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Douglas L Rothman

Publications and source records attributed to Douglas L Rothman.

At least 37 records · Page 2Linked to original sources
PubMed2005

Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy.

BACKGROUND: Given that nicotine modulates amino acid neurotransmission, we sought to examine the impact of nicotine on cortical gamma-aminobutyric acid (GABA) levels in male and female smokers. METHODS: Healthy nicotine-dependent men (n = 10) and women (n = 6) underwent proton magnetic resonance spectroscopy (1H-MRS) to measure occipital cortex GABA concentrations. A subset of the smoking men (n = 5) underwent 1H-MRS scans before and after 48 hours of smoking abstinence, whereas each of the women were scheduled to undergo pre- and postabstinence scans during the follicular and luteal phases of one menstrual cycle. Healthy nonsmoking men (n = 7) and women (n = 13) underwent 1H-MRS for comparison. RESULTS: Short-term abstinence had no significant effect on cortical GABA concentrations in either men or women. There was, however, a significant effect of sex, diagnosis (smoker/nonsmoker), and menstrual cycle phase on cortical GABA levels, such that female smokers experienced a significant reduction in cortical GABA levels during the follicular phase and no cyclicity in GABA levels across the menstrual cycle, whereas cortical GABA levels were similar in smoking and nonsmoking men. CONCLUSIONS: Taken together with previous 1H-MRS data showing abnormalities in occipital cortex GABA concentrations in several affective disorders, our preliminary finding that nicotine modulation of GABA levels varies by sex provides a further rationale for investigating the impact of nicotine on central GABAergic function as a potential risk factor for women to experience depressive symptoms during smoking cessation.

Adult↗
PubMed2005

Adaptation in the rodent olfactory bulb measured by fMRI.

Effective evaluation of the odor environment necessitates the ability to attenuate responses to potent background odors in favor of novel and less robust stimuli. Olfactory receptor neuron studies suggest that some of this adaptation takes place in the primary sensory neurons, but the more extensive adaptation seen in higher cortical areas implies the involvement of additional neural mechanisms. At 7.0 T, high-resolution fMRI was used to assess the response of the rodent olfactory bulb, the most peripheral cortical structure involved in olfactory processing, to a variety of odor stimuli. The results suggest that there are additional regulatory mechanisms in the olfactory bulb that result in greater adaptation in deeper areas than that seen in sensory receptors alone and that the resultant adaptation is positively affected by increasing stimulus duration and concentration and decreasing recovery time. The implications of these findings for the integration of peripheral input with perception are discussed.

Adaptation, Physiological↗
PubMed2004

Regional glucose metabolism and glutamatergic neurotransmission in rat brain in vivo.

Multivolume (1)H-[(13)C] NMR spectroscopy in combination with i.v. [1,6-(13)C(2)]glucose infusion was used to detect regional glucose metabolism and glutamatergic neurotransmission in the halothane-anesthetized rat brain at 7 T. The regional information was decomposed into pure cerebral gray matter, white matter, and subcortical structures by means of tissue segmentation based on quantitative T(1) relaxation mapping. The (13)C turnover curves of [4-(13)C]glutamate, [4-(13)C]glutamine, and [3-(13)C]glutamate + glutamine were fitted with a two-compartment neuronal-astroglial metabolic model. The neuronal tricarboxylic acid cycle fluxes in cerebral gray matter, white matter, and subcortex were 0.79 +/- 0.15, 0.20 +/- 0.11, and 0.42 +/- 0.09 micromol/min per g, respectively. The glutamate-glutamine neurotransmitter cycle fluxes in cerebral gray matter, white matter, and subcortex were 0.31 +/- 0.07, 0.02 +/- 0.04, and 0.18 +/- 0.12 micromol/min per g, respectively. The exchange rate between the mitochondrial and cytosolic metabolite pools was fast relative to the neuronal tricarboxylic acid cycle flux for all cerebral tissue types.

Animals↗
PubMed2004

Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression.

