Abstract:

The feasibility of blood-brain barrier (BBB) opening in the hippocampus of mice using transcranial focused ultrasound (FUS) was investigated on simulations and in vivo experiments. A micro-CT scan of an excised mouse skull was performed (resolution: 0.01 mm) and mappings of porosity, speed of sound, density, and attenuation were calculated. A 1.5-MHz wave propagating through the skull mappings was simulated, revealing a well-formed beam, minimal attenuation, and minute focus displacement. These results were verified with needle hydrophone measurements through five excised mouse skulls. In experiments in vivo, three mice were intravenously injected with a bolus of 0.01-mL ultrasound contrast agents (Optison) and the brains were sonicated transcranially. Ultrasound sonications (frequency: 1.5 MHz; burst length: 20 ms; duty cycle: 20%; acoustic pressure range: 2.0 to 2.7 MPa) were applied five times for 30 s per shot with a 30-s delay between shots. High-resolution (9.4 tesla), contrast-enhanced MR imaging revealed BBB opening and slow permeation of gadolinium from the posterior cerebral artery (10-min postinjection) through the surrounding tissue (35-min postinjection) and to the entire left hippocampus (95-min postinjection). These results demonstrate the feasibility of localized, noninvasive BBB opening in mice using transcranial FUS for potential precise drug delivery.