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Background Idiopathic pulmonary fibrosis (IPF) is a temporally and spatially heterogeneous lung disease. Identifying whether IPF in a patient is progressive or stable is crucial for treatment regimens. Purpose To assess the role of hyperpolarized (HP) xenon 129 (

BackgroundThe objective of this work was to apply quantitative and semiquantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) methods to evaluate lung perfusion in idiopathic pulmonary fibrosis (IPF).MethodsIn this prospective trial 41 subjects, including healthy control and IPF subjects, were studied using DCE-MRI at baseline. IPF subjects were then followed for 1 year; progressive IPF (IPFprog) subjects were distinguished from stable IPF (IPFstable) subjects based on a decline in percent predicted forced vital capacity (FVC % pred) or diffusing capacity of the lung for carbon monoxide (DLCO% pred) measured during follow-up visits. 35 out of 41 subjects were retained for final baseline analysis (control: n=15; IPFstable: n=14; IPFprog: n=6). Seven measures and their coefficients of variation (CV) were derived using temporally resolved DCE-MRI. Two sets of global and regional comparisons were made: controlversusIPF groups and controlversusIPFstableversusIPFproggroups, using linear regression analysis. Each measure was compared with FVC % pred,DLCO% pred and the lung clearance index (LCI % pred) using a Spearman rank correlation.ResultsDCE-MRI identified regional perfusion differences between control and IPF subjects using first moment transit time (FMTT), contrast uptake slope and pulmonary blood flow (PBF) (p≤0.05), while global averages did not. FMTT was shorter for IPFprogcompared with both IPFstable(p=0.004) and control groups (p=0.023). Correlations were observed between PBF CV andDLCO% pred (rs= −0.48, p=0.022) and LCI % pred (rs= +0.47, p=0.015). Significant group differences were detected in age (pDLCO% pred (pConclusionsGlobal analysis obscures regional changes in pulmonary haemodynamics in IPF using DCE-MRI in IPF. Decreased FMTT may be a candidate marker for IPF progression.

Infants admitted to the neonatal intensive care unit (NICU) often suffer from multifaceted pulmonary morbidities that are not well understood. Ultrashort echo time (UTE) magnetic resonance imaging (MRI) is a promising technique for pulmonary imaging in this population without requiring exposure to ionizing radiation. The aims of this study were to investigate the effect of neonatal pulmonary disease on R2 * and tissue density and to utilize numerical simulations to evaluate the effect of different alveolar structures on predicted R2 *.This was a prospective study, in which 17 neonatal human subjects (five control, seven with bronchopulmonary dysplasia [BPD], five with congenital diaphragmatic hernia [CDH]) were enrolled. Twelve subjects were male and five were female, with postmenstrual age (PMA) at MRI of 39.7 ± 4.7 weeks. A 1.5T/multiecho three-dimensional UTE MRI was used. Pulmonary R2 * and tissue density were compared across disease groups over the whole lung and regionally. A spherical shell alveolar model was used to predict the expected R2 * over a range of tissue densities and tissue susceptibilities. Tests for significantly different mean R2 * and tissue densities across disease groups were evaluated using analysis of variance, with subsequent pairwise group comparisons performed using t tests. Lung tissue density was lower in the ipsilateral lung in CDH compared to both controls and BPD patients (both p

Rationale: Dynamic collapse of the tracheal lumen (tracheomalacia) occurs frequently in premature neonates, particularly in those with common comorbidities such as bronchopulmonary dysplasia. The tracheal collapse increases the effort necessary to breathe (work of breathing [WOB]). However, quantifying the increased WOB related to tracheomalacia has previously not been possible. Therefore, it is also not currently possible to separate the impact of tracheomalacia on patient symptoms from parenchymal abnormalities. Objectives: To measure the increase in WOB due to airway motion in individual subjects with and without tracheomalacia and with different types of respiratory support. Methods: Fourteen neonatal intensive care unit subjects not using invasive mechanical ventilation were recruited. In eight, tracheomalacia was diagnosed via clinical bronchoscopy, and six did not have tracheomalacia. Self-gated three-dimensional ultrashort-echo-time magnetic resonance imaging (MRI) was performed on each subject with clinically indicated respiratory support to obtain cine images of tracheal anatomy and motion during the respiratory cycle. The component of WOB due to resistance within the trachea was then calculated via computational fluid dynamics (CFD) simulations of airflow on the basis of the subject’s anatomy, motion, and respiratory airflow rates. A second CFD simulation was performed for each subject with the airway held static at its largest (i.e., most open) position to determine the increase in WOB due to airway motion and collapse. Results: The tracheal-resistive component of WOB was increased because of airway motion by an average of 337% ± 295% in subjects with tracheomalacia and 24% ± 14% in subjects without tracheomalacia (P

