MR-guided Focused Ultrasound System Research Articles

Improving Sonication Efficiency in Transcranial MR-Guided Focused Ultrasound Treatment: A Patient-Data Simulation Study.

The potential improvement in sonication efficiency achieved by tilting the focused ultrasound (FUS) transducer of the transcranial MR-guided FUS system is presented. A total of 56 cases of patient treatment data were used. The relative position of the clinical FUS transducer to the patient's head was reconstructed, and region-specific skull density and porosity were calculated based on the patient's CT volume image. The total transmission coefficient of acoustic waves emitted from each channel was calculated. Then, the total energy penetrating the human skull-which represents the sonication efficiency-was estimated. As a result, improved sonication efficiency was by titling the FUS transducer to a more appropriate angle achieved in all 56 treatment cases. This simulation result suggests the potential improvement in transcranial-focused ultrasound treatment by simply adjusting the transducer angle.

Simultaneous Localized Brain Mild Hyperthermia and Blood-Brain Barrier Opening via Feedback-Controlled Transcranial MR-Guided Focused Ultrasound and Microbubbles.

Non-invasive methods to enhance drug delivery and efficacy in the brain have been pursued for decades. Focused ultrasound hyperthermia (HT) combined with thermosensitive therapeutics have been demonstrated promising in enhancing local drug delivery to solid tumors. We hypothesized that the presence of microbubbles (MBs) combined with transcranial MR-guided focused ultrasound (MRgFUS) could be used to reduce the ultrasound power required for HT while simultaneously increasing drug delivery by locally opening the blood-brain barrier (BBB). Transcranial HT (42 °C, 10 min) was performed in wild-type mice using a small animal MRgFUS system incorporated into a 9.4T Bruker MR scanner, with infusions of saline or Definity MBs with doses of 20 or 100 µl/kg/min (denoted as MB-20 and MB-100). MR thermometry data was continuously acquired as feedback for the ultrasound controller during the procedure. Spatiotemporally precise transcranial HT was achieved in both saline and MB groups. A significant ultrasound power reduction (-45.7%, p = 0.006) was observed in the MB-20 group compared to saline. Localized BBB opening was achieved in MB groups confirmed by CE-T1w MR images. There were no structural abnormalities, edema, hemorrhage, or acutemicroglial activation in all groups, confirmed by T2w MR imaging and histology. Our investigations showed that it is feasible and safe to achieve spatiotemporally precise brain HT at significantly reduced power and simultaneous localized BBB opening via transcranial MRgFUS and MBs. This study provides a new synergistic brain drug delivery method with clinical translation potential.

Simulating an MRgFUS System with Low-Permittivity Bath medium And Slotted Ground for Enhanced MR Signal

Numerical simulations are used to design a method for improving Magnetic Resonance (MR) image Signal-to-Noise Ratio (SNR) during transcranial MR-guided Focused Ultrasound (MRgFUS). The method involved both reduction of the permittivity in the hemispherical fluid bath surrounding the head and adding slots to the ground plane of the dome-shaped ultrasound array. Results indicated SNR could even outperform that with no focused ultrasound present.

Anatomic thermochromic tissue-mimicking phantom of the lumbar spine for pre-clinical evaluation of MR-guided focused ultrasound (MRgFUS) ablation of the facet joint

Objective To develop a thermochromic tissue-mimicking phantom (TTMP) with an embedded 3D-printed bone mimic of the lumbar spine to evaluate MRgFUS ablation of the facet joint and medial branch nerve. Materials and methods Multiple 3D-printed materials were selected and characterized by measurements of speed of sound and linear acoustic attenuation coefficient using a through-transmission technique. A 3D model of the lumbar spine was segmented from a de-identified CT scan, and 3D printed. The 3D-printed spine was embedded within a TTMP with thermochromic ink color change setpoint at 60 °C. Multiple high energy sonications were targeted to the facet joints and medial branch nerve anatomical location using an ExAblate MRgFUS system connected to a 3T MR scanner. The phantom was dissected to assess sonication targets and the surrounding structures for color change as compared to the expected region of ablation on MR-thermometry. Results The measured sound attenuation coefficient and speed of sound of gypsum was 240 Np/m-MHz and 2471 m/s, which is the closest to published values for cortical bone. Following sonication, dissection of the TTMP revealed good concordance between the regions of color change within the phantom and expected areas of ablation on MR-thermometry. No heat deposition was observed in critical areas, including the spinal canal and nerve roots from either color change or MRI. Conclusion Ablated regions in the TTMP correlated well with expected ablations based on MR-thermometry. These findings demonstrate the utility of an anatomic spine phantom in evaluating MRgFUS sonication for facet joint and medial branch nerve ablations.

