Differential Transcriptomic Signatures of Small Airway Cell Cultures Derived from IPF and COVID-19-Induced Exacerbation of Interstitial Lung Disease.

Idiopathic pulmonary fibrosis (IPF) is a pathological condition wherein lung injury precipitates the deposition of scar tissue, ultimately leading to a decline in pulmonary function. Existing research indicates a notable exacerbation in the clinical prognosis of IPF patients following infection with COVID-19. This investigation employed bulk RNA-sequencing methodologies to describe the transcriptomic profiles of small airway cell cultures derived from IPF and post-COVID fibrosis patients. Differential gene expression analysis unveiled heightened activation of pathways associated with microtubule assembly and interferon signaling in IPF cell cultures. Conversely, post-COVID fibrosis cell cultures exhibited distinctive characteristics, including the upregulation of pathways linked to extracellular matrix remodeling, immune system response, and TGF-ß1 signaling. Notably, BMP signaling levels were elevated in cell cultures derived from IPF patients compared to non-IPF control and post-COVID fibrosis samples. These findings underscore the molecular distinctions between IPF and post-COVID fibrosis, particularly in the context of signaling pathways associated with each condition. A better understanding of the underlying molecular mechanisms holds the promise of identifying potential therapeutic targets for future interventions in these diseases.

Simultaneous multislice EPI prospective motion correction by real-time receiver phase correction and coil sensitivity map interpolation.

PURPOSE: To improve the image reconstruction for prospective motion correction (PMC) of simultaneous multislice (SMS) EPI of the brain, an update of receiver phase and resampling of coil sensitivities are proposed and evaluated. METHODS: A camera-based system was used to track head motion (3 translations and 3 rotations) and dynamically update the scan position and orientation. We derived the change in receiver phase associated with a shifted field of view (FOV) and applied it in real-time to each k-space line of the EPI readout trains. Second, for the SMS reconstruction, we adapted resampled coil sensitivity profiles reflecting the movement of slices. Single-shot gradient-echo SMS-EPI scans were performed in phantoms and human subjects for validation. RESULTS: Brain SMS-EPI scans in the presence of motion with PMC and no phase correction for scan plane shift showed noticeable artifacts. These artifacts were visually and quantitatively attenuated when corrections were enabled. Correcting misaligned coil sensitivity maps improved the temporal SNR (tSNR) of time series by 24% (p = 0.0007) for scans with large movements (up to ˜35 mm and 30°). Correcting the receiver phase improved the tSNR of a scan with minimal head movement by 50% from 50 to 75 for a United Kingdom biobank protocol. CONCLUSION: Reconstruction-induced motion artifacts in single-shot SMS-EPI scans acquired with PMC can be removed by dynamically adjusting the receiver phase of each line across EPI readout trains and updating coil sensitivity profiles during reconstruction. The method may be a valuable tool for SMS-EPI scans in the presence of subject motion.

US regulatory considerations for low field magnetic resonance imaging systems.

Although there has been a resurgence of interest in low field magnetic resonance imaging (MRI) systems in recent years, low field MRI is not a new concept. FDA has a long history of evaluating the safety and effectiveness of MRI systems encompassing a wide range of field strengths. Many systems seeking marketing authorization today include new technological features (such as artificial intelligence), but this does not fundamentally change the regulatory paradigm for MR systems. In this review, we discuss some of the US regulatory considerations for low field magnetic resonance imaging (MRI) systems, including applicability of existing laws and regulations and how the U.S. Food and Drug Administration (FDA) evaluates low field MRI systems for market authorization. We also discuss regulatory considerations in the review of low field MRI systems incorporating novel AI technology. We foresee that MRI systems of all field strengths intended for general diagnostic use will continue to be evaluated for marketing clearance by the metric of substantial equivalence set forth in the premarket notification pathway.

Segmented 3D Echo Planar Acquisition for Rapid Susceptibility-Weighted Imaging: Application to Microhemorrhage Detection in Traumatic Brain Injury.

