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The blood-brain barrier (BBB) prevents entry of most drugs into the brain and is a major hurdle to the use of drugs for brain tumors and other central nervous system disorders. Work in small animals has shown that ultrasound combined with an intravenously circulating microbubble agent can temporarily permeabilize the BBB. Here, we evaluated whether this targeted drug delivery method can be applied safely, reliably, and in a controlled manner on rhesus macaques using a focused ultrasound system. We identified a clear safety window during which BBB disruption could be produced without evident tissue damage, and the acoustic pressure amplitude where the probability for BBB disruption was 50% and was found to be half of the value that would produce tissue damage. Acoustic emission measurements seem promising for predicting BBB disruption and damage. In addition, we conducted repeated BBB disruption to central visual field targets over several weeks in animals trained to conduct complex visual acuity tasks. All animals recovered from each session without behavioral deficits, visual deficits, or loss in visual acuity. Together, our findings show that BBB disruption can be reliably and repeatedly produced without evident histologic or functional damage in a clinically relevant animal model using a clinical device. These results therefore support clinical testing of this noninvasive-targeted drug delivery method.

The ability of ultrasonically-induced oscillations of circulating microbubbles to permeabilize vascular barriers such as the blood-brain barrier (BBB) holds great promise for noninvasive targeted drug delivery. A major issue has been a lack of control over the procedure to ensure both safe and effective treatment. Here, we evaluated the use of passively-recorded acoustic emissions as a means to achieve this control. An acoustic emissions monitoring system was constructed and integrated into a clinical transcranial MRI-guided focused ultrasound system. Recordings were analyzed using a spectroscopic method that isolates the acoustic emissions caused by the microbubbles during sonication. This analysis characterized and quantified harmonic oscillations that occur when the BBB is disrupted, and broadband emissions that occur when tissue damage occurs. After validating the system's performance in pilot studies that explored a wide range of exposure levels, the measurements were used to control the ultrasound exposure level during transcranial sonications at 104 volumes over 22 weekly sessions in four macaques. We found that increasing the exposure level until a large harmonic emissions signal was observed was an effective means to ensure BBB disruption without broadband emissions. We had a success rate of 96% in inducing BBB disruption as measured by in contrast-enhanced MRI, and we detected broadband emissions in less than 0.2% of the applied bursts. The magnitude of the harmonic emissions signals was significantly (P<0.001) larger for sonications where BBB disruption was detected, and it correlated with BBB permeabilization as indicated by the magnitude of the MRI signal enhancement after MRI contrast administration (R(2) = 0.78). Overall, the results indicate that harmonic emissions can be a used to control focused ultrasound-induced BBB disruption. These results are promising for clinical translation of this technology.

