A pharmacokinetic model for hyperpolarized 13C-pyruvate MRI when using metabolite-specific bSSFP sequences.

PURPOSE: Metabolite-specific balanced SSFP (MS-bSSFP) sequences are increasingly used in hyperpolarized [1-13C]Pyruvate (HP 13C) MRI studies as they improve SNR by refocusing the magnetization each TR. Currently, pharmacokinetic models used to fit conversion rate constants, kPL and kPB, and rate constant maps do not account for differences in the signal evolution of MS-bSSFP acquisitions. METHODS: In this work, a flexible MS-bSSFP model was built that can be used to fit conversion rate constants for these experiments. The model was validated in vivo using paired animal (healthy rat kidneys n = 8, transgenic adenocarcinoma of the mouse prostate n = 3) and human renal cell carcinoma (n = 3) datasets. Gradient echo (GRE) acquisitions were used with a previous GRE model to compare to the results of the proposed GRE-bSSFP model. RESULTS: Within simulations, the proposed GRE-bSSFP model fits the simulated data well, whereas a GRE model shows bias because of model mismatch. For the in vivo datasets, the estimated conversion rate constants using the proposed GRE-bSSFP model are consistent with a previous GRE model. Jointly fitting the lactate T2 with kPL resulted in less precise kPL estimates. CONCLUSION: The proposed GRE-bSSFP model provides a method to estimate conversion rate constants, kPL and kPB, for MS-bSSFP HP 13C experiments. This model may also be modified and used for other applications, for example, estimating rate constants with other hyperpolarized reagents or multi-echo bSSFP.

A 13C/31P surface coil to visualize metabolism and energetics in the rodent brain at 3 Tesla.

PURPOSE: We constructed a 13C/31P surface coil at 3 T for studying cancer metabolism and bioenergetics. In a single scan session, hyperpolarized 13C-pyruvate MRS and 31P MRS was carried out for a healthy rat brain. METHODS: All experiments were carried out at 3 Tesla. The multinuclear surface coil was designed as two coplanar loops each tuned to either the 13C or 31P operating frequency with an LCC trap on the 13C loop. A commercial volume proton coil was used for anatomical localization and B0 shimming. Single tuned coils operating at either the 13C or 31P frequency were built to evaluate the relative performance of the multinuclear coil. Coil performance metrics consisted of measuring Q factor ratio, calculating system input power using a single-pulse acquisition, and acquiring SNR and flip angle maps using 2D CSI sequences. To observe in vivo spectra, a bolus of hyperpolarized [1-13C] pyruvate was administered via tail vein. In vivo13C and endogenous 31P spectra were obtained in a single scan session using 1D slice selective acquisitions. RESULTS: When compared with single tuned surface coils, the multinuclear coil performance showed a decrease in Q factor ratio, SNR, and transmit efficiency. Flip angle maps showed adequate flip angles within the phantom when the transmit voltage was set using an external phantom. Results show good detection of 13C labeled lactate, alanine, and bicarbonate in addition to ATP from 31P MRS. CONCLUSIONS: The coil enables obtaining complementary information within a scan session, thus reducing the number of trials and minimizing biological variability for studies of metabolism and bioenergetics.

Acquisition and quantification pipeline for in vivo hyperpolarized 13 C MR spectroscopy.

PURPOSE: The goal of this study was to combine a specialized acquisition method with a new quantification pipeline to accurately and efficiently probe the metabolism of hyperpolarized 13 C-labeled compounds in vivo. In this study, we tested our approach on [2-13 C]pyruvate and [1-13 C]α-ketoglutarate data in rat orthotopic brain tumor models at 3T. METHODS: We used a multiband metabolite-specific radiofrequency (RF) excitation in combination with a variable flip angle scheme to minimize substrate polarization loss and measure fast metabolic processes. We then applied spectral-temporal denoising using singular value decomposition to enhance spectral quality. This was combined with LCModel-based automatic 13 C spectral fitting and flip angle correction to separate overlapping signals and rapidly quantify the different metabolites. RESULTS: Denoising improved the metabolite signal-to-noise ratio (SNR) by approximately 5. It also improved the accuracy of metabolite quantification as evidenced by a significant reduction of the Cramer Rao lower bounds. Furthermore, the use of the automated and user-independent LCModel-based quantification approach could be performed rapidly, with the kinetic quantification of eight metabolite peaks in a 12-spectrum array achieved in less than 1 minute. CONCLUSION: The specialized acquisition method combined with denoising and a new quantification pipeline using LCModel for the first time for hyperpolarized 13 C data enhanced our ability to monitor the metabolism of [2-13 C]pyruvate and [1-13 C]α-ketoglutarate in rat orthotopic brain tumor models in vivo. This approach could be broadly applicable to other hyperpolarized agents both preclinically and in the clinical setting.

