Influence of Instantaneous Cavitation Dose on Blood-Brain Barrier Opening under the Same Total Cavitation Dose

Stable cavitation by traditional long pulse ultrasound is known to induce blood-brain barrier opening (BBBO). Recent studies showed rapid short-pulse (RaSP) ultrasound could produce more uniform spatiotemporal distribution of instantaneous stable cavitation dose (ISCD), and improving the spatial uniformity of BBBO. However, due to bubble aggregation and dissolution, ISCD induced by each pulse varied with the time, resulted in uncontrollable BBBO. This study aims to demonstrate the influence of ISCD on BBBO efficacy and biosafety under the same total ISCD. By regulating the applied PNPs through an ultra-fast feedback controller, the decreasing ISCDs within one burst and the whole exposure time were sustained to different expected ISCD (EISCD), including high, median and low ISCD. Under the same total SCD, the amounts of extravasated dextran and EB were decreased with the deceasing ISCD, showed strong dependence of BBBO efficacy and biosafety on the ISCD. High ISCD exhibited notably higher nonuniformity of dextran with more aggregated, patchy extravasation dextran patterns. These results indicated that besides the total cavitation dose, the ISCD has also played an importance in BBBO.