Background: Alveolar development and lung parenchymal simplification are not well characterized in vivo in neonatal patients with respiratory morbidities, such as bronchopulmonary dysplasia (BPD). Hyperpolarized (HP) gas diffusion magnetic resonance imaging (MRI) is a sensitive, safe, nonionizing, and noninvasive biomarker for measuring airspace size in vivo but has not yet been implemented in young infants. Objective: This work quantified alveolar airspace size via HP gas diffusion MRI in healthy and diseased explanted infant lung specimens, with comparison to histological morphometry. Methods: Lung specimens from 8 infants were obtained: 7 healthy left upper lobes (0–16 months, post-autopsy) and 1 left lung with filamin-A mutation, closely representing BPD lung disease (11 months, post-transplantation). Specimens were imaged using HP 3He diffusion MRI to generate apparent diffusion coefficients (ADCs) as biomarkers of alveolar airspace size, with comparison to mean linear intercept (Lm) via quantitative histology. Results: Mean ADC and Lm were significantly increased throughout the diseased specimen (ADC = 0.26 ± 0.06 cm2/s, Lm = 587 ± 212 µm) compared with healthy specimens (ADC = 0.14 ± 0.03 cm2/s, Lm = 133 ± 37 µm; p < 1 × 10−7); increased values reflect enlarged airspaces. Mean ADCs in healthy specimens were significantly correlated to Lm (r = 0.69, p = 0.041). Conclusions: HP gas diffusion MRI is sensitive to healthy and diseased regional alveolar airspace size in infant lungs, with good comparison to quantitative histology in ex vivo specimens. This work demonstrates the translational potential of gas MRI techniques for in vivo assessment of normal and abnormal alveolar development in neonates with pulmonary disease.

PURPOSE Novel demonstration of R2∗ and tissue density estimation in infant lungs using 3D ultrashort echo time MRI. Differences between adult and neonates with no clinical indication of lung pathology is explored, as well as relationships between parameter estimates and gravitationally dependent position and lung inflation state. This provides a tool for probing physiologic processes that may be relevant to pulmonary disease and progression in newborns. METHODS R2∗ and tissue density were estimated in a phantom consisting of standards allowing for ground truth comparisons and in human subjects (N = 5 infants, N = 4 adults, no clinical indication of lung dysfunction) using a 3D radial multiecho ultrashort echo time MRI sequence. Whole lung averages were compared between infants and adults. Dependence of the metrics on anterior-posterior position as well as between end-tidal inspiration and expiration were explored, in addition to the general relationship between R2∗ and tissue density. RESULTS Estimates in the phantom did not differ significantly from ground truth. Neonates had significantly lower mean R2∗ (P = .006) and higher mean tissue density (P = 1.5e-5) than adults. Tissue density and R2∗ were both significantly dependent on anterior-posterior position and lung inflation state (P < .005). An overall inverse relationship was found between R2∗ and tissue density, which was similar in both neonates and adults. CONCLUSION Estimation of tissue density and R2∗ in free breathing, nonsedated, neonatal patients is feasible using multiecho ultrashort echo time MRI. R2∗ was no different between infants and adults when matched for tissue density, although density of lung parenchyma was, on average, lower in adults than neonates.

Background MRI of hyperpolarized 129 Xenon (HP 129 Xe) is increasingly utilized for investigating pulmonary function. The solubility of HP 129 Xe in lung tissue, blood plasma (Barrier), and red blood cells (RBC), with unique chemical shifts, enables spectroscopic imaging of potential imaging biomarkers of gas exchange and microstructural pulmonary physiology. Purpose To quantify global average and regional repeatability of Barrier:gas, RBC:gas, and RBC:Barrier ratios derived from dissolved-phase 129 Xe imaging and their dependence on intervisit changes in lung inflation volume. Study type Prospective. Population Fourteen healthy volunteers. One subject was unable to complete the study resulting in 13 subjects for analysis (eight female, five male, ages 24-69, 53.8 ± 13.9). Field strength 1.5T. Assessment Subjects were imaged using a 3D radial 1-point Dixon method to separate Barrier and RBC component signals, at two different timepoints, with ~1 month between visits. RBC:Gas, Barrier:Gas, and RBC:Barrier measures were compared across time and with pulmonary function tests (PFTs). Statistical tests Repeatablilty was quantified using Bland-Altman plots, coefficient of repeatability, coefficient of variation (CV), and intraclass correlation coefficients (ICCs). Dependence of imaging measures on PFTs and lung volume was evaluated using Spearman and Pearson correlation coefficients, respectively. Statistical significance was determined by F-test for intraclass correlations, and t-test for Spearman correlations and regression. Results Mean RBC:Gas, Barrier:Gas, and RBC:Barrier had CVs of 19.2%, 20.0%, and 11.5%, respectively, and had significant ICCs, equal to 0.78, 0.79, and 0.92, respectively. Intervisit differences in RBC:Barrier were significantly correlated with intervisit differences in DLCO (r = 0.93, P = 0.007). Significant correlations with intervisit lung volume differences and intervisit differences in mean RBC:Gas (r = -0.73, P = 0.005) and Barrier:Gas (r = -0.69, P = 0.009) were found. Data conclusion Three commonly used 129 Xe MRI-based measures of gas-exchange show good repeatability, particularly the Barrier:RBC ratio, which did not depend on lung inflation volume and was strongly associated with intervisit changes in DLCO . Level of evidence 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1182-1190.

