Pharmacodynamic Implications of Transcranial Photobiomodulation and Quantum Physics in Clinical Medicine

Abstract

Photobiomodulation (PBM) is the application of light therapy that utilizes photons to alter the activity of molecular and cellular processes in the tissue where the stimulation is applied. Because the photons associated with the therapeutic mechanisms of PBM affect processes associated with the mitochondria, it is hypothesized that PBM increases ATP synthesis. Alteration of the mitochondrial respiratory enzyme, cytochrome c oxidase (CCO), is hypothesized to induce healing to damaged tissues via regeneration. Utilization of PBM has been examined in clinical disorders which include but are not limited to Alzheimer’s/dementia, epilepsy, and age-related macular degeneration. Transcranial PBM (tPBM) utilizes quantum dot light emitting diodes (QLEDs). QLEDs allow for narrow wavelength emissions from applications of PBM to alter electrophysiological activity and tissue regeneration. This chapter aims to evaluate the mechanisms of QLED applications of PBM and its applications as a photodynamic therapy in the medical sciences. Further, this chapter will examine the quantum mechanics of tPBM and its ability to affect electrophysiological activity according to the electroencephalogram (EEG) across the delta, theta, alpha, beta frequency bands.

1. Introduction

Photobiomodulation (PBM) is the application of light therapy that utilizes photons to alter the activity of molecular and cellular processes in the tissue where the stimulation is applied [1]. Historical contexts of PBM therapy and its development indicate that this intervention has been synonymous with low level laser therapy (LLLT), intensive monochromatic light energy, and light emitting diode (LED) energy interventions [2, 3, 4]. The emission of monochromatic light within the range of 600 to 1000 nm from low level lasers and LEDs is thought to underlie alterations in cellular signaling pathways, as the photons from LLLT interventions can influence ATP synthesis, gene expression, and oxygen consumption [5]. This hypothesis is based upon the ability of cytochrome c oxidase (CCO), an enzyme within the electron transport chain, to alter mitochondrial membrane potential via exposure to photonic energy in the spectra of 360-860 nm [5]. Near infrared light (NIR) is defined as the emission of light within the 700 to 980 nm spectra whereas infrared light (IR) is energy that is emitted at 1000 nm or 300 GHz and above [6].

While PBM has shown efficacy for neurodegenerative disorders, this intervention has been applied to other neurological disorders which include, but are not limited to, retinal disorders, ischemic stroke, and epilepsy [7]. Neurodegenerative diseases are currently considered as incurable as pharmacological interventions have failed to slow the progression of neuronal necrosis [8, 9, 10, 11]. Because many pharmacological interventions induce significant side effects and have largely proven ineffective in curtailing degenerative processes, determining new non-invasive therapies for these disorders is imperative [7]. As the mechanisms by which transcranial PBM (tPBM) are based allow for deep tissue penetration; exposure of subcortical and cortical structures to LLLT interventions is associated with increased perfusion, cellular oxygenation, and renormalization of functional electrophysiological networks [12].

Despite differences in the clinicopathogenesis of neurodegenerative disorders, tPBM is thought to directly influence mitochondrial dysfunction and oxidative inflammatory processes [13, 14]. Neuropathophysiological correlates of Alzheimer’s dementia (AD) include, but are not limited to, neurofibrillary tangles; dystrophic neuritis; amyloid precursor protein deposits and increased phosphorylated tau concentrations [13, 14, 15, 16]. The inability for β-amyloid concentrations to be adequately decreased results in the breakdown of microtubular assemblies due to hyperphosphorylated tau. Hyperphosphorylation is a biological process that mediates the regulation of mitosis. Because hyperphosphorylation is a signaling process that regulates cell division, abnormalities in microtubules can cause toxicity to cells. Disruptions of the polymerization dynamics of microtubules can result in synaptic failure as these cells are implicated in maintenance of cell structure and homeostatic regulation of cellular metabolic demand [13, 14, 15, 16].

