The Introduction of an MR-Conditional Prototype for Cardiopulmonary Bypass Support: Technical Aspects and System Requirements.

INTRODUCTION: The use of cardiopulmonary bypass (CBP; also known as a heart-lung machine) in newborns with complex congenital heart defects may result in brain damage. Magnetic resonance imaging (MRI) assessments cannot be performed safely because the metal components used to construct CBP devices may elicit adverse effects on patients when they are placed in a magnetic field. Thus, this project aimed to develop a prototype MR-conditional circulatory support system that could be used to perform cerebral perfusion studies in animal models. METHODS: The circulatory support device includes a roller pump with two rollers. The ferromagnetic and most of the metal components of the roller pump were modified or replaced, and the drive was exchanged by an air-pressure motor. All materials used to develop the prototype device were tested in the magnetic field according to the American Society for Testing and Materials (ASTM) Standard F2503-13. The technical performance parameters, including runtime/durability as well as achievable speed and pulsation behavior, were evaluated and compared to standard requirements. The behavior of the prototype device was compared with a commercially available pump. RESULTS: The MRI-conditional pump system produced no image artifacts and could be safely operated in the presence of the magnetic field. The system exhibited minor performance-related differences when compared to a standard CPB pump; feature testing revealed that the prototype meets the requirements (i.e., operability, controllability, and flow range) needed to proceed with the planned animal studies. CONCLUSION: This MR-conditional prototype is suitable to perform an open-heart surgery in an animal model to assess brain perfusion in an MR environment.

Bilateral staged magnetic resonance-guided focused ultrasound thalamotomy for the treatment of essential tremor: a case series study.

BACKGROUND: Unilateral magnetic resonance-guided focused ultrasound (FUS) thalamotomy is efficacious for the treatment of medically refractory essential tremor (ET). Viability of bilateral FUS ablation is unexplored. METHODS: Patients diagnosed with medically refractory ET and previously treated with unilateral FUS thalamotomy at least 5 months before underwent bilateral treatment. The timepoints were baseline (before first thalamotomy) and FUS1 and FUS2 (4 weeks before and 6 months after second thalamotomy, respectively). The primary endpoint was safety. Efficacy was assessed through the Clinical Rating Scale for Tremor (CRST), which includes subscales for tremor examination (part A), task performance (part B) and tremor-related disability (part C). RESULTS: Nine patients were treated. No permanent adverse events were registered. Six patients presented mild gait instability and one dysarthria, all resolving within the first few weeks. Three patients reported perioral hypoesthesia, resolving in one case. Total CRST score improved by 71% from baseline to FUS2 (from 52.3±12 to 15.5±9.4, p<0.001), conveying a 67% reduction in bilateral upper limb A+B (from 32.3±7.8 to 10.8±7.3, p=0.001). Part C decreased by 81% (from 16.4±3.6 to 3.1±2.9, p<0.001). Reduction in head and voice tremor was 66% (from 1.2±0.44 to 0.4±0.54, p=0.01) and 45% (from 1.8±1.1 to 1±0.8, p=0.02), respectively. CONCLUSION: Bilateral staged FUS thalamotomy for ET is feasible and might be safe and effective. Voice and head tremor might also improve. A controlled study is warranted.

Investigating the Mechanism of Cyclodextrins in the Treatment of Niemann-Pick Disease Type C Using Crosslinked 2-Hydroxypropyl-ß-cyclodextrin.

