Design of a 1-MHz therapeutic ultrasound array for small volume blood-brain barrier opening at cortical targets in macaques.

Focused ultrasound (FUS) can temporarily open the blood brain barrier (BBB) and increase the delivery of chemotherapeutics, viral vectors, and other agents to the brain parenchyma. To limit FUS BBB opening to a single brain region, the transcranial acoustic focus of the ultrasound transducer must not be larger than the region targeted. In this work, we design and characterize a therapeutic array optimized for BBB opening at the frontal eye field in macaques. We used 115 transcranial simulations in four macaques varying f-number and frequency to optimize the design for focus size, transmission, and small device footprint. The design leverages inward steering for focus tightening, a 1 MHz transmit frequency, and can focus to a simulation predicted 2.5 ± 0.3 mm lateral and 9.5 ± 1.0 mm axial full-width at half maximum spot size at the frontal eye field without aberration correction. The array is capable of steering axially 35 mm outward, 26 mm inward, and laterally 13 mm with > 50% the geometric focus pressure. The simulated design was fabricated, and we characterized the performance of the array using hydrophone beam maps in a water tank and through an ex vivo skull cap to compare measurements with simulation predictions, achieving a 1.8 mm lateral and 9.5 mm axial spot size with a transmission of 37 % (transcranial, phase corrected). The transducer produced by this design process is optimized for BBB opening at the frontal eye field in macaques.