title: Controlled ultrasound-induced blood-brain barrier disruption using passive acoustic emissions monitoring.
abstract: The ability of ultrasonically-induced oscillations of circulating microbubbles to permeabilize vascular barriers such as the blood-brain barrier (BBB) holds great promise for noninvasive targeted drug delivery. A major issue has been a lack of control over the procedure to ensure both safe and effective treatment. Here, we evaluated the use of passively-recorded acoustic emissions as a means to achieve this control. An acoustic emissions monitoring system was constructed and integrated into a clinical transcranial MRI-guided focused ultrasound system. Recordings were analyzed using a spectroscopic method that isolates the acoustic emissions caused by the microbubbles during sonication. This analysis characterized and quantified harmonic oscillations that occur when the BBB is disrupted, and broadband emissions that occur when tissue damage occurs. After validating the system's performance in pilot studies that explored a wide range of exposure levels, the measurements were used to control the ultrasound exposure level during transcranial sonications at 104 volumes over 22 weekly sessions in four macaques. We found that increasing the exposure level until a large harmonic emissions signal was observed was an effective means to ensure BBB disruption without broadband emissions. We had a success rate of 96% in inducing BBB disruption as measured by in contrast-enhanced MRI, and we detected broadband emissions in less than 0.2% of the applied bursts. The magnitude of the harmonic emissions signals was significantly (P<0.001) larger for sonications where BBB disruption was detected, and it correlated with BBB permeabilization as indicated by the magnitude of the MRI signal enhancement after MRI contrast administration (R(2) = 0.78). Overall, the results indicate that harmonic emissions can be a used to control focused ultrasound-induced BBB disruption. These results are promising for clinical translation of this technology.
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. cda@bwh.harvard.edu
authors.forename: Costas D
authors.initials: CD
authors.lastname: Arvanitis
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Livingstone
authors.forename: Natalia
authors.initials: N
authors.lastname: Vykhodtseva
authors.forename: Nathan
authors.initials: N
authors.lastname: McDannold
mesh_terms: D000162:Acoustics; D000465:Algorithms; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000528:radiation effects; D002199:Capillary Permeability / Q000528:radiation effects*; D003287:Contrast Media / Q000493:pharmacokinetics; D005260:Female; D019786:Gadolinium DTPA / Q000493:pharmacokinetics; D005829:Geniculate Bodies / Q000098:blood supply / Q000528:radiation effects; D006179:Gyrus Cinguli / Q000098:blood supply / Q000528:radiation effects; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D045423:Microbubbles; D013010:Sonication / Q000379:methods*; D013016:Sound
chemical_list: D003287:Contrast Media; D019786:Gadolinium DTPA