Biaxial ultrasound driving technique for small animal blood-brain barrier opening

Biaxial driving can more efficiently convert electrical power to forward acoustic power in piezoelectric materials, and the interaction between the orthogonal electric fields can produce a combination of extensional and shear deformations as a function of the phase difference between them to allow dynamic steering of the beam with a single-element. In this study, we demonstrate for the first time the application of a single-element biaxially driven ring transducerin vivofor blood-brain barrier opening in mice, and compare it to that achieved with a conventional single-element highly focused (F# = 0.7) spherical transducer operating at a similar frequency. Transcranial focused ultrasound (0.45 MPa, 10 ms pulse length, 1 Hz repetition frequency, 30 s duration) was applied bilaterally to mice with a 40μl/kg bolus of Definity^TMmicrobubbles, employing either a single-element biaxial ring (1.482 MHz, 10 mm inner diameter, 13.75 mm outer diameter) or spherical (1.5 MHz, 35 mm diameter, F# = 0.7; RK50, FUS Instruments) transducer on each side. Follow-up MRI scans (T1 pre- and post- 0.2 mmol/kg Gd injection, T2) were acquired to assess blood-brain barrier opening volume and potential damage. Compared to blood-brain barrier opening achieved with a conventional single-element spherical focused transducer, the opening volume achieved with a single-element biaxial ring transducer was 35% smaller (p= 0.002) with a device of a ring diameter of 40% the aperture size. Axial refocusing was further demonstrated with the single-element biaxial ring transducer, yielding a 1.63 mm deeper, five-fold larger opening volume (p= 0.048) relative to its small-focus mode. The biaxial ring transducer achieved a more localized opening compared to the spherical focused transducer under the same parameters, and further enabled dynamic axial refocusing with a single-element transducer with a smaller fabrication footprint.