Niemann-Pick disease type C (NPC) is a severe disorder that is characterized by intracellular transport abnormalities leading to cytoplasmic accumulation of lipids such as cholesterol and sphingolipids. The compound 2-hydroxypropyl-ß-cyclodextrin (HPßCD) has high cholesterol complexation capacity and is currently under clinical investigation for the NPC treatment. However, due to its short blood half-life, high doses are required to produce a therapeutic effect. In this work, stable polymerized HPßCD is generated to investigate their in vitro mechanisms of action and in vivo effects. Crosslinked CDs (8-312 kDa) display a ninefold greater cholesterol complexation capacity than monomeric HPßCD but are taken up to a lower extent, resulting in an overall comparable in vitro effect. In vivo, the 19.3 kDa HPßCD exhibits a longer half-life than the monomeric HPßCD but it does not increase the life span of Npc1 mice, possibly due to reduced brain penetration. This is circumvented by the application of magnetic resonance imaging-guided low intensity-pulsed focused ultrasound (MRIg-FUS), which increases the brain penetration of the CD. In conclusion, stable polymerized HPßCDs can elucidate CDs' mechanism of action while the use of MRIg-FUS warrants further investigation, as it may be key to harnessing CDs full therapeutic potential in the NPC treatment.

In-vivo validation of interpolation-based phase offset correction in cardiovascular magnetic resonance flow quantification: a multi-vendor, multi-center study.

BACKGROUND: A velocity offset error in phase contrast cardiovascular magnetic resonance (CMR) imaging is a known problem in clinical assessment of flow volumes in vessels around the heart. Earlier studies have shown that this offset error is clinically relevant over different systems, and cannot be removed by protocol optimization. Correction methods using phantom measurements are time consuming, and assume reproducibility of the offsets which is not the case for all systems. An alternative previously published solution is to correct the in-vivo data in post-processing, interpolating the velocity offset from stationary tissue within the field-of-view. This study aims to validate this interpolation-based offset correction in-vivo in a multi-vendor, multi-center setup. METHODS: Data from six 1.5 T CMR systems were evaluated, with two systems from each of the three main vendors. At each system aortic and main pulmonary artery 2D flow studies were acquired during routine clinical or research examinations, with an additional phantom measurement using identical acquisition parameters. To verify the phantom acquisition, a region-of-interest (ROI) at stationary tissue in the thorax wall was placed and compared between in-vivo and phantom measurements. Interpolation-based offset correction was performed on the in-vivo data, after manually excluding regions of spatial wraparound. Correction performance of different spatial orders of interpolation planes was evaluated. RESULTS: A total of 126 flow measurements in 82 subjects were included. At the thorax wall the agreement between in-vivo and phantom was - 0.2 ± 0.6 cm/s. Twenty-eight studies were excluded because of a difference at the thorax wall exceeding 0.6 cm/s from the phantom scan, leaving 98. Before correction, the offset at the vessel as assessed in the phantom was - 0.4 ± 1.5 cm/s, which resulted in a - 5 ± 16% error in cardiac output. The optimal order of the interpolation correction plane was 1st order, except for one system at which a 2nd order plane was required. Application of the interpolation-based correction revealed a remaining offset velocity of 0.1 ± 0.5 cm/s and 0 ± 5% error in cardiac output. CONCLUSIONS: This study shows that interpolation-based offset correction reduces the offset with comparable efficacy as phantom measurement phase offset correction, without the time penalty imposed by phantom scans. TRIAL REGISTRATION: The study was registered in The Netherlands National Trial Register (NTR) under TC 4865 . Registered 19 September 2014. Retrospectively registered.

Functional lesional neurosurgery for tremor: back to the future?

For nearly a century, functional neurosurgery has been applied in the treatment of tremor. While deep brain stimulation has been in the focus of academic interest in recent years, the establishment of incisionless technology, such as MRI-guided high-intensity focused ultrasound, has again stirred interest in lesional approaches.In this article, we will discuss the historical development of surgical technique and targets, as well as the technological state-of-the-art of conventional and incisionless interventions for tremor due to Parkinson's disease, essential and dystonic tremor and tremor related to multiple sclerosis (MS) and midbrain lesions. We will also summarise technique-inherent advantages of each technology and compare their lesion characteristics. From this, we identify gaps in the current literature and derive future directions for functional lesional neurosurgery, in particularly potential trial designs, alternative targets and the unsolved problem of bilateral lesional treatment. The results of a systematic review and meta-analysis of the consistency, efficacy and side effect rate of lesional treatments for tremor are presented separately alongside this article.

