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This video was created to support their published research. The authors did research using several lasers and slices of a sheep’s brain to try and determine the best parameter for treating TBI (Traumatic Brain Injury) with a desired fluency of 0.9 to 15 joules/cm2 at a depth of 2 cm. They state that getting the energy through the skull is especially difficult so they test multiple options so test the transfer rate. They started out using a continuous output split 980/810nm system (the only company that makes that type of split system, 80% of the power at 980nm and 20% of the power at 810nm, is LiteCure with their LightForce series). The result was less than 1/2% of the energy reached a depth of 2cm. Then they switched to pulsing and got an increase in the energy transfer. When they switched to a 810nm-only 15 watt system with pulsing the transfer rate increased to 16% of the output energy reached the target depth.

 Here are some rough numbers to review the feasibility of using this system for treatment. If the duty cycle is 70%, the system will deliver 1.68 joules per second at a depth 2cm (15wattS*70%*16%). To get 5 joules/cm2 over 15 x 15 cm treatment area would require a total of 1125 joules at depth. This would take 23 minutes.

This research shows that only class 4 systems can delivery the level of power needed for this kind of therapy in a typical rushed doctor's office. A class 3b system with 1 watt would take 4 - 5 hours per treatment to get the same dosage.

The original research publication is titled " Treatments for traumatic brain injury with emphasis on transcranial near-infrared laser phototherapy"

 

video length: (9:18)

 

Original Source: https://www.youtube.com/watch?v=iZbP2IVekh0

There is a notable lack of therapeutic alternatives for what is fast becoming a global epidemic of traumatic brain injury (TBI). Photobiomodulation (PBM) employs red or near-infrared (NIR) light (600-1100nm) to stimulate healing, protect tissue from dying, increase mitochondrial function, improve blood flow and tissue oxygenation. PBM can also act to reduce swelling, increase antioxidants, decrease inflammation, protect against apoptosis, and modulate microglial activation state. All these mechanisms of action strongly suggest that PBM delivered to the head should be beneficial in cases of both acute and chronic TBI. Most reports have used NIR light either from lasers or from light-emitting diodes (LEDs). Many studies in small animal models of acute TBI have found positive effects on neurological function, learning and memory, and reduced inflammation and cell death, in the brain. There is evidence that PBM can help the brain to repair itself by stimulating neurogenesis, upregulating BDNF synthesis, and encouraging synaptogenesis. In healthy human volunteers (including students and healthy elderly women) PBM has been shown to increase regional cerebral blood flow, tissue oxygenation and improve memory, mood and cognitive function. Clinical studies have been conducted in patients suffering from the chronic effects of TBI. There have been reports of improvements in executive function, working memory, and improved sleep. Functional magnetic resonance imaging has shown modulation of activation in intrinsic brain networks likely to be damaged in TBI (default mode network and salience network).

Keywords: photobiomodulation, low-level laser therapy, traumatic brain injury, stroke, chromophores, animal studies, clinical trials, human studies

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1. Introduction

Photobiomodulation (PBM) formerly known as low-level laser (light) therapy (LLLT) is approaching its 50th anniversary, after being discovered by Endre Mester working in Hungary in 1967 (Hamblin et al. 2016). Originally thought to be a property of red lasers (600-700 nm), PBM has broadened to include near-infrared (NIR) wavelengths 760-1200 nm, and even blue and green wavelengths. Moreover the advent of inexpensive and safe light emitting diodes (LEDs) has supplanted the use of expensive lasers in many indications. The better tissue penetration properties of NIR light, together with its good efficacy, has made it the most popular wavelength range overall. The best-known medical applications of PBM have been for indications such as stimulation of wound healing (Hopkins et al. 2004; Kovacs et al. 1974), reduction of pain and inflammation in orthopedic and musculoskeletal conditions (Aimbire et al. 2006; Gam et al. 1993), and mitigation of cancer therapy side-effects (Zecha et al. 2016a; Zecha et al. 2016b). However in recent years there has been growing interest in the use of PBM in various brain disorders (Hamblin 2016b; Hennessy and Hamblin 2016; Naeser and Hamblin 2011; Naeser and Hamblin 2015). The almost complete lack of any adverse side-effects of PBM, coupled with growing disillusion with pharmaceutical drugs that affect brain function, have combined together to suggest an alternative physical therapy approach to improving brain function.

Traumatic brain injury (TBI) is caused by some type of trauma to the head, often resulting from road traffic accidents, assaults, falls, sports injuries, or blast injuries suffered in military conflict. TBI is classified as mild (loss of consciousness 0-30 minutes; altered mental state <24 hours; post-trauma amnesia <1 day); moderate (loss of consciousness 30 minutes to 24 hours; altered mental state >24 hours; post-trauma amnesia >1-7 days), or severe (loss of consciousness >24 hours; altered mental state >24 hours; post-trauma amnesia >7 days) (Blennow et al. 2016). There are three cases of TBI sustained each minute in the US (Faul et al. 2010). Repeated mild episodes of TBI (also known as concussions) even without loss of consciousness, may have devastating cumulative effects (Kamins and Giza 2016). Chronic traumatic encephalopathy is a recently recognized condition resulting from repeated head trauma, found in boxers, football players, and military personnel (McKee et al. 2016; Safinia et al. 2016). There is presently no accepted treatment for TBI, although some investigational approaches are being tested in both the acute (neuroprotection) and chronic (neurorehabilitation) settings (Loane and Faden 2010). One of these novel approaches is PBM or LLLT (Hamblin 2016a; Hamblin 2016b; Huang et al. 2012; Thunshelle and Hamblin 2016).

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2. Mechanisms of action

Uncertainties about the mechanism of action of PBM at the molecular and cellular levels, have undoubtedly held back its acceptance in the wider biomedical community. However in recent years substantial progress has been made in this regard (de Freitas and Hamblin 2016). In the following section the state-of-the-art knowledge about the mechanisms of PBM is summarized. Figure 1 shows a graphical representation of the cellular and molecular mechanisms of PBM.

Figure 1

Molecular mechanisms of tPBM

Light passes through the scalp and skull, where depending on the wavelength it is absorbed by two different chromophores. Red and NIR (up to 940nm) is primarily absorbed by cytochrome c oxidase in the mitochondrial respiratory chain of the cortical neurons. Longer wavelength NIR light (980nm, 1064nm) is primarily absorbed by heat and light-sensitive transient receptor potential ion channels. In both cases cell signaling and messenger molecules are upregulated as a result of stimulated mitochondrial activity, including reactive oxygen species (ROS), and adenosine triphosphate (ATP). hv is light, TRPV is transient receptor potential vanilloid (ion channels).

2.1 Chromophores

The first law of photobiology states that a photon must be absorbed by some molecule within the tissue to have any biological effect. The identity of these chromophores has been the subject of much scientific investigation and speculation. Largely due to the efforts of Tiina Karu in Russia, the enzyme cytochrome c oxidase (CCO) has been identified as a major chromophore of red/NIR light (Karu 1999; Karu and Kolyakov 2005; Karu et al. 2004a; Karu et al. 2004b). CCO is unit IV in the mitochondrial respiratory chain and has absorption peaks reaching well into the NIR spectral region (up to 900 nm) as well as in the red and blue regions. The most discussed hypothesis to explain exactly how photon absorption can stimulate the activity of CCO involves the photodissociation of inhibitory nitric oxide (NO) that can bind to the copper and heme centers in the enzyme and prevent oxygen from gaining access to the active sites (Lane 2006). In experimental models (such as isolated mitochondria) oxygen consumption and ATP production are increased, and the mitochondrial membrane potential is raised (Passarella et al. 1984).

A less well-appreciated mechanism involves light and heat-gated ion channels. These cation ion channels are thought to be members of the transient receptor potential (TRP) superfamily consisting of over 28 distinct members organized into six subfamilies, based on their primary amino acid structures (Caterina and Pang 2016). TRPV (vanilloid sub-family) members including TRPV1 (capsaicin receptor) have been shown to be activated by various wavelengths of light including green, red and NIR.

2.2 Cellular mechanisms

After the primary photon absorption event occurs, whether that the photons are absorbed by CCO, or by TRP ion channels a series of secondary events occurs. One of these events is the generation of reactive oxygen species (ROS), which are thought to be produced inside the mitochondria due to an increase in electron transport, and a rise in the mitochondrial membrane potential above the baseline levels (Suski et al. 2012). It should be noted that mitochondrial ROS can be produced when MMP is raised above normal, and also when ROS is reduced below normal. It is thought that the ROS produced when MMP is lowered (mitochondrial dysfunction) are more damaging than ROS produced when MMP is raised (mitochondrial stimulation). Nitric oxide is produced after PBM (Hamblin 2008), possibly by photodissociation from CCO where it inhibits oxygen consumption and electron transport (Lane 2006). Cyclic adenosine monophosphate (cAMP) (Gao and Xing 2009) and intracellular calcium are increased (Alexandratou et al. 2002). Many of these secondary mediators in the signaling pathways triggered by PBM, can induce activation of transcription factors, that go on to upregulate or downregulate expression levels of a large number of genes. One of the best-known transcription factors is NF-kB that can regulate expression of over one hundred genes including proteins with antioxidant, anti-apoptotic, pro-proliferation, and pro-migration functions. PBM (810 nm 3J/cm2) was shown to activate NF-kB in mouse embryonic fibroblasts via ROS production (Chen et al. 2011a). Since NF-kB is known to be a pro-inflammatory transcription factor, it might be thought that PBM would be pro-inflammatory. However it was shown that NF-KB was decreased in already activated (treated with Toll-like receptor ligands) inflammatory dendritic cells by PBM (810 nm 3J/cm2) (Chen et al. 2011b).

2.3 Tissue mechanisms

The changes in expression levels of proteins involved in antioxidant and redox-regulation, anti-apoptotic and pro-survival, cellular proliferation, etc mean that distinct changes in tissue homeostasis, healing and regeneration can be expected after PBM. For instance, structural proteins such as collagen are newly synthesized in order to repair tissue damage (Tatmatsu-Rocha et al. 2016). Cells at risk of dying in tissue that has been subjected to ischemic or other insults are protected (Sussai et al. 2010). Stem cells are activated to leave their niche, proliferate and differentiate (Oron and Oron 2016; Zhang et al. 2016). Pain and inflammation are reduced (Chow et al. 2009). Blood flow is increased (Samoilova et al. 2008) (possibly as a result of the release of NO (Mitchell and Mack 2013)), which also stimulates lymphatic drainage thereby reducing edema (Dirican et al. 2011).

2.4 Brain specific mechanisms

In addition to the foregoing, there are some PBM tissue mechanisms that are specific to the brain. One of the most important is an increase in cerebral blood flow often reported after transcranial photobiomodualtion (tPBM) (Salgado et al. 2015), leading to increased tissue oxygenation, and more oxidized CCO as measured by NIR spectroscopy (Rojas and Gonzalez-Lima 2013). tPBM has been shown to reduce activated microglia in the brains of TBI mice as measured by IBA1 (ionized calcium-binding adapter molecule-1) expression thus demonstrating reduced neuroinflammation (Khuman et al. 2012). tPBM has been shown to increase neurogenesis (formation of new brain cells derived from neuroprogenitor cells) (Xuan et al. 2014), and synaptogenesis (formation of new connections between existing brain cells) (Xuan et al. 2015) both in TBI mice. Figure 2 shows a graphical representation of a variety of these brain-specific tissue mechanisms.

Figure 2

Brain-specific mechanisms of tPBM

The gene transcription process described in Figure 1 can lead to decreases in neuronal apoptosis and excitotoxicity and lessening of inflammation and reduction of edema due to increased lymphatic flow, which together with protective factors such as antioxidants, will all help to reduce progressive brain damage. Increases in angiogenesis, expression of neurotrophins leading to activation of neural progenitor cells and more cell migration, and increased synaptogenesis may all contribute to the brain repairing itself from damage sustained in the trauma. AUC is area under the curve.

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3. Transcranial photobiomodulation

Transcranial PBM is a growing approach to many different brain disorders that may be classified as sudden onset (stroke, TBI, global ischemia), neurodegenerative (Alzheimer's, Parkinson's, dementia), or psychiatric (depression, anxiety, posttraumatic stress disorder)(Hamblin 2016b; Hennessy and Hamblin 2016; Thunshelle and Hamblin 2016). In the following section some issues concerning where the light should be delivered, and the effects of PBM on uninjured mice and humans are addressed.

3.1 Light penetration

Several laboratories working in the field of tissue optics, have investigated the penetration of light of different wavelengths though the scalp and the skull, and to what depths into the parenchyma of the brain this light can penetrate. Answering the question “can light shone on the head sufficiently penetrate to reach the brain?” is difficult. The main reason is that at present it is unclear exactly what threshold of power density is necessary (expressed in mW/cm2) at some depth inside the brain to have a biological effect. There clearly must be a minimum value below which, the light can be delivered for an infinite time without having any effect, but whether this threshold is in the region of μW/cm2 or mW/cm2 is unknown at present.

