Advertisement

Super-resolution Ultrasound Imaging

      Abstract

      The majority of exchanges of oxygen and nutrients are performed around vessels smaller than 100 μm, allowing cells to thrive everywhere in the body. Pathologies such as cancer, diabetes and arteriosclerosis can profoundly alter the microvasculature. Unfortunately, medical imaging modalities only provide indirect observation at this scale. Inspired by optical microscopy, ultrasound localization microscopy has bypassed the classic compromise between penetration and resolution in ultrasonic imaging. By localization of individual injected microbubbles and tracking of their displacement with a subwavelength resolution, vascular and velocity maps can be produced at the scale of the micrometer. Super-resolution ultrasound has also been performed through signal fluctuations with the same type of contrast agents, or through switching on and off nano-sized phase-change contrast agents. These techniques are now being applied pre-clinically and clinically for imaging of the microvasculature of the brain, kidney, skin, tumors and lymph nodes.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Ultrasound in Medicine and Biology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ackermann D.
        • Schmitz G.
        Detection and tracking of multiple microbubbles in ultrasound B-mode images.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2016; 63: 72-82
      1. Alberti GS, Ammari H, Romero F, Wintz T. Dynamic spike super-resolution and applications to ultrafast ultrasound imaging. arXiv preprint arXiv:180303251. 2018.

        • Bar-Zion A.
        • Tremblay-Darveau C.
        • Solomon O.
        • Adam D.
        • Eldar Y.C.
        Fast vascular ultrasound imaging with enhanced spatial resolution and background rejection.
        IEEE Trans Med Imaging. 2017; 36: 169-180
        • Bar-Zion A.
        • Solomon O.
        • Tremblay-Darveau C.
        • Adam D.
        • Eldar Y.C.
        SUSHI: Sparsity-based super-resolution ultrasound hemodynamic imaging.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2018; 65: 2365-2380
        • Bar-Zion A.
        • Tremblay-Darveau C.
        • Eldar Y.C.
        • Solomon O.
        • Adam D.
        Super-resolution ultrasound imaging of vascular structures with high temporal resolution.
        Sci Rep. 2018; 8 (Article 13918)
        • Basude R.
        • Wheatley M.A.
        Generation of ultraharmonics in surfactant based ultrasound contrast agents: Use and advantages.
        Ultrasonics. 2001; 39: 437-444
        • Bercoff J.
        • Montaldo G.
        • Loupas T.
        • Savery D.
        • Mézière F.
        • Fink M.
        • Tanter M.
        Ultrafast compound Doppler imaging: Providing full blood flow characterization.
        IEEE Trans Ultrason Ferroelectr, and Freq Control. 2011; 58: 134-147
        • Betzig E.
        • Patterson G.H.
        • Sougrat R.
        • Lindwasser O.W.
        • Olenych S.
        • Bonifacino J.S.
        • Davidson M.W.
        • Lippincott-Schwartz J.
        • Hess H.F.
        Imaging intracellular fluorescent proteins at nanometer resolution.
        Science. 2006; 313: 1642-1645
        • Blomgren P.
        • Papanicolaou G.
        • Zhao H.
        Super-resolution in time-reversal acoustics.
        J Acoust Soc Am. 2002; 111: 230-248
        • Blomley M.J.
        • Cooke J.C.
        • Unger E.C.
        • Monaghan M.J.
        • Cosgrove D.O.
        Microbubble contrast agents: a new era in ultrasound.
        BMJ. 2001; 322: 1222-1225
        • Bourdeau R.W.
        • Lee-Gosselin A.
        • Lakshmanan A.
        • Farhadi A.
        • Kumar S.R.
        • Nety S.P.
        • Shapiro M.G.
        Acoustic reporter genes for noninvasive imaging of microorganisms in mammalian hosts.
        Nature. 2018; 553: 86
        • Brown J.
        • Christensen-Jeffries K.
        • Harput S.
        • Zhang G.
        • Zhu J.
        • Dunsby C.
        • Tang M.X.
        • Eckersley R.J.
        Investigation of microbubble detection methods for super-resolution imaging of microvasculature.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2019; 66: 676-691
        • Burns P.N.
        • Powers J.E.
        • Simpson D.H.
        • Brezina A.
        • Kolin A.
        • Chin C.T.
        • Uhlendorf V.
        • Fritzsch T.
        Harmonic power mode Doppler using microbubble contrast agents: An improved method for small vessel flow imaging.
        Proc IEEE Int Ultrason Symp. 1994; : 1547-1550
        • Burns P.N.
        • Wilson S.R.
        Microbubble contrast for radiological imaging: 1.
        Principles. Ultrasound Q. 2006; 22: 5-13
        • Carpentier A.
        • Canney M.
        • Vignot A.
        • Reina V.
        • Beccaria K.
        • Horodyckid C.
        • Karachi C.
        • Leclercq D.
        • Lafon C.
        • Chapelon J.Y.
        Clinical trial of blood–brain barrier disruption by pulsed ultrasound.
        Sci Transl Med. 2016; 8 (re2–343): 343
        • Chomas J.E.
        • Dayton P.
        • Allen J.
        • Morgan K.
        • Ferrara K.W.
        Mechanisms of contrast agent destruction.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2001; 48: 232-248
        • Christensen-Jeffries K.M.
        Super-resolution ultrasound imaging with microbubbles.
        (PhD thesis) King's College London, 2017
        • Christensen-Jeffries K.
        • Browning R.J.
        • Tang M.X.
        • Dunsby C.
        • Eckersley R.J.
        In vivo acoustic super-resolution and super-resolved velocity mapping using microbubbles.
        IEEE Trans Med Imaging. 2015; 34: 433-440
        • Christensen-Jeffries K.
