Photobiomodulation

Photobiomodulation therapy is defined as the utilization of non-ionizing electromagnetic energy to trigger photochemical changes within cellular structures that are receptive to photons. Mitochondria is particularly receptive to this process. At the cellular level, visible red and near infrared light (NIR) energy are absorbed by mitochondria, which perform the function of producing cellular energy called “ATP”. The key to this entire process is a mitochondrial enzyme called cytochrome oxidase c, a chromophore, which accepts photonic energy of specific wavelengths when functioning below par.

Photobiology

Photobiology is the study of the effects of non-ionizing radiation on biological systems. The biological effect varies with the wavelength region of the radiation. The radiation is absorbed by molecules in skin such as DNA, protein or certain drugs. The molecules are changed chemically into products that initiate biochemical responses in the cells.

Biological reaction to light is nothing new, there are numerous examples of light induced photochemical reactions in biological systems. Vitamin D synthesis in our skin is an example of a photochemical reaction. The power density of sunlight is only 105 mW/cm2 yet when ultraviolet B (UVB) rays strikes our skin, it converts a universally present form of cholesterol, 7-dehydrocholesterol to vitamin D3. We normally experience this through our eyes which are obviously photosensitive. Our vision is based upon light hitting our retinas and creating a chemical reaction that allows us to see. Throughout the course of evolution, photons have played a vital role in photo-chemically energizing certain cells. 

Pathways

  • NO (Nitric Oxide)
  • ROS (Reactive Oxygen Series) → PKD (gene) → IkB (Inhibitor κB) + NF-κB (nuclear factor κB) → NF-κB (nuclear factor κB stimulates gene transcription)
  • ATP (Adenosine Triphosphate) → cAMP (catabolite activator protein) → Jun/Fos (oncogenic transcription factors) → AP-1 (activator protein transcription factor stimulates gene transcription)

Mechanism

The current  and widely accepted proposal is that low level visible red to near infrared light (NIR) energy is absorbed by mitochondria and converted into ATP for cellular use. In addition, the process creates mild oxidants (ROS), which leads to gene transcription and then to cellular repair and healing. The process also unclogs the chain that has been clogged by nitric oxide (NO).[1] The nitric oxide is then released back into the system. Nitric oxide is a molecule that our body produces to help its 50 trillion cells communicate with each other. This communication happens by transmission of signals throughout the entire body. Additionally, nitric oxide helps to dilate the blood vessels and improve blood circulation.

Photobiomodulation mechanisms

Ref: Original: “Basic Photomedicine”, Ying-Ying Huang, Pawel Mroz and Michael R. Hamblin, Harvard Medical School.
Current design: Vielight Inc.

Parameters

The correct wavelength for the target cells or chromophores must be employed (633-810 nm). However, if the wavelength is incorrect, optimum absorption will not occur. Thus, as the first law of photobiology, the Grotthus-Draper law, states — without absorption there can be no reaction.[2]

The photon intensity, i.e., spectral irradiance or power density (W/cm2), must be adequate, or absorption of the photons will not be sufficient to attain the desired result. However, if the intensity is too high, the photon energy will be transformed to excessive heat in the target tissue, and that is undesirable.[3]

Finally, the dose or fluence must also be adequate (J/cm2). Consequently, if the power density is too low, then prolonging the irradiation time to achieve the ideal energy density, or dose, will, most likely, not give an adequate final result. This happens because the Bunsen-Roscoe law of reciprocity, the 2nd law of photobiology, does not hold true for low incident power densities.[4]

Brain Bioenergetics

Near-infrared light (NIR) stimulates mitochondrial respiration in neurons by donating photons that are absorbed by cytochrome oxidase. This is a bioenergetics process called photoneuromodulation in nervous tissue.[5]The absorption of luminous energy by the enzyme results in increased brain cytochrome oxidase enzymatic activity and oxygen consumption. Since the enzymatic reaction catalyzed by cytochrome oxidase is the reduction of oxygen to water, acceleration of cytochrome oxidase catalytic activity directly causes an increase in cellular oxygen consumption.[6] Increased oxygen consumption by nerve cells is coupled to oxidative phosphorylation. Hence, ATP production increases as a consequence of the metabolic action of near-infrared light. This type of luminous energy can enter brain mitochondria transcranially, and — independently of the electrons derived from food substrates — it can directly photostimulate cytochrome oxidase activity.[7]

