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A review of low-intensity focused ultrasound for neuromodulation

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Abstracts

The ability of ultrasound to be focused into a small region of interest through the intact skull within the brain has led researchers to investigate its potential therapeutic uses for functional neurosurgery and tumor ablation. Studies have used high-intensity focused ultrasound to ablate tissue in localised brain regions for movement disorders and chronic pain while sparing the overlying and surrounding tissue. More recently, low-intensity focused ultrasound (LIFU) that induces reversible biological effects has been emerged as an alternative neuromodulation modality due to its bi-modal (i.e. excitation and suppression) capability with exquisite spatial specificity and depth penetration. Many compelling evidences of LIFU-mediated neuromodulatory effects including behavioral responses, electrophysiological recordings and functional imaging data have been found in the last decades. LIFU, therefore, has the enormous potential to improve the clinical outcomes as well as to replace the currently available neuromodulation techniques such as deep brain stimulation (DBS), transcranial magnetic stimulation and transcranial current stimulation. In this paper, we aim to provide a summary of pioneering studies in the field of ultrasonic neuromodulation including its underlying mechanisms that were published in the last 60 years. In closing, some of potential clinical applications of ultrasonic brain stimulation will be discussed.

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References

  1. ter Haar G. Therapeutic applications of ultrasound. Prog Biophys Mol Biol. 2007;93(1–3):111–29.

    Google Scholar 

  2. Pahk KJ, Mohammad GH, Malago M, Saffari N, Dhar DK. A novel approach to ultrasound-mediated tissue decellularization and intra-hepatic cell delivery in rats. Ultrasound Med Biol. 2016;42(8):1958–67.

    Article  Google Scholar 

  3. Lipsman N, Schwartz ML, Huang Y, Lee L, Sankar T, Chapman M, Hynynen K, Lozano AM. MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study. Lancet Neurol. 2013;12(5):462–8.

    Article  Google Scholar 

  4. Bauer R, Martin E, Haegele-Link S, Kaegi G, von Specht M, Werner B. Noninvasive functional neurosurgery using transcranial MR imaging-guided focused ultrasound. Parkinsonism Relat Disord. 2014;20(Suppl 1):S197–9.

    Article  Google Scholar 

  5. Yoo SS, Bystritsky A, Lee JH, Zhang Y, Fischer K, Min BK, McDannold NJ, Pascual-Leone A, Jolesz FA. Focused ultrasound modulates region-specific brain activity. Neuroimage. 2011;56(3):1267–75.

    Article  Google Scholar 

  6. Fry FJ, Ades HW, Fry WJ. Production of reversible changes in the central nervous system by ultrasound. Science. 1958;127(3289):83–4.

    Article  Google Scholar 

  7. Ballantine HT Jr, Bell E, Manlapaz J. Progress and problems in the neurological applications of focused ultrasound. J Neurosurg. 1960;17:858–76.

    Article  Google Scholar 

  8. Kim H, Chiu A, Park S, Yoo SS. Image-guided navigation of single-element focused ultrasound transducer. Int J Imag Syst Tech. 2012;22(3):177–84.

    Article  Google Scholar 

  9. Lee W, Kim H, Jung Y, Song I-U, Chung YA, Yoo S-S. Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. Sci Rep. 2015;5:8743.

    Article  Google Scholar 

  10. Bystritsky A, Korb AS, Douglas PK, Cohen MS, Melega WP, Mulgaonkar AP, DeSalles A, Min BK, Yoo SS. A review of low-intensity focused ultrasound pulsation. Brain Stimul. 2011;4(3):125–36.

    Article  Google Scholar 

  11. Takagi SF, Higashino S, Shibuya T, Osawa N. The actions of ultrasound on the myelinated nerve, the spinal cord and the brain. Jpn J Physiol. 1960;10:183–93.

    Article  Google Scholar 

  12. Monti MM, Schnakers C, Korb AS, Bystritsky A, Vespa PM. Non-invasive ultrasonic thalamic stimulation in disorders of consciousness after severe brain injury: a first-in-man report. Brain Stimul. 2016.

  13. Min BK, Yang PS, Bohlke M, Park S, Vago DR, Maher TJ, Yoo SS. Focused ultrasound modulates the level of cortical neurotransmitters: potential as a new functional brain mapping technique. Int J Imag Syst Tech. 2011;21(2):232–40.

    Article  Google Scholar 

  14. Yang PS, Kim H, Lee W, Bohlke M, Park S, Maher TJ, Yoo SS. Transcranial focused ultrasound to the thalamus is associated with reduced extracellular GABA levels in rats. Neuropsychobiology. 2012;65(3):153–60.