        • Brown J.
        • Aljabar P.
        • Tang M.
        • Dunsby C.
        • Eckersley R.J.
        3-D in vitro acoustic super-resolution and super-resolved velocity mapping using microbubbles.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2017; 64: 1478-1486
        • Christensen-Jeffries K.
        • Harput S.
        • Brown J.
        • Wells P.N.T.
        • Aljabar P.
        • Dunsby C.
        • Tang M.-X.
        • Eckersley R.J.
        Microbubble axial localization errors in super-resolution ultrasound imaging.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2017; 64: 1644-1654
        • Christensen-Jeffries K.
        • Harput S.
        • Brown J.
        • Zhang G.
        • Zhu J.
        • Tang M.X.
        • Dunsby C.
        • Eckersley R.
        3D in vitro super-resolution ultrasound imaging using a clinical system.
        Proc IEEE Int Ultrason Symp. 2018; : 1-4
        • Christensen-Jeffries K.
        • Brown J.
        • Harput S.
        • Zhang G.
        • Zhu J.
        • Tang M.X.
        • ...
        • Eckersley R.J.
        Poisson Statistical Model of Ultrasound Super-Resolution Imaging Acquisition Time.
        IEEE transactions on ultrasonics, ferroelectrics, and frequency control. 2019; 66: 1246-1254
        • Clement G.T.
        • Huttunen J.
        • Hynynen K.
        Superresolution ultrasound imaging using back-projected reconstruction.
        J Acoust Soc Am. 2005; 118: 3953-3960
        • Cobbold Richard S.C.
        Foundations of biomedical ultrasound.
        Oxford university press, 2006
        • Cohen R.
        • Zhang Y.
        • Solomon O.
        • Toberman D.
        • Taieb L.
        • van Sloun R.J.G.
        • Eldar Y.C.
        Deep convolutional robust PCA with application to ultrasound imaging.
        in: Proceedings, IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP). IEEE, 2019: 3212-3216
        • Cosgrove D.
        • Lassau N.
        Imaging of perfusion using ultrasound.
        Eur J Nucl Med Mol Imaging. 2010; 37: 65-85
        • Couture O.
        • Bannouf S.
        • Montaldo G.
        • Aubry J.F.
        • Fink M.
        • Tanter M.
        Ultrafast imaging of ultrasound contrast agents.
        Ultrasound Med Biol. 2009; 35: 1908-1916
      2. Couture O, Tanter M, Fink M. Method and device for ultrasound imaging. Patent Cooperation Treaty (PCT)/FR2011/052810. 2010.

        • Couture O.
        • Besson B.
        • Montaldo G.
        • Fink M.
        • Tanter M.
        Microbubble ultrasound super-localization imaging (MUSLI).
        Proc IEEE Int Ultrason Symp. 2011; : 1285-1287
        • Couture O.
        • Fink M.
        • Tanter M.
        Ultrasound contrast plane wave imaging.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2012; 596373790
        • Couture O.
        • Hingot V.
        • Heiles B.
        • Muleki-Seya P.
        • Tanter M.
        Ultrasound localization microscopy and super-resolution: A state of the art.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2018; 65: 1304-1320
        • Culp W.C.
        • Flores R.
        • Brown A.T.
        • Lowery J.D.
        • Roberson P.K.
        • Hennings L.J.
        • Woods S.D.
        • Hatton J.H.
        • Culp B.C.
        • Skinner R.D.
        Successful microbubble sonothrombolysis without tissue-type plasminogen activator in a rabbit model of acute ischemic stroke.
        Stroke. 2011; 42: 2280-2285
        • Danielli A.
        • Maslov K.I.
        • Garcia-Uribe A.
        • Winkler A.M.
        • Li C.
        • Wang L.
        • ...
        • Wang L.V.
        Label-free photoacoustic nanoscopy.
        J Biomed Opt. 2014; 19086006
        • Dean-Ben X.L.
        • Razansky D
        Localization optoacoustic tomography.
        Light Sci Appl. 2018; 7: 18004
        • Deffieux T.
        • Demene C.
        • Pernot M.
        • Tanter M.
        Functional ultrasound neuroimaging: A review of the preclinical and clinical state of the art.
        Curr Opin Neurobiol. 2018; 50: 128-135
        • Demené C.
        • Tiran E.
        • Sieu L.A.
        • Bergel A.
        • Gennisson J.L.
        • Pernot M.
        • Deffieux T.
        • Cohen I.
        • Tanter M.
        4D microvascular imaging based on ultrafast Doppler tomography.
        Neuroimage. 2016; 127: 472-483
        • Dencks S.
        • Piepenbrock M.
        • Schmitz G.
        • Opacic T.
        • Kiessling F.
        Determination of adequate measurement times for super-resolution characterization of tumor vascularization.
        2017 Proc IEEE Int Ultrason Symp. 2017; : 1-4
        • Dencks S.
        • Piepenbrock M.
        • Opacic T.
        • Krauspe B.
        • Stickeler E.
        • Kiessling F.
        • Schmitz G.
        Clinical pilot application of super-resolution US imaging in breast cancer.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2018; 66: 517-526
        • Dencks S.
        • Piepenbrock M.
        • Opacic T.
        • Krauspe B.
        • Stickeler E.
        • Kiessling F.
        • Schmitz G.
        Clinical pilot application of super-resolution US imaging in breast cancer.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2019; 66: 517-526
        • Dertinger T.
        • Colyer R.
        • Iyer G.
        • Weiss S.
        • Enderlein J.
        Fast, background-free, 3D super-resolution optical fluctuation imaging (SOFI).
        Proc Natl Acad Sci USA. 2009; 106: 22287-22292
        • Desailly Y.
