Theranostics 2018; 8(11):2909-2926. doi:10.7150/thno.24911 This issue

Research Paper

Three-dimensional transcranial microbubble imaging for guiding volumetric ultrasound-mediated blood-brain barrier opening

Ryan M. Jones1✉, Lulu Deng1, Kogee Leung1, Dallan McMahon1,2, Meaghan A. O'Reilly1,2, Kullervo Hynynen1,2,3

1. Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada
2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
3. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Jones RM, Deng L, Leung K, McMahon D, O'Reilly MA, Hynynen K. Three-dimensional transcranial microbubble imaging for guiding volumetric ultrasound-mediated blood-brain barrier opening. Theranostics 2018; 8(11):2909-2926. doi:10.7150/thno.24911. Available from

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Graphic abstract

Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening recently entered clinical testing for targeted drug delivery to the brain. Sources of variability exist in the current procedures, motivating the development of real-time monitoring and control techniques to improve treatment safety and efficacy. Here we used three-dimensional (3D) transcranial microbubble imaging to calibrate FUS exposure levels for volumetric BBB opening.

Methods: Using a sparse hemispherical transmit/receive ultrasound phased array, pulsed ultrasound was focused transcranially into the thalamus of rabbits during microbubble infusion and multi-channel 3D beamforming was performed online with receiver signals captured at the subharmonic frequency. Pressures were increased pulse-by-pulse until subharmonic activity was detected on acoustic imaging (psub), and tissue volumes surrounding the calibration point were exposed at 50-100%psub via rapid electronic beam steering.

Results: Spatially-coherent subharmonic microbubble activity was successfully reconstructed transcranially in vivo during calibration sonications. Multi-point exposures induced volumetric regions of elevated BBB permeability assessed via contrast-enhanced magnetic resonance imaging (MRI). At exposure levels ≥75%psub, MRI and histological examination occasionally revealed tissue damage, whereas sonications at 50%psub were performed safely. Substantial intra-grid variability of FUS-induced bioeffects was observed via MRI, prompting future development of multi-point calibration schemes for improved treatment consistency. Receiver array sparsity and sensor configuration had substantial impacts on subharmonic detection sensitivity, and are factors that should be considered when designing next-generation clinical FUS brain therapy systems.

Conclusion: Our findings suggest that 3D subharmonic imaging can be used to calibrate exposure levels for safe FUS-induced volumetric BBB opening, and should be explored further as a method for cavitation-mediated treatment guidance.

Keywords: blood-brain barrier, focused ultrasound, microbubble contrast agents, three-dimensional acoustic imaging, transmit/receive phased array