Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Ultrasound treatment of neurological diseases — current and emerging applications

Nature Reviews Neurology volume 12, pages 161–174 (2016)Cite this article

Subjects

Key Points

  • Ultrasound is a mechanical pressure wave with a frequency above the range of human hearing (>20 kHz) that is increasingly used as a diagnostic, surgical, neuromodulation and drug delivery tool

  • Surgical ultrasound initially required craniotomies, but large phased ultrasound arrays have enabled clinical trials of surgical ultrasound through the skull for essential tremor, Parkinson disease, obsessive–compulsive disorder and chronic pain

  • In addition to surgery and neuromodulation, ultrasound has huge potential in its capacity to open the blood–brain barrier to allow drug delivery to the brain

  • Ultrasound therapy has shown promise in the treatment of Alzheimer disease; the unified biochemical basis of neurodegenerative diseases suggests that ultrasound could be effective in more of these conditions

  • Safety issues and attenuation of ultrasound by the human skull pose major challenges for the translation of ultrasound-based strategies for the prevention and treatment of neurological diseases

  • The combination of ultrasound technology and drug development has the potential to reduce, halt or even prevent neurodegenerative diseases and other brain disorders

Abstract

Like cardiovascular disease and cancer, neurological disorders present an increasing challenge for an ageing population. Whereas nonpharmacological procedures are routine for eliminating cancer tissue or opening a blocked artery, the focus in neurological disease remains on pharmacological interventions. Setbacks in clinical trials and the obstacle of access to the brain for drug delivery and surgery have highlighted the potential for therapeutic use of ultrasound in neurological diseases, and the technology has proved useful for inducing focused lesions, clearing protein aggregates, facilitating drug uptake, and modulating neuronal function. In this Review, we discuss milestones in the development of therapeutic ultrasound, from the first steps in the 1950s to recent improvements in technology. We provide an overview of the principles of diagnostic and therapeutic ultrasound, for surgery and transient opening of the blood–brain barrier, and its application in clinical trials of stroke, Parkinson disease and chronic pain. We discuss the promising outcomes of safety and feasibility studies in preclinical models, including rodents, pigs and macaques, and efficacy studies in models of Alzheimer disease. We also consider the challenges faced on the road to clinical translation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Principles of therapeutic ultrasound.
Figure 2: Diagram of a transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) system, such as ExAblate® Transcranial (INSIGHTEC, Tirat Carmel, Israel).
Figure 3: Ascending pain pathways and the brain regions involved.
Figure 4: Obicodilation transiently opens tight junctions to allow pharmaceuticals to cross the blood–brain barrier.
Figure 5: Use of pulsed ultrasound for microbubble cavitation in obicodilation.
Figure 6: Neuronal uptake of an anti-tau single-chain antibody facilitated by scanning ultrasound.

Similar content being viewed by others

References

  1. Vykhodtseva, N., Sorrentino, V., Jolesz, F. A., Bronson, R. T. & Hynynen, K. MRI detection of the thermal effects of focused ultrasound on the brain. Ultrasound Med. Biol. 26, 871–880 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Arvanitis, C. D. & McDannold, N. Integrated ultrasound and magnetic resonance imaging for simultaneous temperature and cavitation monitoring during focused ultrasound therapies. Med. Phys. 40, 112901 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Fry, W. J., Mosberg, W. H. Jr, Barnard, J. W. & Fry, F. J. Production of focal destructive lesions in the central nervous system with ultrasound. J. Neurosurg. 11, 471–478 (1954).

    Article  CAS  PubMed  Google Scholar 

  4. Hynynen, K. et al. Pre-clinical testing of a phased array ultrasound system for MRI-guided noninvasive surgery of the brain — a primate study. Eur. J. Radiol. 59, 149–156 (2006).

    Article  PubMed  Google Scholar 

  5. Pernot, M. et al. In vivo transcranial brain surgery with an ultrasonic time reversal mirror. J. Neurosurg. 106, 1061–1066 (2007).

    Article  PubMed  Google Scholar 

  6. Bauer, R. et al. Noninvasive functional neurosurgery using transcranial MR imaging-guided focused ultrasound. Parkinsonism Relat. Disord. 20, S197–S199 (2014).

