The Dynamic of FUS-induced BBB Opening in Mouse Brain Assessed by Contrast Enhanced MRI

Focused ultrasound (FUS) in combination with the administration of gas-filled microbubbles, can induce a localized and reversible opening of the blood brain barrier (BBB). Contrast enhanced magnetic resonance imaging (MRI) has been demonstrated as a precise tool to monitor such a local BBB disruption. However, the opening/closing mechanisms of the BBB with FUS are still largely unknown. In this ongoing project, we study the BBB opening dynamics in mouse brain comparing an interstitial and an intravascular MR contrast agent (CA). FUS in mouse brain was performed with an MRI compatible treatment setup (1.7 MHz fix-focus US transducer, f = 68 mm, NA = 0.44; focus: 8.1 mm length; 0 = 1.1 mm) in a 1.5 T whole body MRI system. For BBB opening, forty 10 ms-long FUS-pulses were applied at a repetition rate of 1 Hz at 1 MPa. The i.v. administration of the micro bubbles (50 ill SonoVue) was started simultaneously with FUS exposure. To analyze the BBB opening process, short-term and long-term MRI signal dynamics of the interstitial MR contrast agent Magnevist (R) and the intravascular CA Vasovist (R) (Bayer-Schering) were studied. To assess short-term signal dynamics, T1-weighted inversion recovery turbo FLASH images (Is) were repeatedly acquired. Repeated 3D FLASH acquisitions (90 s) were used to assess long-term MRI signal dynamics. The short-term MRI signal enhancements showed comparable time constants for both types of MR contrast agents: 1.1 s (interstitial) vs. 0.8 s (intravascular). This time constant may serve as a time constant of the BBB opening process with the given FUS exposure parameters. For the long-term signal dynamics the intravascular CA (62 +/- 10 min) showed a fife times greater time constant as the interstitial contrast agent (12 10 min). This might be explained by the high molecular weight (similar to 60 kDa) of the intravascular Vasovist due to its reversible binding to blood serum albumin resulting in a prolonged half-life in the blood stream compared to the interstitial CA. As the intravascular CA offers a much longer time window for therapy assessment, FUS-BBB therapy control with an intravascular CA might be favorable.