Light - Red and Near-infrared
Numerous therapeutic uses in the low level light application of this frequency band

Red and near-infrared light are proven to be biologically active influences ever at a very low intensities, being an almost established method to treat some problematic issues like traumatic brain injury, undesired and painful inflammations or wound repair, and with various experiments that show a variety of effects that surely involve various kind of receptors and/or very systemic ones. ...

As in other non-ionizing exposures, slight variations in the exposure conditions (classical intensity, time or frequency variations and other less know like the subject age, or the phase of the cell cycle) can alter the outcome drastically. As an example, in a study that are recorded the somatosensory evoked potentials of rat sciatic nerves [1] irradiation of the same total energy concentrated in one point or separated over four points, increased or decreased respectively the somatosensory evoked potential amplitudes of those nerves.

Mechanisms of action

Later it will be mentioned the possible role of water in the biological effects of low level red and infrared light exposures. Only to mention, for the moment, that infrared radiation on gel like microscopic structures produces an extension of exclusion zone water (EZ water) that are ordered layers of water with a charge differential and boundary that can serve to organize cellular structures [2], more on EZ water is available on section [3]. It must be highlighted that all life forms have been found to be sensitive to red or near-infrared light [42] so sensitive mechanism(s) must be extended over all biological kingdoms.

In general, it's believed that the primary target of low level infrared and red light is the cytochrome c oxidase in the mitochondrial respiratory chain that leads to the stimulation or inhibition of the cellular metabolism and produces a transduction effect in other cell components (biomodulation effect). This view is not the best valuated here because it's excessively specific and is not probable to be the cause of the all great variety of effects, and some recent experimental studies are questioning this proposed mechanism [4]. Others suggest that this effect is due to photophysical changes on the Ca++ channels in the cell membrane. Anyways there are various possible photoreceptors in the cell, for example other enzymes apart from cytochrome, among others arylsulphatase, lactate dehydrogenase, myosin ATPase, acid phosphatase, creatine kinase and lactate dehydrogenase are shown to be sensitive to light and also, it’s proposed, that the modification of the catalysis of certain enzymes, likely containing metal ions, is a significant contributor to the effects of the red and infrared low level light radiation on biological samples [5].

A variety of biomolecules localized in mitochondria and/or in other cell compartments including some proteins, nucleic acids and adenine nucleotides are also light sensitive with major modifications in their biochemistry when are exposed [5].

As is pointed in the section [6] since there is evidence that proteins have certain conducting or semiconducting properties, a charge moving through the protein backbone and passing different energy stages caused by different amino acid side groups can produce sufficient conditions for a specific electromagnetic radiation or absorption.

And as the resonant recognition model (RRM) proposed [7]:

" ... strong linear correlation exists between the predicted and experimentally determined frequencies corresponding to the absorption of electromagnetic radiation of such proteins []. It is inferred that approximate wavelengths in real frequency space can be calculated from the RRM characteristic frequencies for each biologically related group of sequences. These calculations can be used to predict the wavelength of the light irradiation, λ , that might affect the biological activity of exposed proteins []. The frequency range predicted for protein interactions is from 10¹³ Hz to 10¹⁵ Hz. This estimated range includes IR, visible and UV light."

So is possible that IR radiation interact because it used pre-existent endogenous communication and recognition channels, as those predicted by the RRM.

As mentioned above water and its structural construction, as EZ water, can be also a target for the low level light exposure, Santana et al. are insistent defenders of this theory, and in this section this vision is empowered because its looks very logic when it’s taken into account the, now evident, curious properties of water in its interaction with electromagnetic waves (see section [8]), and it's sufficiently extended and systemic to cover the wide range of effects that different exposures can provoke. As mentioned in a very interesting review [43] it is becoming clear that both local and systemic mechanisms are operating.

In the same above mentioned review [43] it can be read:

" The obvious candidate for this alternative chromophore is water molecules whose absorption spectrum has peaks at 980 nm, and also at most wavelengths longer than 1200 nm. Moreover, water is by the far the most prevalent molecule in biological tissue (particularly considering its low molecule weight = 18). At present the proposed mechanism involves selective absorption of IR photons by structured water layers (also known as interfacial water) [26] or water clusters [27], at power levels that are insufficient to cause any detectable bulk-heating of the tissue."

