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Douglas L Rothman

Publications and source records attributed to Douglas L Rothman.

At least 55 records · Page 3Linked to original sources
PubMed2003

A comparison of (13)C NMR measurements of the rates of glutamine synthesis and the tricarboxylic acid cycle during oral and intravenous administration of [1-(13)C]glucose.

13C-labeled glucose is increasingly used in conjunction with magnetic resonance spectroscopy to measure rates of metabolic pathways in the brain in vivo. Most studies of human subjects have used intravenous infusions to administer the labeled compounds, but the procedure is cumbersome and can be uncomfortable for patients with neurological or psychiatric disorders. It may be possible to improve the practicality of the method by administering the glucose orally instead of intravenously. This report describes the performance and comparison of the oral and intravenous protocols in the same subjects. The conclusion is that oral administration does yield the same result as intravenous administration but with lower precision. That sensitivity of the oral protocol may be improved by several ways that are available today.

Administration, Oral↗
PubMed2003

Cerebral metabolism and consciousness.

In vivo 13C magnetic resonance spectroscopy studies of the brain have measured rates of glutamate-glutamine cycle (Vcyc) and glucose oxidation (CMRglc(ox)) by detecting 13C label turnover from glucose to glutamate and glutamine. In both the awake human and in the anesthetized rat brains Vcyc and CMRglc(ox) are stoichiometrically related, and form a major pathway in which approximately 80% of the energy from glucose oxidation supports events associated with glutamate neurotransmission. The high energy consumption of the brain at rest and its quantitative usage for neurotransmission reflect a high level of neuronal activity for the non-stimulated brain. This high activity supports a reinterpretation of functional imaging data, e.g., where the large baseline signal has commonly been discarded. Independent measurements of energy consumption (delta CMRO2%) obtained from calibrated fMRI equaled percentage changes in neuronal spiking rate (delta nu %) measured by electrodes during sensory stimulation at two depths of anesthesia. These quantitative biophysical relationships between energy consumption and neuronal activity provide novel insights into the nature of brain function. The high resting brain activity is proposed to include the global interactions constituting the subjective aspects of consciousness. Anesthesia by lowering the total firing rates correlates with the loss of consciousness. These results, which measure the localized neuronal response and distinguish inputs of peripheral neurons from inputs of neurons from other brain regions, fit comfortably into the neuronal scheme of a global workspace proposed by Dehaene and Changeux.

Anesthesia↗
PubMed2003

Increased cortical GABA concentrations in depressed patients receiving ECT.

OBJECTIVE: Reduced gamma-aminobutyric acid (GABA) concentrations have been reported in the plasma, CSF, and cortex of depressed subjects. Of interest is that ECT, one of the most effective treatments for severe refractory depression, produces considerable anticonvulsant effects that may be related to increased GABAergic transmission. The purpose of this study was to determine if cortical GABA concentrations increase following a course of ECT. METHOD: Occipital cortex GABA concentrations in eight depressed patients were measured by using proton magnetic resonance spectroscopy before and after a course of ECT. RESULTS: A significant increase in occipital cortex GABA concentrations was seen following ECT treatment of depression. CONCLUSIONS: Occipital cortex GABA concentrations increase two-fold following ECT. This suggests possible GABAergic involvement in ECT's mechanism of anticonvulsant and antidepressant actions.

Anticonvulsants↗
PubMed2003

Clinical studies implementing glutamate neurotransmission in mood disorders.

Emerging evidence suggests that the amino acid neurotransmitter systems are associated with the pathophysiology and treatment of mood disorders. Recent advances in the areas of molecular neurobiology, pharmacology, and magnetic resonance spectroscopy (MRS) now provide better tools to probe the function of the amino acid neurotransmitter systems and are affording us the opportunity to better investigate the relationship of these systems to mood disorders. Here we review the available literature in the field and suggest a possible pathophysiological model that may account for the many of the findings.

Animals↗
PubMed2002

Magnetic resonance spectroscopic approaches to studying neuronal: glial interactions.

