In vivo NMR of hyperpolarized 3He in the human lung at very low magnetic fields

We present NMR measurements of the diffusion of hyperpolarized 3He in the human lung performed at fields much lower than those of conventional MRI scanners. The measurements were made on standing subjects using homebuilt apparatus operating at 3mT. O(2)-limited transverse relaxation (T(2) up to 15-35s) could be measured in vivo. Accurate global diffusion measurements have been performed in vivo and in a plastic bag; the average apparent diffusion coefficient (ADC) in vivo was 14.2+/-0.6mm(2)/s, whereas the diffusion coefficient in the bag (3He diluted in N(2)) was 79.5+/-1mm(2)/s. 1D ADC mapping with high SNR ( approximately 200-300) demonstrates the real possibility of performing quality lung imaging at extremely low fields.     

Quantitative characterization of tissue microstructure with temporal diffusion spectroscopy

The signals recorded by diffusion-weighted magnetic resonance imaging (DWI) are dependent on the micro-structural properties of biological tissues, so it is possible to obtain quantitative structural information non-invasively from such measurements. Oscillating gradient spin echo (OGSE) methods have the ability to probe the behavior of water diffusion over different time scales and the potential to detect variations in intracellular structure. To assist in the interpretation of OGSE data, analytical expressions have been derived for diffusion-weighted signals with OGSE methods for restricted diffusion in some typical structures, including parallel planes, cylinders and spheres, using the theory of temporal diffusion spectroscopy. These analytical predictions have been confirmed with computer simulations. These expressions suggest how OGSE signals from biological tissues should be analyzed to characterize tissue microstructure, including how to estimate cell nuclear sizes. This approach provides a model to interpret diffusion data obtained from OGSE measurements that can be used for applications such as monitoring tumor response to treatment in vivo.     

Measurements and modeling of long range 3He diffusion in the lung using a "slice-washout" method

In healthy lung tissue, pulsed-gradient-spin-echo (PGSE) methods reveal apparent diffusion coefficients (ADC) of the order 0.20 cm2 s(-1); for diffusion times of approximately 2 ms. For these short diffusion times the ADC is only sensitive to structures approximately (2Dt)1/2 approximately 0.6mm in size. Recent work, using magnetic tagging of the longitudinal magnetization has revealed much smaller ADC values for longer length scales. In this work, the in vivo ADC from within the air-spaces, was measured using a new technique. The signal from a series of images was analyzed from a slice that was repeatedly imaged. Diffusion tends to "top-up" the non-renewable polarization within the slice, which leads to a non-exponential decay in image signal. Image data were compared to 1D finite-difference simulations of diffusion to calculate a long range ADC value. The results yield values of the order 0.034 cm2 s(-1), which are nearly an order of magnitude smaller than those reported by PGSE measurements at shorter diffusion times.     

3D MRI of non-Gaussian (3)He gas diffusion in the rat lung

In (3)He magnetic resonance images of pulmonary air spaces, the confining architecture of the parenchymal tissue results in a non-Gaussian distribution of signal phase that non-exponentially attenuates image intensity as diffusion weighting is increased. Here, two approaches previously used for the analysis of non-Gaussian effects in the lung are compared and related using diffusion-weighted (3)He MR images of mechanically ventilated rats. One approach is model-based and was presented by Yablonskiy et al., while the other approach utilizes the second order decay contribution that is predicted from the cumulant expansion theorem. Total lung coverage is achieved using a hybrid 3D pulse sequence that combines conventional phase encoding with sparse radial sampling for efficient gas usage. This enables the acquisition of nine 3D images using a total of only approximately 1 L of hyperpolarized (3)He gas. Diffusion weighting ranges from 0 s/cm(2) to 40 s/cm(2). Results show that the non-Gaussian effects of (3)He gas diffusion in healthy rat lungs are directly attributed to the anisotropic geometry of lung microstructure as predicted by the Yablonskiy model, and that quantitative analysis over the entire lung can be reliably repeated in time-course studies of the same animal.     

