Short symmetric and highly selective asymmetric first and second order gradient modulated offset independent adiabaticity (GOIA) pulses for applications in clinical MRS and MRSI.

Gradient modulated RF pulses, especially gradient offset independent adiabaticity (GOIA) pulses, are increasingly gaining attention for high field clinical magnetic resonance spectroscopy and spectroscopic imaging (MRS/MRSI) due to the lower peak B1 amplitude and associated power demands achievable relative to its non-modulated adiabatic full passage counterparts. In this work we describe the development of two GOIA RF pulses: 1) A power efficient, 3.0 ms wideband uniform rate with smooth truncation (WURST) modulated RF pulse with 15 kHz bandwidth compatible with a clinically feasible peak B1 amplitude of 0.87 kHz (or 20 µT), and 2) A highly selective asymmetric 6.66 ms RF pulse with 20 kHz bandwidth designed to achieve a single-sided, fractional transition width of only 1.7%. Effects of potential asynchrony between RF and gradient-modulated (GM) waveforms for 3 ms GOIA-WURST RF pulses was evaluated by simulation and experimentally. Results demonstrate that a 20+ µs asynchrony between RF and GM functions substantially degrades inversion performance when using large RF offsets to achieve translation. A projection-based method is presented that allows a quick calibration of RF and GM asynchrony on pre-clinical/clinical MR systems. The asymmetric GOIA pulse was implemented within a multi-pulse OVS sequence to achieve power efficient, highly-selective, and B1 and T1-independent signal suppression for extracranial lipid suppression. The developed GOIA pulses were utilized with linear gradient modulation (X, Y, Z gradient fields), and with second-order-field modulations (Z2, X2Y2 gradient fields) to provide elliptically-shaped regions-of-interest for MRS and MRSI acquisitions. Both described GOIA-RF pulses have substantial clinical value; specifically, the 3.0 ms GOIA-WURST pulse is beneficial to realize short TE sLASER localized proton MRS/MRSI sequences, and the asymmetric GOIA RF pulse has applications in highly selective outer volume signal suppression to allow interrogation of tissue proximal to extracranial lipids with full-intensity.

Dynamic multicoil technique (DYNAMITE) MRI on human brain.

PURPOSE: Spatial encoding for MRI is generally based on linear x, y, and z magnetic field gradients generated by a set of dedicated gradient coils. We recently introduced the dynamic multicoil technique (DYNAMITE) for B0 field control and demonstrated DYNAMITE MRI in a preclinical MR environment. In this study, we report the first realization of DYNAMITE MRI of the in vivo human head. METHODS: Gradient fields for DYNAMITE MRI were generated with a 28-channel multicoil hardware arranged in 4 rows of 7 coils on a cylindrical surface (length 359 mm, diameter 344 mm, maximum 5 A per coil). DYNAMITE MRIs of a resolution phantom and in vivo human heads were acquired with multislice gradient-echo, multislice spin-echo, and 3D gradient-echo sequences. The resultant image fidelity was compared to that obtained with conventional gradient coil technology. RESULTS: DYNAMITE field control enabled the realization of all imaging sequences with average gradient errors ≤ 1%. DYNAMITE MRI provided image quality and sensitivity comparable to conventional gradient technology without any obvious artifacts. Some minor geometric deformations were noticed primarily in the image periphery as the result of regional field imperfections. The imperfections can be readily approximated theoretically through numerical integration of the Biot-Savart law and removed through image distortion correction. CONCLUSION: The first realization of DYNAMITE MRI of the in vivo human head has been presented. The obtained image fidelity is comparable to MRI with conventional gradient coils, paving the way for full-fledged DYNAMITE MRI and B0 shim systems for human applications.

On the magnetic field dependence of deuterium metabolic imaging.