In vivo magnetic resonance spectroscopy (MRS) is a noninvasive technique for the measurement of the concentration and synthesis of metabolites in the brain. Application of the state-of-the-art in vivo (13)C and (15)N MRS techniques to studying the synthesis of glutamate and glutamine has revealed that the glutamate-glutamine cycle between neurons and glia is a major metabolic flux, with a flux rate of 60%-80% relative to neuronal oxidative glucose metabolism in the resting human cerebral cortex. The MRS studies leading to the quantification of the glutamate-glutamine cycling flux are reviewed here. The advantages and limitations of different strategies are also discussed.

Animals↗
PubMed2002

Cerebral energetics and spiking frequency: the neurophysiological basis of fMRI.

Functional MRI (fMRI) is widely assumed to measure neuronal activity, but no satisfactory mechanism for this linkage has been identified. Here we derived the changes in the energetic component from the blood oxygenation level-dependent (BOLD) fMRI signal and related it to changes in the neuronal spiking frequency in the activated voxels. Extracellular recordings were used to measure changes in cerebral spiking frequency (Deltanu/nu) of a neuronal ensemble during forepaw stimulation in the alpha-chloralose anesthetized rat. Under the same conditions localized changes in brain energy metabolism (DeltaCMR(O2)/CMR(O2)) were obtained from BOLD fMRI data in conjunction with measured changes in cerebral blood flow (DeltaCBF/CBF), cerebral blood volume (DeltaCBV/CBV), and transverse relaxation rates of tissue water (T(2)(*) and T(2)) by MRI methods at 7T. On stimulation from two different depths of anesthesia DeltaCMR(O2)/CMR(O2) approximately Deltanu/nu. Previous (13)C magnetic resonance spectroscopy studies, under similar conditions, had shown that DeltaCMR(O2)/CMR(O2) was proportional to changes in glutamatergic neurotransmitter flux (DeltaV(cyc)/V(cyc)). These combined results show that DeltaCMR(O2)/CMR(O2) approximately DeltaV(cyc)/V(cyc) approximately Deltanu/nu, thereby relating the energetic basis of brain activity to neuronal spiking frequency and neurotransmitter flux. Because DeltaCMR(O2)/CMR(O2) had the same high spatial and temporal resolutions of the fMRI signal, these results show how BOLD imaging, when converted to DeltaCMR(O2)/CMR(O2), responds to localized changes in neuronal spike frequency.

Animals↗
PubMed2002

Total neuroenergetics support localized brain activity: implications for the interpretation of fMRI.

In alpha-chloralose-anesthetized rats, changes in the blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signal (DeltaS/S), and the relative spiking frequency of a neuronal ensemble (Deltanu/nu) were measured in the somatosensory cortex during forepaw stimulation from two different baselines. Changes in cerebral oxygen consumption (DeltaCMR(O2)/CMR(O2)) were derived from the BOLD signal (at 7T) by independent determinations in cerebral blood flow (DeltaCBF/CBF) and volume (DeltaCBV/CBV). The spiking frequency was measured by extracellular recordings in layer 4. Changes in all three parameters (CMR(O2), nu, and S) were greater from the lower baseline (i.e., deeper anesthesia). For both baselines, DeltaCMR(O2)/CMR(O2) and Deltanu/nu were approximately one order of magnitude larger than DeltaS/S. The final values of CMR(O2) and nu reached during stimulation were approximately the same from both baselines. If only increments were required to support functions then their magnitudes should be independent of the baseline. In contrast, if particular magnitudes of activity were required, then sizes of increments should inversely correlate with the baseline (being larger from a lower baseline). The results show that particular magnitudes of activity support neural function. The disregard of baseline activity in fMRI experiments by differencing removes a large and necessary component of the total activity. Implications of these results for understanding brain function and fMRI experiments are discussed.

Animals↗
PubMed2002

In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function.

