Dataset Information

Feedback control of microbubble cavitation for ultrasound-mediated blood-brain barrier disruption in non-human primates under magnetic resonance guidance.

ABSTRACT: Focused ultrasound (FUS) in combination with microbubbles is capable of noninvasive, site-targeted delivery of drugs through the blood-brain barrier (BBB). Although acoustic parameters are reproducible in small animals, their control remains challenging in primates due to skull heterogeneity. This study describes a 7-T magnetic resonance (MR)-guided FUS system designed for BBB disruption in non-human primates (NHP) with a robust feedback control based on passive cavitation detection (PCD). Contrast enhanced T₁-weighted MR images confirmed the BBB opening in NHP sonicated during 2?min with 500-kHz frequency, pulse length of 10?ms, and pulse repetition frequency of 5?Hz. The safe acoustic pressure range from 185?±?22?kPa to 266?±?4?kPa in one representative case was estimated from combining data from the acoustic beam profile with the BBB opening and hemorrhage profiles obtained from MR images. A maximum amount of MR contrast agent at focus was observed at 30?min after sonication with a relative contrast enhancement of 67%?±?15% (in comparison to that found in muscles). The feedback control based on PCD using relative spectra was shown to be robust, allowing comparisons across animals and experimental sessions. Finally, we also demonstrated that PCD can test acoustic coupling conditions, which improves the efficacy and safety of ultrasound transmission into the brain.

SUBMITTER: Kamimura HA

PROVIDER: S-EPMC6668523 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Feedback control of microbubble cavitation for ultrasound-mediated blood-brain barrier disruption in non-human primates under magnetic resonance guidance.

Kamimura Hermes As HA Flament Julien J Valette Julien J Cafarelli Andrea A Aron Badin Romina R Hantraye Philippe P Larrat Benoît B

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20180130 7

Focused ultrasound (FUS) in combination with microbubbles is capable of noninvasive, site-targeted delivery of drugs through the blood-brain barrier (BBB). Although acoustic parameters are reproducible in small animals, their control remains challenging in primates due to skull heterogeneity. This study describes a 7-T magnetic resonance (MR)-guided FUS system designed for BBB disruption in non-human primates (NHP) with a robust feedback control based on passive cavitation detection (PCD). Contr ...[more]

PMID: 29381130

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Project description:Ultrasound can be used to noninvasively produce different bioeffects via viscous heating, acoustic cavitation, or their combination, and these effects can be exploited to develop a wide range of therapies for cancer and other disorders. In order to accurately localize and control these different effects, imaging methods are desired that can map both temperature changes and cavitation activity. To address these needs, the authors integrated an ultrasound imaging array into an MRI-guided focused ultrasound (MRgFUS) system to simultaneously visualize thermal and mechanical effects via passive acoustic mapping (PAM) and MR temperature imaging (MRTI), respectively.The system was tested with an MRgFUS system developed for transcranial sonication for brain tumor ablation in experiments with a tissue mimicking phantom and a phantom-filled ex vivo macaque skull. In experiments on cavitation-enhanced heating, 10 s continuous wave sonications were applied at increasing power levels (30-110 W) until broadband acoustic emissions (a signature for inertial cavitation) were evident. The presence or lack of signal in the PAM, as well as its magnitude and location, were compared to the focal heating in the MRTI. Additional experiments compared PAM with standard B-mode ultrasound imaging and tested the feasibility of the system to map cavitation activity produced during low-power (5 W) burst sonications in a channel filled with a microbubble ultrasound contrast agent.When inertial cavitation was evident, localized activity was present in PAM and a marked increase in heating was observed in MRTI. The location of the cavitation activity and heating agreed on average after registration of the two imaging modalities; the distance between the maximum cavitation activity and focal heating was -3.4 ± 2.1 mm and -0.1 ± 3.3 mm in the axial and transverse ultrasound array directions, respectively. Distortions and other MRI issues introduced small uncertainties in the PAM∕MRTI registration. Although there was substantial variation, a nonlinear relationship between the average intensity of the cavitation maps, which was relatively constant during sonication, and the peak temperature rise was evident. A fit to the data to an exponential had a correlation coefficient (R(2)) of 0.62. The system was also found to be capable of visualizing cavitation activity with B-mode imaging and of passively mapping cavitation activity transcranially during cavitation-enhanced heating and during low-power sonication with an ultrasound contrast agent.The authors have demonstrated the feasibility of integrating an ultrasound imaging array into an MRgFUS system to simultaneously map localized cavitation activity and temperature. The authors anticipate that this integrated approach can be utilized to develop controllers for cavitation-enhanced ablation and facilitate the optimization and development of this and other ultrasound therapies. The integrated system may also provide a useful tool to study the bioeffects of acoustic cavitation.