    Article  Google Scholar 

  15. Piper RJ, Hughes MA, Moran CM, Kandasamy J. Focused ultrasound as a non-invasive intervention for neurological disease: a review. Br J Neurosurg. 2016;30(3):286–93.

    Article  Google Scholar 

  16. Bronstein JM, Tagliati M, Alterman RL, Lozano AM, Volkmann J, Stefani A, Horak FB, Okun MS, Foote KD, Krack P, Pahwa R, Henderson JM, Hariz MI, Bakay RA, Rezai A, Marks WJ, Moro E, Vitek JL, Weaver FM, Gross RE, DeLong MR. Deep brain stimulation for Parkinson disease an expert consensus and review of key issues. Arch Neurol-Chicago. 2011;68(2):165–71.

    Article  Google Scholar 

  17. Mazoue H, Chauchard P. BUSNEL RG. Nervous excitation with high frequency ultrasonics. J Physiol. 1953;45(1):179–82.

    Google Scholar 

  18. Rinaldi PC, Jones JP, Reines F, Price LR. Modification by focused ultrasound pulses of electrically evoked responses from an in vitro hippocampal preparation. Brain Res. 1991;558(1):36–42.

    Article  Google Scholar 

  19. Bachtold MR, Rinaldi PC, Jones JP, Reines F, Price LR. Focused ultrasound modifications of neural circuit activity in a mammalian brain. Ultrasound Med Biol. 1998;24(4):557–65.

    Article  Google Scholar 

  20. Koroleva VI, Vykhodtseva NI, Elagin VA. Cortical and subcortical spreading depression in rats produced by focused ultrasound. Neurophysiology. 1986;18(1):43–8.

    Article  Google Scholar 

  21. Velling VA, Shklyaruk SP. Modulation of the functional state of the brain with the aid of focused ultrasonic action. Neurosci Behav Physiol. 1988;18(5):369–75.

    Article  Google Scholar 

  22. Manlapaz JS, Astroem KE, Ballantine HTJ, Lele PP. Effects of ultrasonic radiation in experimental focal epilepsy in the cat. Exp Neurol. 1964;10:345–56.

    Article  Google Scholar 

  23. Tyler WJ, Tufail Y, Finsterwald M, Tauchmann ML, Olson EJ, Majestic C. Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound. Plos One. 2008; 3(10).

  24. Tufail Y, Matyushov A, Baldwin N, Tauchmann ML, Georges J, Yoshihiro A, Tillery SI, Tyler WJ. Transcranial pulsed ultrasound stimulates intact brain circuits. Neuron. 2010;66(5):681–94.

    Article  Google Scholar 

  25. King RL, Brown JR, Newsome WT, Pauly KB. Effective parameters for ultrasound-induced in vivo neurostimulation. Ultrasound Med Biol. 2013;39(2):312–31.

    Article  Google Scholar 

  26. King RL, Brown JR, Pauly KB. Localization of ultrasound-induced in vivo neurostimulation in the mouse model. Ultrasound Med Biol. 2014;40(7):1512–22.

    Article  Google Scholar 

  27. Mehic E, Xu JM, Caler CJ, Coulson NK, Moritz CT, Mourad PD. Increased anatomical specificity of neuromodulation via modulated focused ultrasound. PLoS ONE. 2014;9(2):e86939.

    Article  Google Scholar 

  28. Younan Y, Deffieux T, Larrat B, Fink M, Tanter M, Aubry JF. Influence of the pressure field distribution in transcranial ultrasonic neurostimulation. Med Phys. 2013;40(8):082902.

    Article  Google Scholar 

  29. Kim H, Lee SD, Chiu A, Yoo SS, Park S. Estimation of the spatial profile of neuromodulation and the temporal latency in motor responses induced by focused ultrasound brain stimulation. NeuroReport. 2014;25(7):475–9.

    Google Scholar 

  30. Kim H, Chiu A, Lee SD, Fischer K, Yon SS. Focused ultrasound-mediated non-invasive brain stimulation: examination of sonication parameters. Brain Stimul. 2014;7(5):748–56.

    Article  Google Scholar 

  31. Yoo SS, Kim H, Min BK, Franck E, Park S. Transcranial focused ultrasound to the thalamus alters anesthesia time in rats. NeuroReport. 2011;22(15):783–7.

    Article  Google Scholar 

  32. Lee W, Lee SD, Park MY, Foley L, Purcell-Estabrook E, Kim H, Fischer K, Maeng LS, Yoo SS. Image-guided focused ultrasound-mediated regional brain stimulation in sheep. Ultrasound Med Biol. 2016;42(2):459–70.

