Showing papers by "Robin A. de Graaf published in 2015"

Effects of γ-Aminobutyric acid transporter 1 inhibition by tiagabine on brain glutamate and γ-Aminobutyric acid metabolism in the anesthetized rat In vivo.

Abstract: γ-Aminobutyric acid (GABA) clearance from the extracellular space after release from neurons involves reuptake into terminals and astrocytes through GABA transporters (GATs). The relative flows through these two pathways for GABA released from neurons remains unclear. This study determines the effect of tiagabine, a selective inhibitor of neuronal GAT-1, on the rates of glutamate (Glu) and GABA metabolism and GABA resynthesis via the GABA-glutamine (Gln) cycle. Halothane-anesthetized rats were administered tiagabine (30 mg/kg, i.p.) and 45 min later received an intravenous infusion of either [1,6-(13)C2]glucose (in vivo) or [2-(13)C]acetate (ex vivo). Nontreated rats served as controls. Metabolites and (13)C enrichments were measured with (1)H-[(13)C]-nuclear magnetic resonance spectroscopy and referenced to their corresponding endpoint values measured in extracts from in situ frozen brain. Metabolic flux estimates of GABAergic and glutamatergic neurons were determined by fitting a metabolic model to the (13)C turnover data measured in vivo during [1,6-(13)C2]glucose infusion. Tiagabine-treated rats were indistinguishable (P > 0.05) from controls in tissue amino acid levels and in (13)C enrichments from [2-(13)C]acetate. Tiagabine reduced average rates of glucose oxidation and neurotransmitter cycling in both glutamatergic neurons (↓18%, CMR(glc(ox)Glu): control, 0.27 ± 0.05 vs. tiagabine, 0.22 ± 0.04 µmol/g/min; ↓11%, V(cyc(Glu-Gln)): control 0.23 ± 0.05 vs. tiagabine 0.21 ± 0.04 µmol/g/min and GABAergic neurons (↓18-25%, CMR(glc(ox)GABA): control 0.09 ± 0.02 vs. tiagabine 0.07 ± 0.03 µmol/g/min; V(cyc(GABA-Gln)): control 0.08 ± 0.02 vs. tiagabine 0.07 ± 0.03 µmol/g/min), but the changes in glutamatergic and GABAergic fluxes were not significant (P > 0.10). The results suggest that any reduction in GABA metabolism by tiagabine might be an indirect response to reduced glutamatergic drive rather than direct compensatory effects.

Quantification of 1H NMR Spectra from Human Plasma.

Abstract: Human plasma is a biofluid that is high in information content, making it an excellent candidate for metabolomic studies. 1H NMR has been a popular technique to detect several dozen metabolites in blood plasma. In order for 1H NMR to become an automated, high-throughput method, challenges related to (1) the large signal from lipoproteins and (2) spectral overlap between different metabolites have to be addressed. Here diffusion-weighted 1H NMR is used to separate lipoprotein and metabolite signals based on their large difference in translational diffusion. The metabolite 1H NMR spectrum is then quantified through spectral fitting utilizing full prior knowledge on the metabolite spectral signatures. Extension of the scan time by 3 minutes or 15% per sample allowed the acquisition of a 1H NMR spectrum with high diffusion weighting. The metabolite 1H NMR spectra could reliably be modeled with 28 metabolites. Excellent correlation was found between results obtained with diffusion NMR and ultrafiltration. The combination of minimal sample preparation together with minimal user interaction during processing and quantification provides a metabolomics technique for automated, quantitative 1H NMR of human plasma.

Multi‐slice MRI with the dynamic multi‐coil technique

Abstract: To date, spatial encoding for MRI is based on linear X, Y and Z field gradients generated by dedicated X, Y and Z wire patterns. We recently introduced the dynamic multi-coil technique (DYNAMITE) for the generation of magnetic field shapes for biomedical MR applications from a set of individually driven localized coils. The benefits for B0 magnetic field homogenization have been shown, as well as proof of principle of radial and algebraic MRI. In this study the potential of DYNAMITE MRI is explored further and the first multi-slice MRI implementation in which all gradient fields are purely DYNAMITE based is presented. The obtained image fidelity is shown to be virtually identical to that of a conventional MRI system with dedicated X, Y and Z gradient coils. Comparable image quality is a milestone towards the establishment of fully functional DYNAMITE MRI (and shim) systems.

