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.

INTRODUCTION:The objectives of this study were to determine long-term patient-reported outcomes with magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for medication-refractory essential tremor (ET) and to identify risk factors for a poor clinical outcome.METHODS:We administered a telephone or mail-in survey to patients who consecutively underwent unilateral MRgFUS thalamotomy for ET at our institution over an 8-year period. Patients were asked to self-report measures of hand tremor improvement, degree of overall postprocedure improvement, activities of daily life, side effects, and willingness to undergo the procedure again. Specific patient characteristics, ultrasound treatment parameters, and postoperative radiological findings from magnetic resonance imaging performed 1 day after the procedure were analyzed, and multivariable linear regression was used to determine if these factors could serve as predictors of clinical outcome.RESULTS:A total of 85 patients were included in this study with a mean follow-up time of 3.0 years (range 2 months to 1 8.4 years). The mean patient-reported improvement in hand tremor at last follow-up was 66%, and 73% of patients reported meaningful change in their overall condition after the procedure. The percentages of patients reporting normal or only minimal limitations with feeding, drinking, and writing ability at last follow-up were 60%, 71%, and 48%, respectively. In the position of their former selves, 89% of patients would again choose to undergo the procedure. Larger lesions were correlated with a higher risk of adverse events.DISCUSSION/CONCLUSION:While subjective hand tremor improvement declines with time, willingness to undergo the procedure again following MRgFUS thalamotomy for ET remains very high even several years after the procedure.

High-intensity focused ultrasound (HIFU) transducer acoustic output can vary over time as a result of an inconsistent power supply, damage to the transducer or deterioration over time. Therefore, easy implementation of a daily quality assurance (DQA) method is of great importance for pre-clinical research and clinical applications. We present here a thermochromic material-based phantom validated by thermal simulations and found to provide repeatable visual power output assessments in fewer than 15 s that are accurate to within 10%. Whereas current available methods such as radiation force balance measurements provide an estimate of the total acoustic power, we explain here that the thermochromic phantom is sensitive to the shape of the acoustic field at focus by changing the aperture of a multi-element transducer with a fixed acoustic power. The proposed phantom allows the end user to visually assess the transducer's functionality without resorting to expensive, time-consuming hydrophone measurements or image analysis.

INTRODUCTION: Focused ultrasound ablation (FUSA) relies on accurate subthreshold testing to physiologically explore the presumed target before permanent ablation. However, the optimal thermal parameters for subthreshold testing (i.e., thermal dose and spot size thresholds) are not yet defined. METHODS: We performed a retrospective analysis of intraoperative testing data of essential tremor patients undergoing FUSA. Sonications with a thermal dose of less than 25 cumulative equivalent minutes (CEM) were classified as sub-threshold. The intraoperative writing samples were independently rated by two raters using the clinical rating scale for tremor. The association between thermal dose and tremor scores was statistically analyzed, and the thermal dose and spot size thresholds for tremor improvement were computed using leave-one-out cross-validation analysis. RESULTS: From the 331 pairs of sonications and tremor assessments, 97 sonications were classified as subthreshold sonications. Intraoperative tremor improvement was observed in 23 (24%) subthreshold sonications with a median tremor improvement of 20% (interquartile range = 41.6) from the baseline. The thermal dose threshold for tremor improvement was 0.67 CEM (equivalent to 30 seconds thermal exposure at 430C). The spot size threshold for tremor improvement was 2.46 mm. VIM was exposed to TN thermal dose during sub-ablative and ablative sonications. CONCLUSION: The optimal thermal dose and spot size thresholds for subthreshold testing are significantly higher than the current FUSA standard-of-care. We recommend long duration (>30 seconds), subthreshold sonications for intraoperative testing during FUSA. Future investigations should test whether the thermal dose threshold is tissue-specific and determine the mechanisms underlying focused ultrasound TN.

A combination of surgery and chemotherapy is the most effective treatment available for Malignant Pleural Mesothelioma (MPM). However, both cause significant collateral damage and cannot eliminate residual microscopic disease. This investigation aimed to compare and determine the feasibility of utilizing Radiofrequency Ablation (RFA) and Magnetic-Resonance-guided Focused Ultrasound Surgery (MRgFUS) as alternative treatments for MPM. A large animal tumor model was developed in 13 Yorkshire female pigs using the MSTO211H cell line. Two pigs were initially used to determine the cyclosporine dose required for immunosuppression and tumor development. Subsequently, 11 other pigs underwent tumor development. Of these 11, 2 died during cell inoculation. Small tumor masses and adhesions were present in the other 9, indicating mesothelioma development. Five pigs then received RFA treatment, and 4 pigs received MRgFUS treatment. Tumor model development and effect of the two treatments were examined using MRI and by necropsy. RFA and MRgFUS both successfully ablated approximately the same sized area in the same treatment time. This study demonstrates that RFA and MRgFUS are feasible for tumor debulking, and while MRgFUS requires more pretreatment planning compared to RFA, MRgFUS is a completely noninvasive procedure.

