2,766
Views
2
CrossRef citations to date
0
Altmetric
Neurology

Low intensity focused ultrasound: a new prospect for the treatment of Parkinson’s disease

, , , , &
Article: 2251145 | Received 10 May 2023, Accepted 20 Aug 2023, Published online: 26 Aug 2023

References

  • Bowary P, Greenberg BD. Noninvasive focused ultrasound for neuromodulation: a review. Psychiatr Clin North Am. 2018;41(3):1–15. doi:10.1016/j.psc.2018.04.010.
  • Baek H, Pahk KJ, Kim H. A review of low-intensity focused ultrasound for neuromodulation. Biomed Eng Lett. 2017;7(2):135–142. doi:10.1007/s13534-016-0007-y.
  • Yang F-Y, Lu W-W, Lin W-T, et al. Enhancement of neurotrophic factors in astrocyte for neuroprotective effects in brain disorders using low-intensity pulsed ultrasound stimulation. Brain Stimul. 2015;8(3):465–473. doi:10.1016/j.brs.2014.11.017.
  • Zhao L, Feng Y, Hu H, et al. Low-intensity pulsed ultrasound enhances nerve growth factor-induced neurite outgrowth through mechanotransduction-mediated ERK1/2-CREB-Trx-1 signaling. Ultrasound Med Biol. 2016;42(12):2914–2925. doi:10.1016/j.ultrasmedbio.2016.07.017.
  • Zhao L, Feng Y, Shi A, et al. Neuroprotective effect of low-intensity pulsed ultrasound against MPP-induced neurotoxicity in PC12 cells: involvement of K2P channels and stretch-activated ion channels. Ultrasound Med Biol. 2017;43(9):1986–1999. doi:10.1016/j.ultrasmedbio.2017.04.020.
  • Zhang D, Li H, Sun J, et al. Antidepressant-like effect of low-intensity transcranial ultrasound stimulation. IEEE Trans Biomed Eng. 2019;66(2):411–420. doi:10.1109/TBME.2018.2845689.
  • Daffertshofer M, Gass A, Ringleb P, 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. 2005;36(7):1441–1446. doi:10.1161/01.STR.0000170707.86793.1a.
  • Meng Y, Volpini M, Black S, et al. Focused ultrasound as a novel strategy for alzheimer disease therapeutics. Ann Neurol. 2017;81(5):611–617. doi:10.1002/ana.24933.
  • Krishna V, Sammartino F, Rezai A. A review of the current therapies, challenges, and future directions of transcranial focused ultrasound technology: advances in diagnosis and treatment. JAMA Neurol. 2018;75(2):246–254. doi:10.1001/jamaneurol.2017.3129.
  • Neumann W-J, Horn A, Kühn AA. Insights and opportunities for deep brain stimulation as a brain circuit intervention. Trends Neurosci. 2023;46(6):472–487. doi:10.1016/j.tins.2023.03.009.
  • Cavallieri F, Campanini I, Gessani A, et al. Long-term effects of bilateral subthalamic nucleus deep brain stimulation on gait disorders in Parkinson’s disease: a clinical-instrumental study. J Neurol. 2023;270(9):4342–4353. doi:10.1007/s00415-023-11780-5.
  • Fasano A, García-Ramos R, Gurevich T, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson’s disease: long-term results from COSMOS. J Neurol. 2023;270(5):2765–2775. doi:10.1007/s00415-023-11615-3.
  • Martínez-Fernández R, Máñez-Miró JU, Rodríguez-Rojas R, et al. Randomized trial of focused ultrasound subthalamotomy for Parkinson’s disease. N Engl J Med. 2020;383(26):2501–2513. doi:10.1056/NEJMoa2016311.
  • Martínez-Fernández R, Rodríguez-Rojas R, Del Álamo M, et al. Focused ultrasound subthalamotomy in patients with asymmetric Parkinson’s disease: a pilot study. Lancet Neurol. 2018;17(1):54–63. doi:10.1016/S1474-4422(17)30403-9.
  • Eisenberg HM, Krishna V, Elias WJ, et al. MR-guided focused ultrasound pallidotomy for Parkinson’s disease: safety and feasibility. J Neurosurg. 2020;135(3):792–798.
  • Foffani G, Trigo-Damas I, Pineda-Pardo JA, et al. Focused ultrasound in Parkinson’s disease: a twofold path toward disease modification. Mov Disord. 2019;34(9):1262–1273. doi:10.1002/mds.27805.
  • Gallay MN, Moser D, Magara AE, et al. Bilateral MR-guided focused ultrasound pallidothalamic tractotomy for Parkinson’s disease with 1-year follow-up. Front Neurol. 2021;12:601153. doi:10.3389/fneur.2021.601153.
  • Stieglitz LH, Mahendran S, Oertel MF, et al. Bilateral focused ultrasound pallidotomy for Parkinson-related facial dyskinesia-a case report. Mov Disord Clin Pract. 2022;9(5):647–651. doi:10.1002/mdc3.13462.
