1932

Abstract

Functional ultrasound (fUS) is a neuroimaging method that uses ultrasound to track changes in cerebral blood volume as an indirect readout of neuronal activity at high spatiotemporal resolution. fUS is capable of imaging head-fixed or freely behaving rodents and of producing volumetric images of the entire mouse brain. It has been applied to many species, including primates and humans. Now that fUS is reaching maturity, it is being adopted by the neuroscience community. However, the nature of the fUS signal and the different implementations of fUS are not necessarily accessible to nonspecialists. This review aims to introduce these ultrasound concepts to all neuroscientists. We explain the physical basis of the fUS signal and the principles of the method, present the state of the art of its hardware implementation, and give concrete examples of current applications in neuroscience. Finally, we suggest areas for improvement during the next few years.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-neuro-111020-100706
2022-07-08
2024-04-23
Loading full text...

Full text loading...

/deliver/fulltext/neuro/45/1/annurev-neuro-111020-100706.html?itemId=/content/journals/10.1146/annurev-neuro-111020-100706&mimeType=html&fmt=ahah

Literature Cited

  1. Ahrens MB, Orger MB, Robson DN, Li JM, Keller PJ. 2013. Whole-brain functional imaging at cellular resolution using light-sheet microscopy. Nat. Methods 10:5413–20
    [Google Scholar]
  2. Aydin AK, Haselden WD, Goulam Houssen Y, Pouzat C, Rungta RL et al. 2020. Transfer functions linking neural calcium to single voxel functional ultrasound signal. Nat. Commun. 11:2954
    [Google Scholar]
  3. Bandettini PA. 2014. Neuronal or hemodynamic? Grappling with the functional MRI signal. Brain Connect 4:7487–98
    [Google Scholar]
  4. Baranger J, Arnal B, Perren F, Baud O, Tanter M, Demené C. 2018. Adaptive spatiotemporal SVD clutter filtering for ultrafast Doppler imaging using similarity of spatial singular vectors. IEEE Trans. Med. Imaging 37:71574–86
    [Google Scholar]
  5. Baranger J, Demené C, Frerot A, Faure F, Delanoë C et al. 2021. Bedside functional monitoring of the dynamic brain connectivity in human neonates. Nat. Commun. 12:1080
    [Google Scholar]
  6. Bercoff J, Montaldo G, Loupas T, Savery D, Mézière F et al. 2011. Ultrafast compound Doppler imaging: providing full blood flow characterization. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 58:1134–47
    [Google Scholar]
  7. Bergel A, Deffieux T, Demené C, Tanter M, Cohen I. 2018. Local hippocampal fast γ rhythms precede brain-wide hyperemic patterns during spontaneous rodent REM sleep. Nat. Commun. 9:5364
    [Google Scholar]
  8. Bergel A, Tiran E, Deffieux T, Demené C, Tanter M, Cohen I. 2020. Adaptive modulation of brain hemodynamics across stereotyped running episodes. Nat. Commun. 11:6193
    [Google Scholar]
  9. Bertolo A, Nouhoum M, Cazzanelli S, Ferrier J, Mariani J-C et al. 2021. Whole-brain 3D activation and functional connectivity mapping in mice using transcranial functional ultrasound imaging. J. Vis. Exp. 168:e62267
    [Google Scholar]
  10. Bimbard C, Demené C, Girard C, Radtke-Schuller S, Shamma S et al. 2018. Multi-scale mapping along the auditory hierarchy using high-resolution functional ultrasound in the awake ferret. eLife 7:e35028
    [Google Scholar]
  11. Blaize K, Arcizet F, Gesnik M, Ahnine H, Ferrari U et al. 2020. Functional ultrasound imaging of deep visual cortex in awake nonhuman primates. PNAS 117:2514453–63