超极化Xenon 对慢阻肺的可视化加权成像

超极化气体3He 或者¹²⁹Xe 扩散加权成像已经被证明了能够有效检测慢性阻塞性肺部疾病(COPD)中肺部微结构的改变．相比于³He,¹²⁹Xe 更便宜而且更容易获得,但是¹²⁹Xe 成像中较低的信噪比致使¹²⁹Xe 的肺部表面扩散系数(ADC)的测量面临着许多困难．在该研究中,为了得到更高的图像信噪比,作者对气球模型,健康大鼠和COPD大鼠进行了单个b 值(14 cm2/s)的扩散加权超极化¹²⁹Xe 磁共振成像(MRI)．所有的COPD模型大鼠是通过烟熏和注射内毒素(LPS)进行诱导得到的．在7 T 磁共振成像仪上面获得了大鼠肺实质的超极化¹²⁹Xe ADC 值分布图．COPD 大鼠肺实质的¹²⁹Xe ADC 值是0.044 22±0.002 9 和0.042 34±0.002 3 cm2/s (Δ = 0.8/1.2 ms),远大于健康大鼠肺实质的¹²⁹Xe ADC 值0.037 7±0.002 3 和0.036 7±0.001 3 cm2/s．而且COPD 大鼠肺实质相关的¹²⁹Xe ADC 直方图也表现出了一定的展宽．这些结果说明了COPD 大鼠肺泡空腔的增大能够通过129Xe 在肺里面的ADC 增长和相关直方图的拓宽反应出来,从而证明了单个b 值的扩散加权MRI 方法可以有效地对COPD 大鼠进行检测．     

Decreases in ADC observed in tissue areas during activation in the cat visual cortex at 9.4 T using high diffusion sensitization

Recent studies in the human visual cortex using diffusion-weighted functional magnetic resonance imaging (fMRI) have suggested that the apparent diffusion coefficient (ADC) decreases, in contrast to earlier studies that consistently reported ADC increases during neuronal activation. The changes, in either case, are hypothesized to provide the ability to improve the spatial specificity of fMRI over conventional blood-oxygenation-level-dependent (BOLD) methods. Most recently, the ADC decreases have been suggested as originating from transient cell swelling caused by either shrinkage of the extracellular space or some intracellular neuronal process that precedes the hemodynamic response. All of these studies have been conducted in humans and at lower magnetic fields, which can be limited by the signal-to-noise ratio (SNR). The low SNR can lead to significant partial-volume effects because of the lower spatial resolutions required to attain sufficient SNR in diffusion-weighted images. Human studies also have the potential confound of motion. At high magnetic fields and in animal model studies, these limitations are alleviated. At high fields, SNR increases, tissue signals are enhanced and signal changes inside the blood are significantly reduced compared to lower fields. In this work, we were able to measure a small but significant ADC decrease in tissue areas, in conjunction with brain activation in the cat visual cortex at 9.4 T when using highly diffusion-weighted images (b>1200 s/mm2) where intravascular effects are minimal. When using low b-values, delayed increases in the tissue ADC during activation were observed. No significant changes in ADC were observed in surface vessels for any diffusion weighting. Furthermore, we did not observe any temporal differences in the highly diffusion-weighted data compared to BOLD; however, although the changes may likely be vascular in nature, they are highly localized to the tissue areas.     

Assessment of in vitro vs. in vivo lung structure using hyperpolarized helium-3 diffusion magnetic resonance imaging

The purpose of this study was to assess the properties of a model system for hyperpolarized He-3 (HHe) diffusion MR imaging created from the lungs of New Zealand white rabbits by drying the lungs while inflated at constant pressure. The dried lungs were prepared by sacrificing the animal, harvesting the lungs en bloc and dehydrating the lungs for several days using dry compressed air. In four rabbits, the apparent diffusion coefficient (ADC) of HHe gas was measured in vivo and, within 1 week, in vitro in the dried lungs. To assess long-term repeatability, in vitro ADC values were measured again 3 months later. Dried lungs from four additional rabbits were imaged twice on the same day to assess the short-term repeatability of ADC measurements, and tissue samples from these lungs were then removed for histology. In vivo and in vitro ADC maps showed similar features and similar distributions of ADC values; mean in vivo and in vitro ADC values differed by less than 12%. The in vitro mean ADC values were highly reproducible, with no more than 5% difference between measurements for the short-term repeatability and less than 17% difference between measurements for the long-term repeatability. Histological samples from the dried lungs demonstrated that the lung structure remained intact. These results suggest that the dried lungs are a useful and inexpensive alternative to human or in vivo animal studies for HHe diffusion MR sequence development, testing and optimization.     

