title: Noninvasive and localized blood-brain barrier disruption using focused ultrasound can be achieved at short pulse lengths and low pulse repetition frequencies.
abstract: Ultrasound methods in conjunction with microbubbles have been used for brain drug delivery, treatment of stroke, and imaging of cerebral blood flow. Despite advances in these areas, questions remain regarding the range of ultrasound parameters that disrupt the blood-brain barrier (BBB). In this study, several conditions were investigated to either enhance or reduce the likelihood of BBB disruption. Pulsed focused ultrasound (frequency: 1.5 MHz, pressure: 0.46 MPa, pulse repetition frequency (PRF): 0.1 to 25 Hz, pulse length (PL): 0.03 to 30 milliseconds) was noninvasively and locally administered to a predetermined region in the left hemisphere in the presence of circulating preformed microbubbles (Definity, Lantheus Medical Imaging, N. Billerica, MA, USA; 0.01, 0.05, 0.25 μL/g). Trans-BBB delivery of 3-kDa dextran was observed at PRFs as low as 1 Hz, whereas consistent delivery was observed at 5 Hz and above. Delivery was demonstrated at a PL as low as 33 microseconds. Although the delivered dextran concentration increased with the PL, this also increased the heterogeneity of the resulting distribution. In conclusion, key parameters that disrupt the BBB were identified out of a wide range of conditions. Reducing the total number of emitted acoustic cycles by shortening the PL, or decreasing the PRF, was also found to facilitate a more spatially uniform distribution of delivered dextran.
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, New York 10027, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Choi
authors.forename: Kirsten
authors.initials: K
authors.lastname: Selert
authors.forename: Zimeng
authors.initials: Z
authors.lastname: Gao
authors.forename: Gesthimani
authors.initials: G
authors.lastname: Samiotaki
authors.forename: Babak
authors.initials: B
authors.lastname: Baseri
authors.forename: Elisa E
authors.initials: EE
authors.lastname: Konofagou
mesh_terms: D000818:Animals; D018916:Blood-Aqueous Barrier / Q000528:radiation effects*; D002626:Chemistry, Pharmaceutical; D003911:Dextrans / Q000008:administration & dosage / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000493:pharmacokinetics; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D013238:Stereotaxic Techniques; D013997:Time Factors; D014465:Ultrasonics
chemical_list: D003911:Dextrans; D005456:Fluorescent Dyes