2. Applications of PBM to neurodegenerative disorders

Utilization of tPBM in AD populations aims to increase reactive oxygen species (ROS) [17]. Alterations of ROS are associated with improved adenosine triphosphate (ATP) synthesis as this transcription factor is implicated in mitochondrial electron transport, gene expression, and inactivation of pro-apoptotic proteins and nucleic acids [17, 18]. Because the clinicopathology of AD is associated with dysfunction of the mitochondria, clinical implications of hypometabolism and hypoxia are integral to the understanding the mechanisms that underlie tPBM interventions [17, 18]. As the photons from tPBM are absorbed by CCO and hemoproteins within the brain, this suggests that this modality may alter electrochemical reactions and intracellular signaling as a function of improvements in the mitochondrial electron transport chain [19].

Applications of monochromatic wavelengths across the NIR and IR spectra via tPBM interventions affect complexes within functional mitochondrial pathways differentially [20, 21, 22]. NIR is considered as light that is emitted at a frequency between 700 nm and 1 mm whereas IR is photic energy emitted at 1 mm or 300 GHz and above [6]. Examination of homeostatic processes that are mediated by CCO, or complex IV within the electron transport chain, suggests that this target of PBM interventions can be stimulated to increase ROS production, oxygen consumption, and ATP synthesis when activated by red light and NIR frequencies between 633 nm and 808 nm [20, 21, 22]. Evaluations of alterations within complexes I, II, or III were not significant when exposed to frequencies between 633 and 808 nm [20, 21, 22].

Examination of higher irradiances within the NIR spectra indicate that exposure to 980 nm induced significant alterations within complexes III and IV [20]. Similar results were examined for exposure to IR at 1064 nm despite the effects being robust across complexes I, III, and IV. These results suggest that complex II within the electron transport chain may require stimulation within a different spectrum that is not within the wavelength frequencies associated with NIR or IR irradiances to induce physiological modulation for processes related to homeostasis [20, 21, 22].

Dysregulation of mitochondrial signaling negatively affects homeostatic processes and ATP availability as these cells are significantly implicated in metabolic regulation [5, 20, 21, 22]. As the mitochondria influences cellular signaling, proliferation, DNA and RNA synthesis, and gene expression, implications of ATP availability and the mitochondrial membrane potential must be considered. The mitochondrial membrane potential can be modeled as ΔΨm. As changes in mitochondrial signaling are derived as a function of ΔΨm, which can be altered according to electrochemical changes in the photon gradient, this indicates that photic energy can alter the mitochondrial respiratory chain and ATP synthesis [5].

The utilization of animal models in PBM research has allowed for the elucidation that applications of laser light across the 450, 620–680, and 760–895 nm frequency bands may alter complexes within the mitochondrial respiratory chain [5]. These models have allowed for mechanistic evaluations of responsivity to PBM as the elucidation of photoacceptors and photoreceptors are hypothesized to underlie the cellular pathways that are modulated by LLLT therapies [20, 21, 22, 23, 24]. Photoreceptors are specialized neuroepithelial cells that respond to photic stimulation within the range of 660 to 1000 nm whereas photoacceptors are non-specialized cells which alter transcription signaling after the photons have been absorbed [20, 23, 24, 25, 26].

Laws of photobiology indicate that photons must be absorbed within the tissue prior to transformation into chemical, heat, or kinetic energy [27, 28]. Chromophores are molecular compounds that can convert photons into sources of energy [29]. The activation of chromophores by a specific wavelength of light emission is associated with alterations of biological signaling within the tissue by which it is located [29].

3. Mechanisms of PBM

Technological advances have allowed quantum physics to be applied to the development of non-invasive clinical inventions that alter cellular signaling reactivity within mitochondrial pathways [28]. Elucidation of the mechanisms that underlie LLLT therapies may facilitate comprehensive understandings of applications of NIR and IR for energetic restorative medicine. As tPBM alters cellular responsivity via energy particles emitted from light, this suggests that oscillatory properties of cells within the body can be altered by endogenous or exogenous excitation [28].