    Article  Google Scholar 

  33. Harvey EN. The effect of high frequency sound waves on heart muscle and other irritable tissues. Am J Physiol. 1929;91:284–90.

    Google Scholar 

  34. Mihran RT, Barnes FS, Wachtel H. Temporally-specific modification of myelinated axon excitability in vitro following a single ultrasound pulse. Ultrasound Med Biol. 1990;16(3):297–309.

    Article  Google Scholar 

  35. Young RR, Henneman E. Reversible block of nerve conduction by ultrasound: ultrasonic blocking of nerve fibers. Arch Neurol-Chicago. 1961;4(1):83–9.

    Article  Google Scholar 

  36. Colucci V, Strichartz G, Jolesz F, Vykhodtseva N, Hynynen K. Focused ultrasound effects on nerve action potential in vitro. Ultrasound Med Biol. 2009;35(10):1737–47.

    Article  Google Scholar 

  37. Foley JL, Little JW, Vaezy S. Image-guided high-intensity focused ultrasound for conduction block of peripheral nerves. Ann Biomed Eng. 2007;35(1):109–19.

    Article  Google Scholar 

  38. Kim H, Taghados SJ, Fischer K, Maeng LS, Park S, Yoo SS. Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound. Ultrasound Med Biol. 2012;38(9):1568–75.

    Article  Google Scholar 

  39. Juan EJ, Gonzalez R, Albors G, Ward MP, Irazoqui P. Vagus nerve modulation using focused pulsed ultrasound: potential applications and preliminary observations in a rat. Int J Imag Syst Tech. 2014;24(1):67–71.

    Article  Google Scholar 

  40. Wright CJ, Rothwell J, Saffari N. Ultrasonic stimulation of peripheral nervous tissue: an investigation into mechanisms. J Phys Conf Ser. 2015; 581.

  41. Gavrilov LR, Gershuni GV, Ilyinski OB, Popova LA, Sirotyuk MG, Tsirulnikov EM. Sov. Phys. Acoust. 1973; 19(322).

  42. Gavrilov LR, Tsirulnikov EM, Davies IA. Application of focused ultrasound for the stimulation of neural structures. Ultrasound Med Biol. 1996;22(2):179–92.

    Article  Google Scholar 

  43. Gavrilov LR, Tsirulnikov EM. Focused ultrasound as a tool to input sensory information to humans (Review). Acoust Phys. 2012;58(1):1–21.

    Article  Google Scholar 

  44. Lee W, Kim H, Lee S, Yoo S-S, Chung YA. Creation of various skin sensations using pulsed focused ultrasound: evidence for functional neuromodulation. Int J Imag Syst Tech. 2014;24(2):167–74.

    Article  Google Scholar 

  45. Hameroff S, Trakas M, Duffield C, Annabi E, Gerace MB, Boyle P, Lucas A, Amos Q, Buadu A, Badal JJ. Transcranial ultrasound (TUS) effects on mental states: a pilot study. Brain Stimul. 2013;6(3):409–15.

    Article  Google Scholar 

  46. Mueller J, Legon W, Opitz A, Sato TF, Tyler WJ. Transcranial focused ultrasound modulates intrinsic and evoked EEG dynamics. Brain Stimul. 2014;7(6):900–8.

    Article  Google Scholar 

  47. Legon W, Sato TF, Opitz A, Mueller J, Barbour A, Williams A, Tyler WJ. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nat Neurosci. 2014;17(2):322–9.

    Article  Google Scholar 

  48. Lee W, Chung Y-A, Jung Y, Song I-U, Yoo S-S. Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound. BMC Neurosci. 2016;17(1):68.

    Article  Google Scholar 

  49. Lee W, Kim H-C, Jung Y, Chung YA, Song I-U, Lee J-H, Yoo S-S. Transcranial focused ultrasound stimulation of human primary visual cortex. Sci Rep. 2016;6:34026.

    Article  Google Scholar 

  50. Wulff VJ, Fry WJ, Tucker D, Fry FJ, Melton C. Effects of ultrasonic vibrations on nerve tissues. Exp Biol Med. 1951;76:361–6.

    Article  Google Scholar 

  51. Borrelli MJ, Bailey KI, Dunn F. Early ultrasonic effects upon mammalian Cns structures (Chemical Synapses). J Acoust Soc Am. 1981;69(5):1514–6.