The Focused Ultrasound Foundation has developed a low-cost, validated, open-source hydrophone scanner for the spatial characterization of ultrasound transducers. Assembly instructions and a MATLAB control graphical user interface are provided such that the device can be easily replicated for less than $1000 in roughly 40 person-hours. The low-cost scanning tank's performance was compared with data collected with a commercial automated scanning tank. Pressure measurements of a focused transducer and a planar transducer had less than a 10% difference between the two scanning systems. Two-dimensional automated scans (20 × 20 mm at 0.25-mm resolution) took the low-cost scanning tank 45 min compared with the commercial system's 30 min. A reproducibility study found that the low-cost scanner made consistent peak negative pressure measurements as reflected by the low coefficient of variation for both focused (1.88%) and planar (0.98%) transducers. The low-cost scanner described here is a viable alternative for ultrasound laboratories needing efficient, accurate characterization of ultrasound transducers.

Abstract BACKGROUND During focused ultrasound ablation (FUSA), the presumed stereotactic target is tested with subthreshold sonications before permanent ablation. This testing relies on ultrasound-induced reversible clinical effects (thermal neuromodulation, TN). However, the thermal dose and spot size thresholds to induce TN are not yet defined. OBJECTIVE To define the thermal dose and spot size thresholds associated with TN. METHODS We performed a retrospective analysis of intraoperative FUSA data of essential tremor patients. Sonications with a thermal dose of less than 25 cumulative equivalent minutes (CEM) were classified as subthreshold. The intraoperative writing samples were independently rated by 2 raters using the clinical rating scale for tremor. The association between thermal dose and tremor scores was statistically analyzed, and the thermal dose and spot size thresholds for TN were computed using leave-one-out cross-validation analysis. RESULTS A total of 331 pairs of sonications and writing samples were analyzed; 97 were classified as subthreshold sonications. TN was observed in 23 (24%) subthreshold sonications. The median tremor improvement during TN was 20% (interquartile range = 41.6). The thermal dose threshold for TN was 0.67 CEM (equivalent to 30 s thermal exposure at 43°C). The spot size threshold for TN was 2.46 mm. Ventral intermediate medial nucleus was exposed to TN thermal dose during subablative and ablative sonications. CONCLUSION The TN thermal dose and spot size thresholds are significantly higher than the current FUSA standard of care. We recommend long duration (>30 s), subthreshold sonications for intraoperative testing during FUSA. Future investigations should test whether the thermal dose threshold is tissue-specific and determine the mechanisms underlying focused ultrasound TN.

Transcranial high-intensity focused ultrasound is used in clinics for treating essential tremor (ET) and proposed for many other brain disorders. This promising treatment modality requires high energy resulting eventually in undesired cavitation and potential side effects. The goals of the present work were: 1) to evaluate the potential increase of the cavitation threshold using pseudorandom gated sonications and 2) to assess the heating capabilities with such sonications. The experiments were performed with the transcranial magnetic resonance (MR)-compatible ExAblate Neuro system (InSightec, Haifa, Israel) operating at a frequency of 670 kHz, either in continuous wave (CW) or with pseudorandom gated sonications of 50% duty cycle. Cavitation activity with the two types of sonications was compared using chemical dosimetry of hydroxyl radical production at the focus of the transducer, after propagation in water or through a human skull. Heating trials were performed in a hydrogel tissue-mimicking material embedded in a human skull to mimic a clinical situation. The temperature was measured by MR-thermometry when focusing at the geometrical focus and steering off focus up to 15 mm. Compared with CW sonications, the use of gated sonication did not affect the efficiency (60%) nor the steering abilities of the transducer. After propagation through a human skull, gated sonication required a higher pressure level (10 MPa) to initiate cavitation as compared with CW (5.8 MPa). Moreover, at equivalent acoustic power above the cavitation threshold, the level of cavitation activity initiated with gated sonications was much lower with gated sonication than with continuous sonications, almost half after propagation through water and one-third after propagation through a skull. This lowered cavitation activity may be attributed to a breaking of the dynamic of the bubbles moving from monochromatic to more broadband sonications and to the removal of residual cavitation nuclei between pulses with gated sonications. The heating capability was not affected by the gated sonications, and similar temperature increases were reached at focus with both types of sonications when sonicating at equivalent acoustic power, both in water or after propagation through a human skull (+15 °C at 325 W for 10 s). These data, acquired with a clinical system, suggest that gated sonication could be an alternative to continuous sonications when cavitation onset is an issue.

