G. Wilson Miller

Simultaneous magnetic resonance imaging of ventilation distribution and gas uptake in the human lung using hyperpolarized xenon-129

Despite a myriad of technical advances in medical imaging, as well as the growing need to address the global impact of pulmonary diseases, such as asthma and chronic obstructive pulmonary disease, on health and quality of life, it remains challenging to obtain in vivo regional depiction and quantification of the most basic physiological functions of the lung—gas delivery to the airspaces and gas uptake by the lung parenchyma and blood—in a manner suitable for routine application in humans. We report a method based on MRI of hyperpolarized xenon-129 that permits simultaneous observation of the 3D distributions of ventilation (gas delivery) and gas uptake, as well as quantification of regional gas uptake based on the associated ventilation. Subjects with lung disease showed variations in gas uptake that differed from those in ventilation in many regions, suggesting that gas uptake as measured by this technique reflects such features as underlying pathological alterations of lung tissue or of local blood flow. Furthermore, the ratio of the signal associated with gas uptake to that associated with ventilation was substantially altered in subjects with lung disease compared with healthy subjects. This MRI-based method provides a way to quantify relationships among gas delivery, exchange, and transport, and appears to have significant potential to provide more insight into lung disease.

Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood - Brain barrier using MRI-guided focused ultrasound

The blood-brain barrier (BBB) presents a significant obstacle for the treatment of many central nervous system (CNS) disorders, including invasive brain tumors, Alzheimers, Parkinsons and stroke. Therapeutics must be capable of bypassing the BBB and also penetrate the brain parenchyma to achieve a desired effect within the brain. In this study, we test the unique combination of a non-invasive approach to BBB permeabilization with a therapeutically relevant polymeric nanoparticle platform capable of rapidly penetrating within the brain microenvironment. MR-guided focused ultrasound (FUS) with intravascular microbubbles (MBs) is able to locally and reversibly disrupt the BBB with submillimeter spatial accuracy. Densely poly(ethylene-co-glycol) (PEG) coated, brain-penetrating nanoparticles (BPNs) are long-circulating and diffuse 10-fold slower in normal rat brain tissue compared to diffusion in water. Following intravenous administration of model and biodegradable BPNs in normal healthy rats, we demonstrate safe, pressure-dependent delivery of 60nm BPNs to the brain parenchyma in regions where the BBB is disrupted by FUS and MBs. Delivery of BPNs with MR-guided FUS has the potential to improve efficacy of treatments for many CNS diseases, while reducing systemic side effects by providing sustained, well-dispersed drug delivery into select regions of the brain.

Regional mapping of gas uptake by blood and tissue in the human lung using hyperpolarized xenon-129 MRI

To develop a breathhold acquisition for regional mapping of ventilation and the fractions of hyperpolarized xenon‐129 (Xe129) dissolved in tissue (lung parenchyma and plasma) and red blood cells (RBCs), and to perform an exploratory study to characterize data obtained in human subjects.

Hyperpolarized Xenon-129 gas-exchange imaging of lung microstructure: First case studies in subjects with obstructive lung disease

To develop and test a method to noninvasively assess the functional lung microstructure.

Assessment of the lung microstructure in patients with asthma using hyperpolarized 3He diffusion MRI at two time scales: comparison with healthy subjects and patients with COPD.

To investigate short‐ and long‐time‐scale 3He diffusion in asthma.

Time dependence of 3He diffusion in the human lung: measurement in the long-time regime using stimulated echoes.

A stimulated‐echo‐based technique was developed to measure the long‐time‐scale apparent diffusion coefficient (ADC) of hyperpolarized 3He during a single breath‐hold acquisition. Computer simulations were used to evaluate the performance of the technique and guide the selection of appropriate parameter values for obtaining accurate ADC values. The technique was used in 10 healthy subjects and two subjects with chronic obstructive pulmonary disease (COPD) to measure the global ADC for diffusion times between a few tenths of a second and several seconds, and to acquire spatial maps of the ADC for a diffusion time of 1.5 s. The reproducibility of the technique and its sensitivity to the direction of diffusion sensitization were also investigated. In healthy subjects, global ADC values decreased by severalfold over the range of diffusion times measured (mean values = 0.039 and 0.023 cm2/s at diffusion times of 0.61 and 1.54 s, respectively). ADC maps were generally uniform, with mean values similar to the corresponding global values. For the two COPD subjects, global ADC values were substantially greater than those of every healthy subject at all diffusion times measured. In addition, regional elevations of ADC values were far more conspicuous on long‐time‐scale ADC maps than on short‐time‐scale ADC maps. Magn Reson Med, 2006.

Assessment of lung function in asthma and COPD using hyperpolarized 129Xe chemical shift saturation recovery spectroscopy and dissolved-phase MRI.

