Bubble dependence of the mechanism FUS-induced blood-brain barrier opening in mice in vivo.

Abstract

The activation of bubbles by an acoustic field has been shown to temporarily open the blood-brain barrier (BBB) but the physical effects responsible for BBB opening remain unknown. In this study, the physical mechanism of the FUS-induced BBB opening with monodispersed microbubbles is unveiled. Sixty-seven mice were injected intravenously with bubbles of either 1–2, 4–5 or 6–8 μm in diameter. The right hippocampus of each mouse was then sonicated using focused ultrasound (1.5-MHz frequency, 100-cycle (67 μs) pulse length, 10-Hz pulse repetition frequency, and 1 min duration). Peak-rarefactional pressures of 0.15, 0.30, 0.45, or 0.60 MPa were applied to identify the threshold of BBB opening and inertial cavitation (IC). It was found that the BBB opens with nonlinear bubble oscillation when the bubble diameter is similar to the capillary diameter and with inertial cavitation when it is not. The bubble may thus have to be in contact with the capillary wall to induce BBB opening without IC. The BBB opening was induced safely with nonlinear bubble oscillation at the pressure threshold for opening while its volume was highly dependent on both the acoustic pressure and bubble diameter. [This work was supported by NIH Grant No. R01EB009014 and NSF Grant No. CAREER 0644713.]