Accuracy of 3D real-time MRI temperature mapping in gel phantoms during microwave heating.

BACKGROUND: Interventional magnetic resonance imaging (MRI) can provide a comprehensive setting for microwave ablation of tumors with real-time monitoring of the energy delivery using MRI-based temperature mapping. The purpose of this study was to quantify the accuracy of three-dimensional (3D) real-time MRI temperature mapping during microwave heating in vitro by comparing MRI thermometry data to reference data measured by fiber-optical thermometry. METHODS: Nine phantom experiments were evaluated in agar-based gel phantoms using an in-room MR-conditional microwave system and MRI thermometry. MRI measurements were performed for 700 s (25 slices; temporal resolution 2 s). The temperature was monitored with two fiber-optical temperature sensors approximately 5 mm and 10 mm distant from the microwave antenna. Temperature curves of the sensors were compared to MRI temperature data of single-voxel regions of interest (ROIs) at the sensor tips; the accuracy of MRI thermometry was assessed as the root-mean-squared (RMS)-averaged temperature difference. Eighteen neighboring voxels around the original ROI were also evaluated and the voxel with the smallest temperature difference was additionally selected for further evaluation. RESULTS: The maximum temperature changes measured by the fiber-optical sensors ranged from 7.3 K to 50.7 K. The median RMS-averaged temperature differences in the originally selected voxels ranged from 1.4 K to 3.4 K. When evaluating the minimum-difference voxel from the neighborhood, the temperature differences ranged from 0.5 K to 0.9 K. The microwave antenna and the MRI-conditional in-room microwave generator did not induce relevant radiofrequency artifacts. CONCLUSION: Accurate 3D real-time MRI temperature mapping during microwave heating with very low RMS-averaged temperature errors below 1 K is feasible in gel phantoms. RELEVANCE STATEMENT: Accurate MRI-based volumetric real-time monitoring of temperature distribution and thermal dose is highly relevant in clinical MRI-based interventions and can be expected to improve local tumor control, as well as procedural safety by extending the limits of thermal (e.g., microwave) ablation of tumors in the liver and in other organs. KEY POINTS: Interventional MRI can provide a comprehensive setting for the microwave ablation of tumors. MRI can monitor the microwave ablation using real-time MRI-based temperature mapping. 3D real-time MRI temperature mapping during microwave heating is feasible. Measured temperature errors were below 1 °C in gel phantoms. The active in-room microwave generator did not induce any relevant radiofrequency artifacts.

Increasing the scan-efficiency of pulmonary imaging at 0.55 T using iterative concomitant field and motion-corrected reconstruction.

PURPOSE: To develop an iterative concomitant field and motion corrected (iCoMoCo) reconstruction for isotropic high-resolution UTE pulmonary imaging at 0.55 T. METHODS: A free-breathing golden-angle stack-of-spirals UTE sequence was used to acquire data for 8 min with prototype and commercial 0.55 T MRI scanners. The data was binned into 12 respiratory phases based on superior-inferior navigator readouts. The previously published iterative motion corrected (iMoCo) reconstruction was extended to include concomitant field correction directly in the cost function. The reconstruction was implemented within the Gadgetron framework for inline reconstruction. Data were retrospectively reconstructed to simulate scan times of 2, 4, 6, and 8 min. Image quality was assessed using apparent SNR and image sharpness. The technique was evaluated in healthy volunteers and patients with known lung pathology including coronavirus disease 2019 infection, chronic granulomatous disease, lymphangioleiomyomatosis, and lung nodules. RESULTS: The technique provided diagnostic-quality images, and image quality was maintained with a slight loss in SNR for simulated scan times down to 4 min. Parenchymal apparent SNR was 4.33 ± 0.57, 5.96 ± 0.65, 7.36 ± 0.64, and 7.87 ± 0.65 using iCoMoCo with scan times of 2, 4, 6, and 8 min, respectively. Image sharpness at the diaphragm was comparable between iCoMoCo and reference images. Concomitant field corrections visibly improved the sharpness of anatomical structures away from the isocenter. Inline image reconstruction and artifact correction were achieved in <5 min. CONCLUSION: The proposed iCoMoCo pulmonary imaging technique can generate diagnostic quality images with 1.75 mm isotropic resolution in less than 5 min using a 6-min acquisition, on a 0.55 T scanner.