    [Google Scholar]
  12. Brenner K, Ergun AS, Firouzi K, Rasmussen MF, Stedman Q, Khuri-Yakub BP. 2019. Advances in capacitive micromachined ultrasonic transducers. Micromachines 10:2152
    [Google Scholar]
  13. Brunner C, Grillet M, Sans-Dublanc A, Farrow K, Lambert T et al. 2020. A platform for brain-wide volumetric functional ultrasound imaging and analysis of circuit dynamics in awake mice. Neuron 108:5861–75.e7
    [Google Scholar]
  14. Brunner C, Grillet M, Urban A, Roska B, Montaldo G, Macé E. 2021. Whole-brain functional ultrasound imaging in awake head-fixed mice. Nat. Protoc. 16:3547–71
    [Google Scholar]
  15. Brunner C, Isabel C, Martin A, Dussaux C, Savoye A et al. 2017. Mapping the dynamics of brain perfusion using functional ultrasound in a rat model of transient middle cerebral artery occlusion. J. Cereb. Blood Flow Metab. 37:1263–76
    [Google Scholar]
  16. Brunner C, Korostelev M, Raja S, Montaldo G, Urban A, Baron J-C. 2018. Evidence from functional ultrasound imaging of enhanced contralesional microvascular response to somatosensory stimulation in acute middle cerebral artery occlusion/reperfusion in rats: a marker of ultra-early network reorganization?. J. Cereb. Blood Flow Metab. 38:101690–700
    [Google Scholar]
  17. Buxton RB, Wong EC, Frank LR. 1998. Dynamics of blood flow and oxygenation changes during brain activation: the balloon model. Magn. Reson. Med. 39:6855–64
    [Google Scholar]
  18. Chhetri RK, Amat F, Wan Y, Höckendorf B, Lemon WC, Keller PJ. 2015. Whole-animal functional and developmental imaging with isotropic spatial resolution. Nat. Methods 12:121171–78
    [Google Scholar]
  19. Claron J, Hingot V, Rivals I, Rahal L, Couture O et al. 2021. Large-scale functional ultrasound imaging of the spinal cord reveals in-depth spatiotemporal responses of spinal nociceptive circuits in both normal and inflammatory states. Pain 162:41047–59
    [Google Scholar]
  20. Deffieux T, Demené C, Pernot M, Tanter M. 2018. Functional ultrasound neuroimaging: a review of the preclinical and clinical state of the art. Curr. Opin. Neurobiol. 50:128–35
    [Google Scholar]
  21. Demené C, Baranger J, Bernal M, Delanoe C, Auvin S et al. 2017. Functional ultrasound imaging of brain activity in human newborns. Sci. Transl. Med. 9:411eaah6756
    [Google Scholar]
  22. Demené C, Deffieux T, Pernot M, Osmanski B-F, Biran V et al. 2015. Spatiotemporal clutter filtering of ultrafast ultrasound data highly increases Doppler and fUltrasound sensitivity. IEEE Trans. Med. Imaging 34:112271–85
    [Google Scholar]
  23. Demené C, Mairesse J, Baranger J, Tanter M, Baud O. 2019. Ultrafast Doppler for neonatal brain imaging. NeuroImage 185:851–56
    [Google Scholar]
  24. Demené C, Maresca D, Kohlhauer M, Lidouren F, Micheau P et al. 2018. Multi-parametric functional ultrasound imaging of cerebral hemodynamics in a cardiopulmonary resuscitation model. Sci. Rep. 8:16436
    [Google Scholar]
  25. Dijkhuizen RM, Ren J, Mandeville JB, Wu O, Ozdag FM et al. 2001. Functional magnetic resonance imaging of reorganization in rat brain after stroke. PNAS 98:2212766–71
    [Google Scholar]
  26. Dinh TNA, Jung WB, Shim H-J, Kim S-G. 2021. Characteristics of fMRI responses to visual stimulation in anesthetized versus awake mice. NeuroImage 226:117542
    [Google Scholar]
