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1.  Multiband RF Pulses with Improved Performance via Convex Optimization 
Selective RF pulses are commonly designed with the desired profile as a low pass filter frequency response. However, for many MRI and NMR applications, the spectrum is sparse with signals existing at a few discrete resonant frequencies. By specifying a multiband profile and releasing the constraint on “don’t-care” regions, the RF pulse performance can be improved to enable a shorter duration, sharper transition, or lower peak B1 amplitude. In this project, a framework for designing multiband RF pulses with improved performance was developed based on the Shinnar-Le Roux (SLR) algorithm and convex optimization. It can create several types of RF pulses with multiband magnitude profiles, arbitrary phase profiles and generalized flip angles. The advantage of this framework with a convex optimization approach is the flexible trade-off of different pulse characteristics. Designs for specialized selective RF pulses for balanced SSFP hyperpolarized (HP) 13C MRI, a dualband saturation RF pulse for 1H MR spectroscopy, and a pre-saturation pulse for HP 13C study were developed and tested.
Graphical abstract
doi:10.1016/j.jmr.2015.11.010
PMCID: PMC4716678  PMID: 26754063
RF pulse design; Shinnar-Le Roux algorithm; convex optimization; multiband; improved pulse performance; generalized flip angle
2.  A bifunctional spin label reports the structural topology of phospholamban in magnetically-aligned bicelles 
We have applied a bifunctional spin label and EPR spectroscopy to determine membrane protein structural topology in magnetically-aligned bicelles, using monomeric phospholamban (PLB) as a model system. Bicelles are a powerful tool for studying membrane proteins by NMR and EPR spectroscopies, where magnetic alignment yields topological constraints by resolving the anisotropic spectral properties of nuclear and electron spins. However, EPR bicelle studies are often hindered by the rotational mobility of monofunctional Cys-linked spin labels, which obscures their orientation relative to the protein backbone. The rigid and stereospecific TOAC label provides high orientational sensitivity but must be introduced via solid-phase peptide synthesis, precluding its use in large proteins. Here we show that a bifunctional methanethiosulfonate spin label attaches rigidly and stereospecifically to Cys residues at i and i + 4 positions along PLB’s transmembrane helix, thus providing orientational resolution similar to that of TOAC, while being applicable to larger membrane proteins for which synthesis is impractical. Computational modeling and comparison with NMR data shows that these EPR experiments provide accurate information about helix tilt relative to the membrane normal, thus establishing a robust method for determining structural topology in large membrane proteins with a substantial advantage in sensitivity over NMR.
Graphical abstract
doi:10.1016/j.jmr.2015.12.005
PMCID: PMC4716873  PMID: 26720587
bifunctional spin label; phospholamban; bicelles; orientation; EPR; molecular dynamics
3.  Simultaneous Cross Polarization to 13C and 15N with 1H Detection at 60 kHz MAS Solid-state NMR 
We describe high resolution MAS solid-state NMR experiments that utilize 1H detection with 60 kHz magic angle spinning; simultaneous cross-polarization from 1H to 15N and 13C nuclei; bidirectional cross-polarization between 13C and 15N nuclei; detection of both amide nitrogen and aliphatic carbon 1H; and measurement of both 13C and 15N chemical shifts through multi-dimensional correlation experiments. Three-dimensional experiments correlate amide 1H and alpha 1H selectively with 13C or 15N nuclei in a polypeptide chain. Two separate three-dimensional spectra correlating 1Hα/13Cα/1HN and 1HN/15N/1Hα are recorded simultaneously in a single experiment, demonstrating that a two-fold savings in experimental time is potentially achievable. Spectral editing using bidirectional coherence transfer pathways enables simultaneous magnetization transfers between 15N, 13Cα(i) and 13C′(i−1), facilitating intra- and inter- residue correlations for sequential resonance assignment. Non-uniform sampling is integrated into the experiments, further reducing the length of experimental time.