3D motion strategy for online volumetric thermometry using simultaneous multi-slice EPI at 1.5T: an evaluation study.

PURPOSE: In presence of respiratory motion, temperature mapping is altered by in-plane and through-plane displacements between successive acquisitions together with periodic phase variations. Fast 2D Echo Planar Imaging (EPI) sequence can accommodate intra-scan motion, but limited volume coverage and inter-scan motion remain a challenge during free-breathing acquisition since position offsets can arise between the different slices. METHOD: To address this limitation, we evaluated a 2D simultaneous multi-slice EPI sequence with multiband (MB) acceleration during radiofrequency ablation on a mobile gel and in the liver of a volunteer (no heating). The sequence was evaluated in terms of resulting inter-scan motion, temperature uncertainty and elevation, potential false-positive heating and repeatability. Lastly, to account for potential through-plane motion, a 3D motion compensation pipeline was implemented and evaluated. RESULTS: In-plane motion was compensated whatever the MB factor and temperature distribution was found in agreement during both the heating and cooling periods. No obvious false-positive temperature was observed under the conditions being investigated. Repeatability of measurements results in a 95% uncertainty below 2 °C for MB1 and MB2. Uncertainty up to 4.5 °C was reported with MB3 together with the presence of aliasing artifacts. Lastly, fast simultaneous multi-slice EPI combined with 3D motion compensation reduce residual out-of-plane motion. CONCLUSION: Volumetric temperature imaging (12 slices/700 ms) could be performed with 2 °C accuracy or less, and offer tradeoffs in acquisition time or volume coverage. Such a strategy is expected to increase procedure safety by monitoring large volumes more rapidly for MR-guided thermotherapy on mobile organs.

Real-time automatic temperature regulation during in vivo MRI-guided laser-induced thermotherapy (MR-LITT).

Precise control of tissue temperature during Laser-Induced Thermotherapy (LITT) procedures has the potential to improve the clinical efficiency and safety of such minimally invasive therapies. We present a method to automatically regulate in vivo the temperature increase during LITT using real-time rapid volumetric Magnetic Resonance thermometry (8 slices acquired every second, with an in-plane resolution of 1.4 mmx1.4 mm and a slice thickness of 3 mm) using the proton-resonance frequency (PRF) shift technique. The laser output power is adjusted every second using a feedback control algorithm (proportional-integral-derivative controller) to force maximal tissue temperature in the targeted region to follow a predefined temperature-time profile. The root-mean-square of the difference between the target temperature and the measured temperature ranged between 0.5 °C and 1.4 °C, for temperature increases between + 5 °C to + 30 °C above body temperature and a long heating duration (up to 15 min), showing excellent accuracy and stability of the method. These results were obtained on a 1.5 T clinical MRI scanner, showing a potential immediate clinical application of such a temperature controller during MR-guided LITT.

MRI monitoring of temperature and displacement for transcranial focus ultrasound applications.

