Quantitative 129Xe MRI detects early impairment of gas-exchange in a rat model of pulmonary hypertension.

Hyperpolarized 129Xe magnetic resonance imaging (MRI) is capable of regional mapping of pulmonary gas-exchange and has found application in a wide range of pulmonary disorders in humans and animal model analogs. This study is the first application of 129Xe MRI to the monocrotaline rat model of pulmonary hypertension. Such models of preclinical pulmonary hypertension, a disease of the pulmonary vasculature that results in right heart failure and death, are usually assessed with invasive procedures such as right heart catheterization and histopathology. The work here adapted from protocols from clinical 129Xe MRI to enable preclinical imaging of rat models of pulmonary hypertension on a Bruker 7 T scanner. 129Xe spectroscopy and gas-exchange imaging showed reduced 129Xe uptake by red blood cells early in the progression of the disease, and at a later time point was accompanied by increased uptake by barrier tissues, edema, and ventilation defects-all of which are salient characteristics of the monocrotaline model. Imaging results were validated by H&E histology, which showed evidence of remodeling of arterioles. This proof-of-concept study has demonstrated that hyperpolarized 129Xe MRI has strong potential to be used to non-invasively monitor the progression of pulmonary hypertension in preclinical models and potentially to also assess response to therapy.

Generalized Linear Binning to Compare Hyperpolarized 129Xe Ventilation Maps Derived from 3D Radial Gas Exchange Versus Dedicated Multislice Gradient Echo MRI.

RATIONALE: Hyperpolarized 129Xe ventilation MRI is typically acquired using multislice fast gradient recalled echo (GRE), but interleaved 3D radial 129Xe gas transfer MRI now provides dissolved-phase and ventilation images from a single breath. To investigate whether these ventilation images provide equivalent quantitative metrics, we introduce generalized linear binning analysis. METHODS: This study included 36 patients who had undergone both multislice GRE ventilation and 3D radial gas exchange imaging. Images were then quantified by linear binning to classify voxels into one of four clusters: ventilation defect percentage (VDP), Low-, Medium- or High-ventilation percentage (LVP, MVP, HVP). For 3D radial images, linear binning thresholds were generalized using a Box-Cox rescaled reference histogram. We compared the cluster populations from the two ventilation acquisitions both numerically and spatially. RESULTS: Interacquisition Bland-Altman limits of agreement for the clusters between 3D radial vs GRE were (-7% to 5%) for VDP, (-10% to 14%) for LVP, and (-8% to 8%) for HVP. While binning maps were qualitatively similar between acquisitions, their spatial overlap was modest for VDP (Dice = 0.5 ± 0.2), and relatively poor for LVP (0.3 ± 0.1) and HVP (0.2 ± 0.1). CONCLUSION: Both acquisitions yield reasonably concordant VDP and qualitatively similar maps. However, poor regional agreement (Dice) suggests that the two acquisitions cannot yet be used interchangeably. However, further improvements in 3D radial resolution and reconciliation of bias field correction may well obviate the need for a dedicated ventilation scan in many cases.

Diverse cardiopulmonary diseases are associated with distinct xenon magnetic resonance imaging signatures.

