Beam distortions of focused ultrasound (FUS)caused by skull may compromise accurate targeting oftranscranial therapeutic ultrasound applications. Although, theefficacy of the random and chirp modulations in improvingtargeting have been proven in simulations, ex-vivo and inphantom studies, many other parameters that can be observed invivo 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-basedcoded ultrasonic excitation in improving the targeting isinvestigated using a FUS-mediated blood-brain barrier (BBB)opening protocol in mice. The coded ultrasonic excitation signalswere generated with frequency bandwidth: 1.5-1.9 MHz,pressure: 0.52 MPa, and duration: 30 s. Fifteen mice weredivided in three groups (n=5 each). One group was sonicated inthe right caudate putamen with chirp-based signal (frequencyvarying linearly), the other group was sonicated with randombased coded signal (randomly varying frequency) and they werecompared with a third group sonicated with standard monofrequency ultrasound (1.5 MHz, 0.52 MPa, burst duration: 20ms, total duration: 5 min). The mean BBB opening volumesassessed by contrast enhanced magnetic resonance imaging were9.38 ± 5.71 mm3, 8.91 ± 3.91 mm3 and 35.47 ± 5.10 mm3 for thechirp, random and standard sonication, respectively. The meancavitation levels assessed by passive cavitation detection were55.40 ± 28.43 V.s, 63.87 ± 29.97 V.s and 356.52 ± 257.15 V.s forthe same groups. The coded excitation methods improved thetargeting precision, generating lower cavitation levels and moreconfined opening volumes than the conventional sonication. Thecoded excitation methods may thus enable more precise drugdelivery and it may benefit other FUS applications that usehigher-pressure levels and require precision to ablate orstimulate the targeted region.