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

Abstract

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 compared to exposure without pulse inversion, enabling enhanced passive mapping of microbubble activity. Both therapeutic schemes resulted in similar free-field microbubble activation and efficient blood-brain barrier opening .

A Clinical System for Non-invasive Blood–Brain Barrier Opening Using a Neuronavigation-Guided Single-Element Focused Ultrasound Transducer

“…). Furthermore, we plan to use pulse inversion in the short therapeutic pulses, to be able to detect weak cavitation emissions through the thick human skull (Pouliopoulos et al 2018). Future efforts will finally focus on using short pulses and PAM in closedloop (Sun et al 2017;Jones et al 2018;Kamimura et al 2018;Patel et al 2019) to improve the spatiotemporal control of acoustic cavitation activity within the brain.…”

Advances in acoustic monitoring and control of focused ultrasound-mediated increases in blood-brain barrier permeability

“…Passive beamforming methods typically form images based on correlations between the signals received on different elements of the array 125,128 without using absolute time-of-flight information (n.b. synchronized passive acoustic imaging has been achieved in vitro 101 and in vivo 73,76 using absolute time-of-flight information, and has been shown to improve the axial resolution of one-dimensional (1D) arrays when short excitation bursts are used), whereas traditional line-by-line active imaging exploits absolute time-of-flight to encode image depth. As a result, the spatial resolution obtained via conventional delay, sum, and integrate passive beamforming algorithms (e.g.…”

“…One approach to utilizing passive beamforming methods in the brain is to image through acoustic windows (e.g. temporal or suboccipital windows) using a narrow-aperture array, such as a 1D linear diagnostic probe 69,73,75,76,78 (Figure 1b). With this configuration, the local variations in skull morphology over the region of acoustic signal collection are small, and transcranial passive acoustic imaging can be achieved at sufficiently low frequencies without the need for element-specific aberration corrections on receive.…”

“…The acoustic signals detected during FUS exposures with microbubbles for increased BBB permeability have been identified as potential indicators of treatment outcome 41,42,61,62 and have since been investigated for online monitoring and control of the procedures. [63][64][65][66][67][68] Multielement detector arrays can provide spatial information regarding microbubble activity in the brain [69][70][71][72][73][74][75][76] that can be exploited for acoustic exposure level calibration, 74 and element-specific aberration corrections can be incorporated into the reconstruction process to improve image quality in transcranial scenarios. [70][71][72][77][78][79] This review gives a basic overview of the oscillation dynamics, acoustic emissions, and biological effects associated with ultrasound-stimulated microbubbles in vivo, and provides a summary of recent advances in acoustic-based strategies for detecting, controlling, and mapping microbubble activity in the brain during transcranial FUS procedures.…”

Dual apodization with cross‐correlation combined with robust Capon beamformer applied to ultrasound passive cavitation mapping

“…The former makes the image resolution independent of the cavitation emission duration . The resolution of the latter is determined by the received emission duration as with B‐mode ultrasound imaging, so it is not suitable for ultrasound therapies that require long pulses . The most common PAM algorithm utilizing the relative time delays is time exposure acoustics (TEA) or its frequency‐domain variant, which can provide a fine resolution for hemispherical‐array PAM but a poor axial resolution for a linear array or a phased array because its diffraction pattern is limited .…”