Haeussinger et al. estimated that the mean penetration depth (5% remaining intensity) of NIR light through the scalp and skull was 23.6 + 0:7 mm (Haeussinger et al. 2011). Other studies have found comparable results with some variations depending on the precise location on the head and the precise wavelength studied (Okada and Delpy 2003; Strangman et al. 2014).

Jagdeo et al. (Jagdeo et al. 2012) used human cadaver heads (skull with intact soft tissue) to measure penetration of 830 nm light, and found that penetration depended on the anatomical region of the skull (0.9% at the temporal region, 2.1% at the frontal region, and 11.7% at the occipital region). Tedord et al. (Tedford et al. 2015) also used human cadaver heads to compare penetration of 660 nm, 808 nm, and 940 nm light. They found that 808 nm light penetrated best, and could reach a depth in the brain of 40–50 mm. Lapchak et al. compared the transmission of 810 nm light through the skulls (no soft tissue) of four different species, and found the mouse skull transmitted 40%, while for rat it was 21%, for rabbit it was 11.3 and for the human skull it was only 4.2% (Lapchak et al. 2015). Pitzschke and colleagues compared penetration of 670 nm and 810 nm light into the brain when delivered by a transcranial or a transphenoidal approach, and found that the best combination was 810 nm delivered transphenoidally (Pitzschke et al. 2015). Yaroslavsky et al. examined light penetration of different wavelengths through different parts of the brain tissue (white brain matter, gray brain matter, cerebellum, and brainstem tissues, pons, thalamus). Best penetration was found with wavelengths between 1000 and 1100 nm (Yaroslavsky et al. 2002). Henderson and Morries found that between 0.45% and 2.90% of 810 nm or 980 nm light penetrated through 3 cm of scalp, skull and brain tissue in ex vivo lamb heads (Henderson and Morries 2015a).

3.2 Local vs systemic effects of light

It is possible that the beneficial effects of PBM on the brain cannot be entirely explained by penetration of light through the scalp and skull into the brain itself, at a sufficient intensity to have an effect on the brain cells. The surface power density that can be safely applied to the head, is limited by heating of the skin. Perceptible heating of the skin starts to be felt when the power density is over about 500 mW/cm2, and can become severe at 1 W/cm2.

There has been one study that explicitly addressed whether direct transcranial PBM or indirect PBM is best for the brain. In a study of PBM for Parkinson's disease in a mouse model, Mitrofanis and colleagues compared the direct delivery of light to the mouse head, and they also covered up the head with aluminum foil so that the light was delivered to the remainder of the mouse body. They found that there was a highly beneficial effect on brain histology with light delivered to the head, but nevertheless there was also a statistically significant although less pronounced benefit (referred to as an “abscopal effect”) when the head was shielded from light. Moreover Oron and co-workers (Farfara et al. 2015) have shown that delivering NIR light to the mouse tibia (using either surface illumination or a fiber optic) resulted in improvements in memory and spatial learning in a transgenic mouse model of Alzheimer's disease. They proposed the mechanism involved PBM stimulating c-kit-positive mesenchymal stem cells (MSCs) that were normally resident in autologous bone marrow. These MSCs were proposed to be able to infiltrate the brain, and clear β-amyloid plaques (Oron and Oron 2016). It should be noted in general that the calvarial bone marrow of the skull contains substantial numbers of stem cells (Iwashita et al. 2003).

3.3 PBM for brain in uninjured animals

Several laboratories have reported that shining light onto the head of uninjured healthy mice or rats can improve various cognitive and emotional parameters. The first study reported that exposure of the middle aged (12 months) CD1 female mice to 1072 nm LED arrays (Michalikova et al. 2008) produced improved performance in a 3D maze compared to sham treated age-matched controls. Gonzalez-Lima and coworkers (Gonzalez-Lima and Barrett 2014) showed that transcranial PBM (9 mW/cm2 with a 660 nm LED array) delivered to rats induced dose-dependent increases in oxygen consumption (5% after 1 J/cm2 and 16% after 5 J/cm2) [113]. They also found that tPBM reduced fear renewal and prevented the reemergence of the extinguished conditioned fear-responses (Rojas et al. 2012).

3.4 PBM for enhancement of brain function in uninjured human volunteers

Gonzalez-Lima et al delivered transcranial PBM (1064 nm laser, 60 J/cm2 at 250 mW/cm2) to the forehead in uninjured human volunteers in a placebo-controlled, randomized study. The goal was to improve performance of cognitive tasks related to the prefrontal cortex, including a psychomotor vigilance task (PVT), a delayed match-to-sample (DMS) memory task, and improved mood as measured by the positive and negative affect schedule (PANAS-X) (Barrett and Gonzalez-Lima 2013). Subsequent studies in uninjured humans showed that tPBM with 1064 nm laser could improve performance in the Wisconsin Card Sorting Task (considered the gold standard test for executive function) (Blanco et al. 2015). They also showed that tPBM to the right forehead (but not the left forehead) could improve attention bias modification (ABM) in humans with depression (Disner et al. 2016).

Salgado et al. applied transcranial LED to enhance cerebral blood flow in healthy elderly women, as measured by transcranial Doppler ultrasound (TCD) of the right and left middle cerebral artery and basilar artery. Twenty-five non-institutionalized elderly women (mean age 72 years), with cognitive status > 24, were assessed using TCD before and after transcranial LED therapy. tPBM (627 nm, 70 mW/cm2, 10 J/cm2) was performed at four points of the frontal and parietal region for 30 s each twice a week for 4 weeks. There was a significant increase in the systolic and diastolic velocity of the left middle cerebral artery (25 and 30%, respectively) and the basilar artery (up to 17 and 25%), as well as a decrease in the pulsatility index and resistance index values of the three cerebral arteries analyzed (Salgado et al. 2015).

3.5 PBM for acute stroke

Transcranial PBM delivered to the head, has been investigated as a possible treatment for acute stroke (Lapchak 2010). Animal models such as rats and rabbits, were first used as laboratory models, and these animals had experimental strokes induced by a variety of methods and were then treated with light (usually 810 nm laser) within 24 h of stroke onset (Lampl 2007). In these studies intervention by tLLLT within 24 h had meaningful beneficial effects.

Treatment of acute stroke in human patients was then addressed in a series of three clinical trials called “Neurothera Effectiveness and Safety Trials” (NEST-1 (Lampl et al. 2007), NEST-2 (Huisa et al. 2013), and NEST-3 (Zivin et al. 2014)). The protocol used an 810 nm laser applied to the shaved head (20 separate points in the 10/20 EEG system) within 24 h of patients suffering an ischemic stroke. The first study, NEST-1, enrolled 120 patients between the ages of 40 to 85 years of age and found a significantly improved outcome (p < 0.05 real vs sham, NIH Stroke Severity Scale) 5 days after a single laser treatment had been administered (Lampl et al. 2007). This significantly improved status was still present 90 days post-stroke in 70% of the PBM patients (but only 51% of the sham patients). The second clinical trial, NEST-2, enrolled 660 patients, aged 40 to 90, who were randomly assigned to one of two groups (331 to PBM, 327 to sham) (Zivin et al. 2009). Significant improvements (p < 0.04) were found in the moderate and moderate-severe (but not for the severe) stroke patients. The last clinical trial, NEST-3, was planned for 1000 patients enrolled, but the study was prematurely terminated by the DSMB for futility (an expected lack of statistical significance) (Lapchak and Boitano 2016). Many commentators have asked how tPBM could work so well in the first trial, yet fail in the third trial. Insufficient light penetration, too long an interval between stroke onset and PBM, inappropriate stroke severity measurement scale, use of only one single tPBM treatment, and failure to illuminate different specific areas of the brain for individual patients, have all been suggested as contributory reasons (Hamblin 2016b). It is undoubtedly the case that the failure of NEST-3 has cast a cloud over the whole application of PBMT for TBI as well as for stroke. Many commentators have asked “Why are you testing PBMT for TBI, if it has been shown not to work for stroke?” The failure of the investigators not to take into account the anatomical location of the stroke (and also whether it was deep or superficial) was also likely to have played a role in the failure of NEST-3. It is logical that light should be applied to the same side of the head where the lesion was located, not both sides of the head (Naeser et al. 2012). In my opinion the use of a single application of PBMT also bore some of the responsibility. Although a single application of PBM to the head works very well for experimental animals (mice, rats, rabbits) who have suffered a stroke or a TBI, the same may not apply to humans.

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4. Animal studies of PBM in acute TBI models

4.1 Studies from the Oron laboratory

Oron's group was the first (Oron et al. 2007) to demonstrate that a single exposure of the head of a mouse a few hours after creation of a TBI lesion using a NIR laser (808 nm) could improve neurological performance and reduce the size of the brain lesion. A weight-drop device was used to induce a closed-head TBI in the mice. An 808 nm diode laser with two energy densities calculated at the surface of the brain (1.2-2.4 J/cm2 delivered by 2 minutes of irradiation with 200mW laser power to the scalp) was delivered to the head 4 hours after TBI was induced. Neurobehavioral function was assessed by the neurological severity score (NSS). There was no significant difference between the control and laser-treated group in NSS between the power densities (10 vs 20 mW/cm2), and no significant difference at early time points (24 and 48 hours) post TBI. However, there was a significant improvement (27% lower NSS score) in the PBM group at times between 5 days and 4 weeks. The laser treated group also showed a smaller loss of cortical tissue than the sham group (Oron et al.). In another study (Oron et al. 2012) they varied the pulse parameters (CW, 100Hz, or 600Hz) and tested whether the tPBM was equally effective when delivered at 4, 6, or 8 hours post-TBI. They first established that a calculated dose to the cortical surface of 1.2 J/cm2 of 808nm laser at 200mW applied to the head, was more effective when delivered at 6 hours post TBI than at 8 hours. They then selected an even shorter time post-TBI (4 hours) and compared CW with 100Hz and 600Hz. At 56 days, more mice in the 100Hz group (compared to the CW and 600 Hz groups) had fully recovered. The 600Hz group had lower NSS scores than the CW and 100Hz groups up to 20 days. Magnetic resonance imaging (MRI) analysis demonstrated significantly smaller lesion volumes in PBM-treated mice compared to controls.

4.2 Studies from the Hamblin laboratory

Wu et al. (Wu et al. 2012) first explored the effect of varying the laser wavelengths of PBM had on closed-head TBI in mice. Mice were randomly assigned to a PBM treatment group with a particular wavelength, or to a sham treatment group as a control. Closed-head injury (CHI) was induced via a weight- drop apparatus. To analyze the severity of the TBI, the neurological severity score (NSS) was measured and recorded. The injured mice were then treated with varying wavelengths of laser light (665, 730, 810 or 980 nm) at an energy density of 36 J/cm2 directed onto the scalp at 4 hours post-TBI. The 665 nm and 810 nm laser groups showed significant improvement in NSS when compared to the control group between days 5 to 28. By contrast, the 730 nm and 980 nm laser groups did not show any significant improvement in NSS (Wu et al. 2012) (Figure 3). The tissue chromophore cytochrome c oxidase (CCO) is proposed to be responsible for the underlying photon absorption process that underlies many PBM effects. CCO has absorption bands around 665 nm and 810 nm while it has a low absorption region at the wavelength of 730 nm (Karu et al.). It should be noted that this particular study (Wu et al. 2012) found that the 980 nm did not produce the same positive effects as the 665 nm and 810 nm wavelengths did; nevertheless previous studies did find that the 980 nm wavelength was an active one for PBM (Anders et al. 2014). Wu et al. suggested that these dissimilar results may be due to differences in the energy density, irradiance etc. between the other studies and the Wu study (Wu et al. 2012). In particular a much lower dose of 980 nm might have been effective had it been tested (Wang et al. 2016). Ando et al. (Ando et al. 2011) next used the 810 nm wavelength produced by a Ga-Al-As diode laser delivered at parameters used in the Wu study, and varied the pulse modes of the laser. These modes consisted of either pulsed wave at 10 Hz or at 100 Hz (50% duty cycle) or continuous wave laser. They used a different mouse model of TBI induced with a controlled cortical impact device directly inflicting a lesion on the cortex via an open craniotomy. A single treatment with a power density of 50 mW/m2 and an energy density of 36 J/cm2 (duration of 12 minutes) was given via tLLLT to the closed head in mice at 4 hours post CCI. At 48 hours to 28 days post TBI, all laser treated groups had significant decreases in the measured neurological severity score (NSS) when compared to the controls. Although all laser treated groups had similar NSS improvement rates up to day 7, the PW 10 Hz group began to show even greater improvement beyond this point as seen in Figure 4. At day 28, the forced swim test for depression and anxiety was used and showed a significant decrease in the immobility time for the PW 10 Hz group. In the tail suspension test, which measures depression and anxiety, there was also a significant decrease in the immobility time at day 28, and also at day 1, in the PW 10 Hz group.

