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D L Rothman

Publications and source records attributed to D L Rothman.

At least 37 records · Page 2Linked to original sources
PubMed2000

Spectroscopic imaging of glutamate C4 turnover in human brain.

One-dimensional spectroscopic imaging of (13)C-4-glutamate turnover is performed in the human brain with a 6 cc nominal voxel resolution at 4T. Data were acquired with an indirect detection approach using a short spin echo single quantum (1)H-(13)C heteronuclear editing method and a 7 cm surface coil with quadrature (13)C decoupling coils. To analyze the data as a function of tissue type, T(1)-based image segmentation through the surface coil was performed to determine the gray and white matter contributions to each voxel. The tricarboxylic acid (TCA) cycle rate in gray and white matter was then determined using a two-compartment model with the tissue fractionation derived from the image segmentation. The mean values for the TCA cycle rate for occipital gray and white matter from three volunteers was 0.88 +/- 0.12 and 0.28 +/- 0.13 respectively, in agreement with literature data.

Brain↗
PubMed2000

Quantitative multi-modal functional MRI with blood oxygenation level dependent exponential decays adjusted for flow attenuated inversion recovery (BOLDED AFFAIR).

A magnetic resonance imaging (MRI) method is described that allows interleaved measurements of transverse (R(2)(*) and R(2)) and longitudinal (R(1)) relaxation rates of tissue water in conjunction with spin labeling. The image-contrasts are intrinsically blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) weighted, but each contrast is made quantitative by two echo time (TE) and inversion recovery time (TIR) acquisitions with gradient echo (GE) and spin echo (SE) weighted echo-planar imaging (EPI). The EPI data were acquired at 7 Tesla with nominal spatial resolution of 430 x 430 x 1000 microm(3) in rat brain in vivo. The method is termed as blood oxygenation level dependent exponential decays adjusted for flow attenuated inversion recovery (BOLDED AFFAIR) and allows acquisition of R(2)(*), R(2), and CBF maps in an interleaved manner within approximately 12 minute. The basic theory of the method, associated experimental/systematic errors, and temporal restrictions are discussed. The method is validated by comparison of multi-modal maps obtained by BOLDED AFFAIR (i.e., two TE and TIR values with GE and SE sequences) and conventional approach (i.e., multiple TE and TIR values with GE and SE sequences) during varied levels of whole brain activity. Preliminary functional data from a rat forepaw stimulation model demonstrate the feasibility of this method for functional MRI (fMRI) studies. It is expected that with appropriate precautions this method in conjunction with contrast agent-based MRI has great potential for quantitative fMRI studies of mammalian cortex.

Animals↗
PubMed2000

High-resolution CMR(O2) mapping in rat cortex: a multiparametric approach to calibration of BOLD image contrast at 7 Tesla.

The blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) method, which is sensitive to vascular paramagnetic deoxyhemoglobin, is dependent on regional values of cerebral metabolic rate of oxygen utilization (CMR(O2)), blood flow (CBF), and volume (CBV). Induced changes in deoxyhemoglobin function as an endogenous contrast agent, which in turn affects the transverse relaxation rates of tissue water that can be measured by gradient-echo and spin-echo sequences in BOLD fMRI. The purpose here was to define the quantitative relation between BOLD signal change and underlying physiologic parameters. To this end, magnetic resonance imaging and spectroscopy methods were used to measure CBF, CMR(O2), CBV, and relaxation rates (with gradient-echo and spin-echo sequences) at 7 Tesla in rat sensorimotor cortex, where cerebral activity was altered pharmacologically within the autoregulatory range. The changes in tissue transverse relaxation rates were negatively and linearly correlated with changes in CBF, CMR(O2), and CBV. The multiparametric measurements revealed that CBF and CMR(O2) are the dominant physiologic parameters that modulate the BOLD fMRI signal, where the ratios of (deltaCMR(O2)/CMR(O2)/(deltaCBF/ CBF) and (deltaCBV/CBV)/(deltaCBF/CBF) were 0.86 +/- 0.02 and 0.03 +/- 0.02, respectively. The calibrated BOLD signals (spatial resolution of 48 microL) from gradient-echo and spin-echo sequences were used to predict changes in CMR(O2) using measured changes in CBF, CBV, and transverse relaxation rates. The excellent agreement between measured and predicted values for changes in CMR(O2) provides experimental support of the current theory of the BOLD phenomenon. In gradient-echo sequences, BOLD contrast is affected by reversible processes such as static inhomogeneities and slow diffusion, whereas in spin-echo sequences these effects are refocused and are mainly altered by extravascular spin diffusion. This study provides steps by which multiparametric MRI measurements can be used to obtain high-spatial resolution CMR(O2) maps.

