The safest parameters for FUS-induced blood-brain barrier opening without effects on the opening volume

Abstract

Acoustic cavitation has been identified as the main physical mechanism for the focused ultrasound (FUS) induced blood-brain barrier (BBB) opening. In this paper, the mechanism of stable cavitation (SC) and inertial cavitation (IC) responsible for BBB opening was investigated. Thirty-three (n=33) mice were intravenously injected with bubbles of 4-5 μm in diameter. The right hippocampus was then sonicated using focused 1.5-MHz ultrasound and three different studies were carried out. First, pulse lengths (PLs) of 0.1, 0.5, 2, and 5 ms at 0.18- MPa peak rarefactional pressure with 5-Hz pulse repetition frequency (PRF) and 5-minute duration were used to identify the threshold of PL using SC. Second, the effects of the duty cycle and exposure time were investigated. Third, the BBB opening size was compared between the SC and the IC. In the case of IC-induced BBB opening, a burst sequence (3-cycles PL; 5-Hz burst repetition frequency (BRF); 30 s duration) at 0.45 MPa was applied. Passive cavitation detection was performed with each sonication to detect whether a broadband response was obtained, i.e., if IC occurred, during BBB opening. The properties of BBB opening were measured through MRI. The threshold of PL for BBB opening was identified between 0.1 and 0.5 ms using SC, but the BBB can be opened in few cycles using IC. The BBB opening volume and normalized intensity increased with the PL, but reached saturation when the PL was above 2 ms. Once the PL threshold was reached, the same exposure time induced a similar BBB opening volume, but longer sonication duration induced higher MR intensity. The duty cycle was found not to play an important role on the BBB opening. Comparable BBB opening volume (20-25 mm3) could be reached between long PL (7500 cycles, i.e., 5 ms) at 0.18 MPa and 3 cycles at 0.45 MPa. 3-kDa fluorescently tagged dextran may be able to diffuse to the parenchyma after IC-induced BBB opening at 0.45 MPa but not after SC-induced BBB opening at 0.18 MPa.