Article

Photobiomodulation inside the brain: A novel method of applying near-infrared light intracranially and its impact on dopaminergic cell survival in MPTP-treated mice: Laboratory investigation

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Abstract

Object: Previous experimental studies have documented the neuroprotection of damaged or diseased cells after applying, from outside the brain, near-infrared light (NIr) to the brain by using external light-emitting diodes (LEDs) or laser devices. In the present study, the authors describe an effective and reliable surgical method of applying to the brain, from inside the brain, NIr to the brain. They developed a novel internal surgical device that delivers the NIr to brain regions very close to target damaged or diseased cells. They suggest that this device will be useful in applying NIr within the large human brain, particularly if the target cells have a very deep location. Methods: An optical fiber linked to an LED or laser device was surgically implanted into the lateral ventricle of BALB/c mice or Sprague-Dawley rats. The authors explored the feasibility of the internal device, measured the NIr signal through living tissue, looked for evidence of toxicity at doses higher than those required for neuroprotection, and confirmed the neuroprotective effect of NIr on dopaminergic cells in the substantia nigra pars compacta (SNc) in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson disease in mice. Results: The device was stable in freely moving animals, and the NIr filled the cranial cavity. Measurements showed that the NIr intensity declined as distance from the source increased across the brain (65% per mm) but was detectable up to 10 mm away. At neuroprotective (0.16 mW) and much higher (67 mW) intensities, the NIr caused no observable behavioral deficits, nor was there evidence of tissue necrosis at the fiber tip, where radiation was most intense. Finally, the intracranially delivered NIr protected SNc cells against MPTP insult; there were consistently more dopaminergic cells in MPTP-treated mice irradiated with NIr than in those that were not irradiated. Conclusions: In summary, the authors showed that NIr can be applied intracranially, does not have toxic side effects, and is neuroprotective.

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... [13][14][15] In the last few years, various PBM techniques such as intracranial or intranasal methods have been proposed as an alternative light delivery techniques to bring a sufficient amount of light energy to the deeper brain structures. 16,17 However, these approaches are invasive or inefficient and as yet in the early research stage. 18 Upconversion (UC) is an anti-Stokes process that is capable of converting two or more low-energy photons into a single higher energy photon due to the existence of ladder-like long-lifetime energy levels typical of lanthanide ions. ...
... 15,54 Therefore, the expected light intensity at deeper sites within the human brain would be extremely weak and perhaps even undetectable due to its attenuation over a distance of 80-100 mm. 17,55,56 This limits the use of light as an effective and reliable neuroprotective treatment because it cannot reach subcortical and brainstem regions. 17,53 In some of the animal studies, intracranially implantable fiber optics or micro-light-emitting diodes have been used for light delivery into the deeper regions of the brain. ...
... 17,55,56 This limits the use of light as an effective and reliable neuroprotective treatment because it cannot reach subcortical and brainstem regions. 17,53 In some of the animal studies, intracranially implantable fiber optics or micro-light-emitting diodes have been used for light delivery into the deeper regions of the brain. 17,[57][58][59] Although these techniques can deliver the light to subcortical regions, the need for a cable restricts animal movement and may cause tissue incompatibility and inflammatory reactions in the brain. ...
Article
Brain photobiomodulation (PBM) describes the use of visible to near-infrared light for modulation or stimulation of the central nervous system in both healthy individuals and diseased conditions. Although the transcranial approach to delivering light to the head is the most common technique to stimulate the brain, delivery of light to deeper structures in the brain is still a challenge. The science of nanoparticle engineering in combination with biophotonic excitation could provide a way to overcome this problem. Upconversion is an anti-Stokes process that is capable of transforming low energy photons that penetrate tissue well to higher energy photons with a greater biological effect, but poor tissue penetration. Wavelengths in the third optical window are optimal for light penetration into brain tissue, followed by windows II, IV, and I. The combination of trivalent lanthanide ions within a crystalline host provides a nanostructure that exhibits the upconversion phenomenon. Upconverting nanoparticles (UCNPs) have been successfully used in various medical fields. Their ability to cross the brain-blood barrier and their low toxicity make them a good candidate for application in brain disorders. It is possible that delivery of UCNPs to the brainstem or deeper parts of the cerebral tissue, followed by irradiation using light wavelengths with good tissue penetration properties, could allow more efficient PBM of the brain.
... As such, significant technological limitations remain with current devices used to deliver red-near-infrared light therapy in the clinic. Recent reports describing intracranial delivery of near-infrared light via a surgically implanted optical fiber showed beneficial outcomes with minimal side effects (Moro et al., 2014). Clearly, there is a need to further develop technologies that can deliver light deep within the brain, as well as explore new ways to deliver therapeutic light. ...
... To date, most studies on the penetration of light into central nervous system tissues have been confined to animal models (Byrnes et al., 2005;Fitzgerald et al., 2010;Zhang et al., 2000) and have been used to predict that light delivered by laser is unlikely to reach more than 20 mm into the human cortex (Moro et al., 2014). A recent study of transmission of 670 or 830 nm light delivered by LED array through coronal sections of human cadaver skull, showed transmission of 0.3% for frontal skull and 6.3% for right parietal skull. ...
... Thus, current devices, such as the VET75 (0.05 W cm -2 ) and the NeuroThera laser system (0.01 W cm -2 ) probably do not deliver sufficient light to deeper brain areas. Nevertheless, a potential (albeit more invasive) solution is to implant light sources or deliver light via fiber optic beneath the skull (Moro et al., 2014). In such cases, a 50 mW cm -2 source of red-near-infrared light would provide an energy density of 1 mW cm -2 at a depth of approximately 10 mm into the brain mass. ...
Article
Red-near-infrared light has been used for a range of therapeutic purposes. However, clinical trials of near-infrared laser light for treatment of stroke were abandoned after failing interim futility analyses. Lack of efficacy has been attributed to sub-optimal treatment parameters and low penetrance of light to affected brain regions. Here, we assess penetrance of wavelengths from 450-880 nm in human post-mortem samples, and demonstrate that human skin, skull bone and brain transmits therapeutically relevant quantities of light from external sources at wavelengths above 600 nm. Transmission through post-mortem skull bone was dependent upon thickness, and ranged from 5-12% at peak wavelengths of 700-850 nm. Transmission through brain tissue ranged from 1-7%, following an approximately linear relationship between absorbance and tissue thickness. Importantly, natural sunlight encompasses the wavelengths used in red-near-infrared light therapy. Calculations of the average irradiance of light delivered by sunlight demonstrate that sunlight can provide doses of light equivalent to - and in some cases greater than - those used in therapeutic trials. Natural sunlight could, therefore, be used as a source of therapeutic red-near-infrared light, but equally its contribution must be considered when assessing and controlling therapeutic dose in patients. For targets deep within the brain, it is unlikely that sufficient doses of light can be delivered trans-cranially; therapeutic light must be supplied via optical fibers or implanted light sources.
... The neuroprotective agent we used was photobiomodulation (PBM) therapy (⎣ = 670 nm). PBM has been shown to offer neuroprotection in cell culture Ying et al. 2008;Trimmer et al. 2009), as well as in various insect (Vos et al. 2013;Powner et al. 2016), rodent Shaw et al. 2010Shaw et al. , 2012Peoples et al. 2012;Moro et al. 2013Moro et al. , 2014Purushothuman et al. 2013;Johnstone et al. 2014;Reinhart et al. 2014Reinhart et al. , 2015Oueslati et al. 2015;El Massri et al. 2016a) and monkey Moro et al. 2016;El Massri et al. 2016b) models of Parkinson's disease. In addition to neuroprotection, several studies have reported improved locomotor activity and a reduction in clinical signs after PBM Moro et al. 2013;Reinhart et al. 2014Reinhart et al. , 2015Reinhart et al. , 2016Oueslati et al. 2015;Darlot et al. 2016). ...
... In addition to neuroprotection, several studies have reported improved locomotor activity and a reduction in clinical signs after PBM Moro et al. 2013;Reinhart et al. 2014Reinhart et al. , 2015Reinhart et al. , 2016Oueslati et al. 2015;Darlot et al. 2016). In the present study, we took the opportunity to examine our rodent (mouse: Moro et al. 2014;rat: Reinhart et al. 2015) and primate (monkey: Darlot et al. 2016) material further. These animals that had PBM via an intracranial optical fibre device followed by either 6OHDA (rats) or MPTP (mice and monkeys) lesion. ...
... We immunostained striatal and midbrain sections from animals used in previous studies (mouse: Moro et al. 2014;rat:;Reinhart et al. 2015;monkey:;Darlot et al. 2016). There was no overlap of results between the present study and those previous ones. ...
Article
Full-text available
Intracranial application of red to infrared light, known also as photobiomodulation (PBM), has been shown to improve locomotor activity and to neuroprotect midbrain dopaminergic cells in rodent and monkey models of Parkinson’s disease. In this study, we explored whether PBM has any influence on the number of tyrosine hydroxylase (TH)+cells and the expression of GDNF (glial-derived neurotrophic factor) in the striatum. Striatal sections of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mice and monkeys and 6-hydroxydopamine (6OHDA)-lesioned rats that had PBM optical fibres implanted intracranially (or not) were processed for immunohistochemistry (all species) or western blot analysis (monkeys). In our MPTP monkey model, which showed a clear loss in striatal dopaminergic terminations, PBM generated a striking increase in striatal TH+ cell number, 60% higher compared to MPTP monkeys not treated with PBM and 80% higher than controls. This increase was not evident in our MPTP mouse and 6OHDA rat models, both of which showed minimal loss in striatal terminations. In monkeys, the increase in striatal TH+ cell number in MPTP-PBM cases was accompanied by similar increases in GDNF expression, as determined from western blots, from MPTP and control cases. In summary, these results offer insights into the mechanisms by which PBM generates its beneficial effects, potentially with the use of trophic factors, such as GDNF.
... A question that has received little attention thus far is the possibility of toxicity in the case of a long-term PBM. This issue will be briefly discussed in this editorial, and previous scientific articles on it will be identified [1][2][3][4][5][6][7][8][9]. ...
... There is no evidence that PBM is toxic when used at therapeutic or imaging doses. There are no such concerns with intracranial applications (for example, optical fiber) in humans [3,4] or animals [5][6][7][8]. However, the studies cited used the PBM for a short or medium period of time (days to a few weeks), with only one study lasting more than a year [9]. ...
Article
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This editorial briefly discusses the issue of potential toxicity in the case of long-term photobiomodulation (PBM). Scientific articles from PubMed, Google Scholar, and the China National Knowledge Infrastructure were included in a heterogeneous search. There have been very few studies on the long-term effects of PBM, as well as its potential toxicity. There is no evidence that PBM is toxic when used at therapeutic or imaging doses. There are no such concerns with intracranial PBM application (e.g., optical fiber) in either animal or human experiments.
... Although, the penetration depth of NIR light in human brain doesn't exceed 20 mm from the cortical surface [69], which is considered a limitation of the use of tPBM therapy in humans with PD, the only (noncontrolled, non-randomized) study in PD patients revealed an improvement in motor and cognitive functions after two weeks tPBM therapy in [70]. ...
... A different investigation examining 800 nm laser light transmission through postmortem skulls from different species showed the inverse relation between light penetration and skull thickness [92]. Testing 670-nm LED light transmission through brain tissue in alive mice revealed a 65 % decrease in light intensity per millimeter of brain tissue traversed [69]. These findings imply that, while transcranial PBM may be a viable treatment option for the most superficial layers of the brain, it is unlikely to transmit enough light energy to deeper brain structures without affecting the health of the surrounding tissues [93]. ...
