GABA, glutamatergic dynamics and BOLD contrast assessed concurrently using functional MRS during a cognitive task

A recurring issue in functional neuroimaging is how to link task-driven haemodynamic blood oxygen level dependent functional MRI (BOLD-fMRI) responses to underlying neurochemistry at the synaptic level. Glutamate and γ-aminobutyric acid (GABA), the major excitatory and inhibitory neurotransmitters respectively, are typically measured with MRS sequences separately from fMRI, in the absence of a task. The present study aims to resolve this disconnect, developing acquisition and processing techniques to simultaneously assess GABA, glutamate and glutamine (Glx) and BOLD in relation to a cognitive task, at 3 T. Healthy subjects (N = 81) performed a cognitive task (Eriksen flanker), which was presented visually in a task-OFF, task-ON block design, with individual event onset timing jittered with respect to the MRS readout. fMRS data were acquired from the medial anterior cingulate cortex during task performance, using an adapted MEGA-PRESS implementation incorporating unsuppressed water-reference signals at a regular interval. These allowed for continuous assessment of BOLD activation, through T2*-related changes in water linewidth. BOLD-fMRI data were additionally acquired. A novel linear model was used to extract modelled metabolite spectra associated with discrete functional stimuli, building on well established processing and quantification tools. Behavioural outcomes from the flanker task, and activation patterns from the BOLD-fMRI sequence, were as expected from the literature. BOLD response assessed through fMRS showed a significant correlation with fMRI, specific to the fMRS-targeted region of interest; fMRS-assessed BOLD additionally correlated with lengthening of response time in the incongruent flanker condition. While no significant task-related changes were observed for GABA+, a significant increase in measured Glx levels (~8.8%) was found between task-OFF and task-ON periods. These findings verify the efficacy of our protocol and analysis pipelines for the simultaneous assessment of metabolite dynamics and BOLD. As well as establishing a robust basis for further work using these techniques, we also identify a number of clear directions for further refinement in future studies.publishedVersio

Multi-vendor standardized sequence for edited magnetic resonance spectroscopy

Spectral editing allows direct measurement of low-concentration metabolites, such as GABA, glutathione (GSH) and lactate (Lac), relevant for understanding brain (patho)physiology. The most widely used spectral editing technique is MEGA-PRESS, which has been diversely implemented across research sites and vendors, resulting in variations in the final resolved edited signal. In this paper, we describe an effort to develop a new universal MEGA-PRESS sequence with HERMES functionality for the major MR vendor platforms with standardized RF pulse shapes, durations, amplitudes and timings. New RF pulses were generated for the universal sequence. Phantom experiments were conducted on Philips, Siemens, GE and Canon 3 T MRI scanners using 32-channel head coils. In vivo experiments were performed on the same six subjects on Philips and Siemens scanners, and on two additional subjects, one on GE and one on Canon scanners. On each platform, edited MRS experiments were conducted with the vendor-native and universal MEGA-PRESS sequences for GABA (TE = 68 ms) and Lac editing (TE = 140 ms). Additionally, HERMES for GABA and GSH was performed using the universal sequence at TE = 80 ms. The universal sequence improves inter-vendor similarity of GABA-edited and Lac-edited MEGA-PRESS spectra. The universal HERMES sequence yields both GABA- and GSH-edited spectra with negligible levels of crosstalk on all four platforms, and with strong agreement among vendors for both edited spectra. In vivo GABA+/Cr, Lac/Cr and GSH/Cr ratios showed relatively low variation between scanners using the universal sequence. In conclusion, phantom and in vivo experiments demonstrate successful implementation of the universal sequence across all four major vendors, allowing editing of several metabolites across a range of TEs.publishedVersio