        • Couture O.
        • Fink M.
        • Tanter M.
        Sono-activated ultrasound localization microscopy.
        Appl Phys Lett. 2013; 103174107
        • Desailly Y.
        • Pierre J.
        • Couture O.
        • Tanter M.
        Resolution limits of ultrafast ultrasound localization microscopy.
        Phys Med Biol. 2015; 60: 8723-8740
        • Desailly Y.
        • Tissier A.M.
        • Correas J.M.
        • Wintzenrieth F.
        • Tanter M.
        • Couture O.
        Contrast enhanced ultrasound by real-time spatiotemporal filtering of ultrafast images.
        Phys Med Biol. 2017; 62: 31-42
        • Diamantis K.
        • Anderson T.
        • Butler M B.
        • Villagómez-Hoyos C.A.
        • Jensen J.A.
        • Sboros V.
        Resolving ultrasound contrast microbubbles using minimum variance beamforming.
        IEEE Trans Med Imaging. 2018; 38: 194-204
        • Dollet B.
        • Van Der Meer S.M.
        • Garbin V.
        • De Jong N.
        • Lohse D.
        • Versluis M.
        Nonspherical oscillations of ultrasound contrast agent microbubbles.
        Ultrasound Med Biol. 2008; 34: 1465-1473
        • Eckersley R.J.
        • Chin C.T.
        • Burns P.N.
        Optimising phase and amplitude modulation schemes for imaging microbubble contrast agents at low acoustic power.
        Ultrasound Med Biol. 2005; 31: 213-219
        • Eldar Y.C.
        • Kutyniok G.
        Compressed sensing: Theory and applications.
        Cambridge University Press, New York/London2012
        • Eldar Y.C.
        • Mishali M.
        Robust recovery of signals from a structured union of subspaces.
        IEEE Trans Inf Theory. 2009; 55: 5302-5316
        • Enzmann D.R.
        • Pelc N.J.
        Brain motion: Measurement with phase-contrast MR imaging.
        Radiology. 1992; 185: 653-660
        • Errico C.
        • Pierre J.
        • Pezet S.
        • Desailly Y.
        • Lenkei Z.
        • Couture O.
        • Tanter M.
        Ultrafast ultrasound localization microscopy for deep super-resolution vascular imaging.
        Nature. 2015; 527: 499
        • Ertürk A.
        • Becker K.
        • Jährling N.
        • Mauch C.P.
        • Hojer C.D.
        • Egen J.G.
        • Hellal F.
        • Bradke F.
        • Sheng M.
        • Dodt H.U.
        Three-dimensional imaging of solvent-cleared organs using 3 DISCO.
        Nat Protoc. 2012; 7: 1983
        • Espíndola D.
        • Lin F.
        • Soulioti D.E.
        • Dayton P.A.
        • Pinton G.F.
        Adaptive multifocus beamforming for contrast-enhanced-super-resolution ultrasound imaging in deep tissue.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2018; 65: 2255-2263
        • Farhadi A.
        • Ho G.H.
        • Sawyer D.P.
        • Bourdeau R.W.
        • Shapiro M.G.
        Ultrasound imaging of gene expression in mammalian cells.
        Science. 2019; 365: 1469-1475
        • Ferrara K.W.
        • Merritt C.R.
        • Burns P.N.
        • Foster F.S.
        • Mattrey R.F.
        • Wickline S.A.
        Evaluation of tumor angiogenesis with US: Imaging, Doppler, and contrast agents.
        Acad Radiol. 2000; 7: 824-839
        • Ferrara K.
        • Pollard R.
        • Borden M.
        Ultrasound microbubble contrast agents: Fundamentals and application to gene and drug delivery.
        Annu Rev Biomed Eng. 2007; 9: 415-447
        • Fink M.
        • Tanter M.
        Multiwave imaging and super resolution.
        Phys Today. 2010; 63: 28-33
        • Foiret J.
        • Zhang H.
        • Ilovitsh T.
        • Mahakian L.
        • Tam S.
        • Ferrara K.W.
        Ultrasound localization microscopy to image and assess microvasculature in a rat kidney.
        Sci Rep. 2017; 7: 13662
        • Folkman J.
        Angiogenesis.
        Annu Rev Med. 2006; 57: 1-18
        • Foroozan F.
        • O'Reilly M.A.
        • Hynynen K.
        Microbubble localization for three-dimensional superresolution ultrasound imaging using curve fitting and deconvolution methods.
        IEEE Trans Biomed Eng. 2018; 65: 2692-2703
        • Forsberg F.
        • Shi W.T.
        • Goldberg B.B.
        Subharmonic imaging of contrast agents.
        Ultrasonics. 2000; 38: 93-98
        • Frinking P.J.
        • Bouakaz A.
        • Kirkhorn J.
        • Ten Cate F.J.
        • De Jong N.
        Ultrasound contrast imaging: Current and new potential methods.
        Ultrasound Med Biol. 2000; 26: 965-975
        • Fry F.J.
        • Barger J.E.
        Acoustical properties of the human skull.
        J Acoust Soc Am. 1978; 63: 1576-1590
        • Gessner R.
        • Lukacs M.
        • Lee M.
        • Cherin E.
        • Foster F.S.
        • Dayton P.A.
        High-resolution, high-contrast ultrasound imaging using a prototype dual-frequency transducer: In vitro and in vivo studies.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2010; 57: 1772-1781
        • Gessner R.C.
        • Aylward S.R.
        • Dayton P.A.
        Mapping microvasculature with acoustic angiography yields quantifiable differences between healthy and tumor-bearing tissue volumes in a rodent model.
        Radiology. 2012; 264: 733-740
        • Ghosh D.