Article
Noninvasive brain stimulation/modulation is a rapidly emerging technique that has been implemented in different clinical applications. The commonly noninvasive techniques used in neurological manipulations include photobiomodulation (PBM), transcranial electrical stimulation (TES), transcranial magnetic stimulation (TMS), and ultrasound stimulation (USS). These techniques have the ability to excite, inhibit, or modulate neuronal activity in targeted brain areas to obtain the required therapeutic effects. However, each technique owns its unique mechanism of action that relies on specific parameters suitable for treating certain neurological disorders. Neurological disorders such as epilepsy, Parkinson's disease (PD), Alzheimer's disease (AD), and depression have been treated by one or more of these noninvasive techniques. The therapeutic outcomes of these techniques for neurological diseases are promising, yet with limitations. In the present review, the mechanisms of action of these different brain stimulation/modulation modalities were explored and a synopsis of their applications in the treatment of certain neurological disorders was provided. Moreover, methodological issues, limitations, and open questions were presented. Furthermore, some future directions were suggested.
... Hence, in order to offer direct stimulation in the primate brain, an intracranial optical fiber device delivering 670 nm light was developed. The feasibility of this device was tested initially in MPTP-treated mice, with implants into the lateral ventricles [60], and in 6OHDAlesioned rats, with implants into a midline region of the midbrain [61]. In both cases, photobiomodulation was not toxic to the surrounding tissue, even though the photobiomodulation source lay directly on neural tissue, nor did it generate any behavioral deficits; in fact, neuroprotection of dopaminergic neurons in the SNc was evident with this intracranial device, similar in magnitude achieved transcranially. ...
... Only 1-3% of light energy penetrates the skin and skull, with less than 1% of that light energy penetrating 12 mm of brain tissue (reviewed by [34,36,65]). While the intracranial mode of delivery attempts to circumvent this inherent barrier, it is highly unlikely that the more common approach of transcranial photobiomodulation achieves sufficient penetration of light energy to directly stimulate the parts of the brain first affected in Parkinson's disease [35,36,60]. ...
Article
In recent times, photobiomodulation has been shown to be beneficial in animal models of Parkinson’s disease, improving locomotive behavior and being neuroprotective. Early observations in people with Parkinson’s disease have been positive also, with improvements in the non-motor symptoms of the disease being evident most consistently. Although the precise mechanisms behind these improvements are not clear, two have been proposed: direct stimulation, where light reaches and acts directly on the distressed neurons, and remote stimulation, where light influences cells and/or molecules that provide systemic protection, thereby acting indirectly on distressed neurons. In relation to Parkinson’s disease, given that the major zone of pathology lies deep in the brain and that light from an extracranial or external photobiomodulation device would not reach these vulnerable regions, stimulating the distressed neurons directly would require intracranial delivery of light using a device implanted close to the vulnerable regions. For indirect systemic stimulation, photobiomodulation could be applied to either the head and scalp, using a transcranial helmet, or to a more remote body part (e.g., abdomen, leg). In this review, we discuss the evidence for both the direct and indirect neuroprotective effects of photobiomodulation in Parkinson’s disease and propose that both types of treatment modality, when working together using both intracranial and extracranial devices, provide the best therapeutic option.
... In the study conducted by Reinhart et al. (2016), an intracranial NIR delivery device was implanted in the vicinity of the SNpc of 6-hydroxydopamine (6-OHDA) lesioned Wistar rats, demonstrating the feasibility of stereotaxic device implantation into the ventral midbrain. Interestingly, in the experiments conducted by Moro et al. (2014) and Reinhart et al. (2016), pulsed delivery of NIR achieved better results than continuous delivery for the same dose of NIR treatment. Following these accomplishments, Darlot et al. (2016) were the first to report successful PBM treatment via an intracranially implanted NIR device in a monkey model of PD. ...
... The development of an intracranially implanted NIR delivery device for PD is challenging for several reasons. First, based on their studies in mice brains, Moro et al. (2014) realized that the signal intensity of NIR decays at a rate of 65% per millimeter of brain tissue. In comparison with the brains of mice and small monkeys, the human brain is much larger and shielded by a thick bony calvarium. ...
Article
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As the main driver of energy production in eukaryotes, mitochondria are invariably implicated in disorders of cellular bioenergetics. Given that dopaminergic neurons affected in Parkinson’s disease (PD) are particularly susceptible to energy fluctuations by their high basal energy demand, it is not surprising to note that mitochondrial dysfunction has emerged as a compelling candidate underlying PD. A recent approach towards forestalling dopaminergic neurodegeneration in PD involves near-infrared (NIR) photobiomodulation (PBM), which is thought to enhance mitochondrial function of stimulated cells through augmenting the activity of cytochrome C oxidase. Notwithstanding this, our understanding of the neuroprotective mechanism of PBM remains far from complete. For example, studies focusing on the effects of PBM on gene transcription are limited, and the mechanism through which PBM exerts its effects on distant sites (i.e., its “abscopal effect”) remains unclear. Also, the clinical application of NIR in PD proves to be challenging. Efficacious delivery of NIR light to the substantia nigra pars compacta (SNpc), the primary site of disease pathology in PD, is fraught with technical challenges. Concerted efforts focused on understanding the biological effects of PBM and improving the efficiency of intracranial NIR delivery are therefore essential for its successful clinical translation. Nonetheless, PBM represents a potential novel therapy for PD. In this review, we provide an update on the role of mitochondrial dysfunction in PD and how PBM may help mitigate the neurodegenerative process. We also discussed clinical translation aspects of this treatment modality using intracranially implanted NIR delivery devices.
... 6 A remarkable transmission measurement in rodent brain tissue showed a 65% reduction of 670 nm light intensity across each millimeter of living brain tissue. 40 This study measured that at a distance of 10 mm through the Sprague-Dawley rat brain parenchyma, the laser intensity was <0.001%, and at a distance of 5 mm through male BALB/c mouse brain, the LED intensity was <1% of the initial power. 40 In other studies in male BALB/c mice, 34,41 it was reported that about 2.5% and 3% of light with corresponding wavelengths of 670 and 810 nm, respectively, reached a depth of 5 mm in the brain, the distance from the skull surface to the SNc region. ...
... 40 This study measured that at a distance of 10 mm through the Sprague-Dawley rat brain parenchyma, the laser intensity was <0.001%, and at a distance of 5 mm through male BALB/c mouse brain, the LED intensity was <1% of the initial power. 40 In other studies in male BALB/c mice, 34,41 it was reported that about 2.5% and 3% of light with corresponding wavelengths of 670 and 810 nm, respectively, reached a depth of 5 mm in the brain, the distance from the skull surface to the SNc region. 41 In addition, *10% of 660 nm laser light was shown to be transmitted through 1 mm of brain tissue. ...
Article
Background and objective: Photobiomodulation (PBM) therapy is a promising and non-invasive approach to stimulate neuronal function and improve brain repair. The optimization of PBM parameters is important to maximize effectiveness and tolerability. Several studies have reported on the penetration of visible-to-near-infrared (NIR) light through various animal and human tissues. Scientific findings on the penetration of PBM light vary, likely due to use of different irradiation parameters and to different characteristics of the subject such as species, age, and gender. Materials and methods: In this paper, we review published data on PBM penetration through the tissues of the head in both animal and human species. The patterns of visible-to-NIR light penetration are summarized based on the following study specifications: wavelength, coherence, operation mode, beam type and size, irradiation site, species, age, and gender. Results: The average penetration of transcranial red/NIR (630-810 nm) light ranged 60-70% in C57BL/6 mouse (skull), 1-10% in BALB/c mouse (skull), 10-40% in Sprague-Dawley rats (scalp plus skull), 20% in Oryctolagus cuniculus rabbit (skull), 0.11% in pig (scalp plus skull), and 0.2-10% in humans (scalp plus skull). The observed variation in the reported values is due to the difference in factors (e.g., wavelengths, light coherence, tissue thickness, and anatomic irradiation site) employed by researchers. It seems that these data challenge the applicability of the animal models data on transcranial PBM to humans. Nevertheless, two animal models seem particularly promising, as they approximate penetration in humans: (I) Penetration of 808 nm laser through the scalp plus skull was 0.11% in the pig head; (II) Penetration of 810 nm laser through intact skull was 1.75% in BALB/c mouse. Conclusions: In conclusion, it is worthwhile mentioning that since the effectiveness of brain PBM is closely dependent on the amount of light energy reaching the target neurons, further quantitative estimation of light penetration depth should be performed to validate the current findings.
... Despite showing great promise in small rodent models, transcranial PBM is unlikely to be effective for targeting deep-brain structures, such as those affected in PD, in human patients, since light transmittance is considerably attenuated by the scalp, skull and superficial brain tissue (Hart and Fitzgerald, 2016;Lapchak et al., 2015;Moro et al., 2014). However, there is growing evidence that PBM has indirect effects, providing benefits that are not confined to the irradiated tissue. ...
... This apparent discrepancy may be due to the difference in the effect size of MPTP on these two outcome measures; the MPTP-induced lesion in the SNc ($20% reduction in TH + cells relative to saline controls) was modest compared to the increase in the number of FOS + cells in the CPu (>70% relative to saline controls). Given the unexpectedly modest SNc lesion in this cohort -in most of our previous studies the same MPTP dose produces a loss of $40% TH + cells in the SNc Moro et al., 2014) -the study design may have been underpowered to detect an effect for this outcome measure in the 2-and 5-day remote PBM groups. This could be assessed in future studies using a larger sample size and a higher dose of MPTP. ...
Article
Full-text available
Transcranial photobiomodulation (PBM), which involves the application of low-intensity red to near-infrared light (600-1100nm) to the head, provides neuroprotection in animal models of various neurodegenerative diseases. However, the absorption of light energy by the human scalp and skull may limit the utility of transcranial PBM in clinical contexts. We have previously shown that targeting light at peripheral tissues (i.e. "remote PBM") also provides protection of the brain in an MPTP mouse model of Parkinson's disease, suggesting remote PBM might be a viable alternative strategy for overcoming penetration issues associated with transcranial PBM. This present study aimed to determine an effective pre-conditioning regimen of remote PBM for inducing neuroprotection and elucidate the molecular mechanisms by which remote PBM enhances the resilience of brain tissue. Balb/c mice were irradiated with 670nm light (4J/cm2 per day) targeting dorsum and hindlimbs for 2, 5 or 10 days, followed by injection of the parkinsonian neurotoxin MPTP (50mg/kg) over two consecutive days. Despite no direct irradiation of the head, 10 days of pre-conditioning with remote PBM significantly attenuated MPTP-induced loss of midbrain tyrosine hydroxylase-positive dopaminergic cells and mitigated the increase in FOS-positive neurons in the caudate-putamen complex. Interrogation of the midbrain transcriptome by RNA microarray and pathway enrichment analysis suggested upregulation of cell signaling and migration (including CXCR4+ stem cell and adipocytokine signaling), oxidative stress response pathways and modulation of the blood-brain barrier following remote PBM. These findings establish remote PBM preconditioning as a viable neuroprotective intervention and provide insights into the mechanisms underlying this phenomenon.
... In most studies, the tissue under study has been irradiated directly, whether cells in vitro, or skin wounds, painful joints or tooth sockets, or the retina. The brain has also been irradiated directly, either transcranially or by an optical fiber placed deep into the brain, 37 or by an intranasal probe 38 to reach the inferior surface of the frontal lobe. Only a minority of studies, but still many, have tested mechanisms of this direct irradiation, reviewed elsewhere. ...
... One measure of the success of a technology is the investment made in the technology itself. The technology of "PBM" has extended from Finsen's red filters to wavelengthspecific lasers, 11 to wavelength-specific LEDs, 17 to delivery into the brain by optical fibres 37 and intranasal probes, 38 to most recently, the development of infrared-emitting cloth powered by body movement (reviewed by Tsai and Hamblin 41 ). Not all these techniques may prove clinically useful, but there is appeal in the idea, already being tested, 41 of speeding the healing of a skin wound or damaged tendon with a bandage that, powered by limb or body movement, emits an appropriate dose of infrared. ...