Figure 3

Effect of different laser wavelengths of tPBM in closed-head TBI in mice

(A) Sham-treated control versus 665 nm laser. (B) Sham-treated control versus 730 nm laser. (C) Sham-treated control versus 810 nm laser. (D) Sham-treated control versus 980 nm laser. Points are means of 8–12 mice and bars are SD. *P < 0.05; **P < 0.01; ***P < 0.001 (one-way ANOVA). Reprinted with permission from (Wu et al. 2012)

Figure 4

Effects of pulsing in tPBM for CCI-TBI in mice

(A) Time course of neurological severity score (NSS) of mice with TBI receiving either control (no laser-treatment), or 810 nm laser (36 J/cm2 delivered at 50 mW/cm2 with a spot size of 0.78 cm2 in either CW, PW 10 Hz or PW 100 Hz modes. Results are expressed as mean +/- S.E.M ***P < 0.001 vs. the other conditions. (B) Mean areas under the NSS-time curves in the two-dimensional coordinate system over the 28-day study for the 4 groups of mice. Results are means +/- SD (n = 10). Reprinted from (Ando et al. 2011) (open access).

Studies using immunofluorescence staining of sections cut from mouse brains showed that tPBM increased neuroprogenitor cells (incorporating BrdU) in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) at 7 days after the treatment (Xuan et al. 2014). The neurotrophin known as brain derived neurotrophic factor (BDNF) was also increased in the DG and SVZ at 7 days, while the protein marker (synapsin-1) for synaptogenesis and neuroplasticity was increased in the cortex at 28 days but not in the DG, SVZ or in any location at 7 days (Xuan et al. 2015). Learning and memory as measured by the Morris water maze was also improved by tPBM (Xuan et al. 2014).

4.3 Studies from the Wu laboratory

Zhang et al. (Zhang et al. 2014) first showed that secondary brain injury occurred to a worse degree in mice that had been genetically engineered to lack “Immediate Early Response” gene X-1 (IEX-1). When these mice were exposed to a gentle head impact (thought to closely resemble mild TBI in humans) they had a worse NSS than uninjured mice with the same TBI. Exposure of IEX-1 knockout mice to PBM (150 mW/cm2, 4 min, and 36 J/cm2) delivered at 4 hours post injury, restored the NSS to almost baseline levels, suppressed proinflammatory cytokine expression of interleukin (IL)-Iβ and IL-6, but upregulated TNF-α. The original lack of IEX-1 decreased ATP production, but exposing the injured brain to LLLT elevated ATP production back to near normal levels.

Dong et al. (Dong et al. 2015) asked whether the beneficial effects of PBM on TBI in mice could be enhanced by combining PBM with administration of metabolic substrates such as pyruvate and/or lactate. The goal was to even further improve mitochondrial function in the brain. This combinatorial treatment was able to reverse memory and learning deficits in TBI injured mice back to normal levels as well as leaving the hippocampal region completely protected from tissue loss; a stark contrast to control TBI mice that exhibited severe tissue loss from secondary brain injury.

4.4 Studies from the Whalen laboratory

Khuman et al (Khuman et al. 2012) delivered PBM (800nm) either directly to the injured brain tissue (through the craniotomy) or transcranially in mice beginning 60-80 min after CCI TBI. At a dose of 60J/cm2 (500mW/cm2) the mice showed increased performance in the Morris water maze (latency to the hidden platform, p<0.05, and probe trial, p<0.01) compared to non-treated controls. When PBM was delivered via open craniotomy there was reduced microgliosis at 48h (IbA-1+ cells, p<0.05). Little or no effect of tPBM on post-injury cognitive function was observed using lower or higher doses, a 4-h administration time point or 60J/cm2 at 7-days post-TBI.

4.5 Studies from the Whelan laboratory

Quirk et al (Quirk et al. 2012) studied Sprague-Dawley rats who had received a severe CCI TBI and were divided into three groups: real TBI, sham surgery, and anesthetization only. Each group received either real or sham PBM consisting of 670nm LED treatments of 15J/cm2, 50mW/cm2, 5min, given two times per day for 3 days (chemical analysis) or 10 days (behavioral analysis using a TruScan nose-poke device). Significant differences in task entries, repeat entries, and task errors were seen in the TBI rats treated with PBM vs untreated TBI mice, and in sham surgery mice treated with PBM vs untreated sham surgery mice. A statistically significant decrease was found in the pro-apoptotic marker Bax, and increases in the anti-apoptotic marker Bcl-2 and reduced glutathione (GSH) levels in tPBM TBI mice.

4.6 Studies from the Marques laboratory

Moreira et al used a different model of TBI (Moreira et al. 2009). Wistar rats received a craniotomy and a copper probe cooled in liquid nitrogen was applied to the surface of the brain to create a standardized cryogenic injury. They treated the rats with either a 780nm or 660nm laser at one of two different doses (3J/cm2 or 5J/cm2) twice (once immediately after the injury and again 3 hours later). Rats were sacrificed 6h and 24h after the injury. The 780nm laser was better at reducing levels of pro-inflammatory cytokines (TNFα, IL1β, IL6) particularly at early timepoints (Moreira et al. 2009). In a follow-up study using 3 J/cm2 (Moreira et al. 2011) these workers reported on the healing of the injuries in these rats at timepoints 6h, 1, 7 and 14 days after the last irradiation. Cryogenic injury created focal lesions in the cortex characterized by necrosis, edema, hemorrhage and inflammatory infiltrate. The most striking findings were: PBM-treated lesions showed less tissue loss than control lesions at 6h. During the first 24h the amount of viable neurons was significantly higher in the PBM groups. PBM reduced the amount of GFAP (glial fibrillary acidic protein, a marker of astrogliosis) and the numbers of leukocytes and lymphocytes, thus demonstrating its anti-inflammatory effect.

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5. Patients with chronic TBI

The majority of studies of PBM for TBI in laboratory animals have been conducted in the acute setting, while the majority of human studies of PBM for TBI have been conducted in patients who have suffered head injuries at various times in the past (sometimes quite a long time ago).

5.1 Naeser case reports

In 2011 Naeser, Saltmarche et al., published the first report describing two chronic, TBI cases treated with tPBM (Naeser et al. 2011). A 500 mW CW LED source (mixture of 660 nm red and 870 nm NIR LEDs) with a power density of 22.2 mW/cm2 (area of 22.48 cm2), was applied all over the head, for 10 minutes at each placement location (13.3 J/cm2). In the first case study the patient reported that she could concentrate on tasks for a longer period of time (the time able to work at a computer increased from 20 minutes to 3 hours). She had a better ability to remember what she read, decreased sensitivity when receiving haircuts in the spots where PBM was applied, and improved mathematical skills after undergoing PBM. The second patient had statistically significant improvements compared to prior neuropsychological tests after 9 months of treatment. The patient had a 2 standard deviation (SD) increase on tests of inhibition and inhibition accuracy (9th percentile to 63rd percentile on the Stroop test for executive function and a 1 SD increase on the Wechsler Memory scale test for the logical memory test (83rd percentile to 99th percentile) (Naeser et al. 2011).

5.2 Naeser case series

Naeser et al then went on to report a case series containing a further eleven patients (Naeser et al. 2014). This was an open protocol study that examined whether scalp application of red and NIR LED could improve cognition in patients with chronic, mild TBI (mTBI). This study enrolled 11 participants ranging in age from 26 to 62 years (6 males, 5 females) who suffered from persistent cognitive dysfunction after mTBI. The injuries in the participants had been caused by motor vehicle accidents, sports related events and for one participant, an improvised explosive device (IED) blast. tPBM consisted of 18 sessions (Monday, Wednesday, and Friday for 6 weeks) and was started anywhere from 10 months to 8 years post-TBI. A total of 11 LED cluster heads (5.25 cm in diameter, 500 mW, 22.2 mW/cm2, 13 J/cm2) were applied for 10 minutes per set (5 or 6 LED placements per set, Set A and then Set B, in each session). Neuropsychological testing was performed pre-LED application and 1 week, 1 month and 2 months after the final treatment. They found that there was a significant positive linear trend for the Stroop Test for executive function, in trial 3 inhibition (p = 0.004); Stroop, trial 4 inhibition switching (p = 0.003); California Verbal Learning Test (CVLT)-II, total trials 1-5 (p = 0.003); CVLT-II, long delay free recall (p = 0.006). Improved sleep and fewer post-traumatic stress disorder (PTSD) symptoms, if present beforehand, were observed after treatment. Participants and family members also reported better social function and a better ability to perform interpersonal and occupational activities. Although these results were significant, the authors suggested that further placebo-controlled studies would be needed to ensure the reliability of this approach (Naeser et al. 2014).

Naeser has proposed (Naeser et al. 2016; Naeser et al. 2014) that specific scalp placements of the LED cluster heads may affect specific cortical nodes in the intrinsic networks of the brain, such as the default mode network (DMN), the salience network (SN), and the central executive network (CEN). These intrinsic networks are often dysregulated after TBI (Sharp et al. 2014). Naeser proposed that the specific areas of the head to receive light, to target cortical nodes in these networks were as follows:

1. For the DMN, placement of the LED cluster head on the midline of face, centered on the upper forehead and the front hairline, targeted the left and right mesial prefrontal cortex; and on a midline, scalp location half-way between the occipital protuberance and the vertex of the head, targeted the precuneus; and on left and right LED placements superior to the tip of each ear and posterior to each ear, targeted the inferior parietal cortex/angular gyrus areas.

2. For the SN, placement of LED cluster heads on the left and right temple areas, to target the anterior insula (but due to depth of insula, unknown if the photons reached the target); midline of the vertex of the head, to target the left and right presupplementary motor areas; and the LED cluster head placed on the midline of face, centered on the upper forehead and the front hairline, also targeted the left and right dorsal anterior cingulate cortex.

3. For the CEN, left and right scalp LED placements immediately posterior to the front hairline (on a line directly superior from the pupils of the eyes), targeted the dorso-lateral prefrontal cortex areas; and the left and right LED placements superior to the tip of each ear and posterior to each ear, also targeted the posterolateral inferior parietal cortex/angular gyrus areas (also treated as part of the DMN).

 

Further studies from Naeser and colleagues (Naeser et al. 2016) tested an intranasal LED (iLED) device. Two small iLEDs (one red and the other NIR) were clipped into each nostril and used at the same time for 25 min. The parameters were as follows: red, 633nm, 8mW CW, 1 cm2, energy density 12 J/cm2 (25 min); NIR 810nm, 14.2mW, pulsed 10Hz, 1cm2, 21.3J/cm2. The first mTBI participant (24-year old female) who had sustained four sports-related concussions (two during snowboarding and two during field hockey), received iLED PBM three times per week for 6 weeks. Significant improvements were observed in tasks measuring executive function and verbal memory as well as attention and verbal fluency. At 1 week after the 18th iLED treatment, the average total time asleep had increased by 61 min per night and her sleep efficiency (total sleep time divided by total time in bed) had increased by 11%. At 12 weeks after the last iLED treatment, she was able to discontinue all sleep medications that she had previously been using. The second, mTBI participant who received the intranasal only, LED treatment series is a 49 Yr. M (non-Veteran) who sustained mTBI in a MVA, 30 years prior to receiving the intranasal LED treatment series. He showed significant improvement on the Controlled Oral Word Association-FAS Test post- the iLED treatment series, improving by +1.3 SD and +1.5 SD at 1 and 2 months post- the 18th iLED treatment. His sleep data indicated he was already a good sleeper, at entry.

5.3 Bogdanova and Naeser studies

Bogdanova reported (Bogdanova et al. 2014) a case report of two patients (1 female) with moderate TBI (medical records and clinical evaluation) and persistent cognitive dysfunction (as measured by neuropsychological tests of executive function and memory). Patients received 18 sessions of transcranial LED therapy (3×/week for 6 weeks) using the mixed red/NIR cluster described above (Naeser et al. 2011).

Standardized neuropsychological tests for executive function, memory, depression, PTSD and sleep measures (PSQI, actigraphy) were administered to participants pre-(T1), mid-(T2), and one week (T3) post-PBM treatment. Both PBM treated cases (P1 and P2) showed marked improvement in sleep (actigraphy total sleep) 1 week post-LED treatment (T3), as compared to pre-treatment (T1). P1 also improved in executive function, verbal memory, and sleep efficiency; while P2 significantly improved on measures of PTSD (PCL-M) and depression. No adverse events were reported.

5.4 Studies from Henderson and Morries

Henderson and Morries (Henderson and Morries 2015b) used a high-power NIR laser (10-15 W at 810 and 980 nm) and applied it to the head to treat a patient with moderate TBI. The patient received 20 NIR applications over a 2-month period. They carried out anatomical magnetic resonance imaging (MRI) and perfusion single-photon emission computed tomography (SPECT). The patient showed decreased depression, anxiety, headache, and insomnia, whereas cognition and quality of life improved, accompanied by changes in the SPECT imaging.

