129Xe Image Processing Pipeline: An open-source, graphical user interface application for the analysis of hyperpolarized 129Xe MRI.

PURPOSE: Hyperpolarized 129Xe MRI presents opportunities to assess regional pulmonary microstructure and function. Ongoing advancements in hardware, sequences, and image processing have helped it become increasingly adopted for both research and clinical use. As the number of applications and users increase, standardization becomes crucial. To that end, this study developed an executable, open-source 129Xe image processing pipeline (XIPline) to provide a user-friendly, graphical user interface-based analysis pipeline to analyze and visualize 129Xe MR data, including scanner calibration, ventilation, diffusion-weighted, and gas exchange images. METHODS: The customizable XIPline is designed in MATLAB to analyze data from all three major scanner platforms. Calibration data is processed to calculate optimal flip angle and determine129Xe frequency offset. Data processing includes loading, reconstructing, registering, segmenting, and post-processing images. Ventilation analysis incorporates three common algorithms to calculate ventilation defect percentage and novel techniques to assess defect distribution and ventilation texture. Diffusion analysis features ADC mapping, modified linear binning to account for ADC age-dependence, and common diffusion morphometry methods. Gas exchange processing uses a generalized linear binning for data acquired using 1-point Dixon imaging. RESULTS: The XIPline workflow is demonstrated using analysis from representative calibration, ventilation, diffusion, and gas exchange data. CONCLUSION: The application will reduce redundant effort when implementing new techniques across research sites by providing an open-source framework for developers. In its current form, it offers a robust and adaptable platform for 129Xe MRI analysis to ensure methodological consistency, transparency, and support for collaborative research across multiple sites and MRI manufacturers.

A decay-modeled compressed sensing reconstruction approach for non-Cartesian hyperpolarized 129Xe MRI.

PURPOSE: Hyperpolarized 129Xe MRI benefits from non-Cartesian acquisitions that sample k-space efficiently and rapidly. However, their reconstructions are complex and burdened by decay processes unique to hyperpolarized gas. Currently used gridded reconstructions are prone to artifacts caused by magnetization decay and are ill-suited for undersampling. We present a compressed sensing (CS) reconstruction approach that incorporates magnetization decay in the forward model, thereby producing images with increased sharpness and contrast, even in undersampled data. METHODS: Radio-frequency, T1, and T 2 * $$ {\mathrm{T}}_2^{\ast } $$ decay processes were incorporated into the forward model and solved using iterative methods including CS. The decay-modeled reconstruction was validated in simulations and then tested in 2D/3D-spiral ventilation and 3D-radial gas-exchange MRI. Quantitative metrics including apparent-SNR and sharpness were compared between gridded, CS, and twofold undersampled CS reconstructions. Observations were validated in gas-exchange data collected from 15 healthy and 25 post-hematopoietic-stem-cell-transplant participants. RESULTS: CS reconstructions in simulations yielded images with threefold increases in accuracy. CS increased sharpness and contrast for ventilation in vivo imaging and showed greater accuracy for undersampled acquisitions. CS improved gas-exchange imaging, particularly in the dissolved-phase where apparent-SNR improved, and structure was made discernable. Finally, CS showed repeatability in important global gas-exchange metrics including median dissolved-gas signal ratio and median angle between real/imaginary components. CONCLUSION: A non-Cartesian CS reconstruction approach that incorporates hyperpolarized 129Xe decay processes is presented. This approach enables improved image sharpness, contrast, and overall image quality in addition to up-to threefold undersampling. This contribution benefits all hyperpolarized gas MRI through improved accuracy and decreased scan durations.

Quantifying Spatial Distribution of Ventilation Defects in Multiple Pulmonary Diseases With Hyperpolarized 129Xenon MRI.