Article
Full-text available
This review brings together observations on the stress-induced regulation of resilience mechanisms in body tissues. It is argued that the stresses that induce tissue resilience in mammals arise from everyday sources: sunlight, food, lack of food, hypoxia and physical stresses. At low levels, these stresses induce an organised protective response in probably all tissues; and, at some higher level, cause tissue destruction. This pattern of response to stress is well known to toxicologists, who have termed it hormesis. The phenotypes of resilience are diverse and reports of stress-induced resilience are to be found in journals of neuroscience, sports medicine, cancer, healthy ageing, dementia, parkinsonism, ophthalmology and more. This diversity makes the proposing of a general concept of induced resilience a significant task, which this review attempts. We suggest that a system of stress-induced tissue resilience has evolved to enhance the survival of animals. By analogy with acquired immunity, we term this system ‘acquired resilience’. Evidence is reviewed that acquired resilience, like acquired immunity, fades with age. This fading is, we suggest, a major component of ageing. Understanding of acquired resilience may, we argue, open pathways for the maintenance of good health in the later decades of human life.
... To support this finding, only 1% of 670 nm LED light reached the mouse SNc at a depth of 5 mm from the light source in the transcranial method [70]. Besides, a preliminary study regarding the neuroprotective effects of intracranial PBM showed no toxic adverse effects around the implant sites in the midbrain [71]. ...
... On the other hand, PD pathogenesis is linked to abnormalities in the SNc, a midbrain structure that is located at a depth 80-100 mm from the coronal suture, below the dura. Studies have suggested that light in the NIR region may not penetrate the human brain deeper than 20 mm from the cortical surface [71]. This is considered to be a clear limitation in the application of transcranial PBM therapy in human PD. ...
Article
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Brain photobiomodulation (PBM) therapy using red to near-infrared (NIR) light is an innovative treatment for a wide range of neurological and psychological conditions. Red/NIR light is able to stimulate complex IV of the mitochondrial respiratory chain (cytochrome c oxidase) and increase ATP synthesis. Moreover, light absorption by ion channels results in release of Ca²⁺ and leads to activation of transcription factors and gene expression. Brain PBM therapy enhances the metabolic capacity of neurons and stimulates anti-inflammatory, anti-apoptotic, and antioxidant responses, as well as neurogenesis and synaptogenesis. Its therapeutic role in disorders such as dementia and Parkinson’s disease, as well as to treat stroke, brain trauma, and depression has gained increasing interest. In the transcranial PBM approach, delivering a sufficient dose to achieve optimal stimulation is challenging due to exponential attenuation of light penetration in tissue. Alternative approaches such as intracranial and intranasal light delivery methods have been suggested to overcome this limitation. This article reviews the state-of-the-art preclinical and clinical evidence regarding the efficacy of brain PBM therapy.
... Then again, PD pathogenesis is connected to abnormalities in the SNc, a midbrain structure that is situated at a depth 80-100 mm from the coronal suture, underneath the dura. Studies have recommended that light in the NIR area may not enter the human brain more profound than 20 mm from the cortical surface [190]. This is viewed as an unmistakable constraint in the use of transcranial PBM treatment in human PD. ...
Article
Full-text available
Photobiomodulation (PBM) portrays the utilization of red or near infrared light to stimulate, heal, recover, and protect tissue that has either been harmed, is degenerating, or, else likely is in risk of dying. The brain experiences various issues that can be ordered into three general groupings: traumatic (stroke, traumatic brain injury, and global ischemia), degenerative diseases (dementia, Alzheimer's and Parkinson's), and psychiatric (depression, anxiety, post-traumatic stress disorder). There is some proof that this multitude of apparently different circumstances can be advantageously impacted by applying light to the head. There is even the likelihood that PBM could be utilized for cognitive enhancement in normal healthy individuals. In this transcranial PBM (tPBM) application, near infrared (NIR) light is frequently applied to the forehead in view of the better entrance (no hair, longer wavelength). A few workers have utilized lasers, yet as of late the presentation of modest light emitting diode (LED) arrays has permitted the improvement of light radiating head helmets or "brain caps". This review will cover the mechanisms of action of photobiomodulation to the brain and sum up some of the key pre-clinical studies and clinical trials that have been embraced for different brain disorders.
... The bacteroids in the gut that increased with light therapy are considered beneficial to the microbiome through their antiinflammatory properties and production of healthy short chain fatty acids (Inhann, et al. [43]). Light therapy potentially could act as an adjunct to traditional treatments to rebalance the microbiome, especially dopamine and neurotransmitter production, (Johnstone, et al. [44]) and positively affect the outcome of some difficult to treat patients with Parkinson's disease (Jenkins,). ...
... 56 A study showed that PBM (670 nm, 0.16 mW) in the acute MPTP mouse model protected dopaminergic cells when used intracranially and intermittently, and when PBM (4 × 90 seconds over 2 days) was used intermittently, stronger protection was achieved. 57 A study also showed that using PBM (810 nm, 160 µW, 90 s twice a day for 2 days) to the midline of the midbrain improved dopaminergic cells. 58 This study also showed that a higher dose of NIr (125 J) had no toxic effect on cells in the midbrain implantation in the monkey model of PD. ...
Article
Introduction: Parkinson's disease (PD) is a progressive and severe neurodegenerative disorder of the central nervous system (CNS). The most prominent features of this disease are cell reduction in the substantia nigra and accumulation of α-synuclein, especially in the brainstem, spinal cord, and cortical areas. In addition to drug-based treatment, other therapies such as surgery, cell therapy, and laser therapy can be considered. In this study, articles on cell therapy and laser therapy for PD have been collected to evaluate the improvement of motor function, cell differentiation, and dopaminergic cell proliferation.
... This strategy has shown beneficial effects in several rodent models of neurodegenerative disease such as stroke 62 , sleep deprivation 63 , major depressive disorder 64 , traumatic brain injury (TBI) 65 , multiple sclerosis 66 , spinal cord injury (SCI) 60 and Parkinson's disease (PD) 67,68 . Our group and others have demonstrated that NIR protects synapses from binding toxic Aβ oligomers and improves cognitive function in different AD-like mouse models [69][70][71][72] . ...
Article
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Neuroinflammation is a key event in neurodegenerative conditions such as Alzheimer’s disease (AD) and characterizes metabolic pathologies like obesity and type 2 diabetes (T2D). Growing evidence in humans shows that obesity increases the risk of developing AD by threefold. Hippocampal neuroinflammation in rodents correlates with poor memory performance, suggesting that it contributes to cognitive decline. Here we propose that reducing obesity/T2D-driven neuroinflammation may prevent the progression of cognitive decline associated with AD-like neurodegenerative states. Near-infrared light (NIR) has attracted increasing attention as it was shown to improve learning and memory in both humans and animal models. We previously reported that transcranial NIR delivery reduced amyloid beta and Tau pathology and improved memory function in mouse models of AD. Here, we report the effects of NIR in preventing obesity-induced neuroinflammation in a diet-induced obese mouse model. Five-week-old wild-type mice were fed a high-fat diet (HFD) for 13 weeks to induce obesity prior to transcranial delivery of NIR for 4 weeks during 90-s sessions given 5 days a week. After sacrifice, brain slices were subjected to free-floating immunofluorescence for microglia and astrocyte markers to evaluate glial activation and quantitative real-time polymerase chain reaction (PCR) to evaluate expression levels of inflammatory cytokines and brain-derived neurotrophic factor (BDNF). The hippocampal and cortical regions of the HFD group had increased expression of the activated microglial marker CD68 and the astrocytic marker glial fibrillary acidic protein. NIR-treated HFD groups showed decreased levels of these markers. PCR revealed that hippocampal tissue from the HFD group had increased levels of pro-inflammatory interleukin (IL)-1β and tumor necrosis factor-α. Interestingly, the same samples showed increased levels of the anti-inflammatory IL-10. All these changes were attenuated by NIR treatment. Lastly, hippocampal levels of the neurotrophic factor BDNF were increased in NIR-treated HFD mice, compared to untreated HFD mice. The marked reductions in glial activation and pro-inflammatory cytokines along with elevated BDNF provide insights into how NIR could reduce neuroinflammation. These results support the use of NIR as a potential non-invasive and preventive therapeutic approach against chronic obesity-induced deficits that are known to occur with AD neuropathology.
... The scientific and clinical interest in such contexts has a broad evidence base, particularly in: dermatological pathology 17 , burns 18 , wound healing 15 , cancer-related lymphedema 19 and oral inflammatory conditions 20 . Following these successes, attention to the targeting of R/NIR light at deeper biological tissues has since increased in recent years 21-24 , including the central nervous system [25][26][27][28][29] . ...
Article
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Photobiomodulation (PBM) is a therapeutic modality which has gained increasing interest in neuroscience applications, including acute traumatic brain injury (TBI). Its proposed mechanisms for therapeutic effect when delivered to the injured brain include anti-apoptotic and anti-inflammatory effects. This systematic review summarises the available evidence for the value of PBM in improving outcomes in acute TBI and presents a meta-analysis of the pre-clinical evidence for neurological severity score (NSS) and lesion size in animal models of TBI. A systematic review of the literature was performed, with searches and data extraction performed independently in duplicate by two authors. Eighteen published articles were identified for inclusion: seventeen pre-clinical studies of in vivo animal models; and one clinical study in human patients. The available human study supports safety and feasibility of PBM in acute moderate TBI. For pre-clinical studies, meta-analysis for NSS and lesion size were found to favour intervention versus control. Sub-group analysis based on PBM parameter variables for these outcomes was performed. Favourable parameters were identified as: wavelengths in the region of 665 nm and 810 nm; time to first administration of PBM ≤ 4 hours; total number of daily treatments ≤3. No differences were identified between pulsed and continuous wave modes or energy delivery. Mechanistic sub-studies within included in vivo studies are presented and were found to support hypotheses of anti-apoptotic, anti-inflammatory and pro-proliferative effects, and a modulation of cellular metabolism. This systematic review provides substantial meta-analysis evidence of the benefits of PBM on functional and histological outcomes of TBI in in vivo mammalian models. Consideration of study design and PBM parameters should be closely considered for future human clinical studies.
... Access to this is achieved via burr holes in the skull and is undertaken in all cases meeting the minimum severity requirement [52] with or without the requirement for surgical intervention. Intracranial light delivery in in vivo Parkinsonian models has been shown successful previously [53][54][55], demonstrating feasibility. The development of this novel concept has resulted in a patent pending application from our group relating to the invasive delivery of PBM, together with the use of temporarily implanted apparatus to establish an optimal dose feedback loop via an optical spectroscopic brain interface (UK Patent Application No 2006201.4). ...
Article
Full-text available
Apoptotic cell death within the brain represents a significant contributing factor to impaired post-traumatic tissue function and poor clinical outcome after traumatic brain injury. After irradiation with light in the wavelength range of 600–1200 nm (photobiomodulation), previous investigations have reported a reduction in apoptosis in various tissues. This study investigates the effect of 660 nm photobiomodulation on organotypic slice cultured hippocampal tissue of rats, examining the effect on apoptotic cell loss. Tissue optical Raman spectroscopic changes were evaluated. A significantly higher proportion of apoptotic cells 62.8±12.2% vs 48.6±13.7% (P<0.0001) per region were observed in the control group compared with the photobiomodulation group. After photobiomodulation, Raman spectroscopic observations demonstrated 1440/1660 cm ⁻¹ spectral shift. Photobiomodulation has the potential for therapeutic utility, reducing cell loss to apoptosis in injured neurological tissue, as demonstrated in this in vitro model. A clear Raman spectroscopic signal was observed after apparent optimal irradiation, potentially integrable into therapeutic light delivery apparatus for real-time dose metering.
... 16,17 In addition to the direct effect on the target cells, PBM also has a systemic 15,[18][19][20] and a delayed effect, likely due to the activation of DNA transcription factors. 13,14 Treatment of areas remote from the site of injury can be an effective strategy in animal models, 20 including models of PD and Alzheimer's disease 18,[21][22][23][24] even when the head of the animal is shielded from irradiation. 25 The mechanism of this systemic effect may be stimulation of stem cells, 20,26 immunomodulation, 27 stimulation of circulating cell-free mitochondria, 28 modulating circulating chemical messengers, 21 or a combination of these. ...