They next reported (Morries et al. 2015) a series of ten patients with chronic TBI (average time since injury 9.3 years) where each patient received ten treatments over the course of 2 months using a high-power NIR laser (13.2 W/0.89 cm2 equivalent to 14.6 W/cm2 at 810nm; or 9 W/0.89 cm2 equivalent to 10.11 W/cm2 at 980nm). A continuous sweeping motion over the forehead was utilized to minimize skin heating and cover a larger area. Skin temperature increased no more than 3°C. Overall symptoms of headache, sleep disturbance, cognition, mood dysregulation, anxiety, and irritability improved. Symptoms were monitored by depression scales and a novel patient diary system specifically designed for this study. These authors have proposed that high power lasers are preferable for tPBM treatments because the photons can better reach the brain (Henderson and Morries 2015a).

5.5 Case study from Nawashiro

Nawashiro et al (Nawashiro et al. 2012) treated a single patient who had suffered a severe TBI. The patient survived but was left in a persistent vegetative state for 8 months after the accident. He showed no spontaneous movement of limbs and a CT scan of the head 8 months after the accident showed a focal low-density area in the right frontal lobe. The device had 23 individual 850nm LEDs (13mW each; total power 299mW, total area 57cm2). A treatment time of 30 min per session delivered 20.5 J/cm2 over the left and right forehead areas repeated twice daily (6h apart), for 73 days. Five days after beginning the PBM (after 10 treatments), the patient began to spontaneously move his left arm and hand, which had not occurred during the previous 8 months. Single-photon emission computed tomography with N-isopropyl-[123I]p-iodoamphetamine (IMP-SPECT) was performed twice. The IMP-SPECT scans showed a focal increase (20% higher) in cerebral blood flow in the uninjured left anterior frontal lobe 30 min after the last (146th) PBM treatment, compared to before PBM began.

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6. Conclusion and future prospects

As was mentioned above, one of the most important questions to be answered when contemplating clinical treatment of TBI patients with tPBM, is what is the best time to administer the treatment? All the available reports of studies using PBM in laboratory animal models of TBI and stroke, and also in patients treated for stroke, have been in the acute phase where the overall goal of the intervention can be best described as neuroprotection. Not only that but there are several reports (Lapchak et al. 2007; Oron et al. 2012) that PBM for both TBI and stroke is most effective when it is delivered as soon as possible after the actual event (head impact or ischemic stroke). The protocols for the series of NEST clinical trials specified that patients should be treated with PBM within 24 hours of the stroke occurring. By contrast, all the clinical trials of PBM for patients with TBI, that have so far been carried out, have been with chronic TBI, after varying periods of time having elapsed after the original head injury, sometimes as long as 8 years. Although it would be generally supposed that tPBM would be effective when delivered to acute TBI patients, this has not yet been actually tested. If tPBM were to be used for acute TBI patients, then presumably the PBM should be delivered perhaps beginning at 4 to 6 hours post-TBI, for a limited number of times after the injury; perhaps once a day for 7 days?

The dosimetry and optimum delivery apparatus of tPBM is still uncertain. Although there is some consensus that wavelengths in the region of 800-900nm will penetrate the scalp and skull, other workers have used longer NIR wavelengths, 980nm, 1064nm, or 1072nm. Pulsing or CW is another unresolved question. The exact locations on the head that should receive the light are still unknown. Naeser has proposed (Naeser et al. 2016) some interesting considerations regarding the scalp placements of the tLEDS, and their effect on various intrinsic cortical networks of the brain. Targeted LED placements could promote better neuromodulation (activation/deactivation) in specific cortical nodes. It is possible that communication between nodes within one single network, and/or across networks could be improved. Moreover preliminary data indicate that intranasal, red plus near-infrared LEDs can also benefit TBI patients, although the degree to which light incident on the nasal mucosa, and possibly delivered transsphenoidally (Pitzschke et al. 2015) can penetrate directly into the brain, remains to be determined.

An advantage of intranasal and/or transcranial LED PBM therapy is that it can be performed in the home, for long-term use (Naeser et al. 2011). Also, 5 chronic, mild to moderately-severe dementia cases recently showed significant improvement on the Mini-Mental State Examination (p<0.003), and on the Alzheimer's Disease Assessment Scale-Cognitive subscale (p<0.023) after 12 weeks of daily, at-home, intranasal, near-infrared LED PBM treatments (810nm, pulsed at 10 Hz), and once-a-week in-office, tLED treatments applied to the cortical nodes of the Default Mode Network (Saltmarche et al. 2017). Anecdotally, there was also improved sleep, fewer angry outbursts, and less wandering. When all LED treatments were withdrawn after 12 weeks of active LED PBM treatment, there was precipitous decline in cognition and behavior. Thus, at-home, long-term use of iLED plus tLED PBM offers a potential therapy to mitigate the sequelae of Alzheimer's disease and possibly other neurodegenerative disorders, as well as TBI and stroke.

One highly distressing aspect of TBI symptomatology that has not so far been addressed by PBM, is that of post-traumatic epilepsy (PTE). TBI is the most significant cause of symptomatic epilepsy in people from 15 to 24 years of age. The frontal and temporal lobes are the most frequently affected regions, but imaging (MRI) often fails to show the precise cause. During PTE seizures there is an abnormal electrical discharge in the brain, with staring and unresponsiveness, stiffening or shaking of the body, legs, arms or head; strange sounds, tastes, visual images, feelings or smells; inability to speak or understand, etc (Cotter et al. 2017). Epilepsy has traditionally been considered to be a contra-indication for PBMT (Navratil and Kymplova 2002). However the knowledge that has recently been gained concerning the beneficial effects of PBMT on the damaged brain, suggests that this view may need to be critically revisited.

Moreover there is also potential of tPBM to treat a wide range of brain disorders only loosely associated with TBI, including Parkinson's disease (Purushothuman et al. 2013), depression, anxiety, post-traumatic stress disorder, autism spectrum disorder and so on (Hamblin 2016b).

The ongoing and accelerating clinical research efforts in testing PBM for TBI, are expected to lead to the answering of many of these questions in the coming years.

Original Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803455/

INTRODUCTION

Since the introduction of low-level laser (light) therapy in 1967, over two hundred randomized, double-blinded, and placebo-controlled phase III clinical trials have been published from over a dozen countries. Whereas there is some degree of consensus as to the best wavelengths of light and acceptable dosages to be used, there is no agreement on whether continuous wave (CW) or pulsed wave (PW) light is more suitable for the various applications of LLLT. This review will raise (but not necessarily answer) several questions. How does pulsed light differ from CW on the cellular and molecular level, and how is the outcome of LLLT affected? If pulsing is more efficacious, then at what pulse parameters is the optimal outcome achieved? In particular, what is the ideal pulse repetition rate or frequency to use?

PULSE PARAMETERS AND LIGHT SOURCES

There are five parameters that could be specified for pulsed light sources. The pulse width or duration or ON time (PD) and the pulse Interval or OFF time (PI) are measured in seconds. Pulse repetition rate or frequency (F) is measured in Hz. The duty cycle (DC) is a unitless fractional number or %. The peak power and average power are measured in Watts.

Pulse duration, pulse repetition rate, and duty cycle are related by the simple equation:

DC=F×PD

 

Peak power is a measure of light intensity during the pulse duration, and related to the average power (measured in Watts) by:

Average power=Peak power×F×PD

 

Alternatively,

Peak power=Average powerDC

 

In all cases, it is necessary to specify any two out of three of: PD, F, and DC, and either the peak or average power for the pulse parameters to be fully defined.

Figure 1 graphically shows the relationship between peak power and pulse duration.

Fig. 1

Conceptual diagram comparing the structure of CW with pulsed light of various pulse durations.

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TYPES OF PULSED LIGHT SOURCES

Five major types of pulsed lasers (or other light sources) are commonly utilized: (1) Q-switched, (2) Gain-switched, (3) Mode-locked, (4) Superpulsed, and (5) Chopped or gated. Each utilizes a different mechanism to generate light in a pulsed as opposed to continuous manner, and vary in terms of pulse repetition rates, energies, and durations. However the first three classes of “truly” pulsed lasers mentioned above are in general not used for LLLT; instead superpulsed or gated lasers are mainly used. The concept of super-pulsing was originally developed for the carbon dioxide laser used in high power tissue ablative procedures. The idea was that by generating relatively short pulses (µsecond) the laser media could be excited to higher levels than those normally allowed in CW mode where heat dissipation constraints limit the maximum amounts of energy that can be used to excite the lasing media. With the original carbon dioxide superpulsed lasers, the short pulses would confine the thermal energy in the tissue (by making the pulse duration less than the thermal diffusion time) reducing collateral thermal damage to normal tissue.

Another type of laser that particularly benefited from super-pulsing is the gallium-arsenide (GaAs) diode laser. This laser has a wavelength in the region of 904-nm and pulse duration usually in the range of 100–200 nanoseconds. Another semiconductor laser amenable to superpulsing is the indium-gallium-arsenide (In-Ga-As) diode laser. It emits light at a similar wavelength (904–905-nm) as the GaAs diode laser, producing very brief pulses (200 nanoseconds) of high frequencies (in the range of kilohertz). These pulses are of very high peak powers (1–50 W) and an average power of 60 mW. Theoretically, the super-pulsed GaAs and In-Ga-As lasers allow for deep penetration without the unwelcome effects of CW (such as thermal damage), as well as allowing for shorter treatment times.

The other major class of pulsed light sources used in LLLT are simply CW lasers (usually diode lasers) that have a pulsed power supply generated by a laser driver containing a pulse generator. This technology is described as “chopped” or “gated.” It is also equally feasible to use pulse generator technology to pulse LEDs or LED arrays [1].

WHY COULD PULSING BE IMPORTANT IN LLLT?

Pulsed light offers numerous potential benefits. Because there are “quench periods” (pulse OFF times) following the pulse ON times, pulsed lasers can generate less tissue heating. In instances where it is desirable to deliver light to deeper tissues increased powers are needed to provide adequate energy at the target tissue. This increased power can cause tissue heating at the surface layers and in this instance pulsed light could be very useful. Whereas CW causes an increase in temperature of the intervening and target tissues or organ, pulsed light has been shown to cause no measurable change in the temperature of the irradiated area for the same delivered energy density. Anders et al. administered pulsed light to pig craniums, and found no significant change in temperature of the scalp or skull tissue (J.J. Anders, personal communication). Ilic et al. [2] found that pulsed light (peak power densities of 750 mW/cm2) administered for 120 seconds produced no neurological or tissue damage, whereas an equal power density delivered by CW (for the same number of seconds) caused marked neurological deficits.

Aside from safety advantages, pulsed light might simply be more effective than CW. The “quench period” (pulse OFF times) reduces tissue heating, thereby allowing the use of potentially much higher peak power densities than those that could be safely used in CW. For example, when CW power densities at the skin of ≥2 W/cm2 are used, doubling the CW power density would only marginally increase the treatment depth while potentially significantly increasing the risk of thermal damage; in contrast, peak powers of ≥5 W/cm2 pulsed using appropriate ON and OFF times might produce little, or no tissue heating. The higher peak powers that can be safely used by pulsing light can overcome tissue heating problems and improve the ability of the laser to penetrate deep tissues achieving greater treatment depths.

There may be other biological reasons for the improved efficacy of pulsed light (PW) over CW. The majority of the pulsed light sources used for LLLT have frequencies in the 2.5–10,000 Hz range and pulse durations are commonly in the range of a few millisecond. This observation suggests that if there is a biological explanation of the improved effects of pulsed light it is either due to some fundamental frequency that exists in biological systems in the range of tens to hundreds of Hz, or alternatively due to some biological process that has a time scale of a few milliseconds. Two possibilities for what these biological processes could actually be occur to us. Firstly, it is known that mammalian brains have waves that have specific frequencies [3]. Electroencephalography studies have identified four distinct classes of brain waves [4,5]. Alpha waves (8–13 Hz) occur in adults who have their eyes closed or who are relaxed [6]. Beta waves (14–40 Hz) mainly occur in adults who are awake, alert or focused [7]. Delta waves (1–3 Hz) occur mainly in infants, adults in deep sleep, or adults with brain tumors [8]. Theta waves (4–7 Hz) occur mainly in children ages 2–5 years old and in adults in the twilight state between sleeping and waking or in meditation [9]. The possibility of resonance occurring between the frequency of the light pulses and the frequency of the brain waves may explain some of the results with transcranial LLLT using pulsed light.

Secondly, there are several lines of evidence that ion channels are involved in the subcellular effects of LLLT. Some channels permit the passage of ions based solely on their charge of positive (cationic) or negative (anionic) while others are selective for specific species of ion, such as sodium or potassium. These ions move through the channel pore single file nearly as quickly as the ions move through free fluid. In some ion channels, passage through the pore is governed by a “gate,” which may be opened or closed by chemical or electrical signals, temperature, or mechanical force, depending on the variety of channel. Ion channels are especially prominent components of the nervous system. Voltage-activated ion channels underlie the nerve impulse and while transmitter-activated or ligand-gated channels mediate conduction across the synapses.