BACKGROUND: As an increasing number of patients exhibit concomitant cardiac and pulmonary disease, limitations of standard diagnostic criteria are more frequently encountered. Here, we apply noninvasive 129Xe magnetic resonance imaging (MRI) and spectroscopy to identify patterns of regional gas transfer impairment and haemodynamics that are uniquely associated with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), left heart failure (LHF) and pulmonary arterial hypertension (PAH). METHODS: Healthy volunteers (n=23) and patients with COPD (n=8), IPF (n=12), LHF (n=6) and PAH (n=10) underwent 129Xe gas transfer imaging and dynamic spectroscopy. For each patient, three-dimensional maps were generated to depict ventilation, barrier uptake (129Xe dissolved in interstitial tissue) and red blood cell (RBC) transfer (129Xe dissolved in RBCs). Dynamic 129Xe spectroscopy was used to quantify cardiogenic oscillations in the RBC signal amplitude and frequency shift. RESULTS: Compared with healthy volunteers, all patient groups exhibited decreased ventilation and RBC transfer (both p≤0.01). Patients with COPD demonstrated more ventilation and barrier defects compared with all other groups (both p≤0.02). In contrast, IPF patients demonstrated elevated barrier uptake compared with all other groups (p≤0.007), and increased RBC amplitude and shift oscillations compared with healthy volunteers (p=0.007 and p≤0.01, respectively). Patients with COPD and PAH both exhibited decreased RBC amplitude oscillations (p=0.02 and p=0.005, respectively) compared with healthy volunteers. LHF was distinguishable from PAH by enhanced RBC amplitude oscillations (p=0.01). CONCLUSION: COPD, IPF, LHF and PAH each exhibit unique 129Xe MRI and dynamic spectroscopy signatures. These metrics may help with diagnostic challenges in cardiopulmonary disease and increase understanding of regional lung function and haemodynamics at the alveolar-capillary level.

A thermally polarized 129 Xe phantom for quality assurance in multi-center hyperpolarized gas MRI studies.

PURPOSE: Hyperpolarized 129 Xe MR is increasingly being adopted worldwide, but no standards exist for assessing or comparing performance at different 129 Xe imaging centers. Therefore, we sought to develop a thermally polarized xenon phantom assembly, approximating the size of a human torso, along with an associated imaging protocol to enable rapid quality-assurance imaging. METHODS: MR-compatible pressure vessels, with an internal volume of 5.85 L, were constructed from pressure-rated, engineering grade PE4710 high-density polyethylene. They were filled with a mixture of 61% natural xenon and 39% oxygen to approximately 11.6 bar and placed in a loader shell filled with a 0.56% saline solution to mimic the human chest. Imaging employed a 2D spoiled gradient-echo sequence using non-slice-selective excitation (TR/TE = 750/6.13 ms, flip angle = 74°, FOV = 40 × 440 mm, matrix = 64 × 32, bandwidth = 30 Hz/pixel, averages = 4), resulting in a 1.6 min acquisition. System characterization and imaging were performed at 8 different MRI centers. RESULTS: At 3 Telsa, 129 Xe in the pressure vessels was characterized by T1 = 580.5 ± 8.3 ms, linewidth = 0.21 ppm, and chemical shift = +10.2 ppm. The phantom assembly was used to obtain transmit voltage calibrations and 2D and 3D images across multiple coil and scanner configurations at 8 sites. Across the 5 sites that employed a standard flexible chest coil, the SNR was 12.4 ± 1.8. CONCLUSION: The high-density polyethylene pressure vessels filled with thermally polarized xenon and associated loader shell combine to form a phantom assembly that enables spectroscopic and imaging acquisitions that can be used for testing, quality assurance, and performance tracking-capabilities essential for standardizing hyperpolarized 129 Xe MRI within and across institutions.

Applications of 3D printing in small animal magnetic resonance imaging.

Three-dimensional (3D) printing has significantly impacted the quality, efficiency, and reproducibility of preclinical magnetic resonance imaging. It has vastly expanded the ability to produce MR-compatible parts that readily permit customization of animal handling, achieve consistent positioning of anatomy and RF coils promptly, and accelerate throughput. It permits the rapid and cost-effective creation of parts customized to a specific imaging study, animal species, animal weight, or even one unique animal, not routinely used in preclinical research. We illustrate the power of this technology by describing five preclinical studies and specific solutions enabled by different 3D printing processes and materials. We describe fixtures, assemblies, and devices that were created to ensure the safety of anesthetized lemurs during an MR examination of their brain or to facilitate localized, contrast-enhanced measurements of white blood cell concentration in a mouse model of pancreatitis. We illustrate expansive use of 3D printing to build a customized birdcage coil and components of a ventilator to enable imaging of pulmonary gas exchange in rats using hyperpolarized Xe 129 . Finally, we present applications of 3D printing to create high-quality, dual RF coils to accelerate brain connectivity mapping in mouse brain specimens and to increase the throughput of brain tumor examinations in a mouse model of pituitary adenoma.

