Development of high resolution 3D hyperpolarized carbon-13 MR molecular imaging techniques

The goal of this project was to develop and apply techniques for T₂ mapping and 3D high resolution (1.5 mm isotropic; 0.003 cm³) ¹³C imaging of hyperpolarized (HP) probes [1-¹³C]lactate, [1-¹³C]pyruvate, [2-¹³C]pyruvate, and [¹³C,¹⁵N₂]urea in vivo. A specialized 2D bSSFP sequence was implemented on a clinical 3T scanner and used to obtain the first high resolution T₂ maps of these different hyperpolarized compounds in both rats and tumor-bearing mice. These maps were first used to optimize timings for highest SNR for single time-point 3D bSSFP acquisitions with a 1.5 mm isotropic spatial resolution of normal rats. This 3D acquisition approach was extended to serial dynamic imaging with 2-fold compressed sensing acceleration without changing spatial resolution. The T₂ mapping experiments yielded measurements of T₂ values of > 1 s for all compounds within rat kidneys/vasculature and TRAMP tumors, except for [2-¹³C]pyruvate which was ~ 730 ms and ~ 320 ms, respectively. The high resolution 3D imaging enabled visualization the biodistribution of [1-¹³C]lactate, [1-¹³C]pyruvate, and [2-¹³C]pyruvate within different kidney compartments as well as in the vasculature. While the mouse anatomy is smaller, the resolution was also sufficient to image the distribution of all compounds within kidney, vasculature, and tumor. The development of the specialized 3D sequence with compressed sensing provided improved structural and functional assessments at a high (0.003 cm³) spatial and 2 s temporal resolution in vivo utilizing HP ¹³C substrates by exploiting their long T₂ values. This 1.5 mm isotropic resolution is comparable to ¹H imaging and application of this approach could be extended to future studies of uptake, metabolism, and perfusion in cancer and other disease models and may ultimately be of value for clinical imaging.     

Double spin-echo sequence for rapid spectroscopic imaging of hyperpolarized 13C

Dynamic nuclear polarization of metabolically active compounds labeled with (13)C has been introduced as a means for imaging metabolic processes in vivo. To differentiate between the injected compound and the various metabolic products, an imaging technique capable of separating the different chemical-shift species must be used. In this paper, the design and testing of a pulse sequence for rapid magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized (13)C is presented. The pulse sequence consists of a small-tip excitation followed by a double spin echo using adiabatic refocusing pulses and a "flyback" echo-planar readout gradient. Key elements of the sequence are insensitivity to calibration of the transmit gain, the formation of a spin echo giving high-quality spectral information, and a small effective tip angle that preserves the magnetization for a sufficient duration. Experiments in vivo showed three-dimensional coverage with excellent spectral quality and SNR.     

Frequency-specific SSFP for hyperpolarized C metabolic imaging at 14.1 T

Metabolic imaging of hyperpolarized [1-¹³C] pyruvate co-polarized with [¹³C]urea by dynamic nuclear polarization with rapid dissolution is a promising new method for assessing tumor metabolism and perfusion simultaneously in vivo. Novel pulse sequences are required to enable dynamic imaging of multiple ¹³C spectral lines with high spatiotemporal resolution. The goal of this study was to investigate a new frequency-specific approach for rapid metabolic imaging of multiple ¹³C resonances using the spectral selectivity of steady-state free precession pulse (SSFP) trains. Methods developed in simulations were implemented in a dynamic frequency-cycled balanced SSFP pulse sequence on a 14.1-T animal magnetic resonance imaging scanner. This acquisition was tested in thermal and hyperpolarized phantom imaging studies and in a transgenic mouse with prostate cancer.     

