Biomedical subjects

Douglas L Rothman

Publications and source records attributed to Douglas L Rothman.

At least 19 recordsLinked to original sources

PubMed2007

A BOLD search for baseline.

While we occasionally observe negative BOLD signals, its physiological basis has remained uncertain. This is in part due to the qualitative use of fMRI where the baseline is conveniently differenced away to reveal focal area(s) of interest. Recently, however, there has been a noticeable trend towards quantitative neuroimaging where changes in oxidative energetics (CMR(O2)) are quantified by calibrated fMRI. Pasley et al. [Pasley, B.N., Inglis, B.A., Freeman, R.D., 2007. Analysis of oxygen metabolism implies a neural origin for the negative BOLD response in human visual cortex. NeuroImage] used calibrated fMRI in conjunction with a novel stimulus paradigm to investigate the neural basis of the negative BOLD signal in awake humans. They hypothesized - based on prior results - that if the baseline was lowered then DeltaCMR(O2) would have to be larger. While their main findings point to an energetic basis for the negative BOLD signal, their results have far reaching implications for the present definition of baseline as well as for future research investigating the neural and/or energetic basis of baseline.

Adult↗

PubMed2006

Rapid calculations of susceptibility-induced magnetostatic field perturbations for in vivo magnetic resonance.

Static magnetic field perturbations generated by variations of magnetic susceptibility within samples reduce the quality and integrity of magnetic resonance measurements. These perturbations are difficult to predict in vivo where wide variations of internal magnetic susceptibility distributions are common. Recent developments have provided rapid computational means of estimating static field inhomogeneity within the small susceptibility limits of materials typically studied using magnetic resonance. Such a predictive mechanism could be a valuable tool for sequence simulation, field shimming and post-acquisition image correction. Here, we explore this calculation protocol and demonstrate its predictive power in estimating in vivo inhomogeneity within the human brain. Furthermore, we quantitatively explore the predictive limits of the computation. For in vivo comparison, a method of magnetic susceptibility registration using MRI and CT data is presented and utilized to carry out subject-specific inhomogeneity estimation. Using this algorithm, direct comparisons in human brain and phantoms are made between field map acquisitions and calculated inhomogeneity. Distortion correction in echo-planar images due to static field inhomogeneity is also demonstrated using the computed field maps.

Air↗

PubMed2006

Measurements of the anaplerotic rate in the human cerebral cortex using 13C magnetic resonance spectroscopy and [1-13C] and [2-13C] glucose.

Recent studies in rodent and human cerebral cortex have shown that glutamate-glutamine neurotransmitter cycling is rapid and the major pathway of neuronal glutamate repletion. The rate of the cycle remains controversial in humans, because glutamine may come either from cycling or from anaplerosis via glial pyruvate carboxylase. Most studies have determined cycling from isotopic labeling of glutamine and glutamate using a [1-(13)C]glucose tracer, which provides label through neuronal and glial pyruvate dehydrogenase or via glial pyruvate carboxylase. To measure the anaplerotic contribution, we measured (13)C incorporation into glutamate and glutamine in the occipital-parietal region of awake humans while infusing [2-(13)C]glucose, which labels the C2 and C3 positions of glutamine and glutamate exclusively via pyruvate carboxylase. Relative to [1-(13)C]glucose, [2-(13)C]glucose provided little label to C2 and C3 glutamine and glutamate. Metabolic modeling of the labeling data indicated that pyruvate carboxylase accounts for 6 +/- 4% of the rate of glutamine synthesis, or 0.02 micromol/g/min. Comparison with estimates of human brain glutamine efflux suggests that the majority of the pyruvate carboxylase flux is used for replacing glutamate lost due to glial oxidation and therefore can be considered to support neurotransmitter trafficking. These results are consistent with observations made with arterial-venous differences and radiotracer methods.

Carbon Isotopes↗

PubMed2006

Dynamics of changes in blood flow, volume, and oxygenation: implications for dynamic functional magnetic resonance imaging calibration.