[Focused ultrasound ablation as tremor treatment]. / Fokussierter Ultraschall in der Behandlung von Tremor.

BACKGROUND: The development of high-intensity magnetic resonance imaging (MRI)-guided focused ultrasound (MRIgFUS) ablation has widened the spectrum of interventional techniques for stereotactic functional neurosurgery of lesions. This has resulted in novel incisionless intervention approaches for the therapy of tremor disorders. The safety and efficacy is documented by recent study data. OBJECTIVES: This article encompasses a description of the technological basis and typical course of MRIgFUS interventions, a comparison to alternative open or incisionless surgical techniques as well as a review of the current evidence base for MRIgFUS ablation in the context of lesional interventions to treat tremor. MATERIAL AND METHODS: Narrative literature review and comparison. RESULTS: Depending on the surgical target and tremor etiology published trials of MRIgFUS ablation report a reduction of tremor intensity of up to 80% after 6-12 months follow-up without the disadvantages of open brain surgery. CONCLUSION: The MRIgFUS functional neurosurgery is conducted only at a limited number of treatment sites. First data on lesions of the thalamic ventral intermediary nucleus (V.im.) as well as subthalamic fiber tracts have been published. These results indicate an effective and safe treatment of tremor disorders by MRIgFUS ablation. Incisionless lesional surgery using MRIgFUS is a significant addition to the interventional armamentarium for functional stereotactic neurosurgery and a potentially valuable alternative to established interventional therapy options for tremor disorders.

Correcting heat-induced chemical shift distortions in proton resonance frequency-shift thermometry.

PURPOSE: To reconstruct proton resonance frequency-shift temperature maps free of chemical shift distortions. THEORY AND METHODS: Tissue heating created by thermal therapies such as focused ultrasound surgery results in a change in proton resonance frequency that causes geometric distortions in the image and calculated temperature maps, in the same manner as other chemical shift and off-resonance distortions if left uncorrected. We propose an online-compatible algorithm to correct these distortions in 2DFT and echo-planar imaging acquisitions, which is based on a k-space signal model that accounts for proton resonance frequency change-induced phase shifts both up to and during the readout. The method was evaluated with simulations, gel phantoms, and in vivo temperature maps from brain, soft tissue tumor, and uterine fibroid focused ultrasound surgery treatments. RESULTS: Without chemical shift correction, peak temperature and thermal dose measurements were spatially offset by approximately 1 mm in vivo. Spatial shifts increased as readout bandwidth decreased, as shown by up to 4-fold greater temperature hot spot asymmetry in uncorrected temperature maps. In most cases, the computation times to correct maps at peak heat were less than 10 ms, without parallelization. CONCLUSION: Heat-induced proton resonance frequency changes create chemical shift distortions in temperature maps resulting from MR-guided focused ultrasound surgery ablations, but the distortions can be corrected using an online-compatible algorithm. Magn Reson Med 76:172-182, 2016. © 2015 Wiley Periodicals, Inc.

A review of numerical and experimental compensation techniques for skull-induced phase aberrations in transcranial focused ultrasound.

The development of phased array transducers and their integration with magnetic resonance (MR) guidance and thermal monitoring has established transcranial MR-guided focused ultrasound (tcMRgFUS) as an attractive non-invasive modality for neurosurgical interventions. The presence of the skull, however, compromises the efficiency of transcranial FUS (tcFUS) therapy, as its heterogeneous nature and acoustic characteristics induce significant phase aberrations and energy attenuation, especially at the higher acoustic frequencies employed in tcFUS thermal therapy. These aberrations may distort and shift the acoustic focus as well as induce heating at the patient's scalp and skull bone. Phased array transducers feature hundreds of elements that can be driven individually, each with its own phase and amplitude. This feature allows for compensation of skull-induced aberrations by calculation and application of appropriate phase and amplitude corrections. In this paper, we illustrate the importance of precise refocusing and provide a comprehensive review of the wide variety of numerical and experimental techniques that have been used to estimate these corrections.

