Ultrasound flow imaging for assessing cerebrovascular changes following focused-ultrasound blood-brain barrier opening.

Abstract

Rationale: Microbubble-mediated focused ultrasound (Mb-FUS) is a promising non-invasive technique for blood-brain barrier opening (BBBO), enhancing drug delivery and immunomodulation for brain disease treatments. In Mb-FUS, microbubble cavitation exerts mechanical stress on blood vessel walls. While cavitation is commonly used for monitoring, leveraging the vascular response to predict treatment outcomes remains unexplored. This study pioneers the use of ultrasound flow imaging with microbubbles to investigate the cerebrovascular changes induced by Mb-FUS and assesses the feasibility of this imaging technique for predicting BBBO treatment outcomes. Methods: We utilized contrast-enhanced power Doppler (CEPD) and ultrasound localization microscopy (ULM) to monitor and quantify Mb-FUS-induced cerebrovascular changes in mice (n=4 without skull, n=12 with skull). The left hippocampus/thalamus regions were targeted for Mb-FUS BBBO. Pre- and post-FUS images were acquired, with continuous monitoring of CEPD intensity to ensure consistency in microbubble concentration. We observed changes in the number of microbubbles detected, their speeds, and vessel diameter after Mb-FUS. Results: Reductions in blood volume, vessel diameter, and flow speed were observed in the sonicated regions. We demonstrated the transcranial capability of CEPD and ULM to detect Mb-FUS-induced vascular changes by observing linear relationships between the reductions in blood volume and flow, and the size of the opening or edema. Furthermore, local signal reduction detected by transcranial CEPD map spatially co-localized with the edema region identified in T2-weighted MRI. Conclusion: We have developed a method to quantify changes in blood volume, flow speed, and vessel diameter following Mb-FUS using ultrasound flow imaging (CEPD and ULM) with microbubbles. For the first time, the blood vessels post-FUS were assessed by ultrasound flow imaging that visualizes associated vascular changes and potential damage. This technique not only holds potential for predicting treatment outcomes but also paves the way for a unified ultrasound-based system for both treatment and monitoring, with potential for future clinical translation.