BACKGROUND: Hyperpolarized 129Xe MRI assesses lung ventilation, often using the ventilation defect percentage (VDP). Unlike VDP, defect distribution index (DDI) quantifies spatial clustering of defects. PURPOSE: To quantify spatial distribution of 129Xe ventilation defects using DDI across pulmonary diseases. STUDY TYPE: Retrospective. SUBJECTS: Four hundred twenty-one subjects (age = 23.1 ± 17.1, female = 230), comprising healthy controls (N = 60) and subjects with obstructive conditions (asthma [N = 25], bronchiolitis obliterans syndrome [BOS, N = 18], cystic fibrosis [CF, N = 90], lymphangioleiomyomatosis [LAM, N = 50]), restrictive conditions (bleomycin-treated cancer survivors [BLEO, N = 14]; fibrotic lung diseases [FLD, N = 92]), bone marrow transplantation (BMT, N = 53), and bronchopulmonary dysplasia (BPD, N = 19). FIELD STRENGTH/SEQUENCE: 3 T, two-dimensional multi-slice gradient echo. ASSESSMENT: Whole-lung mean DDI was extracted from DDI maps; correlated with VDP (percent of pixels <60% of whole-lung mean signal intensity) and pulmonary function tests (PFTs) including FEV1, FVC, and FEV1/FVC. DDI and DDI/VDP, a marker of defect clustering, were compared across diseases. STATISTICAL TESTS: Pearson correlation analysis and Kruskal-Wallis tests. P < 0.0056 for disease groups, P < 0.0125 for categories. RESULTS: DDI was significantly elevated in BMT (8.3 ± 11.5), BOS (30.1 ± 57.5), BPD (16.0 ± 46.8), CF (15.4 ± 27.2), and LAM (12.6 ± 34.2) compared to controls (1.8 ± 3.1). DDI correlated significantly with VDP in all groups (r ≥ 0.56) except BLEO, and with PFTs in CF, FLD, and LAM (r ≥ 0.56). Obstructive groups had significantly higher mean DDI (14.0 ± 32.0) than controls (1.8 ± 3.0) and restrictive groups (4.0 ± 12.0). DDI/VDP was significantly lower in the restrictive group (0.6 ± 0.6) than controls (0.8 ± 0.6) and obstructive group (1.0 ± 1.0). DATA CONCLUSION: DDI may provide insights into the distribution of ventilation defects across diseases. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Diffusion weighted hyperpolarized 129 Xe MRI of the lung with 2D and 3D (FLORET) spiral.

PURPOSE: To enable efficient hyperpolarized 129 Xe diffusion imaging using 2D and 3D (Fermat Looped, ORthogonally Encoded Trajectories, FLORET) spiral sequences and demonstrate that 129 Xe ADCs obtained using these sequences are comparable to those obtained using a conventional, 2D gradient-recalled echo (GRE) sequence. THEORY AND METHODS: Diffusion-weighted 129 Xe MRI (b-values = 0, 7.5, 15 s/cm2 ) was performed in four healthy volunteers and one subject with lymphangioleiomyomatosis using slice-selective 2D-GRE (scan time = 15 s), slice-selective 2D-Spiral (4 s), and 3D-FLORET (16 s) sequences. Experimental SNRs from b-value = 0 images ( SNR 0 EX $$ SNR{0}_{EX} $$ ) and mean ADC values were compared across sequences. In two healthy subjects, a second b = 0 image was acquired using the 2D-Spiral sequence to map flip angle and correct RF-induced, hyperpolarized signal decay at the voxel level, thus improving regional ADC estimates. RESULTS: Diffusion-weighted images from spiral sequences displayed image quality comparable to 2D-GRE and produced sufficient SNR 0 EX $$ SNR{0}_{EX} $$ (16.8 ± 3.8 for 2D-GRE, 21.2 ± 3.5 for 2D-Spiral, 20.4 ± 3.5 for FLORET) to accurately calculate ADC. Whole-lung means and SDs of ADC obtained via spiral were not significantly different (P > 0.54) from those obtained via 2D-GRE. Finally, 2D-Spiral images were corrected for signal decay, which resulted in a whole-lung mean ADC decrease of ˜15%, relative to uncorrected images. CONCLUSIONS: Relative to GRE, efficient spiral sequences allow 129 Xe diffusion images to be acquired with isotropic lung coverage (3D), higher SNR $$ SNR $$ (2D and 3D), and three-fold faster (2D) within a single breath-hold. In turn, shortened breath-holds enable flip-angle mapping, and thus, allow RF-induced signal decay to be corrected, increasing ADC accuracy.