Multiecho pseudo-golden angle stack of stars thermometry with high spatial and temporal resolution using k-space weighted image contrast.

Implement and evaluate a 3D MRI method to measure temperature changes with high spatial and temporal resolution and large field of view. A multiecho pseudo-golden angle stack-of-stars (SOS) sequence with k-space weighted image contrast (KWIC) reconstruction was implemented to simultaneously measure multiple quantities, including temperature, initial signal magnitude M(0), transverse relaxation time ( T2*), and water/fat images. Respiration artifacts were corrected using self-navigation. KWIC artifacts were removed using a multi-baseline library. The phases of the multiple echo images were combined to improve proton resonance frequency precision. Temperature precision was tested through in vivo breast imaging (N = 5 healthy volunteers) using both coronal and sagittal orientations and with focused ultrasound (FUS) heating in a pork phantom using a breast specific MR-guided FUS system. Temperature measurement precision was significantly improved after echo combination when compared with the no echo combination case (spatial average of the standard deviation through time of 0.3-1.0 and 0.7-1.9°C, respectively). Temperature measurement accuracy during heating was comparable to a 3D seg-EPI sequence. M(0) and T2* values showed temperature dependence during heating in pork adipose tissue. A self-navigated 3D multiecho SOS sequence with dynamic KWIC reconstruction is a promising thermometry method that provides multiple temperature sensitive quantitative values. Magn Reson Med 79:1407-1419, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Evaluation of MRI protocols for the assessment of lumbar facet joints after MR-guided focused ultrasound treatment.

BackgroundMR-guided focused ultrasound (MRgFUS) might be a very safe and effective minimally invasive technique to treat facet joint pain caused by arthritis and other degenerative changes. However, there are still safety concerns for this treatment and challenges regarding MR imaging and temperature mapping due to susceptibility effects between the bone and soft tissue near the joint, which has resulted in poor MR image quality. The goal of this research was to evaluate multiple magnetic resonance imaging (MRI) pulse sequences for characterizing ablated lumbar facet joint lesions created by high-intensity focused ultrasound (FUS) and compare the findings to histological tissue assessment. In particular, we investigated the use of T2-weighted MRI to assess treatment effects without contrast administration.MethodsAn IACUC approved study (n = 6 pigs) was performed using a 3T widebore MRI system equipped with an MRgFUS system. Facet joints of the lumbar vertebra were ablated using 1-MHz frequency and multiple sonication energies (300–800 J). In addition to T2-weighted MRI for treatment planning, T1-, T2-, and T2*-weighted and perfusion MRI sequences were applied. Signal intensity ratios of the lesions were determined. Histopathology was used to characterize cellular changes.ResultsAblation of the facet joint, using MRgFUS, was successful in all animals. T2-weighted images showed high signal intensity in the edematous facet joint and adjacent muscle, while delayed contrast-enhanced T1-weighted images showed an enhanced ring surrounding the target volume. T2*-weighted GRE images revealed inconsistent lesion visualization. Histopathology confirmed the presence of cellular coagulation (shrinkage), extracellular expansion (edema), and hemorrhage in the bone marrow.ConclusionsMRgFUS provided sufficient precision and image quality for visualization and characterization of ablated facet joints directly after ablation. MRI may help in monitoring the efficacy of FUS ablation without contrast after treating patients with back pain.