There is a lot of literature on the kinetics of various classes of ion channels but in broad summary it can be claimed that the time scale or kinetics for opening and closing of ion channels is of the order of a few milliseconds. For instance Gilboa et al. [10] used pulses having a width 10 milliseconds and a period of 40 milliseconds (25 Hz). Other reports on diverse types of ion channels have given kinetics with timescales of 160 milliseconds [11], 3 milliseconds [12] and one paper giving three values of 0.1, 4 and 100 milliseconds [13]. Potassium and calcium ion channels in the mitochondria and the sarcolemma may be involved in the cellular response to LLLT [14–16].

Thirdly there is the possibility that one mechanism of action of LLLT on a cellular level is the photodissociation of nitric oxide from a protein binding site (heme or copper center) such as those found in cyctochrome c oxidase [17]. If this process occurs it is likely that the NO would rebind to the same site even in the presence of continuous light. Therefore if the light was pulsed multiple photodissociation events could occur, while in CW mode the number of dissociations may be much smaller.

PENETRATION DEPTH

The most important parameter that governs the depth of penetration of laser light into tissue is wavelength. Both the absorption and scattering coefficients of living tissues are higher at lower wavelength so near-infrared light penetrates more deeply that red and so on. It is often claimed that pulsed lasers penetrate more deeply into tissue than CW lasers with the same average power. Why exactly should this be so? Let us suppose that at a certain wavelength (for instance 810-nm) the depth of tissue at which the intensity of a laser is reduced to 10% of its value at the surface of the skin is 1-cm. Therefore if we are using a laser with a power density (irradiance) of 100 mW/cm2 at the skin, the power density remaining at 1 cm below the skin is 10 mW/cm2 and at 2-cm deep is 1 mW/cm2. Now let us suppose that a certain threshold power density (minimum number of photons per unit area per unit time) at the target tissue is necessary to have a biological effect and that this value is 10 mW/cm2. The effective penetration depth at CW may be said to be 1-cm. Now let us suppose that the laser is instead pulsed with a 10-milliseconds pulse duration at a frequency of 1 Hz (DC = 1 Hz×0.010 seconds = 0.010) and the same average power. The peak power and peak power densities are now 100 times higher (peak power = average power/DC = average power×100). With a peak power density of 10 W/cm2 at the skin, the tissue depth—at which this peak power density is attenuated to the threshold level of 10 mW/cm2—is now 3-cm rather than 1-cm in CW mode. But what we have to consider is that the laser is only on for 1% of the time so the total fluence delivered to the 3-cm depth in pulsed mode is 100 times less than that delivered to 1-cm depth in CW mode. However it would be possible to increase the illumination time by a factor of 100 to reach the supposed threshold of fluence as well as the threshold of power at the 3-cm depth. In reality the increase in effective penetration depth obtained with pulsed lasers is more modest than simple calculations might suggest. Many applications of LLLT do not require deep penetration such as tendinopathies and joint pain.

Similarly, deep penetration is often not required to alleviate joint pain. The target tissue in such cases is the synovia; with the exception of back, neck, and hip, most joints have readily accessible synovia. Bjordal et al. [19] conducted a review of literature and concluded that “superpulsed” lasers (904 nm) were not significantly more effective than CW lasers (810–830 nm); both types of laser achieved similar results, but half the energy was needed to be used for superpulsed lasers. On the other hand, deeper penetrance is needed to reach back, neck, and hip joints. If power densities greater than a few mW/cm2 are to be safely delivered to target tissues >5 cm below the skin, it appears likely that this can only be done by using pulsed lasers. It is postulated that successful LLLT treatments in such joints bring benefit not by reaching the deep target tissue but by inhibiting superficial nociceptors. In other words, they bring relief primarily by attenuating pain perception, as opposed to decreasing inflammation. Does deeper penetration via pulsed lasers offer any significant benefit over CW? It is quite possible that a relatively higher fluence is necessary to attenuate pain, whereas a lower fluence decreases inflammation. If this is indeed the case, for musculo-skeletal applications achieving higher doses at the level of the target tissue may not be ideal. Further studies must be done to confirm this hypothesis, as well as to determine if there is any real benefit to the deeper penetration attained by pulsed lasers. Muscles such as the biceps and rectus femoris are not small organs, and have quite deep target tissue. Yet, various studies have shown significant improvement with CW lasers and CW LED. It remains to be seen whether or not pulsed lasers offer any additional advantage. Similarly, depression [20] and stroke studies [21] using LLLT have demonstrated that CW LED’s and CW lasers (respectively) produce a beneficial therapeutic effect. There are reports from Anders’ laboratory that fluences as low as 0.1–0.2 J/cm2 may be optimal for cells in the brain [22]. However, further studies must be done to determine whether pulsed light, with higher peak power densities deeper into the brain tissues, might increase the effectiveness of these therapies.

STUDIES COMPARING CW AND PW

In this review thirty-three studies involving pulsed LLLT were examined. Of these studies, nine of them directly compared continuous wave (CW) with pulsed wave (PW) light, as recorded in Table 1. Six of these nine studies found PW to be more effective than CW. One study comparing CW and PW found both modes of operation to be equally effective, with no statistically significant difference between the two. Only two of the nine articles reported better results with CW than PW, although in both of these studies PW treated subjects were found to have better outcomes than placebo groups. One of the recurring limitations of the papers in this review was that like for like irradiation parameters were not used. For instance, Gigo-Benato et al. [23] found CW superior to PW in nerve regeneration, but is this because of the mode of operation (CW or PW) or because the CW laser used 808 nm and the pulsed laser used 905 nm?

TABLE 1

Studies Comparing CW and PW

Of the six studies that found PW to be more effective than CW, four of them involved the use of LLLT to cure the following pathologies in vivo: wound healing, pain, and ischemic stroke. The two remaining studies reported pulsing to be beneficial in vitro; in the first such study, PW promoted bone stimulation more so than CW. The other in vitro study comparing CW and PW found the latter mode of operation better able to penetrate through melanin filters, indicating that pulsing may be beneficial in reaching deep target tissue in dark-skinned patients.

In the wound healing study, Kymplova et al. [24] used a large sample size of women to study the effects of phototherapy on wound repair following surgical episiotomies (one of the most common surgical procedures in women). A pulsed laser emitted light (wavelength of 670 nm) at various frequencies (10, 25, and 50 Hz). The pulsed laser promoted wound repair and healing more so than the CW light source.

In the pain study, Sushko et al. [25] investigated the role of pulsed LLLT to attenuate pain in white male mice. The same wavelength of light was used as in Kymplova et al.’s study (670 nm), with the frequencies of 10, 600, and 8,000 Hz. Both modes of delivery (CW and PW) reduced the behavioral manifestations of somatic pain as compared to controls, but pulsed light (10 and 8,000 Hz in particular) was more effective.

The two studies involving pulsed LLLT and stroke were both done by Lapchak et al. [26]. Ischemic strokes were induced in rabbits, and a pulsed laser with a wavelength of 808 nm was used. In the first study, two frequencies of pulsed light were used (100 and 1,000 Hz), both of which reduced neurological deficits more so than CW. Accordingly, pulsed LLLT may play a major role in the management of stroke patients. Lapchak et al.’s second study attempted to prove the hypothesis that LLLT’s neuroprotective effect following stroke was a result of enhanced mitochondrial energy production (increased ATP synthesis) [27]. As with the previous study, LLLT was administered following stroke induction. CW radiation raised cortical ATP levels but was unable to bring them back to baseline. PW radiation, on the other hand, not only mitigated the effects of stroke on cortical ATP levels, but was able to raise cortical ATP levels to higher than those found in healthy rabbits (those in which stroke was not induced). This study provides valuable insight into one of the potential cellular and molecular mechanisms behind the enhanced neurogenesis (and improved clinical outcomes) observed in subjects receiving transcranial LLLT following stroke.

One of the nine studies reviewed found CW and PW to be equally effective in the promotion of wound healing. This study compared the effects of a CW laser (632.8 nm) and a PW laser (904 nm) on the promotion of wound healing in rabbits. Both lasers improved tensile strength during wound healing, but did not significantly improve wound-healing rates. A combined laser (CW+PW) was also tested. All three of the laser regimens improved tensile strength to a similar extent.

As mentioned earlier, there were nine studies that compared CW and PW, only two of which found CW to be more effective. These two studies involved wound healing and nerve regeneration respectively. Al-Watban and Zhang [28] study involved rats that were inflicted with aseptic wounds. The rats were divided into three groups: a control group, those irradiated with continuous wave light, and those irradiated with pulsed light at various repetition rates (100, 200, 300, 400, and 500 Hz). Of the pulse repetition rates administered, 100 Hz was the most efficacious and 500 Hz the least. Both CW and PW (635 nm) promoted wound healing, but CW was more efficacious. These results conflict with earlier studies that found pulsed light to be more beneficial in the promotion of wound healing. However, it should be noted that the difference between CW and PW treated subjects was small (a relative wound healing rate of 4.81 as compared to 4.32).

The second study that found CW to be more effective than PW involved nerve regeneration. There were three articles involving nerve regeneration, all of which found pulsed LLLT to be ineffective, as discussed in the section below entitled “Studies Involving Nerve Conduction and Regeneration.” Of these three, only Gigo-Benato et al. [23] compared CW (808 nm) and PW (905 nm). This study involved rats in which the left median nerve was completely transected and then repaired by end-to-end neurorrhaphy. The CW laser (808 nm) promoted faster nerve and muscle recovery than the pulsed laser (905 nm). However, Gigo-Benato also tested a combination of the CW and pulsed lasers, finding this to be the most effective of all. In other words, seven of the nine studies comparing CW and PW found pulsing to play a beneficial role. Only one of the nine studies found no role of PW, and even in this study the benefit of CW over PW was minimal.

STUDIES INVOLVING THE USE OF COMBINED LASERS (CW+PW)

We reviewed three studies, as recorded in Table 2, which investigated the role of a combined laser (using both CW and PW). Of these, only Gigo-Benato’s study compared the combined laser to stand alone CW or PW. This study has been discussed in the above section: the combined laser was found to be effective in stimulating nerve regeneration, more so than CW or PW alone.

TABLE 2

Studies Involving the Use of Combined Lasers (CW + PW)

The two other studies used a combined laser (CW and PW) to administer laser acupuncture, along with Transcutaneous Electrical Nerve Stimulation (TENS), to patients with symptoms of pain. Naeser et al. [29] administered this “triple therapy” to patients suffering from carpal tunnel syndrome (CTS). Eleven patients with mild-to-moderate symptoms of CTS were selected, all of who had failed to respond to standard medical or surgical treatment regimens. Subjects were divided into two groups, one of which received sham irradiation and the other that received a combined treatment of LLLT (CW and pulsed) and TENS. As compared to controls, the treated group experienced statistically significant improvement and remained stable for 1–3 years. The results of this study are promising, and indicate a possible role of LLLT and TENS in the conservative management of CTS.

Ceccherelli et al. [30] administered laser acupuncture to patients suffering from myofascial pain. In this double-blinded placebo controlled trial, patients received either the same “triple therapy” as in the Naeser et al. study (CW, PW, and TENS) or sham irradiation, every other day over the course of 24 days. Results were encouraging, with the treatment group experiencing a significant improvement in symptoms, both immediately after the treatment regimen and at a 3-month follow up visit.

In both preceding studies, the combined regimen of CW, PW, and TENS was compared to untreated controls, and found to be effective. However, neither study compared CW and PW or administered CW, PW, or TENS individually. As such, it is difficult to determine whether standalone CW or PW would have produced similar results, or if the combined regimen (along with TENS) was necessary.

STUDIES EVALUATING THE USE OF PULSED LASERS

Of the 33 studies reviewed, 21 of them compared PW treated subjects with untreated controls, as reported in Table 3. Of these, fourteen studies found pulsed LLLT to be effective, whereas seven of them found PW treated subjects to have no benefit over untreated controls. Only one study found PW to have a worse outcome than controls. Of the fourteen studies that found pulsed LLLT to be effective, seven involved the promotion of wound healing, four involved the attenuation of pain, two involved the promotion of bone and cartilage growth respectively, and one involved the treatment of a very rare condition (hyperphagic syndrome caused by traumatic brain injury). Of the seven studies that found no benefit to pulsed light, three involved the promotion of nerve conduction, two involved the promotion of nerve regeneration, and the remaining two involved the attenuation of pain.

TABLE 3

Studies Evaluating the Use of Pulsed Lasers

Studies Comparing Various Pulse Repetition Rates

If pulsed LLLT is effective (or ineffective), then what pulse repetition rates are to be used (or avoided)? Ten of the 33 articles reviewed tested and compared various repetition rates, as reported in Table 4. Four of these studies involved the use of pulsed LLLT to promote wound healing. Longo et al. [31] used the pulse repetition rates of 1,500 and 3,000 Hz, and found only the latter setting to promote wound healing. Korolev et al. [32] similarly used two pulse repetition rates, 500 and 3,000 Hz. In this case, both were found to be effective but 500 Hz was more so. Al-Watban and Zhang [28] compared five different pulse repetition rates (100, 200, 300, 400 and 500 Hz), finding 100 Hz to be the most effective and 500 Hz the least. el Sayed and Dyson [33] compared four different pulse repetition rates (2.5, 20, 292, and 20,000 Hz), and found only the two middle values (20 and 292 Hz) beneficial. The more effective pulse repetition rates in these four studies were very disparate, including 20, 100, 292, 500, and 3,000 Hz (a range of 20–3,000 Hz).