Changes in cerebral blood flow (CBF), volume (CBV), and oxygenation (blood-oxygenation level dependent (BOLD)) during functional activation are important for calculating changes in cerebral metabolic rate of oxygen consumption (CMRo2) from calibrated functional MRI (fMRI). An important part of this process is the CBF/CBV relationship, which is signified by a power-law parameter: gamma=ln (1+DeltaCBV/CBV)/ln (1+DeltaCBF/CBF). Because of difficulty in measuring CBF and CBV with MRI, the value of gamma is therefore assumed to be approximately 0.4 from a prior primate study under hypercapnia. For dynamic fMRI calibration, it is important to know if the value of gamma varies after stimulation onset. We measured transient relationships between DeltaCBF, DeltaCBV, and DeltaBOLD by multimodal MRI with temporal resolution of 500 ms (at 7.0 T) from the rat somatosensory cortex during forepaw stimulation, where the stimulus duration ranged from 4 to 32 secs. Changes in CBF and BOLD were measured before the administration of the contrast agent for CBV measurements in the same subjects. We observed that the relationship between DeltaCBF and DeltaCBV varied dynamically from stimulation onset for all stimulus durations. Typically after stimulation onset and at the peak or plateau of the DeltaCBF, the value of gamma ranged between 0.1 and 0.2. However, after stimulation offset, the value of gamma increased to 0.4 primarily because of rapid and slow decays in DeltaCBF and DeltaCBV, respectively. These results suggest caution in using dynamic measurements of DeltaCBF and DeltaBOLD required for calculating DeltaCMRo2 for functional stimulation, when either DeltaCBV has not been accurately measured or a fixed value of gamma during hypercapnia perturbation is used.

Animals↗

PubMed2006

The interaction of neuroactive steroids and GABA in the development of neuropsychiatric disorders in women.

A growing literature suggests that hormonal fluctuations occurring across the menstrual cycle, during and after pregnancy, and during the menopausal transition are associated with onset of affective disorders or exacerbation of existing disorders. This influence of the neuroendocrine system on psychiatric disorders is thought to be mediated by an abnormality in central nervous system response to neuroactive steroids such as estradiol, progesterone, and the progesterone derivative allopregnanolone (ALLO). This interplay is considerably complex as neuroactive steroids modulate the function of multiple neurotransmitter systems throughout various stages of development. While one could choose to study any number of steroid-neurotransmitter interactions, our group in addition to others has focused our investigative efforts on unraveling the contribution of neuroactive steroids to psychiatric syndromes and disorders via their modulation of gamma aminobutyric acid (GABA), the brain's major inhibitory neurotransmitter. The goal of this article is two-fold: to synthesize the clinical and preclinical research focusing on the interplay between neuroactive steroids and GABA as they relate to neuropsychiatric and substance use disorders in women and to integrate data from our laboratory using proton magnetic resonance spectroscopy into this context.

Affect↗

PubMed2006

Sample-specific diamagnetic and paramagnetic passive shimming.

When homogenizing the static magnetic field over extended in vivo volumes, significant residual inhomogeneity can remain after spherical harmonic shim optimization. This is due to the low spatial orders of shims available on in vivo MR systems and the presence of higher-order inhomogeneity in the vicinity of anatomic air cavities. Mediation of this problem through the development of higher-order spherical harmonic shims is severely impeded by bore space limitations. Sample-specific passive shims are not limited to low-order spatial compensation and offer an alternative means to increased homogenization. Here, we present a novel construction protocol for sample-specific passive shims comprised of both diamagnetic (bismuth) and paramagnetic (zirconium) materials. A prototype shim is constructed and shown to significantly homogenize the mouse brain at 9.4 T. Further homogenization capabilities are simulated through alteration of the shim construction.

Animals↗

PubMed2006

Preliminary evidence of reduced occipital GABA concentrations in puerperal women: a 1H-MRS study.

