Intraoperative Magnetic Resonance Imaging and Magnetic Resonance Imaging-guided Therapy for Brain Tumors

Neuroimaging Clinics of North America. Nov, 2002  |  Pubmed ID: 12687918

Since their introduction into surgical practice in the mid 1990s, intraoperative MRI systems have evolved into essential, routinely used tools for the surgical treatment of brain tumors in many centers. Clear delineation of the lesion, "under-the-surface" vision, and the possibility of obtaining real-time feedback on the extent of resection and the position of residual tumor tissue (which may change during surgery due to "brain-shift") are the main strengths of this method. High-performance computing has further extended the capabilities of intraoperative MRI systems, opening the way for using multimodal information and 3D anatomical reconstructions, which can be updated in "near real time." MRI sensitivity to thermal changes has also opened the way for innovative, minimally invasive (LASER ablations) as well as noninvasive therapeutic approaches for brain tumors (focused ultrasound). Although we have not used intraoperative MRI in clinical applications sufficiently long to assess long-term outcomes, this method clearly enhances the ability of the neurosurgeon to navigate the surgical field with greater accuracy, to avoid critical anatomic structures with greater efficacy, and to reduce the overall invasiveness of the surgery itself.

Effects of Parameter Errors in the Simulation of Transcranial Focused Ultrasound

Physics in Medicine and Biology. Jan, 2002  |  Pubmed ID: 11814226

Previous numerical simulation work has supported experiments showing that a sharply focused transcranial ultrasound field can be generated for noninvasive therapy and surgery in the brain. The predicted pressure gain and optimal sonicating frequency could be affected by uncertainty in the simulation parameters. We estimate the effects of uncertainty in the speed of sound in the skull and brain, and in CT data that specifies the contour of the skull. The results of our simulations indicate that each of these errors may change the predicted pressure gain by up to a few percent, but the predicted optimal frequency is not significantly affected.

The Use of Quantitative Temperature Images to Predict the Optimal Power for Focused Ultrasound Surgery: in Vivo Verification in Rabbit Muscle and Brain

Medical Physics. Mar, 2002  |  Pubmed ID: 11929019

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.

The Temperature Dependence of Ultrasound-stimulated Acoustic Emission

Ultrasound in Medicine & Biology. Mar, 2002  |  Pubmed ID: 11978413

Given the high variability of tissue properties during sonication, temperature monitoring is one of the most crucial components for accurate thermal treatment of tissues with focused ultrasound and other thermotherapy devices. Recently, the method of ultrasound-stimulated acoustic emission (USAE) has been introduced as a potential method for measurements of mechanical properties of tissues. In this paper, the dependence of USAE on tissue temperature is determined. Because USAE depends on the acoustic and mechanical properties, both of which vary with temperature, it is hypothesized that the USAE signal is also temperature-dependent and in such a way that it can be used to guide thermal therapy. In a series of experiments, ex vivo porcine muscle and fat samples were exposed to ultrasound at power levels that induce temperature elevation. In both tissue types, below the coagulation threshold, the USAE amplitude was found to vary linearly with temperature. However, at higher powers, the correlation with temperature was lost due mainly to the irreversible nature of the changes in the tissue properties. Theoretical simulations were used to interpret the USAE response change with temperature involving both reversible and irreversible changes and during both heating and cooling. These results indicate that USAE may have important promise as a potential method for localizing temperature elevation and, thus, thermal surgery monitoring, as well as detection of irreversible changes in tissues.

Micro-receiver Guided Transcranial Beam Steering

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Apr, 2002  |  Pubmed ID: 11989700

A new method for focusing ultrasound energy in brain tissue through the skull is investigated. The procedure is designed for use with a therapeutic transducer array and a small catheter-inserted hydrophone receiver placed in the brain to guide the array's focus. When performed at high-intensity, a focal intensity on the order of several hundred watts per centimeter-squared is achieved, and cells within a target volume are destroyed. The present study tests the feasibility and range of the method using an ex vivo human skull. Acoustic phase information is obtained from the stationary receiver and used to electrically shift the beam to new locations as well as correct for aberrations due to the skull. The method is applied to a 104-element 1.1 MHz array and a 120-element 0.81 MHz array. Using these array configurations, it is determined that the method can reconstruct and steer a focus over a distance of 50 mm. Application of this minimally invasive technique for ultrasound brain therapy and surgery also is investigated in vitro with a 64-element 0.664 MHz hemisphere array designed for transskull surgery. Tissue is placed inside of a skull and a catheter-inserted receiver is inserted into the tissue. A focus intense enough to coagulate the tissue is achieved at a predetermined location 10 mm from the receiver, the maximum distance that this large element array can electronically steer the focus.

Magnetic Resonance Image-guided Focused Ultrasound Surgery

Cancer Journal (Sudbury, Mass.). May-Jun, 2002  |  Pubmed ID: 12075696

The powerful union of focused ultrasound and magnetic resonance imaging (MRI) has created a new approach to noninvasive surgery. By using this integrated therapy delivery system, the physician can correctly localize tumors, optimally target acoustic energy, monitor energy deposition in real time, and accurately control the deposited thermal dose within the entire tumor volume. This satisfies the requirements for "ideal surgery." In a real sense, MRI provides the "road map" by which focused ultrasound surgery (FUS) is followed. The advantages of MRI over ultrasound guidance in controlling FUS lie in the more sensitive detection of tumor target, the real-time detection of tissue temperature, and the confirmation of thermally induced tissue changes-powerful features that eventually can replace the traditional surgical approach. Applying software that connects the therapy and imaging system (the "Dosimetry Workstation"), the physician can generate an entire treatment plan from quantifying temperature changes to positioning the therapy transducer. The noninvasive debulking of tumors without disturbing adjacent, functionally intact structures is thereby accomplished.

Correlation of Ultrasound Phase with Physical Skull Properties

Ultrasound in Medicine & Biology. May, 2002  |  Pubmed ID: 12079698

Noninvasive treatment of brain disorders using focused ultrasound (US) requires a reliable model for predicting the distortion of the field due to the skull using physical parameters obtained in vivo. Previous studies indicate that control of US phase alone is sufficient for producing a focus through the skull using a phased US array. The present study concentrates on identifying methods to estimate phase distortion. This will be critical for the future clinical use of noninvasive brain therapy. Ten ex vivo human calvaria were examined. Each sample was imaged in water using computerized tomography (CT). The information was used to determine the inner and outer skull surfaces, thickness as a function of position, and internal structure. Phase measurement over a series of points was obtained by placing a skull fragment between a transducer and a receiver with the skull normal to the transducer. Correlation was found between the skull thickness and the US phase shift. A linear fit of the data follows that predicted by a homogeneous skull when average speed of sound 2650 m/s was used. Large variance (SD = 60 degrees, mean = 50 degrees ) indicates the additional role of internal bone speed and density fluctuations. In an attempt to reduce the variance, the skull was first studied as a three-layer structure. Next, density-dependent bone speed fluctuation was introduced to both the single-layer and three-layer models. It was determined that adjustment of the mean propagation speeds using density improves the overall phase prediction. Results demonstrate that it is possible to use thickness and density information from CT images to predict the US phase distortion induced by the skull accurately enough for therapeutic aberration correction. In addition, the measurements provide coefficients for phase dependence on skull thickness and density that can be used in clinical treatments.

Association of Rectal Toxicity with Thermal Dose Parameters in Treatment of Locally Advanced Prostate Cancer with Radiation and Hyperthermia

International Journal of Radiation Oncology, Biology, Physics. Jul, 2002  |  Pubmed ID: 12095557

Although hyperthermia has been used for more than two decades in the treatment of pelvic tumors, little is known about the potential impact of heat on rectal toxicity when combined with other treatment modalities. Because rectal toxicity is a concern with radiation and may be exacerbated by hyperthermia, definition of the association of thermal dose parameters with rectal toxicity is important. In this report, we correlate rectal toxicity with thermal dose parameters for patients treated with hyperthermia and radiation for prostate cancer.

Bio-acoustic Thermal Lensing and Nonlinear Propagation in Focused Ultrasound Surgery Using Large Focal Spots: a Parametric Study

Physics in Medicine and Biology. Jun, 2002  |  Pubmed ID: 12108775

It is well known that the acoustic properties of soft tissue have a dependence on tissue temperature. This is of particular interest in focused ultrasound surgery since the mechanism of action of focused ultrasound surgery is to kill targeted tissue by inducing localized heating by ultrasound absorption, and hence cautery of that tissue. However, the act of localized heating induces a change in the acoustic properties of the targeted tissue and tissue surrounding it. This phenomenon distorts the incoming acoustic wavefront, and has been termed the thermal lens effect for this reason. Furthermore, nonlinear effects in acoustic propagation become non-negligible at the ultrasound intensities required for therapeutic action. This paper examines the importance of the thermal lens effect and nonlinear tissue properties by simulating a variety of clinically applicable phased array transducer configurations that have not yet been appropriately analysed using a full three-dimensional nonlinear treatment of acoustic propagation. The significance of the thermal lens effect is characterized by comparing the simulation of coupled acoustic and thermal propagation with an uncoupled treatment; neglecting thermal lensing typically produces a movement of 1 to 2 mm in the predicted position of the focus towards the transducer. The results also show that the classical methods of acoustic propagation can produce grossly erroneous results under certain clinically relevant transducer configurations and that an acoustic field scan with a hydrophone may not accurately predict therapeutic effect.

A Unified Model for the Speed of Sound in Cranial Bone Based on Genetic Algorithm Optimization

Physics in Medicine and Biology. Nov, 2002  |  Pubmed ID: 12476974

The density and structure of bone is highly heterogeneous, causing wide variations in the reported speed of sound for ultrasound propagation. Current research on the propagation of high intensity focused ultrasound through an intact human skull for non-invasive therapeutic action on brain tissue requires a detailed model for the acoustic velocity in cranial bone. Such models have been difficult to derive empirically due to the aforementioned heterogeneity of bone itself. We propose a single unified model for the speed of sound in cranial bone based upon the apparent density of bone by CT scan. This model is based upon the coupling of empirical measurement, theoretical acoustic simulation and genetic algorithm optimization. The phase distortion caused by the presence of skull in an acoustic path is empirically measured. The ability of a theoretical acoustic simulation coupled with a particular speed-of-sound model to predict this phase distortion is compared against the empirical data, thus providing the fitness function needed to perform genetic algorithm optimization. By performing genetic algorithm optimization over an initial population of candidate speed-of-sound models, an ultimate single unified model for the speed of sound in both the cortical and trabecular regions of cranial bone is produced. The final model produced by genetic algorithm optimization has a nonlinear dependency of speed of sound upon local bone density. This model is shown by statistical significance to be a suitable model of the speed of sound in bone. Furthermore, using a skull that was not part of the optimization process, this model is also tested against a published homogeneous speed-of-sound model and shown to return an improved prediction of transcranial ultrasound propagation.

Interlaboratory Acoustic Power Measurement

Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine. Feb, 2003  |  Pubmed ID: 12562125

This article describes an American Institute of Ultrasound in Medicine-sponsored intercomparison of the results of acoustic power measurements performed by several laboratories.

MR Imaging-guided Focused Ultrasound Surgery of Uterine Leiomyomas: a Feasibility Study

Radiology. Mar, 2003  |  Pubmed ID: 12616023

The feasibility and safety of magnetic resonance (MR) imaging-guided focused ultrasound surgery for uterine leiomyomas is reported. Sequential sonications were delivered to nine targets. Temperature-sensitive phase-difference MR imaging monitored the location of the focus and measured tissue temperature elevations, ensuring therapeutic dose. MR images and hysterectomy specimens were evaluated. Six leiomyomas received full therapeutic doses, and 98.5% of the sonications were visualized. MR thermometry was successful in all sonications and cases. Focal necrotic lesions were seen in all cases at MR, and five were pathologically confirmed. MR imaging-guided focused ultrasound causes thermocoagulation and necrosis in uterine leiomyomas and is feasible and safe, without serious consequences.

Feasibility of Internally Referenced Brain Temperature Imaging with a Metabolite Signal

Magnetic Resonance in Medical Sciences : MRMS : an Official Journal of Japan Society of Magnetic Resonance in Medicine. Apr, 2003  |  Pubmed ID: 16210815

The feasibility of using a metabolite signal as an internal reference for self-referenced temperature distribution measurement was examined. Line scan echo-planar spectroscopic imaging (LSEPSI) was applied to obtain quick multi-voxel spectroscopic measurements and to avoid possible spectral degradation from motion. Temperature distribution in a rabbit brain in vivo was successfully visualized by means of the chemical shift of water, which was measured by using naturally abundant (up to 10 mM) N-acetyl-aspartate (NAA) as the reference signal. Unlike the phase-mapping approach, this technique does not require a pixel-by-pixel subtraction. Therefore, in theory, it is more resistant to inter-scan motion or changes in susceptibility. The spatial and temporal resolutions of this technique are 1.5 cm3 and 4.5 min. A higher signal-to-noise ratio and optimization of the water and outer-volume suppression capabilities will be required to further enhance the temperature-mapping capabilities.

The Threshold for Brain Damage in Rabbits Induced by Bursts of Ultrasound in the Presence of an Ultrasound Contrast Agent (Optison)

Ultrasound in Medicine & Biology. Mar, 2003  |  Pubmed ID: 12706199

The purpose of this study was to test the hypothesis that burst ultrasound (US) in the presence of a US contrast agent using parameters similar to those used in brain blood flow measurements causes tissue damage. The brains of 10 rabbits were sonicated in 3-8 locations with 1.5-MHz, 10- micro s bursts repeated at a frequency of 1 kHz at temporal peak acoustic pressure amplitudes ranging from 2 to 12.7 MPa. The total sonication time for each location was 20 s. Before each sonication, a bolus of US contrast agent was injected IV. Contrast-enhanced magnetic resonance (MR) images were obtained after the sonications to detect local enhancement in the brain. Whole brain histological evaluation was performed, and the sections were stained with hematoxylin and eosin (H and E), TUNEL, and vanadium acid fuchsin (VAF) staining to evaluate tissue effects, including apoptosis and ischemia. Both the magnetic resonance imaging (MRI) contrast enhancement and histology findings indicated that brain tissue damage was induced at a pressure amplitude level of 6.3 MPa. The damage included vascular wall damage, hemorrhage and, eventually, necrosis. Mild vascular damage was observed localized in a few microscopic tissue volumes in about half of the sonicated locations at all pressure values tested (down to 2 MPa). However, these sonications did not induce any detectable tissue effects, including ischemia or apoptosis. As a conclusion, the study showed that the US exposure levels currently used for blood flow measurements in brain are below the threshold of blood-brain barrier opening or brain tissue damage. However, one should be aware that brain damage can be induced if the exposure level is increased.

MRI-guided Focused Ultrasound Surgery in the Brain: Tests in a Primate Model

Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. Jun, 2003  |  Pubmed ID: 12768598

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.

The Use of Ultrasound-stimulated Acoustic Emission in the Monitoring of Modulus Changes with Temperature

Ultrasonics. Jul, 2003  |  Pubmed ID: 12788215

It has been previously shown that the amplitude of the ultrasound-stimulated acoustic emission (USAE) signal is sensitive to tissue temperature and, therefore, can help detect it. Its amplitude, however, is sensitive to both acoustical and mechanical parameters, that at most frequencies have opposite effects due to temperature. In this paper, we explore the feasibility of using a frequency shift of the resonant peaks of the USAE signal for monitoring the tissue stiffness variation with temperature. In a numerical simulation, the variation of the frequency shift at different temperatures is shown. Then, in a series of experiments involving a gel phantom and porcine muscle tissue, the frequency shift variation is shown to follow the known stiffness changes due to temperature. It is also shown that this shift indicates reversible changes as well as the onset of thermal coagulative necrosis. The necrosis is marked by a monotonically increasing positive frequency shift. It was thus shown that the USAE spectrum peaks undergo a negative shift (or, downshift) when the stiffness decreases and a positive shift (or, upshift) when the stiffness increases. The experimental frequency shifted around a peak at 22.1-22.5 kHz within a range of -250 to 80 Hz and -200 to 250 Hz for the gel and muscle tissue for the temperatures of 25-70 and 30-70 degrees C, respectively. Simulation and ex vivo experimental results indicate that the USAE frequency shift method can help decouple the mechanical from the acoustical parameter dependence as well as detect the onset of thermal coagulative necrosis.

Ultrasound-mediated Cavitation Thresholds of Liquid Perfluorocarbon Droplets in Vitro

Ultrasound in Medicine & Biology. Sep, 2003  |  Pubmed ID: 14553814

This study was undertaken to measure the ultrasound (US)-mediated cavitation threshold of microdroplets as a function of its content and US parameters (frequency, amplitude and burst length). Albumin-coated droplets were prepared with perfluoropropane, perfluorohexane or perfluoromethylcyclohexane contents. The filtered suspensions were diluted to 1:1000 (v) and compared with Optison. The formulations were injected into an acoustically transparent vessel and sonicated with a single focused transducer. The frequencies employed were 0.74, 1.1, 2.18 and 3.3 MHz and the burst length and acoustic pressure were varied. The inertial cavitation threshold for each experiment was monitored through passive acoustic detection. The formation of droplet emulsion of the perfluorocarbon increased the natural boiling point of the perfluorocarbon. However, perfluorocarbon droplets having contents with higher molecular weights and boiling points did not have detectably higher inertial cavitation thresholds and, thus, the droplets do not need to be in a superheated state to be cavitated by US bursts. Therefore, higher boiling point perfluorocarbons should be investigated for this purpose and may prove to be useful for both imaging and therapy. The inertial cavitation threshold of perfluorocarbon droplets increases with frequency, and was approximately 0.7 MPa at 0.74 MHz and 1.75 MPa at 3.3 MHz. Optison, already in a gaseous state, has the lowest cavitation threshold of all formulations studied. Results show that, for the frequencies tested, there is no dependence between inertial cavitation threshold and burst lengths between 20 and 100 ms. As a conclusion, the inertial cavitation threshold of albumin-coated microdroplets of several perfluorocarbons was determined in vitro. The results indicate that the physical properties of these droplets are such that they may be useful for localized US therapies.

Localized Harmonic Motion Imaging: Theory, Simulations and Experiments

Ultrasound in Medicine & Biology. Oct, 2003  |  Pubmed ID: 14597337

Several techniques have been developed in an effort to estimate mechanical properties of tissues. These techniques typically estimate static or harmonic motion resulting from an externally or internally applied mechanical stimulus. In this paper, we discuss the advantages of utilizing a new technique that performs radiofrequency (RF) signal tracking to estimate the localized oscillatory motion resulting from the harmonic radiation force produced by two focused ultrasound (US) transducer elements with overlapping beams oscillating at distinct frequencies. Finite-element and Monte-Carlo simulations were performed to characterize the range of oscillatory displacements produced by a harmonic radiation force. In the experimental verification, three transducers were used: two single-element focused transducers and one lead zirconate-titanate (PZT) composite 16-element probe. Four agar gels were utilized to determine the effect of stiffness on the motion amplitude. Estimates of the displacement relative to the initial position (i.e., at the onset of the application of the radiation force) were obtained during the application of the radiation force that oscillated at frequencies ranging between 200 Hz and 800 Hz. In the simulations, the estimated oscillatory displacement spanned from -800 to 600 microm and the frequencies of excitation could easily be estimated from the temporal variation of the displacement. In addition, a frequency upshift (on the order of tens of Hz) was estimated with stiffness increase. Furthermore, an exponential decrease of the displacement amplitude with stiffness was observed at all frequencies investigated. An M-mode version to depict both the spatial and temporal variations of the locally induced displacement was used. In experiments with gels of different stiffness, the resulting amplitude of the harmonic displacement estimated oscillated at the same frequencies and ranged from -300 to 250 microm. An exponential decrease of the displacement amplitude with the gel stiffness was also observed. In tissue experiments, the results showed that the method is feasible in tissues and that focused US surgery (FUS) ablation can be detected. These preliminary results demonstrate the feasibility of imaging localized harmonic motion as induced by an oscillatory US radiation force. Due to the highly localized and harmonic nature of the estimated response, this technique may be proven to be highly suitable for simple and accurate estimation of the elastic modulus variation in tissues due to disease.

