Focused-Ultrasound Disruption of the Blood-Brain Barrier Using Closely-Timed Short Pulses: Influence of Sonication Parameters and Injection Rate

Abstract

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 in order 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, 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 PRF under infusion conditions. A semi-log relationship between enhancement mean and the number of cycles in a burst was discovered, with a 1 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, while a decrease in burst PRF showed a statistically significant decrease in enhancement.

Drug delivery across the blood–brain barrier using focused ultrasound

“…due to the large focal spot size at low frequency and high pressure requirements at high frequency [23]. In addition to frequency, other ultrasound parameters including burst duration have been shown to positively correlate with BBB opening [24–26]. With respect to pulse repetition frequency, it has been suggested that adequate time is required to allow time for reperfusion of the microbubbles [27] however, changes in burst repetition frequency did not affect changes in BBB permeability [24].…”

Study of the mechanisms underlying the reversal of multidrug resistance of human neuroblastoma multidrug-resistant cell line SK-N-SH/MDR1 by low-intensity pulsed ultrasound

“…LIPUS may damage the structural integrity of the membrane of tumor cells mechanically via sonoporation (16)(17)(18)(19). In our experiment, the effect of proliferation could be excluded by reason of detecting M value immediately after irradiation.…”

Design of patient-specific focused ultrasound arrays for non-invasive brain therapy with increased trans-skull transmission and steering range

“…The use of a conformal array of focused transducer elements allows for tight focusing at lateral targets in the brain, with sufficient acoustic pressures for a number of therapies involving relatively short ultrasound pulses, including BBB opening, where sonications were performed at a pressure of 0.54 MPa (O’Reilly et al 2011), which is within the range of acoustic pressures presented in Table 1. These studies were performed at 1.18 MHz, however, and the required pressures at 500 kHz could be different as a result.…”