BACKGROUND: Transcranial focus ultrasound applications applied under MRI-guidance benefit from unrivaled monitoring capabilities, allowing the recording of real-time anatomical information and biomarkers like the temperature rise and/or displacement induced by the acoustic radiation force. Having both of these measurements could allow for better targeting of brain structures, with improved therapy monitoring and safety. METHOD: We investigated the use of a novel MRI-pulse sequence described previously in Bour et al., (2017) to quantify both the displacement and temperature changes under various ultrasound sonication conditions and in different regions of the brain. The method was evaluated in vivo in a non-human primate under anesthesia using a single-element transducer (f = 850 kHz) in a setting that could mimic clinical applications. Acquisition was performed at 3 T on a clinical imaging system using a modified single-shot gradient echo EPI sequence integrating a bipolar motion-sensitive encoding gradient. Four slices were acquired sequentially perpendicularly or axially to the direction of the ultrasound beam with a 1-Hz update frequency and an isotropic spatial resolution of 2-mm. A total of twenty-four acquisitions were performed in three different sets of experiments. Measurement uncertainty of the sequence was investigated under different acoustic power deposition and in different regions of the brain. Acoustic simulation and thermal modeling were performed and compared to experimental data. RESULTS: The sequence simultaneously provides relevant information about the focal spot location and visualization of heating of brain structures: 1) The sequence localized the acoustic focus both along as well as perpendicular to the ultrasound direction. Tissue displacements ranged from 1 to 2 µm. 2) Thermal rise was only observed at the vicinity of the skull. Temperature increase ranged between 1 and 2 °C and was observed delayed relative the sonication due to thermal diffusion. 3) The fast frame rate imaging was able to highlight magnetic susceptibility artifacts related to breathing, for the most caudal slices. We demonstrated that respiratory triggering successfully restored the sensitivity of the method (from 0.7 µm to 0.2 µm). 4) These results were corroborated by acoustic simulations. CONCLUSIONS: The current rapid, multi-slice acquisition and real-time implementation of temperature and displacement visualization may be useful in clinical practices. It may help defining operational safety margins, improving therapy precision and efficacy. Simulations were in good agreement with experimental data and may thus be used prior treatment for procedure planning.

MR-ARFI-based method for the quantitative measurement of tissue elasticity: application for monitoring HIFU therapy.

Monitoring thermal therapies through medical imaging is essential in order to ensure that they are safe, efficient and reliable. In this paper, we propose a new approach, halfway between MR acoustic radiation force imaging (MR-ARFI) and MR elastography (MRE), allowing for the quantitative measurement of the elastic modulus of tissue in a highly localized manner. It relies on the simulation of the MR-ARFI profile, which depends on tissue biomechanical properties, and on the identification of tissue elasticity through the fitting of experimental displacement images measured using rapid MR-ARFI. This method was specifically developed to monitor MR-guided high intensity focused ultrasound (MRgHIFU) therapy. Elasticity changes were followed during HIFU ablations (N = 6) performed ex vivo in porcine muscle samples, and were compared to temperature changes measured by MR-thermometry. Shear modulus was found to increase consistently and steadily a few seconds after the heating started, and such changes were found to be irreversible. The shear modulus was found to increase from 1.49 ± 0.48 kPa (before ablation) to 3.69 ± 0.93 kPa (after ablation and cooling). Thanks to its ability to perform quantitative elasticity measurements in a highly localized manner around the focal spot, this method proved to be particularly attractive for monitoring HIFU ablations.

Real-time 3D ultrasound based motion tracking for the treatment of mobile organs with MR-guided high-intensity focused ultrasound.

INTRODUCTION: Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) treatments of mobile organs require locking the HIFU beam on the targeted tissue to maximise heating efficiency. We propose to use a standalone 3 D ultrasound (US)-based motion correction technique using the HIFU transducer in pulse-echo mode. Validation of the method was performed in vitro and in vivo in the liver of pig under MR-thermometry. METHODS: 3 D-motion estimation was implemented using ultrasonic speckle-tracking between consecutive acquisitions. Displacement was estimated along four sub-apertures of the HIFU transducer by computing the normalised cross-correlation of backscattered signals followed by a triangulation algorithm. The HIFU beam was steered accordingly and energy was delivered under real-time MR-thermometry (using the proton resonance frequency shift method with online motion compensation and correction of associated susceptibility artefacts). An MR-navigator echo was used to assess the quality of the US-based motion correction. RESULTS: Displacement estimations from US measurements were in good agreement with 1 D MR-navigator echo readings. In vitro, the maximum temperature increase was improved by 37% as compared to experiments performed without motion correction and temperature distribution remained much more focussed. Similar results were reported in vivo, with an increase of 35% on the maximum temperature using this US-based HIFU target locking. CONCLUSION: This standalone 3D US-based motion correction technique is robust and allows maintaining the HIFU focal spot in the presence of motion without adding any burden or complexity to MR thermal imaging. In vitro and in vivo results showed about 35% improvement in heating efficiency when focus position was locked on the target using the proposed technique.