Feasibility of using hyperpolarized [1-13C]lactate as a substrate for in vivo metabolic 13C MRSI studies

The development of dynamic nuclear polarization in solution has enabled in vivo 13C MR studies at high signal-to-noise ratio following injection of prepolarized 13C substrates. While prior studies have demonstrated the ability to observe metabolism following injection of hyperpolarized 13C pyruvate, the goal of this study was to develop and test a new hyperpolarized agent for investigating in vivo metabolism, [1-13C]lactate. A preparation for prepolarized 13C lactate and the requisite dissolution media were developed to investigate the feasibility for in vivo 13C MRS/MRSI studies following injection of this hyperpolarized agent. This study demonstrated, for the first time, not only the ability to detect hyperpolarized [1-13C]lactate in vivo but also the metabolic products 13C pyruvate, 13C alanine and 13C bicarbonate following injection in normal rats. The use of 13C lactate as a substrate provided the opportunity to study the conversion of lactate to pyruvate in vivo and to detect the secondary conversions to alanine and bicarbonate through pyruvate. This study also demonstrated the potential value of this hyperpolarized agent to investigate in vivo lactate uptake and metabolism in preclinical animal models.     

Investigating tumor perfusion and metabolism using multiple hyperpolarized (13)C compounds: HP001, pyruvate and urea

The metabolically inactive hyperpolarized agents HP001 (bis-1,1-(hydroxymethyl)-[1-(13)C]cyclopropane-d(8)) and urea enable a new type of perfusion magnetic resonance imaging based on a direct signal source that is background-free. The addition of perfusion information to metabolic information obtained by spectroscopic imaging of hyperpolarized [1-(13)C]pyruvate would be of great value in exploring the relationship between perfusion and metabolism in cancer. In preclinical normal murine and cancer model studies, we performed both dynamic multislice imaging of the specialized hyperpolarized perfusion compound HP001 (T(1)=95 s ex vivo, 32 s in vivo at 3 T) using a pulse sequence with balanced steady-state free precession and ramped flip angle over time for efficient utilization of the hyperpolarized magnetization and three-dimensional echo-planar spectroscopic imaging of urea copolarized with [1-(13)C]pyruvate, with compressed sensing for resolution enhancement. For the dynamic data, peak signal maps and blood flow maps derived from perfusion modeling were generated. The spatial heterogeneity of perfusion was increased 2.9-fold in tumor tissues (P=.05), and slower washout was observed in the dynamic data. The results of separate dynamic HP001 imaging and copolarized pyruvate/urea imaging were compared. A strong and significant correlation (R=0.73, P=.02) detected between the urea and HP001 data confirmed the value of copolarizing urea with pyruvate for simultaneous assessment of perfusion and metabolism.     

Rapid sequential injections of hyperpolarized [1-C]pyruvate in vivo using a sub-kelvin,multi-sample DNP polarizer

The development of hyperpolarized technology utilizing dynamic nuclear polarization (DNP) has enabled the rapid measurement of ¹³C metabolism in vivo with very high SNR. However, with traditional DNP equipment, consecutive injections of a hyperpolarized compound in an animal have been subject to a practical minimum time between injections governed by the polarization build-up time, which is on the order of an hour for [1-¹³C]pyruvate. This has precluded the monitoring of metabolic changes occurring on a faster time scale. In this study, we demonstrated the ability to acquire in vivo dynamic magnetic resonance spectroscopy (MRS) and 3D magnetic resonance spectroscopic imaging (MRSI) data in normal rats with a 5 min interval between injections of hyperpolarized [1-¹³C]pyruvate using a prototype, sub-Kelvin dynamic nuclear polarizer with the capability to simultaneously polarize up to 4 samples and dissolve them in rapid succession. There were minimal perturbations in the hyperpolarized spectra as a result of the multiple injections, suggesting that such an approach would not confound the investigation of metabolism occurring on this time scale. As an initial demonstration of the application of this technology and approach for monitoring rapid changes in metabolism as a result of a physiological intervention, we investigated the pharmacodynamics of the anti-cancer agent dichloroacetate (DCA), collecting hyperpolarized data before administration of DCA, 1 min after administration, and 6 min after administration. Dramatic increases in ¹³C-bicarbonate were detected just 1 min (as well as 6 min) after DCA administration.     

