Design of a 1-MHz Therapeutic Ultrasound Array for Small Volume Blood-Brain Barrier Opening at Cortical Targets in Macaques

[[gabstract]][] 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 (FEF) 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 FEF without aberration correction. The array is capable of steering axially 35 mm outward, 26 mm inward, and laterally 13 mm with
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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 FEF in macaques.