Small Animal Multivariate Brain Analysis (SAMBA) - a High Throughput Pipeline with a Validation Framework.

While many neuroscience questions aim to understand the human brain, much current knowledge has been gained using animal models, which replicate genetic, structural, and connectivity aspects of the human brain. While voxel-based analysis (VBA) of preclinical magnetic resonance images is widely-used, a thorough examination of the statistical robustness, stability, and error rates is hindered by high computational demands of processing large arrays, and the many parameters involved therein. Thus, workflows are often based on intuition or experience, while preclinical validation studies remain scarce. To increase throughput and reproducibility of quantitative small animal brain studies, we have developed a publicly shared, high throughput VBA pipeline in a high-performance computing environment, called SAMBA. The increased computational efficiency allowed large multidimensional arrays to be processed in 1-3 days-a task that previously took ~1 month. To quantify the variability and reliability of preclinical VBA in rodent models, we propose a validation framework consisting of morphological phantoms, and four metrics. This addresses several sources that impact VBA results, including registration and template construction strategies. We have used this framework to inform the VBA workflow parameters in a VBA study for a mouse model of epilepsy. We also present initial efforts towards standardizing small animal neuroimaging data in a similar fashion with human neuroimaging. We conclude that verifying the accuracy of VBA merits attention, and should be the focus of a broader effort within the community. The proposed framework promotes consistent quality assurance of VBA in preclinical neuroimaging, thus facilitating the creation and communication of robust results.

A portable ventilator with integrated physiologic monitoring for hyperpolarized 129Xe MRI in rodents.

Hyperpolarized (HP) 129Xe MRI is emerging as a powerful, non-invasive method to image lung function and is beginning to find clinical application across a range of conditions. As clinical implementation progresses, it becomes important to translate back to well-defined animal models, where novel disease signatures can be characterized longitudinally and validated against histology. To date, preclinical 129Xe MRI has been limited to only a few sites worldwide with 2D imaging that is not generally sufficient to fully capture the heterogeneity of lung disease. To address these limitations and facilitate broader dissemination, we report on a compact and portable HP gas ventilator that integrates all the gas-delivery and physiologic monitoring capabilities required for high-resolution 3D hyperpolarized 129Xe imaging. This ventilator is MR- and HP-gas compatible, driven by inexpensive microcontrollers and open source code, and allows for precise control of the tidal volume and breathing cycle in perorally intubated mice and rats. We use the system to demonstrate data acquisition over multiple breath-holds, during which lung motion is suspended to enable high-resolution 3D imaging of gas-phase and dissolved-phase 129Xe in the lungs. We demonstrate the portability and versatility of the ventilator by imaging a mouse model of lung cancer longitudinally at 2 Tesla, and a healthy rat at 7 Tesla. We also report the detection of subtle spectroscopic fluctuations in phase with the heart rate, superimposed onto larger variations stemming from the respiratory cycle. This ventilator was developed to facilitate duplication and gain broad adoption to accelerate preclinical 129Xe MRI research.

Diffusion tensor imaging using multiple coils for mouse brain connectomics.

The correlation between brain connectivity and psychiatric or neurological diseases has intensified efforts to develop brain connectivity mapping techniques on mouse models of human disease. The neural architecture of mouse brain specimens can be shown non-destructively and three-dimensionally by diffusion tensor imaging, which enables tractography, the establishment of a connectivity matrix and connectomics. However, experiments on cohorts of animals can be prohibitively long. To improve throughput in a 7-T preclinical scanner, we present a novel two-coil system in which each coil is shielded, placed off-isocenter along the axis of the magnet and connected to a receiver circuit of the scanner. Preservation of the quality factor of each coil is essential to signal-to-noise ratio (SNR) performance and throughput, because mouse brain specimen imaging at 7 T takes place in the coil-dominated noise regime. In that regime, we show a shielding configuration causing no SNR degradation in the two-coil system. To acquire data from several coils simultaneously, the coils are placed in the magnet bore, around the isocenter, in which gradient field distortions can bias diffusion tensor imaging metrics, affect tractography and contaminate measurements of the connectivity matrix. We quantified the experimental alterations in fractional anisotropy and eigenvector direction occurring in each coil. We showed that, when the coils were placed 12 mm away from the isocenter, measurements of the brain connectivity matrix appeared to be minimally altered by gradient field distortions. Simultaneous measurements on two mouse brain specimens demonstrated a full doubling of the diffusion tensor imaging throughput in practice. Each coil produced images devoid of shading or artifact. To further improve the throughput of mouse brain connectomics, we suggested a future expansion of the system to four coils. To better understand acceptable trade-offs between imaging throughput and connectivity matrix integrity, studies may seek to clarify how measurement variability, post-processing techniques and biological variability impact mouse brain connectomics.