Use of hyperpolarized [1-C]pyruvate and [2-C]pyruvate to probe the effects of the anticancer agent dichloroacetate on mitochondrial metabolism in vivo in the normal rat

Development of hyperpolarized technology utilizing dynamic nuclear polarization has enabled the measurement of ¹³C metabolism in vivo at very high signal-to-noise ratio (SNR). In vivo mitochondrial metabolism can, in principle, be monitored with pyruvate, which is catalyzed to acetyl-CoA via pyruvate dehydrogenase (PDH). The purpose of this work was to determine whether the compound sodium dichloroacetate (DCA) could aid the study of mitochondrial metabolism with hyperpolarized pyruvate. DCA stimulates PDH by inhibiting its inhibitor, pyruvate dehydrogenase kinase. In this work, hyperpolarized [1-¹³C]pyruvate and [2-¹³C]pyruvate were used to probe mitochondrial metabolism in normal rats. Increased conversion to bicarbonate (+ 181±69%, P=.025) was measured when [1-¹³C]pyruvate was injected after DCA administration, and increased glutamate (+ 74±23%, P=.004), acetoacetate (+ 504±281%, P=.009) and acetylcarnitine (+ 377±157%, P=.003) were detected when [2-¹³C]pyruvate was used.     

Highly undersampled supraaortic MRA at 3.0 T: initial results with parallel imaging in two directions using a 16-channel neurovascular coil and parallel imaging factors up to 16

PurposeTo present the feasibility of highly undersampled contrast-enhanced MRA (CE-MRA) of the supraaortic arteries with a 16-channel neurovascular coil at 3.0 T using parallel imaging in two directions with parallel imaging factors (PIF) up to 16.Materials and MethodsInstitutional review board approval and informed consent were obtained. In a prospective study, MRA protocols including PIF of 1, 2, 4, 9 and 16 yielding a spatial resolution from 0.81×0.81×1.0 mm³ to 0.46×.46×0.98 mm³ were acquired. In 32 examinations, image quality and vascular segments were rated independently by two radiologists. SNR estimations were performed for all MRA protocols.ResultsThe use of high PIF allowed to shorten acquisition time from 2:09 min down to 1:13 min and to increase the anatomic coverage while maintaining or even increasing spatial resolution down to 0.46×0.46×0.98 mm³. The larger anatomic coverage that was achieved with the use of high PIF allowed for visualization of vascular structures that were not covered by the standard protocols. Despite the resulting lower SNR using high PIF, image quality was constantly rated to be adequate for diagnosis or better in all cases.ConclusionThe use of high PIF yielded diagnostic image quality and allowed to increase the anatomic coverage while maintaining or even improving spatial resolution and shortening the acquisition time.     

Fast volumetric spatial-spectral MR imaging of hyperpolarized C-labeled compounds using multiple echo 3D bSSFP

Purpose

The goal of this work was to develop a fast 3D chemical shift imaging technique for the noninvasive measurement of hyperpolarized ¹³C-labeled substrates and metabolic products at low concentration.

Materials and Methods

Multiple echo 3D balanced steady state magnetic resonance imaging (ME-3DbSSFP) was performed in vitro on a syringe containing hyperpolarized [1,3,3-2H3; 1-¹³C]2-hydroxyethylpropionate (HEP) adjacent to a ¹³C-enriched acetate phantom, and in vivo on a rat before and after intravenous injection of hyperpolarized HEP at 1.5 T. Chemical shift images of the hyperpolarized HEP were derived from the multiple echo data by Fourier transformation along the echoes on a voxel by voxel basis for each slice of the 3D data set.

Results

ME-3DbSSFP imaging was able to provide chemical shift images of hyperpolarized HEP in vitro, and in a rat with isotropic 7-mm spatial resolution, 93 Hz spectral resolution and 16-s temporal resolution for a period greater than 45 s.