doi:10.1016/j.jmr.2015.12.004
PMCID: PMC4716881  PMID: 26705905
magic angle spinning; dual observation; peptides; proteins; triple-resonance
4.  Sodium inversion recovery MRI on the knee joint at 7 T with an optimal control pulse 
In the field of sodium magnetic resonance imaging (MRI), inversion recovery (IR) is a convenient and popular method to select sodium in different environments. For the knee joint, IR has been used to suppress the signal from synovial fluids, which improves the correlation between the sodium signal and the concentration of glycosaminoglycans (GAGs) in cartilage tissues. For the better inversion of the magnetization vector under the spatial variations of the B0 and B1 fields, the IR sequence usually employ adiabatic pulses as the inversion pulse. On the other hand, it has been shown that RF shapes robust against the variations of the B0 and B1 fields can be generated by numerical optimization based on optimal control theory. In this work, we compare the performance of fluid-suppressed sodium MRI on the knee joint in vivo, between one implemented with an adiabatic pulse in the IR sequence and the other with the adiabatic pulse replaced by an optimal-control shaped pulse. While the optimal-control pulse reduces the RF power deposited to the body by 58%, the quality of fluid suppression and the signal level of sodium within cartilage are similar between two implementations.
Graphical Abstract
doi:10.1016/j.jmr.2015.12.002
PMCID: PMC4716894  PMID: 26705907
Sodium; Knee; MRI; Optimal control; Fermat looped; orthogonally encoded trajectories
5.  Development and testing of hyperpolarized 13C MR calibrationless parallel imaging 
A calibrationless parallel imaging technique developed previously for 1H MRI was modified and tested for hyperpolarized 13C MRI for applications requiring large FOV and high spatial resolution. The technique was demonstrated with both retrospective and prospective under-sampled data acquired in phantom and in vivo rat studies. A 2-fold acceleration was achieved using a 2D symmetric EPI readout equipped with random blips on the phase encode dimension. Reconstructed images showed excellent qualitative agreement with fully sampled data. Further acceleration can be achieved using acquisition schemes that incorporate multi-dimensional under-sampling.
doi:10.1016/j.jmr.2015.10.018
PMCID: PMC4864033  PMID: 26679288
Hyperpolarization; Carbon-13; Parallel imaging
6.  1020 MHz Single-Channel Proton Fast Magic Angle Spinning Solid-State NMR Spectroscopy 
This study reports a first successful demonstration of a single channel proton 3D and 2D high-throughput ultrafast magic angle spinning (MAS) solid-state NMR techniques in an ultra-high magnetic field (1020 MHz) NMR spectrometer comprised of HTS/LTS magnet. High spectral resolution is well demonstrated.
Graphical Abstract
doi:10.1016/j.jmr.2015.10.003
PMCID: PMC4688097  PMID: 26524647
solid-state NMR; Proton detection; Structure Elucidation; Ultra-high field; Ultrafast MAS
7.  Active Cancellation – A Means to Zero Dead-Time Pulse EPR 
The necessary resonator employed in pulse electron paramagnetic resonance (EPR) rings after the excitation pulse and creates a finite detector dead-time that ultimately prevents the detection of signal from fast relaxing spin systems, hindering the application of pulse EPR to room temperature measurements of interesting chemical or biological systems. We employ a recently available high bandwidth arbitrary waveform generator (AWG) to produce a cancellation pulse that precisely destructively interferes with the resonant cavity ring-down. We find that we can faithfully detect EPR signal at all times immediately after, as well as during, the excitation pulse. This is a proof of concept study showcasing the capability of AWG pulses to precisely cancel out the resonator ring-down, and allow for the detection of EPR signal during the pulse itself, as well as the dead-time of the resonator. However, the applicability of this approach to conventional EPR experiments is not immediate, as it hinges on either (1) the availability of low-noise microwave sources and amplifiers to produce the necessary power for pulse EPR experiment or (2) the availability of very high conversion factor micro coil resonators that allow for pulse EPR experiments at modest microwave power.
Graphical Abstract
doi:10.1016/j.jmr.2015.07.005
PMCID: PMC4688155  PMID: 26507308
Pulse EPR; Arbitrary Waveform Generation; Active Cancellation; AWG EPR; dead-time limited EPR; FPGA EPR
8.  Constrained optimization of gradient waveforms for generalized diffusion encoding 
Diffusion MRI is a useful probe of tissue microstructure. The conventional diffusion encoding sequence, the single pulsed field gradient, has recently been challenged as more general gradient waveforms have been introduced. Out of these, we focus on q-space trajectory imaging, which generalizes the scalar b-value to a tensor valued entity. To take full advantage of its capabilities, it is imperative to respect the constraints imposed by the hardware, while at the same time maximizing the diffusion encoding strength. We provide a tool that achieves this by solving a constrained optimization problem that accommodates constraints on maximum gradient amplitude, slew rate, coil heating and positioning of radio frequency pulses. The method's efficacy and flexibility is demonstrated both experimentally and by comparison with previous work on optimization of isotropic diffusion sequences.