BACKGROUND: Measurement of cortical gamma-aminobutyric acid (GABA) and glutamate concentrations is possible using proton magnetic resonance spectroscopy. An initial report, using this technique, suggested that occipital cortex GABA concentrations are reduced in patients with major depressive disorder (MDD) relative to healthy comparison subjects. OBJECTIVES: To replicate the GABA findings in a larger sample of MDD patients, to examine the clinical correlates of the GABA reductions in these subjects, and to examine other critical metabolite levels. DESIGN: Study for association. SETTING: Academic clinical research program. PARTICIPANTS: The GABA measurements were made on 38 healthy control subjects and 33 depressed subjects. INTERVENTIONS: Occipital cortex metabolite levels were measured using proton magnetic resonance spectroscopy. MAIN OUTCOME MEASURES: The levels of occipital cortex GABA, glutamate, N-acetylaspartate, aspartate, creatine, and choline-containing compounds, along with several measures of tissue composition, were compared between the 2 groups. RESULTS: Depressed subjects had significantly lower occipital cortex GABA concentrations compared with healthy controls (P =.01). In addition, mean glutamate levels were significantly increased in depressed subjects compared with healthy controls (P<.001). Significant reductions in the percentage of solid tissue (P =.009) and the percentage of white matter (P =.04) in the voxel were also observed. An examination of a combined database including subjects from the original study suggests that GABA and glutamate concentrations differ among MDD subtypes. CONCLUSIONS: The study replicates the findings of decreased GABA concentrations in the occipital cortex of subjects with MDD. It also demonstrates that there is a change in the ratio of excitatory-inhibitory neurotransmitter levels in the cortex of depressed subjects that may be related to altered brain function. Last, the combined data set suggests that magnetic resonance spectroscopy GABA measures may serve as a biological marker for a subtype of MDD.

Adult↗
PubMed2004

Energetic basis of brain activity: implications for neuroimaging.

The complex activities of the brain need not distract us from the certainty that it uses energy and performs work very efficiently. The human brain, which claims approximately 2% of our body mass, is responsible for approximately 20% of our body oxygen consumption. In vivo magnetic resonance spectroscopy (MRS) follows the metabolic pathways of energy production (as glucose oxidation) and work (as monitored by the cycling of glutamate and GABA neurotransmitters). In the resting awake state, approximately 80% of energy used by the brain supports events associated with neuronal firing and cycling of GABA and glutamate neurotransmitters. Small differences in neuronal activity between stimulation and control conditions can be measured and localized using functional magnetic resonance imaging (fMRI). MRS and fMRI experiments show that the majority of cerebral activity, which is often disregarded in imaging experiments, is ongoing even when the brain appears to be doing nothing.

Animals↗
PubMed2004

Basic principles of metabolic modeling of NMR (13)C isotopic turnover to determine rates of brain metabolism in vivo.

Metabolic modeling is a necessary part of the analysis of isotopic labeling data that is being obtained in the brain and other organs. Here are explained the basic principles of metabolic modeling of isotopic labeling studies, particularly with regard to (13)C isotopic measurements performed in vivo. The basic elements needed to simulate isotopic flows are described, and how to combine them to perform modeling analyses is explained. Procedures to introduce and evaluate model constraints and simplifications are discussed. The basic principle of isotopomer analysis is explained, as are mechanics of least-squares fitting of simulations to data. Closely related to the fitting is the effect of data scatter, which is discussed in the context of the non-normal distributions of uncertainty that are often seen with (13)C labeling measurements in vivo. This article is meant to provide a general background for investigators to begin to apply metabolic modeling analysis to (13)C isotopic labeling studies performed in vivo.

Brain↗
PubMed2004

Dynamic fMRI and EEG recordings during spike-wave seizures and generalized tonic-clonic seizures in WAG/Rij rats.

Generalized epileptic seizures produce widespread physiological changes in the brain. Recent studies suggest that "generalized" seizures may not involve the whole brain homogeneously. For example, electrophysiological recordings in WAG/Rij rats, an established model of human absence seizures, have shown that spike-and-wave discharges are most intense in the perioral somatosensory cortex and thalamus, but spare the occipital cortex. Is this heterogeneous increased neuronal activity matched by changes in local cerebral blood flow sufficient to meet or exceed cerebral oxygen consumption? To investigate this, we performed blood oxygen level-dependent functional magnetic resonance imaging (fMRI) measurements at 7T with simultaneous electroencephalogram recordings. During spontaneous spike-wave seizures in WAG/Rij rats under fentanylhaloperidol anesthesia, we found increased fMRI signals in focal regions including the perioral somatosensory cortex, known to be intensely involved during seizures, whereas the occipital cortex was spared. For comparison, we also studied bicuculline-induced generalized tonic-clonic seizures under the same conditions, and found fMRI increases to be larger and more widespread than during spike-and-wave seizures. These findings suggest that even in regions with intense neuronal activity during epileptic seizures, oxygen delivery exceeds metabolic needs, enabling fMRI to be used for investigation of dynamic cortical and subcortical network involvement in this disorder.

Animals↗
PubMed2004

Glutamatergic neurotransmission and neuronal glucose oxidation are coupled during intense neuronal activation.

