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Most neurological disorders and neurodegenerative diseases, including Alzheimer's and Parkinson's, remain difficult to treat because of the impermeability of the blood-brain barrier (BBB). The activation of bubbles by an acoustic field has been shown to temporarily open the (BBB) but the physical effects responsible for BBB opening remain unknown. In this study, two sets of experiments were performed in order to understand the bubble-dependent mechanism of FUS-induced BBB opening in mice and in monkeys. First, sixty-seven mice were injected intravenously with bubbles of either 1-2, 4-5 or 6-8 μm in diameter. The right hippocampus was then sonicated using focused ultrasound (1.5-MHz frequency; 100-cycles (67 μs) pulse length (PL); 10-Hz pulse repetition frequency (PRF); 1 minute duration). Peak-rarefactional pressures of 0.15-0.60 MPa were applied to identify the threshold of BBB opening and inertial cavitation (IC). Second, three monkeys (7 sonications) were performed using 4-5 μm/Definity microbubbles and focused ultrasound (0.5-MHz, 5000-cycles (10 ms) PL; 2-Hz PRF, 2 minute duration). 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. In monkey experiments, the BBB was opened in all cases with 4-5 μm diameter bubbles, but was only opened at 0.60 MPa using Definity. 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.