Yoav Medan

Hybrid referenceless and multibaseline subtraction MR thermometry for monitoring thermal therapies in moving organs.

PURPOSE Magnetic resonance thermometry using the proton resonance frequency (PRF) shift is a promising technique for guiding thermal ablation. For temperature monitoring in moving organs, such as the liver and the heart, problems with motion must be addressed. Multi-baseline subtraction techniques have been proposed, which use a library of baseline images covering the respiratory and cardiac cycle. However, main field shifts due to lung and diaphragm motion can cause large inaccuracies in multi-baseline subtraction. Referenceless thermometry methods based on polynomial phase regression are immune to motion and susceptibility shifts. While referenceless methods can accurately estimate temperature within the organ, in general, the background phase at organ/tissue interfaces requires large polynomial orders to fit, leading to increased danger that the heated region itself will be fitted by the polynomial and thermal dose will be underestimated. In this paper, a hybrid method for PRF thermometry in moving organs is presented that combines the strengths of referenceless and multi-baseline thermometry. METHODS The hybrid image model assumes that three sources contribute to image phase during thermal treatment: Background anatomical phase, spatially smooth phase deviations, and focal, heat-induced phase shifts. The new model and temperature estimation algorithm were tested in the heart and liver of normal volunteers, in a moving phantom HIFU heating experiment, and in numerical simulations of thermal ablation. The results were compared to multi-baseline and referenceless methods alone. RESULTS The hybrid method allows for in vivo temperature estimation in the liver and the heart with lower temperature uncertainty compared to multi-baseline and referenceless methods. The moving phantom HIFU experiment showed that the method accurately estimates temperature during motion in the presence of smooth main field shifts. Numerical simulations illustrated the methods sensitivity to algorithm parameters and hot spot features. CONCLUSIONS This new hybrid method for MR thermometry in moving organs combines the strengths of both multi-baseline subtraction and referenceless thermometry and overcomes their fundamental weaknesses.

Ultrasound focusing using magnetic resonance acoustic radiation force imaging: application to ultrasound transcranial therapy.

PURPOSE Magnetic resonance guided ultrasonic therapy is a promising minimally invasive technology for constantly growing variety of clinical applications. Delivery of focused ultrasound (FUS) energy to the targeted point with optimal intensity is highly desired; however, due to tissue aberrations, optimal focal intensity is not always achieved. Especially in transcranial applications, the acoustic waves are shifted and distorted mainly by the skull. In order to verify that magnetic resonance acoustic radiation force imaging (MR-ARFI) can be used as a focusing tool in transcranial treatments, such an imaging was appliedin vivo on a porcine brain via ex vivo human skull. Then, by the use of MR-ARFI technique, an improved ultrasound focusing algorithm is proposed and demonstrated for both transcranial and none brain applications. METHODS MR-ARFI images were acquired on a GE 1.5 T scanner equipped with InSightec FUS systems ExAblate 2000 and ExAblate 4000. Imaging was performed with MR-ARFI sequences of line-scan spin-echo and single-shot gradient-echo echo-planar. The in-plane resolution of both acquisitions was 0.9×0.9mm2. The total acquisition time of MR-ARFI image was 31 s by the line-scan sequence and 1 s by the echo-planar sequence. An in vivo experiment was performed using FUS transducer, which is built out of 1024 ultrasound transmitting piezoelectric elements at 220 kHz frequency. The transducer was focused into the brain of a pig, which was wrapped in a human skull, in degassed water environment to resemble human treatments. The pig underwent a wide bilateral craniectomy to prevent a bone heating from the ultrasound beams. Two focusing experiments were performed in phantoms using 1 MHz and 710 kHz FUS transducers working with 208 and 225 elements, respectively. In the first experiment, aberration was added virtually to the apparatus by adding random phases to the phase map of the transducer. A simple focusing correction scheme was used, in which the corrected phase of a group of elements was chosen such that it maximizes the radiation force at the focal point. In the second experiment, aberrations made by a human skull were corrected using geometrical and phase based adjustments on segments of the transducer. RESULTS A maximum displacement of 10μm was obtained using 1.4 kW acoustic power on a live pigs head that its skull was removed and replaced by ex vivo human skull. Aberration correction using MR-ARFI resulted in near optimal focus, as the radiation force was similar to the nonaberration case. Transcranial, MR-ARFI based aberration correction performed better than CT based aberration correction, a technique that is currently used in brain FUS treatments. CONCLUSIONS In the present work, the authors show for the first time a result of MR-ARFI in a live brain throughex vivo human skull. They have demonstrated that aberration correction could be done using MR-ARFI by measuring the radiation force at the focal point. Aberration correction using MR-ARFI is a promising noninvasive technique for transcranial focusing, which may result in near optimal focus and more reliable and safer brain FUS treatments.