Graphical Abstract
doi:10.1016/j.jmr.2015.10.012
PMCID: PMC4752208  PMID: 26583528
Diffusion MR; Generalized gradient waveforms; Q-space trajectory imaging; Optimization; Hardware constraints
9.  Deterministic Multidimensional Nonuniform Gap Sampling 
Born from empirical observations in nonuniformly sampled multidimensional NMR data relating to gaps between sampled points, the Poisson-gap sampling method has enjoyed widespread use in biomolecular NMR. While the majority of nonuniform sampling schemes are fully randomly drawn from probability densities that vary over a Nyquist grid, the Poisson-gap scheme employs constrained random deviates to minimize the gaps between sampled grid points. We describe a deterministic gap sampling method, based on the average behavior of Poisson-gap sampling, which performs comparably to its random counterpart with the additional benefit of completely deterministic behavior. We also introduce a general algorithm for multidimensional nonuniform sampling based on a gap equation, and apply it to yield a deterministic sampling scheme that combines burst-mode sampling features with those of Poisson-gap schemes. Finally, we derive a relationship between stochastic gap equations and the expectation value of their sampling probability densities.
Graphical Abstract
doi:10.1016/j.jmr.2015.09.016
PMCID: PMC4970466  PMID: 26524650
NMR; NUS; Poisson-Gap; Deterministic sampling
10.  Design and characterization of a W-band system for modulated DNP experiments 
Magnetic-field and microwave-frequency modulated DNP experiments have been shown to yield improved enhancements over conventional DNP techniques, and even to shorten polarization build-up times. The resulting increase in signal-to-noise ratios can lead to significantly shorter acquisition times in signal-limited multi-dimensional NMR experiments and pave the way to the study of even smaller sample volumes. In this paper we describe the design and performance of a broadband system for microwave frequency-and amplitude-modulated DNP that has been engineered to minimize both microwave and thermal losses during operation at liquid helium temperatures. The system incorporates a flexible source that can generate arbitrary waveforms at 94 GHz with a bandwidth greater than 1 GHz, as well as a probe that efficiently transmits the millimeter waves from room temperature outside the magnet to a cryogenic environment inside the magnet. Using a thin-walled brass tube as an overmoded waveguide to transmit a hybrid HE11 mode, it is possible to limit the losses to 1 dB across a 2 GHz bandwidth. The loss is dominated by the presence of a quartz window used to isolate the waveguide pipe. This performance is comparable to systems with corrugated waveguide or quasi-optical components. The overall excitation bandwidth of the probe is seen to be primarily determined by the final antenna or resonator used to excite the sample and its coupling to the NMR RF coil. Understanding the instrumental limitations imposed on any modulation scheme is key to understanding the observed DNP results and potentially identifying the underlying mechanisms. We demonstrate the utility of our design with a set of triangular frequency-modulated DNP experiments.
Graphical Abstract
doi:10.1016/j.jmr.2015.09.011
PMCID: PMC4971581  PMID: 26524649
11.  High-Throughput Hyperpolarized 13C Metabolic Investigations using a Multi-Channel Acquisition System 
Magnetic resonance imaging and spectroscopy of hyperpolarized (HP) compounds such as [1-13C]-pyruvate has shown tremendous potential for new insight into disease and response to therapy. New applications of this technology in clinical research and care will require extensive validation in cells and animal models, a process that may be limited by the high cost and modest throughput associated with dynamic nuclear polarization. Relatively wide spectral separation between [1-13C]-pyruvate and its chemical endpoints in vivo are conducive to simultaneous multi-sample measurements, even in the presence of a suboptimal global shim. Multi-channel acquisitions could conserve costs and accelerate experiments by allowing acquisition from multiple independent samples following a single dissolution. Unfortunately, many existing preclinical MRI systems are equipped with only a single channel for broadband acquisitions. In this work, we examine the feasibility of this concept using a broadband multi-channel digital receiver extension and detector arrays that allow concurrent measurement of dynamic spectroscopic data from ex vivo enzyme phantoms, in vitro anaplastic thyroid carcinoma cells, and in vivo in tumor-bearing mice. Throughput and the cost of consumables were improved by up to a factor of four. These preliminary results demonstrate the potential for efficient multi-sample studies employing hyperpolarized agents.
