Conventional Magnetic Resonance Imaging (MRI) relies on high-power Radio-Frequency (RF) pulses to excite nuclear spins and in turn generate NMR signals. These pulses require large high-power RF-amplifiers and cause heat deposition in the tissue, which must be minimized for safety, presenting a growing problem when moving toward ever-higher field MRI. An alternative to RF-pulse excitation is self-excitation of nuclear spins using Radiofrequency Amplification by Stimulated Emission of Radiation (RASER), where the nuclear spins undergo spontaneous transition, without RF excitation, from an over-populated state to a ground state. Here, the feasibility of recording rapid proton RASER MRI images of pyrazine at low concentration (120 mM) with large matrix (128x128 pixels) in as little as 78 ms is demonstrated at 500 MHz (11.7 T). We also recorded a time-series of images using a single bolus hyperpolarized pyrazine highlighting the feasibility of dynamic tracking. The demonstrated approach allows recording MRI scans without transmit-receive electronics of the MRI scanner, which is highly desirable for portable MRI as well as the emerging field of hyperpolarized MRI using, e.g., HP protons, 129Xe gas or HP 13C labeled biomolecules as molecular tracers and imaging agents.

Die konventionelle Magnetresonanztomographie (MRT) basiert auf intensiven Radiofrequenzimpulsen (RF‐Impulsen) zur Anregung von Kernspins, und damit zur Erzeugung von NMR‐Signalen. Diese Impulse erfordern große, leistungsstarke RF‐Verstärker und verursachen Wärme im Gewebe, die aus Sicherheitsgründen minimiert werden muss. Dies stellt bei der Entwicklung von MRT‐Geräten mit immer höheren Feldstärken ein wachsendes Problem dar. Eine Alternative zur RF‐Impulsanregung ist die Selbstanregung von Kernspins mittels Radiofrequenzverstärkung durch stimulierte Emission von Strahlung (Radiofrequency Amplification by Stimulated Emission of Radiation, RASER), bei der die Kernspins ohne RF‐Anregung einen spontanen Übergang von einem energetischen Nichtgleichgewichtszustand in einen Grundzustand durchlaufen. In dieser Arbeit wird die Möglichkeit der Aufzeichnung von „schnellen“ Protonen‐RASER‐MRT‐Bildern von Pyrazin in geringer Konzentration (120 mM) demonstriert. In nur 78 ms werden Bilder mit großer Matrix (128x128 Pixel) bei 500 MHz (11,7 T) aufgenommen. Weiter wurde eine Zeitreihe von Bildern unter Verwendung eines einzelnen Bolus hyperpolarisierten (HP) Pyrazins aufgezeichnet, um die Machbarkeit einer dynamischen Verfolgung zu verdeutlichen. Der demonstrierte Ansatz ermöglicht die Aufzeichnung von MRT‐Scans ohne die Sende‐Empfänger‐Elektronik des MRT‐Scanners, was für tragbare MRT‐Geräte sowie für das aufstrebende Gebiet der hyperpolarisierten MRT, bei der z. B. HP Protonen ( 1 H), 129 Xe‐Gas oder HP 13 C‐markierte Biomoleküle als molekulare Tracer und Bildgebungsmittel verwendet werden, äußerst vorteilhaft ist.

13C hyperpolarized pyruvate is an emerging MRI contrast agent for sensing molecular events in cancer and other diseases with aberrant metabolic pathways. This metabolic contrast agent can be produced via several hyperpolarization techniques. Despite remarkable success in research settings, widespread clinical adoption faces substantial roadblocks because the current sensing technology utilized to sense this contrast agent requires the excitation of 13C nuclear spins that also need to be synchronized with MRI field gradient pulses. Here, we demonstrate sensing of hyperpolarized allyl [1-13C]pyruvate via the stimulated emission of radiation that mitigates the requirements currently blocking broader adoption. Specifically, 13C Radiofrequency Amplification by Stimulated Emission of Radiation (13C RASER) was obtained after pairwise addition of parahydrogen to a pyruvate precursor, detected in a commercial inductive detector with a quality factor (Q) of 32 for sample concentrations as low as 0.125 M with 13C polarization of 4%. Moreover, parahydrogen-induced polarization allowed for the preparation of a mixture of ketone and hemiketal forms of hyperpolarized allyl [1-13C]pyruvate, which are separated by 10 ppm in 13C NMR spectra. This is a good model system to study the simultaneous 13C RASER signals of multiple 13C species. This system models the metabolic production of hyperpolarized [1-13C]lactate from hyperpolarized [1-13C]pyruvate, which has a similar chemical shift difference. Our results show that 13C RASER signals can be obtained from both species simultaneously when the emission threshold is exceeded for both species. On the other hand, when the emission threshold is exceeded only for one of the hyperpolarized species, 13C stimulated emission is confined to this species only, therefore enabling the background-free detection of individual hyperpolarized 13C signals. The reported results pave the way to novel sensing approaches of 13C hyperpolarized pyruvate, potentially unlocking hyperpolarized 13C MRI on virtually any MRI system─an attractive vision for the future molecular imaging and diagnostics.