In vitro and in vivo platforms for focused ultrasound-controlled drug delivery and release

Focused ultrasound (FUS) holds great promise for the development of effective and safe anticancer treatment protocols. FUS does not only allow to modulate the permeability of tumor vessels and enhance the extravasation of large molecules but to also locally trigger the release of their highly penetrating cargo. To utilize this potential in vitro and in vivo, platforms that allow for detailed assessment and optimization of the FUS-controlled drug delivery and release protocols are essential. We will present two such platforms for FUS-controlled drug delivery and release. First, we will introduce a novel acoustofluidic system with temperature and pressure sensor embedded that enables the accurate control of drug-release and the establishment of chemotherapeutic agent concentration gradients in a physiologically relevant 3D tumor model. Next, we will present an integrated US- and MR-guided FUS system for controlling the mechanical and thermal effects of FUS in vivo. Fast methods to visualize and control microbubble oscillations along with real time FUS-induced mild hyperthermia with this system will be shown in brain tumors of rodents. The FUS-induced release of the chemotherapeutic agent doxorubicin from a liposomal carrier is used to demonstrate the utility of the two systems for developing and optimizing new therapeutic protocols.

Phase aberration simulation study of MRgFUS breast treatments.

This simulation study evaluates the effects of phase aberration in breast MR-guided focused ultrasound (MRgFUS) ablation treatments performed with a phased-array transducer positioned laterally to the breast. A quantification of these effects in terms of thermal dose delivery and the potential benefits of phase correction is demonstrated in four heterogeneous breast numerical models. To evaluate the effects of varying breast tissue properties on the quality of the focus, four female volunteers with confirmed benign fibroadenomas were imaged using 3T MRI. These images were segmented into numerical models with six tissue types, with each tissue type assigned standard acoustic properties from the literature. Simulations for a single-plane 16-point raster-scan treatment trajectory centered in a fibroadenoma in each modeled breast were performed for a breast-specific MRgFUS system. At each of the 16 points, pressure patterns both with and without applying a phase correction technique were determined with the hybrid-angular spectrum method. Corrected phase patterns were obtained using a simulation-based phase aberration correction technique to adjust each element's transmit phase to obtain maximized constructive interference at the desired focus. Thermal simulations were performed for both the corrected and uncorrected pressure patterns using a finite-difference implementation of the Pennes bioheat equation. The effect of phase correction was evaluated through comparison of thermal dose accumulation both within and outside a defined treatment volume. Treatment results using corrected and uncorrected phase aberration simulations were compared by evaluating the power required to achieve a 20 °C temperature rise at the first treatment location. The extent of the volumes that received a minimum thermal dose of 240 CEM at 43 °C inside the intended treatment volume as well as the volume in the remaining breast tissues was also evaluated in the form of a dose volume ratio (DVR), a DVR percent change between corrected and uncorrected phases, and an additional metric that measured phase spread. With phase aberration correction applied, there was an improvement in the focus for all breast anatomies as quantified by a reduction in power required (13%-102%) to reach 20 °C when compared to uncorrected simulations. Also, the DVR percent change increased by 5%-77% in seven out of eight cases, indicating an improvement to the treatment as measured by a reduction in thermal dose deposited to the nontreatment tissues. Breast compositions with a higher degree of heterogeneity along the ultrasound beam path showed greater reductions in thermal dose delivered outside of the treatment volume with correction applied than beam trajectories that propagated through more homogeneous breast compositions. An increasing linear trend was observed between the DVR percent change and the phase-spread metric (R(2) = 0.68). These results indicate that performing phase aberration correction for breast MRgFUS treatments is beneficial for the small-aperture transducer (14.4 × 9.8 cm) evaluated in this work. While all breast anatomies could benefit from phase aberration correction, greater benefits are observed in more heterogeneous anatomies.