The LC8 Recognition Motif Preferentially Samples Polyproline II Structure in Its Free State.

LC8 is a ubiquitous hub protein that binds intrinsically disordered proteins and promotes their assembly into higher-order complexes. A common feature among the more than 100 essential LC8 binding proteins is that in the 10-12-amino acid recognition sequence there is a conserved QT motif but variable amino acids N- and C-terminal to the QT pair. The sequence diversity among LC8 binding partners implies that structural factors also contribute to specificity. To investigate whether one such factor is the transient secondary structure favored by an LC8 binding sequence, we report here a molecular ensemble description of ICTL, a domain of the dynein intermediate chain that includes binding sites for light chains LC8 and Tctex1. Nuclear magnetic resonance secondary chemical shifts and residual dipolar coupling values combined with ensemble generation and selection algorithms indicate a deviation from statistical (random) coil behavior with an elevated population of polyproline II (PPII) conformations for the ICTL regions that bind LC8 and Tctex1. Independent measurements of one- and three-bond scalar couplings confirm the PPII transient secondary structure propensity. Given that in the IC/Tctex1/LC8 ternary complex ICTL forms a ß-strand at the interface of Tctex1 and LC8, we hypothesize that a PPII conformation may facilitate its initial docking and insertion into the binding cleft of the ß-sheet LC8 dimer interface. Molecular ensemble calculations for intrinsically disordered LC8 binding partners also reveal PPII conformational sampling within and proximate to the LC8 recognition motifs, suggesting that a preference for a PPII conformation is general for LC8 binding partners.

Real-time monitoring of tissue displacement and temperature changes during MR-guided high intensity focused ultrasound.

PURPOSE: The therapy endpoint most commonly used in MR-guided high intensity focused ultrasound is the thermal dose. Although namely correlated with nonviable tissue, it does not account for changes in mechanical properties of tissue during ablation. This study presents a new acquisition sequence for multislice, subsecond and simultaneous imaging of tissue temperature and displacement during ablation. METHODS: A single-shot echo planar imaging sequence was implemented using a pair of motion-encoding gradients, with alternated polarities. A first ultrasound pulse was synchronized on the second lobe of the motion-encoding gradients and followed by continuous sonication to induce a local temperature increase in ex vivo muscle and in vivo on pig liver. Lastly, the method was evaluated in the brain of two volunteers to assess method's precision. RESULTS: For thermal doses higher than the lethal threshold, displacement amplitude was reduced by 21% and 28% at the focal point in muscle and liver, respectively. Displacement value remained nearly constant for nonlethal thermal doses values. The mean standard deviation of temperature and displacement in the brain of volunteers remained below 0.8 °C and 2.5 µm. CONCLUSION: This new fast imaging sequence provides real-time measurement of temperature distribution and displacement at the focus during HIFU ablation. Magn Reson Med 78:1911-1921, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Improved cardiac magnetic resonance thermometry and dosimetry for monitoring lesion formation during catheter ablation.

PURPOSE: A new real-time MR-thermometry pipeline was developed to measure multiple temperature images per heartbeat with 1.6×1.6×3 mm3 spatial resolution. The method was evaluated on 10 healthy volunteers and during radiofrequency ablation (RFA) in sheep. METHODS: Multislice, electrocardiogram-triggered, echo-planar imaging was combined with parallel imaging, under free breathing conditions. In-plane respiratory motion was corrected on magnitude images by an optical flow algorithm. Motion-related susceptibility artifacts were compensated on phase images by an algorithm based on Principal Component Analysis. Correction of phase drift and temporal filter were included in the pipeline implemented in the Gadgetron framework. Contact electrograms were recorded simultaneously with MR thermometry by an MR-compatible ablation catheter. RESULTS: The temporal standard deviation of temperature in the left ventricle remained below 2 °C on each volunteer. In sheep, focal heated regions near the catheter tip were observed on temperature images (maximal temperature increase of 38 °C) during RFA, with contact electrograms of acceptable quality. Thermal lesion dimensions at gross pathology were in agreement with those observed on thermal dose images. CONCLUSION: This fully automated MR thermometry pipeline (five images/heartbeat) provides direct assessment of lesion formation in the heart during catheter-based RFA, which may improve treatment of cardiac arrhythmia by ablation. Magn Reson Med 77:673-683, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Remodeling of the conformational ensemble of the repeat domain of tau by an aggregation enhancer.

