Magnetic Resonance Imaging Assessment of Pulmonary Vascularity in Preterm Infants with Bronchopulmonary Dysplasia.

INTRODUCTION: Pulmonary hypertension often complicates bronchopulmonary dysplasia (BPD) and infants with BPD plus pulmonary hypertension experience higher mortality rates. Current methods to evaluate pulmonary hypertension fail to evaluate the primary cause of this disease. We hypothesize that preterm infants with BPD experience altered pulmonary vascular growth and that magnetic resonance imaging (MRI) can be used to assess vascularity in BPD. METHODS: In this observational cohort study, preterm infants with BPD (n = 33) and controls (n = 6) received a postnatal chest MRI that included a 2-dimensional time-of-flight acquisition. Semi-automatic segmentation was performed to measure vascularity parameters including vascular volume and density (vascular density = vascular volume/lung volume). RESULTS: Vascular volume on MRI increases with post-menstrual age (877.2 mm3/week); however, the vascular density does not significantly change. Vascular volume is higher in infants with more severe BPD (p < 0.002), but vascular density did not significantly change when comparing mild, moderate, and severe BPD. Vascular density in infants with severe BPD requiring tracheostomy trended lower when compared to infants not requiring tracheostomy (0.18 mm3/mm3 vs. 0.27 mm3/mm3, p = 0.06). Vascular density increases with increasing days of inhaled nitric oxide (iNO) therapy in infants with severe BPD (0.02 mm3/mm3/week of iNO, rho = +0.56, p = 0.03). CONCLUSION: Neonatal MRI can be used to assess pulmonary vascularity in preterm infants with BPD. Infants with BPD experience altered vascular growth and while higher vascular volume is associated with more severe BPD, lower vascular density trends toward worse clinical outcomes. Vascular density increases with iNO therapy in severe BPD.

Comparison of weighting algorithms to mitigate respiratory motion in free-breathing neonatal pulmonary radial UTE-MRI.

Background. Thoracoabdominal MRI is limited by respiratory motion, especially in populations who cannot perform breath-holds. One approach for reducing motion blurring in radially-acquired MRI is respiratory gating. Straightforward 'hard-gating' uses only data from a specified respiratory window and suffers from reduced SNR. Proposed 'soft-gating' reconstructions may improve scan efficiency but reduce motion correction by incorporating data with nonzero weight acquired outside the specified window. However, previous studies report conflicting benefits, and importantly the choice of soft-gated weighting algorithm and effect on image quality has not previously been explored. The purpose of this study is to map how variable soft-gated weighting functions and parameters affect signal and motion blurring in respiratory-gated reconstructions of radial lung MRI, using neonates as a model population.Methods. Ten neonatal inpatients with respiratory abnormalities were imaged using a 1.5 T neonatal-sized scanner and 3D radial ultrashort echo-time (UTE) sequence. Images were reconstructed using ungated, hard-gated, and several soft-gating weighting algorithms (exponential, sigmoid, inverse, and linear weighting decay outside the period of interest), with %Nprojrepresenting the relative amount of data included. The apparent SNR (aSNR) and motion blurring (measured by the maximum derivative of image intensity at the diaphragm, MDD) were compared between reconstructions.Results. Soft-gating functions produced higher aSNR and lower MDD than hard-gated images using equivalent %Nproj, as expected. aSNR was not identical between different gating schemes for given %Nproj. While aSNR was approximately linear with %Nprojfor each algorithm, MDD performance diverged between functions as %Nprojdecreased. Algorithm performance was relatively consistent between subjects, except in images with high noise.Conclusion. The algorithm selection for soft-gating has a notable effect on image quality of respiratory-gated MRI; the timing of included data across the respiratory phase, and not simply the amount of data, plays an important role in aSNR. The specific soft-gating function and parameters should be considered for a given imaging application's requirements of signal and sharpness.

Patent Ductus Arteriosus and Lung Magnetic Resonance Imaging Phenotype in Moderate and Severe Bronchopulmonary Dysplasia-Pulmonary Hypertension.