Microbubble protein delivery for Parkinson’s

Microbubbles (MBs) are small (1-5 μm diameter), perfluorcarbon gas filled lipid microspheres used for contrast enhancement during ultrasound imaging. MBs (Definity®, others) are approved for contrast echocardiography and widely used (6 M patient injections) as ultrasound contrast agents with established pharmacokinetics and clearance data. Recent research has shifted to the therapeutic potential of MBs and the NRC and Artenga Inc. developed a novel strategy (Patent to be filed) to load biologics onto MBs with high, consistent loading using a novel clinically scalable methodology. Investigators at Sunnybrook Research Institute have pioneered MR guided focused ultrasound (MRgFUS) plus MB techniques to deliver a wide range of therapeutic agents through the blood-brain-barrier (BBB) and developed a state of the art MRgFUS system for animal models. MRgFUS can precisely target the substantia nigra (SN) and striatum (ST) for simultaneous targeting of multiple brain regions. Neurotrophic factors (NTFs) are being developed in the hope of halting or reversing the progression of neuronal loss in chronic neurodegenerative diseases, however, their clinical utility is limited by drug delivery issues. Recently the University of Helsinki discovered a novel NTF, cerebral dopamine neurotrophic factor (CDNF), with a unique structure and mode of action. CDNF has demonstrated improved efficacy compared to GDNF in various preclinical models of PD. Artenga, Inc., Sunnybrook Research Institute, the National Research Council of Canada (NRC), and the University of Helsinki plan is to use MR guided focused ultrasound (MRgFUS) and neurotrophic drug-loaded microbubbles (NTF-MBs) for targeted, noninvasive, blood brain barrier (BBB) drug delivery of CDNF.

TH-E-BRA-03: Clinical Experience at Fox Chase Cancer Center for Treatment of Bone Metastases Using ExAblate 2000 with MR Guidance

Purpose: To evaluate the safety and efficacy of MR guided focused ultrasound (MRgFUS) treatment for bone metastases. Methods: Six patients with scapula (2), humeral head, sacrum, ilium and pubic ramus bone metastases were treated using ExAblate 2000 under MR guidance. In addition to the monthly and annual quality assurance (QA), pre-treatment machine calibration was performed before each treatment including the functionality of the treatment software and the mechanical motion control systems. The effective ultrasound focal spot was verified with an acoustic phantom using MR thermometry. The patient was positioned on a gel pad. The interface between the treatment table, the gel pad and the patient was immersed in degassed water for acoustic coupling. Caution was taken to remove all gas bubbles between the interfaces. Treatment was performed under conscious sedation. Six to eighteen sonications were delivered for each patient treatment depending on each lesion's size. Patients were treated with a frequency of 1 MHz; 32 ± 4.0 to 96 ±11W acoustic power and 628 ± 78 to1859 ± 338J energy for 20–30s for each sonication. MR phase images were used to monitor the temperature changes in real-time. Based on the temperature feedback, the acoustic power was adjusted to reach designed temperatures (=60 °C) for individual sonications. Pain was assessed using the visual analog scale (VAS). Results: All patients tolerated the MRgFUS treatment well. No skin toxicity or other complications were observed. The VAS pain rating was significantly reduced for all 6 patients from 8.2 ± 0.8 before treatment to 4.7 ± 3, 2.7 ± 1.5 and 1.8 ± 1.1 at one day, one month and three months respectively. Conclusions: A comprehensive QA program has been developed for the MRgFUS system. Our data suggest that MRgFUS is a safe, effective and noninvasive treatment modality for palliation of bone metastases.

Magnetic Resonance Thermometry at 7T for Real-Time Monitoring and Correction of Ultrasound Induced Mild Hyperthermia