Graphical Abstract
doi:10.1016/j.jmr.2015.08.025
PMCID: PMC4628838  PMID: 26397217
dynamic nuclear polarization; hyperpolarization; 13C spectroscopy; hyperpolarized pyruvate; cancer; multichannel spectroscopy; dynamic spectroscopy; coil array
12.  Micron-scale magnetic resonance imaging of both liquids and solids 
We describe and demonstrate a novel apparatus for magnetic resonance imaging (MRI), suitable for imaging of both liquid and solid samples with micron-scale isotropic resolution. The apparatus includes a solenoidal radio-frequency microcoil with 170 μm inner diameter and a set of planar gradient coils, all wound by hand and supported on a series of stacked sapphire plates. The design ensures efficient heat dissipation during gradient pulses and also facilitates disassembly, sample changes, and reassembly. To demonstrate liquid state 1H MRI, we present an image of polystyrene beads within CuSO4-doped water, contained within a capillary tube with 100 μm inner diameter, with 5.0 μm isotropic resolution. To demonstrate solid state 1H MRI, we present an image of NH4Cl particles within the capillary tube, with 8.0 μm isotropic resolution. High-resolution solid state MRI is enabled by frequency-switched Lee-Goldburg decoupling, with an effective rotating frame field amplitude of 289 kHz. At room temperature, pulsed gradients of 4 T/m (i.e., 170 Hz/μm for 1H MRI) are achievable in all three directions with currents of 10 A or less. The apparatus is contained within a variable-temperature liquid helium cryostat, which will allow future efforts to obtain MRI images at low temperatures with signal enhancement by dynamic nuclear polarization.
Graphical Abstract
doi:10.1016/j.jmr.2015.09.001
PMCID: PMC4628880  PMID: 26397215
MRI; solid state NMR; Lee-Goldburg decoupling; constant-time imaging; microcoil
13.  Effortless assignment with 4D covariance sequential correlation maps 
Traditional Nuclear Magnetic Resonance (NMR) assignment procedures for proteins rely on preliminary peak-picking to identify and label NMR signals. However, such an approach has severe limitations when signals are erroneously labeled or completely neglected. The consequences are especially grave for proteins with substantial peak overlap, and mistakes can often thwart entire projects. To overcome these limitations, we previously introduced an assignment technique that bypasses traditional pick peaking altogether. Covariance Sequential Correlation Maps (COSCOMs) transform the indirect connectivity information provided by multiple 3D backbone spectra into direct (H, N) to (H, N) correlations. Here, we present an updated method that utilizes a single four-dimensional spectrum rather than a suite of three-dimensional spectra. We demonstrate the advantages of 4D-COSCOMs relative to their 3D counterparts. We introduce improvements accelerating their calculation. We discuss practical considerations affecting their quality. And finally we showcase their utility in the context of a 52 kDa cyclization domain from a non-ribosomal peptide synthetase.
Graphical Abstract
doi:10.1016/j.jmr.2015.09.007
PMCID: PMC4628886  PMID: 26432397
backbone assignment; peak picking; covariance sequential correlation maps; COSCOM; 4D
14.  Genetic Algorithm Optimized Triply Compensated Pulses in NMR Spectroscopy 
Sensitivity and resolution in NMR experiments are affected by magnetic field inhomogeneities (of both external and RF), errors in pulse calibration, and offset effects due to finite length of RF pulses. To remedy these problems, built-in compensation mechanisms for these experimental imperfections are often necessary. Here, we propose a new family of phase-modulated constant-amplitude broadband pulses with high compensation for RF inhomogeneity and heteronuclear coupling evolution. These pulses were optimized using a genetic algorithm (GA), which consists in a global optimization method inspired by Nature’s evolutionary processes. The newly designed π and π/2 pulses belong to the ‘Type A’ (or general rotors) symmetric composite pulses. These GA-optimized pulses are relatively short compared to other general rotors and can be used for excitation and inversion, as well as refocusing pulses in spin-echo experiments. The performance of the GA-optimized pulses was assessed in Magic Angle Spinning (MAS) solid-state NMR experiments using a crystalline U – 13C, 15N NAVL peptide as well as U – 13C, 15N microcrystalline ubiquitin. GA optimization of NMR pulse sequences opens a window for improving current experiments and designing new robust pulse sequences.