Across‐vendor standardization of semi‐LASER for single‐voxel MRS at 3T

The semi‐adiabatic localization by adiabatic selective refocusing (sLASER) sequence provides single‐shot full intensity signal with clean localization and minimal chemical shift displacement error and was recommended by the international MRS Consensus Group as the preferred localization sequence at high‐ and ultra‐high fields. Across‐vendor standardization of the sLASER sequence at 3 tesla has been challenging due to the B1 requirements of the adiabatic inversion pulses and maximum B1 limitations on some platforms. The aims of this study were to design a short‐echo sLASER sequence that can be executed within a B1 limit of 15 μT by taking advantage of gradient‐modulated RF pulses, to implement it on three major platforms and to evaluate the between‐vendor reproducibility of its perfomance with phantoms and in vivo. In addition, voxel‐based first and second order B0 shimming and voxel‐based B1 adjustments of RF pulses were implemented on all platforms. Amongst the gradient‐modulated pulses considered (GOIA, FOCI and BASSI), GOIA‐WURST was identified as the optimal refocusing pulse that provides good voxel selection within a maximum B1 of 15 μT based on localization efficiency, contamination error and ripple artifacts of the inversion profile. An sLASER sequence (30 ms echo time) that incorporates VAPOR water suppression and 3D outer volume suppression was implemented with identical parameters (RF pulse type and duration, spoiler gradients and inter‐pulse delays) on GE, Philips and Siemens and generated identical spectra on the GE ‘Braino’ phantom between vendors. High‐quality spectra were consistently obtained in multiple regions (cerebellar white matter, hippocampus, pons, posterior cingulate cortex and putamen) in the human brain across vendors (5 subjects scanned per vendor per region; mean signal‐to‐noise ratio [less than] 33; mean water linewidth between 6.5 Hz to 11.4 Hz). The harmonized sLASER protocol is expected to produce high reproducibility of MRS across sites thereby allowing large multi‐site studies with clinical cohorts

Frequency drift in MR spectroscopy at 3T

Purpose: Heating of gradient coils and passive shim components is a common cause of instability in the B-0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites.Method: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC).Results: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p &lt; 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI.Discussion: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.</p

Imaging of the human heart and NMR thermography in phantoms for deep hyperthermia