    Article  PubMed  Google Scholar 

  7. Chauvet, D. et al. Targeting accuracy of transcranial magnetic resonance-guided high-intensity focused ultrasound brain therapy: a fresh cadaver model. J. Neurosurg. 118, 1046–1052 (2013).

    Article  PubMed  Google Scholar 

  8. Louis, E. D. & Ferreira, J. J. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov. Disord. 25, 534–541 (2010).

    Article  PubMed  Google Scholar 

  9. Hanson, T. L., Fuller, A. M., Lebedev, M. A., Turner, D. A. & Nicolelis, M. A. Subcortical neuronal ensembles: an analysis of motor task association, tremor, oscillations, and synchrony in human patients. J. Neurosci. 32, 8620–8632 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Picillo, M. & Fasano, A. Recent advances in essential tremor: surgical treatment. Parkinsonism Relat. Disord. 22, S171–S175 (2016).

    Article  PubMed  Google Scholar 

  11. Lipsman, N. et al. MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study. Lancet Neurol. 12, 462–468 (2013).

    Article  PubMed  Google Scholar 

  12. Elias, W. J. et al. A pilot study of focused ultrasound thalamotomy for essential tremor. N. Engl. J. Med. 369, 640–648 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Magara, A. et al. First experience with MR-guided focused ultrasound in the treatment of Parkinson's disease. J. Ther. Ultrasound 2, 11 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Na, Y. C., Chang, W. S., Jung, H. H., Kweon, E. J. & Chang, J. W. Unilateral magnetic resonance-guided focused ultrasound pallidotomy for Parkinson disease. Neurology 85, 549–551 (2015).

    Article  PubMed  Google Scholar 

  15. Cetas, J. S., Saedi, T. & Burchiel, K. J. Destructive procedures for the treatment of nonmalignant pain: a structured literature review. J. Neurosurg. 109, 389–404 (2008).

    Article  PubMed  Google Scholar 

  16. Ram, Z. et al. Magnetic resonance imaging-guided, high-intensity focused ultrasound for brain tumor therapy. Neurosurgery 59, 949–955 (2006).

    PubMed  Google Scholar 

  17. Jeanmonod, D. et al. Transcranial magnetic resonance imaging-guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain. Neurosurg. Focus 32, E1 (2012).

    Article  PubMed  Google Scholar 

  18. McDannold, N., Clement, G. T., Black, P., Jolesz, F. & Hynynen, K. Transcranial magnetic resonance imaging-guided focused ultrasound surgery of brain tumors: initial findings in 3 patients. Neurosurgery 66, 323–332 (2010).

    Article  PubMed  Google Scholar 

  19. Medel, R. et al. Magnetic resonance-guided focused ultrasound surgery: part 2: a review of current and future applications. Neurosurgery 71, 755–763 (2012).

    Article  PubMed  Google Scholar 

  20. Coluccia, D. et al. First noninvasive thermal ablation of a brain tumor with MR-guided focused ultrasound. J. Ther. Ultrasound 2, 17 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Barreto, A. D. et al. Safety and dose-escalation study design of Transcranial Ultrasound in Clinical SONolysis for acute ischemic stroke: the TUCSON Trial. Int. J. Stroke 4, 42–48 (2009).

    Article  PubMed  Google Scholar 

  22. Barreto, A. D. et al. CLOTBUST-Hands Free: pilot safety study of a novel operator-independent ultrasound device in patients with acute ischemic stroke. Stroke 44, 3376–3381 (2013).

    Article  PubMed  Google Scholar 

  23. Saqqur, M. et al. The role of sonolysis and sonothrombolysis in acute ischemic stroke: a systematic review and meta-analysis of randomized controlled trials and case–control studies. J. Neuroimaging 24, 209–220 (2014).

    Article  PubMed  Google Scholar 

  24. Daffertshofer, M. et al. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial. Stroke 36, 1441–1446 (2005).

    Article  PubMed  Google Scholar 

  25. Baron, C., Aubry, J. F., Tanter, M., Meairs, S. & Fink, M. Simulation of intracranial acoustic fields in clinical trials of sonothrombolysis. Ultrasound Med. Biol. 35, 1148–1158 (2009).

    Article  PubMed  Google Scholar 

  26. Monteith, S. J. et al. Minimally invasive treatment of intracerebral hemorrhage with magnetic resonance-guided focused ultrasound. J. Neurosurg. 118, 1035–1045 (2013).