Numerous animal studies have demonstrated that ultrasound bursts combined with a microbubble-based ultrasound contrast agent can temporarily disrupt the blood-brain barrier (BBB) with little or no other apparent effects to the brain. As the BBB is a primary limitation to the use of most drugs in the brain, this method could enable a noninvasive means for targeted drug delivery in the brain. This work investigated whether BBB disruption and vessel damage when overexposure occurs can be influenced by choice of anesthesia protocol, which have different vasoactive effects. Four locations were sonicated transcranially in each brain of 16 rats using an unfocused 532 kHz piston transducer. Burst sonications (10 ms bursts applied at 1 Hz for 60 s) were combined with intravenous Definity (10 μl/kg) injections. BBB disruption was evaluated using contrast-enhanced MRI. Half of the animals were anesthetized with i.p. ketamine and xylazine, and the other half with inhaled isoflurane and oxygen. Over the range of exposure levels tested, MRI contrast enhancement was significantly higher (p < 0.05) for animals anesthetized with ketamine/xylazine. Furthermore, the threshold for extensive erythrocyte extravasation was lower with ketamine/xylazine. These results suggest that BBB disruption and/or vascular damage can be affected by vascular or other factors that are influenced by different anesthesia protocol. These experiments may also have been influenced by the recently reported findings that the circulation time for perfluorocarbon microbubbles is substantially reduced when oxygen is used as the carrier gas., (Copyright © 2011 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Objective: This work evaluated the clinical feasibility of transcranial magnetic resonance imaging-guided focused ultrasound surgery., Methods: Transcranial magnetic resonance imaging-guided focused ultrasound surgery offers a potential noninvasive alternative to surgical resection. The method combines a hemispherical phased-array transducer and patient-specific treatment planning based on acoustic models with feedback control based on magnetic resonance temperature imaging to overcome the effects of the cranium and allow for controlled and precise thermal ablation in the brain. In initial trials in 3 glioblastoma patients, multiple focused ultrasound exposures were applied up to the maximum acoustic power available. Offline analysis of the magnetic resonance temperature images evaluated the temperature changes at the focus and brain surface., Results: We found that it was possible to focus an ultrasound beam transcranially into the brain and to visualize the heating with magnetic resonance temperature imaging. Although we were limited by the device power available at the time and thus seemed to not achieve thermal coagulation, extrapolation of the temperature measurements at the focus and on the brain surface suggests that thermal ablation will be possible with this device without overheating the brain surface, with some possible limitation on the treatment envelope., Conclusion: Although significant hurdles remain, these findings are a major step forward in producing a completely noninvasive alternative to surgical resection for brain disorders.

Thermal ablation is an established treatment for tumors. The merging of newly developed imaging techniques has allowed precise targeting and real-time thermal mapping. This article provides an overview of the image-guided thermal ablation techniques in the treatment of uterine fibroids. Background on uterine fibroids, including epidemiology, histology, symptoms, imaging findings, and current treatment options, is first outlined. After describing the principle of magnetic resonance thermal imaging, we introduce the applications of image-guided thermal therapies, including laser ablation, radiofrequency ablation, cryotherapy, and in particular, magnetic resonance-guided focused ultrasound surgery, and how they apply to uterine fibroid treatment.

Purpose: 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., Materials and Methods: Imaging data were analyzed from 45 fibroids in 42 women treated with MRgFUS. The areas of the hyperintense regions in DWI and of nonperfused regions in T1-weighted contrast enhanced imaging (both acquired immediately after treatment) were compared with each other and to thermal dosimetry based estimates. Changes in ADC were also calculated., Results: Hyperintense regions were observed in 35/45 fibroids in DWI. When present, the areas of these regions were comparable on average to the thermal dose estimates and to the nonperfused regions, except for in several large treatments in which the nonperfused region extended beyond the treated area. ADC increased in 19 fibroids and decreased in the others., Conclusion: DWI changes, which includes changes in both in T2 and ADC, may be useful in many cases to delineate the treated region resulting from MRgFUS. However, clear DWI changes were not always observed, and in some large treatments, the extent of the nonperfused region was under estimated. ADC changes immediately after MRgFUS were unpredictable.

Purpose: 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., Materials and Methods: The method ("referenceless thermometry") uses surface fitting in nonheated regions of individual phase images to extrapolate and then remove background phase variations that are unrelated to temperature changes. We tested this method using images from 100 sonications selected from 33 patient MRgFUS treatments. Temperature measurements and thermal dose contours estimated with the referenceless method were compared with those produced with the standard phase-difference technique. Fitting accuracy and noise level were also measured., Results: In 92/100 sonications, the difference between the two measurements was less than 3 degrees C. The average difference in the measurements was 1.5 +/- 1.4 degrees C. Small motion artifacts were observed in the phase-difference imaging when the difference was greater than 3 degrees C. The method failed in two cases. The mean absolute error in the surface fit in baseline images corresponded to a temperature error of 0.8 +/- 1.4 degrees C. The noise level was approximately 40% lower than the phase-difference method. Thermal dose contours calculated from the two methods agreed well on average., Conclusion: Based on the small error when compared with the standard technique, this method appears to be adequate for temperature monitoring of MRgFUS in uterine fibroids and may prove useful for monitoring temperature changes in moving organs., ((c) 2008 Wiley-Liss, Inc.)