        • Xiong F.
        • Sirsi S.R.
        • Shaul P.W.
        • Mattrey R.F.
        • Hoyt K.
        Toward optimization of in vivo super-resolution ultrasound imaging using size-selected microbubble contrast agents.
        Med Phys. 2017; 44: 6304-6313
        • Ghosh D.
        • Peng J.
        • Brown K.
        • Sirsi S.
        • Mineo C.
        • Shaul P.W.
        • Hoyt K.
        Super‐resolution ultrasound imaging of skeletal muscle microvascular dysfunction in an animal model of type 2 diabetes.
        J Ultrasound Med. 2019; 38: 2589-2599
        • Gorelick P.B.
        • Scuteri A.
        • Black S.E.
        • DeCarli C.
        • Greenberg S.M.
        • Iadecola C.
        • Launer L.J.
        • Laurent S.
        • Lopez O.L.
        • Nyenhuis D.
        • Petersen R.C.
        • Schneider J.A.
        • Tzourio C.
        • Arnett D.K.
        • Bennett D.A.
        • Chui H.C.
        • Higashida R.T.
        • Lindquist R.
        • Nilsson P.M.
        • Roman G.C.
        • Sellke F.W.
        • Seshadri S.
        Vascular contributions to cognitive impairment and dementia.
        Stroke. 2011; 42: 2672-2713
        • Gramiak R.
        • Shah P.M.
        Echocardiography of the aortic root.
        Invest Radiol. 1968; 3: 356-366
        • Greis C.
        Ultrasound contrast agents as markers of vascularity and microcirculation.
        Clin Hemorheol Microcirc. 2009; 43: 1-9
        • Grills I.S.
        • Kestin L.L.
        • Goldstein N.
        • Mitchell C.
        • Martinez A.
        • Ingold J.
        • Vicini F.A.
        Risk factors for regional nodal failure after breast-conserving therapy: Regional nodal irradiation reduces rate of axillary failure in patients with four or more positive lymph nodes.
        Int J Radiat Oncol Biol Phys. 2003; 56: 658-670
        • Harput S.
        • Christensen-Jeffries K.
        • Brown J.
        • Li Y.
        • Williams K.J.
        • Davies A.H.
        • Eckersley R.J.
        • Dunsby C.
        • Tang M.X.
        Two-stage motion correction for super-resolution ultrasound imaging in human lower limb.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2018; 65: 803-814
      3. Harput S, Christensen-Jeffries K, Brown J, Zhu J, Zhang G, Eckersley RJ, Dunsby C, Tang MX. 3-D motion correction for volumetric super-resolution ultrasound (SR-US) imaging. arXiv preprint arXiv:190201928. 2019a.

      4. Harput S, Christensen-Jeffries K, Ramalli A, Brown J, Zhu J, Zhang G, Leow CH, Toulemonde M, Boni E, Tortoli P. 3-D super-resolution ultrasound (SR-US) imaging with a 2-D sparse array. arXiv preprint arXiv:190201608. 2019b.

        • Heijblom M.
        • Klaase J.M.
        • Van Den Engh F.M.
        • van Leeuwen T.G.
        • Steenbergen W.
        • Manohar S.
        Imaging tumor vascularization for detection and diagnosis of breast cancer.
        Technol Cancer Res Treat. 2011; 10: 607-623
        • Heiles B.
        • Correia M.
        • Hingot V.
        • Pernot M.
        • Provost J.
        • Tanter M.
        • Couture O.
        Ultrafast 3D ultrasound localization microscopy using a 32×32 matrix array.
        IEEE Trans Med Imaging. 2019; 38: 2005-2015
        • Hess S.T.
        • Girirajan T.P.
        • Mason M.D.
        Ultra-high resolution imaging by fluorescence photoactivation localization microscopy.
        Biophys J. 2006; 91: 4258-4272
        • Hingot V.
        • Bézagu M.
        • Errico C.
        • Desailly Y.
        • Bocheux R.
        • Tanter M.
        • Couture O.
        Subwavelength far-field ultrasound drug-delivery.
        Appl Phys Lett. 2016; 109194102
        • Hingot V.
        • Errico C.
        • Tanter M.
        • Couture O.
        Subwavelength motion-correction for ultrafast ultrasound localization microscopy.
        Ultrasonics. 2017; 77: 17-21
        • Hingot V.
        • Errico C.
        • Heiles B.
        • Rahal L.
        • Tanter M.
        • Couture O.
        Microvascular flow dictates the compromise between spatial resolution and acquisition time in ultrasound localization microscopy.
        Sci Rep. 2019; 9: 2456
        • Hynynen K.
        • McDannold N.
        • Vykhodtseva N.
        • Jolesz F.A.
        Noninvasive MR imaging–guided focal opening of the blood-brain barrier in rabbits.
        Radiology. 2001; 220: 640-646
        • Iadecola C.
        Neurovascular regulation in the normal brain and in Alzheimer's disease.
        Nat Rev Neurosci. 2004; 5: 347-360
        • Iadecola C.
        • Hachinski V.
        • Rosenberg G.A.
        Vascular cognitive impairment introduction.
        Stroke. 2010; 41: S127-S128
        • Ikeda O.
        • Sato T.
        • Suzuki K.
        Super-resolution imaging system using waves with a limited frequency bandwidth.
        J Acoust Soc Am. 1979; 65: 75-81
        • Ilovitsh T.
        • Ilovitsh A.
        • Foiret J.
        • Fite B.Z.
        • Ferrara K.W.
        Acoustical structured illumination for super-resolution ultrasound imaging.
        Commun Biol. 2018; 1: 3
        • Jain R.K.
        Determinants of tumor blood flow: A review.