Animals↗
PubMed2000

Effects of gabapentin on brain GABA, homocarnosine, and pyrrolidinone in epilepsy patients.

PURPOSE: Gabapentin (GBP) was introduced as an antiepileptic drug (AED) and has been used in the management of neuropathic pain. We reported that daily dosing increased brain gamma-aminobutyric acid (GABA) in patients with epilepsy. This study was designed to determine how rapidly brain GABA and the GABA metabolites, homocarnosine and pyrrolidinone, increase in response to the first dose of GBP. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cc volume in the occipital cortex by using a 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Six patients (four women) were studied serially after the first oral dose (1,200 mg) of GBP. Five patients (three women) taking a standard daily dose (range, 1,200-2,000 mg) of GBP were rechallenged with a single high dose (2,400 mg). RESULTS: The first dose of GBP increased median brain GABA by 1.3 mM (range, 0.4-1.8 mM) within 1 h. Homocarnosine and pyrrolidinone did not change significantly by 5 h. Daily GBP therapy increased GABA (0.5 mM; 95% CI, 0.2-0.9), homocarnosine (0.3 mM; 95% CI, 0.2-0.4), and pyrrolidinone (0.10 mM; 95% CI, 0.06-0.14). Rechallenging patients taking GBP daily increased median brain GABA by 0.4 mM (range, 0.3-0.5) within 1 h. CONCLUSIONS: GBP promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Patients may expect to experience the anticonvulsant effects of increased homocarnosine and pyrrolidinone with daily therapy.

Acetates↗
PubMed2000

Glycogen loading alters muscle glycogen resynthesis after exercise.

This study compared muscle glycogen recovery after depletion of approximately 50 mmol/l (DeltaGly) from normal (Nor) resting levels (63.2 +/- 2.8 mmol/l) with recovery after depletion of approximately 50 mmol/l from a glycogen-loaded (GL) state (99.3 +/- 4.0 mmol/l) in 12 healthy, untrained subjects (5 men, 7 women). To glycogen load, a 7-day carbohydrate-loading protocol increased muscle glycogen 1.6 +/- 0.2-fold (P < or = 0.01). GL subjects then performed plantar flexion (single-leg toe raises) at 50 +/- 3% of maximum voluntary contraction (MVC) to yield DeltaGly = 48.0 +/- 1.3 mmol/l. The Nor trial, performed on a separate occasion, yielded DeltaGly = 47.5 +/- 4.5 mmol/l. Interleaved natural abundance (13)C-(31)P-NMR spectra were acquired and quantified before exercise and during 5 h of recovery immediately after exercise. During the initial 15 min after exercise, glycogen recovery in the GL trial was rapid (32.9 +/- 8.9 mmol. l(-1). h(-1)) compared with the Nor trial (15.9 +/- 6.9 mmol. l(-1). h(-1)). During the next 45 min, GL glycogen synthesis was not as rapid as in the Nor trial (0.9 +/- 2.5 mmol. l(-1). h(-1) for GL; 14.7 +/- 3.0 mmol. l(-1). h(-1) for Nor; P < or = 0.005) despite similar glucose 6-phosphate levels. During extended recovery (60-300 min), reduced GL recovery rates continued (1.3 +/- 0.5 mmol. l(-1). h(-1) for GL; 3.9 +/- 0.3 mmol. l(-1). h(-1) for Nor; P < or = 0.001). We conclude that glycogen recovery from heavy exercise is controlled primarily by the remaining postexercise glycogen concentration, with only a transient synthesis period when glycogen levels are not severely reduced.

Adult↗
PubMed2000

Intramuscular glycogen and intramyocellular lipid utilization during prolonged exercise and recovery in man: a 13C and 1H nuclear magnetic resonance spectroscopy study.