Modeling of Anomalies Due to Hydrophones in Continuous-wave Ultrasound Fields

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Nov, 2003  |  Pubmed ID: 14682632

Needle and spot-poled membrane hydrophones using polyvinylidene fluoride (PVDF) sensors are widely used for characterization of biomedical ultrasound fields. It is known that, in measurements of continuous-wave (CW) fields, standing waves may be generated between the transducer and the hydrophone, distorting the field and possibly alternating the signal of the hydrophone. This study uses a three-dimensional, full-wave method to computationally simulate the distortion in the CW field caused by needle and membrane hydrophones. The physical model used in simulations is based on the linear time-harmonic wave equation, which therefore neglects the effects of nonlinear wave propagation. The significance of the distortion is examined by comparing fields emitted by 0.5-5.0 MHz planar circular transducers in the absence and presence of the hydrophones. In addition, the effect of the field distortions on the signal of the hydrophones is studied with simulated measurements. The simulations showed an observable standing wave pattern between the source and the needle hydrophone if the diameter of the needle was larger than a half of the wavelength. However, the standing waves had no clear effect on the signal of the hydrophone. The presence of membrane hydrophone in the CW field generated notable standing waves. Furthermore, the standing waves caused a periodic distortion to the signal of the membrane hydrophone.

Forward Planar Projection Through Layered Media

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Dec, 2003  |  Pubmed ID: 14761040

A planar forward projection algorithm is combined with ray theory to describe longitudinal propagation through an arbitrary number of randomly oriented isotropic layers. This method first measures the space-time pressure field in a plane, then uses wavevector frequency-domain methods to project the field through layered media and to an arbitrary new plane, not necessarily parallel to the initial plane. The approach is valid for longitudinal propagation through liquid layers and in solids, such as soft tissues, that can be approximated as viscous liquids. The algorithm is verified by propagating the field from a 0.5 MHz planar transducer through a combination of rubber, plastic, and water layers. Hydrophone measurements indicate correlation between measured and simulated fields for angles below the longitudinal critical angles of the layered materials.

Heat-activated Liposomal MR Contrast Agent: Initial in Vivo Results in Rabbit Liver and Kidney

Radiology. Mar, 2004  |  Pubmed ID: 14764890

To evaluate by using in vivo magnetic resonance (MR) imaging the functionality of a liposomal paramagnetic contrast agent with T1 relaxivity that rapidly and markedly increases at temperatures above the gel-to-liquid crystalline phase transition temperature (T(c)) of the liposome membrane.

Optical Monitoring of Ultrasound-induced Bioeffects in Glass Catfish

Ultrasound in Medicine & Biology. Jan, 2004  |  Pubmed ID: 14962610

This study is an investigation of the therapeutic ultrasound (US) effects on the blood vessels of optically transparent fish in vivo. Although many investigators have characterized cavitation in vivo using remote-sensing methods (i.e., measuring the acoustic emissions caused by oscillating bubbles) very few have made direct observations of cavitation-induced damage. Anesthetized glass catfish, which are optically transparent, was injected with the contrast agent, Optison, and then insonified at pressures that ranged from 0.5-10 MPa (peak negative pressures). Two focused transducers were used in these experiments to cover a frequency range of 0.7-3.3 MHz. Sonications were pulsed with pulse durations of 100, 10, 1, 0.1 and 0.01 ms and a pulse repetition frequency (PRF) of 1 Hz. The entire length of one sonication at a specific pressure level was 20 s. An inverted microscope combined with a digital camera and video monitor were used optically to monitor and record US interaction with the blood vessels in the tail of the anesthetized fish at 200x magnification. The effects of the burst sonication were analyzed visually at each pressure level. For the 1.091-MHz sonications, the first type of damage that occurred due to the US interaction was structural damage to the cartilage rods that comprise the tail of the fish, and was characterized by a disintegration of the lining of the rod. Damage to the rods occurred, starting at 3.5 MPa, 3.1 MPa, 4.1 MPa and 5.5 MPa for the 100-ms, 10-ms, 1-ms and 100-micros sonications, respectively. The formation of large gas bubbles was observed in the blood vessels of the fish at threshold values of 3.8 MPa, 3.8 MPa and 5.3 MPa, for the 100-ms, 10-ms and 1-ms sonications, respectively. Neither gas bubble formation nor hemorrhaging was observed during 100-micros sonications. Bubble formation was always accompanied by an increase of damage to the rods at the area surrounding the bubble. At 1.091 MHz, petechial hemorrhage thresholds were observed at 4.1 MPa, 4.1 MPa and 6.1 MPa, respectively, for the three pulse durations. The thresholds for damage were the lowest for the 0.747-MHz sonications: they were 2.6 MPa for damage to the rods, 3.7 MPa for gas bubble formation and 2.4 MPa for hemorrhaging.

MRI Investigation of the Threshold for Thermally Induced Blood-brain Barrier Disruption and Brain Tissue Damage in the Rabbit Brain

Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. May, 2004  |  Pubmed ID: 15122673

The ability of MRI-derived thermometry to predict thermally induced tissue changes in the brain was tested, and the thermal thresholds for blood-brain barrier (BBB) disruption and brain tissue damage were estimated. In addition, the ability of standard MRI to detect threshold-level effects was confirmed. These safety thresholds are being investigated to provide guidelines for clinical thermal ablation studies in the brain. MRI-monitored focused ultrasound heating was delivered to 63 locations in 26 rabbits. Tissue changes were detected in T(2)-weighted imaging and T(1)-weighted imaging (with and without contrast) and with light microscopy. The probability for tissue damage as a function of the accumulated thermal dose, the peak temperature achieved, the applied acoustic energy, and the peak acoustic power was estimated with probit regression. The discriminative abilities of these parameters were compared using the areas under the receiver operator characteristic (ROC) curves. In MRI, BBB disruption was observed in contrast-enhanced T(1)-weighted imaging shortly after the ultrasound exposures, sometimes accompanied by changes in T(2)-weighted imaging. Two days later, changes in T(2)-weighted imaging were observed, sometimes accompanied by changes in T(1)-weighted imaging. In histology, tissue damage was seen at every location where MRI changes were observed, ranging from small (diameter <1.0 mm) areas of tissue necrosis to severe vascular damage and associated hemorrhagic infarct. In one location, small (diameter: 0.8 mm) damage was not detected in MRI. The thermal dose and peak temperature thresholds were between 12.3-40.1 equivalent min at 43 degrees C and 48.0-50.8 degrees C, respectively, and values of 17.5 equivalent min at 43 degrees C and 48.4 degrees C were estimated to result in tissue damage with 50% probability. Thermal dose and peak temperature were significantly better predictors than the applied acoustic energy and peak acoustic power (P < 0.01). BBB disruption was always accompanied by tissue damage. The temperature information was better than the applied acoustic power or energy for predicting the damage than the ultrasound parameters. MRI was sensitive in detecting threshold-level damage.

MRI Monitoring of Heating Produced by Ultrasound Absorption in the Skull: in Vivo Study in Pigs

Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. May, 2004  |  Pubmed ID: 15122691

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.

Simulation Study for Thermal Dose Optimization in Ultrasound Surgery of the Breast

Medical Physics. May, 2004  |  Pubmed ID: 15191322

In this paper the previously published optimization algorithm for thermal dose optimization is tested with numerical simulations. The simulations concern the thermal dose optimization in ultrasound surgery of the breast. The optimization algorithm is extended by setting the inequality constraint approximations to temperature in healthy tissue as well as in tumor region. In addition, the simulations are accomplished in realistic 3D geometry with varying thermal parameters. Another topic of the paper is to show the potential of the hemispherical phased array applicator for ultrasound surgery of the breast. With such an applicator larger tissue volumes can be treated with shorter time as compared to single element transducers. In simulations the geometrical focus of the applicator was placed mechanically in the middle of the treatable region. The whole tumor region was then scanned electrically by changing the phase of the emitted wave from individual elements. The simulations indicate that a feasible treatment plan can be achieved. In simulated cases the desired thermal dose was achieved for tumors with diameter from 1.5 to 2.4 cm, depending on the position of tumor. The maximum temperature limitations of 45 degrees C in healthy region and 80 degrees C in tumor region can be maintained in all simulations.

Apoptosis Signals in Lymphoblasts Induced by Focused Ultrasound

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Sep, 2004  |  Pubmed ID: 15231731

We investigated the effects of focused ultrasound (FUS) on specific molecular signaling and cellular response in three closely related human Tk6 lymphoblast cell lines that differed only in their p53 status. The applied ultrasound parameters fell between the physical dose range, which is safely used in medical diagnostics (peak pressure<0.1 MPa) and that used for high-energy FUS thermal ablation therapy (peak pressure>10 MPa). Based on cDNA microarrays and protein analysis, we found that FUS at the intermediate peak pressure of 1.5 MPa induced a complex signaling cascade with upregulation of proapoptotic genes [e.g., p53, p21, Thy1 (CD 90)]. Simultaneously, FUS downregulated cellular survival components (e.g., bcl-2, SOD). The p53 status was important for the reaction of the cells to ultrasound. Apoptosis and G1 arrest were induced primarily in p53+ cells, while p53- cells showed less apoptosis but exhibited G2 arrest. Likewise, the proliferation of lymphoblasts was much more strongly inhibited in p53+ than in p53- cells. Microarray analysis further demonstrated an upregulation of genes involved in oxidative stress (e.g., ferritin), suggesting that indirect sonochemical effects via reactive oxygen species play a causative role in the interaction of ultrasound with lymphoblasts. An important characteristic of FUS in therapeutic ultrasound applications is its ability to be administered to the human body in a targeted manner while sparing intermediate tissues. Therefore, our data indicate that this noninvasive, mechanical wave transmission, which is free of ionizing radiation, has the potential to specifically induce localized cell signals and apoptosis.

500-element Ultrasound Phased Array System for Noninvasive Focal Surgery of the Brain: a Preliminary Rabbit Study with Ex Vivo Human Skulls

Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. Jul, 2004  |  Pubmed ID: 15236372

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.

Cellular Mechanisms of the Blood-brain Barrier Opening Induced by Ultrasound in Presence of Microbubbles

Ultrasound in Medicine & Biology. Jul, 2004  |  Pubmed ID: 15313330

Local blood-brain barrier (BBB) opening is an advantageous approach for targeted drug delivery to the brain. Recently, it has been shown that focused ultrasound (US) exposures (sonications), when applied in the presence of preformed gas bubbles, caused magnetic-resonance (MR) proven reversible opening of the BBB in targeted locations. The cellular mechanisms of such transient barrier disruption are largely unknown. We investigated US-induced changes in endothelial cell fine morphology that resulted in the BBB opening in rabbits. To obtain evidence for the passage of blood-borne macromolecules through the opened transvascular routes, an immunocytochemical procedure for endogenous immunoglobulinG (IgG) was performed, in addition to the routine electron microscopy. An increased number of vesicles and vacuoles, fenestration and channel formation, as well as opening of some tight junctions, were seen in capillaries after low-power (0.55 W) sonication. Immunosignals presented in some of the vesicles and vacuoles, in the cytoplasmic channels and, so rarely, in intercellular clefts; immunosignals could also be seen in neuropil around the blood vessels. Damage to the cellular ultrastructure was not seen in these areas. However, cell destruction and leakage of IgG through defects of the endothelial lining took place at 3 W sonications. The data reveals that several mechanisms of transcapillary passage are possible after such sonications: 1. transcytosis; 2. endothelial cell cytoplasmic openings--fenestration and channel formation; 3. opening of a part of tight junctions; and 4. free passage through the injured endothelium (with the higher power sonications). These findings could be considered in further development of the strategy for drug delivery to brain parenchyma.

Patterns of Thermal Deposition in the Skull During Transcranial Focused Ultrasound Surgery

IEEE Transactions on Bio-medical Engineering. Oct, 2004  |  Pubmed ID: 15490817

The induction of temperature elevation by focused ultrasound is a noninvasive surgical technique for destroying tissue. This technique has been used clinically in soft tissues such as liver, prostate and breast. It has long been desired to extend this technique to noninvasive treatment of brain tumors. Although the skull was once thought to be an unsurpassable barrier to focused ultrasound treatment, it has been shown that the distortion caused by the skull can be corrected to produce a useful intracranial focus. However, the attenuation experienced by the ultrasound in passing through cranial bone is large, and consequently the skull is subject to the deposition of acoustic energy as heat. The nature and extent of this heating process has been difficult to characterize empirically. It is practically difficult to implant a sufficient number of thermocouples to obtain detailed temperature data directly, and bone is an unsuitable medium in which to perform noninvasive thermometry using proton chemical shift magnetic resonance imaging. Furthermore, skull specimens used experimentally lack active blood perfusion of the skull and the overlying scalp. This paper describes the use of large-scale acoustic and thermal simulations to calculate the distribution of temperature within the skull and brain that can be expected to occur during therapeutically useful focused ultrasound sonications of the brain. The results demonstrate that standing waves may be formed within the skull during transcranial sonication leading to nonuniform skull heating. However, the results also show that these effects can be sufficiently controlled to allow therapeutic ultrasound to be focused in the cranial base region of the brain without causing thermal damage to the scalp, skull or outer surface of the brain.

Noninvasive Thermal Ablation of Hepatocellular Carcinoma by Using Magnetic Resonance Imaging-guided Focused Ultrasound

Gastroenterology. Nov, 2004  |  Pubmed ID: 15508090

A number of minimally invasive methods have been tested for the thermal ablation of liver tumors as an alternative to surgical resection. The use of focused ultrasound transducers to ablate deep tumors offers the first completely noninvasive alternative to these techniques. By increasing the flexibility of this technology with modern phased-array transducer design and by combining it with magnetic resonance imaging for targeting and online guidance, a powerful tool results with the potential to offer treatment to a larger population of patients, to reduce trauma to the patient, and to reduce the cost of treatment. In this article, we review previous work with focused ultrasound in the liver and recent experimental results with magnetic resonance imaging guidance.

Local and Reversible Blood-brain Barrier Disruption by Noninvasive Focused Ultrasound at Frequencies Suitable for Trans-skull Sonications

NeuroImage. Jan, 2005  |  Pubmed ID: 15588592

The purpose of this study was to test the hypothesis that burst ultrasound in the presence of an ultrasound contrast agent can disrupt the blood-brain barrier (BBB) with acoustic parameters suitable for completely noninvasive exposure through the skull. The 10-ms exposures were targeted in the brains of 22 rabbits with a frequency of 690 kHz, a repetition frequency of 1 Hz, and peak rarefactional pressure amplitudes up to 3.1 MPa. The total exposure (sonication) time was 20 s. Prior to each sonication, a bolus of ultrasound contrast agent was injected intravenously. Contrast-enhanced MR images were obtained after the sonications to detect localized BBB disruption via local enhancement in the brain. Brain sections were stained with H&E, TUNEL, and vanadium acid fuchsin (VAF)-toluidine blue staining. In addition, horseradish peroxidase (HRP) was injected into four rabbits prior to sonications and transmission electron microscopy was performed. The MRI contrast enhancement demonstrated BBB disruption at pressure amplitudes starting at 0.4 MPa with approximately 50%; at 0.8 MPa, 90%; and at 1.4 MPa, 100% of the sonicated locations showed enhancement. The histology findings following 4 h survival indicated that brain tissue necrosis was induced in approximately 70-80% of the sonicated locations at a pressure amplitude level of 2.3 MPa or higher. At lower pressure amplitudes, however, small areas of erythrocyte extravasation were seen. The electron microscopy findings demonstrated HRP passage through vessel walls via both transendothelial and paraendothelial routes. These results demonstrate that completely noninvasive focal disruption of the BBB is possible.

A Numerical Study of Transcranial Focused Ultrasound Beam Propagation at Low Frequency

Physics in Medicine and Biology. Apr, 2005  |  Pubmed ID: 15815098

The feasibility of transcranial ultrasound focusing with a non-moving phased array and without skull-specific aberration correction was investigated using computer simulations. Three cadaver skull CT image data sets were incorporated into an acoustic wave transmission model to simulate transskull ultrasound wave propagation. Using a 0.25 MHz hemispherical array (125 mm radius of curvature, 250 mm diameter, 24 255 elements), the simulated beams could be focused and steered with transducer element driving phases and amplitude adjusted for focal beam steering in water (water-path). A total of 82 foci, spanning wide ranges of distance in the three orthogonal dimensions, were simulated to test the focal beam steering capability inside the three skulls. The acoustic pressure distribution in a volume of 20 x 20 x 20 mm(3) centred at each focus was calculated with a 0.5 mm spacing in each axis. Clearly defined foci were retained through the skulls (skull-path) in most cases. The skull-path foci were on average 1.6 +/- 0.8 mm shifted from their intended locations. The -3 dB skull-path beam width and length were on average 4.3 +/- 1.0 mm and 7.7 +/- 1.8 mm, respectively. The skull-path sidelobe levels ranged from 25% to 55% of the peak pressure values. The skull-path peak pressure levels were about 10%-40% of their water-path counterparts. Focusing low-frequency beam through skull without skull-specific aberration correction is possible. This method may be useful for applying ultrasound to disrupt the blood-brain barrier for targeted delivery of therapeutic or diagnostic agents, or to induce microbubbles, or for other uses of ultrasound in brain where the required power levels are low and the sharp focusing is not needed.

A Full-wave Helmholtz Model for Continuous-wave Ultrasound Transmission

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Mar, 2005  |  Pubmed ID: 15857048

A full-wave Helmholtz model of continuous-wave (CW) ultrasound fields may offer several attractive features over widely used partial-wave approximations. For example, many full-wave techniques can be easily adjusted for complex geometries, and multiple reflections of sound are automatically taken into account in the model. To date, however, the full-wave modeling of CW fields in general 3D geometries has been avoided due to the large computational cost associated with the numerical approximation of the Helmholtz equation. Recent developments in computing capacity together with improvements in finite element type modeling techniques are making possible wave simulations in 3D geometries which reach over tens of wavelengths. The aim of this study is to investigate the feasibility of a full-wave solution of the 3D Helmholtz equation for modeling of continuous-wave ultrasound fields in an inhomogeneous medium. The numerical approximation of the Helmholtz equation is computed using the ultraweak variational formulation (UWVF) method. In addition, an inverse problem technique is utilized to reconstruct the velocity distribution on the transducer which is used to model the sound source in the UWVF scheme. The modeling method is verified by comparing simulated and measured fields in the case of transmission of 531 kHz CW fields through layered plastic plates. The comparison shows a reasonable agreement between simulations and measurements at low angles of incidence but, due to mode conversion, the Helmholtz model becomes insufficient for simulating ultrasound fields in plates at large angles of incidence.