Comparison of temperature processing methods for monitoring focused ultrasound ablation in the brain.

PURPOSE: To investigate the performance of different reconstruction methods for monitoring temperature changes during transcranial magnetic resonance imaging (MRI)-guided focused ultrasound (MRgFUS). MATERIALS AND METHODS: Four different temperature reconstruction methods were compared in volunteers (without heating) and patients undergoing transcranial MRgFUS: single baseline subtraction, multibaseline subtraction, hybrid single baseline/referenceless reconstruction, and hybrid multibaseline/referenceless reconstruction. Absolute temperature error and temporal temperature uncertainty of the different reconstruction methods were analyzed and compared. RESULTS: Absolute temperature errors and temporal temperature uncertainty were highest with single baseline subtraction and lowest with hybrid multibaseline/referenceless reconstruction in all areas of the brain. Pulsation of the brain and susceptibility changes from tongue motion or swallowing caused substantial temperature errors when single or multibaseline subtraction was used, which were much reduced when the referenceless component was added to the reconstruction. CONCLUSION: Hybrid multibaseline/referenceless thermometry accurately measures temperature changes in the brain with fewer artifacts and errors due to motion than pure baseline subtraction methods.

Application of Zernike polynomials towards accelerated adaptive focusing of transcranial high intensity focused ultrasound.

PURPOSE: To study the phase aberrations produced by human skulls during transcranial magnetic resonance imaging guided focused ultrasound surgery (MRgFUS), to demonstrate the potential of Zernike polynomials (ZPs) to accelerate the adaptive focusing process, and to investigate the benefits of using phase corrections obtained in previous studies to provide the initial guess for correction of a new data set. METHODS: The five phase aberration data sets, analyzed here, were calculated based on preoperative computerized tomography (CT) images of the head obtained during previous transcranial MRgFUS treatments performed using a clinical prototype hemispherical transducer. The noniterative adaptive focusing algorithm [Larrat et al., "MR-guided adaptive focusing of ultrasound," IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57(8), 1734-1747 (2010)] was modified by replacing Hadamard encoding with Zernike encoding. The algorithm was tested in simulations to correct the patients' phase aberrations. MR acoustic radiation force imaging (MR-ARFI) was used to visualize the effect of the phase aberration correction on the focusing of a hemispherical transducer. In addition, two methods for constructing initial phase correction estimate based on previous patient's data were investigated. The benefits of the initial estimates in the Zernike-based algorithm were analyzed by measuring their effect on the ultrasound intensity at the focus and on the number of ZP modes necessary to achieve 90% of the intensity of the nonaberrated case. RESULTS: Covariance of the pairs of the phase aberrations data sets showed high correlation between aberration data of several patients and suggested that subgroups can be based on level of correlation. Simulation of the Zernike-based algorithm demonstrated the overall greater correction effectiveness of the low modes of ZPs. The focal intensity achieves 90% of nonaberrated intensity using fewer than 170 modes of ZPs. The initial estimates based on using the average of the phase aberration data from the individual subgroups of subjects was shown to increase the intensity at the focal spot for the five subjects. CONCLUSIONS: The application of ZPs to phase aberration correction was shown to be beneficial for adaptive focusing of transcranial ultrasound. The skull-based phase aberrations were found to be well approximated by the number of ZP modes representing only a fraction of the number of elements in the hemispherical transducer. Implementing the initial phase aberration estimate together with Zernike-based algorithm can be used to improve the robustness and can potentially greatly increase the viability of MR-ARFI-based focusing for a clinical transcranial MRgFUS therapy.

Transcranial magnetic resonance imaging-guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain.