    Article  PubMed  Google Scholar 

  27. Lindstrom, P. A. Prefrontal ultrasonic irradiation — a substitute for lobotomy. AMA Arch. Neurol. Psychiatry 72, 399–425 (1954).

    Article  CAS  PubMed  Google Scholar 

  28. Nuttin, B. et al. Consensus on guidelines for stereotactic neurosurgery for psychiatric disorders. J. Neurol. Neurosurg. Psychiatry 85, 1003–1008 (2014).

    Article  PubMed  Google Scholar 

  29. Jung, H. H. et al. Bilateral thermal capsulotomy with MR-guided focused ultrasound for patients with treatment-refractory obsessive–compulsive disorder: a proof-of-concept study. Mol. Psychiatry 20, 1205–1211 (2014).

    Article  PubMed  Google Scholar 

  30. Stern, L. & Rothlin, E. Effets de l'action directe du curare sur les différentes parties du cervelet. Schweiz. Arch. Neurol. Psychiatr. 3, 234–254 (in French) (1918).

    Google Scholar 

  31. Coisne, C. & Engelhardt, B. Tight junctions in brain barriers during central nervous system inflammation. Antioxid. Redox Signal. 15, 1285–1303 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Tietz, S. & Engelhardt, B. Brain barriers: crosstalk between complex tight junctions and adherens junctions. J. Cell Biol. 209, 493–506 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bauer, H. C., Krizbai, I. A., Bauer, H. & Traweger, A. “You shall not pass” — tight junctions of the blood brain barrier. Front. Neurosci. 8, 392 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Nag, S. Morphology and molecular properties of cellular components of normal cerebral vessels. Methods Mol. Med. 89, 3–36 (2003).

    CAS  PubMed  Google Scholar 

  35. Wong, A. D. et al. The blood–brain barrier: an engineering perspective. Front. Neuroeng. 6, 7 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pardridge, W. M. Drug transport across the blood–brain barrier. J. Cereb. Blood Flow Metab. 32, 1959–1972 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Levites, Y. et al. Insights into the mechanisms of action of anti-Aβ antibodies in Alzheimer's disease mouse models. FASEB J. 20, 2576–2578 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Krueger, M., Hartig, W., Reichenbach, A., Bechmann, I. & Michalski, D. Blood–brain barrier breakdown after embolic stroke in rats occurs without ultrastructural evidence for disrupting tight junctions. PLoS ONE 8, e56419 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Knowland, D. et al. Stepwise recruitment of transcellular and paracellular pathways underlies blood–brain barrier breakdown in stroke. Neuron 82, 603–617 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gilad, R., Lampl, Y., Eilam, A., Boaz, M. & Loyberboim, M. SPECT–DTPA as a tool for evaluating the blood–brain barrier in post-stroke seizures. J. Neurol. 259, 2041–2044 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Mehta, D. C., Short, J. L. & Nicolazzo, J. A. Altered brain uptake of therapeutics in a triple transgenic mouse model of Alzheimer's disease. Pharm. Res. 30, 2868–2879 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Hawkes, C. A. et al. Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain. Aging Cell 12, 224–236 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Bien-Ly, N. et al. Lack of widespread BBB disruption in Alzheimer's disease models: focus on therapeutic antibodies. Neuron 88, 289–297 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Sirsi, S. & Borden, M. Microbubble compositions, properties and biomedical applications. Bubble Sci. Eng. Technol. 1, 3–17 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gateau, J. et al. In vivo bubble nucleation probability in sheep brain tissue. Phys. Med. Biol. 56, 7001–7015 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Leinenga, G. & Gotz, J. Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer's disease mouse model. Sci. Transl. Med. 7, 278ra33 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Konofagou, E. E. Optimization of the ultrasound-induced blood–brain barrier opening. Theranostics 2, 1223–1237 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Appis, A. W., Tracy, M. J. & Feinstein, S. B. Update on the safety and efficacy of commercial ultrasound contrast agents in cardiac applications. Echo Res. Pract. 2, R55–R62 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Wrenn, S. P. et al. Bursting bubbles and bilayers. Theranostics 2, 1140–1159 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fan, C. H. et al. Submicron-bubble-enhanced focused ultrasound for blood–brain barrier disruption and improved CNS drug delivery. PLoS ONE 9, e96327 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. McDannold, N., Vykhodtseva, N. & Hynynen, K. Targeted disruption of the blood–brain barrier with focused ultrasound: association with cavitation activity. Phys. Med. Biol. 51, 793–807 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Raymond, S. B., Skoch, J., Hynynen, K. & Bacskai, B. J. Multiphoton imaging of ultrasound/Optison mediated cerebrovascular effects in vivo. J. Cereb. Blood Flow Metab. 27, 393–403 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Caskey, C. F., Stieger, S. M., Qin, S., Dayton, P. A. & Ferrara, K. W. Direct observations of ultrasound microbubble contrast agent interaction with the microvessel wall. J. Acoust. Soc. Am. 122, 1191–1200 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Sheikov, N., McDannold, N., Sharma, S. & Hynynen, K. Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med. Biol. 34, 1093–1104 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  55. O'Reilly, M. A. & Hynynen, K. Blood–brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller. Radiology 263, 96–106 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Marty, B. et al. Dynamic study of blood–brain barrier closure after its disruption using ultrasound: a quantitative analysis. J. Cereb. Blood Flow Metab. 32, 1948–1958 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Baseri, B. et al. Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood–brain barrier using focused ultrasound and microbubbles. Phys. Med. Biol. 57, N65–N81 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Baseri, B., Choi, J. J., Tung, Y. S. & Konofagou, E. E. Multi-modality safety assessment of blood–brain barrier opening using focused ultrasound and definity microbubbles: a short-term study. Ultrasound Med. Biol. 36, 1445–1459 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Choi, J. J. et al. Noninvasive and localized blood–brain barrier disruption using focused ultrasound can be achieved at short pulse lengths and low pulse repetition frequencies. J. Cereb. Blood Flow Metab. 31, 725–737 (2011).