PBM applications can be utilized as stimulatory or inhibitory clinical interventions depending upon specific irradiation parameters [28, 30, 31]. Irradiation accounts for the depth, wavelength frequency, and dosage. Stimulatory processes such as cell proliferation, tissue rejuvenation, and reduction of inflammatory processes have been reported within the range of 10–100 mW cm−2 whereas inhibitory processes require higher irradiance levels [28, 30, 31]. While the depth of the tissue for phototherapy applications must be considered, pharmacodynamic considerations such as the time course for light exposure must also be examined.

Applications of photonic therapy require that fluence rate and irradiance are differentiated despite utilizing mW cm−2 as a unit of measurement [28, 32]. Because transcranial applications of PBM are intended for a spherical structure within the body, the quantum mechanics of tPBM must be considered according to fluence rate. Fluence rate considers the geometric properties of tissues targeted by tPBM, scattering effects, and absorption rate as a time average. The time average is calculated according to the dispersion of photic energy in multiple directions within a spherical model. As the photons must be absorbed within a cross sectional area of the model by which it is applied, this calculation considers the average propagation of the emitted wavelength within the targeted tissue [28].

Calculations of fluence rate must use multifactorial analyses that account for divergent properties of biological tissues in tPBM applications. As tPBM interventions target subcortical structures and neurophysiological pathways, considerations of the radiation transfer equation (RTE) allow for derivation of photon transport and alterations in the mitochondrial membrane potential [6]. RTE allows for the derivation of fluence rate as a function of photonic distribution, absorption, and scattering effects across tissues such as the dura, skull, cerebrospinal fluid, and white and gray matter [6, 33].

Computational models of fluence rate as a logarithm using 630 nm, 700 nm, and 810 nm were examined using the Colin27 head atlas [6]. This head model allows for the calculation of fluence rate across divergent biological tissues with anisotropic conductivity. Analyses of penetration depth according to exposure to these NIR frequencies were evaluated at Cz. Cz is the central midline reference point according to the 10-20 International standardized placement system for electroencephalographic analyses [6].

Results indicate that applications of 700 nm and 810 nm had a higher penetration depth reflected by a higher fluence rate compared to 680 nm [6]. Furthermore, the comparison of absorption rate within gray matter was more significant for 810 nm compared to 700 nm and 680 nm. These results suggest that because 810 nm showed a higher fluence and absorption rate, this wavelength may show more efficacy in transcranial stimulatory interventions compared to lower wavelength frequencies within the NIR spectrum [6].

4. Mathematical considerations of phototherapy

Mathematical modeling of power density of tPBM applications must consider photometric units of luminance, wavelength of the light source, and the area by which the light is applied [34, 35]. Luminance, Lv, is calculated as a function of the energy emitted from a light source which accounts for the specific angle, direction, and scattering coefficients across the surface model by which the light source is applied [34, 35]. Thus, d² Φv represents the intensity of light energy according to units of time which is divided by dS. dS represents the area of the surface that the light is directed. dΩs denotes the differential solid angle by which the light source travels in a specified direction whereas θS accounts for the refraction and direction of light observed relative to the surface by which the light is applied [34, 35].

$$Lv=\frac{d^2\Phi v}{\mathit{dSd\Omega scos\theta S}}$$E1

Calculations of luminance and applications of PBM must consider Lambert’s cosine law. Lambert’s cosine law, also known as the cosine emission law, states that the intensity of light covaries according to the distribution area and its angle of incidence [28, 36, 37, 38]. As the power of light received by a surface depends on the cosine of the incidence angle, the power of a light source is significantly attenuated if the direction of light is applied orthogonal to the surface normal [28, 36, 37, 38].

