Lucio Frydman

Recently, a three-spin rotating-frame nuclear magnetic resonance (NMR) analog of the cross effect, whereby polarization was transferred between two 13Cs and an 15N in a single crystal, was reported. This effect is closely related to the mixed rotational and rotary resonance (MIRROR) experiment, where spin-locked magnetization (e.g., from a 13C) could introduce an “anti-longitudinal” magnetization state in neighboring 1Hs, suitable for examining spin-diffusion under magic angle spinning (MAS). The present work revisits these experiments, as applied to the proton-driven enhancement of rare spins in liquids and in solids under MAS NMR. Average Hamiltonian Theory (AHT) is used to derive the conditions needed for implementing such three-spin transfer in liquids and solids, matching, for the latter case, the conditions derived by MIRROR studies based on triple-mode Floquet theory. AHT was also found in good quantitative agreement with numerical simulations and experiments, which predict that under optimal transfer conditions whereby an I-spin RF irradiation field matches the S1–S2 chemical-shift-difference, a maximum polarization enhancement of γS/γI is achieved. Ca. half of this was effectively obtained for I = 13C in powdered solids, and ca. a quarter in multi-spin solution systems. Such processes are of a reciprocal nature, meaning that the transverse spin-locked polarization of a rare spin can also become “anti-longitudinal” ±(S1z– S2z) magnetization of abundant spins. The roles played by many-body interactions, RF inhomogeneities, fast sample spinning, and interference from other coherences during the execution of these cross-polarization experiments were investigated, and are exemplified with experiments and simulations.

Intra- and intertumoral heterogeneities raise fundamental biological questions and have important implications for accurate cancer diagnosis, prognosis, and treatment. These heterogeneities reflect tumor complexity, including a pronounced diversity in metabolic phenotypes and profiles. This study demonstrates that in vivo deuterium metabolic imaging (DMI) data acquired with sufficiently high spatiotemporal resolution provide a minimally invasive approach to assess these heterogeneities. A multifrequency DMI approach was used to examine tumor heterogeneities within and between colon cancer models. Regions of high and low glucose enrichment and labeled lactate accumulation could thus be detected; these were analyzed using unsupervised clustering strategies based on k -means clustering of area-under-the-curve information, and principal components analysis with Gaussian mixture modeling. Spatial alignment of these imaging-derived clusters for ² H-glucose and ² H-lactate showed good agreement with each other as well as with histological sections, validating the biological relevance of the identified subregions. Immunohistochemical analyses showed that glucose-enriched subregions were positively correlated with the expression of GLUT1 and DLAT, while lactate-enriched areas showed elevated expression of LDHA and MCT4. These results demonstrate that in vivo DMI can distinguish metabolically distinct subregions within viable tumors and between tumor models. DMI-based metabolic maps could thus provide the means to characterize intra- and intertumoral heterogeneities, paving the way for imaging-based metabolic phenotyping in precision oncology.

Nuclear magnetic resonance is uniquely endowed to analyze dynamics, with line shape and relaxation measurements covering timescales over several orders of magnitude. Further insights arise from pulse sequences such as chemical exchange saturation-transfer or relaxation dispersion, which facilitate, respectively, the detectability and shift characterization of even lowly populated states and the pinpointing of the exact exchange rates. The present study demonstrates that Steady State Free Precession (SSFP) experiments involving a train of pulses with flip angle α spaced by repetition times (TRs) combine valuable features from both of these experiments. Indeed, in the presence of chemical exchanges, SSFP yields, via its offset-dependent excitation and saturation profiles, detailed information about the number, the chemical shifts, and the populations of the exchanging sites—even when these involve multiple intermediates with dissimilar abundances. Simultaneously, SSFP can provide, via its TR dependence, a controllable timescale yielding kinetic information on a variety of slow/intermediate/fast exchange rates. All this is theoretically demonstrated with the aid of a Liouville-space formalism examining the steady state in the presence of chemical exchange. This formalism leads in both the slow and fast exchange regimes to analytical predictions that match well “brute-force” numerical calculations, lending themselves to rapid and accurate fittings of exchange rates, chemical shifts, and site populations. The basic features associated with this novel approach to examine chemical kinetics are experimentally verified on simple model compounds; potential extensions are briefly discussed.

