A new safety index based on intrapulse monitoring of ultra-harmonic cavitation during ultrasound-induced blood-brain barrier opening procedures.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
22 06 2020
22 06 2020
Historique:
received:
28
12
2019
accepted:
29
05
2020
entrez:
24
6
2020
pubmed:
24
6
2020
medline:
12
1
2021
Statut:
epublish
Résumé
Ultrasound-induced blood-brain barrier (BBB) opening using microbubbles is a promising technique for local delivery of therapeutic molecules into the brain. The real-time control of the ultrasound dose delivered through the skull is necessary as the range of pressure for efficient and safe BBB opening is very narrow. Passive cavitation detection (PCD) is a method proposed to monitor the microbubble activity during ultrasound exposure. However, there is still no consensus on a reliable safety indicator able to predict potential damage in the brain. Current approaches for the control of the beam intensity based on PCD employ a full-pulse analysis and may suffer from a lack of sensitivity and poor reaction time. To overcome these limitations, we propose an intra-pulse analysis to monitor the evolution of the frequency content during ultrasound bursts. We hypothesized that the destabilization of microbubbles exposed to a critical level of ultrasound would result in the instantaneous generation of subharmonic and ultra-harmonic components. This specific signature was exploited to define a new sensitive indicator of the safety of the ultrasound protocol. The approach was validated in vivo in rats and non-human primates using a retrospective analysis. Our results demonstrate that intra-pulse monitoring was able to exhibit a sudden appearance of ultra-harmonics during the ultrasound excitation pulse. The repeated detection of such a signature within the excitation pulse was highly correlated with the occurrence of side effects such as hemorrhage and edema. Keeping the acoustic pressure at levels where no such sign of microbubble destabilization occurred resulted in safe BBB openings, as shown by MR images and gross pathology. This new indicator should be more sensitive than conventional full-pulse analysis and can be used to distinguish between potentially harmful and safe ultrasound conditions in the brain with very short reaction time.
Identifiants
pubmed: 32572103
doi: 10.1038/s41598-020-66994-8
pii: 10.1038/s41598-020-66994-8
pmc: PMC7308405
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10088Références
Pardridge, W. M. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2, 3–14, https://doi.org/10.1602/neurorx.2.1.3 (2005).
doi: 10.1602/neurorx.2.1.3
pubmed: 15717053
pmcid: 539316
Hynynen, K., McDannold, N., Vykhodtseva, N., Jolesz, F. A. & Noninvasive, M. R. imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology 220, 640–646, https://doi.org/10.1148/radiol.2202001804 (2001).
doi: 10.1148/radiol.2202001804
pubmed: 11526261
Tung, Y. S. et al. In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice. Phys. Med. Biol. 55, 6141–6155, https://doi.org/10.1088/0031-9155/55/20/007 (2010).
doi: 10.1088/0031-9155/55/20/007
pubmed: 20876972
pmcid: 4005785
McDannold, N., Vykhodtseva, N. & Hynynen, K. Targeted disruption of the blood-brain barrier with focused ultrasound: association with cavitation activity. Phys. Med. Biol. 51, 793–807, https://doi.org/10.1088/0031-9155/51/4/003 (2006).
doi: 10.1088/0031-9155/51/4/003
pubmed: 16467579
Dasgupta, A. et al. Ultrasound-mediated drug delivery to the brain: principles, progress and prospects. Drug Discov. Today Technol. 20, 41–48, https://doi.org/10.1016/j.ddtec.2016.07.007 (2016).
doi: 10.1016/j.ddtec.2016.07.007
pubmed: 27986222
pmcid: 5166975
Arvanitis, C. D., Livingstone, M. S. & McDannold, N. Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain. Phys. Med. Biol. 58, 4749–4761, https://doi.org/10.1088/0031-9155/58/14/4749 (2013).
doi: 10.1088/0031-9155/58/14/4749
pubmed: 23788054
pmcid: 3955087
Sirsi, S. & Borden, M. Microbubble Compositions, Properties and Biomedical Applications. Bubble Sci. Eng. Technol. 1, 3–17, https://doi.org/10.1179/175889709X446507 (2009).
doi: 10.1179/175889709X446507
pubmed: 20574549
pmcid: 2889676
de Jong, N., Bouakaz, A. & Frinking, P. Basic acoustic properties of microbubbles. Echocardiography 19, 229–240 (2002).
doi: 10.1046/j.1540-8175.2002.00229.x
Haqshenas, S. R. & Saffari, N. Multi-resolution analysis of passive cavitation detector signals. Journal of Physics: Conference Series 581, 012004 (2015).