RATIONALE: Childbirth is associated with rapid neuroendocrine fluctuations, which are thought to contribute to the phatogenesis of postpartum major depression (PPD). OBJECTIVES: The aim of this proton magnetic resonance spectroscopy (1H-MRS) study was two-fold; 1) to examine whether puerperium is associated with alterations in occipital cortex gamma-aminobutyric acid (GABA) concentrations and 2) to determine whether such alterations may be more prominent in women with PPD. MATERIALS AND METHODS: Nine women with PPD, 14 postpartum healthy controls, and ten healthy follicular phase females underwent 1H-MRS at 2.1 Tesla to measure occipital cortex GABA concentrations. Postpartum women were scanned within 6 months of delivery and prior to resumption of menstruation. Healthy non-puerperal controls, drawn from a historical sample, were scanned during the early to mid-follicular phase when ovarian hormone levels would be similar to those found in the puerperium. GABA data were analyzed using analysis of covariance, and regression models were used to explore the relationship between cortical GABA concentrations and blood levels of estradiol, progesterone, and neurosteroids. RESULTS: Cortical GABA and plasma allopregnanolone (ALLO) concentrations were reduced in both groups of postpartum women, regardless of PPD diagnosis, compared to healthy follicular phase women. There was no correlation between cortical GABA concentrations and estradiol, progesterone, ALLO, or pregnenolone (PREG). CONCLUSIONS: This study is the first to describe reductions in occipital cortex GABA levels in the postpartum period, a time of increased vulnerability to mood disturbances in women. The concomitant reduction in peripheral ALLO levels provides further evidence of alterations in the balance between cortical excitation and inhibition during the puerperium. Women with PPD may represent a subgroup of women who fail to adequately adapt to this alteration in the neuroendocrine milieu.

Adult↗

PubMed2006

Reproducibility of odor maps by fMRI in rodents.

The interactions of volatile odorants with the approximately 1000 types of olfactory receptor neurons in the olfactory mucosa are represented in the olfactory bulb by glomerular spatial activity maps. If these spatial maps underlie the perceptual identification of odorants then, for a given organism, they must be both specific and reproducible. However, this intra-organism reproducibility need not be present between organisms because genetic and developmental studies of olfactory bulb wiring suggest that there is substantial variation between the glomerular arrangements of closely related organisms and even between the two bulbs in a given animal. The ability of functional MRI (fMRI) to record responses of the entire rodent olfactory bulb repeatedly within the same subject has made it possible to assess the reproducibility of odor-induced spatial activity maps both within and between subjects exposed to equivalent stimuli. For a range of odorants, representing multiple chemical classes, a level of fMRI reproducibility (at 7.0 T and 9.4 T) comparable or superior to other cortical regions was demonstrated. While the responses of different bulbs to the same odorant could be localized within the same broad regions of the glomerular sheet, the precise magnitude and topology of the response within those regions were both often highly variable. These results demonstrate the robustness of high-field fMRI as a tool for assaying olfactory bulb function and provide evidence that equivalent perceptual outcomes may arise from divergent neural substrates.

Animals↗

PubMed2006

Dynamic shim updating on the human brain.

Dynamic alteration of shim settings during a multi-slice imaging experiment can improve static magnetic-field homogeneity over extended volumes. In this report, a pre-emphasized dynamic shim updating (DSU) system capable of rapidly updating all non-degenerate zeroth through second-order shims is presented and applied to high-field multi-slice imaging studies on the human brain. DSU is utilized in both non-oblique and oblique slicing geometries while updating in-plane and through-slice shims. Image-based magnetic-field maps are used to quantify homogeneity improvements and comparisons are made on a slice-specific basis between static global shimming and increasing orders of shim inclusion utilized DSU. The influence of oblique slicing geometry on DSU-utilized global homogeneity is also quantified computationally. Finally, the effect of DSU on susceptibility artifact reduction in single-shot axial-sliced EPI is analyzed using experimental acquisitions.

Artifacts↗

PubMed2006

Acute regulation of steady-state GABA levels following GABA-transaminase inhibition in rat cerebral cortex.