Intracellular Delivery of Bak BH3 Peptide by Microbubble-enhanced Ultrasound

Pharmaceutical Research. May, 2005  |  Pubmed ID: 15906165

To investigate the possibility of intracellular delivery of Bak BH3 peptide using sonoporation effect by microbubble-enhanced ultrasound.

A New Ultrasound Method for Determining the Acoustic Phase Shifts Caused by the Skull Bone

Ultrasound in Medicine & Biology. Jun, 2005  |  Pubmed ID: 15936493

A potential noninvasive means for obtaining the value of ultrasound (US) phase shifts caused by the skull is examined. Knowledge of these shifts could be used in new methods that restore the focus from an US array after transcranial propagation. In the present study, a pulsed signal was emitted from a single element of a therapeutic US transducer. The reflected signal was then recorded. The data were examined over the band width of the transducer, producing amplitude data as a function of frequency. A periodic appearance of local maxima and minima was observed in the data as a function of frequency. We hypothesize that the amplitude is primarily determined by the superposition of the reflections between the interfaces at the inner and outer surfaces of the skull and between the interior interfaces of trabecular and cortical bone. A homogeneous-layer model was used to predict the forward-propagated phase using the reflection data. Good correlation was found between the numeric calculation and phases measured after propagation through single-layer plastic plates. The method was used on curved three-layer plastic phantoms and four excised human skulls. The procedure could eventually be applied toward phasing multielement arrays. Such an application could have implications in both therapeutic and diagnostic brain procedures.

MRI-guided Ultrasonic Heating Allows Spatial Control of Exogenous Luciferase in Canine Prostate

Ultrasound in Medicine & Biology. Jul, 2005  |  Pubmed ID: 15972202

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.

Focal Beam Distortion and Treatment Planning in Abdominal Focused Ultrasound Surgery

Medical Physics. May, 2005  |  Pubmed ID: 15984679

Recent clinical trials show promising results in using MRI and MRI-based thermometry to guide focused ultrasound surgery to treat uterine fibroids. During treatment, large variation in the focal temperature distribution has been observed. It is possible that some of this variation is due to abdominal tissue inhomogeneity, which might be causing focal beam distortion, and might largely decrease the focusing ability in deep-seated tissues. The purpose of this study was to numerically demonstrate this effect and also show the feasibility of restoring the focal beam patterns by employing the phase correction procedure for phased arrays. Abdominal MR data from four uterine fibroid patients were obtained to reconstruct the three-dimensional meshes of interfaces used in simulations, and one patient was selected to perform the analysis of key parameters in focused ultrasound surgery. Results show that, without phase correction, the focused beam can be severely distorted while using a frequency above 1 MHz or delivering ring-shape focal patterns. Different focal positions at the same depth may require a different power to induce the same ultrasonic intensity level (up to 179% among the different focal patterns). After adding a phase correction procedure, the distorted focal beams can be restored, and the peak intensity can be largely recovered (up to 85% among the different focal patterns). This study may offer important implications and information for treatment planning toward optimizing focused ultrasound surgery in uterine fibroid or other abdominal tumor treatments.

Scanning Path Optimization for Ultrasound Surgery

Physics in Medicine and Biology. Aug, 2005  |  Pubmed ID: 16030378

One of the problems in ultrasound surgery is the long treatment times when large tumour volumes are sonicated. Large tumours are usually treated by scanning the tumour volume using a sequence of individual focus points. During the scanning, it is possible that surrounding healthy tissue suffers from undesired temperature rise. The selection of the scanning path so that the tumour volume is treated as fast as possible while temperature rise in healthy tissue is minimized would increase the efficiency of ultrasound surgery. The main purpose of this paper is to develop a computationally efficient method which optimizes the scanning path. The optimization algorithm is based on the minimum time formulation of the optimal control theory. The developed algorithm uses quadratic cost criteria to obtain the desired thermal dose in the tumour region. The derived method is evaluated with numerical simulations in 3D which are applied to ultrasound surgery of the breast in simplified geometry. Results from the simulations show that the treatment time as well as the total applied energy can be decreased from 16% to 43% as compared to standard sonication. The robustness of the optimized scanning path is studied by varying the perfusion and absorption in the tumour region.

A Magnetic Resonance Imaging-compatible, Large-scale Array for Trans-skull Ultrasound Surgery and Therapy

Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine. Aug, 2005  |  Pubmed ID: 16040827

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.

A Novel Method for the Intracellular Delivery of SiRNA Using Microbubble-enhanced Focused Ultrasound

Biochemical and Biophysical Research Communications. Sep, 2005  |  Pubmed ID: 16081042

Short interfering RNA (siRNA) has attracted much attention for clinical use in various diseases. However, its delivery, especially through the cell membrane, continues to present a challenge. Advances in ultrasound- and ultrasound contrast-agent technologies have made it possible to change transiently the permeability of the cell membrane and, using a focused ultrasound transducer, to narrow and focus the ultrasound energy on a small target, thereby avoiding damage to surrounding tissue. In this in vitro study, we demonstrate that it is possible to deliver siRNA intracellularly via microbubble-enhanced focused ultrasound. Although further optimization is necessary, our novel method for siRNA transduction represents a powerful tool for using siRNA in vivo and possibly in the clinical setting.

MR Imaging-controlled Focused Ultrasound Ablation: a Noninvasive Image-guided Surgery

Magnetic Resonance Imaging Clinics of North America. Aug, 2005  |  Pubmed ID: 16084419

The history of MR-guided FUS demonstrates the need for merging advanced therapy technology with advanced imaging. Without the ability of MR imaging to localize the tumor margins and without the temperature-sensitive imaging that provides the closed-loop control of energy deposition, this method is inadequate for most clinical applications. Given these limitations,high-intensity focused ultrasound initially appeared to have a narrow application area and was not able to compete with other surgical or ablation methods. Today, MR imaging-guided FUS has become a safe and effective means of performing probe-delivered thermal ablations and minimally invasive surgery. Moreover, it has the potential to replace treatments that use ionizing radiation such as radiosurgery and brachytherapy. Although the cost of integrating"big ticket" MR imaging systems with complex and expensive phased arrays is high, this expenditure will largely be offset by eliminating hospitalization and anesthesia and by reducing complications. In effect, an investment in this emerging technology will ultimately redound to the benefit of the health care delivery system and, most important, to the patient. The FUS system provides a safe, repeatable treatment approach for benign tumors (eg, uterine fibroid and breast fibroadenoma) that do not require an aggressive approach. MR-guided FUS can also be used for debulking cancerous tissue. It has already been tested as a breast cancer treatment; its application for other malignancies in the brain, liver, and prostate is under development. MR-guided FUS offers an attractive alternative to conventional surgery because it incorporates intraoperative MR imaging, which provides far more precise target definition than is possible with the surgeon's direct visualization of the lesion. MR-guided FUS is undeniably the most promising interventional MR imaging method in the field of image-guided therapy today. It is applicable not only in the thermal coagulative treatment of tumors but also in several other medical situations for which invasive surgery or radiation may not be treatment options. The use of FUS for treating vascular malformation or functional disorders of the brain is also exciting. It is uniquely applicable for image-guided therapy using targeted drug delivery methods and gene therapy. Further advances in this technology will no doubt improve energy deposition and reduce treatment times. In the near future, FUS will offer a viable alternative to conventional surgery and radiation therapy; in the longer-term, it may also enable a host of targeted treatment methods aimed at eradicating or arresting heretofore intractable diseases such as certain brain malignancies and forms of epilepsy.

Acoustic Transmission Losses and Field Alterations Due to Human Scalp Hair

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Aug, 2005  |  Pubmed ID: 16245611

Hair is a potential transmission barrier for diagnostic and therapeutic ultrasound. We tested hair phantoms for insertion losses and field effects at 0.27-2.8 MHz. The negligible losses observed below 0.5 MHz suggest that, at such frequencies, hair removal is unnecessary for low-power imaging or therapeutic applications.

Hyperthermia Combined with Radiation in Treatment of Locally Advanced Prostate Cancer is Associated with a Favourable Toxicity Profile

International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. Nov, 2005  |  Pubmed ID: 16278168

Hyperthermia is used to treat several pelvic tumours. An important step in establishing a broader role for hyperthermia in treatment of prostate cancer is verification of an acceptable toxicity profile. In this report, short- and long-term toxicity profiles of a completed phase II trial of transrectal ultrasound hyperthermia combined with radiation in treatment of locally advanced prostate cancer are presented.

Transcranial Ultrasound Focus Reconstruction with Phase and Amplitude Correction

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Sep, 2005  |  Pubmed ID: 16285450

Therapeutic and diagnostic ultrasound procedures performed noninvasively through the skull require a reliable method for maintaining acoustic focus integrity after transmission through layered bone structures. This study used a multiple-element, phased-array transducer to reconstruct ultrasound foci through the human skull by amplitude and phase correction. It was previously demonstrated that adaptive phase correction using a multiple-element, focused transducer array yields a significant correction to an acoustic field that has been distorted by the heterogeneities of the skull bone. The introduction of amplitude correction, in a regime in which acoustic pressures from individual transducer array elements are adjusted to be normalized at the focus, has demonstrated a 6% (-0.27 dB) average decrease in acoustic sidelobe acoustic intensity relative to the focal intensity and a 2% (-0.09 dB) average decrease in the full-width-at-half-maximum (FWHM) of the acoustic intensity profile at the focus. These improvements come at the expense of significant ultrasound intensity loss--as much as 30% lower (-1.55 dB)--at the focus because the amplitude correction method requires that, at constant power, a larger proportion of energy is absorbed or reflected by regions of the skull that transmit less energy. In contrast, a second correction method that distributes pressure amplitudes such that the sections of the skull which transmit more ultrasound energy are exposed with higher ultrasound intensities has demonstrated an average sidelobe intensity decrease of 3% (-0.13 dB) with no change in the FWHM at the focus. On average, there was a 2% (0.09 dB) increase in the acoustic intensity at the focus for this inverse amplitude correction method. These results indicate that amplitude correction according to the transmission properties of various segments of the skull have a clear effect on ultrasound energy throughput into a target site within the brain parenchyma.

MRI-guided Targeted Blood-brain Barrier Disruption with Focused Ultrasound: Histological Findings in Rabbits

Ultrasound in Medicine & Biology. Nov, 2005  |  Pubmed ID: 16286030

Focused ultrasound offers a method to disrupt the blood-brain barrier (BBB) noninvasively and reversibly at targeted locations. The purpose of this study was to test the safety of this method by searching for ischemia and apoptosis in areas with BBB disruption induced by pulsed ultrasound in the presence of preformed gas bubbles and by looking for delayed effects up to one month after sonication. Pulsed ultrasound exposures (sonications) were performed in the brains of 24 rabbits under monitoring by magnetic resonance imaging (MRI) (ultrasound: frequency = 1.63 MHz, burst length = 100 ms, PRF = 1 Hz, duration = 20 s, pressure amplitude 0.7 to 1.0 MPa). Before sonication, an ultrasound contrast agent (Optison, GE Healthcare, Milwaukee, WI, USA) was injected IV. BBB disruption was confirmed with contrast-enhanced MR images. Whole brain histologic examination was performed using haematoxylin and eosin staining for general histology, vanadium acid fuchsin-toluidine blue staining for ischemic neurons and TUNEL staining for apoptosis. The main effects observed were tiny regions of extravasated red blood cells scattered around the sonicated locations, indicating affected capillaries. Despite these vasculature effects, only a few cells in some of the sonicated areas showed evidence for apoptosis or ischemia. No ischemic or apoptotic regions were detected that would indicate a compromised blood supply was induced by the sonications. No delayed effects were observed either by MRI or histology up to 4 wk after sonication. Ultrasound-induced BBB disruption is possible without inducing substantial vascular damage that would result in ischemic or apoptotic death to neurons. These findings indicate that this method is safe for targeted drug delivery, at least when compared with the currently available invasive methods.

Targeted Delivery of Antibodies Through the Blood-brain Barrier by MRI-guided Focused Ultrasound

Biochemical and Biophysical Research Communications. Feb, 2006  |  Pubmed ID: 16403441

The blood-brain barrier (BBB) is a persistent obstacle for the local delivery of macromolecular therapeutic agents to the central nervous system (CNS). Many drugs that show potential for treating CNS diseases cannot cross the BBB and there is a need for a non-invasive targeted drug delivery method that allows local therapy of the CNS using larger molecules. We developed a non-invasive technique that allows the image-guided delivery of antibody across the BBB into the murine CNS. Here, we demonstrate that subsequent to MRI-targeted focused ultrasound induced disruption of BBB, intravenously administered dopamine D(4) receptor-targeting antibody crossed the BBB and recognized its antigens. Using MRI, we were able to monitor the extent of BBB disruption. This novel technology should be useful in delivering macromolecular therapeutic or diagnostic agents to the CNS for the treatment of various CNS disorders.

Mechanism of Porphyrin-induced Sonodynamic Effect: Possible Role of Hyperthermia

Radiation Research. Mar, 2006  |  Pubmed ID: 16494518

The biological effects of ultrasound have been investigated vigorously for various applications including the thermal coagulation of tissues, the opening of tight junctions, and localized gene or drug introduction. The synergistic cell killing effect of ultrasound and porphyrin derivatives, the so-called sonodynamic effect, holds promise for cancer treatment. Although several models to explain the sonodynamic effect have been proposed, its exact mechanism, especially in vivo, remains unknown. We examined the effect of a porphyrin derivative, protoporphyrin IX, on ultrasound-induced killing of HeLa cells. In some experiments, the intracellular protoporphyrin IX concentration was increased by 5-aminolevulinic acid treatment of the cells. Although extracellular protoporphyrin IX showed an enhanced cell killing effect by microbubble-enhanced ultrasound, intracellular protoporphyrin IX did not. On the other hand, intracellular protoporphyrin IX enhanced the cell killing effect of hyperthermia, which can be produced by ultrasound exposure, in a moderately acidic environment (pH 6.6). Because porphyrin derivatives are generally imported into the intracellular component in vivo, our results suggest that hyperthermia caused by ultrasound may play an important role in the sonodynamic effect induced by porphyrin derivatives.

Pre-clinical Testing of a Phased Array Ultrasound System for MRI-guided Noninvasive Surgery of the Brain--a Primate Study

European Journal of Radiology. Aug, 2006  |  Pubmed ID: 16716552

MRI-guided and monitored focused ultrasound thermal surgery of brain through intact skull was tested in three rhesus monkeys. The aim of this study was to determine the amount of skull heating in an animal model with a head shape similar to that of a human. The ultrasound beam was generated by a 512 channel phased array system (Exablate 3000, InSightec, Haifa, Israel) that was integrated within a 1.5-T MR-scanner. The skin was pre-cooled by degassed temperature controlled water circulating between the array surface and the skin. Skull surface temperature was measured with invasive thermocouple probes. The results showed that by applying surface cooling the skin and skull surface can be protected, and that the brain surface temperature becomes the limiting factor. The MRI thermometry was shown to be useful in detecting the tissue temperature distribution next to the bone, and it should be used to monitor the brain surface temperature. The acoustic intensity values during the 20 s sonications were adequate for thermal ablation in the human brain provided that surface cooling is used.

Does the Phase of Menstrual Cycle Affect MR-guided Focused Ultrasound Surgery of Uterine Leiomyomas?

European Journal of Radiology. Aug, 2006  |  Pubmed ID: 16766153

To determine whether the phase of menstrual cycle at the time of MR-guided focused ultrasound surgery (MRgFUS) treatment for uterine leiomyomas affects treatment outcome.

Uterine Leiomyomas: MR Imaging-based Thermometry and Thermal Dosimetry During Focused Ultrasound Thermal Ablation

Radiology. Jul, 2006  |  Pubmed ID: 16793983

To retrospectively evaluate magnetic resonance (MR) imaging-based thermometry and thermal dosimetry during focused ultrasound treatments of uterine leiomyomas (ie, fibroids).

Noninvasive Transesophageal Cardiac Thermal Ablation Using a 2-D Focused, Ultrasound Phased Array: a Simulation Study

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Jun, 2006  |  Pubmed ID: 16846146

This simulation study proposes a noninvasive, transesophageal cardiac-thermal ablation using a planar ultrasound phased array (1 MHz, 60 x 10 mm2, 0.525 mm interelement spacing, 114 x 20 elements). Thirty-nine foci in cardiac muscle were defined at 20, 40, and 60-mm distances and at various angles from the transducer surface to simulate the accessible posterior left atrial wall through the esophageal wall window. The ultrasound pressure distribution and the resulting thermal effect in a volume of 60 x 80 x 80 mm3, including esophagus and cardiac muscle, were simulated for each focus. For 1, 10, and 20-s sonications with 60 degrees C and 70 degrees C peak temperatures in cardiac muscle and without thermal damage in esophageal wall, the transducer acoustic powers were 105-727, 28-117, 21-79 W and 151-1044, 40-167, 30-114 W, respectively. The simulated lesions (thermal dose in equivalent minutes at 43 degrees C > or = 240 minutes) at these foci had lengths of 1-6, 3-11, 3-13 mm and 3-15, 5-19, 6-23 mm, respectively, and widths of 1-4, 2-7, 3-9 mm and 3-9, 4-13, 4-17 mm, respectively. As a first step toward feasibility, controllable tissue coagulation in cardiac tissue without damage to the esophagus was demonstrated numerically.

Noninvasive Localized Delivery of Herceptin to the Mouse Brain by MRI-guided Focused Ultrasound-induced Blood-brain Barrier Disruption

Proceedings of the National Academy of Sciences of the United States of America. Aug, 2006  |  Pubmed ID: 16868082

Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood-brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood-brain barrier under image guidance by using an MRI-guided focused ultrasound blood-brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the central nervous system.

Ultrasound Stimulates Proteoglycan Synthesis in Bovine Primary Chondrocytes

Biorheology. 2006  |  Pubmed ID: 16912400

Mechanical forces can stimulate the production of extracellular matrix molecules. We tested the efficacy of ultrasound to increase proteoglycan synthesis in bovine primary chondrocytes. The ultrasound-induced temperature rise was measured and its contribution to the synthesis was investigated using bare heat stimulus. Chondrocytes from five cellular isolations were exposed in triplicate to ultrasound (1 MHz, duty cycle 20%, pulse repetition frequency 1 kHz) at average intensity of 580 mW/cm2 for 10 minutes daily for 1-5 days. Temperature evolution was recorded during the sonication and corresponding temperature history was created using a controllable water bath. This exposure profile was used in 10-minute-long heat treatments of chondrocytes. Heat shock protein 70 (Hsp70) levels after one-time treatment to ultrasound and heat was analyzed by Western blotting, and proteoglycan synthesis was evaluated by 35S-sulfate incorporation. Ultrasound treatment did not induce Hsp70, while heat treatment caused a slight heat stress response. Proteoglycan synthesis was increased approximately 2-fold after 3-4 daily ultrasound stimulations, and remained at that level until day 5 in responsive cell isolates. However, chondrocytes from one donor cell isolation out of five remained non-responsive. Heat treatment alone did not increase proteoglycan synthesis. In conclusion, our study confirms that pulsed ultrasound stimulation can induce proteoglycan synthesis in chondrocytes.

