title: Contrast-enhanced ultrasound imaging for the detection of focused ultrasound-induced blood-brain barrier opening.
abstract: The blood-brain barrier (BBB) can be transiently and locally opened by focused ultrasound (FUS) in the presence of microbubbles (MBs). Various imaging modalities and contrast agents have been used to monitor this process. Unfortunately, direct ultrasound imaging of BBB opening with MBs as contrast agent is not feasible, due to the inability of MBs to penetrate brain parenchyma. However, FUS-induced BBB opening is accompanied by changes in blood flow and perfusion, suggesting the possibility of perfusion-based ultrasound imaging. Here we evaluated the use of MB destruction-replenishment, which was originally developed for analysis of ultrasound perfusion kinetics, for verifying and quantifying FUS-induced BBB opening. MBs were intravenously injected and the BBB was disrupted by 2 MHz FUS with burst-tone exposure at 0.5-0.7 MPa. A perfusion kinetic map was estimated by MB destruction-replenishment time-intensity curve analysis. Our results showed that the scale and distribution of FUS-induced BBB opening could be determined at high resolution by ultrasound perfusion kinetic analysis. The accuracy and sensitivity of this approach was validated by dynamic contrast-enhanced MRI. Our successful demonstration of ultrasound imaging to monitor FUS-induced BBB opening provides a new approach to assess FUS-dependent brain drug delivery, with the benefit of high temporal resolution and convenient integration with the FUS device.
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu, Taiwan 30013;
authors.forename: Ching-Hsiang
authors.initials: CH
authors.lastname: Fan
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu, Taiwan 30013;
authors.forename: Wun-Hao
authors.initials: WH
authors.lastname: Lin
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu, Taiwan 30013;
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Ting
authors.affiliation: 2. Department of Electrical Engineering, Chang-Gung University, 259 Wen-Hwa 1st Road, Kuei-Shan, Tao-Yuan, Taiwan 33302;
authors.forename: Wen-Yen
authors.initials: WY
authors.lastname: Chai
authors.affiliation: 3. Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung University and Memorial Hospital, No. 5, Fu-Shing Road, Kuei-Shan, Tao-Yuan, Taiwan 33305.
authors.forename: Tzu-Chen
authors.initials: TC
authors.lastname: Yen
authors.affiliation: 2. Department of Electrical Engineering, Chang-Gung University, 259 Wen-Hwa 1st Road, Kuei-Shan, Tao-Yuan, Taiwan 33302;
authors.forename: Hao-Li
authors.initials: HL
authors.lastname: Liu
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu, Taiwan 30013;
authors.forename: Chih-Kuang
authors.initials: CK
authors.lastname: Yeh
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000528:radiation effects; D002199:Capillary Permeability; D003287:Contrast Media / Q000493:pharmacokinetics; D019786:Gadolinium DTPA / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D008297:Male; D045423:Microbubbles; D019047:Phantoms, Imaging; D017207:Rats, Sprague-Dawley; D013010:Sonication; D014463:Ultrasonography
chemical_list: D003287:Contrast Media; D019786:Gadolinium DTPA
keywords: blood-brain barrier; destruction- replenishment; dynamic contrast-enhanced MRI.; focused ultrasound; microbubbles