Transcranial Near-Infrared Laser Therapy for Stroke: How to Recover from Futility in the NEST-3 Clinical Trial

  • Paul A. LapchakEmail author
  • Paul D. Boitano
Part of the Acta Neurochirurgica Supplement book series (NEUROCHIRURGICA, volume 121)


Development of drugs and devices for the treatment of stroke is not exempt from current translational research standards, which include Stroke Treatment Academic Industry Roundtable (STAIR) criteria and RIGOR guidelines. Near-infrared laser therapy (NILT) was developed to treat stroke in an era when STAIR criteria were not adhered to, thus NILT was not optimized in multiple species, nor was it optimized for efficacy across barriers in translational animal models before proceeding to expensive and extensive clinical trials. Moreover, the majority of rodent studies did not adhere to RIGOR guidelines. This ultimately led to failure in the NeuroThera Effectiveness and Safety Trial-3. Because NILT remains a promising therapeutic approach to treat stroke, we designed a systematic study to determine laser light penetration profiles across the skull of four different species with increasing skull thickness: mouse, rat, rabbit, and human.

Our study demonstrates that NILT differentially penetrates the skulls. There is especially extensive attenuation of light energy penetration across the human calvaria, compared with animal skulls, which suggests that the power density setting used in stroke clinical trials may not have optimally stimulated neuroprotection and repair pathways. The results of our study suggest that NILT cannot be sufficiently optimized in “small” animals and directly translated to humans because of significant variances of skull thickness and penetration characteristics across species. NILT neuroprotection should be further studied using a research design that endeavors to incorporate human skull characteristics (thickness) into the development plan to increase the probability of success in stroke victims.


Acute ischemic stroke Alzheimer’s disease Amyloid Behavior Laser therapy Mitochondria Neuroprotection NEST trials NILT Parkinson’s disease Translational science Traumatic brain injury Toxicity Victim Unmet clinical need 


Conflict of Interest Statement

This study utilized a K-Laser model K-1200 device. K-Laser, Inc. did not have an editorial influence on the study design or scientific content of this article.

Disclosures and Acknowledgments

Dr. Lapchak serves as editor-in-chief of the Journal of Neurology & Neurophysiology and associate editor of Translational Stroke Research. The scientific content of this work was not directly supported by the National Institutes of Health or any other funding source external to Cedars-Sinai Medical Center. He was supported in part by a U01 translational research grant NS060685. Paul D. Boitano has no disclosures.