Acoustic radiation force impulse imaging is an elastography method developed for ultrasound imaging that maps displacements produced by focused ultrasound pulses systematically applied to different locations. The resulting images are "stiffness weighted" and yield information about local mechanical tissue properties. Here, the feasibility of magnetic resonance acoustic radiation force imaging (MR-ARFI) was tested. Quasistatic MR elastography was used to measure focal displacements using a one-dimensional MRI pulse sequence. A 1.63 or 1.5 MHz transducer supplied ultrasound pulses which were triggered by the magnetic resonance imaging hardware to occur before a displacement-encoding gradient. Displacements in and around the focus were mapped in a tissue-mimicking phantom and in an ex vivo bovine kidney. They were readily observed and increased linearly with acoustic power in the phantom (R2=0.99). At higher acoustic power levels, the displacement substantially increased and was associated with irreversible changes in the phantom. At these levels, transverse displacement components could also be detected. Displacements in the kidney were also observed and increased after thermal ablation. While the measurements need validation, the authors have demonstrated the feasibility of detecting small displacements induced by low-power ultrasound pulses using an efficient magnetic resonance imaging pulse sequence that is compatible with tracking of a dynamically steered ultrasound focal spot, and that the displacement increases with acoustic power. MR-ARFI has potential for elastography or to guide ultrasound therapies that use low-power pulsed ultrasound exposures, such as drug delivery.

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.

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.

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.

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.

The combination of the imaging abilities of magnetic resonance imaging (MRI) with the ability to delivery energy to targets deep in the body noninvasively with focused ultrasound presents a disruptive technology with the potential to significantly affect healthcare. MRI offers precise targeting, visualization, and quantification of temperature changes and the ability to immediately evaluate the treatment. By exploiting different mechanisms, focused ultrasound offers a range of therapies, ranging from thermal ablation to targeted drug delivery. This article reviews recent preclinical and tests clinical of this technology., ((Copyright) 2008 Wiley-Liss, Inc.)

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., ((c) 2007 Wiley-Liss, Inc.)

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.

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.

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.

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.

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.

Object: 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., Methods: Rabbits were placed inside a clinical 1.5-tesla MR imaging unit, and sites in their brains were targeted for 20-second burst sonications (frequency 260 kHz). The peak pressure amplitude during the burst varied between 0.1 and 0.9 MPa. Each sonication was performed after an intravenous injection of an ultrasound contrast agent (Optison). The disruption of the BBB was evaluated with the aid of an injection of an MR imaging contrast agent (MAG-NEVIST). Additional tests involving the use of MION-47, a 20-nm magnetic nanoparticle contrast agent, were also performed. The animals were killed at different time points between 3 minutes and 5 weeks postsonication, after which light or electron microscopic evaluation was performed. The threshold for BBB disruption was approximately 0.2 MPa. More than 80% of the brain sites sonicated showed BBB disruption when the pressure amplitude was 0.3 MPa; at 0.4 MPa, this percentage was greater than 90%. Tissue necrosis, ischemia, and apoptosis were not found in tissue in which the pressure amplitude was less than 0.4 MPa; however, in a few areas of brain tissue erythrocytes were identified outside blood vessels following exposures of 0.4 MPa or higher. Survival experiments did not show any long-term adverse events., Conclusions: These results demonstrate that low-frequency ultrasound bursts can induce local, reversible disruption of the BBB without undesired long-term effects. This technique offers a potential noninvasive method for targeted drug delivery in the brain aided by a relatively simple low-frequency device.

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.

