Using acoustic emissions to monitor and control ultrasound-mediated blood–brain barrier disruption

Using ultrasound and preformed microbubbles to disrupt the blood–brain barrier (BBB) is a promising approach to enable the delivery of drugs that do not normally extravasate into the brain. The safe window where BBB disruption is possible without microhemorrhage is small, and due to large variability in skull properties, it is critical to monitor the ultrasound exposures to ensure a safe and effective outcome. Monitoring the acoustic emissions produced during sonication is an effective method to achieve this goal. Due to nonlinear effects, the acoustic emissions produced when circulating microbubbles are introduced are at frequencies different than the driving frequency. At low exposure levels, the microbubbles oscillate stably and produce increases in harmonic emissions. At higher levels, the microbubbles collapse rapidly and violently and produce vascular damage. This inertial cavitation results in a large increase in broadband emissions. These signatures can be used in real time to control the acoustic exposure level and ensure that only stable, and not inertial cavitation, occurs. This talk will be an overview of our experience using acoustic emissions to control the exposure levels during ultrasound-mediated BBB disruption in pre-clinical and clinical studies. Challenges and pitfalls will be discussed, along with potential strategies to mediate them.