Rationale: Hemodynamically significant patent ductus arteriosus (hsPDA) in premature infants has been associated with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). However, these associations remain incompletely understood. Objectives: To assess the associations between hsPDA duration and clinical outcomes, PH, and phenotypic differences on lung magnetic resonance imaging (MRI). Methods: In this retrospective cohort study, we identified all infants with BPD at <32 weeks' gestation who also underwent research lung MRI at <48 weeks' postmenstrual age (PMA) from 2014 to 2022. Clinical echocardiograms were reviewed for hsPDA and categorized as no hsPDA, hsPDA 1-60 days, and hsPDA >60 days. Outcome variables included BPD severity, PH at 36 weeks' PMA, PH after 36 weeks' PMA in the absence of shunt (PH-pulmonary vascular disease [PVD]), tracheostomy or death, and lung phenotype by MRI via modified Ochiai score, indexed total lung volume, and whole-lung hyperdensity. Logistic regression and ANOVA were used. Measurements and Main Results: In total, 133 infants born at 26.2 ± 1.9 weeks, weighing 776 ± 276 g, were reviewed (47 with no hsPDA, 44 with hsPDA 1-60 days, and 42 with hsPDA >60 d). hsPDA duration > 60 days was associated with BPD severity (P < 0.01), PH at 36 weeks' PMA (adjusted odds ratio [aOR], 9.7 [95% confidence interval (CI), 3.3-28.4]), PH-PVD (aOR, 6.5 [95% CI, 2.3-18.3]), and tracheostomy or death (aOR, 3.0 [95% CI, 1.0-8.8]). Duration of hsPDA > 60 days was associated with higher Ochiai score (P = 0.03) and indexed total lung volume (P = 0.01) but not whole-lung hyperdensity (P = 0.91). Conclusions: In infants with moderate or severe BPD, prolonged exposure to hsPDA is associated with BPD severity, PH-PVD, and increased parenchymal lung disease by MRI.

Tracheomalacia Reduces Aerosolized Drug Delivery to the Lung.

Rationale: Neonates with respiratory issues are frequently treated with aerosolized medications to manage lung disease or facilitate airway clearance. Dynamic tracheal collapse (tracheomalacia [TM]) is a common comorbidity in these patients, but it is unknown whether the presence of TM alters the delivery of aerosolized drugs. Objectives: To quantify the effect of neonatal TM on the delivery of aerosolized drugs. Methods: Fourteen infant subjects with respiratory abnormalities were recruited; seven with TM and seven without TM. Respiratory-gated 3D ultrashort echo time magnetic resonance imaging (MRI) was acquired covering the central airway and lungs. For each subject, a computational fluid dynamics simulation modeled the airflow and particle transport in the central airway based on patient-specific airway anatomy, motion, and airflow rates derived from MRI. Results: Less aerosolized drug reached the distal airways in subjects with TM than in subjects without TM: of the total drug delivered, less particle mass passed through the main bronchi in subjects with TM compared with subjects without TM (33% vs. 47%, p = 0.013). In subjects with TM, more inhaled particles were deposited on the surface of the airway (48% vs. 25%, p = 0.003). This effect becomes greater with larger particle sizes and is significant for particles with a diameter >2 µm (2-5 µm, p ≤ 0.025 and 5-15 µm, p = 0.004). Conclusions: Neonatal patients with TM receive less aerosolized drug delivered to the lungs than subjects without TM. Currently, infants with lung disease and TM may not be receiving adequate and/or expected medication. Particles >2 µm in diameter are likely to deposit on the surface of the airway due to anatomical constrictions such as reduced tracheal and glottal cross-sectional area in neonates with TM. This problem could be alleviated by delivering smaller aerosolized particles.

Evaluation of regional lung mass and growth in neonates with bronchopulmonary dysplasia using ultrashort echo time magnetic resonance imaging.

