Ultrasound guided blood brain barrier opening using a diagnostic probe in a whole brain model

The blood-brain barrier (BBB) poses a significant challenge to drug delivery to the brain. A promising approach involves low-frequency, low-intensity pulsed ultrasound (US) waves combined with intravenously injected microbubbles (MB) to temporarily and non-invasively open the BBB. However, current technologies cannot easily integrate this procedure with US imaging. Passive cavitation detection, tracing the harmonic emissions of MB during sonication, has been the preferred method for real-time monitoring of US-mediated BBB opening. We used an ultrasound advanced open platform (ULA-OP) to simultaneously perform US-mediated BBB opening and US imaging with a single linear-array probe. In vitro guinea pig brains were perfused with MB and sonicated with different plane-wave transmission patterns. The most effective US pattern was interleaved with B-mode imaging pulses, enabling the direct assessment of the MB distribution during treatment. The extent of BBB permeabilization was assessed by quantifying FITC-albumin extravasation into the brain via confocal microscopy. US-treated hemispheres displayed BBB permeabilization, while control hemispheres did not. B-mode imaging allowed direct evaluation of MB distribution and interaction with the US beam. Therefore, we achieved effective BBB opening and simultaneous MB imaging using the same diagnostic probe, paving the way for US-guided therapeutic ultrasound application in the clinical context.