Transcranial Theranostic Ultrasound for Pre-Planning and Blood-Brain Barrier Opening: A Feasibility Study Using an Imaging Phased Array In Vitro and In Vivo.

Abstract

Focused ultrasound (FUS) for blood-brain barrier (BBB) opening is a safe, reversible and non-invasive strategy for targeted drug delivery to the brain, however extensive pre-planning strategies are necessary for successful FUS-mediated BBB opening through the structurally complex primate skull. This study aims to demonstrate a pre-planning pipeline consisting of transcranial simulations and in vitro experimentation used to inform synchronous BBB opening and power cavitation imaging (PCI) with a single theranostic ultrasound (TUS) phased array. Acoustic wave propagation simulation findings of pressure attenuation and focal shift through clinical-CT and micro-CT-based primate skull models were compared, while the latter were used to determine the impact of beam steering angle on focal shift and pressure attenuation. In vitro experimentation with a channel phantom enabled characterization of skull-induced receive focal shift (RFS), while in vivo BBB opening and PCI using in silico and in vitro pre-planning information was conducted using a custom Verasonics/MATLAB script. Simulations confirmed steering angle dependent transcranial focal shift and pressure attenuation, while in vitro experiments revealed minimal (0.30-1.50 mm) skull-induced RFS. In vivo rodent experiments with overlaid primate skull fragments demonstrated successful TUS-mediated BBB opening and spatially correlated power cavitation images (PCI) with regions of BBB opening on T₁-weighted magnetic resonance images (MRI). We demonstrated the feasibility for TUS-mediated BBB opening in vivo using in silico and in vitro pre-planning information. TUS as an ultrasound-guided modality for BBB opening could serve as a promising alternative to current FUS-mediated BBB opening configurations in the clinic.