Study of Flash technique of low-frequency focused ultrasound associated with SonoVue opening the blood brain barrier in mice

Objective To explore the safety and effectiveness of Flash technique of ultrasound associated with SonoVue to open the blood brain barrier(BBB) in mice.Methods Forty-eight mice were randomly divided into four groups:control group,microbubbles group,Flash group、Flash and microbubbles group.The right basal ganglia of the mice was sonicated by the flash procedures of ultrasound,through intact skull,after continuous intravenous injection of SonoVue and Evans blue (EB).The degree of BBB opening was evaluated quantitatively based on the extravasation of EB and qualitatively under the fluorescence microscope.The safety was inspected by observation of cell morphology under light microscopy and electron microscopy.Results Only in the Flash and microbubbles group,EB extravasation in the sonicated region and significantly red EB fluorescence under fluorescence microscope were shown,which couldn't be seen in other three groups.The EB concentration in the sonicated side in this group was also much higher than other groups (P ＜0.01).In all groups,there were no obvious neuronal damage and erythrocyte extravasation showed by HE staining and electron microscopy.Perivascular edema and vesicle within the cytoplasm of endothelial cells can be seen in the Flash and microbubbles group.Conclusions The BBB can be opened targetedly,safely and noninvasively by Flash procedure of ultrasound with the microbubbles in the mice. Key words: Ultrasonography;  Microbubbles; Blood-brain barrier