Precision in nuclear magnetic resonance (NMR) spectroscopy and resolution in magnetic resonance imaging (MRI) are thought to be fundamentally limited by the transverse relaxation time. With the recent advent of radiofrequency amplification by stimulated emission of radiation (RASER), it is becoming apparent that RASERs can break these fundamental limitations and provide significant improvements in the resolution of NMR spectra and the resolution in MRI images. In this article, we show that carbon-13 RASERs can be controlled by changes to the magnetic field homogeneity and the spin coupling network. As illustrative examples of tools commonly employed in high-resolution NMR spectroscopy, we employ the control of magnetic field homogeneity with simple changes to the sample geometry and the spin-coupling network with proton decoupling pulses. These changes control the distance of the NMR system from the RASER threshold. Finally, we demonstrate that the 13C-RASER spectra can be obtained reflecting the usual, thermal NMR spectra without significant distortions except with at least 10-fold narrower spectral-resonance line widths, thereby significantly increasing our precision in determining NMR parameters such as the J-coupling in the spin system. In contrast to 1H RASERs, we discuss how 13C-RASER systems retain the spin information (J-couplings and chemical shifts) with high fidelity.

It has recently been shown that a bolus of hyperpolarized nuclear spins can yield stimulated emission signals similar in nature to maser signals, potentially enabling new ways of sensing hyperpolarized contrast media, including most notably [1-13C]pyruvate that is under evaluation in over 50 clinical trials for metabolic imaging of cancer. The stimulated NMR signal emissions lasting for minutes do not require radio-frequency excitation, offering unprecedented advantages compared to conventional MR sensing. However, creating nuclear spin maser emission is challenging in practice due to stringent fundamental requirements, making practical in vivo applications hardly possible using conventional passive MR detectors. Here, we demonstrate the utility of a wireless NMR maser detector, the quality factor of which was enhanced 22-fold (to 1,670) via parametric pumping. This active-feedback technique breaks the intrinsic fundamental limit of NMR detector circuit quality factor. We show the use of parametric pumping to reduce the threshold requirement for inducing nuclear spin masing at 300 MHz resonance frequency in a preclinical MRI scanner. Indeed, stimulated emission from hyperpolarized protons was obtained under highly unfavorable conditions of low magnetic field homogeneity (T2* of 3 ms). Greater gains of the quality factor of the MR detector (up to 1 million) were also demonstrated.

Conventional nuclear magnetic resonance (NMR) enables detection of chemicals and their transformations by exciting nuclear spin ensembles with a radio-frequency pulse followed by detection of the precessing spins at their characteristic frequencies. The detected frequencies report on chemical reactions in real time and the signal amplitudes scale with concentrations of products and reactants. Here, we employ Radiofrequency Amplification by Stimulated Emission of Radiation (RASER), a quantum phenomenon producing coherent emission of 13C signals, to detect chemical transformations. The 13C signals are emitted by the negatively hyperpolarized biomolecules without external radio frequency pulses and without any background signal from other, nonhyperpolarized spins in the ensemble. Here, we studied the hydrolysis of hyperpolarized ethyl-[1-13C]acetate to hyperpolarized [1-13C]acetate, which was analyzed as a model system by conventional NMR and 13C RASER. The chemical transformation of 13C RASER-active species leads to complete and abrupt disappearance of reactant signals and delayed, abrupt reappearance of a frequency-shifted RASER signal without destroying 13C polarization. The experimentally observed "quantum" RASER threshold is supported by simulations.