  1. 1.
    Chung H, Dai T, Sharma SK, Huang YY, Carroll JD, Hamblin MR (2012) The nuts and bolts of low-level laser (light) therapy. Ann Biomed Eng 40:516–533PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Detaboada L, Ilic S, Leichliter-Martha S, Oron U, Oron A, Streeter J (2006) Transcranial application of low-energy laser irradiation improves neurological deficits in rats following acute stroke. Lasers Surg Med 38:70–73CrossRefPubMedGoogle Scholar
  3. 3.
    De Taboada L, Yu J, El-Amouri S, Gattoni-Celli S, Richieri S, McCarthy T, Streeter J, Kindy MS (2011) Transcranial laser therapy attenuates amyloid-beta peptide neuropathology in amyloid-beta protein precursor transgenic mice. J Alzheimers Dis 23:521–535PubMedGoogle Scholar
  4. 4.
    Desmet KD, Paz DA, Corry JJ, Eells JT, Wong-Riley MT, Henry MM, Buchmann EV, Connelly MP, Dovi JV, Liang HL, Henshel DS, Yeager RL, Millsap DS, Lim J, Gould LJ, Das R, Jett M, Hodgson BD, Margolis D, Whelan HT (2006) Clinical and experimental applications of NIR-LED photobiomodulation. Photomed Laser Surg 24:121–128CrossRefPubMedGoogle Scholar
  5. 5.
    Drochioiu G (2010) Laser-induced ATP formation: mechanism and consequences. Photomed Laser Surg 28:573–574CrossRefPubMedGoogle Scholar
  6. 6.
    Eells JT (2003) Therapeutic photobiomodulation for methanol-induced retinal toxicity. Proc Natl Acad Sci U S A 100:3439PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Fagan SC, Lapchak PA, Liebeskind DS, Ishrat T, Ergul A (2013) Recommendations for preclinical research in hemorrhagic transformation. Transl Stroke Res 4:322–327PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Farfara D, Tuby H, Trudler D, Doron-Mandel E, Maltz L, Vassar RJ, Frenkel D, Oron U (2015) Low-level laser therapy ameliorates disease progression in a mouse model of Alzheimer’s disease. J Mol Neurosci 55(2):430–436CrossRefPubMedGoogle Scholar
  9. 9.
    Hacke W, Schellinger PD, Albers GW, Bornstein NM, Dahlof BL, Fulton R, Kasner SE, Shuaib A, Richieri SP, Dilly SG, Zivin J, Lees KR; NEST 3 Committees and Investigators (2014) Transcranial laser therapy in acute stroke treatment: results of neurothera effectiveness and safety trial 3, a phase III clinical end point device trial. Stroke 45:3187–3193Google Scholar
  10. 10.
    Huang YY, Chen AC, Carroll JD, Hamblin MR (2009) Biphasic dose response in low level light therapy. Dose Response 7:358–383PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Karu T (2010) Mitochondrial mechanisms of photobiomodulation in context of new data about multiple roles of ATP. Photomed Laser Surg 28:159–160CrossRefPubMedGoogle Scholar
  12. 12.
    Lampl Y, Zivin JA, Fisher M, Lew R, Welin L, Dahlof B, Borenstein P, Andersson B, Perez J, Caparo C, Ilic S, Oron U (2007) Infrared laser therapy for ischemic stroke: a new treatment strategy: results of the NeuroThera Effectiveness and Safety Trial-1 (NEST-1). Stroke 38:1843–1849CrossRefPubMedGoogle Scholar
  13. 13.
    Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, Crystal RG, Darnell RB, Ferrante RJ, Fillit H, Finkelstein R, Fisher M, Gendelman HE, Golub RM, Goudreau JL, Gross RA, Gubitz AK, Hesterlee SE, Howells DW, Huguenard J, Kelner K, Koroshetz W, Krainc D, Lazic SE, Levine MS, Macleod MR, McCall JM, Moxley RT 3rd, Narasimhan K, Noble LJ, Perrin S, Porter JD, Steward O, Unger E, Utz U, Silberberg SD (2012) A call for transparent reporting to optimize the predictive value of preclinical research. Nature 490:187–191PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Lapchak PA (2010) Taking a light approach to treating acute ischemic stroke patients: transcranial near-infrared laser therapy translational science. Ann Med 42:576–586PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Lapchak PA (2010) Translational stroke research using a rabbit embolic stroke model: a correlative analysis hypothesis for novel therapy development. Transl Stroke Res 1:96–107PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Lapchak PA (2012) Transcranial near-infrared laser therapy applied to promote clinical recovery in acute and chronic neurodegenerative diseases. Expert Rev Med Devices 9:71–83PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Lapchak PA (2013) Fast neuroprotection (fast-NPRX) for acute ischemic stroke victims: the time for treatment is now. Transl Stroke Res 4:704–709CrossRefPubMedGoogle Scholar
  18. 18.
    Lapchak PA (2013) Recommendations and practices to optimize stroke therapy: developing effective translational research programs. Stroke 44:841–843CrossRefPubMedGoogle Scholar
  19. 19.
    Lapchak PA, Araujo DM, Zivin JA (2004) Comparison of Tenecteplase with Alteplase on clinical rating scores following small clot embolic strokes in rabbits. Exp Neurol 185:154–159CrossRefPubMedGoogle Scholar
  20. 20.
    Lapchak PA, De Taboada L (2010) Transcranial near infrared laser treatment (NILT) increases cortical adenosine-5'-triphosphate (ATP) content following embolic strokes in rabbits. Brain Res 1306:100–105CrossRefPubMedGoogle Scholar