Titel Inhaltsverzeichnis 1 Einleitung 1 2 Grundlagen der Magnetresonanz 5 2.1 Kernmagnetisierung 5 2.2 Blochsche Gleichungen 7 2.3 Relaxation 8 2.4 Kernresonanz 10 2.5 Chemische Verschiebung 12 2.6 Ortskodierung 13 2.7 Magnetresonanzspektroskopie 26 2.8 Kontrast 28 2.9 Signal-Rausch-Verhältnis 30 3 Der Hochfeld-3-Tesla-Tomograph 32 3.1 Supraleitender Magnet 32 3.2 Gradientensystem 33 3.3 HF-System 35 3.4 Spulen 37 4 Tagging-Phantomexperimente 47 4.1 Tagging-Präparations-Sequenz 47 4.2 Experimenteller Aufbau 59 4.3 Experimente 63 4.4 Schlußfolgerung 68 5 Bildgebung des menschlichen Herzens bei 3 Tesla 70 5.1 Anatomie und Physiologie des menschlichen Herzens 71 5.2 Segmentierte TurboGRASS-Sequenz 73 5.3 Messung der T2*-Relaxationszeiten im Myokard 91 5.4 Messung der T1-Relaxationszeiten im Myokard und Blut 93 5.5 Messung der B0-Feldverteilung im Herzen 94 5.6 Messung des Signal-Rausch-Verhältnisses im Myokard 96 5.7 Vergleichsmessung an einem 1,5-Tesla-Tomographen 105 5.8 Messung des Kontrast-Rausch-Verhältnisses zwischen Blut und Myokard 108 5.9 Tagging 108 5.10 Schlußfolgerung 109 6 Grundlagen der MR-Thermometrie 112 6.1 Hyperthermie 112 6.2 Temperaturabhängige Parameter 116 7 Thermosonden-Methode 121 7.1 Pr-MOE-DO3A 124 7.2 Spektroskopische Bildgebung 129 7.3 Schnelle spektroskopische Bildgebung 138 7.4 Schlußfolgerung 145 8 Zusammenfassung 148 A Sequenzen-Programmierung 152 A.1 Puls- und Gradientenprogramm 152 A.2 ACQP und IMND 155 B Messung der k-Raum-Trajektorien 157 C Spektral und räumlich selektiver Anregungspuls 159 D HLSVD 162 Literaturverzeichnis 167 Veröffentlichungen Danksagung LebenslaufZiel der Arbeit war es, für ausgewählte medizinische Anwendungen die Eignung einer NMR-Tomographie bei 3 Tesla und die mit der hohen Feldstärke verbundenen Vor- und Nachteile zu untersuchen. Für die Herzbildgebung bei 3 T wurde eine schnelle EKG-getriggerte und flußkompensierte Gradienten-Echo-Sequenz implementiert und optimiert sowie auf ihr Artefaktverhalten hin untersucht. Mit dieser Sequenz konnten innerhalb einer Atemanhalteperiode (17 Herzschläge) artefaktfreie Schnittbilder beliebiger Orientierung, u.a. auch Kurzachsenschnitte, sowie sogenannte Cine- Sequenzen, d.h. die Abbildung der Herzbewegung in einer Schicht während des Herzzyklus, aufgenommen werden. Durch den Einsatz speziell für die Herzbildgebung entwickelter und gebauter Mehr-Element-Oberflächen- Empfangsspulen in Kombination mit dem Ganzkörperresonator als Sendespule wurde im Mittel eine Steigerung des Signal-Rausch-Verhältnisses (S/R) etwa um den Faktor 2 gegenüber Messungen bei 1,5 T erzielt. Die durch Bereiche unterschiedlicher magnetischer Suszeptibilitäten verursachte größere B0-Feldinhomogenität (± 1 ppm) und die daraus resultierenden kürzeren T2*-Relaxationszeiten im linken Ventrikel (< 20 ms) erschweren die Herzbildgebung bei 3 T im Vergleich zu niedrigeren Feldstärken, wobei insbesondere die artefaktanfällige Echtzeitbildgebung betroffen sein sollte. Die durch Suszeptibilitätseffekte bedingte Verkürzung der T2*-Relaxationszeiten mit steigender Feldstärke läßt hingegen einen höheren BOLD-(Blood Oxygenation Level Dependent)-Kontrast erwarten, der zur Messung der Gewebe-Oxygenierung und Perfusion ausgenutzt werden kann. Bei 3 T erreicht die HF-Wellenlänge im Menschen die Abmessungen im Körper, so daß dielektrische Resonanzen die elektromagnetische Feldverteilung im Körper beeinflussen, was zu einer inhomogenen B1-Feldverteilung führen kann. Zusammen mit der für denselben Drehwinkel der Magnetisierung bei gleicher HF-Pulslänge benötigten höheren Sendeleistung (Faktor 4 gegenüber 1,5 T) wird somit in erheblichem Maße der Einsatz von Spin-Echo- sowie verschiedenen Präparationssequenzen erschwert. Im zweiten Teil der Arbeit wurde eine MR-Thermographiemethode (Thermosonden- Methode), bei der als Kontrastmittel ein paramagnetischer Praseodym-Chelat (Pr-MOE-DO3A) eingesetzt wird, in Kombination mit einem schnellen spektroskopischen Bildgebungsverfahren (Echo Planar Spectroscopic Imaging, EPSI) hinsichtlich der Eignung für eine Therapiekontrolle während einer regionalen Hyperthermie-Behandlung untersucht. In einem Phantom wurde mit der EPSI-Methode die Verteilung der absoluten Temperatur in einem Volumen von 24 ´ 24 ´ 24 cm3 (Voxelgröße 1,5 ´ 1,5 ´ 1,5 cm3) innerhalb von 14 s mit einer Genauigkeit von ± 0,45 °C gemessen. Diese Arbeit hat gezeigt, daß mit der hohen Feldstärke nicht nur Vorteile, sondern auch erhebliche Nachteile verbunden sind. Deshalb erscheint der Einsatz der MR-Bildgebung und -Spektroskopie bei hohen Feldstärken (? 3 T) zwar in der medizinischen Forschung und für spezielle Anwendungen der medizinischen Diagnostik und Therapiekontrolle sinnvoll, jedoch ist ein Ersatz der hochentwickelten MR-Tomographie bei niedrigeren Feldstärken (1,0 1,5 T) eher unwahrscheinlich.The aim of this work was to demonstrate the feasibility of NMR tomography at 3 Tesla for selected medical applications and to investigate the advantages and disadvantages of the high field strength. For cardiac imaging a fast, ECG gated, flow compensated gradient echo sequence was implemented and optimized. Within a breath-hold period (17 heartbeats) artifact-free images of slices of any desired orientation, e.g. short axis slices, and cine-sequences, i.e. the movement of the heart within a slice during the heart cycle, could be acquired. With the use of specially developed multi-element surface coils for receiving in combination with the whole body resonator for transmitting, an increase in signal-to-noise ratio (SNR) by a factor of 2 was achieved compared to a field strength of 1.5 T. Regions of different magnetic susceptibility cause larger B0 inhomogeneities (± 1 ppm), leading to shorter T2* relaxation times within the left ventricle (< 20 ms). Therefore cardiac imaging, and especially the use of real-time imaging sequences, which are prone to artifacts, is likely to be ore difficult at 3 T compared to lower field strength. The decrease of T2* with increasing magnetic field strength is attributed to susceptibility effects; hence a higher BOLD (Blood Oxygenation Level Dependent) contrast is expected at 3 T, which can be exploited for tissue oxygenation and perfusion measurements. At 3 T the RF-wavelength within the body is comparable to body dimensions, thus dielectric resonances influence the electromagnetic field distribution. This may lead to B1 field inhomogeneities. Furthermore, compared to 1.5 T, 4 fold higher RF-power is needed to achieve the same flip angle of the magnetization at the same pulse length. Therefore the use of spin echo sequences and various preparation sequences is more difficult at 3 T. In the second part of the work a MR thermography technique (temperature probe method), using a paramagnetic Praseodymium complex (Pr-MOE-DO3A) as a contrast media, was investigated in combination with a fast spectroscopic imaging technique (Echo Planar Spectroscopic Imaging, EPSI) aiming at therapy control of regional hyperthermia treatment. Using the EPSI method, in a phantom the distribution of absolute temperature was measured in a volume of 24 ´ 24 ´ 24 cm3 (voxel size 1.5 ´ 1.5 ´ 1.5 cm3) within 14 s to an accuracy of ± 0,45 °C. This work demonstrates that the use of higher field strengths is not only accompanied by advantages but also by substantial disadvantages. Although having great potential for medical research and special areas of medical diagnostics and therapy control, MR imaging and spectroscopy at high field strengths (? 3 T) is unlikely to replace the clinically well-established MR tomography at lower field strengths (1.0 1.5 T)

