title: Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller.
abstract: OBJECTIVE
  To determine if focused ultrasound disruption of the blood-brain barrier (BBB) can be safely controlled by using real-time modulation of treatment pressures on the basis of acoustic emissions from the exposed microbubbles.
  
  
  METHODS
  All experiments were performed with the approval of the institutional animal care committee. Transcranial focused ultrasound (551.5 kHz, 10-msec bursts, 2-Hz pulse repetition frequency, 2 minute sonication) in conjunction with circulating microbubbles was applied in 86 locations in 27 rats to disrupt the BBB. Acoustic emissions captured during each burst by using a wideband polyvinylidene fluoride hydrophone were analyzed for spectral content and used to adjust treatment pressures. Pressures were increased incrementally after each burst until ultraharmonic emissions were detected, at which point the pressure was reduced to a percentage of the pressure required to induce the ultraharmonics and was maintained for the remainder of the sonication. Disruption was evaluated at contrast material-enhanced T1-weighted magnetic resonance (MR) imaging. Mean enhancement was calculated by averaging the signal intensity at the focus over a 3 × 3-pixel region of interest and comparing it with that in nonsonicated tissue. Histologic analysis was performed to determine the extent of damage to the tissue. Statistical analysis was performed by using Student t tests.
  
  
  RESULTS
  For sonications resulting in BBB disruption, the mean peak pressure was 0.28 MPa ± 0.05 (standard deviation) (range, 0.18-0.40 MPa). By using the control algorithm, a linear relationship was found between the scaling level and the mean enhancement on T1-weighted MR images after contrast agent injection. At a 50% scaling level, mean enhancement of 19.6% ± 1.7 (standard error of the mean) was achieved without inducing damage. At higher scaling levels, histologic analysis revealed gross tissue damage, while at a 50% scaling level, no damage was observed at high-field-strength MR imaging or histologic examination 8 days after treatment.
  
  
  CONCLUSIONS
  This study demonstrates that acoustic emissions can be used to actively control focused ultrasound exposures for the safe induction of BBB disruption.
authors.affiliation: Physical Science Platform, Sunnybrook Research Institute, Toronto, ON, Canada M4N 3M5. moreilly@sri.utoronto.ca
authors.forename: Meaghan A
authors.initials: MA
authors.lastname: O'Reilly
authors.forename: Kullervo
authors.initials: K
authors.lastname: Hynynen
mesh_terms: D000162:Acoustics; D000465:Algorithms; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging*; D003287:Contrast Media; D019786:Gadolinium DTPA; D007150:Immunohistochemistry; D045423:Microbubbles; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014159:Transducers; D014463:Ultrasonography
chemical_list: D003287:Contrast Media; C064925:gadodiamide; D019786:Gadolinium DTPA