Conclusion

Multiple echo 3D bSSFP imaging can provide chemical shift images of hyperpolarized ¹³C-labeled compounds in vivo with relatively high spatial resolution and moderate spectral resolution. The increased signal-to-noise ratio of this 3D technique will enable the detection of hyperpolarized ¹³C-labeled metabolites at lower concentrations as compared to a 2D technique.     

In vivo measurement of normal rat intracellular pyruvate and lactate levels after injection of hyperpolarized [1-(13)C]alanine

Hyperpolarized technology utilizing dynamic nuclear polarization has enabled rapid and high-sensitivity measurements of ¹³C metabolism in vivo. The most commonly used in vivo agent for hyperpolarized ¹³C metabolic imaging thus far has been [1-¹³C]pyruvate. In preclinical studies, not only is its uptake detected, but also its intracellular enzymatic conversion to metabolic products including [1-¹³C]lactate and [1-¹³C]alanine. However, the ratio of ¹³C-lactate/¹³C-pyruvate measured in this data does not accurately reflect cellular values since much of the [1-¹³C]pyruvate is extracellular depending on timing, vascular properties, and extracellular space and monocarboxylate transporter activity. In order to measure the relative levels of intracellular pyruvate and lactate, in this project we hyperpolarized [1-¹³C]alanine and monitored the in vivo conversion to [1-¹³C]pyruvate and then the subsequent conversion to [1-¹³C]lactate. The intracellular lactate-to-pyruvate ratio of normal rat tissue measured with hyperpolarized [1-¹³C]alanine was 4.89±0.61 (mean±S.E.) as opposed to a ratio of 0.41±0.03 when hyperpolarized [1-¹³C]pyruvate was injected.     

基于同伦l0范数最小化重建的三维动态磁共振成像

高欠采倍数的动态磁共振图像重建具有重要意义,是同时实现高时间分辨率和高空间分辨率动态对比度增强成像的重要环节.本研究提出一种结合黄金角变密度螺旋采样、并行成像和基于同伦l₀范数最小化的压缩感知的图像重建的三维动态磁共振成像方法.黄金角变密度螺旋采样轨迹被用来连续获取k空间数据,具有数据采集效率高、对运动不敏感等优点.在重建算法中,将多线圈稀疏约束应用于时间总变分域,使用基于l₀范数最小化的非线性重建算法代替传统的l₁范数最小化算法,进一步提高了欠采样率.仿真实验和在体实验表明本文所提的方法在保持图像质量的同时,也可以实现较高的空间分辨率和时间分辨率,初步验证了基于同伦l₀范数最小化重建在三维动态磁共振成像上的优势和临床价值.     

基于压缩感知估计的GIS击穿放电定位方法研究*

经典的空间谱估计方法,如多重信号分离(MUSIC)方法,对噪声敏感,难以在低信噪比环境中有效地进行波达方向估计。为提升在复杂电力环境中的气体绝缘金属封闭开关设备(GIS)击穿定位能力,该文提出了一种基于极化内插的压缩感知波达方向估计方法 CSP-DOA。该方法对传声器阵列接收到的数据进行建模,形成多测量矢量模型,结合压缩感知中稀疏重构技术进行波达方向估计;同时,该方法还采用极化内插技术解决了稀疏重构中的费网格问题,进一步提升了波达方向估计精度及计算效率。通过数值模拟对算法的定位效果进行了分析,仿真结果表明CSP-DOA方法对于击穿信号有更好的定位效果。结合可见光图像匹配实现了GIS击穿信源的二维可视化定位,在某高压大厅的GIS模型上进行耐压击穿定位试验研究,试验结果进一步验证了该文方法可较好的应用于GIS的击穿定位。     

Whole-body MR angiography using variable density sampling and dual-injection bolus-chase acquisition

Conventional bolus-chase acquisition generates peripheral runoff images using a single injection of the contrast material. Low spatial resolution, small slice coverage and venous contamination are major problems especially in the distal stations. A technique is presented herein in which whole-body magnetic resonance angiography is performed using a dual-contrast-injection four-station acquisition protocol. Bolus sharing was performed between two stations: the abdomen and calf stations share the first bolus injection, while the thorax and thigh stations share the second bolus injection. The combination of variable density sampling and elliptical centric acquisition order was applied to the abdomen and thorax stations. The scan time was extended to generate high spatial resolution arterial phase images with broad slice coverage for the calf and thigh stations. The feasibility of this technique was demonstrated using phantom and in vivo human volunteer studies.     