Simulations of Localized Harmonic Motions on a Blood Vessel Wall Induced by an Acoustic Radiation Force Used in Ultrasound Elastography

Physics in Medicine and Biology. Sep, 2006  |  Pubmed ID: 16953044

Many noninvasive techniques have been developed recently to explore the mechanical properties of soft tissue. In this paper, dynamic acoustic radiation force induced vibrations on a blood vessel wall were simulated using different stimulation frequencies and stiffness parameters for the vessel wall. The stimulation frequency was varied between 20 Hz and 20 kHz and the stiffness parameter (Young's modulus) was varied between 60 kPa and 360 kPa. The vibration simulations were computed using a finite-element method in a 3D geometry that contained a vessel wall surrounded by soft tissue. The results indicate that vibrations caused by acoustic stimulation are sensitive to the changes in mechanical properties of the vessel wall and that the vibrations are highly dependent on the stimulation frequency and target structure. Therefore, measurements of absolute stiffness parameters may not be accurately achieved because this method is so dependent on the whole target structure, whereas the monitoring of changes during some process may be feasible.

Focal Disruption of the Blood-brain Barrier Due to 260-kHz Ultrasound Bursts: a Method for Molecular Imaging and Targeted Drug Delivery

Journal of Neurosurgery. Sep, 2006  |  Pubmed ID: 16961141

The goal of this study was to explore the feasibility of using low-frequency magnetic resonance (MR) image-guided focused ultrasound as a noninvasive method for the temporary disruption of the blood-brain barrier (BBB) at targeted locations.

Brain Arterioles Show More Active Vesicular Transport of Blood-borne Tracer Molecules Than Capillaries and Venules After Focused Ultrasound-evoked Opening of the Blood-brain Barrier

Ultrasound in Medicine & Biology. Sep, 2006  |  Pubmed ID: 16965980

Previously, activation of vesicular transport in the brain microvasculature was shown to be one of the mechanisms of focused ultrasound-induced blood-brain barrier (BBB) opening. In the present study, we aimed to estimate the rate of the transendothelial vesicular traffic after focused ultrasound sonication in the rabbit brain, using ultrastructural morphometry and horseradish peroxidase (HRP) as a tracer. In the capillaries, the mean endothelial pinocytotic densities (the number of HRP-containing vesicles per microm(2) of the cell cytoplasm) were 0.9 and 1.05 vesicles/microm(2) 1 h after sonication with ultrasound frequencies of 0.69 and 0.26 MHz, respectively. In the arterioles, these densities were 1.63 and 2.43 vesicles/microm(2), values 1.8 and 2.3 times higher. In control locations, the densities were 0.7 and 0.14 vesicles/microm(2) for capillaries and arterioles, respectively. A small number of HRP-positive vesicles were observed in the venules. Focal delivery of HRP tracer was also observed in light microscopy. The results indicate that the precapillary microvessels play an important role in macromolecular transcytoplasmic traffic through the ultrasound-induced BBB modulation, which should be considered in the future development of trans-BBB drug delivery strategies.

Microbubble Contrast Agent with Focused Ultrasound to Create Brain Lesions at Low Power Levels: MR Imaging and Histologic Study in Rabbits

Radiology. Oct, 2006  |  Pubmed ID: 16990673

To evaluate magnetic resonance (MR) imaging-based thermometry for predicting the onset and spatial extent of lesions produced by focused ultrasound combined with a microbubble contrast agent (Optison; GE Healthcare, Milwaukee, Wis) and to compare the resulting induced temperature increase and threshold for damage with those in studies performed without the agent.

Image-guided Neurosurgery at Brigham and Women's Hospital

IEEE Engineering in Medicine and Biology Magazine : the Quarterly Magazine of the Engineering in Medicine & Biology Society. Sep-Oct, 2006  |  Pubmed ID: 17020201

Investigation of Optimal Method for Inducing Harmonic Motion in Tissue Using a Linear Ultrasound Phased Array--a Simulation Study

Ultrasonic Imaging. Apr, 2006  |  Pubmed ID: 17094690

Many noninvasive ultrasound techniques have been developed to explore mechanical properties of soft tissues. One of these methods, Localized Harmonic Motion Imaging (LHMI), has been proposed to be used for ultrasound surgery monitoring. In LHMI, dynamic ultrasound radiation-force stimulation induces displacements in a target that can be measured using pulse-echo imaging and used to estimate the elastic properties of the target. In this initial, simulation study, the use of a one-dimensional phased array is explored for the induction of the tissue motion. The study compares three different dual-frequency and amplitude-modulated single-frequency methods for the inducing tissue motion. Simulations were computed in a homogeneous soft-tissue volume. The Rayleigh integral was used in the simulations of the ultrasound fields and the tissue displacements were computed using a finite-element method (FEM). The simulations showed that amplitude-modulated sonication using a single frequency produced the largest vibration amplitude of the target tissue. These simulations demonstrate that the properties of the tissue motion are highly dependent on the sonication method and that it is important to consider the full three-dimensional distribution of the ultrasound field for controlling the induction of tissue motion.

Quality Assurance and System Stability of a Clinical MRI-guided Focused Ultrasound System: Four-year Experience

Medical Physics. Nov, 2006  |  Pubmed ID: 17153409

To retrospectively evaluate the four-year experience of a quality assurance method for a MRI-guided focused ultrasound system that uses temperature maps acquired during heating in an ultrasound/MRI phantom. This quality assurance method was performed before 148 clinical uterine fibroid thermal ablation treatments. The stability of the peak temperature rise, the targeting accuracy, the shape of the heated zone, and the noise level in the imaging was evaluated. The peak temperature rise was mostly stable for the first three years. An increase in heating was observed when the system was replaced after year three. Detection of this increase was taken into account in the subsequent clinical treatments. A small secondary hotspot was detected by the temperature maps and was seen to be resolved after system calibration. The average standard deviation in unheated regions of the phantom in the temperature maps was 0.5 +/- 0.2 degrees C; it was less than 1 degrees C in all but one procedure. The average initial targeting error was 2.8 +/- 1.8 and 2.8 +/- 2.1 mm in two radial directions and 7.7 +/- 2.9 mm along the ultrasound beam direction. The width of the heating profile was consistent over the four years. This simple method to evaluate the performance appeared to be sensitive to small changes in system performance, which was adequately stable over a four-year time period.

Induction of Apoptosis in Vivo in the Rabbit Brain with Focused Ultrasound and Optison

Ultrasound in Medicine & Biology. Dec, 2006  |  Pubmed ID: 17169704

Histologic effects of focused ultrasound (FUS) exposures combined with an ultrasound contrast agent (Optison) were investigated to examine whether the lesions were dominated by apoptosis or necrosis. The rabbit brains (n = 17) were sonicated (1.5 MHz, peak rarefactional pressure amplitude: 1.4 to 8.8 MPa) after Optison was injected intravenously (IV). MRI and light microscopy were used to examine tissue effects. To detect apoptosis, TUNEL staining based on labeling of DNA strand breaks was used. The average number of apoptotic and necrotic cells in 300 x 220 microm microscopic fields were counted in 18 representative lesions. Lesions in the rabbit brains were created at lowered acoustic power levels when FUS was combined with Optison. In histology, the lesions exhibited red blood cell extravasations and destruction of blood vessels. At 4 h after sonication, the lesions lost many cells, and the remaining cells exhibited both necrotic and apoptotic features. Overall, apoptosis dominated; there were, on average, 32.3 +/- 13.2 apoptotic cells per microscopic field compared with only 5.1 +/- 3.4 necrotic cells per field. In conclusion, FUS combined with Optison could produce lesions that are dominated by apoptosis, presumably induced primarily via ischemia after cavitation-produced damage to the brain vasculature.

Focused Ultrasound for Blood-brain Disruption and Delivery of Therapeutic Molecules into the Brain

Expert Opinion on Drug Delivery. Jan, 2007  |  Pubmed ID: 17184160

Noninvasive, transient and local image-guided blood-brain barrier disruption can be accomplished using focused ultrasound exposure with intravascular injection of preformed microbubbles. MRI-guided blood-brain barrier disruption has been demonstrated and has been shown to heal in within a few hours after exposure. The delivery of several marker molecules has been demonstrated in different animal models with minimal or no damage to the brain tissue. Most notably, the delivery of antibodies and liposomal doxorubicin has been shown. The method may potentially open a new era in CNS drug delivery and perhaps also aid in molecular imaging and targeting. However, effective clinical devices and methods need to be developed further and the clinical feasibility demonstrated.

Activation of Bak in Ultrasound-induced, JNK- and P38-independent Apoptosis and Its Inhibition by Bcl-2

Biochemical and Biophysical Research Communications. Feb, 2007  |  Pubmed ID: 17188240

The molecular mechanisms underlying ultrasound-induced apoptosis remain poorly understood. We have demonstrated that in Jurkat cells, the over-expression of the anti-apoptotic protein Bcl-2 inhibited ultrasound-induced apoptosis, but not necrosis. Inhibition of caspase activity also protected the cells from apoptosis, but not from necrosis, showing the involvement of different mechanisms in ultrasound-induced apoptosis and necrosis. Bak, a pro-apoptotic member of the Bcl-2 family proteins, was activated by ultrasound and its activation was completely inhibited by Bcl-2 over-expression, but not by caspase inhibition. Antioxidant N-acetyl cysteine did not protect the cells from ultrasound-induced apoptosis or necrosis, nor did the inhibition of either c-Jun N-terminal kinase or p38, key factors in the radical oxygen species (ROS)-mediated cell stress response, suggesting that ROS do not play a crucial role in ultrasound-induced apoptosis. Our results confirm that ultrasound induces apoptosis via a pathway that involves Bak, Bcl-2, and caspases, but not ROS.

Modular Design for in Vivo Optical Imaging and Ultrasound Treatment in the Murine Brain

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Feb, 2007  |  Pubmed ID: 17328340

Simultaneous optical imaging and ultrasound exposure to the brain is challenging due to geometric constraints. We demonstrate sonication through the ventral surface of the mouse, leaving the dorsal aspect free for imaging. Ultrasound components are integrated into a commercial multiphoton microscope, and animals are imaged during ultrasound-induced blood-brain barrier disruption.

Use of Ultrasound Pulses Combined with Definity for Targeted Blood-brain Barrier Disruption: a Feasibility Study

Ultrasound in Medicine & Biology. Apr, 2007  |  Pubmed ID: 17337109

We have developed a method to use low-intensity focused ultrasound pulses combined with an ultrasound contrast agent to produce temporary blood-brain barrier disruption (BBBD). This method could provide a means for the targeted delivery of drugs or imaging agents into the brain. In all our previous work, we used Optison as the ultrasound contrast agent. The purpose of this study was to test the feasibility of using the contrast agent Definity for BBBD. A total of 36 non-overlapping locations were sonicated through a craniotomy in experiments in the brains of nine rabbits (four locations per rabbit; ultrasound [US] frequency: 0.69 MHz; burst: 10 ms; pulse repetition frequency (PRF): 1 Hz; duration: 20 s). The peak negative pressure amplitude ranged from 0.2 to 1.5 MPa. An additional 11 locations were sonicated using Optison at pressure amplitude of 0.5 MPa. Definity and Optison dosages were the same as those used clinically for ultrasound imaging: 10 and 50 microl/kg, respectively. The probability for BBBD (determined using MRI contrast agent enhancement) as a function of pressure amplitude was similar to that found earlier with Optison. For both agents, the probability was estimated to be 50% at 0.4 MPa using probit regression. Histologic examination revealed small, isolated areas of extravasated erythrocytes in some locations. At 0.8 MPa and higher, these areas were sometimes accompanied by tiny (dimensions of 100 microm or less) regions of damaged brain parenchyma. The magnitude of the BBBD was larger with Optison than with Definity at 0.5 MPa (signal enhancement: 13.3% +/- 4.4% vs. 8.4% +/- 4.9%; p = 0.04). In addition, more areas with extravasated erythrocytes were observed with Optison (5.0 +/- 3.5 vs. 1.4 +/- 1.9 areas with extravasation in histology section with largest effect; p = 0.03). We concluded that BBBD is possible using Definity at the dosage of contrast agent and the acoustic parameters tested in this study. The probability for BBBD as a function of pressure amplitude and the type of acute tissue effects were similar to what has been observed using Optison. However, under the experimental conditions used in this study, Optison produced a larger effect for the same acoustic pressure amplitude.

Targeted Delivery of Doxorubicin to the Rat Brain at Therapeutic Levels Using MRI-guided Focused Ultrasound

International Journal of Cancer. Journal International Du Cancer. Aug, 2007  |  Pubmed ID: 17437269

The clinical application of chemotherapy to brain tumors has been severely limited because antitumor agents are typically unable to penetrate an intact blood-brain barrier (BBB). Although doxorubicin (DOX) has been named as a strong candidate for chemotherapy of the central nervous system (CNS), the BBB often prevents cytotoxic levels from being achieved. In this study, we demonstrate a noninvasive method for the targeted delivery of DOX through the BBB, such that drug levels shown to be therapeutic in human tumors are achieved in the normal rat brain. Using MRI-guided focused ultrasound with preformed microbubbles (Optison) to locally disrupt the BBB and systemic administration of DOX, we achieved DOX concentrations of 886 +/- 327 ng/g tissue in the brain with minimal tissue effects. Tissue DOX concentrations of up to 5,366 +/- 659 ng/g tissue were achieved with higher Optison doses, but with more significant tissue damage. In contrast, DOX accumulation in nontargeted contralateral brain tissue remained significantly lower for all paired samples (p < 0.001). These results suggest that targeted delivery by focused ultrasound may render DOX chemotherapy a viable treatment option against CNS tumors, despite previous accessibility limitations. In addition, MRI signal enhancement in the sonicated region correlated strongly with tissue DOX concentration (r = 0.87), suggesting that contrast-enhanced MRI could perhaps indicate drug penetration during image-guided interventions. Our technique using MRI-guided focused ultrasound to achieve therapeutic levels of DOX in the brain offers a large step forward in the use of chemotherapy to treat patients with CNS malignancies.

A Novel Phase Assignment Protocol and Driving System for a High-density Focused Ultrasound Array

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Apr, 2007  |  Pubmed ID: 17441588

Currently, most phased-array systems intended for therapy are one-dimensional (1-D) and use between 5 and 200 elements, with a few two-dimensional (2-D) systems using several hundred elements. The move toward lambda/2 interelement spacing, which provides complete 3-D beam steering, would require a large number of closely spaced elements (0.15 mm to 3 mm). A solution to the resulting problem of cost and cable assembly size, which this study examines, is to quantize the phases available at the array input. By connecting elements with similar phases to a single wire, a significant reduction in the number of incoming lines can be achieved while maintaining focusing and beam steering capability. This study has explored the feasibility of such an approach using computer simulations and experiments with a test circuit driving a 100-element linear array. Simulation results demonstrated that adequate focusing can be obtained with only four phase signals without large increases in the grating lobes or the dimensions of the focus. Experiments showed that the method can be implemented in practice, and adequate focusing can be achieved with four phase signals with a reduction of 20% in the peak pressure amplitude squared when compared with the infinite-phase resolution case. Results indicate that the use of this technique would make it possible to drive more than 10,000 elements with 33 input lines. The implementation of this method could have a large impact on ultrasound therapy and diagnostic devices.

Uterine Leiomyomas: MR Imaging-guided Focused Ultrasound Surgery--results of Different Treatment Protocols

Radiology. Jun, 2007  |  Pubmed ID: 17446521

To prospectively assess patient response (after 12 months) to magnetic resonance (MR) imaging-guided focused ultrasound surgery in treatment of uterine leiomyomas by using two treatment protocols.

Temperature Mapping Considerations in the Breast with Line Scan Echo Planar Spectroscopic Imaging

Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. Dec, 2007  |  Pubmed ID: 18046702

A line-scan echo planar spectroscopic imaging (LSEPSI) sequence was used to serially acquire spectra from 4,096 voxels every 6.4 s throughout the breasts of nine female subjects in vivo. Data from the serial acquisitions were analyzed to determine the potential of the technique to characterize temperature changes using either the water frequency alone or the water-methylene frequency difference. Fluctuations of the apparent temperature change under these conditions of no heating were smallest using the water-methylene frequency difference, most probably due to a substantial reduction of motion effects both within and without the imaged plane. The approach offers considerable advantages over other methods for temperature change monitoring in the breast with magnetic resonance but suffers from some limitations, including the unavailability of lipid and water resonances in some voxels as well as a surprisingly large distribution of water-methylene frequency differences, which may preclude absolute temperature measurement.

Multiphoton Imaging of Ultrasound/Optison Mediated Cerebrovascular Effects in Vivo

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. Feb, 2007  |  Pubmed ID: 16685254

Ultrasound (US) enhanced with microbubble contrast agents may transiently disrupt the blood-brain barrier (BBB) with minimal damage, providing a technique for noninvasive, localized drug-delivery deep within the brain. The mechanism and temporal profile of disruption are not understood, owing to the limitations of imaging modalities used previously. In this study, we monitored US-induced BBB disruption with multiphoton microscopy, providing high-resolution temporal and spatial information about the permeabilization mechanism and immediate effects of US exposure. Anesthetized C57 mice were prepared with a craniotomy and injected intravenously with fluorescent dyes to permit visualization of the vasculature and BBB integrity. The animals were imaged through a cranial window while exposed to low-intensity US (f=1.029 MHz, power=0.2 W) with a coincident intravenous injection of Optison (a microbubble contrast agent). We observed arteriolar vasoconstriction on US exposure that disrupted blood flow and lasted up to 5 mins; BBB disruption occurred via two characteristically distinct processes-perivascular fluorescence gradually increased (over minutes) along the length of the affected vessel without apparent rupture of the vessel wall or rapidly (seconds) increased in select, focal regions. These data corroborated previous studies suggesting increased endothelial transcytosis and breached tight junctions and demonstrated vasoconstriction, which might alter BBB permeability by modifying cerebral blood flow.

Chemotherapy Delivery Issues in Central Nervous System Malignancy: a Reality Check

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Jun, 2007  |  Pubmed ID: 17538176

This review assesses the current state of knowledge regarding preclinical and clinical pharmacology for brain tumor chemotherapy and evaluates relevant brain tumor pharmacology studies before October 2006.

Key Factors That Affect Sonoporation Efficiency in in Vitro Settings: the Importance of Standing Wave in Sonoporation

Biochemical and Biophysical Research Communications. Aug, 2007  |  Pubmed ID: 17568561

Ultrasound-induced intracellular drug delivery, sonoporation, is an appealing and promising technique for next generation drug delivery system. Many types of molecules, such as plasmid DNAs, siRNAs and peptides, have been demonstrated to be delivered into the cell by ultrasound with the aid of microbubbles both in vitro and in vivo. Although there are many reports on in vitro sonoporation, the efficiency of successful sonoporation and the viabilities of cells after the procedure documented in each report vary in a wide range, and the reasons for these differences are not fully understood. In this study, we have investigated how different experimental settings would affect sonoporation efficiency and cell viabilities after the procedure. Our results show that the fashion of cell culture (e.g. in suspension or in monolayer culture) and the presence of standing wave have a great impact on the overall results. These results indicate that in vitro sonoporation settings should be carefully evaluated in each experiment. The fact that standing wave is necessary to achieve high sonoporation efficiency may be a problematic issue for clinical application of sonoporation, as it may be difficult (although not impossible) to create standing wave in a human body.