RATIONALE: Bronchopulmonary dysplasia (BPD) is the most common long term pulmonary morbidity in premature infants and is characterized by impaired lung growth and development. We hypothesized that lung mass growth is a critical factor in determining outcomes in infants with BPD. OBJECTIVES: To measure regional lung density and mass in infants with BPD and compare to clinical variables. METHODS: We conducted a retrospective cohort study of neonates (n = 5 controls, n = 46 with BPD). Lung mass and lung density were calculated using ultrashort echo time (UTE) magnetic resonance imaging (MRI). MEASUREMENTS AND MAIN RESULTS: Lung mass increased with increasing corrected gestational age at the time of MRI in all patients. Total, right, and left lung mass in infants with BPD trended higher than control infants (65.7 vs. 49.9 g, 36.2 vs. 26.8 g, 29.5 vs. 23.1 g, respectively). Babies with BPD who survived to discharge had higher relative lung mass than control infants and infants with BPD that did not survive to discharge (21.6 vs. 15.7 g/kg, p = .01). There was a significant association between the rate of lung mass growth and linear growth at the time of MRI (p = .034). CONCLUSIONS: Infants with BPD are capable of building lung mass over time. While this lung mass growth in infants with BPD may not represent fully functional lung tissue, higher lung mass growth is associated with increased linear growth.

GABAB Receptors Tonically Inhibit Motoneurons and Neurotransmitter Release from Descending and Primary Afferent Fibers.

Motoneurons receive thousands of excitatory and inhibitory synapses from descending tracts and primary afferent fibers. The excitability of these neurons must be precisely regulated to respond adequately to the requirements of the environment. In this context, GABAA and GABAB receptors regulate motoneuron synaptic strength. GABAA and GABAB receptors are expressed on primary afferent fibers and motoneurons, while in the descending afferent fibers, only the GABAB receptors are expressed. However, it remains to be known where the GABA that activates them comes from since the GABAergic interneurons that make axo-axonic contacts with primary afferents have yet to be identified in the descending afferent terminals. Thus, the main aim of the present report was to investigate how GABAB receptors functionally modulate synaptic strength between Ia afferent fibers, excitatory and inhibitory descending fibers of the dorsolateral funiculus, and spinal motoneurons. Using intracellular recordings from the spinal cord of the turtle, we provide evidence that the GABAB receptor antagonist, CGP55845, not only prevents baclofen-induced depression of EPSPs but also increases motoneuron excitability and enhances the synaptic strength between the afferent fibers and motoneurons. The last action of CGP55845 was similar in excitatory and inhibitory descending afferents. Interestingly, the action of baclofen was more intense in the Ia primary afferents than in the descending afferents. Even more, CGP55845 reversed the EPSP depression induced by the increased concentration of ambient GABA produced by interneuron activation and GABA transporter blockade. Immunofluorescence data corroborated the expression of GABAB receptors in the turtle's spinal cord. These findings suggest that GABAB receptors are extrasynaptic and tonically activated on descending afferent fibers and motoneurons by GABA released from astrocytes and GABAergic interneurons in the cellular microenvironment. Finally, our results also suggest that the antispastic action of baclofen may be due to reduced synaptic strength between descending fibers and motoneurons.

Initial feasibility and challenges of hyperpolarized 129 Xe MRI in neonates with bronchopulmonary dysplasia.

PURPOSE: The underlying functional and microstructural lung disease in neonates who are born preterm (bronchopulmonary dysplasia, BPD) remains poorly characterized. Moreover, there is a lack of suitable techniques to reliably assess lung function in this population. Here, we report our preliminary experience with hyperpolarized 129 Xe MRI in neonates with BPD. METHODS: Neonatal intensive care patients with established BPD were recruited (N = 9) and imaged at a corrected gestational age of median:40.7 (range:37.1, 44.4) wk using a 1.5T neonatal scanner. 2D 129 Xe ventilation and diffusion-weighted images and dissolved phase spectroscopy were acquired, alongside 1 H 3D radial UTE. 129 Xe images were acquired during a series of short apneic breath-holds (˜3 s). 1 H UTE images were acquired during tidal breathing. Ventilation defects were manually identified and qualitatively compared to lung structures on UTE. ADCs were calculated on a voxel-wise basis. The signal ratio of the 129 Xe red blood cell (RBC) and tissue membrane (M) resonances from spectroscopy was determined. RESULTS: Spiral-based 129 Xe ventilation imaging showed good image quality and sufficient sensitivity to detect mild ventilation abnormalities in patients with BPD. 129 Xe ADC values were elevated above that expected given healthy data in older children and adults (median:0.046 [range:0.041, 0.064] cm2 s-1 ); the highest value obtained from an extremely pre-term patient. 129 Xe spectroscopy revealed a low RBC/M ratio (0.14 [0.06, 0.21]). CONCLUSION: We have demonstrated initial feasibility of 129 Xe lung MRI in neonates. With further data, the technique may help guide management of infant lung diseases in the neonatal period and beyond.