  27. Dizeux A, Gesnik M, Ahnine H, Blaize K, Arcizet F et al. 2019. Functional ultrasound imaging of the brain reveals propagation of task-related brain activity in behaving primates. Nat. Commun. 10:1400
    [Google Scholar]
  28. Edelman BJ, Ielacqua GD, Chan RW, Asaad M, Choy M, Lee JH. 2021. High-sensitivity detection of optogenetically-induced neural activity with functional ultrasound imaging. NeuroImage 242:118434
    [Google Scholar]
  29. Edelman BJ, Macé E. 2021. Functional ultrasound brain imaging: bridging networks, neurons, and behavior. Curr. Opin. Biomed. Eng. 18:100286
    [Google Scholar]
  30. Errico C, Pierre J, Pezet S, Desailly Y, Lenkei Z et al. 2015. Ultrafast ultrasound localization microscopy for deep super-resolution vascular imaging. Nature 527:7579499–502
    [Google Scholar]
  31. Evans DH, McDicken WN. 2000. Doppler Ultrasound: Physics, Instrumentation and Signal Processing New York: Wiley
  32. Ferrier J, Tiran E, Deffieux T, Tanter M, Lenkei Z. 2020. Functional imaging evidence for task-induced deactivation and disconnection of a major default mode network hub in the mouse brain. PNAS 117:2615270–80
    [Google Scholar]
  33. Fonseca MS, Bergomi MG, Mainen ZF, Shemesh N. 2020. Functional MRI of large scale activity in behaving mice. . bioRxiv 044941. https://doi.org/10.1101/2020.04.16.044941
    [Crossref]
  34. Gesnik M, Blaize K, Deffieux T, Gennisson JL, Sahel JA et al. 2017. 3D functional ultrasound imaging of the cerebral visual system in rodents. NeuroImage 149:1267–74
    [Google Scholar]
  35. Girouard H. 2006. Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J. Appl. Physiol. 100:1328–35
    [Google Scholar]
  36. Grandjean J, Bienert T, Hübner N, Karataş M, Mechling A et al. 2020. Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis. NeuroImage 205:15116278
    [Google Scholar]
  37. Heiles B, Terwiel D, Maresca D. 2021. The advent of biomolecular ultrasound imaging. Neuroscience 474:122–33
    [Google Scholar]
  38. Hillman EMC. 2014. Coupling mechanism and significance of the BOLD signal: a status report. Annu. Rev. Neurosci. 37:161–81
    [Google Scholar]
  39. Hingot V, Brodin C, Lebrun F, Heiles B, Chagnot A et al. 2020. Early ultrafast ultrasound imaging of cerebral perfusion correlates with ischemic stroke outcomes and responses to treatment in mice. Theranostics 10:177480–91
    [Google Scholar]
  40. Hirano Y, Stefanovic B, Silva AC. 2011. Spatiotemporal evolution of the functional magnetic resonance imaging response to ultrashort stimuli. J. Neurosci. 31:41440–47
    [Google Scholar]
  41. Iadecola C. 2017. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96:117–42
    [Google Scholar]
  42. Imbault M, Chauvet D, Gennisson J-L, Capelle L, Tanter M. 2017. Intraoperative functional ultrasound imaging of human brain activity. Sci. Rep. 7:7304
    [Google Scholar]
  43. Ji X, Ferreira T, Friedman B, Liu R, Liechty H et al. 2021. Brain microvasculature has a common topology with local differences in geometry that match metabolic load. Neuron 109:71168–87.e13
    [Google Scholar]
  44. Jung J, Lee W, Kang W, Shin E, Ryu J, Choi H. 2017. Review of piezoelectric micromachined ultrasonic transducers and their applications. J. Micromech. Microeng. 27:11113001
    [Google Scholar]
  45. Kılıç K, Tang J, Erdener ŞE, Sunil S, Giblin JT et al. 2020. Chronic imaging of mouse brain: from optical systems to functional ultrasound. Curr. Protoc. Neurosci. 93:e98
    [Google Scholar]
