Feasibility of Hologram-assisted Bilateral Blood-Brain Barrier Opening in Non-Human Primates

Focused ultrasound (FUS) and microbubbles facilitate blood-brain barrier opening (BBBO) non-invasively, transiently and safely for targeted drug delivery. Unlike state-of-the-art approaches, in this study, we demonstrate for the first time the simultaneous, bilateral BBBO in non-human primates (NHP) using acoustic holograms at caudate and putamen structures. The simple and low-cost system with a single-element FUS transducer and 3D-printed acoustic hologram was guided by neuronavigation and a robotic arm. The advantages of holograms are transcranial aberration correction, simultaneous multi-focus and high localization, and target-independent transducer positioning, defining a promising alternative for time- and cost-efficient FUS procedures. Holograms were designed with the k-space method by time-reversal techniques. T1-weighted MRI was used for treatment planning, while the CT scan provided the head tissues acoustic properties. For the BBBO procedure, a robotic arm allowed transducer positioning errors below 0.1 mm and 0.1°. Following positioning, 0.5-0.6-MPa 513-kHz microbubble-enhanced FUS was applied for 4 minutes. For BBBO assessment, post-FUS T1-weighted MRI was acquired, and contrast enhancement indicated bilateral gadolinium extravasation at both caudate or putamen structures. The two BBBO locations were separated by 13.13 mm with a volume of 91.81 mm