Radio-frequency Amplification by Stimulated Emission of Radiation (RASER) is a promising tool to study nonlinear phenomena or measure NMR parameters with unprecedented precision. Magnetic fields, J -couplings, and chemical shifts can be recorded over long periods of time without the need for radiofrequency excitation and signal averaging. One key feature of RASER NMR spectroscopy is the improvement in precision, which grows with the measurement time T_m^3/2 , unlike conventional NMR spectroscopy, where the precision increases with T_m^1/2 . However, when detecting NMR signals over minutes to hours, using available NMR magnets (ppb homogeneity), the achieved frequency resolution will eventually be limited by magnetic field fluctuations. Here, we demonstrate that full compensation is possible even for open low-field electromagnets, where magnetic field fluctuations are intrinsically present (in the ppm regime). A prerequisite for compensation is that the spectrum contains at least one isolated RASER line to be used as a reference, and the sample experiences exclusively common magnetic field fluctuations, that is, ones that are equal over the entire sample volume. We discuss the current limits of precision for RASER NMR measurements for two different cases: The single-compartment RASER involving J -coupled modes, and the two-compartment RASER involving chemically shifted species. In the first case, the limit of measurable difference approaches the Cramér-Rao lower bound (CRLB), achieving a measurement precision σ_f<10^-4 Hz. In the second case, the measured chemical shift separation is plagued by independently fluctuating distant dipolar fields (DDF). The measured independent field fluctuation between the two chambers is in the order of tens of mHz. In both cases, new limits of precision are achieved, which paves the way for sub-mHz detection of NMR parameters, rotational rates, and non-linear phenomena such as chaos and synchrony.

A nuclear-spin-based RASER (radio-frequency amplification by stimulated emission of radiation) is an ideal experimental system to explore nonlinear interaction phenomena of nuclear spins coupled via virtual photons to a resonator. This is due to the RASER being stable for several hours, allowing for extended observation of these phenomena. Nonlinear phenomena in multimode RASERs range from mode oscillations in synchrony, frequency shifts, frequency combs, period doublings, and even chaos. These phenomena are observed in a parahydrogen-pumped two-compartment proton RASER. In two independently pumped compartments, the separation in frequency space between the two RASER modes is precisely controlled with a magnetic field gradient. By controlling the mode separation, we can select the type of nonlinear phenomena observed. A key finding is that the ranges of mode separation where chaos and synchrony occur are very close together. The experimental results are supported by numerical simulations, based on two-mode RASER equations.

Carbon-13 radiofrequency amplification by stimulated emission of radiation (C-13 RASER) is demonstrated on a bolus of liquid hyperpolarized ethyl [1-13C]acetate, as reported by Thomas Theis, Eduard Y. Chekmenev et al. in their Communication (e202215678). Spontaneous RASER signal emissions were detected using a 1.4 T NMR spectrometer equipped with a standard radiofrequency detection coil for over three minutes. RASER detection enables new detection schemes for 13C-hyperpolarized contrast agents and particular new opportunities for next-generation molecular imaging on clinical MRI scanners.

The spatial resolution of magnetic resonance imaging (MRI) is limited by the width of Lorentzian point spread functions associated with the transverse relaxation rate 1/T2*. Here, we show a different contrast mechanism in MRI by establishing RASER (radio-frequency amplification by stimulated emission of radiation) in imaged media. RASER imaging bursts emerge out of noise and without applying radio-frequency pulses when placing spins with sufficient population inversion in a weak magnetic field gradient. Small local differences in initial population inversion density can create stronger image contrast than conventional MRI. This different contrast mechanism is based on the cooperative nonlinear interaction between all slices. On the other hand, the cooperative nonlinear interaction gives rise to imaging artifacts, such as amplitude distortions and side lobes outside of the imaging domain. Contrast mechanism and artifacts are explored experimentally and predicted by simulations on the basis of a proposed RASER MRI theory.