The ExAblate Neuro allows for the non-invasive treatment of a wide variety of neurological problems, however is subject to smearing of its focal spot when the transducer arrays come in contact with the skull. Partnering with the Focused Ultrasound Foundation, this project had the ultimate goal of designing and testing a new model that allows for better prediction of phase shift for each individual array within the ExAblate Neuro when compared to the current model. This report explores the data exploration steps taken to obtain preliminary findings as well as details the conclusions reached in phase 1 of this project.

Transcranial focused ultrasound (FUS) is a non-invasive therapeutic modality that can be used to treat essential tremor via local thermal ablation of a small spot in the thalamus. Acoustic energy is focused through the skull using a multi-element transducer. Per-element phase delay is derived using individual patient’s skull CT to compensate for skull heterogeneity, but MRI thermometry is still required for precise targeting and localization of the focal spot. There exists an opportunity for improved and accurate numerical simulations through skull to improve focal spot positioning and treatment, to allow treatment pre-planning, and to permit parametric studies that will identify important acoustic and thermal properties of human skull bones and tissues. Here, we report on a novel 3D numeric simulation framework, based on the CIVA Healthcare simulation platform, to simulate propagation through skulls and the resulting heating. This simulation platform has been developed to pilot various fast algorithms and to simulate the heating in tissues induced by FUS by solving Pennes’ BioHeat Transfer Equation. Simulations of propagation through human skulls with the Insightec 650 kHz clinical system, with 1024 elements, were performed and validated by comparison to experimental acoustic signals acquired with a hydrophone and to MRI thermometry data.

Overcoming the resistant to change - is there a strategy that could bring all the different stakeholders to combine and align efforts?

Thermal dose and absorbed radiation dose have historically been difficult to compare because different biological mechanisms are at work. Thermal dose denatures proteins and the radiation dose causes DNA damage in order to achieve ablation. The purpose of this paper is to use the proportion of cell survival as a potential common unit by which to measure the biological effect of each procedure.Survival curves for both thermal and radiation doses have been extracted from previously published data for three different cell types. Fits of these curves were used to convert both thermal and radiation dose into the same quantified biological effect: fraction of surviving cells. They have also been used to generate and compare survival profiles from the only indication for which clinical data are available for both focused ultrasound (FUS) thermal ablation and radiation ablation: essential tremor thalamotomy.All cell types could be fitted with coefficients of determination greater than 0.992. As an illustration, survival profiles of clinical thalamotomies performed by radiosurgery and FUS are plotted on a same graph for the same metric: fraction of surviving cells.FUS and Gamma Knife have the potential to be used in combination to deliver a more effective treatment (for example, FUS may be used to debulk the main tumour mass, and radiation to treat the surrounding tumour bed). In this case, a model which compares thermal and radiation treatments is valuable in order to adjust the dose between the two.

Axial T1 projection showing the relation of VIM target 3 mm medial and anterior to pyramidal tract and medial lemniscus respectively

PURPOSE:In the ongoing endeavor of fine-tuning, the clinical application of transcranial MR-guided focused ultrasound (tcMRgFUS), ex-vivo studies wlkiith whole human skulls are of great use in improving the underlying technology guiding the accurate and precise thermal ablation of clinically relevant targets in the human skull. Described here are the designs, methods for fabrication, and notes on utility of three different ultrasound phantoms to be used for brain focused ultrasound research.METHODS:Three different models of phantoms are developed and tested to be accurate, repeatable experimental options to provide means to further this research. The three models are a cadaver, a gel-filled skull, and a head mold containing a skull and filled with gel that mimics the brain and the skin. Each was positioned in a clinical tcMRgFUS system and sonicated at 1100 W (acoustic) for 12 s at different locations. Maximum temperature rise as measured by MR thermometry was recorded and compared against clinical data for a similar neurosurgical target. Results are presented as heating efficiency in units (°C/kW/s) for direct comparison to available clinical data. The procedure for casting thermal phantom material is presented. The utility of each phantom model is discussed in the context of various tcMRgFUS research areas.RESULTS:The cadaveric phantom model, gel-filled skull model, and full head phantom model had heating efficiencies of 5.3, 4.0, and 3.9 °C/(kW/s), respectively, compared to a sample clinical heating efficiency of 2.6 °C/(kW/s). In the seven research categories considered, the cadaveric phantom model was the most versatile, though less practical compared to the ex-vivo skull-based phantoms.CONCLUSIONS:Casting thermal phantom material was shown to be an effective way to prepare tissue-mimicking material for the phantoms presented. The phantom models presented are all useful in tcMRgFUS research, though some are better suited to a limited subset of applications depending on the researchers needs.