TABLE 4

Studies Comparing Various Pulse Repetition Rates

Two studies compared the role of various pulse repetition rates in the attenuation of pain. Ponnudurai et al. [34] used laser photobiostimulation to decrease pain levels in rats, and investigated the effect of using various pulsing frequencies (4, 60, and 200 Hz). The rat tail-flick test was utilized, and tail-flick latencies were measured at five intervals between 30 minutes and 7 days following irradiation. The pulsing frequency of 4 Hz increased pain threshold rapidly but very transiently, whereas 60 Hz produced a delayed but longer lasting effect. On the other hand, 200 Hz failed to produce any hypoalgesic effect whatsoever. Sushko et al. [25] conducted a similar experiment, using mice instead of rats. The center of pain was irradiated (610–910 nm) for 10 minutes with either CW or pulsed light (10, 600, and 8,000 Hz). Both modes of delivery (CW and pulsed) reduced the behavioral manifestations of somatic pain as compared to controls, but pulsed light was more effective. In particular, 10 and 8,000 Hz produced the best effect. The more effective pulse repetition rates from these two studies (involving pain attenuation) included 4, 10, 60, and 8,000 Hz (a range of 4–8,000 Hz), and the less effective pulse repetition rates included 200 and 600 Hz.

Lapchak et al. [26] not only compared CW and PW, but also pulsed light at two different repetition rates, P1 (1,000 Hz) and P2 (100 Hz). Ischemic strokes were induced in rabbits, and the neuroprotective effects of LLLT were assessed via behavioral analysis 48 hours post-stroke. Both P1 (1,000 Hz) and P2 (100 Hz) produced a similar effect (superior to CW).

Rezvani et al. [35] studied the use of low level light therapy to prevent X-ray induced late dermal necrosis. An X-ray dose of 23.4 Gy is known to invariably cause dermal necrosis after 10–16 weeks. This dose was delivered to pigs, which were then treated with LLLT for several weeks using various wavelengths (660, 820, 880, and 950 nm) pulsed at either 2.5 or 5,000 Hz. Light pulsed at 2.5 Hz did not reduce the incidence of dermal necrosis. On the other hand, light pulsed at 5,000 Hz significantly reduced (P = 0.001) the incidence to 52% when given 6–16 weeks after irradiation.

Of the 10 articles reviewed that compared various pulse repetition rates, two of them involved in vitro experiments. Brondon et al. [36] undertook a study to determine if pulsing light would overcome the filtering effects of melanin. Melanin filters were placed in front of human HEP-2 cells, which were then irradiated for 72 hours (670 nm wavelength) with either CW or pulsed light at various repetition rates (6, 18, 36, 100, and 600 Hz). Both cell proliferation and oxidative burst activity, were increased in the group treated with pulsed light, indicating that pulsed light is indeed better able to penetrate melanin rich skin. Specifically, cell proliferation was maximal at 100 Hz at 48 and 72 hours (n = 4, P≤0.05), and oxidative burst was maximal at 600 Hz (n = 4, P≤0.05).

Ueda and Shimizu [37] studied the effects of pulsed low-level light on bone formation in vitro. Osteoblast-like cells were isolated from fetal rat calvariae; one group was not irradiated at all, another was irradiated with continuous wave light, and the third group with pulsed light at three repetition rates (1, 2, and 8 Hz). As compared to the control group, both CW and PW light resulted in increased cellular proliferation, bone nodule formation, alkaline phosphatase (ALP) gene expression, and ALP activity. Pulsed light at 2 Hz stimulated these factors the most.

Out of all 10 articles that compared various pulse repetition rates, the following pulse repetition rates were found to be beneficial: 2, 10, 20, 100, 292, 500, 600, 1,000, 3,000, 5,000, and 8,000 Hz. In this wide range of frequencies (2–8,000 Hz), no particular frequencies stood out as being particularly more or less useful than others.

STUDIED INVOLVING WOUND HEALING

Ten studies out of the 33 involved LLLT’s role in the promotion of wound healing, as recorded in Table 5. Only two of these studies compared CW and PW. Kymplova et al. [24] found pulsed LLLT to promote wound healing over CW, whereas Al-Watban and Zhang [28] found CW to be slightly more effective than PW. Both studies used light of a similar wavelength (670 vs. 635 nm), although the pulse repetition rates used by Kymplova et al. were lower (10–50 Hz vs. 100–500 Hz in Al-Watban et al.’s study). The energy densities applied were also different (2 J/cm2 vs. 1 J/cm2).

TABLE 5

Studied Involving Wound Healing

Every study reviewed found pulsed LLLT effective in promoting wound healing (as compared to untreated controls), including the Al-Watban et al. study. Six of these studies used light in the wavelength range of 820–956 nm, and four in the range of 632.8–670 nm. Once again, a wide range of frequencies were used (2.5–20,000 Hz), most of which were found to promote wound healing. (Tested frequencies included 2.5, 5, 8.58, 10, 15.6, 20, 25, 31.2, 50, 78, 80, 287, 292, 500, 700, 3,000, 4,672, 9,000, and 20,000 Hz). Most of these articles also reported energy densities, usually in the range of 1–2 J/cm2.

STUDIES INVOLVING NERVE CONDUCTION AND REGENERATION

We reviewed three articles evaluating the role of pulsed LLLT in the promotion of nerve conduction, and another three involving nerve regeneration, as reported in Table 6. Unlike the studies involving wound healing where positive outcomes were reported, all six of these studies reported negative outcomes with pulsed light. Five of these studies found PW to have no statistically significant effect on outcome, whereas one of them found PW to have a deleterious effect. There was no study that directly compared CW and PW in regards to nerve conduction. Walsh et al. [38] conducted a study with 32 human volunteers to determine if pulsed LLLT would influence nerve conduction in the superficial radial nerve. Action potentials were measured pre- and post-irradiation (at 5, 10, and 15 minutes). No significant difference was appreciated between control and treatment groups, indicating that LLLT with those particular pulsing parameters and dosimetry had no specific neurophysiologic effects on nerve conduction. Bagis et al. [39] and Comelekoglu et al. [40] obtained similar negative results using frog nerves. Walsh et al. used a wavelength of 820 nm, whereas Bagis et al. used a 904 nm laser. All three studies tested pulse repetition rates within the range of 1–128 Hz.

TABLE 6

Studies Involving Nerve Conduction and Regeneration

Similarly, the nerve regeneration studies reviewed reported negative outcomes. Chen et al. [41] found PW to have a counterproductive effect, reducing nerve regeneration as compared to untreated controls. Only one study compared CW with PW, and found the former to be superior to the latter. However, the combined laser (CW+PW) was superior to CW alone, indicating that there might in fact be a role of pulsing in nerve regeneration.

STUDIES INVOLVING PAIN ATTENUATION

Nine of the thirty-three studies involved pulsed LLLT’s role in the attenuation of pain, as reported in Table 7. Of these, only one of them directly compared CW and PW. This study was conducted by Sushko et al. [25] and found that although both CW and PW decreased pain levels, PW was more effective. This study also determined that pulse repetition rates of 10 and 8,000 Hz were more effective than 600 Hz. Ponnudurai et al. [34] similarly compared various pulse repetition rates (4, 60, and 200 Hz). A rapid but transient analgesic effect was exhibited with 4 Hz, whereas a delayed but longer lasting effect was achieved with 60 Hz. On the other hand, 200 Hz failed to produce any analgesic effect whatsoever.

TABLE 7

Studies Involving Pain Attenuation

Two of the studies used a combined laser (CW+PW) along with TENS; both found the combined regimen to be effective. The five remaining studies compared pulsed LLLT with untreated controls. Three of these studies found pulsed LLLT to be effective, whereas two did not. Of the nine total studies on pain attenuation, seven found pulsed LLLT to be effective in its role of attenuating pain. Only two studies found no statistically significant effect. However, it should be noted that both of these involved pain of a different nature than commonly tested in pulsed LLLT studies. The first of these was by Craig et al. [42] and involved the use of pulsed LLLT to relieve the symptoms of delayed-onset muscle soreness (DOMS). DOMS refers to the feeling of pain and muscle stiffness that can result 1–3 days after intense sporting activity such as weightlifting. This pain is duller in quality than that tested in the other studies. The second study that showed no benefit to pulsed LLLT, published by de Bie et al. [43], involved the treatment of lateral ankle sprains.

STUDIES INVOLVING ISCHEMIC STROKE

Table 8 records the two studies that involved pulsed LLLT and stroke. In the first study, PW but not CW decreased neurological deficits when delivered six hours post-stroke. Two pulse repetition rates were tested (100 and 1,000 Hz) and found to be equally effective. On the other hand, both CW and PW produced no benefit if delivered 12 hours post-stroke, indicating that timely administration of LLLT is essential.

TABLE 8

Studies Involving Stroke

The second study investigated the possible mechanisms behind the neuroprotective effect of LLLT. It was postulated that LLLT enhances mitochondrial energy production (and ATP synthesis), which allows for enhanced neurogenesis. This hypothesis was tested using the rabbit small clot embolic stroke model (RSCEM). Four groups of rabbits were used: (1) a naïve control group which was neither embolized or irradiated, (2) a placebo group which was embolized and sham irradiated, (3) an embolized group which was irradiated with CW (808 nm), and (4) an embolized group which was irradiated with pulsed light (808 nm) at two different frequencies. Forty-five percent less cortical ATP was measured in the second group (placebo) as compared to the first (naïve), confirming the hypothesis that ischemic strokes decrease cortical mitochondrial energy. All laser irradiated groups were able to mitigate this effect. CW radiation managed to raise the cortical ATP levels by 41%, whereas PW administration raised these levels by over 150%. Surprisingly, this was even higher than the cortical ATP content measured in naïve rabbits that had never suffered stroke.

OTHER APPLICATIONS OF PULSED MODALITIES IN BIOMEDICINE

Many of the modalities of treatment employed in biomedicine and physical therapy are used in pulsed format [44]. Electricity, electromagnetic fields and ultrasound are applied with particular pulse structures. It may be possible to gain some insight into the effect of pulsing structures in LLLT by a brief review of the other pulsed modalities. Transcutaneous electrical neural stimulation (TENS) is the application of pulses of electric current to the skin [45]. This application stimulates the brain and has been used for the treatment of various psychological and neurological conditions, including Parkinson’s, epilepsy, chronic pain, depression, and neuromuscular rehabilitation. Frequencies usually fall between 5 and 25 Hz, but may range from 2 to 80 Hz [46]. Deep brain stimulation (DBS) is a surgical treatment involving the implantation of a brain pacemaker, a medical device that sends electrical impulses to specific parts of the brain. DBS has the potential to provide substantial benefit to patients suffering from a variety of neurological conditions, including epilepsy, Parkinson’s disease, dystonia, Tourette’s syndrome, and depression [47]. The Food and Drug Administration (FDA) approved DBS at 130 Hz as a treatment for essential tremor in 1997, for Parkinson’s disease in 2002, and dystonia in 2003. Pulsed electromagnetic field (PEMF) therapy has been used for a wide range of conditions, including bone healing and regeneration [48], osteoporosis [49], arthritis [50] wound healing and pain [51], carpal tunnel syndrome [52], spinal cord injury [53], nerve regeneration [54], soft tissue injuries [55], and cancer [56]. Frequencies used for these conditions range from 1 Hz (“low”) to 200 Hz (“high”). Transcranial magnetic stimulation (TMS) is a noninvasive method used to excite neurons in the brain. Weak electric currents are induced by butterfly coils positioned above the head. TMS has been approved for the treatment of resistant depression in several countries and is under investigation for migraine [57], aphasia [58], and tinnitus [59]. Low-intensity pulsed ultrasound (LIPUS) utilizes a non-thermal mechanism of action, which can be used to promote bone healing by inducing the expression of growth factors and prostaglandins, which stimulate osteoblasts, chondrocytes and fibroblasts [60].

CONCLUSION

There has been remarkably little information available in the peer-reviewed literature on the rationale for using pulsed lasers or pulsed light in LLLT rather than CW. Moreover there is no consensus on the effects of different frequencies and pulse parameters on the physiology and therapeutic response of the various disease states that are often treated with laser therapy. This has allowed manufacturers to claim advantages of pulsing without hard evidence to back up their claims.