But we can go further than a theoretical proposition (supported by studies of water-EM waves interaction as mentioned), firstly, reviewing experimental evidence of pre-existent studies in low level light therapy where some properties of water are measured, and search for data that contribute to corroborate this theory as for example is done in [9]:

" Photo-induced effects on the water dynamics of burned rat tissue monitored by 1H-NMR transverse relaxation times (1/T2) indicate significantly greater structuring of water. A microdensitometry study of T2 weighted tumor heterogeneities from a phase I clinical trial in patients with advanced neoplasias and an algorithm for tumor characterization also shows significantly increased structuring of water associated with biopolymers and macromolecules."

Another Santana et al. retrospective analysis of published data in low level light therapy (LLLT) indicative of EZ phenomena that is related, in this case, to the retina and optic nerve (ON) also show evidences [10]:

" Images showing removal of the internal limiting membrane (ILM) aided by preservative-free triamcinolone acetonide (TA) during macular hole surgery show continuous whitish lines indicative of water-layer ordering at the interface between collagen matrices and TA crystals. Apparent diffusion coefficient (ADC) results further exhibit an axis parallel to the ON, which may be an ocular expression of the EZ linked to the steady potential of the eye."

There is an interesting summary of the investigations of the authors in [11].

Another experimental procedure by other authors [12] shows that water near to proteins surface provoke the proteins order and crystallization, nucleating them, when the solute is exposed to low level infrared radiation:

" We show that a physical trigger, a non-ionizing infrared (IR) radiation at wavelengths strongly absorbed by liquid water, can be used to induce and kinetically control protein (periodic) self-assembly in solution. This phenomenon is explained by considering the effect of IR light on the structuring of protein interfacial water. Our results indicate that the IR radiation can promote enhanced mutual correlations of water molecules in the protein hydration shell. We report on the radiation-induced increase in both the strength and cooperativeness of H-bonds. The presence of a structured dipolar hydration layer can lead to attractive interactions between like-charged biomacromolecules in solution (and crystal nucleation events). Furthermore, our study suggests that enveloping the protein within a layer of structured solvent (an effect enhanced by IR light) can prevent the protein non-specific aggregation favoring periodic self-assembly."

On the other hand in [13] it is argued that the specific environment of each cell causes one kind of effect or other and that membrane receptors are the targets:

" According to our homeostasis theory [], we have suggested that the membrane receptors of cells or organelles were the primary photoreceptors of LIL, and LPBM was mediated by receptor-activated signal transduction pathways []. Several signaling pathways have been identified that target COX including protein kinase A and C, receptor tyrosine kinase, and inflammatory signaling []."

Finally it is interesting to keep in mind the data provided by [14] that suggest that non-coherent light sources with power-densities about 1000 times lower than contemporary low-power laser settings remain effective in generating photobiostimulatory effects.

Therapeutical uses

Low level laser light or LED light therapy is a globally expanding intervention method that now includes post-traumatic brain disorders, nerve regeneration, diabetic wound repair, arthritis, cancer radiation protection (oral mucositis), dental, sports medicine and skeletal muscle disorders (trauma and pain), etc.

Numerous studies are now oriented to the extracranial application of red and near infrared light and the therapeutic outcomes that can generate.

LLLT causes increased neurogenesis in the hippocampus and subventricular zone, and better learning and memory scores in mice after traumatic brain injury [15], in [44] it is also shown that near-infrared (NIR) light (although in this case not specifically transcranialy applied) improves memory and spatial learning ability and reduces plaques moderately in mouse brain slices, being also a potential treatment for Alzheimer disease. In an experimental study with humans suffering from mild traumatic brain injury [16] therapeutic application of LLLT provides improved sleep, and fewer post-traumatic stress disorder (PTSD) symptoms, and better ability to perform social, interpersonal, and occupational functions.

Similar results can be extracted from a recent review on the topic [17] where is concluded that application of red/near-infrared LED light in subjects with traumatic brain injury causes significant improvements in executive function and verbal memory of the subjects and fewer reports of post-traumatic stress disorder symptoms.

Moreover, in another review [18] there are highlighted the positive outcomes of LLLT to treat various mental dysfunctions apart from traumatic disorders, like depressive disorders:

" Studies suggest the processes aforementioned are potentially effective targets for PBM to treat depression. There is also clinical preliminary evidence suggesting the efficacy of PBM in treating major depressive disorders, and comorbid anxiety disorders, suicidal ideation, and traumatic brain injury."