References

[1] – “Biphasic Dose Response in Low Level Light Therapy”; Sulbha K. Sharma (PhD), Ying-Ying Huang (MD), James Carroll, Michael R. Hamblin (PhD)

[2, 3, 4] – “Is light-emitting diode phototherapy (LED-LLLT) really effective?”; Won-Serk Kim (PhD, MD), R Glen Calderhead (PhD)

[5, 6, 7] – “Augmentation of cognitive brain functions with transcranial infrared light”; Francisco Gonzalez-Lima (PhD), Douglas W Barrett (MD)

Brain Photobiomodulation

Mechanisms of Brain Photobiomodulation

“Low-energy photon irradiation in the near-IR spectral range with low-energy lasers or LEDs positively modulates various important biological processes in cell culture and animal models. Photobiomodulation is applied clinically in the treatment of soft tissue injuries and accelerated wound healing. The mechanism of photobiomodulation by red to near-IR light at the cellular level has been ascribed by research institutions to the activation of cellular mitochondrial respiratory chain components, resulting in a signaling cascade that promotes cellular proliferation and cytoprotection.

Research indicates that cytochrome c oxidase is a key photo-acceptor of irradiation in the far-red to near-IR spectral range. Cytochrome c oxidase is an integral membrane protein that contains multiple redox active metal centers. Additionally, it has a strong absorbency in the far-red to near-IR spectral range detectable in-vivo by near-IR spectroscopy.

Additionally, photobiomodulation increases the rate of electron transfer in purified cytochrome oxidase, increasing mitochondrial respiration and ATP synthesis in isolated mitochondria, and up-regulating cytochrome oxidase activity in cultured neuronal cells – leading to neuroprotective effects and neuronal function.

In addition to increased oxidative metabolism, red to near-IR light stimulation of mitochondrial electron transfer is known to increase the generation of reactive oxygen species (ROS). ROS functions as signaling molecules, providing communication between mitochondria and the nucleus.”[1]

[1] – Proc Natl Acad Sci U S A. 2003 Mar 18; 100(6): 3439–3444.

Brain Bioenergetics

Neurons contain mitochondria.

The process of utilizing the non-ionizing electromagnetic energy (light) to energize neuronal mitochondria triggers a cascade of beneficial cellular events.

Some potential effects are : neuroprotective effects, self-repair mechanisms and enhanced function.[1]

[1] : “Neurological and psychological applications of transcranial LEDs“, Department of Psychology and Institute for Neuroscience, University of Texas

Photonic Diffusion

Paolo Cassano, Anh Phong Tran, Husam Katnani, Benjamin S. Bleier, Michael R. Hamblin, Yaoshen Yuan, and Qianqian Fang “Selective photobiomodulation for emotion regulation: model-based dosimetry study,” Neurophotonics 6(1), 015004 (7 February 2019). https://doi.org/10.1117/1.NPh.6.1.015004

Electromagnetic radiation within the NIR range carries the most potent form of photonic diffusion through tissue, blood and brain.

In the entire electromagnetic spectrum, the 810 nm wavelength exhibits the least photonic scattering. Furthermore, it presents good absorption by blood and water.

Clinical studies have shown that NIR light of sufficient power density is capable of diffusing transcranially. Thus, the light can penetrate through the scalp, skull and brain to depths of 4 cm or more.  Furthermore, the NIR light can also diffuse intranasally, through the nasal channel.

