Blood-Brain Barrier Opening by Individualized Closed-Loop Feedback Control of Focused Ultrasound.

Objective and Impact Statement. To develop an approach for individualized closed-loop feedback control of microbubble cavitation to achieve safe and effective focused ultrasound in combination with microbubble-induced blood-brain barrier opening (FUS-BBBO). Introduction. FUS-BBBO is a promising strategy for noninvasive and localized brain drug delivery with a growing number of clinical studies currently ongoing. Real-time cavitation monitoring and feedback control are critical to achieving safe and effective FUS-BBBO. However, feedback control algorithms used in the past were either open-loop or without consideration of baseline cavitation level difference among subjects. Methods. This study performed feedback-controlled FUS-BBBO by defining the target cavitation level based on the baseline stable cavitation level of an individual subject with "dummy" FUS sonication. The dummy FUS sonication applied FUS with a low acoustic pressure for a short duration in the presence of microbubbles to define the baseline stable cavitation level that took into consideration of individual differences in the detected cavitation emissions. FUS-BBBO was then achieved through two sonication phases: ramping-up phase to reach the target cavitation level and maintaining phase to control the stable cavitation level at the target cavitation level. Results. Evaluations performed in wild-type mice demonstrated that this approach achieved effective and safe trans-BBB delivery of a model drug. The drug delivery efficiency increased as the target cavitation level increased from 0.5 dB to 2 dB without causing vascular damage. Increasing the target cavitation level to 3 dB and 4 dB increased the probability of tissue damage. Conclusions. Safe and effective brain drug delivery was achieved using the individualized closed-loop feedback-controlled FUS-BBBO.