Purpose: 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., Methods: We enrolled all patients participating in a prospective phase III clinical trial from our center who completed 6 months of clinical and imaging follow-up. Patients with irregular cycles and those on oral contraceptives were excluded. Data prospectively documenting the date of the last menstrual period (LMP) at the time of treatment, length and duration of cycle, and raw symptom severity score (SSS) from the Uterine Fibroid Symptom and Quality of Life questionnaire, at baseline and 6 months were collected. Proliferative phase patients were determined retrospectively as those who were treated within less than 14 days from LMP; secretory phase patients were classified as those who were treated greater than 14 days from LMP., Results: A total of 58 patients were enrolled. There was no significant difference in the mean SSS at baseline and mean SSS at 6 months between patients treated in the proliferative versus secretory phase of the cycle. No significant difference in the SSS change from baseline to 6 months was seen between the two groups., Conclusions: Menstrual cycle phase does not influence MRgFUS treatment outcome. Symptomatic improvement occurs with treatment during either phase of the menstrual cycle. Thus, the scheduling of MRgFUS treatment need not be based upon the phase of the menstrual cycle.

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.

Purpose: To retrospectively evaluate magnetic resonance (MR) imaging-based thermometry and thermal dosimetry during focused ultrasound treatments of uterine leiomyomas (ie, fibroids)., Materials and Methods: All patients gave written informed consent for the focused ultrasound treatments and the current HIPAA-compliant retrospective study, both of which were institutional review board approved. Thermometry performed during the treatments of 64 fibroids in 50 women (mean age, 46.6 years +/- 4.5 [standard deviation]) was used to create thermal dose maps. The areas that reached dose values of 240 and 18 equivalent minutes at 43 degrees C were compared with the nonperfused regions measured on contrast material-enhanced MR images by using the Bland-Altman method. Volume changes in treated fibroids after 6 months were compared with volume changes in nontreated fibroids and with MR-based thermal dose estimates., Results: While the thermal dose estimates were shown to have a clear relationship with resulting nonperfused regions, the nonperfused areas were, on average, larger than the dose estimates (means of 1.9 +/- 0.7 and 1.2 +/- 0.4 times as large for areas that reached 240- and 18-minute threshold dose values, respectively). Good correlation was observed for smaller treatment volumes at the lower dose threshold (mean ratio, 1.0 +/- 0.3), but for larger treatment volumes, the nonperfused region extended to locations within the fibroid that clearly were not heated. Variations in peak temperature increase were as large as a factor of two, both between patients and within individual treatments. On average, the fibroid volume reduction at 6 months increased as the ablated volume estimated by using the thermal dose increased., Conclusion: Study results showed good correlation between thermal dose estimates and resulting nonperfused areas for smaller ablated volumes. For larger treatment volumes, nonperfused areas could extend within the fibroid to unheated areas., (RSNA, 2006)

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.

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.

Objective: 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., Methods: The transducer was tested by focusing ultrasound through ex vivo human skulls and into a brain phantom by means of a phase-adaptive focusing technique. Simultaneously, the procedure was monitored by the use of magnetic resonance guidance and thermometry., Results: The ultrasound focus of a 500-element 30-cm-diameter, 0.81-MHz array could be steered electronically through the skull over a volume of approximately 30 x 30 x 26 mm. Furthermore, temperature monitoring of the inner and outer surfaces of the skull showed that the array could coagulate targeted brain tissue without causing excessive skull heating., Conclusions: The successful outcome of these experiments indicates that intensities high enough to destroy brain tissue can be produced without excessive heating of the surrounding areas and without producing large magnetic resonance noise and artifacts.

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.

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.

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.

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.

