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Kullervo Hynynen - One of the best experts on this subject based on the ideXlab platform.
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a novel flat electronically steered phased array transducer for tissue ablation preliminary results
Physics in Medicine and Biology, 2015Co-Authors: Kullervo Hynynen, Nicholas Ellens, Benjamin B C Lucht, Samuel T Gunaseelan, John M HudsonAbstract:Flat, λ/2-spaced phased arrays for therapeutic ultrasound were examined in silico and in vitro. All arrays were made by combining modules made of 64 square elements with 1.5 mm inter-element spacing along both major axes. The arrays were designed to accommodate integrated, co-aligned diagnostic transducers for targeting and monitoring. Six arrays of 1024 elements (16 modules) and four arrays of 6144 elements (96 modules) were modelled and compared according to metrics such as peak Pressure Amplitude, focal size, ability to be electronically-steered far off-axis and grating lobe Amplitude. Two 1024 element prototypes were built and measured in vitro, producing over 100 W of acoustic power. In both cases, the simulation model of the Pressure Amplitude field was in good agreement with values measured by hydrophone. Using one of the arrays, it was shown that the peak Pressure Amplitude dropped by only 24% and 25% of the on-axis peak Pressure Amplitude when steered to the edge of the array (40 mm) at depths of 30 mm and 50 mm. For the 6144 element arrays studied in in silico only, similarly high steerability was found: even when steered 100 mm off-axis, the Pressure Amplitude decrease at the focus was less than 20%, while the maximum Pressure grating lobe was only 20%. Thermal simulations indicate that the modules produce more than enough acoustic power to perform rapid ablations at physiologically relevant depths and steering angles. Arrays such as proposed and tested in this study have enormous potential: their high electronic steerability suggests that they will be able to perform ablations of large volumes without the need for any mechanical translation.
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effects of acoustic parameters and ultrasound contrast agent dose on focused ultrasound induced blood brain barrier disruption
Ultrasound in Medicine and Biology, 2008Co-Authors: Nathan Mcdannold, Natalia Vykhodtseva, Kullervo HynynenAbstract: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.
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blood brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index
Ultrasound in Medicine and Biology, 2008Co-Authors: Nathan Mcdannold, Natalia Vykhodtseva, Kullervo HynynenAbstract: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.
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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, 2006Co-Authors: Kullervo Hynynen, Nathan Mcdannold, Natalia Vykhodtseva, Scott B Raymond, Ralph Weissleder, Ferenc A Jolesz, Nickolai SheikovAbstract: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 (MAGNEVIST). 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.
Rafal Krenke - One of the best experts on this subject based on the ideXlab platform.
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patterns of pleural Pressure Amplitude and respiratory rate changes during therapeutic thoracentesis
BMC Pulmonary Medicine, 2018Co-Authors: Monika Zielinskakrawczyk, Marcin Michnikowski, Tomasz Golczewski, Piotr Korczynski, Anna Stecka, Elżbieta M. Grabczak, Krzysztof Zieliński, Rafal KrenkeAbstract:Although the impact of therapeutic thoracentesis on lung function and blood gases has been evaluated in several studies, some physiological aspects of pleural fluid withdrawal remain unknown. The aim of the study was to assess the changes in pleural Pressure Amplitude (Pplampl) during the respiratory cycle and respiratory rate (RR) in patients undergoing pleural fluid withdrawal. The study included 23 patients with symptomatic pleural effusion. Baseline pleural Pressure curves were registered with a digital electronic manometer. Then, the registrations were repeated after the withdrawal of consecutive portions of pleural fluid (200 ml up to 1000 ml and 100 ml above 1000 ml). In all patients the pleural Pressure curves were analyzed in five points, at 0, 25%, 50%, 75% and 100% of the relative volume of pleural effusion withdrawn in particular patients. There were 11 and 12 patients with right sided and left sided pleural effusion, respectively (14 M, 9F, median age 68, range 46–85 years). The most common cause of pleural effusion were malignancies (20 pts., 87%). The median total volume of withdrawn pleural fluid was 1800 (IQR 1500–2400) ml. After termination of pleural fluid withdrawal Pplampl increased in 22/23 patients compared to baseline. The median Pplampl increased from 3.4 (2.4–5.9) cmH2O to 10.7 (8.1–15.6) cmH2O (p < 0.0001). Three patterns of Pplampl changes were identified. Although the patterns of RR changes were more diversified, a significant increase between RR at baseline and the last measurement point was found (p = 0.0097). In conclusion, therapeutic thoracentesis is associated with significant changes in Pplampl during the respiratory cycle. In the vast majority of patients Pplampl increased steadily during pleural fluid withdrawal. There was also an increase in RR. The significance of these changes should be elucidated in further studies. ClinicalTrial.gov, registration number: NCT02192138 , registration date: July 1st, 2014.