Establishing an accurate gas phase reference frequency to quantify 129 Xe chemical shifts in vivo.

PURPOSE: 129 Xe interacts with biological media to exhibit chemical shifts exceeding 200 ppm that report on physiology and pathology. Extracting this functional information requires shifts to be measured precisely. Historically, shifts have been reported relative to the gas-phase resonance originating from pulmonary airspaces. However, this frequency is not fixed-it is affected by bulk magnetic susceptibility, as well as Xe-N2 , Xe-Xe, and Xe-O2 interactions. In this study, we addressed this by introducing a robust method to determine the 0 ppm 129 Xe reference from in vivo data. METHODS: Respiratory-gated hyperpolarized 129 Xe spectra from the gas- and dissolved-phases were acquired in four mice at 2T from multiple axial slices within the thoracic cavity. Complex spectra were then fitted in the time domain to identify peaks. RESULTS: Gas-phase 129 Xe exhibited two distinct resonances corresponding to 129 Xe in conducting airways (varying from -0.6 ± 0.2 to 1.3 ± 0.3 ppm) and alveoli (relatively stable, at -2.2 ± 0.1 ppm). Dissolved-phase 129 Xe exhibited five reproducible resonances in the thorax at 198.4 ± 0.4, 195.5 ± 0.4, 193.9 ± 0.2, 191.3 ± 0.2, and 190.7 ± 0.3 ppm. CONCLUSION: The alveolar 129 Xe resonance exhibits a stable frequency across all mice. Therefore, it can provide a reliable in vivo reference frequency by which to characterize other spectroscopic shifts. Magn Reson Med 77:1438-1445, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Tumor location, but not H3.3K27M, significantly influences the blood-brain-barrier permeability in a genetic mouse model of pediatric high-grade glioma.

Pediatric high-grade gliomas (pHGGs) occur with strikingly different frequencies in infratentorial and supratentorial regions. Although histologically these malignancies appear similar, they represent distinct diseases. Recent genomic studies have identified histone K27M H3.3/H3.1 mutations in the majority of brainstem pHGGs; these mutations are rarely encountered in pHGGs that arise in the cerebral cortex. Previous research in brainstem pHGGs suggests a restricted permeability of the blood-brain-barrier (BBB). In this work, we use dynamic contrast-enhanced (DCE) MRI to evaluate BBB permeability in a genetic mouse model of pHGG as a function of location (cortex vs. brainstem, n = 8 mice/group) and histone mutation (mutant H3.3K27M vs. wild-type H3.3, n = 8 mice/group). The pHGG models are induced either in the brainstem or the cerebral cortex and are driven by PDGF signaling and p53 loss with either H3.3K27M or wild-type H3.3. T2-weighted MRI was used to determine tumor location/extent followed by 4D DCE-MRI for estimating the rate constant (K (trans) ) for tracer exchange across the barrier. BBB permeability was 67 % higher in cortical pHGGs relative to brainstem pHGGs (t test, p = 0.012) but was not significantly affected by the expression of mutant H3.3K27M versus wild-type H3.3 (t-test, p = 0.78). Although mice became symptomatic at approximately the same time, the mean volume of cortical tumors was 3.6 times higher than the mean volume of brainstem tumors. The difference between the mean volume of gliomas with wild-type and mutant H3.3 was insignificant. Mean K (trans) was significantly correlated to glioma volume. These results present a possible explanation for the poor response of brainstem pHGGs to systemic therapy. Our findings illustrate a potential role played by the microenvironment in shaping tumor growth and BBB permeability.