OBJECT: Recent technological developments open the field of therapeutic application of focused ultrasound to the brain through the intact cranium. The goal of this study was to apply the new transcranial magnetic resonance imaging-guided focused ultrasound (tcMRgFUS) technology to perform noninvasive central lateral thalamotomies (CLTs) as a treatment for chronic neuropathic pain. METHODS: In 12 patients suffering from chronic therapy-resistant neuropathic pain, tcMRgFUS CLT was proposed. In 11 patients, precisely localized thermal ablations of 3-4 mm in diameter were produced in the posterior part of the central lateral thalamic nucleus at peak temperatures between 51 ° C and 64 ° C with the aid of real-time patient monitoring and MR imaging and MR thermometry guidance. The treated neuropathic pain syndromes had peripheral (5 patients) or central (6 patients) origins and covered all body parts (face, arm, leg, trunk, and hemibody). RESULTS: Patients experienced mean pain relief of 49% at the 3-month follow-up (9 patients) and 57% at the 1-year follow-up (8 patients). Mean improvement according to the visual analog scale amounted to 42% at 3 months and 41% at 1 year. Six patients experienced immediate and persisting somatosensory improvements. Somatosensory and vestibular clinical manifestations were always observed during sonication time because of ultrasound-based neuronal activation and/or initial therapeutic effects. Quantitative electroencephalography (EEG) showed a significant reduction in EEG spectral overactivities. Thermal ablation sites showed sharply delineated ellipsoidal thermolesions surrounded by short-lived vasogenic edema. Lesion reconstructions (18 lesions in 9 patients) demonstrated targeting precision within a millimeter for all 3 coordinates. There was 1 complication, a bleed in the target with ischemia in the motor thalamus, which led to the introduction of 2 safety measures, that is, the detection of a potential cavitation by a cavitation detector and the maintenance of sonication temperatures below 60 ° C. CONCLUSIONS: The authors assert that tcMRgFUS represents a noninvasive, precise, and radiation-free neurosurgical technique for the treatment of neuropathic pain. The procedure avoids mechanical brain tissue shift and eliminates the risk of infection. The possibility of applying sonication thermal spots free from trajectory restrictions should allow one to optimize target coverage. The real-time continuous MR imaging and MR thermometry monitoring of targeting accuracy and thermal effects are major factors in optimizing precision, safety, and efficacy in an outpatient context.

Sequence optimization to reduce velocity offsets in cardiovascular magnetic resonance volume flow quantification--a multi-vendor study.

PURPOSE: Eddy current induced velocity offsets are of concern for accuracy in cardiovascular magnetic resonance (CMR) volume flow quantification. However, currently known theoretical aspects of eddy current behavior have not led to effective guidelines for the optimization of flow quantification sequences. This study is aimed at identifying correlations between protocol parameters and the resulting velocity error in clinical CMR flow measurements in a multi-vendor study. METHODS: Nine 1.5T scanners of three different types/vendors were studied. Measurements were performed on a large stationary phantom. Starting from a clinical breath-hold flow protocol, several protocol parameters were varied. Acquisitions were made in three clinically relevant orientations. Additionally, a time delay between the bipolar gradient and read-out, asymmetric versus symmetric velocity encoding, and gradient amplitude and slew rate were studied in adapted sequences as exploratory measurements beyond the protocol. Image analysis determined the worst-case offset for a typical great-vessel flow measurement. RESULTS: The results showed a great variation in offset behavior among scanners (standard deviation among samples of 0.3, 0.4, and 0.9 cm/s for the three different scanner types), even for small changes in the protocol. Considering the absolute values, none of the tested protocol settings consistently reduced the velocity offsets below the critical level of 0.6 cm/s neither for all three orientations nor for all three scanner types. Using multilevel linear model analysis, oblique aortic and pulmonary slices showed systematic higher offsets than the transverse aortic slices (oblique aortic 0.6 cm/s, and pulmonary 1.8 cm/s higher than transverse aortic). The exploratory measurements beyond the protocol yielded some new leads for further sequence development towards reduction of velocity offsets; however those protocols were not always compatible with the time-constraints of breath-hold imaging and flow-related artefacts. CONCLUSIONS: This study showed that with current systems there was no generic protocol which resulted into acceptable flow offset values. Protocol optimization would have to be performed on a per scanner and per protocol basis. Proper optimization might make accurate (transverse) aortic flow quantification possible for most scanners. Pulmonary flow quantification would still need further (offline) correction.