Visualizing the effects of lactate dehydrogenase (LDH) inhibition and LDH-A genetic ablation in breast and lung cancer with hyperpolarized pyruvate NMR.

In many tumors, cancer cells take up large quantities of glucose and metabolize it into lactate, even in the presence of sufficient oxygen to support oxidative metabolism. It has been hypothesized that this malignant metabolic phenotype supports cancer growth and metastasis, and that reversal of this so-called "Warburg effect" may selectively harm cancer cells. Conversion of glucose to lactate can be reduced by ablation or inhibition of lactate dehydrogenase (LDH), the enzyme responsible for conversion of pyruvate to lactate at the endpoint of glycolysis. Recently developed inhibitors of LDH provide new opportunities to investigate the role of this metabolic pathway in cancer. Here we show that magnetic resonance spectroscopic imaging of hyperpolarized pyruvate and its metabolites in models of breast and lung cancer reveal that inhibition of LDH was readily visualized through reduction in label exchange between pyruvate and lactate, while genetic ablation of the LDH-A isoform alone had smaller effects. During the acute phase of LDH inhibition in breast cancer, no discernible bicarbonate signal was observed and small signals from alanine were unchanged.

Disentangling the effects of high permittivity materials on signal optimization and sample noise reduction via ideal current patterns.

PURPOSE: To investigate how high-permittivity materials (HPMs) can improve SNR when placed between MR detectors and the imaged body. METHODS: We used a simulation framework based on dyadic Green's functions to calculate the electromagnetic field inside a uniform dielectric sphere at 7 Tesla, with and without a surrounding layer of HPM. SNR-optimizing (ideal) current patterns were expressed as the sum of signal-optimizing (signal-only) current patterns and dark mode current patterns that minimize sample noise while contributing nothing to signal. We investigated how HPM affects the shape and amplitude of these current patterns, sample noise, and array SNR. RESULTS: Ideal and signal-only current patterns were identical for a central voxel. HPMs introduced a phase shift into these patterns, compensating for signal propagation delay in the HPMs. For an intermediate location within the sphere, dark mode current patterns were present and illustrated the mechanisms by which HPMs can reduce sample noise. High-amplitude signal-only current patterns were observed for HPM configurations that shield the electromagnetic field from the sample. For coil arrays, these configurations corresponded to poor SNR in deep regions but resulted in large SNR gains near the surface due to enhanced fields in the vicinity of the HPM. For very high relative permittivity values, HPM thicknesses corresponding to even multiples of λ/4 resulted in coil SNR gains throughout the sample. CONCLUSION: HPMs affect both signal sensitivity and sample noise. Lower amplitude signal-only optimal currents corresponded to higher array SNR performance and could guide the design of coils integrated with HPM.

Improved detection of fMRI activation in the cerebellum at 7T with dielectric pads extending the imaging region of a commercial head coil.

BACKGROUND: There is growing interest in detecting cerebro-cerebellar circuits, which requires adequate blood oxygenation level dependent contrast and signal-to-noise ratio (SNR) throughout the brain. Although 7T scanners offer increased SNR, coverage of commercial head coils is currently limited to the cerebrum. PURPOSE: To improve cerebellar functional MRI (fMRI) at 7T with high permittivity material (HPM) pads extending the sensitivity of a commercial coil. STUDY TYPE: Simulations were used to determine HPM pad configuration and assess radiofrequency (RF) safety. In vivo experiments were performed to evaluate RF field distributions and SNR and assess improvements of cerebellar fMRI. SUBJECTS: Eight healthy volunteers enrolled in a prospective motor fMRI study with and without HPM. FIELD STRENGTH/SEQUENCE: Gradient echo (GRE) echo planar imaging for fMRI, turbo FLASH for flip angle mapping, GRE sequence for SNR maps, and T1 -weighted MPRAGE were acquired with and without HPM pads at 7T. ASSESSMENT: Field maps, SNR maps, and anatomical images were evaluated for coverage. Simulation results were used to assess SAR levels of the experiment. Activation data from fMRI experiments were compared with and without HPM pads. STATISTICAL TESTS: fMRI data were analyzed using FEAT FSL for each subject followed by group level analysis using paired t-test of acquisitions with and without HPM. RESULTS: Simulations showed 52% improvement in transmit efficiency in cerebellum with HPM and SAR levels well below recommended limits. Experiments showed 27% improvement in SNR in cerebellum and improvement in coverage on T1 -weighted images. fMRI showed greater cerebellar activation in individual subjects with the HPM pad present (Z > = 4), especially in inferior slices of cerebellum, with 59% average increase in number of activated voxels in the cerebellum. Group-level analysis showed improved functional activation (Z > = 2.3) in cerebellar regions with HPM pads without loss of measured activation elsewhere. DATA CONCLUSION: HPM pads can improve cerebellar fMRI at 7T with a commonly-used head coil without compromising RF safety. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:431-440.