Article
Objective: To assess whether remote application of photobiomodulation (PBM) is effective in reducing clinical signs of Parkinson's disease (PD). Background: PD is a progressive neurodegenerative disease for which there is no cure and few treatment options. There is a strong link between the microbiome-gut-brain axis and PD. PBM in animal models can reduce the signs of PD and protect the neurons from damage when applied directly to the head or to remote parts of the body. In a clinical study, PBM has been shown to improve clinical signs of PD for up to 1 year. Methods: Seven participants were treated with PBM to the abdomen and neck three times per week for 12 weeks. Participants were assessed for mobility, balance, cognition, fine motor skill, and sense of smell on enrolment, after 12 weeks of treatment in a clinic and after 33 weeks of home treatment. Results: A number of clinical signs of PD were shown to be improved by remote PBM treatment, including mobility, cognition, dynamic balance, spiral test, and sense of smell. Improvements were individual to the participant. Some improvements were lost for certain participants during at-home treatment, which coincided with a number of enforced coronavirus disease 2019 (COVID-19) pandemic lockdown periods. Conclusions: Remote application of PBM was shown to be an effective treatment for a number of clinical signs of PD, with some being maintained for 45 weeks, despite lockdown restrictions. Improvements in clinical signs were similar to those seen with the application of remote plus transcranial PBM treatment in a previous study. Clinical Trial Registration number: U1111-1205-2035.
... In terms of light penetration through the brain tissues of BALB/c mice, it has been reported that approximately 3% of 810 nm laser photons reach a depth in the brain of 5 mm, the distance from skull surface to substantia nigra compacta (SNc) region (Reinhart et al., 2017). Therefore, it could be presumed that in this study 0.25 J/cm 2 of NIR light reaches the brainstem, which is in the biostimulatory range for PBM therapy (Sharma et al., 2011;Moro et al., 2014). ...
Chapter
Salehpour et al. for PBM and CoQ10 Brain Ischemia During Aging and CoQ10 treatments. Collectively, the findings of this preclinical study imply that the procognitive effects of NIR PBM and CoQ10 treatments, separately or in combination, are beneficial in a model of transient global brain ischemia superimposed on a model of aging in mice.
... Recently, several studies have investigated the effects of tNIR light and PBM in treatment of PD using mice and monkey models [36][37][38]. Most commonly used diseasemodels were transgenic mice and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) compound induced Parkinson's model [39,40]. ...
Article
Full-text available
Dementia is a complex syndrome with various presentations depending on the underlying pathologies. Low emission of transcranial near-infrared (tNIR) light can reach human brain parenchyma and be beneficial to a number of neurological and neurodegenerative disorders. We hereby examined the safety and potential therapeutic benefits of tNIR light stimulations in the treatment of dementia. Patients of mild to moderate dementia were randomized into active and sham treatment groups at 2:1 ratio. Active treatment consisted of low power tNIR light stimulations with an active photobiomodulation for 6 min twice daily during 8 consequent weeks. Sham treatment consisted of same treatment routine with a sham device. Neuropsychological battery was obtained before and after treatment. Analysis of variance (ANOVA) was used to analyze outcomes. Sixty subjects were enrolled. Fifty-seven subjects completed the study and had not reported health or adverse side effects during or after the treatment. Three subjects dropped out from trial for health issues unrelated to use of tNIR light treatment. Treatment with active device resulted in improvements of cognitive functions and changes were: an average increase of MMSE by 4.8 points; Logical Memory Tests I and II by ~3.0 points; Trail Making Tests A and B by ~24%; Boston Naming Test by ~9%; improvement of both Auditory Verbal Learning Tests in all subtest categories and overall time of performance. Many patients reported improved sleep after ~7 days of treatment. Caregivers noted that patients had less anxiety, improved mood, energy, and positive daily routine after ~14-21 days of treatment. The tNIR light treatments demonstrated safety and positive cognitive improvements in patients with dementia. Developed treatment protocol can be conveniently used at home. This study suggests that additional dementia treatment trials are warranted with a focus on mitigating caregivers' burden with tNIR light treatment of dementia patients.
... To date over 30 in vitro and in vivo studies of PBM in PD models have explored variations on the theme (Hong, 2019;Salehpour and Hamblin, 2020). The most comprehensive and compelling research on the neuroprotective effect of PBM in PD has come from studies of transcranial and intracranial PBM in chemically-induced rodents Shaw et al., 2012;Moro et al., 2013Moro et al., , 2014Purushothuman et al., 2013;O'Callaghan et al., 2015;Reinhart et al., 2015Reinhart et al., , 2016aReinhart et al., 2017) and non-human primate PD models (Moro et al., 2016El Massri et al., 2017). Evidence suggests that PBM need not be directly applied to neurons, instead showing that non-invasive remote PBM treatment (i.e., to extremities or the abdomen) has a so-called "abscopal" neuroprotective effect (Johnstone et al., 2014;Kim et al., 2018), although the precise mechanisms are still uncertain. ...
Article
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The underlying pathophysiology of Parkinson's disease is complex, but mitochondrial dysfunction has an established and prominent role. This is supported by an already large and rapidly growing body of evidence showing that the role of mitochondrial (dys)function is central and multifaceted. However, there are clear gaps in knowledge, including the dilemma of explaining why inherited mitochondriopathies do not usually present with parkinsonian symptoms. Many aspects of mitochondrial function are potential therapeutic targets, including reactive oxygen species production, mitophagy, mitochondrial biogenesis, mitochondrial dynamics and trafficking, mitochondrial metal ion homeostasis, sirtuins, and endoplasmic reticulum links with mitochondria. Potential therapeutic strategies may also incorporate exercise, microRNAs, mitochondrial transplantation, stem cell therapies, and photobiomodulation. Despite multiple studies adopting numerous treatment strategies, clinical trials to date have generally failed to show benefit. To overcome this hurdle, more accurate biomarkers of mitochondrial dysfunction are required to detect subtle beneficial effects. Furthermore, selecting study participants early in the disease course, studying them for suitable durations, and stratifying them according to genetic and neuroimaging findings may increase the likelihood of successful clinical trials. Moreover, treatments involving combined approaches will likely better address the complexity of mitochondrial dysfunction in Parkinson's disease. Therefore, selecting the right patients, at the right time, and using targeted combination treatments, may offer the best chance for development of an effective novel therapy targeting mitochondrial dysfunction in Parkinson's disease.
... In addition, 810 nm PBM treatment improved the autonomous activities of MPTP-induced PD mice [34]. The delivery of light from a 670 nm LED or 670 nm laser by a surgically implanted intracranial optical fiber to the lateral ventricle of MPTP-treated mice was found to effectively preserve SNpc cells [35]. Mitrofanis' group further studied the effects of PBM on monkeys with PD induced by MPTP. ...
... Of interest to sports medicine are observations of improved collagen deposition in skeletal muscle [8], reduced oedema [9] and inflammatory infiltrates into tissues [8,10,11], improved bone density [12,13], the acceleration of recovery from tendinopathy [14], sprains [9], and peripheral nerve damage [15,16], and the reduction of pain [11,17]. PBM has also been shown to be neuroprotective without adverse effects [18], improve functional outcomes after stroke in rabbits [19] and spinal cord injury in rodents [10,11], as well as prevent dopaminergic cell loss in Parkinson's disease animal models [20]. Toward the end of 2018, PBM was featured as an innovative option to US Congress for addressing a domestic opioid-use epidemic. ...
Article
Individuals with spinal cord injury (SCI) often develop debilitating neuropathic pain, which may be driven by neuronal damage and neuroinflammation. We have previously demonstrated that treatment using 670 nm (red) light irradiation alters microglia/macrophage responses and alleviates mechanical hypersensitivity at 7-days post-injury. Here, we investigated the effect of red-light on the development of mechanical hypersensitivity, neuronal markers, and glial response in the subacute stage (days 1-7) following SCI. Wistar rats were subjected to a mild T10 hemi-contusion SCI or sham surgery followed by daily red-light treatment (30 min/day; 670 nm LED; 35 mW/cm2) or sham treatment. Mechanical sensitivity of the rat dorsum was assessed from 1-day post-injury and repeated every second day. Spinal cords were collected at 1, 3, 5 and 7-days post injury for analysis of myelination, neurofilament protein NF200 expression, neuronal cell death, reactive astrocytes (GFAP+ cells), interleukin1β (IL1β) expression, and inducible nitric oxide synthase (iNOS) production in IBA1+ microglia/macrophages. Red-light treatment significantly reduced the cumulative mechanical sensitivity and the hypersensitivity incidence following SCI. This effect was accompanied by significantly reduced neuronal cell death, reduced astrocyte activation and reduced iNOS expression in IBA1+ cells at the level of the injury. However, myelin and NF200 immunoreactivity and IL1β expression in GFAP+ and IBA1+ cells were not altered by red-light treatment. Thus, red-light therapy may represent a useful non-pharmacological approach for treating pain during the subacute period after SCI by decreasing neuronal loss and modulating the inflammatory glial response.
... Recently, several studies have investigated the effects of tNIR light and PBM in treatment of PD using mice and monkey models [36][37][38]. Most commonly used diseasemodels were transgenic mice and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) compound induced Parkinson's model [39,40]. ...
Article
Full-text available
ABSTRACT: Dementia is a complex syndrome with various presentations depending on the underlying pathologies. Low emission of transcranial near-infrared (tNIR) light can reach human brain parenchyma and be beneficial to a number of neurological and neurodegenerative disorders. We hereby examined the safety and potential therapeutic benefits of tNIR light stimulations in the treatment of dementia. Patients of mild to moderate dementia were randomized into active and sham treatment groups at 2:1 ratio. Active treatment consisted of low power tNIR light stimulations with an active photobiomodulation for 6 min twice daily during 8 consequent weeks. Sham treatment consisted of same treatment routine with a sham device. Neuropsychological battery was obtained before and after treatment. Analysis of variance (ANOVA) was used to analyze outcomes. Sixty subjects were enrolled. Fifty-seven subjects completed the study and had not reported health or adverse side effects during or after the treatment. Three subjects dropped out from trial for health issues unrelated to use of tNIR light treatment. Treatment with active device resulted in improvements of cognitive functions and changes were: an average increase of MMSE by 4.8 points; Logical Memory Tests I and II by ~3.0 points; Trail Making Tests A and B by ~24%; Boston Naming Test by ~9%; improvement of both Auditory Verbal Learning Tests in all subtest categories and overall time of performance. Many patients reported improved sleep after ~7 days of treatment. Caregivers noted that patients had less anxiety, improved mood, energy, and positive daily routine after ~14-21 days of treatment. The tNIR light treatments demonstrated safety and positive cognitive improvements in patients with dementia. Developed treatment protocol can be conveniently used at home. This study suggests that additional dementia treatment trials are warranted with a focus on mitigating caregivers’ burden with tNIR light treatment of dementia patients.
... Other risk factors are smoking, no physical activity, obesity, untreated diabetes, cholesterol, hypertension and emotional events. The cerebral scenario is characterized by altered cerebral metabolism, absence of cellular nutrient (oxygen and sugar), altered blood flow and altered ability of discard waste substances [41,42]. tPBM in Cerebral Vasculopathy induces increase of CCO concentration and oxygenated hemoglobin concentration allowing the damaged cerebral region to be sustained by the oxygen and nutrient supply. ...
Article
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Photobiomodulation is known to become a very important tool in treatment and support of neurological disease. The cellular processes involved during Red and Infrared Light Stimulation allows alleviating and improving cognitive and motor functions. The aim of this article is to highlight the use of NIR by Cerebro® in patients with neurological disease and to assess, as it is a pilot study, the perceived improvements in everyday life. 29 Italian patients underwent NIR stimulation therapy for 1-month and were tested before and after this stimulation period in order to assess whether there will be a difference in their perception of cognitive failures that occur in everyday life based on the Cognitive Self-Assessment Questionnaire. Although the sample is small, the data collected show that there is an improvement in the perceived quality of life in each pathological group taken into account. This allows us to carry on research in this field trying to understand and improve the role of NIR during physical and neurological rehabilitation.