  • Martínez-Fernández R, Natera-Villalba E, Máñez Miró JU, et al. Prospective long-term follow-up of focused ultrasound unilateral subthalamotomy for Parkinson disease. Neurology. 2023;100(13):e1395–e1405. doi:10.1212/WNL.0000000000206771.
  • Gallay MN, Moser D, Jeanmonod D. Safety and accuracy of incisionless transcranial MR-guided focused ultrasound functional neurosurgery: single-center experience with 253 targets in 180 treatments. J Neurosurg. 2018;130(4):1234–1243. doi:10.3171/2017.12.JNS172054.
  • Xiong Y, Lin J, Pan L, et al. Pretherapeutic functional connectivity of tractography-based targeting of the ventral intermediate nucleus for predicting tremor response in patients with Parkinson’s disease after thalamotomy with MRI-guided focused ultrasound. J Neurosurg. 2022;18;1–10. doi:10.3171/2022.1.JNS212449
  • Magara A, Bühler R, Moser D, et al. First experience with MR-guided focused ultrasound in the treatment of Parkinson’s disease. J Ther Ultrasound. 2014;2(1):11. doi:10.1186/2050-5736-2-11.
  • Sharma VD, Patel M, Miocinovic S. Surgical treatment of Parkinson’s disease: devices and lesion approaches. Neurotherapeutics. 2020;17(4):1525–1538. doi:10.1007/s13311-020-00939-x.
  • Karmacharya MB, Kim KH, Kim SY, et al. Low intensity ultrasound inhibits brain oedema formation in rats: potential action on AQP4 membrane localization. Neuropathol Appl Neurobiol. 2015;41(4):e80–e94. doi:10.1111/nan.12182.
  • Hou J, Zhou J, Chang M, et al. LIFU-responsive nanomedicine enables acoustic droplet vaporization-induced apoptosis of macrophages for stabilizing vulnerable atherosclerotic plaques. Bioact Mater. 2022;16:120–133. doi:10.1016/j.bioactmat.2022.02.022.
  • Yang A, Qiao B, Strohm EM, et al. Thrombin-responsive engineered nanoexcavator with full-thickness infiltration capability for pharmaceutical-free deep venous thrombosis theranostics. Biomater Sci. 2020;8(16):4545–4558. doi:10.1039/d0bm00917b.
  • Amaya C, Smith ER, Xu X-X. Low intensity ultrasound as an antidote to taxane/paclitaxel-induced cytotoxicity. J Cancer. 2022;13(7):2362–2373. doi:10.7150/jca.71263.
  • Yin T, Chen H, Ma A, et al. Cleavable collagenase-assistant nanosonosensitizer for tumor penetration and sonodynamic therapy. Biomaterials. 2023;293:121992. doi:10.1016/j.biomaterials.2022.121992.
  • Hua Z, Li S, Liu Q, et al. Low-intensity pulsed ultrasound promotes osteogenic potential of iPSC-derived MSCs but fails to simplify the iPSC-EB-MSC differentiation process. Front Bioeng Biotechnol. 2022;10:841778. doi:10.3389/fbioe.2022.841778.
  • Min S, Byeon Y, Kim M, et al. Production enhancement of human adipose-derived mesenchymal stem cells by low-intensity ultrasound stimulation. Sci Rep. 2022;12(1):22041. doi:10.1038/s41598-022-24742-0.
  • Seo Y, Han S, Song B-W, et al. Endogenous neural stem cell activation after low-intensity focused ultrasound-induced blood-brain barrier modulation. Int J Mol Sci. 2023;24(6):5712. doi: 10.3390/ijms24065712.
  • Liu X, Zou D, Hu Y, et al. Research progress of low-intensity pulsed ultrasound in the repair of peripheral nerve injury. Tissue Eng Part B Rev. 2023;29(4):414–428. doi:10.1089/ten.TEB.2022.0194.
  • Wang Y, Xiao Q, Zhong W, et al. Low-intensity pulsed ultrasound promotes periodontal regeneration in a beagle model of furcation involvement. Front Bioeng Biotechnol. 2022;10:961898. doi:10.3389/fbioe.2022.961898.
  • Wang Y, Li J, Zhou J, et al. Low-intensity pulsed ultrasound enhances bone marrow-derived stem cells-based periodontal regenerative therapies. Ultrasonics. 2022;121:106678. doi:10.1016/j.ultras.2021.106678.
  • Mueller J, Legon W, Opitz A, et al. Transcranial focused ultrasound modulates intrinsic and evoked EEG dynamics. Brain Stimul. 2014;7(6):900–908. doi:10.1016/j.brs.2014.08.008.
  • Legon W, Sato TF, Opitz A, et al. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nat Neurosci. 2014;17(2):322–329. doi:10.1038/nn.3620.
  • Zhu L, Zhao H, Zhou Z, et al. Peptide-functionalized phase-transformation nanoparticles for low intensity focused ultrasound-assisted tumor imaging and therapy. Nano Lett. 2018;18(3):1831–1841. doi:10.1021/acs.nanolett.7b05087.