BACKGROUND: Susceptibility-weighted imaging (SWI) provides superior image contrast of cerebral microhemorrhages (CMBs). It is based on a three-dimensional (3D) gradient echo (GRE) sequence with a relatively long imaging time. PURPOSE: To evaluate whether an accelerated 3D segmented echo planar imaging SWI is comparable to GRE SWI in detecting CMBs in traumatic brain injury (TBI). STUDY TYPE: Prospective. SUBJECTS: Four healthy volunteers and 46 consecutive subjects (38.0 ± 14.4 years, 16 females; 12 mild, 13 moderate, and 7 severe TBI). FIELD STRENGTH/SEQUENCE: A 3 T scanner/3D gradient echo and 3D segmented echo planar imaging (segEPI). ASSESSMENT: Brain images were acquired using GRE and segEPI in a single session (imaging time = 9 minutes 47 seconds and 1 minute 30 seconds, respectively). The signal-to-noise ratio (SNR) calculated from healthy volunteer thalamus and centrum semiovale were compared. CMBs were counted by three raters blinded to diagnostic information. STATISTICAL TESTS: A t-test was used to assess SNR difference. Pearson correlation and Wilcoxon signed-rank test were performed using CMB counts. The intermethod agreement was evaluated using Bland-Altman method. Intermethod and interrater reliabilities of image-based diffuse axonal injury (DAI) diagnoses were evaluated using Cohen's kappa and percent agreement. P ≤ 0.05 was considered statistically significant. RESULTS: Thalamus SNRs were 16.9 ± 2.2 and 16.5 ± 3 for GRE and segEPI (P = 0.84), respectively. Centrum semiovale SNRs were 25.8 ± 4.6 and 21.1 ± 2.7 (P = 0.13). The correlation coefficient of CMBs was 0.93, and differences were not significant (P = 0.56-0.85). For DAI diagnoses, Cohen's kappa was 0.62-0.84 and percent agreement was 85%-94%. DATA CONCLUSION: CMB counts on segEPI and GRE were highly correlated, and DAI diagnosis was made equally effectively. segEPI SWI can potentially replace GRE SWI in detecting TBI CMBs, especially when time constraints are critical. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Quantification of in vivo transverse relaxation of glutamate in the frontal cortex of human brain by radio frequency pulse-driven longitudinal steady state.

PURPOSE: The principal excitatory neurotransmitter glutamate plays an important role in many central nervous system disorders. Because glutamate resides predominantly in glutamatergic neurons, its relaxation properties reflect the intracellular environment of glutamatergic neurons. This study developed an improved echo time-independent technique for measuring transverse relaxation time and demonstrated that this radio frequency (RF)-driven longitudinal steady state technique can reliably measure glutamate transverse relaxation in the frontal cortex, where structural and functional abnormalities have been associated with psychiatric symptoms. METHOD: Bloch and Monte Carlo simulations were performed to improve and optimize the RF-driven, longitudinal, steady-state (MARzss) technique to significantly shorten scan time and increase measurement precision. Optimized four-flip angle measurements at 0°,12°, 24°, and 36° with matched repetition time were used in nine human subjects (6F, 3M; 27-49 years old) at 7 Tesla. Longitudinal and transverse relaxation rates for glutamate were measured from a 2 x 2 x 2 cm3 voxel placed in three different brain regions: gray matter-dominated medial prefrontal lobe, white matter-dominated left frontal lobe, and gray matter-dominated occipital lobe. RESULTS: Compared to the original MARzss technique, the scan time per voxel for measuring glutamate transverse relaxation was shortened by more than 50%. In the medial frontal, left frontal, and occipital voxels, the glutamate T2 was found to be 117.5±12.9 ms (mean ± standard deviation, n = 9), 107.3±12.1 (n = 9), and 124.4±16.6 ms (n = 8), respectively. CONCLUSIONS: The improvements described in this study make the MARZSS technique a viable tool for reliably measuring glutamate relaxation from human subjects in a typical clinical setting. It is expected that this improved technique can be applied to characterize the intracellular environment of glutamatergic neurons in a variety of brain disorders.

7T 1H-MRS in major depressive disorder: a Ketamine Treatment Study.