Until very recently, non-invasive measurement of the glutamate-glutamine cycle in the intact mammalian brain had not been possible. In this review, we describe some studies that have led to quantitative assessment of the glutamate-glutamine cycle (Vcyc), as well as other important metabolic fluxes (e.g., glucose oxidation, CMRglc(ox)), with (13)C magnetic resonance spectroscopy (MRS) in vivo. These (13)C MRS studies clearly demonstrate that glutamate released from presynaptic neurons is taken up by the astrocyte for subsequent glutamine synthesis. Contrary to the earlier concept of a small, metabolically inactive neurotransmitter pool, in vivo (13)C MRS studies demonstrate that glutamate release and recycling is a major metabolic pathway that cannot be distinguished from its actions of neurotransmission. Furthermore, the in vivo (13)C MRS studies demonstrate in the rat cerebral cortex that increases in Vcyc and neuronal CMRglc(ox) are linearly related with a close to 1:1 slope. Measurements in human cerebral cortex are in agreement with this result. This relationship is consistent with more than two thirds of the energy yielded by glucose oxidation being used to support events associated with glutamate neurotransmission, and it supports a molecular model of a stoichiometric coupling between glutamate neurotransmission and functional glucose oxidation. (13)C MRS measurements of resting human cerebral cortex have found a high level of glutamate-glutamine cycling. This high resting neuronal activity, which is subtracted away in brain mapping studies by positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), has significant implications for the interpretations of functional imaging data. Here we review and discuss the importance of neurotransmission and neuroenergetics as measured by (13)C MRS for understanding brain function and interpreting fMRI.

Animals↗
PubMed2002

Astroglial contribution to brain energy metabolism in humans revealed by 13C nuclear magnetic resonance spectroscopy: elucidation of the dominant pathway for neurotransmitter glutamate repletion and measurement of astrocytic oxidative metabolism.

Increasing evidence supports a crucial role for glial metabolism in maintaining proper synaptic function and in the etiology of neurological disease. However, the study of glial metabolism in humans has been hampered by the lack of noninvasive methods. To specifically measure the contribution of astroglia to brain energy metabolism in humans, we used a novel noninvasive nuclear magnetic resonance spectroscopic approach. We measured carbon 13 incorporation into brain glutamate and glutamine in eight volunteers during an intravenous infusion of [2-13C] acetate, which has been shown in animal models to be metabolized specifically in astroglia. Mathematical modeling of the three established pathways for neurotransmitter glutamate repletion indicates that the glutamate/glutamine neurotransmitter cycle between astroglia and neurons (0.32 +/- 0.07 micromol x gm(-1) x min(-1)) is the major pathway for neuronal glutamate repletion and that the astroglial TCA cycle flux (0.14 +/- 0.06 micromol x gm(-1) x min(-1)) accounts for approximately 14% of brain oxygen consumption. Up to 30% of the glutamine transferred to the neurons by the cycle may derive from replacement of oxidized glutamate by anaplerosis. The further application of this approach could potentially enlighten the role of astroglia in supporting brain glutamatergic activity and in neurological and psychiatric disease.

Acetates↗
PubMed2002

Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study.

BACKGROUND: There is increasing support for the hypothesis that gonadal steroids involved in the regulation of the human menstrual cycle modulate gamma-aminobutyric acid (GABA) neuronal function. This study tests the hypothesis that cortical GABA neuronal function, reflected in brain GABA concentrations, fluctuates across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder (PMDD) and that a menstrual cycle phase-dependent abnormality in brain GABA concentrations in women diagnosed as having PMDD would reflect altered central response to circulating gonadal and neuroactive steroids. METHODS: Fourteen healthy menstruating women and 9 women diagnosed as having PMDD were recruited from a women's behavioral health research program located at a university-based medical center. The women underwent serial proton magnetic resonance spectroscopic measurements of occipital cortex GABA levels across the menstrual cycle (primary outcome measure) and had blood drawn for gonadal hormone and neurosteroid levels determined on each scan day (secondary outcome measure). RESULTS: There was a significant group x phase interaction with most of the finding explained by the reduction in cortical GABA levels during the follicular phase in those with PMDD compared with healthy controls. Cortical GABA levels declined across the menstrual cycle in healthy women, whereas women with PMDD experienced an increase in cortical GABA levels from the follicular phase to the mid luteal and late luteal phases. Significant between-group differences in the relationship between hormones and GABA were observed for estradiol, progesterone, and allopregnanolone. CONCLUSIONS: These data strongly suggest that the GABAergic system is substantially modulated by menstrual cycle phase in healthy women and those with PMDD. Furthermore, they raise the possibility of disturbances in cortical GABA neuronal function and modulation by neuroactive steroids as potentially important contributors to the pathogenesis of PMDD.

Adult↗
PubMed2002

Neuronal and glial metabolite content of the epileptogenic human hippocampus.

