Prediction of the reversibility of the ultrasound-induced blood-brain barrier opening using passive cavitation detection with magnetic resonance imaging validation

Abstract

Various molecules have been shown to cross the blood-brain barrier (BBB) upon exposure to focused ultrasound combined with microbubbles and exhibit therapeutic effects. Real-time monitoring, thereof, remains one of the key elements before clinical translation of this technique. The dependence of acoustic emissions on the closing timelines of the BBB opening volume and its permeability was investigated under different pressures (0.30, 0.45, and 0.60 MPa) and microbubble sizes (diameters: 1–2, 4–5, or 6–8 μm). A 10-MHz passive cavitation detector was used to acquire cavitation signals during sonication at the mouse right hippocampus (n = 45). Contrast-enhanced dynamic and T1-weighted MR scans were performed immediately after sonication and up to 6 days thereafter. Contrast-enhanced volumes and diffusion rates of the contrast agent were quantified as indicators for the BBB opening. It was found that the stable cavitation dose increased with the number of days required for closing while it reached a plateau after day 4. However, the inertial cavitation dose exhibited an exponential increase with the duration of the opening. A linear correlation between the total cavitation dose and BBB opening days was found. Moreover, the volume and permeability indicator K trans were found to be both pressure- and bubble size-dependent. The dependence on the bubble-diameter and pressure allows us to predict and control the safety profile of this technique.