Blood-Brain Barrier Closure Time After Controlled Ultrasound-Induced Opening Is Independent of Opening Volume

Abstract

Objectives—Microbubble-mediated focused ultrasound (US) opening of the blood-brain barrier (BBB) has shown promising results for the treatment of brain tumors and conditions such as Alzheimer disease. Practical clinical implementation of focused US treatments would aim to treat a substantial portion of the brain; thus, the safety of opening large volumes must be investigated. This study investigated whether the opened volume affects the time for the BBB to be restored after treatment. Methods—Sprague Dawley rats (n 5 5) received bilateral focused US treatments. One hemisphere received a single sonication, and the contralateral hemisphere was targeted with 4 overlapping foci. Contrast-enhanced T1-weighted magnetic resonance imaging was used to assess the integrity of the BBB at 0, 6, and 24 hours after focused US. Results—At time 0, there was no significant difference in the mean enhancement between the single-and multi-point sonications (mean 6 SD, 29.7% 6 18.4% versus 29.7% 6 24.1%; P 5 .9975). The mean cross-sectional area of the BBB opening resulting from the multi-point sonication was approximately 3.5-fold larger than that of the single-point case (14.2 6 4.7 versus 4.1 6 3.3 mm2; P < .0001). The opened volumes in 9 of 10 hemispheres were closed by 6 hours after focused US. The remaining treatment location had substantially reduced enhancement at 6 hours and was closed by 24 hours. Histologic analysis revealed small morphologic changes associated with this location. T2-weighted images at 6 and 24 hours showed no signs of edema. T2*-weighted images obtained at 6 hours also showed no signs hemor-rhage in any animal. Conclusions—The time for the BBB to close after focused US was independent of the opening volume on the time scale investigated. No differences in treatment effects were observable by magnetic resonance imaging follow-up between larger-and smaller-volume sonications, suggesting that larger-volume BBB opening can be performed safely.