        Cancer Res. 1988; 48: 2641-2658
        • Jellinger K.A.
        The pathology of “vascular dementia”: A critical update.
        J Alzheimer's Dis. 2008; 14: 107-123
        • Jia Y.
        • Tan O.
        • Tokayer J.
        • Potsaid B.
        • Wang Y.
        • Liu J.J.
        • Kraus M.F.
        • Subhash H.
        • Fujimoto J.G.
        • Hornegger J.
        Split-spectrum amplitude-decorrelation angiography with optical coherence tomography.
        Opt Express. 2012; 20: 4710-4725
      5. Johnson KW, Powers JE. Ultrasonic detection of contrast agents. Patent, 1995; US5456257A.

        • Jones H.W.
        Superresolution in ultrasonic imaging. Acoustical Imaging. 19. Springer, Boston1992: 71-76
        • Kanoulas E.
        • Butler M.
        • Rowley C.
        • Voulgaridou V.
        • Diamantis K.
        • Duncan W.C.
        • McNeilly A.
        • Averkiou M.
        • Wijkstra H.
        • Mischi M.
        Super-resolution contrast-enhanced ultrasound methodology for the identification of in vivo vascular dynamics in 2D.
        Invest Radiol. 2019; 54: 500-516
        • Kawabata K.
        • Sugita N.
        • Yoshikawa H.
        • Azuma T.
        • Umemura S.
        Nanoparticles with multiple perfluorocarbons for controllable ultrasonically induced phase shifting.
        Jpn J Appl Phys. 2005; 44: 4548
        • Kiessling F.
        • Fokong S.
        • Bzyl J.
        • Lederle W.
        • Palmowski M.
        • Lammers T.
        Recent advances in molecular, multimodal and theranostic ultrasound imaging.
        Adv Drug Deliv Rev. 2014; 72: 15-27
        • Kim S.G.
        • Ogawa S.
        Biophysical and physiological origins of blood oxygenation level-dependent fMRI signals.
        J Cereb Blood Flow Metab. 2012; 32: 1188-1206
        • Kripfgans O.D.
        • Fowlkes J.B.
        • Miller D.L.
        • Eldevik O.P.
        • Carson P.
        L Acoustic droplet vaporization for therapeutic and diagnostic applications.
        Ultrasound Med Biol. 2000; 26: 1177-1189
        • Kuhn H.W.
        The Hungarian method for the assignment problem.
        Naval Res Logistics Q. 1955; 2: 83-97
        • Leahy M.J.
        Microcirculation imaging.
        Wiley, New York2012
        • Lehman S.K.
        • Devaney A.J.
        Transmission mode time-reversal super-resolution imaging.
        J Acoust Soc Am. 2003; 113: 2742-2753
        • Lin F.
        • Shelton S.E.
        • Espíndola D.
        • Rojas J.D.
        • Pinton G.
        • Dayton P.A.
        3-D ultrasound localization microscopy for identifying microvascular morphology features of tumor angiogenesis at a resolution beyond the diffraction limit of conventional ultrasound.
        Theranostics. 2017; 7: 196
        • Lin F.
        • Tsuruta J.K.
        • Rojas J.D.
        • Dayton P.A.
        Optimizing sensitivity of ultrasound contrast-enhanced super-resolution imaging by tailoring size distribution of microbubble contrast agent.
        Ultrasound Med Biol. 2017; 43: 2488-2493
        • Lin S.
        • Zhang G.
        • Jamburidze A.
        • Chee M.
        • Leow C.H.
        • Garbin V.
        • Tang M.X.
        Imaging of vaporised sub-micron phase change contrast agents with high frame rate ultrasound and optics.
        Phys Med Biol. 2018; 63065002
        • Lindsey B.D.
        • Light E.D.
        • Nicoletto H.A.
        • Bennett E.R.
        • Laskowitz D.T.
        • Smith S.W.
        The ultrasound brain helmet: New transducers and volume registration for in vivo simultaneous multi-transducer 3-D transcranial imaging.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2011; 58: 1189-1202
        • Lindsey B.D.
        • Nicoletto H.A.
        • Bennett E.R.
        • Laskowitz D.T.
        • Smith S.W.
        3-D transcranial ultrasound imaging with bilateral phase aberration correction of multiple isoplanatic patches: A pilot human study with microbubble contrast enhancement.
        Ultrasound Med Biol. 2014; 40: 90-101
        • Lipsman N.
        • Meng Y.
        • Bethune A.J.
        • Huang Y.
        • Lam B.
        • Masellis M.
        • Herrmann N.
        • Heyn C.
        • Aubert I.
        • Boutet A.
        Blood–brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound.
        Nat Commun. 2018; 9: 2336
        • Lockwood G.R.
        • Turnball D.H.
        • Christopher D.A.
        • Foster F.S.
        Beyond 30 MHz (applications of high-frequency ultrasound imaging).
        IEEE Eng Med Biol Mag. 1996; 15: 60-71
        • Luke G.P.
        • Hannah A.S.
        • Emelianov S.Y.
        Super-resolution ultrasound imaging in vivo with transient laser-activated nanodroplets.
        Nano letters. 2016; 16: 2556-2559
        • Mallart R.
        • Fink M.
        Adaptive focusing in scattering media through sound‐speed inhomogeneities: The van Cittert Zernike approach and focusing criterion.
        J Acoust Soc Am. 1994; 96: 3721-3732
      6. Microcirculation revisited: From molecules to clinical practice.
        in: Lenasi H. Microcirculation revisited: From molecules to clinical practice. Books on Demand, 2016
        • Mainprize T.
        • Lipsman N.
        • Huang Y.
        • Meng Y.
        • Bethune A.
        • Ironside S.