Magnetic fluid hyperthermia for bladder cancer: a preclinical dosimetry study.

PURPOSE: This paper describes a preclinical investigation of the feasibility of thermotherapy treatment of bladder cancer with magnetic fluid hyperthermia (MFH), performed by analysing the thermal dosimetry of nanoparticle heating in a rat bladder model. MATERIALS AND METHODS: The bladders of 25 female rats were instilled with magnetite-based nanoparticles, and hyperthermia was induced using a novel small animal magnetic field applicator (Actium Biosystems, Boulder, CO). We aimed to increase the bladder lumen temperature to 42 °C in <10 min and maintain that temperature for 60 min. Temperatures were measured within the bladder lumen and throughout the rat with seven fibre-optic probes (OpSens Technologies, Quebec, Canada). An MRI analysis was used to confirm the effectiveness of the catheterisation method to deliver and maintain various nanoparticle volumes within the bladder. Thermal dosimetry measurements recorded the temperature rise of rat tissues for a variety of nanoparticle exposure conditions. RESULTS: Thermal dosimetry data demonstrated our ability to raise and control the temperature of rat bladder lumen ≥1 °C/min to a steady state of 42 °C with minimal heating of surrounding normal tissues. MRI scans confirmed the homogenous nanoparticle distribution throughout the bladder. CONCLUSION: These data demonstrate that our MFH system with magnetite-based nanoparticles provides well-localised heating of rat bladder lumen with effective control of temperature in the bladder and minimal heating of surrounding tissues.

Quantitative analysis of hyperpolarized 129Xe ventilation imaging in healthy volunteers and subjects with chronic obstructive pulmonary disease.

In this study, hyperpolarized (129) Xe MR ventilation and (1) H anatomical images were obtained from three subject groups: young healthy volunteers (HVs), subjects with chronic obstructive pulmonary disease (COPD) and age-matched controls (AMCs). Ventilation images were quantified by two methods: an expert reader-based ventilation defect score percentage (VDS%) and a semi-automated segmentation-based ventilation defect percentage (VDP). Reader-based values were assigned by two experienced radiologists and resolved by consensus. In the semi-automated analysis, (1) H anatomical images and (129) Xe ventilation images were both segmented following registration to obtain the thoracic cavity volume and ventilated volume, respectively, which were then expressed as a ratio to obtain the VDP. Ventilation images were also characterized by generating signal intensity histograms from voxels within the thoracic cavity volume, and heterogeneity was analyzed using the coefficient of variation (CV). The reader-based VDS% correlated strongly with the semi-automatically generated VDP (r = 0.97, p < 0.0001) and with CV (r = 0.82, p < 0.0001). Both (129) Xe ventilation defect scoring metrics readily separated the three groups from one another and correlated significantly with the forced expiratory volume in 1 s (FEV1 ) (VDS%: r = -0.78, p = 0.0002; VDP: r = -0.79, p = 0.0003; CV: r = -0.66, p = 0.0059) and other pulmonary function tests. In the healthy subject groups (HVs and AMCs), the prevalence of ventilation defects also increased with age (VDS%: r = 0.61, p = 0.0002; VDP: r = 0.63, p = 0.0002). Moreover, ventilation histograms and their associated CVs distinguished between subjects with COPD with similar ventilation defect scores, but visibly different ventilation patterns.

In vivo MR imaging of pulmonary perfusion and gas exchange in rats via continuous extracorporeal infusion of hyperpolarized 129Xe.