Dependence of temporal diffusion spectra on microstructural properties of biological tissues

The apparent diffusion coefficient (ADC) measured using magnetic resonance imaging methods provides information on microstructural properties of biological tissues, and thus has found applications as a useful biomarker for assessing changes such as those that occur in ischemic stroke and cancer. Conventional pulsed gradient spin echo methods are in widespread use and provide information on, for example, variations in cell density. The oscillating gradient spin echo (OGSE) method has the additional ability to probe diffusion behaviors more readily at short diffusion times, and the temporal diffusion spectrum obtained by the OGSE method provides a unique tool for characterizing tissues over different length scales, including structural features of intracellular spaces. It has previously been reported that several tissue properties can affect ADC measurements significantly, and the precise biophysical mechanisms that account for ADC changes in different situations are still unclear. Those factors may vary in importance depending on the time and length scale over which measurements are made. In the present work, a comprehensive numerical simulation is used to investigate the dependence of the temporal diffusion spectra measured by OGSE methods on different microstructural properties of biological tissues, including cell size, cell membrane permeability, intracellular volume fraction, intranucleus and intracytoplasm diffusion coefficients, nuclear size and T₂ relaxation times. Some unique characteristics of the OGSE method at relatively high frequencies are revealed. The results presented in the paper offer a framework for better understanding possible causes of diffusion changes and may be useful to assist the interpretation of diffusion data from OGSE measurements.     

Measurement of hyperpolarized gas diffusion at very short time scales

We present a new pulse sequence for measuring very-short-time-scale restricted diffusion of hyperpolarized noble gases. The pulse sequence is based on concatenating a large number of bipolar diffusion-sensitizing gradients to increase the diffusion attenuation of the MR signal while maintaining a fundamentally short diffusion time. However, it differs in several respects from existing methods that use oscillating diffusion gradients for this purpose. First, a wait time is inserted between neighboring pairs of gradient pulses; second, consecutive pulse pairs may be applied along orthogonal axes; and finally, the diffusion-attenuated signal is not simply read out at the end of the gradient train but is periodically sampled during the wait times between neighboring pulse pairs. The first two features minimize systematic differences between the measured (apparent) diffusion coefficient and the actual time-dependent diffusivity, while the third feature optimizes the use of the available MR signal to improve the precision of the diffusivity measurement in the face of noise. The benefits of this technique are demonstrated using theoretical calculations, Monte-Carlo simulations of gas diffusion in simple geometries, and experimental phantom measurements in a glass sphere containing hyperpolarized (3)He gas. The advantages over the conventional single-bipolar approach were found to increase with decreasing diffusion time, and thus represent a significant step toward making accurate surface-to-volume measurements in the lung airspaces.     

Hyperpolarized He diffusion MRI and histology of secreted frizzled related protein-1 (SFRP1) deficient lungs in a Murine model

Secreted frizzled related protein-1 (SFRP1) plays a key role in many diverse processes, including embryogenesis, tissue repair, bone formation, and tumor genesis. Previous studies have shown the effects of the SFRP1 gene on lung development using the SFRP1 knockout mouse model via histological and physiological studies. In this study, the feasibility of ADC (acquired via HP ³He) to detect altered lung structure in the SFRP1 knockout (SFRP1^−/−) mice was investigated, and compared to analysis by histology. This study consisted of two groups, the wild-type (WT) mice and the knockout (KO) mice with n = 6 mice for each group. ³He ADC MRI and histology were performed on all of the animals. The global L_m values of WT and KO mice were 35.0 ± 0.8 μm and 38.4 ± 3.8 μm, respectively, which translated to an increase of 9.58% in the L_m of KO mice. The mean global ADCs for the WT and KO mice were 0.12 ± 0.01 cm²/s and 0.13 ± 0.01 cm²/s, respectively, which equated to a relative increase of 8.0% in the KO mice compared to the WT mice. In the sub-analysis of the anterior, medial and posterior lung regions, L_m increased by 10.50%, 6.66% and 11.84% in the KO mice, respectively, whereas the differences in ADC between the two groups in the anterior, medial, and posterior regions were 7.3%, 8.3%, and 4.6%, respectively. These results suggest that HP MRI measurements can be used as a suitable substitute for histology to obtain valuable information about lung geometry non-invasively. This technique is also advantageous as regional measurements can be performed, which can identify lung destruction more precisely. Most importantly, this approach extends far beyond the specific pathology analyzed in this study, as it can be applied to many other pathological conditions in the lung tissue, as well to many other embryonic studies.     

