Focused ultrasound with submicron bubbles producing inertial cavitation suppression in blood-brain barrier opening application

Focused ultrasound (FUS) with microbubbles (MBs) induces transient blood-brain barrier disruption (BBBD). However, when MBs interact with FUS in the form of inertial cavitation, intracerebral hemorrhaging (ICH) can occur. The aim of this study was to investigate whether the induction of submicron MBs to oscillate at their resonant frequency would suppress inertial cavitation during BBBD and eliminate ICH. FUS was delivered to the rat left hemisphere brain with pressures from 0.5 to 2.5 MPa (PRF: 10 Hz, cycle number: 10000, exposure time: 60 s) to induce BBBD. Submicron in-house MBs and SonoVue® were used in the BBBD process. BBBD was assessed by quantifying the amount of Evans blue leakage into the brain. Magnetic resonance susceptibility-weighted images were acquired to confirm the occurrence of ICH. Wideband and subharmonic emissions from MBs were both measured to quantify the dosages of inertial and stable cavitation, respectively. Excitation of MBs with matched resonant frequency FUS (10 MHz in our case) can greatly limit the occurrence of inertial cavitation, enhance the appearance of stable cavitation and thereby eliminate ICH. Subharmonic-frequency signals closely correlate with the occurrence of BBBD, whereas wideband acoustic emission correlates with the occurrence of ICH. BBBD can be achieved with extensively suppressed inertial cavitation using this technique. This study provides important information toward the goal of successfully translating FUS brain drug delivery into clinical usage.