... and compared the scans in subjects after active-and sham-light sessions. Previous studies have indicated that transcranially applied light can penetrate 20-30 mm through body tissues (Lapchak et al., 2004;Byrnes et al., 2005;Zivin et al., 2009;Haeussinger et al., 2011;Moro et al., 2014;Henderson and Morries, 2015), so light penetration through the cranium to the brain, at least to the superficial regions, is more than feasible (Hamblin, 2016). Our fMRI study here on the effects of transcranially applied light on brain activity in young normal subjects will lay the template for our planned explorations into the effects of light in both Alzheimer's and Parkinson's disease patients. ...
Article
We explore whether near infrared light can change patterns of resting (task-negative) and/or evoked (task-positive; eg finger-tapping) brain activity in normal, young human subjects using fMRI (functional magnetic resonance imaging). To this end, we used a vielight transcranial device (810nm) and compared the scans in subjects after active- and sham-light sessions. Our fMRI results showed that, while light had no effect on cerebral blood flow and global resting state brain activity (task-negative), there were clear differences between the active- and sham-light sessions in the patterns of evoked brain activity after finger-tapping (task-positive). The evoked brain regions included the putamen, primary somatosensory and parietal association cortex, and the overall effect of the light was to suppress or reduce their activity. We also found that while light had no effect on the resting functional connectivity of the putamen and primary somatosensory cortex and the rest of the brain, it did have an effect on the functional connectivity of parietal association cortex. In summary, our fMRI findings indicated that transcranially applied light did have a major impact on brain activity in normal subjects, but only when the brain region was itself functionally active, when undertaking a particular task. We suggest that these light-induced changes, particularly those in parietal association cortex, were associated with attention and novelty, and served to deactivate the so-called default mode network. Our results lay the template for our planned fMRI explorations into the effects of light in both Alzheimer's and Parkinson's disease patients.
... PBM therapy applies light at lower power and energy densities (total irradiance of ,700 mW/cm 2 and fluencies of 0.04À120 J/cm 2 at scalp surface) as compared to other forms of light application in medicine that are used for ablation, cutting, and thermally coagulating tissue (Chung et al., 2012). In order to improve cerebral function, many light delivering approaches have been used in the literature, including transcranial (Rojas and Gonzalez-Lima, 2013), intracranial (Moro et al., 2014), and intranasal irradiation methods (Saltmarche et al., 2017). Brain PBM therapy using transcranial irradiation method is a new approach in specialized settings (Salehpour et al., 2018b). ...
... Of interest to sports medicine are observations of improved collagen deposition in skeletal muscle [8], reduced oedema [9] and inflammatory infiltrates into tissues [8,10,11], improved bone density [12,13], the acceleration of recovery from tendinopathy [14], sprains [9], and peripheral nerve damage [15,16], and the reduction of pain [11,17]. PBM has also been shown to be neuroprotective without adverse effects [18], improve functional outcomes after stroke in rabbits [19] and spinal cord injury in rodents [10,11], as well as prevent dopaminergic cell loss in Parkinson's disease animal models [20]. Toward the end of 2018, PBM was featured as an innovative option to US Congress for addressing a domestic opioid-use epidemic. ...
Article
Red‐light treatment is emerging as a novel therapy for promoting tissue recovery but data on red‐light penetration through human tissues are lacking. We aimed to: i) determine the effect of light irradiance, tissue thickness, skin tone, sex, and bone/muscle content on 660 nm light penetration through common sites of sports injuries, and ii) establish if cadaver tissues serve as a useful model for predicting red‐light penetration in live tissues. Live and cadaver human tissues were exposed to 660 nm light at locations across the skull, spinal cord and upper and lower limbs. Red‐light was produced by a light emitting diode array of various irradiances (15‐500 mW/cm²) and measured by a light‐probe positioned on the tissue surface opposite the LEDs. 100 mW/cm² successfully penetrated tissue < 50 mm thick; a disproportionate irradiance increase was required to achieve deeper penetration. Penetration was unaffected by skin tone, increased with irradiance and relative bone/muscle composition, and decreased with greater tissue thickness and in males. Live and cadaveric tissue penetration did not differ statistically for tissues < 50 mm but cadavers required more red‐light to penetrate > 50 mm. These results assist clinicians and researchers in determining red‐light treatment intensities for penetrating human tissues. This article is protected by copyright. All rights reserved.
... In terms of light penetration through the brain tissues of BALB/c mice, it has been reported that approximately 3% of 810 nm laser photons reach a depth in the brain of 5 mm, the distance from skull surface to substantia nigra compacta (SNc) region (Reinhart et al., 2017). Therefore, it could be presumed that in this study 0.25 J/cm 2 of NIR light reaches the brainstem, which is in the biostimulatory range for PBM therapy (Sharma et al., 2011;Moro et al., 2014). ...
Article
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Disturbances in mitochondrial biogenesis and bioenergetics, combined with neuroinflammation, play cardinal roles in the cognitive impairment during aging that is further exacerbated by transient cerebral ischemia. Both near-infrared (NIR) photobiomodulation (PBM) and Coenzyme Q10 (CoQ10), administration are known to stimulate mitochondrial electron transport that potentially may reverse the effects of cerebral ischemia in aged animals. We tested the hypothesis that the effects of PBM and CoQ10, separately or in combination improve cognition in a mouse model of transient cerebral ischemia superimposed on a model of aging. We modeled aging by 6-week administration of D-galactose (500 mg/kg/subcutaneous) to mice. We subsequently, induced transient cerebral ischemia by bilateral occlusion of the common carotid artery (BCCAO). We treated the mice with PBM (810 nm transcranial laser) or CoQ10 (500 mg/kg; by gavage), or both, for two weeks after surgery. We assessed cognitive function by the Barnes and Lashley III mazes and the What-Where-Which (WWWhich) task. PBM or CoQ10, or both, improved spatial and episodic memory in the mice. Separately and together, the treatments lowered reactive oxygen species, and raised ATP and general mitochondrial activity, as well as biomarkers of mitochondrial biogenesis, including SIRT1, PGC-1α, NRF1, and TFAM. Neuroinflammatory responsiveness declined, as indicated by decreased iNOS, TNF-α, and IL-1β levels with the PBM and CoQ10 treatments. Collectively, the findings of this preclinical study imply that the procognitive effects of NIR PBM and CoQ10 treatments, separately or in combination, are beneficial in a model of transient global brain ischemia superimposed on a model of aging in mice.
... Based on the results of the experiment, an approximate value of 10% was measured as laser transmittance through a 1 mm slice of aged brain, corresponding to a light fluence of approximately 1.6 J/cm 2 reaching 1 mm deep from the cortical surface. Data from other studies using BALB/c mouse brain have revealed a 65% reduction of 670 nm LED light intensity across each millimeter of cerebral tissue 21 . It has also been shown that approximately 2.5% of 670 nm LED light reaches a depth in the brain tissue of 5 mm, the distance from the skull surface to the substantia nigra compacta (SNc) area 22 . ...
Article
Transcranial photobiomodulation is a potential innovative noninvasive therapeutic approach for improving brain bioenergetics, brain function in a wide range of neurological and psychiatric disorders, and memory enhancement in age-related cognitive decline and neurodegenerative diseases. We describe a laboratory protocol for transcranial photobiomodulation therapy (PBMT) in mice. Aged BALB/c mice (18 months old) are treated with a 660 nm laser transcranially, once daily for 2 weeks. Laser transmittance data shows that approximately 1% of the incident red light on the scalp reaches a 1 mm depth from the cortical surface, penetrating the dorsal hippocampus. Treatment outcomes are assessed by two methods: a Barnes maze test, which is a hippocampus-dependent spatial learning and memory task evaluation, and measuring hippocampal ATP levels, which is used as a bioenergetics index. The results from the Barnes task show an enhancement of the spatial memory in laser-treated aged mice when compared with age-matched controls. Biochemical analysis after laser treatment indicates increased hippocampal ATP levels. We postulate that the enhancement of memory performance is potentially due to an improvement in hippocampal energy metabolism induced by the red laser treatment. The observations in mice could be extended to other animal models since this protocol could potentially be adapted to other species frequently used in translational neuroscience, such as rabbit, cat, dog, or monkey. Transcranial photobiomodulation is a safe and cost-effective modality which may be a promising therapeutic approach in age-related cognitive impairment.
... Hanczyc et al. (2012) suggested that heightened multi-photon absorption is the outcome of a mechanism comprising dipolar through-space pairing between excited states of aromatic amino acids compacted in fibrous assemblies. Moro et al. (2014), using mouse models, investigated the neuroprotection offered by PBM. Mice were treated with PBM 20 times over four weeks and histochemistry-quantified Alzheimer's disease (AD)-related pathological markers were examined in the neocortex and hippocampus. ...
Article
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Research into photobiomodulation reveals beneficial effects of light therapy for a rapidly expanding list of medical conditions and illnesses. Although it has become more widely accepted by the mainstream medicine, the effects and mechanisms of action appear to be poorly understood. The therapeutic benefits of photobiomodulation using low-energy red lasers extend far beyond superficial applications, with a well-described physics allowing an understanding of how red lasers of certain optimum intensities may cross the cranium. We now have a model for explaining potential therapeusis for applications in functional neurology that include stroke, traumatic brain injury, and neurodegenerative conditions in addition to the currently approved functions in lipolysis, in onychomycosis treatment, and in pain management.
... The search for new neuroprotective avenues continues. Emerging neuroprotective therapies, such as near infrared photobiomodulation [142][143][144], are passing the preclinical stage, leading to upcoming clinical trials. ...
Article
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Abstract Although there have been many pharmacological agents considered to be neuroprotective therapy in Parkinson’s disease (PD) patients, neurosurgical approaches aimed to neuroprotect or restore the degenerative nigrostriatal system have rarely been the focus of in depth reviews. Here, we explore the neuroprotective strategies involving invasive surgical approaches (NSI) using neurotoxic models 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), which have led to clinical trials. We focus on several NSI approaches, namely deep brain stimulation of the subthalamic nucleus, glial neurotrophic derived factor (GDNF) administration and cell grafting methods. Although most of these interventions have produced positive results in preclinical animal models, either from behavioral or histological studies, they have generally failed to pass randomized clinical trials to validate each approach. We argue that NSI are promising approaches for neurorestoration in PD, but preclinical studies should be planned carefully in order not only to detect benefits but also to detect potential adverse effects. Further, clinical trials should be designed to be able to detect and disentangle neuroprotection from symptomatic effects. In summary, our review study evaluates the pertinence of preclinical models to study NSI for PD and how this affects their efficacy when translated into clinical trials. View Full-Text Keywords: neuroprotection; Parkinson disease; surgery; cell grafts; glial neurotrophic derived factor; deep brain stimulation
... Data from mice showed that 2.5 and 3 % of light with corresponding wavelengths of 670 and 810 nm, respectively, could reach a depth in the brain of 5 mm (Reinhart et al., 2017). Based on this, it could be assumed that in our study ~0.25 J/cm 2 of red or NIR lights (at cortical fluence of 8 J/cm 2 ) reach brainstem which is somewhat in the biostimulatory range for LLLT (Moro et al., 2014;Sharma et al., 2011). In the human cases, using high-power laser device, 2.9% of 810 nm light reach 30 mm depth of brain tissue (Henderson and Morries, 2015). ...