    Article  Google Scholar 

  52. Menz MD, Oralkan O, Khuri-Yakub PT, Baccus SA. Precise neural stimulation in the retina using focused ultrasound. J Neurosci. 2013;33(10):4550.

    Article  Google Scholar 

  53. Tyler WJ. Opinion the mechanobiology of brain function. Nat Rev Neurosci. 2012;13(12):867–78.

    Article  Google Scholar 

  54. Kubanek J, Shi JY, Marsh J, Chen D, Deng CR, Cui JM. Ultrasound modulates ion channel currents. Sci Rep. 2016; 6.

  55. Krasovitski B, Frenkel V, Shoham S, Kimmel E. Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects. Proc Natl Acad Sci USA. 2011;108(8):3258–63.

    Article  Google Scholar 

  56. Plaksin M, Shoham S, Kimmel E. Intramembrane cavitation as a predictive bio-piezoelectric mechanism for ultrasonic brain stimulation. J Mol Neurosci. 2014;53:S103.

    Article  Google Scholar 

  57. Chu PC, Liu HL, Lai HY, Lin CY, Tsai HC, Pei YC. Neuromodulation accompanying focused ultrasound-induced blood-brain barrier opening. Scientific Reports. 2015; 5.

  58. Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA. Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology. 2001;220(3):640–6.

    Article  Google Scholar 

  59. Liu HL, Fan CH, Ting CY, Yeh CK. Combining microbubbles and ultrasound for drug delivery to brain tumors: current progress and overview. Theranostics. 2014;4(4):432–44.

    Article  Google Scholar 

  60. Neppiras EA. Acoustic cavitation series: part one: acoustic cavitation: an introduction. Ultrasonics. 1984;22(1):25–8.

    Article  Google Scholar 

  61. Bailey MR, Khokhlova VA, Sapozhnikov OA, Kargl SG, Crum LA. Physical mechanisms of the therapeutic effect of ultrasound: a review. Acoust Phys. 2003;49(4):369–88.

    Article  Google Scholar 

  62. Plaksin M, Kimmel E, Shoham S. Cell-type-selective effects of intramembrane cavitation as a unifying theoretical framework for ultrasonic neuromodulation. eNeuro. 2016; 3(3).

  63. Rezayat E, Ghodrati Toostani I. A review on brain stimulation using low intensity focused ultrasound. Basic Clin Neurosci. 2016;7(3):187–94.

    Google Scholar 

  64. Sapareto SA, Dewey WC. Thermal dose determination in cancer therapy. Int J Radiat Oncol Biol Phys. 1984;10(6):787–800.

    Article  Google Scholar 

  65. Nelson TR, Fowlkes JB, Abramowicz JS, Church CC. Ultrasound biosafety considerations for the practicing sonographer and sonologist. J Ultras Med. 2009;28(2):139–50.

    Article  Google Scholar 

  66. Naor O, Hertzberg Y, Zemel E, Kimmel E, Shoham S. Towards multifocal ultrasonic neural stimulation II: design considerations for an acoustic retinal prosthesis. J Neural Eng. 2012;9(2):026006.

    Article  Google Scholar 

  67. Bigelow TA, Church CC, Sandstrom K, Abbott JG, Ziskin MC, Edmonds PD, Herman B, Thomenius KE, Teo TJ. The thermal index: its strengths, weaknesses, and proposed improvements. J Ultrasound Med. 2011;30(5):714–34.

    Article  Google Scholar 

  68. Duck FA. Medical and non-medical protection standards for ultrasound and infrasound. Prog Biophys Mol Biol. 2007;93(1–3):176–91.

    Article  Google Scholar 

  69. Sanguinetti JL, Smith EE, Tyler WJ, Hameroff S, Allen JJB. Transcranial ultrasound (Tus) brain stimulation affects mood in healthy human volunteers with a prototype ultrasound device. Psychophysiology. 2014;51:S42.

    Article  Google Scholar 

  70. Leinenga G, Gotz J. Scanning ultrasound removes amyloid-beta and restores memory in an Alzheimer’s disease mouse model. Sci. Transl. Med. 2015;7(278):278ra33.

    Article  Google Scholar 

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Acknowledgements

This work was supported by the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2015M3C7A1064833).

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Correspondence to Hyungmin Kim.

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Hongchae Baek and Ki Joo Pahk equally contributed to this paper and will be designated as co-first authors.

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Baek, H., Pahk, K.J. & Kim, H. A review of low-intensity focused ultrasound for neuromodulation. Biomed. Eng. Lett. 7, 135–142 (2017). https://doi.org/10.1007/s13534-016-0007-y

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