Permeability and reversibility timeline study of the focused-ultrasound induced blood-brain barrier opening at distinct pressures and microbubble sizes in vivo

Most currently available therapeutic compounds cannot cross the blood-brain barrier (BBB), and their delivery to the brain remains a critical impediment. Focused Ultrasound (FUS) in conjunction with systemically administered microbubbles has been shown to open the BBB locally, non-invasively and reversibly. The objective of this study was to assess the permeability changes and the reversibility timeline of the FUS-induced BBB opening using different acoustic pressures, varying from 0.30 MPa to 0.60 MPa, and monodispersed microbubbles of different diameters, 1-2, 4-5 or 6-8 μm. Using Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI), the transfer rates were estimated, yielding permeability maps and quantitative K_trans values for a predefined region of interest. Permeability and volume of opening were both found to increase with acoustic pressure and microbubble diameter. A K_trans plateau of approximately 0.05 min^-1 was reached at higher pressures (0.45 and 0.60 MPa) for the larger-sized bubbles (4-5 and 6-8 μm), which was on the same order as the K_trans of the epicranial muscle (no barrier). The duration required for closing was found to be proportional to the volume of opening on the day of opening, and ranged from 24 hours, for the 1-2 μm and 0.45 MPa, to 5 days for the 6-8 μm and higher pressures. Overall, larger bubbles did not show significant differences, and the BBB-opened region reduced steadily and radially towards the focal region until complete reinstatement was achieved.