Deuterium metabolic imaging (DMI) is a novel MR-based method to spatially map metabolism of deuterated substrates such as [6,6'-2 H2 ]-glucose in vivo. Compared with traditional 13 C-MR-based metabolic studies, the MR sensitivity of DMI is high due to the larger 2 H magnetic moment and favorable T1 and T2 relaxation times. Here, the magnetic field dependence of DMI sensitivity and transmit efficiency is studied on phantoms and rat brain postmortem at 4, 9.4 and 11.7 T. The sensitivity and spectral resolution on human brain in vivo are investigated at 4 and 7 T before and after an oral dose of [6,6'-2 H2 ]-glucose. For small animal surface coils (Ø 30 mm), the experimentally measured sensitivity and transmit efficiency scale with the magnetic field to a power of +1.75 and -0.30, respectively. These are in excellent agreement with theoretical predictions made from the principle of reciprocity for a coil noise-dominant regime. For larger human surface coils (Ø 80 mm), the sensitivity scales as a +1.65 power. The spectral resolution increases linearly due to near-constant linewidths. With optimal multireceiver arrays the acquisition of DMI at a nominal 1 mL spatial resolution is feasible at 7 T.

Deuterium metabolic imaging (DMI) for MRI-based 3D mapping of metabolism in vivo.

Currently, the only widely available metabolic imaging technique in the clinic is positron emission tomography (PET) detection of the radioactive glucose analog 2-18F-fluoro-2-deoxy-d-glucose (18FDG). However, 18FDG-PET does not inform on metabolism downstream of glucose uptake and often provides ambiguous results in organs with intrinsic high glucose uptake, such as the brain. Deuterium metabolic imaging (DMI) is a novel, noninvasive approach that combines deuterium magnetic resonance spectroscopic imaging with oral intake or intravenous infusion of nonradioactive 2H-labeled substrates to generate three-dimensional metabolic maps. DMI can reveal glucose metabolism beyond mere uptake and can be used with other 2H-labeled substrates as well. We demonstrate DMI by mapping metabolism in the brain and liver of animal models and human subjects using [6,6'-2H2]glucose or [2H3]acetate. In a rat glioma model, DMI revealed pronounced metabolic differences between normal brain and tumor tissue, with high-contrast metabolic maps depicting the Warburg effect. We observed similar metabolic patterns and image contrast in two patients with a high-grade brain tumor after oral intake of 2H-labeled glucose. Further, DMI used in rat and human livers showed [6,6'-2H2]glucose stored as labeled glycogen. DMI is a versatile, robust, and easy-to-implement technique that requires minimal modifications to existing clinical magnetic resonance imaging scanners. DMI has great potential to become a widespread method for metabolic imaging in both (pre)clinical research and the clinic.

Elliptical localization with pulsed second-order fields (ECLIPSE) for robust lipid suppression in proton MRSI.

Proton MRSI has great clinical potential for metabolic mapping of the healthy and pathological human brain. Unfortunately, the promise has not yet been fully achieved due to numerous technical challenges related to insufficient spectral quality caused by magnetic field inhomogeneity, insufficient RF transmit power and incomplete lipid suppression. Here a robust, novel method for lipid suppression in 1 H MRSI is presented. The method is based on 2D spatial localization of an elliptical region of interest using pulsed second-order spherical harmonic (SH) magnetic fields. A dedicated, high-amplitude second-order SH gradient setup was designed and constructed, containing coils to generate Z2, X2Y2 and XY magnetic fields. Simulations and phantom MRI results are used to demonstrate the principles of the method and illustrate the manifestation of chemical shift displacement. 1 H MRSI on human brain in vivo demonstrates high quality, robust suppression of extracranial lipids. The method allows a wide range of inner or outer volume selection or suppression and should find application in MRSI, reduced-field-of-view MRI and single-volume MRS.

Selective proton-observed, carbon-edited (selPOCE) MRS method for measurement of glutamate and glutamine 13 C-labeling in the human frontal cortex.