doi:10.1016/j.jmr.2015.09.010
PMCID: PMC4628891  PMID: 26473327
Triply compensated pulses; composite pulses; genetic algorithm; RF inhomogeneity; zz interactions; resonance offset; pulse imperfections
15.  Can NMR solve some significant challenges in metabolomics? 
The field of metabolomics continues to witness rapid growth driven by fundamental studies, methods development, and applications in a number of disciplines that include biomedical science, plant and nutrition sciences, drug development, energy and environmental sciences, toxicology, etc. NMR spectroscopy is one of the two most widely used analytical platforms in the metabolomics field, along with mass spectrometry (MS). NMR's excellent reproducibility and quantitative accuracy, its ability to identify structures of unknown metabolites, its capacity to generate metabolite profiles using intact biospecimens with no need for separation, and its capabilities for tracing metabolic pathways using isotope labeled substrates offer unique strengths for metabolomics applications. However, NMR's limited sensitivity and resolution continue to pose a major challenge and have restricted both the number and the quantitative accuracy of metabolites analyzed by NMR. Further, the analysis of highly complex biological samples has increased the demand for new methods with improved detection, better unknown identification, and more accurate quantitation of larger numbers of metabolites. Recent efforts have contributed significant improvements in these areas, and have thereby enhanced the pool of routinely quantifiable metabolites. Additionally, efforts focused on combining NMR and MS promise opportunities to exploit the combined strength of the two analytical platforms for direct comparison of the metabolite data, unknown identification and reliable biomarker discovery that continue to challenge the metabolomics field. This article presents our perspectives on the emerging trends in NMR-based metabolomics and NMR's continuing role in the field with an emphasis on recent and ongoing research from our laboratory.
doi:10.1016/j.jmr.2015.07.014
PMCID: PMC4646661  PMID: 26476597
Metabolomics; Quantitation; Isotope tagging; Unknown metabolite identification; qNMR; Biomarker discovery
16.  Imaging Disulfide Dinitroxides at 250 MHz to Monitor Thiol Redox Status 
Measurement of thiol-disulfide redox status is crucial for characterization of tumor physiology. The electron paramagnetic resonance (EPR) spectra of disulfide-linked dinitroxides are readily distinguished from those of the corresponding monoradicals that are formed by cleavage of the disulfide linkage by free thiols. EPR spectra can thus be used to monitor the rate of cleavage and the thiol redox status. EPR spectra of 1H,14N- and 2H,15N-disulfide dinitroxides and the corresponding monoradicals resulting from cleavage by glutathione have been characterized at 250 MHz, 1.04 GHz, and 9 GHz and imaged by rapid-scan EPR at 250 MHz.
Graphical Abstract
doi:10.1016/j.jmr.2015.08.027
PMCID: PMC4731354  PMID: 26415686
disulfide dinitroxide; disulfide cleavage; glutathione; image reconstruction; rapid-scan EPR; thiol redox status
17.  Broadband Adiabatic Inversion Pulses for Cross-Polarization in Wideline Solid-State Nuclear Magnetic Resonance Spectroscopy 
Efficient acquisition of wideline solid-state NMR powder patterns is a continuing challenge. In particular, when the breadth of the powder pattern is much larger than the cross-polarization (CP) excitation bandwidth, transfer efficiencies suffer and experimental times are greatly increased. Presented herein is a CP pulse sequence with an excitation bandwidth that is up to ten times greater than that available from a conventional spin-locked CP pulse sequence. The pulse sequence, broadband adiabatic inversion CP (BRAIN-CP), makes use of the broad, uniformly large frequency profiles of inversion chirped pulses, to provide these same characteristics to the polarization transfer process. A detailed theoretical analysis is given, providing insight into the polarization transfer process involved in BRAIN-CP. Experiments on spin-1/2 nuclei including 119Sn, 199Hg and 195Pt nuclei are presented, and the large bandwidth improvements possible with BRAIN-CP are demonstrated. Furthermore, it is shown that BRAIN-CP can be combined with broadband frequency-swept versions of the Carr-Purcell-Meiboom-Gill experiment (for instance with WURST-CPMG, or WCPMG for brevity); the combined BRAIN-CP/WCPMG experiment then provides multiplicative signal enhancements of both CP and multiple-echo acquisition over a broad frequency region.