On the other hand, red light irradiation also increases lymphocyte count in subjects in which this cell count was reduced after a stroke provoked by middle cerebral artery occlusion [19]. Some experiment are done with in-vitro neurons showing results that are supposed to be majorly maintained when transcranial light is applied, and for example in [20] it has been found that low intensity NIR radiation can protect neurons against oxygen-glucose deprivation by rescuing mitochondrial function and restoring neuronal energetics. And very similarly in [45] it has been found that NIR light reduces the oxidative damage (in this case provoked by sleep deprivation) in mice hippocampus and increases its mitochondrial activity.

Also in primary cultured rat cortical neurons where oxigen-glucose deprivation is provoked it's shown an augmented neurite outgrow with an increase in the levels of synaptic markers such as PSD 95, GAP 43, and synaptophysin after infrared LED treatment [21].

Another experimental study with in vitro neurons and, in this case, with far infrared radiation (FIR) [22], suggest the possible therapeutic use to treat some kind of neuronal disorders, like Spinocerebellar ataxia type 3 (that are characterized by progressive and selective loss of neuronal cell bodies, dendrites and/or axons in the central nervous system). In this case it’s demonstrated that FIR treatment individually rescued ataxin-3-78Q and ataxin-3-26Q expressing cells, that have decreased viability, from pathological and non-pathological mechanisms involved, by preventing mutant PolyQ protein accumulation and protecting mitochondrial function in both cells. The data also suggested that FIR triggers autophagy as a major rescue mechanism and that did not seem to involve reactive oxygen species scavenging.

As is put forward by a review of the transcranial light application experiments made by a experimental group [46]:

" We have studied PBM for treating traumatic brain injury in mice using a NIR laser spot delivered to the head. Mice had improved memory and learning, increased neuroprogenitor cells in the dentate gyrus and subventricular zone, increased BDNF and more synaptogenesis in the cortex. These highly beneficial effects on the brain suggest that the applications of LLLT are much broader than first conceived."

Regeneration is also a medical field of research where red and infrared light are increasingly used as a possible therapeutic tools, for example in [23] is studied the effect of low intensity laser irradiation (LILI) on the growth potential and cell-cycle progression of cultured myoblasts, that are a type of myogenic progenitor cells and considered as the major candidates responsible for muscle regeneration, and it's viewed that exposure increased the expression of cellular proliferation marker and the amount of cell subpopulations in the proliferative phase and upregulated expressions of cell-cycle regulatory proteins:

" These results suggest that LILI at certain fluences could promote their proliferation, thus contributing to the skeletal muscle regeneration following trauma and myopathic diseases."

Also, nerve regeneration can be a therapheutical objective of LLLT, in a study where histological examination, after lesion, of rats sciatic nerve is done it is shown that low level light treatment during some days causes better organized myelin sheets with fewer areas of myelin debris [24]. Here, related to the above mentioned possible role of water it’s interesting to note that myelin fiber has been theorized to be an optical fiber for biophotons (like microtubules), see section [25], and that it’s proposed that ordered water have a crucial function in this, where collective behavior of water molecules is characterized by coherent water states analogous to Bloch states, whose main feature is to trap biophotons in a collective fashion [26].

One of the most promising therapeutic use to be promptly standardized is to reduce inflammations of many kinds. In a review [27] is pointed out its utility to treat oral mucositis (an inflammation derived from cancer treatment), and there are a lot of recent experiments on this topic with more supporting results, moreover, in [28] experimental results shown that monochromatic light (LED) is at least as effective as low level light therapy (LLLT) in treating mucositis, and LED light is more cheap and affordable than laser, so its implementation can be faster and more extended. Another interesting review on infrared light treatment to address inflammation can be found in [29] were among other facts are commented various experimental findings in which the therapeutical light application have better results than classical pharmacological therapy.

Inflammation is also, as we know, part of the wound healing process and this process in general is also objective of LLLT in numerous studies, because it is known that it ameliorate the process in numerous ways, in this [30] experimental study it can be read:

" We demonstrated the possible utility of a GaAlInP laser with an appropriate energy density (4 J/cm2) as an adjunctive modality for wound healing in clinical practice as well as a correlation between epidermal MMP-2 expression and angiogenesis. In fact, LLLT improved wound healing, especially at 14 days, as evidenced by wound contraction, anti-inflammatory activity, neocollagenesis, and neoangiogenesis."