Objective: The purpose of this study was to explore our hypothesis that MRI-guided focused ultrasound therapy for the treatment of uterine fibroids will lead to a significant reduction in symptoms and improvement in quality of life. We describe focused ultrasound therapy applications and the method for monitoring the thermal energy deposited in the fibroids, including the MRI parameters required, in a prospective review of 108 treatments., Materials and Methods: Patients presenting with symptomatic uterine fibroids who attained a minimal symptom severity score and who would otherwise have been offered a hysterectomy were recruited. Thermal lesions were created within target fibroids using an MRI-guided focused ultrasound therapy system. The developing lesion was monitored using real-time MR thermometry, which was used to assess treatment outcome in real time to change treatment parameters and achieve the desired outcome. Fibroid volume, fibroid symptoms, and quality-of-life scores were measured before treatment and 6 months after treatment. Adverse events were actively monitored and recorded., Results: In this study, 79.3% of women who had been treated reported a significant improvement in their uterine fibroid symptoms on follow-up health-related quality-of-life questionnaires, which supports our hypothesis. The mean reduction in fibroid volume at 6 months was 13.5%, but nonenhancing volume (mean, 51 cm(3)) remained within the treated fibroid at 6 months., Conclusion: This early description of MRI-guided focused ultrasound therapy treatment of fibroids includes follow-up data and shows that, although the volume reduction is moderate, it correlates with treatment volume and the symptomatic response to this treatment is encouraging.

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.

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., (Copyright 2004 Wiley-Liss, Inc.)

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., (Copyright 2004 Wiley-Liss, Inc.)

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., (Copyright 2004 Wiley-Liss, Inc.)

Purpose: 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., Materials and Methods: Liposomal gadolinium diethylenetriaminepentaacetic acid bis(methylamide) was injected intravenously at a dose of 0.4 or 1.2 mL (containing 10 or 30 micromol of gadolinium, respectively) per kilogram of body weight shortly before the application of focused ultrasound in liver (seven rabbits) or kidney (three rabbits). VX2 tumors had been implanted in liver in four of the rabbits. Eighteen locations in liver (13 in normal tissue, five in tumor) and 12 locations in kidney were sonicated. MR thermometry was performed during sonications. Signal intensity enhancement was evaluated on T1-weighted images acquired after the tissue cooled, and enhanced zones were compared with isotherms at T(c) of the liposome membrane (approximately 57 degrees C) by using Bland-Altman analysis. In liver, enhanced zones also were compared with areas of histologically verified thermal damage. The threshold temperature of enhancement at T1-weighted imaging was verified by monitoring the signal intensity increase after 10 sonications at varied powers in two locations in normal liver tissue., Results: Persistent enhancement was observed on T1-weighted images at all sonicated liver locations. In liver, enhanced zones on T1-weighted images were contiguous both with 57 degrees C isotherms (25 measurements; mean difference +/- SD, 0.4 mm +/- 1.2) and with histologically verified areas of necrosis (seven measurements; mean difference +/- SD, 0.1 mm +/- 0.9). The threshold temperature of enhancement at T1-weighted imaging in normal liver was 53 degrees -57 degrees C. In kidney, enhanced zones on T1-weighted images did not match the isotherms., Conclusion: The liposomal contrast agent was effective at in vivo MR thermometry in liver but not in kidney., (Copyright RSNA, 2004)

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., (Copyright 2003 Wiley-Liss, Inc.)

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.

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.

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.

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.

Purpose: To determine if focused ultrasound beams can be used to locally open the blood-brain barrier without damage to surrounding brain tissue and if magnetic resonance (MR) imaging can be used to monitor this procedure., Materials and Methods: The brains of 18 rabbits were sonicated (pulsed sonication) in four to six locations, with temporal peak acoustic power ranging from 0.2 to 11.5 W. Prior to each sonication, a bolus of ultrasonographic (US) contrast agent was injected into the ear vein of the rabbit. A series of fast or spoiled gradient-echo MR images were obtained during the sonications to monitor the temperature elevation and potential tissue changes. Contrast material-enhanced MR images obtained minutes after sonications and repeated 1-48 hours later were used to depict blood-brain barrier opening. Whole brain histologic evaluation was performed., Results: Opening of the blood-brain barrier was confirmed with detection of MR imaging contrast agent at the targeted locations. The lowest power levels used produced blood-brain barrier opening without damage to the surrounding neurons. Contrast enhancement correlated with the focal signal intensity changes in the magnitude fast spoiled gradient-echo MR images., Conclusion: The blood-brain barrier can be consistently opened with focused ultrasound exposures in the presence of a US contrast agent. MR imaging signal intensity changes may be useful in the detection of blood-brain barrier opening during sonication.