        • Heyn C.
        • Alkins R.
        • Trudeau M.
        • Sahgal A.
        • Perry J.
        • Hynynen K.
        Blood–brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: A clinical safety and feasibility study.
        Sci Rep. 2019; 9: 321
        • Marien K.M.
        • Croons V.
        • Waumans Y.
        • Sluydts E.
        • De Schepper S.
        • Andries L.
        • Waelput W.
        • Fransen E.
        • Vermeulen P.B.
        • Kockx M.M.
        • De Meyer G.R.Y.
        Development and validation of a histological method to measure microvessel density in whole-slide images of cancer tissue.
        PLoS One. 2016; 11 (Ribatti D, ed.)e0161496
        • Mayo R.P.
        Advances in human placental biomechanics.
        Comput Struct Biotechnol J. 2018; 16: 298-306
        • McDannold N.
        • Vykhodtseva N.
        • Hynynen K.
        Targeted disruption of the blood–brain barrier with focused ultrasound: Association with cavitation activity.
        Phys Med Biol. 2006; 51: 793
        • Miles K.A.
        Measurement of tissue perfusion by dynamic computed tomography.
        Br J Radiol. 1991; 64: 409-412
        • Montgomery M.
        Uncertainty during breast diagnostic evaluation: State of the science.
        Oncol Nurs Forum. 2010; 37: 77-83
        • Montgomery M.
        • McCrone S.H.
        Psychological distress associated with the diagnostic phase for suspected breast cancer: systematic review.
        J Adv Nurs. 2010; 66: 2372-2390
        • Munkres J.
        Algorithms for the assignment and transportation problems.
        J Soc Ind Appl Math. 1957; 5: 32-38
        • Nedosekin D.A.
        • Galanzha E.I.
        • Dervishi E.
        • Biris A.S.
        • Zharov V.P.
        Super-resolution nonlinear photothermal microscopy.
        Small. 2014; 10: 135-142
        • OˈReilly M.A.
        • Hynynen K.
        A super-resolution ultrasound method for brain vascular mapping.
        Med Phys. 2013; 40110701
        • Opacic T.
        • Dencks S.
        • Theek B.
        • Piepenbrock M.
        • Ackermann D.
        • Rix A.
        • Lammers T.
        • Stickeler E.
        • Delorme S.
        • Schmitz G.
        Motion model ultrasound localization microscopy for preclinical and clinical multiparametric tumor characterization.
        Nat Commun. 2018; 9: 1527
        • Pajek D.
        • Burgess A.
        • Huang Y.
        • Hynynen K.
        High-intensity focused ultrasound sonothrombolysis: The use of perfluorocarbon droplets to achieve clot lysis at reduced acoustic power.
        Ultrasound Med Biol. 2014; 40: 2151-2161
        • Pantoni L.
        Cerebral small vessel disease: From pathogenesis and clinical characteristics to therapeutic challenges.
        Lancet Neurol. 2010; 9: 689-701
        • Petersen E.T.
        • Zimine I.
        • Ho Y.L.
        • Golay X.
        Non-invasive measurement of perfusion: A critical review of arterial spin labelling techniques.
        Br J Radiol. 2006; 79: 688-701
        • Pichardo S.
        • Sin V.W.
        • Hynynen K.
        Multi-frequency characterization of the speed of sound and attenuation coefficient for longitudinal transmission of freshly excised human skulls.
        Phys Med Biol. 2011; 56: 219
        • Pieczynski J.
        • Grzybowski A.
        Review of diabetic retinopathy screening methods and programmes adopted in different parts of the world.
        Eur Ophthalmic Rev. 2015; 9: 49-55
        • Postema M.
        • Van Wamel A.
        • Lancée C.T.
        • De Jong N.
        Ultrasound-induced encapsulated microbubble phenomena.
        Ultrasound Med Biol. 2004; 30: 827-840
        • Prada C.
        • Thomas J.L.
        Experimental subwavelength localization of scatterers by decomposition of the time reversal operator interpreted as a covariance matrix.
        J Acoust Soc Am. 2003; 114: 235-243
        • Provost J.
        • Papadacci C.
        • Arango J.E.
        • Imbault M.
        • Fink M.
        • Gennisson -L.
        • Tanter M.
        • Pernot M.
        3D ultrafast ultrasound imaging in vivo.
        Phys Med Biol. 2014; 59: L1
        • Pugsley M.K.
        • Tabrizchi R.
        The vascular system: An overview of structure and function.
        J Pharmacol Toxicol Methods. 2000; 44: 333-340
        • Ragan T.
        • Kadiri L.R.
        • Venkataraju K.U.
        • Bahlmann K.
        • Sutin J.
        • Taranda J.
        • Arganda-Carreras I.
        • Kim Y.
        • Seung H.S.
        • Osten P.
        Serial two-photon tomography for automated ex vivo mouse brain imaging.
        Nat Methods. 2012; 9: 255
        • Rao S.R.
        • Shelton S.E.
        • Dayton P.A.
        The “fingerprint” of cancer extends beyond solid tumor boundaries: Assessment with a novel ultrasound imaging approach.
        IEEE Trans Biomed Eng. 2015; 63: 1082-1086
        • Rapoport N.Y.
        • Kennedy A.M.
        • Shea J.E.
        • Scaife C.L.
        • Nam K.H.
        Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/microbubbles.
        J Control Release. 2009; 138: 268-276
        • Renier N.
        • Wu Z.
        • Simon D.J.
        • Yang J.
        • Ariel P.
        • Tessier-Lavigne M.
        iDISCO: A simple, rapid method to immunolabel large tissue samples for volume imaging.
        Cell. 2014; 159: 896-910
        • Rey J.E.