Mathematical considerations of Lambert’s cosine law and the clinical utility of tPBM require examination of implications related to the inverse square law of illuminance [39, 40]. The inverse square law of illuminance states that the light received by any surface is dependent upon the distance of the targeted surface in relation to the source of light. As this law indicates that the light received by a surface is inversely proportional to the square distance between the surface normal and a source of light; as distance increases, the power of the light significantly decreases. Eq. (2) indicates that illuminance, I, varies proportionately to the square distance, d, which is measured in meters and the intensity of the radiation is measured in candela [39, 40].

$$I\propto \frac{1}{d^2}$$E2

Mathematical modeling of the inverse square law may also apply geometric properties to evaluate light absorption within spherical models [41]. I represents the intensity of the light source at the surface of the sphere, whereas S represents the source strength divided by, $4\pi r^2$, the spherical area [41].

$$I=\frac{S}{4\pi r^2}$$E3

5. Quantum mechanics and pharmacodynamic implications of PBM

Quantum biology indicates that molecules derived from water can be converted to provide free energy to cells [23, 42, 43, 44]. Theoretical applications of electron transfer were developed that allowed for later technological advances such as femtosecond spectroscopy [23, 42, 43, 44]. The advent of femtosecond spectroscopy, which examines the dynamics of chemical reactions and the movement of atoms due to exposure to laser technology, has revolutionized non-invasive clinical medicine [23, 42, 43, 44, 45, 46, 47].

Light water interactions are applicable to the treatment of complex diseases as water comprises 70% of the mass and 99% of the total molecules of the human body [23]. Because homeostatic regulation and biological signaling are mediated by energy and water interactions, physiological processes within humans can be considered as electrochemically and electrodynamically dependent. As muscle contraction, cardiovascular and neurological functioning are influenced by biochemical processes which facilitate electrical currents derived from ion gating and action potentials, considerations of tPBM and other LLLT interventions must be examined in relation to the clinicopathogenesis of divergent disorders [23].

Pharmacodynamic determinations of wavelength and dosage within LLLT modalities must be examined as increased water concentrations in target areas may increase the infrared energy absorption [48]. While limited research has established how scattering coefficients and the rate of light absorption can be altered due to water content within human skin, considerations of age, gender, and body mass suggest that clinical responses may be attenuated if variance across these factors is not accounted for. Furthermore, as altered water concentrations within a targeted area may attenuate clinical responsivity, clinicians that utilize these methodologies must also consider the depth of the targeted tissue [48].

6. Clinical implications of tPBM and neurodegenerative disorders

Because the clinicopathogenesis of neurodegenerative disorders often implicates alterations of neuronal communication between divergent Brodmann areas and functional connectivity networks, the conversion of photons from light therapies may improve cognitive functioning [12]. While comprehensive understanding of the factors that interact to induce the pathognomonic correlates of AD remain elusive, a prominent hypothesis of the etiopathogenesis of AD is related to the brain’s inability to adequately produce cellular energy [12, 13, 14, 15, 16].

Current diagnostic criteria of AD delineate three stages of progression according to symptomatic presentation and neurological alterations [49, 50]. The preclinical stage of AD is characterized by a lack of significant clinical presentation of symptoms despite phenotypic alterations of volumetric and structural integrity, amyloid plaque buildup, and degeneration of neurons among other cellular changes. The second stage, mild cognitive impairment, is characterized by alterations in episodic memory retrieval, visual imagery performance, logical reasoning, and executive functioning that are not explained by educational level or age. Diagnosis of AD represents the last stage of neurodegeneration and is characterized by a loss of independence due to significant impairments across visuospatial, language, sensory processing, and memory domains [49, 50].

As the clinicopathogenic processes that underlie AD include diffuse neural degeneration and functional connectivity alterations, this suggests that dysregulation of the posterior dominant rhythm is a cardinal feature of severe disease progression [12]. Neurophysiological assessments within AD populations often indicate reduced signal complexity, reducing synchrony consistent with disease progression, and robust slowing across the electroencephalographic (EEG) frequency spectrum [12].