The feasibility of Carbon-13 Radiofrequency (RF) Amplification by Stimulated Emission of Radiation (C-13 RASER) is demonstrated on a bolus of liquid hyperpolarized ethyl [1-13 C]acetate. Hyperpolarized ethyl [1-13 C]acetate was prepared via pairwise addition of parahydrogen to vinyl [1-13 C]acetate and polarization transfer from nascent parahydrogen-derived protons to the carbon-13 nucleus via magnetic field cycling yielding C-13 nuclear spin polarization of approximately 6 %. RASER signals were detected from samples with concentration ranging from 0.12 to 1 M concentration using a non-cryogenic 1.4T NMR spectrometer equipped with a radio-frequency detection coil with a quality factor (Q) of 32 without any modifications. C-13 RASER signals were observed for several minutes on a single bolus of hyperpolarized substrate to achieve 21 mHz NMR linewidths. The feasibility of creating long-lasting C-13 RASER on biomolecular carriers opens a wide range of new opportunities for the rapidly expanding field of C-13 magnetic resonance hyperpolarization.

RASER (radiofrequency amplification by stimulated emission radiation) ist die Variante von Laser und Maser, die im Hochfrequenzspektralbereich arbeitet. Eduard Y. Chekmenev et al. setzen in ihrer Zuschrift auf S. 26502 61-MHz-Protonen-RASER ein, um eine robuste, untergrundfreie Detektion biomolekularer NMR-Resonanzen zu demonstrieren, selbst in den extremen Fällen von vollständig protonierten Lösungsmitteln und biologischen Flüssigkeiten. Dieser Ansatz ebnet den Weg für vielzählige hochauflösenden NMR- und In-vivo-MRT-Anwendungen zur untergrundfreien Protonendetektion hyperpolarisierter Moleküle.

We introduce a Spin Transfer Automated Reactor (STAR) that produces continuous parahydrogen induced polarization (PHIP), which is stable for hours to days. We use the PHIP variant called signal amplification by reversible exchange (SABRE), which is particularly well suited to produce continuous hyperpolarization. The STAR is operated in conjunction with benchtop (1.1 T) and high field (9.4 T) NMR magnets, highlighting the versatility of this system to operate with any NMR or MRI system. The STAR uses semipermeable membranes to efficiently deliver parahydrogen into solutions at nano to milli Tesla fields, which enables H-1, C-13, and N-15 hyperpolarization on a large range of substrates including drugs and metabolites. The unique features of the STAR are leveraged for important applications, including continuous hyperpolarization of metabolites, desirable for examining steady-state metabolism in vivo, as well as for continuous RASER signals suitable for the investigation of new physics.

Radiofrequency amplification by stimulated emission radiation (RASER) is the version of lasers and masers operating in the radiofrequency spectral range. In their Communication on page 26298, Eduard Y. Chekmenev and co-workers employ 61 MHz proton RASER to demonstrate robust background-free detection of biomolecular NMR resonances even in the extreme cases of fully protonated solvents and biological fluids. This approach paves the way to a wide range of high-resolution NMR and in vivo MRI applications of background-free proton detection of hyperpolarized molecules.

We report on the utility of Radiofrequency Amplification by Stimulated Emission Radiation (RASER) for background-free proton detection of hyperpolarized biomolecules. We performed hyperpolarization of ≈0.3 M ethyl acetate via pairwise parahydrogen addition to vinyl acetate. A proton NMR signal with signal-to-noise ratio exceeding 100 000 was detected without radio-frequency excitation at the clinically relevant magnetic field of 1.4 T using a standard (non-cryogenic) inductive detector with quality factor of Q=68. No proton background signal was observed from protonated solvent (methanol) or other added co-solvents such as ethanol, water or bovine serum. Moreover, we demonstrate RASER detection without radio-frequency excitation of a bolus of hyperpolarized contrast agent in biological fluid. Completely background-free proton detection of hyperpolarized contrast agents in biological media paves the way to new applications in the areas of high-resolution NMR spectroscopy and in vivo spectroscopy and imaging.

High-field nuclear magnetic resonance (NMR) spectroscopy is an indispensable technique for identification and characterization of chemicals and biomolecular structures. In the vast majority of NMR experiments, nuclear spin polarization arises from thermalization in multi-Tesla magnetic fields produced by superconducting magnets. In contrast, NMR instruments operating at low magnetic fields are emerging as a compact, inexpensive, and highly accessible alternative but suffer from low thermal polarization at a low field strength and consequently a low signal. However, certain hyperpolarization techniques create high polarization levels on target molecules independent of magnetic fields, giving low-field NMR a significant sensitivity boost. In this study, SABRE (Signal Amplification By Reversible Exchange) was combined with high homogeneity electromagnets operating at mT fields, enabling high resolution 1H, 13C, 15N, and 19F spectra to be detected with a single scan at magnetic fields between 1 mT and 10 mT. Chemical specificity is attained at mT magnetic fields with complex, highly resolved spectra. Most spectra are in the strong coupling regime where J-couplings are on the order of chemical shift differences. The spectra and the hyperpolarization spin dynamics are simulated with SPINACH. The simulations start from the parahydrogen singlet in the bound complex and include both chemical exchange and spin evolution at these mT fields. The simulations qualitatively match the experimental spectra and are used to identify the spin order terms formed during mT SABRE. The combination of low field NMR instruments with SABRE polarization results in sensitive measurements, even for rare spins with low gyromagnetic ratios at low magnetic fields.