The glutamatergic modulator ketamine has striking and rapid antidepressant effects in major depressive disorder (MDD), but its mechanism of action remains unknown. Proton magnetic resonance spectroscopy (1H-MRS) is the only non-invasive method able to directly measure glutamate levels in vivo; in particular, glutamate and glutamine metabolite concentrations are separable by 1H-MRS at 7T. This double-blind, placebo-controlled, crossover study that included 1H-MRS scans at baseline and at 24 h post ketamine and post-placebo infusions sought to determine glutamate levels in the pregenual anterior cingulate (pgACC) of 20 medication-free MDD subjects and 17 healthy volunteers (HVs) 24 h post ketamine administration, and to evaluate any other measured metabolite changes, correlates, or predictors of antidepressant response. Metabolite levels were compared at three scan times (baseline, post-ketamine, and post-placebo) in HVs and MDD subjects at 7T using a 1H-MRS sequence specifically optimized for glutamate. No significant between-group differences in 1H-MRS-measured metabolites were observed at baseline. Antidepressant response was not predicted by baseline glutamate levels. Our results suggest that any infusion-induced increases in glutamate at the 24-h post ketamine time point were below the sensitivity of the current technique; that these increases may occur in different brain regions than the pgACC; or that subgroups of MDD subjects may exist that have a differential glutamate response to ketamine.

A novel approach to probing in vivo metabolite relaxation: Linear quantification of spatially modulated magnetization.

PURPOSE: Conventional sequences for metabolite transverse relaxation quantification all generally measure signal changes at different echo times (TEs). However, quantification results obtained via these conventional methods can be very different and are highly dependent on the type of sequence being applied. TE-dependent effects such as diffusion, macromolecule baseline, and J-coupling modulation contribute significantly to these differences. Here, we propose a novel technique-multiple flip angle pulse-driven ratio of longitudinal steady states (MARzss)-for preparing magnetization with T2 /T1 weighting. Using premeasured T1 values, T2 values for metabolites can thereby be determined. The measurement procedure does not require varying TE and is TE independent; T2 , diffusion, and J-coupling effects induced by the readout sequence are cancelled. METHOD: Longitudinal steady states at different flip angles were prepared with trains of radio frequency pulses interspersed with field gradients. The resulting spatially modulated longitudinal magnetization was acquired with a PRESS readout module. A new linear equation for quantification of MARzss was derived from Bloch equations. RESULTS: By implementing this readout-independent method, T2 measurement of brain metabolites at 7T was demonstrated through Bloch simulations, phantom, and in vivo experiments. CONCLUSIONS: The proposed MARzss technique can be used to largely avoid multi-TE associated interference, including diffusion, macromolecules, and J modulation. This MARzss technology, which is uniquely insensitive to readout sequence type and TE, is a promising technique for more accurately probing in vivo metabolite relaxation. Magn Reson Med 79:2491-2499, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

High Field In vivo13C Magnetic Resonance Spectroscopy of Brain by Random Radiofrequency Heteronuclear Decoupling and Data Undersampling.

In vivo13C magnetic resonance spectroscopy (MRS) is a unique and effective tool for studying dynamic human brain metabolism and the cycling of neurotransmitters. One of the major technical challenges for in vivo13C-MRS is the high radio frequency (RF) power necessary for heteronuclear decoupling. In the common practice of in vivo13C-MRS, alkanyl carbons are detected in the spectra range of 10-65 ppm. The amplitude of decoupling pulses has to be significantly greater than the large one-bond 1H-13C scalar coupling (1JCH = 125-145 Hz). Two main proton decoupling methods have been developed: broadband stochastic decoupling and coherent composite or adiabatic pulse decoupling (e.g., WALTZ); the latter is widely used because of its efficiency and superb performance under inhomogeneous B1 field. Because the RF power required for proton decoupling increases quadratically with field strength, in vivo13C-MRS using coherent decoupling is often limited to lowmagnetic fields [<=4 Tesla (T)] to keep the local and averaged specific absorption rate (SAR) under the safety guidelines established by the International Electrotechnical Commission (IEC) and the US Food and Drug Administration (FDA). Alternately, carboxylic/amide carbons are coupled to protons via weak long-range 1H-13C scalar couplings, which can be decoupled using low RF power broadband stochastic decoupling. Recently, the carboxylic/amide 13C-MRS technique using low power random RF heteronuclear decoupling was safely applied to human brain studies at 7T. Here, we review the two major decoupling methods and the carboxylic/amide 13C-MRS with low power decoupling strategy. Further decreases in RF power deposition by frequency-domain windowing and time-domain random under-sampling are also discussed. Low RF power decoupling opens the possibility of performing in vivo13C experiments of human brain at very high magnetic fields (such as 11.7T), where signal-to-noise ratio as well as spatial and temporal spectral resolution are more favorable than lower fields.