13C nuclear magnetic resonance (NMR) experiments have previously shown that glutamatergic neurotransmitter flux (Vcycle(Glu/Gln)) changes proportionately with neuronal glucose oxidation (CMRglc(ox)N) in the nonactivated cortex of anesthetized rats. Positron Emission Tomography measurements of glucose and oxygen uptake during sensory stimulation had shown that the incremental glucose utilization is greater than oxygen leading to the suggestion that the energy required for stimulated neuronal activity arises from nonoxidative glucose metabolism. In this study, the authors used spatially localized 1H-observed, 13C-edited NMR spectroscopy during an infusion of [1,6-13C2]glucose to assess the relationship between changes in Vcycle(Glu/Gln) and glucose utilization (CMRglc(ox)N and CMRglc(nonox)) during the intense cortical activity associated with bicuculline-induced seizures. Metabolic fluxes were determined by model-based analysis of the 13C-enrichment time courses of glutamate-C4 and glutamine-C4 (CMRglc(ox)N, Vcycle(Glu/Gln)) and lactate-C3 (CMRglc(nonox)). The exchange rate between alpha-ketoglutarate and glutamate was found to be significantly faster than TCA cycle flux both for control (41 micromol.g(-1).min(-1); 95% CI, 5 to 109 micromol.g(-1).min(-1)) and during seizures (21 micromol.g(-1).min(-1); 95% CI, 4.4 to 51.8 micromol.g(-1).min(-1)). During seizures, total glucose utilization (CMRglc(ox+nonox)) increased substantially (466% between 0 and 6 minutes; 277% between 6 and 55 minutes). Glucose oxidation (CMRglc(ox)N) also increased (214%; from 0.26 +/- 0.02 to 0.57 +/- 0.07 micromol.g(-1).min(-1)) but to a lesser degree, resulting in a large increase in cortical lactate concentration. Vcycle(Glu/Gln) increased 233% (from 0.22 +/- 0.04 to 0.52 +/- 0.07 micromol.g(-1).min(-1)), which was similar to the increase in glucose oxidation. The value of Vcycle(Glu/Gln) and CMRglc(ox)N obtained here lie on the line predicted in a previous study. These results indicate that neuronal glucose oxidation and not total glucose utilization is coupled to the glutamate/glutamine cycle during intense cortical activation.

Animals↗
PubMed2004

Impaired GABA neuronal response to acute benzodiazepine administration in panic disorder.

OBJECTIVE: Disturbances in the metabolism of the brain amino acid transmitter gamma-aminobutyric acid (GABA) may contribute to the pathophysiology of human anxiety disorders. Animal studies indicate that deletions or reductions in the expression of the gene for the GABA synthetic enzyme, glutamate decarboxylase 65 (GAD(65)), reduce basal cortical GABA levels or stress-induced release of GABA in the cerebral cortex and increase fear behaviors. Complementing these findings, the authors recently observed lower than normal cortical GABA levels in patients with panic disorder. In the current study, the authors tested the hypothesis that panic disorder patients have a deficient GABA neuronal response to benzodiazepine (clonazepam) administration. METHOD: In a parallel-group, repeated-measures design, occipital cortex GABA responses to acute oral, open-label benzodiazepine administration were tested in 10 panic disorder patients and nine healthy comparison subjects. Occipital cortex total GABA levels were measured before and after medication administration by means of a novel proton magnetic resonance spectroscopic technique. RESULTS: Panic disorder patients had a deficient GABA neuronal response (blunted reduction of occipital cortex GABA level) to acute benzodiazepine administration, compared to the healthy subjects, who exhibited a significant decrease in occipital cortex GABA levels after this intervention. The patients also appeared to have persistently low occipital cortex GABA after chronic benzodiazepine treatment. CONCLUSIONS: Overall, these data are consistent with the hypothesis that a trait-like abnormality in GABA neuronal function contributes to the pathogenesis of human panic disorder. The data raise the possibility that GAD(65) enzyme dysfunction could be a pathogenic factor in panic disorder.

Adult↗
PubMed2003

Odor maps of aldehydes and esters revealed by functional MRI in the glomerular layer of the mouse olfactory bulb.

