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.

A Weighted Head Accelerator Mechanism (WHAM) for visualizing brain rheology using magnetic resonance imaging.

BACKGROUND: A device for moving the head during MR imaging, called a Weighted Head Accelerator Mechanism (WHAM), rotates the head of a supine subject within programmable rotation limits and acceleration profiles. The WHAM can be used with custom MRI sequences to visualize the deformation and recoil of in vivo brain parenchyma with high temporal resolution, allowing element-wise calculation of strain and shear forces in the brain. Unlike previous devices, the WHAM can be configured to provide a wide range of motion and acceleration profiles. NEW METHOD: The WHAM was calibrated using a high-speed camera on a laboratory bench and in 1.5 Tesla and 3.0 Tesla MRI scanners using gel phantoms and human subjects. The MR imaging studies employed a spatial spin-saturation tagging sub-sequence, followed by serial image acquisition. In these studies, 256 images were acquired with a temporal resolution of 2.56 ms. Deformation of the brain was quantified by following the spatial tags in the images. RESULTS: MR imaging showed that the WHAM drove quantifiable brain motions using g forces less than those typically observed in day-to-day activities, with peak accelerations of ∼250 rad/sec2. COMPARISON WITH EXISTING METHODS: The peak pre-contact accelerations and velocities achieved by the WHAM device in this study are both higher than devices used in previous studies, while also allowing for modification of these factors. CONCLUSIONS: MR imaging performed with the WHAM provides a direct method to visualize and quantify "brain slosh" in response to rotational acceleration. Consequently, this approach might find utility in evaluating strategies to protect the brain from mild traumatic brain injury (mTBI).

Preclinical hyperpolarized 129 Xe MRI: ventilation and T2 * mapping in mouse lungs at 7 T using multi-echo flyback UTE.

Fast apparent transverse relaxation (short T2 *) is a common obstacle when attempting to perform quantitative 1 H MRI of the lungs. While T2 * times are longer for pulmonary hyperpolarized (HP) gas functional imaging (in particular for gaseous 129 Xe), T2 * can still lead to quantitative inaccuracies for sequences requiring longer echo times (such as diffusion weighted images) or longer readout duration (such as spiral sequences). This is especially true in preclinical studies, where high magnetic fields lead to shorter relaxation times than are typically seen in human studies. However, the T2 * of HP 129 Xe in the most common animal model of human disease (mice) has not been reported. Herein, we present a multi-echo radial flyback imaging sequence and use it to measure HP 129 Xe T2 * at 7 T under a variety of respiratory conditions. This sequence mitigates the impact of T1 relaxation outside the animal by using multiple gradient-refocused echoes to acquire images at a number of effective echo times for each RF excitation. After validating the sequence using a phantom containing water doped with superparamagnetic iron oxide nanoparticles, we measured the 129 Xe T2 * in vivo for 10 healthy C57Bl/6 J mice and found T2 * ~ 5 ms in the lung airspaces. Interestingly, T2 * was relatively constant over all experimental conditions, and varied significantly with sex, but not age, mass, or the O2 content of the inhaled gas mixture. These results are discussed in the context of T2 * relaxation within porous media.

Mapping and correcting hyperpolarized magnetization decay with radial keyhole imaging.

PURPOSE: Hyperpolarized (HP) media enable biomedical imaging applications that cannot be achieved with conventional MRI contrast agents. Unfortunately, quantifying HP images is challenging, because relaxation and radio-frequency pulsing generate spatially varying signal decay during acquisition. We demonstrate that, by combining center-out k-space sampling with postacquisition keyhole reconstruction, voxel-by-voxel maps of regional HP magnetization decay can be generated with no additional data collection. THEORY AND METHODS: Digital phantom, HP 129 Xe phantom, and in vivo 129 Xe human (N = 4 healthy; N = 2 with cystic fibrosis) imaging was performed using radial sampling. Datasets were reconstructed using a postacquisition keyhole approach in which 2 temporally resolved images were created and used to generate maps of regional magnetization decay following a simple analytical model. RESULTS: Mean, keyhole-derived decay terms showed excellent agreement with the decay used in simulations (R2 = 0.996) and with global attenuation terms in HP 129 Xe phantom imaging (R2 > 0.97). Mean regional decay from in vivo imaging agreed well with global decay values and displayed spatial heterogeneity that matched expected variations in flip angle and oxygen partial pressure. Moreover, these maps could be used to correct variable signal decay across the image volume. CONCLUSIONS: We have demonstrated that center-out trajectories combined with keyhole reconstruction can be used to map regional HP signal decay and to quantitatively correct images. This approach may be used to improve the accuracy of quantitative measures obtained from hyperpolarized media. Although validated with gaseous HP 129 Xe in this work, this technique can be generalized to any hyperpolarized agent.