Modified oscillating gradient pulses for direct sampling of the diffusion spectrum suitable for imaging sequences

A variation of the oscillating gradient spin echo method had been developed, which isolates temporal frequencies of the dephasing spectrum. This allows sampling of the diffusion spectrum, the Fourier transform of the velocity correlation function (VCF). It has been shown that restriction and flow alter this function in ways that can be mathematically characterized, yielding quantitative information on restriction geometry and flow parameters. It is demonstrated that in many systems of interest, dispersion of velocity will produce a peak in the VCF spectrum near omega=0, while restricted diffusion will manifest itself in the spectrum at higher frequencies. The method, therefore, may be useful for decoupling their effects on the apparent diffusion coefficient (ADC), as well as in revealing the physics of both phenomena. This method has been implemented in model systems of packed beads, yielding data consistent with theoretical models of restricted diffusion spectra and data from one previous study. The method may have significant application to biology and medicine, as well as the study of transport phenomena in porous media and complex flow.     

A diffusion gradient optimization framework for spinal cord diffusion tensor imaging

The uncertainty in the estimation of diffusion model parameters in diffusion tensor imaging (DTI) can be reduced by optimally selecting the diffusion gradient directions utilizing some prior structural information. This is beneficial for spinal cord DTI, where the magnetic resonance images have low signal-to-noise ratio and thus high uncertainty in diffusion model parameter estimation. Presented is a gradient optimization scheme based on D-optimality, which reduces the overall estimation uncertainty by minimizing the Rician Cramer-Rao lower bound of the variance of the model parameter estimates. The tensor-based diffusion model for DTI is simplified to a four-parameter axisymmetric DTI model where diffusion transverse to the principal eigenvector of the tensor is assumed isotropic. Through simulations and experimental validation, we demonstrate that an optimized gradient scheme based on D-optimality is able to reduce the overall uncertainty in the estimation of diffusion model parameters for the cervical spinal cord and brain stem white matter tracts.     

Diffusion-weighted MRI: influence of intravoxel fat signal and breast density on breast tumor conspicuity and apparent diffusion coefficient measurements

Promising recent investigations have shown that breast malignancies exhibit restricted diffusion on diffusion-weighted imaging (DWI) and may be distinguished from normal tissue and benign lesions in the breast based on differences in apparent diffusion coefficient (ADC) values. In this study, we assessed the influence of intravoxel fat signal on breast diffusion measures by comparing ADC values obtained using a diffusion-weighted single shot fast spin-echo sequence with and without fat suppression. The influence of breast density on ADC measures was also evaluated. ADC values were calculated for both tumor and normal fibroglandular tissue in a group of 21 women with diagnosed breast cancer. There were systematic underestimations of ADC for both tumor and normal breast tissue due to intravoxel contribution from fat signal on non–fat-suppressed DWI. This ADC underestimation was more pronounced for normal tissue values (mean difference=40%) than for tumors (mean difference=27%, P<.001) and was worse in women with low breast tissue density vs. those with extremely dense breasts (P<.05 for both tumor and normal tissue). Tumor conspicuity measured by contrast-to-noise ratio was significantly higher on ADC maps created with fat suppression and was not significantly associated with breast density. In summary, robust fat suppression is important for accurate breast ADC measures and optimal lesion conspicuity on DWI.     