Brain Photobiomodulation Science References

Penetration

Selective photobiomodulation for emotion regulation: penetration study
Harvard Psychiatry Department, Harvard Medical School : Link ]

Red and NIR light dosimetry in the human deep brain
Institute of Chemical Sciences and Engineering, Switzerland : Link 1 | Link 2 ]

Photon Penetration Depth in Human Brains
The University of Southern California : Link ]

Monte Carlo analysis of the enhanced transcranial penetration using distributed near-infrared emitter array.
Institute of Biomedical Engineering, Chinese Academy of Medical Science : Link ]

Transcranial Red and Near Infrared Light Penetration in Cadavers
State University of New York Downstate Medical Center : Link ]

Quantitative analysis of transcranial and intraparenchymal light penetration in human cadaver brain tissue
Oregon Health and Science University : Link 1 | Link 2 ]

Cellular Effects

Photobiomodulation Directly Benefits Primary Neurons Functionally Inactivated by Toxins
Medical College of Wisconsin : [ Link ]

Neuroprotective effects of photobiomodulation : Evidence from assembly/disassembly of the Cytoskeleton
University of Sydney : [ Link ]

Photobiomodulation – mitochondrial ROS generation and calcium increase in neuronal synapses.
Lin-Kou Medical Center, Taiwan : [ Link ]

Infrared neural stimulation and functional recruitment of the peripheral Nerve
Department of Biomedical Engineering, Case Western Reserve University : [ Link ]

Cognition

Brain Photobiomodulation Therapy: a Narrative Review
Department of Medical Physics, Tabriz University of Medical Sciences : [ Link ]

Review of brain photobiomodulation : targeting brain metabolism, inflammation, oxidative stress, and neurogenesis
Wellman Center for Photomedicine, Massachusetts General Hospital : [ Link ]

Shining light on the head : Photobiomodulation for brain disorders
Wellman Center for Photomedicine, Massachusetts General Hospital : [ Link ]

Augmentation of cognitive brain functions with transcranial lasers
Department of Psychology and Institute for Neuroscience, University of Texas : Link ]

Neurological and psychological applications of transcranial lasers and LEDs
Department of Neurology and Neurotherapeutics, University of Texas : Link ]

Novel Methods

A novel method of applying NIR light intracranially, impact on dopaminergic cell survival
University of Sydney, CEA-Leti : [ Link ]

Systemic Photobiomodulation Science References

General research

Blood contains circulating cell-free respiratory competent mitochondria
Université de Montpellier : [ Link ]

Interplay between up-regulation of cytochrome-c-oxidase and hemoglobin oxygenation induced by near-infrared laser
University of Austin at Texas : [ Link ]

Red/Near Infrared Light Stimulates Release of an Endothelium Dependent Vasodilator and Rescues Vascular Dysfunction
US Veterans Affairs : [ Link ]

Low-Level Light Therapy Protects Red Blood Cells Against Oxidative Stress and Hemolysis During Extracorporeal Circulation
Regional Specialist Hospital, Poland : Link ]

How Photons Modulate Wound Healing via the Immune System
King’s College London (KCL), University of London : [ Link ]

Randomized, Double-Blind, and Placebo-Controlled Clinic Report of Intranasal Low-Intensity Laser Therapy on Vascular Diseases
Ministry of Education, Key Laboratory of Laser Life Science, China : [ Link ]

Blood Laser Irradiation : current state and future perspectives
ABER Institute, Helsinki, Finland : [ Link ]

Intravenous Laser Blood Irradiation
MH Weber : [ Link ]

Applications of Intranasal Low Intensity Laser Therapy In Sports Medicine
Journal of Innovative Optical Health Sciences, World Scientific : [ Link ]

Formation of gigantic mitochondria in human blood lymphocytes under the effect of a low level laser source
Institute on Laser and Informatic Technologies of Russian Acad. : [ Link ]

Irradiation with He-Ne laser increases ATP level in cells cultivated in vitro
National Cancer Research Centre of the Academy of Medicine and Science : [ Link ]

Cellular Mechanisms

Therapeutic Photobiomodulation: Nitric Oxide and a Novel Function of Mitochondrial Cytochrome C Oxidase : [ Link ]

Mechanisms of Low Level Light Therapy : [ Link ]

Basic Photomedicine : [ Link ]

The Nuts and Bolts of Low Level Light Therapy : [ Link ]