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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