Phase-encoded single-voxel magnetic resonance spectroscopy for suppressing outer volume signals at 7 Tesla.

BACKGROUND: Due to imperfect slice profiles, unwanted signals from outside the selected voxel may significantly contaminate metabolite signals acquired using in vivo magnetic resonance spectroscopy (MRS). The use of outer volume suppression may exceed the SAR threshold, especially at high field. OBJECTIVE: We propose using phase-encoding gradients after radiofrequency (RF) excitation to spatially encode unwanted signals originating from outside of the selected single voxel. METHODS: Phase-encoding gradients were added to a standard single voxel point-resolved spectroscopy (PRESS) sequence which selects a 2 × 2 × 2 cm3 voxel. Subsequent spatial Fourier transform was used to encode outer volume signals. Phantom and in vivo experiments were performed using both phase-encoded PRESS and standard PRESS at 7 Tesla. Quantification was performed using fitting software developed in-house. RESULTS: Both phantom and in vivo studies showed that spectra from the phase-encoded PRESS sequence were relatively immune from contamination by oil signals and have more accurate quantification results than spectra from standard PRESS spectra of the same voxel. CONCLUSION: The proposed phase-encoded single-voxel PRESS method can significantly suppress outer volume signals that may appear in the spectra of standard PRESS without increasing RF power deposition.

Reconstruction of randomly under-sampled spectra for in vivo13C magnetic resonance spectroscopy.

PURPOSE: Over the past decade, many techniques have been developed to reduce radiofrequency (RF) power deposition associated with proton decoupling in in vivo Carbon-13 (13C) magnetic resonance spectroscopy (MRS). In this work we propose a new strategy that uses data under-sampling to achieve reduction in RF power deposition. MATERIALS AND METHODS: Essentially, proton decoupling is required only during randomly selected segments of data acquisition. By taking advantage of the sparse spectral pattern of the carboxylic/amide region of in vivo13C spectra of brain, we developed an iterative algorithm to reconstruct spectra from randomly under-sampled data. Fully sampled data were used as references. Reconstructed spectra were compared with the fully sampled references and evaluated using residuals and relative signal intensity errors. RESULTS: Numerical simulations and in vivo experiments at 7Tesla demonstrated that this novel decoupling and data processing strategy can effectively reduce decoupling power deposition by greater than 30%. CONCLUSION: This study proposes and evaluates a novel approach to acquire 13C data with reduced proton decoupling power deposition and reconstruct in vivo13C spectra of carboxylic/amide metabolite signals using randomly under-sampled data. Because proton decoupling is not needed over a significant portion of data acquisition, this novel approach can effectively reduce the required decoupling power and thus SAR. It opens the possibility of performing in vivo13C experiments of human brain at very high magnetic fields.

Spectral fitting using basis set modified by measured B0 field distribution.

This study sought to demonstrate and evaluate a novel spectral fitting method to improve quantification accuracy in the presence of large magnetic field distortion, especially with high fields. MRS experiments were performed using a point-resolved spectroscopy (PRESS)-type sequence at 7 T. A double-echo gradient echo (GRE) sequence was used to acquire B0 maps following MRS experiments. The basis set was modified based on the measured B0 distribution within the MRS voxel. Quantification results were obtained after fitting the measured MRS data using the modified basis set. The proposed method was validated using numerical Monte Carlo simulations, phantom measurements, and comparison of occipital lobe MRS measurements under homogeneous and inhomogeneous magnetic field conditions. In vivo results acquired from voxels placed in thalamus and prefrontal cortex regions close to the frontal sinus agreed well with published values. Instead of noise-amplifying complex division, the proposed method treats field variations as part of the signal model, thereby avoiding inherent statistical bias associated with regularization. Simulations and experiments showed that the proposed approach reliably quantified results in the presence of relatively large magnetic field distortion. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Artifactual microhemorrhage generated by susceptibility weighted image processing.