Mesial temporal lobe epilepsy is characterized by hippocampal atrophy, hypometabolism, and decreased N-acetylaspartate, often attributed to neuron loss and gliosis. Twenty hippocampal specimens were obtained during temporal lobectomy and frozen quickly. Perchloric acid extracts of the small metabolites were analyzed by proton magnetic resonance spectroscopy. There were no significant associations between hippocampal neuron loss and the cellular content of N-acetylaspartate, glutamate, GABA, glutamine, or aspartate. The mean metabolite content of hippocampi with less than 30% of neurons remaining was the same as those with greater than 65% of neurons surviving. Mean N-acetylaspartate levels were below those reported by in vivo studies of control subjects. The highest and the lowest glutamate concentrations were seen in specimens with the worst neuron loss. A highly significant association between hippocampal N-acetylaspartate and glutamate content was seen with weak associations between N-acetylaspartate and aspartate and glutamate and aspartate. The hippocampal content of N-acetylaspartate, glutamate, GABA, glutamine, and aspartate is altered minimally by severe neuron loss in mesial temporal lobe epilepsy. The epileptic human hippocampus has increased intracellular glutamate content that may contribute to the epileptogenic nature of hippocampal sclerosis.

Adult↗
PubMed2002

In vivo GABA editing using a novel doubly selective multiple quantum filter.

A novel multiple quantum filtering method is proposed that uses a doubly selective pulse termed Delays Alternating with Nutations for Tailored Excitation (DANTE) for multiple quantum preparation. This method selectively prepares GABA-3 and GABA-4 into a multiple quantum state and suppresses all other resonances at 3.0 ppm in each single scan. Phantom tests demonstrated excellent GABA signal retention and complete suppression of overlapping metabolites. It is shown using numerical simulations that overlapping macromolecules are suppressed because the frequency of the first upfield 2pi rotation of the doubly selective DANTE pulse coincides with that of the macromolecules at 1.72 ppm. Excellent suppression of overlapping macromolecules was demonstrated in vivo. Using this method the concentration of GABA in the occipital lobe of healthy volunteers was measured to be 1.21 +/- 0.28 micromol/mL (mean +/-SD, N = 9).

Adult↗
PubMed2002

Graded image segmentation of brain tissue in the presence of inhomogeneous radio frequency fields.

Image segmentation is used increasingly to interpret MR spectroscopic data of the brain, using image contrast to identify gray matter (GM), white matter (WM), and cerebral spinal fluid (CSF). T(1)- or T(2)-weighted images are typically used, but poor shimming, susceptibility effects, and small variations in B(1) and receptivity cause difficulties in tissue identification. Quantitative imaging of T(1) can reduce many of these difficulties but is still subject to complications when B(1) has large variations like those observed with the surface coils often used for spectroscopy. In this study, B(1) imaging was implemented to support quantitative imaging of T(1) with either a surface coil or a volume coil. The T(1) observed by this method is a continuous function across mixtures of WM/GM and GM/CSF, and this function was measured and used to convert the images of T(1) to maps of percent GM, WM, and CSF.

Brain↗
PubMed2002

Biophysical basis of brain activity: implications for neuroimaging.

In vivo 13C magnetic resonance spectroscopy (MRS) studies of the brain have quantitatively assessed rates of glutamate-glutamine cycle (Veye) and glucose oxidation (CMRGle(ox)) by detecting 13C label turnover from glucose to glutamate and glutamine. Contrary to expectations from in vitro and ex vivo studies, the in vivo 13C-MRS results demonstrate that glutamate recycling is a major metabolic pathway, inseparable from its actions of neurotransmission. Furthermore, both in the awake human and in the anesthetized rat brain, Veye and CMRGle(ox) are stoichiometrically related, where more than two thirds of the energy from glucose oxidation supports events associated with glutamate neurotransmission. The high energy consumption of the brain measured at rest and its quantitative relation to neurotransmission reflects a sizeable activity level for the resting brain. The high activity of the non-stimulated brain, as measured by cerebral metabolic rate of oxygen use (CMRO2), establishes a new neurophysiological basis of cerebral function that leads to reinterpreting functional imaging data because the large baseline signal is commonly discarded in cognitive neuroscience paradigms. Changes in energy consumption (delta CMRO2%) can also be obtained from magnetic resonance imaging (MRI) experiments, using the blood oxygen level-dependent (BOLD) image contrast, provided that all the separate parameters contributing to the functional MRI (fMRI) signal are measured. The BOLD-derived delta CMRO2% when compared with alterations in neuronal spiking rate (delta v%) during sensory stimulation in the rat reveals a stoichiometric relationship, in good agreement with 13C-MRS results. Hence fMRI when calibrated so as to provide delta CMRO2% can provide high spatial resolution evaluation of neuronal activity. Our studies of quantitative measurements of changes in neuroenergetics and neurotransmission reveal that a stimulus does not provoke an arbitrary amount of activity in a localized region, rather a total level of activity is required where the increment is inversely related to the level of activity in the non-stimulated condition. These biophysical experiments have established relationships between energy consumption and neuronal activity that provide novel insights into the nature of brain function and the interpretation of fMRI data.