Comprehensive cardiac magnetic resonance imaging at 3.0 Tesla: feasibility and implications for clinical applications

OBJECTIVE: The objective of this study was to examine the applicability of high magnetic field strengths for comprehensive functional and structural cardiac magnetic resonance imaging (MRI). SUBJECTS AND METHODS: Eighteen subjects underwent comprehensive cardiac MRI at 1.5 T and 3.0 T. The following imaging techniques were implemented: double and triple inversion prepared FSE for anatomic imaging, 4 different sets of echocardiographic-gated CINE strategies for functional and flow imaging, inversion prepared gradient echo for delayed enhancement imaging, T1-weighted segmented EPI for perfusion imaging and 2-dimensional (2-D) spiral, and volumetric SSFP for coronary artery imaging. RESULTS:: Use of 3 Tesla as opposed to 1.5 Tesla provided substantial baseline signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) improvements for anatomic (T1-weighted double IR: DeltaSNR = 29%, DeltaCNR = 20%, T2-weighted double IR: DeltaSNR = 39%, DeltaCNR = 33%, triple IR: DeltaSNR = 74%, DeltaCNR = 60%), functional (conventional CINE: DeltaSNR = 123%, DeltaCNR = 74%, accelerated CINE: DeltaSNR = 161%, DeltaCNR = 86%), myocardial tagging (DeltaSNRsystole = 54%, DeltaCNRsystole = 176%), phase contrast flow measurements (DeltaSNR = 79%), viability (DeltaSNR = 48%, DeltaCNR = 40%), perfusion (DeltaSNR = 109%, DeltaCNR = 87%), and breathhold coronary imaging (2-D spiral: DeltaSNRRCA = 54%, DeltaCNRRCA = 69%, 3-D SSFP: DeltaSNRRCA = 60%, DeltaCNRRCA = 126%), but also revealed image quality issues, which were successfully tackled by adiabatic radiofrequency pulses and parallel imaging. CONCLUSIONS: Cardiac MRI at 3.0 T is feasible for the comprehensive assessment of cardiac morphology and function, although SAR limitations and susceptibility effects remain a concern. The need for speed together with the SNR benefit at 3.0 T will motivate further advances in routine cardiac MRI while providing an image-quality advantage over imaging at 1.5 Tesla

STEAM-MiTiS: An MR Spectroscopy Method for the Detection of Scalar-Coupled Metabolites and Its Application to Glutamate at 7 T

Purpose: We herein present a spectroscopic technique for the detection of scalar-coupled metabolites based on stimulated echo acquisition mode (STEAM). The method is based on the time evolution of scalar-coupled metabolites at different mixing times and a constant echo time. The technique is optimized for targeting the metabolite glutamate at 7T. Methods: Numerical simulations were used to optimize the parameters to maximize the chosen metabolite signal. The maximum detection efficiency and metabolite signal as a function of echo time were used to identify the optimal parameters. In vitro and in vivo validations of the method were also performed. Results: This method canceled all the strong singlet lines and signals from macromolecules and preserved signals originating from the scalar-coupled metabolites. The subtracted spectrum was strongly simplified, but the complete spectral information of the traditional STEAM acquisition was retained in the sum spectrum. Conclusions: The simulations performed in this study were in agreement with the experimental results, and a clear detection of the metabolite of interest was obtained. The applicability in vivo was also demonstrated, with the selective detection of glutamate in human brain. This technique is simple, suitable for standard MR systems without sequence programming and could be used to detect other metabolites

