Improved feedback loop control for ultrasound-assisted blood-brain barrier opening in non-human primates based on the discrimination between intra- and extra-cerebral cavitation.

Abstract

Objective. Temporary, non-invasive, and localized permeabilization of the blood-brain barrier (BBB) can be achieved through focused ultrasound and microbubbles (MB). This technique has been extensively employed in rodent and non-human primate (NHP) studies for testing various drugs but requires precise control of ultrasonic pressure. However, controlling cavitation in NHP is challenging due to their thicker skull inducing strong ultrasonic attenuation. Furthermore, extra-cranial cavitation may occur masking the cavitation signal at the focal region (cerebral cavitation). Particularly in larger male NHP, temporal muscles are highly perfused and filled with MB.Approach. This study proposes a feedback loop control strategy to distinguish between intra- and extra-cerebral cavitation by analyzing broadband noise recorded by passive cavitation detection sensors.Main results. The frequency-dependent low-pass filtering effect by the skull allows differentiation of distinct frequency components, providing insights into cavitation origin. The present study involved 17 BBB opening experiments in NHP.Significance. Although successful BBB disruption can be achieved in NHP with thin temporal muscles (<5 mm) using a regular feedback loop algorithm, NHP having thicker muscles (>15 mm) require the use of an optimized algorithm able to specifically extract the signature of intra-cerebral cavitation.