resonance images. The absolute brain glucose concentration as a function of the plasma glucose level was fitted with two kinetic transport models, based on standard (irreversible) or reversible MichaelisMenten kinetics. The steady-state brain glucose levels were similar for cerebral gray and white matter, although the white matter levels were consistently 15% to 20% higher. The ratio of the maximum glucose transport rate, V max , to the cerebral metabolic utilization rate of glucose, CMR Glc , was 3.2 ± 0.10 and 3.9 ± 0.15 for gray matter and white matter using the standard transport model and 1.8 ± 0.10 and 2.2 ± 0.12 for gray matter and white matter using the reversible transport model. The Michaelis-Menten constant K m was 6.2 ± 0.85 and 7.3 ± 1.1 mmol/L for gray matter and white matter in the standard model and 1.1 ± 0.66 and 1.7 ± 0.88 mmol/L in the reversible model. Taking into account the threefold lower rate of CMR Glc in white matter, this finding suggests that blood-brain barrier glucose transport activity is lower by a similar amount in white matter. The regulation of glucose transport activity at the blood-brain barrier may be an important mechanism for maintaining glucose homeostasis throughout the cerebral cortex.

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“…Physiological variables were maintained within normal limits by small adjustments in ventilation [pCO 2 ϭ 33-42 mmHg; pO 2 Ͼ 120 mmHg; pH ϭ 7.30-7.58; blood pressure ϭ 95-110 mmHg (1 mmHg ϭ 133 Pa)]. A femoral vein was cannulated for infusion of [1,[6][7][8][9][10][11][12][13] C 2 ]glucose. After all of the surgeries were completed, anesthesia was maintained by 0.3-0.8% halothane in combination with 70% nitrous oxide.…”

mentioning

confidence: 99%

Regional glucose metabolism and glutamatergic neurotransmission in rat brainin vivo

Graaf

Mason²,

Patel³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

108

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, and is indicative of a glutamate (Glu)͞glutamine (Gln) neurotransmitter cycling flux between glutamatergic neurons and surrounding astroglia. Although 13 C NMR spectroscopy offers a high spectral resolution (1), it suffers from an inherently low sensitivity, thereby limiting the detection to relatively large volumes. As an alternative to direct 13 C NMR spectroscopy, the protons bound to 13 C atoms can be detected by proton-observed, carbon-edited 1 H-[ C]Glx (Glx ϭ Glu ϩ Gln) is measured in volumes that span the cerebral cortex, corpus callosum, hippocampus, and thalamus. In combination with quantitative tissue segmentation by T 1 relaxation mapping and multicompartment metabolic modeling, the rates of the neuronal TCA cycle and the Glu͞Gln neurotransmitter cycle can be calculated in pure cerebral gray matter and white matter. MethodsAnimal Preparation. Six male Sprague-Dawley rats (140 Ϯ 12 g, mean Ϯ SD) were studied in accordance with the guidelines established by the Yale Animal Care and Use Committee. After an overnight fast (12-16 h), the animals were tracheotomized and ventilated with a mixture of 70% nitrous oxide and 28.5% oxygen under 1.5% halothane anesthesia. A femoral artery was cannulated for monitoring of blood gases (pO 2 and pCO 2 ), pH, and blood pressure. Physiological variables were maintained within normal limits by small adjustments in ventilation [pCO 2 ϭ 33-42 mmHg; pO 2 Ͼ 120 mmHg; pH ϭ 7.30-7.58; blood pressure ϭ 95-110 mmHg (1 mmHg ϭ 133 Pa)]. A femoral vein was cannulated for infusion of [1,[6][7][8][9][10][11][12][13] C 2 ]glucose. After all of the surgeries were completed, anesthesia was maintained by 0.3-0.8% halothane in combination with 70% nitrous oxide. During NMR experiments animals were restrained in a head holder, and additional immobilization was achieved with D-tubocurarine chloride (0.5 mg͞kg every 40 min, i.p.). The core body temperature was measured with a rectal thermosensor and was maintained at 37 Ϯ 1°C by means of a heated water pad. The animals were infused with [1,6-13 C 2 ]glucose (Cambridge Isotope Laboratories, Cambridge, MA) according to a protocol described in ref.13. Blood samples were taken before infusion and every 25 min after the start of infusion. The plasma glucose fractional 13 C enrichments were measured by GC-MS.In Vivo 1 H NMR Spectroscopy. Experiments were performed on a 7.05-T Bruker magnet and console (Billerica, MA) equipped with a 12-cm-diameter actively shielded gradient coil insert (190 mT͞m in 200 s). Radiofrequency pulse transmission and NMR signal reception for protons (300.3 MHz) were performed with a 14-mm-diameter surface coil. Radiofrequency pulse transmission on carbon-13 (75.5 MHz) was achieved with two orthogonal 21-mm-diameter surface coils driven in quadrature. The magnetic field homogeneity over the volume-of-interest was optimized with the FASTMAP algorithm (14), which resulted in signal linewidths of 10-13 Hz for water and 8-9 Hz for metabolites in a volume of 100 l. (15), an adiabatic sequence employing frequency-selectiv...

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Spectroscopic imaging of glutamate C4 turnover in human brain

Cited by 67 publications

References 14 publications

The neural basis of the blood–oxygen–level–dependent functional magnetic resonance imaging signal

The neural basis of the blood–oxygen–level–dependent functional magnetic resonance imaging signal

Differentiation of Glucose Transport in Human Brain Gray and White Matter

Regional glucose metabolism and glutamatergic neurotransmission in rat brainin vivo

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