Consensus Statement on High-Intensity Focused Ultrasound for Functional Neurosurgery in Switzerland.

Background: Magnetic resonance-guided high-intensity focused ultrasound (MRgHiFUS) has evolved into a viable ablative treatment option for functional neurosurgery. However, it is not clear yet, how this new technology should be integrated into current and established clinical practice and a consensus should be found about recommended indications, stereotactic targets, patient selection, and outcome measurements. Objective: To sum up and unify current knowledge and clinical experience of Swiss neurological and neurosurgical communities regarding MRgHiFUS interventions for brain disorders to be published as a national consensus paper. Methods: Eighteen experienced neurosurgeons and neurologists practicing in Switzerland in the field of movement disorders and one health physicist representing 15 departments of 12 Swiss clinical centers and 5 medical societies participated in the workshop and contributed to the consensus paper. All experts have experience with current treatment modalities or with MRgHiFUS. They were invited to participate in two workshops and consensus meetings and one online meeting. As part of workshop preparations, a thorough literature review was undertaken and distributed among participants together with a list of relevant discussion topics. Special emphasis was put on current experience and practice, and areas of controversy regarding clinical application of MRgHiFUS for functional neurosurgery. Results: The recommendations addressed lesioning for treatment of brain disorders in general, and with respect to MRgHiFUS indications, stereotactic targets, treatment alternatives, patient selection and management, standardization of reporting and follow-up, and initialization of a national registry for interventional therapies of movement disorders. Good clinical evidence is presently only available for unilateral thalamic lesioning in treating essential tremor or tremor-dominant Parkinson's disease and, to a minor extent, for unilateral subthalamotomy for Parkinson's disease motor features. However, the workgroup unequivocally recommends further exploration and adaptation of MRgHiFUS-based functional lesioning interventions and confirms the need for outcome-based evaluation of these approaches based on a unified registry. MRgHiFUS and DBS should be evaluated by experts familiar with both methods, as they are mutually complementing therapy options to be appreciated for their distinct advantages and potential. Conclusion: This multidisciplinary consensus paper is a representative current recommendation for safe implementation and standardized practice of MRgHiFUS treatments for functional neurosurgery in Switzerland.

High-intensity focused ultrasound for noninvasive functional neurosurgery.

Transcranial magnetic resonance (MR)-guided high-intensity focused ultrasound (tcMRgHIFU) implies a novel, noninvasive treatment strategy for various brain diseases. Nine patients with chronic neuropathic pain were treated with selective medial thalamotomies. Precisely located thermal ablations of 4mm in diameter were produced at peak temperatures of 51 degrees C to 60 degrees C under continuous visual MR guidance and MR thermometry. The resulting lesions are clearly visible on follow-up MR imaging. All treatments were well tolerated, without side effects or neurological deficits. This is the first report on successful clinical application of tcMRgHIFU in functional brain disorders, portraying it as safe and reliable for noninvasive neurosurgical interventions.

Flow measurement by cardiovascular magnetic resonance: a multi-centre multi-vendor study of background phase offset errors that can compromise the accuracy of derived regurgitant or shunt flow measurements.