    Article  PubMed  Google Scholar 

  60. Choi, J. J. et al. Microbubble-size dependence of focused ultrasound-induced blood–brain barrier opening in mice in vivo. IEEE Trans. Biomed. Eng. 57, 145–154 (2010).

    Article  PubMed  Google Scholar 

  61. Arvanitis, C. D., Livingstone, M. S., Vykhodtseva, N. & McDannold, N. Controlled ultrasound-induced blood–brain barrier disruption using passive acoustic emissions monitoring. PLoS ONE 7, e45783 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Liu, H. L. et al. Design and experimental evaluation of a 256-channel dual-frequency ultrasound phased-array system for transcranial blood–brain barrier opening and brain drug delivery. IEEE Trans. Biomed. Eng. 61, 1350–1360 (2014).

    Article  PubMed  Google Scholar 

  63. Choi, J. J., Selert, K., Vlachos, F., Wong, A. & Konofagou, E. E. Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles. Proc. Natl Acad. Sci. USA 108, 16539–16544 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. McDannold, N., Vykhodtseva, N. & Hynynen, K. Blood–brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index. Ultrasound Med. Biol. 34, 834–840 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  65. McDannold, N., Vykhodtseva, N. & Hynynen, K. Effects of acoustic parameters and ultrasound contrast agent dose on focused-ultrasound induced blood–brain barrier disruption. Ultrasound Med. Biol. 34, 930–937 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Beccaria, K. et al. Opening of the blood–brain barrier with an unfocused ultrasound device in rabbits. J. Neurosurg. 119, 887–898 (2013).

    Article  PubMed  Google Scholar 

  67. McDannold, N., Arvanitis, C. D., Vykhodtseva, N. & Livingstone, M. S. Temporary disruption of the blood–brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques. Cancer Res. 72, 3652–3663 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Downs, M. E. et al. Long-term safety of repeated blood–brain barrier opening via focused ultrasound with microbubbles in non-human primates performing a cognitive task. PLoS ONE 10, e0125911 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Choi, J. J., Pernot, M., Small, S. A. & Konofagou, E. E. Noninvasive, transcranial and localized opening of the blood–brain barrier using focused ultrasound in mice. Ultrasound Med. Biol. 33, 95–104 (2007).

