Contrast-enhanced ultrasound imaging for the detection of focused ultrasound-induced blood-brain barrier opening.

Authors: Fan CH, Lin WH, Ting CY, Chai WY, Yen TC, Liu HL, Yeh CK

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.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To evaluate whether microbubble destruction-replenishment ultrasound perfusion kinetics can be used to monitor and quantify focused ultrasound-induced blood-brain barrier opening.

Outcomes and Safety

Summary of Outcomes Focused ultrasound (FUS) with microbubbles transiently opened the blood–brain barrier, producing local vasoconstriction and reduced perfusion that were detectable and quantifiable by ultrasound microbubble destruction–replenishment perfusion kinetics (rate constant α) and correlated well with DCE‑MRI. Successful FUS conditions included 2 MHz sonication at ~0.5 MPa (burst length 2000 cycles, PRF 1 Hz, 60 s) for localized BBB opening and 0.7 MPa for a stronger opening (occasionally causing RBC extravasation); MB‑destruction imaging used 0.6 MPa (10 cycles, PRF 4000 Hz, 0.5 s), with in vitro MB destruction observed from ~0.5–1.6 MPa.

Duration of biological effect 120 s

Safety-related matter MB-destroying pulses (0.6 MPa) did not alter BBB integrity and 0.5 MPa FUS opened the BBB without gross pathological changes, but 0.7 MPa exposures produced more pronounced BBB opening and occasionally induced scattered red blood cell extravasations; transient vasoconstriction and temporary reductions in local perfusion were also observed.

Brain Region

Visualization unavailable

Ultrasound Parameters

FUS Frequency 2 MHz

FUS Pressure 0.5-0.7 MPa

FUS Mode pulsed

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

Treatment frequency Single session

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