The purpose of this review is to acquaint the reader with recent advances in ultra-short echo time (UTE) magnetic resonance imaging (MRI) of the lung and its implications for pulmonary MRI when used in conjunction with functional MRI techniques. UTE MRI has three critical advantages for lung applications: 1) high resolution, whole-lung morphological images without the use of ionizing radiation; 2) mitigation of the short transverse relaxation time constant (T2*) caused by magnetic susceptibility effects prominent at air-tissue interfaces; and 3) in conjunction with a radial acquisition and hard respiratory gating, mitigation of cardiac and respiratory motion artifacts, enabling free breathing exams. UTE MRI clearly shows the lung parenchymal changes due to idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF). The use of UTE MRI, in conjunction with established functional lung MRI in chronic lung diseases, will serve to mitigate the need for computed tomography (CT) in children. Current limitations of UTE MRI include long scan times, poor delineation of thin walled structures (e.g. cysts and reticulation) due to limited spatial resolution, low signal to noise (SNR), and imperfect motion compensation. Despite these limitations, UTE MRI can now be considered as an alternative to multi-detector CT for the longitudinal follow up of the morphological changes from lung diseases in neonates, children and young adults, particularly as a complement to the unique functional capabilities of MRI.

Background In pediatrics, tracheomalacia is an airway condition that causes tracheal lumen collapse during breathing and may lead to the patient requiring respiratory support. Adult patients can narrow their glottis to self-generate positive end-expiratory pressure (PEEP) to raise the pressure in the trachea and prevent collapse. However, auto-PEEP has not been studied in newborns with tracheomalacia. The objective of this study was to measure the glottis cross-sectional area throughout the breathing cycle and to quantify total pressure difference through the glottis in patients with and without tracheomalacia. Research Question Do neonates with tracheomalacia narrow their glottises? How does the glottis narrowing affect the total pressure along the airway? Study Design and Methods Ultrashort echo time MRI was performed in 21 neonatal ICU patients (11 with tracheomalacia, 10 without tracheomalacia). MRI scans were reconstructed at four different phases of breathing. All patients were breathing room air or using noninvasive respiratory support at the time of MRI. Computational fluid dynamics simulations were performed on patient-specific virtual airway models with airway anatomic features and motion derived via MRI to quantify the total pressure difference through the glottis and trachea. Results The mean glottis cross-sectional area at peak expiration in the patients with tracheomalacia was less than half that in patients without tracheomalacia (4.0 ± 1.1 mm2 vs 10.3 ± 4.4 mm2; P = .002). The mean total pressure difference through the glottis at peak expiration was more than 10 times higher in patients with tracheomalacia compared with patients without tracheomalacia (2.88 ± 2.29 cm H2O vs 0.26 ± 0.16 cm H2O; P = .005). Interpretation Neonates with tracheomalacia narrow their glottises, which raises pressure in the trachea during expiration, thereby acting as auto-PEEP.

BACKGROUND: Infants admitted to the neonatal intensive care unit (NICU) often suffer from multifaceted pulmonary morbidities that are not well understood. Ultrashort echo time (UTE) MRI is a promising technique for pulmonary imaging in this population without requiring exposure to ionizing radiation. PURPOSE: To investigate the effect of neonatal pulmonary disease on R(2)* and tissue density and to utilize numerical simulations to evaluate the effect of different alveolar structures on predicted R(2)*. STUDY TYPE: Prospective. POPULATION: 17 neonatal human subjects (5 control, 7 with bronchopulmonary dysplasia (BPD), 5 with congenital diaphragmatic hernia (CDH)). 12 male, 5 female, post-menstrual age (PMA) at MRI 39.7±4.7 weeks. FIELD STRENGTH/SEQUENCES: 1.5T/multi-echo 3D UTE MRI. ASSESSMENT: Pulmonary R(2)* and tissue density were compared across disease groups over the whole lung and regionally. A spherical shell alveolar model was used to predict the expected R(2)* over a range of tissue densities and tissue susceptibilities. STATISTICAL TESTS: Tests for significantly different mean R(2)* and tissue densities across disease groups were evaluated using analysis of variance (ANOVA), with subsequent pairwise group comparisons performed using t-tests. RESULTS: Lung tissue density was lower in the ipsilateral lung in CDH compared to both controls and BPD patients (both P

Background: There are few prognostic indicators of need for tracheostomy in preterm infants with chronic lung disease (bronchopulmonary dysplasia, BPD). Aims: To develop a clinically-useful tracheostomy prediction model in neonatal BPD using quantitative biomarkers from respiratory MRI. Methods: Infants with and without BPD (N=61) underwent 3D lung and airway MRI (0.7 mm3) near term-age. Lung disease scores (0-14 points) were used to create a binomial logistic regression model (⅔*N) to determine likelihood of tracheostomy (yes/no tracheostomy outcome assigned by 75% probability threshold), with validation in a separate cohort (⅓*N). A sub-cohort model also included MRI-quantified tracheomalacia severity (n=36). Results: The model correctly classified 95% of the validation cohort. The full-cohort model had 89% accuracy, 100% positive predictive value, and 85% negative predictive value. The lung+airway model values were 83%, 92%, and 78%, respectively. Conclusions: Quantitative respiratory MRI can predict need for tracheostomy in neonatal BPD with high sensitivity and accuracy, providing an objective tool for clinical decision-making.