Cavitation Threshold of Microbubbles in Gel Tunnels by Focused Ultrasound

Ultrasound in Medicine & Biology. Oct, 2007  |  Pubmed ID: 17590501

The investigation of inertial cavitation in micro-tunnels has significant implications for the development of therapeutic applications of ultrasound such as ultrasound-mediated drug and gene delivery. The threshold for inertial cavitation was investigated using a passive cavitation detector with a center frequency of 1 MHz. Micro-tunnels of various diameters (90 to 800 microm) embedded in gel were fabricated and injected with a solution of Optison(trade mark) contrast agent of concentrations 1.2% and 0.2% diluted in water. An ultrasound pulse of duration 500 ms and center frequency 1.736 MHz was used to insonate the microbubbles. The acoustic pressure was increased at 1-s intervals until broadband noise emission was detected. The pressure threshold at which broadband noise emission was observed was found to be dependent on the diameter of the micro-tunnels, with an average increase of 1.2 to 1.5 between the smallest and the largest tunnels, depending on the microbubble concentration. The evaluation of inertial cavitation in gel tunnels rather than tubes provides a novel opportunity to investigate microbubble collapse in a situation that simulates in vivo blood vessels better than tubes with solid walls do.

Circumferential Lesion Formation Around the Pulmonary Veins in the Left Atrium with Focused Ultrasound Using a 2D-array Endoesophageal Device: a Numerical Study

Physics in Medicine and Biology. Aug, 2007  |  Pubmed ID: 17671344

Atrial fibrillation (AF) is the most frequently sustained cardiac arrhythmia affecting humans. The electrical isolation by ablation of the pulmonary veins (PVs) in the left atrium (LA) of the heart has been proven as an effective cure of AF. The ablation consists mainly in the formation of a localized circumferential thermal coagulation of the cardiac tissue surrounding the PVs. In the present numerical study, the feasibility of producing the required circumferential lesion with an endoesophageal ultrasound probe is investigated. The probe operates at 1 MHz and consists of a 2D array with enough elements (114 x 20) to steer the acoustic field electronically in a volume comparable to the LA. Realistic anatomical conditions of the thorax were considered from the segmentation of histological images of the thorax. The cardiac muscle and the blood-filled cavities in the heart were identified and considered in the sound propagation and thermal models. The influence of different conditions of the thermal sinking in the LA chamber was also studied. The circumferential ablation of the PVs was achieved by the sum of individual lesions induced with the proposed device. Different scenarios of lesion formation were considered where ultrasound exposures (1, 2, 5 and 10 s) were combined with maximal peak temperatures (60, 70 and 80 degrees C). The results of this numerical study allowed identifying the limits and best conditions for controlled lesion formation in the LA using the proposed device. A controlled situation for the lesion formation surrounding the PVs was obtained when the targets were located within a distance from the device in the range of 26 +/- 7 mm. When combined with a maximal temperature of 70 degrees C and an exposure time between 5 and 10 s, this distance ensured preservation of the esophageal structures, controlled lesion formation and delivery of an acoustic intensity at the transducer surface that is compatible with existing materials. With a peak temperature of 70 degrees C, the device and setup presented here induced highly localized lesions with a lesion volume varying from 10 +/- 4 to 18 +/- 7 mm(3) for an ultrasound exposure between 5 and 10 s, respectively, while the intensity varied from 26 +/- 7 to 20 +/- 6 W cm(-2).

The Effects of Desiccation on Skull Bone Sound Speed in Porcine Models

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Aug, 2007  |  Pubmed ID: 17703676

Pre- and postdesiccation sound speeds through ex vivo porcine skull specimens were determined by time-of-flight measurements with propagated broadband pulses centered at 0.97 MHz (Os 12.7 mm, -6-dB band-width = 58%). The measured longitudinal sound speed in the 13 porcine samples (predesiccation average sound speed = 1727 +/- 57 ms(-1)) changed by a statistically significant +2.3% after deionized water reconstitution (paired t-test, alpha = 0.05, p = 0.0332).

A Computer-controlled Ultrasound Pulser-receiver System for Transskull Fluid Detection Using a Shear Wave Transmission Technique

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Sep, 2007  |  Pubmed ID: 17941383

The purpose of this study was to evaluate the performance of a computer-controlled ultrasound pulser-receiver system incorporating a shear mode technique for transskull fluid detection. The presence of fluid in the sinuses of an ex vivo human skull was examined using a pulse-echo method by transmitting an ultrasound beam through the maxilla bone toward the back wall on the other side of the sinus cavity. The pulser was programmed to generate bipolar pulse trains with 5 cycles at a frequency of 1 MHz, repetition frequency of about 20 Hz, and amplitude of 100 V to drive a 1-MHz piezoelectric transducer. Shear and longitudinal waves in the maxilla bone were produced by adjusting the bone surface incident angle to 45 degrees and 0 degrees, respectively. Computer tomography (CT) scans of the skull were performed to verify the ultrasound experiment. Using the shear mode technique, the echo waveform clearly distinguishes the presence of fluid, and the estimated distance of the ultrasound traveled in the sinus is consistent with the measurement from the CT images. Contrarily, using the longitudinal mode, no detectable back wall echo was observed under the same conditions. As a conclusion, this study demonstrated that the proposed pulser-receiver system with the shear mode technique is promising for transskull fluid detecting, such as mucus in a sinus.

Treatment of Near-skull Brain Tissue with a Focused Device Using Shear-mode Conversion: a Numerical Study

Physics in Medicine and Biology. Dec, 2007  |  Pubmed ID: 18065841

Shear mode transmission through the skull has been previously proposed as a new trans-skull propagation technique for noninvasive therapeutic ultrasound (Clement 2004 J. Acoust. Soc. Am. 115 1356-64). The main advantage of choosing shear over longitudinal mode resides on the fact that there is less wavefront distortion with the former. In the present study, the regions of the brain suitable for shear-mode transmission were established for a simple focused ultrasound device. The device consists of a spherically curved transducer that has a focal length of 10 cm, an aperture between 30 degrees and 60 degrees and operates at 0.74 MHz. The regions suitable for shear-mode transmission were determined by the shear wave acoustic windows that matched the shape of the device acoustic field. The acoustic windows were calculated using segmentation and triangulation of outer and inner faces of skull from 3D-MRI head datasets. Nine heads of healthy adults were analyzed. The surface considered for the calculations was the head region found above the supra-orbital margin. For every inspected point in the brain volume, the axis of the device was determined by the vector between this inspection point and a point located in the center of the brain. Numerical predictions of the acoustic field, where shear-mode conversion through the skull was considered, were obtained and compared to the case of water-only conditions. The brain tissue that is close to the skull showed suitable acoustic windows for shear waves. The central region of the brain seems to be unreachable using shear-mode. Analysis of the acoustic fields showed a proportional relation between the acoustic window for shear mode and the effective degree of focusing. However, this relation showed significant differences among specimens. In general, highly focused fields were obtained when the acoustic window for shear waves (A(SW)) intersected more than 67% of the entering acoustic window (A(TX)) of the device. The average depth from the inner surface of the skull showing this intersection value was 13 +/- 10 mm (mean +/- SD). The differences of the degree of focusing observed among patients suggest that the intersection A(SW) intersection A(TX) can be used as a preliminary criterion for screening and calculation of the acoustic fields should confirm the degree of focusing patient by patient. In conclusion, shear waves provide a useful method for trans-cranial focusing in regions close to the skull surface.

Progress in Multimodality Imaging: Truly Simultaneous Ultrasound and Magnetic Resonance Imaging

IEEE Transactions on Medical Imaging. Dec, 2007  |  Pubmed ID: 18092742

Multimodality medical imaging takes advantage of the strengths of different imaging modalities to provide a more complete picture of the anatomy under investigation. Many complementary modalities have been combined to form such systems and some are gaining use clinically. One combination that has not been developed, in large part due to technical difficulties, is a combined magnetic resonance (MR) and ultrasound (US) imaging system. Such a system offers the potential to combine the strengths of these modalities in a wide range of diagnostic and therapeutic applications. The goal of this study was to evaluate the feasibility of performing simultaneous multimodality US and MR imaging. An US imaging system capable of operation in a clinical MR imager was developed, and methods to perform simultaneous imaging were investigated. Simultaneous imaging was feasible without any mutual interference by either filtering the transmitted and received US signal, or by synchronizing data acquisition between the two imaging systems. Spatial registration between the two modalities was achieved by using a reference phantom with implanted glass beads in orthogonal planes. Excellent agreement was observed between spatial measurements of an object made with both modalities, and the feasibility of using this system in vivo was demonstrated in a rabbit model. Simultaneous US and MR imaging is achievable, and can provide complementary information about an object under investigation. This demonstration of technical feasibility and the development of a prototype system open up the potential to investigate the promising clinical applications of this combined technology.

Evaluation of Referenceless Thermometry in MRI-guided Focused Ultrasound Surgery of Uterine Fibroids

Journal of Magnetic Resonance Imaging : JMRI. Oct, 2008  |  Pubmed ID: 18821603

To clinically assess a previously described method (Rieke et.al., Magn Reson Med 2004) to produce more motion-robust MRI-based temperature images using data acquired during MRI-guided focused ultrasound surgery (MRgFUS) of uterine fibroids.

Genome-wide Microarray Analysis of MG-63 Osteoblastic Cells Exposed to Ultrasound

Biorheology. 2008  |  Pubmed ID: 18836235

It is well documented that low intensity pulsed ultrasound can be clinically used to accelerate bone fracture healing. Additionally, in vitro studies have shown that ultrasound can, for instance, increase mineralization, collagen production and alkaline phosphatase activity in osteoblasts. Despite the extensive research on the subject, the exact mechanism of ultrasound effect on bone cell gene regulation has not yet been deduced. In this study, we made an effort to reveal the features of genome-wide transcriptional response of osteoblast-type cells to ultrasound. MG-63 osteoblastic cell transcriptome was analyzed with whole genome microarray either 6 or 24 h after 30 min long exposure to 1.035 MHz pulsed ultrasound with three different acoustic pressures. Special attention was paid to the experimental design to minimize thermal effects and unwanted reflections of ultrasound. Microarray analysis suggested that ultrasound affects the genes involved with cellular membranes, and regulation of transcription as well. Several plasma membrane solute carriers were also regulated by ultrasound. It also changed the transcript level of several transcription factors belonging to the zinc finger proteins. However, ultrasound did not clearly promote genes involved with osteoblast differentiation.

Blood-brain Barrier Disruption Induced by Focused Ultrasound and Circulating Preformed Microbubbles Appears to Be Characterized by the Mechanical Index

Ultrasound in Medicine & Biology. May, 2008  |  Pubmed ID: 18207311

This work investigated the effect of ultrasonic frequency on the threshold for blood-brain barrier (BBB) disruption induced by ultrasound pulses combined with an ultrasound contrast agent. Experiments were performed in rabbits using pulsed sonications at 2.04 MHz with peak pressure amplitudes ranging from 0.3 to 2.3 MPa. BBB disruption was evaluated using contrast-enhanced magnetic resonance imaging. The threshold for BBB disruption was estimated using probit regression. Representative samples with similar amounts of contrast enhancement were examined in light microscopy. Results from these experiments were compared with data from previous studies that used ultrasound frequencies between 0.26 and 1.63 MHz. We found that the BBB disruption threshold (value where the probability for disruption was estimated to be 50%) expressed in terms of the peak negative pressure amplitude increased as a function of the frequency. It appeared to be constant, however, when the exposures were expressed as a function of the mechanical index (peak negative pressure amplitude estimated in situ divided by square root of frequency). Regression of data from all frequencies resulted in an estimated mechanical index threshold of 0.46 (95% confidence intervals: 0.42 to 0.50). Histologic examination of representative samples with similar amounts of blood-brain barrier disruption found that the number of regions containing extravasated red blood cells per unit area was substantially lower on average for lower ultrasound frequencies. This data suggests that the mechanical index is a meaningful metric for ultrasound-induced blood-brain barrier disruption, at least for when other parameters that are not taken into account by the mechanical index are not varied. It also suggests that lower frequency sonication produces less red blood cell extravasation per unit area.

Effects of Acoustic Parameters and Ultrasound Contrast Agent Dose on Focused-ultrasound Induced Blood-brain Barrier Disruption

Ultrasound in Medicine & Biology. Jun, 2008  |  Pubmed ID: 18294757

Previously, it was shown that low-intensity focused ultrasound pulses applied along with an ultrasound contrast agent results in temporary blood-brain barrier (BBB) disruption. This effect could be used for targeted drug delivery in the central nervous system. This study examined the effects of burst length, pulse repetition frequency (PRF), and ultrasound contrast agent dose on the resulting BBB disruption. One hundred nonoverlapping brain locations were sonicated through a craniotomy in experiments in 26 rabbits (ultrasound frequency: 0.69 MHz, burst: 0.1, 1, 10 ms, PRF: 0.5, 1, 2, 5 Hz, duration: 20 s, peak negative pressure amplitude: 0.1 to 1.5 MPa, Optison dosage 50, 100, 250 microl/kg). For each sonication, BBB disruption was evaluated using contrast-enhanced magnetic resonance imaging. The BBB disruption threshold (the pressure amplitude yielding a 50% probability for BBB disruption) was determined using probit regression for the three burst lengths tested. Tissue effects were examined in light microscopy for representative locations with similar amounts of contrast enhancement from each group. While changing the PRF or the Optison dosage did not result in a significant difference in the magnitude of the BBB disruption (p > 0.05), reducing the burst length resulted in significantly less contrast enhancement (p < 0.01). The BBB disruption thresholds were estimated to be 0.69, 0.47 and 0.36 MPa for 0.1, 1 and 10 ms bursts, respectively. No difference was detected in histology between any experimental groups. This data suggests that over the range of parameters tested, BBB disruption is not affected by PRF or ultrasound contrast agent dose. However, both the BBB disruption magnitude and its threshold depend on the burst length.

Fetal Thermal Effects of Diagnostic Ultrasound

Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine. Apr, 2008  |  Pubmed ID: 18359908

Processes that can produce a biological effect with some degree of heating (ie, about 1 degrees C above the physiologic temperature) act via a thermal mechanism. Investigations with laboratory animals have documented that pulsed ultrasound can produce elevations of temperature and damage in biological tissues in vivo, particularly in the presence of bone (intracranial temperature elevation). Acoustic outputs used to induce these adverse bioeffects are within the diagnostic range, although exposure times are usually considerably longer than in clinical practice. Conditions present in early pregnancy, such as lack of perfusion, may favor bioeffects. Thermally induced teratogenesis has been shown in many animal studies, as well as several controlled human studies; however, human studies have not shown a causal relationship between diagnostic ultrasound exposure during pregnancy and adverse biological effects to the fetus. All human epidemiologic studies, however, were conducted with commercially available devices predating 1992, that is, with acoustic outputs not exceeding a spatial-peak temporal-average intensity of 94 mW/cm2. Current limits in the United States allow a spatial-peak temporal-average intensity of 720 mW/cm2 for fetal applications. The synergistic effect of a raised body temperature (febrile status) and ultrasound insonation has not been examined in depth. Available evidence, experimental or epidemiologic, is insufficient to conclude that there is a causal relationship between obstetric diagnostic ultrasound exposure and obvious adverse thermal effects to the fetus. However, very subtle effects cannot be ruled out and indicate a need for further research, although research in humans may be extremely difficult to realize.

Effect of Focused Ultrasound Applied with an Ultrasound Contrast Agent on the Tight Junctional Integrity of the Brain Microvascular Endothelium

Ultrasound in Medicine & Biology. Jul, 2008  |  Pubmed ID: 18378064

Previous studies have investigated a potential method for targeted drug delivery in the central nervous system that uses focused ultrasound bursts combined with an ultrasound contrast agent to temporarily disrupt the blood-brain barrier (BBB). The purpose of this work was to investigate the integrity of the tight junctions (TJs) in rat brain microvessels after this BBB disruption. Ultrasound bursts (1.5-MHz) in combination with a gas contrast agent (Optison) was applied at two locations in the brain in 25 rats to induce BBB disruption. Using immunoelectron microscopy, the distributions of the TJ-specific transmembrane proteins occludin, claudin-1, claudin-5, and of submembranous ZO-1 were examined at 1, 2, 4, 6 and 24 h after sonication. A quantitative evaluation of the protein expression was made by counting the number of immunosignals per micrometer in the junctional clefts. BBB disruption at the sonicated locations was confirmed by the leakage of i.v. administered horseradish peroxidase (HRP, m.w. 40,000 Da) and lanthanum chloride (La(3+), m.w. approximately 139 Da). Leakage of these agents was observed at 1 and 2 h and, in a few vessels, at 4 h after ultrasound application. These changes were paralleled by the apparent disintegration of the TJ complexes, as evidenced by the redistribution and loss of the immunosignals for occludin, claudin-5 and ZO-1. Claudin-1 seemed less involved. At 6 and 24 h after sonication, no HRP or lanthanum leakage was observed and the barrier function of the TJs, as indicated by the localization and density of immunosignals, appeared to be completely restored. This study provides the first direct evidence that ultrasound bursts combined with a gas contrast agent cause disassembling of the TJ molecular structure, leading to loss of the junctional barrier functions in brain microvessels. The BBB disruption appears to last up to 4 h after sonication and permits the paracellular passage of agents with molecular weights up to at least 40 kDa. These promising features can be exploited in the future development of this method that could enable the delivery of drugs, antibodies or genes to targeted locations in the brain.

Ultrasound Enhanced Delivery of Molecular Imaging and Therapeutic Agents in Alzheimer's Disease Mouse Models

PloS One. 2008  |  Pubmed ID: 18478109

Alzheimer's disease is a neurodegenerative disorder typified by the accumulation of a small protein, beta-amyloid, which aggregates and is the primary component of amyloid plaques. Many new therapeutic and diagnostic agents for reducing amyloid plaques have limited efficacy in vivo because of poor transport across the blood-brain barrier. Here we demonstrate that low-intensity focused ultrasound with a microbubble contrast agent may be used to transiently disrupt the blood-brain barrier, allowing non-invasive, localized delivery of imaging fluorophores and immunotherapeutics directly to amyloid plaques. We administered intravenous Trypan blue, an amyloid staining red fluorophore, and anti-amyloid antibodies, concurrently with focused ultrasound therapy in plaque-bearing, transgenic mouse models of Alzheimer's disease with amyloid pathology. MRI guidance permitted selective treatment and monitoring of plaque-heavy anatomical regions, such as the hippocampus. Treated brain regions exhibited 16.5+/-5.4-fold increase in Trypan blue fluorescence and 2.7+/-1.2-fold increase in anti-amyloid antibodies that localized to amyloid plaques. Ultrasound-enhanced delivery was consistently reproduced in two different transgenic strains (APPswe:PSEN1dE9, PDAPP), across a large age range (9-26 months), with and without MR guidance, and with little or no tissue damage. Ultrasound-mediated, transient blood-brain barrier disruption allows the delivery of both therapeutic and molecular imaging agents in Alzheimer's mouse models, which should aid pre-clinical drug screening and imaging probe development. Furthermore, this technique may be used to deliver a wide variety of small and large molecules to the brain for imaging and therapy in other neurodegenerative diseases.