  46. Landemard A, Bimbard C, Demené C, Shamma S, Norman-Haignere S, Boubenec Y 2021. Distinct higher-order representations of natural sounds in human and ferret auditory cortex. eLife 10e65566
  47. Logothetis NK. 2008. What we can do and what we cannot do with fMRI. Nature 453:7197869–78
    [Google Scholar]
  48. Logothetis NK, Pauls J, Augath M, Trinath T, Oeltermann A. 2001. Neurophysiological investigation of the basis of the fMRI signal. Nature 412:6843150–57
    [Google Scholar]
  49. Macé E, Montaldo G, Cohen I, Baulac M, Fink M, Tanter M. 2011. Functional ultrasound imaging of the brain. Nat. Methods 8:8662–64
    [Google Scholar]
  50. Macé E, Montaldo G, Osmanski B-F, Cohen I, Fink M, Tanter M. 2013. Functional ultrasound imaging of the brain: theory and basic principles. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 60:3492–506
    [Google Scholar]
  51. Macé E, Montaldo G, Trenholm S, Cowan C, Brignall A et al. 2018. Whole-brain functional ultrasound imaging reveals brain modules for visuomotor integration. Neuron 100:51241–51.e7
    [Google Scholar]
  52. Maresca D, Payen T, Lee-Gosselin A, Ling B, Malounda D et al. 2020. Acoustic biomolecules enhance hemodynamic functional ultrasound imaging of neural activity. NeuroImage 209:116467
    [Google Scholar]
  53. Montaldo G, Tanter M, Bercoff J, Benech N, Fink M. 2009. Coherent plane-wave compounding for very high frame rate ultrasonography and transient elastography. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 56:3489–506
    [Google Scholar]
  54. Nayak R, Lee J, Chantigian S, Fatemi M, Chang S-Y, Alizad A 2021. Imaging the response to deep brain stimulation in rodent using functional ultrasound. Phys. Med. Biol. 66:05LT01
    [Google Scholar]
  55. Norman SL, Maresca D, Christopoulos VN, Griggs WS, Demené C et al. 2021. Single-trial decoding of movement intentions using functional ultrasound neuroimaging. Neuron 109:91554–66.e4
    [Google Scholar]
  56. Nunez-Elizalde AO, Krumin M, Reddy CB, Montaldo G, Urban A et al. 2022. Neural correlates of blood flow measured by ultrasound. Neuron. In press
    [Google Scholar]
  57. Ogawa S, Lee TM, Kay AR, Tank DW. 1990. Brain magnetic resonance imaging with contrast dependent on blood oxygenation. PNAS 87:249868–72
    [Google Scholar]
  58. Osmanski B-F, Martin C, Montaldo G, Lanièce P, Pain F et al. 2014a. Functional ultrasound imaging reveals different odor-evoked patterns of vascular activity in the main olfactory bulb and the anterior piriform cortex. NeuroImage 95:176–84
    [Google Scholar]
  59. Osmanski B-F, Pezet S, Ricobaraza A, Lenkei Z, Tanter M. 2014b. Functional ultrasound imaging of intrinsic connectivity in the living rat brain with high spatiotemporal resolution. Nat. Commun. 5:5023
    [Google Scholar]
  60. Peng C, Wu H, Kim S, Dai X, Jiang X. 2021. Recent advances in transducers for intravascular ultrasound (IVUS) imaging. Sensors 21:103540
    [Google Scholar]
  61. Pisauro MA, Dhruv NT, Carandini M, Benucci A. 2013. Fast hemodynamic responses in the visual cortex of the awake mouse. J. Neurosci. 33:4618343–51
    [Google Scholar]
  62. Provansal M, Labernède G, Joffrois C, Rizkallah A, Goulet R et al. 2021. Functional ultrasound imaging of the spreading activity following optogenetic stimulation of the rat visual cortex. Sci. Rep. 11:12603
    [Google Scholar]
  63. Rabut C, Correia M, Finel V, Pezet S, Pernot M et al. 2019. 4D functional ultrasound imaging of whole-brain activity in rodents. Nat. Methods 16:10994–97
    [Google Scholar]
