Abstract

Abstract

Introduction

Low-level light therapy (LLLT) has gained attention in recent years as a novel tool for experimental therapeutic applications in a variety of medical conditions. The current paradigm shift in the field of neurotherapeutics has allowed consideration of this innovative approach in attempts to modify the function of the nervous system. Patients, research laboratories, the media, and industry around the world are devoting attention to the potential therapeutic applications of LLLT in neurology and other medical fields that have traditionally had a limited therapeutic contribution to patient care. In recent years, the use of LLLT has extended beyond the realms of pain and wound healing, and recent research supports its potential benefits in retinal disease, stroke, neurodegeneration, neuromuscular disorders, and memory and mood disorders. This therapeutic revolution is being favored by progress in the field of photobiology, aided by a twenty-first century reemergence of interest in bioenergetics. Current progress in photochemistry, genetics, informatics, and neuroimaging has allowed quantifying and differentiating the effects of light and other forms of electromagnetic radiation on biological tissues at different levels of analysis.

Throughout its development in the last 40 years, the concept of using “light to heal” has had an esoteric and suspicious connotation to the western contemporary biomedical mind. As illustrated by a reviewer’s comments from a reputable biomedical journal to a recent manuscript on LLLT, the “curious effects” of light therapy have had the misfortune of being classified as a laughable school of thought in the tradition of astrology and Mesmer’s animal magnetism. We are constantly exposed to light with apparently innocuous or trivial biological effects. Even when biological effects of light can be demonstrated, these are highly variable, present nontraditional dose-response curves, or lack a mechanistic explanation within traditional pharmacodynamic paradigms. A recent review stated that “widespread uncertainty and confusion exists about the mechanisms of action of LLLT at the molecular, cellular, and tissue levels.”1Thus, it is not surprising that LLLT lacks scientific appeal and has been denied entrance into mainstream medicine. Even when the benefit of doubt is allowed, LLLT could easily be regarded as a science-fiction construct or wishful thinking. Yet, compelling data on the potential clinical value of LLLT is available. A sound theory on the mechanism of action of LLLT implicating regulation of mitochondrial function has been advanced, and available data support that light-tissue interactions have special implications in highly metabolically-active excitable tissues, including the retina and the brain. Although there is still a lot to learn about mechanistic light-tissue interactions in the nervous system and the retina, evidence shows that LLLT can enhance neural metabolism by regulating mitochondrial function, intraneuronal signaling systems, and redox states. This review will briefly describe the current proposed photochemical mechanisms underlying the neurobiological effects of LLLT. A summary of current knowledge about LLLT dosimetry relevant for its variable effects in the nervous system, including noninvasive in vivo transcranial effects is also presented. A summary of key in vitro, preclinical, and clinical studies supporting the protective and enhancing effects of LLLT in a number of pathogenic conditions including cytotoxicity, mitochondrial dysfunction, and hypoxia/ischemia in the retina and the central nervous system is presented. The data on LLLT suggest it can exert effective, reproducible, and meaningful changes in the normal and dysfunctional nervous tissue. This highlights the value of LLLT as a novel and useful paradigm to treat visual, neurological, and psychological conditions, and supports that neuronal energy metabolism could constitute a major target for neurotherapeutics of the eye and brain.

What is LLLT?

Light is a type of electromagnetic radiation with both wave-like and particle-like properties. Living organisms are immersed in a vast ocean of electromagnetic radiation, which consists of periodic oscillations in electromagnetic fields that travel space and are thus able to transfer energy. Hence, light is a form of energy called luminous energy. A wave of electromagnetic radiation has a unidirectional vector and can be characterized in terms of its wavelength (λ = the distance between successive peaks or troughs), frequency (the number of oscillations per second), and amplitude (the difference between trough and peak). A complex mixture of waves with different frequencies, amplitudes, and wavelengths are absorbed, scattered, and reflected by objects, including biological material. Light of only one wavelength is called monochromatic. In modern quantum physics, electromagnetic radiation consists of photons, which are particles (quanta) of energy that travel at a speed of 3 × 108 m/second. The brightness of light is the number of photons and the color of the light is the energy contained in each photon. LLLT can be defined as the use of directional low-power and high-fluence monochromatic or quasimonochromatic light from lasers or light-emitting diodes (LEDs) in the red to near-infrared wavelengths (λ = 600–1100 nm) to modulate a biological function or induce a therapeutic effect in a nondestructive and nonthermal manner.2,3The effects of LLLT implicate conversion of luminous energy to metabolic energy with a subsequent modulation of the biological functioning of cells. Thus, LLLT is commonly known as photobiomodulation. It could also be called photoneuromodulation when nerve cells are the target. LLLT differs from the conventional effects of high-energy photon delivery commonly associated with lasers, which are mediated by a greater release of energy and result in heating and tissue destruction through dissection, ablation, coagulation, and vaporization. Compared to these commonly known destructive effects of lasers, LLLT is catalogued as “low-level” because the energy content of electromagnetic radiation is inversely proportional to its wavelength. In addition, the target tissue is generally exposed to low irradiances (ie, low Watts per cm2 of tissue), when compared to the energy delivered for ablative applications. Energy doses delivered by LLLT are too low to cause concerns about heating and tissue destruction, yet they are high enough to modulate cell functions. In fact, the typical irradiances used for photobiomodulation applications overlap with those used in topical photodynamic therapy for skin conditions.4 Early experiments demonstrated that photoneuromodulation of electrical activity in neurons can be achieved independently of thermal effects.5

Although cells in vitro are responsive to a variety of wavelengths in the electromagnetic spectrum, beneficial responses in vivo are observed preferentially within a more narrow wavelength range. Obviously, visible light (400–700 nm) penetrates the eyes and activates retinal cells that contain specialized photopigments (rods, cones, and some ganglion cells). But it is unknown whether in vivo exposure to light below 600 nm (such as blue or green light) can have beneficial effects on other nerve cells that are not specialized for photoreception. The red to near-infrared wavelength range has shown to be the most effective at inducing in vivo beneficial effects in cells that do not appear to have specialized photopigments. This is attributed in part to the capacity of different wavelengths to penetrate tissue: lower wavelengths such as violet and ultraviolet appear to penetrate less, whereas those in the red and infrared range have higher penetration. Also, energy at wavelengths shorter than 600 nm is generally scattered in biological tissues in vivo and they tend to be absorbed by melanin, whereas water significantly absorbs energy at wavelengths higher than 1150 nm.6 For clinical purposes, this implies the existence of an in vivo therapeutic “optical window” that corresponds to red and near-infrared wavelengths. As discussed below, this window also matches the ability of luminous energy to excite susceptible intracellular molecules.6For this reason, LLLT has also been referred to as near-infrared light therapy. LLLT is based on the principle that certain molecules in living systems are able to absorb photons and trigger signaling pathways in response to light.7 This process is termed energy conversion, and implies that the molecule excited by light reaches an electronically excited state that temporarily changes its conformation and function.