Cellular GABA levels are determined by the dynamic balance between synthesis and catabolism and are regulated at the level of glutamate decarboxylase, precursor availability (e.g., glutamate and glutamine), and possibly GABA degradation. GABA levels rise and stabilize within hours in human cortex following orally administered vigabatrin, an irreversible inhibitor of GABA-T, suggesting potential product inhibition of GABA synthesis or enhanced GABA degradation through the non-inhibited GABA-T fraction. In this study time courses of the rise in cortical GABA were measured in anesthetized rats in vivo after vigabatrin treatment using localized (1)H magnetic resonance spectroscopy and the times to reach steady-state for a given dose were determined. Rates of GABA synthesis were estimated for the period of constant GABA level from the accumulation of [2-(13)C]GABA following a short intravenous infusion (20 min) of either [1,6-(13)C(2)]glucose or [2-(13)C]acetate. No evidence of product inhibition of glutamate decarboxylase by the increased GABA concentration or reduced synthesis from [1,6-(13)C(2)]glucose (control, 0.031+/-0.010; vigabatrin-treated, 0.037+/-0.004 micromol/g/min, P=0.30) or [2-(13)C]acetate (control, 0.078+/-0.010; vigabatrin-treated, 0.084+/-0.006 micromol/g/min, P=0.42) was found. Fractional changes in steady-state GABA levels and GABA-T activities 5-6 h after vigabatrin treatment were approximately equal. The lack of change in GABA synthesis (and GABA catabolic flux for constant GABA levels) suggests that GABA-T has a near-zero flux control coefficient in vivo-capable of greatly altering the steady-state GABA concentration but exerting little or no control on GABA synthesis or GABA/glutamine cycling flux. The findings are consistent with a Michaelis-Menten kinetic model whereby cellular GABA levels increase until flux through the remaining (uninhibited) transaminase equals the rate of GABA synthesis. The findings suggest that astroglia may be the site of continuing GABA catabolism after acute vigabatrin treatment.

4-Aminobutyrate Transaminase↗

PubMed2006

Neuronal-glial glucose oxidation and glutamatergic-GABAergic function.

Prior 13C magnetic resonance spectroscopy (MRS) experiments, which simultaneously measured in vivo rates of total glutamate-glutamine cycling (V(cyc(tot))) and neuronal glucose oxidation (CMR(glc(ox), N)), revealed a linear relationship between these fluxes above isoelectricity, with a slope of approximately 1. In vitro glial culture studies examining glutamate uptake indicated that glutamate, which is cotransported with Na+, stimulated glial uptake of glucose and release of lactate. These in vivo and in vitro results were consolidated into a model: recycling of one molecule of neurotransmitter between glia and neurons was associated with oxidation of one glucose molecule in neurons; however, the glucose was taken up only by glia and all the lactate (pyruvate) generated by glial glycolysis was transferred to neurons for oxidation. The model was consistent with the 1:1 relationship between DeltaCMR(glc(ox), N) and DeltaV(cyc(tot)) measured by 13C MRS. However, the model could not specify the energetics of glia and gamma-amino butyric acid (GABA) neurons because quantitative values for these pathways were not available. Here, we review recent 13C and 14C tracer studies that enable us to include these fluxes in a more comprehensive model. The revised model shows that glia produce at least 8% of total oxidative ATP and GABAergic neurons generate approximately 18% of total oxidative ATP in neurons. Neurons produce at least 88% of total oxidative ATP, and take up approximately 26% of the total glucose oxidized. Glial lactate (pyruvate) still makes the major contribution to neuronal oxidation, but approximately 30% less than predicted by the prior model. The relationship observed between DeltaCMR(glc(ox), N) and DeltaV(cyc(tot)) is determined by glial glycolytic ATP as before. Quantitative aspects of the model, which can be tested by experimentation, are discussed.

Animals↗

PubMed2006

High magnetic field water and metabolite proton T1 and T2 relaxation in rat brain in vivo.

