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Potential for Transcranial Laser or LED Therapy to Treat Stroke, Traumatic

Brain Injury, and Neurodegenerative Disease

Article in Photomedicine and Laser Surgery · July 2011

DOI: 10.1089/pho.2011.9908 · Source: PubMed

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 Potential for Transcranial Laser or LED Therapy to Treat
Stroke, Traumatic Brain Injury, and Neurodegenerative
Disease

Citation Naeser, Margaret A., and Michael R. Hamblin. “Potential for

Transcranial Laser or LED Therapy to Treat Stroke, Traumatic
Brain Injury, and Neurodegenerative Disease.” Photomedicine
and Laser Surgery 29, no.7 (2011): 443-446. Copyright © 2011,
Mary Ann Liebert, Inc.
As Published http://dx.doi.org/10.1089/pho.2011.9908
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Photomedicine and Laser Surgery
Volume 29, Number 7, 2011 Editorial
ª Mary Ann Liebert, Inc.
Pp. 443–446
DOI: 10.1089/pho.2011.9908

Potential for Transcranial Laser or LED Therapy

to Treat Stroke, Traumatic Brain Injury,
and Neurodegenerative Disease

Margaret A. Naeser, Ph.D., L.Ac.,1,2 and Michael R. Hamblin, Ph.D.3,4,5

memory.8 In small animal models neurogenesis can be

N ear-infrared (NIR) light passes readily through the
scalp and skull and a small percentage of incident power
density can arrive at the cortical surface in humans.1 The
readily detected by incorporation of bromodeoxyuridine
(BrdU), injected before euthanasia, into proliferating brain
primary photoreceptors for red and NIR light are mitochon- cells. Increased neurogenesis after TLT, has been demon-
dria, and cortical neurons are exceptionally rich in mito- strated in a rat model of stroke,9 and in the Hamblin labo-
chondria. It is likely that brain cells are ideally set up to ratory after TLT for acute traumatic brain injury (TBI) in mice
respond to light therapy. The basic biochemical pathways (W. Xuan, T. Ando, et al., unpublished data). These two
activated by NIR light, e.g., increased adenosine-5’-triphos- mechanisms of action of TLT in ameliorating brain damage
phate (ATP) production, and signaling pathways activated by (prevention of neuronal death and increased neurogenesis)
reactive oxygen species, nitric oxide release, and increased have motivated studies in both animals and humans for di-
cyclic adenosine monophosphate (AMP) all work together to verse brain disorders and diseases. TLT for acute stroke is the
produce beneficial effects in brains whose function has been most developed,10 but acute TBI has also been shown to
compromised by ischemia, traumatic injury, or neurodegen- benefit from TLT.11 These areas are reviewed further.
eration. One of the main mechanisms of action of transcranial
light therapy (TLT) is to prevent neurons from dying, when
they have been subjected to some sort of hypoxic, traumatic, Stroke
or toxic insult. This is probably because of light-mediated In an early study with TLT to treat acute stroke in rats,
upregulation of cytoprotective gene products such as anti- significant beneficial results were obtained whether TLT was
oxidant enzymes, heat shock proteins, and anti-apoptotic applied in a bilateral, ipsilesional or contralesional manner.12
proteins. Light therapy in vitro has been shown to protect TLT (808 nm) significantly improved recovery ( p < 0.01) at 3
neurons from death caused by methanol,2 cyanide or tetro- weeks following ischemic stroke when treated once, at 24 h
dotoxin,3 and amyloid beta peptide.4 post-stroke (contralesional; power density, 7.5 mW/cm2 to
There is also probably a second mechanism operating in brain tissue).9 The number of newly formed neuronal cells,
TLT; increased neurogenesis. Neurogenesis is the generation assessed by double immunoreactivity to BrdU and tubulin
of neuronal precursors and birth of new neural cells.5 Two isotype III, as well as migrating cells (doublecortin immuno-
key sites for adult neurogenesis include the subventricular reactivity), was significantly elevated in the ipsilesional SVZ.
zone (SVZ) of the lateral ventricles, and the subgranular There was no significant difference in the stroke lesion area
layer (SGL) of the dentate gyrus in the hippocampus.6 between control and laser-irradiated rats. The authors sug-
Neurogenesis can be stimulated by physiological factors, gested that an underlying mechanism for the functional ben-
such as growth factors and environmental enrichment, efit post-TLT was possible induction of neurogenesis. Other
and by pathological processes, including ischemia and studies have also suggested that because improvement in
neurodegeneration.7 Adult neurogenesis (in the hippocam- neurologic outcome may not be evident for 2–4 weeks in the
pus particularly) is now recognized as a major determinant post-stroke rat model, delayed benefits may be caused, in part,
of brain function both in experimental animals and in hu- by induction of neurogenesis and migration of neurons.13,14
mans. Neural progenitor cells in their niche in the SGL of the A recent study with embolized rabbits showed a direct
dentate gyrus give birth to newly formed neurons that relationship between level of cortical fluence (energy density,
are thought to play a role in brain function, particularly in J/cm2) delivered, and cortical ATP content.15 Five minutes
olfaction and in hippocampal-dependent learning and following embolization (right carotid), rabbits were exposed