O’Reilly, M. A. & Hynynen, K. Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller. Radiology 263, 96–106, https://doi.org/10.1148/radiol.11111417 (2012).
doi: 10.1148/radiol.11111417
pubmed: 22332065
pmcid: 3309801
Choi, J. J., Carlisle, R. C., Coviello, C., Seymour, L. & Coussios, C. C. Non-invasive and real-time passive acoustic mapping of ultrasound-mediated drug delivery. Phys. Med. Biol. 59, 4861–4877, https://doi.org/10.1088/0031-9155/59/17/4861 (2014).
doi: 10.1088/0031-9155/59/17/4861
pubmed: 25098262
Kamimura, H. A. et al. Feedback control of microbubble cavitation for ultrasound-mediated blood-brain barrier disruption in non-human primates under magnetic resonance guidance. J. Cereb. Blood Flow Metab., 271678X17753514, https://doi.org/10.1177/0271678X17753514 (2018).
Huang, Y., Alkins, R., Schwartz, M. L. & Hynynen, K. Opening the Blood-Brain Barrier with MR Imaging-guided Focused Ultrasound: Preclinical Testing on a Trans-Human Skull Porcine Model. Radiology 282, 123–130, https://doi.org/10.1148/radiol.2016152154 (2017).
doi: 10.1148/radiol.2016152154
pubmed: 27420647
Arvanitis, C. D., Livingstone, M. S., Vykhodtseva, N. & McDannold, N. Controlled ultrasound-induced blood-brain barrier disruption using passive acoustic emissions monitoring. PLoS One 7, e45783, https://doi.org/10.1371/journal.pone.0045783 (2012).
doi: 10.1371/journal.pone.0045783
pubmed: 23029240
pmcid: 3454363
Tsai, C. H., Zhang, J. W., Liao, Y. Y. & Liu, H. L. Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: implementation of confocal dual-frequency piezoelectric transducers. Phys. Med. Biol. 61, 2926–2946, https://doi.org/10.1088/0031-9155/61/7/2926 (2016).
doi: 10.1088/0031-9155/61/7/2926
pubmed: 26988240
Sun, T. et al. Acoustic cavitation-based monitoring of the reversibility and permeability of ultrasound-induced blood-brain barrier opening. Phys. Med. Biol. 60, 9079–9094, https://doi.org/10.1088/0031-9155/60/23/9079 (2015).
doi: 10.1088/0031-9155/60/23/9079
pubmed: 26562661
pmcid: 4668271
Bing, C. et al. Characterization of different bubble formulations for blood-brain barrier opening using a focused ultrasound system with acoustic feedback control. Sci. Rep. 8, 7986, https://doi.org/10.1038/s41598-018-26330-7 (2018).
doi: 10.1038/s41598-018-26330-7
pubmed: 29789589
pmcid: 5964106
Sun, T. et al. Closed-loop control of targeted ultrasound drug delivery across the blood-brain/tumor barriers in a rat glioma model. Proc. Natl. Acad. Sci. USA 114, E10281–E10290, https://doi.org/10.1073/pnas.1713328114 (2017).
doi: 10.1073/pnas.1713328114
pubmed: 29133392
Patel, A., Schoen, S. J., Jr. & Arvanitis, C. D. Closed Loop Spatial and Temporal Control of Cavitation Activity with Passive Acoustic Mapping. IEEE Trans. Biomed. Eng., https://doi.org/10.1109/TBME.2018.2882337 (2018).
Shekhar, H., Awuor, I., Thomas, K., Rychak, J. J. & Doyley, M. M. The delayed onset of subharmonic and ultraharmonic emissions from a phospholipid-shelled microbubble contrast agent. Ultrasound Med. Biol. 40, 727–738, https://doi.org/10.1016/j.ultrasmedbio.2014.01.002 (2014).
doi: 10.1016/j.ultrasmedbio.2014.01.002
pubmed: 24582298
pmcid: 3997117
Kooiman, K. et al. Focal areas of increased lipid concentration on the coating of microbubbles during short tone-burst ultrasound insonification. PLoS One 12, e0180747, https://doi.org/10.1371/journal.pone.0180747 (2017).