High-sensitivity, broadband-decoupled (13) C MR spectroscopy in humans at 7T using two-dimensional heteronuclear single-quantum coherence.

Abstract: Purpose Carbon-13 (13C) magnetic resonance spectroscopy (MRS) has an intrinsically low NMR sensitivity that often leads to large acquisition volumes or long scan times. While the use of higher magnetic fields can overcome the sensitivity limitations, high radiofrequency (RF) power deposition associated with proton-decoupling limits the achievable gain. Two-dimensional (2D) heteronuclear single quantum coherence (HSQC) MRS is a method that uses the high chemical specificity of 13C MRS while retaining the high sensitivity of 1H detection. Due to the 2D nature of the method, proton-decoupled 13C MR spectra can be obtained without the use of high-powered decoupling pulses. Methods A novel three-dimensional (3D) localized 2D HSQC method based on 3D STEAM localization is presented and implemented at 7T. The low RF power deposition of the method allows TR variation along the indirect dimension which, in combination with controlled aliasing, leads to an acceleration of 11.8 relative to a standard 2D NMR acquisition. Results Artifact-free, high-quality and high-sensitivity 2D HSQC spectra were obtained for all subjects in 19 min from a small (9 mL) volume placed in the leg adipose tissue. Complete proton decoupling was achieved along the indirect 13C dimension despite the absence of broadband proton-decoupling pulses. The high chemical specificity along the indirect 13C dimension allowed the detection of 19 unique resonances from which the lipids could be characterized in terms of saturation and omega-6/omega-3 fatty acid ratio. Conclusion It has been demonstrated that high-quality 2D HSQC NMR spectra can be acquired from human adipose tissue at 7T. The HSQC method is methodologically simple and robust and is flexible regarding trade-offs between temporal and spectral resolution. 2D HSQC has a strong potential to become a default method in natural-abundance or 13C-enriched studies of human metabolism in vivo. Magn Reson Med 74:903–914, 2015. © 2014 Wiley Periodicals, Inc.

Superconductor Analog-to-Digital Converter for High-Resolution Magnetic Resonance Imaging

Abstract: Magnetic resonance imaging (MRI) requires a sensitive radio receiver to detect the weak resonant magnetic field from nuclear spins, usually hydrogen in biological tissues. In a typical static magnetic field of 1.5 T, a transient RF magnetic field at 63 MHz must be measured to fT amplitudes. This must be amplified and then digitized with an analog-to-digital converter (ADC) with a high dynamic range (typically 16 bits), in order to obtain high image resolution. As the magnetic field is increased in order to obtain even finer resolution, the required dynamic range is expected to increase further. A superconductor ADC (oversampling at 20 GHz) has previously been demonstrated to exhibit very high dynamic range (up to 24 bits) as part of a receiver for broadband digital-RF communication. Here, we present preliminary results on a similar ADC applied to a 4 T commercial small-animal MRI system, substituted for the built-in 16-bit ADC. The superconductor ADC was mounted on a 4 K cryocooler in a magnetically shielded container outside the MRI room and functioned well despite the presence nearby of a large static field and a high-power RF transmitter. Images were obtained either using direct digitization of the 170-MHz signals or, alternatively, using a low-noise analog mixer and digitization of a 1-MHz intermediate frequency signal. While the results demonstrated the superior dynamic range of the superconductor ADC, further improvement was limited by the thermal noise from the room-temperature pickup coil. Current work is investigating the use of a cryocooled coil (which may be superconducting) and a cold low-noise preamplifier in order to take full advantage of the large dynamic range of the superconductor ADC. This should permit improved spatial resolution, allowing one to “zoom in” to a region of interest.