3D hyperpolarized C-13 EPI with calibrationless parallel imaging.

With the translation of metabolic MRI with hyperpolarized 13C agents into the clinic, imaging approaches will require large volumetric FOVs to support clinical applications. Parallel imaging techniques will be crucial to increasing volumetric scan coverage while minimizing RF requirements and temporal resolution. Calibrationless parallel imaging approaches are well-suited for this application because they eliminate the need to acquire coil profile maps or auto-calibration data. In this work, we explored the utility of a calibrationless parallel imaging method (SAKE) and corresponding sampling strategies to accelerate and undersample hyperpolarized 13C data using 3D blipped EPI acquisitions and multichannel receive coils, and demonstrated its application in a human study of [1-13C]pyruvate metabolism.

Direct and cost-efficient hyperpolarization of long-lived nuclear spin states on universal (15)N2-diazirine molecular tags.

Conventional magnetic resonance (MR) faces serious sensitivity limitations which can be overcome by hyperpolarization methods, but the most common method (dynamic nuclear polarization) is complex and expensive, and applications are limited by short spin lifetimes (typically seconds) of biologically relevant molecules. We use a recently developed method, SABRE-SHEATH, to directly hyperpolarize (15)N2 magnetization and long-lived (15)N2 singlet spin order, with signal decay time constants of 5.8 and 23 minutes, respectively. We find >10,000-fold enhancements generating detectable nuclear MR signals that last for over an hour. (15)N2-diazirines represent a class of particularly promising and versatile molecular tags, and can be incorporated into a wide range of biomolecules without significantly altering molecular function.

Development and testing of hyperpolarized (13)C MR calibrationless parallel imaging.

A calibrationless parallel imaging technique developed previously for (1)H MRI was modified and tested for hyperpolarized (13)C 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.

Long-lived polarization protected by symmetry.

In this paper we elucidate, theoretically and experimentally, molecular motifs which permit Long-Lived Polarization Protected by Symmetry (LOLIPOPS). The basic assembly principle starts from a pair of chemically equivalent nuclei supporting a long-lived singlet state and is completed by coupling to additional pairs of spins. LOLIPOPS can be created in various sizes; here we review four-spin systems, introduce a group theory analysis of six-spin systems, and explore eight-spin systems by simulation. The focus is on AA'XnX'n spin systems, where typically the A spins are (15)N or (13)C and X spins are protons. We describe the symmetry of the accessed states, we detail the pulse sequences used to access these states, we quantify the fraction of polarization that can be stored as LOLIPOPS, we elucidate how to access the protected states from A or from X polarization and we examine the behavior of these spin systems upon introduction of a small chemical shift difference.

Accessing long-lived disconnected spin-1/2 eigenstates through spins > 1/2.

Pairs of chemically equivalent (or nearly equivalent) spin-1/2 nuclei have been shown to create disconnected eigenstates that are very long-lived compared with the lifetime of pure magnetization (T1). Here the classes of molecules known to have accessible long-lived states are extended to include those with chemically equivalent spin-1/2 nuclei accessed by coupling to nuclei with spin > 1/2, in this case deuterium. At first, this appears surprising because the quadrupolar interactions present in nuclei with spin > 1/2 are known to cause fast relaxation. Yet it is shown that scalar couplings between deuterium and carbon can guide population into and out of long-lived states, i.e., those immune from the dominant relaxation mechanisms. This implies that it may be practical to consider compounds with (13)C pairs directly bound to deuterium (or even (14)N) as candidates for storage of polarization. In addition, experiments show that simple deuteration of molecules with (13)C pairs at their natural abundance is sufficient for successful lifetime measurements.

Measuring long-lived 13C2 state lifetimes at natural abundance.

Long-lived disconnected eigenstates (for example, the singlet state in a system with two nearly equivalent carbons, or the singlet-singlet state in a system with two chemically equivalent carbons and two chemically equivalent hydrogens) hold the potential to drastically extend the lifetime of hyperpolarization in molecular tracers for in vivo magnetic resonance imaging (MRI). However, a first-principles calculation of the expected lifetime (and thus selection of potential imaging agents) is made very difficult because of the large variety of relevant intra- and intermolecular relaxation mechanisms. As a result, all previous measurements relied on costly and time consuming syntheses of (13)C labeled compounds. Here we show that it is possible to determine (13)C singlet state lifetimes by detecting the naturally abundant doubly-labeled species. This approach allows for rapid and low cost screening of potential molecular biomarkers bearing long-lived states.

Storage of hydrogen spin polarization in long-lived 13C2 singlet order and implications for hyperpolarized magnetic resonance imaging.

Hyperpolarized magnetic resonance imaging (MRI) is a powerful technique enabling real-time monitoring of metabolites at concentration levels not accessible by standard MRI techniques. A considerable challenge this technique faces is the T1 decay of the hyperpolarization upon injection into the system under study. Here we show that A(n)A'(n)XX' spin systems such as (13)C2-1,2-diphenylacetylene ((13)C2-DPA) sustain long-lived polarization for both (13)C and (1)H spins with decay constants of almost 4.5 min at high magnetic fields of up to 16.44 T without spin-locking; the T1 of proton polarization is only 3.8 s. Therefore, storage of the proton polarization in a (13)C2-singlet state causes a 69-fold extension of the spin lifetime. Notably, this extension is demonstrated with proton-only pulse sequences, which can be readily implemented on standard clinical scanners.

Enhanced refocusing of fat signals using optimized multipulse echo sequences.

Endogenous magnetic resonance contrast based on the localized composition of fat in vivo can provide functional information. We found that the unequal pulse timings of the Uhrig's dynamical decoupling multipulse echo sequences significantly alter the signal intensity compared to conventional, equal-spaced Carr-Purcell-Meiboom-Gill sequences. The signal increases and decreases depending on the tissue and sequence parameters, as well as on the interpulse spacings; particularly strong differences were observed in fatty tissues, which have a highly structured morphology and a wide range of chemical shifts and J-couplings. We found that the predominant mechanism for fat refocusing under multipulse echo sequences is the chemical structure, with stimulated echoes playing a pivotal role. As a result, specialized pulse sequences can be designed to optimize refocusing of the fat chemical shifts and J-couplings, where the degree of refocusing can be tailored to specific types of fats. To determine the optimal time delays, we simulated various Uhrig dynamical decoupling and Carr-Purcell-Meiboom-Gill pulse sequence timings, and these results are compared to experimental results obtained on excised and in vivo fatty tissue. Applications to intermolecular multiple quantum coherence imaging, where the improved echo refocusing translates directly into signal enhancements, are presented as well.

Accessing long-lived nuclear singlet states between chemically equivalent spins without breaking symmetry.

Long-lived nuclear spin states could greatly enhance the applicability of hyperpolarized nuclear magnetic resonance. Using singlet states between inequivalent spin pairs has been shown to extend the signal lifetime by more than an order of magnitude compared to the spin lattice relaxation time (T1), but they have to be prevented from evolving into other states. In the most interesting case the singlet is between chemically equivalent spins, as it can then be inherently an eigenstate. However this presents major challenges in the conversion from bulk magnetization to singlet. In the only case demonstrated so far, a reversible chemical reaction to break symmetry was required. Here we present a pulse sequence technique that interconverts between singlet spin order and bulk magnetization without breaking the symmetry of the spin system. This technique is independent of field strength and is applicable to a broad range of molecules.