In [24] LED phototherapy with 940 nm wavelength reduced the areas of edema, the number of mononuclear cells present in the inflammatory infiltration, and increased functional recovery scores.

Other possible therapeutic use is for cancer treatment and there are some efforts in this direction [31][32]. In [33] it is pointed that previous studies show that low level infrared radiation significantly inhibited cell proliferation in several breast cancer cells but did not affect the growth of normal breast epithelial cells, and that in this study irradiation:

" caused G2/M cell cycle arrest, remodeled the microtubule network to an astral pole arrangement, altered the actin filament formation and focal adhesion molecule localization, and reduced cell migration activity and invasion ability."

Anyways this possible use of light to treat cancer is not sufficiently certain and free of possible counterproductive effects at now, for example in [34] LLLT promotes cancer aggressiveness in anaplastic thyroid cancer cell lines. Therefore more research is needed to expose the specific conditions (of the exposure or the exposure target) that causes some outcomes or others. It is mentionable that other non-ionizing electromagnetic waves like those that fall in the extremely low frequencies are also subject of study [35] as possible anticancer treatment, and possibly have less risks than LLLT.

Another therapeutic approach would be the improvement sperm function and reproductive performance, in this case in an experiment in [36] it is observed and highlighted an extremely interesting fact:

" ... effects observed rely upon the specific pattern used. In this way, it is worth noting that Procedure #1 (10-10-10; L-phase: 10 min, D-phase: 10 min and L-phase: 10 min) was the most effective. In contrast, patterns with longer exposure times to light, such as Procedures #2 (15-10-15) and #3 (20-10-20) had less effect. Additionally, our preliminary experiments conducted before setting the experimental conditions also showed that continuous light-exposure patterns without a D-phase, of 5 min, 10 min, 15 min and 20 min of continuous L-phase, were much less effective than the 10-10-10 photo-stimulation pattern. These data clearly point out that the improving effect on boar sperm function induced by red LED-based light depends on the photo-stimulation pattern. A similar phenomenon has been described when laser systems are applied to sperm from other mammalian species like dog, buffalo and human []. Therefore, it seems that light-effects on mammalian sperm rely on precise rhythms and rates of application, regardless of light source and wIncluded in the therapeutic array of uses of non-thermal photobiomodulation (other of the nomenclatures of low level light therapy) are photorejuvenation oriented ones. As an example in this study [38] treated subjects experienced significantly improved skin complexion and skin feeling, better profilometrically assessed skin roughness, and improved ultrasonographically measured collagen density.Included in the therapeutic array of uses of non-thermal photobiomodulation (other of the nomenclatures of low level light therapy) are photorejuvenation oriented ones. As an example in this study [38] treated subjects experienced significantly improved skin complexion and skin feeling, better profilometrically assessed skin roughness, and improved ultrasonographically measured collagen density.avelength range."

So rhythms are important… we must have in mind that this include the wavelength or frequency itself, as it can be view in numerous examples, in this [37] concrete example, when light is applied over cell population in vitro, variations in the frequency can provoke that that population increases or not. And in [47] it has been found also that pulsed waves are much more effective than continuous waves on dentinogenesis of dental pulp stem cells.

Included in the therapeutic array of uses of non-thermal photobiomodulation (other of the nomenclatures of low level light therapy) are photorejuvenation oriented ones. As an example in this study [38] treated subjects experienced significantly improved skin complexion and skin feeling, better profilometrically assessed skin roughness, and improved ultrasonographically measured collagen density.

In this last paragraph of possible therapeutic uses, only as an extract of the variety of possibles uses, it will be mentioned some more uses. As the title of [39] explicitly says combination of laser light and LED light “is beneficial in improvement of muscular performance (strength and muscular endurance), dyspnea, and fatigue sensation in patients with chronic obstructive pulmonary disease”. In [40] improvements in functional and anatomical outcomes in dry AMD (a retinal degenerative disease) subject has reached. In [14] increased stem cell proliferation was observed. While other non necessarily therapeutic but interesting results include, for example, the increase in growth rate and overall length and width of C. elegans (a nemanode) after low level laser light exposure [41].

References:

Very related sections:

Applied Fields - Experimental
Light - Red and near-infrared - (630-1000 nm)