    Article  PubMed  Google Scholar 

  70. Choi, J. J., Pernot, M., Brown, T. R., Small, S. A. & Konofagou, E. E. Spatio-temporal analysis of molecular delivery through the blood–brain barrier using focused ultrasound. Phys. Med. Biol. 52, 5509–5530 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Kinoshita, M., McDannold, N., Jolesz, F. A. & Hynynen, K. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood–brain barrier disruption. Proc. Natl Acad. Sci. USA 103, 11719–11723 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Raymond, S. B. et al. Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models. PLoS ONE 3, e2175 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Etame, A. B. et al. Enhanced delivery of gold nanoparticles with therapeutic potential into the brain using MRI-guided focused ultrasound. Nanomedicine 8, 1133–1142 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Mead, B. P. et al. Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound. J. Control. Release 223, 109–117 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Reth, M. Matching cellular dimensions with molecular sizes. Nat. Immunol. 14, 765–767 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Hynynen, K., McDannold, N., Sheikov, N. A., Jolesz, F. A. & Vykhodtseva, N. Local and reversible blood–brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications. NeuroImage 24, 12–20 (2005).

    Article  PubMed  Google Scholar 

  77. Chen, H. & Konofagou, E. E. The size of blood–brain barrier opening induced by focused ultrasound is dictated by the acoustic pressure. J. Cereb. Blood Flow Metab. 34, 1197–1204 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Thevenot, E. et al. Targeted delivery of self-complementary adeno-associated virus serotype 9 to the brain, using magnetic resonance imaging-guided focused ultrasound. Hum. Gene Ther. 23, 1144–1155 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang, S., Olumolade, O. O., Sun, T., Samiotaki, G. & Konofagou, E. E. Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus. Gene Ther. 22, 104–110 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. Winkler, E. A., Bell, R. D. & Zlokovic, B. V. Central nervous system pericytes in health and disease. Nat. Neurosci. 14, 1398–1405 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Choi, J. J. et al. Noninvasive and transient blood–brain barrier opening in the hippocampus of Alzheimer's double transgenic mice using focused ultrasound. Ultrason. Imaging 30, 189–200 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Burgess, A., Nhan, T., Moffatt, C., Klibanov, A. L. & Hynynen, K. Analysis of focused ultrasound-induced blood–brain barrier permeability in a mouse model of Alzheimer's disease using two-photon microscopy. J. Control. Release 192, 243–248 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Murugesan, N., Demarest, T. G., Madri, J. A. & Pachter, J. S. Brain regional angiogenic potential at the neurovascular unit during normal aging. Neurobiol. Aging 33, 1004.e1–1004.e16 (2012).

    Article  CAS  Google Scholar 

  84. Lucke-Wold, B. P., Logsdon, A. F., Turner, R. C., Rosen, C. L. & Huber, J. D. Aging, the metabolic syndrome, and ischemic stroke: redefining the approach for studying the blood–brain barrier in a complex neurological disease. Adv. Pharmacol. 71, 411–449 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. Scarcelli, T. et al. Stimulation of hippocampal neurogenesis by transcranial focused ultrasound and microbubbles in adult mice. Brain Stimul. 7, 304–307 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Li, B. et al. Failure of neuronal maturation in Alzheimer disease dentate gyrus. J. Neuropathol. Exp. Neurol. 67, 78–84 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Tufail, Y. et al. Transcranial pulsed ultrasound stimulates intact brain circuits. Neuron 66, 681–694 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Reher, P., Doan, N., Bradnock, B., Meghji, S. & Harris, M. Effect of ultrasound on the production of IL-8, basic FGF and VEGF. Cytokine 11, 416–423 (1999).

    Article  CAS  PubMed  Google Scholar 

  89. Lin, W. T., Chen, R. C., Lu, W. W., Liu, S. H. & Yang, F. Y. Protective effects of low-intensity pulsed ultrasound on aluminium-induced cerebral damage in Alzheimer's disease rat model. Sci. Rep. 5, 9671 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Jordao, J. F. et al. Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-β plaque load in the TgCRND8 mouse model of Alzheimer's disease. PLoS ONE 5, e10549 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Jordao, J. F. et al. Amyloid-β plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp. Neurol. 248, 16–29 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Burgess, A. et al. Alzheimer disease in a mouse model: MR imaging-guided focused ultrasound targeted to the hippocampus opens the blood–brain barrier and improves pathologic abnormalities and behavior. Radiology 273, 736–745 (2014).