Quantitative EEG (qEEG) analyses were applied by Williams to evaluate functional connectivity alterations within a PAD sample after exposure to an active infrared treatment using 1070 nm or placebo treatment that mimicked the tPBM intervention [12]. Diagnosis of PAD was determined using guidelines put forth by the National Institute on Aging-Alzheimer’s Association [50]. The sample (n=42) was composed of individuals between the ages of 40 to 85 which were randomly assigned to the active or control treatment group [12, 50]. All participants received 6 to 8 minute eyes open and eyes closed qEEG assessments prior to exposure to the tPBM or sham intervention and at the conclusion of the 8 week study [12, 50].

While statistically significant functional connectivity alterations were examined between pre and post measures for the tPBM and control group across the delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz) and beta (12-30 Hz) bands, the most significant alterations were focal to the EC tPBM group between 8 to 12 Hz [12]. Because AD is associated with diffuse neural degeneration that inherently affects the posterior dominant rhythm, it is interpreted that tPBM interventions may temporarily influence the posterior dominant rhythm via increases of ATP within subcortical structures [12].

These results are consistent with implications associated with neural packing density as the occipital regions have a greater metabolic demand than the frontal cortices [12, 51]. Implications of neurophysiological arrangement of cell distribution suggest that the number of cells in a specific area of the cerebral cortex is attributable to the amount of sensory processing and sensory integration demands of the specific region of interest. Thus, because the occipital regions have a significant metabolic demand where absorption of photons is associated with improvements in ROS, oxygen consumption, cerebral perfusion, the findings of this research suggest that the improvements in cognition may be attributable improvements in ATP synthesis and mitochondrial dysfunction [7, 12, 51, 52, 53, 54, 55, 56, 57, 58].

7. Retinal disorders

Pharmacodynamic parameters and dosimetry of PBM in retinal disorders are not well understood [59]. Evaluations of clinical applicability of quantum dot light emitting diodes (QLEDs) have utilized narrow wavelength emissions of 670 nm while responsivity to other wavelengths have been limited [59, 60, 61]. Examination of responsivity to PBM at 670 nm and 830 nm were compared for age related macular degeneration in animal subjects [59]. Results suggest that reductions of cell death were observed in the animals that received 670 nm of PBM while no alterations in disease progression were reported for animals that received 830 nm [61].

Further examination of responsivity to 670 and 810 nm PBM were compared using ex vivo retina tissue cultivation [59]. The animal subjects were exposed to blue light irradiation to induce oxidative stress to the photoreceptors. As the photoreceptors contain high concentrations of mitochondria, assessments of improvement of the pathological effects after exposure to blue light allow for evaluations of molecular responses to near infrared and red light therapies [59].

Results indicate that exposure to 670 nm of red light and 810 nm of NIR increased activity of mitochondrial ATP [59]. Examination of oxidative phosphorylation (OXPHOS) activity after exposure to 670 nm and 810 nm was conducted using immunohistochemical staining of the retinal inner and outer segments. Mitochondrial pathways within the inner and outer layer of the retinal cells were damaged using blue light irradiation to elucidate specific alterations in OXPHOS complexes. Complexes I and II were emphasized in these analyses as they are implicated as the first two enzymes of the mitochondrial respiratory chain [59]. Alteration of the complex I+III+IV pathway approached statistical significance after exposure to 670 nm of red light and 810 nm of NIR as the oxygen consumption was restored to a normative range following mitochondrial induced apoptosis via blue light irradiation [59]. A similar trend was reported for the complex II+ III+ IV pathway after exposure to 670 nm of red light and 810 nm of NIR. Normalization of complex II after exposure to red light and NIR PBM suggests that improvements of ATP synthesis may be attributable to restoration of oxygen consumption within functional extramitochondrial pathways [59].

This study suggests that despite the robust hypothesis that CCO alterations are the primary mechanism that underlies responsivity to PBM in macular degenerative disorders, that functional extramitochondrial complexes may mediate this interaction [59]. As the results of this study did not show alterations in concentrations of CCO after exposure to PBM, it is suggested that CCO is mediated as a secondary effect of interactions between extramitochondrial complexes [59].

