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Behavioral alterations following blood-brain barrier disruption stimulated by focused ultrasound.

Authors: Yang FY, Huang SF, Cheng IH

The purpose of this study was to investigate the behavioral alterations and histological changes of the brain after FUS-induced BBB disruption (BBBD). Rats were behaviorally tested using the open field, hole-board, and grip strength tests from day 1 through day 32 after undergoing BBBD induced by FUS with either a mild or heavy parameter. In the open field test, we found an increase in center entries on day 1 and day 9 following heavy FUS treatment and a decrease in center entries at day 18 following mild FUS treatment. With regard to memory-related alterations, rats subjected to heavy FUS treatment exhibited longer latency to start exploring and to find the first baited hole. However, rats subjected to mild FUS treatment exhibited no significant differences in terms of memory performance or grip force. The obtained data suggest that heavy FUS treatment might induce hyperactivity, spatial memory impairment, and forelimb gripping deficits. Furthermore, while mild FUS treatment may have an impact on anxiety-related behaviors, the data suggested it had no impact on locomotor activity, memory, or grip force. Thus, the behavioral alterations following FUS-induced BBBD require further investigation before clinical application.

Introduction

Purpose Drug delivery with BBB opening
Study Objective To investigate behavioral alterations and brain histological changes following focused ultrasound-induced blood-brain barrier disruption in rats.
Animal model / Human subject Sprague-Dawley rats (sex: male)
Disease model healthy
MRI or image guidance method stereotaxic apparatus (Stoelting, Wood Dale, IL, USA)
Targeted brain region(s) Nr
Target coordinates 3.5 mm posteriod and 2.5 mm lateral to the bregma, 5.7 mm below the surface of the skull
Cargo name and characteristics ultrasound contrast agent
Route of administration intravenous (femoral vein)

Outcomes and Safety

Summary of Outcomes Heavy FUS-induced BBB disruption produced hyperactivity and habituation deficits, spatial memory impairment, reduced forelimb grip strength, and increased hippocampal/cortical apoptosis and hemorrhage; mild FUS produced only transient anxiety-related behavior with minimal effects on locomotion, memory, or grip.
Duration of biological effect 32 days
Safety-related matter Heavy FUS-induced BBBD produced adverse behavioral and histological effects including hyperactivity, habituation deficit, impaired spatial memory, reduced forelimb grip strength, increased hippocampal/cortical apoptosis and acute red blood cell extravasation (hemorrhage), although BBB integrity appeared re-established by 24 h; mild FUS produced anxiety-like behavior, transient TUNEL-positive cells on day 1 and a body-weight decrease by day 32 but showed no significant deficits in locomotor activity, memory or grip force.

Brain Region

Ultrasound Parameters

Ultrasound instrument single-element focused transducer (A392S, Panametrics, Waltham, MA, USA)
FUS Frequency 1 MHz
FUS Pressure 1.2, 0.7
FUS Mode pulsed
Pulse duration 50 ms
Duration of a single FUS session NR
Focal Characteristics diameter: 38 mm, radius of curvature: 63.5 mm
Treatment frequency single

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