Characterization of Microbubble Cavitation in Theranostic Ultrasound-mediated Blood-Brain Barrier Opening and Gene Delivery.

Rationale: The characterization of microbubble activity has proven critical in assessing the safety and efficacy of ultrasound-mediated blood-brain barrier (BBB) opening and drug and gene delivery. In this study, we build upon our previous work on theranostic ultrasound (ThUS)-mediated BBB opening (ThUS-BBBO) and conduct for the first time a comprehensive characterization of the role of microbubble cavitation in ThUS-BBBO, as well as its impact on gene delivery with adeno-associated viruses (AAV). Methods: A repurposed imaging phased array was used throughout the study to generate focused transmits and record microbubble activity through high-resolution power cavitation imaging (PCI). The cavitation of microbubbles under ThUS pulses was first characterized in flow phantom using pulse lengths ranging from 1.5 to 20 cycles and under varying microbubble flow rates using a separate single-element transducer a passive cavitation detector (PCD). A comprehensive Results: Frequency domain analysis in the phantoms revealed a broadband-cavitation dominance at the shorter pulse lengths, while harmonic cavitation components are significantly increased for longer pulses. The PCD was better at detecting higher frequency harmonics, while the signal received by the theranostic array was more broadband dominated. Analysis of signals in the time domain showed that the longer pulses induce higher microbubble collapse compared to short pulses. In the transcranial Conclusions: This is the first comprehensive study into the microbubble cavitation under theranostic ultrasound. The phantom and