  • Rezai AR, Ranjan M, D’Haese P-F, et al. Noninvasive hippocampal blood-brain barrier opening in Alzheimer’s disease with focused ultrasound. Proc Natl Acad Sci U S A. 2020;117(17):9180–9182. doi:10.1073/pnas.2002571117.
  • Yoo S-S, Bystritsky A, Lee J-H, et al. Focused ultrasound modulates region-specific brain activity. Neuroimage. 2011;56(3):1267–1275. doi:10.1016/j.neuroimage.2011.02.058.
  • Yu K, Sohrabpour A, He B. Electrophysiological source imaging of brain networks perturbed by low-intensity transcranial focused ultrasound. IEEE Trans Biomed Eng. 2016;63(9):1787–1794. doi:10.1109/TBME.2016.2591924.
  • Wang X, Yan J, Wang Z, et al. Neuromodulation effects of ultrasound stimulation under different parameters on mouse motor cortex. IEEE Trans Biomed Eng. 2020;67(1):291–297. doi:10.1109/TBME.2019.2912840.
  • Ellis JM, Fell MJ. Current approaches to the treatment of Parkinson’s disease. Bioorg Med Chem Lett. 2017;27(18):4247–4255. doi:10.1016/j.bmcl.2017.07.075.
  • Xie J, Shen Z, Anraku Y, et al. Nanomaterial-based blood-brain-barrier (BBB) crossing strategies. Biomaterials. 2019;224:119491. doi:10.1016/j.biomaterials.2019.119491.
  • Krasovitski B, Frenkel V, Shoham S, et al. Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects. Proc Natl Acad Sci U S A. 2011;108(8):3258–3263. doi:10.1073/pnas.1015771108.
  • Durand E, Petit O, Tremblay L, et al. Social behavioral changes in MPTP-treated monkey model of Parkinson’s disease. Front Behav Neurosci. 2015;9:42. doi:10.3389/fnbeh.2015.00042.
  • Lee W, Kim H, Jung Y, et al. Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. Sci Rep. 2015;5(1):8743. doi:10.1038/srep08743.
  • Xu T, Lu X, Peng D, et al. Ultrasonic stimulation of the brain to enhance the release of dopamine - A potential novel treatment for Parkinson’s disease. Ultrason Sonochem. 2020;63:104955. doi:10.1016/j.ultsonch.2019.104955.
  • Lee W, Kim H-C, Jung Y, et al. Transcranial focused ultrasound stimulation of human primary visual cortex. Sci Rep. 2016;6(1):34026. doi:10.1038/srep34026.
  • Bystritsky A, Korb AS, Douglas PK, et al. A review of low-intensity focused ultrasound pulsation. Brain Stimul. 2011;4(3):125–136. doi:10.1016/j.brs.2011.03.007.
  • Kim H, Park MY, Lee SD, et al. Suppression of EEG visual-evoked potentials in rats through neuromodulatory focused ultrasound. Neuroreport. 2015;26(4):211–215. doi:10.1097/WNR.0000000000000330.
  • Yuan Y, Zhao Z, Wang Z, et al. The effect of low-intensity transcranial ultrasound stimulation on behavior in a mouse model of Parkinson’s disease induced by MPTP. IEEE Trans Neural Syst Rehabil Eng. 2020;28(4):1017–1021. doi:10.1109/TNSRE.2020.2978865.
  • Zhou H, Niu L, Xia X, et al. Wearable ultrasound improves motor function in an MPTP mouse model of Parkinson’s disease. IEEE Trans Biomed Eng. 2019;66(11):3006–3013. doi:10.1109/TBME.2019.2899631.
  • Karmacharya MB, Hada B, Park SR, et al. Low-intensity ultrasound decreases α-synuclein aggregation via attenuation of mitochondrial reactive oxygen species in MPP(+)-treated PC12 cells. Mol Neurobiol. 2017;54(8):6235–6244. doi:10.1007/s12035-016-0104-z.
  • Naor O, Hertzberg Y, Zemel E, et al. Towards multifocal ultrasonic neural stimulation II: design considerations for an acoustic retinal prosthesis. J Neural Eng. 2012;9(2):026006. doi:10.1088/1741-2560/9/2/026006.
  • Kim H, Chiu A, Lee SD, et al. Focused ultrasound-mediated non-invasive brain stimulation: examination of sonication parameters. Brain Stimul. 2014;7(5):748–756. doi:10.1016/j.brs.2014.06.011.
  • Chen X, Wang D, Zhang L, et al. Neuroprotective effect of low-intensity pulsed ultrasound on the mouse MPTP/MPP model of dopaminergic neuron injury. Ultrasound Med Biol. 2021;47(8):2321–2330. doi:10.1016/j.ultrasmedbio.2021.03.034.