BACKGROUND: Hyperpolarized (HP) (129)Xe magnetic resonance imaging (MRI) permits high resolution, regional visualization of pulmonary ventilation. Additionally, its reasonably high solubility (>10%) and large chemical shift range (>200 ppm) in tissues allow HP (129)Xe to serve as a regional probe of pulmonary perfusion and gas transport, when introduced directly into the vasculature. In earlier work, vascular delivery was accomplished in rats by first dissolving HP (129)Xe in a biologically compatible carrier solution, injecting the solution into the vasculature, and then detecting HP (129)Xe as it emerged into the alveolar airspaces. Although easily implemented, this approach was constrained by the tolerable injection volume and the duration of the HP (129)Xe signal. METHODS AND PRINCIPAL FINDINGS: Here, we overcome the volume and temporal constraints imposed by injection, by using hydrophobic, microporous, gas-exchange membranes to directly and continuously infuse (129)Xe into the arterial blood of live rats with an extracorporeal (EC) circuit. The resulting gas-phase (129)Xe signal is sufficient to generate diffusive gas exchange- and pulmonary perfusion-dependent, 3D MR images with a nominal resolution of 2×2×2 mm(3). We also show that the (129)Xe signal dynamics during EC infusion are well described by an analytical model that incorporates both mass transport into the blood and longitudinal relaxation. CONCLUSIONS: Extracorporeal infusion of HP (129)Xe enables rapid, 3D MR imaging of rat lungs and, when combined with ventilation imaging, will permit spatially resolved studies of the ventilation-perfusion ratio in small animals. Moreover, EC infusion should allow (129)Xe to be delivered elsewhere in the body and make possible functional and molecular imaging approaches that are currently not feasible using inhaled HP (129)Xe.

Effects of corticosteroid treatment on airway inflammation, mechanics, and hyperpolarized ³He magnetic resonance imaging in an allergic mouse model.

The purpose of this study was to assess the effects of corticosteroid therapy on a murine model of allergic asthma using hyperpolarized (3)He magnetic resonance imaging (MRI) and respiratory mechanics measurements before, during, and after methacholine (MCh) challenge. Three groups of mice were prepared, consisting of ovalbumin sensitized/ovalbumin challenged (Ova/Ova, n = 5), Ova/Ova challenged but treated with the corticosteroid dexamethasone (Ova/Ova+Dex, n = 3), and ovalbumin-sensitized/saline-challenged (Ova/PBS, n = 4) control animals. All mice underwent baseline 3D (3)He MRI, then received a MCh challenge while 10 2D (3)He MR images were acquired for 2 min, followed by post-MCh 3D (3)He MRI. Identically treated groups underwent respiratory mechanics evaluation (n = 4/group) and inflammatory cell counts (n = 4/group). Ova/Ova animals exhibited predominantly large whole lobar defects at baseline, with significantly higher ventilation defect percentage (VDP = 19 ± 4%) than Ova/PBS (+2 ± 1%, P = 0.01) animals. Such baseline defects were suppressed by dexamethasone (0%, P = 0.009). In the Ova/Ova group, MCh challenge increased VDP on both 2D (+30 ± 8%) and 3D MRI scans (+14 ± 2%). MCh-induced VDP changes were diminished in Ova/Ova+Dex animals on both 2D (+21 ± 9%, P = 0.63) and 3D scans (+7 ± 2%, P = 0.11) and also in Ova/PBS animals on 2D (+6 ± 3%, P = 0.07) and 3D (+4 ± 1%, P = 0.01) scans. Because MCh challenge caused near complete cessation of ventilation in four of five Ova/Ova animals, even as large airways remained patent, this implies that small airway (<188 µm) obstruction predominates in this model. This corresponds with respiratory mechanics observations that MCh challenge significantly increases elastance and tissue damping but only modestly affects Newtonian airway resistance.

Chronic obstructive pulmonary disease: safety and tolerability of hyperpolarized 129Xe MR imaging in healthy volunteers and patients.

