Noninvasive and Localized Blood—Brain Barrier Disruption using Focused Ultrasound can be Achieved at Short Pulse Lengths and Low Pulse Repetition Frequencies

TLDR

Ultrasound combined with microbubbles is used for brain drug delivery, stroke treatment, and cerebral blood‑flow imaging, yet the optimal ultrasound parameters for safely disrupting the blood‑brain barrier remain uncertain. The study aimed to identify conditions that either promote or inhibit blood‑brain‑barrier disruption. Pulsed focused ultrasound (1.5 MHz, 0.46 MPa, PRF 0.1–25 Hz, PL 0.03–30 ms) was applied locally to the left hemisphere in the presence of circulating Definity microbubbles (0.01–0.25 µL g⁻¹). BBB disruption was achieved at PRFs as low as 1 Hz and PLs as short as 33 µs, with higher PL increasing dextran concentration but also heterogeneity; reducing PL or PRF produced a more uniform distribution, identifying key parameters for effective, localized BBB opening.

Abstract

Ultrasound methods in conjunction with microbubbles have been used for brain drug delivery, treatment of stroke, and imaging of cerebral blood flow. Despite advances in these areas, questions remain regarding the range of ultrasound parameters that disrupt the blood-brain barrier (BBB). In this study, several conditions were investigated to either enhance or reduce the likelihood of BBB disruption. Pulsed focused ultrasound (frequency: 1.5 MHz, pressure: 0.46 MPa, pulse repetition frequency (PRF): 0.1 to 25 Hz, pulse length (PL): 0.03 to 30 milliseconds) was noninvasively and locally administered to a predetermined region in the left hemisphere in the presence of circulating preformed microbubbles (Definity, Lantheus Medical Imaging, N. Billerica, MA, USA; 0.01, 0.05, 0.25 μL/g). Trans-BBB delivery of 3-kDa dextran was observed at PRFs as low as 1 Hz, whereas consistent delivery was observed at 5 Hz and above. Delivery was demonstrated at a PL as low as 33 microseconds. Although the delivered dextran concentration increased with the PL, this also increased the heterogeneity of the resulting distribution. In conclusion, key parameters that disrupt the BBB were identified out of a wide range of conditions. Reducing the total number of emitted acoustic cycles by shortening the PL, or decreasing the PRF, was also found to facilitate a more spatially uniform distribution of delivered dextran.