PURPOSE: The MR properties (chemical shifts and R(2)* decay rates) of dissolved-phase hyperpolarized (HP) (129)Xe are confounded by the large magnetic field inhomogeneity present in the lung. This work improves measurements of these properties using a model-based image reconstruction to characterize the R(2)* decay rates of dissolved-phase HP (129)Xe in healthy subjects and patients with idiopathic pulmonary fibrosis (IPF). METHODS: Whole lung MRS and 3D radial MRI with four gradient echoes were performed after inhalation of HP (129)Xe in healthy subjects and patients with IPF. A model-based image reconstruction formulated as a regularized optimization problem was solved iteratively to measure regional signal intensity in the gas, barrier, and red blood cell (RBC) compartments, while simultaneously measuring their chemical shifts and R(2)* decay rates. RESULTS: The estimation of spectral properties reduced artifacts in images of HP (129)Xe in the gas, barrier, and RBC compartments and improved image SNR by over 20%. R(2)* decay rates of the RBC and barrier compartments were lower in patients with IPF compared to healthy subjects (P < 0.001 and P=0.005, respectively) and correlated to DL(CO) (R=0.71 and 0.64, respectively). Chemical shift of the RBC component measured with whole lung spectroscopy was significantly different between IPF and normal subjects (P = 0.022). CONCLUSION: Estimates for R(2)* in both barrier and RBC dissolved-phase HP (129)Xe compartments using a regional signal model improved image quality for dissolved phase images and provided additional biomarkers of lung injury in IPF.

Bronchopulmonary dysplasia (BPD) is a serious neonatal pulmonary condition associated with premature birth, but the underlying parenchymal disease and trajectory are poorly characterized. The current National Institute of Child Health and Human Development (NICHD)/NHLBI definition of BPD severity is based on degree of prematurity and extent of oxygen requirement. However, no clear link exists between initial diagnosis and clinical outcomes.We hypothesized that magnetic resonance imaging (MRI) of structural parenchymal abnormalities will correlate with NICHD-defined BPD disease severity and predict short-term respiratory outcomes.A total of 42 neonates (20 severe BPD, 6 moderate, 7 mild, 9 non-BPD control subjects; 40 ± 3-wk postmenstrual age) underwent quiet-breathing structural pulmonary MRI (ultrashort echo time and gradient echo) in a neonatal ICU-sited, neonatal-sized 1.5 T scanner, without sedation or respiratory support unless already clinically prescribed. Disease severity was scored independently by two radiologists. Mean scores were compared with clinical severity and short-term respiratory outcomes. Outcomes were predicted using univariate and multivariable models, including clinical data and scores.MRI scores significantly correlated with severities and predicted respiratory support at neonatal ICU discharge (P 0.0001). In multivariable models, MRI scores were by far the strongest predictor of respiratory support duration over clinical data, including birth weight and gestational age. Notably, NICHD severity level was not predictive of discharge support.Quiet-breathing neonatal pulmonary MRI can independently assess structural abnormalities of BPD, describe disease severity, and predict short-term outcomes more accurately than any individual standard clinical measure. Importantly, this nonionizing technique can be implemented to phenotype disease, and has potential to serially assess efficacy of individualized therapies.

BACKGROUND Neonatal dynamic tracheal collapse (tracheomalacia, TM) is a common and serious comorbidity in infants, particularly those with chronic lung disease of prematurity (bronchopulmonary dysplasia, BPD) or congenital airway or lung-related conditions such as congenital diaphragmatic hernia (CDH), but the underlying pathology, impact on clinical outcomes, and response to therapy are not well understood. There is a pressing clinical need for an accurate, objective, and safe assessment of neonatal TM. PURPOSE To use retrospectively respiratory-gated ultrashort echo-time (UTE) MRI to noninvasively analyze moving tracheal anatomy for regional, quantitative evaluation of dynamic airway collapse in quiet-breathing, nonsedated neonates. STUDY TYPE Prospective. POPULATION/SUBJECTS Twenty-seven neonatal subjects with varying respiratory morbidities (control, BPD, CDH, abnormal polysomnogram). FIELD STRENGTH/SEQUENCE High-resolution 3D radial UTE MRI (0.7 mm isotropic) on 1.5T scanner sited in the neonatal intensive care unit. ASSESSMENT Images were retrospectively respiratory-gated using the motion-modulated time-course of the k-space center. Tracheal surfaces were generated from segmentations of end-expiration/inspiration images and analyzed geometrically along the tracheal length to calculate percent-change in luminal cross-sectional area (A % ) and ratio of minor-to-major diameters at end-expiration (r D,exp ). Geometric results were compared to clinically available bronchoscopic findings (n = 14). STATISTICAL TESTS Two-sample t-test. RESULTS Maximum A % significantly identified subjects with/without a bronchoscopic TM diagnosis (with: 46.9 ± 10.0%; without: 27.0 ± 5.8%; P < 0.001), as did minimum r D,exp (with: 0.346 ± 0.146; without: 0.671 ± 0.218; P = 0.008). Subjects with severe BPD exhibited a far larger range of minimum r D,exp than subjects with mild/moderate BPD or controls (0.631 ± 0.222, 0.782 ± 0.075, and 0.776 ± 0.030, respectively), while minimum r D,exp was reduced in CDH subjects (0.331 ± 0.171) compared with controls (P < 0.001). DATA CONCLUSION Respiratory-gated UTE MRI can quantitatively and safely evaluate neonatal dynamic tracheal collapse, as validated with the clinical standard of bronchoscopy, without requiring invasive procedures, anesthesia, or ionizing radiation. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:659-667.