While Magnetic Resonance Thermometry (MRT) has been extensively utilized for non-invasive temperature measurement, there is limited data on the use of high field (≥7T) scanners for this purpose. MR-guided Focused Ultrasound (MRgFUS) is a promising non-invasive method for localized hyperthermia and drug delivery. MRT based on the temperature sensitivity of the proton resonance frequency (PRF) has been implemented in both a tissue phantom and in vivo in a mouse Met-1 tumor model, using partial parallel imaging (PPI) to speed acquisition. An MRgFUS system capable of delivering a controlled 3D acoustic dose during real time MRT with proportional, integral, and derivative (PID) feedback control was developed and validated. Real-time MRT was validated in a tofu phantom with fluoroptic temperature measurements, and acoustic heating simulations were in good agreement with MR temperature maps. In an in vivo Met-1 mouse tumor, the real-time PID feedback control is capable of maintaining the desired temperature with high accuracy. We found that real time MR control of hyperthermia is feasible at high field, and k-space based PPI techniques may be implemented for increasing temporal resolution while maintaining temperature accuracy on the order of 1°C.

SU‐GG‐I‐143: An in Vivo Study on the Enhancement of Gene Therapy with MR‐Guided Focused Ultrasound (MRgFUS)

Purpose: The purpose of this study is to investigate the feasibility of increasing the cellular uptake of AS‐MDM2 for prostate cancer with image‐guided focused ultrasound (MRgFUS). Materials and Method: A GE/InSightec MRgFUS system was used in this experimental study. Human prostate cancer cells LNCaP (5×105) were grown orthotopically in the prostates of 28 nude mice. Animals were divided randomly into 4 Groups (n=7/group): Group 1: MRgFUS+AS‐MDM2; Group 2: MRgFUS only; Group 3: AS‐MDM2 i.v injection only; Group 4: control. For group one the tumors were treated using MRgFUS with the acoustic power of 4 W, pulse width of 0.1 sec and 300 pulses in one sonication. The focal peak was set within the target under MR guidance. Multiple sonications were used to cover the whole tumor. Immediately after the ultrasound treatment 0.1 ml of AS‐MDM2, dissolved in PBS, was given by tail vein injection at 25 mg/kg. For group 2 animals were treated with the same as for group one except for AS‐MDM2 injection. Animals in group 3 were treated with AS‐MDM2 injection only and group 4 used as control. Mice were sacrificed 6 and 24 hr after treatment. The tumors were removed and processed for assessment of protein expression by immunohistochemical staining. The expression levels of MDM2, p53 and p21 proteins were quantified using an image‐analysis system. Results: We observed blood cell extravasations on H&E staining in the MRgFUS treated tumors, as compared to the other groups. There are no significant differences between groups with and without MRgFUS treated groups both 6 hours and 24 hours after treatment. Conclusions: One single AS‐MDM injection did not knock down MDM2 or result in increases in p53 and p21. The effect of multiple MRgFUS and AS‐MDM2 treatments on the LNCaP tumor growth is warranted in future studies.

SU‐FF‐T‐472: Quality Assurance for MR Guided Focused Ultrasound as a Multi‐Modality Platform for Cancer Therapy

Purpose: The purpose of this work is to develop an effective and efficient quality assurance (QA) program for the application of MR guided focused ultrasound (MRgFUS) as a multi‐modality platform for cancer therapy. Materials and Method: An MRgFUS system has been installed in our institution, which consists of an InSightec ExAblate 2000 high‐intensity focused ultrasound (HIFU) system and a 1.5T GE MR scanner. This system has been FDA approved for the treatment of uterine fibroids clinically and is being investigated under local IRB approval for treating bone metastases, prostate and breast cancers and the enhancement of drug delivery for gene therapy and chemotherapy. In addition to the daily, monthly and annual calibration and commissioning measurements for the MRI unit special QA procedures were developed for the HIFU system including the mechanical motion of the couch and transducer, the safety system and patient panic buttons, the functionality of the temperature mapping and treatment software, the acoustic power output and the localization of the treatment focal spot. Results: The MRgFUS system has been operational since the fall of 2006. Successful experiments have been performed on in vitro bio‐samples and in vivo animal models for pre‐clinical studies and for drug enhancement experiments. Patients with bone metastases have been treated successfully using the MRgFUS system for pain relief with a pre‐treatment QA procedure. Patients tolerated the HIFU treatment well. No skin damage was observed after treatment. The pain scale was significantly reduced within 24 hours and further reduced at later follow‐ups. Conclusions: Comprehensive QA procedures have been developed for the safe and successful operation of the MRgFUS system as a multi‐modality platform for breast surgery, bone palliation, and prostate boost in combination with radiotherapy clinically and for drug delivery enhancement investigations for gene therapy and chemotherapy using animal models.