  64. Rabut C, Ferrier J, Bertolo A, Osmanski B, Mousset X et al. 2020a. Pharmaco-fUS: quantification of pharmacologically-induced dynamic changes in brain perfusion and connectivity by functional ultrasound imaging in awake mice. NeuroImage 222:117231
    [Google Scholar]
  65. Rabut C, Yoo S, Hurt RC, Jin Z, Li H et al. 2020b. Ultrasound technologies for imaging and modulating neural activity. Neuron 108:193–110
    [Google Scholar]
  66. Rahal L, Thibaut M, Rivals I, Claron J, Lenkei Z et al. 2020. Ultrafast ultrasound imaging pattern analysis reveals distinctive dynamic brain states and potent sub-network alterations in arthritic animals. Sci. Rep. 10:10485
    [Google Scholar]
  67. Rau R, Kruizinga P, Mastik F, Belau M, De Jong N, Bosch J et al. 2018. 3D functional ultrasound imaging of pigeons. NeuroImage 183:469–77
    [Google Scholar]
  68. Réaux-Le-Goazigo A, Beliard B, Delay L, Rahal L, Claron Jet al 2022. Ultrasound localization microscopy and functional ultrasound imaging reveal atypical features of the trigeminal ganglion vasculature. Commun. Biol 5330
    [Google Scholar]
  69. Roy CS, Sherrington CS. 1890. On the regulation of the blood-supply of the brain. J. Physiol. 11:1/285–158
    [Google Scholar]
  70. Rubin JM, Adler RS, Fowlkes JB, Spratt S, Pallister JE et al. 1995. Fractional moving blood volume: estimation with power Doppler US. Radiology 197:1183–90
    [Google Scholar]
  71. Rubin JM, Bude RO, Carson PL, Bree RL, Adler RS. 1994. Power Doppler US: a potentially useful alternative to mean frequency-based color Doppler US. Radiology 190:3853–56
    [Google Scholar]
  72. Rungta RL, Chaigneau E, Osmanski B-F, Charpak S. 2018. Vascular compartmentalization of functional hyperemia from the synapse to the pia. Neuron 99:2362–75.e4
    [Google Scholar]
  73. Rungta RL, Osmanski B-F, Boido D, Tanter M, Charpak S. 2017. Light controls cerebral blood flow in naive animals. Nat. Commun. 8:14191
    [Google Scholar]
  74. Sans-Dublanc A, Chrzanowska A, Reinhard K, Lemmon D, Nuttin B et al. 2021. Optogenetic fUSI for brain-wide mapping of neural activity mediating collicular-dependent behaviors. Neuron 109:111888–905.e10
    [Google Scholar]
  75. Sauvage J, Poree J, Rabut C, Ferin G, Flesch M et al. 2020. 4D functional imaging of the rat brain using a large aperture row-column array. IEEE Trans. Med. Imaging 39:61884–93
    [Google Scholar]
  76. Sforazzini F, Schwarz AJ, Galbusera A, Bifone A, Gozzi A. 2014. Distributed BOLD and CBV-weighted resting-state networks in the mouse brain. NeuroImage 87:403–15
    [Google Scholar]
  77. Shapiro MG, Goodwill PW, Neogy A, Yin M, Foster FS et al. 2014. Biogenic gas nanostructures as ultrasonic molecular reporters. Nat. Nanotechnol. 9:4311–16
    [Google Scholar]
  78. Shattuck DP, Weinshenker MD, Smith SW, von Ramm OT 1984. Explososcan: a parallel processing technique for high speed ultrasound imaging with linear phased arrays. J. Acoust. Soc. Am. 75:41273–82
    [Google Scholar]
  79. Shih AY, Blinder P, Tsai PS, Friedman B, Stanley G et al. 2013. The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit. Nat. Neurosci. 16:155–63
    [Google Scholar]
  80. Sieu L-A, Bergel A, Tiran E, Deffieux T, Pernot M et al. 2015. EEG and functional ultrasound imaging in mobile rats. Nat. Methods 12:9831–34
    [Google Scholar]
  81. Silva AC, Koretsky AP, Duyn JH. 2007. Functional MRI impulse response for BOLD and CBV contrast in rat somatosensory cortex. Magn. Reson. Med. 57:61110–18
