Dynamic perfusion assessment by contrast-enhanced ultrasound in blood-brain barrier disruption.

Authors: Lin WH, Fan CH, Ting CY, Liu HL, Yeh CK

Recently, blood-brain barrier disruption (BBBD) has been performed by focused ultrasound (FUS) combining with microbubbles (MBs). The outcome of BBBD enhances local drug or gene delivery for improving the treatment efficiency of brain diseases. However, over-excitation of FUS may cause brain damage such as shutdown blood flow, intracerebral hemorrhage and brain edema. Therefore, it is essential to develop a an imaging system to assess dynamic perfusion changes during FUS-induced BBBD process. Here, we used the high-frequency destruction/reperfusion contrast-enhanced imaging technique to observe the cerebral perfusion under the cases of with/without hemorrhage in BBBD procedure. The BBB was disrupted by a 2.25 MHz FUS combining with MBs at 0.5-0.7 MPa (pulse repetition frequency: 1 Hz, pulse length: 1 ms, sonication time: 60 s). The results showed that the velocity of blood flow decreased after BBBD induced by FUS sonication. Particularly, the plateau of time-intensity curve was higher than prior to MBs destruction at 20 s after sonication and the blood flow would be obstructed due to the blood coagulates at 60s after sonication. The pattern of hemorrhagic damage caused by FUS can be monitored by the TIC. In addition, the location of blood flow velocity decrease was consistent with the areas of BBBD and the variation of blood flow depends on the applied acoustic pressure. In conclusion, the blood flow velocity changes have potential as an in vivo tool for quantifying the extent of the FUS-induced BBBD and detecting intracerebral hemorrhage occurrence.

Introduction

Purpose drug delivery with BBB opening

Study Objective Develop a contrast-enhanced ultrasound method using destruction/reperfusion technique to assess dynamic cerebral perfusion changes during focused ultrasound-induced blood-brain barrier disruption and detect hemorrhagic damage

Animal model / Human subject Sprague-Dawley rat, male, 300-350 g

Disease model healthy

MRI or image guidance method Other: ultrasound B-mode imaging (40 MHz transducer for guidance)

Targeted brain region(s) Cortex (Craniotomy Window, Hemisphere)

Route of administration intravenous (jugular vein

Outcomes and Safety

Summary of Outcomes FUS+MB (2.25 MHz, 0.5-0.7 MPa, 1 ms pulse, 1 Hz PRF, 60 s) induced BBBD and decreased blood flow velocity. At 0.7 MPa (hemorrhagic), time-intensity curve plateau increased at 20 s post-FUS and became noisy at 60 s due to blood coagulation. Flow velocity decrease maps matched EB staining area, suggesting potential for real-time hemorrhage detection.

Safety-related matter 0.7 MPa caused hemorrhagic damage, blood flow obstruction, and coagulation. 0.5 MPa induced BBBD without hemorrhage.

Brain Region

Ultrasound Parameters

Ultrasound instrument in-house dual-transducer system: 2.25 MHz spherical-focused annulus (V3966, Panametrics; diameter 28 mm, focal length 26.16 mm) for BBBD + 40 MHz piston transducer for imaging

FUS Frequency 2.25MHz

FUS Pressure 0.5 MPa (safe BBBD) or 0.7 MPa (hemorrhagic damage)

FUS Mode pulsed

Pulse duration 1ms

Duration of a single FUS session 60s

Focal Characteristics Outer transducer: a spherical-focused annulus with a central frequency of 2.25 MHz (model V3966, Panameterics, OLYMPUS; diameter = 28 mm, focal length = 26.16 mm)

Treatment frequency single session

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