  • Zhou H, Meng L, Xia X, et al. Transcranial ultrasound stimulation suppresses neuroinflammation in a chronic mouse model of Parkinson’s disease. IEEE Trans Biomed Eng. 2021;68(11):3375–3387. doi:10.1109/TBME.2021.3071807.
  • Allen SJ, Watson JJ, Shoemark DK, et al. GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther. 2013;138(2):155–175. doi:10.1016/j.pharmthera.2013.01.004.
  • Tufail Y, Matyushov A, Baldwin N, et al. Transcranial pulsed ultrasound stimulates intact brain circuits. Neuron. 2010;66(5):681–694. doi:10.1016/j.neuron.2010.05.008.
  • Lin W-T, Chen R-C, Lu W-W, et al. Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer’s disease rat model. Sci Rep. 2015;5(1):9671. doi:10.1038/srep09671.
  • Müller HW, Junghans U, Kappler J. Astroglial neurotrophic and neurite-promoting factors. Pharmacol Ther. 1995;65(1):1–18. doi:10.1016/0163-7258(94)00047-7.
  • Liu S-H, Lai Y-L, Chen B-L, et al. Ultrasound enhances the expression of brain-derived neurotrophic factor in astrocyte through activation of TrkB-Akt and calcium-CaMK signaling pathways. Cereb Cortex. 2017;27(6):3152–3160.
  • Zhang Y, Ren L, Liu K, et al. Transcranial ultrasound stimulation of the human motor cortex. iScience. 2021;24(12):103429. doi:10.1016/j.isci.2021.103429.
  • Dallapiazza RF, Timbie KF, Holmberg S, et al. Noninvasive neuromodulation and thalamic mapping with low-intensity focused ultrasound. J Neurosurg. 2018;128(3):875–884. doi:10.3171/2016.11.JNS16976.
  • Calabresi P, Picconi B, Tozzi A, et al. Direct and indirect pathways of basal ganglia: a critical reappraisal. Nat Neurosci. 2014;17(8):1022–1030. doi:10.1038/nn.3743.
  • Marogianni C, Sokratous M, Dardiotis E, et al. Neurodegeneration and Inflammation-An interesting interplay in Parkinson’s disease. Int J Mol Sci. 2020;21(22):8421. doi: 10.3390/ijms21228421.
  • Guo T, Li H, Lv Y, et al. Pulsed transcranial ultrasound stimulation immediately after the ischemic brain injury is neuroprotective. IEEE Trans Biomed Eng. 2015;62(10):2352–2357. doi:10.1109/TBME.2015.2427339.
  • Altland OD, Dalecki D, Suchkova VN, et al. Low-intensity ultrasound increases endothelial cell nitric oxide synthase activity and nitric oxide synthesis. J Thromb Haemost. 2004;2(4):637–643. doi:10.1111/j.1538-7836.2004.00655.x.
  • Block ML, Wu X, Pei Z, et al. Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase. FASEB J. 2004;18(13):1618–1620. doi:10.1096/fj.04-1945fje.
  • Chen Y, Zhu G, Liu D, et al. Subthalamic nucleus deep brain stimulation suppresses neuroinflammation by fractalkine pathway in Parkinson’s disease rat model. Brain Behav Immun. 2020;90:16–25. doi:10.1016/j.bbi.2020.07.035.
  • Kovacs ZI, Kim S, Jikaria N, et al. Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation. Proc Natl Acad Sci U S A. 2017;114(1):E75–E84.
  • Shin WH, Lee D-Y, Park KW, et al. Microglia expressing interleukin-13 undergo cell death and contribute to neuronal survival in vivo. Glia. 2004;46(2):142–152. doi:10.1002/glia.10357.
  • Strle K, Zhou JH, Shen WH, et al. Interleukin-10 in the brain. Crit Rev Immunol. 2001;21(5):23. doi:10.1615/CritRevImmunol.v21.i5.20.
  • Yang M-S, Ji K-A, Jeon S-B, et al. Interleukin-13 enhances cyclooxygenase-2 expression in activated rat brain microglia: implications for death of activated microglia. J Immunol. 2006;177(2):1323–1329. doi:10.4049/jimmunol.177.2.1323.
  • Suzumura A, Takeuchi H, Zhang G, et al. Roles of glia-derived cytokines on neuronal degeneration and regeneration. Ann N Y Acad Sci. 2006;1088(1):219–229. doi:10.1196/annals.1366.012.
  • Bobola MS, Chen L, Ezeokeke CK, et al. Transcranial focused ultrasound, pulsed at 40 Hz, activates microglia acutely and reduces Aβ load chronically, as demonstrated in vivo. Brain Stimul. 2020;13(4):1014–1023. doi:10.1016/j.brs.2020.03.016.
  • Javitch JA, D’Amato RJ, Strittmatter SM, et al. Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci U S A. 1985;82(7):2173–2177. doi:10.1073/pnas.82.7.2173.