doi:10.1016/j.jmr.2012.08.015
PMCID: PMC5081099  PMID: 23023623
18.  Rapid-scan coherence signals in X-band EPR spectra of semiquinones with small hyperfine splittings 
Rapid-scan EPR signals for semiquinones with very-small well-resolved hyperfine splittings exhibit coherence signals at a time after passing through the EPR line that is proportional to the reciprocal of the hyperfine splitting. Such coherences are a general phenomenon due to constructive interference of the responses to transient excitation of spins by rapid scan of the magnetic field across equally spaced spin packets. Examples are shown for 2,3,5,6-tetramethoxy-1,4-benzosemiquinone with aH = 46 mG for 12 protons and for 2,5-di-t-butyl-1,4-benzosemiquinone with aH = 59 mG for 18 protons.
doi:10.1016/j.jmr.2015.07.010
PMCID: PMC4594194  PMID: 26277376
19.  15N CSA Tensors and 15N-1H Dipolar Couplings of Protein Hydrophobic Core Residues Investigated by Static Solid-State NMR 
In this work, we assess the usefulness of static 15N NMR techniques for the determination of the 15N chemical shift anisotropy (CSA) tensor parameters and 15N-1H dipolar splittings in powder protein samples. By using five single labeled samples of the villin headpiece subdomain protein in a hydrated lyophilized powder state, we determine the backbone 15N CSA tensors at two temperatures, 22 and –35°C, in order to get a snapshot of the variability across the residues and as a function of temperature. All sites probed belonged to the hydrophobic core and most of them were part of α-helical regions. The values of the anisotropy (which include the effect of the dynamics) varied between 130 and 156 ppm at 22°C, while the values of the asymmetry were in the 0.32–0.082 range. The Leu-75 and Leu-61 backbone sites exhibited high mobility based on the values of their temperature-dependent anisotropy parameters. Under the assumption that most differences stem from dynamics, we obtained the values of the motional order parameters for the 15N backbone sites. While a simple one-dimensional line shape experiment was used for the determination of the 15N CSA parameters, a more advanced approach based on the “magic sandwich” SAMMY pulse sequence (Nevzorov & Opella, J. Magn. Reson. (2003) 164, 182-186) was employed for the determination of the 15N-1H dipolar patterns, which yielded estimates of the dipolar couplings. Accordingly, the motional order parameters for the dipolar interaction were obtained. It was found that the order parameters from the CSA and dipolar measurements are highly correlated, validating that the variability between the residues is governed by the differences in dynamics. The values of the parameters obtained in this work can serve as reference values for developing more advanced magic-angle spinning recoupling techniques for multiple labeled samples.
Graphical abstract
doi:10.1016/j.jmr.2015.08.019
PMCID: PMC4600402  PMID: 26367322
static NMR; 15N CSA; SAMMY; protein dynamics
20.  Dissolution DNP NMR With Solvent Mixtures: Substrate Concentration and Radical Extraction 
Dynamic nuclear polarization (DNP) followed by sudden sample dissolution, is a topic of active investigation owing to the method’s unique prospects for the delivery of NMR spectra and images with unprecedented sensitivity. This experiment achieves hyperpolarization by the combined effects of electron-nuclear irradiation and cryogenic operation; the exploitation of these states occurs following a sudden melting and flushing of the resulting pellet from its original environment into a conventional, liquid-state setting. This melting and flushing usually demands using the equivalent of a few milliliters of hot solvent, a procedure which although well suited for in vivo studies leads to an excessive sample volume when considering typical applications within analytical settings. The present study explores a way of reducing the ensuing dilution of the hyperpolarized analytes, by employing a combination of immiscible liquids for performing the melting and flushing. It is shown that suitable combinations of immiscible solvents –both in terms of their heat capacities and densities– allow one to melt the targeted cryogenic pellet and dissolve the hyperpolarized analytes in a fraction of the solvent hitherto required. By tailoring the resulting volume to the needs of a conventional 5mm NMR probe, a substantial sensitivity enhancement can be added to the hyperpolarization process. An extra benefit may arise from using radicals that preferentially dissolve in the immiscible organic phase, by way of a lengthening of the relaxation time of the investigated analytes. Examples of these principles are given, and further potential extensions of this approach are discussed.