³He lung morphometry technique: accuracy analysis and pulse sequence optimization

The (3)He lung morphometry technique (Yablonskiy et al., JAP, 2009), based on MRI measurements of hyperpolarized gas diffusion in lung airspaces, provides unique information on the lung microstructure at the alveolar level. 3D tomographic images of standard morphological parameters (mean airspace chord length, lung parenchyma surface-to-volume ratio, and the number of alveoli per unit lung volume) can be created from a rather short (several seconds) MRI scan. These parameters are most commonly used to characterize lung morphometry but were not previously available from in vivo studies. A background of the (3)He lung morphometry technique is based on a previously proposed model of lung acinar airways, treated as cylindrical passages of external radius R covered by alveolar sleeves of depth h, and on a theory of gas diffusion in these airways. The initial works approximated the acinar airways as very long cylinders, all with the same R and h. The present work aims at analyzing effects of realistic acinar airway structures, incorporating airway branching, physiological airway lengths, a physiological ratio of airway ducts and sacs, and distributions of R and h. By means of Monte-Carlo computer simulations, we demonstrate that our technique allows rather accurate measurements of geometrical and morphological parameters of acinar airways. In particular, the accuracy of determining one of the most important physiological parameter of lung parenchyma - surface-to-volume ratio - does not exceed several percent. Second, we analyze the effect of the susceptibility induced inhomogeneous magnetic field on the parameter estimate and demonstrate that this effect is rather negligible at B(0) ≤ 3T and becomes substantial only at higher B(0) Third, we theoretically derive an optimal choice of MR pulse sequence parameters, which should be used to acquire a series of diffusion-attenuated MR signals, allowing a substantial decrease in the acquisition time and improvement in accuracy of the results. It is demonstrated that the optimal choice represents three not equidistant b-values: b(1)=0, b(2)～2 s/cm(2), b(3)～8 s/cm(2).     

The effect of impermeable boundaries of arbitrary geometry on the apparent diffusion coefficient

The apparent diffusion coefficient (ADC) obtained from NMR measurements is modelled for diffusion in a compartment restricted by an impermeable boundary. For a given pulse sequence, the ADC can be determined from the connected velocity autocorrelation function (the second-order velocity cumulant), which we show can be expressed as a double surface integral over the boundary, involving the probability for molecules to diffuse from one boundary point to another. There is no restriction on the geometry of the boundary. This result allows a fast calculation of the ADC for an arbitrary time course of the diffusion-sensitizing gradient. Explicit examples are given for diffusion within three basic geometries for different pulse sequences. The ADCs measured with the Stejskal-Tanner pulse sequence and a more realistic pulse sequence with slice selection gradient and eddy current compensation are found to yield almost identical results. The application of the results are discussed in relation to determination of the microscopic structure of brain white matter.     

A comparison study of multishot vs. single-shot DWI-EPI in the neonatal brain: reduced effects of ghosting compared to adults

In the neonatal brain, it is important to use a fast imaging technique to acquire all diffusion weighted images (DWI) for apparent diffusion coefficient (ADC) calculation. Taking into account the occurrence of typical echo planar imaging (EPI) artifacts, we have investigated whether single-shot (SSh) or multishot (MSh) DWI-EPI should be preferred. In 14 neonates, 17 adult patients and 5 adult volunteers, DWIs are obtained both with SSh and MSh EPI. The occurrence of artifacts and their influence on the ADC are explored and further quantified using simulations and phantom studies. Two radiologists scored overall image quality and diagnosability of all images. Single-shot and MSh DWI-EPI scored equally well in neonates with respect to overall image quality and diagnosability. In newborns, more motion artifacts in MSh can be noticed while N/2-ghost artifacts in SSh occur less frequently than in adults. Both N/2-ghost and motion artifacts result in significant ADC abnormalities. There is a serious risk that these artifacts will be mistaken for genuine diffusion abnormalities. N/2-ghost artifacts are hardly noticed in the neonatal brain, which might be due to smaller cerebrospinal fluid (CSF) velocity than in adults. Apparent diffusion coefficient values in MSh are unreliable if motion occurs. We conclude that for ADC calculations in neonates SSh DWI-EPI is more reliable than MSh.     