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Patterns of pleural Pressure Amplitude and respiratory rate changes during therapeutic thoracentesis
BMC, 2018Co-Authors: Monika Zielinska-krawczyk, Marcin Michnikowski, Tomasz Golczewski, Piotr Korczynski, Anna Stecka, Elżbieta M. Grabczak, Krzysztof Zieliński, Rafal KrenkeAbstract:Abstract Background Although the impact of therapeutic thoracentesis on lung function and blood gases has been evaluated in several studies, some physiological aspects of pleural fluid withdrawal remain unknown. The aim of the study was to assess the changes in pleural Pressure Amplitude (Pplampl) during the respiratory cycle and respiratory rate (RR) in patients undergoing pleural fluid withdrawal. Methods The study included 23 patients with symptomatic pleural effusion. Baseline pleural Pressure curves were registered with a digital electronic manometer. Then, the registrations were repeated after the withdrawal of consecutive portions of pleural fluid (200 ml up to 1000 ml and 100 ml above 1000 ml). In all patients the pleural Pressure curves were analyzed in five points, at 0, 25%, 50%, 75% and 100% of the relative volume of pleural effusion withdrawn in particular patients. Results There were 11 and 12 patients with right sided and left sided pleural effusion, respectively (14 M, 9F, median age 68, range 46–85 years). The most common cause of pleural effusion were malignancies (20 pts., 87%). The median total volume of withdrawn pleural fluid was 1800 (IQR 1500–2400) ml. After termination of pleural fluid withdrawal Pplampl increased in 22/23 patients compared to baseline. The median Pplampl increased from 3.4 (2.4–5.9) cmH2O to 10.7 (8.1–15.6) cmH2O (p
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therapeutic thoracentesis impact on respiratory rate and intrapleural Pressure Amplitude change
European Respiratory Journal, 2017Co-Authors: Elżbieta M. Grabczak, Marcin Michnikowski, Tomasz Golczewski, Monika Zielinskakrawczyk, Piotr Korczynski, Anna Stecka, Krzysztof Zieliński, Rafal KrenkeAbstract:Introduction: Although therapeutic thoracentesis is a common procedure, some physiological aspects of pleural fluid removal have not been adequately studied. Aim: To assess the changes in pleural Pressure Amplitude (Ppl ampl ) and respiratory rate(RR) during pleural fluid withdrawal. Material and Methods: This was a prospective study in consecutive patients referred for therapeutic thoracentesis. 23 subjects with symptomatic pleural effusion underwent thoracentesis with pleural Pressure (Ppl) measurement. A computer based electronic system was used to register the Ppl curve at baseline and after the withdrawal of consecutive portions of pleural fluid. In all patients the Ppl curves were analyzed in five points at 0,25%,50%,75% and 100% of the total volume of withdrawn pleural fluid. Results: There were 11 patients with right sided pleural effusion, male predominance (14/9), median age 68(range 46-85 years). In 20(87%) patients pleural effusion was related to malignant diseases. The median total volume of withdrawn pleural fluid was 1800(IQR 1500-2400) ml. An increase of Ppl ampl between the first and last measurement point was registered in 22/23 patients(median Ppl ampl 3.4(2.4-5.9) cmH 2 O vs. 10.7(8.1-15.6) cmH 2 O, respectively(p=0.0000)). Three patterns of Ppl ampl changes were identified.Also, significant increase in RR was registered(p=0.0097), however the patterns of RR changes were more diversified. Conclusion: The therapeutic thoracentesis is associated with significant increase of Ppl ampl and respiratory rate. The significance of these changes should be elucidated in further studies. Acknowledgment The study received financial support from the Polish National Science Centre (grant No 2012/05/B/NZ5/01343).