doi:10.1016/j.jmr.2011.04.001
PMCID: PMC5040482  PMID: 21531156
Dynamic Nuclear Polarization; Analytical NMR; Hyperpolarization; Dissolution DNP; Radical Extraction
21.  Diffusion Weighted MRI by Spatiotemporal Encoding: Analytical Description and In Vivo Validations 
Diffusion-Weighted (DW) MRI is a powerful modality for studying microstructure in normal and pathological tissues. DW MRI, however, is of limited use in regions suffering from large magnetic field or chemical shift heterogeneities. Spatio-temporal encoding (SPEN) is a single-scan imaging technique that can deliver its information with a remarkable insensitivity to field inhomogeneities; this study explores the use of diffusion-weighted SPEN (dSPEN) MRI as an alternative for acquiring this kind of information. Owing to SPEN’s combined use of gradients and radiofrequency-swept pulses, spatially-dependent diffusion weightings arise in these sequences that are not present in conventional k-space DW MRI. In order to account for these phenomena an analytical formalism is presented that extends Stejskal & Tanner’s and Karlicek & Lowe’s work, to derive the b-values arising upon taking into account the effects of adiabatic pulses, of imaging as well as diffusion gradients, and of cross-terms between them. Excellent agreement is found between the new features predicted by these analytical and numerical derivations, and SPEN diffusion experiments in phantoms and in anisotropic ex vivo systems. Examinations of apparent diffusion coefficients in human breast volunteers also verify the advantages of the new methods in vivo, which exhibit substantial robustness vis-à-vis comparable DW echo planar imaging.
doi:10.1016/j.jmr.2013.02.014
PMCID: PMC5040484  PMID: 23562003
Diffusion weighted MRI; spatiotemporal encoding; PGSE; b-value calculations; breast ADC determinations
22.  Compressed Sensing Reconstruction of Ultrafast 2D NMR Data: Principles and Biomolecular Applications 
A topic of active investigation in 2D NMR relates to the minimum number of scans required for acquiring this kind of spectra, particularly when these are dictated by sampling rather than by sensitivity considerations. Reductions in this minimum number of scans have been achieved by departing from the regular sampling used to monitor the indirect domain, and relying instead on non-uniform sampling and iterative reconstruction algorithms. Alternatively, so-called “ultrafast” methods can compress the minimum number of scans involved in 2D NMR all the way to a minimum number of one, by spatially encoding the indirect domain information and subsequently recovering it via oscillating field gradients. Given ultrafast NMR’s simultaneous recording of the indirect- and direct-domain data, this experiment couples the spectral constraints of these orthogonal domains –often calling for the use of strong acquisition gradients and large filter widths to fulfill the desired bandwidth and resolution demands along all spectral dimensions. This study discusses a way to alleviate these demands, and thereby enhance the method’s performance and applicability, by combining spatial encoding with iterative reconstruction approaches. Examples of these new principles are given based on the compressed-sensed reconstruction of biomolecular 2D HSQC ultrafast NMR data, an approach that we show enables a decrease of the gradient strengths demanded in this type of experiments by up to 80%.