B1 and magnetization decay correction for hyperpolarized 129 Xe lung imaging using sequential 2D spiral acquisitions.

PURPOSE: To mitigate signal variations caused by inhomogeneous RF and magnetization decay in hyperpolarized 129 Xe ventilation images using flip-angle maps generated from sequential 2D spiral ventilation images acquired in a breath-hold. Images and correction maps were compared with those obtained using conventional, 2D gradient-recalled echo. THEORY AND METHODS: Analytical expressions to predict signal intensity and uncertainty in flip-angle measurements were derived from the Bloch equations and validated by simulations and phantom experiments. Imaging in 129 Xe phantoms and human subjects (1 healthy, 1 cystic fibrosis) was performed using 2D gradient-recalled echo and spiral. For both sequences, consecutive images were acquired with the same slice position during a breath-hold (Cartesian scan time = 15 s; spiral scan time = 5 s). The ratio of these images was used to calculate flip-angle maps and correct intensity inhomogeneities in ventilation images. RESULTS: Mean measured flip angle showed excellent agreement with the applied flip angle in simulations (R2 = 0.99) for both sequences. Mean measured flip angle agreed well with the globally applied flip angle (∼15% difference) in 129 Xe phantoms and in vivo imaging using both sequences. Corrected images displayed reduced coil-dependent signal nonuniformity relative to uncorrected images. CONCLUSIONS: Flip-angle maps were obtained using sequentially acquired, 2D spiral, 129 Xe ventilation images. Signal intensity variations caused by RF-coil inhomogeneity can be corrected by acquiring sequential single-breath ventilation images in less than 5-s scan time. Thus, this method can be used to remove undesirable heterogeneity while preserving physiological effects on the signal distribution.

Improving hyperpolarized 129 Xe ADC mapping in pediatric and adult lungs with uncertainty propagation.

RATIONALE: Hyperpolarized (HP) 129 Xe-MRI provides non-invasive methods to quantify lung function and structure, with the 129 Xe apparent diffusion coefficient (ADC) being a well validated measure of alveolar airspace size. However, the experimental factors that impact the precision and accuracy of HP 129 Xe ADC measurements have not been rigorously investigated. Here, we introduce an analytical model to predict the experimental uncertainty of 129 Xe ADC estimates. Additionally, we report ADC dependence on age in healthy pediatric volunteers. METHODS: An analytical expression for ADC uncertainty was derived from the Stejskal-Tanner equation and simplified Bloch equations appropriate for HP media. Parameters in the model were maximum b-value (bmax ), number of b-values (Nb ), number of phase encoding lines (Nph ), flip angle and the ADC itself. This model was validated by simulations and phantom experiments, and five fitting methods for calculating ADC were investigated. To examine the lower range for 129 Xe ADC, 32 healthy subjects (age 6-40 years) underwent diffusion-weighted 129 Xe MRI. RESULTS: The analytical model provides a lower bound on ADC uncertainty and predicts that decreased signal-to-noise ratio yields increases in relative uncertainty (ϵADC) . As such, experimental parameters that impact non-equilibrium 129 Xe magnetization necessarily impact the resulting ϵADC . The values of diffusion encoding parameters (Nb and bmax ) that minimize ϵADC strongly depend on the underlying ADC value, resulting in a global minimum for ϵADC . Bayesian fitting outperformed other methods (error < 5%) for estimating ADC. The whole-lung mean 129 Xe ADC of healthy subjects increased with age at a rate of 1.75 × 10-4  cm2 /s/yr (p = 0.001). CONCLUSIONS: HP 129 Xe diffusion MRI can be improved by minimizing the uncertainty of ADC measurements via uncertainty propagation. Doing so will improve experimental accuracy when measuring lung microstructure in vivo and should allow improved monitoring of regional disease progression and assessment of therapy response in a range of lung diseases.

Impact of undersampling on preclinical lung T2* mapping with 3D radial UTE MRI at 7 T.

