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Molecular Neurobiology

, Volume 55, Issue 8, pp 7079–7089 | Cite as

Transcranial Ultrasound Stimulation Improves Long-Term Functional Outcomes and Protects Against Brain Damage in Traumatic Brain Injury

  • Szu-Fu Chen
  • Wei-Shen Su
  • Chun-Hu Wu
  • Tsuo-Hung Lan
  • Feng-Yi YangEmail author
Article

Abstract

The purpose of this study was to assess the long-term treatment efficacy of low-intensity pulsed ultrasound (LIPUS) on functional outcomes, brain edema, and the possible involvement of reactions in mice following traumatic brain injury (TBI). Mice subjected to controlled cortical impact injury received LIPUS treatment daily for a period of 4 weeks. The effects of LIPUS on edema were detected by MR imaging in the mouse brain at 148 days following TBI. Long-term functional outcomes of LIPUS stimulation were evaluated by behavioral analyses. One-way or two-way analysis of variance and Student’s t test were used for statistical analyses, with a significant level of .05. Up to post-injury day 148, treatment with LIPUS significantly improved functional outcomes (all p < 0.05). LIPUS also significantly attenuated brain edema and neuronal death at day 148 after TBI (all p < 0.05). Furthermore, LIPUS reduced MMP9 activity, neutrophil infiltration, and microglial activation at day 1 or day 4 following TBI (all p < 0.05). Meanwhile, LIPUS increased the Bcl-2/Bax ratio and enhanced the phosphorylation of Bad and FOXO-1 at day 1 or day 4 following TBI (all p < 0.05). Almost 5 months of follow-up showed that the treatment efficacy of post-injury LIPUS stimulation on reduced brain edema and improved functional outcomes persisted over time after TBI. The neuroprotective effects of LIPUS are associated with a reduction of early inflammatory events and inhibition of apoptotic progression.

Keywords

Ultrasound Traumatic brain injury Brain edema Apoptosis Inflammation 

Notes

Acknowledgements

This study was supported by grants from the Ministry of Science and Technology of Taiwan (no. MOST 105-2221-E-010-003, MOST 104-2314-B-010-003-MY3, and 101-2314-B-350-001-MY3), the Veterans General Hospitals University System of Taiwan Joint Research Program (VGHUST107-G7-6-1 and VGHUST106-G7-6-1), the Cheng Hsin General Hospital Foundation (no. CY10721, CY10622, and CHGH103-34), and the Biophotonics & Molecular Imaging Research Center.