Hyperpolarized 13C MRS Cardiac Metabolism Studies in Pigs: Comparison Between Surface and Volume Radiofrequency Coils

Cardiac metabolism assessment with hyperpolarized ¹³C magnetic resonance spectroscopy in pig models requires the design of dedicated coils capable of providing large field of view with high signal-to-noise ratio (SNR) data. This work presents a comparison between a commercial ¹³C quadrature birdcage coil and a homebuilt ¹³C circular coil both designed for hyperpolarized studies of pig heart with a clinical 3T scanner. In particular, the simulation of the two coils is described by developing an SNR model for coil performance prediction and comparison. While coil resistances were calculated from Ohm’s law, the magnetic field patterns and sample-induced resistances were calculated using a numerical finite-difference time-domain algorithm. After the numerical simulation of both coils, the results are presented as SNR-versus-depth profiles using experimental SNR extracted from the [1-¹³C]acetate phantom chemical shift image and with a comparison of metabolic maps acquired by hyperpolarized [1-¹³C]pyruvate injected in a pig. The accuracy of the developed SNR models was demonstrated by good agreement between the theoretical and experimental coil SNR-versus-depth profiles.     

压缩感知技术在激光惯性约束聚变研究中的应用

激光驱动惯性约束聚变（ICF）研究是当前国际前沿科学中一个具有挑战性的研究领域,它以高能激光作为驱动源,在极短的时间内将大量能量注入靶丸中使聚变材料达到高温高密度的状态从而在靶丸中心形成热斑并引燃整个燃料层,最终实现可控核聚变。由于内爆热斑直径为50～100 μm,其持续时间为100～200 ps,离子温度达到5 keV,压力可达4.0×1016 Pa。因此,发展极端瞬态条件下的诊断技术具有重要意义。介绍了两种基于压缩感知技术的诊断方法,第一种是基于数字微镜阵列（DMD）进行编码的反射式可见光压缩感知技术,这种技术将现有的一维任意反射面速度干涉仪（VISAR）与压缩超快成像（CUP）系统相结合,有望实现一种全新的具有高时间分辨的二维VISAR诊断技术,将诊断维度从一维扩展至二维,同时它克服了现有的二维VISAR单幅成像的缺点,有望实现对内爆压缩过程流体力学不稳定性演化过程的连续诊断。由于基于DMD进行编码的反射式可见光压缩感知技术只能用于可见光波段,无法用于紫外与X光波段,为此还发展了一种透射式压缩感知技术。这种透射式压缩感知技术采用一种新颖的透射式元件实现对待测信号的编码,可以实现对紫外和X光波段信号的二维超快探测,有望实现对内爆热斑超快时空演化过程进行精密诊断。此外,针对单通道CUP技术的高时间分辨的优势和低空间分辨的不足,还提出了多通道编码、分别扫描、解码、再合成的全新的高时空分辨诊断系统基本思路,有望实现高时间分辨的同时,实现高空间分辨的二维新型诊断技术。     

SNR phase order k-space encoding (SPOKE)