Magnetic Resonance Imaging-Based Evaluation of Anatomy and Outcome Prediction in Infants with Esophageal Atresia.

INTRODUCTION: There is currently no validated diagnostic modality to characterize the anatomy and predict outcomes of tracheal esophageal defects, such as esophageal atresia (EA) and tracheal esophageal fistulas (TEFs). We hypothesized that ultra-short echo-time MRI would provide enhanced anatomic information allowing for evaluation of specific EA/TEF anatomy and identification of risk factors that predict outcome in infants with EA/TEF. METHODS: In this observational study, 11 infants had pre-repair ultra-short echo-time MRI of the chest completed. Esophageal size was measured at the widest point distal to the epiglottis and proximal to the carina. Angle of tracheal deviation was measured by identifying the initial point of deviation and the farthest lateral point proximal to the carina. RESULTS: Infants without a proximal TEF had a larger proximal esophageal diameter (13.5 ± 5.1 mm vs. 6.8 ± 2.1 mm, p = 0.07) when compared to infants with a proximal TEF. The angle of tracheal deviation in infants without a proximal TEF was larger than infants with a proximal TEF (16.1 ± 6.1° vs. 8.2 ± 5.4°, p = 0.09) and controls (16.1 ± 6.1° vs. 8.0 ± 3.1°, p = 0.005). An increase in the angle of tracheal deviation was positively correlated with duration of post-operative mechanical ventilation (Pearson r = 0.83, p < 0.002) and total duration of post-operative respiratory support (Pearson r = 0.80, p = 0.004). DISCUSSION: These results demonstrate that infants without a proximal TEF have a larger proximal esophagus and a greater angle of tracheal deviation which is directly correlated with the need for longer post-operative respiratory support. Additionally, these results demonstrate that MRI is a useful tool to assess the anatomy of EA/TEF.

Predicting tracheal work of breathing in neonates based on radiological and pulmonary measurements.

Tracheomalacia is an airway condition in which the trachea excessively collapses during breathing. Neonates diagnosed with tracheomalacia require more energy to breathe, and the effect of tracheomalacia can be quantified by assessing flow-resistive work of breathing (WOB) in the trachea using computational fluid dynamics (CFD) modeling of the airway. However, CFD simulations are computationally expensive; the ability to instead predict WOB based on more straightforward measures would provide a clinically useful estimate of tracheal disease severity. The objective of this study is to quantify the WOB in the trachea using CFD and identify simple airway and/or clinical parameters that directly relate to WOB. This study included 30 neonatal intensive care unit subjects (15 with tracheomalacia and 15 without tracheomalacia). All subjects were imaged using ultrashort echo time (UTE) MRI. CFD simulations were performed using patient-specific data obtained from MRI (airway anatomy, dynamic motion, and airflow rates) to calculate the WOB in the trachea. Several airway and clinical measurements were obtained and compared with the tracheal resistive WOB. The maximum percent change in the tracheal cross-sectional area (ρ = 0.560, P = 0.001), average glottis cross-sectional area (ρ = -0.488, P = 0.006), minute ventilation (ρ = 0.613, P < 0.001), and lung tidal volume (ρ = 0.599, P < 0.001) had significant correlations with WOB. A multivariable regression model with three independent variables (minute ventilation, average glottis cross-sectional area, and minimum of the eccentricity index of the trachea) can be used to estimate WOB more accurately (R2 = 0.726). This statistical model may allow clinicians to estimate tracheal resistive WOB based on airway images and clinical data.NEW & NOTEWORTHY The work of breathing due to resistance in the trachea is an important metric for quantifying the effect of tracheal abnormalities such as tracheomalacia, but currently requires complex dynamic imaging and computational fluid dynamics simulation to calculate it. This study produces a method to predict the tracheal work of breathing based on readily available imaging and clinical metrics.

Dynamic imaging using motion-compensated smoothness regularization on manifolds (MoCo-SToRM).