Depletion of muscle glycogen is considered a limiting performance factor during prolonged exercise, whereas the role of the intramyocellular lipid (IMCL) pool is not yet fully understood. We examined 1) intramyocellular glycogen and lipid utilization during prolonged exercise, 2) resynthesis of muscle glycogen and lipids during recovery, and 3) changes in glycogen content between nonexercising and exercising muscles during recovery. Subjects ran on a treadmill at submaximal intensity until exhaustion. Glycogen concentrations were assessed in thigh, calf, and nonexercising forearm muscle, and IMCL content was measured in soleus muscle using magnetic resonance spectroscopy techniques. At the time of exhaustion, glycogen depletion was 2-fold greater in calf than in thigh muscles, but a significant amount of glycogen was left in both leg muscles. The glycogen concentration in nonexercising forearm muscle decreased during the initial 5 h of recovery to 73% of the baseline value. Duringthe exercise, the IMCL content decreased to 67% and subsequently during recovery increased to 83% of the baseline value. In summary, we found during prolonged running 1) significantly greater muscle glycogen utilization in the calf muscle group than in the thigh muscle group, 2) significant utilization of IMCL in the soleus muscle, and 3) a decrease in glycogen content in nonexercising muscle and an increase in glycogen content in recovering muscles during the postexercise phase. These latter data are consistent with the hypothesis that there is transfer of glycogen by the glucose-lactate and the glucose-->alanine cycle from the resting muscle (forearm) to recovering muscles (thigh and calf) after running exercise.

Blood Glucose↗
PubMed1999

In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics.

In this article we review recent studies, primarily from our laboratory, using 13C NMR (nuclear magnetic resonance) to non-invasively measure the rate of the glutamate-glutamine neurotransmitter cycle in the cortex of rats and humans. In the glutamate-glutamine cycle, glutamate released from nerve terminals is taken up by surrounding glial cells and returned to the nerve terminals as glutamine. 13C NMR studies have shown that the rate of the glutamate-glutamine cycle is extremely high in both the rat and human cortex, and that it increases with brain activity in an approximately 1:1 molar ratio with oxidative glucose metabolism. The measured ratio, in combination with proposals based on isolated cell studies by P. J. Magistretti and co-workers, has led to the development of a model in which the majority of brain glucose oxidation is mechanistically coupled to the glutamate-glutamine cycle. This model provides the first testable mechanistic relationship between cortical glucose metabolism and a specific neuronal activity. We review here the experimental evidence for this model as well as implications for blood oxygenation level dependent magnetic resonance imaging and positron emission tomography functional imaging studies of brain function.

Ammonia↗
PubMed1999

Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes.

BACKGROUND: Insulin resistance, a major factor in the pathogenesis of type 2 diabetes mellitus, is due mostly to decreased stimulation of glycogen synthesis in muscle by insulin. The primary rate-controlling step responsible for the decrease in muscle glycogen synthesis is not known, although hexokinase activity and glucose transport have been implicated. METHODS: We used a novel nuclear magnetic resonance approach with carbon-13 and phosphorus-31 to measure intramuscular glucose, glucose-6-phosphate, and glycogen concentrations under hyperglycemic conditions (plasma glucose concentration, approximately 180 mg per deciliter [10 mmol per liter]) and hyperinsulinemic conditions in six patients with type 2 diabetes and seven normal subjects. In vivo microdialysis of muscle tissue was used to determine the gradient between plasma and interstitial-fluid glucose concentrations, and open-flow microperfusion was used to determine the concentrations of insulin in interstitial fluid. RESULTS: The time course and concentration of insulin in interstitial fluid were similar in the patients with diabetes and the normal subjects. The rates of whole-body glucose metabolism and muscle glycogen synthesis and the glucose-6-phosphate concentrations in muscle were approximately 80 percent lower in the patients with diabetes than in the normal subjects under conditions of matched plasma insulin concentrations. The mean (+/-SD) intracellular glucose concentration was 2.0+/-8.2 mg per deciliter (0.11+/-0.46 mmol per liter) in the normal subjects. In the patients with diabetes, the intracellular glucose concentration was 4.3+/-4.9 mg per deciliter (0.24+/-0.27 mmol per liter), a value that was 1/25 of what it would be if hexokinase were the rate-controlling enzyme in glucose metabolism. CONCLUSIONS: Impaired insulin-stimulated glucose transport is responsible for the reduced rate of insulin-stimulated muscle glycogen synthesis in patients with type 2 diabetes mellitus.