  • Li J, Zhang D-D, Wang C-Q, et al. Protective effects of low-intensity pulsed ultrasound on aluminum overload-induced cerebral damage through epigenetic regulation of brain-derived neurotrophic factor expression. Biosci Rep. 2019;39(1):BSR20181185. doi: 10.1042/BSR20181185.
  • Surmeier DJ, Obeso JA, Halliday GM. Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci. 2017;18(2):101–113. doi:10.1038/nrn.2016.178.
  • Choi W-S, Kruse SE, Palmiter RD, et al. Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP+, or paraquat. Proc Natl Acad Sci U S A. 2008;105(39):15136–15141. doi:10.1073/pnas.0807581105.
  • Cassarino DS, Parks JK, Parker WD, et al. The parkinsonian neurotoxin MPP + opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism. Biochim Biophys Acta. 1999;1453(1):49–62. doi:10.1016/s0925-4439(98)00083-0.
  • Chang C-J, Hsu S-H, Lin F-T, et al. Low-intensity-ultrasound-accelerated nerve regeneration using cell-seeded poly(D, L-lactic acid-co-glycolic acid) conduits: an in vivo and in vitro study. J Biomed Mater Res B Appl Biomater. 2005;75(1):99–107. doi:10.1002/jbm.b.30269.
  • Jiang W, Wang Y, Tang J, et al. Low-intensity pulsed ultrasound treatment improved the rate of autograft peripheral nerve regeneration in rat. Sci Rep. 2016;6(1):22773. doi:10.1038/srep22773.
  • Weiwei W, Li L, Wei W, editors. et al. Effects of ultrasound on behavior and dopamine content in striatum of Parkinson’s disease model mouse. Proceedings of the 2017 International Conference on Material Science, Energy and Environmental Engineering (MSEEE 2017); 2017. Atlantis Press.
  • Hu Y, Zhong W, Wan JMF, et al. Ultrasound can modulate neuronal development: impact on neurite growth and cell body morphology. Ultrasound Med Biol. 2013;39(5):915–925. doi:10.1016/j.ultrasmedbio.2012.12.003.
  • Crisci AR, Ferreira AL. Low-intensity pulsed ultrasound accelerates the regeneration of the sciatic nerve after neurotomy in rats. Ultrasound Med Biol. 2002;28(10):1335–1341. doi:10.1016/s0301-5629(02)00576-8.
  • Zhang H, Lin X, Wan H, et al. Effect of low-intensity pulsed ultrasound on the expression of neurotrophin-3 and brain-derived neurotrophic factor in cultured Schwann cells. Microsurgery. 2009;29(6):479–485. doi:10.1002/micr.20644.
  • Tsuang Y-H, Liao L-W, Chao Y-H, et al. Effects of low intensity pulsed ultrasound on rat Schwann cells metabolism. Artif Organs. 2011;35(4):373–383. doi:10.1111/j.1525-1594.2010.01086.x.
  • Kusuyama J, Bandow K, Shamoto M, et al. Low intensity pulsed ultrasound (LIPUS) influences the multilineage differentiation of mesenchymal stem and progenitor cell lines through ROCK-Cot/Tpl2-MEK-ERK signaling pathway. J Biol Chem. 2014;289(15):10330–10344. doi:10.1074/jbc.M113.546382.
  • Lv Y, Zhao P, Chen G, et al. Effects of low-intensity pulsed ultrasound on cell viability, proliferation and neural differentiation of induced pluripotent stem cells-derived neural crest stem cells. Biotechnol Lett. 2013;35(12):2201–2212. doi:10.1007/s10529-013-1313-4.
  • Ling L, Wei T, He L, et al. Low-intensity pulsed ultrasound activates ERK1/2 and PI3K-Akt signalling pathways and promotes the proliferation of human amnion-derived mesenchymal stem cells. Cell Prolif. 2017;50(6):e12383. doi: 10.1111/cpr.12383.
  • Budhiraja G, Sahu N, Subramanian A. Low-intensity ultrasound upregulates the expression of cyclin-D1 and promotes cellular proliferation in human mesenchymal stem cells. Biotechnol J. 2018;13(4):e1700382. doi:10.1002/biot.201700382.
  • Rich MC, Sherwood J, Bartley AF, et al. Focused ultrasound blood brain barrier opening mediated delivery of MRI-visible albumin nanoclusters to the rat brain for localized drug delivery with temporal control. J Control Release. 2020;324:172–180. doi:10.1016/j.jconrel.2020.04.054.
  • Xhima K, Nabbouh F, Hynynen K, et al. Noninvasive delivery of an α-synuclein gene silencing vector with magnetic resonance-guided focused ultrasound. Mov Disord. 2018;33(10):1567–1579. doi:10.1002/mds.101.
  • Kroll RA, Neuwelt EA. Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery. 1998;42(5):1083. doi:10.1097/00006123-199805000-00082.
  • Baseri B, Choi JJ, Deffieux T, 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. 2012;57(7):N65–N81. doi:10.1088/0031-9155/57/7/N65.