PURPOSE: 13 C magnetic resonance spectroscopy (MRS) in combination with infusion of 13 C-labeled substrates has led to unique insights into human brain metabolism and neurotransmitter cycling. However, the low sensitivity of direct 13 C MRS and high radiofrequency power requirements has limited 13 C MRS studies to predominantly data acquisition in large volumes of the occipital cortex. The purpose of this study is to develop an MRS technique for localized detection of 13 C-labeling of glutamate and glutamine in the human frontal lobe. METHODS: We used an indirect (1 H-[13 C]), proton-observed, carbon-edited MRS sequence (selPOCE) for detection of 13 C-labeled metabolites in relatively small volumes located in the frontal lobe at 4 T. The SelPOCE method allows for selective and separate detection of glutamate and glutamine resonances, which significantly overlap at magnetic field strengths used for clinical MRI. RESULTS: Phantom data illustrate how selPOCE can be tuned to selectively detect 13 C labeling in different metabolites. Three-dimensional specific absorption rate simulations of radiofrequency power deposition show that the selPOCE method operates comfortably within the global and local Food and Drug Administration specific absorption rate guidelines. In vivo selPOCE data are presented, which were acquired from a 45-mL volume in the frontal lobe of healthy subjects. The in vivo data show the time-dependent 13 C-labeling of glutamate and glutamine during intravenous infusion of [1-13 C]-glucose. Metrics describing spectral fitting quality of the glutamate and glutamine resonances are reported. CONCLUSIONS: The SelPOCE sequence allows the detection of 13 C-labeling in glutamate and glutamine from a relatively small volume in the human frontal lobe at low radiofrequency power requirements. Magn Reson Med 80:11-20, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Comparison of direct 13C and indirect 1H-[13C] MR detection methods for the study of dynamic metabolic turnover in the human brain.

A wide range of direct 13C and indirect 1H-[13C] MR detection methods exist to probe dynamic metabolic pathways in the human brain. Choosing an optimal detection method is difficult as sequence-specific features regarding spatial localization, broadband decoupling, spectral resolution, power requirements and sensitivity complicate a straightforward comparison. Here we combine density matrix simulations with experimentally determined values for intrinsic 1H and 13C sensitivity, T1 and T2 relaxation and transmit efficiency to allow selection of an optimal 13C MR detection method for a given application and magnetic field. The indirect proton-observed, carbon-edited (POCE) detection method provides the highest accuracy at reasonable RF power deposition both at 4T and 7T. The various polarization transfer methods all have comparable performances, but may become infeasible at 7T due to the high RF power deposition. 2D MR methods have limited value for the metabolites considered (primarily glutamate, glutamine and γ-amino butyric acid (GABA)), but may prove valuable when additional information can be extracted, such as isotopomers or lipid composition. While providing the lowest accuracy, the detection of non-protonated carbons is the simplest to implement with the lowest RF power deposition. The magnetic field homogeneity is one of the most important parameters affecting the detection accuracy for all metabolites and all acquisition methods.

Detection of cerebral NAD+ in humans at 7T.

PURPOSE: To develop 1 H-based MR detection of nicotinamide adenine dinucleotide (NAD+ ) in the human brain at 7T and validate the 1 H results with NAD+ detection based on 31 P-MRS. METHODS: 1 H-MR detection of NAD+ was achieved with a one-dimensional double-spin-echo method on a slice parallel to the surface coil transceiver. Perturbation of the water resonance was avoided through the use of frequency-selective excitation. 31 P-MR detection of NAD+ was performed with an unlocalized pulse-acquire sequence. RESULTS: Both 1 H- and 31 P-MRS allowed the detection of NAD+ signals on every subject in 16 min. Spectral fitting provided an NAD+ concentration of 107 ± 28 µM for 1 H-MRS and 367 ± 78 µM and 312 ± 65 µM for 31 P-MRS when uridine diphosphate glucose (UDPG) was excluded and included, respectively, as an overlapping signal. CONCLUSIONS: NAD+ detection by 1 H-MRS is a simple method that comes at the price of reduced NMR visibility. NAD+ detection by 31 P-MRS has near-complete NMR visibility, but it is complicated by spectral overlap with NADH and UDPG. Overall, the 1 H- and 31 P-MR methods both provide exciting opportunities to study NAD+ metabolism on human brain in vivo. © 2016 International Society for Magnetic Resonance in Medicine. Magn Reson Med 78:828-835, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

DYNAmic Multi-coIl TEchnique (DYNAMITE) shimming of the rat brain at 11.7 T.

