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Photobiomodulation of the Brain: Shining Light on Alzheimer’s and Other Neuropathological Diseases

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Background: Transcranial photobiomodulation (tPBM) has recently emerged as a potential cognitive enhancement technique and clinical treatment for various neuropsychiatric and neurodegenerative disorders by delivering invisible near-infrared light to the scalp and increasing energy metabolism in the brain. Objective: We assessed whether transcranial photobiomodulation with near-infrared light modulates cerebral electrical activity through electroencephalogram (EEG) and cerebral blood flow (CBF). Methods: We conducted a single-blind, sham-controlled pilot study to test the effect of continuous (c-tPBM), pulse (p-tPBM), and sham (s-tPBM) transcranial photobiomodulation on EEG oscillations and CBF using diffuse correlation spectroscopy (DCS) in a sample of ten healthy subjects [6F/4 M; mean age 28.6±12.9 years]. c-tPBM near-infrared radiation (NIR) (830 nm; 54.8 mW/cm2; 65.8 J/cm2; 2.3 kJ) and p-tPBM (830 nm; 10 Hz; 54.8 mW/cm2; 33%; 21.7 J/cm2; 0.8 kJ) were delivered concurrently to the frontal areas by four LED clusters. EEG and DCS recordings were performed weekly before, during, and after each tPBM session. Results: c-tPBM significantly boosted gamma (t = 3.02, df = 7, p < 0.02) and beta (t = 2.91, df = 7, p < 0.03) EEG spectral powers in eyes-open recordings and gamma power (t = 3.61, df = 6, p < 0.015) in eyes-closed recordings, with a widespread increase over frontal-central scalp regions. There was no significant effect of tPBM on CBF compared to sham. Conclusion: Our data suggest a dose-dependent effect of tPBM with NIR on cerebral gamma and beta neuronal activity. Altogether, our findings support the neuromodulatory effect of transcranial NIR.
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Background: Recent studies of photobiomodulation (PBM) in patients with cognitive or psychological disorders (including traumatic brain injury, stroke, and dementia) have yielded some encouraging results. Objective: In this study, we aimed to investigate the effect of a single stimulation on memory in older adults with mild cognitive impairment (MCI). Methods: After PBM, hemodynamic changes, as a measure of functional brain activity, were evaluated using functional near-infrared spectroscopy (fNIRS). Eighteen subjects who met the criteria of MCI were randomly assigned to control and experimental groups. A single real or sham PBM session was administered to the forehead of each patient in the experimental and control groups, respectively. All subjects performed a visual memory span test before and after the stimulation, and their hemodynamic responses during the tasks were measured using fNIRS. Results: The results showed that among the MCI subjects, only those who received PBM, but not those who received the sham stimulation, demonstrated significant improvement in the visual memory performance and a reduction in the hemodynamic response during the tasks. Conclusion: These findings suggest that PBM may reduce the cognitive efforts needed to complete tasks that require high memory loads, and thus improve the cognitive performance of individuals with MCI.
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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.
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Photobiomodulation (PBM) describes the use of red or near-infrared light to stimulate, heal, regenerate, and protect tissue that has either been injured, is degenerating, or else is at risk of dying. One of the organ systems of the human body that is most necessary to life, and whose optimum functioning is most worried about by humankind in general, is the brain. The brain suffers from many different disorders that can be classified into three broad groupings: traumatic events (stroke, traumatic brain injury, and global ischemia), degenerative diseases (dementia, Alzheimer's and Parkinson's), and psychiatric disorders (depression, anxiety, post traumatic stress disorder). There is some evidence that all these seemingly diverse conditions can be beneficially affected by applying light to the head. There is even the possibility that PBM could be used for cognitive enhancement in normal healthy people. In this transcranial PBM (tPBM) application, near-infrared (NIR) light is often applied to the forehead because of the better penetration (no hair, longer wavelength). Some workers have used lasers, but recently the introduction of inexpensive light emitting diode (LED) arrays has allowed the development of light emitting helmets or “brain caps”. This review will cover the mechanisms of action of photobiomodulation to the brain, and summarize some of the key pre-clinical studies and clinical trials that have been undertaken for diverse brain disorders.
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Photobiomodulation also known as low-level laser (or light) therapy (LLLT), has been known for almost 50 years but still has not gained widespread acceptance, largely due to uncertainty about the molecular, cellular, and tissular mechanisms of action. However, in recent years, much knowledge has been gained in this area, which will be summarized in this review. One of the most important chromophores is cytochrome c oxidase (unit IV in the mitochondrial respiratory chain), which contains both heme and copper centers and absorbs light into the near-infrared region. The leading hypothesis is that the photons dissociate inhibitory nitric oxide from the enzyme, leading to an increase in electron transport, mitochondrial membrane potential, and adenosine triphosphate production. Another hypothesis concerns light-sensitive ion channels that can be activated allowing calcium (Ca2+) to enter the cell. After the initial photon absorption events, numerous signaling pathways are activated via reactive oxygen species, cyclic AMP, NO, and Ca2+, leading to activation of transcription factors. These transcription factors can lead to increased expression of genes related to protein synthesis, cell migration and proliferation, anti-inflammatory signaling, anti-apoptotic proteins, and antioxidant enzymes. Stem cells and progenitor cells appear to be particularly susceptible to LLLT.