        • Gardner S.M.
        • Cushing R.D.
        Determinants of surgical site infection after breast biopsy.
        Am J Infect Control. 2005; 33: 126-129
        • Reznik N.
        • Williams R.
        • Burns P.N.
        Investigation of vaporized submicron perfluorocarbon droplets as an ultrasound contrast agent.
        Ultrasound Med Biol. 2011; 37: 1271-1279
        • Rust M.J.
        • Bates M.
        • Zhuang X.
        Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM).
        Nat Methods. 2006; 3: 793
        • Sandrin L.
        • Catheline S.
        • Tanter M.
        • Hennequin X.
        • Fink M.
        Time-resolved pulsed elastography with ultrafast ultrasonic imaging.
        Ultrason Imaging. 1999; 21: 259-272
        • Schrope B.
        • Newhouse V.L.
        • Uhlendorf V.
        Simulated capillary blood flow measurement using a nonlinear ultrasonic contrast agent.
        Ultrason Imaging. 1992; 14: 134-158
        • Sheeran P.S.
        • Luois S.H.
        • Mullin L.B.
        • Matsunaga T.O.
        • Dayton P.A.
        Design of ultrasonically-activatable nanoparticles using low boiling point perfluorocarbons.
        Biomaterials. 2012; 33: 3262-3269
        • Sheeran P.S.
        • Rojas J.D.
        • Puett C.
        • Hjelmquist J.
        • Arena C.B.
        • Dayton P.A.
        Contrast-enhanced ultrasound imaging and in vivo circulatory kinetics with low-boiling-point nanoscale phase-change perfluorocarbon agents.
        Ultrasound Med Biol. 2015; 41: 814-831
        • Shekhawat G.S.
        • Dravid V.P.
        Nanoscale imaging of buried structures via scanning near-field ultrasound holography.
        Science. 2005; 310: 89-92
        • Shelton S.E.
        • Lee Y.Z.
        • Lee M.
        • Cherin E.
        • Foster F.S.
        • Aylward S.R.
        • Dayton P.A.
        Quantification of microvascular tortuosity during tumor evolution using acoustic angiography.
        Ultrasound Med Biol. 2015; 41: 1896-1904
        • Shi W.T.
        • Forsberg F.
        Ultrasonic characterization of the nonlinear properties of contrast microbubbles.
        Ultrasound Med Biol. 2000; 26: 93-104
        • Shpak O.
        • Verweij M.
        • Vos H.J.
        • de Jong N.
        • Lohse D.
        • Versluis M.
        Acoustic droplet vaporization is initiated by superharmonic focusing.
        Proceedings of the National Academy of Sciences. 2014; 111: 1697-1702
        • Siepmann M.
        • Schmitz G.
        • Bzyl J.
        • Palmowski M.
        • Kiessling F.
        Imaging tumor vascularity by tracing single microbubbles.
        Proc IEEE Int Ultrason Symp. 2011; : 1906-1909
        • Simpson D.H.
        • Chin C.T.
        • Burns P.N.
        Pulse inversion Doppler: A new method for detecting nonlinear echoes from microbubble contrast agents.
        IEEE Trans Ultrason Ferroelectr Freq Control. 1999; 46: 372-382
        • Soeller C.
        • Cannell M.B.
        Examination of the transverse tubular system in living cardiac rat myocytes by 2-photon microscopy and digital image–processing techniques.
        Circulation Res. 1999; 84: 266-275
      7. Solomon O, van Sloun RJ, Wijkstra H, Mischi M, Eldar YC. Exploiting flow dynamics for super-resolution in contrast-enhanced ultrasound. arXiv preprint arXiv:180403134. 2018;

        • Solomon O.
        • Eldar Y.C.
        • Mutzafi M.
        • Segev M.
        SPARCOM: Sparsity based super-resolution correlation microscopy.
        SIAM J Imaging Sci. 2019; 12: 392-419
        • Song P.
        • Trzasko J.D.
        • Manduca A.
        • Huang R.
        • Kadirvel R.
        • Kallmes D.F.
        • Chen S.
        Improved super-resolution ultrasound microvessel imaging with spatiotemporal nonlocal means filtering and bipartite graph-based microbubble tracking.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2017; 65: 149-167
        • Song P.
        • Manduca A.
        • Trzasko J.D.
        • Daigle R.E.
        • Chen S.
        On the effects of spatial sampling quantization in super-resolution ultrasound microvessel imaging.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2018; 65: 2264-2276
        • Soulioti D.E.
        • Espindola D.
        • Dayton P.A.
        • Pinton G.
        Super-resolution imaging through the human skull.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2020; 67: 25-36
        • Stanimirovic D.B.
        • Friedman A.
        Pathophysiology of the neurovascular unit: Disease cause or consequence?.
        J Cereb Blood Flow Metab. 2012; 32: 1207-1221
        • Storkebaum E.
        • Lambrechts D.
        • Carmeliet P.
        VEGF: Once regarded as a specific angiogenic factor, now implicated in neuroprotection.
        Bioessays. 2004; 26: 943-954
        • Stride E.
        • Saffari N.
        Microbubble ultrasound contrast agents: A review.
        Proc Inst Mech Eng H. 2003; 217: 429-447
        • Theek B.
        • Opacic T.
        • Magnuska Z.
        • Lammers T.
        • Kiessling F.
        Radiomic analysis of contrast-enhanced ultrasound data.
        Sci Rep. 2018; 8: 11359
        • Underwood S.R.
        • Anagnostopoulos C.
        • Cerqueira M.
        • Ell P.J.
        • Flint E.J.
        • Harbinson M.
        • Kelion A.D.
        • Al-Mohammad A.
        • Prvulovich E.M.