Purpose A novel technique is presented for retrospective estimation and removal of gas-phase hyperpolarized Xenon-129 (HP 129 Xe) from images of HP 129 Xe dissolved in the barrier (comprised of parenchymal lung tissue and blood plasma) and red blood cell (RBC) phases. The primary aim is mitigating RF pulse performance limitations on measures of gas exchange (e.g., barrier-gas and RBC-gas ratios). Correction for gas contamination would simplify technical dissemination of HP 129 Xe applications across sites with varying hardware performance, scanner vendors, and models. Methods Digital lung phantom and human subject experiments (N = 8 healthy; N = 1 with idiopathic pulmonary fibrosis) were acquired with 3D radial trajectory and 1-point Dixon spectroscopic imaging to assess the correction method for mitigating barrier and RBC imaging artifacts. Dependence of performance on TE, image SNR, and gas contamination level were characterized. Inter- and intra-subject variation in the dissolved-phase ratios were quantified and compared to human subject experiments before and after correction. Results Gas contamination resulted in image artifacts similar to those in disease that were mitigated after correction in both simulated and human subject data; for simulation experiments performance varied with TE, but was independent of image SNR and the amount of gas contamination. Artifacts and variation of barrier and RBC components were reduced after correction in both simulation and healthy human lungs (barrier, P = 0.01; RBC, P = 0.045). Conclusion The proposed technique significantly reduced regional variations in barrier and RBC ratios, separated using a 1-point Dixon approach, with improved accuracy of dissolved-phase HP 129 Xe images confirmed in simulation experiments.

Background A previous study demonstrated the feasibility of using 3D radial ultrashort echo time (UTE) oxygen-enhanced MRI (UTE OE-MRI) for functional imaging of healthy human lungs. The repeatability of quantitative measures from UTE OE-MRI needs to be established prior to its application in clinical research. Purpose To evaluate repeatability of obstructive patterns in asthma and cystic fibrosis (CF) with UTE OE-MRI with isotropic spatial resolution and full chest coverage. Study Type Volunteer and patient repeatability. Population Eighteen human subjects (five asthma, six CF, and seven normal subjects). Field Strength/Sequence Respiratory-gated free-breathing 3D radial UTE (80 μs) sequence at 1.5T. Assessment Two 3D radial UTE volumes were acquired sequentially under normoxic and hyperoxic conditions. A subset of subjects underwent repeat acquisitions on either the same day or ≤15 days apart. Asthma and CF subjects also underwent spirometry. A workflow including deformable registration and retrospective lung density correction was used to compute 3D isotropic percent signal enhancement (PSE) maps. Median PSE (MPSE) and ventilation defect percent (VDP) of the lung were measured from the PSE map. Statistical Tests The relations between MPSE, VDP, and spirometric measures were assessed using Spearman correlations. The test–retest repeatability was evaluated using Bland–Altman analysis and intraclass correlation coefficients (ICC). Results Ventilation measures in normal subjects (MPSE = 8.0%, VDP = 3.3%) were significantly different from those in asthma (MPSE = 6.0%, P = 0.042; VDP = 21.7%, P = 0.018) and CF group (MPSE = 4.5%, P = 0.0006; VDP = 27.2%, P = 0.002). MPSE correlated significantly with forced expiratory lung volume in 1 second percent predicted (ρ = 0.72, P = 0.017). The ICC of the test–retest VDP and MPSE were both ≥0.90. In all subject groups, an anterior/posterior gradient was observed with higher MPSE and lower VDP in the posterior compared to anterior regions (P ≤ 0.0021 for all comparisons). Data Conclusion 3D radial UTE OE-MRI supports quantitative differentiation of diseased vs. healthy lungs using either whole lung VDP or MPSE with excellent test–retest repeatability. Level of Evidence: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017.