BACKGROUND: To report that artifactual microhemorrhages are introduced by the two-dimensional (2D) homodyne filtering method of generating susceptibility weighted images (SWI) when open-ended fringelines (OEF) are present in phase data. METHODS: SWI data from 28 traumatic brain injury (TBI) patients was obtained on a 3 tesla clinical Siemens scanner using both the product 3D gradient echo sequence (GRE) with generalized autocalibrating partially parallel acquisition acceleration and an in-house developed segmented echo planar imaging (sEPI) sequence without GRAPPA acceleration. SWI processing included (i) 2D homodyne method implemented on the scanner console and (ii) a 3D Fourier-based phase unwrapping followed by 3D high pass filtering. Original and enhanced magnitude and phase images were carefully reviewed for sites of type III OEFs and microhemorrhages by a neuroradiologist on a PACS workstation. RESULTS: Nineteen of 28 (68%) phase datasets acquired using GRAPPA-accelerated GRE acquisition demonstrated type III OEFs. In SWI images, artifactual microhemorrhages were found on 17 of 19 (89%) cases generated using 2D homodyne processing. Application of a 3D Fourier-based unwrapping method prior HP filtering minimized the appearance of the phase singularities in the enhanced phase, and did not generate microhemorrhage-like artifacts in magnitude images. CONCLUSION: The 2D homodyne filtering method may introduce artifacts mimicking intracranial microhemorrhages in SWI images when type III OEFs are present in phase images. Such artifacts could lead to overestimation of pathology, e.g., TBI. This work demonstrates that 3D phase unwrapping methods minimize this artifact. However, methods to properly combine phase across coils are needed to eliminate this artifact.

Quantitative assessment of susceptibility-weighted imaging processing methods.

PURPOSE: To evaluate different susceptibility-weighted imaging (SWI) phase processing methods and parameter selection, thereby improving understanding of potential artifacts, as well as facilitating choice of methodology in clinical settings. MATERIALS AND METHODS: Two major phase processing methods, homodyne-filtering and phase unwrapping-high pass (HP) filtering, were investigated with various phase unwrapping approaches, filter sizes, and filter types. Magnitude and phase images were acquired from a healthy subject and brain injury patients on a 3T clinical Siemens MRI system. The results were evaluated based on image contrast-to-noise ratio and presence of processing artifacts. RESULTS: When using a relatively small filter size (32 pixels for the matrix size 512 × 512 pixels), all homodyne-filtering methods were subject to phase errors leading to 2% to 3% masked brain area in lower and middle axial slices. All phase unwrapping-filtering/smoothing approaches demonstrated fewer phase errors and artifacts compared to the homodyne-filtering approaches. For performing phase unwrapping, Fourier-based methods, although less accurate, were 2-4 orders of magnitude faster than the PRELUDE, Goldstein, and Quality-guide methods. CONCLUSION: Although homodyne-filtering approaches are faster and more straightforward, phase unwrapping followed by HP filtering approaches perform more accurately in a wider variety of acquisition scenarios.

Spin-echo SS-PARSE: a PARSE MRI method to estimate frequency, R(2) and R(2)(') in a single shot.

Spin-echo signals allow separate measurements of irreversible and reversible relaxation rates in MRI. A spin-echo version of single-shot parameter assessment by retrieval from signal encoding (SE-SS-PARSE) method has been developed to quantitatively and accurately map transverse magnetization magnitude, frequency, irreversible and reversible relaxation rates in a single shot. These image parameters can be applied to fMRI research as well as a number of neuroimaging applications. Following a description of the signal model, this article demonstrates the performance of SE-SS-PARSE in simulations with different noise levels and in phantom experiments. By solving an inverse problem, the estimated irreversible and reversible relaxation rates in SE-SS-PARSE are highly correlated with the reference relaxation rates from a standard technique (correlation coefficients: r(1)=0.9636 for reversible relaxation rate, r(2)=0.9788 for irreversible relaxation rate). The rapid SE-SS-PARSE technique has the potential to monitor transient changes in R(2) and R(2)(') while minimizing motion artifacts and also is free of geometric and ghosting errors. It is expected that this fast scan technique will find applications in both scientific research and clinical diagnosis.