    Article  PubMed  Google Scholar 

  93. Ittner, L. M. et al. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer's disease mouse models. Cell 142, 387–397 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Yamamoto, K., Shimada, H., Koh, H., Ataka, S. & Miki, T. Serum levels of albumin-amyloid β complexes are decreased in Alzheimer's disease. Geriatr. Gerontol. Int. 14, 716–723 (2014).

    Article  PubMed  Google Scholar 

  95. Dickson, D. W. Neuropathology of non-Alzheimer degenerative disorders. Int. J. Clin. Exp. Pathol. 3, 1–23 (2009).

    PubMed  Google Scholar 

  96. US National Library of Science. ClinicalTrials.gov[online], (2015).

  97. US National Library of Science. ClinicalTrials.gov[online], (2016).

  98. Jun, S. B. Ultrasound as a noninvasive neuromodulation tool. Biomed. Eng. Lett. 2, 8–12 (2012).

    Article  Google Scholar 

  99. Tyler, W. J. Noninvasive neuromodulation with ultrasound? A continuum mechanics hypothesis. Neuroscientist 17, 25–36 (2011).

    Article  PubMed  Google Scholar 

  100. Harvey, E. N. The effect of high frequency sound waves on heart muscle and other irritable tissues. Am. J. Physiol. 91, 284–290 (1929).

    Article  Google Scholar 

  101. Juan, E. J., Gonzalez, R., Albors, G., Ward, M. P. & Irazoqui, P. Vagus nerve modulation using focused pulsed ultrasound: potential applications and preliminary observations in a rat. Int. J. Imaging Syst. Technol. 24, 67–71 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Krasovitski, B., Frenkel, V., Shoham, S. & Kimmel, E. Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects. Proc. Natl Acad. Sci. USA 108, 3258–3263 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ibsen, S., Tong, A., Schutt, C., Esener, S. & Chalasani, S. H. Sonogenetics is a non-invasive approach to activating neurons in Caenorhabditis elegans. Nat. Commun. 6, 8264 (2015).

    Article  CAS  PubMed  Google Scholar 

  104. McDannold, N. et al. Targeted, noninvasive blockade of cortical neuronal activity. Sci. Rep. 5, 16253 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tsai, S. J. Transcranial focused ultrasound as a possible treatment for major depression. Med. Hypotheses 84, 381–383 (2015).

    Article  PubMed  Google Scholar 

  106. Fernandes, B. S. et al. Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies. BMC Med. 13, 289 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Fry, F. J. Transkull transmission of an intense focused ultrasonic beam. Ultrasound Med. Biol. 3, 179–184 (1977).

    Article  CAS  PubMed  Google Scholar 

  108. Marsac, L. et al. MR-guided adaptive focusing of therapeutic ultrasound beams in the human head. Med. Phys. 39, 1141–1149 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Deffieux, T. & Konofagou, E. E. Numerical study of a simple transcranial focused ultrasound system applied to blood–brain barrier opening. IEEE Trans. Ultrason. Ferroelectr. Freq. Control. 57, 2637–2653 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Martin, E., Jeanmonod, D., Morel, A., Zadicario, E. & Werner, B. High-intensity focused ultrasound for noninvasive functional neurosurgery. Ann. Neurol. 66, 858–861 (2009).

    Article  PubMed  Google Scholar 

  111. Aubry, J. F. & Tanter, M. MR-Guided transcranial focused ultrasound. Adv. Exp. Med. Biol. 880, 97–111 (2016).

    Article  CAS  PubMed  Google Scholar 

  112. Kyriakou, A. et al. A review of numerical and experimental compensation techniques for skull-induced phase aberrations in transcranial focused ultrasound. Int. J. Hyperthermia 30, 36–46 (2014).

    Article  PubMed  Google Scholar 

  113. Tufail, Y., Yoshihiro, A., Pati, S., Li, M. M. & Tyler, W. J. Ultrasonic neuromodulation by brain stimulation with transcranial ultrasound. Nat. Protoc. 6, 1453–1470 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Min, B. K. et al. Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity. BMC Neurosci. 12, 23 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Younan, Y. et al. Influence of the pressure field distribution in transcranial ultrasonic neurostimulation. Med. Phys. 40, 082902 (2013).

    Article  PubMed  Google Scholar 

  116. Deffieux, T. et al. Low-intensity focused ultrasound modulates monkey visuomotor behavior. Curr. Biol. 23, 2430–2433 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Lee, W. et al. Image-guided focused ultrasound-mediated regional brain stimulation in sheep. Ultrasound Med. Biol. 42, 459–470 (2016).