Comprehensive and quantitative measurements of T1 and T2 relaxation times of water, metabolites, and macromolecules in rat brain under similar experimental conditions at three high magnetic field strengths (4.0 T, 9.4 T, and 11.7 T) are presented. Water relaxation showed a highly significant increase (T1) and decrease (T2) with increasing field strength for all nine analyzed brain structures. Similar but less pronounced effects were observed for all metabolites. Macromolecules displayed field-independent T2 relaxation and a strong increase of T1 with field strength. Among other features, these data show that while spectral resolution continues to increase with field strength, the absolute signal-to-noise ratio (SNR) in T1/T2-based anatomical MRI quickly levels off beyond approximately 7 T and may actually decrease at higher magnetic fields.

Animals↗

PubMed2006

Brain homocarnosine and seizure control of patients taking gabapentin or topiramate.

PURPOSE: To assess the relation between seizure control and brain homocarnosine and gamma-aminobutyric acid (GABA) levels of patients with complex partial seizures taking gabapentin (GBP) or topiramate (TPM) as adjunctive therapy. METHODS: In vivo measurements of GABA and homocarnosine were made of a 14-cc volume in the occipital cortex by using (1)H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Poor seizure control was defined as more recent seizures than the median for the two groups of patients studied. RESULTS: Homocarnosine levels were higher in patients with better seizure control than in those with poor control. No differences were found in the intracellular GABA levels between the patients who responded to GBP or TPM compared with those who did not. CONCLUSIONS: In the visual neocortex, which is remote from the presumed seizure-onset zone, higher homocarnosine levels were associated with better seizure control in the patients taking GBP or TPM as adjunctive therapy; elevated intracellular GABA levels appeared to offer no additional protection.

Adult↗

PubMed2006

Increased brain monocarboxylic acid transport and utilization in type 1 diabetes.

We hypothesized that increased capacity for brain utilization of nonglucose substrates (monocarboxylic acids [MCAs]) by upregulation of the MCA transporters may contribute metabolic substrates during hypoglycemia. To test this hypothesis, we assessed brain acetate metabolism in five well-controlled type 1 diabetic subjects and six nondiabetic control subjects using 13C magnetic resonance spectroscopy during infusions of [2-(13)C]acetate during hypoglycemia (approximately 55 mg/dl). Acetate is transported into the brain through MCA transporters that are also used for lactate and ketones. Brain acetate concentrations were over twofold higher in the subjects with diabetes than the control subjects (P = 0.01). The fraction of oxidative metabolism from acetate (P = 0.015) and the rate of MCA transport (P = 0.01) were also approximately twofold higher in the diabetic subjects. We conclude that during hypoglycemia MCA transport in the brain was increased by approximately twofold in patients with well-controlled type 1 diabetes, as reflected by higher brain acetate concentrations and rates of acetate oxidation. This upregulation would potentially allow a similar twofold increase in the transport of other MCAs, including lactate, during insulin-induced hypoglycemia. These data are consistent with the hypothesis that upregulation of MCA transport may contribute to the maintenance of brain energetics during hypoglycemia in patients with type 1 diabetes.

Acetates↗

PubMed2005

Cortical gamma-aminobutyric acid levels and the recovery from ethanol dependence: preliminary evidence of modification by cigarette smoking.

BACKGROUND: Gamma-aminobutyric acid (GABA)ergic adaptations contribute to the neurobiology of ethanol dependence and withdrawal. Clinical data suggest that tobacco smoking attenuates alcohol withdrawal symptoms. This study's objective was to measure time-dependent cortical GABA levels with sobriety in ethanol-dependent patients with mild to moderate withdrawal severity, controlling for alcoholism-related neurotoxicity and smoking. METHODS: Proton magnetic resonance spectroscopy (MRS) was used to measure occipital cortical N-acetylaspartate (NAA), glutamate plus glutamine, and GABA in 12 ethanol-dependent men at approximately 1 week and 1 month of medication-free sobriety on an inpatient unit. Eight healthy men were studied once. The tissue composition of the MRS volume was determined. RESULTS: Adjusting for less white matter in patients, GABA differed insignificantly between ethanol-dependent patients (smokers plus nonsmokers) and healthy subjects. In early sobriety, nonsmoking patients had more GABA than did smoking patients, but by 1 month, GABA decreased in nonsmokers without changing in smokers. Smoking was associated with increased glutamate plus glutamine in patients and healthy subjects, adjusting for NAA levels. CONCLUSIONS: These data do not show that deficits in cortical GABA contribute directly to acute ethanol withdrawal. If smoking prevents withdrawal-related changes in cortical GABA systems, it may contribute to comorbidity of alcoholism and tobacco smoking.

