Permeability dependence study of the focused ultrasound-induced blood-brain barrier opening at distinct pressures and microbubble diameters using DCE-MRI. Magn Reson Med.

Blood-brain barrier opening using focused ultrasound and microbubbles has been experimentally established as a noninvasive and localized brain drug delivery technique. In this study, the permeability of the opening is assessed in the murine hippocampus after the application of focused ultrasound at three different acoustic pressures and microbubble sizes. Using dynamic contrast-enhanced MRI, the transfer rates were estimated, yielding permeability maps and quantitative K trans values for a predefined region of interest. The volume of blood-brain barrier opening according to the K trans maps was proportional to both the pressure and the microbubble diameter. A K trans plateau of~0.05 min 21 was reached at higher pressures (0.45 and 0.60 MPa) for the larger sized bubbles (4-5 and 6-8 mm), which was on the same order as the K trans of the epicranial muscle (no barrier). The key to the treatment of various neurological diseases resides in the safe opening of the blood-brain barrier (BBB), a specialized structure that impedes the delivery of therapeutic agents to the parenchyma (1,2). Under normal physiological conditions, the BBB blocks molecules that are larger than 400 Da (3) from penetrating the brain parenchyma. Several techniques have been proposed over the years for the opening of the BBB. Hyperosmolar solutions, such as lactamide or mannitol, have been used clinically and experimentally (4,5) and have been found to increase the permeability of the interendothelial tight junctions. Intracranial operations with a needle have also been performed in patients allowing for a more localized BBB opening (6). More recently, focused ultrasound (FUS) in the presence of circulating microbubbles has been suggested as the only noninvasive, localized, and transient method for BBB opening A series of studies have assessed the extent of the FUS-induced BBB opening and its dependence on various acoustic parameters. With the use of MR (7,8) and fluorescence imaging (9,10), the opening has been found to have a significant ...