Two numerical models for predicting the temperature elevations resulting from focused ultrasound heating of muscle tissue were tested against experimental data. Both models use the Rayleigh-Sommerfeld integral to calculate the pressure field from a source distribution. The first method assumes a source distribution derived from a uniformly radiating transducer whereas the second uses a source distribution obtained by numerically projecting pressure field measurements from an area near the focus backward toward the transducer surface. Both of these calculated ultrasound fields were used as heat sources in the bioheat equation to calculate the temperature elevation in vivo. Experimental results were obtained from in vivo rabbit experiments using eight-element sector-vortex transducers at 1.61 and 1.7 MHz and noninvasive temperature mapping with MRI. Results showed that the uniformly radiating transducer model over-predicted the peak temperature by a factor ranging from 1.4 to 2.8, depending on the operating mode. Simulations run using the back-projected sources were much closer to experimental values, ranging from 1.0 to 1.7 times the experimental results, again varying with mode. Thus, a significant improvement in the treatment planning can be obtained by using actual measured ultrasound field distributions in combination with backward projection.

Purpose: To test the feasibility of noninvasive magnetic resonance (MR) imaging-guided focused ultrasound surgery (FUS) of benign fibroadenomas in the breast., Materials and Methods: Eleven fibroadenomas in nine patients under local anesthesia were treated with MR imaging-guided FUS. Based on a T2-weighted definition of target volumes, sequential sonications were delivered to treat the entire target. Temperature-sensitive phase-difference-based MR imaging was performed during each sonication to monitor focus localization and tissue temperature changes. After the procedure, T2-weighted and contrast material-enhanced T1-weighted MR imaging were performed to evaluate immediate and long-term effects., Results: Thermal imaging sequences were improved over the treatment period, with 82% (279 of 342) of the hot spots visible in the last seven treatments. The MR imager was used to measure temperature elevation (12.8 degrees -49.9 degrees C) from these treatments. Eight of the 11 lesions treated demonstrated complete or partial lack of contrast material uptake on posttherapy T1-weighted images. Three lesions showed no marked decrease of contrast material uptake. This lack of effective treatment was most likely due to a lower acoustic power and/or patient movement that caused misregistration. No adverse effects were detected, except for one case of transient edema in the pectoralis muscle 2 days after therapy., Conclusion: MR imaging-guided FUS can be performed to noninvasively coagulate benign breast fibroadenomas.

Unlabelled: A new magnetic resonance imaging method, line scan echo planar spectroscopic imaging (LSEPSI), is shown capable of providing rapid, internally referenced temperature monitoring from water and fat chemical shifts., Methods: Orthogonal 90 degrees and 180 degrees slice selective RF pulses inclined by 45 degrees from the image plane solicit a spin echo from a tissue column. The echo is read by asymmetric sampling of 32 gradient echoes spaced 1.4-1.8 ms apart. Sixty-four adjacent columns are sequentially sampled in 4.2-6.4 s with 4,096 voxels sampled with voxel volumes of 0.08-0.13 cm3. Mixed mayonnaise/water phantoms were used to correlate LSEPSI-derived chemical shifts and thermocouple-based temperature measurements from 23 to 60 degrees C with a 1.5 T scanner. Measurement artifacts unrelated to temperature were investigated with the phantom, as was the feasibility of applying the sequence in human breast in vivo., Results: The correlation between LSEPSI and thermocouple-based temperature measurements in the phantom was excellent (r2>0.99). Field drifts affecting the temperature measurements using the water peak alone were corrected by using the water/lipid peak difference. The sequence had an average temperature resolution of 1.4 degrees C in the phantom. The frequency difference measurement reduced the sensitivity to artifacts related to temperature. Both water and lipid peaks were detectable throughout many locations in the breast, suggesting the applicability of LSEPSI in this organ., Discussion: T1-saturation losses occur in conventional and echo-planar based 2D CSI sequences using phase encoding methods with short TR periods. These losses are eliminated when individual columns are sampled in snapshot fashion with LSEPSI since the effective TR becomes the time between scans rather than excitations. T1 saturation can make small spectral peaks difficult to detect at high temperatures and generally lowers the signal-to-noise ratio of the spectra. The rapid acquisition and insensitivity to T1 saturation effects make LSEPSI an attractive technique for monitoring thermal therapies in breast using the internally referenced fat/water frequency separation.