Magnetic‐resonance spectroscopy and imaging using hyperpolarized xenon‐129 show great potential for evaluation of the most important function of the human lung ‐‐ gas exchange. In particular, chemical shift saturation recovery (CSSR) xenon‐129 spectroscopy provides important physiological information for the lung as a whole by characterizing the dynamic process of gas exchange, while dissolved‐phase (DP) xenon‐129 imaging captures the time‐averaged regional distribution of gas uptake by lung tissue and blood. Herein, we present recent advances in assessing lung function using CSSR spectroscopy and DP imaging in a total of 45 subjects (23 healthy, 13 chronic obstructive pulmonary disease (COPD) and 9 asthma). From CSSR acquisitions, the COPD subjects showed red blood cell to tissue–plasma (RBC‐to‐TP) ratios below the average for the healthy subjects (p < 0.001), but significantly higher septal wall thicknesses as compared with the healthy subjects (p < 0.005); the RBC‐to‐TP ratios for the asthmatic subjects fell outside two standard deviations (either higher or lower) from the mean of the healthy subjects, although there was no statistically significant difference for the average ratio of the study group as a whole. Similarly, from the 3D DP imaging acquisitions, we found that all the ratios (TP to gas phase (GP), RBC to GP, RBC to TP) measured in the COPD subjects were lower than those from the healthy subjects (p < 0.05 for all ratios), while these ratios in the asthmatic subjects differed considerably between subjects. Despite having been performed at different lung inflation levels, the RBC‐to‐TP ratios measured by CSSR and 3D DP imaging were fairly consistent with each other, with a mean difference of 0.037 (ratios from 3D DP imaging larger). In ten subjects the RBC‐to‐GP ratios obtained from the 3D DP imaging acquisitions were also highly correlated with their diffusing capacity of the lung for carbon monoxide per unit alveolar volume ratios measured by pulmonary function testing (R = 0.91). Copyright

A short-breath-hold technique for lung pO2 mapping with 3He MRI.

A pulse‐sequence strategy was developed for generating regional maps of alveolar oxygen partial pressure (pO2) in a single 6‐sec breath hold, for use in human subjects with impaired lung function. Like previously described methods, pO2 values are obtained by measuring the oxygen‐induced T1 relaxation of inhaled hyperpolarized 3He. Unlike other methods, only two 3He images are acquired: one with reverse‐centric and the other with centric phase‐encoding order. This phase‐encoding arrangement minimizes the effects of regional flip‐angle variations, so that an accurate map of instantaneous pO2 can be calculated from two images acquired a few seconds apart. By combining this phase‐encoding strategy with variable flip angles, the vast majority of the hyperpolarized magnetization goes directly into the T1 measurement, minimizing noise in the resulting pO2 map. The short‐breath‐hold pulse sequence was tested in phantoms containing known O2 concentrations. The mean difference between measured and prepared pO2 values was 1 mm Hg. The method was also tested in four healthy volunteers and three lung‐transplant patients. Maps of healthy subjects were largely uniform, whereas focal regions of abnormal pO2 were observed in diseased subjects. Mean pO2 values varied with inhaled O2 concentration. Mean pO2 was consistent with normal steady‐state values in subjects who inhaled 3He diluted only with room air. Magn Reson Med 63:127–136, 2010.

Phase-shift perfluorocarbon agents enhance high intensity focused ultrasound thermal delivery with reduced near-field heating

Ultrasound contrast agents are known to enhance high intensity focused ultrasound (HIFU) ablation, but these perfluorocarbon microbubbles are limited to the vasculature, have a short half-life in vivo, and may result in unintended heating away from the target site. Herein, a nano-sized (100-300 nm), dual perfluorocarbon (decafluorobutane/dodecafluoropentane) droplet that is stable, is sufficiently small to extravasate, and is convertible to micron-sized bubbles upon acoustic activation was investigated. Microbubbles and nanodroplets were incorporated into tissue-mimicking acrylamide-albumin phantoms. Microbubbles or nanodroplets at 0.1 × 10(6) per cm(3) resulted in mean lesion volumes of 80.4 ± 33.1 mm(3) and 52.8 ± 14.2 mm(3) (mean ± s.e.), respectively, after 20 s of continuous 1 MHz HIFU at a peak negative pressure of 4 MPa, compared to a lesion volume of 1.0 ± 0.8 mm(3) in agent-free control phantoms. Magnetic resonance thermometry mapping during HIFU confirmed undesired surface heating in phantoms containing microbubbles, whereas heating occurred at the acoustic focus of phantoms containing the nanodroplets. Maximal change in temperature at the target site was enhanced by 16.9% and 37.0% by microbubbles and nanodroplets, respectively. This perfluorocarbon nanodroplet has the potential to reduce the time to ablate tumors by one-third during focused ultrasound surgery while also safely enhancing thermal deposition at the target site.

Multiple-exchange-time xenon polarization transfer contrast (MXTC) MRI: initial results in animals and healthy volunteers.

Hyperpolarized xenon‐129 is a noninvasive contrast agent for lung MRI, which upon inhalation dissolves in parenchymal structures, thus mirroring the gas‐exchange process for oxygen in the lung. Multiple‐exchange‐time xenon polarization transfer contrast (MXTC) MRI is an implementation of the XTC MRI technique in four dimensions (three spatial dimensions plus exchange time). The aim of this study was to evaluate the sensitivity of MXTC MRI for the detection of microstructural deformations of the healthy lung in response to gravity‐induced tissue compression and the degree of lung inflation. MXTC MRI was performed in four rabbits and in three healthy human volunteers. Two lung function parameters, one related to tissue‐ to alveolar‐volume ratio and the other to average septal‐wall thickness, were determined regionally. A significant gradient in MXTC MRI parameters, consistent with gravity‐induced lung tissue deformation in the supine imaging position, was found at low lung volumes. At high lung volumes, parameters were generally lower and the gradient in parameter values was less pronounced. Results show that MXTC MRI permits the quantification of subtle changes in healthy lung microstructure. Further, only structures participating in gas exchange are represented in MXTC MRI data, which potentially makes the technique especially sensitive to pathological changes in lung microstructure affecting gas exchange. Magn Reson Med, 2011.