  • Samiotaki G, Acosta C, Wang S, et al. Enhanced delivery and bioactivity of the neurturin neurotrophic factor through focused ultrasound—mediated blood—brain barrier opening in vivo. J Cereb Blood Flow Metab. 2015;35(4):611–622. 1doi:10.1038/jcbfm.2014.236.
  • Lu B, Nagappan G, Guan X, et al. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci. 2013;14(6):401–416. doi:10.1038/nrn3505.
  • Wang F, Shi Y, Lu L, et al. Targeted delivery of GDNF through the blood-brain barrier by MRI-guided focused ultrasound. PLoS One. 2012;7(12):e52925. doi:10.1371/journal.pone.0052925.
  • Ji R, Smith M, Niimi Y, et al. Focused ultrasound enhanced intranasal delivery of brain derived neurotrophic factor produces neurorestorative effects in a Parkinson’s disease mouse model. Sci Rep. 2019;9(1):19402. doi:10.1038/s41598-019-55294-5.
  • Yan Y, Chen Y, Liu Z, et al. Brain delivery of curcumin through low-intensity ultrasound-induced blood-brain barrier opening via lipid-PLGA nanobubbles. Int J Nanomedicine. 2021;16:7433–7447. doi:10.2147/IJN.S327737.
  • Niu J, Xie J, Guo K, et al. Efficient treatment of Parkinson’s disease using ultrasonography-guided rhFGF20 proteoliposomes. Drug Deliv. 2018;25(1):1560–1569. doi:10.1080/10717544.2018.1482972.
  • Todd N, Zhang Y, Power C, et al. Modulation of brain function by targeted delivery of GABA through the disrupted blood-brain barrier. Neuroimage. 2019;189:267–275. doi:10.1016/j.neuroimage.2019.01.037.
  • Burgess A, Ayala-Grosso CA, Ganguly M, et al. Targeted delivery of neural stem cells to the brain using MRI-guided focused ultrasound to disrupt the blood-brain barrier. PLoS One. 2011;6(11):e27877. doi:10.1371/journal.pone.0027877.
  • Kordower JH, Emborg ME, Bloch J, et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science. 2000;290(5492):767–773. doi:10.1126/science.290.5492.767.
  • Huang Q, Deng J, Wang F, et al. Targeted gene delivery to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Exp Neurol. 2012;233(1):350–356. doi:10.1016/j.expneurol.2011.10.027.
  • Fan C-H, Ting C-Y, Lin C-Y, et al. Noninvasive, targeted, and non-viral ultrasound-mediated GDNF-plasmid delivery for treatment of Parkinson’s disease. Sci Rep. 2016;6(1):19579. doi:10.1038/srep19579.
  • Ye D, Sultan D, Zhang X, et al. Focused ultrasound-enabled delivery of radiolabeled nanoclusters to the pons. J Control Release. 2018;283:143–150. doi:10.1016/j.jconrel.2018.05.039.
  • Long L, Cai X, Guo R, et al. Treatment of Parkinson’s disease in rats by Nrf2 transfection using MRI-guided focused ultrasound delivery of nanomicrobubbles. Biochem Biophys Res Commun. 2017;482(1):75–80. doi:10.1016/j.bbrc.2016.10.141.
  • Mead BP, Mastorakos P, Suk JS, et al. Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound. J Control Release. 2016;223:109–117. doi:10.1016/j.jconrel.2015.12.034.
  • Mead BP, Kim N, Miller GW, et al. Novel focused ultrasound gene therapy approach noninvasively restores dopaminergic neuron function in a rat Parkinson’s disease model. Nano Lett. 2017;17(6):3533–3542. doi:10.1021/acs.nanolett.7b00616.
  • Hu K, Chen X, Chen W, et al. Neuroprotective effect of gold nanoparticles composites in Parkinson’s disease model. Nanomedicine. 2018;14(4):1123–1136. doi:10.1016/j.nano.2018.01.020.
  • Zhao Y-Z, Jin R-R, Yang W, et al. Using gelatin nanoparticle mediated intranasal delivery of neuropeptide substance P to enhance neuro-recovery in ­hemiparkinsonian rats. PLoS One. 2016;11(2):e0148848. doi:10.1371/journal.pone.0148848.
  • Huang R, Ma H, Guo Y, et al. Angiopep-conjugated nanoparticles for targeted long-term gene therapy of Parkinson’s disease. Pharm Res. 2013;30(10):2549–2559. doi:10.1007/s11095-013-1005-8.
  • You L, Wang J, Liu T, et al. Targeted brain delivery of rabies virus glycoprotein 29-modified deferoxamine-loaded nanoparticles reverses functional deficits in parkinsonian mice. ACS Nano. 2018;12(5):4123–4139. doi:10.1021/acsnano.7b08172.
  • Chen Y, Sun J, Lu Y, et al. Complexes containing cationic and anionic pH-sensitive liposomes: comparative study of factors influencing plasmid DNA gene delivery to tumors. Int J Nanomedicine. 2013;8:1573–1593.