Ultrasound for Drug and Gene Delivery to the Brain

Advanced Drug Delivery Reviews. Jun, 2008  |  Pubmed ID: 18486271

Noninvasive, transient, and local image-guided blood-brain barrier disruption (BBBD) has been demonstrated with focused ultrasound exposure in animal models. Most studies have combined low pressure amplitude and low time average acoustic power burst sonications with intravascular injection of pre-formed micro-bubbles to produce BBBD without damage to the neurons. The BBB has been shown to be healed within a few hours after the exposure. The combination of focused ultrasound beams with MR image guidance allows precise anatomical targeting as demonstrated by the delivery of several marker molecules in different animal models. This method may in the future have a significant impact on the diagnosis and treatment of central nervous system (CNS) disorders. Most notably, the delivery of the chemotherapy agents (liposomal Doxorubicin and Herceptin) has been shown in a rat model.

Progress and Problems in the Application of Focused Ultrasound for Blood-brain Barrier Disruption

Ultrasonics. Aug, 2008  |  Pubmed ID: 18511095

Advances in neuroscience have resulted in the development of new diagnostic and therapeutic agents for potential use in the central nervous system (CNS). However, the ability to deliver the majority of these agents to the brain is limited by the blood-brain barrier (BBB), a specialized structure of the blood vessel wall that hampers transport and diffusion from the blood to the brain. Many CNS disorders could be treated with drugs, enzymes, genes, or large-molecule biotechnological products such as recombinant proteins, if they could cross the BBB. This article reviews the problems of the BBB presence in treating the vast majority of CNS diseases and the efforts to circumvent the BBB through the design of new drugs and the development of more sophisticated delivery methods. Recent advances in the development of noninvasive, targeted drug delivery by MRI-guided ultrasound-induced BBB disruption are also summarized.

Uterine Leiomyomas: MR Imaging-guided Focused Ultrasound Surgery--imaging Predictors of Success

Radiology. Oct, 2008  |  Pubmed ID: 18695211

To retrospectively assess the magnetic resonance (MR) imaging predictors of success at reducing uterine leiomyoma volume and achieving patient symptom relief 12 months after MR imaging-guided focused ultrasound surgery.

Simulations of Lesion Detection Using a Combined Phased Array LHMI-technique

Ultrasonics. Nov, 2008  |  Pubmed ID: 18778843

Ultrasound based elasticity imaging techniques have been developed during the past decades. Some of these techniques are based on an internal radiation force stimulation in which a transient or dynamic radiation force is produced by using a single or dual-frequency sonication. In addition, sonication and data acquisition can be implemented using combined or separate transducers. In this simulation study of lesion detection using localized harmonic motion imaging (LHMI), we used a combined phased array designed for simultaneous thermal ablation and lesion detection. In the sonication mode, a focused single-frequency amplitude-modulated sonication is used to induce harmonic motion and in the tracking mode, some of the array elements are used for pulse-echo tracking of the induced displacements. The results showed that the size of the lesion affected the induced displacement around the sonication point. The displacement tracking simulations demonstrated that these changes in the displacement distributions can be detected using only a few of the array elements in the tracking mode but the exact size of the lesion can not be detected accurately. The simulations also showed that two lesions having the radius of 2.5mm can be distinguished if distance between these lesions is at least 2.5mm.

In Vivo Monitoring of Focused Ultrasound Surgery Using Local Harmonic Motion

Ultrasound in Medicine & Biology. Jan, 2009  |  Pubmed ID: 18805626

The present study established the feasibility of a technique for monitoring focused ultrasound (FUS) lesion formation in vivo using localized harmonic motion (LHM) measurements. Oscillatory motion (frequencies between 50 and 300 Hz) was generated within tissues by induction of a periodic radiation force with a FUS transducer. The harmonic motion was estimated using cross correlation of RF ultrasonic signals acquired at different instances during the motion by using a confocal diagnostic ultrasound transducer. The technique was evaluated in vivo in rabbit muscle (14 locations) in an magnetic resonance (MR) imager for simultaneous ultrasound harmonic motion tracking and MR thermometry. The measured maximum amplitude of the induced harmonic motion before and after the lesion formation was significantly different for all the tested motion frequencies, and decreased between 17 and 81% depending on the frequency and location. During the FUS exposure a drop in the maximum amplitude value was observed and a threshold value could be associated to the formation of a thermal lesion. A series of controlled sonications was performed by stopping the exposure when the threshold value in LHM amplitude was reached and the presence of a thermal lesion was confirmed by MR imaging. LHM measurements were also used to perform a spatial scan of the tissues across the exposure region and the thermal lesions could be detected as a reduction in the maximum motion amplitude value at the sonication region.

Macromolecular Delivery Across the Blood-brain Barrier

Methods in Molecular Biology (Clifton, N.J.). 2009  |  Pubmed ID: 19085123

The delivery of macromolecules into the central nervous system (CNS) via the blood stream is seriously limited by the blood-brain barrier (BBB). Noninvasive, transient, and local image-guided blood-brain barrier disruption (BBBD) can be accomplished using focused ultrasound exposure with intravascular injection of pre-formed microbubbles. A detailed description of the method for MRI-guided focal BBBD in animals will be described in this chapter. The method may open a new era in CNS macromolecular drug delivery.

Transcranial Shear-mode Ultrasound: Assessment of Imaging Performance and Excitation Techniques

IEEE Transactions on Medical Imaging. May, 2009  |  Pubmed ID: 19150789

Transcranial ultrasound imaging is limited by poor acoustic windows and skull induced distortions to the beam. Shear waves in the skull have a better impedance match with longitudinal waves in water and thereby produce a more coherent focus inside the skull. This study presents work on an imaging technique that utilizes shear-wave propagation through the skull. The pulse-echo lateral distortion introduced by the skull was analyzed by imaging a point scatterer behind ex vivo human craniums at 1 MHz. Brightness images of the target obtained with either shear-mode or conventional longitudinal-mode transmission in the bone were assessed to quantify lateral resolution. As compared to longitudinal-mode transmission, it was found that the use of shear-mode resulted in improved localization along the propagation (depth) axis at the expense of degraded lateral resolution. The signal-to-noise ratio (SNR) limitations introduced by severe attenuation of shear-waves in the skull were overcome with frequency modulated (FM) coded excitations. This gain in SNR was exchanged with resolution and used for compensation of frequency-dependent attenuation in the skull, resulting in a greater than 20% improvement in lateral resolution for both modes of transcranial transmission. The results are an important step towards enhancing the quality of transcranial sonography.

MRI-based Thermal Dosimetry and Diffusion-weighted Imaging of MRI-guided Focused Ultrasound Thermal Ablation of Uterine Fibroids

Journal of Magnetic Resonance Imaging : JMRI. Feb, 2009  |  Pubmed ID: 19161196

To investigate tissue changes observed in diffusion-weighted imaging (DWI) and its relation to contrast imaging, thermal dosimetry, and changes in the apparent diffusion coefficient (ADC) after MRI-guided focused ultrasound surgery (MRgFUS) of uterine fibroids.

Lateral Mode Coupling to Reduce the Electrical Impedance of Small Elements Required for High Power Ultrasound Therapy Phased Arrays

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Mar, 2009  |  Pubmed ID: 19411214

A method that uses lateral coupling to reduce the electrical impedance of small transducer elements in generating ultrasound waves was tested. Cylindrical, radially polled transducer elements were driven at their length resonance frequency. Computer simulation and experimental studies showed that the electrical impedance of the transducer element could be controlled by the cylinder wall thickness, while the operation frequency was determined by the cylinder length. Acoustic intensity (averaged over the cylinder diameter) over 10 W / cm(2) (a therapeutically relevant intensity) was measured from these elements.

New Design for an Endoesophageal Sector- Based Array for the Treatment of Atrial Fibrillation: a Parametric Simulation Study

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Mar, 2009  |  Pubmed ID: 19411218

Atrial fibrillation (AF) is the most frequent and sustained cardiac arrhythmia affecting humans. The electrical isolation by ablation of the pulmonary veins (PV) in the left atrium (LA) of the heart has proved to be an effective cure for the AF. The ablation consists mainly of the formation of a localized circumferential thermal coagulation of the cardiac tissue surrounding the PVs. In this article, a parametric study was carried out to establish an optimal configuration of endesophageal ultrasound phased arrays intended to treat the AF. The devices are spherical-surface sections truncated at 15 mm, with a depth of 4 mm, and they are cut in concentric-rings, each composed of independently driven sectors. The number of independent elements (N(e)) was minimized for different values of ratio of pressure amplitude of the secondary lobe over the main lobe (eta) of 0.35, 0.4, 0.45, and 0.5 inside a volume of interest (VOI). After assuming a Cartesian system with the origin in the center of the device, the VOI was defined as the prism enclosed by the coordinates (-12, 10, -9) mm and (12, 37, 9) mm. The VOI has its center at (0, 23.5, 0) mm and is large enough to contain all the targets identified in the Visible Human Project Male specimen. Operating at 1 MHz, eta and N(e)were calculated in function of the element size and focal length (F). Four devices for each value of eta were found. After keeping values of F and normalized dimensions of the independent elements in terms of wavelength, higher frequencies were considered: 1.25 MHz, 1.5 MHz, and 2 MHz. In total, 16 device configurations were obtained. Realistic modeling of lesion formation in the heart chamber showed that the 16 configurations were able to produce the typical lesion used to treat the AF while preserving surrounding structures. At higher frequencies, lower power was required, and a greater number of array elements was required. For an exposure of 5 s and a maximum temperature of 70 degrees C, the average (+/-s.d.) acoustical intensity at transducer surface varied from 22.3(+/-5.8) W/cm(2) for a device with F = 98 mm at 1 MHz to 5.8(+/-1.2) W/cm(2) for a device with F = 186 mm at 2 MHz, while requiring 319 and 2093 elements, respectively, and achieving values of eta of 0.5 and 0.41, respectively. For the intended application, the selected devices implied a better focusing when compared with more traditional planar 2-D arrays, while requiring less power and fewer independent elements.

Focused Ultrasound Treatment of VX2 Tumors Controlled by Local Harmonic Motion

Physics in Medicine and Biology. Jun, 2009  |  Pubmed ID: 19436103

The purpose of this study was to evaluate the feasibility of using localized harmonic motion (LHM) to monitor and control focused ultrasound surgery (FUS) in VX2 tumors in vivo. FUS exposures were performed on 13 VX2 tumors implanted in nine rabbits. The same transducer induced coagulation and generated a localized oscillatory motion by periodically varying the radiation force. A separate diagnostic ultrasound transducer tracked motion by cross-correlating echo signals at different instances. A threshold in motion amplitude was instituted to cease exposure. Coagulation was confirmed by T2-weighted MR images, thermal dose obtained through MR thermometry and histological examinations. For tumor locations achieving coagulation, the LHM amplitude was 9% (p = 0.04) to 57% (p < 0.0001) lower than that before exposure. Control was successful for 74 (69%) out of 108 cases, with 52 (48%) reaching the threshold and achieving coagulation and 22 (21%) never reaching threshold nor coagulating. For the 34 (31%) unsuccessful exposures, 16 (15%) never reached the threshold but coagulation occurred, and 18 (16%) reached threshold without coagulation confirmed. Noise or radio-frequency signal changes explained motion over- or underestimation in 24 (22%) cases; the remaining 10 (9%) had other causes of error. The control was generally successful, but sudden change or noise in the acquired echo signal caused failure. Coagulation after exposure could be validated by comparing amplitudes before and after exposure.

An MRI-compatible System for Focused Ultrasound Experiments in Small Animal Models

Medical Physics. May, 2009  |  Pubmed ID: 19544806

The development of novel MRI-guided therapeutic ultrasound methods including potentiated drug delivery and targeted thermal ablation requires extensive testing in small animals such as rats and mice due to the widespread use of these species as models of disease. An MRI-compatible, computer-controlled three-axis positioning system was constructed to deliver focused ultrasound exposures precisely to a target anatomy in small animals for high-throughput preclinical drug delivery studies. Each axis was constructed from custom-made nonmagnetic linear ball stages driven by piezoelectric actuators and optical encoders. A range of motion of 5 x 5 x 2.5 cm3 was achieved, and initial bench top characterization demonstrated the ability to deliver ultrasound to the brain with a spatial accuracy of 0.3 mm. Operation of the positioning system within the bore of a clinical 3 T MR imager was feasible, and simultaneous motion and MR imaging did not result in any mutual interference. The system was evaluated in its ability to deliver precise sonications within the mouse brain, linear scanned exposures in a rat brain for blood barrier disruption, and circular scans for controlled heating under MR temperature feedback. Initial results suggest that this is a robust and precise apparatus for use in the investigation of novel ultrasound-based therapeutic strategies in small animal preclinical models.

MR Acoustic Radiation Force Imaging: in Vivo Comparison to Ultrasound Motion Tracking

Medical Physics. Jun, 2009  |  Pubmed ID: 19610290

MR acoustic radiation force (ARF) imaging was developed for measuring tiSsue elastic properties using focused ultrasound to deliver a localized tissue motion. In this study, an imaging ultrasound transducer was mounted on the focused ultrasound transducer and ultrasound motion tracking was performed simultaneously to MR ARF imaging to validate the measurement results. In vivo studies on rabbit thigh muscle were performed and results showed a general agreement between the two modalities (slope=0.96 and R2=0.67). The temporal information by the ultrasound measurement indicates that the parameters in MR ARF imaging should be optimized according to the tissue type, acoustic power, and envelope and frequency of the ARF modulation.

Focused Ultrasound Effects on Nerve Action Potential in Vitro

Ultrasound in Medicine & Biology. Oct, 2009  |  Pubmed ID: 19647923

Minimally invasive applications of thermal and mechanical energy to selective areas of the human anatomy have led to significant advances in treatment of and recovery from typical surgical interventions. Image-guided focused ultrasound allows energy to be deposited deep into the tissue, completely noninvasively. There has long been interest in using this focal energy delivery to block nerve conduction for pain control and local anesthesia. In this study, we have performed an in vitro study to further extend our knowledge of this potential clinical application. The sciatic nerves from the bullfrog (Rana catesbeiana) were subjected to focused ultrasound (at frequencies of 0.661 MHz and 1.986 MHz) and to heated Ringer's solution. The nerve action potential was shown to decrease in the experiments and correlated with temperature elevation measured in the nerve. The action potential recovered either completely, partially or not at all, depending on the parameters of the ultrasound exposure. The reduction of the baseline nerve temperature by circulating cooling fluid through the sonication chamber did not prevent the collapse of the nerve action potential; but higher power was required to induce the same endpoint as without cooling. These results indicate that a thermal mechanism of focused ultrasound can be used to block nerve conduction, either temporarily or permanently.

Feasibility of Using Lateral Mode Coupling Method for a Large Scale Ultrasound Phased Array for Noninvasive Transcranial Therapy

IEEE Transactions on Bio-medical Engineering. Jan, 2010  |  Pubmed ID: 19695987

A hemispherical-focused, ultrasound phased array was designed and fabricated using 1372 cylindrical piezoelectric transducers that utilize lateral coupling for noninvasive transcranial therapy. The cylindrical transducers allowed the electrical impedance to be reduced by at least an order of magnitude, such that effective operation could be achieved without electronic matching circuits. In addition, the transducer elements generated the maximum acoustic average surface intensity of 27 W/cm(2). The array, driven at the low (306-kHz) or high frequency (840-kHz), achieved excellent focusing through an ex vivo human skull and an adequate beam steering range for clinical brain treatments. It could electronically steer the ultrasound beam over cylindrical volumes of 100-mm in diameter and 60-mm in height at 306 kHz, and 30-mm in diameter and 30-mm in height at 840 kHz. A scanning laser vibrometer was used to investigate the radial and length mode vibrations of the element. The maximum pressure amplitudes through the skull at the geometric focus were predicted to be 5.5 MPa at 306 kHz and 3.7 MPa at 840 kHz for RF power of 1 W on each element. This is the first study demonstrating the feasibility of using cylindrical transducer elements and lateral coupling in construction of ultrasound phased arrays.

MRI-guided Focused Ultrasound Treatments

Ultrasonics. Feb, 2010  |  Pubmed ID: 19818981

Focused ultrasound (FUS) allows noninvasive focal delivery of energy deep into soft tissues. The focused energy can be used to modify and eliminate tissue for therapeutic purposes while the energy delivery is targeted and monitored using magnetic resonance imaging (MRI). MRI compatible methods to deliver these exposures have undergone rapid development over the past 10 years such that clinical treatments are now routinely performed. This paper will review the current technical and clinical status of MRI-guided focused ultrasound therapy and discuss future research and development opportunities.

Local Harmonic Motion Monitoring of Focused Ultrasound Surgery--a Simulation Model

IEEE Transactions on Bio-medical Engineering. Jan, 2010  |  Pubmed ID: 19822463

In this paper, a computational model for localized harmonic motion (LHM) imaging-based monitoring of high-intensity focused ultrasound surgery (FUS) is presented. The LHM technique is based on a focused, time-varying ultrasound radiation force excitation, which induces local oscillatory motions at the focal region. These vibrations are tracked, using pulse-echo imaging, and then, used to estimate the mechanical properties of the sonication region. LHM is feasible for FUS monitoring because changes in the material properties during the coagulation process affect the measured displacements. The presented model includes separate models to simulate acoustic sonication fields, sonication-induced temperature elevation and mechanical motion, and pulse-echo imaging of the induced motions. These 3-D simulation models are based on Rayleigh-Sommerfield integral, finite element, and spatial impulse response methods. Simulated-tissue temperature elevation and mechanical motion were compared with previously published in vivo measurements. Finally, the simulation model was used to simulate coagulation and LHM monitoring, as would occur with multiple, neighbouring sonication locations covering a large tumor.

Transcranial Magnetic Resonance Imaging- Guided Focused Ultrasound Surgery of Brain Tumors: Initial Findings in 3 Patients

Neurosurgery. Feb, 2010  |  Pubmed ID: 20087132

This work evaluated the clinical feasibility of transcranial magnetic resonance imaging-guided focused ultrasound surgery.

Hyperthermia Classic Commentary: 'A Scanned, Focused, Multiple Transducer Ultrasonic System for Localised Hyperthermia Treatments', by K. Hynynen, R. Roemer, D. Anhalt, Et Al., International Journal of Hyperthermia 1987;3:21-35

International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. Feb, 2010  |  Pubmed ID: 20100047

This commentary reviews the development of image-guided focused ultrasound treatments since the publication of the above paper. The impact of the research presented in the paper on the development of the current image-guided noninvasive surgery and treatments will also be discussed.

Temperature Change Near Microbubbles Within a Capillary Network During Focused Ultrasound

Physics in Medicine and Biology. Mar, 2010  |  Pubmed ID: 20164536

Preformed gas bubbles can increase energy absorption from an ultrasound beam and therefore they have been proposed for an enhancer of ultrasound treatments. Although tissue temperature measurements performed in vivo using invasive thermocouple probes and MRI thermometry have demonstrated increased tissue temperature, the microscopic temperature distribution has not been investigated so far. In this study the transfer of heat between bubbles and tissue during focused ultrasound was simulated. Microbubble oscillations were simulated within a rat cortical microvascular network reconstructed from in vivo dual-photon microscopy images and the power density of these oscillations was used as an input term in the Pennes bioheat transfer equation. The temperature solution from the bioheat transfer equation was mapped onto vascular data to produce a three-dimensional temperature map. The results showed high temperatures near the bubbles and slow temperature rise in the tissue. Heating was shown to increase with increasing bubble frequency and insonation pressure, and showed a frequency-dependent peak. The goal of this research is to characterize the effect of various parameters on bubble-enhanced therapeutic ultrasound to allow better treatment planning. These results show that the induced temperature elevations have nonuniformities which may have a significant impact on the bio-effects of the exposure.