Purpose To demonstrate that ultrashort echo time (UTE) magnetic resonance imaging (MRI) can achieve computed tomography (CT)-like quantification of lung parenchyma in free-breathing, non-sedated neonates. Because infant CTs are used sparingly, parenchymal disease evaluation via UTE MRI has potential for translational impact. Materials and Methods Two neonatal control cohorts without suspected pulmonary morbidities underwent either a research UTE MRI (n = 5; 1.5T) or a clinically-ordered CT (n = 9). Whole-lung means and anterior–posterior gradients of UTE-measured image intensity (arbitrary units, au, normalized to muscle) and CT-measured density (g/cm3) were compared (Mann–Whitney U-test). Separately, a diseased neonatal cohort (n = 5) with various pulmonary morbidities underwent both UTE MRI and CT. UTE intensity and CT density were compared with Spearman correlations within ∼33 anatomically matched regions of interest (ROIs) in each diseased subject, spanning low- to high-density tissues. Radiological classifications were evaluated in all ROIs, with mean UTE intensities and CT densities compared in each classification. Results In control subjects, whole-lung UTE intensities (0.51 ± 0.04 au) were similar to CT densities (0.44 ± 0.09 g/cm3) (P = 0.062), as were UTE (0.021 ± 0.020 au/cm) and CT (0.034 ± 0.024 [g/cm3]/cm) anterior–posterior gradients (P = 0.351). In diseased subjects' ROIs, significant correlations were observed between UTE and CT (P ≤0.007 in each case). Relative differences between UTE and CT were small in all classifications (4–25%). Conclusion These results demonstrate a strong association between UTE image intensity and CT density, both between whole-lung tissue in control patients and regional radiological pathologies in diseased patients. This indicates the potential for UTE MRI to longitudinally evaluate neonatal pulmonary disease and to provide visualization of pathologies similar to CT, without sedation/anesthesia or ionizing radiation. Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:992–1000.

BACKGROUND: MRI of hyperpolarized (129)Xenon (HP (129)Xe) is increasingly utilized for investigating pulmonary function. Solubility of HP (129)Xe in lung tissue, blood plasma (Barrier), and red blood cells (RBC), with unique chemical shifts, enables spectroscopic imaging of potential imaging biomarkers of gas exchange and microstructural pulmonary physiology. PURPOSE: Quantifying global average and regional repeatability of Barrier:gas, RBC:gas and RBC:Barrier ratios derived from dissolved-phase (129)Xe imaging and their dependence on inter-visit changes in lung inflation volume. STUDY TYPE: Prospective. POPULATION: 14 healthy volunteers. One subject was unable to complete the study resulting in 13 subjects for analysis (8 female, 5 male, ages 24–69, 53.8±13.9). FIELD STRENGTH: 1.5 Tesla. ASSESSMENT: Subjects were imaged using a 3D radial 1-point Dixon method to separate Barrier and RBC component signals, at 2 different time points, with approximately 1 month between visits. RBC:Gas, Barrier:Gas and RBC:Barrier measures were compared across time and with pulmonary function tests (PFTs). STATISTICAL TESTS: Repeatablilty was quantified using Bland Atlman plots, coefficient of repeatability, coefficient of variation (CV) and intra-class correlation coefficients (ICC). Dependence of imaging measures on PFTs and lung volume was evaluated using Spearman and Pearson correlation coefficients, respectively. Statistical significance was determined by F-test for intra-class correlations, and t-test for Spearman correlations and regression. RESULTS: Mean RBC:Gas, Barrier:Gas and RBC:Barrier had CVs of 19.2%, 20.0% and 11.5%, respectively, and had significant ICCs, equal to 0.78, 0.79 and 0.92, respectively. Inter-visit differences in RBC:Barrier were significantly correlated with inter-visit differences in DLCO (r=0.93,P=0.007). Significant correlations with inter-visit lung volume differences and inter-visit differences in mean RBC:Gas (r=−0.73,P=0.005) and Barrier:Gas (r=−0.69,P=0.009) were found. DATA CONCLUSION: Three commonly used (129)Xe MRI based measures of gas-exchange show good repeatability, particularly Barrier:RBC ratio which did not depend on lung inflation volume and was strongly associated with inter-visit changes in DLCO.

PURPOSE To determine the feasibility of pulmonary magnetic resonance imaging (MRI) of neonatal lung structures enabled by combining two novel technologies: first, a 3D radial ultrashort echo time (UTE) pulse sequence capable of high spatial resolution full-chest imaging in nonsedated quiet-breathing neonates; and second, a unique, small-footprint 1.5T MRI scanner design adapted for neonatal imaging and installed within the neonatal intensive care unit (NICU). MATERIALS AND METHODS Ten patients underwent MRI within the NICU, in accordance with an approved Institutional Review Board protocol. Five had clinical diagnoses of bronchopulmonary dysplasia (BPD), and five had putatively normal lung function. Pulmonary imaging was performed at 1.5T using 3D radial UTE and standard 3D fast gradient recalled echo (FGRE). Diagnostic quality, presence of motion artifacts, and apparent severity of lung pathology were evaluated by two radiologists. Quantitative metrics were additionally used to evaluate lung parenchymal signal. RESULTS UTE images showed significantly higher signal in lung parenchyma (P < 0.0001) and fewer apparent motion artifacts compared to FGRE (P = 0.046). Pulmonary pathology was more severe in patients diagnosed with BPD relative to controls (P = 0.001). Infants diagnosed with BPD also had significantly higher signal in lung parenchyma, measured using UTE, relative to controls (P = 0.002). CONCLUSION These results demonstrate the technical feasibility of pulmonary MRI in free-breathing, nonsedated infants in the NICU at high, isotropic resolutions approaching that achievable with computed tomography (CT). There is potential for pulmonary MRI to play a role in improving how clinicians understand and manage care of neonatal and pediatric pulmonary diseases. J. Magn. Reson. Imaging 2016. LEVEL OF EVIDENCE 2 J. Magn. Reson. Imaging 2017;45:463-471.