8. Epilepsy

Investigations of the clinical utility of tPBM in pediatric epileptic patients suggests that the addition of this intervention with Antiepileptic Drugs (AEDs) may yield better results compared to administration of AEDs alone [62, 63]. Applications of 808 nm tPBM were utilized in prepubescent rats that received low doses of valproic acid after exposure to Pentylenetetrazole [62, 63]. Pentylenetetrazole is a non-competitive antagonist of gamma-aminobutyric acid (GABA). This drug is utilized to study the GABA-ergic mechanisms that underlie epilepsy as it induces clonic convulsions [63].

The utilization of tPBM as an additive therapy reduced the seizure latency of Convulsive Status Epilepticus (CSE) [62]. Comparison of the seizure latency offset in animal models with Pentylenetetrazol induced CSE suggests that tPBM may serve as a seizure prophylaxis. While future research is required to establish dosage parameters of AEDs in combination with tPBM, the clinical utility of LLLTs may induce significant synergistic effects for epileptic populations that experience CSE, Refractory Status and Super Refractory Status Epilepticus [62].

9. Conclusion

tPBM is the utilization of LLLT which is thought to modulate mitochondrial activity, ATP synthesis, and biosignaling processes [13, 14]. While comprehensive understanding of the mechanisms that underlie this modality remain elusive, LLLT interventions have shown efficacy in pediatric epilepsy as adjunctive therapies to AEDs and across neurodegenerative disorders [12, 59, 62].

Considerations of quantum mechanics suggest that the clinical utility of tPBM is related to the ability of cells to derive free energy from water [23, 41, 42, 43]. As the advent of femtosecond spectroscopy has allowed for the study of the dynamic processes that underlie chemical reactions and molecular rearrangement after exposure to laser technology, the ability of LLLT therapies to induce photochemical alterations within mitochondrial pathways has become possible [12, 23, 42, 43, 44, 45, 46, 47].

CCO is an endogenous photoreceptor which is implicated in electron transfer and metabolic processes [59]. This molecule is implicated as a targeted mechanism of tPBM as it is a photoreceptor that can absorb photons to increase ATP synthesis within the mitochondrial respiratory chain [19, 59]. As hypoxia is thought to underlie the etiopathogenesis of AD, the ability of tPBM to alter biological signaling via exposure to QLEDs is a significant advancement in clinical medicine [12, 16, 42, 43, 44, 45, 46, 47].

Applications of quantum mechanics to the study of light therapy interventions suggest that the cosine emission law and the inverse square law of illuminance are relevant to the pharmacodynamic processes that underlie clinical responsivity to tPBM [28, 36, 37, 38, 39, 40]. The inverse square law of illuminance states that the light received by any surface is dependent upon the distance of the targeted surface in relation to the source of light [39, 40]. Considerations of the cosine emissions law indicate that the intensity of light covaries according to the distribution area of the light and its angle of incidence [28, 36, 37, 38].

As the pharmacodynamic parameters tPBM may vary according to water concentration levels across human tissues, considerations of wavelength, time course of exposure, and scattering effects must be examined prior to clinical applications of this intervention [48]. These factors suggest that individualized dose response curves may be required despite robust utilization of 670 to 1040 nm of near infrared and infrared light tPBM interventions [59, 60, 61].

Continued research of applications of quantum physics and photochemical responses in the development of precision medicine therapeutics is required. As the clinical efficacy of LLLTs is being examined as electromagnetic interventions that may curtail neurodegenerative processes, this suggests that exposure to NIR and IR therapies may modulate functional mitochondrial pathways [1, 7, 12, 16, 27, 28]. Current examinations of therapeutic responses to LLLTs suggest that the clinical utility and pharmacodynamics of these interventions may require multifactorial analyses which include, but are not limited to age, depth of the targeted tissue, and body mass [48]. Future directions of clinical research for LLLT interventions must seek to establish proper irradiation parameters and time course exposure to near infrared and infrared light therapeutics [28, 30, 31]. These implications suggest that clinical responsivity may not only vary according to the frequency of exposure to tPBM interventions but also according to the severity level and symptomatic profile of the disorder by which this intervention is applied.