Quantification of stable cavitation dose during FUS-induced blood-brain barrier opening in mice and in non-human primates

摘要

A passive cavitation detector (PCD) has previously been developed and used to transcranially acquire the acoustic emissions stemming from the interaction between the microbubble and the brain tissue during FUS-induced blood-brain barrier (BBB) opening, thereby determining the pressure threshold of inertial cavitation (IC) based on the quantification of the broadband response, i.e. inertial cavitation dose (ICD). Given that at certain pressures the BBB opens as a result of stable cavitation only, the stable cavitation dose (SCD) is introduced and quantified during BBB opening in mice and in non-human primates using monodisperse bubbles at varying pressures. In mice, the SCD was quantified with respect to the microbubble diameter and shell properties. Three different diameters (1–2, 4–5, and 6–8 µm) with C18 acyl-chain length of the lipid shell, and three shell acyl-chain lengths (C16, C18, and C24) with a diameter of 4–5-µm were used to induce BBB opening in the right hippocampus (1.5-MHz frequency; 100-cycles (67 µs) pulse length; 10-Hz pulse repetition frequency; 1 minute duration, 0.15 or 0.30 MPa peak-rarefactional pressure). In monkeys, 4–5-µm monodispersed bubbles were used to target different brain regions (500 kHz frequency; 5000 cycles (10 ms) pulse length; 2 Hz pulse repetition frequency; 2 minute sonication duration; 0.20 or 0.25 MPa peak-rarefactional pressure). A 10-MHz Pulse/Echo transducer and a broadband hydrophone were used as a passive cavitation detector (PCD) in mice and monkeys, respectively. The RMS PCD signal amplitude corresponding to the ultra-harmonics (SCDu) and at harmonics (SCDh) in the range of 4–16 MHz (mice) or 1–5 MHz (monkeys) was estimated. Due to the skull effect, there was no difference in SCDu between before and after microbubble administration in mice or monkeys, but the SCDh was found to be signif- cantly higher in the 4–5-µm and 6–8-µm bubble cases compared to the 1–2-µm case at 0.30 MPa in mice. In addition, the BBB opening threshold and SCD were not affected by the acyl-chain length of the shell, although the SCDh in the case of all bubble shells studied was significantly higher than the sham at 0.30 MPa. In monkeys, the SCDh was found to be significantly higher than the sham. As a result, the SCDh can serve as an indicator for BBB opening occurrence in mice and monkeys.