Project description:Therapeutic focused ultrasound in combination with encapsulated microbubbles is being widely investigated for its ability to elicit bioeffects in the microvasculature, such as transient permeabilization for drug delivery or at higher pressures to achieve 'antivascular' effects. While it is well established that the behaviors of microbubbles are altered when they are situated within sufficiently small vessels, there is a paucity of data examining how the bubble population dynamics and emissions change as a function of channel (vessel) diameter over a size range relevant to therapeutic ultrasound, particularly at pressures relevant to antivascular ultrasound. Here we use acoustic emissions detection and high-speed microscopy (10 kframes/s) to examine the behavior of a polydisperse clinically employed agent (Definity®) in wall-less channels as their diameters are scaled from 1200 to 15 µm. Pressures are varied from 0.1 to 3 MPa using either a 5 ms pulse or a sequence of 0.1 ms pulses spaced at 1 ms, both of which have been previously employed in an in vivo context. With increasing pressure, the 1200 µm channel - on the order of small arteries and veins - exhibited inertial cavitation, 1/2 subharmonics and 3/2 ultraharmonics, consistent with numerous previous reports. The 200 and 100 µm channels - in the size range of larger microvessels less affected by therapeutic focused ultrasound - exhibited a distinctly different behavior, having muted development of 1/2 subharmonics and 3/2 ultraharmonics and reduced persistence. These were associated with radiation forces displacing bubbles to the distal wall and inducing clusters that then rapidly dissipated along with emissions. As the diameter transitioned to 50 and then 15 µm - a size regime that is most relevant to therapeutic focused ultrasound - there was a higher threshold for the onset of inertial cavitation as well as subharmonics and ultraharmonics, which importantly had more complex orders that are not normally reported. Clusters also occurred in these channels (e.g. at 3 MPa, the mean lateral and axial sizes were 23 and 72 µm in the 15 µm channel; 50 and 90 µm in the 50 µm channel), however in this case they occupied the entire lumens and displaced the wall boundaries. Damage to the 15 µm channel was observed for both pulse types, but at a lower pressure for the long pulse. Experiments conducted with a 'nanobubble' (<0.45 µm) subpopulation of Definity followed broadly similar features to 'native' Definity, albeit at a higher pressure threshold for inertial cavitation. These results provide new insights into the behavior of microbubbles in small vessels at higher pressures and have implications for therapeutic focused ultrasound cavitation monitoring and control.

Project description:Focused ultrasound (FUS) in combination with systemically injected microbubbles can be used to non-invasively open the blood-brain barrier (BBB) in targeted regions for a variety of therapeutic applications. Over the past two decades, preclinical research into the safety and efficacy of FUS-induced BBB opening has proven this technique to be transient and efficacious, propelling FUS-induced BBB opening into several clinical trials in recent years. However, as clinical trials further progress, the neuroinflammatory response to FUS-induced BBB opening needs to be better understood. In this study, we provide further insight into the relationship of microbubble cavitation and the resulting innate immune response to FUS-induced BBB opening. By keeping ultrasound parameters fixed (i.e. frequency, pressure, pulse length, etc.), three groups of mice were sonicated using a real-time cavitation controller until a target cavitation dose was reached (1 x 107 V2•s, 5 x 107 V2•s, 1 x 108 V2•s). The change in relative gene expression of the mouse inflammatory cytokines and receptors were evaluated at three different time-points (6 h, 24 h, and 72 h) after FUS. At both 6 and 24 h time-points, significant changes in relative gene expression of inflammatory cytokines and receptors were observed across all cavitation groups. However, the degree of changes in relative expression levels and the number of genes with significant changes in expression varied across the cavitation groups. Groups with a higher cavitation dose exhibited both greater changes in relative expression levels and greater number of significant changes. By 72 h post-opening, the gene expression levels returned to baseline in all cavitation dose groups, signifying a transient inflammatory response to FUS-induced BBB opening at the targeted cavitation dose levels. Furthermore, the real-time cavitation controller was able to produce consistent and significantly different BBB permeability enhancement volumes across the three different cavitation dose groups. These results indicate that cavitation monitoring and controlling during FUS-induced BBB opening can be used to potentially modulate or limit the degree of neuroinflammation, further emphasizing the importance of implementing cavitation controllers as FUS-induced BBB opening is translated into the clinic.

Dataset Information

Feedback control of microbubble cavitation for ultrasound-mediated blood-brain barrier disruption in non-human primates under magnetic resonance guidance.

Publications

Feedback control of microbubble cavitation for ultrasound-mediated blood-brain barrier disruption in non-human primates under magnetic resonance guidance.

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