The in vivo rat model is a workhorse in neuroscience research, preclinical studies and drug development. A repertoire of MR tools has been developed for its investigation; however, high levels of B0 magnetic field homogeneity are required for meaningful results. The homogenization of magnetic fields in the rat brain, i.e. shimming, is a difficult task because of a multitude of complex, susceptibility-induced field distortions. Conventional shimming with spherical harmonic (SH) functions is capable of compensating for shallow field distortions in limited areas, e.g. in the cortex, but performs poorly in difficult-to-shim subcortical structures or for the entire brain. Based on the recently introduced multi-coil approach for magnetic field modeling, the DYNAmic Multi-coIl TEchnique (DYNAMITE) is introduced for magnetic field shimming of the in vivo rat brain and its benefits for gradient-echo echo-planar imaging (EPI) are demonstrated. An integrated multi-coil/radiofrequency (MC/RF) system comprising 48 individual localized DC coils for B0 shimming and a surface transceive RF coil has been developed that allows MR investigations of the anesthetized rat brain in vivo. DYNAMITE shimming with this MC/RF set-up is shown to reduce the B0 standard deviation to a third of that achieved with current shim technology employing static first- through third-order SH shapes. The EPI signal over the rat brain increased by 31%, and a 24% gain in usable EPI voxels could be realized. DYNAMITE shimming is expected to critically benefit a wide range of preclinical and neuroscientific MR research. Improved magnetic field homogeneity, together with the achievable large brain coverage of this method, will be crucial when signal pathways, cortical circuitry or the brain's default network are studied. Together with the efficiency gains of MC-based shimming compared with SH approaches demonstrated recently, DYNAMITE shimming has the potential to replace conventional SH shim systems in small-bore animal scanners.

Assessment of early diastolic strain-velocity temporal relationships using spatial modulation of magnetization with polarity alternating velocity encoding (SPAMM-PAV).

A novel MR imaging technique, spatial modulation of magnetization with polarity alternating velocity encoding (SPAMM-PAV), is presented to simultaneously examine the left ventricular early diastolic temporal relationships between myocardial deformation and intra-cavity hemodynamics with a high temporal resolution of 14 ms. This approach is initially evaluated in a dynamic flow and tissue mimicking phantom. A comparison of regional longitudinal strains and intra-cavity pressure differences (integration of computed in-plane pressure gradients within a selected region) in relation to mitral valve inflow velocities is performed in eight normal volunteers. Our results demonstrate that apical regions have higher strain rates (0.145 ± 0.005 %/ms) during the acceleration period of rapid filling compared to mid-ventricular (0.114 ± 0.007 %/ms) and basal regions (0.088 ± 0.009 %/ms), and apical strain curves plateau at peak mitral inflow velocity. This pattern is reversed during the deceleration period, when the strain-rates in the basal regions are the highest (0.027 ± 0.003 %/ms) due to ongoing basal stretching. A positive base-to-apex gradient in peak pressure difference is observed during acceleration, followed by a negative base-to-apex gradient during deceleration. These studies shed insight into the regional volumetric and pressure difference changes in the left ventricle during early diastolic filling.

Multicoil shimming of the mouse brain.

MR imaging and spectroscopy allow the noninvasive measurement of brain function and physiology, but excellent magnetic field homogeneity is required for meaningful results. The homogenization of the magnetic field distribution in the mouse brain (i.e., shimming) is a difficult task due to complex susceptibility-induced field distortions combined with the small size of the object. To date, the achievement of satisfactory whole brain shimming in the mouse remains a major challenge. The magnetic fields generated by a set of 48 circular coils (diameter 13 mm) that were arranged in a cylinder-shaped pattern of 32 mm diameter and driven with individual dynamic current ranges of ±1 A are shown to be capable of substantially reducing the field distortions encountered in the mouse brain at 9.4 Tesla. Static multicoil shim fields allowed the reduction of the standard deviation of Larmor frequencies by 31% compared to second order spherical harmonics shimming and a 66% narrowing was achieved with the slice-specific application of the multicoil shimming with a dynamic approach. For gradient echo imaging, multicoil shimming minimized shim-related signal voids in the brain periphery and allowed overall signal gains of up to 51% compared to spherical harmonics shimming.