AIMS: Cardiovascular magnetic resonance (CMR) allows non-invasive phase contrast measurements of flow through planes transecting large vessels. However, some clinically valuable applications are highly sensitive to errors caused by small offsets of measured velocities if these are not adequately corrected, for example by the use of static tissue or static phantom correction of the offset error. We studied the severity of uncorrected velocity offset errors across sites and CMR systems. METHODS AND RESULTS: In a multi-centre, multi-vendor study, breath-hold through-plane retrospectively ECG-gated phase contrast acquisitions, as are used clinically for aortic and pulmonary flow measurement, were applied to static gelatin phantoms in twelve 1.5 T CMR systems, using a velocity encoding range of 150 cm/s. No post-processing corrections of offsets were implemented. The greatest uncorrected velocity offset, taken as an average over a 'great vessel' region (30 mm diameter) located up to 70 mm in-plane distance from the magnet isocenter, ranged from 0.4 cm/s to 4.9 cm/s. It averaged 2.7 cm/s over all the planes and systems. By theoretical calculation, a velocity offset error of 0.6 cm/s (representing just 0.4% of a 150 cm/s velocity encoding range) is barely acceptable, potentially causing about 5% miscalculation of cardiac output and up to 10% error in shunt measurement. CONCLUSION: In the absence of hardware or software upgrades able to reduce phase offset errors, all the systems tested appeared to require post-acquisition correction to achieve consistently reliable breath-hold measurements of flow. The effectiveness of offset correction software will still need testing with respect to clinical flow acquisitions.

Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes.

In glioblastoma, the benefit from temozolomide chemotherapy is largely limited to a subgroup of patients (30-35%) with tumors exhibiting methylation of the promoter region of the O6-methylguanine-DNA methyltransferase (MGMT) gene. In order to allow more patients to benefit from this treatment, we explored magnetic resonance image-guided microbubble-enhanced low-intensity pulsed focused ultrasound (LIFU) to transiently open the blood-brain barrier and deliver a first-in-class liposome-loaded small molecule MGMT inactivator in mice bearing temozolomide-resistant gliomas. We demonstrate that a liposomal O6-(4-bromothenyl)guanine (O6BTG) derivative can efficiently target MGMT, thereby sensitizing murine and human glioma cells to temozolomide in vitro. Furthermore, we report that image-guided LIFU mediates the delivery of the stable liposomal MGMT inactivator in the tumor region resulting in potent MGMT depletion in vivo. Treatment with this new liposomal MGMT inactivator facilitated by LIFU-mediated blood-brain barrier opening reduced tumor growth and significantly prolonged survival of glioma-bearing mice, when combined with temozolomide chemotherapy. Exploring this novel combined approach in the clinic to treat glioblastoma patients with MGMT promoter-unmethylated tumors is warranted.

Closed-loop cavitation control for focused ultrasound-mediated blood-brain barrier opening by long-circulating microbubbles.

Focused ultrasound (FUS) exposure in the presence of microbubbles (MBs) has been successfully used in the delivery of various sizes of therapeutic molecules across the blood-brain barrier (BBB). While acoustic pressure is correlated with the BBB opening size, real-time control of BBB opening to avoid vascular and neural damage is still a challenge. This arises mainly from the variability of FUS-MB interactions due to the variations of animal-specific metabolic environment and specific experimental setup. In this study, we demonstrate a closed-loop cavitation control framework to induce BBB opening for delivering large therapeutic molecules without causing macro tissue damages. To this end, we performed in mice long-term (5 min) cavitation monitoring facilitated by using long-circulating MBs. Monitoring the long-term temporal kinetics of the MBs under varying level of FUS pressure allowed to identify in situ, animal specific activity regimes forming pressure-dependent activity bands. This enables to determine the boundaries of each activity band (i.e. steady oscillation, transition, inertial cavitation) independent from the physical and physiological dynamics of the experiment. However, such a calibration approach is time consuming and to speed up characterization of the in situ, animal specific FUS-MB dynamics, we tested a novel method called 'pre-calibration' that closely reproduces the results of long-term monitoring but with a much shorter duration. Once the activity bands are determined from the pre-calibration method, an operation band can be selected around the desired cavitation dose. To drive cavitation in the selected operation band, we developed an adaptive, closed-loop controller that updates the acoustic pressure between each sonication based on measured cavitation dose. Finally, we quantitatively assessed the safety of different activity bands and validated the proposed methods and controller framework. The proposed framework serves to optimize the FUS pressure instantly to maintain the targeted cavitation level while improving safety control.