1
VA Boston Healthcare System, West Roxbury, Massachusetts.
2
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.
3
Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts.
4
Department of Dermatology, Harvard Medical School, Boston, Massachusetts.
5
Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts.

443
444 NAESER AND HAMBLIN

to 2 min of NIR TLT using 808-nm laser on skin surface, observed in anterior corona radiata and fronto-temporal re-
posterior to bregma at midline. Three hours later, the cere- gions.28 Cognitive problems result from tissue damage in the
bral cortex was excised. Use of continuous wave (CW) TLT prefrontal cortex and anterior cingulate gyrus within the
(7.5 mW/cm2, 0.9 J/cm2) resulted in a 41% increase in corti- frontal lobes.
cal ATP. Use of 100-Hz pulsed wave (PW) TLT (37.5 mW/ TLT has been used to treat acute TBI in animal models.11
cm2, 4.5 J/cm2) resulted in a 157% increase in cortical ATP. Mice were subjected to closed-head injury (CHI) using a
Surprisingly, the increased cortical ATP level of 157% was weight drop procedure, and 4 h post- CHI, either sham, or
higher than that measured in naive rabbits that had never real NIR TLT (200 mW, 808 nm) was administered on the
suffered stroke. The authors suggested in future studies, skull (skin incision made) 4 mm caudal to the coronal suture
greater improvement might be achieved by optimizing line, on the midline (2 min, 1.2–2.4 J/cm2, 10 or 20 mW/cm2).
length of treatment, and mode of treatment (PW, perhaps at After 5 days the motor behavior was significantly better
100 Hz). ( p < 0.05) in the laser-treated group. At 28 days post- CHI,
TLT has been shown to significantly improve outcome in the brain tissue volume was examined. The mean lesion size
human acute stroke patients, when applied at *18 h post- in the laser-treated group (1.4%, SD 0.1) was significantly
stroke, over the entire surface of the head (20 points in 10/20 smaller ( p < .001), than in the control group (12.1%, SD 1.3).
EEG system) regardless of stroke location.16–18 Significant Additional TLT animal studies in acute TBI have produced
improvements ( p < 0.04) were observed in the moderate and beneficial effects, including the balance of IL-1b, TNF-a, and
moderate–severe stroke patients only (n = 434), who received IL-6, thereby preventing cell death;29 and using either 665-
the real laser protocol (vs. sham), but not in severe stroke nm or 810-nm TLT (36 J/cm2) was highly effective in im-
patients.17 proving the neurological performance of mice for 4 weeks
To date, there are no TLT studies to treat chronic stroke post-CHI.30
patients. The use of laser light to stimulate acupuncture In humans, two chronic, mTBI cases showed improved
points on the body (instead of needles) to treat paralysis in cognition following a series of TLT treatments with red/NIR
chronic stroke patients ( > 10 months post-stroke onset) has LED cluster heads.31 These were applied to midline, and
resulted in similar levels of improvement, following a series bilateral forehead/scalp areas (hair not shaved off, but par-
of 20 or 40 laser (or needle) treatments.19–21 A 20-mW, 780- ted, under each 2-inch diameter 500-mW cluster head). Each
nm, CW laser with 1-mm diameter aperture (Unilaser, cluster head contained 52, 870-nm diodes and 9, 633-nm
Denmark) was used (51–103 J/cm2 per point). Overall, 5/7 diodes (12–15 mW each diode); 22.2 mW/cm2; 13.3 J/cm2 at
(71.4%) of the patients showed improvement, with an in- skin, estimated 0.4 J/cm2 at 1 cm deep (at cortex). Case 1 (66-