Animals↗
PubMed2002

Glutamate-glutamine cycling in the epileptic human hippocampus.

PURPOSE: Several findings suggest that energy metabolism and the glutamate-glutamine cycle may be impaired in epilepsy. Positron emission tomography often shows interictal hypometabolism of the epileptogenic hippocampus. In vivo microdialysis studies show that seizure-associated glutamate release is doubled, and clearance is slowed. We hypothesized that the glutamate-glutamine cycle between neurons and glia may be decreased in the epileptic human hippocampus. METHODS: A 20% solution of 2-13C-glucose was infused before resection of the epileptogenic hippocampus. Blood glucose isotopic fractions were measured every 30 min. Blood and brain specimens were frozen quickly; perchloric acid extracts of the small metabolites were prepared and analyzed by proton and carbon magnetic resonance spectroscopy (MRS) at 11.75 Tesla. RESULTS: Standard histology showed 12 with hippocampal sclerosis and five with minimal neuron loss. The relative rates of glutamate-glutamine cycling with respect to glutamate synthesis were decreased in biopsies affected by hippocampal sclerosis (mean, 0.08; 95% confidence interval, 0.04-0.12) compared with those with minimal neuron loss (0.52; 95% CI, 0.30-0.75). Mean cellular glutamate concentrations were higher in minimal neuron loss (8.9 mM; 95% CI, 7.4-10.4) than hippocampal sclerosis (7.3 mM; 95% CI, 5.9-8.7). Cellular glutamine concentrations (mean, 2.8 mM; 95% CI, 2.4-3.2; n = 17) were the same in all groups. CONCLUSIONS: The epileptogenic, gliotic human hippocampus appears to be characterized metabolically by slow rates of glutamate-glutamine cycling, decreased glutamine content, and a relative increase in glutamate content. We hypothesize that the low rate of glutamate-glutamine cycling that results from a failure of glial glutamate detoxification could account for slow glutamate clearance from synapses and continuing low-grade excitotoxicity.

Adolescent↗
PubMed2002

[2,4-13 C2 ]-beta-Hydroxybutyrate metabolism in human brain.

Infusions of [2,4-13C2]-beta-hydroxybutyrate and 1H-13C polarization transfer spectroscopy were used in normal human subjects to detect the entry and metabolism of beta-hydroxybutyrate in the brain. During the 2-hour infusion study, 13C label was detectable in the beta-hydroxybutyrate resonance positions and in the amino acid pools of glutamate, glutamine, and aspartate. With a plasma concentration of 2.25 +/- 0.24 mmol/L (four volunteers), the apparent tissue beta-hydroxybutyrate concentration reached 0.18 +/- 0.06 mmol/L during the last 20 minutes of the study. The relative fractional enrichment of 13C-4-glutamate labeling was 6.78 +/- 1.71%, whereas 13C-4-glutamine was 5.68 +/- 1.84%. Steady-state modeling of the 13C label distribution in glutamate and glutamine suggests that, under these conditions, the consumption of the beta-hydroxybutyrate is predominantly neuronal, used at a rate of 0.032 +/- 0.009 mmol. kg-1. min-1, and accounts for 6.4 +/- 1.6% of total acetyl coenzyme A oxidation. These results are consistent with minimal accumulation of cerebral ketones with rapid utilization, implying blood-brain barrier control of ketone oxidation in the nonfasted adult human brain.

3-Hydroxybutyric Acid↗