A new safety index based on intrapulse monitoring of ultra-harmonic cavitation during ultrasound-induced blood-brain barrier opening procedures

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 nonhuman 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.

Recent Advances on Ultrasound Contrast Agents for Blood-Brain Barrier Opening with Focused Ultrasound

“…Additionally, FUS combined with microbubbles can achieve therapeutic results alone: it can induce, for example, neurogenesis [ 16 ] or reduce the amyloid load in Alzheimer’s disease [ 17 ]. The approach is usually combined with magnetic resonance imaging (MRI), which enables the treatment guidance, the evaluation of BBB disruption using MR contrast agents, and the monitoring of potential damages during the procedure [ 3 , 18 , 19 , 20 , 21 , 22 ].…”

“…Those two different regimens are respectively called stable and inertial cavitation. Inertial cavitation can induce microbubble collapse accompanied by micro-jetting, fragmentation, and shock-wave formation, which may induce vascular endothelium damages [ 20 , 22 , 24 , 25 ]. On the other hand, the mechanical stress generated by the stable cavitation can locally and reversibly disrupt the tight junctions present in the vascular endothelial tissue, which increases the BBB permeability [ 26 ].…”

Effect of Gambogic Acid–Loaded Porous-Lipid/PLGA Microbubbles in Combination With Ultrasound-Triggered Microbubble Destruction on Human Glioma

“…In addition, passive cavitation detection (PCD) is a method proposed to monitor the microbubble activity during US exposure ( Sun et al, 2015 ; Novell et al, 2020 ), which is frequently now used in clinical trials ( Pouliopoulos et al, 2020 ). In the next step, we plan to detect the GA/PLGA microbubbles activity in vivo by using PCD.…”

Evaluation of capacitive micromachined ultrasonic transducers for passive monitoring of microbubble-assisted ultrasound therapies

“…8,9 Very recently, a new indicator based on the intra-pulse detection of ultra-harmonic events was introduced to discriminate between potentially dangerous and safe ultrasound-induced BBB opening conditions. 14 This intra-pulse monitoring made it possible to observe microbubble destabilization related to the occurrence of unwanted side effects. However, for application in the human brain, PCD transducers are hindered by a lack of sensitivity due to (i) the restricted bandwidth of standard piezoelectric transducers, making it difficult to recover a wide frequency content; and (ii) the attenuation induced by the skull that reduces the signal amplitude (low-pass filter).…”