Purpose: To investigate in vivo the feasibility of using magnetic resonance (MR) imaging-derived temperature and thermal dose measurements to find the threshold of thermal tissue damage., Materials and Methods: Sonications were delivered in rabbit thigh muscles at varying powers. Temperature-sensitive MR images obtained during the sonications were used to estimate the temperature and thermal dose. The temperature, thermal dose, and applied power were then correlated to the occurrence of tissue damage observed on postsonication images. An eight-element phased-array transducer was used to produce spatially flat temperature profiles that allowed for averaging to reduce the effects of noise and the voxel size., Results: The occurrence of tissue damage correlated well with the MR imaging-derived temperature and thermal dose measurements but not with the applied power. Tissue damage occurred at all locations with temperatures greater than 50.4 degrees C and thermal doses greater than 31.2 equivalent minutes at 43.0 degrees C. No tissue damage occurred when these values were less than 47.2 degrees C and 4.3 equivalent minutes., Conclusion: MR imaging thermometry and dosimetry provide an index to predict the threshold for tissue damage in vivo. This index offers improved online control over minimally invasive thermal treatments and should allow for more accurate target volume coagulation.

The aim of the study was to test the hypothesis that fast spin echo T(1)-weighted images can be used to quantify the temperature in fat during thermal therapy in vivo. An MR compatible positioning device was used to manipulate focused ultrasound transducers in an MRI scanner. This system was used to sonicate fat tissue around the kidneys of 12 rabbits at various power levels for 10 to 20 sec. The scan parameters of T(1)-weighted fast spin echo (FSE) sequence were varied to optimize signal intensity characteristics while maintaining short scan times. An invasive optical probe was used to calibrate the temperature related signal intensity changes. For the T(1)-weighted FSE sequence, the signal intensity decreased with the temperature elevation at the rate of 0.97+/-0.02%/ degrees C. The single focused transducer produced a contrast-to-noise ratio more than 10 at power levels below the tissue damage threshold. The signal intensity was linearly dependent on the power, despite the measured temperatures being well above the coagulation threshold. This study demonstrates that T(1)-weighted FSE MRI sequences can be used to quantify the temperature elevation in fat in vivo during short focused ultrasound exposures. This can be very important for breast tumor surgery, fat ablation, and for treating deep seated tumors through superficial fat layers. Magn Reson Med 43:901-904, 2000., (Copyright 2000 Wiley-Liss, Inc.)

Purpose: To use magnetic resonance (MR) imaging to monitor thermal buildup and its effects in treated tissues during sequentially delivered sonications in vivo to optimize the intersonication delay for any set of ultrasound and tissue parameters., Materials and Methods: Sequential sonications were delivered next to each other in both thighs in 10 male New Zealand white rabbits. The time between sonications was 11-60 seconds. Phase-difference MR imaging was used to monitor temperature rise, which was used to estimate the thermal dose delivered to the tissue. T2-weighted and contrast agent-enhanced T1-weighted imaging were used to gauge the extent of tissue coagulation., Results: With a short intersonication delay (11-40 seconds), the estimated temperature rise and the extent of tissue coagulation increased dramatically in subsequent sonications. However, when the delay was long (50-60 seconds), the size and shape of the destroyed tissue with subsequent sonications was uniform, and the temperature buildup was substantially lower., Conclusion: MR imaging can be used to monitor thermal buildup and its effects due to sequential, neighboring sonications in vivo to produce evenly shaped regions of tissue coagulation. The temperature information obtained from the monitoring can be used to optimize the intersonication delay for any set of ultrasound and tissue parameters.