STEAM-MiTiS: An MR Spectroscopy Method for the Detection of Scalar-Coupled Metabolites and Its Application to Glutamate at 7 T

Purpose: We herein present a spectroscopic technique for the detection of scalar-coupled metabolites based on stimulated echo acquisition mode (STEAM). The method is based on the time evolution of scalar-coupled metabolites at different mixing times and a constant echo time. The technique is optimized for targeting the metabolite glutamate at 7T. Methods: Numerical simulations were used to optimize the parameters to maximize the chosen metabolite signal. The maximum detection efficiency and metabolite signal as a function of echo time were used to identify the optimal parameters. In vitro and in vivo validations of the method were also performed. Results: This method canceled all the strong singlet lines and signals from macromolecules and preserved signals originating from the scalar-coupled metabolites. The subtracted spectrum was strongly simplified, but the complete spectral information of the traditional STEAM acquisition was retained in the sum spectrum. Conclusions: The simulations performed in this study were in agreement with the experimental results, and a clear detection of the metabolite of interest was obtained. The applicability in vivo was also demonstrated, with the selective detection of glutamate in human brain. This technique is simple, suitable for standard MR systems without sequence programming and could be used to detect other metabolites

Imaging glutamate redistribution after acute N-acetylcysteine administration: A simultaneous PET/MR study

Glutamate is the most abundant excitatory neurotransmitter in the human brain, but in vivo imaging of acute fluctuations in glutamatergic levels has not been well established. The purpose of this study was to examine acute changes in glutamate after stimulation with N-acetylcysteine (NAC) using a simultaneous positron emission tomography/magnetic resonance spectroscopy (PET/MRS) approach. Ten healthy adult males were examined in two scanning sessions, and 5g NAC was administered 1 h prior to one of the scan sessions. Simultaneous PET/MR data were acquired using an integrated 3T PET/MR scanner. Glutamate (Glu), glutamine (Gln), and glutamate + glutamine (Glx) levels were assessed from MRS data collected from the basal ganglia with PRESS and from the left prefrontal cortex with PRESS and MEGAPRESS, and mGluR5 binding (BPND) was assessed from PET data collected with [F-18]PSS232. NAC administration was associated with a significant reduction in Glx and Gln in the basal ganglia spectra, and in Glx in the frontal MEGAPRESS spectra (p < 0.05); no differences in [F-18]PSS232 BPND were observed with NAC, although a correlation between pre-/post-treatment Glx and baseline BPnd was found. The MRS-visible Glx signal is sensitive to acute fluctuations in glutamate. The change in Glx was mostly driven by a change in Gln, lending weight to the notion that Gln can provide a proxy marker for neurotransmitter/synaptic glutamate. [F-18]PSS232 binding is not sensitive to acute glutamate shifts independently, but was associated with the extent of glutamate liberation upon NAC stimulation

Imaging glutamate redistribution after acute N-acetylcysteine administration: A simultaneous PET/MR study

Glutamate is the most abundant excitatory neurotransmitter in the human brain, but in vivo imaging of acute fluctuations in glutamatergic levels has not been well established. The purpose of this study was to examine acute changes in glutamate after stimulation with N-acetylcysteine (NAC) using a simultaneous positron emission tomography/magnetic resonance spectroscopy (PET/MRS) approach. Ten healthy adult males were examined in two scanning sessions, and 5g NAC was administered 1 h prior to one of the scan sessions. Simultaneous PET/MR data were acquired using an integrated 3T PET/MR scanner. Glutamate (Glu), glutamine (Gln), and glutamate + glutamine (Glx) levels were assessed from MRS data collected from the basal ganglia with PRESS and from the left prefrontal cortex with PRESS and MEGAPRESS, and mGluR5 binding (BP) was assessed from PET data collected with [F]PSS232. NAC administration was associated with a significant reduction in Glx and Gln in the basal ganglia spectra, and in Glx in the frontal MEGAPRESS spectra (p < 0.05); no differences in [F]PSS232 BP were observed with NAC, although a correlation between pre-/post-treatment Glx and baseline BPnd was found. The MRS-visible Glx signal is sensitive to acute fluctuations in glutamate. The change in Glx was mostly driven by a change in Gln, lending weight to the notion that Gln can provide a proxy marker for neurotransmitter/synaptic glutamate. [F]PSS232 binding is not sensitive to acute glutamate shifts independently, but was associated with the extent of glutamate liberation upon NAC stimulation