Lung diseases are almost invariably heterogeneous and progressive, making it imperative to capture temporally and spatially explicit information to understand the disease initiation and progression. Imaging the lung with MRI-particularly in the preclinical setting-has historically been challenging because of relatively low lung tissue density, rapid cardiac and respiratory motion, and rapid transverse (T2*) relaxation. These limitations can largely be mitigated using ultrashort-echo-time (UTE) sequences, which are intrinsically robust to motion and avoid significant T2* decay. A significant disadvantage of common radial UTE sequences is that they require inefficient, center-out k-space sampling, resulting in long acquisition times relative to conventional Cartesian sequences. Therefore, pulmonary images acquired with radial UTE are often undersampled to reduce acquisition time. However, undersampling reduces image SNR, introduces image artifacts, and degrades true image resolution. The level of undersampling is further increased if offline gating techniques like retrospective gating are employed, because only a portion (∼40-50%) of the data is used in the final image reconstruction. Here, we explore the impact of undersampling on SNR and T2* mapping in mouse lung imaging using simulation and in-vivo data. Increased scatter in both metrics was noticeable at around 50% sampling. Parenchymal apparent SNR only decreased slightly (average decrease âˆ¼ 1.4) with as little as 10% sampling. Apparent T2* remained similar across undersampling levels, but it became significantly increased (p < 0.05) below 80% sampling. These trends suggest that undersampling can generate quantifiable, but moderate changes in the apparent value of T2*. Moreover, these approaches to assess the impact of undersampling are straightforward to implement and can readily be expanded to assess the quantitative impact of other MR acquisition and reconstruction parameters.

Hyperpolarized 129Xe Lung MRI and Spectroscopy in Mechanically Ventilated Mice.

Hyperpolarized (HP) xenon-129 (129Xe) is an inhaled magnetic resonance imaging (MRI) contrast agent with unique spectral and physical properties that can be exploited to quantify pulmonary physiology, including ventilation, restricted diffusion (alveolar-airspace size), and gas exchange. In humans, it has been used to evaluate disease severity and progression in a variety of pulmonary disorders and is approved for clinical use in the United States and United Kingdom. Beyond its clinical applications, the ability of 129Xe MRI to noninvasively assess pulmonary pathophysiology and provide spatially resolved information is valuable for preclinical research. Among animal models, mice are the most widely used due to the accessibility of genetically modified disease models. Here, 129Xe MRI is promising as a minimally invasive, radiation-free, and sensitive technique to longitudinally monitor lung disease progression and therapy response (e.g., in drug discovery). This technique can extend to preclinical applications by incorporating an MRI-triggered, free-breathing apparatus or mechanical ventilator to deliver gas. Here, we describe the steps and provide checklists to ensure robust data collection and analysis, including creating a thermally polarized xenon gas phantom for quality control, optimizing polarization, animal handling (sedation, intubation, ventilation, and care for mice), and protocols for ventilation, restricted diffusion, and gas exchange data. While preclinical 129Xe MRI can be applied in various animal models (e.g., rats, pigs, sheep), this protocol focuses on mice due to the challenges posed by their small anatomy, which are balanced by their affordability and the availability of many disease models.

Improved Diffusion-Weighted Hyperpolarized 129Xe Lung MRI with Patch-Based Higher-Order, Singular Value Decomposition Denoising.