Radio amplification by stimulated emission of radiation (RASER) was recently discovered in a low-field NMR spectrometer incorporating a highly specialized radio-frequency resonator, where a high degree of proton-spin polarization was achieved by reversible parahydrogen exchange. RASER activity, which results from the coherent coupling between the nuclear spins and the inductive detector, can overcome the limits of frequency resolution in NMR. Here we show that this phenomenon is not limited to low magnetic fields or the use of resonators with high-quality factors. We use a commercial bench-top 1.4 T NMR spectrometer in conjunction with pairwise parahydrogen addition producing proton-hyperpolarized molecules in the Earth's magnetic field (ALTADENA condition) or in a high magnetic field (PASADENA condition) to induce RASER without any radio-frequency excitation pulses. The results demonstrate that RASER activity can be observed on virtually any NMR spectrometer and measures most of the important NMR parameters with high precision.

In a RASER (Radio-frequency Amplification by Stimulated Emission of Radiation), the fast relaxing electromagnetic modes of an LC resonator are enslaved by the slow nuclear spin motion, whose coherence decays with the transverse relaxation rate γm=1/T2∗. Such a system obeys the slaving principle, mathematically identical with the adiabatic elimination procedure, leading to multi-mode RASER equations. If the pumping rate of nuclear spin polarization Γ>>γm, a second adiabatic elimination process applies and the spectral properties of the RASER can be predicted. The resulting model is similar to the model of two non-linear coupled oscillators and predicts the observed RASER phenomena, including frequency combs and mode collapse. If the second adiabatic elimination is not applicable, mode collapse is completely absent and successive period doubling processes and chaos occur at very high population inversions. We compare these theoretical predictions with experimental results from a PHIP (Para-Hydrogen Induced Polarization) pumped 1H RASER. Moreover, in SABRE (Signal Amplification By Reversible Exchange) pumped 1H experiments, RASER revivals are observed long after the parahydrogen pumping source has been switched off. All these findings shed light onto the links between NMR spectroscopy, RASER physics, synergetics and chaos theory. Several new applications are envisioned in the fields of quantum sensor technology, structure investigation or magnetic resonance imaging (MRI).

The properties of the LASER with respect to self-organization are compared with the key features of the p-H2 pumped RASER. According to LASER theory the equations of motion for the LASER can be derived from the enslaving principle, i.e. the slowest-changing order parameter (the light field in the resonator) enslaves the rapidly relaxing atomic degrees of freedom. Likewise, it is shown here that the equations of motion for the p-H2 pumped RASER result from a set of order parameters, where the transverse magnetization of the RASER-active spin states enslaves the electromagnetic modes. The consequences are striking for nuclear magnetic resonance (NMR) spectroscopy, since long-lasting multi-mode RASER oscillations enable unprecedented spectroscopic resolution down to the micro-Hertz regime. Based on the theory for multi-mode RASER operation we analyze the conditions that reveal either the collapse of the entire NMR spectrum, the occurrence of self-organized frequency-combs, or RASER spectra which reflect the J-coupled network of the molecule. Certain RASER experiments involving the protons of 15N pyridine or 3-picoline molecules pumped with p-H2 via SABRE (Signal Amplification By Reversible Exchange) show either a single RASER oscillation in the time domain, giant RASER pulses or a complex RASER beat pattern. The corresponding 1H spectra consist of one narrow line, equidistant narrow lines (frequency-comb), or highly resolved lines reporting NMR properties, respectively. Numerous applications in the areas of material sciences, fundamental physics and medicine involving high precision sensors for magnetic fields, rotational motions or molecular structures become feasible.