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In JoVE (1)
Other Publications (12)
- Medical Physics
- Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
- Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
- Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
- Ultrasound in Medicine & Biology
- Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine
- The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society
- BMC Bioinformatics
- The Journal of the Acoustical Society of America
- The Journal of the Acoustical Society of America
- NMR in Biomedicine
- IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control
Articles by Randy King in JoVE
JoVE General
Long-term Imaging Mammalian Cells using Wide-Field Microscopy
Dept. of Cell Biology, Harvard Medical School
Other articles by Randy King on PubMed
The Use of Quantitative Temperature Images to Predict the Optimal Power for Focused Ultrasound Surgery: in Vivo Verification in Rabbit Muscle and Brain
In this study, we investigated the use of MRI-derived thermal imaging for determining the exposure parameters for focused ultrasound (FUS) surgery. Since the temperature rise induced by a FUS beam scales linearly with power, the temperature maps acquired during subthreshold sonications can be used to determine the power necessary to produce thermal tissue damage with a desired size. Thermal images acquired during multiple sonications delivered at different locations in rabbit thigh muscle and brain tissue in vivo were analyzed to test this hypothesis. First, the linearity of the induced temperature rise with the acoustic power was tested. Next, the temperature maps acquired during preliminary low power sonications were scaled up until the estimated size of the tissue damage was equal to the tissue damage size of subsequent high power sonications. A threshold thermal dose was used to estimate the onset of thermal damage. The predicted power (based on amount of scaling required to reach the target size) was then compared to the true high power value. Overall, the temperature rise varied linearly with power (slope of deltaThigh/deltaTlow vs Power(high)/Power(low) = 0.97, 0.93 for pairs of sonications at each location in brain, muscle). The predicted power matched the true high power in the brain sonications (slope = 1.04). The predicted power underestimated the true high power in the muscle sonications (slope = 0.87). This under-prediction was due to a deviation from linearity in those cases where tissue damage was detected in subsequent MR images (slope of deltaThigh/deltaTlow vs Power(high)/Power(low) = 1.02, 0.84 for no tissue damage, tissue damage). The source of this deviation was not clear from these experiments. Even with this underestimation of the power, this method will be useful because it will allow an estimate of the proper power to use during FUS surgery without exact knowledge of the tissue parameters.
MRI-guided Focused Ultrasound Surgery in the Brain: Tests in a Primate Model
MRI-guided focused ultrasound was tested in the brains of rhesus monkeys. Locations up to 4.8 cm deep were targeted. Focal heating was observed in all cases with MRI-derived temperature imaging. Subthreshold heating was observed at the focus when the ultrasound beam was targeted with low power sonications, and in the ultrasound beam path during high-power exposures. Lethal temperature values and histologically confirmed tissue damage were confined to the focal zone (e.g., not in the ultrasound beam path), except when the focus was close to the bone. In that case, damage to the neighboring brain tissue was observed. Focal lesions were observed on histological examination and, in some cases, in MR images acquired immediately after the ultrasound exposures. The capabilities demonstrated in this study will be of benefit for clinical ultrasound therapies in the brain.
MRI Monitoring of Heating Produced by Ultrasound Absorption in the Skull: in Vivo Study in Pigs
The purpose of this study was to test the utility of MR thermometry for monitoring the temperature rise on the brain surface and in the scalp induced by skull heating during ultrasound exposures. Eleven locations in three pigs were targeted with unfocused ultrasound exposures (frequency = 690 kHz; acoustic power = 8.2-16.5 W; duration = 20 s). MR thermometry (a chemical shift technique) showed an average temperature rise in vivo of 2.8 degrees C +/- 0.6 degrees C and 4.4 degrees C +/- 1.4 degrees C on the brain surface and scalp, respectively, at an acoustic power level of 10 W. The temperature rise on the scalp agreed with that measured with a thermocouple probe inserted adjacent to the skull (average temperature rise = 4.6 degrees C +/- 1.0 degrees C). Characterization of the transducer showed that the average acoustic intensity was 1.3 W/cm(2) at an acoustic power of 10 W. The ability to monitor the temperature rise next to the skull with MRI-based thermometry, as shown here, will allow for safety monitoring during clinical trials of transcranial focused ultrasound.