Article
Mitochondrial function plays a key role in the aging-related cognitive impairment and photoneuromodulation of mitochondria by transcranial low-level laser therapy (LLLT) may contribute to its improvement. This study focused on transcranial LLLT effects on the D-galactose (DG) induced mitochondrial dysfunction, apoptosis and cognitive impairment in mice. For this purpose, red and near-infrared (NIR) laser wavelengths (660 and 810 nm) at two different fluencies (4 and 8 J/cm²) at 10-Hz pulsed wave mode were administrated transcranially 3 days/week in DG-received (500 mg/kg/subcutaneous) mice model of aging for six weeks. Spatial and episodic-like memories were assessed by the Barnes maze and What-Where-Which (WWWhich) tasks. Brain tissues were analyzed for mitochondrial function including active mitochondria, ATP and reactive oxygen species levels, as well as membrane potential and cytochrome c oxidase activity. Apoptosis-related biomarkers, namely, Bax, Bcl-2, and caspase3 were evaluated by western blotting method. Laser treatments at wavelengths of 660 and 810 nm at 8 J/cm² attenuated DG-impaired spatial and episodic-like memories. Also, results showed an obvious improvement in the mitochondrial function aspects and modulatory effects on apoptotic markers in aged mice. However, same wavelengths at the fluency of 4 J/cm² had poor effect on the behavioral and molecular indexes in aging model. This data indicates that transcranial LLLT at both of red and NIR wavelengths at the fluency of 8 J/cm² has a potential to ameliorate aging-induced mitochondrial dysfunction, apoptosis, and cognitive impairment.
Article
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Photobiomodulation, also known as low-level light therapy, has gained popularity in treating a variety of dermatologic and non-dermatologic conditions. The near-infrared (NIR) portion ranging from 700 to 1440 nm has a broad spectrum but most current research focuses on relatively shorter wavelengths. To date, clinical research regarding the application of 1072 NIR is limited to treatments for infections and photorejuvenation treatment in females. However, 1072 NIR light therapy may benefit male patients. This theoretical application is based on the biological properties of this subgroup having increased cutaneous density and thickness and the physical properties of 1072 NIR allowing it to penetrate increased depth. 1072 NIR can reach more cells throughout the epidermis and dermis compared to other parts of the electromagnetic spectrum traditionally used in phototherapy to provide unique and targeted benefits. 1072 NIR light-emitting diodes are commercially available and therefore hold tremendous potential to become accessible, affordable treatment options. Given the increased demand and market size for aesthetics for men that remains untapped, there is opportunity for future research to elucidate the potential for this wavelength as a safe and effective treatment.
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Parkinson's disease (PD) is a neurodegenerative disease with global burden. The mechanisms and therapeutic effects of photobiomodulation (PBM) correspond to main mechanisms in the pathogenesis of PD. Numerous research results applying PBM for PD were published during the past two decades. Although several systematic review or review articles provided complete introduction, they are either mainly basic research or clinical research, and the year of the article publication is up to 2020. Comprehensive systematic review or review articles containing basic and clinical studies including those articles published in 2021 and 2022 are lacking. Hence, this systematic review aimed to include both basic and clinical studies published up to 2022. Results were obtained by retrieving articles from PubMed with the intersection of the articles derived from the terms of PBM synonyms and Parkinson's disease followed by exclusion. Sixty-nine articles were included ultimately. Among them, 40 original articles were identified, which were composed of 31 basic research and 9 original articles of clinical research. Twenty-one review articles, a systematic review with focused content on PD, and 7 review articles with the term PD under general illustration of PBM were presented. Mechanisms regarding the therapeutic effects of PBM on the in vitro studies were reviewed. Positive outcomes on motor symptoms after PBM treatments were shown in most in vivo and clinical studies. The immunohistochemical examination of in vivo studies reflect the therapeutic effects of PBM on the preservation even reverse of the pathogenic insults of PD on the in vitro studies. The most frequently used wavelength among original articles included was 670nm. Considering the acceptability of PBM for patients with PD, noninvasive transcranial PBM (tPBM) had crucial roles in respect to invasive intracerebral PBM. To match the penetration depth reaching deep brain target, Substantia nigra pars compacta, in human brains of patients with PD, the wavelength 810nm might match the need in the clinical setting of tPBM. More future clinical studies were needed. In conclusion, therapeutic approaches applying PBM for PD are promising. Recent studies revealed positive outcomes. Future clinical practices containing PBM are to be expected.
Article
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Over the last seventy years or so, many previous studies have shown that photobiomodulation, the use of red to near infrared light on body tissues, can improve central and peripheral neuronal function and survival in both health and in disease. These improvements are thought to arise principally from an impact of photobiomodulation on mitochondrial and non-mitochondrial mechanisms in a range of different cell types, including neurones. This impact has downstream effects on many stimulatory and protective genes. An often-neglected feature of nearly all of these improvements is that they have been induced during the state of wakefulness. Recent studies have shown that when applied during the state of sleep, photobiomodulation can also be of benefit, but in a different way, by improving the flow of cerebrospinal fluid and the clearance of toxic waste-products from the brain. In this review, we consider the potential differential effects of photobiomodulation dependent on the state of arousal. We speculate that the effects of photobiomodulation is on different cells and systems depending on whether it is applied during wakefulness or sleep, that it may follow a circadian rhythm. We speculate further that the arousal-dependent photobiomodulation effects are mediated principally through a biophoton – ultra-weak light emission – network of communication and repair across the brain.
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Photobiomodulation (PBM) has received attention due to its potential for improving tissue function and enhancing regeneration in stroke. A lightweight, compact, and simple system of miniaturized electronic devices consisting of packaged light‐emitting diodes (LEDs) that incorporates a flexible substrate for in vivo brain PBM in a mouse model is developed. Using this device platform, the preventive and therapeutic effects of PBM affixed to the exposed skull of mice in the photothrombosis and middle cerebral artery occlusion stroke model are evaluated. Among the wavelength range of 630, 850, and 940 nm LED array, the PBM with 630‐nm LED array is proved to be the most effective for reducing the infarction volume and neurological impairment after ischemic stroke. Moreover, the PBM with 630 nm LED array remarkably improves the capability of spatial learning and memory in the chronic poststroke phase, attenuates AIM2 inflammasome activation and inflammasome‐mediated pyroptosis, and modulates microglial polarization in the hippocampus and cortex 7 days following ischemic stroke. Thus, PBM may prevent tissue and functional damage in acute ischemic injury, thereby attenuating the development of cognitive impairment after stroke.
Article
Photobiomodulation using light in the red or near-infrared region is an innovative treatment strategy for a wide range of neurological and psychological conditions. Photobiomodulation can promote neurogenesis and elicit anti-apoptotic, anti-inflammatory and antioxidative responses. Its therapeutic effects have been demonstrated in studies on neurological diseases, peripheral nerve injuries, pain relief and wound healing. We conducted a comprehensive literature review of the application of photobiomodulation in patients with central nervous system diseases in February 2019. The NCBI PubMed database, EMBASE database, Cochrane Library and ScienceDirect database were searched. We reviewed 95 papers and analyzed. Photobiomodulation has wide applicability in the treatment of stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, major depressive disorder, and other diseases. Our analysis provides preliminary evidence that PBM is an effective therapeutic tool for the treatment of central nervous system diseases. However, additional studies with adequate sample size are needed to optimize treatment parameters.
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Photobiomodulation (PBM) takes advantage of red and near‐infrared light to induce therapeutic effects on various kinds of diseases, with transcranial PBM (tPBM) attracting most attention on neurological diseases. Displaying a noninvasive superiority over traditional treatment, tPBM is increasingly studied among research groups. Growing numbers of studies have been conducted in the last decade regarding neurological diseases; however, the research objects and lighting parameters among these papers varied from each other. This article introduces the biophotonics nature of PBM, detailly records the experimental parameters of preclinical studies since 2014 and summarizes the application of transcranial PBM on the neurobiological diseases in the past two decades. Under the summarized guidance of parameter setup, tPBM will be shining light in the prevention and treatment of neurological diseases.
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Given the increasing incidence of neurodegenerative disease (ND), recent research efforts have intensified the search for curative treatments. Despite significant research, however, existing therapeutic options for ND can only slow down the progression of the disease, but not provide a cure. Light therapy (LT) has been used to treat some mental and sleep disorders. This review illustrates recent studies of the use of LT in patients with ND and highlights its potential for clinical applications. The literature was collected from PubMed through June 2020. Selected studies were primarily English articles or articles that could be obtained with English abstracts and Chinese main text. Articles were not limited by type. Additional potential publications were also identified from the bibliographies of identified articles and the authors' reference libraries. The identified literature suggests that LT is a safe and convenient physical method of treatment. It may alleviate sleep disorders, depression, cognitive function, and other clinical symptoms. However, some studies have reported limited or no effects. Therefore, LT represents an attractive therapeutic approach for further investigation in ND. LT is an effective physical form of therapy and a new direction for research into treatments for ND. However, it requires further animal experiments to elucidate mechanisms of action and large, double-blind, randomized, and controlled trials to explore true efficacy in patients with ND.
Article
Background and Objectives Light delivery is an essential part of therapy forms like photodynamic therapy (PDT), laser‐induced thermotherapy, and endovenous laser therapy. While there are approaches to the light application for all three therapies, there is no diffuser that can be used for all three approaches. This diffuser must meet the following criteria: Homogeneous radiation profile over a length of 40 mm, efficient light extraction in the diffuser area, mechanical breakage resistance as well as thermal stability when applying high power. Study Design/Materials and Methods An ultrashort pulse laser was used to inscribe inhomogeneities into the core of a fused‐silica fiber core while scanning the laser focus within a linear arrangement of cuboids centered around the fiber axis. The manufactured diffuser was optically and mechanically characterized and examined to determine the maximum power that can be applied in a tissue environment. Results Based on the analysis of all examined diffusers, the manufactured diffuser exhibits an emission efficiency ε = (81.5 ± 5.9)%, an intensity variability of (19 ± 5)% between distal and proximal diffuser end, and a minimum bending radius Rb = (15.4 ± 1.5) mm. It was taken advantage of the fact that the outer areas of the fiber core do not undergo any structural changes due to the machining and therefore do not suffer a major loss of stability. Tissue experiments revealed that a maximal power of 15 W was deliverable from the diffuser without harming the diffuser itself. Conclusions It could be shown that a diffuser manufactured by ultrafast‐laser processing can be used for low power applications as well as for high power applications. Further tests have to show whether the mechanical stability is still maintained after the application of high power in a tissue environment. Lasers Surg. Med. © 2020 Wiley Periodicals LLC
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Infrared neuromodulation (INM) is a branch of photobiomodulation that offers direct or indirect control of cellular activity through elevation of temperature in a spatially confined region of the target tissue. Research on INM started about 15 ago and is gradually attracting the attention of the neuroscience community, as numerous experimental studies have provided firm evidence on the safe and reproducible excitation and inhibition of neuronal firing in both in vitro and in vivo conditions. However, its biophysical mechanism is not fully understood and several engineered interfaces have been created to investigate infrared stimulation in both the peripheral and central nervous system. In this review, recent applications and present knowledge on the effects of INM on cellular activity are summarized, and an overview of the technical approaches to deliver infrared light to cells and to interrogate the optically evoked response is provided. The micro- and nanoengineered interfaces used to investigate the influence of INM are described in detail.
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The tissue-protective properties of photobiomodulation (PBM) (low-intensity red to near-infrared light therapy) have been demonstrated for a number of diseases and injuries, including those of the central nervous system. By modifying mitochondrial function and stimulating a mild adaptive stress response, PBM appears to enhance cellular and tissue resilience against existing or subsequent insults, providing significant neuroprotection to vulnerable neurons. There is considerable evidence that transcranial PBM mitigates the loss of dopaminergic cells and functional deficits in small animal models of Parkinson's disease (PD). However, the absorption of light by the scalp, skull, and cerebral cortex makes the translation of this therapy to human patients difficult. Creative approaches to irradiating the deep brain stem structures affected in PD, by delivering light intracranially or intranasally, have been trialed to overcome this barrier to clinical translation. Perhaps most remarkable and promising are demonstrations that the beneficial effects of PBM are not confined to the tissue irradiated; and that irradiation of a peripheral, easily accessed tissue can induce resilience in all tissues of the body, including the PD-critical midbrain. This chapter reviews the evidence of PBM-induced neuroprotection in the context of PD and the challenges that remain in translating PBM into a viable intervention for PD patients.
