A new safety index based on intrapulse monitoring of ultra-harmonic cavitation during ultrasound-induced blood-brain barrier opening procedures
In: ISSN: 2045-2322, 2020
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Zugriff:
International audience ; 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.
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A new safety index based on intrapulse monitoring of ultra-harmonic cavitation during ultrasound-induced blood-brain barrier opening procedures
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Autor/in / Beteiligte Person: | Novell, Anthony ; Kamimura, Hermes, A-S ; Cafarelli, Andrea ; Gerstenmayer, Matthieu ; Flament, Julien ; Valette, Julien ; Agou, Pauline ; Conti, Allegra ; Selingue, Erwan ; Aron Badin, Romina ; Hantraye, Philippe ; Larrat, Benoît ; Building large instruments for neuroimaging: from population imaging to ultra-high magnetic fields (BAOBAB) ; Service NEUROSPIN (NEUROSPIN) ; Université Paris-Saclay-Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS) ; LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS) ; Service Hospitalier Frédéric Joliot (SHFJ) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN) ; Molecular Imaging Research Center Fontenay-aux-Roses (MIRCEN) ; Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) ; Columbia University New York ; Scuola Universitaria Superiore Sant'Anna Pisa (SSSUP) ; This work is part of the 3BOPUS project, supported by the Agence National de la Recherche (ANR-17-CE19-0025). This study was also supported in part by the European Union (FEDER-2007-2013, agreement #44475), by the Groupement d’intérêt scientifique “GIS IBiSA”, and by the Large National Infrastructure for translational Neuroscience NeurATRIS (ANR-11-INBS-0011). ; ANR-17-CE19-0025,3BOPUS,Développement et validation d'un dispositif clinique d'ouverture de la barrière hémato-encéphalique par ultrasons focalisés transcraniens(2017) ; ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011) |
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Zeitschrift: | ISSN: 2045-2322, 2020 |
Veröffentlichung: | HAL CCSD ; Nature Publishing Group, 2020 |
Medientyp: | academicJournal |
DOI: | 10.1038/s41598-020-66994-8 |
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