crease of 11–28% in isolated, active range of motion for year-old woman) began TLT treatments at 7 years after
shoulder abduction, knee flexion, and/or knee extension. closed-head TBI (car accident). Pre-LED, she could focus
The two patients who showed no improvement had severe sustained attention on her computer for only 20 min. After 8
paralysis, with results similar to TLT results with severe, weekly LED treatments, her sustained computer time in-
acute stroke patients.17 Therefore, stroke patients with pa- creased to 3 h. To date, she has treated herself at home, al-
ralysis improved when the paralysis was not severe, al- most daily for 6 years, and maintains her improved cognition
though a reduction in spasticity has been observed in severe (she is now 72 years of age). Case 2 (52-year-old woman) is a
cases (M.A.N., personal observation). Stroke patients with military officer who had a history of repeated closed-head
only mild or moderate hemiparesis (including only hand traumas. Brain MRI showed fronto-parietal atrophy. She was
paresis) appear to have the best potential for improvement. medically disabled for 5 months before TLT. After 4 months
On brain CT scan, these mild–moderate cases have smaller of nightly TLT at home, she returned to work full time as an
areas of infarction adjacent to the body of the lateral ven- executive consultant at an international technology consul-
tricle, than those with severe paralysis in whom the lesion is ting firm and was able to discontinue receiving medical
often adjacent to the body of the lateral ventricle, closer to the disability payments. Neuropsychological tests performed
SVZ, possibly impeding potential for neurogenesis. Depth of after 9 months of TLT showed significant improvement (+ 1,
white matter lesion appears to be more important regarding + 2 SD) in memory (immediate and delayed recall), and in
potential for recovery than is the overall size of the cortical cognition (executive function, inhibition, and inhibition ac-
lesion.19–22 (See also: www.bu.edu/naeser/acupuncture) curacy). Case 2 also showed improvement in post-traumatic
stress disorder (PTSD) symptomatology.
TBI Mechanisms that may be associated with improved cog-
nition in the mTBI cases treated with TLT include:
Each year, an estimated 1.7 million people sustain a TBI.23
Patients with mild TBI (mTBI) have problems with poor 1. Increase in ATP, which would increase cellular respi-
memory and cognition at 6 months post-TBI, and for years ration and oxygenation in hypoxic, compromised cells.
afterwards. In 2000, the direct medical costs and indirect 2. Acupuncture points treated along the Governing Vessel
costs (including lost productivity from TBI) totaled an esti- (GV) acupuncture meridian, located in part, along the
mated $60 billion in the United States.24 There is a great need mid-sagittal suture line. These points, GV 16 (inferior to
for effective treatment to promote cognitive recovery, but no occipital protuberance), GV 20 (vertex), and GV 24
standard, empirically validated interventions are available.25 (near center-front hairline) have been used historically
Mild TBI from single and multiple events (often blast- to help treat patients in coma,32 and with stroke.33
related) is the most frequent type of brain injury experienced 3. Red/NIR TLT that may have irradiated the blood via
by Operation Enduring Freedom and Operation Iraqi Free- the valveless, emissary veins located on the scalp sur-
dom military personnel.26 Diffuse axonal injury27 is often face, but were interconnecting with veins in the supe-
GUEST EDITORIAL 445

