Pulse inversion enhances the passive mapping of microbubble-based ultrasound therapy

Therapeutic ultrasound combined with preformed circulating microbubbles has enabled non-invasive and targeted drug delivery into the brain, tumors, and blood clots. Monitoring the microbubble activity is essential for the success of such therapies; however, skull and tissues limit our ability to detect low acoustic signals. Here, we show that by emitting consecutive therapeutic pulses of inverse polarity, the sensitivity in the detection of weak bubble acoustic signals during blood-brain barrier opening is enhanced compared to therapeutic pulses of the same polarity. Synchronous passive mapping of the cavitation activity was conducted using delay-and-sum beamforming with absolute time delays, which offers superior spatial resolution compared to the existing asynchronous passive imaging techniques. Sonication with pulse inversion allowed filter-free suppression of the tissue signals by up to 8 dB in a tissue-mimicking phantom and by 7 dB in vivo, compared to exposure without pulse inversion, enabling enhanced passive mapping of microbubble activity. Both therapeutic schemes resulted in similar free-field microbubble activation in vitro and efficient blood-brain barrier opening in vivo.