Misfolding of the microtubule-associated protein Tau is a hallmark of Alzheimer disease and several other neurodegenerative disorders. Because of the dynamic nature of the Tau protein, little is known about the changes in Tau structure that occur during misfolding. Here we studied the structural consequences upon binding of the repeat domain of Tau, which plays a key role in pathogenic aggregation, to an aggregation enhancer. By combining NMR experiments with molecular simulations we show that binding of the aggregation enhancer polyglutamic acid remodels the conformational ensemble of Tau. Our study thus provides insight into an early event during misfolding of Tau.

Structural Impact of Tau Phosphorylation at Threonine 231.

Phosphorylation of the microtubule-associated protein Tau influences the assembly and stabilization of microtubules and is deregulated in several neurodegenerative diseases. The high flexibility of Tau, however, has prevented an atomic-level description of its phosphorylation-induced structural changes. Employing an extensive set of distance and orientational restraints together with a novel ensemble calculation approach, we determined conformational ensembles of Tau fragments in the non-phosphorylated state and, when phosphorylated at T231/S235 or T231/S235/S237/S238, four important sites of phosphorylation in Alzheimer disease. Comparison of the molecular ensembles showed that phosphorylation of the regulatory T231 does not perturb the backbone conformation of the proximal microtubule-binding (225)KVAVVR(230) motif. Instead, phosphorylated T231 selectively engages in a salt bridge with R230 that can compete with the formation of intermolecular salt bridges to tubulin. Our study provides an ensemble description which will be useful for the analysis of conformational transitions in Tau and other intrinsically disordered proteins.

Predictive atomic resolution descriptions of intrinsically disordered hTau40 and α-synuclein in solution from NMR and small angle scattering.

The development of molecular descriptions of intrinsically disordered proteins (IDPs) is essential for elucidating conformational transitions that characterize common neurodegenerative disorders. We use nuclear magnetic resonance, small angle scattering, and molecular ensemble approaches to characterize the IDPs Tau and α-synuclein. Ensemble descriptions of IDPs are highly underdetermined due to the inherently large number of degrees of conformational freedom compared with available experimental measurements. Using extensive cross-validation we show that five different types of independent experimental parameters are predicted more accurately by selected ensembles than by statistical coil descriptions. The improvement increases in regions whose local sampling deviates from statistical coil, validating the derived conformational description. Using these approaches we identify enhanced polyproline II sampling in aggregation-nucleation sites, supporting suggestions that this region of conformational space is important for aggregation.

Mapping the potential energy landscape of intrinsically disordered proteins at amino acid resolution.

Intrinsically disordered regions are predicted to exist in a significant fraction of proteins encoded in eukaryotic genomes. The high levels of conformational plasticity of this class of proteins endows them with unique capacities to act in functional modes not achievable by folded proteins, but also places their molecular characterization beyond the reach of classical structural biology. New techniques are therefore required to understand the relationship between primary sequence and biological function in this class of proteins. Although dependences of some NMR parameters such as chemical shifts (CSs) or residual dipolar couplings (RDCs) on structural propensity are known, so that sampling regimes are often inferred from experimental observation, there is currently no framework that allows for a statistical mapping of the available Ramachandran space of each amino acid in terms of conformational propensity. In this study we develop such an approach, combining highly efficient conformational sampling with ensemble selection to map the backbone conformational sampling of IDPs on a residue specific level. By systematically analyzing the ability of NMR data to map the conformational landscape of disordered proteins, we identify combinations of RDCs and CSs that can be used to raise conformational degeneracies inherent to different data types, and apply these approaches to characterize the conformational behavior of two intrinsically disordered proteins, the K18 domain from Tau protein and N(TAIL) from measles virus nucleoprotein. In both cases, we identify the enhanced populations of turn and helical regions in key regions of the proteins, as well as contiguous strands that show clear and enhanced polyproline II sampling.