Ultra‐wideline nuclear magnetic resonance (NMR) spectra arising from large chemical shift anisotropy and/or quadrupolar broadening can span several MHz, rendering two‐dimensional (2D) correlations between low‐γ nuclei subject to these interactions exceptionally challenging. The limited pulse excitation bandwidth, poor sensitivity, and weak internuclear couplings make correlations between such spins nearly impossible in practice. To deal with such cases, this study introduces the PROgressive Saturation of the Protons Enhanced Correlation Technique (PROSPECT) experiment. PROSPECT correlates the powder spectra of low‐ γ nuclei through their independent dipolar interactions with a common ¹ H reservoir, without requiring direct coupling between the correlated spins. 2D homonuclear and heteronuclear correlations are demonstrated experimentally using this method between ¹⁹⁵ Pt and ¹⁴ N spins, dealing with resonances that span over 1 MHz. Spin dynamic numerical simulations reproduce very well the experimental 2D line shapes, and support our physical description of the method. In this way, PROSPECT extends multidimensional solid‐state NMR to regimes previously considered inaccessible, enabling correlations between ultra‐wideline anisotropic interactions.

The exceptionally high spin polarizations that result from dissolution dynamic nuclear polarization (d-DNP), can lead to unusual liquid-state nuclear magnetic resonance (NMR) spectral features. This study analyzes such features, when performing d-DNP of hyperpolarized water to dissolve and sensitize the NMR spectra of co-dissolved molecules. Most evident among the collective spin effects that arise in such “HyperW” experiments is the very strong radiation damping (RD) affecting the water resonance. In addition, the presence of such strongly magnetized water signal alters both the amplitude and the phase of resonances emerging from the solutes co-dissolved in the hyperpolarized H₂O, for as long as these remain within the RD-broadened line width of water's resonance. These phase- and amplitude RD effects are superimposed on cross-relaxation and chemical exchange effects, which will also affect the phases and amplitudes of all peaks. Demonstrations and derivations of these effects, as well as a discussion of their consequences in HyperW experiments on solute-oriented measurements, are presented.

Liquid-state ¹⁹F Overhauser dynamic nuclear polarization (DNP) was applied to several organic compounds using 1,3-bis(diphenylene)-2-phenylallyl (BDPA) as the polarizing agent. ¹⁹F DNP enhancement factors ranging between 3- and 37-fold were achieved upon microwave irradiation at 395 GHz/14.1 T. These results were obtained using a conventional liquid-state NMR probehead, modified to incorporate a waveguide for the microwaves capable of delivering ≈13–30 W of power emanating from a gyrotron source, as well as a field-sweeping coil for precise tuning of the Overhauser effect resonance condition. Experiments were conducted on ≈70 μL sample volumes, yielding spectral resolutions that were comparable to those of standard liquid-state ¹⁹F NMR. These studies were complemented with quantitative determinations of BDPA’s T_1e and T_2e relaxation times in these liquids, using pulsed-echo and inversion–recovery measurements at 94 GHz. From these data, saturation factors, leakage factors and BDPA coupling factors, could be extracted for each fluorinated system. The resulting coupling factors ranged from −0.0067 to −0.14, depending on the analyte and solvent system used. While heating issues remain to be resolved, these results open new vistas for performing high-field ¹⁹F DNP NMR on organic liquids, on sample volumes of relevance in chemical analysis. Such approaches could significantly broaden the applicability of liquid-state ¹⁹F DNP for small-molecule NMR in analytical and pharmaceutical chemistry, and eventually for the detection and characterization of environmentally persistent PFAS compounds.

Purpose: To evaluate the utility of Deuterium Metabolic Imaging (DMI) as a tool for monitoring disease progression and assessing the therapeutic efficacy of cyclophosphamide in pancreatic ductal adenocarcinoma (PDAC). Methods: The study utilized C57BL mice implanted with a PDAC model, and separated into two experimental groups: One cohort served as an untreated control, while the second was treated with the chemotherapeutic agent cyclophosphamide (CP). Metabolic mapping for the two cohorts was performed over the course of weeks using 2H MRSI at 15.2T, tracking the metabolic pathway of deuterated glucose as it converts by the PDAC into lactate. Results: CP administration led to a significant reduction in tumor growth and improved survival rates compared to the control group. Tumor growth rates for the untreated, control group, showed a strong inverse correlation for glucose’s uptake and a strong direct correlation with the glucose-to-lactate conversion rates as seen by DMI. CP treatment disrupted both these correlations: Post-treatment, tumor growth rates became statistically uncorrelated with either glucose consumption or lactate production which, when normalized for tumor size, remained relatively constant during the treatment period. Conclusion: The study demonstrates that CP treatment fundamentally alters the metabolic kinetics of glucose in PDAC tumors, inducing disruptions in metabolic correlations that may serve for distinguishing therapeutic success from failure.