RATIONALE AND OBJECTIVES: Hyperpolarized xenon (129Xe) MRI is a noninvasive method to assess pulmonary structure and function. To measure lung microstructure, diffusion-weighted imaging-commonly the apparent diffusion coefficient (ADC)-can be employed to map changes in alveolar-airspace size resulting from normal aging and pulmonary disease. However, low signal-to-noise ratio (SNR) decreases ADC measurement certainty, and biases ADC to spuriously low values. Further, these challenges are most severe in regions of the lung where alveolar simplification or emphysematous remodeling generate abnormally high ADCs. Here, we apply Global Local Higher Order Singular Value Decomposition (GLHOSVD) denoising to enhance image SNR, thereby reducing uncertainty and bias in diffusion measurements. MATERIALS AND METHODS: GLHOSVD denoising was employed in simulated images and gas phantoms with known diffusion coefficients to validate its effectiveness and optimize parameters for analysis of diffusion-weighted 129Xe MRI. GLHOSVD was applied to data from 120 subjects (34 control, 39 cystic fibrosis (CF), 27 lymphangioleiomyomatosis (LAM), and 20 asthma). Image SNR, ADC, and distributed diffusivity coefficient (DDC) were compared before and after denoising using Wilcoxon signed-rank analysis for all images. RESULTS: Denoising significantly increased SNR in simulated, phantom, and in-vivo images, showing a greater than 2-fold increase (p < 0.001) across diffusion-weighted images. Although mean ADC and DDC remained unchanged (p > 0.05), ADC and DDC standard deviation decreased significantly in denoised images (p < 0.001). CONCLUSION: When applied to diffusion-weighted 129Xe images, GLHOSVD improved image quality and allowed airspace size to be quantified in high-diffusion regions of the lungs that were previously inaccessible to measurement due to prohibitively low SNR, thus providing insights into disease pathology.

Quantifying abnormal alveolar microstructure in cystic fibrosis lung disease via hyperpolarized 129Xe diffusion MRI.

RATIONALE: Cystic Fibrosis (CF) progresses through recurrent infection and inflammation, causing permanent lung function loss and airway remodeling. CT scans reveal abnormally low-density lung parenchyma in CF, but its microstructural nature remains insufficiently explored due to clinical CT limitations. To this end, diffusion-weighted 129Xe MRI is a non-invasive and validated measure of lung microstructure. In this work, we investigate microstructural changes in people with CF (pwCF) relative to age-matched, healthy subjects using comprehensive imaging and analysis involving pulmonary-function tests (PFTs), and 129Xe MRI. METHODS: 38 healthy subjects (age 6-40; 17.2 ± 9.5 years) and 39 pwCF (age 6-40; 15.6 ± 8.0 years) underwent 129Xe-diffusion MRI and PFTs. The distribution of diffusion measurements (i.e., apparent diffusion coefficients (ADC) and morphometric parameters) was assessed via linear binning (LB). The resulting volume percentages of bins were compared between controls and pwCF. Mean ADC and morphometric parameters were also correlated with PFTs. RESULTS: Mean whole-lung ADC correlated significantly with age (P < 0.001) for both controls and CF, and with PFTs (P < 0.05) specifically for pwCF. Although there was no significant difference in mean ADC between controls and pwCF (P = 0.334), age-adjusted LB indicated significant voxel-level diffusion (i.e., ADC and morphometric parameters) differences in pwCF compared to controls (P < 0.05). CONCLUSIONS: 129Xe diffusion MRI revealed microstructural abnormalities in CF lung disease. Smaller microstructural size may reflect compression from overall higher lung density due to interstitial inflammation, fibrosis, or other pathological changes. While elevated microstructural size may indicate emphysema-like remodeling due to chronic inflammation and infection.

Short-term structural and functional changes after airway clearance therapy in cystic fibrosis.

BACKGROUND: Airway clearance therapy (ACT) with a high-frequency chest wall oscillation (HFCWO) vest is a common but time-consuming treatment. Its benefit to quality of life for cystic fibrosis (CF) patients is well established but has been questioned recently as new highly-effective modulator therapies begin to change the treatment landscape. 129Xe ventilation MRI has been shown to be very sensitive to lung obstruction in mild CF disease, making it an ideal tool to identify and quantify subtle, regional changes. METHODS: 20 CF patients (ages 20.7 ± 5.1 years) refrained from performing ACT before arriving for a single-day visit. Multiple-breath washout (MBW), spirometry, Xe MRI, and ultrashort echo-time (UTE) MRI were obtained twice-before and after patients performed ACT using their prescribed HFCWO vests (average 4.7 ± 0.5 h). UTE MRIs were scored for structural abnormalities, and standard functional metrics were obtained from MBW, spirometry, and Xe MRI-FEV1,pp, LCI2.5, and VDPN4, respectively. RESULTS: Spirometry and Xe MRI detected significant improvements in lung function post-ACT. 15/20 patients showed improvements from a baseline median of 92% FEV1,pp. Similarly, 16/20 patients showed improvements in Xe MRI from a baseline median of 15.2% VDPN4. Average individual changes were +2.6% in FEV1,pp and -1.3% in VDPN4, but without spatial correlations to easily-identifiable causative structural defects (e.g. mucus plugs or bronchiectasis) on UTE MRI. CONCLUSIONS: Lung function improved after a single instance of HFCWO-vest ACT and was detectable by spirometry and Xe MRI. The only common structural abnormalities were mucus plugs, which corresponded to ventilation defects, but ventilation defects were often present without visible abnormalities.