PURPOSE: To evaluate the safety and tolerability of inhaling multiple 1-L volumes of undiluted hyperpolarized xenon 129 ((129)Xe) followed by up to a 16-second breath hold and magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was approved by the institutional review board and was HIPAA compliant. Written informed consent was obtained. Forty-four subjects (19 men, 25 women; mean age, 46.1 years ± 18.8 [standard deviation]) were enrolled, consisting of 24 healthy volunteers, 10 patients with chronic obstructive pulmonary disease (COPD), and 10 age-matched control subjects. All subjects received three or four 1-L volumes of undiluted hyperpolarized (129)Xe, followed by breath-hold MR imaging. Oxygen saturation, heart rate and rhythm, and blood pressure were continuously monitored. These parameters, along with respiratory rate and subjective symptoms, were assessed after each dose. Subjects' serum biochemistry and hematology were recorded at screening and at 24-hour follow-up. A 12-lead electrocardiogram (ECG) was obtained at these times and also within 2 hours prior to and 1 hour after (129)Xe MR imaging. Xenon-related symptoms were evaluated for relationship to subject group by using a χ(2) test and to subject age by using logistic regression. Changes in vital signs were tested for significance across subject group and time by using a repeated-measures multivariate analysis of variance test. RESULTS: The 44 subjects tolerated all xenon inhalations, no subjects withdrew, and no serious adverse events occurred. No significant changes in vital signs (P > .27) were observed, and no subjects exhibited changes in laboratory test or ECG results at follow-up that were deemed clinically important or required intervention. Most subjects (91%) did experience transient xenon-related symptoms, most commonly dizziness (59%), paresthesia (34%), euphoria (30%), and hypoesthesia (30%). All symptoms resolved without clinical intervention in 1.6 minutes ± 0.9. CONCLUSION: Inhalation of hyperpolarized (129)Xe is well tolerated in healthy subjects and in those with mild or moderate COPD. Subjects do experience mild, transient, xenon-related symptoms, consistent with its known anesthetic properties.

Diffusion-weighted hyperpolarized 129Xe MRI in healthy volunteers and subjects with chronic obstructive pulmonary disease.

Given its greater availability and lower cost, (129) Xe apparent diffusion coefficient (ADC) MRI offers an alternative to (3) He ADC MRI. To demonstrate the feasibility of hyperpolarized (129) Xe ADC MRI, we present results from healthy volunteers (HV), chronic obstructive pulmonary disease (COPD) subjects, and age-matched healthy controls (AMC). The mean parenchymal ADC was 0.036 ± 0.003 cm(2) sec(-1) for HV, 0.043 ± 0.006 cm(2) sec(-1) for AMC, and 0.056 ± 0.008 cm(2) sec(-1) for COPD subjects with emphysema. In healthy individuals, but not the COPD group, ADC decreased significantly in the anterior-posterior direction by ∼ 22% (P = 0.006, AMC; 0.0059, HV), likely because of gravity-induced tissue compression. The COPD group exhibited a significantly larger superior-inferior ADC reduction (∼ 28%) than the healthy groups (∼ 24%) (P = 0.00018, HV; P = 3.45 × 10(-5) , AMC), consistent with smoking-related tissue destruction in the superior lung. Superior-inferior gradients in healthy subjects may result from regional differences in xenon concentration. ADC was significantly correlated with pulmonary function tests (forced expiratory volume in 1 sec, r = -0.77, P = 0.0002; forced expiratory volume in 1 sec/forced vital capacity, r = -0.77, P = 0.0002; diffusing capacity of carbon monoxide in the lung/alveolar volume (V(A) ), r = -0.77, P = 0.0002). In healthy groups, ADC increased with age by 0.0002 cm(2) sec(-1) year(-1) (r = 0.56, P = 0.02). This study shows that (129) Xe ADC MRI is clinically feasible, sufficiently sensitive to distinguish HV from subjects with emphysema, and detects age- and posture-dependent changes.

Ventilation defects observed with hyperpolarized 3He magnetic resonance imaging in a mouse model of acute lung injury.