A method of determining the phase-encode order for MR Fourier-encoded imaging is described, which provides an additional option for optimizing images from samples with signals that change during data acquisition. Examples are in hyperpolarized helium gas imaging of the lungs where polarization is lost with each RF pulse or the signal changes observed in rapid dynamic studies with T₁ or T₂* contrast agents when mixing is taking place. The method uses a single frequency-encoded projection in the proposed phase-encoding direction. The projection is subsequently sorted into signal-to-noise ratio (SNR) order. The indices of the sorted array are then used to create the phase-encode table to be used for the scan. This phase table is sorted in descending SNR order for signals that decrease during data acquisition and in ascending order for signals that increase during data acquisition. Simulations suggest that this technique can produce higher resolution than centric-ordered phase encoding at the expense of increased modulation (ghosting) artifact for dynamically changing signals. Initial practical implementation of the technique has been carried out on a dedicated 0.2-T Niche MR system, and the test object results agree well with simulations. Hyperpolarized 3-He lung images have also been acquired and postprocessed using the SNR phase order k-space encoding (SPOKE) methodology and show potential for improved imaging with high flip angles where polarization is rapidly lost. Applications may also be found for 3D volumetric acquisitions where two dimensions can be SPOKE encoded.     

Multi-band frequency encoding method for metabolic imaging with hyperpolarized [1-(13)C]pyruvate

A new method was developed for simultaneous spatial localization and spectral separation of multiple compounds based on a single echo, by designing the acquisition to place individual compounds in separate frequency encoding bands. This method was specially designed for rapid and robust metabolic imaging of hyperpolarized (13)C substrates and their metabolic products, and was investigated in phantom studies and studies in normal mice and transgenic models of prostate cancer to provide rapid metabolic imaging of hyperpolarized [1-(13)C]pyruvate and its metabolic products [1-(13)C]lactate and [1-(13)C]alanine at spatial resolutions up to 3mm in-plane. Elevated pyruvate and lactate signals in the vicinity of prostatic tissues were observed in transgenic tumor mice. The multi-band frequency encoding technique enabled rapid metabolic imaging of hyperpolarized (13)C compounds with important advantages over prior approaches, including less complicated acquisition and reconstruction methods.     

Dipolar cross-relaxation modulates signal amplitudes in the (1)H NMR spectrum of hyperpolarized [(13)C]formate

The asymmetry in the doublet of a spin coupled to hyperpolarized (13)C has been used previously to measure the initial polarization of (13)C. We tested the hypothesis that a single observation of the (1)H NMR spectrum of hyperpolarized (13)C formate monitors (13)C polarization. Depending on the microwave frequency during the polarization process, in-phase or out-of-phase doublets were observed in the (1)H NMR spectrum. Even in this simple two-spin system, (13)C polarization was not reflected in the relative area of the J(CH) doublet components due to strong heteronuclear cross-relaxation. The Solomon equations were used to model the proton signal as a function of time after polarization and to estimate (13)C polarization from the (1)H NMR spectra.     

Nuclear hyperpolarization in solids and the prospects for nuclear spintronics

Nuclear hyperpolarization can be achieved in a number of ways. This article focuses on the use of coupling of nuclei to (nearly) pure quantum states, with particular emphasis on those states obtained by optical excitation in bulk semiconductors. I seek an answer to this question: “What is to prevent the design and analysis of nuclear spintronics devices that use the extremely long-lived hyperpolarized nuclear spin states, and their weak couplings to each other, to affect computation, memory, or informational technology schemes?” The answer, I argue, is in part because there remains a lack of fundamental understanding of how to generate and control nuclear polarization with schemes other than with rf coils.     

基于-OTDR和POTDR结合的分布式光纤微扰传感系统

提出了一种-OTDR和POTDR相结合的分布式光纤微扰传感系统.该系统将窄线宽DFB激光器作为传感光源同时应用到-OTDR和POTDR中,在不增加成本的前提下使两种系统合为一体,可同时检测传输光脉冲的相位和偏振态的变化,并使它们并行运行以提高传感系统对微扰远程定位检测的准确度,从而大幅减小误判率和漏报率.同时采用小波分析的方法来降低传感信号的噪音以进行后续的处理.实验结果表明,传感系统在14 km处获得具有较高信噪比的扰动信号,同时系统的空间分辨率也达到了50 m.