Atypical Case of Schmidt's Syndrome in a Young Male.

Autoimmune polyendocrine syndrome type 2, also known as Schmidt's syndrome, is a rare autosomal dominant life-threatening syndrome. It is defined by the presence of Addison's disease in combination with at least one of the known autoimmune diseases: thyroid autoimmune disease, type 1 diabetes, and hypogonadism. It is more common in middle-aged females and is treatable if diagnosed early. However, in this case, we report Schmidt's syndrome in a young male without a family history. A 20-year-old male with a past medical history of hypothyroidism, adrenal insufficiency, and type 1 diabetes presented to the emergency department (ED) feeling lethargic, somnolent, and diaphoretic. Laboratory blood tests showed elevated thyroid-stimulating hormone, hyperkalemia of 6.4 mmol/L, and hyponatremia of 131 mmol/l indicating an Addisonian crisis. The patient had low blood glucose (at home: 60 mg/dL, and at ED: 85 mg/dL), hypotensive blood pressure of approximately 85/55 mmHg, and a peaked T-wave on EKG, which were consistent with the diagnosis of Schmidt's syndrome. Based on the laboratory findings and history, the patient was diagnosed with polyendocrine syndrome Type 2 (Schmidt's syndrome). The patient was treated for adrenal insufficiency first followed by thyroid insufficiency. Schmidt's syndrome is a rare disease and difficult to diagnose because the presentation depends on which gland is initially involved. A few cases have been reported in the literature of atypical presentations of Schmidt's syndrome. Therefore, this case report can contribute to the medical literature on Schmidt's syndrome, which can help in early diagnosis and improve patient outcomes.

Categorizing cortical dysplasia lesions for surgical outcome using network functional connectivity.

OBJECTIVE: Focal cortical dysplasia (FCD) is often associated with drug-resistant epilepsy, leading to a recommendation to surgically remove the seizure focus. Predicting outcome for resection of FCD is challenging, requiring a new approach. Lesion-symptom mapping is a powerful and broadly applicable method for linking neurological symptoms or outcomes to damage to particular brain regions. In this work, the authors applied lesion network mapping, an expansion of the traditional approach, to search for the association of lesion network connectivity with surgical outcomes. They hypothesized that connectivity of lesion volumes, preoperatively identified by MRI, would associate with seizure outcomes after surgery in a pediatric cohort with FCD. METHODS: This retrospective study included 21 patients spanning the ages of 3 months to 17.7 years with FCD lesions who underwent surgery for drug-resistant epilepsy. The mean brain-wide functional connectivity map of each lesion volume was assessed across a database of resting-state functional MRI data from healthy children (spanning approximately 2.9 to 18.9 years old) compiled at the authors' institution. Lesion connectivity maps were averaged across age and sex groupings from the database and matched to each patient. The authors sought to associate voxel-wise differences in these maps with subject-specific surgical outcome (seizure free vs persistent seizures). RESULTS: Lesion volumes with persistent seizures after surgery tended to have stronger connectivity to attention and motor networks and weaker connectivity to the default mode network compared with lesion volumes with seizure-free surgical outcome. CONCLUSIONS: Network connectivity-based lesion-outcome mapping may offer new insight for determining the impact of lesion volumes discerned according to both size and specific location. The results of this pilot study could be validated with a larger set of data, with the ultimate goal of allowing examination of lesions in patients with FCD and predicting their surgical outcomes.