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Photobiomodulation (PBM) is a rapidly growing as an innovative therapeutic modality for various types of diseases in recent years. Neuronal degeneration is irreversible process and it is proven to be difficult to slow down or stop the progression. Pharmacologic approaches to slow neuronal degeneration have been studied, but are limited due to concerns about the side effects. Therefore, it is necessary to develop a new therapeutic approach to stabilize neuronal degeneration and achieve neuronal protection against several neurodegenerative diseases. In this review, we have introduced several previous studies showing the positive effect of PBM over neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and different types of epilepsy. Despite excellent outcomes of animal researches, not many clinical studies are conducted or showed positive outcome of PBM against neurodegenerative disease. To achieve clinical application of PBM against neurodegenerative disorder, determination of exact mechanism and establishment of effective clinical protocol seems to be necessary.
Article
Aim Cell‐based transplantation is an alternate method of liver transplantation to delay the on‐set of end‐stage liver diseases. For successful treatment, cells need to be expended in vitro expeditiously. However, autogenetic hepatocytes as the ideal cell source for therapy remain quiescence so proliferation is rare. While photobiomodulation therapy (PBT) has been used to stimulate some kinds of cell proliferation, it is unknown if red light emitting diodes (LED) irradiation can promote primary hepatocyte proliferation. The aim of this study was to evaluate the effect of red LED irradiation on hepatocytes in vitro. Materials and Methods Mouse primary hepatocytes were isolated and received red LED treatment. The cell viability, reactive oxygen species (ROS) levels, phosphorylated extracellular signal‐regulated kinase1/2 (pERK1/2) and some cell cycle‐related proteins were observed. Additionally, ROS inhibition and pERK1/2 inhibition were performed to determine the effect of ROS and ERK1/2 in red LED irradiation. Results The red LED irradiation increased hepatocyte proliferation, elevated intracellular ROS levels and stimulated ERK1/2 activation and cell cycle‐related genes expression. The mitosis promoting the effect of red LED irradiation could be disturbed by ROS or pERK inhibition. The red LED irradiation promoted hepatocyte proliferation through the ROS/pERK1/2 pathway. Conclusions Red LED irradiation could accelerate hepatocyte proliferation through the ROS/pERK1/2 pathway. Red LED irradiation might be a potential method to expand hepatocyte in vitro and support cell‐based transplantation in clinical work.
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In this study, we explored the effects of a longer term application, up to 12 weeks, of photobiomodulation in normal, naïve macaque monkeys. Monkeys (n = 5) were implanted intracranially with an optical fibre device delivering photobiomodulation (red light, 670 nm) to a midline midbrain region. Animals were then aldehyde-fixed and their brains were processed for immunohistochemistry. In general, our results showed that longer term intracranial application of photobiomodulation had no adverse effects on the surrounding brain parenchyma or on the nearby dopaminergic cell system. We found no evidence for photobiomodulation generating an inflammatory glial response or neuronal degeneration near the implant site; further, photobiomodulation did not induce an abnormal activation or mitochondrial stress in nearby cells, nor did it cause an abnormal arrangement of the surrounding vasculature (endothelial basement membrane). Finally, because of our interest in Parkinson’s disease, we noted that photobiomodulation had no impact on the number of midbrain dopaminergic cells and the density of their terminations in the striatum. In summary, we found no histological basis for any major biosafety concerns associated with photobiomodulation delivered by our intracranial approach and our findings set a key template for progress onto clinical trial on patients with Parkinson’s disease.
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Deep brain stimulation (DBS) is a well-established treatment modality for patients with Parkinson’s disease (PD), especially in those with motor complications such as fluctuations and dyskinesias. There is good long-term evidence confirming the efficacy of DBS in improving motor symptoms and quality of life in advanced PD. A recent study has additionally confirmed significant benefit where DBS is utilised earlier in the course of PD. In carefully selected patients, improvements in non-motor symptoms are also seen. The key challenge with DBS, therefore, remains the careful selection of suitable patients, facilitated by multidisciplinary assessment. In this chapter, we provide an overview of the DBS procedure focusing on the technical aspects and complications associated with it. A succinct overview of the various targets and pertinent literature on the impact of DBS on motor and non-motor symptoms in PD patients is presented. Finally, possible future directions involving the use of stem cell therapy, optogenetics and near-infrared light therapy are highlighted.
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The use of low levels of visible or near infrared light for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing tissue damage has been known for almost forty years since the invention of lasers. Originally thought to be a peculiar property of laser light (soft or cold lasers), the subject has now broadened to include photobiomodulation and photobiostimulation using non-coherent light. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial. This likely is due to two main reasons; firstly the biochemical mechanisms underlying the positive effects are incompletely understood, and secondly the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. In particular a biphasic dose response has been frequently observed where low levels of light have a much better effect than higher levels. This introductory review will cover some of the proposed cellular chromophores responsible for the effect of visible light on mammalian cells, including cytochrome c oxidase (with absorption peaks in the near infrared) and photoactive porphyrins. Mitochondria are thought to be a likely site for the initial effects of light, leading to increased ATP production, modulation of reactive oxygen species and induction of transcription factors. These effects in turn lead to increased cell proliferation and migration (particularly by fibroblasts), modulation in levels of cytokines, growth factors and inflammatory mediators, and increased tissue oxygenation. The results of these biochemical and cellular changes in animals and patients include such benefits as increased healing in chronic wounds, improvements in sports injuries and carpal tunnel syndrome, pain reduction in arthritis and neuropathies, and amelioration of damage after heart attacks, stroke, nerve injury and retinal toxicity.
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A puzzling feature of reports of near infrared light (NIr) treatment of soft tissue wounds is the lack of laterality in the tissue response - it is typically bilateral after a unilateral exposure. This has led to the idea that NIr has an ‘indirect’ effect on non-irradiated tissues, mediated by circulating ‘factors’. We have recently reported that NIr protects midbrain dopaminergic cells of mice from parkinsonian insult. In those studies, NIr was directed to the head, on the assumption that it would penetrate the skull and brain to reach the midbrain; in practice the whole dorsum of the mouse was irradiated. In this study, we applied NIr to the body only, preventing the radiation reaching the head with a ‘helmet’ of aluminium foil. NIr radiation of the body only was effective in protecting these cells, although less protective than radiation of both body and head. The results suggest that the neuroprotective effect of NIr may be mediated at least partially by a systemic or indirect effect. The possibility of immune system involvement will be discussed.
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Background We have shown previously that near-infrared light (NIr) treatment or photobiomodulation neuroprotects dopaminergic cells in substantia nigra pars compacta (SNc) from degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Balb/c albino mice, a well-known model for Parkinson’s disease. The present study explores whether NIr treatment offers neuroprotection to these cells in C57BL/6 pigmented mice. In addition, we examine whether NIr influences behavioural activity in both strains after MPTP treatment. We tested for various locomotive parameters in an open-field test, namely velocity, high mobility and immobility. Results Balb/c (albino) and C57BL/6 (pigmented) mice received injections of MPTP (total of 50 mg/kg) or saline and NIr treatments (or not) over 48 hours. After each injection and/or NIr treatment, the locomotor activity of the mice was tested. After six days survival, brains were processed for TH (tyrosine hydroxylase) immunochemistry and the number of TH+ cells in the substantia nigra pars compacta (SNc) was estimated using stereology. Results showed higher numbers of TH+ cells in the MPTP-NIr groups of both strains, compared to the MPTP groups, with the protection greater in the Balb/c mice (30% vs 20%). The behavioural tests revealed strain differences also. For Balb/c mice, the MPTP-NIr group showed greater preservation of locomotor activity than the MPTP group. Behavioural preservation was less evident in the C57BL/6 strain however, with little effect of NIr being recorded in the MPTP-treated cases of this strain. Finally, there were differences between the two strains in terms of NIr penetration across the skin and fur. Our measurements indicated that NIr penetration was considerably less in the pigmented C57BL/6, compared to the albino Balb/c mice. Conclusions In summary, our results revealed the neuroprotective benefits of NIr treatment after parkinsonian insult at both cellular and behavioural levels and suggest that Balb/c strain, due to greater penetration of NIr through skin and fur, provides a clearer model of protection than the C57BL/6 strain.
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This is the first controlled study demonstrating the beneficial effects of transcranial laser stimulation on cognitive and emotional functions in humans. Photobiomodulation with red to near-infrared light is a novel intervention shown to regulate neuronal function in cell cultures, animal models, and clinical conditions. Light that intersects with the absorption spectrum of cytochrome oxidase was applied to the forehead of healthy volunteers using the laser diode CG-5000, which maximizes tissue penetration and has been used in humans for other indications. We tested whether low-level laser stimulation produces beneficial effects on frontal cortex measures of attention, memory and mood. Reaction time in a sustained-attention psychomotor vigilance task (PVT) was significantly improved in the treated (n = 20) vs. placebo control (n = 20) groups, especially in high novelty-seeking subjects. Performance in a delayed match-to-sample (DMS) memory task showed also a significant improvement in treated vs. control groups as measured by memory retrieval latency and number of correct trials. The Positive and Negative Affect Schedule (PANAS-X), which tracks self-reported positive and negative affective (emotional) states over time, was administered immediately before treatment and two weeks after treatment. The PANAS showed that while participants generally reported more positive affective states than negative, overall affect improved significantly in the treated group due to more sustained positive emotional states as compared to the placebo control group. These data imply that transcranial laser stimulation could be used as a non-invasive and efficacious approach to increase brain functions such as those related to cognitive and emotional dimensions. Transcranial infrared laser stimulation has also been proven to be safe and successful at improving neurological outcome in humans in controlled clinical trials of stroke. This innovative approach could lead to the development of non-invasive, performance-enhancing interventions in healthy humans and in those in need of neuropsychological rehabilitation.
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Low level light therapy has garnered significant interest within the past decade. The exact molecular mechanisms of how red and near infrared light result in physiologic modulation are not fully understood. Heme moieties and copper within cells are red and near infrared light photoreceptors that induce the mitochondrial respiratory chain component cytochrome C oxidase, resulting in a cascade linked to cytoprotection and cellular metabolism. The copper centers in cytochrome C oxidase have a broad absorption range that peaks around 830 nm. Several in vitro and in vivo animal and human models exist that have demonstrated the benefits of red light and near infrared light for various conditions. Clinical applications for low level light therapy are varied. One study in particular demonstrated improved durable functional outcomes status post-stroke in patients treated with near infrared low level light therapy compared to sham treatment [1]. Despite previous data suggesting the beneficial effect in treating multiple conditions, including stroke, with low level light therapy, limited data exists that measures transmission in a human model. To investigate this idea, we measured the transmission of near infrared light energy, using red light for purposes of comparison, through intact cadaver soft tissue, skull bones, and brain using a commercially available LED device at 830 nm and 633 nm. Our results demonstrate that near infrared measurably penetrates soft tissue, bone and brain parenchyma in the formalin preserved cadaveric model, in comparison to negligible red light transmission in the same conditions. These findings indicate that near infrared light can penetrate formalin fixed soft tissue, bone and brain and implicate that benefits observed in clinical studies are potentially related to direct action of near infrared light on neural tissue.
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We have shown previously that near-infrared light (NIr) treatment or photobiomodulation neuroprotects dopaminergic cells in substantia nigra pars compacta (SNc) from degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. The present study explores whether NIr treatment changes the patterns of Fos expression in the subthalamic region, namely, the subthalamic nucleus (STN) and zona incerta (ZI); both cell groups have abnormally overactive cells in parkinsonian cases. BALB/c mice were treated with MPTP (100-250 mg/kg) or saline either over 30 hours followed by either a two-hour or six-day survival period (acute model) or over five weeks followed by a three-week survival period (chronic model). NIr and MPTP were applied simultaneously. Brains were processed for Fos immunochemistry, and cell number was estimated using stereology. Our major finding was that NIr treatment reduced (30-45%) the increase in Fos(+) cell number evident in the STN and ZI after MPTP insult. This reduction was concurrent with the neuroprotection of dopaminergic SNc cells shown previously and was evident in both MPTP models (except for the 2 hours survival period which showed no changes in cell number). In summary, our results indicated that NIr had long lasting effects on the activity of cells located deep in the brain and had repaired partially the abnormal activity generated by the parkinsonian toxin.
