MR-guided blood-brain barrier opening induced by rapid short-pulse ultrasound in non-human primates.

Abstract

Opening the blood-brain barrier (BBB) with focused ultrasound and microbubbles (MBs) has potential use in non-invasive targeted therapy for central nervous system (CNS) diseases. Rapid short-pulse (RaSP) ultrasound with a microsecond sequence has been proposed as a minimally disruptive and efficient method for opening the BBB. This work aimed to test the feasibility and safety of BBB opening in a non-human primate model using combined RaSP ultrasound sequence and MBs. The BBB of 2 rhesus macaques were opened with RaSP and the commonly used 10 millisecond long pulse (LP), combined with microbubble (SonoVueTM, 0.2 µL/g) injection in a bolus. The transducer's central frequency was 300 kHz, and the acoustic pressure was set to 0.56 MPa calibrated in water. The BBB opening procedure was guided and evaluated with contrast-enhanced magnetic resonance imaging. The relative signal enhancement was compared between RaSP and LP sonication. T2-weighted fast-spin echo (FSE) and T2*-weighted gradient echo (GRE) sequences were scanned to evaluate edema and micro-bleeding at the end of the procedure. The relative signal enhancement was significantly higher (P<0.01) in the focal area compared to a similar area of the opposite hemisphere at all time points after sonication in each monkey, indicating the successful opening of the BBB. The relative signal enhancement in RaSP reached more than 60% of that with LP in our experiment, while the energy deposition was only 6% of LP. No edema or hemorrhage was found on magnetic resonance images after RaSP. Combined RaSP ultrasound and MBs for the BBB opening is a practical method in large animal models.