rior sagittal sinus (Mary Dyson, personal communica- 5. Galvan V., and Jin K., (2007). Neurogenesis in the aging
tion). Direct, in vitro, blood irradiation with red-beam brain. Clin. Interv. Aging 2, 605–610.
laser has been observed to improve erythrocyte de- 6. Eriksson, P.S., Perfilieva E., Bjork–Eriksson T., et al. (1998).
formability (flexibility) and rheology.34 35 Neurogenesis in the adult human hippocampus. Nat. Med.
4. A possible increase in regional cerebral blood flow 4, 1313–1317.
(rCBF), specifically to the frontal lobes, as was observed 7. Jin K., Wang X., Xie L., et al., (2006). Evidence for stroke-
in the recent NIR TLT study to treat major depression.36 induced neurogenesis in the human brain. Proc. Natl. Acad.
Sci. U.S.A. 103, 13,198–13,202.
8. Lazarov, O., et al., (2010). When neurogenesis encounters
Neurodegenerative Diseases
aging and disease. Trends Neurosci. 33, 569–579.
There was a recent study of TLT having significant bene- 9. Oron, A., et al., (2006). Low-level laser therapy applied
ficial effects in a transgenic mouse model of Alzheimer’s transcranially to rats after induction of stroke significantly
disease (AD).37 Another study38 obtained some benefit in a reduces long-term neurological deficits. Stroke 37, 2620–
transgenic SOD1 mouse model of familial amyotrophic lat- 2624.
eral sclerosis. Light therapy for Parkinson’s disease (PD) has 10. Lapchak, P.A. (2010). Taking a light approach to treating
been studied in an in vitro model of PD human transmi- acute ischemic stroke patients: transcranial near-infrared
tochondrial cybrid ‘‘cytoplastic hybrid’’ neuronal cells,39 and laser therapy translational science. Ann. Med. 42, 576–586.
in a clinical study of 70 patients in Russia.40 The realization 11. Oron, A., Oron, U., Streeter, J., et al. (2007). Low-level laser
therapy applied transcranially to mice following traumatic
that impaired neurogenesis plays an important role in de-
brain injury significantly reduces long-term neurological
pression41 suggested that TLT could have beneficial effects in
deficits. J. Neurotrauma 24, 651–656.
patients with major depression and anxiety, and this was
12. Zhang, R.L. Chopp M., Zhang, Z.G., et al. (1997). A rat model
confirmed in a pilot clinical trial with 10 subjects receiving a of focal embolic cerebral ischemia. Brain Res. 766, 83–92.
single TLT to the forehead.36 13. Shen, J., Xie, L., Mao, X., et al. (2008). Neurogenesis after
TLT may be thought to be just in its infancy, but we be- primary intracerebral hemorrhage in adult human brain. J.
lieve the stage is set for rapid growth, especially in view of Cereb. Blood Flow Metab. 28, 1460–1468.
the massive and continuing failure of clinical trials of phar- 14. Detaboada, L., Ilic, S., Leichliter–Martha, S., et al. (2006).
maceuticals for many brain disorders. As the population Transcranial application of low-energy laser irradiation im-
continues to age, and the epidemic of degenerative diseases proves neurological deficits in rats following acute stroke.
of aging such as AD and other dementias continues to grow, Lasers Surg. Med. 8, 70–73.
TLT may make a real contribution to patient health. The LED 15. Lapchak, P.A., and De Taboada, L. (2010). Transcranial near
technology is not expensive ( < $5,000 for a unit with three infrared laser treatment (NILT) increases cortical adenosine-
LED cluster heads). A TLT protocol with LEDs has potential 5’-triphosphate (ATP) content following embolic strokes in
for home treatment. Additional controlled studies with real rabbits. Brain Res. 1306, 100–105.
and sham, transcranial low-level laser therapy and LED are 16. Lampl, Y., Zivin, J.A., Fisher, M., et al. (2007). Infrared laser
recommended. therapy for ischemic stroke: a new treatment strategy: re-
sults of the NeuroThera Effectiveness and Safety Trial-1
Acknowledgments (NEST-1). Stroke 38, 1843–1849.
17. Zivin, J.A., Albers, G.W., Bornstein, N., et al. (2009). Effec-
Research in the Naeser laboratory is supported by the tiveness and safety of transcranial laser therapy for acute
Medical Research Service, Department of Veterans Affairs. ischemic stroke. Stroke 40, 1359–1364.
Research in the Hamblin laboratory is supported by the 18. Stemer, A.B., Huisa, B.N., and Zivin, J.A. (2010). The evo-
National Institutes of Health (grants R01AI50875 and lution of transcranial laser therapy for acute ischemic stroke,
R01CA/AI838801 to M.R.H. and R01CA137108 to Long Y including a pooled analysis of NEST-1 and NEST-2. Curr.
Chiang), the Center for Integration of Medicine and In- Cardiol. Rep. 12, 29–33.
novative Technology (DAMD17-02-2-0006), the Con- 19. Naeser, M.A., Alexander, M.P., Stiassny–Eder, D. et al.
gressionally Directed Medical Research Program (CDMRP) (1995). Laser acupuncture in treatment of paralysis in stroke
Program in TBI (W81XWH-09-1-0514) and the Air Force patients: CT scan lesion site study. Am. J. Acupuncture 23,
Office of Scientific Research (F9950-04-1-0079). 13–28.
20. Naeser, M.A., Alexander, M.P., Stiassny–Eder, D., et al.
(1994a). Acupuncture in the treatment of paralysis in chronic
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