Ultrasound-induced Activation of Wnt Signaling in Human MG-63 Osteoblastic Cells

Bone. Aug, 2010  |  Pubmed ID: 20435172

The benefit from an ultrasound (US) exposure for fracture healing has been clearly shown. However, the molecular mechanisms behind this effect are not fully known. Recently, the canonical Wnt signaling pathway has been recognized as one of the essential regulators of osteoblastogenesis and bone mass, and thereby considered crucial for bone health. Mechanical loading and fluid shear stress have been reported to activate the canonical Wnt signaling pathway in bone cells, but previous reports on the effects of therapeutic US on Wnt signaling in general or in bone, in particular, have not been published yet. Therefore, activation of Wnt signaling pathway was assayed in human osteoblastic cells, and indeed, this pathway was found to be activated in MG-63 cells through the phosphoinositol 3-kinase/Akt (PI3K/Akt) and mTOR cascades following a single 10 min US exposure (2 W, 1.035 MHz). In addition to the reporter assay results, the Wnt pathway activation was also observed as nuclear localization of beta-catenin. Wnt activation showed also temperature dependence at elevated temperatures, and the expression of canonical Wnt ligands was induced under the thermal exposures. However, existence of a specific, non-thermal US component was evident as well, perhaps evidence of a potential dual action of therapeutic US on bone. Neither US nor heat exposures affected cell viability in our experiments. In summary, this is the first study to report that Wnt signaling cascade, important for osteoblast function and bone health, is one of the pathways activated by therapeutic US as well as by hyperthermia in human osteoblastic cells. Our results provide evidence for the potential molecular mechanisms behind the beneficial effects of US on fracture healing. Combinations of US, heat, and possible pharmacological treatment could provide useful flexibility for clinical cases in treating various bone disorders.

Contrast Agent Kinetics in the Rabbit Brain During Exposure to Therapeutic Ultrasound

Ultrasound in Medicine & Biology. Jun, 2010  |  Pubmed ID: 20447757

Ultrasound-stimulated microbubbles are currently under investigation as a means of transiently disrupting the blood-brain barrier (BBB) and it has been shown that the strength of this effect is highly dependent on ultrasound exposure conditions. The objective of this study was to investigate the potential for contrast agent destruction in the brain under conditions relevant to BBB disruption with a view to determining its possible influence on effective exposure parameters. An ultrasound imaging array was mounted within the aperture of a 1.68-MHz focused therapy transducer. Pulse lengths of 10 ms were used at repetition rates of 0.1-2.0 Hz and pressures from 0.30-0.88 MPa. Contrast imaging was performed after the bolus injection of Definity, and contrast time-intensity curves were then analyzed for regions-of-interest exposed to the therapy beam. Individual therapy pulses resulted in microbubble destruction, with the degree of agent depletion and replenishment time increasing with transmit pressure. As the pulse repetition rate was increased, agent reperfusion between pulses was incomplete and the concentration within the beam was progressively diminished, to a degree dependent on both pressure and repetition rates. These results demonstrate that microbubble concentration can be substantially influenced by destruction induced by therapeutic ultrasound pulses. The kinetics of this effect may therefore be a significant factor influencing the efficiency of BBB disruption, suggesting that monitoring of the spatial and temporal distribution of contrast agents may be warranted to guide and optimize BBB disruption therapy in both preclinical and clinical contexts.

Antibodies Targeted to the Brain with Image-guided Focused Ultrasound Reduces Amyloid-beta Plaque Load in the TgCRND8 Mouse Model of Alzheimer's Disease

PloS One. 2010  |  Pubmed ID: 20485502

Immunotherapy for Alzheimer's disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (Abeta), which circulate in the bloodstream and remove Abeta from the brain. In mouse models of AD, the administration of anti-Abeta antibodies directly into the brain, in comparison to the bloodstream, was shown to be more efficient at reducing Abeta plaque pathology. Therefore, delivering anti-Abeta antibodies to the brain of AD patients may also improve treatment efficiency. Transcranial focused ultrasound (FUS) is known to transiently-enhance the permeability of the blood-brain barrier (BBB), allowing intravenously administered therapeutics to enter the brain. Our goal was to establish that anti-Abeta antibodies delivered to the brain using magnetic resonance imaging-guided FUS (MRIgFUS) can reduce plaque pathology. To test this, TgCRND8 mice received intravenous injections of MRI and FUS contrast agents, as well as anti-Abeta antibody, BAM-10. MRIgFUS was then applied transcranially. Within minutes, the MRI contrast agent entered the brain, and BAM-10 was later found bound to Abeta plaques in targeted cortical areas. Four days post-treatment, Abeta pathology was significantly reduced in TgCRND8 mice. In conclusion, this is the first report to demonstrate that MRIgFUS delivery of anti-Abeta antibodies provides the combined advantages of using a low dose of antibody and rapidly reducing plaque pathology.

A PVDF Receiver for Ultrasound Monitoring of Transcranial Focused Ultrasound Therapy

IEEE Transactions on Bio-medical Engineering. Sep, 2010  |  Pubmed ID: 20515709

Focused ultrasound (FUS) shows great promise for use in the area of transcranial therapy. Currently dependent on MRI for monitoring, transcranial FUS would benefit from a real-time technique to monitor acoustic emissions during therapy. A polyvinylidene fluoride receiver with an active area of 17.8 mm (2) and a film thickness of 110 mum was constructed. A compact preamplifier was designed to fit within the receiver to improve the receiver SNR and allow the long transmission line needed to remove the receiver electronics outside of the MRI room. The receiver was compared with a 0.5 mm commercial needle hydrophone and focused and unfocused piezoceramics. The receiver was found to have a higher sensitivity than the needle hydrophone, a more wideband response than the piezoceramic, and sufficient threshold for detection of microbubble emissions. Sonication of microbubbles directly and through a fragment of human skull demonstrated the ability of the receiver to detect harmonic bubble emissions, and showed potential for use in a larger scale array. Monitoring of disruption of the blood-brain barrier in rats showed functionality in vivo and the ability to detect subharmonic, harmonic, and wideband emissions during therapy. The receiver shows potential for monitoring acoustic emissions during treatments and providing additional parameters to assist treatment planning. Future work will focus on developing a multi-element array for transcranial treatment monitoring.

Influence of Exposure Time and Pressure Amplitude on Blood-brain-barrier Opening Using Transcranial Ultrasound Exposures

ACS Chemical Neuroscience. May, 2010  |  Pubmed ID: 20563295

Pulsed ultrasound exposures of brain tissue in the presence of micro-bubble contrast agents have been shown to achieve transient focal disruption of the blood brain barrier without significant damage to surrounding brain tissue. The effects of overall exposure duration on the extent of blood brain barrier disruption was studied in these experiments to determine operating conditions for increasing the amount of therapeutic agents delivered to the brain. Exposures at 1.08 MHz ranging from 0.2 to 0.8 MPa in amplitude were delivered transcranially to the brains of rabbits and rats for durations ranging from 30 to 1200 seconds. The amount of signal enhancement on contrast-enhanced T1-weighted MR images were used to quantify the extent of blood brain barrier disruption and histological evaluation of the exposed regions was performed to evaluate the impact on brain tissue. A subset of four rats underwent weekly exposures for 3 weeks to evaluate the feasibility of repeat sonications to the brain. The results suggest that exposures less than 180 seconds in duration are associated with a low probability of irreversible damage to brain tissue at pressure amplitudes of 0.38 MPa. Although exposures greater than 300 seconds were associated with an increase in the proportion of irreversible damage, this may be acceptable for chemotherapy delivery, where the therapeutic goal is tissue destruction. Repeat exposures to the brain were feasible, but resulted in evidence of focal brain damage in 50% of animals.

In Vitro Characterization of Perfluorocarbon Droplets for Focused Ultrasound Therapy

Physics in Medicine and Biology. Sep, 2010  |  Pubmed ID: 20693614

Focused ultrasound therapy can be enhanced with microbubbles by thermal and cavitation effects. However, localization of treatment is difficult as bioeffects can occur outside of the target region. Spatial control of bubbles can be achieved by ultrasound-induced conversion of liquid perfluorocarbon droplets to gas bubbles. This study was undertaken to determine the acoustic parameters for bubble production by droplet conversion and how it depends on the acoustic conditions and droplet physical parameters. Lipid-encapsulated droplets containing dodecafluoropentane were manufactured with sizes ranging from 1.9 to 7.2 microm in diameter and diluted to a concentration of 8 x 10(6) droplets mL(-1). The droplets were sonicated in vitro with a focused ultrasound transducer and varying frequency and exposure under flow conditions through an acoustically transparent vessel. The sonications were 10 ms in duration at frequencies of 0.578, 1.736 and 2.855 MHz. The pressure threshold for droplet conversion was measured with an active transducer operating in pulse-echo mode and simultaneous measurements of broadband acoustic emissions were performed with passive acoustic detection. The results show that droplets cannot be converted at low frequency without broadband emissions occurring. However, the pressure threshold for droplet conversion decreased with increasing frequency, exposure and droplet size. The pressure threshold for broadband emissions was independent of the droplet size and was 2.9, 4.4 and 5.3 MPa for 0.578, 1736 and 2.855 MHz, respectively. In summary, we have demonstrated that droplet conversion is feasible for clinically relevant sized droplets and acoustic exposures.

The Impact of Standing Wave Effects on Transcranial Focused Ultrasound Disruption of the Blood-brain Barrier in a Rat Model

Physics in Medicine and Biology. Sep, 2010  |  Pubmed ID: 20720286

Microbubble-mediated disruption of the blood-brain barrier (BBB) for targeted drug delivery using focused ultrasound shows great potential as a therapy for a wide range of brain disorders. This technique is currently at the pre-clinical stage and important work is being conducted in animal models. Measurements of standing waves in ex vivo rat skulls were conducted using an optical hydrophone and a geometry dependence was identified. Standing waves could not be eliminated through the use of swept frequencies, which have been suggested to eliminate standing waves. Definitive standing wave patterns were detected in over 25% of animals used in a single study. Standing waves were successfully eliminated using a wideband composite sharply focused transducer and a reduced duty cycle. The modified pulse parameters were used in vivo to disrupt the BBB in a rat indicating that, unlike some other bioeffects, BBB disruption is not dependent on standing wave conditions. Due to the high variability of standing waves and the inability to correctly estimate in situ pressures given standing wave conditions, attempts to minimize standing waves should be made in all future work in this field to ensure that results are clinically translatable.

Focused Ultrasound-mediated Bbb Disruption is Associated with an Increase in Activation of AKT: Experimental Study in Rats

BMC Neurology. 2010  |  Pubmed ID: 21078165

The Blood Brain Barrier (BBB) maintains the homeostasis of central nervous system by preventing the free passage of macromolecules from the systemic circulation into the brain. This normal physiological function of the BBB presents a challenge for delivery of therapeutic compounds into the brain. Recent studies have shown that the application of focused ultrasound together with ultrasound contrast agent (microbubbles) temporarily increases the permeability of the BBB. This effect is associated with breakdown of tight junctions, the structures that regulate the paracellular permeability of the endothelial cell layer. The influence of this ultrasound effect on the activation of intracellular signaling proteins is currently not well understood. Therefore, the aim of this study was to investigate the activation of cell survival signaling molecules in response to ultrasound-mediated BBB opening;

Multi-frequency Characterization of the Speed of Sound and Attenuation Coefficient for Longitudinal Transmission of Freshly Excised Human Skulls

Physics in Medicine and Biology. Jan, 2011  |  Pubmed ID: 21149950

For medical applications of ultrasound inside the brain, it is necessary to understand the relationship between the apparent density of skull bone and its corresponding speed of sound and attenuation coefficient. Although there have been previous studies exploring this phenomenon, there is still a need to extend the measurements to cover more of the clinically relevant frequency range. The results of measurements of the longitudinal speed of sound and attenuation coefficient are presented for specimens of human calvaria. The study was performed for the frequencies of 0.27, 0.836, 1.402, 1.965 and 2.525 MHz. Specimens were obtained from fresh cadavers through a protocol with the Division of Anatomy of the University of Toronto. The protocol was approved by the Research Ethics Board of Sunnybrook Health Sciences Centre. The specimens were mounted in polycarbonate supports that were marked for stereoscopic positioning. Computer tomography (CT) scans of the skulls mounted on their supports were performed, and a three-dimensional skull surface was reconstructed. This surface was used to guide a positioning system to ensure the normal sound incidence of an acoustic signal. This signal was produced by a focused device with a diameter of 5 cm and a focal length of 10 cm. Measurements of delay in time of flight were carried out using a needle hydrophone. Measurements of effective transmitted energy were carried out using a radiation force method with a 10 µg resolution scale. Preliminary functions of speed of sound and attenuation coefficient, both of which are related to apparent density, were established using a multi-layer propagation model that takes into account speed of sound, density and thickness of the layer. An optimization process was executed from a large set of random functions and the best functions were chosen for those ones that closest reproduced the experimental observations. The final functions were obtained after a second pass of the optimization process was executed, but this time using a finite-difference time-difference solution of the Westervelt equation, which is more precise than the multi-layer model but much more time consuming for computation. For six of seven specimens, measurements were carried out on five locations on the calvaria, and for the other specimen three measurements were made. In total, measurements were carried out on 33 locations. Results indicated the presence of dispersion effects and that these effects are different according to the type of bone in the skull (cortical and trabecular). Additionally, both the speed of sound and attenuation showed dependence on the skull density that varied with the frequency. Using the optimal functions and the information of density from the CT scans, the average values (±s.d.) of the speed of sound for cortical bone were estimated to be 2384(± 130), 2471(± 90), 2504(± 120), 2327(± 90) and 2053(± 40) m s(-1) for the frequencies of 270, 836, 1402, 1965 and 2526 kHz, respectively. For trabecular bone, and in the same order of frequency values, the speeds of sound were 2140(± 130), 2300(± 100), 2219(± 200), 2133(± 130) and 1937(± 40) m s(-1), respectively. The average values of the attenuation coefficient for cortical bone were 33(± 9), 240(± 9) and 307(± 30) Np m(-1) for the frequencies of 270, 836, and 1402, respectively. For trabecular bone, and in the same order of frequency values, the average values of the attenuation coefficient were 34(± 13), 216(± 16) and 375(± 30) Np m(-1), respectively. For frequencies of 1.965 and 2.525 MHz, no measurable radiation force was detected with the setup used.

Localised Drug Release Using MRI-controlled Focused Ultrasound Hyperthermia

International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. 2011  |  Pubmed ID: 21158487

Thermosensitive liposomes provide a mechanism for triggering the local release of anticancer drugs, but this technology requires precise temperature control in targeted regions with minimal heating of surrounding tissue. The objective of this study was to evaluate the feasibility of using MRI-controlled focused ultrasound (FUS) and thermosensitive liposomes to achieve thermally mediated localised drug delivery in vivo.

MR-guided Focused Ultrasound for Brain Ablation and Blood-brain Barrier Disruption

Methods in Molecular Biology (Clifton, N.J.). 2011  |  Pubmed ID: 21279624

MR-guided transcranial focused ultrasound (FUS) has been demonstrated as a non-invasive tool for treating various brain diseases. First, FUS can thermally ablate brain tissues under real-time MR thermometry monitoring. The MRI guidance significantly improves the precision of the thermal dose deposition. Second, in conjunction with microbubble contrast agents, FUS can reversibly disrupt the blood-brain barrier for delivery of macromolecular drugs to the brain parenchyma. This offers huge potential for treating brain diseases with a much higher local drug concentration than other drug delivery methods. In this chapter, a detailed protocol of MR-guided focused ultrasound for brain thermal ablation and BBB disruption in an animal research setting is presented.

Focused-ultrasound Disruption of the Blood-brain Barrier Using Closely-timed Short Pulses: Influence of Sonication Parameters and Injection Rate

Ultrasound in Medicine & Biology. Apr, 2011  |  Pubmed ID: 21376455

Blood-brain barrier disruption (BBBD) shows promise for drug delivery in the brain; however, optimal parameters for disruption have yet to be firmly established. Previous work has shown that BBBD can be achieved using bursts comprised of microsecond-length pulses at 50% duty cycle to eliminate standing waves and variability. The capabilities and limitations of this sort of pulse sequence comprising short bursts were examined. Ultrasound-induced BBBD was performed in 28 rats using Definity contrast agent. The spacing between 3-μs pulses at 1.18 MHz was either 6 μs, 60 μs, 300 μs or 600 μs during a 10-ms pulse, or 1 s for a single-pulse burst. The rate of infusion of the microbubbles was also examined, as well as the burst pulse repetition frequency (PRF) under infusion conditions. A semi-log relationship between enhancement mean and the number of cycles in a burst was discovered, with a one-pulse burst (i.e., a 3-μs burst at 1 Hz) still capable of disrupting the BBB. No increased efficacy or safety benefit over bursts containing more cycles was found, however. Microbubble infusions showed no improvement in T1w enhancement, but did improve consistency. Increased burst PRF combined with infusion improved T1w enhancement but without statistical significance, whereas a decrease in burst PRF showed a statistically significant decrease in enhancement.

Focused Ultrasound Surgery in Oncology: Overview and Principles

Radiology. Apr, 2011  |  Pubmed ID: 21436096

Focused ultrasound surgery (FUS) is a noninvasive image-guided therapy and an alternative to surgical interventions. It presents an opportunity to revolutionize cancer therapy and to affect or change drug delivery of therapeutic agents in new focally targeted ways. In this article the background, principles, technical devices, and clinical cancer applications of image-guided FUS are reviewed.

Two-photon Fluorescence Microscopy Study of Cerebrovascular Dynamics in Ultrasound-induced Blood-brain Barrier Opening

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. Sep, 2011  |  Pubmed ID: 21505473

Blood-brain barrier (BBB) disruption can be achieved with ultrasound (US) and circulating microbubble (MB) contrast agent. Using dorsal US sonication and Definity, an MB contrast agent, responses of the cortical cerebral vasculature to BBB opening were observed with varying acoustic peak negative pressure (0.071 to 0.25 MPa) under two-photon microscope. Wistar rats with a craniotomy were sonicated with a single piezoelectric transducer following the intravenous injection of Texas Red for visualization of vasculature and leakage from BBB opening. Based on time-dependent intensity change in the extravascular area, the leakage was classified into three types: fast, sustained, and slow. Fast leakage was characterized by a rapid increase to peak intensity during sonication, but a decrease afterwards, occurring at all pressures and vessels sizes analyzed in our study. Sustained leakage was indicated by a similar, immediate increase to peak intensity but one that remained elevated for the duration of imaging, occurring at low-to-intermediate pressures. Slow leakage began 5 to 15 minutes after sonication, dominating at low pressures, and was more prevalent among smaller vessels than fast and sustained leakage. Our study showed the possibility of controlling leakage type and vessel size in US-induced BBB opening through varying acoustic pressure.