Conditional velocity statistics in the double scalar mixing layer – A mapping closure approach

In this work we use 3D direct numerical simulations (DNS) to investigate the average velocity conditioned on a conserved scalar in a double scalar mixing layer (DSML). The DSML is a canonical multistream flow designed as a model problem for the extensively studied piloted diffusion flames. The conditional mean velocity appears as an unclosed term in advanced Eulerian models of turbulent non-premixed combustion, like the conditional moment closure and transported probability density function (PDF) methods. Here it accounts for inhomogeneous effects that have been found significant in flames with relatively low Damköhler numbers. Today there are only a few simple models available for the conditional mean velocity and these are discussed with reference to the DNS results. We find that both the linear model of Kutznetzov and the Li and Bilger model are unsuitable for multi stream flows, whereas the gradient diffusion model of Pope shows very close agreement with DNS over the whole range of the DSML. The gradient diffusion model relies on a model for the conserved scalar PDF and here we have used a presumed mapping function PDF, that is known to give an excellent representation of the DNS. A new model for the conditional mean velocity is suggested by arguing that the Gaussian reference field represents the velocity field, a statement that is evidenced by a near perfect agreement with DNS. The model still suffers from an inconsistency with the unconditional flux of conserved scalar variance, though, and a strategy for developing fully consistent models is suggested.     

Gas diffusion in a pulmonary acinus model: experiments with hyperpolarized helium-3

Diffusion of hyperpolarized helium-3 in epoxy phantoms was experimentally studied by pulsed-gradient nuclear magnetic resonance (NMR). One phantom with a dichotomic branching structure densely filling a cubic volume was built using the Kitaoka algorithm to model a healthy human acinus. Two other phantoms, one with a different size and the other one with a partial destruction of the branched structure, were built to simulate changes occurring at the early stages of emphysema. Gas pressure and composition (mixture with nitrogen) were varied, thus exploring different diffusion regimes. Preliminary measurements in a cylindrical glass cell allowed us to calibrate the gradient intensity with 1% accuracy. Measurements of NMR signal attenuation due to gas diffusion were compared to a classical Gaussian model and to Monte Carlo simulations. In the slow diffusion regime, the Gaussian model was in reasonable agreement with experiments for low gradient intensity, but there was a significant systematic deviation at larger gradient intensity. An apparent diffusion coefficient Dapp was deduced, and in agreement with previous findings, a linear decrease of Dapp/D0 with D0(1/2) was observed, where D0 is the free diffusion coefficient. In the regime of intermediate diffusion, experimental data could be described by the Gaussian model for very small gradient intensities only. The corresponding Dapp/D0 values seemed to reach a constant value. Monte Carlo simulations were generally in fair agreement with the measurements in both regimes. Our results suggest that, for diffusion times typical of medical magnetic resonance imaging, an increase in alveolar size has more impact on signal attenuation than a partial destruction of the branched structure at equivalent surface-to-volume ratio.     

Directional sensitivity of anomalous diffusion in human brain assessed by tensorial fractional motion model

Anisotropic diffusion in the nervous system is most commonly modeled by apparent diffusion tensor, which is based on regular diffusion theory. However, the departure of diffusion-induced signal attenuation from a mono-exponential form implies that there is anomalous diffusion. Recently, a novel diffusion NMR theory based on the fractional motion (FM) model, which is an anomalous diffusion model, has been proposed. While the FM model has been applied to both healthy subjects and tumor patients, its anisotropy in the nervous system remains elusive. In this study, this issue was addressed by measuring the FM-related parameters in 12 non-collinear directions. A metric to quantify the directional deviation was derived. Furthermore, the FM-related parameters were modeled as tensors and analyzed in analogy with the conventional diffusion tensor imaging (DTI). Experimental results, which were obtained for 15 healthy subjects at 3T, exhibited pronounced anisotropy of the FM-related parameters, although the effects were smaller than the apparent diffusion coefficient (ADC). The tensorial nature for α, which is the Noah exponent in the FM model, showed behavior similar to the ADC, especially the principal eigenvector for α aligned with the dominant white matter fiber directions. The Hurst exponent H in the FM model, however, showed no correlation with the major fiber directions. The anisotropy of the FM model may provide complementary information to DTI and may have potential for tractography and detecting brain abnormalities.