Local and reversible blood–brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications
Abstract
The purpose of this study was to test the hypothesis that burst ultrasound in the presence of an ultrasound contrast agent can disrupt the blood-brain barrier (BBB) with acoustic parameters suitable for completely noninvasive exposure through the skull. The 10-ms exposures were targeted in the brains of 22 rabbits with a frequency of 690 kHz, a repetition frequency of 1 Hz, and peak rarefactional pressure amplitudes up to 3.1 MPa. The total exposure (sonication) time was 20 s. Prior to each sonication, a bolus of ultrasound contrast agent was injected intravenously. Contrast-enhanced MR images were obtained after the sonications to detect localized BBB disruption via local enhancement in the brain. Brain sections were stained with H&E, TUNEL, and vanadium acid fuchsin (VAF)-toluidine blue staining. In addition, horseradish peroxidase (HRP) was injected into four rabbits prior to sonications and transmission electron microscopy was performed. The MRI contrast enhancement demonstrated BBB disruption at pressure amplitudes starting at 0.4 MPa with approximately 50%; at 0.8 MPa, 90%; and at 1.4 MPa, 100% of the sonicated locations showed enhancement. The histology findings following 4 h survival indicated that brain tissue necrosis was induced in approximately 70-80% of the sonicated locations at a pressure amplitude level of 2.3 MPa or higher. At lower pressure amplitudes, however, small areas of erythrocyte extravasation were seen. The electron microscopy findings demonstrated…
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FUS waves induce oscillation of intravenously injected microbubbles in the desired brain region, leading to transient BBB compromise by physically disrupting tight junctions between endothelial cells.
“The FUS waves induce oscillation of intravenously injected microbubbles in the desired brain region, leading to transient BBB compromise by physically disrupting tight junctions between endothelial cells [138, 139].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [139]
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- Authors
- Hynynen, K., McDannold, N., Sheikov, N. A., Jolesz, F. A., & Vykhodtseva, N.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Hynynen, Kullervo
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 24
- Issue
- 1
- Pages
- 12-20
- ISSN
- 1053-8119 (ISSN-L)
- OpenAlex
- W2021883922
- Cited by
- 679
- References
- 0
- Citations by year
- 2026: 13 · 2025: 26 · 2024: 33 · 2023: 25 · 2022: 37 · 2021: 41 · 2020: 42 · 2019: 37 · 2018: 43 · 2017: 27 · 2016: 39 · 2015: 35 · 2014: 37 · 2013: 38 · 2012: 32
- FWCI
- 14.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- NeuroImage (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R25CA089017, R01CA076550, CA76550, CA089017)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
- Keywords
- blood-brain barrier disruption, focused ultrasound, ultrasound contrast agents, erythrocyte extravasation, acoustic pressure amplitude, rabbits
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Contrast Media, Echoencephalography, Extravasation of Diagnostic and Therapeutic Materials, Magnetic Resonance Imaging, Male, Microscopy, Electron, Necrosis, Rabbits, Apoptosis, Gadolinium DTPA, In Situ Nick-End Labeling
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