Approaching ultimate intrinsic specific absorption rate in radiofrequency shimming using high-permittivity materials at 7 Tesla.

PURPOSE: The aim of this study was to evaluate the effect of integrated high-permittivity materials (HPMs) on excitation homogeneity and global specific absorption rate (SAR) for transmit arrays at 7T. METHODS: A rapid electrodynamic simulation framework was used to calculate L-curves associated with excitation of a uniform 2D profile in a dielectric sphere. We used ultimate intrinsic SAR as an absolute performance reference to compare different transmit arrays in the presence and absence of a layer of HPM. We investigated the optimal permittivity for the HPM as a function of its thickness, the sample size, and the number of array elements. RESULTS: Adding a layer of HPM can improve the performance of a 24-element array to match that of a 48-element array without HPM, whereas a 48-element array with HPM can perform as well as a 64-element array without HPM. Optimal relative permittivity values changed based on sample and coil geometry, but were always within a range obtainable with readily available materials (εr = 100-200). CONCLUSION: Integration of HPMs could be a practical method to improve RF shimming performance, alternative to increasing the number of coils. The proposed simulation framework could be used to explore the design of novel transmit arrays for head imaging at ultra-high field strength. Magn Reson Med 80:391-399, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Manipulating transmit and receive sensitivities of radiofrequency surface coils using shielded and unshielded high-permittivity materials.

OBJECTIVE: To use high-permittivity materials (HPM) positioned near radiofrequency (RF) surface coils to manipulate transmit/receive field patterns. MATERIALS AND METHODS: A large HPM pad was placed below the RF coil to extend the field of view (FOV). The resulting signal-to-noise ratio (SNR) was compared with that of other coil configurations covering the same FOV in simulations and experiments at 7 T. Transmit/receive efficiency was evaluated when HPM discs with or without a partial shield were positioned at a distance from the coil. Finally, we evaluated the increase in transmit homogeneity for a four-channel array with HPM discs interposed between adjacent coil elements. RESULTS: Various configurations of HPM increased SNR, transmit/receive efficiency, excitation/reception sensitivity overlap, and FOV when positioned near a surface coil. For a four-channel array driven in quadrature, shielded HPM discs enhanced the field below the discs as well as at the center of the sample as compared with other configurations with or without unshielded HPM discs. CONCLUSION: Strategically positioning HPM at a distance from a surface coil or array can increase the overlap between excitation/reception sensitivities, and extend the FOV of a single coil for reduction of the number of channels in an array while minimally affecting the SNR.

Dependence of B1+ and B1- Field Patterns of Surface Coils on the Electrical Properties of the Sample and the MR Operating Frequency.

In high field MRI, the spatial distribution of the radiofrequency magnetic ( B1) field is usually affected by the presence of the sample. For hardware design and to aid interpretation of experimental results, it is important both to anticipate and to accurately simulate the behavior of these fields. Fields generated by a radiofrequency surface coil were simulated using dyadic Green's functions, or experimentally measured over a range of frequencies inside an object whose electrical properties were varied to illustrate a variety of transmit [Formula: see text] and receive [Formula: see text] field patterns. In this work, we examine how changes in polarization of the field and interference of propagating waves in an object can affect the B1 spatial distribution. Results are explained conceptually using Maxwell's equations and intuitive illustrations. We demonstrate that the electrical conductivity alters the spatial distribution of distinct polarized components of the field, causing "twisted" transmit and receive field patterns, and asymmetries between [Formula: see text] and [Formula: see text]. Additionally, interference patterns due to wavelength effects are observed at high field in samples with high relative permittivity and near-zero conductivity, but are not present in lossy samples due to the attenuation of propagating EM fields. This work provides a conceptual framework for understanding B1 spatial distributions for surface coils and can provide guidance for RF engineers.

Radiofrequency energy deposition and radiofrequency power requirements in parallel transmission with increasing distance from the coil to the sample.