Adult↗

PubMed2005

Simultaneous activation of mouse main and accessory olfactory bulbs by odors or pheromones.

It is generally believed that the main olfactory system processes common odors and the accessory olfactory system is specifically for pheromones. The potential for these two systems to respond simultaneously to the same stimuli has not been fully explored due to methodological limitations. Here we examine this phenomenon using high-resolution functional magnetic resonance imaging (fMRI) to reveal simultaneously the responses in the main (MOB) and accessory olfactory bulbs (AOB) to odors and pheromones. Common odorants elicited strong signals in the MOB and weak signals in the AOB. 2-Heptanone, a known mouse pheromone, elicited strong signals in both the MOB and AOB. Urine odor, a complicated mixture of pheromones and odorants, elicited significant signals in limited regions of the MOB and large regions of the AOB. The fMRI results demonstrate that both the main and the accessory olfactory systems may respond to volatile compounds but with different selectivity, suggesting a greater integration of the two olfactory pathways than traditionally believed.

Animals↗

PubMed2005

Cortical gamma-aminobutyric acid concentrations in depressed patients receiving cognitive behavioral therapy.

BACKGROUND: Reduced gamma-aminobutyric acid (GABA) concentrations have been reported in plasma, cerebrospinal fluid, and cortex of depressed subjects. Treatment with both electroconvulsive therapy (ECT) and selective serotonin reuptake inhibitors (SSRI) increased occipital cortex GABA concentrations in prior studies. The purpose of this study was to determine whether treatment of major depression with cognitive behavioral therapy (CBT) produces similar changes in cortical GABA concentrations. METHODS: Occipital cortex GABA concentrations were measured in eight subjects with Major Depressive Disorder prior to and after a course of CBT using proton magnetic resonance spectroscopy. RESULTS: The effect of CBT on occipital cortex GABA content was different than that seen for ECT and SSRI medication treatment of depressed patients. CONCLUSIONS: This preliminary finding suggests CBT has a less robust effect on cortical GABA content than ECT and SSRI treatments and might indicate a difference between the mechanisms of antidepressant action.

Adult↗

PubMed2005

The contribution of GABA to glutamate/glutamine cycling and energy metabolism in the rat cortex in vivo.

Previous studies have shown that the glutamate/glutamine (Glu/Gln) neurotransmitter cycle and neuronal glucose oxidation are proportional (1:1), with increasing neuronal activity above isoelectricity. GABA, a product of Glu metabolism, is synthesized from astroglial Gln and contributes to total Glu/Gln neurotransmitter cycling, although the fraction contributed by GABA is unknown. In the present study, we used (13)C NMR spectroscopy together with i.v. infusions of [1,6-(13)C(2)]glucose and [2-(13)C]acetate to separately determine rates of Glu/Gln and GABA/Gln cycling and their respective tricarboxylic acid cycles in the rat cortex under conditions of halothane anesthesia and pentobarbital-induced isoelectricity. Under 1% halothane anesthesia, GABA/Gln cycle flux comprised 23% of total (Glu plus GABA) neurotransmitter cycling and 18% of total neuronal tricarboxylic acid cycle flux. In isoelectric cortex, glucose oxidation was reduced >3-fold in glutamatergic and GABAergic neurons, and neurotransmitter cycling was below detection. Hence, in both cell types, the primary energetic costs are associated with neurotransmission, which increase together as cortical activity is increased. The contribution of GABAergic neurons and inhibition to cortical energy metabolism has broad implications for the interpretation of functional imaging signals.

Acetates↗