Preparation of PEGylated liposomes incorporating lipophilic lomeguatrib derivatives for the sensitization of chemo-resistant gliomas.

Liposomal delivery is a well-established approach to increase the therapeutic index of drugs, mainly in the field of cancer chemotherapy. Here, we report the preparation and characterization of a new liposomal formulation of a derivative of lomeguatrib, a potent O6-methylguanine-DNA methyltransferase (MGMT) inactivator. The drug had been tested in clinical trials to revert chemoresistance, but was associated with a low therapeutic index. A series of lomeguatrib conjugates with distinct alkyl chain lengths - i.e. C12, C14, C16, and C18 - was synthesized, and the MGMT depleting activity as well as cytotoxicity were determined on relevant mouse and human glioma cell lines. Drug-containing liposomes were prepared and characterized in terms of loading and in vitro release kinetics. The lipophilic lomeguatrib conjugates did not exert cytotoxic effects at 5 µM in the mouse glioma cell line and exhibited a similar MGMT depleting activity pattern as lomeguatrib. Overall, drug loading could be improved by up to 50-fold with the lipophilic conjugates, and the slowest leakage was achieved with the C18 derivative. The present data show the applicability of lipophilic lomeguatrib derivatization for incorporation into liposomes, and identify the C18 derivative as the lead compound for in vivo studies.

Spatially-segmented undersampled MRI temperature reconstruction for transcranial MR-guided focused ultrasound.

BACKGROUND: Volumetric thermometry with fine spatiotemporal resolution is desirable to monitor MR-guided focused ultrasound (MRgFUS) procedures in the brain, but requires some form of accelerated imaging. Accelerated MR temperature imaging methods have been developed that undersample k-space and leverage signal correlations over time to suppress the resulting undersampling artifacts. However, in transcranial MRgFUS treatments, the water bath surrounding the skull creates signal variations that do not follow those correlations, leading to temperature errors in the brain due to signal aliasing. METHODS: To eliminate temperature errors due to the water bath, a spatially-segmented iterative reconstruction method was developed. The method fits a k-space hybrid signal model to reconstruct temperature changes in the brain, and a conventional MR signal model in the water bath. It was evaluated using single-channel 2DFT Cartesian, golden angle radial, and spiral data from gel phantom heating, and in vivo 8-channel 2DFT data from a FUS thalamotomy. Water bath signal intensity in phantom heating images was scaled between 0-100% to investigate its effect on temperature error. Temperature reconstructions of retrospectively undersampled data were performed using the spatially-segmented method, and compared to conventional whole-image k-space hybrid (phantom) and SENSE (in vivo) reconstructions. RESULTS: At 100% water bath signal intensity, 3 ×-undersampled spatially-segmented temperature reconstruction error was nearly 5-fold lower than the whole-image k-space hybrid method. Temperature root-mean square error in the hot spot was reduced on average by 27 × (2DFT), 5 × (radial), and 12 × (spiral) using the proposed method. It reduced in vivo error 2 × in the brain for all acceleration factors, and between 2 × and 3 × in the temperature hot spot for 2-4 × undersampling compared to SENSE. CONCLUSIONS: Separate reconstruction of brain and water bath signals enables accelerated MR temperature imaging during MRgFUS procedures with low errors due to undersampling using Cartesian and non-Cartesian trajectories. The spatially-segmented method benefits from multiple coils, and reconstructs temperature with lower error compared to measurements from SENSE-reconstructed images. The acceleration can be applied to increase volumetric coverage and spatiotemporal resolution.