Compliance with Ethical Standards

All procedures involving animals were conducted in accordance with the guidelines for the Care and Use of Laboratory Animals. This study protocol was approved by our Animal Care and Use Committee.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Zhang X, Chen Y, Jenkins LW, Kochanek PM, Clark RS (2005) Bench-to-bedside review: apoptosis/programmed cell death triggered by traumatic brain injury. Crit Care 9(1):66–75.  https://doi.org/10.1186/cc2950 CrossRefPubMedGoogle Scholar
  2. 2.
    Clark RS, Kochanek PM, Chen M, Watkins SC, Marion DW, Chen J, Hamilton RL, Loeffert JE et al (1999) Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. FASEB J 13(8):813–821CrossRefPubMedGoogle Scholar
  3. 3.
    Clark RS, Kochanek PM, Adelson PD, Bell MJ, Carcillo JA, Chen M, Wisniewski SR, Janesko K et al (2000) Increases in bcl-2 protein in cerebrospinal fluid and evidence for programmed cell death in infants and children after severe traumatic brain injury. J Pediatr 137(2):197–204.  https://doi.org/10.1067/mpd.2000.106903 CrossRefPubMedGoogle Scholar
  4. 4.
    Nakamura M, Raghupathi R, Merry DE, Scherbel U, Saatman KE, McIntosh TK (1999) Overexpression of Bcl-2 is neuroprotective after experimental brain injury in transgenic mice. J Comp Neurol 412(4):681–692.  https://doi.org/10.1002/(SICI)1096-9861(19991004)412:4<681::AID-CNE9>3.0.CO;2-F CrossRefPubMedGoogle Scholar
  5. 5.
    Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB, Korsmeyer SJ (1995) Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc Natl Acad Sci U S A 92(17):7834–7838.  https://doi.org/10.1073/pnas.92.17.7834 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Marmarou A (2003) Pathophysiology of traumatic brain edema: current concepts. Acta Neurochir Suppl 86:7–10PubMedGoogle Scholar
  7. 7.
    Donkin JJ, Vink R (2010) Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments. Curr Opin Neurol 23(3):293–299.  https://doi.org/10.1097/WCO.0b013e328337f451 CrossRefPubMedGoogle Scholar
  8. 8.
    Candelario-Jalil E, Yang Y, Rosenberg GA (2009) Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 158(3):983–994.  https://doi.org/10.1016/j.neuroscience.2008.06.025 CrossRefPubMedGoogle Scholar
  9. 9.
    Ding JY, Kreipke CW, Schafer P, Schafer S, Speirs SL, Rafols JA (2009) Synapse loss regulated by matrix metalloproteinases in traumatic brain injury is associated with hypoxia inducible factor-1alpha expression. Brain Res 1268:125–134.  https://doi.org/10.1016/j.brainres.2009.02.060 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Rosenberg GA, Yang Y (2007) Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus 22(5):E4CrossRefPubMedGoogle Scholar
  11. 11.
    Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, Fini ME, Lo EH (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci 21(19):7724–7732CrossRefPubMedGoogle Scholar
  12. 12.
    Gasche Y, Fujimura M, Morita-Fujimura Y, Copin JC, Kawase M, Massengale J, Chan PH (1999) Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brain barrier dysfunction. J Cereb Blood Flow Metab 19(9):1020–1028.  https://doi.org/10.1097/00004647-199909000-00010 CrossRefPubMedGoogle Scholar
  13. 13.
    Hayashi T, Kaneko Y, Yu S, Bae E, Stahl CE, Kawase T, van Loveren H, Sanberg PR et al (2009) Quantitative analyses of matrix metalloproteinase activity after traumatic brain injury in adult rats. Brain Res 1280:172–177.  https://doi.org/10.1016/j.brainres.2009.05.040 CrossRefPubMedGoogle Scholar
  14. 14.
    Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J (2008) Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med 34(8):1384–1392.  https://doi.org/10.1007/s00134-008-1056-1 CrossRefPubMedGoogle Scholar
  15. 15.
    Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH (2008) BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A 105(7):2711–2716.  https://doi.org/10.1073/pnas.0711863105 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Tufail Y, Matyushov A, Baldwin N, Tauchmann ML, Georges J, Yoshihiro A, Tillery SI, Tyler WJ (2010) Transcranial pulsed ultrasound stimulates intact brain circuits. Neuron 66(5):681–694.  https://doi.org/10.1016/j.neuron.2010.05.008 CrossRefPubMedGoogle Scholar
  17. 17.
    Lin WT, Chen RC, Lu WW, Liu SH, Yang FY (2015) Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer's disease rat model. Sci Rep 5(1):9671.  https://doi.org/10.1038/srep09671 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Huang SL, Chang CW, Lee YH, Yang FY (2017) Protective effect of low-intensity pulsed ultrasound on memory impairment and brain damage in a rat model of vascular dementia. Radiology 282(1):113–122.  https://doi.org/10.1148/radiol.2016160095 CrossRefPubMedGoogle Scholar
  19. 19.
    Yang FY, Lu WW, Lin WT, Chang CW, Huang SL (2015) Enhancement of neurotrophic factors in astrocyte for neuroprotective effects in brain disorders using low-intensity pulsed ultrasound stimulation. Brain Stimul 8(3):465–473.  https://doi.org/10.1016/j.brs.2014.11.017 CrossRefPubMedGoogle Scholar
  20. 20.