By untangling information using deterministic frequency-domain linear combinations, the Hadamard Transform (HT) offers a robust way to extract spectral information. Hadamard-based encoding schemes can shorten the acquisition times of nuclear magnetic resonance (NMR) experiments, and lead to substantial sensitivity gains/unit time. However, the presence of spin-spin couplings, spin-spin cross-relaxation, or other mechanisms that break simple one-to-one relationships between a peak intensity and its frequency-domain position can complicate this approach. A case where manipulations at a given peak frequency position may affect the intensity of other peaks in the spectra arises in chemical exchange. Thus, in frequency-domain NMR experiments such as chemical exchange saturation transfer (CEST), saturation at one frequency position may bring about significant intensity changes at another frequency. This study shows that when based on classical frequency-domain Hadamard encodings, strong artifacts will then arise in NMR CEST experiments. The origin of these artifacts is explained and a way to eliminate them while preserving HT's desirable characteristics is proposed, utilizing an extended HT (eHT) scheme. CEST NMR experiments performed and processed using the eHT are shown to be free from artifacts, while leveraging Hadamard's sensitivity-enhanced performance over step-by-step frequency-domain implementations. Good performance is also observed when eHT CEST is compared against other accelerated versions of protein CEST NMR. A summary of the features and potential opened by these new experiments is provided.

Although nuclear magnetic resonance (NMR) is well established to study crystalline and amorphous solids, such experiments are often challenged in sensitivity and resolution. A common approach to improve both of these is magic-angle spinning (MAS); another potential sensitivity-enhancing technique is Steady-State Free Precession (SSFP), an experiment that applies a train of pulses spaced by short repetition delay times, TR. It has recently been shown that, under certain conditions, SSFP could be a method of choice to tackle wide-line solids NMR. But can SSFP and MAS coexist in the same experiment? This study investigates this matter by re-examining SSFP’s spin dynamics under MAS for an ensemble of isolated spins subject to a time-dependent second-rank interaction. It is found that if SSFP’s interpulse time is rotor-synchronized with the sample spinning rate ωR, then the SSFP MAS response will be like that observed in solutions for identical relaxation parameters. However, without rotor synchronization, the SSFP MAS NMR magnetization behaves non-trivially. If the spin anisotropies are much larger than ωR, no steady state is in fact achieved by a single crystal’s evolution. However, under similar mis-synchronization conditions, a steady state can still arise when considering spins over a powdered sample. The dependence of the ensuing steady state on the strength of the anisotropy and the degree of mis-synchronization is not monotonic; the former shows oscillations arising from a series of Bessel-derived functions, while the latter reflects a number of “resonant” dips given by the TR=π2n+1/ωRn=1,2… condition. A rationalization for these behaviors, together with supporting experimental data, is provided.

Purpose: To achieve highly accelerated high‐resolution imaging with PE‐xSPEN that efficiently utilizes the spatiotemporal encoded signals to physically distinguish contributions from distinct spatial locations prior to k‐space acquisition, enabling the differentiation of aliased localized information in k‐space. Methods: In the conventional k‐space, undersampling along the phase‐encoding dimension results in aliasing and overlapping replicas of the object along the spatial direction. The modulated hyperbolic phase arising from the PE‐xSPEN encoding induces coupling between the and dimensions. So that for a given k‐space location, the signal is predominantly contributed by local voxels. While undersampling along the PE dimension still causes aliased spatial replicas, these replicas remain distinguishable even without multi‐channel coils after applying the traditional inverse Fourier transform along the undersampled dimension. Combining with parallel imaging, this approach enhances unfolding efficiency compared to traditional Fourier‐encoded signals. Results: Combining with GRAPPA, the undersampled signals along the dimension can be reconstructed with fewer residual aliasing in PE‐xSPEN compared to the traditional Fourier‐encoded signals. The performance gain is demonstrated by MRI simulation, phantom tests, and in vivo brain experiments on 3T scanner. Conclusion: The proposed PE‐xSPEN GRAPPA framework utilizes hyperbolic phase modulation to control aliasing artifacts and generate ‐dependent coil response, reducing artifacts and noise amplification.