Article
Background: Major depressive disorder (MDD) is prevalent and has significant impact on individuals and society. Cognitive symptoms are frequent in MDD and insufficiently treated by antidepressant medications. Transcranial photobiomodulation (t-PBM) is a novel device therapy which shows promise as an antidepressant and pro-cognitive treatment. To date, despite the encouraging results, the optimal stimulation parameters of t-PBM to treat MDD are not established, and clinical studies are very heterogeneous in terms of these parameters. While the literature provides guidance on the appropriate fluence to achieve therapeutic results, little is known on the other parameters. Objective: To evaluate the relationship between different parameters and the antidepressant effect of t-PBM. Methods: We reviewed clinical studies on MDD and on depressive symptoms comorbid with other diseases. We calculated the standardized effect size of the change in symptoms severity before and after t-PBM and we performed a descriptive analysis of the reviewed papers. Results: The greatest effect sizes for the antidepressant effect were found in studies using pulse-wave t-PBM with high peak irradiance (but low average irradiance) over large skin surface. One well-designed and sufficiently powered, double-blind, sham-controlled trial indicated that t-PBM with low irradiance over a small skin surface is ineffective to treat depression. Conclusion: The use of t-PBM for Alzheimer's disease and for dementia is still at its inception; these dosimetry lessons from the use of t-PBM for depression might serve as guidance.
Article
Background: Photobiomodulation (PBM) affects local blood flow regulation through nitric oxide generation, and various studies have reported on its effect on improving cognitive function in neurodegenerative diseases. However, the effect of PBM in the areas of the vertebral arteries (VA) and internal carotid arteries (ICA), which are the major blood-supplying arteries to the brain, has not been previously investigated. Objective: We aimed to determine whether irradiating PBM in the areas of the VA and ICA, which are the major blood-supplying arteries to the brain, improved regional cerebral blood flow (rCBF) and cognitive function. Methods: Fourteen patients with mild cognitive impairments were treated with PBM. Cognitive assessment and single-photon emission computed tomography were implemented at the baseline and at the end of PBM. Results: Regarding rCBF, statistically significant trends were found in the medial prefrontal cortex, lateral prefrontal cortex, anterior cingulate cortex, and occipital lateral cortex. Based on the cognitive assessments, statistically significant trends were found in overall cognitive function, memory, and frontal/executive function. Conclusion: We confirmed the possibility that PBM treatment in the VA and ICA areas could positively affect cognitive function by increasing rCBF. A study with a larger sample size is needed to validate the potential of PBM.
Article
Background: Anxious-depressive-like behavior has been recognized as an early endophenotype in Alzheimer's disease (AD). Recent studies support early treatment of anxious-depressive-like behavior as a potential target to alleviate memory loss and reduce the risk of developing dementia. We hypothesize that photobiomodulation (PBM) could be an effective method to alleviate depression and anxiety at the early stage of AD pathogenesis. Objective: To analyze the effect of PBM treatment on anxious-depressive-like behavior at the early stage of AD. Methods: Using a novel transgenic AD rat model, animals were divided into wild-type, AD+sham PBM, and AD+PBM groups. Two-minute daily PBM was applied transcranially to the brain of AD animals from 2 months of age to 10 months of age. After completing PBM treatment at 10 months of age, behavioral tests were performed to measure learning, memory, and anxious-depressive-like behavior. Neuronal apoptosis, neuronal degeneration, neuronal damage, mitochondrial function, neuroinflammation, and oxidative stress were measured to test the effects of PBM on AD animals. Results: Behavioral tests showed that: 1) no spatial memory deficits were detected in TgF344 rats at 10 months of age; 2) PBM alleviated anxious-depressive-like behavior in TgF344 rats; 3) PBM attenuated neuronal damage, degeneration, and apoptosis; and 4) PBM suppresses neuroinflammation and oxidative stress. Conclusion: Our findings support our hypothesis that PBM could be an effective method to alleviate depression and anxiety during the early stage of AD development. The mechanism underlying these beneficial effects may be due to the improvement of mitochondria function and integrity and the inhibition of neuroinflammation and oxidative stress.
Article
Background: Neuroprotection against Parkinson's disease degeneration by photobiomodulation has been reported in animal models but no true placebo-controlled human studies have been published. Objective: To understand if photobiomodulation therapy can produce clinically significant differences in physical performance measures in people with Parkinson's disease; and what frequency of treatment is necessary to initiate clinical change. Methods: In a participant and assessor-blinded, randomized, placebo-controlled pilot study, 22 participants received either sham and/or active laser photobiomodulation (904 nm, 60 mW/diode, 50 Hz) for 33 s to each of 21 points at the cranium and intra-orally, on one, two or three times/week for 4 weeks. Two treatment phases were separated by a 4-week wash-out (Phase 2). Upper and lower limb physical outcome measures were assessed before and after each treatment phase. The Montreal Cognitive Assessment was evaluated prior to treatment Phase 1, and at the end of treatment Phase 3. Results: Montreal Cognitive Assessment remained stable between start and end of study. No measures demonstrated statistically significant changes. With regular treatment, the spiral (writing) test and the dynamic step test were most sensitive to change in a positive direction; and the 9-hole peg test demonstrated a minimum clinically important difference worthy of further investigation in a larger, adequately powered clinical trial. A placebo effect was noted. Conclusion: The results support the notion that combined transcranial and intra-oral photobiomodulation therapy needs to be applied at least 2 to 3 times per week for at least four weeks before some improvement in outcome measures becomes evident. Longer courses of treatment may be required.