Surgically implantable magnetic resonance angiography coils improve resolution to allow visualization of blood flow dynamics.

BACKGROUND: Magnetic resonance angiography (MRA) is clinically useful but of limited applicability to small animal models due to poor signal resolution, with typical voxel sizes of 1 mm(3) that are insufficient to analyze vessels of diameter <1 mm. We determined whether surgically implantable, extravascular MRA coils increase signal resolution adequately to examine blood flow dynamics METHODS: A custom MRA coil was surgically implanted near the carotid artery of a New Zealand White rabbit. A stenosis was created in the carotid artery to induce complicated, non-laminar flow. Phase contrast images were obtained on multiple axial planes with 3T MRA and through-plane velocity profiles were calculated under laminar and complicated flow conditions. These velocity profiles were fit to a laminar flow model using ordinary least squares in order to quantify the degree of flow complication (Matlab). Flow was also measured with a Doppler flow probe; vessel diameters and flow velocities were compared with duplex ultrasound RESULTS: Carotid artery blood flow was 24.7 +/- 2.6 ml/min prior to stenosis creation and reduced to 12.0 +/- 1.7 ml/min following injury (n=3). An MRA voxel size of 0.1 x 0.1 x 5 mm was achieved. The control carotid artery diameter was 1.9 +/- 0.1 mm, and cross-sectional images containing 318 +/- 22 voxels were acquired (n=26). Velocity profiles resembled laminar flow proximal to the stenosis, and then became more complicated just proximal and distal to the stenosis. Laminar flow conditions returned downstream of the stenosis CONCLUSION: Implantable, extra-vascular coils enable small MRA voxel sizes to reproducibly calculate complex velocity profiles under both laminar and complicated flow in a small animal model. This technique may be applied to study blood flow dynamics of vessel remodeling and atherogenesis.

In situ 3D magnetic resonance metabolic imaging of microwave-irradiated rodent brain: a new tool for metabolomics research.

The rapid elevation in rat brain temperature achieveable with focused beam microwave irradiation (FBMI) leads to a permanent inactivation of enzymes, thereby minimizing enzyme-dependent post-mortem metabolic changes. An additional characteristic of FBMI is that the NMR properties of the tissue are close to those of the in vivo condition and remain so for at least 12 h. These features create an opportunity to develop magnetic resonance spectroscopy and imaging on microwave-irradiated samples into a technique with a resolution, coverage and sensitivity superior to any experiment performed directly in vivo. Furthermore, when combined with pre-FBMI infusion of (13)C-labeled substrates, like [1-(13)C]-glucose, the technique can generate maps of metabolic fluxes, like the tricarboxylic acid and glutamate-glutamine neurotransmitter cycle fluxes at an unprecedented spatial resolution.

Natural abundance (17)O NMR spectroscopy of rat brain in vivo.

Oxygen is an abundant element that is present in almost all biologically relevant molecules. NMR observation of oxygen has been relatively limited since the NMR-active isotope, oxygen-17, is only present at a 0.037% natural abundance. Furthermore, as a spin 5/2 nucleus oxygen-17 has a moderately strong quadrupole moment which leads to fairly broad resonances (T(2)=1-4 ms). However, the similarly short T(1) relaxation constants allow substantial signal averaging, whereas the large chemical shift range (>300 ppm) improves the spectral resolution of (17)O NMR. Here it is shown that high-quality, natural abundance (17)O NMR spectra can be obtained from rat brain in vivo at 11.74 T. The chemical shifts and line widths of more than 20 oxygen-containing metabolites are established and the sensitivity and potential for (17)O-enriched NMR studies are estimated.

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.

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.

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.

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.