A parallel FFT on an MIMD machine

Abstract In this paper we present a parallelization of the Cooley- Tukey FFT algorithm that is implemented on a shared-memory MIMD (non-vector) machine that was built in the Dept. of Computer Science, Tel Aviv University. A parallel algorithm is presented for one dimension Fourier transform with performance analysis. For a large array of complex numbers to be transformed, an almost linear speed-up is demonstrated. This algorithm can be executed by any number of processors, but generally the number is much less than the length of the input data.

Respiration based steering for high intensity focused ultrasound liver ablation.

Respiratory motion makes hepatic ablation using high intensity focused ultrasound (HIFO) challenging. Previous HIFU liver treatment had required apnea induced during general anesthesia. We describe and test a system that allows treatment of the liver in the presence of breathing motion.

In vivo MR acoustic radiation force imaging in the porcine liver.

PURPOSE High intensity focused ultrasound (HIFU) in the abdomen can be sensitive to acoustic aberrations that can exist in the beam path of a single sonication. Having an accurate method to quickly visualize the transducer focus without damaging tissue could assist with executing the treatment plan accurately and predicting these changes and obstacles. By identifying these obstacles, MR acoustic radiation force imaging (MR-ARFI) provides a reliable method for visualizing the transducer focus quickly without damaging tissue and allows accurate execution of the treatment plan. METHODS MR-ARFI was used to view the HIFU focus, using a gated spin echo flyback readout-segmented echo-planar imaging sequence. HIFU spots in a phantom and in the livers of five live pigs under general anesthesia were created with a 550 kHz extracorporeal phased array transducer initially localized with a phase-dithered MR-tracking sequence to locate microcoils embedded in the transducer. MR-ARFI spots were visualized, observing the change of focal displacement and ease of steering. Finally, MR-ARFI was implemented as the principle liver HIFU calibration system, and MR-ARFI measurements of the focal location relative to the thermal ablation location in breath-hold and breathing experiments were performed. RESULTS Measuring focal displacement with MR-ARFI was achieved in the phantom and in vivo liver. In one in vivo experiment, where MR-ARFI images were acquired repeatedly at the same location with different powers, the displacement had a linear relationship with power [y = 0.04x + 0.83 μm (R(2) = 0.96)]. In another experiment, the displacement images depicted the electronic steering of the focus inside the liver. With the new calibration system, the target focal location before thermal ablation was successfully verified. The entire calibration protocol delivered 20.2 J of energy to the animal (compared to greater than 800 J for a test thermal ablation). ARFI displacement maps were compared with thermal ablations during seven breath-hold ablations. The error was 0.83 ± 0.38 mm in the S/I direction and 0.99 ± 0.45 mm in the L/R direction. For six spots in breathing ablations, the mean error in the nonrespiration direction was 1.02 ± 0.89 mm. CONCLUSIONS MR-ARFI has the potential to improve free-breathing plan execution accuracy compared to current calibration and acoustic beam adjustment practices. Gating the acquisition allows for visualization of the focal spot over the course of respiratory motion, while also being insensitive to motion effects that can complicate a thermal test spot. That MR-ARFI measures a mechanical property at the focus also makes it insensitive to high perfusion, of particular importance to highly perfused organs such as the liver.

In Vitro Investigation of the Individual Contributions of Ultrasound-Induced Stable and Inertial Cavitation in Targeted Drug Delivery.

Ultrasound-mediated targeted drug delivery is a therapeutic modality under development with the potential to treat cancer. Its ability to produce local hyperthermia and cell poration through cavitation non-invasively makes it a candidate to trigger drug delivery. Hyperthermia offers greater potential for control, particularly with magnetic resonance imaging temperature measurement. However, cavitation may offer reduced treatment times, with real-time measurement of ultrasonic spectra indicating drug dose and treatment success. Here, a clinical magnetic resonance imaging-guided focused ultrasound surgery system was used to study ultrasound-mediated targeted drug delivery in vitro. Drug uptake into breast cancer cells in the vicinity of ultrasound contrast agent was correlated with occurrence and quantity of stable and inertial cavitation, classified according to subharmonic spectra. During stable cavitation, intracellular drug uptake increased by a factor up to 3.2 compared with the control. Reported here are the value of cavitation monitoring with a clinical system and its subsequent employment for dose optimization.