Localized Harmonic Motion Imaging for Focused Ultrasound Surgery Targeting

Ultrasound in Medicine & Biology. Aug, 2011  |  Pubmed ID: 21683514

Recently, an in vivo real-time ultrasound-based monitoring technique that uses localized harmonic motion (LHM) to detect changes in tissues during focused ultrasound surgery (FUS) has been proposed to control the exposure. This technique can potentially be used as well for targeting imaging. In the present study, we evaluated the potential of using LHM to detect changes in stiffness and the feasibility of using it for imaging purposes in phantoms and in vivo tumor detection. A single-element FUS transducer (80 mm focal length, 100 mm diameter, 1.485 MHz) was used for inducing a localized harmonic motion and a separate ultrasound diagnostic transducer excited by a pulser/receiver (5 kHz PRF, 5 MHz) was used to track motion. The motion was estimated using cross-correlation techniques on the acquired radio-frequency (RF) signal. Silicon phantom studies were performed to determine the size of inclusion that was possible to detect using this technique. Inclusions were discerned from the surroundings as a reduction on LHM amplitude and it was possible to depict inclusions as small as 4 mm. The amplitude of the induced LHM was always lower at the inclusions compared with the one obtained at the surroundings. Ten New Zealand rabbits had VX2 tumors implanted on their thighs and LHM was induced and measured at the tumor region. Tumors (as small as 10 mm in length and 4 mm in width) were discerned from the surroundings as a reduction on LHM amplitude.

Simulations and Measurements of Transcranial Low-frequency Ultrasound Therapy: Skull-base Heating and Effective Area of Treatment

Physics in Medicine and Biology. Aug, 2011  |  Pubmed ID: 21734333

Measurements of temperature elevations induced by sonications in a single intact cadaver skull filled with soft-tissue mimicking phantom material were performed using magnetic resonance thermometry. The sonications were done using a clinical transcranial ultrasound therapy device operating at 230 kHz and the measurements were compared with simulations done using a model incorporating both the longitudinal and shear wave propagation. Both the measurements and simulations showed that in some situations the temperature increase could be higher in the phantom material adjacent to the skull-base than at the focus, which could lead to undesired soft-tissue damage in treatment situations. On average the measurements of the sonicated locations, as well as the comparative simulations, showed 32 ± 64% and 49 ± 32% higher temperature elevations adjacent to the skull-base than at the focus, respectively. The simulation model was used to extend the measurements by simulating multiple sonications of brain tissue in five different skulls with and without correcting the aberrations caused by the skull on the ultrasound. Without aberration correction the closest sonications to the skulls that were treatable in any brain location without undesired tissue damage were at a distance of 19.1 ± 2.6 mm. None of the sonications beyond a distance of 41.2 ± 5.3 mm were found to cause undesired tissue damage. When using the aberration correction closest treatable, safe distances for sonications were found to be 16.0 ± 1.6  and 38.8 ± 3.8 mm, respectively. New active cooling of the skull-base through the nasal cavities was introduced and the treatment area was investigated. The closest treatable distance without aberration correction reduced to 17.4 ± 1.9 mm with the new cooling method. All sonications beyond a distance of 39.7 ± 6.6 mm were found treatable. With the aberration correction no difference in the closest treatable or the safety distance was found in comparison to sonications without nasal cavity cooling. To counteract undesired skull-base heating a new anti-focus within solid media was developed along with a new regularized phasing method. Mathematical bases for both the methods and simulations utilizing them were presented. It was found that utilizing the anti-focus in solid media and regularized phasing, the fraction of temperature increase of the brain tissue at the focus and the peak temperature increase adjacent to the skull-base can be increased from 1.00 to 1.95. This improves the efficiency of the sonication by reducing the energy transfer to the skull-base.

The Utility of Sparse 2D Fully Electronically Steerable Focused Ultrasound Phased Arrays for Thermal Surgery: a Simulation Study

Physics in Medicine and Biology. Aug, 2011  |  Pubmed ID: 21772081

Sparse arrays are widely used in diagnostic ultrasound for their strong performance and relative technical simplicity. This simulation study assessed the efficacy of phased arrays of varied sparseness for thermal surgery, especially with regard to power consumption and near-field heating. It employs a linear ultrasound propagation model and a semi-analytical solution to the Pennes' bioheat transfer equation. The basic design had 4912 cylindrical transducers (500 kHz) arranged on a flat 12 cm disk (1.5 mm spacing). This array was compared to randomly-thinned sparse arrays with 75%, 50% and 25% populations. Temperature elevations of 60 and 70 °C were induced in sonication times of 5-20 s, at foci spanning depths of 50-150 mm and radii of 0-60 mm. The sparse arrays produced nearly indistinguishable focal patterns but, averaged across the foci, required 132%, 200% and 393% of the power of the full array, respectively, applied through fewer transducer elements. Comparable results were found at 1 MHz from equivalent arrays. Simulated lesions were formed (thermal dose ⩾ 240 equivalent minutes at 43 °C (T(43))) and 'transition' and 'unsafe' regions (both defined as 5 min < T(43) < 240 min) were identified, the former immediately surrounding the lesion and the latter anywhere else. At a depth of 100 mm, sparse arrays were found to produce comparable lesions to the full array at the focus, but 'unsafe', over-heated near-field regions after some ablated lesion volume: about 12 mL for the 25% array, around 100 mL for the 50% array, while the 75% and full arrays produced 150 mL lesions safely.

Targeted Delivery of Neural Stem Cells to the Brain Using MRI-guided Focused Ultrasound to Disrupt the Blood-brain Barrier

PloS One. 2011  |  Pubmed ID: 22114718

Stem cell therapy is a promising strategy to treat neurodegenerative diseases, traumatic brain injury, and stroke. For stem cells to progress towards clinical use, the risks associated with invasive intracranial surgery used to deliver the cells to the brain, needs to be reduced. Here, we show that MRI-guided focused ultrasound (MRIgFUS) is a novel method for non-invasive delivery of stem cells from the blood to the brain by opening the blood brain barrier (BBB) in specific brain regions. We used MRI guidance to target the ultrasound beam thereby delivering the iron-labeled, green fluorescent protein (GFP)-expressing neural stem cells specifically to the striatum and the hippocampus of the rat brain. Detection of cellular iron using MRI established that the cells crossed the BBB to enter the brain. After sacrifice, 24 hours later, immunohistochemical analysis confirmed the presence of GFP-positive cells in the targeted brain regions. We determined that the neural stem cells expressed common stem cell markers (nestin and polysialic acid) suggesting they survived after transplantation with MRIgFUS. Furthermore, delivered stem cells expressed doublecortin in vivo indicating the stem cells were capable of differentiating into neurons. Together, we demonstrate that transient opening of the BBB with MRIgFUS is sufficient for transplantation of stem cells from the blood to targeted brain structures. These results suggest that MRIgFUS may be an effective alternative to invasive intracranial surgery for stem cell transplantation.

Ultrasound Insertion Loss of Rat Parietal Bone Appears to Be Proportional to Animal Mass at Submegahertz Frequencies

Ultrasound in Medicine & Biology. Nov, 2011  |  Pubmed ID: 21925788

Transcranial ultrasound therapy is an increasing area of research for noninvasive treatments in the brain including targeted drug delivery. Measurements of ultrasound transmission through rat parietal bone at five frequencies (0.268 MHz, 0.841 MHz, 1.409 MHz, 1.972 MHz and 2.53 MHz) were performed at 88 locations in 22 ex vivo rat skullcaps (Wistar) using a fiber-optic hydrophone system. At submegahertz frequencies, the skull insertion loss was found to be proportional to animal mass, while at higher frequencies this trend was lost. Maps of the transverse pressure profile of the transducer before and after skull insertion showed increased distortion effects at higher frequencies. Parietal bone thickness was measured and was found to increase with increasing body mass. Additional measurements were made through mouse and rabbit skulls at 2.53 MHz. At this frequency, aberration effects through mouse skull were negligible, while large distortions were observed through rat and rabbit skull. Preclinical transcranial ultrasound studies in rats may be improved by scaling applied powers according to body mass to produce more consistent in situ pressures.

Driving Circuitry for Focused Ultrasound Noninvasive Surgery and Drug Delivery Applications

Sensors (Basel, Switzerland). 2011  |  Pubmed ID: 22346589

Recent works on focused ultrasound (FUS) have shown great promise for cancer therapy. Researchers are continuously trying to improve system performance, which is resulting in an increased complexity that is more apparent when using multi-element phased array systems. This has led to significant efforts to reduce system size and cost by relying on system integration. Although ideas from other fields such as microwave antenna phased arrays can be adopted in FUS, the application requirements differ significantly since the frequency range used in FUS is much lower. In this paper, we review recent efforts to design efficient power monitoring, phase shifting and output driving techniques used specifically for high intensity focused ultrasound (HIFU).

Hyperthermia Combined with Radiation for the Treatment of Locally Advanced Prostate Cancer: Long-term Results from Dana-Farber Cancer Institute Study 94-153

Cancer. Feb, 2011  |  Pubmed ID: 20886629

The authors present long-term results from a phase 2 study that assessed the efficacy of transrectal ultrasound hyperthermia plus radiation with or without androgen suppression for the treatment of locally advanced prostate cancer.

Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential into the Brain Using MRI-guided Focused Ultrasound

Nanomedicine : Nanotechnology, Biology, and Medicine. Feb, 2012  |  Pubmed ID: 22349099

The blood brain barrier (BBB) is a major impediment to the delivery of therapeutics into the central nervous system (CNS). Gold nanoparticles (AuNPs) have been successfully employed in multiple potential therapeutic and diagnostic applications outside the CNS. However, AuNPs have very limited biodistribution within the CNS following intravenous administration. Magnetic resonance imaging guided focused ultrasound (MRgFUS) is a novel technique that can transiently increase BBB permeability allowing delivery of therapeutics into the CNS. MRgFUS has not been previously employed for delivery of AuNPs into the CNS. This work represents the first demonstration of focal enhanced delivery of AuNPs into the CNS using MRgFUS in a rat model both safely and effectively. Histologic visualization and analytical quantification of AuNPs within the brain parenchyma suggest BBB transgression. These results suggest a role for MRgFUS in the delivery of AuNPs with therapeutic potential into the CNS for targeting neurological diseases.

In Vitro and In Vivo High-Intensity Focused Ultrasound Thrombolysis

Investigative Radiology. Feb, 2012  |  Pubmed ID: 22373533

OBJECTIVES: To characterize the ability of high-intensity focused ultrasound to achieve thrombolysis in vitro and investigate the feasibility of this approach as a means of restoring blood flow in thrombus-occluded arteries in vivo. MATERIALS AND METHODS: All experiments were approved by the Institutional Animal Care Committee. Thrombolysis was performed with a 1.51-MHz focused ultrasound transducer with pulse lengths of 0.1 to 10 milliseconds and acoustic powers up to 300 W. In vitro experiments were performed with blood clots formed from rabbit arterial blood and situated in 2-mm diameter tubing. Both single location and flow bypass recanalization experiments were conducted. In vitro clot erosion was assessed with 30-MHz ultrasound, with debris size measured with filters and a Coulter counter. In vivo clots were initiated in the femoral arteries of rabbits (n = 26). Cavitation signals from bubbles formed during exposure were monitored. In vivo flow restoration was assessed with 23-MHz Doppler ultrasound. RESULTS: At a single location, in vitro clot erosion volumes increased with exposure power and pulse length, with debris size reducing with increasing pulse length. Flow bypass experiments achieved 99.2% clot erosion with 1.1% of debris above 0.5 mm in size. In vivo, 10 milliseconds pulses were associated with bleeding, but at 1 millisecond, it was feasible to achieve partial flow restoration in 6of the 10 clots with only 1of the 10 showing evidence of bleeding. In all cases, thrombolysis occurred only in the presence of cavitation. CONCLUSION: High-intensity focused ultrasound thrombolysis is feasible as a means of restoring partial blood flow in thrombus-occluded arteries in the absence of thrombolytic agents. The potential for bleeding with this approach requires further investigation.

Investigation of Standing-wave Formation in a Human Skull for a Clinical Prototype of a Large-aperture, Transcranial MR-guided Focused Ultrasound (MRgFUS) Phased Array: an Experimental and Simulation Study

IEEE Transactions on Bio-medical Engineering. Feb, 2012  |  Pubmed ID: 22049360

Standing-wave formation in an ex vivo human skull was investigated using a clinical prototype of a 30-cm diameter with 15-cm radius of curvature, low-frequency (230 kHz), hemispherical transcranial magnetic resonance-guided focused ultrasound phased array. Experimental and simulation studies were conducted with changing aperture size and f -number configurations of the phased array and qualitatively and quantitatively examined the acoustic pressure variation at the focus due to standing waves. The results demonstrated that the nodes and antinodes of standing wave produced by the small-aperture array were clearly seen at approximately every 3 mm. The effect of the standing wave became more pronounced as the focus was moved closer to skull base. However, a sharp focus was seen for the full array, and there was no such standing-wave pattern in the acoustic plane or near the skull base. This study showed that the fluctuation pressure amplitude would be greatly reduced by using a large-scale, hemispherical phased array with a low f-number.

Pulsed Focused Ultrasound-induced Displacements in Confined in Vitro Blood Clots

IEEE Transactions on Bio-medical Engineering. Mar, 2012  |  Pubmed ID: 22194235

Ultrasound has been shown to potentiate the effects of tissue plasminogen activator to improve clot lysis in a range of in vitro and in vivo studies as well as in clinical trials. One possible mechanism of action is acoustic radiation force-induced clot displacements. In this study, we investigate the temporal and spatial dynamics of clot displacements and strain initiated by focused ultrasound pulses. Displacements were produced by a 1.51 MHz f-number 1 transducer over a range of acoustic powers (1-85 W) in clots constrained within an agar vessel phantom channel. Displacements were tracked during and after a 5.45 ms therapy pulse using a 20 MHz high-frequency ultrasound imaging probe. Peak thrombus displacements were found to be linear as a function of acoustic power up to 60 W before leveling off near 128 μm for the highest transmit powers. The time to peak displacement and recovery time of blood clots was largely independent of acoustic powers with measured values near 2 ms. A linear relationship between peak axial strain and transmit power was observed, reaching a peak value of 11% at 35 W. The peak strain occurred ∼0.75 mm from the focal zone for all powers investigated in both lateral and axial directions. These results indicate that substantial displacements can be induced by focused ultrasound in confined blood clots, and that the spatial and temporal displacement patterns are complex and highly dependent on exposure conditions, which has implications for future work investigating their link to clot lysis and for developing approaches to exploit these effects.

Focused Ultrasound Disruption of the Blood-brain Barrier: a New Frontier for Therapeutic Delivery in Molecular Neurooncology

Neurosurgical Focus. Jan, 2012  |  Pubmed ID: 22208896

Recent advances in molecular neurooncology provide unique opportunities for targeted molecular-based therapies. However, the blood-brain barrier (BBB) remains a major limitation to the delivery of tumor-specific therapies directed against aberrant signaling pathways in brain tumors. Given the dismal prognosis of patients with malignant brain tumors, novel strategies that overcome the intrinsic limitations of the BBB are therefore highly desirable. Focused ultrasound BBB disruption is emerging as a novel strategy for enhanced delivery of therapeutic agents into the brain via focal, reversible, and safe BBB disruption. This review examines the potential role and implications of focused ultrasound in molecular neurooncology.

Blood-Brain Barrier: Real-time Feedback-controlled Focused Ultrasound Disruption by Using an Acoustic Emissions-based Controller

Radiology. Feb, 2012  |  Pubmed ID: 22332065

Purpose:To determine if focused ultrasound disruption of the blood-brain barrier (BBB) can be safely controlled by using real-time modulation of treatment pressures on the basis of acoustic emissions from the exposed microbubbles.Materials and Methods:All experiments were performed with the approval of the institutional animal care committee. Transcranial focused ultrasound (551.5 kHz, 10-msec bursts, 2-Hz pulse repetition frequency, 2 minute sonication) in conjunction with circulating microbubbles was applied in 86 locations in 27 rats to disrupt the BBB. Acoustic emissions captured during each burst by using a wideband polyvinylidene fluoride hydrophone were analyzed for spectral content and used to adjust treatment pressures. Pressures were increased incrementally after each burst until ultraharmonic emissions were detected, at which point the pressure was reduced to a percentage of the pressure required to induce the ultraharmonics and was maintained for the remainder of the sonication. Disruption was evaluated at contrast material-enhanced T1-weighted magnetic resonance (MR) imaging. Mean enhancement was calculated by averaging the signal intensity at the focus over a 3 × 3-pixel region of interest and comparing it with that in nonsonicated tissue. Histologic analysis was performed to determine the extent of damage to the tissue. Statistical analysis was performed by using Student t tests.Results:For sonications resulting in BBB disruption, the mean peak pressure was 0.28 MPa ± 0.05 (standard deviation) (range, 0.18-0.40 MPa). By using the control algorithm, a linear relationship was found between the scaling level and the mean enhancement on T1-weighted MR images after contrast agent injection. At a 50% scaling level, mean enhancement of 19.6% ± 1.7 (standard error of the mean) was achieved without inducing damage. At higher scaling levels, histologic analysis revealed gross tissue damage, while at a 50% scaling level, no damage was observed at high-field-strength MR imaging or histologic examination 8 days after treatment.Conclusion:This study demonstrates that acoustic emissions can be used to actively control focused ultrasound exposures for the safe induction of BBB disruption.© RSNA, 2012.

Hyperthermia in Bone Generated with MR Imaging-controlled Focused Ultrasound: Control Strategies and Drug Delivery

Radiology. Feb, 2012  |  Pubmed ID: 22344400

Purpose:To evaluate the feasibility of achieving image-guided drug delivery in bone by using magnetic resonance (MR) imaging-controlled focused ultrasound hyperthermia and temperature-sensitive liposomes.Materials and Methods:Experiments were approved by the institutional animal care committee. Hyperthermia (43°C, 20 minutes) was generated in 10-mm-diameter regions at a muscle-bone interface in nine rabbit thighs by using focused ultrasound under closed-loop temperature control with MR thermometry. Thermosensitive liposomal doxorubicin was administered systemically during heating. Heating uniformity and drug delivery were evaluated for control strategies with the temperature control image centered 10 mm (four rabbits) or 0 mm (five rabbits) from the bone. Simulations estimated temperature elevations in bone. Drug delivery was quantified by using the fluorescence of doxorubicin extracted from bone marrow and muscle and was compared between treated and untreated thighs by using the one-sided Wilcoxon signed rank test.Results:With ultrasound focus and MR temperature control plane 0 mm and 10 mm from the bone interface, average target region temperatures were 43.1°C and 43.3°C, respectively; numerically estimated bone temperatures were 46.8°C and 78.1°C. The 10-mm offset resulted in thermal ablation; numerically estimated muscle temperature was 66.1°C at the bone interface. Significant increases in doxorubicin concentration occurred in heated versus unheated marrow (8.2-fold, P = .002) and muscle (16.8-fold, P = .002). Enhancement occurred for 0- and 10-mm offsets, which suggests localized drug delivery in bone is possible with both hyperthermia and thermal ablation.Conclusion:MR imaging-controlled focused ultrasound can achieve localized hyperthermia in bone for image-guided drug delivery in bone with temperature-sensitive drug carriers.© RSNA, 2012Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12111189/-/DC1.

Ultrafast 1D MR Thermometry Using Phase or Frequency Mapping

Magma (New York, N.Y.). Feb, 2012  |  Pubmed ID: 21800192

To develop an ultrafast MRI-based temperature monitoring method for application during rapid ultrasound exposures in moving organs.