  • Lentacker I, Wang N, Vandenbroucke RE, et al. Ultrasound exposure of lipoplex loaded microbubbles facilitates direct cytoplasmic entry of the lipoplexes. Mol Pharm. 2009;6(2):457–467. doi:10.1021/mp800154s.
  • Yue P, Miao W, Gao L, et al. Ultrasound-triggered effects of the microbubbles coupled to GDNF plasmid-loaded PEGylated liposomes in a rat model of Parkinson’s disease. Front Neurosci. 2018;12:222. doi:10.3389/fnins.2018.00222.
  • Lin C-Y, Hsieh H-Y, Chen C-M, et al. Non-invasive, neuron-specific gene therapy by focused ultrasound-induced blood-brain barrier opening in Parkinson’s disease mouse model. J Control Release. 2016;235:72–81. doi:10.1016/j.jconrel.2016.05.052.
  • Lin C-Y, Lin Y-C, Huang C-Y, et al. Ultrasound-responsive neurotrophic factor-loaded microbubble- liposome complex: preclinical investigation for Parkinson’s disease treatment. J Control Release. 2020;321:519–528. doi:10.1016/j.jconrel.2020.02.044.
  • Bartus RT, Johnson EM. Clinical tests of neurotrophic factors for human neurodegenerative diseases, part 1: where have we been and what have we learned? Neurobiol Dis. 2017;97(Pt B):156–168. doi:10.1016/j.nbd.2016.03.027.
  • Thévenot E, Jordão JF, O’Reilly MA, 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. 2012;23(11):1144–1155. doi:10.1089/hum.2012.013.
  • Alonso A, Reinz E, Leuchs B, et al. Focal delivery of AAV2/1-transgenes into the rat brain by localized ultrasound-induced BBB opening. Mol Ther Nucleic Acids. 2013;2(2):e73. doi:10.1038/mtna.2012.64.
  • Wang S, Olumolade OO, Sun T, et al. Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus. Gene Ther. 2015;22(1):104–110. doi:10.1038/gt.2014.91.
  • Trinh D, Nash J, Goertz D, et al. Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3. Drug Deliv. 2022;29(1):1176–1183. doi:10.1080/10717544.2022.2035855.
  • Kantor B, McCown T, Leone P, et al. Chapter two - clinical applications involving CNS gene transfer. In: Friedmann T, Dunlap JC, Goodwin SF, editors. Advances in genetics. Vol. 87. Academic Press; 2014. p. 71–124. doi: 10.1016/B978-0-12-800149-3.00002-0.
  • Quadri SA, Waqas M, Khan I, et al. High-intensity focused ultrasound: past, present, and future in neurosurgery. Neurosurg Focus. 2018;44(2):E16. doi:10.3171/2017.11.FOCUS17610.
  • Kim H, Taghados SJ, Fischer K, et al. Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound. Ultrasound Med Biol. 2012;38(9):1568–1575. doi:10.1016/j.ultrasmedbio.2012.04.023.
  • Darrow DP, O’Brien P, Richner TJ, et al. Reversible neuroinhibition by focused ultrasound is mediated by a thermal mechanism. Brain Stimul. 2019;12(6):1439–1447. doi:10.1016/j.brs.2019.07.015.
  • Hamill OP, Martinac B. Molecular basis of mechanotransduction in living cells. Physiol Rev. 2001;81(2):685–740. doi:10.1152/physrev.2001.81.2.685.
  • Tyler WJ. The mechanobiology of brain function. Nat Rev Neurosci. 2012;13(12):867–878. doi:10.1038/nrn3383.
  • Ibsen S, Tong A, Schutt C, et al. Sonogenetics is a non-invasive approach to activating neurons in Caenorhabditis elegans. Nat Commun. 2015;6(1):8264. doi:10.1038/ncomms9264.
  • Tyler WJ, Tufail Y, Finsterwald M, et al. Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound. PLoS One. 2008;3(10):e3511. doi:10.1371/journal.pone.0003511.
  • Kubanek J, Shi J, Marsh J, et al. Ultrasound modulates ion channel currents. Sci Rep. 2016;6(1):24170. doi:10.1038/srep24170.
  • Boland LM, Drzewiecki MM. Polyunsaturated fatty acid modulation of voltage-gated ion channels. Cell Biochem Biophys. 2008;52(2):59–84. doi:10.1007/s12013-008-9027-2.
  • Rinaldi PC, Jones JP, Reines F, et al. Modification by focused ultrasound pulses of electrically evoked responses from an in vitro hippocampal preparation. Brain Res. 1991;558(1):36–42. doi:10.1016/0006-8993(91)90711-4.
  • 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. doi:10.1016/0301-5629(90)90008-z.
  • Arnadóttir J, Chalfie M. Eukaryotic mechanosensitive channels. Annu Rev Biophys. 2010;39(1):111–137. doi:10.1146/annurev.biophys.37.032807.125836.