Article
Background: Photobiomodulation (PBM) involves the use of red and/or near-infrared light from lasers or LEDs to improve a wide range of medical disorders. Transcranial PBM, sometimes accompanied by intranasal PBM, has been tested to improve many brain disorders, including dementia. Objective: To conduct a systematic review according to PRISMA guidelines of pre-clinical and clinical studies reporting the use of PBM, which were considered relevant to dementia. Methods: Literature was searched between 1967 and 2020 using a range of keywords relevant to PBM and dementia. The light source and wavelength(s), output power, irradiance, irradiation time, fluence or total energy (dose), operation mode (continuous or pulsed) irradiation, approach and site, number of treatment sessions, as well as study outcome(s) were extracted. Results: Out of 10,473 initial articles, 36 studies met the inclusion criteria. Nine articles reported in vitro studies, 17 articles reported studies in animal models of dementia, and 10 studies were conducted in dementia patients. All of the included studies reported positive results. The clinical studies were limited by the small number of patients, lack of placebo controls in some instances, and only a few used objective neuroimaging methods. Conclusion: The preliminary evidence of clinical benefit, the lack of any adverse effects, and the remarkable ease of use, suggest larger clinical trials should be conducted as soon as possible.
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.
Article
Background: Given that there is no specific drug to treat Alzheimer's disease, non-pharmacologic interventions in people with subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are one of the most important treatment strategies. Objective: To clarify the efficacy of blue-green (500 nm) light therapy on sleep, mood, and physiological parameters in patients with SCD and aMCI is an interesting avenue to explore. Methods: This is a monocentric, randomized, and controlled trial that will last for 4 weeks. We will recruit 150 individuals aged 45 years or older from memory clinics and divide them into 5 groups: SCD treatment (n = 30), SCD control (n = 30), aMCI treatment (n = 30), aMCI control (n = 30), and a group of healthy adult subjects (n = 30) as a normal control (NC). Results: The primary outcome is the change in subjective and objective cognitive performance between baseline and postintervention visits (4 weeks after baseline). Secondary outcomes include changes in performance assessing from baseline, postintervention to follow-up (3 months after the intervention), as well as sleep, mood, and physiological parameters (including blood, urine, electrophysiology, and neuroimaging biomarkers). Conclusion: This study aims to provide evidence of the impact of light therapy on subjective and objective cognitive performance in middle-aged and older adults with SCD or aMCI. In addition, we will identify possible neurophysiological mechanisms of action underlying light therapy. Overall, this trial will contribute to the establishment of light therapy in the prevention of Alzheimer's disease.
Article
Background: Transcranial photobiomodulation (t-PBM) is a noninvasive modality that may improve cognitive function in both healthy and diseased subjects. Objective: This systematic review and meta-analysis addresses the question of whether t-PBM improves cognitive function in healthy adults. Methods: We searched MEDLINE using PubMed, EMBASE, SCOPUS, Web of Science, and Cochrane Library up to March 2019. We also searched ProQuest and Google Scholar databases for unpublished material. The search was limited to articles on the procognitive effects of t-PBM in healthy adults. The initial search resulted in 871 studies, of which nine publications met our criteria for inclusion and exclusion. Seven studies were performed on young, healthy subjects (17–35 years), and two studies were conducted on older (‡49 years), normal subjects. A meta-analysis was performed on six full-text publications whose subjects were young adults. Results: t-PBM administration improved cognition-related outcomes by an 0.833 standardized mean difference (SMD; 95% confidence interval (CI): 0.458–1.209, 14 comparisons) in young, healthy participants. Funnel plotting revealed asymmetry, which was validated using Egger’s ( p = 0.030) and Begg’s regression ( p = 0.006) tests. However after reanalysis, this asymmetry disappeared in the attention subgroup, but not in the memory subgroup. The trim-and-fill analysis indicated two studies were lacking required data. Thus, the effect size was adjusted from an SMD of 0.761 (95% CI: 0.573–0.949) to 0.949 (0.779–1.120). The overall quality score of the studies was modest. Conclusions: We demonstrated a significant, beneficial effect of t-PBM on cognitive performance of young, healthy individuals; however, the heterogeneity of the data was high. This could be due to the modest quality or to the low number of included studies, or to the differences between the various subdomains assessed. These shortcomings should be meticulously addressed before concluding that t-PBM is a cognitive-enhancing intervention in healthy individuals.
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.
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