Temporal lobe epilepsy remains a significant cause of disabling morbidity. Patients that are refractory to medical treatment are often considered for invasive surgery to remove the epileptogenic focus originating from the structures of the medial temporal lobe. A range of surgical options now exist with varying degrees of efficacy. The goal of any surgical intervention is to minimize disruption of adjacent normal cortical tissue while removing the offending structures. MRgFUS provides the opportunity to perform this task in an elegant fashion. We tested the feasibility of this approach in a cadaveric model.

Errors in power output ranging from −100% to +210% have been reported in a multitude of physiotherapy transducers.[1] Differences in power output can arise even after careful calibration on an annual or bi-annual schedule, which can either result in harm to the patient or non-effective treatment. Therefore, easy implementation of daily quality assurance is of great importance. We propose a simple, easy to use DQA phantom which allows the user to assess the power output of the focused ultrasound transducer, and determine if it has changed significantly after calibration. The basis of this phantom is the use of a highly attenuating ultrasound absorber with a surface layer of thermochromic liquid crystals (TLC). The use of thermochromic materials as a technique for use in ultrasound phantoms has been an ongoing area of interest. Many of these techniques require complicated set-ups, with large water tanks and imaging systems to produce very accurate data.[2,3] Simpler phantoms have been developed for use in benchtop settings, but still with a large emphasis on complicated image analysis.[4] Our proposed phantom will be a product where the end-user can visually assess the size of the lesion formed as a function of power output, without resorting to complicated image analysis.

OBJECT In biological tissues, it is known that the creation of gas bubbles (cavitation) during ultrasound exposure is more likely to occur at lower rather than higher frequencies. Upon collapsing, such bubbles can induce hemorrhage. Thus, acoustic inertial cavitation secondary to a 220-kHz MRI-guided focused ultrasound (MRgFUS) surgery is a serious safety issue, and animal studies are mandatory for laying the groundwork for the use of low-frequency systems in future clinical trials. The authors investigate here the in vivo potential thresholds of MRgFUS-induced inertial cavitation and MRgFUS-induced thermal coagulation using MRI, acoustic spectroscopy, and histology. METHODS Ten female piglets that had undergone a craniectomy were sonicated using a 220-kHz transcranial MRgFUS system over an acoustic energy range of 5600-14,000 J. For each piglet, a long-duration sonication (40-second duration) was performed on the right thalamus, and a short sonication (20-second duration) was performed on the left thalamus. An acoustic power range of 140-300 W was used for long-duration sonications and 300-700 W for short-duration sonications. Signals collected by 2 passive cavitation detectors were stored in memory during each sonication, and any subsequent cavitation activity was integrated within the bandwidth of the detectors. Real-time 2D MR thermometry was performed during the sonications. T1-weighted, T2-weighted, gradient-recalled echo, and diffusion-weighted imaging MRI was performed after treatment to assess the lesions. The piglets were killed immediately after the last series of posttreatment MR images were obtained. Their brains were harvested, and histological examinations were then performed to further evaluate the lesions. RESULTS Two types of lesions were induced: thermal ablation lesions, as evidenced by an acute ischemic infarction on MRI and histology, and hemorrhagic lesions, associated with inertial cavitation. Passive cavitation signals exhibited 3 main patterns identified as follows: no cavitation, stable cavitation, and inertial cavitation. Low-power and longer sonications induced only thermal lesions, with a peak temperature threshold for lesioning of 53°C. Hemorrhagic lesions occurred only with high-power and shorter sonications. The sizes of the hemorrhages measured on macroscopic histological examinations correlated with the intensity of the cavitation activity (R2 = 0.74). The acoustic cavitation activity detected by the passive cavitation detectors exhibited a threshold of 0.09 V·Hz for the occurrence of hemorrhages. CONCLUSIONS This work demonstrates that 220-kHz ultrasound is capable of inducing a thermal lesion in the brain of living swines without hemorrhage. Although the same acoustic energy can induce either a hemorrhage or a thermal lesion, it seems that low-power, long-duration sonication is less likely to cause hemorrhage and may be safer. Although further study is needed to decrease the likelihood of ischemic infarction associated with the 220-kHz ultrasound, the threshold established in this work may allow for the detection and prevention of deleterious cavitations.

The purpose of this study was to investigate the thresholds for inducing two possible means of tissue destruction with low frequency Magnetic Resonance guided Focused Ultrasound (MRgFUS): either mechanical lesioning in presence of ultrasonic cavitation or pure thermal lesioning (without cavitation).