Adult↗
PubMed1999

Determination of the rate of the glutamate/glutamine cycle in the human brain by in vivo 13C NMR.

Recent 13C NMR studies in rat models have shown that the glutamate/glutamine cycle is highly active in the cerebral cortex and is coupled to incremental glucose oxidation in an approximately 1:1 stoichiometry. To determine whether a high level of glutamatergic activity is present in human cortex, the rates of the tricarboxylic acid cycle, glutamine synthesis, and the glutamate/glutamine cycle were determined in the human occipital/parietal lobe at rest. During an infusion of [1-13C]-glucose, in vivo 13C NMR spectra were obtained of the time courses of label incorporation into [4-13C]-glutamate and [4-13C]-glutamine. Using a metabolic model we have validated in the rat, we calculated a total tricarboxylic acid cycle rate of 0.77 +/- 0.07 micromol/min/g (mean +/- SD, n = 6), a glucose oxidation rate of 0.39 +/- 0.04 micromol/min/g, and a glutamate/glutamine cycle rate of 0.32 +/- 0.05 micromol/min/g (mean +/- SD, n = 6). In agreement with studies in rat cerebral cortex, the glutamate/glutamine cycle is a major metabolic flux in the resting human brain with a rate approximately 80% of glucose oxidation.

Adult↗
PubMed1999

Stimulated changes in localized cerebral energy consumption under anesthesia.

Focal changes in the cerebral metabolic rate of glucose utilization (CMRglc) are small (10-40%) during sensory activation in awake humans, as well as in awake rodents and primates (20-50%). They are significantly larger (50-250%) in sensory activation studies of anesthetized rats and cats. Our data, in agreement with literature values, show that in the resting anesthetized state values of CMRglc are lower than in the resting nonanesthetized state whereas the final state values, reached upon activation, are similar for the anesthetized and nonanesthetized animals. The lower resting anesthetized state values of CMRglc explain why the increments upon activation from anesthesia are larger than when starting from the nonanesthetized conditions. Recent 13C NMR measurements in our laboratory have established a quantitative relationship between the energetics of glucose oxidation, CMRglc (oxidative), and the flux of the glutamate/gamma-aminobutyric acid/glutamine neurotransmitter cycle, Vcycle. In both the resting awake value of CMRglc(oxidative), and its increment upon stimulation, a large majority (approximately 80%) of the brain energy consumption is devoted to Vcycle. In the differencing methods of functional imaging, it is assumed that the incremental change in the measured signal represents the modular activity that supports the functional response. However, the same amount of activity must be present during the response to stimulation, irrespective of the initial basal state of the cortex. Thus, whereas the incremental signals of DeltaCMRglc can localize neurotransmitter activity, the magnitude of such activity during the response is represented by the total localized CMRglc, not the increment.

Anesthesia↗
PubMed1999

Energy on demand.

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Adenosine Triphosphate↗
PubMed1999

Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy.

BACKGROUND: Several lines of emerging evidence suggest that dysfunction of gamma-aminobutyric acid (GABA) systems is associated with major depression. However, investigation of this hypothesis is limited by difficulty obtaining noninvasive in vivo measures of brain GABA levels. In this study we used in vivo proton magnetic resonance spectroscopy to investigate the hypothesis that abnormalities in the GABA neurotransmitter system are associated with the neurobiologic processes of depression. METHODS: The GABA levels were measured in the occipital cortex of medication-free depressed patients meeting DSM-IV criteria (n = 14) and healthy control subjects with no history of mental illness (n = 18) using a localized difference editing proton magnetic resonance spectroscopy protocol. An analysis of covariance was employed to examine the effects of depression, sex, and age. RESULTS: The depressed patients demonstrated a highly significant (52%) reduction in occipital cortex GABA levels compared with the group of healthy subjects. While there were significant age and sex effects, there was no interaction of diagnosis with either age or sex. CONCLUSION: This study provides the first evidence of abnormally low cortical GABA concentrations in the brains of depressed patients.

Adult↗
PubMed1999

In vivo chemical shift imaging of gamma-aminobutyric acid in the human brain.