Optimizing accuracy and precision of micro-coil localization in active-MR tracking.

OBJECTIVE: To examine whether a centroid peak detection algorithm and micro-transmit tracking improve the accuracy and precision of active-MR tracking when combined with previously published strategies of Hadamard Multiplexing and Phase-field Dithering. MATERIALS AND METHODS: The dipole magnetic field of a solenoid tracking coil was modeled and MR spin excitation using both a uniform body coil and the tracking coil was simulated for 5329 orientations of the solenoid coil with respect to B0. A lumenless micro-coil was built onto a rotation platform and MR-tracking accuracy and precision were experimentally assessed for 576 orientations within a 1.5-T MRI scanner. Peak identification strategies (i.e. maximum pixel detection and the centroid pixel method) and transmit modes (body transmit and micro-transmit tracking) were employed and localization accuracy was assessed for each orientation in both simulation and experimentation. RESULTS: The simultaneous use of the centroid pixel method, micro-transmit tracking, Phase-field Dithering, and Hadamard Multiplexing resulted in high MR tracking accuracy and precision: 0.52±0.41 mm and 0.34 mm respectively. Furthermore, all four methods combined offered a tracking error less than the size of the micro-coil, despite the lack of a signal source within the micro-coil. CONCLUSIONS: Micro-transmit tracking and the centroid pixel method improve MR tracking accuracy and precision when combined with Phase-field Dithering and Hadamard Multiplexing compared to using Phase-field Dithering and Hadamard Multiplexing alone.

A novel acoustically quiet coil for neonatal MRI system.

MRI acoustic exposure has the potential to elicit physiological distress and impact development in preterm and term infants. To mitigate this risk, a novel acoustically quiet coil was developed to reduce the sound pressure level experienced by neonates during MR procedures. The new coil has a conventional high-pass birdcage RF design, but is built on a framework of sound abating material. We evaluated the acoustic and MR imaging performance of the quiet coil and a conventional body coil on two small footprint NICU MRI systems. Sound pressure level and frequency response measurements were made for six standard clinical MR imaging protocols. The average sound pressure level, reported for all six imaging pulse sequences, was 82.2 dBA for the acoustically quiet coil, and 91.1 dBA for the conventional body coil. The sound pressure level values measured for the acoustically quiet coil were consistently lower, 9 dBA (range 6-10 dBA) quieter on average. The acoustic frequency response of the two coils showed a similar harmonic profile for all imaging sequences. However, the amplitude was lower for the quiet coil, by as much as 20 dBA.

p62 is required for stem cell/progenitor retention through inhibition of IKK/NF-κB/Ccl4 signaling at the bone marrow macrophage-osteoblast niche.

In the bone marrow (BM), hematopoietic progenitors (HPs) reside in specific anatomical niches near osteoblasts (Obs), macrophages (MΦs), and other cells forming the BM microenvironment. A connection between immunosurveillance and traffic of HP has been demonstrated, but the regulatory signals that instruct the immune regulation of HP circulation are unknown. We discovered that the BM microenvironment deficiency of p62, an autophagy regulator and signal organizer, results in loss of autophagic repression of macrophage contact-dependent activation of Ob NF-κB signaling. Consequently, Ob p62-deficient mice lose bone, Ob Ccl4 expression, and HP chemotaxis toward Cxcl12, resulting in egress of short-term hematopoietic stem cells and myeloid progenitors. Finally, Ccl4 expression and myeloid progenitor egress are reversed by deficiency of the p62 PB1-binding partner Nbr1. A functional "MΦ-Ob niche" is required for myeloid progenitor/short-term stem cell retention, in which Ob p62 is required to maintain NF-κB signaling repression, osteogenesis, and BM progenitor retention.

Characterization of acoustic noise in a neonatal intensive care unit MRI system.