500-element Ultrasound Phased Array System for Noninvasive Focal Surgery of the Brain: a Preliminary Rabbit Study with Ex Vivo Human Skulls
The aim of this study was to test a prototype MRI-compatible focused ultrasound phased array system for trans-skull brain tissue ablation. Rabbit thigh muscle and brain were sonicated with a prototype, hemispherical 500-element ultrasound phased array operating at frequencies of 700-800 kHz. An ex vivo human skull sample was placed between the array and the animal tissue. The temperature elevation during 20-30-sec sonications was monitored using MRI thermometry. The induced focal lesions were observed in T2 and contrast-enhanced T1-weighted fast spin echo images. Whole brain histology evaluation was performed after the sonications. The results showed that sharp temperature elevations can be produced both in the thigh muscle and in the brain. High-power sonications (600-1080 W) produced peak temperatures up to 55 degrees C and focal lesions that were consistent with thermal tissue damage. The lesion size was found to increase with increasing peak temperature. The device was then modified to operate in the orientation that will be used in the clinic and successfully tested in phantom experiments. As a conclusion, this study demonstrates that it is possible to create ultrasound-induced lesions in vivo through a human skull under MRI guidance with this large-scale phased array.
MRI-guided Ultrasonic Heating Allows Spatial Control of Exogenous Luciferase in Canine Prostate
The need for efficient and controlled delivery is one of the major obstacles to clinical use of gene therapy. In this study, we investigated the use of magnetic resonance imaging-monitored ultrasound (US) to induce expression of luciferase after local injection of the construct Ad-HSP-Luc, an adenoviral vector containing a transgene encoding firefly luciferase under the control of the human hsp70B promoter. The hsp promoter allows induction of the associated transgene only in areas that are subsequently heated after infection. US imaging was used to guide the injection of purified virus into both lobes of the prostates of three beagles. At 48 h after injection, the left lobe of the prostate was heated using a 1.5-MHz US transducer driven by a multichannel radiofrequency system and employing an magnetic resonance imaging guidance system. High levels of luciferase expression were observed only in areas exposed to ultrasonic heating. This study demonstrates the feasibility of using ultrasonic heating to control transgene expression spatially using a minimally-invasive approach.
A Magnetic Resonance Imaging-compatible, Large-scale Array for Trans-skull Ultrasound Surgery and Therapy
Advances in ultrasound transducer array and amplifier technologies have prompted many intriguing scientific proposals for ultrasound therapy. These include both mildly invasive and noninvasive techniques to be used in ultrasound brain surgery through the skull. In previous work, it was shown how a 500-element hemisphere-shaped transducer could correct the wave distortion caused by the skull with a transducer that operates at a frequency near 0.8 MHz. Because the objective for trans-skull focusing is its ultimate use in a clinical context, a new hemispheric phased-array system has now been developed with acoustic parameters that are optimized to match the values determined in preliminary studies.
Ultrasound-accelerated Tissue Fixation/processing Achieves Superior Morphology and Macromolecule Integrity with Storage Stability
We demonstrate that high-frequency and high-intensity ultrasound (US) can be applied to both tissue fixation and tissue processing to complete the conventional overnight formalin-fixation and paraffin-embedding (FFPE) procedures within 1 hr. US-facilitated FFPE retains superior tissue morphology and long-term room temperature storage stability than conventional FFPE. There is less alteration of protein antigenicity after US-FFPE preservation so that rapid immunohistochemical reactions occur with higher sensitivity and intensity, reducing the need for antigen retrieval pretreatment. US-FFPE tissues present storage stability so that room temperature storage up to 7 years does not significantly affect tissue morphology, protein antigenic properties, RNA distribution, localization, and quantitation. In addition, during fixation, tissue displays physical changes that can be monitored and reflected as changes in transmission US signals. As far as we know, this is the first effort to monitor tissue physical changes during fixation. Further study of this phenomenon may provide a method to control and to monitor the level of fixation for quality controls. The mechanism of less alteration of protein antigenicity by US-FFPE was discussed.
Context Based Mixture Model for Cell Phase Identification in Automated Fluorescence Microscopy
Automated identification of cell cycle phases of individual live cells in a large population captured via automated fluorescence microscopy technique is important for cancer drug discovery and cell cycle studies. Time-lapse fluorescence microscopy images provide an important method to study the cell cycle process under different conditions of perturbation. Existing methods are limited in dealing with such time-lapse data sets while manual analysis is not feasible. This paper presents statistical data analysis and statistical pattern recognition to perform this task.
