Comparing rapid short-pulse to tone burst sonication sequences for focused ultrasound and microbubble-mediated blood-brain barrier permeability enhancement

Objective Transcranial focused ultrasound and microbubble (FUS + MB) exposure enables targeted, noninvasive drug delivery to the brain. Given the protective nature of the blood-brain barrier (BBB), the development of sonication strategies that maximize therapeutic efficacy while minimizing the risk of tissue damage are essential. This work aimed to compare the safety of 10 ms tone bursts, widely used in the field, to a recently described rapid short-pulse (RaSP) sequence, while accounting for drug delivery potential. Materials and methods Forty-one male wild-type mice received FUS + MB exposure (1.78 MHz driving frequency; 0.5 Hz burst repetition frequency; 250 s duration; 40 μl/kg Definity) at a range of fixed pressure amplitudes. A RaSP sequence (13 five-cycle pulses/10 ms burst) was compared to 10 ms tone bursts (B10). For animals in cohort #1 (n = 26), T1 mapping was used to quantify gadobutrol extravasation. Three targets, temporarily separated by 10 min, were sonicated in each brain to compare the time dependence of BBB permeability enhancement between sequences. Red blood cell (RBC) extravasation was quantified to assess vascular damage. For animals in cohort #2 (n = 18), a single target was sonicated per brain. BBB permeability enhancement was compared between sequences by T1 mapping and the extravasation of a 3 kDa fluorescent dextran. Results At a peak negative pressure of 400 kPa, the B10 sequence produced an order of magnitude greater gadobutrol and dextran extravasation compared to RaSP (p < 0.01). When accounting for BBB permeability enhancement magnitude, as measure by T1 mapping, no differences were observed between sequences in the pattern of dextran or albumin extravasation in tissue sections; however, the frequency of RBC extravasation was found to be 5 times greater with the RaSP sequence (p = 0.02). At pressure amplitudes resulting in similar levels of gadobutrol extravasation, no significant differences were observed in the time dependence of BBB permeability enhancement between sequences. Conclusion When accounting for the magnitude of BBB permeability enhancement, and thus the potential for drug delivery, the RaSP sequence tested here did not produce measurable improvements over the B10 sequence and may present an increased risk of vascular damage.