Regions of diminished ventilation are often evident during functional pulmonary imaging studies, including hyperpolarized gas magnetic resonance imaging (MRI), positron emission tomography, and computed tomography (CT). The objective of this study was to characterize the hypointense regions observed via (3)He MRI in a murine model of acute lung injury. LPS at doses ranging from 15-50 µg was intratracheally administered to C57BL/6 mice under anesthesia. Four hours after exposure to either LPS or saline vehicle, mice were imaged via hyperpolarized (3)He MRI. All images were evaluated to identify regions of hypointense signals. Lungs were then characterized by conventional histology, or used to obtain tissue samples from regions of normal and hypointense (3)He signals and analyzed for cytokine content. The characterization of (3)He MRI images identified three distinct types of hypointense patterns: persistent defects, atelectatic defects, and dorsal lucencies. Persistent defects were associated with the administration of LPS. The number of persistent defects depended on the dose of LPS, with a significant increase in mean number of defects in 30-50-µg LPS-dosed mice versus saline-treated control mice. Atelectatic defects predominated in LPS-dosed mice under conditions of low-volume ventilation, and could be reversed with deep inspiration. Dorsal lucencies were present in nearly all mice studied, regardless of the experimental conditions, including control animals that did not receive LPS. A comparison of (3)He MRI with histopathology did not identify tissue abnormalities in regions of low (3)He signal, with the exception of a single region of atelectasis in one mouse. Furthermore, no statistically significant differences were evident in concentrations of IL-1ß, IL-6, macrophage inflammatory protein (MIP)-1α, MIP-2, chemokine (C-X-C motif) ligand 1 (KC), TNFα, and monocyte chemotactic protein (MCP)-1 between hypointense and normally ventilated lung regions in LPS-dosed mice. Thus, this study defines the anatomic, functional, and biochemical characteristics of ventilation defects associated with the administration of LPS in a murine model of acute lung injury.

Hyperpolarized Xe MR imaging of alveolar gas uptake in humans.

BACKGROUND: One of the central physiological functions of the lungs is to transfer inhaled gases from the alveoli to pulmonary capillary blood. However, current measures of alveolar gas uptake provide only global information and thus lack the sensitivity and specificity needed to account for regional variations in gas exchange. METHODS AND PRINCIPAL FINDINGS: Here we exploit the solubility, high magnetic resonance (MR) signal intensity, and large chemical shift of hyperpolarized (HP) (129)Xe to probe the regional uptake of alveolar gases by directly imaging HP (129)Xe dissolved in the gas exchange tissues and pulmonary capillary blood of human subjects. The resulting single breath-hold, three-dimensional MR images are optimized using millisecond repetition times and high flip angle radio-frequency pulses, because the dissolved HP (129)Xe magnetization is rapidly replenished by diffusive exchange with alveolar (129)Xe. The dissolved HP (129)Xe MR images display significant, directional heterogeneity, with increased signal intensity observed from the gravity-dependent portions of the lungs. CONCLUSIONS: The features observed in dissolved-phase (129)Xe MR images are consistent with gravity-dependent lung deformation, which produces increased ventilation, reduced alveolar size (i.e., higher surface-to-volume ratios), higher tissue densities, and increased perfusion in the dependent portions of the lungs. Thus, these results suggest that dissolved HP (129)Xe imaging reports on pulmonary function at a fundamental level.

Rapid production of specialized animal handling devices using computer-aided design and solid freeform fabrication.

PURPOSE: To develop a process for rapidly and inexpensively producing customized animal handling devices for small animal imaging. MATERIALS AND METHODS: To meet the specific needs of a particular imaging experiment, measurements are taken from imaging data and the animal handling devices are designed using 3D computer-aided design (CAD) software. Parts are produced in a few days using solid freeform fabrication (SFF, a.k.a. rapid prototyping). RESULTS: This process is illustrated with the production of an animal handling system for stereotaxically prescribed therapeutic ultrasound and MRI of the mouse brain. The device provides integrated head-fixation, anesthesia delivery, and physiological monitoring in a modular system. Design and production took approximately 1 week and the cost was a small fraction of a traditional machine shop. CONCLUSION: Commercial animal handling products typically have limited functionality and are not integrated with other laboratory infrastructure. However, using CAD and SFF, sophisticated animal handling devices can be produced to meet the specific experimental needs. This process is typically faster and less expensive than using a traditional machine shop, and the products are more robust than typical homemade devices. Using high-quality purpose-built devices permits experiments to be executed with greater consistency and higher throughput.