Acoustic Power Calibration of High-intensity Focused Ultrasound Transducers Using a Radiation Force Technique
To address the challenges associated with measuring the ultrasonic power from high-intensity focused ultrasound transducers via radiation force, a technique based on pulsed measurements was developed and analyzed. Two focused ultrasound transducers were characterized in terms of an effective duty factor, which was then used to calculate the power during the pulse at high applied power levels. Two absorbing target designs were used, and both gave comparable results and displayed no damage and minimal temperature rise if placed near the transducer and away from the focus. The method yielded reproducible results up to the maximum pulse power generated of approximately 230 W, thus allowing the radiated power to be calibrated in terms of the peak-to-peak voltage applied to the transducer.
Development and Characterization of a Blood Mimicking Fluid for High Intensity Focused Ultrasound
A blood mimicking fluid (BMF) has been developed for the acoustic and thermal characterizations of high intensity focused ultrasound (HIFU) ablation devices. The BMF is based on a degassed and de-ionized water solution dispersed with low density polyethylene microspheres, nylon particles, gellan gum, and glycerol. A broad range of physical parameters, including attenuation coefficient, speed of sound, viscosity, thermal conductivity, and diffusivity, were characterized as a function of temperature (20-70 degrees C). The nonlinear parameter B/A and backscatter coefficient were also measured at room temperature. Importantly, the attenuation coefficient is linearly proportional to the frequency (2-8 MHz) with a slope of about 0.2 dB cm(-1) MHz(-1) in the 20-70 degrees C range as in the case of human blood. Furthermore, sound speed and bloodlike backscattering indicate the usefulness of the BMF for ultrasound flow imaging and ultrasound-guided HIFU applications. Most of the other temperature-dependent physical parameters are also close to the reported values in human blood. These properties make it a unique HIFU research tool for developing standardized exposimetry techniques, validating numerical models, and determining the safety and efficacy of HIFU ablation devices.
T(2) Relaxation Times of (13)C Metabolites in a Rat Hepatocellular Carcinoma Model Measured in Vivo Using (13)C-MRS of Hyperpolarized [1-(13)C]pyruvate
A single-voxel Carr-Purcell-Meibloom-Gill sequence was developed to measure localized T(2) relaxation times of (13)C-labeled metabolites in vivo for the first time. Following hyperpolarized [1-(13)C]pyruvate injections, pyruvate and its metabolic products, alanine and lactate, were observed in the liver of five rats with hepatocellular carcinoma and five healthy control rats. The T(2) relaxation times of alanine and lactate were both significantly longer in HCC tumors than in normal livers (p < 0.002). The HCC tumors also showed significantly higher alanine signal relative to the total (13)C signal than normal livers (p < 0.006). The intra- and inter-subject variations of the alanine T(2) relaxation time were 11% and 13%, respectively. The intra- and inter-subject variations of the lactate T(2) relaxation time were 6% and 7%, respectively. The intra-subject variability of alanine to total carbon ratio was 16% and the inter-subject variability 28%. The intra-subject variability of lactate to total carbon ratio was 14% and the inter-subject variability 20%. The study results show that the signal level and relaxivity of [1-(13)C]alanine may be promising biomarkers for HCC tumors. Its diagnostic values in HCC staging and treatment monitoring are yet to be explored.
Development and Characterization of a Tissue-mimicking Material for High-intensity Focused Ultrasound
A tissue-mimicking material (TMM) for the acoustic and thermal characterization of high-intensity focused ultrasound (HIFU) devices has been developed. The material is a high-temperature hydrogel matrix (gellan gum) combined with different sizes of aluminum oxide particles and other chemicals. The ultrasonic properties (attenuation coefficient, speed of sound, acoustical impedance, and the thermal conductivity and diffusivity) were characterized as a function of temperature from 20 to 70°C. The backscatter coefficient and nonlinearity parameter B/A were measured at room temperature. Importantly, the attenuation coefficient has essentially linear frequency dependence, as is the case for most mammalian tissues at 37°C. The mean value is 0.64f(0.95) dB·cm(-1) at 20°C, based on measurements from 2 to 8 MHz. Most of the other relevant physical parameters are also close to the reported values, although backscatter signals are low compared with typical human soft tissues. Repeatable and consistent temperature elevations of 40°C were produced under 20-s HIFU exposures in the TMM. This TMM is appropriate for developing standardized dosimetry techniques, validating numerical models, and determining the safety and efficacy of HIFU devices.