PURPOSE: We investigated global specific absorption rate (SAR) and radiofrequency (RF) power requirements in parallel transmission as the distance between the transmit coils and the sample was increased. METHODS: We calculated ultimate intrinsic SAR (UISAR), which depends on object geometry and electrical properties but not on coil design, and we used it as the reference to compare the performance of various transmit arrays. We investigated the case of fixing coil size and increasing the number of coils while moving the array away from the sample, as well as the case of fixing coil number and scaling coil dimensions. We also investigated RF power requirements as a function of lift-off, and tracked local SAR distributions associated with global SAR optima. RESULTS: In all cases, the target excitation profile was achieved and global SAR (as well as associated maximum local SAR) decreased with lift-off, approaching UISAR, which was constant for all lift-offs. We observed a lift-off value that optimizes the balance between global SAR and power losses in coil conductors. We showed that, using parallel transmission, global SAR can decrease at ultra high fields for finite arrays with a sufficient number of transmit elements. CONCLUSION: For parallel transmission, the distance between coils and object can be optimized to reduce SAR and minimize RF power requirements associated with homogeneous excitation.

Approaching Ultimate Intrinsic SNR in a Uniform Spherical Sample with Finite Arrays of Loop Coils.

We investigated to what degree and at what rate the ultimate intrinsic (UI) signal-to-noise ratio (SNR) may be approached using finite radiofrequency detector arrays. We used full-wave electromagnetic field simulations based on dyadic Green's functions to compare the SNR of arrays of loops surrounding a uniform sphere with the ultimate intrinsic SNR (UISNR), for increasing numbers of elements over a range of magnetic field strengths, voxel positions, sphere sizes, and acceleration factors. We evaluated the effect of coil conductor losses and the performance of a variety of distinct geometrical arrangements such as "helmet" and "open-pole" configurations in multiple imaging planes. Our results indicate that UISNR at the center is rapidly approached with encircling arrays and performance is substantially lower near the surface, where a quadrature detection configuration tailored to voxel position is optimal. Coil noise is negligible at high field, where sample noise dominates. Central SNR for practical array configurations such as the helmet is similar to that of close-packed arrangements. The observed trends can provide physical insights to improve coil design.

Combined PET/CT image characteristics for radiotherapy tumor response in lung cancer.

BACKGROUND AND PURPOSE: Prediction of local failure in radiotherapy patients with non-small cell lung cancer (NSCLC) remains a challenging task. Recent evidence suggests that FDG-PET images can be used to predict outcomes. We investigate an alternative multimodality image-feature approach for predicting post-radiotherapy tumor progression in NSCLC. MATERIAL AND METHODS: We analyzed pre-treatment FDG-PET/CT studies of twenty-seven NSCLC patients for local and loco-regional failures. Thirty-two tumor region features based on SUV or HU, intensity-volume-histogram (IVH) and texture characteristics were extracted. Statistical analysis was performed using Spearman's correlation (rs) and multivariable logistic regression. RESULTS: For loco-regional recurrence, IVH variables had the highest univariate association. In PET, IVH-slope reached rs=0.3426 (p=0.0403). Motion correction slightly improved correlation of texture features. In CT, coefficient of variation had the highest association rs=-0.2665 (p=0.0871). Similarly for local failure, a CT-IVH parameter reached rs=0.4530 (p=0.0105). For loco-regional and local failures, a 2-parameter model of PET-V(80) and CT-V(70) yielded rs=0.4854 (p=0.0067) and rs=0.5908 (p=0.0013), respectively. Addition of dosimetric variables provided improvement in cases of loco-regional but not local failures. CONCLUSIONS: We proposed a feature-based approach to evaluate radiation tumor response. Our study demonstrates that multimodality image-feature modeling provides better performance compared to existing metrics and holds promise for individualizing radiotherapy planning.

A Bayesian network approach for modeling local failure in lung cancer.

Locally advanced non-small cell lung cancer (NSCLC) patients suffer from a high local failure rate following radiotherapy. Despite many efforts to develop new dose-volume models for early detection of tumor local failure, there was no reported significant improvement in their application prospectively. Based on recent studies of biomarker proteins' role in hypoxia and inflammation in predicting tumor response to radiotherapy, we hypothesize that combining physical and biological factors with a suitable framework could improve the overall prediction. To test this hypothesis, we propose a graphical Bayesian network framework for predicting local failure in lung cancer. The proposed approach was tested using two different datasets of locally advanced NSCLC patients treated with radiotherapy. The first dataset was collected retrospectively, which comprises clinical and dosimetric variables only. The second dataset was collected prospectively in which in addition to clinical and dosimetric information, blood was drawn from the patients at various time points to extract candidate biomarkers as well. Our preliminary results show that the proposed method can be used as an efficient method to develop predictive models of local failure in these patients and to interpret relationships among the different variables in the models. We also demonstrate the potential use of heterogeneous physical and biological variables to improve the model prediction. With the first dataset, we achieved better performance compared with competing Bayesian-based classifiers. With the second dataset, the combined model had a slightly higher performance compared to individual physical and biological models, with the biological variables making the largest contribution. Our preliminary results highlight the potential of the proposed integrated approach for predicting post-radiotherapy local failure in NSCLC patients.