Odorant identity is believed to be encoded in the olfactory bulb (OB) by glomerular activity patterns. It has not yet been possible to visualize and compare entire patterns for different odorants in the same animal because of technical limitations. For this purpose we used high-resolution functional MRI at 7 T, combined with glomerular-layer flat maps, to reveal responses to aliphatic homologues in the mouse OB. These odorants elicited reproducible patterns in the OB, with the medial and lateral regions containing the most intense signals. Unexpectedly, in view of the symmetrical projections of olfactory receptor neurons to medial and lateral glomeruli, the activity patterns in these regions were asymmetrical. The highly activated medial and lateral areas were shared by homologous members, generating a conserved "family signature" for a homologous series. The moderately active areas, including the dorsal region that has been extensively studied by optical imaging, were more sensitive to the length of the carbon chain, producing more subtle features of individual members and different changing trends among homologues. The global mapping with functional MRI not only extended previous studies but also revealed additional rules for representation of homologues in the OB. Insights into possible relations between the functional patterns, molecular projections, and odor perception may now be obtained based on the global from the olfactory epithelium to the OB glomerular activity patterns.

Aldehydes↗
PubMed2003

Mitochondrial dysfunction in the elderly: possible role in insulin resistance.

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes in the elderly. To investigate how insulin resistance arises, we studied healthy, lean, elderly and young participants matched for lean body mass and fat mass. Elderly study participants were markedly insulin-resistant as compared with young controls, and this resistance was attributable to reduced insulin-stimulated muscle glucose metabolism. These changes were associated with increased fat accumulation in muscle and liver tissue assessed by 1H nuclear magnetic resonance (NMR) spectroscopy, and with a approximately 40% reduction in mitochondrial oxidative and phosphorylation activity, as assessed by in vivo 13C/31P NMR spectroscopy. These data support the hypothesis that an age-associated decline in mitochondrial function contributes to insulin resistance in the elderly.

Adipose Tissue↗
PubMed2003

Smoking impairs muscle recovery from exercise.

Cigarette smoking is a leading cause of many adverse health consequences. Chronic nicotine exposure leads to insulin resistance and may increase the risk of developing non-insulin-dependent diabetes mellitus in young otherwise healthy smokers. To evaluate smoking-induced effects on carbohydrate metabolism, we studied muscle glycogen recovery from exercise in a young healthy population of smokers. The study used 31P-13C NMR spectroscopy to compare muscle glycogen and glucose 6-phosphate levels during recovery in exercised gastrocnemius muscles of randomized cohorts of healthy male smokers (S) and controls (C). Data for the two groups were as follows: S, > or =20 cigarettes/day (n = 8), 24 +/- 2 yr, 173 +/- 3 cm, 70 +/- 4 kg and age- and weight-matched nonsmoking C (n = 10), 23 +/- 1 yr, 175 +/- 3 cm, 67 +/- 3 kg. Subjects performed single-leg toe raises to deplete glycogen to approximately 20 mmol/l, and glycogen resynthesis was measured during the first 4 h of recovery. Plasma samples were assayed for glucose and insulin at rest and during recovery. Test subjects were recruited from the general community surrounding Yale University. Glycogen was depleted to similar levels in the two groups [23.5 +/- 1.2 (S) and 19.1 +/- 1.3 (C) mmol/l]. During the 1st h of recovery, glycogen synthesis rates were similar [13.8 +/- 1.1 (S) and 15.3 +/- 1.3 (C) mmol x l-1 x h-1]. Between hours 1 and 4, glycogen synthesis was impaired in smokers [0.8 +/- 0.2 (S) and 4.5 +/- 0.5 (C) mmol x l-1 x h-1, P = 0.0002] compared with controls. Glucose 6-phosphate was reduced in smokers during hours 1-4 [0.105 +/- 0.006 (S) and 0.217 +/- 0.019 (C) mmol/l, P = 0.0212]. We conclude that cigarette smoking impairs the insulin-dependent portion of muscle recovery from glycogen-depleting exercise. This impairment likely results from a reduction in glucose uptake.

Adult↗
PubMed2003

Magnetic resonance spectroscopy of neurotransmitters in human brain.

Magnetic resonance spectroscopy (MRS) is a noninvasive method that permits measurement of the concentration of specific biochemical compounds in the brain and other organ systems in precisely defined regions guided by MR imaging (MRI). Recently, MRS methods have been developed to measure specific neurotransmitters in the brain. More advanced MRS methods have been developed to measure the synthesis rates and turnover of specific neurotransmitters. These turnover rates can provide measures of brain metabolism similar to radioisotope techniques. Also, investigations of the relationship of brain metabolism and specific neurotransmitter systems are now possible using MRS. Here, we review the MRS techniques and studies of neurotransmitters in the human brain. A discussion of the potential use of these techniques in the context of certain pediatric neurotransmitter disorders will be presented.

Brain Chemistry↗
PubMed2003

Detection of [1,6-13C2]-glucose metabolism in rat brain by in vivo 1H-[13C]-NMR spectroscopy.