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Objective: The authors proposed an intraventricular 'floating' electrode inserted in the third ventricle (V3) adjacent to the ventromedian hypothalamus (VMH) in a freely moving Macaca fascicularis to modulate food intake (FI), body fat (BF), body weight (BW) and body mass index (BMI), as a potential treatment of obesity. Methods: Five adult Macaca fascicularis monkeys were implanted stereotactically in the V3 contiguous to the VMH with one deep brain stimulation (DBS) electrode. The study was divided in two phases: (a) acute 24 h-fasting trials: different electrical stimulation parameters were applied to a fasting primate to determine the best combination in reducing FI; and (b) chronic 8-week stimulation trials: three cycles of intraventricular-VMH DBS lasting 8-10 weeks were performed at 130 Hz, 80 Hz (most effective frequency reducing FI) and 30 Hz, respectively. BMI, BW, BF content, skinfolds and hormones were measured during baseline and at the end of each session of stimulation. Results: Acute 24 h-fasting trials: there was a decrease in FI in all subjects at 80 Hz, (11-19%, mean 15%). Chronic 8-week stimulation trials: a significant decrease in BW and BMI was observed in three out of four monkeys at 80 Hz (mean 8 ± 4.4%). Subcutaneous skinfolds were reduced in all four subjects at 80 Hz and slightly increased at 130 Hz. The sham monkey remained stable. No significant adverse effects were recorded. Conclusion: The stimulation of the VMH region through an intraventricular approach might acutely modulate FI and induce a sustained decrease in BW and fat mass in normal non-human primate.
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The approved immunomodulatory agents for the treatment of multiple sclerosis (MS) are only partially effective. It is thought that the combination of immunomodulatory and neuroprotective strategies is necessary to prevent or reverse disease progression. Irradiation with far red/near infrared light, termed photobiomodulation, is a therapeutic approach for inflammatory and neurodegenerative diseases. Data suggests that near-infrared light functions through neuroprotective and anti-inflammatory mechanisms. We sought to investigate the clinical effect of photobiomodulation in the Experimental Autoimmune Encephalomyelitis (EAE) model of multiple sclerosis. The clinical effect of photobiomodulation induced by 670 nm light was investigated in the C57BL/6 mouse model of EAE. Disease was induced with myelin oligodendrocyte glycoprotein (MOG) according to standard laboratory protocol. Mice received 670 nm light or no light treatment (sham) administered as suppression and treatment protocols. 670 nm light reduced disease severity with both protocols compared to sham treated mice. Disease amelioration was associated with down-regulation of proinflammatory cytokines (interferon-γ, tumor necrosis factor-α) and up-regulation of anti-inflammatory cytokines (IL-4, IL-10) in vitro and in vivo. These studies document the therapeutic potential of photobiomodulation with 670 nm light in the EAE model, in part through modulation of the immune response.
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Parkinson's disease (PD) is a neurodegenerative disorder that affects large numbers of people, particularly those of a more advanced age. Mitochondrial dysfunction plays a central role in PD, especially in the electron transport chain. This mitochondrial role allows the use of inhibitors of complex I and IV in PD models, and enhancers of complex IV activity, such as NIR light, to be used as possible therapy. PD models fall into two main categories; cell cultures and animal models. In cell cultures, primary neurons, mutant neuroblastoma cells, and cell cybrids have been studied in conjunction with NIR light. Primary neurons show protection or recovery of function and morphology by NIR light after toxic insult. Neuroblastoma cells, with a gene for mutant alpha-synuclein, show similar results. Cell cybrids, containing mtDNA from PD patients, show restoration of mitochondrial transport and complex I and IV assembly. Animal models include toxin-insulted mice, and alpha-synuclein transgenic mice. Functional recovery of the animals, chemical and histological evidence, and delayed disease progression show the potential of NIR light in treating Parkinson's disease.
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One of the most promising methods to treat neurodegeneration is noninvasive transcranial near-infrared laser therapy (NILT), which appears to promote acute neuroprotection by stimulating mitochondrial function, thereby increasing cellular energy production. NILT may also promote chronic neuronal function restoration via trophic factor-mediated plasticity changes or possibly neurogenesis. Clearly, NILT is a treatment that confers neuroprotection or neurorestoration using pleiotropic mechanisms. The most advanced application of NILT is for acute ischemic stroke based upon extensive preclinical and clinical studies. In laboratory settings, NILT is also being developed to treat traumatic brain injury, Alzheimer's disease and Parkinson's disease. There is some intriguing data in the literature that suggests that NILT may be a method to promote clinical improvement in neurodegenerative diseases where there is a common mechanistic component, mitochondrial dysfunction and energy impairment. This article will analyze and review data supporting the continued development of NILT to treat neurodegenerative diseases.
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Soon after the discovery of lasers in the 1960s it was realized that laser therapy had the potential to improve wound healing and reduce pain, inflammation and swelling. In recent years the field sometimes known as photobiomodulation has broadened to include light-emitting diodes and other light sources, and the range of wavelengths used now includes many in the red and near infrared. The term "low level laser therapy" or LLLT has become widely recognized and implies the existence of the biphasic dose response or the Arndt-Schulz curve. This review will cover the mechanisms of action of LLLT at a cellular and at a tissular level and will summarize the various light sources and principles of dosimetry that are employed in clinical practice. The range of diseases, injuries, and conditions that can be benefited by LLLT will be summarized with an emphasis on those that have reported randomized controlled clinical trials. Serious life-threatening diseases such as stroke, heart attack, spinal cord injury, and traumatic brain injury may soon be amenable to LLLT therapy.
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Transcranial low-level laser therapy (LLLT) using near-infrared light can efficiently penetrate through the scalp and skull and could allow non-invasive treatment for traumatic brain injury (TBI). In the present study, we compared the therapeutic effect using 810-nm wavelength laser light in continuous and pulsed wave modes in a mouse model of TBI. TBI was induced by a controlled cortical-impact device and 4-hours post-TBI 1-group received a sham treatment and 3-groups received a single exposure to transcranial LLLT, either continuous wave or pulsed at 10-Hz or 100-Hz with a 50% duty cycle. An 810-nm Ga-Al-As diode laser delivered a spot with diameter of 1-cm onto the injured head with a power density of 50-mW/cm(2) for 12-minutes giving a fluence of 36-J/cm(2). Neurological severity score (NSS) and body weight were measured up to 4 weeks. Mice were sacrificed at 2, 15 and 28 days post-TBI and the lesion size was histologically analyzed. The quantity of ATP production in the brain tissue was determined immediately after laser irradiation. We examined the role of LLLT on the psychological state of the mice at 1 day and 4 weeks after TBI using tail suspension test and forced swim test. The 810-nm laser pulsed at 10-Hz was the most effective judged by improvement in NSS and body weight although the other laser regimens were also effective. The brain lesion volume of mice treated with 10-Hz pulsed-laser irradiation was significantly lower than control group at 15-days and 4-weeks post-TBI. Moreover, we found an antidepressant effect of LLLT at 4-weeks as shown by forced swim and tail suspension tests. The therapeutic effect of LLLT for TBI with an 810-nm laser was more effective at 10-Hz pulse frequency than at CW and 100-Hz. This finding may provide a new insight into biological mechanisms of LLLT.
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Two chronic, traumatic brain injury (TBI) cases, where cognition improved following treatment with red and near-infrared light-emitting diodes (LEDs), applied transcranially to forehead and scalp areas, are presented. Significant benefits have been reported following application of transcranial, low-level laser therapy (LLLT) to humans with acute stroke and mice with acute TBI. These are the first case reports documenting improved cognitive function in chronic, TBI patients treated with transcranial LED. Treatments were applied bilaterally and to midline sagittal areas using LED cluster heads [2.1″ diameter, 61 diodes (9 × 633 nm, 52 × 870 nm); 12-15 mW per diode; total power: 500 mW; 22.2 mW/cm(2); 13.3 J/cm(2) at scalp (estimated 0.4 J/cm(2) to cortex)]. Seven years after closed-head TBI from a motor vehicle accident, Patient 1 began transcranial LED treatments. Pre-LED, her ability for sustained attention (computer work) lasted 20 min. After eight weekly LED treatments, her sustained attention time increased to 3 h. The patient performs nightly home treatments (5 years); if she stops treating for more than 2 weeks, she regresses. Patient 2 had a history of closed-head trauma (sports/military, and recent fall), and magnetic resonance imaging showed frontoparietal atrophy. Pre-LED, she was on medical disability for 5 months. After 4 months of nightly LED treatments at home, medical disability discontinued; she returned to working full-time as an executive consultant with an international technology consulting firm. Neuropsychological testing after 9 months of transcranial LED indicated significant improvement (+1, +2SD) in executive function (inhibition, inhibition accuracy) and memory, as well as reduction in post-traumatic stress disorder. If she stops treating for more than 1 week, she regresses. At the time of this report, both patients are continuing treatment. Transcranial LED may improve cognition, reduce costs in TBI treatment, and be applied at home. Controlled studies are warranted.
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Transcranial near-infrared laser therapy (NILT) has been investigated as a novel neuroprotective treatment for acute ischemic stroke (AIS), for approximately 10 years. Two clinical trials, NeuroThera Effectiveness and Safety Trial (NEST)-1 and NEST-2, have evaluated the use of NILT to promote clinical recovery in patients with AIS. This review covers preclinical, translational, and clinical studies documented during the period 1997-2010. The primary aim of this article is to detail the development profile of NILT to treat AIS. Secondly, insight into possible mechanisms involved in light therapy will be presented. Lastly, possible new directions that should be considered to improve the efficacy profile of NILT in AIS patients will be discussed. The use of NILT was advanced to clinical trials based upon extensive translational research using multiple species. NILT, which may promote functional and behavioral recovery via a mitochondrial mechanism and by enhancing cerebral blood flow, may eventually be established as an Food and Drug Administration (FDA)-approved treatment for stroke. The NEST-3 trial, which is the pivotal trial for FDA approval, should incorporate hypotheses derived from translational studies to ensure efficacy in patients. Future NILT studies should consider administration of a thrombolytic to enhance cerebral reperfusion alongside NILT neuroprotection.
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Growing interest exists in the use of near-infrared laser therapies for the treatment of numerous neurologic conditions, including acute ischemic stroke, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. In consideration of these trends, the objective of this study was to evaluate the long-term safety of transcranial laser therapy with continuous-wave (CW) near-infrared laser light (wavelength, 808 ± 10 nm, 2-mm diameter) with a nominal radiant power of 70 mW; power density, 2,230 mW/cm(2), and energy density, 268 J/cm(2) at the scalp (10 mW/cm(2) and 1.2 J/cm(2) at the cerebral cortical surface) in healthy Sprague-Dawley rats. In this study, 120 anesthetized rats received sequential transcranial laser treatments to the right and left parietal areas of the head on the same day (minimum of 5 min between irradiation of each side), on either Day 1 or on each of Days 1, 3, and 5. Sixty anesthetized rats served as sham controls. Rats were evaluated 1 year after treatment for abnormalities in clinical hematology and brain and pituitary gland histopathology. No toxicologically important differences were found in the clinical hematology results between sham-control and laser-treated rats for any hematologic parameters examined. All values fell within historic control reference ranges for aged Sprague-Dawley rats. Similarly, brain and pituitary gland histopathology showed no treatment-related abnormalities or induced neoplasia. Single and multiple applications of transcranial laser therapy with 808-nm CW laser light at a nominal power density of 10 mW/cm(2) at the surface of the cerebral cortex appears to be safe in Sprague-Dawley rats 1 year after treatment.
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