Objective. We introduce an unsupervised motion-compensated reconstruction scheme for high-resolution free-breathing pulmonary magnetic resonance imaging.Approach. We model the image frames in the time series as the deformed version of the 3D template image volume. We assume the deformation maps to be points on a smooth manifold in high-dimensional space. Specifically, we model the deformation map at each time instant as the output of a CNN-based generator that has the same weight for all time-frames, driven by a low-dimensional latent vector. The time series of latent vectors account for the dynamics in the dataset, including respiratory motion and bulk motion. The template image volume, the parameters of the generator, and the latent vectors are learned directly from the k-t space data in an unsupervised fashion.Main results. Our experimental results show improved reconstructions compared to state-of-the-art methods, especially in the context of bulk motion during the scans.Significance. The proposed unsupervised motion-compensated scheme jointly estimates the latent vectors that capture the motion dynamics, the corresponding deformation maps, and the reconstructed motion-compensated images from the raw k-t space data of each subject. Unlike current motion-resolved strategies, the proposed scheme is more robust to bulk motion events during the scan.

Quantitative cardiopulmonary magnetic resonance imaging in neonatal congenital diaphragmatic hernia.

BACKGROUND: Pulmonary arterial hypertension, impaired cardiac function and lung hypoplasia are common in infants with congenital diaphragmatic hernia (CDH) and are associated with increased morbidity and mortality. Robust noninvasive methods to quantify these abnormalities in early infancy are lacking. OBJECTIVE: To determine the feasibility of MRI to quantify cardiopulmonary hemodynamics and function in infants with CDH and to investigate left-right blood flow and lung volume discrepancies. MATERIALS AND METHODS: We conducted a prospective MRI study of 23 neonates (isolated left CDH: 4 pre-repair, 7 post-repair, 3 pre- and post-repair; and 9 controls) performed on a small-footprint 1.5-tesla (T) scanner. We calculated MRI-based pulmonary arterial blood flow, left ventricular eccentricity index, cardiac function and lung volume. Using the Wilcoxon rank sum test for continuous data and Fisher exact test for categorical data, we made pairwise group comparisons. RESULTS: The right-to-left ratios for pulmonary artery blood flow and lung volume were elevated in pre-repair and post-repair CDH versus controls (flow: P<0.005; volume: P<0.05 pre-/post-repair). Eccentricity index at end-systole significantly differed between pre-repair and post-repair CDH (P<0.01) and between pre-repair CDH and controls (P<0.001). CONCLUSION: Cardiopulmonary MRI is a viable method to serially evaluate cardiopulmonary hemodynamics and function in critically ill infants and is useful for capturing left-right asymmetries in pulmonary blood flow and lung volume.

Bronchopulmonary dysplasia from chest radiographs to magnetic resonance imaging and computed tomography: adding value.

Bronchopulmonary dysplasia (BPD) is a common long-term complication of preterm birth. The chest radiograph appearance and survivability have evolved since the first description of BPD in 1967 because of improved ventilation and clinical strategies and the introduction of surfactant in the early 1990s. Contemporary imaging care is evolving with the recognition that comorbidities of tracheobronchomalacia and pulmonary hypertension have a great influence on outcomes and can be noninvasively evaluated with CT and MRI techniques, which provide a detailed evaluation of the lungs, trachea and to a lesser degree the heart. However, echocardiography remains the primary modality to evaluate and screen for pulmonary hypertension. This review is intended to highlight the important findings that chest radiograph, CT and MRI can contribute to precision diagnosis, phenotyping and prognosis resulting in optimal management and therapeutics.

Tracheostomy prediction model in neonatal bronchopulmonary dysplasia via lung and airway MRI.