Purpose To implement pulmonary three-dimensional (3D) radial ultrashort echo-time (UTE) MRI in non-sedated, free-breathing neonates and adults with retrospective motion tracking of respiratory and intermittent bulk motion, to obtain diagnostic-quality, respiratory-gated images. Methods Pulmonary 3D radial UTE MRI was performed at 1.5 tesla (T) during free breathing in neonates and adult volunteers for validation. Motion-tracking waveforms were obtained from the time course of each free induction decay's initial point (i.e., k-space center), allowing for respiratory-gated image reconstructions that excluded data acquired during bulk motion. Tidal volumes were calculated from end-expiration and end-inspiration images. Respiratory rates were calculated from the Fourier transform of the motion-tracking waveform during quiet breathing, with comparison to physiologic prediction in neonates and validation with spirometry in adults. Results High-quality respiratory-gated anatomic images were obtained at inspiration and expiration, with less respiratory blurring at the expense of signal-to-noise for narrower gating windows. Inspiration-expiration volume differences agreed with physiologic predictions (neonates; Bland-Altman bias = 6.2 mL) and spirometric values (adults; bias = 0.11 L). MRI-measured respiratory rates compared well with the observed rates (biases = -0.5 and 0.2 breaths/min for neonates and adults, respectively). Conclusions Three-dimensional radial pulmonary UTE MRI allows for retrospective respiratory self-gating and removal of intermittent bulk motion in free-breathing, non-sedated neonates and adults. Magn Reson Med 77:1284-1295, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

The purpose of this work was to quantify the redistribution of ventilation-weighted signal in the lungs of asthmatic subjects during a breath-hold using high temporal-spatial resolution hyperpolarized (HP) He-3 MRI. HP He-3 MRI was used to obtain time-resolved, volumetric images of lung ventilation during breath-hold in 39 human subjects classified as either healthy/nondiseased ( n = 14), mild-to-moderate asthmatic ( n = 17), or severely asthmatic ( n = 8). Signals were normalized to a standard lung volume, so that voxels within the lung from all 39 subjects could be analyzed as a group to increase statistical power and enable semiautomated classification of voxels into 1 of 5 ventilation level categories (ranging from defect to hyperintense). End-inspiratory ventilation distribution and temporal rates of mean signal change for each of the five ventilation categories were compared using ANOVA. Time rates of signal change were hypothesized to represent underlying gas redistribution processes, potentially influenced by disease. We found that mild-to-moderate asthmatic subjects showed the greatest rate of signal change, even though those with severe asthma had the greatest end-inspiration ventilation heterogeneity. The observed results support the existence of local differences in airway resistances associated with the different obstructive patterns in the lungs for severe vs. mild-to-moderate asthmatic subjects.

Functional magnetic resonance imaging (fMRI) time series analysis is typically performed using only the magnitude portion of the data. The phase information remains unused largely due to its sensitivity to temporal variations in the magnetic field unrelated to the functional response of interest. These phase changes are commonly the result of physiologic processes such as breathing or motion either inside or outside the imaging field of view. As a result, although the functional phase response carries pertinent physiological information concerning the vasculature, one aspect of which is the location of large draining veins, the full hemodynamic phase response is understudied and is poorly understood, especially in comparison with the magnitude response. It is likely that the magnitude and phase contain disjoint information, which could be used in tandem to better characterize functional hemodynamics. In this work, simulated and human fMRI experimental data are used to demonstrate how statistical analysis of complex-valued fMRI time series can be problematic, and how robust analysis using these powerful and flexible complex-valued statistics is possible through postprocessing with correction for dynamic magnetic field fluctuations in conjunction with estimated motion parameters. These techniques require no special pulse sequence modifications and can be applied to any complex-valued echo planar imaging data set. This analysis shows that the phase component appears to contain information complementary to that in the magnitude and that processing and analysis techniques are available to investigate it in a robust and flexible manner.