CW light is the gold standard and has been used for all LLLT applications. However, this review of the literature indicates that overall pulsed light may be superior to CW light with everything else being equal. This seemed to be particularly true for wound healing and post-stroke management. On the other hand, PW as a solo treatment may be less beneficial than CW in patients requiring nerve regeneration. This could possibly be explained by the mechanism of action LLLT that can either cause cell stimulation or cell inhibition or both stimulation and inhibition at the same time on different cell types. It is possible that stimulation in neurons is desired to promote neurogenesis following stroke (increased mitochondrial synthesis of ATP results in more energy for neurons to regenerate themselves), whereas inhibition of inflammatory cells, inhibition of immune response or inhibition of the glial scar may also occur at the same time. The logic in favor of PW is that cells may need periods of rest, without which they can no longer be stimulated further.

Considering that the biology of LLLT is known to be complex, it is likely that there may several optimal sets of pulse parameters and that these may relate to the specific wavelengths and chromophores and may well also be affected by other optical properties of tissues.

It was impossible to draw any meaningful correlations between pulse frequency and pathological condition, due to the wide-ranging and disparate data. As for other pulse parameters, these were in general poorly and inconsistentl

Intro: Low level light (or laser) therapy (LLLT) is a rapidly growing modality used in physical therapy, chiropractic, sports medicine and increasingly in mainstream medicine. LLLT is used to increase wound healing and tissue regeneration, to relieve pain and inflammation, to prevent tissue death, to mitigate degeneration in many neurological indications. While some agreement has emerged on the best wavelengths of light and a range of acceptable dosages to be used (irradiance and fluence), there is no agreement on whether continuous wave or pulsed light is best and on what factors govern the pulse parameters to be chosen.

Background: Low level light (or laser) therapy (LLLT) is a rapidly growing modality used in physical therapy, chiropractic, sports medicine and increasingly in mainstream medicine. LLLT is used to increase wound healing and tissue regeneration, to relieve pain and inflammation, to prevent tissue death, to mitigate degeneration in many neurological indications. While some agreement has emerged on the best wavelengths of light and a range of acceptable dosages to be used (irradiance and fluence), there is no agreement on whether continuous wave or pulsed light is best and on what factors govern the pulse parameters to be chosen.

Abstract: Abstract BACKGROUND AND OBJECTIVE: Low level light (or laser) therapy (LLLT) is a rapidly growing modality used in physical therapy, chiropractic, sports medicine and increasingly in mainstream medicine. LLLT is used to increase wound healing and tissue regeneration, to relieve pain and inflammation, to prevent tissue death, to mitigate degeneration in many neurological indications. While some agreement has emerged on the best wavelengths of light and a range of acceptable dosages to be used (irradiance and fluence), there is no agreement on whether continuous wave or pulsed light is best and on what factors govern the pulse parameters to be chosen. STUDY DESIGN/MATERIALS AND METHODS: The published peer-reviewed literature was reviewed between 1970 and 2010. RESULTS: The basic molecular and cellular mechanisms of LLLT are discussed. The type of pulsed light sources available and the parameters that govern their pulse structure are outlined. Studies that have compared continuous wave and pulsed light in both animals and patients are reviewed. Frequencies used in other pulsed modalities used in physical therapy and biomedicine are compared to those used in LLLT. CONCLUSION: There is some evidence that pulsed light does have effects that are different from those of continuous wave light. However further work is needed to define these effects for different disease conditions and pulse structures. (c) 2010 Wiley-Liss, Inc.

Methods: The published peer-reviewed literature was reviewed between 1970 and 2010.

Results: The basic molecular and cellular mechanisms of LLLT are discussed. The type of pulsed light sources available and the parameters that govern their pulse structure are outlined. Studies that have compared continuous wave and pulsed light in both animals and patients are reviewed. Frequencies used in other pulsed modalities used in physical therapy and biomedicine are compared to those used in LLLT.

Conclusions: There is some evidence that pulsed light does have effects that are different from those of continuous wave light. However further work is needed to define these effects for different disease conditions and pulse structures.

Original Source: http://www.ncbi.nlm.nih.gov/pubmed/20662021

Dr. Hamblin discusses the use of low level laser therapy for all type of brain injuries. He is an expert in all type of light healing (see below). He has performed much of his research on rats. He claims several key points:

• 10 Hertz is the preferred pulsing frequency for the brain
• 810nm is the preferred wavelength for cell interaction.
• The best treatment period is about 7 sessions but  less than 14 days of  treatments. Going to longer term treatments seems to reduce the effectiveness.

This video is mainly about TBI but the principals are universal. Dr Hamblin is associated with Thor laser so there is some potential for bias but he is also assocated with Harvard and the Wellman Centre. Introduction to Low Level Laser Therapy (LLLT) for Traumatic Brain Injury (TBI) by Mike Hamblin. Wellman Centre for Photomedicine, Harvard Medical School.

 

video length: (6:18)

This video is restricted for minors.

Original Source: https://www.youtube.com/watch?v=sl5T1Lw0B5o

The presentation includes research done on rats for the following conditions:

• Traumatic Brain Injury (TBI)
• Spinal Cord Injury
• Nerve regeneration

The research was supported by Thor so it could be biased but their research indicates that 810nm provides better stimulation of the cells.

 

video length: (17:09)

Original Source: https://www.youtube.com/watch?v=XxRIds1EKqk

Intro: The aim of the present study was to investigate whether Ga-As laser irradiation can enhance adenosine triphosphate (ATP) production in normal human neural progenitor (NHNP) cells in culture.

Background: The aim of the present study was to investigate whether Ga-As laser irradiation can enhance adenosine triphosphate (ATP) production in normal human neural progenitor (NHNP) cells in culture.

Abstract: Abstract OBJECTIVE: The aim of the present study was to investigate whether Ga-As laser irradiation can enhance adenosine triphosphate (ATP) production in normal human neural progenitor (NHNP) cells in culture. METHODS: NHNP were grown in tissue culture and were treated by Ga-As laser (808 nm, 50 mW/cm(2), 0.05 J/cm(2)), and ATP was determined at 10 min after laser application. RESULTS: The quantity of ATP in laser-treated cells was 7513 +/- 970 units, which was significantly higher (p < 0.05) than the non-treated cells, which comprised 3808 +/- 539 ATP units. CONCLUSION: Laser application to NHNP cells significantly increases ATP production in these cells. These findings may explain the beneficial effects of low-level laser therapy (LLLT) in stroked rats. Tissue culture of NHNP cells might offer a good model to study the mechanisms associated with promotion of ATP production in the nervous system by LLLT.

Methods: NHNP were grown in tissue culture and were treated by Ga-As laser (808 nm, 50 mW/cm(2), 0.05 J/cm(2)), and ATP was determined at 10 min after laser application.

Results: The quantity of ATP in laser-treated cells was 7513 +/- 970 units, which was significantly higher (p < 0.05) than the non-treated cells, which comprised 3808 +/- 539 ATP units.

Conclusions: Laser application to NHNP cells significantly increases ATP production in these cells. These findings may explain the beneficial effects of low-level laser therapy (LLLT) in stroked rats. Tissue culture of NHNP cells might offer a good model to study the mechanisms associated with promotion of ATP production in the nervous system by LLLT.

Original Source: http://www.ncbi.nlm.nih.gov/pubmed/17603858

Intro: The aim of this investigation was to compare by light microscopy the effects of laser photobiomodulation (LPBM) at lambda = 660 nm and lambda = 780 nm on third-degree burns in diabetic Wistar rats.

Background: The aim of this investigation was to compare by light microscopy the effects of laser photobiomodulation (LPBM) at lambda = 660 nm and lambda = 780 nm on third-degree burns in diabetic Wistar rats.

Abstract: Abstract OBJECTIVE: The aim of this investigation was to compare by light microscopy the effects of laser photobiomodulation (LPBM) at lambda = 660 nm and lambda = 780 nm on third-degree burns in diabetic Wistar rats. BACKGROUND DATA: Burns are severe injuries that result in fluid loss, tissue destruction, infection, and shock, that may result in death. Diabetes is a disease that reduces the body's ability to heal properly. LPBM has been suggested as an effective method of improving wound healing. MATERIALS AND METHODS: A third-degree burn measuring 1.5 x 1.5 cm was created in the dorsum of each of 55 animals, and they were divided into three groups that were or were not treated with LPBM (lambda = 660 nm or lambda = 780 nm, 35 mW, varphi = 2 mm, 20 J/cm(2)). The treatments were started immediately post-burn at four points within the burned area (5 J/cm(2)) and were repeated at 24-hour intervals over 21 d. The animals were humanely killed after 3, 5, 7, 14, and 21 d by an overdose of intraperitoneal general anesthetic. The specimens were routinely cut and stained and analyzed by light microscopy. RESULTS: We found that healing in the animals receiving 660-nm laser energy was more apparent at early stages, with positive effects on inflammation, the amount and quality of granulation tissue, fibroblast proliferation, and on collagen deposition and organization. Epithelialization and local microcirculation were also positively affected by the treatment. CONCLUSION: The use of 780-nm laser energy was not as effective as 660-nm energy, but it had positive effects at early stages on the onset and development of inflammation. At the end of the experimental period the primary effect seen was on the amount and quality of the granulation tissue. The 660-nm laser at 20 J/cm(2), when used on a daily basis, was more effective than the 780-nm laser for improving the healing of third-degree burns in the diabetic rats beginning at the early stages post-burn.

Methods: Burns are severe injuries that result in fluid loss, tissue destruction, infection, and shock, that may result in death. Diabetes is a disease that reduces the body's ability to heal properly. LPBM has been suggested as an effective method of improving wound healing.

Results: A third-degree burn measuring 1.5 x 1.5 cm was created in the dorsum of each of 55 animals, and they were divided into three groups that were or were not treated with LPBM (lambda = 660 nm or lambda = 780 nm, 35 mW, varphi = 2 mm, 20 J/cm(2)). The treatments were started immediately post-burn at four points within the burned area (5 J/cm(2)) and were repeated at 24-hour intervals over 21 d. The animals were humanely killed after 3, 5, 7, 14, and 21 d by an overdose of intraperitoneal general anesthetic. The specimens were routinely cut and stained and analyzed by light microscopy.

Conclusions: We found that healing in the animals receiving 660-nm laser energy was more apparent at early stages, with positive effects on inflammation, the amount and quality of granulation tissue, fibroblast proliferation, and on collagen deposition and organization. Epithelialization and local microcirculation were also positively affected by the treatment.

Original Source: http://www.ncbi.nlm.nih.gov/pubmed/18248161

Intro: The aim of the present study was to compare the effectiveness of four different laser wavelengths used for low-level laser therapy(LLLT) on healing of mucositis in an animal model of wound healing, by investigating expression of transient receptor potential melastatin(TRPM) ion channels. Forty-five rats were intraperitoneally injected with 100 mg/kg 5-fluorouracil on day 1 and 65 mg/kg on day 3. Superficial scratching on left cheek pouch mucosa was performed on days 3 and 5. After ulcerative mucositis was clinically detected, LLLT was started (660 nm, HELBO; 810 nm, Fotona-XD; 980 nm, ARC-Fox; and 1064 nm, Fidelis-Plus3) at 8 J/cm(2)/day from days 1 to 4. Oval excisional biopsy was performed at the wound site, and expression of TRPM2 to TRPM8 was evaluated. Student's t test was used for evaluation of significance of TRPM gene expression according to "0" value (α = 0.05). In 980-nm group, TRPM4, TRPM6, and TRPM7 were significantly higher than in the control group (p < 0.005). In 660, 810, and 1064 nm groups, only TRPM6 was significantly higher than in control group (p < 0.005). There were no significant differences between control and sham groups (p > 0.05). These findings suggest that expression of TRPM6 gene was significantly affected by irradiation with lasers at different wavelengths, whereas the TRPM4 and TRPM7 genes were only expressed in the 980-nm diode laser group. TRPM6 gene was highly expressed during LLLT, which may lead to accelerated wound healing and tissue repair. In contrast, there was some evidence that the 980-nm diode laser caused increased expression of TRPM4, TRPM6, and TRPM7 which are responsible for stimulation of Ca(2+) and Mg(2+) metabolism, as well as apoptotic pathways of controlled cell death.

Background: The aim of the present study was to compare the effectiveness of four different laser wavelengths used for low-level laser therapy(LLLT) on healing of mucositis in an animal model of wound healing, by investigating expression of transient receptor potential melastatin(TRPM) ion channels. Forty-five rats were intraperitoneally injected with 100 mg/kg 5-fluorouracil on day 1 and 65 mg/kg on day 3. Superficial scratching on left cheek pouch mucosa was performed on days 3 and 5. After ulcerative mucositis was clinically detected, LLLT was started (660 nm, HELBO; 810 nm, Fotona-XD; 980 nm, ARC-Fox; and 1064 nm, Fidelis-Plus3) at 8 J/cm(2)/day from days 1 to 4. Oval excisional biopsy was performed at the wound site, and expression of TRPM2 to TRPM8 was evaluated. Student's t test was used for evaluation of significance of TRPM gene expression according to "0" value (α = 0.05). In 980-nm group, TRPM4, TRPM6, and TRPM7 were significantly higher than in the control group (p < 0.005). In 660, 810, and 1064 nm groups, only TRPM6 was significantly higher than in control group (p < 0.005). There were no significant differences between control and sham groups (p > 0.05). These findings suggest that expression of TRPM6 gene was significantly affected by irradiation with lasers at different wavelengths, whereas the TRPM4 and TRPM7 genes were only expressed in the 980-nm diode laser group. TRPM6 gene was highly expressed during LLLT, which may lead to accelerated wound healing and tissue repair. In contrast, there was some evidence that the 980-nm diode laser caused increased expression of TRPM4, TRPM6, and TRPM7 which are responsible for stimulation of Ca(2+) and Mg(2+) metabolism, as well as apoptotic pathways of controlled cell death.

