Improving targeting of ultrasound-mediated blood-brain barrier opening using chirp and random-based modulations

Beam distortions of focused ultrasound (FUS) caused by skull may compromise accurate targeting of transcranial therapeutic ultrasound applications. Although, the efficacy of the random and chirp modulations in improving targeting have been proven in simulations, ex-vivo and in phantom studies, many other parameters that can be observed in vivo are disregarded such as the heterogeneity of the soft tissue, the variability of the drug uptake and clearance among subjects. In this study, the capability of the chirp- and random-based coded ultrasonic excitation in improving the targeting is investigated using a FUS-mediated blood-brain barrier (BBB) opening protocol in mice. The coded ultrasonic excitation signals were generated with frequency bandwidth: 1.5-1.9 MHz, pressure: 0.52 MPa, and duration: 30 s. Fifteen mice were divided in three groups (n=5 each). One group was sonicated in the right caudate putamen with chirp-based signal (frequency varying linearly), the other group was sonicated with random-based coded signal (randomly varying frequency) and they were compared with a third group sonicated with standard mono-frequency ultrasound (1.5 MHz, 0.52 MPa, burst duration: 20 ms, total duration: 5 min). The mean BBB opening volumes assessed by contrast enhanced magnetic resonance imaging were 9.38 ± 5.71 mm
³
, 8.91 ± 3.91 mm
³
and 35.47 ± 5.10 mm
³
for the chirp, random and standard sonication, respectively. The mean cavitation levels assessed by passive cavitation detection were 55.40 ± 28.43 V.s, 63.87 ± 29.97 V.s and 356.52 ± 257.15 V.s for the same groups. The coded excitation methods improved the targeting precision, generating lower cavitation levels and more confined opening volumes than the conventional sonication. The coded excitation methods may thus enable more precise drug delivery and it may benefit other FUS applications that use higher-pressure levels and require precision to ablate or stimulate the targeted region.