A gradient-based multiple quantum filtering method is presented for in vivo chemical shift imaging of gamma-aminobutyric acid (GABA) in the human brain, which provides effective suppression of the overlapping creatine singlet with close to optimal detection efficiency. It is shown by product operator calculations and coherence pathway analysis that under conditions of no B1 and B0 inhomogeneity gradient filtering retains 75% of the two outer resonance lines of the GABA-4 triplet with no creatine contamination. A variation of the method with 100% retention of the GABA-4 outer resonance lines but higher sensitivity to B1 inhomogeneity is also discussed. By using a localized version of the sequence with an 8-cm surface coil for transmission and detection, it was found in phantom experiments at 2.1 T that a 69% signal retention of the two outer resonance lines of the GABA-4 triplet was achieved relative to a spin echo sequence with inhibition of GABA J modulation. A creatine suppression ratio of 2000:1 was measured. The use of the method for chemical shift imaging of GABA is demonstrated by coronal images obtained from phantoms and from the occipital lobe of a healthy volunteer.

Brain↗
PubMed1999

Localized 1H NMR measurements of 2-pyrrolidinone in human brain in vivo.

Localized 1H NMR homonuclear J editing spectroscopy was used to measure the concentration of 2-pyrrolidinone (PRDN) in the human occipital lobe of five normal and six epileptic subjects taking vigabatrin. PRDN is a lactam cyclization product of gamma-aminobutyric acid (GABA). From a localized volume of 13.5 cm3 in the occipital cortex, the concentration of PRDN ranged from 0.2 to 0.3 micromol/g in normal subjects, whereas in epileptic subjects on vigabatrin PRDN was elevated to 0.6 +/- 0.1 micromol/g. The elevated PRDN in patients on vigabatrin was in accord with raised GABA levels compared with normals. 1H NMR measurements of PRDN will be important in assessment of the role of this metabolite for improved seizure control.

Adult↗
PubMed1999

Linear projection method for automatic slice shimming.

A fast, reliable automatic slice shimming method is described. In-slice shim adjustments are based on one-dimensional phase mapping of four in-slice linear projections through the slice center. For axial, coronal, and sagittal slices it is shown that all in-slice first-, second-, and third-order spherical harmonic terms of B(0) inhomogeneity can be unequivocally determined and corrected. Through-slice shim adjustment is achieved using a one-dimensional projection of the entire slice or ROI along the slice-selection direction. Applications of this method to single-slice in vivo spectroscopic imaging of human brain have resulted in reproducible, high-quality spectroscopic data. Magn Reson Med 42:1082-1088, 1999.

Brain↗
PubMed1999

In vivo carbon-edited detection with proton echo-planar spectroscopic imaging (ICED PEPSI): [3,4-(13)CH(2)]glutamate/glutamine tomography in rat brain.

A method for in vivo carbon-edited detection with proton echo-planar spectroscopic imaging (ICED PEPSI) is described. This method is composed of an echo-planar based acquisition implemented with (13)C-(1)H J editing spectroscopy and is intended for high temporal and spatial resolution in vivo spectroscopic imaging of (13)C turnover, from D-[1,6-(13)C]glucose to glutamate and glutamine, in the brain. At a static magnetic field strength of 7 T, both in vitro and in vivo chemical shift imaging data are presented with a spatial resolution of 8 microL (i.e., 1.25 x 1.25 x 5.00 mm(3)) and a maximum spectral bandwidth of 5.2 ppm in (1)H. Chemical shift imaging data acquired every 11 minutes allowed detection of regional [4-(13)CH(2)]glutamate turnover in rat brain. The [4-(13)CH(2)]glutamate turnover curves, which can be converted to tricarboxylic acid cycle fluxes, showed that the tricarboxylic acid cycle flux (V(TCA)) in pure gray and white matter can range from 1.2 +/- 0.2 to 0.5 +/- 0.1 micromol/g/min, respectively, for morphine-anesthetized rats. The mean cortical V(TCA) from 32 voxels of 1.0 +/- 0.3 micromol/g/min (N = 3) is in excellent agreement with previous localized measurements that have demonstrated that V(TCA) can range from 0.9-1.1 micromol/g/min under identical anesthetized conditions. Magn Reson Med 42:997-1003, 1999.

Animals↗