Focused Ultrasound Microbubble Destruction-mediated Changes In Blood-brain Barrier Permeability Assessed By Contrast-enhanced Magnetic Resonance Imaging

ObjectiveThe purpose of this study was to use enhanced magnetic resonance imaging (MRI) to evaluate the changes of blood-brain barrier (BBB) permeability in target and nontarget areas of rabbit brains after BBB disruption induced by focused ultrasound-mediated microbubble destruction.MethodsFocused ultrasound (1.1 MHz) in combination with a sulfur hexafluoride microbubble contrast agent was applied at 1 or 3 target locations in 1 hemisphere of 29 rabbit brains to induce BBB disruption. The non-target locations of opposite side was used as a control, and a normal group contained another 14 rabbits that did not undergo sonication. The MRI signal intensity enhancement in the target locations was detected to evaluate gadolinium (Ga) retention after sonication, and extravasation of Evans blue (EB) dye was detected to evaluate the BBB disruption quantitatively at different times after sonication (0.5, 2, 4, 6, 8, and 24 hours and 1 week).Results1. There were significant quantitative differences in Ga retention at 0.5, 2, and 4 hours in the ROI group compared with the control group (opposite hemisphere; P < .01). However, at 6, 8, and 24 hours and 1 week after sonication, there were no quantitative differences. There were significant quantitative differences in Ga retention at 0.5, 2, 4, and 6 hours in the ROI group compared with the normal group (P < .01), but no differences were observed 8 h after sonication. Ga retention was highest at 2 hours in the entire time series(P < .01).2. In the 43 rabbits we examined at 0.5, 2, 4, 6, and 8 hours after sonication, fluorospectrophotometric analysis of the treated side of the brain (ROI group) showed significantly higher EB extravasation compared with the control group (P < .01). At 24 hours and 1 week after sonication, there were no differences between the two sides. Throughout the entire time series, the EB extravasation was highest 2 hours after sonication. The EB extravasation recovered between 8 and 24 hours after sonication. There were significant quantitative differences in EB content in the ROI group at 0.5, 2, 4, 6, and 8 hours compared with the normal group (P < .01), but there were no differences at 24 hours and 1 week after sonication. EB content was highest at 2 hours in the entire time series(P < .01).3. The changes in the MRI signal intensity were in conformity with EB extravasation. The correlation coefficient was 0.964 (P < .01). Gadolinium retention, changes in EB content, and extravasation in the cerebral cortex of the sonication group peaked at 2 hours (P< .01) and returned to normal levels 8 hours after sonication.Conclusion1. Magnetic resonance imaging–guided focused ultrasound can disruptthe BBB reversibly and can allow targeted delivery of some molecules that normally cannot cross the BBB to locations in the brain. Changes in BBB permeability develop within minutes after sonication as a result of a combination of factors. The BBB has a self-repairing characteristic, which is activated after ultrasound sonication.2. Focused ultrasound microbubble destruction-mediated changes in blood-brain barrier permeability could be assessed by contrast-enhanced magnetic resonance imaging. This may offer an improvement in future clinical applications for central nervous system diseases.