Abstract: Abstract The aim of the present study was to compare the effectiveness of four different laser wavelengths used for low-level laser therapy(LLLT) on healing of mucositis in an animal model of wound healing, by investigating expression of transient receptor potential melastatin(TRPM) ion channels. Forty-five rats were intraperitoneally injected with 100 mg/kg 5-fluorouracil on day 1 and 65 mg/kg on day 3. Superficial scratching on left cheek pouch mucosa was performed on days 3 and 5. After ulcerative mucositis was clinically detected, LLLT was started (660 nm, HELBO; 810 nm, Fotona-XD; 980 nm, ARC-Fox; and 1064 nm, Fidelis-Plus3) at 8 J/cm(2)/day from days 1 to 4. Oval excisional biopsy was performed at the wound site, and expression of TRPM2 to TRPM8 was evaluated. Student's t test was used for evaluation of significance of TRPM gene expression according to "0" value (α = 0.05). In 980-nm group, TRPM4, TRPM6, and TRPM7 were significantly higher than in the control group (p < 0.005). In 660, 810, and 1064 nm groups, only TRPM6 was significantly higher than in control group (p < 0.005). There were no significant differences between control and sham groups (p > 0.05). These findings suggest that expression of TRPM6 gene was significantly affected by irradiation with lasers at different wavelengths, whereas the TRPM4 and TRPM7 genes were only expressed in the 980-nm diode laser group. TRPM6 gene was highly expressed during LLLT, which may lead to accelerated wound healing and tissue repair. In contrast, there was some evidence that the 980-nm diode laser caused increased expression of TRPM4, TRPM6, and TRPM7 which are responsible for stimulation of Ca(2+) and Mg(2+) metabolism, as well as apoptotic pathways of controlled cell death.

Original Source: http://www.ncbi.nlm.nih.gov/pubmed/25863514

 BACKGROUND AND OBJECTIVE: Photobiomodulation (PBM) also known as low-level light therapy has been used successfully for the treatment of injury and disease of the nervous system. The use of PBM to treat injury and diseases of the brain requires an in-depth understanding of light propagation through tissues including scalp, skull, meninges, and brain. This study investigated the light penetration gradients in the human cadaver brain using a Transcranial Laser System with a 30 mm diameter beam of 808 nm wavelength light. In addition, the wavelength-dependence of light scatter and absorbance in intraparenchymal brain tissue using 660, 808, and 940 nm wavelengths was investigated. in vivo. Lasers Surg. Med. 47:312-322, 2015. (c) 2015 Wiley Periodicals, Inc.

STUDY DESIGN/MATERIAL AND METHODS: Intact human cadaver heads (n = 8) were obtained for measurement of light propagation through the scalp/skull/meninges and into brain tissue. The cadaver heads were sectioned in either the transverse or mid-sagittal. The sectioned head was mounted into a cranial fixture with an 808 nm wavelength laser system illuminating the head from beneath with either pulsed-wave (PW) or continuous- wave (CW) laser light. A linear array of nine isotropic optical fibers on a 5 mm pitch was inserted into the brain tissue along the optical axis of the beam. Light collected from each fiber was delivered to a multichannel power meter. As the array was lowered into the tissue, the power from each probe was recorded at 5 mm increments until the inner aspect of the dura mater was reached. Intraparenchymal light penetration measurements were made by delivering a series of wavelengths (660, 808, and 940 nm) through a separate optical fiber within the array, which was offset from the array line by 5 mm. Local light penetration was determined and compared across the selected wavelengths.

RESULTS: Unfixed cadaver brains provide good anatomical localization and reliable measurements of light scatter and penetration in the CNS tissues. Transcranial application of 808 nm wavelength light penetrated the scalp, skull, meninges, and brain to a depth of approximately 40 mm with an effective attenuation coefficient for the system of 2.22 cm(-1) . No differences were observed in the results between the PW and CW laser light. The intraparenchymal studies demonstrated less absorption and scattering for the 808 nm wavelength light compared to the 660 or 940 nm wavelengths.

CONCLUSIONS: Transcranial light measurements of unfixed human cadaver brains allowed for determinations of light penetration variables. While unfixed human cadaver studies do not reflect all the conditions seen in the living condition, comparisons of light scatter and penetration and estimates of fluence levels can be used to establish further clinical dosing. The 808 nm wavelength light demonstrated superior CNS tissue penetration.

Original Source: https://www.ncbi.nlm.nih.gov/pubmed/?term=25772014

This tool is a searchable collection of technical publications, books, videos and other resources about the use of lasers and light for PhotoBioModulation (PBM). Enter a keyword above or see some of our favorite queries below. 

Here are some of our favorite queries:

• Information for Beginners
• Best wavelength for PBM (980nm vs. 810nm vs 660nm...)
• Compare Lasers and LEDs
• Pulsing versus Continuous Wave (CW)
• Dosage: The best practices for dosage
• How NOT to promote laser therapy (by Turner and Hode)
• Great summary of positive double blind studies
• Whole Body Systems

• See all videos
• See all books about laser therapy and cold lasers


• Testimonials
• Amazing results
• Video testimonials from patients
• Video testimonials from doctors
• Incredible results in animals
• Increasing Athletic Performance


• Research Info for other Applications
• Stem cell production in laser therapy
• Cosmetic and skin therapy parameters
• Intro to laser acupuncture
• Traumatic brain injury research
• Soft Tissue


• Autoimmune
• Lyme's Disease
• Parkinson's research
• Alzheimer's research
• Hashimoto's research
• Covid


• Contraindications
• LLLT and Cancer

 

All the resources include links to the original source so we are not making any statement about the use of lasers for treating non-FDA cleared application, we are simple summarizing what others have said.

Where every possible, we have included a link to the orginal publication.

This tool uses a broad match query so:

• It does not correct spelling and searches only cold laser related subjects so do not use LLLT, cold or laser in the search bar
• It works better with shorter search terms or even parts of search terms
• It searches all the available fields so you can enter a body part, author, condition or laser brand.
• Where ever possible, the detailed section about the resource will link to the sources.
• This system is only for photobiomodulation or cold laser therapy research (including LLLT, laser acupuncture and high power laser therapy) only. It does NOT include photodynamic laser therapy (where the laser is used to react with a pharmaceutical), hot surgery lasers or cosmetic lasers. It does include some resources on weight loss and smoking cessation.

The results of the search are sorted based on 3 quality factors on a scale of 1 to 10 with 10 being the best score. Originally all the resources were given a 5-5-5 until they could be individually evaluated. These scores are purely opinion and are only used to simplify the rank of the results from more valuable to least valuable. This should not be considered a critique of any work. This system was created to help researchers (including ourselves) find the most usable resources for any cold laser therapy research. The resources are assigned values based on the following 3 factors:

• Efficacy: The resource (especially research papers) should show a significant improvement in the condition being treated. Resources that show better results are given a higher quality score.
• Detail: The source must give enough information that the results can be duplicated. If a resource lacks too many details that it cannot be recreated, it is given a lower detail score.
• Lack of Bias: Many resources are created to try and show that one device is superior to its competition. Many manufacturers have staff that crank out biased papers on a regular basis on the hope that this will make their product look superior. If the author of the resource is paid by a manufacturer of the resource appears to be biased towards one device and not one technology, the resource has much less value.

Over the past few years of working with research, we found that a majority of the published resources are lacking in one of these three ranking factors.
The original goal of this research tool was to tie published resources to the protocols in the laser-therapy.us library. This connection allows users to trace each protocol back to a list of resources so the protocol can be researched and improved.

General Comments

POWER
When many of the first research papers were published, the most power laser available for therapy were less than 100mW and many systems had to be pulsed to keep the laser from burning out too quickly. Today, system are available that will deliver up to 60,000mW of continuous output. Because of these power limitation, many early studies were limited to extremely low dosages by today’s standards. It takes a 50mW system 17 minutes to deliver 50 joules at the surface of the skin. If this was spread over a large area of damage or was treating a deeper problem, the actual dosages were much less than 1J/cm2.  Today, we know that these dosages typically produce very little or no results.
WAVELENGTH
About 80% of the resources in this database are in the near infrared wavelength. There is also some interest in the red wavelength (600 to 660nm) . Other wavelengths like blue, purple, and green have very little scientific research behind them and have not gotten much traction in the core therapy market with the exception of some fringe consumer products.
Legal Disclaimer
This research tool is free to use but we make no claims about the accuracy of the information. It is an aggregation of existing published resources and it is up to the user to determine if the source of the resources has any value. The information provided through this web site should not be used for diagnosing or treating a health problem or disease. If you have or suspect you may have a health problem, you should consult your local health care provider.

Welcome to the BioPhotonica Education Center. There are over 5000 successful studies showing the efficacy of PBM, light therapy and sound therapy. This is a searchable collection of technical publications, books, videos and other resources about the best practices in the industry and about treating a wide variety of problems. All the resources include links to the original source (where available) so we are not making any claims about the use of our technology for treating "non-FDA cleared" applications, we are simply summarizing what the expert are saying about proper application of these technologies.

Enter a keyword above and click on one of the following links to see a set of publications about that subject. HINT: Shorter keywords work better.

Here are some of our favorite queries:

• Whole Body Systems
• Treating Post Covid with PBMT
• Info for beginners (See several graphic representation of the PBM chemical process)
• Best wavelength for light therapy (980nm vs. 810nm vs 660nm...)
• Pulsing Versus continuous wave
• Dosage: Searching for the best practices for dosage
• Great summary of positive double blind studies

Testimonials

• Amazing results
• Video testimonials from patients
• Video testimonials from doctors
• Incredible results in animals
• Increasing athletic performance

Research Info for other Applications

• Stem cell production in laser therapy
• Cosmetic and skin therapy parameters
• Laser acupuncture
• Traumatic Brain Injury (TBI)
• Soft Tissue Injury
• Fertility and Reproductive Health

Autoimmune Research

• Lyme's Disease
• Parkinson's research
• Alzheimer's research
• Hashimoto's research

Contraindications

• LLLT and Cancer

This tool uses a broad match query so:

• It does not correct spelling and searches only PBM related subjects so do not use LLLT, cold or laser in the search bar
• It works better with shorter search terms or even parts of search terms
• It searches all the available fields so you can enter a body part, author, condition or laser brand.
• This system is only for photobiomodulation or cold laser therapy research (including LLLT, laser acupuncture and high power laser therapy) only. It does NOT include photodynamic laser therapy (where the laser is used to react with a pharmaceutical), hot surgery lasers or cosmetic therapies.

Welcome to the Lighthouse Health Education Center. There are over 5000 successful studies showing the efficacy of PBM, light therapy and sound therapy. This is a searchable collection of technical publications, books, videos and other resources about the best practices in the industry and about treating a wide variety of problems. All the resources include links to the original source (where available) so we are not making any claims about the use of our technology for treating "non-FDA cleared" applications, we are simply summarizing what the expert are saying about proper application of these technologies.

Enter a keyword above and click on one of the following links to see a set of publications about that subject. HINT: Shorter keywords work better.

Here are some of our favorite queries:

• Whole Body Systems
• Treating Post Covid with PBMT
• Info for beginners (See several graphic representation of the PBM chemical process)
• Best wavelength for light therapy (980nm vs. 810nm vs 660nm...)
• Pulsing Versus continuous wave
• Dosage: Searching for the best practices for dosage
• Great summary of positive double blind studies

Testimonials

• Amazing results
• Video testimonials from patients
• Video testimonials from doctors
• Incredible results in animals
• Increasing athletic performance

Research Info for other Applications

• Stem cell production in laser therapy
• Cosmetic and skin therapy parameters
• Laser acupuncture
• Traumatic Brain Injury (TBI)
• Soft Tissue Injury

Autoimmune Research

• Lyme's Disease
• Parkinson's research
• Alzheimer's research
• Hashimoto's research

Contraindications

• LLLT and Cancer

This tool uses a broad match query so:

• It does not correct spelling and searches only cold laser related subjects so do not use LLLT, cold or laser in the search bar
• It works better with shorter search terms or even parts of search terms
• It searches all the available fields so you can enter a body part, author, condition or laser brand.
• This system is only for photobiomodulation or cold laser therapy research (including LLLT, laser acupuncture and high power laser therapy) only. It does NOT include photodynamic laser therapy (where the laser is used to react with a pharmaceutical), hot surgery lasers or cosmetic therapies.