doi:10.1016/j.jmr.2011.01.017
PMCID: PMC5040485  PMID: 21316276
23.  In vivo single-shot 13C spectroscopic imaging of hyperpolarized metabolites by spatiotemporal encoding 
Hyperpolarized metabolic imaging is a growing field that has provided a tool for analyzing metabolism, particularly in cancer. Given the short life times of the hyperpolarized signal, fast and effective spectroscopic imaging methods compatible with dynamic metabolic characterizations are necessary. Several approaches have been customized for hyperpolarized 13C MRI, including CSI with a center-out k-space encoding, EPSI, and spectrally selective pulses in combination with spiral EPI acquisitions. Recent studies have described the potential of single-shot alternatives based on spatiotemporal encoding (SPEN) principles, to derive chemical-shift images within a sub-second period. By contrast to EPSI, SPEN does not require oscillating acquisition gradients to deliver chemical-shift information: its signal encodes both spatial as well as chemical shift information, at no extra cost in experimental complexity. SPEN MRI sequences with slice-selection and arbitrary excitation pulses can also be devised, endowing SPEN with the potential to deliver single-shot multi-slice chemical shift images, with a temporal resolution required for hyperpolarized dynamic metabolic imaging. The present work demonstrates this with initial in vivo results obtained from SPEN-based imaging of pyruvate and its metabolic products, after injection of hyperpolarized [1-13C]pyruvate. Multi-slice chemical-shift images of healthy rats were obtained at 4.7 T in the region of the kidney, and 4D (2D spatial, 1D spectral, 1D temporal) data sets were obtained at 7 T from a murine lymphoma tumor model.
doi:10.1016/j.jmr.2013.12.013
PMCID: PMC5040493  PMID: 24486720
Ultrafast MRI; Chemical Shift Imaging; Spatiotemporal encoding; Hyperpolarized dynamic imaging; Hyperpolarized MRI; DNP; Spectroscopic Imaging; Cancer Diagnosis
24.  Correcting surface coil excitation inhomogeneities in single-shot SPatiotemporal ENcoding (SPEN) MRI 
Given their high sensitivity and ability to limit the field of view (FOV), surface coils are often used in magnetic resonance spectroscopy (MRS) and imaging (MRI). A major downside of surface coils is their inherent radiofrequency (RF) B1 heterogeneity across the FOV, decreasing with increasing distance from the coil and giving rise to image distortions due to non-uniform spatial responses. A robust way to compensate for B1 inhomogeneities is to employ adiabatic inversion pulses, yet these are not well adapted to all imaging sequences –including to single-shot approaches like echo planar imaging (EPI). Hybrid spatiotemporal encoding (SPEN) sequences relying on frequency-swept pulses provide another ultrafast MRI alternative, that could help solve this problem thanks to their built-in heterogeneous spatial manipulations. This study explores how this intrinsic SPEN-based spatial discrimination, could be used to compensate for the B1 inhomogeneities inherent to surface coils. Experiments carried out in both phantoms and in vivo rat brains demonstrate that, by suitably modulating the amplitude of a SPEN chirp pulse that progressively excites the spins in a direction normal to the coil, it is possible to reduce RF transmit inhomogeneities and thus improve sensitivity and image fidelity.
doi:10.1016/j.jmr.2015.08.018
PMCID: PMC5035682  PMID: 26363583
Ultrafast MRI; Spatiotemporal encoding; B1 corrections; swept pulses; surface coil MRI
25.  MRSI via Fully-Refocused Spatiotemporal Encoding with Polychromatic Spectral Pulses 
A novel method for the rapid acquisition of quality multi-slice 2D images targeting a small number of spectroscopic resonances, is introduced and illustrated. The method exploits the robustness derived from recently proposed spatiotemporal encoding (SPEN) methods, when operating in the so-called “fully refocused” mode. Fully-refocused SPEN provides high-fidelity single-shot images thanks to its refocusing of all offset-derived effects throughout the course of the acquisition. This, however, prevents exploiting such robustness also for spectroscopic imaging. This work proposes a solution to this limitation, based on the use of polychromatic refocusing pulses. It is shown that if used to address a series of a priori known resonance positions, these pulses can lead to quality spectroscopic images in a small number of scans – generally equal or slightly larger than the number of targeted peaks. This strategy is explored in combination with both fully-refocused SPEN and echo-planar-imaging (EPI) acquisitions. The expected SPEN advantages were observed in both phantom-based models, and in in vivo results of fat and water separation in mice at 7T.
doi:10.1016/j.jmr.2015.07.008
PMCID: PMC5035683  PMID: 26282060
MRSI; SPEN MRI; polychromatic RF pulses; fully-refocused acquisitions; fast spectroscopic imaging

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