  • Siechen S, Yang S, Chiba A, et al. Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals. Proc Natl Acad Sci U S A. 2009;106(31):12611–12616. doi:10.1073/pnas.0901867106.
  • Chen K-T, Wei K-C, Liu H-L. Theranostic strategy of focused ultrasound induced Blood-Brain barrier opening for CNS disease treatment. Front Pharmacol. 2019;10:86. doi:10.3389/fphar.2019.00086.
  • 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):ENEURO.0136-15.2016. doi:10.1523/ENEURO.0136-15.2016.
  • Wall PD, Fry WJ, Stephens R, et al. Changes produced in the central nervous system by ultrasound. Science. 1951;114(2974):686–687. doi:10.1126/science.114.2974.686.
  • Liu H-L, Fan C-H, Ting C-Y, et al. Combining microbubbles and ultrasound for drug delivery to brain tumors: current progress and overview. Theranostics. 2014;4(4):432–444. doi:10.7150/thno.8074.
  • Kushner J, Kim D, So PTC, et al. Dual-channel two-photon microscopy study of transdermal transport in skin treated with low-frequency ultrasound and a chemical enhancer. J Invest Dermatol. 2007;127(12):2832–2846. doi:10.1038/sj.jid.5700908.
  • Chen H, Kreider W, Brayman AA, et al. Blood vessel deformations on microsecond time scales by ultrasonic cavitation. Phys Rev Lett. 2011;106(3):034301. doi:10.1103/PhysRevLett.106.034301.
  • Hu S, Zhang X, Unger M, et al. Focused ultrasound-induced cavitation sensitizes cancer cells to radiation therapy and hyperthermia. Cells. 2020;9(12):2595. doi:10.3390/cells9122595.
  • Xia C-y, Zhang Z, Xue Y-X, et al. Mechanisms of the increase in the permeability of the blood-tumor barrier obtained by combining low-frequency ultrasound irradiation with small-dose bradykinin. J Neurooncol. 2009;94(1):41–50. doi:10.1007/s11060-009-9812-9.
  • Deng J, Huang Q, Wang F, et al. The role of caveolin-1 in blood-brain barrier disruption induced by focused ultrasound combined with microbubbles. J Mol Neurosci. 2012;46(3):677–687. doi:10.1007/s12031-011-9629-9.
  • Davies PF, Dewey CF, Bussolari SR, et al. Influence of hemodynamic forces on vascular endothelial function. In vitro studies of shear stress and pinocytosis in bovine aortic cells. J Clin Invest. 1984;73(4):1121–1129. doi:10.1172/JCI111298.
  • Apodaca G. Modulation of membrane traffic by mechanical stimuli. Am J Physiol Renal Physiol. 2002;282(2):F179–F190. doi:10.1152/ajprenal.2002.282.2.F179.
  • van Wamel A, Kooiman K, Harteveld M, et al. Vibrating microbubbles poking individual cells: drug transfer into cells via sonoporation. J Control Release. 2006;112(2):149–155. doi:10.1016/j.jconrel.2006.02.007.
  • Sheikov N, McDannold N, Sharma S, et al. Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med Biol. 2008;34(7):1093–1104. doi:10.1016/j.ultrasmedbio.2007.12.015.
  • Park J, Zhang Y, Vykhodtseva N, et al. The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound. J Control Release. 2012;162(1):134–142. doi:10.1016/j.jconrel.2012.06.012.
  • Rousou C, de Maar J, Qiu B, et al. The effect of microbubble-assisted ultrasound on molecular permeability across cell barriers. Pharmaceutics. 2022;14(3):494. doi:10.3390/pharmaceutics14030494.
  • O’Reilly MA, Hynynen K. Ultrasound enhanced drug delivery to the brain and Central nervous system. Int J Hyperthermia. 2012;28(4):386–396. doi:10.3109/02656736.2012.666709.
  • Balestrino R, Schapira AHV. Parkinson disease. Eur J Neurol. 2020;27(1):27–42. doi:10.1111/ene.14108.
  • Meng Y, Voisin MR, Suppiah S, et al. Is there a role for MR-guided focused ultrasound in Parkinson’s disease? Mov Disord. 2018;33(4):575–579. doi:10.1002/mds.27308.
  • Truong T-T, Chiu W-T, Lai Y-S, et al. Ca signaling-mediated low-intensity pulsed ultrasound-induced proliferation and activation of motor neuron cells. Ultrasonics. 2022;124:106739. doi:10.1016/j.ultras.2022.106739.
  • Jiang Y, Lee HJ, Lan L, et al. Optoacoustic brain stimulation at submillimeter spatial precision. Nat Commun. 2020;11(1):881. doi:10.1038/s41467-020-14706-1.
  • Kong C, Park SH, Shin J, et al. Factors associated with energy efficiency of focused ultrasound through the skull: a study of 3D-printed skull phantoms and its comparison with clinical experiences. Front Bioeng Biotechnol. 2021;9:783048. doi:10.3389/fbioe.2021.783048.