Nathan Mcdannold - One of the best experts on this subject based on the ideXlab platform.
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effects of acoustic parameters and ultrasound contrast agent dose on focused ultrasound induced blood brain barrier disruption
Ultrasound in Medicine and Biology, 2008Co-Authors: Nathan Mcdannold, Natalia Vykhodtseva, Kullervo HynynenAbstract: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.
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blood brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index
Ultrasound in Medicine and Biology, 2008Co-Authors: Nathan Mcdannold, Natalia Vykhodtseva, Kullervo HynynenAbstract: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.
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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, 2006Co-Authors: Kullervo Hynynen, Nathan Mcdannold, Natalia Vykhodtseva, Scott B Raymond, Ralph Weissleder, Ferenc A Jolesz, Nickolai SheikovAbstract: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 (MAGNEVIST). 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.
Yuning Zhang - One of the best experts on this subject based on the ideXlab platform.
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chaotic oscillations of gas bubbles under dual frequency acoustic excitation
Ultrasonics Sonochemistry, 2018Co-Authors: Yuning ZhangAbstract:Chaotic oscillation of bubbles in liquids reduces the efficiency of the sonochemical system and should be suppressed in the practical applications. In the present paper, a chaos control method based on the dual-frequency approach is numerically investigated and is proved to be an effective method even for cases with intensive energy input. It was found that the chaos could be successfully suppressed by the application of dual-frequency approach in a wide range of parameter zone (even with high acoustic Pressure Amplitude). Furthermore, influences of power allocation between two waves on the chaos control are quantitatively discussed with clear descriptions of the routes from stable oscillations to chaos.
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the secondary bjerknes force between two gas bubbles under dual frequency acoustic excitation
Ultrasonics Sonochemistry, 2016Co-Authors: Yuning Zhang, Shengcai LiAbstract:The secondary Bjerknes force is one of the essential mechanisms of mutual interactions between bubbles oscillating in a sound field. The dual-frequency acoustic excitation has been applied in several fields such as sonochemistry, biomedicine and material engineering. In this paper, the secondary Bjerknes force under dual-frequency excitation is investigated both analytically and numerically within a large parameter zone. The unique characteristics (i.e., the complicated patterns of the parameter zone for sign change and the combination resonances) of the secondary Bjerknes force under dual-frequency excitation are revealed. Moreover, the influence of several parameters (e.g., the Pressure Amplitude, the bubble distance and the phase difference between sound waves) on the secondary Bjerknes force is also investigated numerically.
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rectified mass diffusion of gas bubbles in liquids under acoustic field with dual frequencies
International Communications in Heat and Mass Transfer, 2012Co-Authors: Yuning ZhangAbstract:Abstract In this letter, rectified mass diffusion of gas bubbles in liquids under acoustic field with dual frequencies is theoretically investigated. Comparing with gas bubbles under single-frequency acoustic field, if the acoustic Pressure Amplitude is above a certain value determined in the present work, a wider range of bubbles can grow through rectified mass diffusion with more rapid growth rate under dual-frequency acoustic field.
Natalia Vykhodtseva - One of the best experts on this subject based on the ideXlab platform.
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effects of acoustic parameters and ultrasound contrast agent dose on focused ultrasound induced blood brain barrier disruption
Ultrasound in Medicine and Biology, 2008Co-Authors: Nathan Mcdannold, Natalia Vykhodtseva, Kullervo HynynenAbstract: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.
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blood brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index
Ultrasound in Medicine and Biology, 2008Co-Authors: Nathan Mcdannold, Natalia Vykhodtseva, Kullervo HynynenAbstract: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.
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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, 2006Co-Authors: Kullervo Hynynen, Nathan Mcdannold, Natalia Vykhodtseva, Scott B Raymond, Ralph Weissleder, Ferenc A Jolesz, Nickolai SheikovAbstract: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 (MAGNEVIST). 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.