    Liu SH, Lai YL, Chen BL, Yang FY (2016) Ultrasound enhances the expression of brain-derived neurotrophic factor in astrocyte through activation of TrkB-Akt and calcium-CaMK signaling pathways. Cereb Cortex:bhw169.  https://doi.org/10.1093/cercor/bhw169
  21. 21.
    Chen SF, Tsai HJ, Hung TH, Chen CC, Lee CY, Wu CH, Wang PY, Liao NC (2012) Salidroside improves behavioral and histological outcomes and reduces apoptosis via PI3K/Akt signaling after experimental traumatic brain injury. PLoS One 7(9):e45763.  https://doi.org/10.1371/journal.pone.0045763 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yang FY, Chang WY, Chen JC, Lee LC, Hung YS (2014) Quantitative assessment of cerebral glucose metabolic rates after blood-brain barrier disruption induced by focused ultrasound using FDG-MicroPET. NeuroImage 90:93–98.  https://doi.org/10.1016/j.neuroimage.2013.12.033 CrossRefPubMedGoogle Scholar
  23. 23.
    Su WS, Tsai ML, Huang SL, Liu SH, Yang FY (2015) Controllable permeability of blood-brain barrier and reduced brain injury through low-intensity pulsed ultrasound stimulation. Oncotarget 6(39):42290–42299.  https://doi.org/10.18632/oncotarget.5978 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Chen CC, Hung TH, Lee CY, Wang LF, Wu CH, Ke CH, Chen SF (2014) Berberine protects against neuronal damage via suppression of glia-mediated inflammation in traumatic brain injury. PLoS One 9(12):e115694.  https://doi.org/10.1371/journal.pone.0115694 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Goldstein LB, Davis JN (1990) Beam-walking in rats: studies towards developing an animal model of functional recovery after brain injury. J Neurosci Methods 31(2):101–107.  https://doi.org/10.1016/0165-0270(90)90154-8 CrossRefPubMedGoogle Scholar
  26. 26.
    Chen CC, Hung TH, Wang YH, Lin CW, Wang PY, Lee CY, Chen SF (2012) Wogonin improves histological and functional outcomes, and reduces activation of TLR4/NF-kappaB signaling after experimental traumatic brain injury. PLoS One 7(1):e30294.  https://doi.org/10.1371/journal.pone.0030294 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Nag S, Manias JL, Stewart DJ (2009) Pathology and new players in the pathogenesis of brain edema. Acta Neuropathol 118(2):197–217.  https://doi.org/10.1007/s00401-009-0541-0 CrossRefPubMedGoogle Scholar
  28. 28.
    Feickert HJ, Drommer S, Heyer R (1999) Severe head injury in children: impact of risk factors on outcome. J Trauma 47(1):33–38CrossRefPubMedGoogle Scholar
  29. 29.
    Alluri H, Wiggins-Dohlvik K, Davis ML, Huang JH, Tharakan B (2015) Blood-brain barrier dysfunction following traumatic brain injury. Metab Brain Dis 30(5):1093–1104.  https://doi.org/10.1007/s11011-015-9651-7 CrossRefPubMedGoogle Scholar
  30. 30.
    Karmacharya MB, Kim KH, Kim SY, Chung J, Min BH, Park SR, Choi BH (2015) Low intensity ultrasound inhibits brain oedema formation in rats: potential action on AQP4 membrane localization. Neuropathol Appl Neurobiol 41(4):e80–e94.  https://doi.org/10.1111/nan.12182 CrossRefPubMedGoogle Scholar
  31. 31.
    Yoon SH, Kwon SK, Park SR, Min BH (2012) Effect of ultrasound treatment on brain edema in a traumatic brain injury model with the weight drop method. Pediatr Neurosurg 48(2):102–108.  https://doi.org/10.1159/000343011 CrossRefPubMedGoogle Scholar
  32. 32.
    Nakao J, Fujii Y, Kusuyama J, Bandow K, Kakimoto K, Ohnishi T, Matsuguchi T (2014) Low-intensity pulsed ultrasound (LIPUS) inhibits LPS-induced inflammatory responses of osteoblasts through TLR4-MyD88 dissociation. Bone 58:17–25.  https://doi.org/10.1016/j.bone.2013.09.018 CrossRefPubMedGoogle Scholar
  33. 33.
    Sato M, Kuroda S, Mansjur KQ, Khaliunaa G, Nagata K, Horiuchi S, Inubushi T, Yamamura Y et al (2015) Low-intensity pulsed ultrasound rescues insufficient salivary secretion in autoimmune sialadenitis. Arthritis Res Ther 17(1):278.  https://doi.org/10.1186/s13075-015-0798-8 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Rostami E, Krueger F, Zoubak S, Dal Monte O, Raymont V, Pardini M, Hodgkinson CA, Goldman D et al (2011) BDNF polymorphism predicts general intelligence after penetrating traumatic brain injury. PLoS One 6(11):e27389.  https://doi.org/10.1371/journal.pone.0027389 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Su WS, Wu CH, Chen SF, Yang FY (2017) Transcranial ultrasound stimulation promotes brain-derived neurotrophic factor and reduces apoptosis in a mouse model of traumatic brain injury. Brain Stimul 10(6):1032–1041.  https://doi.org/10.1016/j.brs.2017.09.0173 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Physical Medicine and RehabilitationCheng Hsin General HospitalTaipeiTaiwan
  2. 2.Departments of Physiology and BiophysicsNational Defense Medical CenterTaipeiTaiwan
  3. 3.Department of Biomedical Imaging and Radiological Sciences, School of Biomedical Science and EngineeringNational Yang-Ming UniversityTaipeiTaiwan
  4. 4.Graduate Institute of Life SciencesNational Defense Medical CenterTaipeiTaiwan
  5. 5.Departments of PsychiatryNational Yang-Ming UniversityTaipeiTaiwan
  6. 6.Department of PsychiatryTaichung Veterans General HospitalTaichungTaiwan
  7. 7.Biophotonics and Molecular Imaging Research CenterNational Yang-Ming UniversityTaipeiTaiwan

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