Focused Ultrasound-Induced Blood-Brain Barrier Opening: Association with Mechanical Index and Cavitation Index Analyzed by Dynamic Contrast-Enhanced Magnetic-Resonance Imaging.

Po-Chun Chu,Chih-Kuang Yeh,Wen-Yen Chai,Chih-Hung Tsai,Hao-Li Liu,Shih-Tsung Kang

doi:10.1038/srep33264

Po-Chun Chu, Chih-Kuang Yeh + Show 4 more

Open Access

https://doi.org/10.1038/srep33264

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Abstract

Focused ultrasound (FUS) with microbubbles can temporally open the blood-brain barrier (BBB), and the cavitation activities of microbubbles play a key role in the BBB-opening process. Previous attempts used contrast-enhanced magnetic resonance imaging (CE-MRI) to correlate the mechanical index (MI) with the scale of BBB-opening, but MI only partially gauged acoustic activities, and CE-MRI did not fully explore correlations of pharmacodynamic/pharmacokinetic behaviors. Recently, the cavitation index (CI) has been derived to serve as an indicator of microbubble-ultrasound stable cavitation, and may also serve as a valid indicator to gauge the level of FUS-induced BBB opening. This study investigates the feasibility of gauging FUS-induced BBB opened level via the two indexes, MI and CI, through dynamic contrast-enhanced (DCE)-MRI analysis as well as passive cavitation detection (PCD) analysis. Pharmacodynamic/pharmacokinetic parameters derived from DCE-MRI were characterized to identify the scale of FUS-induced BBB opening. Our results demonstrated that DCE-MRI can successfully access pharmacodynamic/pharmacokinetic BBB-opened behavior, and was highly correlated both with MI and CI, implying the feasibility in using these two indices to gauge the scale of FUS-induced BBB opening. The proposed finding may facilitate the design toward using focused ultrasound as a safe and reliable noninvasive CNS drug delivery.

Highlights

Focused ultrasound (FUS) with microbubbles can temporally open the blood-brain barrier (BBB), and the cavitation activities of microbubbles play a key role in the BBB-opening process
This study uses dynamic contrast-enhanced (DCE)-MRI analysis to investigate the association of the two important indexes, mechanical index (MI) and cavitation index (CI), and evaluates their effectiveness for gauging FUS-induced BBB opening
While microbubbles play a significant role in the process of FUS-induced BBB opening, the level of inertial cavitation and stable cavitation involved in the microbubble-ultrasound interaction must be evaluated to guarantee BBB-opening level and quality

Summary

Introduction

Focused ultrasound (FUS) with microbubbles can temporally open the blood-brain barrier (BBB), and the cavitation activities of microbubbles play a key role in the BBB-opening process. Low-intensity burst-type focused ultrasound (FUS) combined with microbubbles administration has recently been shown to open the BBB in a non-invasive, localized, and transient manner[4,5], raising new possibilities for delivering therapeutic agents directly into the brain. Before these developments can be translated into clinical applications, indexes must be developed to gauge the likelihood of the FUS-induced BBB opening, so that CNS therapeutic molecule delivery can be well gauged and estimated. Passive cavitation dose (PCD) analysis is used to detect and characterize backscattered acoustic emissions to reflect microbubble activities that accompany FUS-induced BBB opening, and a growing number of recent studies suggest that the occurrence of FUS-induced BBB opening relates to inertial cavitation but more likely is caused by stable cavitation[14,17,18,19]

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