    [Google Scholar]
  82. Soloukey S, Vincent AJPE, Satoer DD, Mastik F, Smits M et al. 2020. Functional ultrasound (fUS) during awake brain surgery: the clinical potential of intra-operative functional and vascular brain mapping. Front. Neurosci. 2019.01384
    [Google Scholar]
  83. Song P, Cuellar CA, Tang S, Islam R, Wen H et al. 2019. Functional ultrasound imaging of spinal cord hemodynamic responses to epidural electrical stimulation: a feasibility study. Front. Neurol. 10:279
    [Google Scholar]
  84. Szabo TL. 2018. Diagnostic Ultrasound Imaging: Inside Out Amsterdam: Elsevier
  85. Takahashi DY, El Hady A, Zhang YS, Liao DA, Montaldo G et al. 2021. Social-vocal brain networks in a non-human primate. bioRxiv 2021.12.01.470701. https://doi.org/10.1101/2021.12.01.470701
    [Crossref]
  86. Tang J, Kılıç K, Szabo TL, Boas DA. 2021. Improved color Doppler for cerebral blood flow axial velocity imaging. IEEE Trans. Med. Imaging 40:2758–64
    [Google Scholar]
  87. Tiran E, Ferrier J, Deffieux T, Gennisson J-L, Pezet S et al. 2017. Transcranial functional ultrasound imaging in freely moving awake mice and anesthetized young rats without contrast agent. Ultrasound Med. Biol. 43:81679–89
    [Google Scholar]
  88. Urban A, Brunner C, Dussaux C, Chassoux F, Devaux B, Montaldo G. 2015a. Functional ultrasound imaging of cerebral capillaries in rodents and humans. Jacobs J. Mol. Transl. Med. 1:1007
    [Google Scholar]
  89. Urban A, Dussaux C, Martel G, Brunner C, Macé E, Montaldo G. 2015b. Real-time imaging of brain activity in freely moving rats using functional ultrasound. Nat. Methods 12:873–78
    [Google Scholar]
  90. Urban A, Golgher L, Brunner C, Gdalyahu A, Har-Gil H et al. 2017. Understanding the neurovascular unit at multiple scales: advantages and limitations of multi-photon and functional ultrasound imaging. Adv. Drug Deliv. Rev. 119:73–100
    [Google Scholar]
  91. Urban A, Macé E, Brunner C, Heidmann M, Rossier J, Montaldo G. 2014. Chronic assessment of cerebral hemodynamics during rat forepaw electrical stimulation using functional ultrasound imaging. NeuroImage 101:138–49
    [Google Scholar]
  92. Vidal B, Droguerre M, Valdebenito M, Zimmer L, Hamon M et al. 2020a. Pharmaco-fUS for characterizing drugs for Alzheimer's disease—the case of THN201, a drug combination of donepezil plus mefloquine. Front. Neurosci. 14:835
    [Google Scholar]
  93. Vidal B, Droguerre M, Venet L, Zimmer L, Valdebenito M et al. 2020b. Functional ultrasound imaging to study brain dynamics: application of pharmaco-fUS to atomoxetine. Neuropharmacology 179:108273
    [Google Scholar]
  94. Wang C, Qi B, Lin M, Zhang Z, Makihata M et al. 2021. Continuous monitoring of deep-tissue haemodynamics with stretchable ultrasonic phased arrays. Nat. Biomed. Eng. 5:7749–58
    [Google Scholar]
  95. Wygant IO, Zhuang X, Yeh DT, Oralkan O, Sanli Ergun A et al. 2008. Integration of 2D CMUT arrays with front-end electronics for volumetric ultrasound imaging. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 55:2327–42
    [Google Scholar]
  96. Yiu BYS, Tsang IKH, Yu ACH. 2010. Real-time GPU-based software beamformer designed for advanced imaging methods research. 2010 IEEE International Ultrasonics Symposium1920–23 Piscataway, NJ: IEEE
    [Google Scholar]
/content/journals/10.1146/annurev-neuro-111020-100706
Loading
/content/journals/10.1146/annurev-neuro-111020-100706
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error