Abstract

Ultrasound-induced blood-brain barrier (BBB) opening using microbubbles is a promising technique for local delivery of therapeutic molecules into the brain. The real-time control of the ultrasound dose delivered through the skull is necessary as the range of pressure for efficient and safe BBB opening is very narrow. Passive cavitation detection (PCD) is a method proposed to monitor the microbubble activity during ultrasound exposure. However, there is still no consensus on a reliable safety indicator able to predict potential damage in the brain. Current approaches for the control of the beam intensity based on PCD employ a full-pulse analysis and may suffer from a lack of sensitivity and poor reaction time. To overcome these limitations, we propose an intra-pulse analysis to monitor the evolution of the frequency content during ultrasound bursts. We hypothesized that the destabilization of microbubbles exposed to a critical level of ultrasound would result in the instantaneous generation of subharmonic and ultra-harmonic components. This specific signature was exploited to define a new sensitive indicator of the safety of the ultrasound protocol. The approach was validated in vivo in rats and non-human primates using a retrospective analysis. Our results demonstrate that intra-pulse monitoring was able to exhibit a sudden appearance of ultra-harmonics during the ultrasound excitation pulse. The repeated detection of such a signature within the excitation pulse was highly correlated with the occurrence of side effects such as hemorrhage and edema. Keeping the acoustic pressure at levels where no such sign of microbubble destabilization occurred resulted in safe BBB openings, as shown by MR images and gross pathology. This new indicator should be more sensitive than conventional full-pulse analysis and can be used to distinguish between potentially harmful and safe ultrasound conditions in the brain with very short reaction time.

Highlights

  • Ultrasound-induced blood-brain barrier (BBB) opening using microbubbles is a promising technique for local delivery of therapeutic molecules into the brain

  • The peak amplitude increased by 15 dB, 14 dB, and 10 dB for the 1st (1.5 f0), the 2nd (2.5 f0), and the 3rd (3.5 f0) ultra-harmonic components, respectively

  • The presence of an initial low-amplitude peak at 1.5 f0 slightly masked the ultra-harmonic increase at this frequency, suggesting that this detection method would be more sensitive by including the 2nd and the 3rd ultra-harmonic components

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Summary

Introduction

Ultrasound-induced blood-brain barrier (BBB) opening using microbubbles is a promising technique for local delivery of therapeutic molecules into the brain. Keeping the acoustic pressure at levels where no such sign of microbubble destabilization occurred resulted in safe BBB openings, as shown by MR images and gross pathology This new indicator should be more sensitive than conventional full-pulse analysis and can be used to distinguish between potentially harmful and safe ultrasound conditions in the brain with very short reaction time. The occurrence of subharmonic and ultra-harmonic frequencies is typically interpreted as a threshold for inertial cavitation that is associated with a risky oscillation regime of microbubbles[9] These unique acoustic signatures provide monitoring information about microbubble activity through passive cavitation detection (PCD)[6,10,11]. The results indicated successful BBB-disruption using different contrast agents, no safety study assessed potential damage to surrounding tissues

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