    Article  PubMed  Google Scholar 

  118. Legon, W. et al. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nat. Neurosci. 17, 322–329 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. George, P. M. & Steinberg, G. K. Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments. Neuron 87, 297–309 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Theismann, H. & Pfander, F. The permeability of bone for ultrasound. Strahlentherapie 80, 607–610 (in German) (1949).

    CAS  PubMed  Google Scholar 

  121. Hueter, H. F. Messung der Ultraschallabsorption im menschlichen Schädelknochen und ihre Abhängigkeit von der Frequenz. Naturwissenschaften 39, 21–22 (in German) (1952).

    Article  Google Scholar 

  122. White, D. N., Curry, G. R. & Stevenson, R. J. The acoustic characteristics of the skull. Ultrasound Med. Biol. 4, 225–252 (1978).

    Article  CAS  PubMed  Google Scholar 

  123. Fry, F. J. & Barger, J. E. Acoustical properties of the human skull. J. Acoust. Soc. Am. 63, 1576–1590 (1978).

    Article  CAS  PubMed  Google Scholar 

  124. Phillips, D. J., Smith, S. W., von Ramm, O. T. & Thurnstone, F. L. in Acoustical Holography 1st edn Vol. 6 Ch. 6 (ed. Booth, N.) 103–120 (Springer Science + Business Media, 1975).

    Book  Google Scholar 

  125. Hynynen, K. & Sun, J. Trans-skull ultrasound therapy: the feasibility of using image-derived skull thickness information to correct the phase distortion. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 46, 752–755 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. O'Reilly, M. A. & Hynynen, K. A super-resolution ultrasound method for brain vascular mapping. Med. Phys. 40, 110701 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Ittner, L. M. & Götz, J. Amyloid-β and tau — a toxic pas de deux in Alzheimer's disease. Nat. Rev. Neurosci. 12, 65–72 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. Zhu, C. W. & Sano, M. Economic considerations in the management of Alzheimer's disease. Clin. Interv. Aging 1, 143–154 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Golde, T. E. Open questions for Alzheimer's disease immunotherapy. Alzheimers Res. Ther. 6, 3 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Wu, S. Y. et al. Transcranial cavitation detection in primates during blood–brain barrier opening — a performance assessment study. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 61, 966–978 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Gateau, J., Aubry, J. F., Pernot, M., Fink, M. & Tanter, M. Combined passive detection and ultrafast active imaging of cavitation events induced by short pulses of high-intensity ultrasound. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 58, 517–532 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Miller, G. W., Eames, M., Snell, J. & Aubry, J. F. Ultrashort echo-time MRI versus CT for skull aberration correction in MR-guided transcranial focused ultrasound: in vitro comparison on human calvaria. Med. Phys. 42, 2223–2233 (2015).

    Article  PubMed  Google Scholar 

  133. Schweinhardt, P. & Bushnell, M. C. Pain imaging in health and disease — how far have we come? J. Clin. Invest. 120, 3788–3797 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors' work is supported by the Estate of Dr Clem Jones AO and by grants from the Australian Research Council (DP130101932), the National Health and Medical Research Council of Australia (APP1037746, APP1003150) and the Australian Research Council Linkage Infrastructure, Equipment and Facilities scheme (LE100100074). We thank Matt Pelekanos for suggesting the term 'obicodilation', and Rowan Tweedale for critically reading the manuscript.

Author information

Authors and Affiliations

  1. Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia Campus, Brisbane, 4072, Queenland, Australia

    Gerhard Leinenga, Rebecca Nisbet & Jürgen Götz

  2. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Campus, Brisbane, 4059, Queenland, Australia

    Christian Langton

Authors
  1. Gerhard Leinenga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian Langton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rebecca Nisbet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jürgen Götz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article and made substantial contributions to discussion of the content. J.G., G.L. and C.L. wrote the manuscript. J.G., G.L. and R.N. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Jürgen Götz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

FURTHER INFORMATION

Focused Ultrasound Foundation

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leinenga, G., Langton, C., Nisbet, R. et al. Ultrasound treatment of neurological diseases — current and emerging applications. Nat Rev Neurol 12, 161–174 (2016). https://doi.org/10.1038/nrneurol.2016.13

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2016.13

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research