BACKGROUND: To eliminate the medical risks and logistical challenges of transporting infants from the neonatal intensive care unit (NICU) to the radiology department for magnetic resonance imaging, a small-footprint 1.5-T MRI scanner has been developed for neonatal imaging within the NICU. MRI is known to be noisy, and exposure to excessive acoustic noise has the potential to elicit physiological distress and impact development in the term and preterm infant. OBJECTIVE: To measure and compare the acoustic noise properties of the NICU MRI system against those of a conventional 1.5-T MRI system. MATERIALS AND METHODS: We performed sound pressure level measurements in the NICU MRI scanner and in a conventional adult-size whole-body 1.5-T MRI system. Sound pressure level measurements were made for six standard clinical MR imaging protocols. RESULTS: The average sound pressure level value, reported in unweighted (dB) and A-weighted (dBA) decibels for all six imaging pulse sequences, was 73.8 dB and 88 dBA for the NICU scanner, and 87 dB and 98.4 dBA for the conventional MRI scanner. The sound pressure level values measured on the NICU scanner for each of the six MR imaging pulse sequences were consistently and significantly (P = 0.03) lower, with an average difference of 14.2 dB (range 10-21 dB) and 11 dBA (range 5-18 dBA). The sound pressure level frequency response of the two MR systems showed a similar harmonic structure above 200 Hz for all imaging sequences. The amplitude, however, was appreciably lower for the NICU scanner, by as much as 30 dB, for frequencies below 200 Hz. CONCLUSION: The NICU MRI system is quieter than conventional MRI scanners, improving safety for the neonate and facilitating siting of the unit within the NICU.

MRI in the neonatal ICU: initial experience using a small-footprint 1.5-T system.

OBJECTIVE: The objective of our study was to develop a small 1.5-T MRI system for neonatal imaging that can be installed in the neonatal ICU (NICU) and to evaluate its performance in 15 neonates. SUBJECTS AND METHODS: A 1.5-T MR system designed for orthopedic use was adapted for neonatal imaging. Modifications included raising and leveling the magnet, construction of a patient table, and integration of imaging electronics from a high-performance adult-sized scanner. The system was used to perform MR examinations of the brain, abdomen, and chest in 15 medically stable neonates using standard clinical protocols. The scanning time was limited to 60 minutes. The MR examinations were performed without administering sedation to the patients. ECG, heart rate, oxygen saturation, and temperature were monitored continuously throughout the examination. The images were evaluated by two pediatric radiologists for overall study quality, motion artifact, spatial resolution, signal-to-noise ratio, and contrast. RESULTS: All 15 neonates were successfully imaged without sedation. No adverse MRI-related events were noted. In total, 19 brain and seven abdominal examinations were performed. Six chest and two cardiac examinations were also obtained. Gross (versus physiologic) subject motion proved to be the most influential factor in determining overall study and image quality. High-quality diagnostic images were obtained at each anatomic location. CONCLUSION: The customized neonatal MRI system provides state-of-the-art MRI capabilities in the NICU.

Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations.

A gain of function mutation in SHP2, a protein phosphatase encoded by PTPN11, causes Noonan syndrome (NS), which is characterized in part by developmental deficits in both the cardiac and skull fields. Previously, we found that expression of the mutated protein SHP2 Q79R in the heart led to a phenotypic presentation that mimicked some aspects of NS and that this was dependent upon activation of the ERK1/2 pathway. To understand the role that ERK1/2 signaling plays in skull development through signaling in the neural crest, we explored the consequences of Q79R expression in neural crest cells, which contribute to a subset of the bony and cartilaginous structures of the skull. Hyperactivation of ERK1/2 led to craniofacial defects that included smaller skull lengths, greater inner canthal distances, and taller frontal bone heights. In proportion to the smaller skull length, mandibular bone length was also reduced. Inhibition of ERK1/2 hyperactivity as a result of Q79R expression was achieved by injection of the MAPK/ERK kinase inhibitor U0126 during pregnancy. The drug effectively decreased the severity of the craniofacial defects and restored normal skull shape and fontanelle closure. X-ray computer-assisted microtomography analysis of the head confirmed that decreasing ERK1/2 activity led to an abrogation of the craniofacial deficits and brain shape changes that presented in the mice. These data show that normal ERK1/2 signaling in the neural crest is imperative for normal craniofacial development and offer insight into how the heart and craniofacial developmental fields might be affected in some congenital syndromic presentations.