In functional magnetic resonance imaging (fMRI), the process of determining statistically significant brain activation is commonly performed in terms of voxel time series measurements after image reconstruction and magnitude-only time series formation. The image reconstruction and statistical activation processes are treated separately. In this manuscript, a framework is developed so that statistical analysis is performed in terms of the original, prereconstruction, complex-valued k-space measurements. First, the relationship between complex-valued (Fourier) encoded k-space measurements and complex-valued image measurements from (Fourier) reconstructed images is reviewed. Second, the voxel time series measurements are written in terms of the original spatiotemporal k-space measurements utilizing this k-space and image relationship. Finally, voxelwise fMRI activation can be determined in image space in terms of the original k-space measurements. Additionally, the spatiotemporal covariance between reconstructed complex-valued voxel time series can be written in terms of the spatiotemporal covariance between complex-valued k-space measurements. This allows one to utilize the originally measured data in its more natural, acquired state rather than in a transformed state. The effects of modeling preprocessing in k-space on voxel activation and correlation can then be examined.

Image processing is common in functional magnetic resonance imaging (fMRI) and functional connectivity magnetic resonance imaging (fcMRI). Such processing may have deleterious effects on statistical maps computed from the processed images. In this manuscript, we describe a mathematical framework to evaluate the effects of image processing on observed voxel means, covariances and correlations resulting from linear processes on k-space and image space data. We develop linear operators for common image processing operations, including: zero filling, apodization, smoothing and partial Fourier reconstruction; and unmodeled physical processes, including: Fourier encoding anomalies caused by eddy currents, intra-acquisition decay and magnetic field inhomogeneities. With such operators, we theoretically compute the exact image-space means, covariances and correlations which result from their common implementation and verify their behavior in experimental phantom data. Thus, a very powerful framework is described to consider the effects of image processing on observed voxel means, covariances and correlations. With this framework, researchers can theoretically consider observed voxel correlations while understanding the extent of artifactual correlations resulting from image processing. Furthermore, this framework may be utilized in the future to theoretically optimize image acquisition parameters, and examine the order of image processing steps.

To implement pulmonary three-dimensional (3D) radial ultrashort echo-time (UTE) MRI in non-sedated, free-breathing neonates and adults with retrospective motion tracking of respiratory and intermittent bulk motion, to obtain diagnostic-quality, respiratory-gated images.Pulmonary 3D radial UTE MRI was performed at 1.5 tesla (T) during free breathing in neonates and adult volunteers for validation. Motion-tracking waveforms were obtained from the time course of each free induction decay's initial point (i.e., k-space center), allowing for respiratory-gated image reconstructions that excluded data acquired during bulk motion. Tidal volumes were calculated from end-expiration and end-inspiration images. Respiratory rates were calculated from the Fourier transform of the motion-tracking waveform during quiet breathing, with comparison to physiologic prediction in neonates and validation with spirometry in adults.High-quality respiratory-gated anatomic images were obtained at inspiration and expiration, with less respiratory blurring at the expense of signal-to-noise for narrower gating windows. Inspiration-expiration volume differences agreed with physiologic predictions (neonates; Bland-Altman bias = 6.2 mL) and spirometric values (adults; bias = 0.11 L). MRI-measured respiratory rates compared well with the observed rates (biases = -0.5 and 0.2 breaths/min for neonates and adults, respectively).Three-dimensional radial pulmonary UTE MRI allows for retrospective respiratory self-gating and removal of intermittent bulk motion in free-breathing, non-sedated neonates and adults. Magn Reson Med 77:1284-1295, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Magnetic resonance (MR) and positron emission tomography (PET) imaging techniques were coregistered to demonstrate regional ventilation and inflammation in the lung for in vivo, noninvasive evaluation of regional lung function associated with allergic inflammation. Four Brown Norway rats were imaged pre- and post segmental allergen challenge using respiratory-gated He-3 magnetic resonance imaging (MRI) to visualize ventilation, T1-weighted proton MRI to depict inflammatory infiltrate, and [F-18]fluorodeoxyglucose-PET to detect regional glucose metabolism by inflammatory cells. Segmental allergen challenges were delivered and the pre- and postchallenge lung as well as the contralateral lung were compared. Coregistration of the imaging results demonstrated that regions of ventilation defects, inflammatory infiltrate, and increased glucose metabolism correlated well with the site of allergen challenge delivery and inflammatory cell recruitment, as confirmed by histology. This method demonstrates that fusion of functional and anatomic PET and MRI image data may be useful to elucidate the functional correlates of inflammatory processes in the lungs. Magn Reson Med 53:1243–1250, 2005. © 2005 Wiley-Liss, Inc.

As more evidence is presented suggesting that the phase, as well as the magnitude, of functional MRI (fMRI) time series may contain important information and that there are theoretical drawbacks to modeling functional response in the magnitude alone, removing noise in the phase is becoming more important. Previous studies have shown that retrospective correction of noise from physiologic sources can remove significant phase variance and that dynamic main magnetic field correction and regression of estimated motion parameters also remove significant phase fluctuations. In this work, we investigate the performance of physiologic noise regression in a framework along with correction for dynamic main field fluctuations and motion regression. Our findings suggest that including physiologic regressors provides some benefit in terms of reduction in phase noise power, but it is small compared to the benefit of dynamic field corrections and use of estimated motion parameters as nuisance regressors. Additionally, we show that the use of all three techniques reduces phase variance substantially, removes undesirable spatial phase correlations and improves detection of the functional response in magnitude and phase.