doi: 10.1371/journal.pone.0180747
pubmed: 28686673
pmcid: 5501608
Luan, Y. et al. Lipid shedding from single oscillating microbubbles. Ultrasound Med. Biol. 40, 1834–1846, https://doi.org/10.1016/j.ultrasmedbio.2014.02.031 (2014).
doi: 10.1016/j.ultrasmedbio.2014.02.031
pubmed: 24798388
Guidi, F., Vos, H. J., Mori, R., de Jong, N. & Tortoli, P. Microbubble characterization through acoustically induced deflation. IEEE transactions on ultrasonics, ferroelectrics, and frequency control 57, 193–202, https://doi.org/10.1109/TUFFC.2010.1398 (2010).
doi: 10.1109/TUFFC.2010.1398
pubmed: 20040446
Borden, M. A. et al. Influence of lipid shell physicochemical properties on ultrasound-induced microbubble destruction. IEEE transactions on ultrasonics, ferroelectrics, and frequency control 52, 1992–2002 (2005).
doi: 10.1109/TUFFC.2005.1561668
Postema, M., Marmottant, P., Lancee, C. T., Hilgenfeldt, S. & de Jong, N. Ultrasound-induced microbubble coalescence. Ultrasound Med. Biol. 30, 1337–1344, https://doi.org/10.1016/j.ultrasmedbio.2004.08.008 (2004).
doi: 10.1016/j.ultrasmedbio.2004.08.008
pubmed: 15582233
Marmottant, P., Van Der Meer, S., Emmer, M. & Versluis, M. A model for large amplitude oscillations of coated bubbles accounting for buckling and rupture. J. Acoust. Soc. Am. 118, 3499–3505 (2005).
doi: 10.1121/1.2109427
Sijl, J. et al. Subharmonic behavior of phospholipid-coated ultrasound contrast agent microbubbles. J. Acoust. Soc. Am. 128, 3239–3252, https://doi.org/10.1121/1.3493443 (2010).
doi: 10.1121/1.3493443
pubmed: 21110619
Thomas, D. H. et al. The “quasi-stable” lipid shelled microbubble in response to consecutive ultrasound pulses. Applied Physics Letter 101, 071601 (2012).
doi: 10.1063/1.4746258
O’Brien, J. P., Stride, E. & Ovenden, N. Surfactant shedding and gas diffusion during pulsed ultrasound through a microbubble contrast agent suspension. J. Acoust. Soc. Am. 134, 1416–1427, https://doi.org/10.1121/1.4812860 (2013).
doi: 10.1121/1.4812860
pubmed: 23927137
Magnin, R. et al. Magnetic resonance-guided motorized transcranial ultrasound system for blood-brain barrier permeabilization along arbitrary trajectories in rodents. J. Ther. Ultrasound 3, 22, https://doi.org/10.1186/s40349-015-0044-5 (2015).
doi: 10.1186/s40349-015-0044-5
pubmed: 26705473
pmcid: 4690289
Khalili, S. & Mahdi, M. Numerical analyses of nonlinear behavior of microbubble contrast agents in ultrasound field and effective parameters. J. Acoust. Soc. Am. 143, 2111, https://doi.org/10.1121/1.5031017 (2018).
doi: 10.1121/1.5031017
pubmed: 29716268
Li, T. et al. Passive cavitation detection during pulsed HIFU exposures of ex vivo tissues and in vivo mouse pancreatic tumors. Ultrasound Med. Biol. 40, 1523–1534, https://doi.org/10.1016/j.ultrasmedbio.2014.01.007 (2014).
doi: 10.1016/j.ultrasmedbio.2014.01.007
pubmed: 24613635
pmcid: 4048799
Gerstenmayer, M., Fellah, B., Magnin, R., Selingue, E. & Larrat, B. Acoustic Transmission Factor through the Rat Skull as a Function of Body Mass, Frequency and Position. Ultrasound Med. Biol. 44, 2336–2344, https://doi.org/10.1016/j.ultrasmedbio.2018.06.005 (2018).
doi: 10.1016/j.ultrasmedbio.2018.06.005
pubmed: 30076032
Choi, J. J. et al. Noninvasive and localized blood-brain barrier disruption using focused ultrasound can be achieved at short pulse lengths and low pulse repetition frequencies. J. Cereb. Blood Flow Metab. 31, 725–737, https://doi.org/10.1038/jcbfm.2010.155 (2011).
