Focused Ultrasound-Induced Blood-Spinal Cord Barrier Opening Using Short-Burst Phase-Keying Exposures in Rats: A Parameter Study

Abstract

Transient opening of the blood-spinal cord barrier has the potential to improve drug delivery options to the spinal cord. We previously developed short-burst phase-keying exposures to reduce focal depth of field and mitigate standing waves in the spinal canal. However, optimal short-burst phase-keying parameters for drug delivery have not been identified. Here, the effects of pressure, treatment duration, pulse length, burst repetition frequency and burst length on resulting tissue effects were investigated. Increased in situ pressures (0.23-0.33 MPa) led to increased post-treatment T₁-weighted contrast enhancement in magnetic resonance imaging (p = 0.015). Increased treatment duration (120 vs. 300 s) led to increased enhancement, but without statistical significance (p = 0.056). Increased burst repetition frequency (20 vs. 40 kHz) yielded a non-significant increase in enhancement (p = 0.064) but corresponded with increased damage observed on histology. No difference was observed in enhancement between pulse lengths of 2 and 10 ms (p = 0.912), corresponding with a sharp drop in the recorded second harmonic signal during the first 2 ms of the pulse. Increasing the burst length from two to five cycles (514 kHz) led to increased enhancement (p = 0.014). Results indicate that increasing the burst length may be the most effective method to enhance drug delivery. Additionally, shorter pulse lengths may allow more interleaved targets, and therefore a larger treatment volume, within one sonication.

Keywords: Blood–spinal cord barrier; Focused ultrasound; Spinal cord; Trans-spinous ultrasound therapy.