Focused-ultrasound disruption of the blood-brain barrier using closely-timed short pulses: influence of sonication parameters and injection rate

Blood-brain barrier disruption (BBBD) shows promise for drug delivery in the brain; however, optimal parameters for disruption have yet to be firmly established. Previous work has shown that BBBD can be achieved using bursts comprised of microsecond-length pulses at 50% duty cycle to eliminate standing waves and variability. The capabilities and limitations of this sort of pulse sequence comprising short bursts were examined. Ultrasound-induced BBBD was performed in 28 rats using Definity contrast agent. The spacing between 3-μs pulses at 1.18 MHz was either 6 μs, 60 μs, 300 μs or 600 μs during a 10-ms pulse, or 1 s for a single-pulse burst. The rate of infusion of the microbubbles was also examined, as well as the burst pulse repetition frequency (PRF) under infusion conditions. A semi-log relationship between enhancement mean and the number of cycles in a burst was discovered, with a one-pulse burst (i.e., a 3-μs burst at 1 Hz) still capable of disrupting the BBB. No increased efficacy or safety benefit over bursts containing more cycles was found, however. Microbubble infusions showed no improvement in T1w enhancement, but did improve consistency. Increased burst PRF combined with infusion improved T1w enhancement but without statistical significance, whereas a decrease in burst PRF showed a statistically significant decrease in enhancement.