doi: 10.1038/jcbfm.2010.155
pubmed: 20842160
Choi, J. J., Selert, K., Vlachos, F., Wong, A. & Konofagou, E. E. Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles. Proc. Natl. Acad. Sci. USA 108, 16539–16544, https://doi.org/10.1073/pnas.1105116108 (2011).
doi: 10.1073/pnas.1105116108
pubmed: 21930942
Poon, C., McMahon, D. & Hynynen, K. Noninvasive and targeted delivery of therapeutics to the brain using focused ultrasound. Neuropharmacology 120, 20–37, https://doi.org/10.1016/j.neuropharm.2016.02.014 (2017).
doi: 10.1016/j.neuropharm.2016.02.014
pubmed: 26907805
McDannold, N., Vykhodtseva, N. & Hynynen, K. Effects of acoustic parameters and ultrasound contrast agent dose on focused-ultrasound induced blood-brain barrier disruption. Ultrasound Med. Biol. 34, 930–937, https://doi.org/10.1016/j.ultrasmedbio.2007.11.009 (2008).
doi: 10.1016/j.ultrasmedbio.2007.11.009
pubmed: 18294757
pmcid: 2459318
Hynynen, K., McDannold, N., Martin, H., Jolesz, F. A. & Vykhodtseva, N. The threshold for brain damage in rabbits induced by bursts of ultrasound in the presence of an ultrasound contrast agent (Optison). Ultrasound Med. Biol. 29, 473–481, https://doi.org/10.1016/s0301-5629(02)00741-x (2003).
doi: 10.1016/s0301-5629(02)00741-x
pubmed: 12706199
Morse, S. V. et al. Rapid Short-pulse Ultrasound Delivers Drugs Uniformly across the Murine Blood-Brain Barrier with Negligible Disruption. Radiology 291, 459–466, https://doi.org/10.1148/radiol.2019181625 (2019).
doi: 10.1148/radiol.2019181625
pubmed: 30912718
pmcid: 6493324
Guedra, M., Cleve, S., Mauger, C., Blanc-Benon, P. & Inserra, C. Dynamics of nonspherical microbubble oscillations above instability threshold. Phys. Rev. E 96, 063104, https://doi.org/10.1103/PhysRevE.96.063104 (2017).
doi: 10.1103/PhysRevE.96.063104
pubmed: 29347307
Viti, J. et al. Correspondence - Nonlinear oscillations of deflating bubbles. IEEE transactions on ultrasonics, ferroelectrics, and frequency control 59, 2818–2824, https://doi.org/10.1109/TUFFC.2012.2524 (2012).
doi: 10.1109/TUFFC.2012.2524
pubmed: 23221232
Cleve, S., Guedra, M., Inserra, C., Mauger, C. & Blanc-Benon, P. Surface modes with controlled axisymmetry triggered by bubble coalescence in a high-amplitude acoustic field. Phys. Rev. E 98, 033115, https://doi.org/10.1103/PhysRevE.98.033115 (2018).
doi: 10.1103/PhysRevE.98.033115
Collin, J. R. & Coussios, C. C. Quantitative observations of cavitation activity in a viscoelastic medium. J. Acoust. Soc. Am. 130, 3289–3296, https://doi.org/10.1121/1.3626156 (2011).
doi: 10.1121/1.3626156
pubmed: 22088001
Gyongy, M. & Coussios, C. C. Passive cavitation mapping for localization and tracking of bubble dynamics. J. Acoust. Soc. Am. 128, EL175–180, https://doi.org/10.1121/1.3467491 (2010).
doi: 10.1121/1.3467491
pubmed: 20968322
Novell, A., Escoffre, J. M. & Bouakaz, A. Second harmonic and subharmonic for non-linear wideband contrast imaging using a capacitive micromachined ultrasonic transducer array. Ultrasound Med. Biol. 39, 1500–1512, https://doi.org/10.1016/j.ultrasmedbio.2013.03.002 (2013).
doi: 10.1016/j.ultrasmedbio.2013.03.002
pubmed: 23743105
Cornu, C. et al. Ultrafast monitoring and control of subharmonic emissions of an unseeded bubble cloud during pulsed sonication. Ultrason. Sonochem. 42, 697–703, https://doi.org/10.1016/j.ultsonch.2017.12.026 (2018).
doi: 10.1016/j.ultsonch.2017.12.026
pubmed: 29429720