Reversible blood-brain barrier disruption by repeated transcranial focused ultrasound allows enhanced extravasation

The permeability of blood-brain barrier (BBB) for albumin can be enhanced by focused ultrasound (FUS) in a targeted region when this is applied in the presence of ultrasound contrast agent (UCA). In this study, we demonstrate that, using this noninvasive treatment, Evans Blue (EB) extravasation can be enhanced by repeated sonication. Sonications were applied at an ultrasound frequency of 1 MHz with a 5% duty cycle, and a repetition frequency of 1 Hz. The brains of male Sprague-Dawley rats were subjected to FUS exposure at the same targeted site. At the same acoustic power, the extravasation caused by leakage of EB into the brain was found to be dependent on the applied sonication time. In vivo, both single and repeated sonications increased the extravasation of the albumin binding EB, especially for the repeated sonication group. In the retreatment experiment, there was a nearly twofold increase in EB extravasation in groups with a second sonication compared with the single sonication group. BBB disruption can be prolonged by repeated FUS sonication and the duration is dependent on the time point of the resonication after the first sonication. Compared to a single sonication, the MR imaging analysis and histological examination of the affected brains indicated that the pattern of contrast enhancement was changed and that vacuolation occurred after repeated sonication. This noninvasive technology offers the possibility of controlling the extent of drug delivery by means of repeated treatment and adjusting the duration and interval between sonications.