Ultrasound Activated Nano-Encapsulated Targeted Drug Delivery and Tumour Cell Poration

INTRODUCTION Recently, ultrasonic drug release has been a focus of many research groups for stimuli responsive drug release. It has been demonstrated that a focused ultrasound (FUS) beam rapidly increases the temperature at the focused tissue area. One potential mechanism of drug targeting is to utilize the induced heat to release or increase penetration of chemotherapy to cancer cells. The efficiency of targeted drug delivery may increase by using FUS beam in conjugation with nano--encapsulated drug carriers.The aim of this study is to investigate the effect of heat and ultrasound on the cellular uptake and therapeutic efficacy of an anticancer drug using Magnetic Resonance Imaging guided Focused Ultrasound (MRgFUS). MATERIALS AND METHODS Human KB cells (CCL-17 cells) were seeded into 96-well plates and heat treated at 37-55°C for 2-10 min. Cell viability was determined using the colorimetric MTT assay. The cells were also subjected to MRgFUS and the degree of cell viability was determined. These experiments were conducted using an ExAblate 2000 system (InSightec, Haifa, Israel) and a GE 1.5 T MRI system, software release 15. RESULTS We have observed a significant decrease in human KB cell viability due to heat (>41°C) in the presence of Doxorubicin (DOX), in comparison with DOX at normal culture temperature (37°C). The synergistic effect of heat with DOX may be explained by several mechanisms. One potential mechanism may be increased penetration of DOX to the cells during heating. In addition, we have shown that ultrasound induced cavitation causes cell necrosis. DISCUSSION AND FUTURE WORK: Further investigation is required to optimize the potential of MRgFUS to enhance cellular uptake of therapeutic agents. A novel delivery nano-vehicle developed by CapsuTech will be investigated with MRgFUS for its potential as a stimuli responsive delivery system.

Rapid HIFU autofocusing using the entire MR-ARFI image

Phase aberrations and attenuations caused by bone can defocus HIFU in the brain and organs behind the ribcage. To refocus the beam, MR-ARFI can be used to measure tissue displacements created by each element in the transducer, and optimize driving signal delays and amplitudes. We introduce a new MR-ARFI-based autofocusing method that requires many fewer image acquisitions than current methods. The method is validated in simulations of bone and brain HIFU transducers, and compared to a conventional method.

Applicator for in-vitro ultrasound-activated targeted drug delivery

Reducing toxicity and improving uptake of cancer drugs in tumors are important goals of targeted drug delivery (TDD). Ultrasonic drug release from various encapsulants has been a focus of many research groups. However, a single standard ultrasonic device, viable for use by biologists, is not currently present in the market. The device reported here is designed to allow investigation of the impact of ultrasound on cellular uptake and cell viability in-vitro. In it, single-element transducers with different operating frequencies are mounted below a standard 96-well plate. The plate is moved above the transducers, such that each line of wells can be sonicated at a different frequency. To assess the device, 96-well plates were seeded with cells and sonicated using different ultrasonic parameters, with and without doxorubicin. Cell viability was measured by colorimetric MTT assay and the uptake of doxorubicin by cells was also determined. The device proved to be highly viable in preliminary tests; it demonstrated that change in ultrasonic parameters produces different effect on cells. For example, increase in uptake of doxorubicin was demonstrated following ultrasound application. The growing interest in ultrasound-activated TDD emphasizes the need for standardization of the ultrasound device and the one reported here may offer some indications of how that may be achieved. It is planned to further improve the prototype by increasing the number of ultrasonic frequencies and degrees of freedom for each transducer.

Alternative Focal Spot Geometry for More Efficient HIFU Treatment Assessment

In this work a more time efficient approach for tissue assessment with MR‐ARFI is proposed. During HIFU treatments gadolinium‐free assessment of treated tissue is highly desirable. MR‐ARFI allows measuring tissue displacement in the focal spot. Therefore raster‐scanning the ultrasound focal spot through the tissue of interest can give information about tissue stiffness in the “probed” area. To enhance efficiency of such ultrasound “probing,” we replaced a conventional point focus with a line focus that allows greater area coverage during MR‐ARFI acquisitions. This approach was tested in a phantom and in ex vivo bovine muscle. The results of the study showed that the line focus produces a fairly uniform line shape focal spot in both temperature and displacement maps. Using one line focus position, the displacement maps obtained in the muscle tissue well depicted the difference in displacement in the area where lesion was created. This shows great potential for line focus geometry combined with MR‐ARFI as a...