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

Acta Neurochir Suppl. 2016;121:7-12. doi: 10.1007/978-3-319-18497-5_2.


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.

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

MeSH terms

  • Adenosine Triphosphate
  • Animals
  • Disease Models, Animal
  • Electron Transport Complex IV
  • Humans
  • In Vitro Techniques
  • Low-Level Light Therapy / methods*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria
  • Organ Size
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Skull / anatomy & histology*
  • Stroke / therapy*
  • Tomography, X-Ray Computed


  • Adenosine Triphosphate
  • Electron Transport Complex IV