Testing Different Combinations of Acoustic Pressure and Doses of Quinolinic Acid for Induction of Focal Neuron Loss in Mice Using Transcranial Low-Intensity Focused Ultrasound.
Authors: Zhang Y, Liao C, Qu H, Huang S, Jiang H, Zhou H, Abrams E, Habte FG, Yuan L, Bertram EH, Lee KS, Pauly KB, Buckmaster PS, Wintermark M
The goal of this study was to test different combinations of acoustic pressure and doses of quinolinic acid (QA) for producing a focal neuronal lesion in the murine hippocampus without causing unwanted damage to adjacent brain structures. Sixty male CD-1 mice were divided into 12 groups that underwent magnetic resonance-guided focused ultrasound at high (0.67 MPa), medium (0.5 MPa) and low (0.33 MPa) acoustic peak negative pressures and received QA at high (0.012 mmol), medium (0.006 mmol) and low (0.003 mmol) dosages. Neuronal loss occurred only when magnetic resonance-guided focused ultrasound with adequate acoustic power (0.67 or 0.5 MPa) was combined with QA. The animals subjected to the highest acoustic power had larger lesions than those treated with medium acoustic power, but two mice had evidence of bleeding. When the intermediate acoustic power was used, medium and high dosages of QA produced lesions larger than those produced by the low dosage.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To determine which combinations of MR-guided focused ultrasound acoustic pressure and quinolinic acid dose produce a focal neuronal lesion in the murine hippocampus without damaging adjacent brain structures.
Animal model / Human subject
Mouse (Mus musculus), CD-1 strain, age None, male
MRI or image guidance method
MR-guided (MRgFUS)
Targeted brain region(s)
Hippocampus
Cargo name and characteristics
Quinolinic acid (QA), a small-molecule excitotoxin; administered at low (0.003 mmol), medium (0.006 mmol), and high (0.012 mmol) doses to produce focal neuronal lesions
Outcomes and Safety
Summary of Outcomes
Neuronal loss occurred only when MRgFUS at medium (0.5 MPa) or high (0.67 MPa) acoustic peak negative pressure was combined with quinolinic acid; the highest pressure (0.67 MPa) produced larger lesions but caused bleeding in 2 mice. At 0.5 MPa, medium (0.006 mmol) and high (0.012 mmol) QA doses produced larger lesions than the low QA dose (0.003 mmol); low pressure (0.33 MPa) was ineffective.
Safety-related matter
The study aimed to avoid damage to adjacent brain structures; neuronal loss occurred only when MRgFUS was combined with QA and lesion size increased with higher acoustic power and QA dose. At the highest acoustic power (0.67 MPa), two mice showed evidence of bleeding.
Brain Region
Ultrasound Parameters
FUS Pressure
0.67 MPa, 0.5 MPa, 0.33 MPa
Focal Characteristics
Focal depth: None; Focal length: None; Aperture size: None
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