        • Shaw L.J.
        Myocardial perfusion scintigraphy: The evidence.
        Eur J Nucl Med Mol Imaging. 2004; 31: 261-291
        • Van Heel M.
        • Schatz M
        Fourier shell correlation threshold criteria.
        J Struct Biol. 2005; 151: 250-262
        • van Sloun R.J.G.
        • Solomon O.
        • Eldar Y.C.
        • Wijkstra H.
        • Mischi M.
        Sparsity-driven super-resolution in clinical contrast-enhanced ultrasound.
        Proc IEEE Int Ultrason Symp. 2017; (Available at:)
      8. van Sloun RJG, Solomon O, Bruce M, Khaing ZZ, Wijkstra H, Eldar YC, Mischi M. Super-resolution ultrasound localization microscopy through deep learning. arXiv preprint arXiv:180407661. 2018a.

        • van Sloun R.J.G.
        • Demi L.
        • Schalk S.G.
        • Caresio C.
        • Mannaerts C.
        • Postema A.W.
        • Molinari F.
        • van der Linden H.C.
        • Huang P.
        • Wijkstra H.
        • Mischi M.
        Contrast-enhanced ultrasound tractography for 3D vascular imaging of the prostate.
        Sci Rep. 2018; 8: 14640
        • van Sloun R.J.G.
        • Solomon O.
        • Bruce M.
        • Khaing Z.Z.
        • Eldar Y.C.
        • Mischi M.
        Deep learning for super-resolution vascular ultrasound imaging.
        in: IEEE International Conference on Acoustics, Speech and Signal Processing—ICASSP 2019. IEEE, 2019
        • Viessmann O.M.
        • Eckersley R.J.
        • Christensen-Jeffries K.
        • Tang M.X.
        • Dunsby C.
        Acoustic super-resolution with ultrasound and microbubbles.
        Phys Med Biol. 2013; 58: 6447-6458
        • Vilov S.
        • Arnal B.
        • Bossy E.
        Overcoming the acoustic diffraction limit in photoacoustic imaging by localization of flowing absorbers.
        Opt Lett. 2017; 42: 4379-4382
        • Walker W.F.
        • Trahey G.E.
        A fundamental limit on delay estimation using partially correlated speckle signals.
        IEEE Trans Ultrason Ferroelectr Freq Control. 1995; 42: 301-308
        • Wang L.V.
        • Hu S.
        Photoacoustic tomography: In vivo imaging from organelles to organs.
        Science. 2012; 335: 1458-1462
        • Wardlaw J.M.
        • Smith E.E.
        • Biessels G.J.
        • Cordonnier C.
        • Fazekas F.
        • Frayne R.
        • Lindley R.I.
        • T O'Brien J.
        • Barkhof F.
        • Benavente O.R.
        Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration.
        Lancet Neurol. 2013; 12: 822-838
        • Webb A.J.
        • Simoni M.
        • Mazzucco S.
        • Kuker W.
        • Schulz U.
        • Rothwell P.M.
        Increased cerebral arterial pulsatility in patients with leukoaraiosis: Arterial stiffness enhances transmission of aortic pulsatility.
        Stroke. 2012; 43: 2631-2636
        • Weidner N.
        Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors.
        Breast Cancer Res Treat. 1995; 36: 169-180
        • Wheatley M.A.
        • Schrope B.
        • Shen P.
        Contrast agents for diagnostic ultrasound: Development and evaluation of polymer-coated microbubbles.
        Biomaterials. 1990; 11: 713-717
        • Williams D.S.
        • Detre J.A.
        • Leigh J.S.
        • Koretsky A.P.
        Magnetic resonance imaging of perfusion using spin inversion of arterial water.
        Proc Natl Acad Sci. 1992; 89: 212-216
        • World Cancer Research Fund International
        Breast cancer statistics.
        Author, London2018 (Available at:)
        • World Health Organization (WHO)
        Early detection of cancer.
        Author, Geneva2019 (Available at:)
        • Zhang G.
        • Harput S.
        • Lin S.
        • Christensen-Jeffries K.
        • Leow C.H.
        • Brown J.
        • Dunsby C.
        • Eckersley R.J.
        • Tang M.X.
        Acoustic wave sparsely activated localization microscopy (AWSALM): Super-resolution ultrasound imaging using acoustic activation and deactivation of nanodroplets.
        Appl Phys Lett. 2018; 113014101
        • Zhang G.
        • Harput S.
        • Hu H.
        • Christensen-Jeffries K.
        • Zhu J.
        • Brown J.
        • Leow C.H.
        • Eckersley R.J.
        • Dunsby C.
        • Tang M.
        Fast acoustic wave sparsely activated localization microscopy: Super-resolution ultrasound using plane-wave activation of nanodroplets.
        IEEE Trans Ultrason Ferroelectr Freq Control. 2019; 66: 1039-1046
        • Zhang G.
        • Lin S.
        • Leow C.H.
        • Pang K.T.
        • Hernández-Gil J.
        • Long N.J.
        • Eckersley R.
        • Matsunaga T.
        • Tang M.X.
        Quantification of vaporised targeted nanodroplets using high-frame-rate ultrasound and optics.
        Ultrasound Med Biol. 2019; 45: 1131-1142
        • Zhu J.
        • Rowland E.M.
        • Harput S.
        • Riemer K.
        • Leow C.H.
        • Clark B.
        • Cox K.
        • Lim A.
        • Christensen-Jeffries K.
        3D super-resolution US imaging of rabbit lymph node vasculature in vivo by using microbubbles.
        Radiology. 2019; 291: 642-650
        • Zlokovic Berislav V.
        Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders.
        Nat Rev Neurosci. 2011; 12: 723-738