Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: implementation of confocal dual-frequency piezoelectric transducers

Abstract

Burst-tone focused ultrasound exposure in the presence of microbubbles has been demonstrated to be effective at inducing temporal and local opening of the blood-brain barrier (BBB), which promises significant clinical potential to deliver therapeutic molecules into the central nervous system (CNS). Traditional contrast-enhanced imaging confirmation after focused ultrasound (FUS) exposure serves as a post-operative indicator of the effectiveness of FUS-BBB opening, however, an indicator that can concurrently report the BBB status and BBB-opening effectiveness is required to provide effective feedback to implement this treatment clinically. In this study, we demonstrate the use of subharmonic acoustic emission detection with implementation on a confocal dual-frequency piezoelectric ceramic structure to perform real-time monitoring of FUS-BBB opening. A confocal dual-frequency (0.55 MHz/1.1 MHz) focused ultrasound transducer was designed. The 1.1 MHz spherically-curved ceramic was employed to deliver FUS exposure to induce BBB-opening, whereas the outer-ring 0.55 MHz ceramic was employed to detect the subharmonic acoustic emissions originating from the target position. In stage-1 experiments, we employed spectral analysis and performed an energy spectrum density (ESD) calculation. An optimized 0.55 MHz ESD level change was shown to effectively discriminate the occurrence of BBB-opening. Wideband acoustic emissions received from 0.55 MHz ceramics were also analyzed to evaluate its correlations with erythrocyte extravasations. In stage-2 real-time monitoring experiments, we applied the predetermined ESD change as a detection threshold in PC-controlled algorithm to predict the FUS exposure intra-operatively. In stage-1 experiment, we showed that subharmonic ESD presents distinguishable dynamics between intact BBB and opened BBB, and therefore a threshold ESD change level (5.5 dB) can be identified for BBB-opening prediction. Using this ESD change threshold detection as a surrogate to on/off control the FUS exposure in stage-2 experiments, we demonstrated both excellent sensitivity (92%) and specificity (92.3%) in discriminating BBB-opening occurrence can be obtained in animal treatments, while concurrently achieving a high positive predicted value (95.8%). Wideband ESD was also highly correlated with the occurrence and level of erythrocyte extravasations (r (2) = 0.81). The proposed system configuration and corresponding analysis based on subharmonic acoustic emissions has the potential to be implemented as a real-time feedback control structure for reliable indication of intact FUS-BBB opening for CNS brain drug delivery.

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

“…These main factors can be estimated beforehand, using CT scans and simulation to estimate the acoustic attenuation (39) and MRI or other imaging methods to estimate the vascular density. It may also be possible to use the onset of subharmonic or ultraharmonic emissions observed when the exposure level is increased as a means to estimate (27,30). This onset may represent a distinct threshold that depends predominately on the microbubble properties.…”

“…The strengths of the subharmonics or ultraharmonics can also be used as measures of stable cavitation behavior and have been previously reported to be associated with BBBD outcomes (27,30). Microbubbles in acoustic field typically experience linear to relatively stronger nonlinear oscillation before breaking up.…”

“…McDannold et al (24) proposed the potential of using microbubble emissions to control the BBBD, based on a correlation found between the strength of second/ third harmonic components and MRI contrast enhancement post BBBD. This potential has been further suggested by several BBBD works with cavitation monitoring (21,(25)(26)(27) and other microbubble-mediated therapies (28,29). O'Reilly and Hynynen (30) designed an active controller that increases the acoustic pressure until ultraharmonic emission is detected and then reduces it by a predetermined amount.…”

Characterizing Focused-Ultrasound Mediated Drug Delivery to the Heterogeneous Primate Brain In Vivo with Acoustic Monitoring

“…Since its initial use during BBB opening in small animals19, PCD has been expanded to various types of contrast agents such as microbubbles of various sizes25, various shells26, and nanodroplets27 reporting a positive correlation between BBB opening and cavitation dose. A feedback control mechanism for BBB opening based on ultraharmonics and subharmonics was established in small animals2829. The permeability and reversibility of BBB opening could also be predicted based on cavitation in mice30.…”

Highly Sensitive Piezoelectric Response of Sodium Nitrite Nano-crystals to Low Applied Mechanical Pressures

“…Detection of ultra-low mechanical pressure changes in the range of few Pascal in an atmospheric environment is of high a technological interest in various applications such as a remote infants breathing monitoring [1], a leakage alert of hazardous gases [2], a mechanical stability control of intelligent systems [1] and acoustic propagation disturbances [3]. A substantial progress in detection of low mechanical pressure changes has been achieved during the last decade through various methods [1].…”