Localized, water-suppressed (1)H-[(13)C]-NMR spectroscopy was used to detect (13)C-label accumulation in cerebral metabolites following the intravenous infusion of [1,6-(13)C(2)]-glucose (Glc). The (1)H-[(13)C]-NMR method, based on adiabatic RF pulses, 3D image-selected in vivo spectroscopy (ISIS) localization, and optimal shimming, yielded high-quality (1)H-[(13)C]-NMR spectra with optimal NMR sensitivity. As a result, the (13)C labeling of [4-(13)C]-glutamate (Glu) and [4-(13)C]-glutamine (Gln) could be detected from relatively small volumes (100 microL) with a high temporal resolution. The formation of [n-(13)C]-Glu, [n-(13)C]-Gln (n = 2 or 3), [2-(13)C]-aspartate (Asp), [3-(13)C]-Asp, [3-(13)C]-alanine (Ala), and [3-(13)C]-lactate (Lac) was also observed to be reproducible. The (13)C-label incorporation curves of [4-(13)C]-Glu and [4-(13)C]-Gln provided direct information on metabolic pathways. Using a two-compartment metabolic model, the tricarboxylic acid (TCA) cycle flux was determined as 0.52 +/- 0.04 micromol/min/g, while the glutamatergic neurotransmitter flux equaled 0.25 +/- 0.05 micromol/min/g, in good correspondence with previously determined values.

Animals↗
PubMed2003

Dynamic shim updating (DSU) for multislice signal acquisition.

Dynamic shim updating (DSU) is a technique for achieving optimal magnetic field homogeneity over extended volumes by dynamically updating an optimal shim setting for each individual slice in a multislice acquisition protocol. Here the practical implementation of DSU using all first- and second-order shims is described. In particular, the hardware modifications and software requirements are demonstrated. Furthermore, the temporal effects of dynamically switching shim currents are investigated and a Z(2)-to-Z(0) compensation unit is described and implemented to counteract the temporal Z(0) variations following a change in the Z(2) shim current. The optimal shim settings for all slices are determined with a quantitative and user-independent, multislice phase-mapping sequence. The performance of DSU is evaluated from multislice phase maps and spectroscopic images acquired on rat brain in vivo. DSU improved the magnetic field homogeneity over all spatial slices, with a more pronounced effect on the slices positioned away from the magnet isocenter, thereby making the magnetic field homogeneity highly uniform over an extended volume.

Animals↗
PubMed2003

Adiabatic RARE imaging.

The practical implementation of ultra-fast spin-echo, or RARE imaging with adiabatic RF pulses and surface coil transmission at 7 T is described. Despite the large RF inhomogeneities, the adiabatic character of the 180 degrees BIR-4 refocusing pulses ensures optimal sensitivity and minimal image artifacts. An internal 'phase-cycle' is used to remove spurious unwanted coherences. The short T(2) relaxation times in rat brain at 7 T demand a centric, rather than a linear coverage of k-space in order to avoid excessive signal loss. T(2) relaxation during k-space coverage also leads to image blurring, which can be counteracted by interleaved k-space sampling. The coverage of k-space in four acquisitions provides high-quality anatomical images comparable to conventional spin-echo images. A two-scan RARE implementation provides sufficient spatial and temporal resolution for most applications. Quantitative mapping of T(1) relaxation and cerebral blood flow changes during forepaw stimulation in the rat are demonstrated.

Animals↗
PubMed2003

Dominant events that modulate mass transfer coefficient of oxygen in cerebral cortex.

Recently, a model of cerebral oxygen delivery was described (J Appl Physiol 85:554) which yields a relationship similar to that used to depict substrate transport across the endothelium. Because the endothelium is not a diffusion barrier for oxygen, the permeability surface area product was replaced by an effective mass transfer coefficient term for oxygen, D. The cerebral metabolic rate of oxygen utilization (CMRO2) was linked to cerebral blood flow (CBF) and volume (CBV) through properties that modify the vessel-to-tissue oxygen tension giving rise to changes in D. Changes in the value of D were correlated with changes in CBF, CMRO2, and CBV as measured using NMR methods in a 48 microL volume of the cerebral cortex of anesthetized rats at different levels of activity. We conclude that the changes in total vascular volume (i.e., swelling or shrinking of the capillary bed) contributes < 5% to changes in D, whereas variations in the number of hematic vs. plasmatic capillaries, or intra-capillary stacking vs. unpacking of erythrocytes, or increase vs. decrease of dissolved oxygen in the tissue (i.e., processes which modify vessel-to-tissue oxygen tension) contribute(s) > 95% to changes in D.

Animals↗