Microbubbles (MBs) serve as a critical catalyst to amplify local cavitation in CNS capillary lumen to facilitate focused ultrasound (FUS) to transiently open the blood-brain barrier (BBB). However, limited understanding is available regarding the effect of different microbubbles to induce BBB opening. The aim of this study is to characterize different MBs on their effect in FUS-induced BBB opening. Three MBs, SonoVue, Definity, and USphere, were tested, with 0.4-MHz FUS exposure at 0.62–1.38 of mechanical index (MI) on rats. Evans blue, dynamic contrast-enhanced (DCE) MRI and small-animal ultrasound imaging were used as surrogates to allow molecule-penetrated quantification, BBB-opened observation, and MBs circulation/persistence. Cavitation activity was measured via the passive cavitation detection (PCD) setup to correlate with the exposure level and the histological effect. Under given and identical MB concentrations, the three MBs induced similar and equivalent BBB-opening effects and persistence. In addition, a treatment paradigm by adapting exposure time is proposed to compensate MB decay to retain the persistence of BBB-opening efficiency in multiple FUS exposures. The results potentially improve understanding of the equivalence among MBs in focused ultrasound CNS drug delivery, and provide an effective strategy for securing persistence in this treatment modality.

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Purpose: To optimize the timing of contrast-enhanced magnetic resonance imaging (MRI) that best indicates blood-brain barrier (BBB) disruption induced by focused ultrasound (FUS) along with an ultrasound contrast agent (UCA) and to verify that the contrast-enhanced spin-echo MRI sequence can indicate the degree and location of BBB disruption in the presence of hemorrhage better than a gradient-echo sequence. Materials and Methods:Sonication was applied to 12 rat brains with four different doses of UCA to cause variable degrees of hemorrhage. Two imaging sequences were performed to acquire T1-weighted (T1W) images at two timepoints after the administration of a T1-shortening contrast agent. The contrast enhancement at the sonicated regions was quantified and correlated against Evans blue (EB) staining. Results:The spin-echo T1W images at 10 minutes postcontrast enhancement showed the best correlation with EB staining in both quantity of EB extravasation (r ¼ 0.812; P < 0.01) and spatial distribution (r ¼ 0.528, P < 0.01). This capability was more robust than the gradientecho sequence. Conclusion:Our results suggest that contrast-enhanced T1W spin-echo sequence acquired in the early phase post-contrast enhancement should be considered to monitor the degree and location of BBB disruption under the possibility of hemorrhage induced by FUS.