RATIONALE: Clinical management of neonatal bronchopulmonary dysplasia (BPD) is often imprecise and can vary widely between different institutions and providers, due to limited objective measurements of disease pathology severity. There is critical need to improve guidance on the application and timing of interventional treatments, such as tracheostomy. OBJECTIVES: To generate an imaging-based clinical tool for early identification of those patients with BPD who are likely to require later tracheostomy and long-term mechanical ventilation. METHODS: We conducted a prospective cohort study of n = 61 infants (55 BPD, 6 preterm non-BPD). Magnetic resonance imaging (MRI) scores of lung parenchymal disease were used to create a binomial logistic regression model for predicting tracheostomy requirement. This model was further investigated using clinical variables and MRI-quantified tracheomalacia (TM). MEASUREMENTS AND MAIN RESULTS: A model for predicting tracheostomy requirement was created using MRI parenchymal score. This model had 89% accuracy, 100% positive predictive value (PPV), and 85% negative predictive value (NPV), compared with 84%, 60%, and 83%, respectively, when using only relevant clinical variables. In a subset of patients with airway MRI (n = 36), a model including lung and TM measurements had 83% accuracy, 92% PPV, and 78% NPV. CONCLUSIONS: MRI-based measurements of parenchymal disease and TM can be used to predict need for tracheostomy in infants with BPD, more accurately than clinical factors alone. This prediction model has strong potential as a clinical tool for physicians and families for early determination of tracheostomy requirement.

Fetal lung development via quantitative biomarkers from diffusion MRI and histological validation in rhesus macaques.

OBJECTIVE: To demonstrate sensitivity of diffusion-weighted MRI (DW-MRI) to pulmonary cellular-space changes during normal in utero development using fetal rhesus macaques, compared to histological biomarkers. STUDY DESIGN: In vivo/ex vivo DW-MRI was acquired in 26 fetal rhesus lungs (early-canalicular through saccular stages). Apparent diffusion coefficients (ADC) from MRI and tissue area density (H&E), alveolar type-II cells (ABCA3), and epithelial cells (TTF1) from histology were compared between gestational stages. RESULTS: In vivo/ex vivo ADC correlated with each other (Spearman ρ = 0.47, P = 0.038; Bland-Altman bias = 0.0835) and with area-density (in vivo ρ = -0.56, P = 0.011; ex vivo ρ = -0.83, P < 0.0001). In vivo/ex vivo ADC increased exponentially toward saturation with gestational stage (R2 = 0.49/0.49), while area-density decreased exponentially (R2 = 0.53). ABCA3 and TTF1 stains demonstrated expected fetal cellular development. CONCLUSIONS: Fetal DW-MRI provides a non-invasive biomarker for pulmonary structural maturation, with a strong correlation to histological markers during tissue development in rhesus macaques. This method has strong potential for assessing human fetal development, particularly in patients with pulmonary hypoplasia.

The role of spinal cord extrasynaptic α5 GABAA receptors in chronic pain.

Chronic pain is an incapacitating condition that affects a large population worldwide. Until now, there is no drug treatment to relieve it. The impairment of GABAergic inhibition mediated by GABAA receptors (GABAA R) is considered a relevant factor in mediating chronic pain. Even though both synaptic and extrasynaptic GABAA inhibition are present in neurons that process nociceptive information, the latter is not considered relevant as a target for the development of pain treatments. In particular, the extrasynaptic α5 GABAA Rs are expressed in laminae I-II of the spinal cord neurons, sensory neurons, and motoneurons. In this review, we discuss evidence showing that blockade of the extrasynaptic α5 GABAA Rs reduces mechanical allodynia in various models of chronic pain and restores the associated loss of rate-dependent depression of the Hoffmann reflex. Furthermore, in healthy animals, extrasynaptic α5 GABAA R blockade induces both allodynia and hyperalgesia. These results indicate that this receptor may have an antinociceptive and pronociceptive role in healthy and chronic pain-affected animals, respectively. We propose a hypothesis to explain the relevant role of the extrasynaptic α5 GABAA Rs in the processing of nociceptive information. The data discussed here strongly suggest that this receptor could be a valid pharmacological target to treat chronic pain states.

Case Report: Esophageal Bronchus in a Neonate, With Image, Histological, and Molecular Analysis.

In this case report, we describe the clinical course of a neonate who presented initially with respiratory distress and later with choking during feeding. He was subsequently found to have an esophageal bronchus to the right upper lung lobe, a rare communicating bronchopulmonary foregut malformation. Histological and molecular analysis of the fistula and distal tissues revealed that the proximal epithelium from the esophageal bronchus has characteristics of both esophageal and respiratory epithelia. Using whole exome sequencing of the patient's and parent's DNA, we identified gene variants that are predicted to impact protein function and thus could potentially contribute to the phenotype. These will be the subject of future functional analysis.