  21. 21.
    Lapchak PA, Salgado KF, Chao CH, Zivin JA (2007) Transcranial near-infrared light therapy improves motor function following embolic strokes in rabbits: an extended therapeutic window study using continuous and pulse frequency delivery modes. Neuroscience 148:907–914CrossRefPubMedGoogle Scholar
  22. 22.
    Lapchak PA, Wei J, Zivin JA (2004) Transcranial infrared laser therapy improves clinical rating scores after embolic strokes in rabbits. Stroke 35:1985–1988CrossRefPubMedGoogle Scholar
  23. 23.
    Lapchak PA, Zhang JH, Noble-Haeusslein LJ (2013) RIGOR guidelines: escalating STAIR and STEPS for effective translational research. Transl Stroke Res 4:279–285PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Lapchak PA, Boitano PD, Butte PV, Fisher DJ, Hölscher T, Ley EJ, et al. (2015) Transcranial Near-Infrared Laser Transmission (NILT) Profiles (800 nm): Systematic Comparison in Four Common Research Species. PLoS ONE 10(6):e0127580. doi: 10.1371/journal.pone.0127580 Google Scholar
  25. 25.
    Leung MC, Lo SC, Siu FK, So KF (2002) Treatment of experimentally induced transient cerebral ischemia with low energy laser inhibits nitric oxide synthase activity and up-regulates the expression of transforming growth factor-beta 1. Lasers Surg Med 31:283–288CrossRefPubMedGoogle Scholar
  26. 26.
    Liang HL, Whelan HT, Eells JT, Wong-Riley MT (2008) Near-infrared light via light-emitting diode treatment is therapeutic against rotenone- and 1-methyl-4-phenylpyridinium ion-induced neurotoxicity. Neuroscience 153:963–974PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Lyden P, Lu M, Jackson C, Marler J, Kothari R, Brott T, Zivin J, The National Institute of Neurological Disorders and Stroke rt PASSG (1999) Underlying structure of the National Institutes of Health Stroke Scale: results of a factor analysis. Stroke 30:2347Google Scholar
  28. 28.
    Naeser MA, Hamblin MR (2011) Potential for transcranial laser or LED therapy to treat stroke, traumatic brain injury, and neurodegenerative disease. Photomed Laser Surg 29:443–446PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Naeser MA, Saltmarche A, Krengel MH, Hamblin MR, Knight JA (2011) Improved cognitive function after transcranial, light-emitting diode treatments in chronic, traumatic brain injury: two case reports. Photomed Laser Surg 29:351–358PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Oron A, Oron U, Chen J, Eilam A, Zhang C, Sadeh M, Lampl Y, Streeter J, DeTaboada L, Chopp M (2006) Low-level laser therapy applied transcranially to rats after induction of stroke significantly reduces long-term neurological deficits. Stroke 37:2620–2624CrossRefPubMedGoogle Scholar
  31. 31.
    Saver JL (2006) Time is brain–quantified. Stroke 37:263–266CrossRefPubMedGoogle Scholar
  32. 32.
    Saver JL, Albers GW, Dunn B, Johnston KC, Fisher M (2009) Stroke Therapy Academic Industry Roundtable (STAIR) recommendations for extended window acute stroke therapy trials. Stroke 40:2594–2600PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Tajiri N, Dailey T, Metcalf C, Mosley YI, Lau T, Staples M, van Loveren H, Kim SU, Yamashima T, Yasuhara T, Date I, Kaneko Y, Borlongan CV (2013) In vivo animal stroke models: a rationale for rodent and non-human primate models. Transl Stroke Res 4:308–321PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Turner R, Jickling G, Sharp F (2011) Are underlying assumptions of current animal models of human stroke correct: from STAIRS to high hurdles? Transl Stroke Res 2:138–143PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Uozumi Y, Nawashiro H, Sato S, Kawauchi S, Shima K, Kikuchi M (2010) Targeted increase in cerebral blood flow by transcranial near-infrared laser irradiation. Lasers Surg Med 42:566–576CrossRefPubMedGoogle Scholar
  36. 36.
    Voie A, Dirnbacher M, Fisher D, Holscher T (2014). Parametric mapping and quantitative analysis of the human calvarium. Computerized medical imaging and graphics: the official journal of the Computerized Medical Imaging Society. 38(8):675–682. doi:  10.1016/j.compmedimag.2014.06.022. pmid:25069430.Google Scholar
  37. 37.
    Wan S, Parrish JA, Anderson RR, Madden M (1981) Transmittance of nonionizing radiation in human tissues. Photochem Photobiol 34:679–681CrossRefPubMedGoogle Scholar
  38. 38.
    Wang MM, Xi G, Keep RF (2013) Should the STAIR criteria be modified for preconditioning studies? Transl Stroke Res 4:3–14PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Zivin JA, Albers GW, Bornstein N, Chippendale T, Dahlof B, Devlin T, Fisher M, Hacke W, Holt W, Ilic S, Kasner S, Lew R, Nash M, Perez J, Rymer M, Schellinger P, Schneider D, Schwab S, Veltkamp R, Walker M, Streeter J (2009) Effectiveness and safety of transcranial laser therapy for acute ischemic stroke. Stroke 40:1359–1364Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Neurology and NeurosurgeryCedars-Sinai Medical Center (CSMC)Los AngelesUSA
  2. 2.Department of NeurologyCedars-Sinai Medical Center (CSMC)Los AngelesUSA

Personalised recommendations