SU‐FF‐J‐46: Treatment of Bone Metastases Using MR Guided Focused Ultrasound

Purpose: To evaluate the safety and efficacy of MR guided focused ultrasound (MRgFUS) treatment for bone metastases. Method and Materials: A 50‐year‐old patient with painful scapula bone metastases refractory to pain medication was recruited in this study. The treatment was performed under local IRB approval using an MRgFUS system consisting of an Insightec ExAblate 2000 with a GE 1.5T MR scanner. The focal region is approximately 2mm in diameter and 10mm in length. Beside the regular monthly and annual quality assurance (QA) measurements, pre‐treatment machine calibration included the functionality of the treatment software and the mechanical motion control. The focal spot was verified using MR thermometry. The safety system and panic buttons were checked. The patient is positioned on a gel pad on the treatment table in line with the transducer. The gel pad was immersed in degassed water that acts as an interface between the treatment table and the gel pad for acoustic coupling. Caution was taken with all gas bubbles removed between the interfaces. Treatment was performed under conscious sedation. Six sonications were delivered with frequency 1 MHz, acoustic power 32 ±4 W, energy 628±78 J and 20s durations. Phase MR Images were used to monitor the temperature change in real‐time. Based on the treatment feed back, acoustic power was adjusted to reach designed temperatures (⩾60 °C) for individual sonications. Results: The patient tolerated the MRgFUS treatment well. There were no treatment‐related adverse events including skin toxicity. The patient reported rapid pain decrease from 8 out of 10 (0 – 10 scale) pretreatment to 2 within 24 hrs, and has continued to report between 2 – 2.5 up to 2 months following treatment.Conclusions: MRgFUS is a safe, effective and noninvasive treatment modality for bone palliation and pain relief. A comprehensive QA program has been developed for the MRgFUS system.

Initial evaluation of acoustic reflectors for the preservation of sensitive abdominal skin areas during MRgFUS treatment

During MR-guided focused ultrasound (MRgFUS) treatments of uterine fibroids using ExAblate®2000 (InSightec, Haifa, Israel), individual tissue ablations are performed extracorporeally through the patient's abdomen using an annular array FUS transducer embedded within the MR table. Ultrasound intensities in the near field are below therapeutic levels and, under normal conditions, heating of the patient skin is minimal. However, increased absorption of ultrasound energy within sensitive skin areas or areas with differing acoustic properties, such as scars, may lead to skin burns and therefore these areas must be kept outside the near field of the FUS beam. Depending on their location and size the sensitive areas may either obstruct parts of the fibroid from being treated or prevent the entire MRgFUS treatment altogether. The purpose of this work is to evaluate acoustic reflector materials that can be applied to protect skin and the underlying sensitive areas. Reflection coefficients of cork (0.88) and foam (0.91) based materials were evaluated with a hydrophone. An ExAblate 2000 MRgFUS system was used to simulate clinical treatment with discs of reflector materials placed in a near field underneath a gel phantom. MR thermometry was used to monitor temperature elevations as well as the integrity of the focal spot. The phantom measurements showed acoustic shadow zones behind the reflectors with zone depths changing between 7 and 27 mm, for reflector disc diameters increasing from 10 to 30 mm (40 mm diameter discs completely blocked the FUS beam at the depth evaluated). The effects on thermal lesions due to the presence of the reflectors in the FUS beam were found to diminish with decreasing disc diameter and increasing sonication depth. For a 20 mm diameter disc and beyond 50 mm sonication depth, thermal lesions were minimally affected by the presence of the disc. No heating was observed on the skin side of the foam reflectors, as confirmed by measurements performed with adhesive temperature labels. We present these data and discuss possible applications to clinical MRgFUS treatments.