Feasibility of transcranial, localized drug-delivery in the brain of Alzheimer's-model mice using focused ultrasound

Therapeutic agents are difficult to deliver to the brain because of brains natural defense: the Blood-Brain Barrier (BBB). It has been shown that Focused Ultrasound can produce reversible and localized BBB opening in the brain when applied in the presence of ultrasound contrast agents (1). However, a major limitation of ultrasound in the brain is the strong phase aberration and attenuation of the skull bone. Thus, despite the high potential of non-invasive adaptive focusing techniques, no study of trans-cranial ultrasound-targeted drug treatment in the brain has been reported as of yet. In this study, the feasibility of BBB opening in the hippocampus of Alzheimers-model mice using focused ultrasound through the intact skull and skin was investigated. A high power focused transducer (1.5 MHz central frequency) was mounted on a 3D positioning system and a 7.5 MHz single element diagnostic transducer was placed through the center of the focused transducer and aligned with the high power beam in order to achieve high precision targeting. In order to investigate the effect of the skull, simulations of ultrasound wave propagation through the skull using µCT data, and needle hydrophone measurements through an ex-vivo skull were made. The pressure field showed minimal attenuation (18% of the pressure amplitude was attenuated) and a well-focused pattern through the left and right halves of the parietal bone. In in-vivo experiments, the brains of four mice were sonicated through intact skull and skin. Ultrasound sonications were set to a burst length of 20 ms at a 20% duty cycle and was applied 5 times for 30 s per shot with a 30 s delay between shots. The acoustic pressure ranged from 2.0 to 2.7 MPa. Prior to sonication, ultrasonographic contrast agents (Optison; 0.05 mL) were injected in the mice intravenously. Contrast-enhanced high resolution T1 and T2-weighted MR Imaging (9.4 Tesla) with an in-plane resolution of 75 µm was able to distinguish opening of large vessels in the region of the hippocampus. These results demonstrate the feasibility of potentially, locally opening the BBB in the mouse hippocampus using focused ultrasound through the intact skull and skin. Future investigations will deal with optimization and repeatability of the technique as well as feasibility on Alzheimer's-affected mice.