Ultrafast Ultrasound Localization Microscopy. Olivier Couture Institut Langevin Wave Physics for Medicine Team. January 20 th 2017

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1 Ultrafast Ultrasound Localization Microscopy Olivier Couture Institut Langevin Wave Physics for Medicine Team January 20 th 2017

2 The trade-off between resolution and penetration is often seen as incompressible Spatial Resolution Penetration Mouse Foetus 40 MHz Human Foetus 3 MHz

3 In optics, the diffraction limit was surpassed Betzig et al, 2006, Science Nobel prize Betzig, Moerner, Hell Millions of individual events are required to reconstruct super-resolved images: - Ultrafast cameras - Blinking sources

4 In ultrasound, penetration vs resolution should also be surpassed Spatial Resolution Penetration Contrast Time Resolution

5 Blinking sources are microbubbles and fast cameras is plane-wave ultrafast imaging Microbubbles Contrast

6 Blinking sources are microbubbles and fast cameras is plane-wave ultrafast imaging Microbubbles RAM Ultrafast imaging Contrast Time Resolution

7 Plane-wave imaging of microbubbles reveals distinct punctual events Frame rate: 5000 khz Differential imaging Ultrafast contrast imaging (Couture et al. 2009, Couture et al., 2011)

8 Plane-wave imaging of microbubbles reveals distinct punctual events Optics FPALM Ultrasound Frame rate: 5000 khz Differential imaging

9 Super-resolution in ultrasound was introduced in 2011 Ultrafast Ultrasound Localization Microscopy (uulm) Cross-section of a channel with flowing microbubbles, imaged with ultrafast ultrasound Microbubble ultrasound super-localization imaging (MUSLI), O. Couture et al., IEEE-IUS Symposium 2011 Patent: Couture O, Fink M, Tanter M (2010), Method and Device for Ultrasound Imaging, PCT/FR2011/052810

10 A model of microvasculature can be reconstructed with sonoactivated ultrasound localization of microbubbles (real 3D) Optical microscopy Conventional US Sono-activated Superlocalization Desailly et al., APL, 2013

11 uulm could attain a resolution down to 5 µm σ x A c. σ τ n z 0 L x A: Constant c: Speed of sound σ τ : Timing resolution of the system z 0 : Target depth Biomedical application US Frequency Imaging depth (mm) Number of elements Predicted Lateral Resolution Breast 7 MHz µm Liver, Heart 3 MHz µm Brain (rodents) 15 MHz µm Resolution limits in ultrafast ultrasound localization microscopy, Y. Desailly et al., PMB, 2015

12 uulm experimental set-up Ultrasound imaging parameters Imaging Frequency=15MHz 128 emitting elements Pitch=0,08 mm Frame Rate=500Hz Ultrasound contrast agents Initial concentration : 2*10 8 µbubbles/ml Boluses of 150 µl were injected every 15 minutes

13 Bubbles are isolated through spatiotemporal filtering NOT nonlinear imaging Large fraction of the echo is lost when using nonlinear imaging Desailly et al., PMB, 2016 High coherence (Phantom) Intermediate coherence (Bubbles)

14 Ultrafast imaging discriminates unique sources in space and time in the rat brain cortex Raw image After Spatiotemporal filtering (Singular value decomposition) Institut Langevin Ondes et Images C. Errico et al., Nature, 2015 O. Couture et al., January 2017

15 Depth (mm) Depth (mm) Depth (mm) Depth (mm) Ultrafast imaging discriminates unique sources in space and time in-vivo ms Lateral position (mm) ms Lateral position (mm) ms Lateral position (mm) ms Lateral position (mm) C. Errico et al., Nature, 2015

16 uulm improves the conventional resolution 10-fold Conventional ultrasound imaging 500μm C. Errico et al., Nature, 2015

17 uulm improves the conventional resolution 10-fold Conventional ultrasound imaging 500μm C. Errico et al., Nature, 2015

18 Tracking each moving bubble allows quantitative in-plane velocity measurements

19 Tracking each moving bubble allows quantitative in-plane velocity measurements

20 Ultrafast imaging quantifies a large dynamic range of blood flow velocities C. Errico et al., Nature, 2015

21 Ultrafast imaging makes ultrasound localization clinically feasible Millions of individual sources per minute (patient-friendly imaging time) High dynamic range in blood velocities Clinically compatible contrast doses Do not use nonlinear imaging, but rather singular value decomposition C. Errico et al., Nature, 2015

22 Various approaches to super-resolution ultrasound FPALM PAINT SOFI Ultrasound localization microscopy (ultrafast + UCA) Point-accumulation super-resolution Dertinger et al., 2009 Super-resolution acoustical fluctuation imaging (SAFI)? Slepmann et al. IEEE IUS 2011 Couture et al. IEEE IUS 2011 O Reilly and Hynynen, 2013 Viessmann et al., 2013 Bar-Zion, arxiv, 2016 Errico et al Christensen-Jeffries et al, 2015

23 Super-resolution creates new trade-offs Spatial Resolution Penetration Bubble count - SNR - Concentration X Time Resolution - Motion Data overdose Volumetric

24 Dayton s group showed that tumor vascular characterization can be directly obtained from the images acquired by uulm Lin et al., 3-D Ultrasound Localization Microscopy for Identifying Microvascular Morphology Features of Tumor Angiogenesis at a Resolution Beyond the Diffraction Limit of Conventional Ultrasound, Theranostics (2016)

25 Phase-correlation can correct motion at subwavelength scale 100 µm Corrected motion Hingot et al, Ultrasonics (accepted, 2017) Next

26 Ultrasound-triggered delivery can be performed with a quarter wavelength resolution Hingot et al, APL, 2016 Poster

27 Contributed: Mickael Tanter, Claudia Errico, Yann Desailly, Marine Bézagu, Vincent Hingot, Juliette Pierre, Sophie Pezet, Zsolt Lenkei Funding: ANR Musli, Labex WIFI, Fondation Pierre-Gilles-de-Gennes Wave Physics for Medicine Team Paris We have 1 open POST-DOC positions : please send your CV to Olivier.couture@espci.fr